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Core Submission Dossier PTJA11

Cefiderocol For the treatment of infections due to aerobic Gram-negative organisms in adults with limited

treatment options

Submitted by: Shionogi

Disclaimer: The sole responsibility for the content of this document lies with the submitting manufacturer and neither the European Commission nor EUnetHTA are responsible for any use that may be made of the information contained therein.

Contact details for administrative purposes Shionogi BV 33 Kingsway London WC2B 6UF Email address: [email protected]

For agency completion Date of receipt: 14-04-2020 Version 3: Amended dossier reflecting additional PK/PD analysis. Identifier: PTJA11


Abbreviations

A Aerobic

AAT Appropriate antibacterial therapy

ABC transporter ATP-binding cassette transporter

ABSSSI Acute bacterial skin and skin structure infection

Ac-BSI Acinetobacter spp. Bacteraemia

AE Adverse event

AET Appropriate empirical therapy

ALAT Asociación Latinoamericana del Tórax

AMK Amikacin

AMR Antimicrobial resistance

AN Anaerobic

AR Antimicrobial-resistance

AS Antimicrobial susceptibility

AST Antimicrobial susceptibility tests

AT Antibacterial therapy

ATS American Thoracic Society

AUC Area under the curve

BAT Best available therapy

BD Becton Dickinson

BIA Budget impact analysis

BIM Budget impact model

BAL Bacterial β-lactamase

BLI β-lactamase inhibitor

BSI Bloodstream infection

BSIMRS Bloodstream infection mortality risk score

CAI Community-acquired infection

CarbNS Carbapenem non-susceptible

CASR Carbapenem- and ampicillin-sulbactam-resistant

CAZ Ceftazidime/avibactam

CDC Centres for Disease Control and Prevention

CDI Clostridium difficile infection

CFU Colony forming unit

CHMP Committee for Medicinal Products for Human Use

CI Confidence interval


cIAI Complicated intra-abdominal infection

CLSI US Clinical & Laboratory Standards Institute

CNSE Carbapenem-non-susceptible Enterobacteriaceae

CPE Carbapenemase Producing Enterobacteriaceae

CPFX Ciprofloxacin

CR Carbapenem-resistant

CRAB Carbapenem-resistant A. baumannii

CRAc Carbapenem-resistant Acinetobacter spp.

CRE Carbapenem-resistant Enterobacteriaceae

CRGNB Carbapenem-resistant Gram-negative

CRGNIs Carbapenem-resistant Gram-negative infections

CRPA Carbapenem-resistant P. aeruginosa

CSE Carbapenem-susceptible Enterobacteriaceae

CSPA Carbapenem-susceptible P. aeruginosa

CTX Cefotaxime

cUTI Complicated urinary tract infection

DALYs Disability-adjusted life-years

DBO Diazabicyclooctane

DGI German Society for Infectious Diseases Association

DRG Disease-related groups

EA Early assessment

EAU European Association of Urology

ECDC European Centre for Disease Prevention and Control

EEA European Economic Area

eHRB Emerging highly antibacterial resistant bacteria

EMA European Medicines Agency

EMEA Europe, Middle East, and Africa

EOT End of treatment

ERS European Respiratory Society

ESBLs Extended-spectrum β-lactamases

ESCMID European Society of Clinical Microbiology and Infectious

Diseases

ESICM European Society of Intensive Care Medicine

EU European Union

EUCAST European Committee on Antimicrobial Susceptibility Testing


FA Facultative anaerobic

FDA U.S. Food and Drug Administration

FUP Follow-up

G3CREC Third-generation cephalosporin-resistant E. coli

G3CSEC third-generation cephalosporin-susceptible E. coli

GDP Gross domestic product

GEIH-SEIMC Spanish Society of Infectious Diseases and Clinical

Microbiology

GNO Gram-negative organisms

GVD Global Value Dossier

HAI Hospital-acquired infection

HAP Hospital acquired pneumonia

HAS Haute Authorite de la Sante

HCAI Healthcare-associated infection

HCAP Healthcare-associated pneumonia

Hr Hour

HTA Health Technology Assessment

HTAB Health Technology Assessment Body

(c)IAI (complicated) Intra-abdominal infection

IAT Inappropriate antibacterial therapy

ICD International Classification of Disease

ICU Intensive care unit

ID-CAMHB Iron-depleted cation-adjusted Mueller Hinton broth

IDSA Infectious Disease Society

IET Inappropriate empiric therapy

IMP IMP-type carbapenemases

IPM/CS Imipenem/Cilastatin

IQR Inter-quartile range

IRAB Imipenem-resistant Acinetobacter baumannii

ITT Intention-to-treat

IV Intravenous

KAPE Klebsiella pneumoniae, Acinetobacter baumannii,

Pseudomonas aeruginosa, and Enterobacter

KPC Klebsiella pneumoniae carbapenemase

LOS Length of stay


MA Marketing Authorization

MAA Marketing Authorization Application

MBLs Metallo-β-lactamases

MCO Managed care organization

MCR-1 Plasmid-mediated colistin-resistance

MDR Multidrug resistant

MDRA Multidrug resistant Acinetobacter

MDRAB Multidrug resistant A. baumannii

MDRP Multidrug resistant P. aeruginosa

MDS Multidrug-sensitive

ME Microbiologically evaluable

(HD) MEPM (high dose) Meropenem

MIC Minimum inhibitory concentration

mITT Microbiological intention to treat

MoA Mode of action

NDA New drug application

NDM New Delhi metallo-β-lactamase

NHS National Health Service

NI Nosocomial infections

NICE National Institute of Health and Care Excellence

NR Non-resistant

NS Non- survivors

OM Osteomyelitis

OMT Outer membrane transporters

OR Odds ratio

OXA Oxacillinase

PBC Positive blood culture

PBPs Penicillin-binding proteins

PCR Polymerase Chain Reaction

PD Pharmacodynamic

PDCO Paediatric Committee

PDR Pan-drug-resistant

PEG Percutaneous endoscopic gastroscopy

PER Pseudomonas extended resistant β-lactamases

PK Pharmacokinetic


PP Per Protocol

PTA Probability of target attainment

q8h Every 8 hours

R Resistant

RCT Randomized controlled trial

RESP Respiratory tract

RR Relative risk

r-GNR Resistant gram-negative rod

RTI Respiratory tract infection

S Survivors

SAE Serious adverse event

SC Subcutaneous

SCCM Society of Critical Care Medicine

SD Standard deviation

SEFH Spanish Society of Hospital Pharmacies

SEMPSPH Spanish Society of Preventive Medicine, Public Health and

Hygiene

SICU Surgical intensive care unit

SIS Surgical Infection Society

SMC Siderophore monobactam conjugate

sNDA Supplemental new drug application

SOC Standard of care

spp Species

SSI Surgical site infection

TOC Test of Cure

tRNA Transfer ribonucleic acid

UTI Urinary tract infection

VAP Ventilator-acquired pneumonia

VABP Ventilator-associated bacterial pneumonia

VIM Verona integrin-encoded metallo-β-lactamase

w/wo With or without

WHO World Health Organization

WSES World Society of Emergency Surgery

XDR Extensively drug-resistance


Contents

EXECUTIVE SUMMARY .......................................................................................... 14 1 Description and technical characteristics of the technology .......................... 23 1.1 Characteristics of the technology ................................................................... 25

1.1.1 Cefiderocol Structure .......................................................................... 26 1.1.2 Mechanism of action and cell entry .................................................... 27

1.1.3 Stability against β-lactamases ............................................................ 28 1.2 Regulatory status of the technology .............................................................. 29 2 Health problem and current clinical practice .................................................. 31 2.1 Overview of the disease or health condition .................................................. 32

2.1.1 Overview of Gram-negative bacteria .................................................. 33 2.1.2 Antimicrobial resistance ...................................................................... 35 2.1.3 Overview of infection sites .................................................................. 39

2.1.4 Risk and prognostic factors for MDR and CR infections ..................... 41 2.1.5 Epidemiology ...................................................................................... 42 2.1.6 Mortality .............................................................................................. 47 2.1.7 Quality of Life ...................................................................................... 48

2.1.8 Disability Adjusted Life Years (DALYs) ............................................... 48 2.1.9 Delayed effective therapy ................................................................... 49

2.2 Target population ........................................................................................... 52

2.3 Clinical management of the disease or health condition ................................ 57 2.3.1 Key information on currently available treatments in Europe .............. 59

2.3.2 Site-specific vs. pathogen-specific guidelines..................................... 63 2.3.3 Specific recommendations.................................................................. 63

2.3.4 Specific considerations of CR infections ............................................. 63 2.4 Comparators in the assessment .................................................................... 87

2.4.1 General considerations ....................................................................... 87 2.4.2 Selection of relevant comparators for the assessment ....................... 89

3 Current use of the technology........................................................................ 94

3.1 Current use of the technology........................................................................ 95 3.2 Reimbursement and assessment status of the technology ........................... 96

4 Investments and tools required...................................................................... 97 4.1 Requirements to use the technology ............................................................. 98

4.1.1 Conditions for use ............................................................................... 99

4.1.2 Good stewardship and societal considerations................................... 99 5 Clinical effectiveness and safety .................................................................. 102 5.1 Identification and selection of relevant studies ............................................ 105

5.1.1 PRISMA Chart .................................................................................. 111

5.1.2 Study categorisation ......................................................................... 111 5.2 Relevant studies .......................................................................................... 112 5.3 Main characteristics of studies..................................................................... 134

5.3.1 APEKS-cUTI STUDY ........................................................................ 144 5.3.2 APEKS-NP STUDY .......................................................................... 151

5.3.3 CREDIBLE-CR STUDY .................................................................... 155 5.3.4 Summary of compassionate use cases and published evidence ...... 160

5.4 Individual study results (clinical outcomes) .................................................. 164 5.4.1 Individual study results (in vitro surveillance outcomes) ................... 164

5.4.2 Individual study results (PK/PD data, study report S-649266-CPK-004-B) ...................................................................................................... 189


5.4.3 Retrospective analysis of cefiderocol and comparators by population PK/PD simulation .............................................................................. 192

5.4.4 Clinical study results (clinical outcomes) .......................................... 194 5.4.5 Resistance against Cefiderocol ........................................................ 233

5.5 Individual study results (safety outcomes) ................................................... 259 5.5.1 Overall safety results: pooled analysis and individual studies: APEKS-

cUTI, APEKS-NP, and CREDIBLE CR ............................................. 259 5.5.2 Safety analyses by clinical trial ......................................................... 265

5.6 Conclusions ................................................................................................. 287 5.6.1 Evidence to support use of cefiderocol in patients with infections by

suspected MDR/CR pathogens: ....................................................... 289 5.6.2 Evidence to support use of cefiderocol in patients with infections by

confirmed CR pathogens: ................................................................. 291 5.6.3 Quality of Life .................................................................................... 293 5.6.4 Comparators ..................................................................................... 293

5.7 Strengths and limitations ............................................................................. 297 5.7.1 Risk of bias assessment ................................................................... 297

5.7.2 Discussion ........................................................................................ 301

REFERENCES ....................................................................................................... 306


List of Figures Figure 1: Cefiderocol structure ............................................................................................ 27 Figure 2: Cefiderocol mechanism of cell entry ..................................................................... 28 Figure 3: Antibacterial activity against β-lactamase-producing pathogens ........................... 28 Figure 4: Classification of Gram-negative bacteria .............................................................. 34 Figure 5: Global burden of AMR .......................................................................................... 35 Figure 6: Mechanisms of beta lactam bacterial resistance .................................................. 37 Figure 7: Hospital-acquired infections in acute care hospitals (EU/EEA 2011-2012) ........... 40 Figure 8: Worldwide carbapenem resistance ...................................................................... 42 Figure 9: Prevalence of CR Gram-negative infections in the EU-5 ...................................... 43 Figure 10: Epidemiology of carbapenemases in EU 5 ......................................................... 44 Figure 11: Confirmed carbapenemase-producing Enterobacteriaceae isolates (Public Health England: 2008–17) .............................................................................................................. 45 Figure 12: Distribution of carbapenem resistance mechanisms in Enterobacteriaceae species in the Europe.......................................................................................................... 45 Figure 13: Summary of effect of appropriate versus inappropriate initial antibacterial therapy on mortality ......................................................................................................................... 51 Figure 14: Summary of effect of delay versus no delay in receiving initially appropriate antibacterials on mortality ................................................................................................... 51 Figure 15: Summary of effect of appropriate versus inappropriate therapy on treatment failure .................................................................................................................................. 52 Figure 16 - Treatment of patients with highly suspected infection by CR or other MDR GN pathogens ........................................................................................................................... 55 Figure 17: Treatment of patients with confirmed infection by carbapenem-resistant or other MDR Gram-negative pathogen ........................................................................................... 55 Figure 18: Current treatment approach for bacterial infections ............................................ 57 Figure 19: Current clinical reasoning for the treatment of serious MDR Gram-negative infections ............................................................................................................................. 59 Figure 20 - Search strategy for OVD MEDLINE ALL ......................................................... 106 Figure 21 - PRISMA flow diagram of record selection process .......................................... 111 Figure 22: APEKS-cUTI study design ............................................................................... 144 Figure 23: Subject disposition (all randomized subjects) ................................................... 145 Figure 24: Distribution of uropathogens (mITT population) ................................................ 150 Figure 25: APEKS-NP study design and patient flow ........................................................ 152 Figure 26: Patient demographics and baseline characteristics .......................................... 153 Figure 27: CREDIBLE-CR study design and patient flow .................................................. 156 Figure 28: Subjects disposition (all randomized subjects) ................................................. 157 Figure 29: APEKS-cUTI study design and endpoints ........................................................ 196 Figure 30: Primary efficacy results: Composite outcome at TOC in the MITT population .. 197 Figure 31: Primary efficacy results: Composite outcome at TOC by predefined subgroups198 Figure 32: Maximum Network Chart for Network Meta-analysis ........................................ 209 Figure 33: Network Diagram for Microbiological Eradication Secondary Outcome ............ 209 Figure 34: Microbiological Eradication Rates at TOC - Frequentist Analysis ..................... 210 Figure 35: Microbiological Eradication Rates at TOC - Bayesian Analysis ........................ 210 Figure 36: Network Diagram for Clinical Cure Outcome .................................................... 210 Figure 37: Clinical cure rates at TOC - Frequentist Analysis ............................................. 211 Figure 38: Clinical Cure rate at TOC - Bayesian Analysis ................................................. 211 Figure 39: Clinical cure rates at FU - Frequentist Analysis ................................................ 211 Figure 40: APEKS-NP study design .................................................................................. 213 Figure 41: All-cause Mortality (mITT) ................................................................................ 214 Figure 42: Primary efficacy results: Day 14 All-cause Mortality by Subgroups .................. 215 Figure 43: Day 14 and Day 28 all-cause mortality according to MIC for meropenem ........ 218 Figure 44: Microbiological eradication by MIC at EOT ....................................................... 219 Figure 45: CREDIBLE CR study design ............................................................................ 223


Figure 46: Clinical cure by Clinical Diagnosis and time point ............................................. 224 Figure 47: Microbiological eradication by Clinical Diagnosis and time point ...................... 224 Figure 48: Clinical and Microbiological Outcomes at TOC in Enterobacteriaceae by Carbapenemase or Porin Channel Mutation (CR Micro-ITT Population) ........................... 226 Figure 49: Clinical and Microbiological Outcomes in Metallo Β-lactamase Producing Gram-negative Pathogens (CR Micro-ITT Population) ................................................................ 226 Figure 50: All-cause Mortality Rates by Type of Infection .................................................. 227 Figure 51: Mortality rates comparison across studies ........................................................ 230 Figure 52: Network Diagram for Safety Analysis ............................................................... 271 Figure 53: Safety Analysis for All Adverse Events - Frequentist Analysis .......................... 271 Figure 54: Network for safety analysis for Treatment related AEs ..................................... 271 Figure 55: safety analysis for Treatment related AEs – Frequentist analysis ..................... 271


List of Tables Table 1: Features of the technology .................................................................................... 25

Table 2: Administration and dosing of the technology ......................................................... 25

Table 3: Regulatory status of the technology ...................................................................... 29

Table 4: List of the highest priority bacteria (WHO) ............................................................. 35

Table 5: In vitro activity profile of antibacterials for GN Infections with limited treatment options ................................................................................................................................ 39

Table 6: Most common CR causal pathogens across available EU-5 data sources ............ 43

Table 7: Proportion of CR infection sites in the EU-5........................................................... 44

Table 8: Overview of disease burden according to the infection site ................................... 46

Table 9: In Vitro Gram-negative activity profiles .................................................................. 54

Table 10a: Relevant guidelines for diagnosis and management – MDR/GN Bacteria ......... 65

Table 11b: Relevant guidelines for diagnosis and management – HAP/VAP(HCAP) .......... 70

Table 11c: Relevant guidelines for diagnosis and management – cUTI .............................. 75

Table 11d: Relevant guidelines for diagnosis and management – BSI/Sepsis .................... 78

Table 11e: Relevant guidelines for diagnosis and management- cIAI ................................. 83

Table 12: Cefiderocol assessment ...................................................................................... 90

Table 13: Overview of the reimbursement status of the technology in European countries . 96

Table 14: Databases and information sources searched ................................................... 107

Table 15: Inclusion and exclusion criteria .......................................................................... 109

Table 16: List of all relevant studies .................................................................................. 113

Table 17: Study characteristics ......................................................................................... 135

Table 18: Patient demographics and baseline characteristics (mITT population) .............. 147

Table 19: Patient demographics and baseline characteristics (mITT population) .............. 154

Table 20: Top 5 baseline Gram-negative pathogens, n (%) .............................................. 154

Table 21: Patient demographics and baseline characteristics (ITT population) ................. 158

Table 22: Summary of study regimen for Gram-negative pathogen at day 1 and day 2 (CR-mITT population) ............................................................................................................... 159

Table 23: Baseline Gram-negative pathogens, n (%) ........................................................ 160

Table 24: Patient demographics and baseline characteristics ........................................... 162

Table 25: SIDERO Surveillance studies ............................................................................ 165

Table 26: In vitro activity data for all tested clinical strains (SIDERO-WT-2014/2015/2016 and Proteeae) of cefiderocol (at MIC of 4mg/L) versus ceftazidime-avibactam, ceftolozane-tazobactam, and colistin .................................................................................................... 167

Table 27: In vitro activity of cefiderocol and comparators against Gram-negative bacilli isolated by 55 clinical laboratories in Europe in 2015 (n=5352) ......................................... 170

Table 28: In vitro activity of cefiderocol and comparators against non-fermenters ............. 172

Table 29: Breakpoints for non-susceptibility used in definition of DTR (μg/mL) ................. 173

Table 30: Susceptibility of cefiderocol and comparators to pathogens .............................. 173

Table 31: In vitro activity data for CR Gram-negative pathogens (SIDERO-WT-2016-2017) of cefiderocol versus ceftazidime-avibactam, ceftolozane-tazobactam and colistin ............... 174

Table 32: Number of MEM-NS isolates by year and species ............................................. 175

Table 33: Number of MEM-NS isolates by country and species ........................................ 175

Table 34: Susceptibility breakpoints according to the CLSI (cefiderocol) and/or EUCAST (all comparators) ..................................................................................................................... 176

Table 35: Percentage of susceptibility of MEM-NS A. baumannii complex by country ....... 177

Table 36: Percentage of susceptibility of MEM-NS P. aeruginosa complex by country ...... 177

Table 37: Percentage of susceptibility of MEM-NS K. pneumoniae by country .................. 177

Table 38: Percentage of susceptibility of other MEM-NS Enterobacteriaceae by country .. 177

Table 39: In vitro activity data for all tested clinical strains (SIDERO-CR 2014-2016) of cefiderocol versus ceftazidime-avibactam, ceftolozane-tazobactam, and colistin .............. 178

Table 40: MIC of cefiderocol and comparators in Germany ............................................... 179

Table 41: MIC of cefiderocol and comparators in Greece .................................................. 180

Table 42: MIC of cefiderocol and comparators in Spain .................................................... 181


Table 43: MIC of cefiderocol and comparators against in United Kingdom and Ireland ..... 182

Table 44: Activity of antimicrobial agents tested against carbapenem-resistant P. aeruginosa and S. maltophilia ............................................................................................................. 183

Table 45: MIC of cefiderocol and comparators for MDR-GN isolated ................................ 184

Table 46: Number of cefiderocol non-susceptible isolated in global surveillance studies (MIC ≥8 μg/mL).......................................................................................................................... 185

Table 47: EUCAST breakpoints for cefiderocol ................................................................. 186

Table 48: Susceptibility to Cefiderocol and comparators in all sites of infections for MDR3 pathogens ......................................................................................................................... 187

Table 49- Theoretical success of antibacterial therapy in Gram‐negative 3MDR pathogens in gastrointestinal site of infections (A) Pneumonia; (B) cUTI; (C) BSI; (D) Gastrointestinal .. 187

Table 50: Summary table Theoretical percentage of success for Gram‐negative antibacterial

therapy on aerobic Gram‐negative pathogens in different infection type ........................... 188

Table 51: PTA per infectious disease renal function, and dose ......................................... 190

Table 52. Estimated CFR for MIC distributions corresponding to Enterobacterales and Pseudomonas spp. More simulation results for corresponding PTA, MIC and T>MIC target values are shown in Appendix C. The applied MIC distributions can be seen in Appendix D of the study report. ............................................................................................................ 193

Table 53: Endpoint Analysis as per EUnetHTA Request ................................................... 194

Table 54: Summary for Composite of Clinical and Microbiological Outcome by Time Point (Microbiological Intent-to-Treat Population) ....................................................................... 197

Table 55: Composite of Clinical Response and Microbiological Outcome per Pathogen at TOC (microbiological ITT population) ................................................................................ 199

Table 56: Summary of Clinical Outcomes per Subject by Time Point (Microbiological Intent-to-Treat Population) .......................................................................................................... 200

Table 57: Summary of Clinical Outcome per Uropathogen (E. coli, K. pneumoniae, P. aeruginosa, and P. mirabilis) by Time Point (Microbiological ITT Population) .................... 201

Table 58: Summary of Microbiological Outcome per Subject by Time Point (Microbiological ITT Population) ................................................................................................................. 203

Table 59: Summary of Microbiological Outcome per Uropathogen (E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis) by Time Point (Microbiological ITT Population)........................... 205

Table 60: Day 14 All-cause Mortality (mITT and ME-PP Populations) ............................... 214

Table 61: Secondary Endpoints (mITT Population) ........................................................... 216

Table 62: Secondary Endpoints (mITT Population) ........................................................... 216

Table 63: Clinical and microbiological outcome per baseline pathogen ............................. 217

Table 64: Microbiological and Clinical Outcome for the Meropenem-non-susceptible Subgroup (mITT Population) ............................................................................................. 219

Table 65: Susceptibility and effectiveness model predicting outcomes for Cefiderocol versus comparators in UTI ........................................................................................................... 221

Table 66: Susceptibility and effectiveness model predicting outcomes for Cefiderocol versus comparators in Pneumonia ............................................................................................... 221

Table 67: Clinical cure and microbiological eradication by baseline CR-pathogen ............ 225

Table 68: Summary for All-cause Mortality in the Study (Intent to treat Population) .......... 227

Table 69: Summary for all-cause mortality overall by pathogens subgroup (Enterobactereacea and non-fermenters) .......................................................................... 229

Table 70: CREDIBLE-CR study: Mortality subgroup Analysis for Subjects with A. baumannii (safety population) ............................................................................................................ 229

Table 71: Mortality and serious adverse events ................................................................ 231

Table 72: Summary of MIC shift ........................................................................................ 234

Table 73a: Methods of data collection and analysis of Mortality ........................................ 235

Table 80b: Methods of data collection and analysis of Clinical outcomes .......................... 237

Table 80c: Methods of data collection and analysis of Composite microbiological eradication and cure ............................................................................................................................ 245

Table 80d: Methods of data collection and analysis of Microbiological outcomes .............. 249

Table 80e: Methods of data collection and analysis of Susceptibility rates ........................ 258


Table 81: Dose and Duration of Exposure to cefiderocol* (Number of Patients by Indication) ......................................................................................................................................... 259

Table 82: Subjects with Treatment Related Adverse Events by System Organ Class and Preferred Term (All Phase II/III Studies) Safety Population ............................................... 261

Table 83: Summary of duration of exposure (safety population) ........................................ 266

Table 84: Summary of treatment-emergent adverse events (safety population) ................ 266

Table 85: Number (%) of subjects with adverse events by maximum severity (safety population) ........................................................................................................................ 268

Table 86: Number (percent) of subjects with serious adverse events (SAEs) by organ class and preferred term (safety population) .............................................................................. 269

Table 87: Number (%) of subjects with treatment-related serious adverse events (SAEs) 270

Table 88: Overview of Treatment-emergent Adverse Events (Safety Population) ............. 272

Table 89 – Number (percent) of subjects with serious adverse events (SAEs) by organ class and preferred term (safety population) .............................................................................. 275

Table 90: Overview of Treatment-emergent Adverse Events (Safety Population) ............. 279

Table 91: Subjects with Treatment-related Adverse Events by Preferred Term (Safety Population) ........................................................................................................................ 280

Table 92: Subjects with Serious Adverse Events by System Organ Class and Preferred Term (Safety Population) .................................................................................................. 281

Table 93: Limitations to detect adverse events in clinical trial programmes ....................... 283

Table 94: Methods of data collection and analysis of AE, TEAE and SAE ......................... 284

Table 95 - Comparator overview ....................................................................................... 294

Table 96: Risk of bias on study level – Randomized trials with cefiderocol ........................ 300


EXECUTIVE SUMMARY

AMR is a major, growing threat to public health

Anti-microbial resistance (AMR) is a major and growing threat to global public health [1].

Infection by multi-drug-resistant (MDR) and particularly carbapenem-resistant (CR) pathogens

is associated with a high mortality rate and increased morbidity and economic burden [2, 3].

In 2015 in the EU, 33,110 deaths were attributable to infections due to antibacterial-resistant

bacteria [4] and it has been estimated that, if significant action is not taken by the year 2050,

10 million lives will be lost each year due to AMR [1].

Nosocomial MDR infections (including CR), caused by Gram-negative (GN), aerobic bacteria

including CR Escherichia coli, CR Klebsiella pneumoniae, CR Pseudomonas aeruginosa, CR

Acinetobacter baumannii (WHO priority pathogens; [5-7]) and intrinsically CR

Stenotrophomonas maltophilia [8, 9] are particularly relevant, as there are limited treatment

options for these and particularly for carbapenem resistant pathogens [5, 6]. They primarily

occur in vulnerable hospitalised patients resulting in hospital acquired pneumonia and

ventilator acquired pneumonia (HAP/VAP), bloodstream infections (BSI), complicated urinary

tract infection (cUTI) and complicated intra-abdominal infections (cIAI), amongst other

infections [10-12].

Currently, an antibacterial susceptibility test (AST) is needed for a definitive prescription, which

can take more than 3 days [13, 14], so patients with infections involving resistant pathogens

are more difficult to treat and therefore, patients are more likely to receive multiple courses of

inappropriate therapies before an effective treatment is initiated. This delay can lead to

increased mortality and clinical burden, poorer outcomes, increasing the likelihood of

developing new resistances [15-21]. Furthermore, where CR infection is suspected in critically

ill patients, an antibacterial regimen is started immediately, despite incomplete information on

pathogen susceptibility, with the antibacterial (or combination of antibacterials) that has the

highest likelihood of success. The selection of antibacterial(s) should be guided by knowledge

of local epidemiology (local resistance profile and local pathogen distribution), as well as by

site of infection and patient specific factors, such as severity of illness and previous

antibacterial exposure or comorbidities. Treatment may be de-escalated to a more targeted

treatment once the AST results have been obtained [13]. This further emphasizes the critical

importance of susceptibility testing and the need for antibacterials with a wider spectrum of

activity targeting MDR/PDR strains, especially because studies found that inappropriate initial

treatment and the subsequent delay in effective treatment results in worse outcomes including

increased mortality, length of stay and treatment costs [15-21].


Given the lack of treatment options, there are few defined standard of care (SoC) or guidelines

defining the most appropriate treatment strategy for MDR and CR Gram-negative bacteria

(GNB) [22]. Specific treatments for MDR-GNB infections are predominantly multiple drug

combinations that include one or more of the following: aminoglycosides (amikacin,

gentamicin); tetracyclines (tigecycline; eravacycline; minocycline) carbapenems (e.g.

ertapenem; imipenem-cilastatin, meropenem; meropenem/vaborbactam;

imipenem/relebactam/cilastatin); β-lactamase inhibitor combinations (ceftazidime/avibactam;

ceftolozane/tazobactam); fosfomycin; or polymyxins (colistin and polymyxin B) [23-27].

Carbapenems, due to their potency, broad-spectrum activity, and less frequent resistance,

have until recently for reasons of antimicrobial stewardship, been reserved for use in treatment

of patients with resistant bacterial infections that could not be treated with other beta-lactams.

Current treatment options, for treatment of CR pathogens [28], have either suboptimal efficacy

(e.g. carbapenems), limited pathogen and/or mechanism of resistance coverage (e.g.

ceftolozane/tazobactam; ceftazidime/avibactam; meropenem/vaborbactam) [29, 30] and/or

significant safety and tolerability concerns [e.g. colistin, tigecycline]) [31-34].

Even recently approved combinations of cephalosporins with established β-lactam/β-

lactamase inhibitors have activity against MDR Gram-negative infections, including P.

aeruginosa, but their limitations include a lack of activity against metallo-β-lactamase-

producing organisms and these new antibacterials remain vulnerable to resistance

mechanisms due to porin channel mutations or overexpression of efflux pumps [28, 35-43].

Despite having high rates of renal toxicity, the broad Gram-negative spectrum of colistin and

polymyxin B mean that they are still used in the absence of alternative effective treatment

options for increasingly emerging CR in Gram-negative bacteria [31].

New treatments that can overcome the known resistance mechanisms, are therefore needed,

contributing to more effective eradication of MDR pathogens and increase antibacterial

diversity, thus, supporting good stewardship and the overall effectiveness of the existing

arsenal of antibacterials.

CEFIDEROCOL overcomes the 3 main mechanisms of antibacterial resistance present

in Gram-negative pathogens and is active on WHO critical priority pathogens


Cefiderocol is the first siderophore cephalosporin [44] to be approved. The cephalosporin core

of cefiderocol exerts it’s activity through inhibition of Gram-negative bacterial cell wall

biosynthesis leading to cell lysis. Its unique molecular structure catecholate siderophore

moiety, exploits the bacteria’s own active iron uptake mechanism via siderophores to enter

the periplasmic space of GNB where it exerts its bactericidal activity. This is a novel

mechanism of bacterial cell entry which means that cefiderocol, unlike other antibacterials,

bypasses pathways traditionally used by other antibacterials such as efflux pumps or porin

channels, which bacteria can regulate to reduce their exposure to antibacterials. Cefiderocol

also has a higher stability to both serine- and metallo-type β -lactamases, key enzymes

rendering resistance to β–lactam antibacterials, including carbapenems. All these factors

contribute to cefiderocol’s unique breadth of activity and efficacy, covering a wide range of

aerobic, GN bacteria, demonstrated by its potent activity (both in vitro and in-vivo) against all

three WHO priority CR pathogens (Enterobacteriaceae, A. baumannii and P. aeruginosa) [29,

30, 45-49]. In addition, cefiderocol has in vitro activity against intrinsically CR Stenotrophomas

maltophilia and Burkholderia cepacia [30].

The dosing regimen of cefiderocol is 2g administered every 8 hours by IV infusion over 3 hour

period, with treatment duration dependent on the site of infection, e.g. 5-10 days for cUTI and

cIAI and 7-14 days for hospital-acquired pneumonia, but treatment up to 21 days may be

required [50].

The indication for cefiderocol is expected to be:

Fetcroja is indicated for the treatment of infections due to aerobic Gram-negative

organisms in adults with limited treatment options.

This indication will therefore be pathogen focused, not restricted to any specific site of infection and supports the use of cefiderocol in two types of patients:

Hospitalised patients with suspected (but prior laboratory confirmation) MDR/CR

infection who are critically ill and require immediate antibacterial treatment that

provides full cover against CR pathogens and potential resistant mechanisms, to

avoid the risk of rapid clinical deterioration (with the option to de-escalate to a more

targeted treatment when the pathogen and susceptibility profile is subsequently

confirmed)

Hospitalised patients where CR infection has been confirmed and cefiderocol is

best option based on pathogen susceptibility information and/or where other

treatment choices are inappropriate (efficacy, contra-indication or tolerability).


OVERVIEW OF PRE-CLINICAL AND CLINICAL EVIDENCE

Unlike other therapeutic areas, the evaluation of the effectiveness of an antibacterial relies on

the combined consideration of in vitro, Pharmacokinetic (PK)/Pharmacodynamic (PD) and

clinical data. Cefiderocol’s favourable in vitro minimum inhibitory concentrations (MICs)

correlate well with in vivo efficacy in PK/PD in vivo efficacy in validated animal models of

infection, including MDR pathogens. Randomized clinical trials in patients with complicated

urinary tract infections (cUTI) [51], nosocomial pneumonia (HAP/VAP/HCAP), and BSI have

provided confirmation of the good efficacy and safety of cefiderocol in key target patient

populations.

In vitro evidence shows cefiderocol has activity in >95% of CR Gram-negative isolates

In vitro activity of cefiderocol has been studied in two large surveillance studies (SIDERO-

WT/Proteeae and SIDERO-CR 2014/2016) [29, 30, 45, 46] and many country specific smaller

similar studies. The SIDERO-WT study tested the in vitro antibacterial activity of cefiderocol

against Gram-negative bacteria [29]. A total of 30,459 clinical isolates of Gram-negative bacilli

were systematically collected from USA, Canada, and 11 European countries between 2014

and 2017. Cefiderocol demonstrated activity against 99.5% of Gram-negative isolates at a

MIC of 4 mg/L. Isolates were less susceptible to the comparators including colistin (95.5%),

ceftazidime-avibacatam (90.2%) and ceftolozane-tazobactam (84.3%).

In the SIDERO-CR-2014-2016 study [30], which was a global study of 52 countries, focusing

only on CR isolates, cefiderocol demonstrated potent in vitro activity at a MIC of 4 mg/L against

96.4% of isolates of carbapenem-nonsusceptible pathogens including all of the WHO priority

pathogens and Stenotrophomas maltophilia. Cefiderocol was found to provide a wider Gram-

negative coverage, and more potent in vitro antimicrobial activity than comparators including

ceftazidime/avibactam (39.8%), ceftolozane/tazobactam (37%), and colistin (91.5%).

PK/PD studies predict (probability >90%) that the dosing regimen achieves a

concentration of free drug in plasma > MIC for 75% dosing period

As for other cephalosporins, %fT>MIC is the best predictor of efficacy for cefiderocol. A dosing

regimen delivering 75% T>MIC succeeded achieving at least 1 log10 kill reducing the number

of viable bacterial cells in both murine thigh infection and murine lung infection by at least 90%

regardless of the isolate used to induce the infection (E. coli, K. pneumoniae, P. aeruginosa,

A. baumannii or S. maltophilia).


A 3-compartment model was used to describe the plasma concentrations of cefiderocol. A 3-

compartment pharmacokinetic population model was developed based on pharmacokinetic

data from healthy volunteers, patients with renal impairment and patients from the clinical

trials. Probability of Target Attainment (PTA) for 75% fT>MIC was above 97% for a MIC of 4

mg/L regardless of the site of infection or the renal function. In the epithelial lining fluid (ELF),

PTA for 75% fT>MIC was above 88% for a MIC of 4 mg/L confirming the adequacy of the

dosing regimen in the different patient populations. The dosing regimen therefore ensures

sufficient drug exposure to maximise the efficacy of cefiderocol.

Evidence from a streamlined clinical trial programme supports the in vitro data

An improved in vitro potency in addition to a well-characterized favorable PK/PD profile are

crucial to achieve both adequate exposure to the antibacterial over the MIC for the pathogen,

and clinical cure in patients infected with drug-resistant pathogens [52]. Therefore, clinical

studies in antimicrobials, provide only supportive safety and efficacy evidence to the pivotal in

vitro and PK/PD data. Furthermore, in the context of antibacterial resistance, the standard

clinical trial approach aiming at demonstrating superiority over existing treatments is not

feasible. Treatment options for MDR infections do not allow a superiority trial and it would be

unethical to wihthold effective treatment to pateints in such trials [52]. Hence, clinical trials

have an important role to confirm clinical efficacy, but a limited role in providing comparative

evidence outside the trial, as only pathogens that fall within the in vitro spectrum of the tested

treatments and comparators are included in the study. This is particularly relevant for

antimicrobial treatment selection in the absence of antibiogram.

The clinical efficacy and safety of cefiderocol was demonstrated in 2 randomised double-

blinded clinical trials and 1 open label, descriptive study.

The APEKS-NP study compared treatment with cefiderocol against the combination of high-

dose (HD), prolonged infusion meropenem in patients with nosocomial pneumonia caused by

MDR Gram-negative pathogens. Three hundred (300) patients were randomized 1:1 to

cefiderocol or HD meropenem, a regimen only used in more difficult-to-treat pathogens which

optimizes exposure and efficacy for meropenem. Cefiderocol met the primary endpoint of non-

inferiority in all-cause mortality (ACM) at day 14 versus HD meropenem (12.4% for cefiderocol

and 11.6% for HD meropenem; [95 % CI: -6.6, 8.2]) and similar results maintained for ACM at

Day 28 and end of study (EOS). Rates of clinical cure and microbiological eradication at TOC

were also similar between the treatment groups. Although patients with CR-pathogens known

prior to randomization were excluded from the study, in a meropenem-nonsusceptible

subgroup (MIC>8mg/L) later identified, the rates of ACM at Day 14 were 17.1% in the


cefiderocol group and 20.0% in the HD meropenem group. Adverse events were similar

between cefiderocol and HD meropenem and cefiderocol safety profile was consistent with

other cephalosporins.

APEKS-cUTI was an international, multicenter, randomised, double-blind, active-controlled,

parallel-group, non-inferiority study to investigate the efficacy and safety of cefiderocol vs

imipenem/cilastatin (IPM/CS) in cUTI caused by Gram-negative MDR pathogens in hospitalisd

adults [51, 53]. 448 patients were randomized, of whom 300 received cefiderocol and 148

received IPM/CS. The primary efficacy endpoint was the composite of clinical response and

microbiological response rate at TOC assessment, in the MITT (microbiological Intent-to-treat)

population. The results demonstrated that 73% of patients in the cefiderocol group achieved

the primary endpoint, vs only 55 % of patients in the IPM/CS group, with an adjusted treatment

difference of 18.6% (95 % CI: 8.2, 28.9). This difference showed superiority in favour of

cefiderocol in a post-hoc analysis. Adverse events were similar in type and rate between

treatment groups and cefiderocol safety profile was consistent with other cephalosporins.

A Network Meta-Analysis (NMA) was feasible for cUTI, given the similarity of patients and

pathogens included across trials. All results were consistent with APEKS-cUTI trial and

showed no statistically significant differences compared to ceftazidime/avibactam and

ceftolozane/tazobactam in a similar patient population with similar pathogen distribution.

The CREDIBLE CR study was a small, exploratory, open label, randomised, descriptive study

to evaluate efficacy of cefiderocol and best available therapy (BAT) in critically ill patients with

confirmed CR infections, but was not designed or powered for statistical comparison between

arms. The study included 150 severely ill patients, (48 allocated to BAT) consistent with

compassionate use cases, with a range of infection sites including nosocomial pneumonia,

cUTI, BSI/sepsis. Many patients had end stage comorbidities and had failed multiple lines of

therapy. Clinical and microbiological outcomes were similar between the 2 arms, but there

were marked imbalances in some baseline clinical relevant characteristics and pathogen

distribution of the cefiderocol and BAT arms.

Cefiderocol has proven efficacy in complex compassionate use cases to date

More than 200 patients to date have been treated with cefiderocol within the compassionate

use programme around the world, highlighting the unmet medical need for alternative

antibacterials active against CR Gram-negative pathogens. Confirmed information on 74

patients who have completed treatment in this program showed that over 60% of the severely

ill patients infected with CR Gram-negative pathogens survived when no other treatment

option was available to them.


In the absence of AST results, cefiderocol is estimated to provide better predicted

susceptibility rates and projected clinical success rates considering the European

Gram-negative pathogen epidemiology

When critically ill patients require immediate treatment in the absence of AST results, the

likelihood of treatment success with cefiderocol and comparators can be predicted through an

effectiveness model based on estimates of pathogen prevalence for the specific site of

infection, combined with pathogen susceptibility results for each infection site (taken from the

SIDERO surveillance studies); relying on the drug’s ability to achieve effective concentrations

at the site of infection. Such methodologies are used when ethical considerations limit the

prospective clinical evaluation of treatments by randomized control trials, i.e. where the risk of

exposing patients to potentially ineffective drugs in a clinical trial setting is too great.

Results from this effectiveness model showed that cefiderocol is expected to have higher

predicted susceptibility rates than comparators across different infection sites in the European

prevalent Gram-negative bacteria, and higher projected treatment success rates in cUTI and

pneumonia. These were consistent with trials results from APEKS cUTI and APEKS NP for

cefiderocol, but not for comparators as it includes pathogens for which they are not

susceptible. This modelling approach highlights the limitations of the existing clinical trials, and

the potential difference for the effectiveness rates, when antimicrobials are used in the

absence of AST.

Cefiderocol presents a safety profile consistent with other cephalosporins

The clinical safety for cefiderocol was established in the three randomised clinical trials,

including 549 treated patients, and showed a similar profile compared to other cephalosporins.

Pooled adverse event analyses showed that there were overall less treatment emergent

adverse events with cefiderocol (344/549 [67.1%]) vs comparators (252/347 [72.6%]), as well

as less treatment related AEs, (56/549 [10.2%]) with cefiderocol vs compartors (45/347

[13.0%]).

In the nosociomial pneumonia study treatment-emergent adverse events (TEAEs) and

treatment-related TAEs were balanced between arms. SAEs occurred in 36% of patients

treated with cefiderocol and 30% of patients treated with meropenem. The most frequently

observed AE was urinary tract infection (15.5% in cefiderocol and 10.7% in meropenem

group), hypokalemia (10.8% vs 15.3%) and anemia (8.1% vs 8%).

In the cUTI study the proportion of patients who experienced at least one adverse event (AE)

was lower in the cefiderocol group than in the IPM/CS group (41 % vs 51%). The most


frequently observed AEs were gastrointestinal, such as diarrhoea [experienced by 4.3% and

6.1% of cefiderocol- and IPM/CS-treated subjects, respectively], and there was an numerical

increased incidence of C. difficile colitis in the IPM/CS arm compared with cefiderocol. Serious

adverse events (SAE) occurred less in cefiderocol-treated patients than in IPM/CS-treated

patients (5% vs 8%).

CR study (CREDIBLE-CR): The cefiderocol group had a lower incidence of AEs and

treatment-related AEs, but a higher incidence of death, SAEs and discontinuation due to AEs,

than was observed for patients receiving BAT. The incidence of treatment-related AEs leading

to discontinuation was similar between treatment groups. A blinded adjudication committee

concluded that none of the deaths in the cefiderocol arm was due to a drug-related AE,

although one death due to acute kidney injury in the BAT arm was attributed to colistin-based

therapy. Furthermore, whereas the mortality rate in the cefiderocol group was consistent with

previous studies in similar populations the evidence suggests that the mortality rate in the BAT

group was unexpectedly low for the population randomised.

CONCLUSION

Cefiderocol is an innovative, effective and well tolerated treatment for aerobic GN infections

in patients with limited treatment options. Cefiderocol overcomes the common resistance

mechanisms of GN pathogens and covers a broad range of aerobic, GN bacteria including all

three WHO priority CR pathogens (Enterobacteriaceae, A. baumannii and P. aeruginosa) and

the CR Stenotrophomas maltophilia and Burkholderia cepacia. It provides an important

alternative for physician managing patients with MDR/CR infections.

Cefiderocol’s favourable in vitro MICs across all relevant pathogens correlates well with in vivo

efficacy in PK/PD analyses. Randomized clinical trials in patients with cUTI, nosocomial

pneumonia (HAP/VAP/ HCAP), and BSI and sepsis have provided confirmation of the good

efficacy and safety of cefiderocol in key target patient populations, alongside compassionate

use case reports.

The combination of in vitro, PK/PD, and clinical data predicts that cefiderocol has a greater

likelihood of obtaining clinical success rates, in patients with suspected MDR/CR infections

than relevant comparators across different infection sites.

Cefiderocol provides an important new option for treating critically ill, hospitalised patients

where MDR/CR infection is suspected and time to effective treatment must be minimised, and

for patients where an MDR/CR infection has been confirmed and it is the most appropriate

option, due to pathogen susceptibility or where other treatment choices are inappropriate.


1 Description and technical characteristics of the technology

Summary of the characteristics of the technology

Cefiderocol is the first siderophore cephalosporin [44] to be approved. It’s unique

molecular structure and novel mechanism of cell entry allow it to overcome the three

major resistance mechanisms found in Gram-negative pathogens (i.e., degradation by

β-lactamase enzymes, porin channel mutations and overexpression of efflux pumps):

o Cefiderocol has improved stability to hydrolysis by β-lactamases, including all

4 types of carbapenemases, key enzymes rendering resistance to β–lactam

antibacterials, including carbapenems.

o Cefiderocol exploits the bacteria’s need for iron and mimics the action of

bacterial own siderophores. A chelate complex with free iron is formed, which

is then actively transported into the bacterial cell via iron transporters,

circumventing pathways traditionally used by other antibacterials such as efflux

pumps or porin channels, which bacteria can regulate to reduce their exposure

to antibacterials.

Cefiderocol is active against a wider range of aerobic, GN bacteria than its

comparators (including all WHO priority pathogens: CR Enterobacteriaceae, CR P.

aeruginosa and CR A. baumannii). In addition, cefiderocol is also active against

intrinsically CR Stenotrophomas maltophilia and Burkholderia cepacia.

In Europe, Shionogi seeks a pathogen-focused indication for cefiderocol, and it is

expected to be approved for the treatment of infections due to aerobic GN organisms

in adults with limited treatment options. Within this indication, it is proposed that

cefiderocol offers most value in two clinical scenarios, and evidence for cefiderocol

and its relevant comparators is provided for each:

o Hospitalised patients with suspected (but prior laboratory confirmation)

MDR/CR infection who are critically ill and require immediate antibacterial

treatment that provides full cover against CR pathogens and potential resistant

mechanisms, to avoid the risk of rapid clinical deterioration (with the option to

de-escalate to a more targeted treatment when the pathogen and susceptibility

profile is subsequently confirmed).

o Hospitalised patients where CR infection has been confirmed and cefiderocol

is best option based on pathogen susceptibility information and/or where other

treatment choices are inappropriate (efficacy, contra-indication or tolerability).


Cefiderocol was approved by the U.S. Food and Drug Administration (FDA) on

November 14, 2019, for treatment of cUTI in adult patients with limited or no alternative

treatment options. Based on the results of the recently presented APEKS NP study

Shionogi is preparing a sNDA submission to FDA for approval of cefiderocol for

pneumonia in 2020.

Evaluation of the effectiveness of an antibacterial requires the integrated analysis of in

vitro, PKPD and clinical data.

o Two large susceptibility studies, SIDERO-WT/Protea and SIDERO-CR

2014/2016), showed cefiderocol to have activity against 99.5% of GN isolates

and 96.2% of CR GN isolates respectively. This was higher than other tested

antibacterials, according to CLSI breakpoints. This was replicated in several

small country specific studies, with consistency results.

o Cefiderocol’s favourable in vitro MICs correlate well with in vivo efficacy in

PK/PD analyses conducted.

o Three clinical trials (APEK cUTI, APEKS NP and CREDIBLE CR) have

provided confirmation of the efficacy and safety of cefiderocol in key infection

types: cUTI, nosocomial pneumonia (HAP/VAP/HCAP), and BSI.

o In the absence of AST results, and in an integrated effectiveness model

analysis of European pathogen epidemiology, in vitro/in vivo data, and clinical

data, cefiderocol provides the best predicted susceptibility rates and projected

clinical success rates considering for the EU setting.

Cefiderocol provides an important new option for treating critically ill, hospitalised

patients where MDR/CR infection is suspected and time to effective treatment must

be minimised, and also for patients where an MDR/CR infection has been confirmed

and it is the most appropriate option, due to pathogen susceptibility or where other

treatment choices are inappropriate


1.1 Characteristics of the technology

1. In Table 1 provide an overview of the technology.

Table 1: Features of the technology

Non-proprietary name Cefiderocol

Proprietary name FETCROJA

Marketing

authorisation holder

Shionogi B.V., Amsterdam, Netherlands

Class Antibacterials for systemic use

Active substance(s) Siderophore cephalosporin

Pharmaceutical

formulation(s)

Powder for concentrate for solution for infusion (powder for concentrate).

White to off-white powder.

ATC code J01DI04 cefiderocol

Mechanism of action Cefiderocol is a siderophore cephalosporin. In addition to passive

diffusion through outer membrane porin channels, cefiderocol can bind to

extracellular free iron via its siderophore side chain, allowing active

transport into the periplasmic space of Gram-negative bacteria through

siderophore uptake systems. Cefiderocol subsequently binds to penicillin

binding proteins (PBPs), inhibiting bacterial peptidoglycan cell wall

synthesis which leads to cell lysis and death.

2. In Table 2, summarise the information about administration and dosing of the

technology.

Table 2: Administration and dosing of the technology

Method of administration Intravenous use; administered by intravenous infusion over 3

hours.

Doses 1 g/vial; the recommended dose for individuals with normal

renal function is 2g over 3h infusion

Dosing frequency Every 8 hours (three times daily)

Average length of a course of

treatment

3-hour infusion of 2g; Overall duration of treatment is in

accordance with the site of infection.

Anticipated average interval

between courses of treatments

Each treatment cycle lasts 8 hours; 3h of infusion and then 5h

until the next cycle begins.

Anticipated number of repeat

courses of treatments

For complicated urinary tract infections including

pyelonephritis and complicated intra-abdominal infections the


recommended treatment duration is 5 to 10 days. For hospital-

acquired pneumonia including ventilator-associated

pneumonia the recommended treatment duration is 7 to 14

days. Treatment up to 21 days may be required.

Dose adjustments Dose adjustments are necessary for patients with renal

impairment (reduced dose) or augmented renal function

(increased dose)

3. State the context and level of care for the technology (for example, primary healthcare,

secondary healthcare, tertiary healthcare, outside health institutions or as part of public

health or other).

Cefiderocol is administered by intravenous infusion over 3h every 8h. It is intended for

hospitalised, critically ill patients and therefore, is intended for hospital-use only.

4. State the claimed benefits of the technology, including whether the technology should

be considered innovative.

Cefiderocol is the first siderophore cephalosporin [44] to be approved. Its unique molecular

structure catecholate siderophore moeity, exploits the bacteria’s own active iron uptake

mechanism via siderophores to enter the periplasmic space of GNB where it exerts its

bactericidal activity by inhibiting bacteria cell wall synthesis. This is a novel mechanism of

bacterial cell entry which means that, unlike other antibacterials, cefiderocol bypasses

pathways traditionally used by other antibacterials such as efflux pumps or porin channels,

which bacteria can regulate to reduce their exposure to antibacterials. Cefiderocol also has a

higher stability to both serine- and metallo-type β -lactamases, key enzymes rendering

resistance to β–lactam antibacterials, including carbapenems. All these factors contribute to

cefiderocol’s unique breadth of activity and efficacy, covering a wide range of aerobic, GN

bacteria, demonstrated by its potent activity (both in vitro and in vivo) against all three WHO

priority CR pathogens (Enterobacteriaceae, A. baumannii and P. aeruginosa) [29, 30, 45-49].

In addition, cefiderocol has in vitro activity against intrinsically CR Stenotrophomas maltophilia

and Burkholderia cepacia [30].

1.1.1 Cefiderocol Structure

Cefiderocol has a pyrrolidinium group on the C-3 side chain, which improves antibacterial

activity and stability against β-lactamases (Figure 1) [48]. The major difference in the chemical


structure of cefiderocol and other cephalosporins is the addition of a chlorocatechol group on

the end of the C-3 side chain, which confers the siderophore activity (Figure 1) [48].

Figure 1: Cefiderocol structure

Source: Sato, 2019 [54]

Cefiderocol has been granted with an ATC code J01DI04: cefiderocol.1 The J01D group (other

β-lactam antibacterials) comprises beta-lactam antibacterial, other than penicillins.

1.1.2 Mechanism of action and cell entry

The low levels of free iron in the human body during an infection induce pathogens to

upregulate iron acquisition factors, such as secretion of iron-binding small molecules called

siderophores into their environment and production of membrane-bound active iron

transporters [44, 55-58]. Bacterial siderophores tightly bind to host iron, forming a chelated

iron complex, which then penetrates through the outer membrane via active iron transporters

located in the GN outer membrane [44, 54].

Cefiderocol exploits the bacteria’s need for iron for cell growth and uses the bacteria’s own

active iron uptake mechanism to enter the periplasmic space of GN bacteria where it binds to

penicillin binding proteins (PBPs), inhibiting the bacterial cell wall synthesis causing killing the

bacteria [44, 48, 59].

1 https://www.whocc.no/ddd/lists_of_new_atc_ddds_and_altera/new_atc/?order_by=1


Cefiderocol has been designed to chelate iron to form an iron complex similar to a bacterial

catecholate siderophore (Figure 1) [44, 54]. When bound to iron, the cefiderocol iron complex

mimics a bacterial siderophore-iron complex and therefore is actively transported through the

outer membrane using the bacteria’s active iron transporters, bypassing pathways traditionally

used by other antibacterials such as efflux pumps or porin channels, which bacteria can

regulate to reduce their exposure to antibacterials [44, 54, 60]. Even in the absence of forming

a complex with iron, cefiderocol can still function as other antibacterials, entering the bacterial

periplasm via passive diffusion through porin channels (Figure 2) [59].

Cefiderocol activity against bacterial strains with porin channel mutations and overexpression

of efflux pumps has been demonstrated in two in vitro studies [61, 62].

Figure 2: Cefiderocol mechanism of cell entry

Source: Image adapted from Zhanel 2019 [44]

1.1.3 Stability against β-lactamases

Figure 3: Antibacterial activity against β-lactamase-producing pathogens


*Color-coding based on the pathogen susceptibility: Green – Activity reported, yellow – undetermined

activity reported, and red – no clinically relevant activity reported. Source: Thalhammer F, 2018 [63],

Theuretzbacher, 2019 [64]

The structure of cefiderocol also presents higher stability to hydrolysis across a wide range of

bacterially produced β-lactamase enzymes (including carbapenemases of the serine and

metallo-β-lactamase classes) and thus overcomes the primary mechanism of bacterial

resistance to beta–lactam antibacterials, without adding a β-lactamase inhibitor.

The image above (Figure 3) shows that whilst there are effective alternatives for Extended

Spectrum Β-lactamase (ESBL), there are limited treatment options for serine cabapenemases,

and metallo-bectalactamases, as well as other mechanisms of resistance. This is particulary

relevant for non-fermenters Pseudomonas aeruginosa, Acinetobacter baumanii, and

Stenotrophomonas maltophilia.

All these factors contribute to cefiderocol’s unique breadth of activity and demonstrated

efficacy, covering a wide range of aerobic, GN bacteria and cefiderocol’s demonstrated potent

activity (both in vitro and in vivo) against all three WHO priority carbapenem resistant

pathogens (Enterobacterales, A. baumannii and P. aeruginosa). In addition, cefiderocol has

in vitro activity against carbapenem resistant Stenotrophomas maltophilia and Burkholderia

cepacia.

1.2 Regulatory status of the technology

1. Complete Table 3 with the marketing authorisation status of the technology.

Table 3: Regulatory status of the technology

Organisation

issuing

approval

Verbatim wording of the (expected)

indication(s)

(Expected)

Date of

approval

Launched

(yes/no).

If no include

proposed date of

launch

FDA

FETROJA is a cephalosporin

antibacterial indicated in patients 18

years of age or older who have limited

November 14,

2019

Not launched.

Expected to be

launch in Q1 2020


or no alternative treatment options, for

the treatment of complicated urinary

tract infections (cUTI), including

pyelonephritis caused by susceptible

Gram-negative microorganisms

EMA

Fetcroja is indicated for the treatment of

infections due to aerobic Gram-negative

organisms in adults with limited

treatment options

May, 2020

Not launched

Expected to launch

in 2H, 2020

EMA: European Medicines Agency, FDA: U.S. Food and Drug Administration

2. State any other indications not included in the assessment for which the technology

has marketing authorisation.

Not applicable. This corresponds to a new marketing authorization for a new chemical entity.

3. State any contraindications or groups for whom the technology is not recommended.

It is recommended that Fetcroja should be used to treat patients that have limited treatment

options only after consultation with a physician with appropriate experience in the

management of infectious diseases.

Cefiderocol should not be given to the following patients:

Patients with hypersensitivity to the active substance or to any of the excipients

listed

Patients with hypersensitivity to any cephalosporin antibacterial medicinal product.

Patients with severe hypersensitivity (e.g. anaphylactic reaction, severe skin

reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins,

monobactams or carbapenems).

The safety and efficacy of cefiderocol in children below 18 years of age has not yet been

established. No data are available. Patients with Central Nervous System infections were also

not included in the cefiderocol clinical trials.

4. List the other countries in which the technology has marketing authorisation.

Currently cefiderocol only has marketing authorization in the United States of America, under

the brand name of Fetroja, with the indication mentioned in Table 3.


2 Health problem and current clinical practice

Summary of issues relating to the health problem and current clinical practice

AMR is a major and growing, threat to global public health. Infections by MDR (and

particularly CR) pathogens are associated with a high mortality rate and increased

morbidity and economic burden. In 2015 in the EU, 33,110 deaths were attributable to

infections due to antibacterial-resistant bacteria and it has been estimated that, if

significant action is not taken by the year 2050, 10 million lives will be lost each year

due to AMR. [4]

MDR and particularly CR infections are predominantly caused by Gram-negative,

aerobic bacteria. Given the increasing prevalence of resistant pathogens, WHO has

declared that the availability of new treatments for CR Gram-negative pathogens to be

a critical priority for CR strains of Enterobacteriaceae, Pseudomonas aeruginosa and

Acinetobacter baumannii including them on the WHO “Priority One CRITICAL List”

[65].

Current treatment options, including antibacterial combinations, have either suboptimal

efficacy (carbapenems), limited pathogen and mechanism of resistance coverage

(ceftolozane/tazobactam; ceftazidime/avibactam; meropenem-vaborbactam), and/or

significant safety and tolerability concerns (e.g. colistin, tigecycline).

o Treatment of confirmed CR infections must be tailored to each patient based

on results of AST results, knowledge of hospital and regional pathogen

epidemiology and patient specific factors, such as severity of concomitant

illness and infection. Therefore, few guidelines exist in Europe identifying a

specific treatment approach in CR infection.

o resistance to many antimicrobial classes almost invariably reduces the

probability of adequate empirical coverage, with possible unfavourable

consequences

o In the absence of an AST results (which commonly takes 3 days) and

suspected MDR/CR infection, treatment should start immediately in critically ill

patients to avoid risk of rapid deterioration. However, resistance to many

antimicrobial classes almost invariably reduces the probability of adequate

initial treatment, with possible unfavourable consequences vs those where the

pathogen is susceptible, and therefore easier to treat with available treatments


(46.5% vs. 11.8%, p < 0.001). These patients experience delays in receiving

effective treatment which may lead to worse outcomes, increased mortality,

and increased length of hospital stay and treatment costs.

The integrated cefiderocol data-set (susceptibility, PK/PD and clinical trials) shows it

has a greater likelihood of treatment success in patients with MDR/CR infections than

relevant comparators. Cefiderocol therefore provides an important new option for

treating critically ill, hospitalised patients where MDR/CR infection is suspected and

time to effective treatment must be minimised, and also for patients where an MDR/CR

infection has been confirmed and it is the most appropriate option, due to pathogen

susceptibility or where other treatment choices are inappropriate.

The availability of cefiderocol as an additional effective agent against Gram-negative

bacteria can contribute to good antibacterial stewardship by allowing physicians to

increase the diversity of prescribing, reducing selective pressure on any one agent and

minimize development of resistance.

2.1 Overview of the disease or health condition

1. Define the disease or health condition in the scope of this assessment.

The human body harbours over 1000 types of bacteria constituting the normal microbial flora.

In healthy individuals, these bacteria do not usually cause infection and exist on the host for

long periods without causing harm [66]. However, invasion of the host by pathogenic

microorganisms that proliferate results in tissue injury [67]. Pathogenic bacteria can infect any

part of the human body. Infections can be acquired in the community setting (community-

acquired infection [CAI]), acquired in hospital setting (Hospital-acquired infection – [HAI] or

nosocomial infection) or acquired in long-term care facilities (Healthcare-associated infection

[HCAI]) such as intensive care wards, ambulatory settings, nursing homes or rehabilitation

facilities. Infections caused by multidrug-resistant bacteria (MDR) are more likely to be a HAI.

Nosocomial infections primarily occur in vulnerable hospitalised patients. These patients are

often ≥ 50 years of age, likely to be severely ill, e.g. transplanted patients, possibly in intensive

care units (ICU), or undergoing chemotherapy, or patients who have compromised

immunogenicity, and generally wuth multiple comorbidities (e.g. heart disease, diabetes or

kidney disease) [68, 69]. Infections caused by MDR pathogens can occur at many sites

including the urinary tract (complicated urinary tract infections [cUTI]), lungs (Hospital-


acquired and ventilator-associated pneumonia [HAP/ VAP]), blood (bloodstream infections

[BSI]), and intra-abdominal sites (complicated intra-abdominal infections [cIAI]).

The International Classification of Disease (ICD, version 10) contains separate codes for

pathogens as well as for infections sites. ICD-codes for nosocomial Gram-negative infections

are included as an appendix [70].

2.1.1 Overview of Gram-negative bacteria

Gram-negative bacteria can be classified into fermenters and non-fermenters based on their

ability to ferment glucose [71]. While non-fermenting Gram-negative bacteria (non-fermenters)

are usually found in nature, they are harmful when colonizing and infecting

immunocompromised people or when the infections are a consequence of trauma or invasive

procedures (e.g. surgery, intravenous catheters, respiratory care equipment or endotracheal

tubes) [71]. Bacteria are also differentiated based on cellular morphology (most commonly

bacilli and cocci) and oxygen requirements (aerobes and anaerobes) (Figure 4) [72].


Figure 4: Classification of Gram-negative bacteria

Pathogens highlighted in blue are of interest when exploring the topic of carbapenem resistance

Source: The Ohio State University, 2017 [73]; Adeolu, 2016 [74]


2.1.2 Antimicrobial resistance

Anti-microbial resistance (AMR) is a major, and growing, threat to global public health.

Treatment of pathogens has become more and more challenging due to the emergence of

resistance, especially to carbapenems which are usually reserved for use where other

alternative options have failed [5, 6, 75-79]. AMR is estimated to contribute to 700,000 deaths

every year globally, with 33,110 lives lost per year in Europe [1, 4, 80]. The burden of infections

with bacteria resistant to antibacterials in the European population is comparable to that of

influenza, tuberculosis and HIV/AIDS combined [81]. It has been estimated that, if significant

action is not taken, by the year 2050 10 million lives will be lost each year due to AMR (Figure

5) [1]. While the global consumption in antibacterials is predicted to rise three-fold by 2030,

the current treatment options may address only a subset of resistance mechanisms [1].

Figure 5: Global burden of AMR

Source: O’Neill [1]

An overview of medically important GN bacteria classified based on WHO’s priority criteria

for Drug development is provided in Table 4 [1].

Table 4: List of the highest priority bacteria (WHO)

Priority Pathogen

Critical Carbapenem-resistant Acinetobacter baumannii,

Carbapenem-resistant Pseudomonas aeruginosa,


Carbapenem-resistant/3rd generation cephalosporin-resistant Enterobacterales,

(including Klebsiella pneumonia, Escherichia coli, Enterobacter spp., Serratia spp.,

Proteus spp., and Providencia spp, Morganella spp.)

High Clarithromycin-resistant Helicobacter pylori,

Fluoroquinolone-resistant Campylobacter

Fluoroquinolone-resistant Salmonella spp

3rd generation cephalosporin-resistant/fluoroquinolone-resistant Neisseria gonorrhoeae,

Medium Ampicillin-resistant Haemophilus influenzae

Fluoroquinolone-resistant Shigella spp

Source: WHO 2017 [5, 6]

GN pathogens are challenging to treat due to their potential intrinsic resistance to

antibacterials and the emergence of acquired resistance [75]. This development has been

recognized to be a major public health threat. Outbreaks of infections with resistant strains

have been reported in several European countries [82, 83]).

Facultative anaerobes E. coli, A. baumannii, K. pneumoniae and P. aeruginosa, are a

cause of great concern with regard to antimicrobial resistance (AMR) [8, 79]. Non-

fermenters such as P. aeruginosa, A. baumannii, and S. maltophilia, are often resistant to

a large number of antibacterial treatments and also differ in their pathogenic potential and

transmissibility [84].

The widespread use of antibacterials has led to new mechanisms of resistance to develop

[85]. Bacteria have adjusted by producing new types of β-lactamases, which can cleave

the otherwise resistant carbapenems [86]. Additional resistance-causing mutations can

modify and/or downregulate the cell wall proteins, porin channels and other molecules that

the antibacterials use to enter and kill the bacteria. Some bacteria have acquired the ability

to up-regulate efflux pumps to eliminate the antibacterial faster. Figure 6 illustrates the

main mechanisms of beta lactam bacterial resistance.

Additionally, bacteria have developed the ability to transfer resistant genes not only

vertically, but also horizontally to other members of their own or even different species [87]

[88, 89] [90], thus became a global problem of interspecies transmission.

Carbapenems, due to their potent efficacy, broad-spectrum activity, and relative resistance to

hydrolysis by the majority of β-lactamases, are usually reserved for use when other options

have failed [28].


Figure 6: Mechanisms of beta lactam bacterial resistance

Β-lactamases and carbapenemases are the most common cause of resistance to beta-

lactam antibacterials (e.g. penicillin) in GN bacteria [75, 91]. Β-lactamases hydrolyse the

beta-lactam ring of beta-lactam antibacterials and render them inactive [92, 93]. They can

be classified into four molecular classes (A-D). Carbapenemases, a subset of β-

lactamases that hydrolyse carbapenems as well as almost all beta-lactam antibacterials,

include enzymes from classes A, B and D [86, 94]. Class A carbapenemases, the most

common carbapenemases primarily identified in Enterobacterales can hydrolyse

carbapenems as well as cephalosporins, penicillins, and aztreonam [86, 91, 95]. Class B

carbapenemases, found in K. pneumoniae and A. baumannii, usually exhibit resistance to

penicillins, cephalosporins, carbapenems, and the available β-lactamase inhibitors [91,

96]. Β-lactamases from class D, also known as OXA β-lactamases, can confer resistance

to penicillins, cephalosporins, extended-spectrum cephalosporins, and carbapenems

(OXA-type carbapenemases) and are poorly inhibited by currently available β-lactamase

inhibitors. These enzymes are expressed in A. baumannii and P. aeruginosa [91, 95, 97].

While resistance based on carbapenemases is mostly acquired, it can be intrinsic in some

species, such as S. maltophilia [98].

Changes to porin channels, reducing the permeability of the outer membrane, is a common

mechanism of intrinsic antibacterial resistance in GN bacteria [99]. These changes include

both reducing the number of porin channels and altering their conformation resulting in a

reduced ability of antimicrobial agents to cross the outer membrane and reach the

intracellular antibacterial target [75]. In Enterobacterales, P. aeruginosa, and A.

baumannii, reductions in porin expression significantly contribute to resistance to

carbapenems and cephalosporins [99].


Another common mechanism of resistance is overexpression of efflux pumps. Efflux

pumps actively pump antibacterials from the bacterial cytoplasm, inhibiting their function

within the cell [99]. When overexpressed, efflux pumps can confer high levels of resistance

to previously clinically useful antibacterials such as carbapenems [100]. Efflux pumps are

a common mechanism of resistance in non-fermenting bacteria such as P. aeruginosa,

and A. baumannii [101].

All these mechanisms can co-exist in the same organism.

Furthermore, while use of colistin was largely abandoned due to the high rates of renal

toxicity, in recent years, the increasing emergence of CR GN bacteria has led to its clinical

renaissance [102], given its wider spectrum of activity and lack of effective alternatives.

However, resistance to colistin is rapidly increasing. In Europe for instance, 28% of CR K.

pneumoniae have been identified as resistant to colistin [103]. Also, reports of resistance

to the recently approved treatments such as ceftolozane/tazobactam and

ceftazidime/avibactam have raised concerns [42, 43].

Table 5 shows the limited in vitro efficacy of several antibacterials against different GN

bacteria (Enterobactereacea, Pseudomonas aeruginosa, Acinetobacter baumannii,

Stenotrophomonas maltophilia), particularly for CR non-fermenters and pathogens,

including serine carbapenemases. ([104]). Stenotrophomonas maltophilia is intrinsically

resistant against carbapenems [98, 105].


Table 5: In vitro activity profile of antibacterials for GN Infections with limited treatment options

CP: carbapenemase; CR: carbapenem resistant. OXA-48, KPC, MBL, AmpC: types of carbapenemases.

Green – Activity reported, yellow – undetermined activity reported, and red – no clinically relevant activity

reported. Source: Adapted from Thalhammer F. (2018). [63]

2.1.3 Overview of infection sites

Aerobic GN pathogens are the most common causes of nosocomial infections and are most

commonly seen pneumonia, BSI and UTI, which together represent over 50% of the HAI in

Europe.


Figure 7: Hospital-acquired infections in acute care hospitals (EU/EEA 2011-2012)

HAI, hospital-acquired infection

Source: ECDC, 2012 [10]

2.1.3.1 Nosocomial Pneumonia

According to the European Centre for Disease Prevention and Control (ECDC) prevalence

survey database, pneumonia is the most common infection site accounting for 23% of HAIs

[10], of which 67.6% are caused by GN pathogens, and can be defined as HAP, VAP or

healthcare-associated pneumonia (HCAP) (Figure 7) [106]. The main causal pathogens of

HAP/VAP include Pseudomonas aeruginosa, Acinetobacter spp. and Enterobacterales [11].

Patients with HAP/VAP are at risk of experiencing acute respiratory failure and may require

mechanical ventilation [107]. In the 2012 ECDC report, intensive care unit (ICU)-acquired

pneumonia was reported to be associated with 5,495 deaths annually resulting in an

attributable mortality rate of approximately 3.5% [108].

2.1.3.2 Complicated urinary tract infection (cUTI)

According to the ECDC prevalence survey database, UTI accounts for 19% of HAIs, of which

76.7% are caused by GN pathogens [10, 106]. The main causal pathogens of cUTI include

Escherichia coli, Enterococcus spp., Klebsiella spp., Pseudomonas aeruginosa and Proteus

spp. [11]. Patients with cUTI can develop bacteraemia and sepsis in 10% to 30% of cases,

with risk of death reaching up to 40% [109, 110].

2.1.3.3 Bloodstream infection and sepsis

Bloodstream infections account for 11% of HAIs, of which 43.8% are caused by Gram-

negative pathogens [10, 106]. It is defined as the presence of bacteria in the blood and can

be also referred to as bacteraemia. In some cases, it can result in sepsis developing, which is

a life-threatening condition mediated by the inflammatory response to infection [27]. The main


causal pathogens of BSI include Staphylococcus spp., Streptococcus pneumonia,

Enterobacterales and Enterococcus spp. [11]. In the 2012 ECDC report, ICU-acquired BSI

was reported to be associated with 4,505 deaths annually resulting in an attributable mortality

rate of approximately 5% ([108].

2.1.3.4 Complicated intra-abdominal infection

Complicated intra-abdominal infections account for 1 to2.8% of CR infections [111] [4, 112].

The percentage of IAI caused by Gram-negative pathogen is 15.9% [106]. It is associated with

either abscess formation or peritonitis [113]. cIAI generally extends beyond local viscera into

peritoneal or retroperitoneal spaces and are associated with systemic signs and symptoms of

illness [114]. The main causal pathogens of cIAI are Enterobacterales, Streptococci and

Anaerobes (particularly Bacteroides fragilis) [23].

2.1.4 Risk and prognostic factors for MDR and CR infections

2.1.4.1 Risk factors

Risk factors for CR Gram-negative infections consist of a combination of patient clinical

setting/healthcare exposure and patient-level characteristics [115-117] and include risk factors

that are common to all nosocomial infections (e.g. long term hospitalisation, invasive

procedures, long-term ventilation, or depressed host immune system), and some are more

specific to CR infections (e.g. previous colonization or infection with CR pathogen, prior

exposure to carbapenems, and recent hospitalisation in a endemic CR infections country, or

where there was a recent outbreak). Risk factors can vary by infection site (e.g. ventilation is

more frequently reported in pneumonia). [85, 118-122].

A summary of the most commonly reported risk factors according to different pathogens is

included as an appendix [123] (see Table 6.1:Most commonly reported risk factors per

pathogen).

2.1.4.2 Prognostic factors

Time to effective therapy impacts patient’s overall outcomes. Delays in the determination of

the pathogen identity and AST results frequently lead to inadequate initial treatment, which

causes increased morbidity and mortality. The impact of treatment delay of appropriate

treatment was analysed in an SLR [124, 125] reviewing 145 studies and considering three

types of outcome comparisons: delay vs. no delay in receiving appropriate therapy, duration

of delay of appropriate therapy, and appropriate vs. inappropriate initial therapy. A delay in

patients receiving appropriate effective treatment was shown to lead to worse patient


outcomes, including higher mortality rates. Early treatment with appropriate initial therapy

represents an important prognostic factor in the treatment of patients with GN infections with

limited treatment options. This is further detailed in this section

2. Present an estimate of prevalence and/or incidence for the disease or health condition

including recent trends.

2.1.5 Epidemiology

The rate of infections caused by multidrug-resistant (MDR) bacteria continues to increase and

limit the utility of existing antibacterial agents. In its surveillance report (2018), European

Centre for Disease Prevention and Control (ECDC) reported an increase in resistance to

currently available treatments across some Gram-negative pathogens between 2015 and

2018 [126]. ECDC estimate that nearly 700,000 infections and 33,000 deaths in the EU and

European Economic Area (EEA) in 2015 are a consequence of MDR bacterial infection [4].

Carbapenem-resistance (CR) in Pseudomonas aeruginosa, Klebsiella pneumoniae and

Acinetobacter spp. contributed significantly to the number of estimated deaths (in total

approximately 9,000 deaths).

Reports on CR isolates are highly heterogeneous across the globe (Figure 8), but the

prevalence of carbapenem resistance has been found to be particularly high in Mediterranean

countries, South America and Asia-Pacific countries, with the exception of Japan [127, 128].

Figure 8: Worldwide carbapenem resistance

Source: CDC 2013[80]; ECDC 2017[79]; Mendes et al.[129]; Kiratisin et al.[130]

In the EU-5, the number of CR Gram-negative infections has been reported to be 65,592 in

2015, 123,069 in 2018 and 124,630 in 2019 with P. aeruginosa and A. baumannii as the most


frequently diagnosed CR pathogens [4, 79, 111]. Across EU-5 countries, prevalence of CR

Gram-negative infections is reported to range between 0.14 per 100,000 in the UK to 3.05 per

100,000 in Italy (Figure 9) [4].

Figure 9: Prevalence of CR Gram-negative infections in the EU-5

Source: Cassini, 2018[4]

Prevalence estimates are available from multiple sources, generated thorugh different

methodologies. Furthermore, pathogen resistance is a constantly evolving, and therefore,

results may vary significantly with time, and region/country. Also relevant to account is the fact

that the epidemiology varies across the different pathogens, and infections sites:

Non-fermenters P. aeruginosa and Acinetobacter spp. are the most common

pathogens. P. aeruginosa was found in 17% to 61% of CR infections and

Acinetobacter spp. in 19% to 50%. The second most common CR pathogen is K.

pneumoniae (6% to 20% of infections) followed by E.coli (0.1% to 2.8%) [4, 79, 111].

The most prevalent CR Gram-negative infection site is the respiratory tract with

reported ranges from approximately 41% [4] to 57%[111], followed by UTI and

BSI/Sepsis (Table 7).

Table 6: Most common CR causal pathogens across available EU-5 data sources

Pathogen % of causal pathogen for CR Gram-negative infections

P. aeruginosa 17%-60.7%

A. baumannii 19%-50%

K. pneumoniae 6%-20.0%

S. maltophilia 1%a

E. coli 0.1%-2.8%

1,20

0,31

3,05

0,64

0,14

1,07

France Germany Italy Spain UK EU-5 average

Cases/100,000


A proportion of S. maltophilia that caused HAIs Suetens 2018[106]

Sources: ECDC 2018[79]; Cassini et al, 2018[4] and DRG 2017[111]

Table 7: Proportion of CR infection sites in the EU-5

Infection site % of infection sites for CR Gram-negative infection

Respiratory tract 41.3%-57%

Urinary tract 17.0%-19.1%

Bloodstream 11.2%-21%

Abdomen 2.0%

Skin/wound 10.7%-12.8%

Other 7.8%

Sources: Cassini et al, 2018[4] ; DRG 2017[111]

While there appears to be geographical variation in different types of carbapenemases, recent

surveillance study reports an overall increase in these enzymes.

While carbapenem resistance affects both non-fermenters and fermenters in all regions,

mechanisms of resistance appear to vary geographically [48, 128].

Analyses from SIDERO-CR surveillance studies [131] confirmed the diversity in

carbapenemases across Europe, reporting prevalences of carbapenemas producing

Enterobacteriaceae (CRE), P. aeruginosa (CRP), and A. baumannii (CRA) (Figure 10).

Overall there is an increase in the prevalence of isolates with carbapenemases with significant

divrsity (Figure 11) [103] and non-carbapenemase mechanisms of resistance are present in a

significant proportion of isolates, particularly in E. coli. (Figure 12) [103, 132]

Figure 10: Epidemiology of carbapenemases in EU 5

Source: Shionogi data on file (Data adapted from SIDERO-CR study)[131]


Figure 11: Confirmed carbapenemase-producing Enterobacteriaceae isolates (Public Health

England: 2008–17)

Source: ESPAUR, 2019[132]

Figure 12: Distribution of carbapenem resistance mechanisms in Enterobacteriaceae species in

the Europe

Source: Nordmann, 2019 [128]

3. Describe the symptoms and burden of the disease or health condition for

patients.

Multi Drug Resistant Gram-negative infections primarily occur in vulnerable hospitalized

patients. These pateints are often ≥ 50 years of age, severely transplanted patients, possibly

in intensive care units (ICU), or undergoing chemotherapy, or patients who have compromised

immunogenicity, and generally wuth multiple comorbidities (e.g. heart disease, diabetes or

kidney disease) [68, 69].

The clinical burden of bacterial infection has an impact on key outcomes such as longer

treatment, extended hospital admission, additional healthcare professional time, healthcare

resource use, adverse events, greater disability (morbidity) and increased risk of death


(mortality) [76]. The need to treat patients empirically before pathogen susceptibility has been

confirmed means that this initial treatment choice in MDR is often inappropriate and this can

have a significant impact on the individual patient due to the negative clinical consequences

of a delay on effective treatment [133, 134].

An overview of signs and symptoms of common CR infections by infection site is provided in

Table 8.

Table 8: Overview of disease burden according to the infection site

Site of infection Signs and Symptoms2 Mortality

pneumonia Dyspnoea a Productive cough a Fever a Chest pain a Loss of appetite a

5,495 annual number of deaths in Europe due to ICU-acquired

pneumonia (2008–12)[108]

Attributable mortality rate: ~3.5%

cUTI Fever b Increased urinary frequency b and urgency b Haematuria b Dysuria b Suprapubic/flank pain b

Can develop bacteraemia and sepsis in 10% to 30% of cases,

with risk of death reaching up to 40%[109, 110]

BSI Fever c Chills c Tachycardia c Tachypnoea c Potential complications: Infective endocarditis d Osteomyelitis d Infectious arthritis d Septic shock/sepsis d

4,505 Annual number of deaths in Europe due to ICU-acquired

bloodstream infections (2008–12) [108]

Attributable mortality rate: ~5%

sepsis Dyspnoea e Confusion e Tachycardia e Fever/shivering/feeling very cold e Extreme pain e Clammy/sweaty skin e

A rate of hospital mortality for sepsis: 17%-26% in severe cases

[135]

Extrapolation to global estimates: ~ 5.3 million deaths annually

from sepsis

cIAI Fever f Tachycardia f Tachypnoea f

Hypotension f Abdominal pain f Nausea and vomiting f Diarrhea f Abdominal fullness e Obstipation e

Severe infections: mortality rate of 30-50%

In case of sepsis: mortality rate > 70%g

Sources: a. https://www.blf.org.uk/support-for-you/pneumonia/symptoms ; b. Sabih et al, 2019[136]; c. MedlinePlus -

Medical Dictionary[137] d. Hassoun et al, 2017 [138];

Symptoms of MDR (including CR) Gram-negative infections vary according to the infection

site, but for the same infection site, are no different than that caused by other serious

infections.

2 Symptoms of MDR (including CR) Gram-negative infections do not differ from those of other serious

infections.


2.1.6 Mortality

Multidrug resistant infections, including CR, are associated with 1.6 to 5.0 times higher

mortality risk compared non-MDR/CR infections [21, 139, 140]. Mortality rates can reach up

to 70% in the most severe cases such as bacteraemia [141]. In Europe, the mortality

associated with MDR and CR Gram-negative infections is estimated to be 35% [142-148] .

The extent of the clinical burden of infections with Gram-negative pathogen depends on the

severity of infection but generally the burden increases when coinciding with resistant

pathogens. The risk of mortality is more than doubled when the cause of an infection is MDR

Gram-negative bacilli, in comparison to susceptible organisms [134] For carbapenem-

resistant Gram-negative infections, mortality has been estimated to range between 26-44% in

one meta-analysis [149], and between 30-75% in another review of studies [150].

Clinical outcomes and burden from Gram-negative bacterial infection can vary depending on

the site of infection:

HAP/VAP: Mortality rate estimates in patients with pneumonia ranged from 48.6% to 64.7%

[115]. The crude mortality rate associated with VAP has been observed to range from 25% to

76% [151] but mortality directly attributed to VAP could be less than 10% because patients

with VAP are already being treated for life-threatening illnesses and may die from the comorbid

disease [152-154].

BSI: Hospital-acquired BSI has been associated with substantial morbidity and mortality [155,

156]. According to ECDC, patients with BSIs due to carbapenem-resistant Enterobacteriaceae

have mortality rates reaching 50% [157].

In Europe, sepsis caused by the most frequent resistant bacteria is responsible for

approximately 25,000 deaths per year, and that two-thirds of these are due to Gram-negative

pathogens [158].

UTI: Patients with cUTI can develop, in 10% to 30% of the cases, bacteraemia being

associated with a mortality rate ranging between 30% and 40% [110].

The clinical burden of Gram-negative bacilli infections varies depending on the causal

pathogen. Infection by Gram-negative pathogens, and specifically MDR Gram-negative

pathogens such as E. coli, K. pneumoniae, P. aeruginosa, and Acinetobacter spp. can result

in significant clinical burden due to the increase in the length of hospital stay, lack of clinical

efficacy, treatment-related adverse events, morbidity and mortality. The reported hospital

mortality rates were highest for A. baumannii (23.4 to 50%) and P. aeruginosa (50 to 59.5%),


followed by K. pneumonia (14.4 to 24%) and E. coli (2.5%) [115] [159] [160] [142, 161].

However, quantifiable research at the pathogen level is limited and influenced by global

variation in epidemiology, small study sizes and varying definitions of resistance to

antimicrobials, leading to difficulties with cross-pathogen comparisons of the pathogen-

specific impact of an AMR Gram-negative infection.

Patient factors such as health status and functional status can further contribute to the clinical

burden of Gram-negative infection. Mortality associated with CR infections can reach up to

100% in severe cases such as mechanically ventilated patients with bacteraemia [115]. In

addition, admission to a hospital with a high prevalence of MDR Gram-negative pathogens

and inpatient stay due to invasive procedures (e.g. surgery, ventilators, catheters) increases

the risk of infection and thus the risk of poor clinical outcome if the procedure [134].

2.1.7 Quality of Life

There is limited and confounded information available on the impact of infections over the

quality of life of these patients, as these are severely ill patients who are frequently treated in

ICU units and may be intubated and unconscious, and unable to complete these

questionnaires. The quality of life of these patients is also impacted by their underlying

disease, and most importantly by the severity of the infection and the infection site (i.e. patients

with BSI and sepsis are expected to have lower quality of life compared to a patient with cUTI).

The fact that these patients are hospitalised already has detrimental impact on their quality of

life. The ward in the hospital also impacts the patient’s quality of life (i.e. patients on ICU or

isolation, are expected to have lower quality of life compared to general ward), although this

may be correlated with the severity of the infection and underlying condition. All these factors

make investigating quality of life in antimicrobial clinical trials difficult and infrequent. However,

any therapy that resolves the infection and/or reduces length of hospitalization is expected to

improve patient’s quality of life.

2.1.8 Disability Adjusted Life Years (DALYs)

The estimated burden of infections with antibacterial-resistant bacteria in Europe is substantial

compared with that of other infectious diseases [4]. A study based on EARS-Net data from

2015 estimated that infections due to antibacterial-resistant bacteria3 accounted for 33,110

attributable deaths and 874,541 DALYs [4]. Infections with colistin-resistant or CR pathogens

The included antibacterial resistance-bacterium combinations were colistin-resistant, carbapenem-resistant, or multidrug-resistant Acinetobacter spp; vancomycin-resistant Enterococcus faecalis and Enterococcus faecium; colistin-resistant, carbapenem-resistant, or third-

generation cephalosporin-resistant

Escherichia coli; colistin-resistant, carbapenem-resistant, or third-generation cephalosporin-resistant Klebsiella pneumoniae; colistin-resistant, carbapenem-resistant, or multidrug-resistant Pseudomonas aeruginosa; meticillin-resistant

Staphylococcus aureus (MRSA); and penicillin-resistant and macrolide-resistant Streptococcus pneumoniae


accounted for 38.7% of the total DALYs. The highest burden in terms of lost DALYs and deaths

was noted in Italy and Greece.

The burden due to DALYs associated with antibacterial-resistant bacteria including CR and

colistin-resistant infections is reported to have increased between 2007 and 2015. The

proportion of the DALYs due to all CR infections increased from 18% in 2007 to 28% in 2015.

With regards to specific pathogens, the proportion of the DALYs due to CR K. pneumoniae

and CR E. coli doubled from 4.3% in 2007 to 8.79% in 2015.

In terms of infection sites, the highest DALYs burden was associated with BSI reaching up to

71,201 DALYs, and with respiratory infections, reaching up to 19,132 DALYs. The main CR

pathogen contributing to DALY was P. aeruginosa except in Italy, where the most burdensome

pathogen was K. pneumoniae. The annual number of DALYs attributable to P. aeruginosa

ranged from 1,576 to 34,717. In Italy, CR K. pneumoniae was associated with 37,394 DALYs.

2.1.9 Delayed effective therapy

Given that conventional pathogen identification and AST results can take up to 3 days to

provide a diagnostic result, the current treatment approach for patients with bacterial infections

suspected to be caused by an MDR pathogen, involves initial administration of empiric therapy

with wider-spectrum of activity antimicrobial followed by de-escalation to targeted therapy

when AST results are available [13, 14]. However, in many instances, the antibiogram is not

retrieved. The Point prevalence survey of healthcare-associated infections and antimicrobial

use in European acute care hospitals 2011–2012 indicated that between 40.2% and 80.5% of

HAIs are documented with microbiological results [11]. The percentage of pathogens with

known AST results is reported to vary between 47.4% and 100% [11].

Increasing antibacterial resistance has made the empiric antibacterial selection more difficult

particularly as fewer appropriate treatments for resistant pathogens are available [162]. As a

result, many patients with severe bacterial infections receive inappropriate therapy and

consequently experience delays in receiving appropriate effective therapy. As the severity of

infection increases, patients are more likely to be cycled through a number of inappropriate

therapies in the attempt to successfully treat the infection. According to two recent systematic

literature reviews ((1) 2015, n=27 and (2) 2019, n=122), patients receiving inappropriate

empiric treatment were reported to have a higher mortality risk [163, 164].

A systematic literature review including studies on the incidence and outcome of

inappropriate in-hospital empiric antibacterials for severe infections published


between 2004 and 2014 reported that the percentage of inappropriate empiric

antibacterial treatment ranges between 14.1% and 78.9% [163].

A retrospective cohort study including 40,137 patients with Enterobactereacea in

UTI, pneumonia or sepsis reported that patients with CR Enterobactereacea

(CRE) were three times more likely to receive inappropriate empiric treatment

(IET) than non-CRE (46.5% vs. 11.8%, p < 0.001) [165].

A systematic literature review (2007-2018, n=37) assessing the impact of delay in

appropriate antibacterial therapy for patients with severe bacterial infections

treated in hospital settings concluded that approximately 27% of patients

experience delays [166].

A delay in effective treatment of an infection may lead to sepsis, a life-threatening condition,

irrespective of the initial infection site. A range of studies have confirmed that inappropriately

treated patients had 5-times higher mortality risk, twice longer hospital stays and increased

risk of readmission, compared to patients receiving appropriate initial therapy. Moreover,

patients who fail initial therapies and reach last resort antibacterials are exposed to additional

burden associated with severe adverse events and toxicity [167].

In a more recent (2019) systematic literature review, Bassetti et al reported significantly lower

mortality rates in patients with appropriate therapy compared to those with inappropriate

therapy (OR 0.44 [95% CI, 0.39–0.50]) and these findings were consistent across all time

points (Figure 13) [164]. In a pooled subgroup analysis, mortality rates were significantly lower

in patients with bacteraemia, sepsis and septic shock in patients with pneumonia who had

received appropriate therapy compared to those having inappropriate treatment [164]. This

burden increases with resistant pathogens, whereby patients with CR P. aeruginosa infections

who receive initial inappropriate treatment have mortality risk that is twice as high as that seen

in susceptible patients (27.3% vs 13.8% respectively) [15].

In another recent systematic literature review of 37 studies by Zasowki et al. (2019), patients

receiving initial appropriate therapy had significantly lower mortality rates (OR 0.57, 95% CI:

0.45–0.72]) in comparison to those receiving initial inappropriate treatment and a consequent

delay in effective treatment (Figure 14) [166]. These findings were consistent across all time

points. Published literature reports that patient prognosis worsens with each day and hour of

delay in appropriate treatment. A retrospective cohort study including 480 patients with BSIs

due to carbapenemase-producing Enterobacteriaceae (CPE) reported an increase in mortality

risk with each day of delay (HR=1.02; (95% CI: 1.01, 1.04; p < .0001) [168].


Figure 13: Summary of effect of appropriate versus inappropriate initial antibacterial therapy on

mortality

Source: Bassetti, 2019[164]

Figure 14: Summary of effect of delay versus no delay in receiving initially appropriate

antibacterials on mortality

Source: Zasowski, 2019[166]

Inappropriate antibacterial therapy is associated with higher rates of treatment failure. Bassetti

et al assessed the impact of appropriate versus inappropriate initial antibacterial therapy on

the treatment failure. The findings suggest that patients receiving appropriate had a

significantly lower incidence of treatment failure compared to patients with inappropriate

therapy (OR 0.33; 95% CI: 0.16, 0.66) (Figure 15) [164]. These findings were consistent


across all time points and subgroup of patients with UTIs or acute pyelonephritis and with

bacteremia or sepsis (Figure 15) [164].

Figure 15: Summary of effect of appropriate versus inappropriate therapy on treatment failure

Source: Bassetti, 2019[164]

2.2 Target population

1. Describe the target population and the proposed position of the target population in

the patient pathway of care.



organisms in adults with limited treatment options. Limited treatment options can be

pragmatically translated into infections by MDR (including CR) pathogens.

This indication will therefore be pathogen focused, not restricted to any specific site of infection

and predicts 2 different populations:

Hospitalised critically ill patients with suspected (but prior AST results availability)

MDR/CR infection where effective treatment should be administered as soon as

possible (followed by de-escalation to a more targeted treatment when the

pathogen and susceptibility profile is subsequently confirmed), resistance to many

antimicrobial classes almost invariably reduces the probability of adequate

empirical coverage, with possible unfavourable consequences. In this light, readily


available patient’s medical history and updated information about the local

microbiological epidemiology remain critical for defining the baseline risk of MDR-

GNB infections and firmly guiding empirical treatment choices, with the aim of

avoiding both undertreatment and overtreatment ([13, 14] and Clinical guidelines

overview). Given its wide Gram-negative spectrum of activity, and safety profile,

cefiderocol would be an appropriate treatment choice for these patients.

Hospitalised patients where CR infection has been confirmed the selection of

treatment is predominantly based on AST results regarding pathogen, its

mechanism of resistance, and susceptibility results for the different antibacterials

tested. Based on its in vitro data, cefiderocol would be an appropriate option, in

aerobic Gram-negative pathogens, particularly non-fermenters such as P.

aeruginosa, A. baumannii and S. maltophilia, and presence of metallo-β-

lactamases, where there is limited in vitro activity from newer regimens, and other

treatment choices may be inappropriate due to safety and tolerability concerns.

The treatment of these patients will require an expert and complex clinical reasoning, taking

into account the peculiar characteristics of the target population, but also the need for

adequate empirical coverage and the more and more specific enzyme-level activity of novel

antimicrobials with respect to the different resistance mechanisms of MDR-GNB, resulting to

variations in the use of specific treatments even within regions of countries [169]. Thus,

treatment decisions differ for patients with suspected or confirmed infection by MDR/CR

pathogens.

2. Provide a justification for the proposed positioning of the technology and the definition of

the target population.

The intended indication for cefiderocol is for the treatment of aerobic, Gram-negative infections

in adults with limited treatment options (i.e. confirmed or suspected MDR infections, including

CR infections).

Cefiderocol can be used when the antibacterial susceptibility results have been obtained and

show that no other treatment is likely to have an effect against the disease pathogen,

particularly in non-fermenters and Acinetobacter baumanii, Stenotrophomonas maltophilia

and Pseudomonas aeruginosa, as well as in the metallo-carbapenemases in

Enterobacteriaceae, as per Table 9 below. It can also be used earlier, as a pre-emptive

treatment to ensure appropriate antibacterial coverage as early as possible given its wider

spectrum of activity as per image below in Gram-negative pathogens.


Table 9: In Vitro Gram-negative activity profiles

Predicted clinical activity based on CSLI breakpoints; *Color-coding based on the pathogen susceptibility

Source: Thalhammer F, 2018 [63], Theuretzbacher, 2019 [64]

The target population thus comprises two groups:

Critically ill, adult patients with highly suspected infection by a carbapenem-resistant or other

MDR Gram-negative pathogen.

These patients often require immediate treatment. Initiation of treatment for these

patients cannot be deferred until antibiogram is available.

Knowledge of local pathogen epidemiology and patient-specific factors can

support initial antibacterial treatment decisions.

Aligned with stewardship recommendations, when results from susceptibility tests

are available, de-escalation to other treatments should occur whenever possible

to avoid undertreatment and overtreatment.

For these patients, cefiderocol has demonstrated broad efficacy according to

current evidentiary standards for antimicrobials (in vitro, PK/PD and clinical data,

see sections 5.3-5.5.). They include patients with common infections such as cUTI,

pneumonia, blood infection/sepsis, and IAI.

In line with good antimicrobial stewardship, cefiderocol should be regarded as a

first treatment choice in this context, replacing current treatment attempts with

carbapenems in high dose and/or in combinations and where there is high

suspicion of susceptibility to cefiderocol.

Placing cefiderocol in the management of hospitalised patients with suspected

difficult to treat GNI as first treatment choice, replacing current treatment attempts


with carbapenems in high dose and/or in combinations, or recently approved

medicines, followed by de-escalation to reduce the risk of development of

resistance [170]. This strategy reduces time to effective treatment and is

associated with lower mortality as well as LOS in patients with severe sepsis and

septic shock Fout! Verwijzingsbron niet gevonden.[171, 172]. In line with good

antimicrobial stewardship, cefiderocol should be regarded as an early, targeted

treatment based on advanced risk determination methods (Figure 16) [124].

Figure 16 - Treatment of patients with highly suspected infection by CR or other MDR GN pathogens

Adult patients with confirmed infection by a carbapenem-resistant Gram-negative pathogen

or multidrug resistant Gram-negative pathogen including carbapenem-resistant

Enterobacteriaceae (CRE) such as K. pneumoniae and E. coli, and non-fermenters such as

A. baumannii, P. aeruginosa, and S. maltophilia.

For these patients, cefiderocol has demonstrated broad efficacy according to

current evidentiary standards for antimicrobials (in vitro, PK/PD and clinical data,

see section 5.4). They include patients with common infections such as cUTI,

pneumonia, blood infection/sepsis, and IAI. (Figure 17)

In line with good antimicrobial stewardship, cefiderocol should be regarded as a

first treatment choice in this context, replacing current treatment attempts with

colistin in combination with several other antimicrobials from different classes,

which carry a very substantial side effect burden (see chapter 2.1).

Figure 17: Treatment of patients with confirmed infection by carbapenem-resistant or other MDR

Gram-negative pathogen

3. Estimate the size of the target population. Include a description of how the size of the

target population was obtained and whether it is likely to increase or reduce over time.


As outlined in section 2.1 MDR/CR, resistances are increasing with estimates of deaths related

to serious infections being updated frequently. The European Centre for Disease Prevention

and Control (ECDC) estimate that nearly 700,000 infections and 33,000 deaths in the EU and

European Economic Area (EEA) in 2015 are a consequence of MDR bacterial infection [4]

WHO the predicted annual deaths by AMR is expected to rise from 700,000 cases in 2014 to

10,000,000 in 2050 (WHO, 2014, Review on AMR [78]. The prevalence of resistance to last-

resort antibacterials, particularly with regards to carbapenems and colistin, has been

increasing globally. An alarming spread of CR Gram-negative infections through healthcare

facilities has been reported and is expected to transfer to the community [8, 76]. Even for the

more recently approved antibacterials such as ceftolozane/tazobactam and

ceftazidime/avibactam, there have been reported cases of resistance [40-43]. This is also

expected to expand to the community, similarly to what has been previously observed with

ESBL-producing pathogens, via environment and traveling [76, 173]. For example, in 2018,

Sweden and Norway reported a cluster of returning travellers who carried or were infected

with carbapenemase (OXA-48)-producing K. pneumoniae that were associated with hospital

admissions in Gran Canaria [173].

The size target population for cefiderocol in Europe is difficult to estimate, as incidence

strongly depends on:

epidemiology data (local resistance profile and local pathogen distribution, which

is constantly evolving),

potentially regional outbreaks may occur changing substantially the patient

numbers,

patient population characteristics and risk factors (e.g. travels to CR endemic

countries),

introduction of new medicines with overlapping activity profile that will change the

unmet need,

how data is reported: there is a wealth of epidemiology information available, but

using different methodologies, increasing the uncertainty of the actual numbers of

MDR or CR infections,

also, the 2 different target populations are interlinked and self-exclusive.

Cassini, et al, [4] estimates that there are 107,801 Carbapenem resistant infections in Europe,

not account for those caused by Stenotrophomonas maltophilia, and as mentioned in the

previous section, this is likely to increase in the future [4]. Only a Dynamic infection disease

modeling considering the mentioned factors, upcoming treatments and future trends could

provide plausible predictions [123], but still with significant degree of uncertainty.


2.3 Clinical management of the disease or health condition

1. Describe the clinical pathway of care for different stages and /or subtypes of the

disease being considered in the assessment.

With the emergence of antibacterial resistance, antimicrobial stewardship programs have

been put in place in various healthcare settings to attempt achieve as rapid as possible,

identification of pathogens causing bacterial infections and the most appropriate treatment.

Treatment is determined by clinical state and local epidemiology to minimise the chance of

ineffective therapy. The current treatment approach for patients with bacterial infections when

there is suspicion of MDR pathogen, involves initial administration of empiric therapy with

wide-spectrum antimicrobial (or combination of antibcterials) followed by de-escalation to

targeted antimicrobials antibacterials when the antibiogram is available (i.e., identification of

the underlying pathogen and susceptibility testing (Figure 18)) [13].

Figure 18: Current treatment approach for bacterial infections

Treatment selection is based on information on pathogen identification as well as susceptibility

and mechanism of resistance. According to proportions of main pathogens in the infection and

in vitro susceptibility of potential treatments the treatment with the highest predicted treatment

success is being selected [13].

Resistance to many antimicrobial classes in MDR pathogens almost invariably reduces the

probability of adequate empirical coverage, with possible unfavorable consequences. Timely

administration of antibacterials is vital to improve patient’s outcomes [14] and in line with

antimicrobial stewardship, includes treatment with the most appropriate drug regimen [174,

175]. While microbiological testing is carried out (this can take up to 3 days), early clinical

decisions are based on environmental and patient factors including clinical state and local

epidemiology to minimize the chance of ineffective therapy. Empirical treatment with wide-

spectrum antibacterials is usually administered to severely ill patients when a quick treatment

decision is required [13]. However, this creates pressure for the selection or development of

resistant organisms over time [13, 176].


If the patient is confirmed to have multidrug resistant (MDR) including carbapenem resistant

(CR) infection, treatment is selected based on the susceptibility results. [170]. Good

antibacterial stewardship mandates more restrictive use of antibacterials and regardless which

treatment is being used, guidelines always urge to de-escalate the treatment whenever

possible [170] (see below).

Clinical reasoning for the treatment of suspected MDR-GNB infections in critically ill patients

aims to reduce time to effective therapy [124]. Current standard practice for this population is

not well defined, and highly variable across different geographies and infection sites.

Traditionally however, carbapenems in higher dose regimens tha toptimizes exposure, and/or

combination with other antibacterials, have been used but with limited success in resistant

pathogens [177]. Recently approved antibacterials such as ceftazidime/avibactam and

ceftolozane/tazobactam, have also been used in this setting, as already proposed by Bassetti

et al. [177]

However, there is still no defined standard of care for the treatment of severe MDR (including

CR) Gram-negative infections. A recent literature review of current and upcoming therapeutic

approaches for severe MDR Gram-negative infections in critically-ill patients reported that the

availability of newly approved antibacterials such as ceftolozane/tazobactam,

ceftazidime/avibactam, meropenem/vaborbactam, plazomicin and eravacycline, have

addressed some challenges due to antimicrobial resistance [177]. However, these treatment

options are reported to have suboptimal activity against some pathogens especially against

CR A. baumannii and against carbapenem-resistant Enterobacteriaceae (CRE) of novel beta-

lactam/β-lactamase inhibitors is dependent of the type of carbapenemase conferring

resistance to carbapenems [177]. The existing therapies for MDR including CR infections

include newly approved beta-lactam/β-lactamase inhibitor combinations such as

ceftolozane/tazobactam, ceftazidime/avibactam and meropenem/vaborbactam, novel

aminoglycoside plazomicin and a novel fluorocycline eravacycline. Other treatments include

polymyxins (polymyxin E [colistin] and polymyxin B), glycylcyclines (e.g., tigecycline), and

aminoglycosides [177]. Figure 19 gives an overview of current clinical reasoning for the

treatment of serious MDR-GNB infections in critically-ill patients.


Figure 19: Current clinical reasoning for the treatment of serious MDR Gram-negative infections

DR-GNB, Multi-drug resistant Gram-negative bacteria; CRE, carbapenem-resistant Enterobacterales; CRPA, carbapenem-

resistant Pseudomonas aeruginosa; CRAB, carbapenem-resistant Acinetobacter baumannii; BL-BLI, b-lactam/b-lactamase

inhibitors; VAP, ventilator-associated pneumonia. Source: Bassetti, 2019[177]

2.3.1 Key information on currently available treatments in Europe

As outlined before, treatment options for infections with MDR/CR aerobic Gram-negative

pathogens are very limited. Susceptibility tests have shown that to date broad coverage,

including pathogens affecting patients with limited treatment options (such as CR A.

baumannii, CR P. aeruginosa, S. maltophilia, and CR Enterobacteriaceae) is only achieved

by cefiderocol [29, 30]. In a recent analysis of the global clinical antibacterial pipeline by WHO,

cefiderocol was reported to be the only antibacterial providing coverage against all three

critical priority pathogens: CR A baumannii, CR P aeruginosa, and CR Enterobacteriaceae

(Figure 7) [64].

Ceftazidime/avibactam is a recently approved combination of a well-known beta-lactam with

a novel β-lactamase inhibitor for cIAI, cUTI, HAP/VAP and aerobic Gram-negative infections

in adults with limited treatment options (EU)[178]. It is active against class A (e.g., KPC) and

class D (e.g., OXA) carbapenemase-producing CRE and has demonstrated activity against

some CR P. aeruginosa isolates [177]. Recent results of in vitro study, SIDERO-WT, reported

CRE

• Ceftazidime/avibactam (as preferred empiricalchoice when both KPC and OXA carbapenemases are reported locally) or meropenem/vaborbactam

• Although in the lack of high-level evidence, for both empirical and targetedtreatment a combination with old (collistin, polymyxin B, tigecycline, oldaminoglycosides, fosformycin) or novel agents (plazomicin, eravacycline, double BL-BLI combinations) could be considered in the attempt of delayig emergence ofrestistance, after having carefully balanced potentional additional toxicity on a case-by-case basis (expert opinion)

• In case of resistance to novel BL-BLI, consider polymyxins-based or aminoglycosides-based combination with carbepenems and/or (tigecyclineor eravacycline) and/orfosformycin

• Consider concomitant adminitration of inhaled polymyxins/aminoglycosides whenthey are used intravenously for VAP

• Ceftolozane/tazobactam (as preferred empirical choice in absence of concomitantrisk of CRE) or ceftazidime/avibactam

• For empirical therapy, administer a second anti-pseudomonal agent (an aminoglycosideor a polymyxin or fosformycin)

• Although in the lack of high-level evidence, for targeted therapy combination withold (collistin, polymyxin B, old aminoglycosides, fosformycin) or novel agents(plazomicin, double BL-BLI combinations) could be considered in the attempt ofdelaying emergence of restistance, after having carefully balanced potential additional toxicity on a case-by-case basis (expert opinion)

• In case of restistance to novel BL-BLI, consider polymyxins-based or aminoglycosides-based combinations with carbapernems and/or fosformycin and/or rifampin

• Consider concomitant administration of inhaled polymyxins/aminoglycosides whenthey are used intravenously for VAP

CRPA

CRAB

• Administer a polymyxin as the backbone agent• Consider combination with old (carbapenems, old aminoglycosides, tigecycline,

fosformycin, rifampin) or novel agents (plazomicin, eravacyclin)• Consider concomitant administration of inhaled polymyxins/aminoglycosides when

they are used intravenously for VAP


a poor activity of ceftazidime/avibactam against CR A. baumannii with minimum inhibitory

concentration (MIC50) for meropenem-non-susceptible A. baumannii of 32 mg/L3 [46] and

stenotrophomonas maltophilia. Currently widely available on the EU countries, with

reimbursement.

Ceftolozane/tazobactam is a novel combination of a beta-lactam antimicrobial with a well

known β-lactamase inhibitor, with EMA approval for cIAI and cUTI [179]. It has demonstrated

a potent in vitro activity against CR P. aeruginosa isolates; however, without activity against

CRE [177]. Tazobactam (β-lactamase inhibitor) protects ceftolozane from degradation by

Class A β-lactamase enzymes [179], but has not demonstrated activity against KPC Class A

carbapenemases, and Class B (metallo-), or Class D β-lactamases [179]. Currently widely

available on the EU countries, with reimbursement.

Meropenem/vaborbactam is a novel combination of a well know carbapenem in a higher

dose, and a novel β-lactamase inhibitor approved for cIAI, cUTI, HAP/VAP, and infections due

to aerobic Gram-negative organisms in adults with limited treatment options [180]. It has

activity against class A (e.g., KPC) carbapenemase-producing CRE. Vaborbactam has limited

activity against Class D β-lactamases and no activity against Class B (metallo-) β-lactamases

and does not improve the activity of meropenem against CR A. baumannii, P. aeruginosa or

S. maltophilia [181]. However, is it not yet reimbursed in most of the European markets.

Currently approved by EMA, but not yet reimbursed in many countries and therefore, not

widely available on the European countries.

Eravacycline is a novel synthetic fluorocycline that was approved by EMA for the treatment

of cIAI [182]. It has demonstrated activity against Gram-negative pathogens including CRE

and CR A. baumannii with exception of P. aeruginosa and Burkholderia cepacia [177, 183,

184]. Currently approved by EMA, but not yet reimbursed in many countries and therefore, not

widely available on the European countries.

While colistin once was abandoned due to the high rates of renal toxicity in recent years, the

increasing emergence of MDR Gram-negative bacteria appears to have led to its

reintroduction in clinical practice [102]. Colistin has antibacterial activity against a wide variety

of Gram-negative pathogens including E. coli, Klebsiella spp., Enterobacter spp., P.

aeruginosa, and Acinetobacter spp. [185]. Some Gram-negative pathogens such as Proteus

spp., Providencia spp. and most isolates of Serratia spp. are intrinsically resistant to colistin

[185]. While it covers a broad spectrum of Gram-negative pathogens, colistin is associated

with severe adverse events [102, 134]. Among the more severe adverse events are

neurotoxicity, nephrotoxicity, and ototoxicity [102, 134]. Renal failure is reported to reach up


to 60% in patients treated with colistin[186]. A recent systematic literature review (n=224)

including data on 33,573 patients reported that the overall rate of nephrotoxicity in patients

treated with polymyxins was 0.277 (95% CI: 0.252, 0.303). Nephrotoxicity rates were found to

differ between patients treated with CMS, colistin and PMB (0.260 [95% CI: 0.216, 0.30]),

0.274 [95% CI: 0.239, 0.312] and 0.348 [95% CI: 0.301, 0.397], respectively; p=0.016) [187].

Aminoglycosides have been frequently used for the treatment of CR infections, particularly

in case of polymyxin resistance [177]. However, their efficacy is hindered by their impaired

safety profile (i.e., nephrotoxicity and ototoxicity) and increasing rates of resistance [177] [188].

While nephrotoxicity often can be reversed, the hearing loss is irreversible [188].

Aminoglycosides have been also associated with neuromuscular blockade [189].

Tigecycline, a glycylcycline antibacterial, is active against CRE and CR A. baumannii [177].

P. aeruginosa is inherently resistant to tigecycline with > 90% of pathogens reported to be

resistant to it [177, 190]. Of note, tigecycline is reported to have been associated with

increased mortality in comparison with other regimens in patients with VAP [177]. Currently

approved by EMA for cIAI and cABSSI.

Relebactam/imipenem/cilastatin has recently been granted positive CHMP opinion for

approval in Europe for Gram-negative infections in patients with limited treatment options. It

shows activity against resistant strains of P. aeruginosa and K. pneumoniae carbapenemase

in CR bacterial infections, but not those of A. baumannii or S. maltophilia (Merck and CID) or

metallo-betalactamases. Currently with positive CHMP opinion and not yet widely available on

the European countries.

While clinical guidelines on the management of multidrug resistant (MDR) including

carbapenem resistant (CR) Gram-negative infections are usually included in infection-site

specific treatment guidelines, they have not yet caught up to date with the new EMA regulatory

guidance that is focused on pathogens. Therefore, there is a lack of integrated

recommendations for the management of these resistant infections looking at pathogens,

regardless of infection site, and therefore a lack of well-defined standard of care. A survey

from 2017 including >100 hospitals in the US and Europe, reported that almost half of the

respondents (54/111, 48.6%) had no guidelines for the treatment of infections caused by CR

Gram-negative pathogens [22]. As outlined before the treatment of Gram-negative infections

is based on multiple factors, including the underlying condition, infection sites, and local

epidemiology, but most importantly taking into account local resistance. This leads to

variations in the use of specific treatments even within regions of countries.


The management of carbapenem-resistant Gram-negative infections is particularly

challenging due to the paucity of antimicrobials active against these bacteria; various

treatment options are used, very often in double or triple combinations with no consensus on

the most appropriate treatment strategy [22]. Current treatment options have limited activity

and/or have safety concerns. Recently marketed treatment options only partially cover

carbapenem resistance, and for example, none can address all 3 critical pathogens identified

by the WHO [38, 191]; ceftazidime/avibactam covers K. pneumoniae carbapenemase (KPC)-

producing carbapenem-resistant Enterobacteriaceae (CRE), ceftolozane/tazobactam covers

P. aeruginosa carbapenem-resistant strains and tigecycline, rather used as combination

therapy, covers carbapenem-resistant Enterobacteriaceae and A. baumannii [192, 193].

Polymyxins provide additional treatment options; recently re-introduced as a last alternative

due to the increasing CR resistance, they provide broader coverage for carbapenem-resistant

Gram-negative infections [33], but polymyxin resistance is already prevalent both in North

America and Europe [102] and these agents have serious side effects, such as nephrotoxicity

and neurotoxicity [194, 195]. Trimethoprim/sulfamethoxazole is considered as the treatment

of choice for S. maltophilia infections, though limited by toxicities [196].

In summary, available treatments consist of last resource drugs and multiple antibacterial

combinations, often with limited pathogen and/or mechanism of resistance coverage, and/or

with significant safety/tolerability concerns (e.g. colistin, tigecycline) [23-27].

2. Clinical guidelines overview

Search approach

A targeted search for relevant guidelines and review articles on the treatment of Gram-

negative bacteria was conducted in December 2019 and complemented by Internet searches

for national guidelines from Denmark, England (UK), France, Germany, Italy, Norway, Spain

and Sweden. Focus of selection and analysis were recommendations for treatment of

infections with MDR Gram-negative bacteria as well as for CR infections in hospital settings

[197]. Key results are provided in the tables below.

Summary of findings

Recommendations refer either to most common infection sites (e.g. pneumonia, sepsis, IAI,

cUTI) or, more recently, to pathogen types, e.g., infections with MDR/CR Gram-negative

bacteria (UK: [122] Spain: [198, 199] Italy Klebs:[200]) or more specific, ESBL-producing

bacteria or CR bacteria [201].


Fewer guidelines refer to specific treatments [202, 203]. As clinical data are rare,

recommendations are often based on evidence derived from in vitro susceptibility testing

results, case studies, observational studies, and expert opinion, which is standard and the

most appropriate approach in antimicrobial treatment decisions. In general, all guidelines

recommend that treatment should be started early for suspected infections (within hours),

support the antibacterial de-escalation strategy and recommend that empirical antibacterial

therapy should be implemented in accordance with local microbiological data and previous

treatment.

2.3.2 Site-specific vs. pathogen-specific guidelines

While infection-site-specific guidelines have been issued regularly for many years,

recommendations for treatment of MDR/CR Gram-negative infections dependent on the type

of resistance and pathogen with reference to the infections site have been developed at an

increasing rate in recent years by International/European/National Societies [23-25, 122, 201,

204].

2.3.3 Specific recommendations

Mono- and combination therapies of carbapenems (e.g. meropenem, imipenem, ertapenem),

or in combination with polymixins (colistin), colistin in combination with tigecycline, or newer

treatments such as ceftolozane/tazobactam prevail. Accordingly for CR Gram-negative

infections, guideline recommendations include combination treatment of colistin with

meropenem or with tigecycline, ceftazidime/avibactam, high dose tigecycline, fosfomycin and

colistin [23-25, 27, 122, 201].

An overview of recent guideline recommendations for MDR/CR Gram-negative infections as

well as for respective infection sites is provided in Table 10a-Table 11e.

The guidelines identified for MDR/CR Gram-negative infections are aligned in terms of

recommendations on the first line empiric therapies, use of mono- or combination therapies

and recommended antibacterial class(es) across indications, but may differ in use of specific

antibacterials within the same class. There was no evidence of incompatible recommendation

(e.g., one country recommending a treatment that another country specifically excludes).

2.3.4 Specific considerations of CR infections

International consensus guidelines recommend that patients with CR Gram-negative

infections including Enterobacteriaceae (CRE), A. baumannii (CRAB) and P. aeruginosa

(CRPA) are managed with polymyxin B or colistin in combination with one or more additional


agents to which the pathogen is susceptible. If additional susceptible agents are unavailable,

polymyxin B or colistin should be used in combination with a non-susceptible agent (e.g., a

carbapenem) in patients with CRE and CRPA, and in monotherapy in patients with CRAB [24].

Recent national guideline recommend targeted combination therapies according to type of

carbapenemases [122, 200, 205] and include newer agents ceftazidime/avibactamand

ceftolozane-tazobactam. Therapeutic approaches with infusion of high-dose antimicrobials is

considered for meropenem [201, 205] and ceftolozane/tazobactam [204] in high risk patients.


Table 10a: Relevant guidelines for diagnosis and management – MDR/GN Bacteria

Name of society/organisation issuing guidelines Date of

issue or

last update

Country (s)

to which

guideline

applies

Summary of

recommendations

-MDR infections-

Summary of

recommendations

-CR infections-

AWMF (Registry Nr. 092/001 (S3 guideline:

Strategies to ensure rational use of antibacterials in

hospitals)

[206] 1

2018 Germany Reports on measures to

prevent or reduce resistant

germs in hospitals.

NR

Paul-Ehrlich-Gesellschaft für Chemotherapie e.V.

(PEG)

AWMF 082-006

Chapter 16. Infections with MDR gram neg sticks

(Stäbchen) – ESBL-producing bacteria,

Carbapenemase-producing Enterobact083eriaceae,

Carbapenem-resistant Acinetobacter baumannii

[201]2

2019 Germany Pneumonia/Sepsis:

• meropenem plus colistin

• colistin plus tigecycline

(potentially plus fosfomycin)

CR Enterobacteriaceae

Pneumonia/sepsis:

• meropenem plus colistin

• colistin plus tigecycline

(potentially plus fosfomycin);

CR Acinetobacter-baumannii

Pneumonia/sepsis/wound/cUTI:

colistin, sulbactam, high dose

tigecycline; (cotrimoxazole

only for cUTI)

Infectious Diseases Working

Party (AGIHO) of the German Society of

Haematology and

Medical Oncology (DGHO)

(2015)

(Publication

year)

(Europe)

Stenotrophomonas maltophilia

pneumonia:

• High dose trimethoprim–

sulfamethoxazole;

Pseudomonas aeruginosa

pneumonia:

• Combination therapy

Piperacillin (±tazobactam),


[207] • tigecycline-based therapy ceftazidime, imipenem/

cilastatin, meropenem and

cefepime

Gruppo Italiano Trapianto Midollo Osseo (GITMO),

Associazione Microbiologi Clinici Italiani (AMCLI),

Società Italiana Malattie Infettive e Tropicali (SIMIT),

and the Centro Nazionale Trapiantt (CNT)

[200]

2015 Italy NR CRKp-targeted antibacterial

therapy: combination therapy

including at least two among

colistin/polymyxin B,

tigecycline and gentamicin;

addition of meropenem, and

eventually fosfomycin preferred

Helsedirektoratet. Antibiotikabruk i sykehus,

Nasjonal faglige retningslinje.

[208] 3

2018 Norway Resistant to 3rd generation

cephalosporins:

• Meropenem

• Imipenem / cilastatin

• Doripenem or Ertapenem

[Not for Pseudomonas or

Acinetobacter]

Resistant to 3rd generation

cephalosporins

• Colistin

• Tigecycline

Infectious Diseases and Clinical Microbiology

(SEIMC) 2015

[199]

2015 Spain Fosfomycin (as part of a

combination regimen including

at least one more active agent)

NR

Spanish Society of Chemotherapy

[198]

(2018) Spain • Colistin,

• Amikacin

NR


“Antibacterial selection in the treatment of acute

invasive infections by Pseudomonas aeruginosa:

Guidelines by the Spanish Society of Chemotherapy”

(Review article)

(Publication

year)

• Ceftolozane/ tazobactam

• High doses of β-lactam

antibacterials

Spanish Society of Transplantation (SET)/ Group for

Study of Infection in Transplantation of the Spanish

Society of Infectious Diseases and Clinical

Microbiology (GESITRA-EIMC)/ Spanish Network for

Research in Infectious Diseases (REIPI)

[204]

2018 Spain • Amoxicillin-clavulanic acid

• Piperacillin-tazobactam

• Meropenem

• Aztreonam

• Tigecycline

• Fosfomycin

• Ceftazidime-avibactam

• Ceftolozane-tazobactam

• Colistin

NR

Spanish Society of Infectious Diseases and Clinical

Microbiology (SEIMC) and the Spanish Association

of Haematology and Hemotherapy (SEHH)

[205] 4

2019 Spain (ESBL)-producing

Enterobacteriaceae:

• beta-lactam/β-lactamase

inhibitor (BLBLI)


and meropenem (extended

infusion)

AmpC-producing

Enterobacteriaceae

• Cefepime and

fluoroquinolones

KPC-producing

Enterobacteriaceae:

• at least two active drugs from

the options included in the

antibiogram (meropenem,

colistin, tigecycline,

fosfomycin and

aminoglycosides)

strains with meropenem MICs <

16 mg/L:



• combination regimen should

include high-dose meropenem

(extended infusion)

KPC-producing or OXA-48-

producing Enterobacteriaceae:

• Ceftazidime-avibactam

Extensively drug-resistant

(XDR) and pandrug-resistant

(PDR):

• single-agent treatment,

prioritizing the use of (in

following order) beta-lactams,

sulbactam (in infections due to

A. baumannii) and colistin.

XDR or PDR P. Aeruginosa

infections:

• Ceftolozane-tazobactam or

ceftazidime-avibactam

ESBL-producing intestinal bacteria Knowledge base

with proposals for management to limit the spread of

Enterobacteriaceae with ESBL

2014 Sweden • Cephalosporins and

quinolones

Cephalosporins should not be

reduced by increasing the

consumption of carbapenems,


[209] 5 • Alternative: Piperacillin-

tazobactam for sepsis,

pneumonia, abdominal

infections; also, to reduce

cephalosporins consumption

as this increases the risk of

selection of carbapenem-

resistant strains.

British Society for Antimicrobial

Chemotherapy/Healthcare Infection Society/British

Infection Association. Joint Working Party

[122]

2018 UK ESBL and AmpC-producing

Enterobacteria

• Meropenem, imipenem or

ertapenem

Susceptibility of past/current

infection not known (inpatient

setting):

• Meropenem and imipenem

or Meropenem-sparing:

temocillin (if urinary),

ceftolozane/ tazobactam

Susceptibility of past/current

infection known, along with

urinary infection:

• Co-amoxiclav or

piperacillin/tazobactam or

gentamicin or amikacin

IKPC-carbapenemase: Colistin

& meropenem (if unknown/S in

past)

(Consider tigecycline to colistin

or ceftazidime/avibactam to

meropenem)

OXA-48: Aztreonam or

ceftazidime Ceftazidime/

avibactam if R or unknown.

Metallo-carbapenemase:

Fosfomycin and colistin,

consider tigecycline, Use co-

trimoxazole if

Stenotrophomonas

1https://www.awmf.org/uploads/tx_szleitlinien/092-001l_S3_Strategien-zur-Sicherung-rationaler-Antibiotika-Anwendung-im-Krankenhaus_2019-04.pdf

2https://www.awmf.org/uploads/tx_szleitlinien/082-006l_S2k_Parenterale_Antibiotika_2019-08.pdf

3https://www.helsedirektoratet.no/Retningslinjer/Antibiotika-i-sykehus

https://www.awmf.org/uploads/tx_szleitlinien/092-001l_S3_Strategien-zur-Sicherung-rationaler-Antibiotika-Anwendung-im-Krankenhaus_2019-04.pdf

https://www.awmf.org/uploads/tx_szleitlinien/082-006l_S2k_Parenterale_Antibiotika_2019-08.pdf

https://www.helsedirektoratet.no/Retningslinjer/Antibiotika-i-sykehus


4https://seimc.org/contenidos/documentoscientificos/seimc-dc-2019-Febrile_Neutropenia.pdf

5https://www.folkhalsomyndigheten.se/contentassets/f4df42e7e643414ba3499a9ee1801915/esbl-producerande-tarmbakterier.pdf

Table 11b: Relevant guidelines for diagnosis and management – HAP/VAP(HCAP)

Name of society/organisation

issuing guidelines

Date of

issue or

last

update

Country (s)

to which

guideline

applies

Summary of recommendations

-MDR infections-

Summary of

recommendations

-CR infections-

ERS/ESICM/ESCMID/ALAT

guidelines EU

[210]

2017 Europe • No septic shock: single agent (carbapenem,

cephalosporin, piperacillin/ tazobactam or

fluoroquinolone)

• Severely ill or in septic shock: combination therapy

(antipseudomonal β-lactam plus a second agent

such as an aminoglycoside or an antipseudomonal

fluoroquinolone or, in some cases polymyxins)

Combination therapy; similar

approach as in MDR patients

(carbapenem-resistant

Enterobacteriaceae)

pro. medicin Information til

sundhedsfaglige -

Antibiotikavejledning

[211] 1

2020 Denmark

No specific recommendation for MDR infections

Pneumonia: Phenoxymethylpenicillin or

Clarithromycin

HAP: Piperacillin/Tazobactam or Cefuroxime

Mycoplasma and Chlamydophila pneumonia:

Clarithromycin or Roxithromycin

Legionella pneumonia: Clarithromycin or

Roxithromycin or Ciprofloxacin

Chlamydophila psittaci: Doxycycline

NR

https://seimc.org/contenidos/documentoscientificos/seimc-dc-2019-Febrile_Neutropenia.pdf

https://www.folkhalsomyndigheten.se/contentassets/f4df42e7e643414ba3499a9ee1801915/esbl-producerande-tarmbakterier.pdf


The French Society of

Anaesthesia and Intensive Care

Medicine and the French

Society of Intensive

Care

[212]

Leone et al: Summary of French

guidelines for the prevention,

diagnosis and treatment of

hospital‐acquired pneumonia in

ICU (Review article)

2017

(2018

publication

year)

France Late pneumonia ≥5 days or nonfermenting GNB: in

case of ESBL: Imipenem-cilastatin or meropenem +

amikacin or ciprofloxacin

HAP (when no other antibacterials can be used):

nebulised colimycine (sodium colistiméthate) and/or

aminoglycosides

NR

AWMF (Registry Nr: 020-013)

(S3 guideline Epidemiology,

diagnosis and therapy of adult

patients with nosocomial

pneumonia)

[213] 2

Update

2017

Germany At risk of MDR:

• Piperacillin/Tazobactam

or

• Cefepime

• Ceftazidime

or

• Imipenem/Cilastatin

• Meropenem

Plus/minus

• Fluorchinolon (Ciprofloxacin, Levofloxacin)

or

• Aminoglycosides (Gentamicin, Tobramycin,

Amikacin)

Colistin in combination with

Aminoglycosides

or

Fosfomycin,

or

Carbapenem

or

Ceftazidime/Avibactam

(depending on in vitro-Tests and

adverse reactions)


In suspected MRSA: combination with Glycopeptid or

Oxazolidinone, Vancomycin or Linezolid

AWMF (Registry Nr: 082-006)

(Calculated initial parenteral

therapy for bacterial diseases in

adults - update 2018)

[201] 3

2019 Germany • Nosocomial pneumonia:

Group 3a cephalosporins, aminopenicillin / β-

lactamase inhibitor combinations,

• or pneumococcal fluoroquinolones

However, it should be noted that the use of group 3

cephalosporins increases the selection of vancomycin-

resistant enterococci (VRE), ESBL-producing

Enterobacteriaceae and beta-lactam antibacterial-

resistant Acinetobacter spp. Fluoro-quinolones should

also be used with caution due to the frequent

resistance selection.

ESBL strains with additional

resistance to carbapenems,

• Colistin in combination

therapy

• Ceftazidime / Avibactam.

“Guidelines for the management

of community-acquired

pneumonia in the elderly

patient”

[214]

2014 Spain • Patients without frailty:

Outpatient setting - Amoxicillin/clavulanate or

cefditoren + clarithromycin or moxifloxacin or

levofloxacin

•Treatment at admission - Amoxicillin/ clavulanate or

ceftriaxone + azithromycin or moxifloxacin or

levofloxacin

• Patients with frailty:

Mild cases - Amoxicillin/clavulanate or ceftriaxone

+ azithromycin or moxifloxacin or levofloxacin

Moderate-severe cases – Ertapenem or

amoxicillin/clavulanate

Pseudomonas aeruginosa:

Piperacillin/tazobactam or

imipenem or meropenem or

cefepime + levofloxacin or

ciprofloxacin or amikacin or

tobramycin


• Enterobacteriaceae/anaerobes: Ertapenem or

amoxicillin/clavulanate

Infectious Diseases and Clinical

Microbiology (SEIMC) 2015

[199]

2015 Spain KPC-producing Klebsiella pneumonia:

• Combination therapy: carbapenem (see preferred

drug and recommended dose below) plus one or two

fully active drugs (including colistin, tigecycline, and

aminoglycoside or fosfomycin, the latter preferably

as a third drug) is recommended if the carbapenem

MIC is ≤8 mg/L; this applies mainly to patients with

severe infections caused by

NR

Spanish Society of

Transplantation (SET)/ Group

for Study of Infection in

Transplantation of the Spanish

Society of Infectious Diseases

and Clinical Microbiology

(GESITRA-EIMC)/ Spanish

Network for Research in

Infectious Diseases (REIPI)

[204]

2018 Spain VAP or Enterobacteriaceae with MIC ≥1 mg/L:

• Tigecycline

P. aeruginosa: High-dose

ceftolozane-tazobactam could

be prescribed to solid organ

transplantation (SOT) recipients

Spanish Society of Infectious

Diseases and Clinical

Microbiology (SEIMC) and the

Spanish Association of

Haematology and Hemotherapy

(SEHH)

2019 Spain • Cefepime


• Imipenem or meropenem

+/-

• Fluoroquinolones, aminoglycosides, colistin

NR


[205] 4 In critically ill patients, or patients previously

colonized/infected with multidrug-resistant gram-

negative bacilli, it is advisable to use a dual therapy

strategy, according to local epidemiology.

NICE guideline [NG139]:

Pneumonia (hospital-acquired):

antimicrobial prescribing”

[215] 5

2019 UK • Piperacillin with tazobactam

• Ceftazidime

• Ceftriaxone

• Cefuroxime

• Meropenem

• Ceftazidime/ avibactam

Antibacterials to be added if suspected or confirmed

MRSA infection (dual therapy with an IV antibacterial

for empirical therapy)

• Vancomycin, Teicoplanin, Linezolid

NR

1https://pro.medicin.dk/Specielleemner/Emner/318019

2https://www.awmf.org/uploads/tx_szleitlinien/020-013l_S3_Nosokomiale_Pneumonie_Erwachsener_2017-11.pdf



5https://www.nice.org.uk/guidance/ng139/resources/pneumonia-hospitalacquired-antimicrobial-prescribing-pdf-66141727749061

https://pro.medicin.dk/Specielleemner/Emner/318019

https://www.awmf.org/uploads/tx_szleitlinien/020-013l_S3_Nosokomiale_Pneumonie_Erwachsener_2017-11.pdf



https://www.nice.org.uk/guidance/ng139/resources/pneumonia-hospitalacquired-antimicrobial-prescribing-pdf-66141727749061


Table 11c: Relevant guidelines for diagnosis and management – cUTI

Name of

society/organisation

issuing guidelines

Date of

issue or

last update

Country (s) to

which

guideline

applies


-MDR infections-


-CR infections-

European Association of

Urology EAU [25]

2018 Europe No specific recommendation for MDR

infections.

Recommendations:

• 3rd generation cephalosporin as empirical

treatment of cUTI with systemic symptoms

No specific recommendation for CR

infections.

Comparison of

antibacterial treatment

guidelines for urinary tract

infections in 15 European

countries: Results of an

online survey ([216]

Guidelines

from 2012-

2017

(one from

2004,

Serbia)

Europe (15

countries)

Dosage according to resistance pattern

• Ampicillin iv

• Gentamicin

• Amoxicillin / clavulanic acid

• Trimethoprim / sulfamethoxazole

• Cefuroxime iv

• Ciprofloxacin

NR


sundhedsfaglige -


[211] 1

2019 Denmark

No specific recommendation for MDR

infections

NR


Complicated cystitis/ Acute pyelonephritis:

Pivmecillinam or Ciprofloxacin in penicillin

allergy

With urosepsis: Mecillinam +/- Gentamicin or

Ampicillin +/- Gentamicin or

Piperacillin/Tazobactam

UTI in catheter carriers: Pivmecillinam or

Ciprofloxacin

Update on a proper use of

systemic fluoroquinolones

in adult patients –

Recommendations

[202]

2015 France Severe pyelonephritis: ESBL-producing

Enterobacteriaceae 1st-line treatment,

systematically with an aminoglycoside

NR

French Infectious Diseases

Society (SPILF)

[217]

Updated

2015,

changes

decided in

2017

included

France Combination treatment: β-lactam,

aminoglycoside

ESBL-E: Amikacin (risk of cross-resistance is

substantially lower with amikacin than with

gentamicin or tobramycin).

NR

AWMF (Registry Nr: 082-

006) (Calculated initial

parenteral therapy for

bacterial diseases in adults

- update 2018)

[201]2

2018

(2019

publication

year)

Germany nosocomial acquired or catheter-associated

UTIs •Group 3b cephalosporins, including

the cephalosporin / BLI combinations

ceftolozane / tazobactam and ceftazidime /

avibactam, or 4 (cefepime),

• Group 2 or group 3 fluoroquinolones

• Group 1 carbapenems

• Ceftolozane / tazobactam

• Ceftazidime / avibactam


Spanish Society of Clinical

Microbiology and Infectious

Diseases (SEIMC)

[218]3

2016 Spain • Patients with healthcare acquired acute

polynephritis (non-severe and severe):

Antipseudomonal carbapenem plus

ceftolozane-tazobactam or piperacillin-

tazobactam

• Severe sepsis: Amikacin

• CA APN (complicated and uncomplicated):

APN with specific risk factors for ESBL

producing Enterobacteriaceae: First choice:

ertapenem is an acceptable option, Second

choice: other carbapenems or piperacillin-

tazobactam

• CA-APN with penicillin allergy: Amikacin or

sodium fosfomycin

NR

Spanish Society of

Infectious Diseases and

Clinical Microbiology

(SEIMC) and the Spanish

Association of

Haematology and

Hemotherapy (SEHH)

[205]4

2019 Spain • Cefepime


• Imipenem or carbapenem

• Consider the addition of an aminoglycoside

or glycopeptide in critically ill patients, those

with indwelling urinary catheters, and/or a

history of colonization/infection with multidrug-

resistant microorganisms

NR


British Society for

Antimicrobial

Chemotherapy/

Healthcare Infection

Society/British Infection

Association

Joint Working Party

[122]

2018

UK Pyelonephritis and cUTI caused by MDR

GNB:

• Meropenem or, ceftolozane/tazobactam or

temocillin

• Piperacillin/tazobactam

• Amikacin

• Ceftazidime/avibactam or non-b-lactam

agents in combination with meropenem



3https://pdfs.semanticscholar.org/95c8/f85c6122ced97ad0d4076427b4fcba7e0214.pdf


Table 11d: Relevant guidelines for diagnosis and management – BSI/Sepsis

Name of society/organisation issuing guidelines Date of

issue or

last update

Country (s)

to which

guideline

applies

Summary of

recommendations

-MDR infections-

Summary of

recommendations

-CR infections-

Surviving Sepsis Campaign

[27]

Update

2018

International

(Europe and

North

America)

Combination therapy: two drugs

from different classes of

antibacterials- usually a β-

lactam with a

Combination therapy:

broad coverage

antibacterial + pathogen-

specific agent:



https://pdfs.semanticscholar.org/95c8/f85c6122ced97ad0d4076427b4fcba7e0214.pdf



fluoroquinolone,

aminoglycoside or macrolide

Broad-spectrum

carbapenem (e.g.,

meropenem,

imipenem/cilastatin or

doripenem) or extended-

range penicillin/β-

lactamase inhibitor

combination (e.g.,

piperacillin/tazobactam or

ticarcillin/clavulanate.

third- or higher generation

cephalosporins can also

be used, especially as part

of a multidrug regimen.

pro. medicin Information til sundhedsfaglige -


https://www.pro.medicin.dk.

[211]1

2019

(bacterial

section

Revised

13.01.2020)

Denmark

No specific recommendation for

MDR infections

Septic shock: Ampicillin +

Gentamicin or Piperacillin /

Tazobactam + Gentamicin

Suspected/detected

Enterococci: add Vancomycin

NR


Suspected/detected

Pseudomonas aeruginosa:

Ceftazidime + Gentamicin

AWMF (Registry Nr: 079/001) (Prevention, diagnosis,

therapy and aftercare of sepsis)

[219] 2

2010

(currently

under

revision)

Germany Treatment of Sepsis:

It is recommended to use a

Pseudomonas-effective

antibacterial ureidopenicillins

(piperacillin) or third-party or

fourth generation

cephalosporins (ceftazidime

or cefepime) or carbapenems

(imipenem or meropenem)

under consideration use local

resistance patterns

NR

Infectious Diseases Working Party of the German

Society of Haematology and Medical Oncology

[220]

2012 Germany CVC-related bloodstream

infections (CRBSI) caused by

Stenotrophomonas maltophilia:

• Co-trimoxazole

NR

Infectious Diseases Working Party of the German Society

of Haematology and Medical

Oncology

[221]

2014 Germany Neutropenic patients with

sepsis:

• Imipenem/cilastatin or

piperacillin/ tazobactam

• Combination treatment with

aminoglycoside in case of

severe sepsis

NR


Helsedirektoratet, Antibiotikabruk i sykehus, Nasjonal

faglig retningslinje

https://www.helsedirektoratet.no/Retningslinjer/Antibiotika-

i-sykehus

[208]3

Update

2018

Norway • Broad-spectrum beta-lactam

antibacterial if suspected

resistant microorganisms

• Aminoglycosides

(gentamicin or tobramycin)

for severe sepsis and septic

shock

• Septic shock and suspected

gram-negative aetiology:

gentamicin or ciprofloxacin

No specific

recommendation for CR

infections

Infectious Diseases and Clinical Microbiology (SEIMC)

2015

[199]

2015 Spain • Enterobacteriaceae:

carbapenem

• Nosocomial sepsis and

previous receipt of

cephalosporins:

fluoroquinolones or

carbapenems

NR

Spanish Society of Transplantation (SET)/ Group for Study

of Infection in Transplantation of the Spanish Society of

Infectious Diseases and Clinical Microbiology (GESITRA-

EIMC)/ Spanish Network for Research in Infectious

Diseases (REIPI)

[204]

2018 Spain • Enterobacteriaceae:

Tigecycline

• mild infections: Carbapenem

monotherapy (extended-

infusion)

• SOT recipients

diagnosed with BSI and/or

pneumonia caused by P.

aeruginosa resistant to

carbapenems and other β-

lactams, if the strain shows

in vitro susceptibility:


High-dose ceftolozane-

tazobactam

Spanish Society of Clinical Microbiology and Infectious

Diseases (SEIMC), Spanish Society of Intensive Care

Medicine and Coronary Units (SEMICYUC)

[222]

2018 Spain Based on local epidemiology:

piperacillin-tazobactam,

carbapenems, a fourth-

generation cephalosporin,

aztreonam, quinolones or

aminoglycosides

NR

Spanish Society of Infectious Diseases and Clinical

Microbiology (SEIMC) and the Spanish Association of

Haematology and Hemotherapy (SEHH)

[205]4

2019 Spain Use of carbapenems is

recommended for patients with

sepsis or septic shock criteria

The UK joint specialist societies guideline on the diagnosis

and management of acute

meningitis and meningococcal sepsis in immunocompetent

adults”

[223]

2016 UK Suspected cases:

Ceftriaxone/cefotaxime

>60 years old &

immunocompromised patients:

Ampicillin/amoxicillin +

cephalosporin

GN diplococci: continued

Ceftriaxone/cefotaxime

Suspected ESBL infection:

Meropenem

Confirmed Neisseria

meningitidis:

Ceftriaxone/cefotaxime,

NR


benzylpenicillin,

ciprofloxacin (if not given

ceftriaxone)


2https://www.awmf.org/uploads/tx_szleitlinien/079-001l_S2k_Sepsis_2010-abgelaufen.pdf

3https://www.helsedirektoratet.no/Retningslinjer/Antibiotika-i-sykehus


Table 11e: Relevant guidelines for diagnosis and management- cIAI

Name of

society/organisation

issuing guidelines

Date of

issue or

last

update

Country (s) to

which

guideline

applies


-MDR infections-


-CR infections-

World Society of

Emergency Surgery

(WSES) and World Society

of Abdominal Compartment

Syndrome (WSACS)

[224]

Check update?

2017 Global Ceftolozone/tazobactam and

ceftazidime/avibactam (both in combination

with metronidazole)

-Aminoglycosides with β-lactams

-Polymyxins and fosfomycin (in critically ill

patients)

Tigecycline (against carbapenemase-

producing Enterobacteriaceae and

Stenotrophomonas maltophilia)

-Ceftazidime/avibactam (against

carbapenemase producing K.

pneumoniae)


https://www.awmf.org/uploads/tx_szleitlinien/079-001l_S2k_Sepsis_2010-abgelaufen.pdf




The Surgical Infection

Society ([24]

2017 USA • High risk patients with Pseudomonas

aeruginosa: ceftolozane-tazobactam +

metronidazole

• High-risk patients with Klebsiella pneumoniae

carbapenemase (KPC)-producing

Enterobacteriaceae: ceftolozane-avibactam

+ metronidazole

NR


sundhedsfaglige -


https://www.pro.medicin.dk.

[211]1

2019 Denmark No specific recommendation for MDR

infections

Piperacillin / tazobactam + metronidazole +

fluconazole

or

Cefuroxime + metronidazole + fluconazole

in penicillin allergy

NR

Update on a proper use of

systemic fluoroquinolones

in adult patients –

Recommendations

[202]

2015 France Shigella sonnei diarrhea: ciprofloxacin or

ofloxacin

First-line use of fluoroquinolones not

recommended in IAI; instead ciprofloxacin or

ofloxacin

NR

Société française

d'anesthésie et de

réanimation (Sfar)

[225]2

2015 France • Amoxicillin / clavulanic acid + gentamicin

• Cefotaxime or ceftriaxone + imidazoles.

NR


Severe IAI: piperacillin / tazobactam

gentamicin.

Haute Autorité de Santé

(HAS), la Société de

pathologie infectieuse de

langue française (SPILF) et

la Société de réanimation

de langue française (SRLF)

[226]3

2019 France In IA EBLSE infections: piperacillin-

tazobactam

• With septic shock: carbapenem (imipenem

or meropenem).

IA Enterobacteriaceae resistant to C3G by

hyperproduction of cephalosporinase and

without production of ESBL: cefepime

combined with metronidazole or ornidazole

Serious IAI: piperacillin-tazobactam

combined with amikacin

NR

AWMF (Registry Nr: 082-

006) (Calculated initial

parenteral therapy for

bacterial diseases in adults

- update 2018)

[201]4

2018 Germany The following antibacterials are recommended

if suspected pathogens are suspected:

MRSA Tigecycline

Linezolid+

Vancomycin+

VRE Tigecycline

Linezolid+

ESBL

(E. coli,

Klebsiella

spp.)

Tigecycline

Ceftolozane/Tazobactam

Ceftazidim/Avibactam

Imipenem

Meropenem

Ertapenem

The following antibacterials are

recommended if suspected pathogens

are suspected to be CR

Tigecycline

Colistin


Meropenem (High doses)


Fosfomycin

(no Monotherapy)

Acinetobacter

spp.

Colistin

Tigecycline

Sulbactam

Pseudomonas

spp.

Imipenem, Meropenem

Piperacillin/Tazobactam

Cefepime

Gentamicin, Amikacin

Ciprofloxacin2,

Levofloxacin2

Ceftolozane/Tazobactam



2https://www.infectiologie.com/UserFiles/File/medias/Recos/2014-inf-intra-abdo-SFAR.pdf

3https://www.infectiologie.com/UserFiles/File/spilf/recos/2019-synthese-infections-enterobacteries.pdf



https://www.infectiologie.com/UserFiles/File/medias/Recos/2014-inf-intra-abdo-SFAR.pdf

https://www.infectiologie.com/UserFiles/File/spilf/recos/2019-synthese-infections-enterobacteries.pdf



2.4 Comparators in the assessment

1. Based on the alternatives presented, identify the technologies to be used as

comparator(s) for the assessment.

2.4.1 General considerations

In general, in antibacterial research and development, in vitro, PK/PD models and clinical trials

provide integrated sources of information for comparative analysis of effectiveness.

Clinical trials can provide reliable information regarding comparative efficacy when the

pathogens have confirmed or expected susceptibility to both drugs. This is consistent with

prescription based on AST results, which occurs in patients with confirmed CR infections.

In this setting, Network meta-analysis (NMA) if feasible provide additional reliable information

of comparative effectiveness, in the absence of direct comparative data, but rendered to show

no significant differences between treatments included in the NMA, as all clinical trials are

designed as non-inferiority and conducted in a population where all pathogens are expected

to be susceptible to both treatments.

However, in patients with infections suspected to be caused by MDR/CR pathogens,

clinical trials only provide limited comparative evidence regarding the efficacy of new

antibacterials. This is because trials must include only pathogens for which the tested agents

and comparators are effective, as it would be unethical to knowingly allow patients to have

ineffective treatment. In this setting, standard NMAs also provide little information, as they

never account for pathogens not susceptible to the treatment regimens included in the

network. A comparison of efficacy against all relevant comparators can only be obtained from

in vitro surveillance studies. Hence approaches integrating all available evidence from in vitro,

PK/PD and clinical data (such as effectiveness models), are the necessary to predict

susceptibility rates and clinical effectiveness rates.

Specific findings supporting the chosen comparators

The guideline review revealed that the comparators used in the clinical trials of cefiderocol

were commonly used across different countries. For suspected MDR infections, carbapenems

are (alone or in combination) recommended throughout, while for confirmed MDR/CR

resistance, colistin-based regimens are considered (A. Baumannii, S. maltophilia, metalloβ-

lactamases). Newer treatments are recommended in case of P. Aeruginosa

(ceftolozane/tazobactam) and Enterobactereacea (ceftazidime/avibactam) for suspected and

confirmed MDR pathogens.


This review results confirm that the comparators in clinical trials APEKS-NP, APEKS-cUTI and

CREDIBLE-CR reflect the guideline recommendations for the different target populations. The

trials have been designed in line with recommendations from regulatory authorities and

allowed clinicians to select specific treatments (“best available care”) in the CR population

(CREDIBLE-CR trial), for which different treatment options may be combined to combat very

difficult-to-treat infections.

Comparator in APEKS-NP (Meropenem - high-dose and prolonged infusion)

For APEKS-NP high-dose and prolonged infusion (HD) of meropenem was the selected

comparator, as per FDA recommendations, given the severity of the population expected in

the trial and likelihood of including patients with infections resistant to carbapenems (confirmed

after trials inclusion). This regimen optimises exposure and time over MIC for Carbapenems,

can be active in pathogens with MIC up to 16mg/L and has shown to improve prognosis in

severe infections compared with short-term infusions (Microbiology (SEIMC) and the Spanish

Association of Haematology and Hemotherapy (SEHH), Gudiol 2019)). In alignment with this

strategy, some guidelines recommend high doses of β-lactam antibacterials for treatment of

acute invasive infections by Pseudomonas aeruginosa (Mensa, Antibacterial selection in the

treatment of acute invasive infections by Pseudomonas aeruginosa: Guidelines by the

Spanish Society of Chemotherapy” (2018).

The fact that this HD meropenem was a regimen not used in other clinical trials as comparator,

as well as including pathogens which other antibacterials were not active against (e.g. A.

baumannii) did not allow a network to be built and therefore, an NMA could not be performed

in patients with nosocomial infections. For more information on this topic please refer to the

systematic literature review and feasibility assessment for a network meta-analysis of

treatments of Gram-negative bacterial infections [227].

Comparator in APEKS-cUTI (imipenem/cilastatin)

Given the probability of resistance to 3rd-class cephalosporins, imipenem / cilastatin was

among the recommended treatments (e.g. Helsedirektoratet. Antibiotikabruk i sykehus,

Kortversjon av Nasjonal faglige retningslinje for antibiotikabruk i sykehus 2014 [208]) and

chosen as the comparator alongside imipenem, a recommended and commonly used

carbapenem for the treatment of cUTI.

In addition to the trial-based comparison, an NMA was possible in cUTI, given the overlapping

pathogen profile and similar patient baseline characteristics, across all relevant published

studies. Treatments for suspected MDR Gram-negative infection were identified through a


systematic review of the literature. Trials focusing on efficacy and safety of current treatments

for Gram-negative urinary tract infections were identified (see APEKS-cUTI section of chapter

5.4.3), including all trials that compared any parenteral antibacterials for the treatment of

Gram-negative infection to placebo or another parenteral antibacterial. Based on selection

according to bacteria, the potential network was designed in line with the intended label for

cefiderocol. The NMA results were consistent with APEKS-cUTI trial results and expectedly

found no statistically significant difference between cefiderocol and other comparators, given

the considerations in section 2.4.1. For more information on this topic please refer to the

relevant appendix [227].

This NMA provides supportive comparative information for patients with infections caused by

confirmed CR resistant pathogens.

Comparator in CREDIBLE-CR (BAT based on combinations with colistin)

As requested by regulatory authorities, the comparator in CREDIBLE-CR was BAT in order to

enable the variable treatment approaches required where there are very limited options and

given variable local epidemiology and resistance patterns. The heterogeneity of BAT drug

combinations reflects the current treatment reality and selection of treatment choice according

to most likely effective treatment in a given place and setting, consisting predominantly of

colistin based regimens.

2.4.2 Selection of relevant comparators for the assessment

Following the EMA’s guidance and expected label approval, the comparators are defined

predominantly based on pathogens (as opposed to infection sites). To address the high priority

pathogens and based on recommendations and susceptibility tests, the following comparators

are most relevant for each target treatment population

- Suspected MDR infection - carbapenems (including meropenem and imipenem, in

monotherapy with high dose & prolonged infusion or combinations),

ceftolozane/tazobactam, and ceftazidime/avibactam.

- Confirmed MDR infection- colistin-based (combination) regimens for (A. Baumannii, S.

maltophilia, and other Gram-negative pathogens containing metalloβ-lactamases);

ceftolozane/tazobactam (P. Aeruginosa), ceftazidime/avibactam (Enterobactereacea)

Given the important role of in vitro surveillance studies for antibacterials, an assessment of

cefiderocol needs to be based on a combination of comparisons of surveillance data and

clinical evidence, as outlined below (Table 12).


Table 12: Cefiderocol assessment

Population Comparator Data source Result (cefiderocol vs. comparator)

Suspected MDR/CR

High dose Meropenem SIDERO WT surveillance

Broader coverage of Gram-negative, aerobic pathogens. Lower MIC value and preserved efficacy in the presence of carbapenemases.

APEKS-NP RCT

Non-inferior with regard to mortality (primary outcome) and all clinical and microbiological secondary outcomes.

High dose Meropenem Ceftalozane-tazobactam, Ceftazidime-avibactam

Integrated epidemiology and in vitro data analysis

Cefiderocol presents higher weighed susceptibility rates in cUTI, pneumonia, BSI, and gastrointestinal samples vs comparators


Effectiveness model integrating epidemiology, in vitro data and clinical data

Cefiderocol presents higher likelihood of clinical and microbiological effectiveness in pneumonia and cUTI vs comparators.

Imipenem/Cilastatin APEKS-cUTI RCT

Non-inferior to comparator, but proven superiority in a post-hoc analysis, on the primary endpoint of combined microbiological eradication / clinical cure at TOC, and secondary endpoint microbiological eradication at TOC.

Ceftalozane-tazobactam, ceftazidime-avibactam, doripenem, imipenem/cilastatin

network meta-analysis for cUTI

In similar patient populations with similar pathogen distribution across different trials, and consistent with APEKS-cUTI there was statistical significant difference in microbiological eradication at TOC vs Imipenem/cilastatin, but in all other endpoints there was no statistically significant difference, including clinical cure rates and adverse events

Ceftolozane/tazobactam SIDERO WT surveillance

Lower MIC90 (0.25 vs. 8 for Pseudomonas, 0.25 vs. 32 for Acinetobacter, 1 vs. 64 for Enterobacteriaceae)4 Higher % isolates susceptible to cefiderocol

Ceftazidime/avibactam SIDERO WT surveillance

Same MIC90 for Enterobacteriaceae (1 vs. 1), otherwise superiority of cefiderocol Higher % isolates susceptible to cefiderocol

Confirmed CR

Colistin-based (combination) regimens (most relevant for for A. Baumanii, S. maltophilia,

SIDERO CR surveillance

Higher % isolates susceptible to cefiderocol; Similar in vitro efficacy. Colistin is known to have severe side effects, especially kidney toxicity. Resistances against colistin have

4 Longshaw et al., 2019 ID Week


pathogens with metalloβ-lactamases)

been reported to increase in epidemiological studies.

Ceftolozane/tazobactam (most relevant for P. aeruginosa, except pathogens with metalloβ-lactamases)


Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)5

Ceftazidime/avibactam (most relevant for Enterobacterales, except pathogens with metalloβ-lactamases)


Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)

Best available therapy (BAT), predominantly (combination) regimens (most relevant for A. Baumanii, S. maltophilia, pathogens with metalloβ-lactamases)

CREDIBLE-CR Descriptive results only. Evidence of eradication of resistant pathogens. Numerical, non-significant disadvantage with regard to mortality for cefiderocol compared to BAT.

The important question, raised during the scoping process, was: Given the large amount of

heterogeneity in the treatment recommendation and the limited number of comparators in the

surveillance data and the clinical studies, how can clinicians determine when to use

cefiderocol over another potential candidate?

The answer combines the intended label with the target populations, as follows:



organisms in adults with limited treatment options.

This indication will therefore be pathogen focused, not restricted to any specific site of infection

and supports the use of cefiderocol in two types of patients:



provides full cover against CR pathogens and potential resistant mechanisms, to avoid

the risk of rapid clinical deterioration (with the option to de-escalate to a more targeted

treatment when the pathogen and susceptibility profile is subsequently confirmed).

Hospitalised patients where CR infection has been confirmed and cefiderocol is best

option based on pathogen susceptibility information and/or where other treatment

choices are inappropriate (efficacy, contra-indication or tolerability).

5 Sato et al. 2019 ID Week


Thus, clinicians will encounter three types of patients in their clinical practice that would be

treated according to the identified guidelines:

1) Patients with infections for which there are sufficient treatment options

listed in the guidelines. These fall out of the scope of the cefiderocol

label and are thus not relevant for the current assessment.

2) At the other end of the spectrum, patients with confirmed MDR/CR

infections, for which the antibacterial susceptibility test shows that

there are no other options but cefiderocol. These patients would gain

an important new, last-resort option with cefiderocol.

3) Patients with suspected MDR/CR options, for which local surveillance

data indicate that many of the currently available comparators will not

provide cover against certain possible carbapenem-resistant

pathogens, and who are critically ill and at risk of clinical deterioration.

These patients would gain a new treatment option to reduce the risk

of insufficient pathogen coverage leading to a delay in appropriate

treatment and consequent clinical deterioration

The clinician could optimize the chances of success by considering different treatment options

based on their indications, the MICs and breakpoints published by EUCAST, and the

outcomes in trials of susceptible patient populations. Based on the local epidemiology, the

clinician would then select an agent (or combination of agents) that would maximize the

likelihood to cover the suspected pathogen.

All this data was integrated into an effectiveness model, where European epidemiological data

for MDR pathogen prevalence rates for specific infection sites was used alongside with results

from the SIDERO surveillance studies, and clinical cure rates from clinical trials, to estimate

the likelihood of success of cefiderocol compared with the most relevant comparators.

The results indicate that cefiderocol would have the highest likelihood of success of clinical

cure and microbiological eradication at these infection sites. For more information please see

section 5.4.1 and 5.4.3

These calculations would have to be adjusted for individual cases by taking into account local

variability of pathogen frequencies, but the approach illustrates a practical solution for the

complex challenge of optimizing treatments in patients with suspected MDR/CR infections.


Once the antibacterial susceptibility test becomes available, doctors should again follow the

guideline recommendations and de-escalate the treatment to the choice with the narrowest

and specific spectrum for the identified pathogen.

In summary, the combined consideration of international guidelines, the growing unmet need

of antimicrobial resistance, the fact that delays in appropriate treatment cause worse

outcomes, indicate that cefiderocol constitutes a valuable addition to the current treatment

landscape of Gram-negative pathogens for patients with limited treatment options.


3 Current use of the technology

Summary of issues relating to current use of the technology

Cefiderocol is not yet approved in Europe with the only current use being in

compassionate use programmes. Over 200 patients globally were treated to date under

the compassionate use programme of cefiderocol, underlining the clear unmet need in

patients with highly resistant infections with no treatment options.

o The criteria for fulfilling these requests are highly restrictive. All other available

treatments must be ruled out through susceptibility testing and/or where there is

evidence of treatment failure (efficacy or safety).

o In addition, patients must be unable to enrol in clinical studies of cefiderocol.

Case reports for three patients in the compassionate use programme have been

published.

o A patient was treated successfully for endocarditis due to extensively drug resistant

(XDR) Pseudomonas aeruginosa.

o A patient with multiple comorbidities and a complicated intra-abdominal infection

(IAI) due to MDR Pseudomonas aeruginosa was released from hospital care within

six weeks of completion of cefiderocol treatment.

o A patient with VAP and BSI caused by XDR Acinetobacter baumannii and

carbapenemase-producing Klebsiella pneumoniae had potentially serious organ

failure from older anti-infectives. Six weeks after cefiderocol administration, chest

X-rays showed complete resolution of infection.

An abstract submitted (not accepted) for ECCMID 2020 summarizes results from a case

series of seven severely ill patients with CR Acinetobacter infections treated with

cefiderocol. The two patients who died had received cefiderocol for only two days prior to

death.

While the compassionate use program is restricted to the use of cefiderocol for the

treatment of XDR infections with no other options, the EMA-approved indication will be

broader and encompass early targeted treatment of suspected MDR/CR/difficult-to-treat

infections in addition to treatment of confirmed resistant pathogens.


3.1 Current use of the technology

1. Describe the experience of using the technology, for example the health conditions

and populations, and the purposes for which the technology is currently used. Include

whether the current use of the technology differs from that described in the (expected)

authorisation.

Since cefiderocol is currently not approved in Europe, the only use has been within the

compassionate use program. This program is registered in https://www.clinicaltrials.gov/

registry under NCT03780140: Expanded Access to Cefiderocol for the Intravenous Treatment

of Severe Gram-Negative Bacterial Infections. Expanded access may be provided for

cefiderocol for qualified patients who have limited treatment options and are not eligible for a

clinical trial.

Case reports for three patients in the compassionate use programme have been published.

o A patient was treated successfully for endocarditis due to extensively drug resistant (XDR)

Pseudomonas aeruginosa.

o A patient with multiple comorbidities and a complicated intra-abdominal infection (IAI) due

to MDR Pseudomonas aeruginosa was released from hospital care within six weeks of

completion of cefiderocol treatment.

o A patient with VAP and BSI caused by XDR Acinetobacter baumannii and

carbapenemase-producing Klebsiella pneumoniae had potentially serious organ failure

from older anti-infectives. Six weeks after cefiderocol administration, chest X-rays showed

complete resolution of infection.

To date over 200 patients have been treated with cefiderocol through this programme.

Detailed information on 74 patients which have completed treatment with cafiderocol are

presented in section 5.4 and are part of the data pacage that substantiates the efficacy of

cefiderocol in patients with confirmed CR infections alongside CREDIBLE CR.

The criteria for compassionate use of cefiderocol are highly restrictive. All other available

treatments must be ruled out through susceptibility testing, and/or there must be evidence of

treatment failure (efficacy or safety). Enrolled patients will have confirmed CR infection and

are likely to be consistent with the target population where patients have confirmed CR

infections. However, EMA-approved indication will be broader and encompass both the

treatment of confirmed resistant infection and patients with infections by suspected MDR

pathogens.

https://www.clinicaltrials.gov/

https://clinicaltrials.gov/ct2/show/NCT03780140


2. Indicate the scale of current use of the technology, for example the number of people

currently being treated with the technology, or the number of settings in which the

technology is used.

200 patients have been treated to date with cefiderocol in this programme. Results from 74

patients are available (see section 5.4).

Compassionate use of cefiderocol is restricted to seriously ill, hospitalised patients.

Cefiderocol is and will be used in critically ill hospitalised patients, many of whom will be

treated in ICU units. These patients will often be unconscious, and on many occasions require

ventilation (intubation). This is consistent with existing intravenous use of antibacterials in

critically ill hospitalised patients.

3.2 Reimbursement and assessment status of the technology

1. Complete Table 13 with the reimbursement status of the technology in Europe.

Table 13: Overview of the reimbursement status of the technology in European countries

Country and

issuing

organisation

Status of recommendation

(positive/negative/ongoing/not

assessed)

If positive, level of reimbursement*

NA NA NA

Include a reference to any publicly available guidance documents

*For example, full reimbursement or only partial reimbursement. If partial reimbursement gives a

percentage of reimbursement.


4 Investments and tools required

Summary of issues relating to the investments and tools required to introduce

the technology

The use of cefiderocol is for hospital use only, and is not expected to require any

specialized equipment, or to demand additional resources beyond the standard ability to

store, prepare and administer intravenous infusion treatments, alongside susceptibility

testing to cefiderocol and standard monitoring microbiological evaluation tests, as it is

current practice with all hospital use antibacterials in nosocomial infections.

Cefiderocol is formulated as a freeze-dried (lyophilized) powder (1g/vial) for powder for

concentrate for solution for infusion. Following reconstitution, it is administered as a 3-

hour infusion of 2g every eight hours.

o Consideration should be given to official guidance on the appropriate use of

antibacterial agents. Treatment should commence for pathogens highly suspected

to be susceptible to cefiderocol, and susceptibility should be confirmed through

appropriate diagnostic testing as soon as possible.

o It is recommended that cefiderocol should be used to treat patients that have limited

treatment options only after consultation with a physician with appropriate

experience in the management of infectious diseases.

o Cefiderocol may be used in combination with other antibacterial agents active

against anaerobic pathogens and/or Gram-positive pathogens when these are

known or suspected to be contributing to the infectious process.

o Dose adjustments are necessary for patients with renal impairment, but not for

hepatic impairment. No adjustment is required in elderly populations. The safety

and efficacy of cefiderocol in children below 18 years of age has not yet been

established.

Treatment of severe MDR-GNB infections in critically ill patients will require an expert and

complex clinical reasoning, taking into account the peculiar characteristics of the target

population, but also the need for adequate empirical coverage and the more and more

specific enzyme-level activity of novel antimicrobials with respect to the different

resistance mechanisms of MDR-GNB.

The unmet need of developing additional effective antibacterials is accompanied by needs

to further establish improved antimicrobial stewardship programs, to provide an


alternative treatment option when there are limited effective alternatives, and reducing the

likelihood of initial inappropriate pre-emptive therapy, while the identification of pathogens

and their susceptibility patterns is not available.

o For hospitalised patients with infection by suspected (but unconfirmed by an

antibiogram) GN MDR/CR pathogens who are critically ill and cannot wait for

results of an AST, cefiderocol will fill an important unmet need providing a more

likely initial appropriate treatment. With these factors, therefore it is likely that

patient outcomes improve, and length of stay associated with reduced time to

effective therapy are minimised. Early appropriate treatment with cefiderocol is

more likely to avoid delays in effective treatment. This may reduce healthcare

resource utilization and costs associated with prolonged stay in, or admission to,

intensive care units and/or delays in hospital discharge.

o Cefiderocol can be added to a combination regimen in case of multiple pathogens

with diverse Gram status or administered alone for the treatment of Gram-negative

MDR bacteria.

Additional reductions in healthcare resource utilization are possible, when considering the

broad context of AMR and how cefiderocol as a new treatment option contributes to it;

i.e., possible fewer hospital quarantine due to spread of CR bacteria (within hospitals and

across countries), potential reduction of complications when treating immunosuppressed

patients (e.g., cancer patients with febrile neutropenia, who require effective antimicrobial

treatment options). These additional values of new antibacterials have recently been

highlighted by several European initiatives (see EEPRU report in the UK) focusing on

innovative reimbursement models that aim to capture the full value that new antibacterials

convey.

4.1 Requirements to use the technology

1. If any special conditions are attached to the regulatory authorisation more information

should be provided, including reference to the appropriate sections of associated

documents (for example, the EPAR and SPC). Include:

conditions relating to settings for use, for example inpatient or outpatient,

presence of resuscitation facilities

restrictions on professionals who can use or may prescribe the technology

conditions relating to clinical management, for example patient monitoring,

diagnosis, management and concomitant treatments.


4.1.1 Conditions for use

Cefiderocol is used as IV infusion and intended for hospital use only in patients that are

hospitalised. It is recommended that cefiderocol should be used to treat patients that have

limited treatment options only after consultation with a physician with appropriate experience

in the management of infectious diseases.

Consideration should be given to official guidance on the appropriate use of antibacterial

agents. Treatment should commence for pathogens highly suspected to be susceptible to

cefiderocol, and susceptibility should be confirmed through appropriate diagnostic testing as

soon as possible

4.1.2 Good stewardship and societal considerations

As applicable to all antibacterials, cefiderocol should be used according to good stewardship

practices. Such use holds the promise to decrease the total use of resources in the hospital

and area, due to the ability of new, infective antimicrobials to decrease resistances to existing

last-resort agents and to avoid hospital shutdowns.

Antimicrobials thus provide additional value to society that is not measured in clinical trials.

These elements of value have been summarized in a recent report based on a multi-

stakeholder conference in 2017 [228-231]. They include transmission, insurance, diversity,

novel action, enablement, and spectrum value. “Transmission value” refers to the fact that

novel antibacterials contribute to slowing the spread of resistant genes. Insights from the

evaluations of vaccines can be useful to support a quantitative assessment of this value.

“Insurance value” means that the general population is protected from catastrophic

outbreaks by having a last-resort antibacterial available. This value is independent of the

actual quantities used in the clinics and applies even if a new, last-resort treatment is being

kept for emergency use only. “Diversity value” means that additional treatments increase

the value of older treatments over time, because those become effective. Few other

therapeutic areas deal with medicines that provide such value, and standard HTA procedures

are optimized to compare alternative options in head-to-head comparisons but do not yet

account for such additional, synergistic value. “Novel-action value” refers to the fact that

antibacterials with new mechanisms of action are especially valuable due to the lower risk of

cross-resistance. “Enablement value” arises when the availability of antibacterials ensures

safe surgeries and chemotherapies. Due to the availability of effective treatments, this can

easily be taken for granted and may be challenged by resistant bacteria in the foreseeable

future. “Spectrum value” means that antibacterials with a narrower (i.e.,“more specific”)


spectrum are more valuable for the treatment of susceptible pathogens than those with a

broader spectrum due to the lower risk of inducing additional resistances.

These additional elements of value due to improved resource utilization are important

considerations for the evaluation of novel antibacterials, which have the potential to lead to

substantial savings of resources if used in accordance with good stewardship practices.

Finally, antimicrobial stewardship includes the rapid identification of bacterial infections and

treatment with the most appropriate drug regimen [174, 175]. Improved early-detection and

characterization methods for bacterial infections used in hospital environments in which

cefiderocol and/or other modern antibacterials are available can thus lead to further resource

optimization, by allowing antibacterials use to be optimized for patients with infections

susceptible to certain treatments. While these resources are not a requirement for the use of

cefiderocol, they may help to optimize its use and effectiveness.

No special conditions are attached to the regulatory authorisation for cefiderocol with respect

to settings for use of cefiderocol. It will be used in critically ill hospitalised patients, many of

whom will be treated in ICU units. This is consistent with normal intravenous use of

antibacterials in these patients.

Clinical Particulars of the SmPC [232] highlight the following information:

Consideration should be given to official guidance on the appropriate use of

antibacterial agents. Treatment should commence for pathogens highly suspected

to be susceptible to cefiderocol, and susceptibility should be confirmed through

appropriate diagnostic testing as soon as possible.

It is recommended that Fetcroja should be used to treat patients that have limited

treatment options only after consultation with a physician with appropriate

experience in the management of infectious diseases

Cefiderocol may be used in combination with antibacterial agents active against

anaerobic pathogens and/or Gram-positive pathogens when these are known or

suspected to be contributing to the infectious process.

Dose adjustments are necessary for patients with renal impairment, but not for

hepatic impairment. No adjustment is required in elderly populations. The safety

and efficacy of cefiderocol in children below 18 years of age has not yet been

established.


Pathogen susceptibility should be determined as quickly as possible to identify the most

appropriate antibacterial to achieve microbiological eradication. AST is an integral part of

antibacterial treatment in the hospital. Use of cefiderocol will not require any capital investment

for AST beyond standard diagnostic microbiology lab equipment and consumables.

Shionogi is working with several diagnostics manufacturers and the EUCAST Development

Laboratory (EDL) to ensure a standard Kirby–Bauer test assay (disc-diffusion sensitivity

assay) is available for cefiderocol. This widely used assay will be accredited and cross-

referenced to both microdilution (BMD) Minimum Inhibitory Concentration (MIC) results, with

corresponding EDL breakpoints and inhibition zone diameter correlates. If microbiology

laboratories have the appropriate KB discs, AST determination for cefiderocol can be

conducted alongside other drugs with no need for specialised equipment or growth media.

There will also be a available methodology for BMD MIC determination which in the manual

read version requires no specialist devices other than standard incubation and plate reading

equipment.

Shionogi also has collaborations with several diagnostics manufacturers to develop other AST

technologies, including epsilometer strips (eTest), inclusion in various automated AST panels

and ready-made BMD strips for MIC determination. These should be commercially available

shortly after launch.

2. Describe the equipment required to use the technology.

Cefiderocol is provided as a 1g powder for concentrate for solution for infusion. For each

complete infusion, 2 vials are needed. It needs to be stored in a refrigerator (2 to 8°C) and

should be stored in the original carton in order to protect it from light (see SmPC). Each vial is

for single use only.

The use of cefiderocol is not expected to require any other specialized equipment, or to

demand additional resources beyond those already required to administer an intra-venous

antibacterial to hospitalised patients and to determine pathogen susceptibility.

3. Describe the supplies required to use the technology.

The powder should be reconstituted with 10 mL of either sodium chloride 9 mg/ml (0.9%)

solution for injection or 5% dextrose injection taken from the 100 mL bags that will be used to

prepare the final infusion solution. Standard infusion equipment and training is required.


5 Clinical effectiveness and safety

Summary of the effectiveness (combined evaluation of in vitro, PK/PD, and clinical

data)

The anti-microbial efficacy of cefiderocol has been investigated in several major in vitro

susceptibility studies (SIDERO-WT/Proteeae 2014/2015/2016 surveillance studies),

including both European and US clinical isolates. In addition multiple smaller, country

specific replicate studies were also conducted with similar results. These studies support

the use of cefiderocol in both target populations: suspected and confirmed infections in

several infection sites with MDR/CR/difficult-to-treat pathogens.

o Patients with infection caused by suspected MDR pathogen: The SIDERO-

WT-2014-2016 study (which tested the in vitro antibacterial activity of

cefiderocol against Gram-negative bacteria in 30,459 isolates across the world

that included MDR and difficult-to-treat strains), cefiderocol demonstrated

potent inhibition activity against 99.5% of Gram-negative isolates at a MIC of 4

mg/L (as defined by CLSI) including European clinical isolates, of K.

pneumoniae, P. aeruginosa, A. baumannii, S. maltophilia and B. cepacia

complex. Isolates were less susceptible to the comparators including

ceftazidime-avibactam (90.2%) and ceftolozane-tazobactam (84.28%).

o Patients with infection caused by a confirmed CR pathogen: The SIDERO-

CR-2014-2016 study (which tested the in vitro antibacterial activity of

cefiderocol against CRE and MDR non-fermenters), cefiderocol demonstrated

potent in vitro activity at a MIC of 4 mg/L (as defined by CSLI) against 96.2%

of isolates of carbapenem non-susceptible pathogens including all of the WHO

priority pathogens and Stenotrophomonas maltophilia. Cefiderocol was found

to have a wider Gram-negative coverage, and more potent in vitro activity than

comparators (cefepime, ceftazidime/avibactam, ceftolozane/tazobactam,

ciprofloxacin, colistin, and meropenem) against a range of CR-GN isolates,

including those non-susceptible to colistin.

The antimicrobial efficacy results from the in vitro studies are further supported by

in-vivo studies in animal models showing that cefiderocol penetrates into the target

tissues at therapeutic doses.

The clinical efficacy and safety of cefiderocol was demonstrated in two randomised

double-blinded clinical trials and one open label, randomised descriptive study.

The two randomised double-blinded clinical trials (APEKS NP and APEKS cUTI)


provide confirmatory clinical evidence of cefiderocol’s efficacy and safety in

patients with suspected MDR/difficult-to-treat infections at risk of carbapenem

resistance. Reports of compassionate use cases also contribute to the overall

efficacy characterization of cefiderocol.

o APEKS-NP trial, compared treatment with cefiderocol against the high-dose,

prolonged infusion (HD) meropenem in patients with nosocomial pneumonia

caused by MDR Gram-negative pathogens. Cefiderocol met the primary

endpoint of non-inferiority in ACM at day 14 versus HD meropenem (12.4% for

cefiderocol and 11.6% for meropenem; (95 % CI: -6.6, 8.2)) and similar results

were obtained between arms for ACM at Day 28 and EOS. Rates of clinical

cure and microbiological eradication at TOC and other time points were also

similar between the treatment groups.

o APEKS-cUTI, cefiderocol demonstrated an adjusted treatment difference vs

imipenem/cilastatin of 18.6% (95 % CI: 8.2, 28.9), which proven superiority in

a post-hoc analysis, in cUTI caused by Gram-negative MDR pathogens in

hospitalized adults, in the primary composite endpoint (microbiological

eradication and clinical cure).

A Network Meta-Analysis (NMA) was feasible for cUTI, given the similarity of

patients and pathogens included across trials. All results showed no statistically

significant difference compared with ceftazidime/avibactam and

ceftolozane/tazobactam in a similar patient population with similar pathogen

distribution.

Furthermore, in an effectiveness model that incorporated European pathogen

epidemiology and susceptibility rates (based on EUCAST breakpoints), and

clinical trials data, cefiderocol provides the best predicted susceptibility rates and

estimated clinical and microbiological success rates, in the absence of an

antibiogram for the critically ill patients with infections caused by suspected MDR

pathogen infection requiring immediate treatment.

The third, small, descriptive, exploratory, open-label study in patients with

confirmed carbapenem-resistant pathogen infections, supports cefiderocol’s use

in the confirmed-resistant population alongside with the compassionate use cases:

o CREDIBLE CR study was a small, exploratory, randomised, open label,

descriptive study, conducted to evaluate efficacy in patients with confirmed CR

infections for cefiderocol and BAT, but not designed or powered for statistical

comparison between arms. The study included 150 severely ill patients,


consistent with compassionate use cases (many patients had end stage

comorbidities and had failed multiple lines of therapy), with a range of infection

sites including nosocomial pneumonia, cUTI, BSI/sepsis. Clinical and

microbiological outcomes were similar between the 2 arms, but there were

marked clinical differences in some baseline characteristics and pathogen

distribution of the cefiderocol and BAT arms.

Summary of safety

Overall, cefiderocol was generally well tolerated, and the safety profile of

cefiderocol was found to be consistent with that of other cephalosporin

antibacterials. The clinical safety for cefiderocol as observed in the three

randomised clinical trials, including 549 treated patients.

o Pooled adverse event analyses there overall less treatment emergent

adverse events with cefiderocol (344/549 [67.1%]) vs comparators

(252/347 [72.6%]). The most common adverse reactions for cefiderocol

were diarrhoea (8.2%), constipation (4.6%), pyrexia (4.0%) and UTI

(4.7%).

o In the total sample, 56/549 (10.2%) patients treated with cefiderocol

experienced treatment related AEs and 45/347 (13.0%) patients treated

with comparators.

The clinical safety for cefiderocol has been investigated in three randomised

clinical trials, two specific to different infection sites and one specific to

carbapenem-resistant pathogens.

o HAP/VAP/ HCAP study (APEKS-NP): Overall, TEAEs and treatment-

related TEAEs were balanced between treatment arms. Serious adverse

events occurred in 36% of patients treated with cefiderocol and 30% of

patients treated with meropenem. The most frequently observed AE was

urinary tract infection (15.5% in cefiderocol group and 10.7% in

meropenem group), hypokalaemia (10.8% in cefiderocol group and 15.3%

in meropenem group) and anaemia (8.1% in cefiderocol group and 8% in

meropenem group).

o cUTI study (APEKS-cUTI): The proportion of patients who experienced at

least one adverse event (AE) was lower in the cefiderocol group than in

the IPM/CS group (41 % vs 51%). Gastrointestinal disorders, such as

diarrhoea and constipation, were the most common adverse events and


there was an increased incidence of C. difficile colitis in the

imipenem/cilastatin arm compared with cefiderocol. Serious adverse

events (SAE) occurred in a numerically lower proportion of cefiderocol-

treated patients than of IPM/CS-treated patients (5% vs 8%). The most

frequently observed AEs were gastrointestinal, such as diarrhoea

[experienced by 4.3% (13/300) and 6.1% (9/148) of cefiderocol- and

IPM/CS-treated subjects, respectively.

o CR study (CREDIBLE-CR): The cefiderocol group had lower incidence of

AEs and treatment-related AEs, but higher incidence of death, SAEs and

discontinuation due to AEs, compared with BAT. The incidence of

treatment-related AEs leading to discontinuation was similar between

treatment groups. An imbalance in mortality was observed in the

cefiderocol arm compared to BAT (18/49 vs 5/25). No deaths were found

to be causally associated with cefiderocol through assessment by the

investigator and two independent committees. Furthermore, whereas the

mortality rate in the cefiderocol group was consistent with previous studies

in similar populations the evidence suggests that the mortality rate in the

BAT group was unexpectedly low for the population randomised. No single

factor that would explain the imbalance was identified. Small patient

numbers and multiple confounders preclude definitive conclusions.

Like in any other beta-lactam antibacterial, patients who have a history of

hypersensitivity to carbapenems, penicillins or other beta-lactam antibacterial

medicinal products may also be hypersensitive to cefiderocol. Before initiating

therapy with cefiderocol, careful inquiry should be made concerning previous

hypersensitivity reactions to beta-lactam antibacterials.

5.1 Identification and selection of relevant studies

The research question for this assessment is: “Do patients with aerobic Gram-negative

infections and limited treatment option benefit from cefiderocol as an additional treatment

option?”

Cefiderocol is expected to be approved for adult patients with aerobic, Gram-negative

infections with limited treatment options. This indication comprises:


critically ill patients with suspected infection by a carbapenem-resistant Gram-

negative pathogen or other Gram-negative pathogen difficult to treat with limited

treatment options

and

patients with confirmed infection by a carbapenem-resistant Gram-negative

pathogen or other Gram-negative pathogen difficult to treat with limited treatment

options.

As outlined in chapter 2.4, clinical trials can only provide limited evidence regarding the

efficacy of new antibacterials because trials must focus on pathogens for which the tested

agents and comparators are effective. Comparison of efficacy against all relevant comparators

in the antibacterial setting can only be obtained from in vitro surveillance studies. Unlike in

other therapeutic areas, the evaluation of the effectiveness of an antibacterial relies on the

combined consideration of in vitro, PK/PD and clinical data.

To identify all relevant studies for cefiderocol and comparators for the two patient populations

a comprehensive systematic literature review was conducted comprising in vitro and in-vivo

studies, as well as any comparative or non-comparative studies and RCTs (including cross-

over RCTs).

The search strategy was broad to ensure that all relevant studies were captured. The only

restriction was that cefiderocol or any of its synonyms had to be an intervention in the study.

The search strategy is shown below in Figure 20.

Figure 20 - Search strategy for OVD MEDLINE ALL


Through this methodology, all studies of cefiderocol in various populations were captured and

a complete study pool defined as the primary evidence base:

Surveillance studies provide evidence for the expected efficacy of cefiderocol

compared to other treatment options for patients with suspected MDR/CR

infection.

o Site-specific clinical studies in patients with suspected MDR/CR infections

amend the evidence pool.

o In addition, to amend the evidence for cefiderocol versus comparators for the

population with suspected infection, a systematic literature review was

conducted, to retrieve data for a potential network meta-analyses of cefiderocol

versus approved comparators in the indication cUTI and nosocomial

pneumonia. Details and results are described in chapter 5.4.3.

Surveillance studies from confirmed infections provide evidence for expected

efficacy of cefiderocol versus comparators in patients with suspected MDR/CR

infection.

o The evidence is amended by subpopulations from RCTs, descriptive clinical

study and by compassionate use cases.

The combined evidence is appropriate for the assessment of cefiderocol considering the

scope outlined in EUnetHTA project plan.

In addition, a systematic literature was conducted to evaluate the feasibility of conducting 2

NMAs: 1 in cUTI and another in nosocomial pneumonia, identifying all relevant comparators

and their clinical data for each NMA. All information on this SLR is available in the appendix

[227].

1. State the databases and trial registries searched and, when relevant, the platforms

used to do this.

A literature search in the following databases and information resources (Table 14) identified

a total of 428 records.

Table 14: Databases and information sources searched

Database / information source Interface / URL Coverage

MEDLINE ALL Ovid SP Biomedical journal literature


Database / information source Interface / URL Coverage

PubMed https://www.ncbi.nlm.nih.gov/p

ubmed/ Biomedical journal literature

Embase OvidSP Biomedical journal literature

Cochrane Central Register of

Controlled Trials (CENTRAL) Wiley Cochrane Library

Randomized and quasi-

randomized controlled trials

Cochrane Database of

Systematic Reviews Wiley Cochrane Library Systematic reviews

Database of Abstracts of Reviews

of Effects (DARE) CRD website Systematic reviews

Health Technology Assessment

(HTA) CRD website Health technology assessment

Web of Science http://apps.webofknowledge.co

m/

Science, social science, arts,

humanities

BIOSIS Citation Index http://apps.webofknowledge.co

m/

Life sciences and biomedical

research

ClinicalTrials.gov https://www.clinicaltrials.gov/ct Records for registered clinical

studies

WHO International Clinical Trials

Registry Platform (WHO ICTRP) http://www.who.int/ictrp/en/ Trial registration data sets

The PubMed search was restricted to records not yet fully indexed for MEDLINE. The trials

register sources listed above (ClinicalTrials.gov and ICTRP) were searched to identify

information on studies in progress.

Recent research published as conference abstracts were identified by searching Embase

(which indexes a significant number of conference publications). In addition, where the

following conferences (identified as highly relevant by the research team) were not indexed in

Embase from 2016 to 2019, we conducted hand-searches for abstracts via conference

webpages:

European Congress of Clinical Microbiology & Infectious Diseases (ECCMID)

IDWeek

European Respiratory Society (ERS) International Congress.

Reference lists of any relevant reviews or systematic reviews for eligible records were also

checked.


2. State the date the searches were done and any limits (for example date, language)

placed on the searches.

The searches were conducted between 7th October 2019 and 11th October 2019. A

supplementary set of abstracts relevant to cefiderocol from the IDWeek 2019

conference (October 2-9, Washington DC, USA) was obtained in a grey literature

search on December 19, 2019.

3. Include as an appendix the search terms and strategies used to interrogate each

database or registry.

The report “Systematic Searches and Study Selection to Identify Clinical and Non-

Clinical Evidence Available for Cefiderocol” contains the full strategies (including

search dates) for all sources searched [233].

4. In Table 15, state the inclusion and exclusion criteria used to select studies and justify

these.

Table 15: Inclusion and exclusion criteria

Criterion Inclusion criteria Exclusion criteria

Population

Cell based (bacteria, human or animal)

Animal (healthy and infected)

Human (healthy and infected)

NA

Intervention Cefiderocol Any other

intervention

Comparators Any intervention, placebo or best standard of care

Studies with no comparator NA

Outcomes

Clinical cure

Microbiological eradication

All-cause mortality

Adverse events

Microbiology

Pharmacodynamic

Pharmacokinetic

Toxicology

NA


Criterion Inclusion criteria Exclusion criteria

Study designs

RCTs of any duration

Cross-over RCTs if data are presented at time of

cross-over

Any comparative or non-comparative studies both

prospective and retrospective

In vitro studies

In vivo studies

Systematic

reviews, reviews,

opinion pieces (for

listing in the final

report only)

Limits No date or language limits

Note that the search strategy shown above included all cefiderocol references,

regardless of the measured outcomes. A second screening step then assigned the

identified publications to different topics of interest (see below).

5. Provide a flow chart showing the number of studies identified and excluded. The

PRISMA statement can be used; the PRISMA flow chart is included below, as an

example.

Figure 21 shows the PRISMA flow diagram of the numbers of records included and excluded

at each stage of the selection process.

Following deduplication, 254 records remained for assessment. Twelve records were

excluded after an assessment of the information in the title and abstract. 242 full text

documents were assessed and 129 records were included.

Additional eligible records identified through reference checking of reviews or systematic

reviews which had not been identified through the database searches or hand searched

conferences, have been included in the PRISMA flow diagram as identified from other

sources.

http://www.prisma-statement.org/statement.htm


5.1.1 PRISMA Chart

Figure 21 - PRISMA flow diagram of record selection process

5.1.2 Study categorisation

Studies were first categorised into the following five primary categories:

In vitro

In vivo

Clinical

Multiple categories

Modelling simulation

Systematic review protocol


Then, for each study, the type of outcome data was reported:

Efficacy

Frequency of spontaneous resistance

Method reproducibility

Mode of action

Pharmacokinetic/pharmacodynamic

Pharmacokinetic

Pharmacodynamic

Safety

Additionally, based on the identified scope, we screened the identified publications for possible

results regarding hospital utilization and quality of life. No such studies were identified, as

expected in the context of antibiotic treatment trials.

Of the 129 identified records:

39 were conducted in vitro, two of which were letters reporting data on cefiderocol

37 records reported in vitro investigations of specifically identified clinical isolates

16 records reported in vivo investigations

25 records reported details of clinical studies, eight of these records reported

protocol information only

Five records reported details of mixed study investigations e.g. both in vitro and in

vivo

Six records reported details of modelling simulations

One record reported details of a Cochrane systematic review protocol which

cefiderocol is an eligible intervention

The supplementary search of the IDWeek 2019 conference (October 2-6, 2019), the

presentations of which became available after the cut-off date for the SLR (October 7-

11, 2019), yielded 12 additional relevant presentations involving company staff from the

manufacturer of cefiderocol. These presentations were added to the table of identified

studies and screened for relevant content. References were added to Table 16 – List

of all relevant studies - below.

5.2 Relevant studies

1. In Table 16 provide a list of the relevant studies identified.


Table 16: List of all relevant studies

Study reference/ID Available documentation* Status

(ongoing**/

complete)

In vitro

Surveillance

SIDERO WT Tsuji M, Hackel M, Yamano Y, Echols R, Longshaw C, Manissero D, et al. Cefiderocol in vitro activity against

gram-negative clinical isolates collected in Europe: result from three SIDERO-WT surveillance studies between

2014-2017. In: ECCMID, 2019.

Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. In vitro activity of the siderophore

cephalosporin, cefiderocol, against a recent collection of clinically relevant gram-negative bacilli from North

America and Europe, including carbapenem-nonsusceptible isolates (sidero-wt-2014 study). Antimicrob Agents

Chemother. 2017;61(9):1-9.

Ito A, Kuroiwa M, Rokushima M, Hackel M, Sahm D, Tsuji M, et al. Characterization of isolates showing high

MICs to cefiderocol from global surveillance study SIDERO-WT-2014. In: ASM Microbe 2019, San Francisco;

2019.

Kazmierczak KM, Tsuji M, Wise MG, Hackel M, Yamano Y, Echols R, et al. In vitro activity of cefiderocol, a

siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-

negative bacilli, including serine carbapenemase- and metallo-β-lactamase-producing isolates (SIDERO-WT-

2014 Study). Int J Antimicrob Agents. 2019;53(2):177-84.

Tsuji M, Hackel M, Yamano Y, Echols R, D S. Surveillance of cefiderocol in vitro activity against gram-negative

clinical isolates collected in Europe: SIDERO-WT-2014. In: ECCMID, 2017.

Continuous

collection of world-

wide isolates

(currently ca. 38k

isolates)


Tsuji M, Hackel M, Echols R, Yamano Y, D S. Global surveillance of cefiderocol (S-649266) against Gram-

negative clinical strains collected in North America: SIDERO-WT-2014. In: ASM Microbe 2017, New Orleans;

2017.

Tsuji M, Kazmierczak K, Hackel M, Echols R, Yamano Y, D S. Cefiderocol susceptibility against globally isolated

meropenem-non-susceptible gram-negative bacteria containing serine-and metallo-carbapenemase genes:

SIDERO-WT-2014 and -2015. In: ASM Microbe, San Francisco; 2019.

Yamano Y, Tsuji M, Echols R, Hackel M, Sahm D. In vitro activity of cefiderocol against gram-negative clinical

isolates from respiratory specimens: Sidero-WT-2014. Am J Respir Crit Care Med. 2018;197

Tsuji M, Hackel M, Echols R, Yamano Y, D S. In vitro activity of cefiderocol against gram-negative clinical

isolates collected from urinary track source: SIDERO-WT-2014/SIDERO-WT-2015 In: IDWeek, 2017.

Nguyen S, Hackel M, Hayes J, Sahm D, Echols R, Tsuji M, et al. In vitro antibacterial activity of cefiderocol

against an international collection of carbapenem-non-susceptible gram-negative bacteria isolated from

respiratory, blood, skin/soft tissue and urinary sources of infection: SIDERO-WT2014-2016. In: ECCMID, 2019.

Mackenzie T, Nguyen S, Haynes J, Hackel M, Echols R, Sahm D, et al. Cefiderocol activity against North

American clinical isolates SIDERO-WT-2014–2017. In: ASM Microbe 2019, San Francisco; 2019.

Nguyen S, Hackel M, Hayes J, Sahm D, Echols R, Tillotson G, et al. In vitro antibacterial activity of cefiderocol

against carbapenem-non-susceptible gram-negative bacteria from hospitalized patients in the United States:

SIDERO-WT-2014–2017. In: ASM Microbe 2019, San Francisco; 2019.


Karlowsky JA, Hackel MA, Tsuji M, Yamano Y, Echols R, Sahm DF. In vitro activity of cefiderocol, a siderophore

cephalosporin, against gram-negative bacilli isolated by clinical laboratories in north america and europe in

2015-2016: SIDERO-WT-2015. Int J Antimicrob Agents. 2019;53(4):456-66.

Tsuji M, Hackel M, Echols R, Yamano Y, D S. In vitro antibacterial activity of cefiderocol (S-649266) against

gram-negative clinical strains collected in North America and Europe: SIDERO-WT-2015. In: ASM Microbe

2017, New Orleans; 2017.

Tsuji M, Hackel M, Echols R, Yamano Y, D S. Global surveillance of cefiderocol against gram-negative clinical

strains collected in North America: SIDERO-WT-2015. In: IDWeek, 2018.

Tsuji M, Hackel M, Echols R, Yamano Y, D S. In vitro antibacterial activity of cefiderocol against gram-negative

clinical strains collected in North America and Europe: SIDERO-WT-2016. In: ASM Microbe 2019, San

Francisco; 2019.

SIDERO CR Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. In vitro activity of the siderophore

cephalosporin, cefiderocol, against carbapenem-nonsusceptible and multidrug-resistant isolates of gram-

negative bacilli collected worldwide in 2014 to 2016. Antimicrob Agents Chemother. 2018;62(2):1-13.

Tsuji M, Kazmierczak K, Hackel M, Wise M, Echols R, Sahm D, et al. Cefiderocol susceptibility and geographical

analysis against globally isolated meropenem non-susceptible gram-negative bacteria containing serineand

metallo-carbapenemase gene In: ECCMID, 2019.

Ito A, Hackel M, Sahm D, Tsuji M, Y Y. Characterization of isolates showing high MICs to cefiderocol from global

surveillance study SIDERO-CR-2014/2016. In: ECCMID, 2019.

Completed


Tsuji M, Hackel M, Echols R, Yamano Y, D S. In vitro activity of cefiderocol against globally collected

carbapenem-resistant gramnegative bacteria isolated from urinary track source: SIDERO-CR-2014/2016. In:

IDWeek, San Diego; 2017. 1199

Tsuji M, Hackel M, Yamano Y, Echols R, Longshaw C, Manissero D, et al. Cefiderocol in vitro activity against

Gram-negative clinical isolates collected in Europe: result from SIDERO-CR-2014/2016. In: ECCMID, 2019.

Yamano Y, Tsuji M, Hackel M, Echols R, Sahm D. In vitro activity of cefiderocol against gram-negative clinical

isolates collected from Asia and South Pacific in 2014-2016 (SIDERO-CR Study). Int J Antimicrob Agents.

2017;50(Supplement 2):S48.

Yamano Y, Tsuji M, Hackel M, Echols R, D S. In vitro activity of cefiderocole against globally collected

carbapenem-resistant Gramnegative bacteria including isolates resistant to ceftazidime/avibactam,

ceftolozane/tazobactam and colistin: SIDERO-CR-2014/2016 study. In: ECCMID, 2017.

Independent

Studies

Kresken M, Berwian E, Wernicke S, Frank A, G A. In vitro activity of cefiderocol against gram-negative

pathogens circulating in Germany. In: ECCMID, 2019.

Falagas ME, Skalidis T, Vardakas KZ, Legakis NJ, Hellenic Cefiderocol Study G. Activity of cefiderocol (S-

649266) against carbapenem-resistant gram-negative bacteria collected from inpatients in Greek hospitals. J

Antimicrob Chemother. 2017;72(6):1704-08.

Falagas ME, Skalidis T, Vardakas K, N L. Activity of cefiderocol (S-649266) against carbapenem-resistant gram-

negative bacteria collected from inpatients in Greek hospitals. In: ECCMID, 2017.

Completed


Tsuji M, Yamaguchi T, Nakamura R, Kanazawa S, Ito-Horiyama T, Sato T, et al. S-649266, a novel siderophore

cephalosporin: in vitro activity against gram-negative bacteria isolated in Japan including carbapenem resistant

strains. In: IDWeek, San Diego; 2015.

Hackel M, Tsuji M, Echols R, D S. In vitro antibacterial activity of s-649266 against gram-negative clinical strains

collected in North America and Europe. In: IDWeek, 2016.

Hsueh SC, Huang YT, Liao CH, Lee YJ, Hsueh PR. In vitro activities of cefiderocol (S-649266),

ceftazidimeavibactam, ceftolozane-tazobactam, and other comparative drugs against pseudomonas

aeruginosa, acinetobacter baumannii and stenotrophomonas maltophilia associated with bloodstream

infections. Int J Antimicrob Agents. 2017;50(Supplement 2):S48-S49.

Hsueh S-C, Lee Y-J, Huang Y-T, Liao C-H, Tsuji M, Hsueh P-R. In vitro activities of cefiderocol,

ceftolozane/tazobactam, ceftazidime/avibactam and other comparative drugs against imipenem-resistant

pseudomonas aeruginosa and acinetobacter baumannii, and stenotrophomonas maltophilia, all associated with

bloodstream infections in Taiwan. J Antimicrob Chemother. 2019;74(2):380-86.

Mushtaq S, Sadouki Z, Vickers A, Livermore D, N W. In vitro activity of cefiderocol against extensively drug-

resistant pseudomonas aeruginosa and acinetobacter baumannii from the UK. In: ECCMID, 2019.

Mushtaq S, Vickers A, Hussain A, Livermore D, N W. In vitro activity of cefiderocol (S-649266) against multidrug-

resistant enterobacteriaceae from the UK. In: ECCMID, 2017.

Other

Mode of Action Coppi M, Antonelli A, Baglio G, Giani T, GM R. Activity of cefiderocol on a reference collection of

carbapenemase-,ESBL-, and acquired class C β-lactamases-producing gram-negative pathogens. In: ECCMID,

2019.

Completed


Dobias J, Denervaud V, Poirel L, P N. Activity of the novel siderophore cephalosporin cefiderocol (S-649266)

against Gramnegative pathogens. In: ECCMID, 2017.

Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs

for the novel siderophore cephalosporin, cefiderocol, determined using iron-depleted cation-adjusted Mueller-

Hinton broth. Diagn Microbiol Infect Dis. 2019;94(4):321-25.

Huband MD, Ito A, Tsuji M, Sader HS, Fedler KA, Flamm RK. Cefiderocol mic quality control ranges in iron-

depleted cation-adjusted mueller-hinton broth using a clsi m23-a4 multi-laboratory study design. Diagn Microbiol

Infect Dis. 2017;88(2):198-200.

Ito A, Kohira N, Bouchillon SK, West J, Rittenhouse S, Sader HS, et al. In vitro antimicrobial activity of S-649266,

a catechol-substituted siderophore cephalosporin, when tested against non-fermenting gram-negative bacteria.

J Antimicrob Chemother. 2016;71(3):670-7.

Ito A, Nishikawa T, Matsumoto S, Fukuhara N, Nakamura R, Tsuji M, et al. S-649266, a novel siderophore

cephalosporin: II. Impact of active transport via iron regulated outer membrane proteins on resistance selection.

Abstract F-1563. In: ICAAC, 2014.

Ito A, Nishikawa T, Matsumoto S, Yoshizawa H, Sato T, Nakamura R, et al. Siderophore cephalosporin

cefiderocol utilizes ferric iron transporter systems for antibacterial activity against pseudomonas aeruginosa.

Antimicrob Agents Chemother. 2016;60(12):7396-401.

Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, et al. In vitro antibacterial properties of cefiderocol, a

novel siderophore cephalosporin, against gram-negative bacteria. Antimicrob Agents Chemother. 2018;62(1):1-

11.


Ito A, Ishibashi N, Ishii R, Tsuji M, Maki H, Sato T, et al. Changes of responsible iron-transporters for the activity

of cefiderocol against pseudomonas aeruginosa depending on the culture conditions. In: ASM Microbe 2019,

San Francisco; 2019.

Ito A, Nishikawa T, Ishii R, Kuroiwa M, Ishioka Y, Kurihara N, et al. Mechanism of Cefiderocol high MIC mutants

obtained in non-clinical FoR studies In: IDWeek, 2018.

Luscher A, Moynie L, Auguste PS, Bumann D, Mazza L, Pletzer D, et al. TonB-dependent receptor repertoire

of pseudomonas aeruginosa for uptake of siderophore-drug conjugates. Antimicrob Agents Chemother.

2018;62(6):1-11.

Nordmann P, Vazquez-Rojo L, L P. Stability of cefiderocol against clinically-significant broad-spectrum

oxacillinases. In: ECCMID, 2018.

Poirel L, Kieffer N, Nordmann P. Stability of cefiderocol against clinically significant broad-spectrum

oxacillinases. Int J Antimicrob Agents. 2018;52(6):866-67.

Robertson G, Henderson A, Paterson DL, P H. In vitro activity of cefiderocol (S-649266) against clinical isolates

of burkholderia pseudomallei. In: ECCMID, 2019.

Takemura M, Ito A, Nishikawa T, Oota M, Horiyama T, Satou T, et al. Stability and low induction potential of

cefiderocol against chromosomal AmpC β-lactamases of pseudomonas aeruginosa and enterobacter cloacae.

In: ECCMID, 2018.

Tsuji M, Hackel M, Yamano Y, Echols R, D S. Correlations between cefidercol broth microdilution MICs and

disk diffusion inhibitory zone diameters among target gram-negative organisms. In: ECCMID, 2018.


Tsuji M, Ito A, Toba S, Nishikawa T, Oota M, Kanazawa S, et al. S-649266, a novel siderophore cephalosporin:

binding affinity to PBP and in vitro bactericidal activity. In: ECCMID, Copenhagen; 2015.

Tsuji M, Jakielaszek C, LCL M. S-649266, a novel siderophore cephalosporin: in vitro activity against biothreat

pathogen. In: IDWeek, 2016.

Tsuji M, Nakamura R, Kohira N, Ito A, Sato T, Y Y. S-649266, a novel siderophore cephalosporin: in vitro

combination effect of S-649266 and other antibacterials against gram-negative bacteria. In: ECCMID, 2016.

Rolston KVI, Gerges B, Raad I, Aitken SL, Reitzel R, R P. In vitro activity of cefiderocol and comparator agents

against gramnegative isolates from cancer patients. In: IDWeek, 2018.

Ito A, Ota M, Nakamura R, Tsuji M, Sato T, Y Y. In vitro and in vivo activity of cefiderocol against

stenotrophomonas maltophilia clinical isolates. In: IDWeek, 2018.

Tsuji M, Ito-Horiyama T, Nakamura R, Sato T, Y Y. S-649266, a Novel Siderophore Cephalosporin:

Pharmacodynamic assessment by using MIC in Iron-depleted Cation-adjusted Mueller Hinton Broth (ID-

CAMHB) In: IDWeek, 2016.

Tsuji M, Nakamura R, Sato T, Hackel M, Sahm D, Echols R, et al. Use of iron depleted mueller hinton broth

(IDMHB) for microdilution testing of S649266, a novel siderophore cephalosporin. In: ECCMID, 2016.

Ito A, Miyagawa S, Ishibashi N, Nishikawa T, Kohira N, Sato T, et al. Anti-Acinetobacter activity of cefiderocol

(S-649266), a novel siderophore cephalosporin: bactericidal activity due to penicillin-binding proteins inhibition

and antibacterial activity against globally collected clinical isolates, abstr SATURDAY-115. In: ASM Microbe

2017, New Orleans; 2017.

Resistance Aoki T, Yoshizawa H, Yamawaki K, Yokoo K, Sato J, Hisakawa S, et al. Cefiderocol (S-649266), A new

siderophore cephalosporin exhibiting potent activities against pseudomonas aeruginosa and other gram-

Completed


negative pathogens including multi-drug resistant bacteria: structure activity relationship. Eur J Med Chem.

2018;155:847-68.

Aoki T, Yoshizawa H, Yamawaki K, Yokoo K, Sato J, Hisakawa S, et al. Cefiderocol (S-649266): A new

siderophore cephalosporin exhibiting potent activities against pseudomonas aeruginosa and other gram

negative-pathogens including multi-drug resistant bacteria: structure activity relationship. Abstr. Pap. Am. Chem.

Soc. 2017;254

Boyd S, Anderson K, Albrecth V, Campbell D, Karlsson MS, JK R. In vitro activity of cefiderocol against multi-

drug resistant carbapenemase-producing gramnegative pathogens. In: IDWeek, 2017.

Delgado-Valverde M, Conejo MC, Serrano-Rocha L, Fernandez-Cuenca F, AP H. Activity of cefiderocol (S-

649266), a new siderophore cephalosporin, against multidrug-resistant Enterobacteriaceae, Acinetobacter

baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. In: ECCMID, 2019.

Dobias J, Denervaud-Tendon V, Poirel L, Nordmann P. Activity of the novel siderophore cephalosporin

cefiderocol against multidrug-resistant Gram-negative pathogens. Eur J Clin Microbiol Infect Dis.

2017;36(12):2319-27.

Ishii Y, Horiyama T, Nakamura R, Fukuhara N, Tsuji M, Yamano Y, et al. S-649266, a novel siderophore

cephalosporin: III. Stability against clinically relevant β-lactamases. In: ICAAC, 2014. 1557

Ito A, Nishikawa T, Ota M, Ito-Horiyama T, Ishibashi N, Sato T, et al. Stability and low induction propensity of


J Antimicrob Chemother. 2018;73(11):3049-52.


Ito A, Nishikawa T, Ota M, Ito-Horiyama T, Ishibashi N, Sato T, et al. Stability and low induction propensity of


J Antimicrob Chemother. 2019;74(2):539.

Ito-Horiyama T, Ishii Y, Ito A, Sato T, Nakamura R, Fukuhara N, et al. Stability of novel siderophore

cephalosporin S-649266 against clinically relevant carbapenemases. Antimicrob Agents Chemother.

2016;60(7):4384-6.

Jacobs M, Bbajaksouzian S, Good C, Hujer K, Hujer A, R B. In vitro activity of cefiderocol (S-649266), a

siderophore cephalosporin, against carbapenem-susceptible and resistant non-fermenting gram-negative

bacteria. In: ECCMID, 2018.

Jacobs MR, Abdelhamed AM, Good CE, Rhoads DD, Hujer KM, Hujer AM, et al. ARGONAUT-I: activity of

cefiderocol (S-649266), a siderophore cephalosporin, against gram-negative bacteria, including carbapenem-

resistant nonfermenters and enterobacteriaceae with defined extended-spectrum β-lactamases and

carbapenemases. Antimicrob Agents Chemother. 2019;63(1):1-9.

Jacobs MR, Abdelhamed AM, Good CE, Rhoads DD, Hujer KM, Hujer AM, et al. In vitro activity of cefiderocol

(S-649266), a siderophore cephalosporin, against enterobacteriaceae with defined extended-spectrum β-

lactamases and carbapenemases. In: IDWeek, 2018.

Kanazawa S, Sato T, Kohira N, Ito-Horiyama T, Tsuji M, Yamano Y. Susceptibility of imipenem-susceptible but

meropenem-resistant blaIMP-6-carrying enterobacteriaceae to various antibacterials, including the siderophore

cephalosporin cefiderocol. Antimicrob Agents Chemother. 2017;61(7):1-3.


Kohira N, West J, Ito A, Ito-Horiyama T, Nakamura R, Sato T, et al. In vitro antimicrobial activity of a siderophore

cephalosporin, S-649266, against enterobacteriaceae clinical isolates, including carbapenem-resistant strains.

Antimicrob Agents Chemother. 2016 ;60(2) :729-34.

Kohira N, Nakamura R, Ito A, Nishikawa T, Ota M, Sato T, et al. Resistance acquisition studies of cefderocol by

serial passage and in vitro pharmacodynamic model under human simulated exposure. In: ASM Microbe,

Atlanta; 2018.

Kohira N, Oota M, Nishikawa T, Kuroiwa M, Ishioka Y, Naoko K, et al. Frequency of resistance acquisition and

resistance mechanisms to cefiderocol. In: ASM Microbe, Atlanta; 2018.

Tsuji M, Ito A, Nakamura R, Yamano Y, J S. S-649266, a novel siderophore cephalosporin: in vitro activity

against gram-negative bacteria including multidrug-resistant strains. In: IDWeek, 2014. 252

Tsuji M, Kazmierczak K, Hackel M, Echols R, Yamano Y, D S. Cefiderocol (S-649266) susceptibility against

globally isolated meropenem non-susceptible gram-negative bacteria containing serine- and metallo-

carbapenemase genes. In: ASM Microbe, New Orleans; 2017.

Tsuji M, Matsumoto S, Kanazawa S, Nakamura R, Sato T, Y Y. S-649266, a novel siderophore cephalosporin:

in vitro activities against multidrug-resistant and carbapenem resistant gram-negative pathogens in an in vitro

pharmacodynamic model. In: IDWeek, San Diego; 2015. 767

Yamano Y, Tsuji M, Hackel M, Sahm D, R E. Mode of action of cefiderocol, a novel siderophore cephalosporin,

active against highly resistant gram-negative bacteria including carbapenem-resistant strains of

Enterobacteriaceae and non-fermenting bacteria. In: ECCMID, 2017.


Tsuji M, Hackel M, Echols R, Tillotson G, Fam D, Yamano Y, et al. In vitro and in vivo activity of cefiderocol

against burkholderia cepacia complex clinical isolates. In: ECCMID, 2019.

Tsuji M, Hackel M, Echols R, Yamano Y, D S. The in vitro activity of cefiderocol, a novel siderophore

cephalosporin, against a global collection of stenotrophomonas maltophilia. In: ECCMID, 2017.

Tsuji M, Hackel M, Yamano Y, Echols R, D S. Cefiderocol, a novel siderophore cephalosporin: in vitro activity

against Stenotrophomonos maltophillia isolated globally. In: ECCMID, 2018.

A. Ito, H. Yoshizawa, R. Nakamura, M. Tsuji, Y. Yamano, Shimada J. S-649266, a novel siderophore

cephalosporin: I. In vitro activity against gram-negative bacteria including multidrug-resistant strains. ICAAC

Abstracts. 2014

PK/PD data

Animal models

Thigh Monogue ML, Tsuji M, Yamano Y, Echols R, Nicolau DP. Efficacy of humanized exposures of cefiderocol (S-

649266) against a diverse population of gram-negative bacteria in a murine thigh infection model. Antimicrob

Agents Chemother. 2017;61(11):1-10.

Nakamura R, Toba S, Ito A, Tsuji M, Yamano Y, Shimada J. S-649266, a novel siderophore cephalosporin. V.

Pharmacodynamic assessment in murine thigh infection models, abstr F1-1559. In: ICAAC, 2014.

Ghazi IM, Monogue ML, Tsuji M, Nicolau DP. Pharmacodynamics of cefiderocol, a novel siderophore

cephalosporin, in a pseudomonas aeruginosa neutropenic murine thigh model. Int J Antimicrob Agents.

2018;51(2):206-12.

Completed


Horiyama T, Toba S, Nakamura R, Tsuji M, Yamano Y, Shimada J. S-649266, a novel siderophore

cephalosporin: vii. Magnitude of pk/pd parameter required for efficacy in murine thigh infection model. In: ICAAC,

2014. 1561

Monogue M, Tsuji M, Yamano Y, Echols R, DP N. In vivo efficacy of humanized exposures of cefiderocol

compared with cefepime (FEP) and meropenem (MEM) against Gram-negative bacteria in a murine thigh model.

In: IDWeek, 2017.

Stainton S, Monogue M, Tsuji M, Yamano Y, Echols R, DP N. Efficacy of humanized cefiderocol exposures over

72 hours against a diverse group of gram-negative isolates in the neutropenic murine thigh infection model. In:

IDWeek, 2018.

Stainton SM, Monogue ML, Tsuji M, Yamano Y, Echols R, Nicolau DP. Efficacy of humanized cefiderocol

exposures over 72 hours against a diverse group of gram-negative isolates in the neutropenic murine thigh

infection model. Antimicrob Agents Chemother. 2019;63(2):1-7.

Lung Horiyama T, Singley CM, Nakamura R, Tsuji M, Roger E, Rittenhouse S, et al. S-649266, a novel siderophore

cephalosporin: viii. Efficacy against pseudomonas aeruginosa and acinetobacter baumannii in rat lung infection

model with humanized exposure profile of 2 gram dose with 1 hour and 3 hours infusion. In: ICAAC, 2014. 1556

Matsumoto S, Singley CM, Hoover J, Nakamura R, Echols R, Rittenhouse S, et al. Efficacy of cefiderocol against

carbapenem-resistant gram-negative bacilli in immunocompetent-rat respiratory tract infection models

recreating human plasma pharmacokinetics. Antimicrob Agents Chemother. 2017;61(9):1-8.

Takemura M, Matsumoto S, Miyagawa S, Satou T, Tsuji M, Y Y. Efficacy of humanized cefiderocol exposure

against Stenotrophomonas maltophilia in a rat respiratory tract infection mode. In: ECCMID, 2018.

Completed


Takemura M, Nakamura R, Satou T, Tsuji M, Y Y. In vivo pharmacokinetic/pharmacodynamic (PK/PD)

assessment of cefiderocol against Stenotrophomonas maltophilia in a neutropenic murine lung infection model.

In: ECCMID, 2018.

Lung & Thigh Horiyama T, Toba S, Nakamura R, Tsuji M, Yamano Y, Shimada J. S-649266, a novel siderophore

cephalosporin: vi. Magnitude of pk/pd parameter required for efficacy in murine lung infection model. In: ICAAC,

2014. 1560

Nakamura R, Ito-Horiyama T, Takemura M, Toba S, Matsumoto S, Ikehara T, et al. In vivo pharmacodynamic

study of cefiderocol, a novel parenteral siderophore cephalosporin, in murine thigh and lung infection models.

Antimicrob Agents Chemother. 2019;63(9)







Yamano Y, Nakamura R, Sato T, Tsuji M, R E. Good correlation of cefiderocol between in vivo efficacy murine

thigh/lung infection models and mic determined in iron-depleted conditions. In: IDWeek, 2017.

Completed

Kidney Matsumoto S, Kanazawa S, Nakamura R, Tsuji M, Sato T, Y Y. In vivo efficacy of cefiderocol against

carbapenem-resistant gram-negative bacilli in murine urinary tract infection models. In: IDWeek, 2017.

Completed

Multiple Nakamura R, Toba S, Tsuji M, Yamano Y, Shimada J. S-649266, a novel siderophore cephalosporin: IV. In vivo

efficacy in various murine infection models. In: ICAAC, 2014. 1558

Completed


Ito A, Ota M, Nakamura R, Tsuji M, Sato T, Y Y. In vitro and in vivo activity of cefiderocol against

stenotrophomonas maltophilia clinical isolates. In: IDWeek, 2018.

Tsuji M, Hackel M, Echols R, Tillotson G, Fam D, Yamano Y, et al. In vitro and in vivo activity of cefiderocol

against burkholderia cepacia complex clinical isolates. In: ECCMID, 2019.

Human

Thigh Ghazi IM, Monogue ML, Tsuji M, Nicolau DP. Humanized exposures of cefiderocol, a siderophore

cephalosporin, display sustained in vivo activity against siderophore-resistant pseudomonas aeruginosa.

Pharmacology. 2018;101(5-6):278-84.

Completed

Lung Shionogi. Cefiderocol Concentrations in the Lungs of Hospitalized Patients With Bacterial Pneumonia. Identifier:

NCT03862040. In: ClinicalTrials.gov [internet]. Bethesda: US National Library of Medicine: 2019. Available from

https://ClinicalTrials.gov/show/NCT03862040.

Terminated due to

slow enrolment on

November 26,

2019

Kidney Contreras DA, Fitzwater SP, Nanayakkara DD, Schaenman J, Aldrovandi GM, Garner OB, et al. Co-infections

of two strains of NDM-1 and OXA-232 co-producing klebsiella pneumoniae in a kidney transplant patient.

Antimicrob Agents Chemother. 2019;16:1-12.

Echols R, Katsube T, F A, C J, Krenz H. S-649266, a siderophore cephalosporin for Gram-negative bacterial

infection: pharmacokinetics and safety in subjects with renal impairment. In: ESCMID, Denmark; 2015.

Katsube T, Echols R, Arjona Ferreira JC, Krenz HK, Berg JK, Galloway C. Cefiderocol, a siderophore

cephalosporin for gram-negative bacterial infections: pharmacokinetics and safety in subjects with renal

impairment. J Clin Pharmacol. 2017;57(5):584-91.


Katsube T, Kawaguchi N, Echols R, Wajima T. Population pharmacokinetic and

pharmacokinetic/pharmacodynamic analyses of cefiderocol in subjects without infection and patients with

complicated urinary tract infection and acute uncomplicated pyelonephritis. In: IDWeek, 2017.

Katsube T, Miyazaki S, Narukawa Y, Hernandez-Illas M, Wajima T. Drug-drug interaction of cefiderocol, a

siderophore cephalosporin, via human drug transporters. Eur J Clin Pharmacol. 2018;74(7):931-38.

Clinical Studies

Early Katsube T, Saisho Y, Shimada J, Furuie H. Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore

cephalosporin, in healthy adult subjects. J Antimicrob Chemother. 2019;74(7):1971-74.

Miyazaki S, Katsube T, Shen H, Tomek C, Narukawa Y. Metabolism, excretion, and pharmacokinetics of [14 C]-

cefiderocol (S-649266), a siderophore cephalosporin, in healthy subjects following intravenous administration.

J Clin Pharmacol. 2019;59(7):958-67.

Saisho Y, Katsube T, White S, Fukase H, Shimada J. Pharmacokinetics, safety, and tolerability of cefiderocol,

a novel siderophore cephalosporin for gram-negative bacteria, in healthy subjects. Antimicrob Agents

Chemother. 2018;62(3):1-12.

Sanabria C, Migoya E, Mason JW, Stanworth SH, Katsube T, Machida M, et al. Effect of cefiderocol, a

siderophore cephalosporin, on QT/QTc interval in healthy adult subjects. Clin Ther. 2019;41(9):1724-36.e4.

Shimada J, Saisho Y, Katsube T, White S, Fukase H. S-649266, a novel cephalosporin for gram negative

bacterial infection: pharmacokinetics (PK), safety and tolerability in healthy subjects. In: ICAAC, 2014 2014. F-

1564

Completed


Shiro M, Katsube T, Narukawa Y, E M. Metabolism and excretion of [14C]-cefiderocol, a siderophore

cephalosporin, and drug-drug interaction potential via transporters of cefiderocol in healthy subjects. In:

ECCMID, 2018.

Kawaguchi N, Katsube T, Echols R, Wajima T. Population pharmacokinetic analysis of cefiderocol, a parenteral

siderophore cephalosporin, in healthy subjects, subjects with various degrees of renal function, and patients

with complicated urinary tract infection or acute uncomplicated pyelonephritis. Antimicrob Agents Chemother.

2018;62(2):1-11.

RCT

Results

Blind Bass A, Echols R, Portsmouth S, A H. Heterogeneity of recent phase 3 cUTI clinical trials with new antibacterials.

In: IDWeek 2018.

Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JCA, Ariyasu M, et al. Cefiderocol versus

imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative

uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319-

28.

Portsmouth S, van Veenhuyzen D, Echols R, Mitsuaki M, Camilo Arjona Ferreira J, Ariyasu M, et al. Cefiderocol

compared with imipenem/cirastatin in the treatment of adults with complicated urinary tract infections with or

without pyelonephritis or acute uncomplicated pyelonephritis: results from a multicenter, double-blind,

randomized study. In: ECCMID, 2017.

Portsmouth S, Van Veenhuyzen V, Echols R, Machida M, Arjona Ferreira JC, Ariyasu M, et al. Clinical response

of cefiderocol compared with imipenem/cilastatin in the treatment of adults with complicated urinary tract

Completed


infections with or without pyelonephritis or acute uncomplicated pyelonephritis: results from a multicenter, double

blind, randomized study (APEKS-cUTI). In: IDWeek, 2017.

Shionogi. A randomized study in hospitalised patients with complicated urinary tract infections caused by gram-

negative bacteria to compare the efficacy and safety of S-649266 to imipenem/cilastin, both administered by

intravenous infusion. Identifier: EUCTR2014-000914-76-HU. In: London [internet]. European Medicines

Agency: 2014. Available from http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-000914-76-HU.

Shionogi. A Study of Efficacy/Safety of Intravenous S-649266 Versus Imipenem/Cilastatin in Complicated

Urinary Tract Infections. Identifier: NCT02321800. In: ClinicalTrials.gov [internet]. Bethesda: US National

Library of Medicine: 2014. Available from https://ClinicalTrials.gov/show/NCT02321800.

Matsunaga Y, Echols R, Katsube T, Yamano Y, Ariyasu M, Nagata T. Cefiderocol (S-649266) for nosocomial

pneumonia caused by gram-negative pathogens: study design of apeks-NP, a phase 3 double-blind parallel-

group randomized clinical trial. Am J Respir Crit Care Med. 2018;197

Shionogi. Clinical Study of S-649266 for the Treatment of Nosocomial Pneumonia Caused by Gram-negative

Pathogens. Identifier: NCT03032380. In: ClinicalTrials.gov [internet]. Bethesda: US National Library of

Medicine: 2017. Available from https://ClinicalTrials.gov/show/NCT03032380.

Open-label Shionogi. Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by

Carbapenem-resistant Gram-negative Pathogens. Identifier: NCT02714595. In: ClinicalTrials.gov [internet].

Bethesda: US National Library of Medicine: 2016. Available from https://ClinicalTrials.gov/show/NCT02714595.

Shionogi. RCT Cefiderocol vs BAT for Treatment of Gram Negative BSI. Identifier: NCT03869437. In:

ClinicalTrials.gov [internet]. Bethesda: US National Library of Medicine: 2019. Available from

https://ClinicalTrials.gov/show/NCT03869437.

Completed

Recruiting


Compassionate

Use

Edgeworth JD, Merante D, Patel S, Young C, Jones P, Vithlani S, et al. Compassionate use of cefiderocol as

adjunctive treatment of native aortic valve endocarditis due to extremely drug-resistant pseudomonas

aeruginosa. Clin Infect Dis. 2019;68(11):1932-34.

Stevens RW, Clancy M. Compassionate use of cefiderocol in the treatment of an intraabdominal infection due

to multidrug resistant pseudomonas aeruginosa: a case report. Pharmacotherapy. 2019;24:1-14.

Trecarichi EM, Quirino A, Scaglione V, Longhini F, Garofalo E, Bruni A, et al. Successful treatment with

cefiderocol for compassionate use in a critically ill patient with XDR acinetobacter baumannii and KPC-producing

klebsiella pneumoniae: a case report. J Antimicrob Chemother. 2019;01:3399–401.

Ongoing program.

200 patients

treated to date.

Three case reports

published.

Expanded Access Shionogi. Expanded Access to Cefiderocol for the Intravenous Treatment of Severe Gram Negative Bacterial

Infections. Identifier: NCT03780140. In: ClinicalTrials.gov [internet]. Bethesda: US National Library of Medicine:

2018. Available from https://ClinicalTrials.gov/show/NCT03780140.

Ongoing

Modelling/SLR protocol

Katsube T, Tenero D, Wajima T, T I. S-649266 modeling and simulation for prediction of efficacy and dose

optimization. In: IDWeek, Philadelphia; 2014.

Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, Echols R. Pharmacokinetic/pharmacodynamic modeling

and simulation of cefiderocol, a parenteral siderophore cephalosporin, for dose adjustment based on renal

function. Antimicrob Agents Chemother. 2017;61(1):1-12.

Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, R E. S-649266 dose adjustment for patients with impaired

renal function. In: ECCMID, 2015.

Completed


Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, R. E. Dose adjustment of S-649266, a siderophore

cephalosporin, for patients requiring haemodialysis. . In: ECCMID, 2016.

McCullough A, Scott AM, Macindoe C, Clark J, Hansen MP, Beller EM, et al. Adverse events in patients taking

cephalosporins versus placebo for any indication. Cochrane Database Syst Rev. 2016(11)

IDweek 2019 Jason M. Pogue, Hemanth Kanakamedala, Yun Zhou, Bin Cai. Burden of Illness in Carbapenem-resistant

Acinetobacter baumannii Infections in US Hospitals (2014 to 2018)

Ryan K. Shields, Hemanth Kanakamedala, Yun Zhou, Bin Cai. Burden of Illness in Patients with Urinary Tract

Infections with or without Bacteremia Caused by Carbapenem-resistant Gram-negative Pathogens in US

Hospitals (2014 to 2018)

Thomas Lodise, Hemanth Kanakamedala, Wen-Chun Hsu, Bin Cai. Association between Days to Initiate

Appropriate Therapy and Hospital Length of Stay among Adult Hospitalized Patients with Gram-negative

Bloodstream Infections (GN-BSI)

Thomas Lodise, Hemanth Kanakamedala, Wei-Chun Hsu, Bin Cai. Analysis of Adult, Hospitalized Patients with

Carbapenem-resistant (CR) Gram-negative Bloodstream Infections (GN-BSIs) due to Lactose Fermenters (LFs)

and Non-Lactose Fermenters (NLFs): Is there a Difference in Outcomes?

Simon Portsmouth, Roger Echols, Mitsuaki Machida, Juan Camilo Arjona Ferreira, Mari Ariyasu, Tsutae Den

Nagata. Efficacy and Safety of Cefiderocol According to Renal Impairment in Patients with Complicated Urinary

Tract Infection (cUTI) in a Phase 2 Study

Simon Portsmouth, Kiichiro Toyoizumi, Tsutae Den Nagata, Glenn S. Tillotson, Roger Echols. Structured Patient

Interview in Complicated Urinary Tract Infections to Assess Clinical Outcomes versus Investigator’s Evaluation

in the APEKS-cUTI Study.


Takafumi Sato, Masakatsu Tsuji, Krystyna M. Kazmierczak, Meredith Hackel, Roger Echols, Yoshinori Yamano,

Daniel F Sahm. Cefiderocol Susceptibility Against Molecularly Characterized Carbapenemase-Producing Gram-

negative Bacteria in North America and Europe between 2014 and 2017: SIDERO-WT-2014 to -2016 Studies.

Sonia Rao, Sean Nguyen, Melinda Soriano, Jennifer Hayes, Meredith Hackel, Daniel Sahm, Glenn Tillotson,

Roger Echols, Masakatsu Tsuji, Yoshinori Yamano. In Vitro Antibacterial Activity of Cefiderocol against a Multi-

national Collection of Carbapenem-non-susceptible Gram-negative Bacteria from Respiratory Infections:

SIDERO-WT-2014–2017.

Chris Longshaw, Masakatsu Tsuji, Meredith Hackel, Daniel F. Sahm, Yoshinori Yamano. In Vitro Activity of

Cefiderocol (CFDC), a Novel Siderophore Cephalosporin, Against Difficult-to-Treat Resistant (DTR) Gram-

negative Bacterial Pathogens from the Multi-national Sentinel Surveillance Study, SIDERO-WT (2014–2017).

Yoshinori Yamano, Masakatsu Tsuji, Roger Echols. Synergistic Effect of Cefiderocol Combined with Other

Antibiotics Against Cefiderocol High MIC Isolates from the Multi-national SIDERO-WT Studies.

Takayuki Katsube, Roger Echols, Toshihiro Wajima. Prediction of Cefiderocol Pharmacokinetics and Probability

of Target Attainment in Pediatric Subjects for Proposing Dose Regimens.

Richard G. Wunderink (Presenting Author), Yuko Matsunaga, Mari Ariyasu, Roger Echols, Anju Menon, Tsutae

Den Nagata. Efficacy and Safety of Cefiderocol versus High-Dose Meropenem in Patients with Nosocomial

Pneumonia – Results of a Phase 3 Randomized, Multicenter, Double-Blind, Non-Inferiority Study. (Late-

breaking abstract).

*Include references to all linked documents and indicate the expected date of publication for any unpublished clinical studies

**Include expected date of completion


5.3 Main characteristics of studies

For a rigorous comprehension of the evidence package, it is fundamental to understand the

challenges associated to the design of clinical trials to assess the efficacy of antibacterials.

The development of clinical trials can be challenging for a number of reasons [234, 235]:

Clinical trials for antimicrobials must be designed as non-inferior studies. The clinical

studies must focus on specific pathogens for which the tested agents and comparators are

effective; otherwise, they would be un-ethical.

For serious bacterial diseases, there is a need to urgently initiate early targeted antibacterial

drug therapy, which may obscure the effect of the antibacterial drug under study because

patients receive effective antibacterial therapy before enrolling in the trial.

Patients with serious acute bacterial diseases can be acutely ill (e.g., delirium in the setting

of acute infection) and obtaining informed consent and performing other trial enrolment

procedures in a timely fashion may be difficult.

There may be diagnostic uncertainty with respect to the aetiology of the patients’ underlying

disease, including identifying a bacterial aetiology.

There may be a need for concomitant antibacterial drug therapy with a spectrum of activity

that may overlap with the antibacterial drug being studied.

The recruitment of patients with infections due to specific pathogens and with limited

treatment options that would be required for inferential testing is challenging. MDR/CR

pathogens are still rare, and this rigorous selection strategy must be applied to include

patients with resistant pathogens. Otherwise large patient numbers and subgroup analyses

are required.

A comparison of efficacy against all relevant comparators can only be obtained from in vitro

surveillance studies. The evaluation of the effectiveness of an antibacterial is derived from

the combined consideration of in vitro, PK/PD and clinical data.

1. In Table 17, describe the main characteristics of the studies.

2. For each study provide a flow diagram of the numbers of patients moving through the

trial.

3. For each study provide a comparison of patients (including demographic, clinical and

social information [if applicable]) in treatment arms at baseline.

Cefiderocol studies are summarized with patient flow diagram and comparison of patients

after Table 17.


Table 17: Study characteristics

Study

reference/ID

Objective Study design Eligibility criteria Intervention and

Comparator

(N enrolled)

Primary outcome

measure and

follow-up time

point

Secondary

outcome

measures and

follow-up time

points

SIDERO-WT

analysis*

To calculate the

indices related to

the antibacterial

activity of

cefiderocol and the

ratio of susceptible

strains of

cefiderocol and

other reference

compounds based

on the breakpoint

criteria of Clinical

and Laboratory

Standards Institute

(CLSI) standards.

In vitro surveillance Study tested the in

vitro antibacterial

activity of cefiderocol

against Gram-negative

bacteria clinically

isolated from medical

institutions in the EU

and USA

Cefiderocol,

ceftazidime-

avibactam (CZA),

ceftolozane-

tazobactam (C/T),

colistin (CST),

cefepime (FEP),

meropenem

(MEM), and

ciprofloxacin (CIP)

(30,459 Gram-

negative isolates) +

To determine the

minimum inhibitory

concentration

(MIC) of

cefiderocol against

Gram-negative

bacteria clinically

isolated from

medical institutions

in the EU and USA

Annual analysis;

Cumulative

recurrent annual

analysis

Analysis in the

difficult to treat

pathogens

Analysis of MDR

3 and MDR 4

pathogens

SIDERO-CR-2014-

2016 study*

To test the in vitro

activity of

cefiderocol and

comparators

In vitro surveillance Study tested the in

vitro antibacterial


against CRE and MDR

Cefiderocol,

ceftazidime-

avibactam (CZA),

ceftolozane-

To determine the

minimum inhibitory

concentration

(MIC) of

Annual analysis;

Cumulative

recurrent annual

analysis


against a collection

of 1,873 clinical

isolates of Gram-

negative bacilli

provided by a

worldwide network

of laboratories (52

countries) in 2014-

2016, using current

CLSI broth

microdilution

methodology

non-fermenters

(defined as resistant to

carbapenems,

fluoroquinolones, and

aminoglycosides)

collected globally

tazobactam (C/T),

colistin (CST),

cefepime (FEP),

meropenem

(MEM), and

ciprofloxacin (CIP)

(1,873 MDR and

CarbNS isolates

Gram-negative

Bacilli) +

cefiderocol against

CRE and MDR

non-fermenters

(defined as

resistant to

carbapenems,

fluoroquinolones,

and

aminoglycosides)

collected globally

Analysis in the

difficult to treat

pathogens

Several

independent

national validations

studies*

To determine

cefiderocol activity

against difficult-to-

treat CR pathogens

gathered from

various countries

including Germany,

Greece, Italy,

Spain, UK/Ireland,

and the US

In vitro surveillance to investigate the in

vitro antimicrobial


and that of

commercially available

comparator

antibacterials against

a collection of

contemporary, clinical,

carbapenem-resistant

Gram-negative

bacteria from

Cefiderocol,

ceftazidime-

avibactam (CZA),

ceftolozane-

tazobactam (C/T),

colistin (CST),

cefepime (FEP),

meropenem

(MEM), and

ciprofloxacin (CIP),

tigecycline

To determine

MIC50 and MIC90

of the

antibacterials for

the tested bacterial

isolates and their

respective

resistance

percentages


inpatients from various

hospitals

Independent world-

wide collection*

To determine

cefiderocol activity

against difficult-to-

treat CR pathogens

gathered from a

worldwide

collection

In vitro To evaluate

antimicrobial activity of

cefiderocol and other

Gram-negative

antibiotics (aztreonam,

amikacin, cefepime,

ceftazidime,

ceftazidime–

avibactam,

ceftolozane–

tazobactam,

ciprofloxacin,

meropenem, colistin,

and tigecycline)

against a panel of

multidrug-resistant

bacterial isolates from

human clinical sources

with characterized

antibacterial

resistance

mechanisms.

Cefiderocol,

aztreonam,

amikacin,

cefepime,

ceftazidime,

ceftazidime–

avibactam,

ceftolozane–

tazobactam,

ciprofloxacin,

meropenem,

colistin, and

tigecycline

To determine

MIC50 and MIC90

of the

antibacterials for


isolates and their

respective

resistance

percentages


Identify

mechanisms of

resistance studies*

To investigate

features of

cefiderocol, namely

antibacterial

activity against

AmpC

overproducers,

stability against

AmpC b-

lactamases and

propensity for

AmpC induction

using

Pseudomonas

aeruginosa and

Enterobacter

cloacae.

In vitro resistance

and mechanism of

action studies

To reveal cefiderocol

features relating to

antibacterial activity

against AmpC

overproducers,

stability against AmpC

b-lactamases, and

propensity for AmpC

induction for E.

cloacae and P.

aeruginosa.

Cefiderocol,

ceftazidime-

avibactam (CZA),

ceftolozane-

tazobactam (C/T),

colistin (CST),

cefepime (FEP),

meropenem

(MEM), and

ciprofloxacin (CIP),

tigecycline

To determine

MIC50 and MIC90

of the

antibacterials for


isolates and their

respective

resistance

percentages

Single ascending

dose

(SAD)/multiple

dose (MAD) study

(1203R2111)

To evaluate the

safety, tolerability

and PK of

cefiderocol in 70

healthy Japanese

and Caucasian

adult subjects

Randomized,

double-blind,

placebo controlled,

ascending single

and multiple dose

study

Healthy adult subjects 70 subjects split

into two study

parts

Evaluate the

safety, tolerability,

and PK


The renal

impairment study

(1222R2113)

Evaluate the

influence of renal

impairment and

hemo-dialysis on

PK

A multi-centre,

open-label, non-

randomized study

Healthy adult

subjects and

subjects with various

degrees of renal

impairment

38 subjects

enrolled in 5

cohorts

Evaluate the

influence of renal

impairment and

hemo-dialysis

onPK

APEKS-cUTI To compare the

composite outcome

efficacy and safety

of cefiderocol with

IPM/CS in a subject

population cUTI by

MDR Gram-

negative

pathogens, with or

without

pyelonephritis or

acute

uncomplicated

pyelonephritis at

the Test of Cure

(TOC, defined as 7

days following the

End of Treatment

(EOT).

International, multi

centre,

randomised,

double-blind,

Phase II, active-

controlled, parallel-

group, non-

inferiority

Adults (≥18 years) who

had a symptomatic

cUTI, defined as a

clinical syndrome

characterized by

pyuria and a

documented or

suspected microbial

pathogen on culture of

urine or blood,

accompanied by local

and systemic signs

and symptoms,

including fever (i.e.,

temperature ≥ 38ºC),

chills, malaise, flank

pain, back pain, and /

or costovertebral angle

pain or tenderness that

(in the case of cUTI

Cefiderocol

compared to

imipenem/cilastatin

(N=452

randomised 2:1 for

cefiderocol)

The primary

efficacy endpoint

was the composite

of clinical response

and

microbiological

response at the

test of cure (TOC)

assessment in

MITT population,

defined as 7 days

(±2 days) after the

end of antibacterial

treatment.

Secondary

endpoints were

safety, clinical and

microbiological

response at early

assessment, end of

treatment, and

follow-up,

microbiological and

clinical response

per-pathogen and

per-patient at early

assessment, end of

treatment, test of

cure, and follow-up.


with or without

pyelonephritis)

occurred in the

presence of a

functional or

anatomical

abnormality of the

urinary tract or in the

presence of

catheterization and

who required

hospitalization for the

IV treatment of cUTIs

were enrolled in the

study.

Number of patients

with acute

uncomplicated

pyelonephritis was

restricted

APEKS-NP To compare all-

cause mortality at

Day 14 of

cefiderocol with

high-dose,

prolonged infusion

Phase 3,

multicentre

(multinational),

double-blind,

parallel-group,

randomized,

Adults (≥18 years) who

have a documented

nosocomial

pneumonia

(HABP/VABP/HCABP)

caused by an aerobic

Cefiderocol plus

linezolid,

compared to high

dose, prolonged

infusion

meropenem (plus

The primary

endpoint was all-

cause mortality at

Day 14

Secondary

endpoints included

safety, clinical and

microbiological

outcomes at the

test of cure (TOC),


meropenem, in

adults with

hospital-acquired

bacterial

pneumonia (HAP),

ventilator-

associated

bacterial

pneumonia (VAP),

or healthcare-

associated

bacterial

pneumonia (HCAP)

caused by Gram-

negative

pathogens

active-controlled

study

Gram-negative

pathogen only, or in

combination with an

aerobic Gram-positive

or anaerobic

pathogen, and who

require hospitalization

for the parenteral

(intravenous)

treatment of the

infection may be

enrolled in the study

linezolid for at least

5 days, and up to

21 days)

(N=300,

randomised 1:1)

clinical and

microbiological

outcomes at early

assessment, end of

treatment, and

follow-up, all-cause

mortality at day 28,

during treatment,

and at follow-up,

and resource

utilization.

CREDIBLE-CR The primary

objective of

CREDIBLE CR

study was to

assess at TOC, the

clinical outcome of

treatment with

cefiderocol and

BAT in adult

Phase 3,

descriptive, multi

centre, open label,

parallel group,

randomized study

Adult patients (≥18

years) with gram-

negative pathogen

infection, with

evidence of

carbapenem

resistance prior to

randomisation

Cefiderocol

compared with

best available

therapy (BAT)

(N=152,

randomised 2:1 to

cefiderocol); BAT

was chosen by the

investigator before

The primary

endpoints were:

Clinical cure per

patient at TOC in

patients with

HAP/VAP/HCAP

or BSI/sepsis

Microbiologic

Secondary

endpoints included:

Clinical outcome

per

patient/pathogen at

EOT, and TOC

(cUTI)Microbiologic

outcome (for Gram-

negative pathogen)


patient’s hospital

acquired

pneumonia

(HAP)/ventilator

associated

pneumonia

(VAP)/healthcare-

associated

pneumonia (HCAP)

or bloodstream

infections/sepsis

(BSI/sepsis)

caused by

carbapenem-

resistant Gram-

negative

pathogens. Only

descriptive

statistics were

performed.

randomization and

could include up to

3 different

medicines;

cefiderocol could

be added 1 other

molecule

eradication per

patient at TOC in

patients with cUTI

per

patient/pathogen at

EOT, TOC, and

FUP (HAP / VAP /

HCAP or

BSI/sepsis)

Safety

Compassionate

use studies

Expanded Access

to Cefiderocol for

the Intravenous

Treatment of

Severe Gram-

Cefiderocol has

been provided

upon request from

attending

physicians to

patients with

The criteria for fulfilling

these requests are

highly restrictive

including that all other

available treatments

must be ruled out

Over 200 patients

have been treated

with cefiderocol

through this

programme

Clinical cure per

patient


negative Bacterial

Infections

serious CR Gram-

negative infections

who have no other

treatment options

through susceptibility

testing and/or

evidence of treatment

failure in efficacy or

safety, and patients

must be unable to

enrol in clinical studies

of cefiderocol

*Detailed comparisons of patients and patient flow diagrams are not available for in vitro studies

+Ongoing studies, to date (January 2020), 38288 samples have been tested in SIDERO-WT program.


5.3.1 APEKS-cUTI STUDY

A Multicenter, Double-blind, Randomized, Clinical Study to Assess the Efficacy and Safety of

Intravenous S-649266 (Cefiderocol) in Complicated Urinary Tract Infections With or Without

Pyelonephritis or Acute Uncomplicated Pyelonephritis Caused by Gram-Negative Pathogens

in Hospitalized Adults in Comparison With Intravenous Imipenem/Cilastatin.

APEKS-cUTI was an international, multicenter, randomised, double-blind, Phase II, active-

controlled, parallel-group, non-inferiority study to investigate the efficacy and safety of

intravenous cefiderocol vs imipenem/cilastatin (IPM/CS) in cUTI with or without pyelonephritis

or acute uncomplicated pyelonephritis (restricted to ≤ 30%) caused by Gram-negative

pathogens in hospitalized adults with MDR infections (Figure 22). 448 patients were

randomized, of whom 300 received cefiderocol and 148 received IPM/CS (Figure 23). The

primary efficacy endpoint was the composite of clinical response and microbiological response

at TOC assessment in MITT population according to FDA guidance document. Secondary

endpoints were safety, clinical and microbiological response at EA, EOT and FU,

microbiological and clinical response per-pathogen and per-patient at EA, EOT, TOC and FU.

Safety was assessed daily while the subject was hospitalized and specifically at EOT, TOC,

and FU.

Figure 22: APEKS-cUTI study design


Figure 23: Subject disposition (all randomized subjects)

Overall, 495 patients were screened for inclusion. One subject withdrew during screening and

8.5% (42/495) of subjects were screen failures (mostly for lack of symptoms and signs

confirming eligibility). The flow diagram of the numbers of patients moving through the trial is

provided in Figure 23.

Of the 452 subjects randomized, 448 subjects were treated and 421 subjects completed the

study: 93.4% (283/303) of subjects in the cefiderocol group and 92.6% (138/149) of subjects

in the IPM/CS group. The most frequent reasons in the total population for discontinuing from

the study were “lost to follow up” (3.1% [14/452]) and “withdrawal by subject” (1.3% [6/452]).

By treatment group, 3.3% (10/303) of subjects in the cefiderocol group and 2.7% (4/149) of

subjects in the IPM/CS group were “lost to follow up,” and 1.0% (3/303) of subjects in the


cefiderocol group and 2.0% (3/149) of subjects in the IPM/CS group did not complete the study

due to “withdrawal by subject.”

Completion of treatment was defined as achieving 5 or more days of study treatment. The

most frequent reasons for subjects not completing treatment (2.4% [11/452] in the total

population) were withdrawal by subject (0.7% [2/303] of subjects in the cefiderocol group and

1.3% [2/149] of subjects in the IPM/CS group) and “other” (1.0% [3/303] of subjects in the

cefiderocol group and 0.7% [1/149] of subjects in the IPM/CS group).

5.3.1.1 Demographics and baseline characteristics

The demographics and baseline characteristics are provided in the overview Table 18 below.

The mean age of the Micro-ITT Population was 62.0 years (range 18 to 93 years), and 55.0%

(204/371) of subjects were ≥ 65 years. For clinical diagnosis at baseline, 25.3% (94/371) of

subjects had cUTI with pyelonephritis, 47.7% (177/371) of subjects had cUTI without

pyelonephritis, and 27.0% (100/371) of subjects had acute uncomplicated pyelonephritis.

Complicated urinary tract infection was complicated most commonly by obstructive uropathy

(33.2% [123/371] of subjects). For the severity of disease, 18.9% (70/371) of subjects had

severe disease as judged by the investigator, and 71.2% (264/371) of subjects had moderate

disease. The remaining subjects had mild disease. A greater proportion of subjects in the

cefiderocol group (19.8% [50/252]) had severe disease compared with subjects in the IPM/CS

group (16.8% [20/119]). This may be due to a greater proportion of subjects in the cefiderocol

group with a diagnosis of cUTI compared with the IPM/CS group that had more acute

uncomplicated pyelonephritis.

Prior infection history was reported for 40.4% (150/371) of subjects, and the most frequently

reported prior infection was cUTI (29.9% [111/371] of subjects). Prior antimicrobial medication

treatments were reported for 9.4% (35/371) of subjects, and most received treatment for UTI

(7.5% [28/371] of subjects).

Baseline subject characteristics for the Micro-ITT Population were broadly similar to the ME

Population, ITT Population, and Safety Population.


Table 18: Patient demographics and baseline characteristics (mITT population)


Patient baseline characteristics were generally well balanced between the 2 treatment arms

(Table 18) and were consistent with more complicated infections whereby 7% of patients had

BSI [51, 236]. The main pathogen reported at the baseline in the microbiologically evaluable

population was E. coli (Figure 24) [51, 236]. The cefiderocol-treated group had 53% cefepime-

and levofloxacin-resistant K. pneumoniae strains and 17% cefepime-resistant and 38%

levofloxacin-resistant E. coli strains; which were similar in the IPM/CS group [51, 236].


Figure 24: Distribution of uropathogens (mITT population)

MITT, modified intent-to-treat. Source: Portsmouth, 2018 [51]; Data on file [236]

The most frequently reported Gram-negative uropathogens isolated at baseline for both cUTI

with or without pyelonephritis or acute uncomplicated pyelonephritis in the Micro-ITT

Population were E. coli (60.3% [152/252] of subjects in the cefiderocol group and 66.4%

[79/119] of subjects in the IPM/CS group) and K. pneumoniae (19.0% [48/252] of subjects in

the cefiderocol group and 21.0% [25/119] of subjects in the IPM/CS group) (Figure 24). In

subjects diagnosed with cUTI with or without pyelonephritis, E. coli was isolated in 51.3%

(96/187) of subjects in the cefiderocol group and 60.7% (51/84) of subjects in the IPM/CS

group, and K. pneumoniae was isolated in 22.5% (42/187) of subjects in the cefiderocol group

and 23.8% (20/84) of subjects in the IPM/CS group. In subjects diagnosed with acute

uncomplicated pyelonephritis, E. coli was isolated in 86.2% (56/65) of subjects in the

cefiderocol group and 80.0% (28/35) of subjects in the IPM/CS group, and K. pneumoniae

was isolated in 9.2% (6/65) of subjects in the cefiderocol group and 14.3% (5/35) of subjects

in the IPM/CS group.

Gram-negative uropathogens isolated at baseline for the ME Population were similar to the

Micro-ITT Population in subjects diagnosed with cUTI with or without pyelonephritis or acute

uncomplicated pyelonephritis for both E. coli and K. pneumoniae and in both treatment groups.

A similar distribution was noted in the ME Population. E. coli was the most frequently identified

Gram-negative pathogen isolated from the blood culture for the Micro-ITT Population: 14/252

(5.6%) subjects in the cefiderocol group and 7/119 subjects (5.9%) in the IPM/CS group.

For E. coli, the most frequent uropathogen, MIC distribution for cefiderocol in both treatment

groups was similar and all strains were susceptible to IPM. For K. pneumoniae at baseline, a

lower percentage (86.7% [39/45]) of isolates were susceptible to IPM in the cefiderocol group


compared with the IPM/CS group (95.7% [22/23] of isolates). A greater percentage of K.

pneumoniae isolates were susceptible to cefepime (44.4% [20/45] in the cefiderocol group

compared with 34.8% [8/23] in the IPM/CS group). E. coli and K. pneumoniae rates of

resistance to levofloxacin were similar between treatment groups. For the MIC of other Gram-

negative baseline uropathogens, the numbers of subjects with isolates were too small to make

a meaningful comparison between treatment groups.

The summary of MIC of baseline Gram-negative pathogens isolated from the blood culture

that were the same as the uropathogen at baseline in ME Population is consistent with the

findings in the Micro-ITT Population [237].

5.3.2 APEKS-NP STUDY

A Multicenter, Randomized, Double-blind, Parallel-group, Clinical Study of S-649266

(Cefiderocol) Compared With Meropenem for the Treatment of Hospital-acquired Bacterial

Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated Bacterial

Pneumonia Caused by Gram-negative Pathogens.

The APEKS-NP study was a Phase 3, multicenter, randomized, double-blind, parallel-group,

active-controlled study to assess the efficacy and safety of cefiderocol vs high dose prolonged

infusion (HD) meropenem in subjects with nosocomial pneumonia caused by Gram-negative

bacteria. Subjects meeting eligibility criteria and assessed by the investigator as requiring 7 to

14 days of intravenous (IV) treatment in the hospital were randomized (1:1) to either

cefiderocol, 2 g, administered IV over 3 hours every 8 hours (q8h) or meropenem, 2 g,

administered IV over 3 hours, q8h. The dose of meropenem was increased from the labelled

dose of 1 g to 2 g and extended to a 3-hour infusion to optimize the exposure to meropenem

thereby the antibacterial activity of meropenem in this MDR pathogens, at risk of carbapenem

resistance. Dose adjustment based on renal function was required for cefiderocol and

comparator. Linezolid was administered for at least 5 days to subjects in both arms to provide

coverage for methicillin-resistant Staphylococcus aureus (MRSA), maintain the study blind

and, in the cefiderocol arm, provide coverage for Gram-positive bacteria. The recommended

duration of treatment with IV study drugs was 7 to 14 days in the hospital, but treatment could

have been extended up to 21 days based on the investigator’s clinical assessment of the

subject.


Figure 25: APEKS-NP study design and patient flow

EA, early assessment; EOS, end of study; EOT, end of treatment; PE, Primary Endpoint; FUP, follow up; HD, high dose; Q8h,

every 8 hours; TOC, test of cure

A total of 300 subjects (150 in the cefiderocol group and 150 in the HD meropenem group)

were randomized 1 to 1 to cefiderocol or HD meropenem. All randomized subjects who

received at least 1 dose of study treatment were included in the Intent-to-treat (ITT)/Safety

population (298 subjects: 148 in the cefiderocol group and 150 in the HD meropenem group).

The primary efficacy population was the mITT population (145 in the cefiderocol group and

147 in the HD meropenem group), which included all ITT subjects with evidence of a Gram-

negative infection of the lower respiratory tract and those who had evidence of a lower

respiratory tract infection but whose culture or other diagnostic tests did provide a

microbiological diagnosis; subjects with Gram-positive only infections were excluded. Figure

26 below provides an overview of the patient flow.


Figure 26: Patient demographics and baseline characteristics

5.3.2.1 DEMOGRAPHICS AND BASELINE CHARACTERISTICS

Demographic characteristics of gender, age, race, and region in the ITT population were

generally similar between the treatment groups (Table 19).[238] Most subjects were male

(68.2% in the cefiderocol group and 69.3% in the HD meropenem group) and white (68.9% in

the cefiderocol group and 66.7% in the HD meropenem group). The mean age was 64.7 years

in the cefiderocol group and 65.6 years in the HD meropenem group; 27.0% of subjects in the

cefiderocol group and 31.3% in the HD meropenem group were ≥ 75 years of age. Most

subjects were enrolled from Europe (66.9% in the cefiderocol group and 66.7% in the HD

meropenem group); 29.1% of subjects in the cefiderocol group and 29.3% in the HD

meropenem group were enrolled from the Asia-Pacific region.

Baseline characteristics of clinical diagnosis, ventilation status, baseline pathogens, and blood

culture status in the ITT population were also similar between the treatment groups. The

percentage of subjects with VABP was 40.5% in the cefiderocol group and 43.3% in the HD

meropenem group; the percentage with HABP was 40.5% in the cefiderocol group and 40.7%

in the HD meropenem group, and the percentage with HCABP was 18.9% in the cefiderocol

group and 16.0% in the HD meropenem group. Subjects on ventilation at baseline represented

61.5% of the cefiderocol group and 58.0% of the HD meropenem group.


Table 19: Patient demographics and baseline characteristics (mITT population)

ITT Population Cefiderocol (N=148)

HD meropenem (N=150)

Gender (Male), n (%) 101 (68.2) 104 (69.3)

Age, mean 64.7 65.6

Race (White), n (%) 102 (68.9) 100 (66.7)

Clinical diagnosis at baseline, n (%)

VABP 60 (40.5) 65 (43.3)

HABP 60 (40.5) 61 (40.7)

HCABP 28 (18.9) 24 (16)

Ventilation status at randomisation, n (%)

Ventilated 91 (61.5) 87 (58)

Non-ventilated 57 (38.5) 63 (42)

APACHE II, n (%)

≤ 15 75 (50.7) 78 (52)

16-19 32 (21.6) 26 (17.3)

≥ 20 41 (27.7) 46 (30.7)

Renal function, n (%)

Mild renal impairment (50-80 ml/min)

44 (29.7) 37 (24.7)

Moderate renal impairment (30-50 ml/min)

29 (19.6) 32 (21.3)

Severe renal impairment (<30 ml/min)

20 (13.5) 20 (13.3)

APACHE, Acute Physiology, Age, Chronic Health Evaluation; HD, high dose; Source: Data on file [239]

Most subjects in both treatment groups had only Gram-negative pathogens at baseline (76.4%

in the cefiderocol group and 70.0% in the HD meropenem group). The most frequently

occurring Gram-negative pathogen in both treatment groups at baseline was Klebsiella

pneumoniae (32.4% in the cefiderocol group and 29.3% in the HD meropenem group),

followed by Pseudomonas aeruginosa (16.2% and 16.0% in the cefiderocol and HD

meropenem groups, respectively) and Acinetobacter baumannii (15.5% and 16.0% in the

cefiderocol and HD meropenem group, respectively), as shown in Table 20. Blood cultures

positive for Gram-negative pathogens were observed in 5.4% of subjects in the cefiderocol

group and 6.7% of the HD meropenem group. The mean APACHE II score was 16.1 in the

cefiderocol group and 16.3 in the HD meropenem group.

Table 20: Top 5 baseline Gram-negative pathogens, n (%)

ITT Population Cefiderocol (N=148)

HD meropenem (N=150)

Klebsiella pneumoniae 48 (32.4) 44 (29.3)

Pseudomonas aeruginosa 24 (16.2) 24 (16)

Acinetobacter baumannii 23 (15.5) 24 (16)

Escherichia coli 19 (12.8) 22 (14.7)

Enterobacter cloacae 7 (4.7) 8 (5.3)

Source: Data on file [239]


5.3.3 CREDIBLE-CR STUDY

A Descriptive, Open-label, Multicenter, Randomized, Clinical Study of cefiderocol or Best

Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant

Gram-negative Pathogens

The small, descriptive CREDIBLE-CR study is a pathogen-focused randomised clinical trial

that investigated the efficacy and safety of cefiderocol versus an individualized best available

therapy (BAT) in 150 seriously ill patients with confirmed carbapenem-resistant (CR) Gram-

negative infections, independent of the host’s infection site (HCAP/HAP/VAP, cUTI,

BSI/sepsis are included). The objective of the study was to provide descriptive evidence of the

efficacy and safety of cefiderocol for the target population of patients with CR infections,

including the non-fermenters. The study was conducted in patients with evidence of CR Gram-

negative infections at 100 sites in 17 countries covering 4 regions: Asia-Pacific, Europe, North

America, and South America.

This study was not designed or powered to conduct hypothesis but to start gaining experience

in patients with CR infections, with life-threatening, or end-of-life conditions with a high risk of

mortality, often failing multiple lines of therapy (i.e. salvage therapy). No stratification for

pathogen or terminal disease was done and differences in baseline characteristics between

the two arms were observed. Study design and patient flow are presented in Figure 27:

CREDIBLE-CR study design and patient flow

The study key inclusion criteria were [240, 241]:

Patients who were diagnosed with HAP/VAP/HCAP, BSI or sepsis, or cUTI and

Documented or suspected CR Gram-negative infections [240, 241].

Key exclusion criteria were [240, 241]:

Effective antibacterial regimen for the current CR infection within 72 hrs prior to

randomization for a continuous duration of ≥24 hrs in cUTI, or ≥36 hrs in

HAP/VAP/HCAP or BSI/sepsis,

Moderate or severe hypersensitivity or allergic reaction to any beta-lactam antibacterial

Requirement of >3 systemic antibacterials for the treatment of the current infection if

randomised to the BAT arm

Infections: endocarditis, osteomyelitis, meningitis and co-infections with invasive mold

Conditions: cystic fibrosis/bronchiectasis, refractory septic shock or severe

neutropenia (<100 cells/μL blood)


Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score >

30Patients (n = 152) were randomised 2:1 to either cefiderocol, 2 g, administered IV over 3

hours every 8 hours (q8h) or BAT (

Figure 28) [240, 241]. Patients with cUTI received cefiderocol as monotherapy, whereas for

patients with HAP/VAP/HCAP or BSI/sepsis, physicians could choose to add one additional

antibacterial [240, 241]. Patients were stratified by primary clinical diagnosis

(HAP/VAP/HCAP, BSI/sepsis, cUTI), APACHE II score (≤15 or ≥16–≤30 at screening), and

region (North America, South America, Europe, Asia-Pacific) [240]. Of note, the stratification

did not account for pathogens at baseline or other severity indicators such as mechanical

ventilation status, shock, and location in the intensive care unit (ICU).

Best Available Therapy was chosen by the investigator before randomization, and could

include up to three antibacterials with Gram-negative coverage used in combination [240,

241]. Best Available Therapy was chosen by the investigator before randomization, and could

include up to three antibacterials with Gram-negative coverage used in combination [240,

241]. Due to the enrolment of patients with a broad range of CR Gram-negative bacteria and

infection types, BAT was considered to be the appropriate comparator reflecting the variation

in the combination of treatments within the clinical practice [240, 241]. This was also in

accordance with the regulatory guidance by EMA [240].

Figure 27: CREDIBLE-CR study design and patient flow


Figure 28: Subjects disposition (all randomized subjects)

5.3.3.1 BASELINE CHARACTERISTICS

The population in the CREDIBLE-CR study was expected to be very heterogeneous as it was

a pathogen-focussed study which included subjects with many underlying conditions, different

infection sites and infections due to a variety of Gram-negative CR pathogens also including

non-fermenters (Acinetobacter spp. and Stenotrophomonas spp) [240, 242]. The study

included a substantial number of patients with life-threatening, or end-of-life conditions with a

high risk of mortality reflecting a compassionate use scenario. Baseline demographics were

generally balanced between the 2 treatment arms (Table 21) with some clinical exceptions

that can influence the results [242]. There was a higher proportion of patients of ≥ 65 years

old (63.4% vs 44.9%) and patients with moderate (22.8% vs 16.3%) and severe renal

impairment (19.8% vs 14.3%) in cefiderocol group than in BAT arm (Table 21) [242]. Due to

the heterogeneity of the population the treatment groups do not appear to be balanced for

baseline characteristics such as shock (which has a major impact on mortality) in the subgroup

of subjects with A. baumannii infections. Twenty-six out of 150 (17%) patients in CREDIBLE-

CR trial had polymicrobial infections at baseline, and all patients with 3-4 co-pathogens were

randomised to the cefiderocol arm (Table 21).


Table 21: Patient demographics and baseline characteristics (ITT population)

Parameter Cefiderocol n=101

BAT n=49

Sex, (%) Men (%) 65.3 71.4

Age, y Median 69.0 (19, 92) 62.0 (19, 92)

≥65 (%) 63.4 44.9

CrCl, mL/min Median (min, max) 59.2 (9.4, 539.6) 69.4 (4.6, 270.8)

CrCl renal grading group in mL/min, n (%)

<50 (Moderate and Severe) (%) 42.6 30.6

Clinical diagnosis at baseline, n (%)

HAP/VAP/HCAP (%) 44.6 44.9

BSI/sepsis (%) 29.7 34.7

cUTI (%) 25.7 20.4

APACHE II score Median (min, max) 15 (2, 29) 14 (2, 28)

SOFA Score Median (min, max) 4.0 (0, 17) 4.0 (0, 16)

Clinical Pulmonary Infection Score

Median (min, max) 5.0 (2, 9) 5.0 (0, 7)

BAT, best available therapy; BSI, bloodstream infection; cIAI, complicated intra-abdominal infection; cUTI, complicated urinary

tract infection; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; ITT, intent-to-treat;

VAP, ventilator-associated pneumonia. Source: Data on file [242]

5.3.3.2 Baseline Study Drug Regimen

In the cefiderocol group, 82.5% (66/80) of the subjects received monotherapy, while 28.9%

(11/38) of the subjects in the BAT group received monotherapy (Table 22). A colistin-based

regimen was given to 65.8% (25/38) of the subjects in the BAT group. Other than colistin

monotherapy (received by 6 subjects in the BAT group), 5 subjects in the BAT group received

other monotherapy (amikacin, ceftazidime/avibactam, doripenem, fosfomycin, and

gentamicin).

Colistin was a prohibited medication in the cefiderocol group; however, one patient received

cefiderocol and colistin. In the cefiderocol group only 1 additional drug for Gram-negative

pathogens could be added; however, one patient received cefiderocol, gentamicin, and

tigecycline. Overall there was a significant diversity of regimens in combination with colistin.


Table 22: Summary of study regimen for Gram-negative pathogen at day 1 and day 2 (CR-

mITT population)


5.3.3.3 Baseline Pathogens

The study was not considering pathogens as a stratification factor, therefore, there was an

imbalance on the baseline pathogens, where cefiderocol arm contained more patients with

multiple pathogens and more non-fermenters, particularly Stenotrophomonas spp. All

infections caused by S. maltophilia were randomised to the cefiderocol arm (Table 23) [242].

Table 23: Baseline Gram-negative pathogens, n (%)

Diagnosis Pathogen [a]

Cefiderocol (N = 86)

n (%)

BAT (N = 44)

n (%)

All Infection Sites Combined N' = 86 N' = 44

Acinetobacter baumannii 39 (45.3) 17 (38.6)

Klebsiella pneumoniae 34 (39.5) 16 (36.4)

Pseudomonas aeruginosa 17 (19.8) 12 (27.3)

Escherichia coli 6 (7.0) 3 (6.8)

Stenotrophomonas maltophilia 5 (5.8) 0

Acinetobacter nosocomialis 2 (2.3) 0

Enterobacter cloacae 2 (2.3) 0

Acinetobacter radioresistens 1 (1.2) 0

Chryseobacterium indologenes 1 (1.2) 0

Klebsiella oxytoca 1 (1.2) 0

Klebsiella variicola 1 (1.2) 1 (2.3)

Serratia marcescens 1 (1.2) 0

Enterobacter asburiae 0 1 (2.3)

Morganella morganii 0 1 (2.3) BAT, best available therapy; Micro-ITT, microbiological intent-to-treat

Source: Data on file

Of note, of the subjects with HAP/VAP/HCAP, 64.3% in the cefiderocol group and 47.6% in

the BAT group had A. baumannii at baseline (Attachment: R2131_CREDIBLE-CR Final Study

Summary) [243].

A comparison of the characteristics of APEKS-NP and CREDIBLE-CR and CREDIBLE-CR

with HAP/VAP/HCAP (ITT population) is on file [243]. An analysis of APEKS NP subgroup

with CR infection is presented in chapter 5.4.3.

5.3.4 Summary of compassionate use cases and published evidence

Cefiderocol has been provided upon request from attending physicians to patients with serious

CR Gram-negative infections who have no other treatment options [244]. The criteria for

fulfilling these requests are highly restrictive including that all other available treatments must

be ruled out through susceptibility testing and/or evidence of treatment failure in efficacy or

safety, and patients must be unable to enroll in clinical studies of cefiderocol [244]. Data for


74 patients completed cefiderocol therapy in compassionate use [244], and are presented

here.

5.3.4.1 Patient characteristics in the compassionate use program

The mean age of patients in the compassionate use program was 46.8 years which is lower

compared to other studies of cefiderocol, mainly due to the inclusion of children and infants in

the compassionate use program [245]. There were 9/74 patients who were < 18 years with

the youngest patients of 5 months old [245]. In addition to the infection sites included in the

clinical trials of cefiderocol, compassionate use program also included patients with bone

infections (18.9%) (Table 24) [245]. With regards to causal pathogens, non-fermenter species

accounted for almost all isolates, with the most common being P. aeruginosa (n = 30); A.

baumannii (n = 24), Achromobacter xylosoxidans (n = 10), Burkholderia cepacia complex (n

= 9), Enterobacterales (n = 9), and S. maltophilia (n = 3) (Table 24) [244]. Eight patients had

mixed infections with various MDR organisms [244]. All isolates were MDR with some being

pan-resistant to currently available classes of antimicrobial agents [244]. The median duration

of cefiderocol treatment was 21 days (range: 1-94 days) and patients received up to seven

concomitant therapies alongside cefiderocol including polymixins (43.2%), cephalosporins

(33.8%), carbapenems (23%), β-lactams (21.6%), sulphonamides (18.9%) and

aminoglycosides (14.9%) [245]. (details of compassionate use program are provided in

chapter 3.).

Patients in compassionate us program are only eligible if all other available treatments have

been ruled out through susceptibility testing and/or evidence of treatment failure in efficacy or

safety. TheTheThe severity of infections included in compassionate and based on the

pathogen distribution reminds of the infections from the patient populationThe severity of

infection included in CREDIBLE CR and is more severe than observed in APEKS trials.


Table 24: Patient demographics and baseline characteristics

Parameter Cefiderocol N=74

Gender (Male), n (%) 44 (59.5)

Age, mean 46.8

≥65 years, n (%) 19 (25.7)

Infection type at baseline, n (%)

BSI 21 (28.4)

Pneumonia and respiratory infection 25 (33.8)

Bone infection 14 (18.9)

Bacteraemia 4 (5.4)

Sepsis 3 (4.1)

cUTI 1 (1.4)

Other 6 (8.1)

Most common pathogen at diagnosis, n (%)

Pseudomonas aeruginosa 31 (41.9)

Acinetobacter baumannii 22 (29.7)

Burkholderia cenocepacia 10 (13.5)

Klebsiella pneumoniae 6 (8.1)

Escherichia coli 1 (1.4) BSI, bloodstream infection; cUTI, complicated urinary tract infection

Source: NDA briefing document[244]; Data on file [245]

5.3.4.2 Published case reports

Case reports for three patients from the expanded access program have been published so

far.

A patient was treated successfully for endocarditis due to extensively drug resistant (XDR)

Pseudomonas aeruginosa.(Edgeworth et al., 2019)[246]

A patient with multiple comorbidities and a complicated intra-abdominal infection (IAI) due to

MDR Pseudomonas aeruginosa was released from hospital care within six weeks of

completion of cefiderocol treatment. (Stevens et al., 2019)[247]

A patient with VAP and BSI caused by XDR Acinetobacter baumannii and carbapenemase-

producing Klebsiella pneumoniae had potentially serious organ failure from older anti-

infectives. Six weeks after cefiderocol administration, chest X-rays showed complete

resolution of infection (Trecarichi et al., 2019)[248]


Single and Multiple Dose Study

A single-center, randomised, double-blind, placebo-controlled, ascending single and multiple

dose study to evaluate the safety, tolerability and PK of cefiderocol in 70 healthy Japanese

and Caucasian adult subjects. In the single-dose cohort, single doses of 100 mg, 250 mg, 500

mg, 1 g, and 2 g over a 1-hour infusion were tested. A single dose of 4 g was planned but was

not initiated according to the study protocol dose escalation guidelines; a cohort would not

proceed if the predicted maximum plasma concentration (Cmax) exceeds a 10-fold lower

exposure than the rat no-observed-adverse-effect-level (C0 = 1660 μg/mL). In the multiple-

dose cohort, once daily doses of 1 and 2 g over a 1-hour infusion on Day 1 followed by q8h

doses of 1 and 2 g over a 1-hour infusion for 8 days on Days 2 to 9 and a once daily dose of

1 and 2 g over a 1-hour infusion on Day 10 were tested. The active drug and the placebo were

administered to 6 subjects and 2 subjects, respectively, in each single-dose group and 8

subjects and 2 subjects, respectively, in each multiple-dose group [249].

Renal Impairment Study

A multicenter, open-label, nonrandomised study to evaluate the PK, safety and tolerability of

cefiderocol in subjects with varying degrees of renal impairment and in subjects with normal

renal function. The PK of a single-dose 1 g of cefiderocol in subjects with mild, moderate, or

severe renal impairment, or end-stage renal disease (ESRD) requiring haemodialysis (HD)

was compared with that of healthy subjects with normal renal function who were

demographically matched with moderate renal impairment. A total of 38 subjects were enrolled

in 5 cohorts.

The clearance of cefiderocol with HD was determined based on plasma concentration data

both before and after HD. Renal function was classified at screening visit based on creatinine

clearance estimated by Cockcroft-Gault equation (CrCl) for subjects with normal renal function

(≥ 90 mL/min) and estimated glomerular filtration rate (eGFR) using the modification of diet in

renal disease (MDRD) equation for subjects with renal impairment (mild, 60 to < 90; moderate,

30 to < 60; severe, 15 to < 30 mL/min/1.73 m2). A single-dose of 1 g cefiderocol over a 1-hour

infusion was administered to subjects with normal renal function or mild, moderate or severe

renal impairment. Subjects with ESRD requiring HD were dosed approximately 1 to 2 hours

after completion of a HD session on Day 1, and 2 hours prior to start of HD following at least

a 72-hour washout period [249].


5.4 Individual study results (clinical outcomes)

1. Describe the relevant endpoints, including the definition of the endpoint, and method

of analysis (Table 73a - Table 80e).

2. Provide a summary of the study results for each relevant comparison and outcome.

Due to the need to consider in-vitro data in combination with PK/PD and supportive trial data

for an assessment of a novel antibacterial, such as cefiderocol, the data of the individual

studies cannot be summarized across trials. Each clinical study used its own comparator and

was conducted in different patient populations. For this reason, no overall results summary

table is shown here, and section 5.4 has been modified to account for the specific

circumstances.

The individual study results, including all requested stratifications by pathogen and time-point

during the scoping process, are discussed in sections 5.4.1 through 5.4.3 below; the standard

dossier section 5.4 has thus been split to accommodate all relevant results (in-vitro, PK/PD,

and clinical).

In addition, for the APEKs trials, a feasibility analysis for an NMA was conducted. This

feasibility analysis [227], showed that an NMA was feasible for APEKS-cUTI. Appendix F of

that document contains the summary tables of all relevant outcomes across the trials included

in the NMA.

5.4.1 Individual study results (in vitro surveillance outcomes)

In vitro activity of cefiderocol has been studied in large-scale multinational surveillance and

small independent national studies [250]. Large multinational surveillance studies include

SIDERO-WT studies initiated in North America and Europe and SIDERO-CR program

collecting CR isolates from Europe, North America, South America, and the Asia-Pacific region

(Table 25) [250]. In the section below, the results are reported for all global Gram-negative

isolates. Of note, the susceptibility to cefiderocol was assessed based on the CLSI

breakpoints. The EUCAST breakpoints are expected to be determined in February after the

Committee for Medicinal Products for Human Use (CHMP) opinion. Data for the US clinical

strains is reported in the appendix and data for European strains will be included after the

availability of EUCAST breakpoints [251].

In addition, several independent validation studies carried out to determine cefiderocol activity

have included collections of difficult-to-treat CR pathogens gathered from various countries


including Italy, Germany, Greece, Spain, UK/Ireland, Switzerland, and the US [250]. The list

of these studies is reported in section “Study categorisation.”

Table 25: SIDERO Surveillance studies

SIDERO-WT in vitro studies

Scope Systematic surveillance studies of cefiderocol in vitro activity compared to key

antibacterials against a total of 30,459 Gram-negative isolates collecting

isolates from three consecutive 12-month periods from 2014 to 2015

(SIDERO-WT-2014), from 2015 to 2016 (SIDERO-WT-2015), and from 2016

to 2017 (SIDERO-WT-2016) as well as cumulative.

Geographic

location

North America and Europe

Comparator

treatments

Ceftolozane/tazobactam, ceftazidime/avibactam, cefepime, ciprofloxacin,

polymyxin E (colistin), and meropenem

Included

pathogens

Carbapenem susceptible and carbapenem non-susceptible pathogens

(CarbNS): Enterobacteriaceae (including but not limited to Escherichia coli,

K. pneumoniae, Enterobacter spp., Citrobacter spp., Serratia spp.), non-

fermenters (including but not limited P. aeruginosa, A. baumannii, S.

maltophilia, B. cepacia), and Proteeae (M. morgannii, P. vulgaris, P.

mirabilis).

SIDERO-CR

Scope In vitro study from 2014 – 2016 evaluating the activity of cefiderocol against

a total of 1,873 MDR and CarbNS isolates Gram-negative Bacilli.

Geographic

location

World-wide (Europe, North America, Latin America, Asia, South Pacific,

Africa, and the Middle East)

Comparator

treatments

Ceftolozane/tazobactam, ceftazidime/avibactam, cefepime, ciprofloxacin,

polymyxin E (colistin), and meropenem

Included

pathogens

CarbNS Enterobacteriaceae, MDR A. baumannii, MDR P. aeruginosa, S.

maltophilia and B. cepacia. The test isolates of MDR non-fermenters were

defined to be resistant to meropenem, amikacin and ciprofloxacin.

Source: Longshaw 2019 [47]; Hackel 2017 [29]; Hackel 2018 [30]

In vitro efficacy has been demonstrated in several independent world-wide pathogen

collections:

1. A total of 30,459 clinical isolates of Gram-negative bacilli were systematically collected

from USA, Canada, and 11 European countries between 2014 and 2017. All isolates were


sent to a central laboratory, IHMA (Schaumburg, Illinois), where the isolates were further

evaluated and stored.

a. The SIDERO-WT analysis (study report S-649266-EB-344-N) was an extensive effort

to determine susceptibility of cefiderocol and relevant comparators against

cabapenem-susceptible and carbapenem-resistant pathogens. The purpose of this

study was to calculate the indices related to the antibacterial activity of cefiderocol and

the ratio of susceptible strains of cefiderocol and other reference compounds based

on the breakpoint criteria of Clinical and Laboratory Standards Institute (CLSI)

standards. MICs were determined by broth microdilution for a panel of 7 antibacterials,

including cefiderocol, ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T),

colistin (CST), cefepime (FEP), meropenem (MEM), and ciprofloxacin (CIP) according

to the Clinical & Laboratory Standards Institute (CLSI). Included herein are results from

the total sample and from the European subsample (overall and non-fermenters) [29,

45, 46, 49, 250].

b. A subsequent analysis focused on a Difficult-to-treat resistant (DTR) subset of

pathogens, which were non-susceptible to fluoroquinolones (CIP), extended-spectrum

cephalosporins (FEP), and carbapenems (MEM) according to CLSI M100-E28:2018

breakpoints. (Longshaw et al., Poster presentation, IDWeek 2019 [47]).

c. A molecular analysis based on the same collection investigated acquired

carbapenem-hydrolyzing enzymes (carbapenemases) identified in meropenem-

non-susceptible (MEM-NS) strains and antibacterial susceptibility by year and country

for the included strains. (Sato et al, Poster presentation, IDWeek 2019).

2. The SIDERO-CR-2014-2016 study (protocol S-649266-EF-115-N) included CR

Enterobacteriaceae and MDR non-fermenters (defined as resistant to carbapenems,

fluoroquinolones, and aminoglycosides) and demonstrated the potent in vitro activity of

cefiderocol against these pathogens [30].

3. Several independent national validation studies were carried out to determine

cefiderocol activity against difficult-to-treat CR pathogens gathered from various countries

including Germany, Greece, Italy, Spain, UK/Ireland, and the US [252-257]. In these

studies, cefiderocol demonstrated consistent activity against Gram-negative pathogens

regardless of the geographic origin.

4. A validation study by a Swiss team of scientists confirmed cefiderocol activity in an

independent world-wide collection of Gram-negative pathogens [258].


5. Several studies followed up on the surveillance results and aimed to characterize rare

resistant pathogens and identify their mechanisms of resistance. [61, 62] (Ito et al.,

Poster presentation, ASM Microbe 2019).

Results from these studies and relevant published sub-analyses involving European samples

are summarized in the following sections, followed by a summary analysis of the expected

efficacy of cefiderocol based on in vitro susceptibility results, compared to other treatment

options.

It is important to highlight that there these studies are continuously being updated and new

isolates analysed and incorporated, with correspondent publications following, showing the

results by year, cumulative, or for specific groups of pathogens of interest.

5.4.1.1 1a) SIDERO-WT results for all Gram-negative isolates[45, 49, 250]

In the SIDERO-WT in vitro studies, cefiderocol demonstrated activity against the majority of

Gram-negative isolates at MIC of <4 µg/mL (only MIC90 for B. multivorans was 32 µg/mL) with

higher coverage rates than other comparators included in these studies [250]. The SIDERO-

WT program included 4 multinational surveillance analyses testing a total of 9205 Gram-

negative bacterial clinical isolates in 2014–2015, 8954 in 2015–2016, and 10 470 in 2016–

2017 [250] and continues to include more isolates every year. To date (January, 2020), 30,459

459samples have been tested. Of note, >99% of isolates had low cefiderocol MIC values in

each testing period [250]. The latest surveillance SIDERO-WT study (2016-2017) showed that

cefiderocol demonstrated activity against 99.45% of GN pathogens at MIC of 4 mg/L

compared to 90.2% for ceftazidime-avibactam, 84.28% for ceftolozane-tazobactam, and

95.49% for colistin (Table 26) [49].

With regards to in vitro activity across different pathogens, cefiderocol demonstrated potent in

vitro activity against Enterobacteriaceae (99.9%) and non-fermenters including A. baumannii,

P. aeruginosa, S. maltophilia, and B. cepacia (98.53%) which was higher than for other

available treatments (Table 26) [49].

Table 26: In vitro activity data for all tested clinical strains (SIDERO-WT-2014/2015/2016 and Proteeae) of

cefiderocol (at MIC of 4mg/L) versus ceftazidime-avibactam, ceftolozane-tazobactam, and colistin


Organism Cefiderocol %

Polymyxin E (colistin) % S MIC ≤2 µg/mL

Ceftolozane / tazobactam %S MIC ≤2 µg/mL for Enterobacteriaceae, ≤4 µg/mL for non-fermenters

Ceftazidime / avibactam % S MIC ≤8 µg/mL

All Gram-negative (N=30,459) 99.45

95.49b (n=25372)

84.28 90.20

Enterobacteriaceae (N=20,949)

99.86 96.54c (n=16026)

91.43 99.23

Non-fermentersa (N=9,510)

98.53 93.67d (n=9346)

68.52 70.33

CR

Enterobacteriaceae (N=654)

(MEPM MIC ≥ 2 µg/mL)

98.16 75.55c (n=581)

8.40 77.67

CR (N=4,331)

(MEPM MIC ≥ 4 µg/mL) 97.57

86.85d (n=4208)

34.61 40.96

CR P. aeruginosa (N=1,154)

(MEPM MIC ≥ 4 µg/mL) 99.91 98.35 76.08 75.38

CR A. baumannii (N=1,891)

(MEPM MIC ≥ 4 µg/mL) 94.87 85.14 7.77 16.23

S. maltophilia (N=1,173)

99.82 78.17 34.27 42.88

Source: [49]. CarbNS - carbapenem non-susceptible; MEPM - meropenem; MIC - minimum inhibitory concentration. Green: More

than 80% susceptible; yellow: between 60-80% susceptible, red: less than 60% susceptible.

a Non-fermenters include P. aeruginosa, S. maltophilia, Burkholderia spp, and Acinetobacter spp.

b Burkholderia spp, Proteeae and Serratia spp. were excluded because they are intrinsically resistant to Polymyxin E

(Colistin)

c Serratia spp. and Proteeae was excluded.

d Burkholderia spp was excluded.

5.4.1.1.1 European sub-sample

The in vitro activities of cefiderocol and six comparators are summarized in Table 27 for the

5352 isolates from European clinical laboratories from the 2015 collection. (Karlowsky et al.,

2018). The concentration of antimicrobial agent inhibiting 50% (MIC50) and 90% (MIC90) of

Enterobacteriaceae isolates tested against cefiderocol were 0.25 and 1 mg/L for European

isolates (MIC range ≤0.002-8 mg/L). Cefiderocol inhibited 99.9% (6005/6013) of all isolates of

Enterobacteriaceae tested, from European clinical laboratories, at a concentration (MIC) of ≤4

mg/L. Of the eight isolates of Enterobacteriaceae with cefiderocol MICs of ≥8 mg/L, three were

European isolates (two isolates of E. coli and one isolate of Citrobacter freundii), all with

cefiderocol MICs of 8 mg/L. Each isolate of Enterobacteriaceae with a cefiderocol MIC ≥8

mg/L was from a unique clinical laboratory location. Seven of the eight isolates with cefiderocol

MICs of 8 mg/L were susceptible to both meropenem and ceftazidime-avibactam compared

with six isolates susceptible to colistin, four isolates susceptible to ciprofloxacin, and only one

isolate susceptible to cefepime and ceftolozane-tazobactam. Against meropenem-non-

susceptible (MIC ≥2 mg/L) isolates of Enterobacteriaceae from Europe (n = 196), cefiderocol


MIC50 and MIC90 values were 2 and 4 mg/L, respectively; 99.6% (245/246) of all meropenem-

non-susceptible Enterobacteriaceae had MICs to cefiderocol of ≤4 mg/L.


Table 27: In vitro activity of cefiderocol and comparators against Gram-negative bacilli isolated

by 55 clinical laboratories in Europe in 2015 (n=5352)


An updated analysis of the European sample (Shionogi, data on file) investigated the in vitro

activity of cefiderocol and comparators specifically against non-fermenters (SIDERO-WT-

2014-2016; European isolates).


Table 28: In vitro activity of cefiderocol and comparators against non-fermenters

Source: Shionogi, data on file.

Cefiderocol demonstrated greater potency than all comparators against the pathogens P.

aeruginosa and A. baumannii, based on MIC50 and MIC90 values:

o Against P. aeruginosa, and based on MIC90 values, cefiderocol (MIC90 0.5

mg/L) was 4 times more potent than colistin and ≥8 times more potent than all

other comparators.

o The activity of cefiderocol against A. baumannii (MIC90 2 mg/L) was ≥32 times

greater than cefepime, ceftazidime/avibactam, ceftolozane/tazobactam, and

meropenem, and was 4 times greater than colistin.

o Cefiderocol (MIC90 0.25 mg/L) also demonstrated activity against S. maltophilia

that was ≥256 times more potent than cefepime, ceftazidime/avibactam,

ceftolozane/tazobactam, and meropenem, and 32 times more potent than

ciprofloxacin and colistin.

o All comparators showed lower activity than cefiderocol (MIC90 0.5 mg/L) against

B. cepacia complex, with cefiderocol being ≥16 times more potent.

The cefiderocol MIC90 against CarbNS-P. aeruginosa was 1 mg/L and, with the exception of

colistin (MIC90 2 mg/L) and ciprofloxacin (MIC90 >8 mg/L), comparator MIC90s were ≥64 mg/L.

Cefiderocol maintained activity against CarbNS-A. baumannii (MIC90 2 mg/L), and

demonstrated >4 times greater potency than all comparators.

5.4.1.2 1b) SIDERO-WT-based analysis of difficult-to-treat resistant (DTR)

pathogens [47]

All antibacterials were tested in cation-adjusted Mueller-Hinton Broth (CAMHB) except

cefiderocol, for which iron-depleted CAMHB was used. Susceptibility was determined


according to CLSI interpretive breakpoints (CLSI M100-E28: 2018) except CST, where

EUCAST breakpoints were used (Table 29).

Pathogens were defined as ‘Difficult-to-Treat Resistant’ (DTR) if they were non-susceptible to

fluoroquinolones (CIP), extended-spectrum cephalosporins (FEP), and carbapenems (MEM)

according to CLSI M100-E28:2018 breakpoints (Table 29). Pathogens were defined as

carbapenem non-susceptible if they had MICs to meropenem of >1 μg/mL (Enterobacterales);

>2 μg/mL (Pseudomonas spp./ Acinetobacter sppspp.); >4 μg/mL (Burkholderia cepacia

complex). Stenotrophomonas maltophilia was considered inherently non-susceptible to

carbapenems, however, an arbitrary breakpoint of >4 μg/mL was used. Among 30,459 Gram-

negative isolates collected between 2014 and 2017, 9.3% were non-susceptible to FEP, MEM,

and CIP and could be defined as DTR.

Table 29: Breakpoints for non-susceptibility used in definition of DTR (μg/mL)

Cefiderocol demonstrated activity in 94.5% of DTR A. baumannii, 99.8% of P. aeruginosa and

98.3% of Enterobacterales [47]. Susceptibility of these pathogens were lower for other

available treatments (Table 30) [47].

Table 30: Susceptibility of cefiderocol and comparators to pathogens

Pathogen Cefiderocola % Ceftazidime / avibactama %

Ceftolozane / tazobactama

Colistina %

DTR Enterobacterales (n=573)

98.3 78.2 2.05 68.2

DTR P. aeruginosa (n=470)

99.8 49.5 48.8 98.3

DTR A. baumannii

(N=3,451) 94.5 14.2 5.8 85

Table 31 below shows that 98.7% of CarbNS Enterobacteriaceae, and 96.4% of CarbNS non-

fermenters were calculated to be sensitive to cefiderocol at a MIC of ≤4 μg/mL.


Table 31: In vitro activity data for CR Gram-negative pathogens (SIDERO-WT-2016-2017) of cefiderocol

versus ceftazidime-avibactam, ceftolozane-tazobactam and colistin



Colistina %

CarbNSb Enterobacteriaceae (225)

98.7 81.3 11.1 71d

CarbNSb non-fermentersc (1427)

96.4 39.8 37.0 91.5e

CarbNSb P. aeruginosa

(406) 100 75.6 77.3 97.3

CarbNSb A. baumannii (565)

91 11.0 9.0 90.8

S. maltophilia (405)

100 38.8 31.4 86

CarbNS, carbapenem-non-susceptible

a Ratios (%) susceptible strains were calculated by using the following MIC criteria: Cefiderocol MIC ≤4 μg/mL,

ceftazidime/avibactam MIC ≤8 μg/mL, ceftolozane/tazobactam MIC ≤2 μg/mL for Enterobacteriaceae, ≤4 μg/mL for non-

fermenters, colistin MIC ≤2 μg/mL.

b CR strain was defined as meropenem MIC ≥2 μg/mL for Enterobacteriaceae, ≥4 μg/mL for non-fermenters

c Non-fermenters include P. aeruginosa, S. maltophilia, Burkholderia spp, and Acinetobacter spp.

d Serratia spp. and Proteeae were excluded.

e Burkholderia spp. was excluded.

Source: Tsuji 2019[49]

The DTR phenotype was most frequently observed in Acinetobacter spp. (55.5%), followed

by Burkholderia spp. (19%), Pseudomonas aeruginosa (9.5%) and Enterobacterales (2.7%).

From 1173 S. maltophilia isolates tested, 60.7% were non-susceptible to meropenem,

cefepime and ciprofloxacin, however, trimethoprim-sulfamethoxazole was not tested and

could be considered a treatment option for these infections, thus we were not able to state

how many isolates might be considered DTR.

In summary, the results from this analysis showed that cefiderocol demonstrated potent

activity against ‘Difficult-to-Treat Resistant’ Gram-negative pathogens which leave physicians

with limited options for high efficacy, low toxicity first-line treatment.

5.4.1.3 1c) Study of acquired carbapenem-hydrolyzing enzymes (carbapenemases) identified in meropenem-non-susceptible (MEM-NS) strains [48]

In a subgroup analysis of SIDERO-WT-2014-2016 studies including meropenem-non-

susceptible strains, cefiderocol demonstrated potent in vitro activity irrespective of the

presence of specific carbapenemases [48].The isolates were stratified per resistance

determinants detected through the conventional polymerase chain reaction (PCR) method and


included VIM-, NDM-1-, KPC-, and OXA-producing Enterobacteriaceae, VIM-, IMP-, and GES-

producing P. aeruginosa, and OXA-, GES- and NDM-producing A. baumannii [48].

In all, 3691 Gram-negative isolates of MEM-NS A. baumannii complex, P. aeruginosa, K.

pneumoniae, other Klebsiella spp., Serratia marcescens, Enterobacter spp., Citrobacter spp.,

and Escherichia coli, from SIDERO-WT-2014 (Year 1: 2014–2015), SIDERO-WT-2015 (Year

2: 2015–2016), and SIDERO-WT-2016 (Year 3: 2016–2017) were molecularly characterized.

Information on the number of isolates by year and by country of collection is shown in Table

32 and Table 33, respectively.

Table 32: Number of MEM-NS isolates by year and species

Table 33: Number of MEM-NS isolates by country and species

5.4.1.3.1.1 Detection of β-lactamase genes

Screening for the carriage of genes encoding carbapenemases and sequencing are described

by Kazmierczak et al. Briefly, multiplex polymerase chain reaction assays were used to screen

oxacillin carbapenemase (OXA)-23-like, OXA-24/40-like, OXA-48-like, OXA-58-like, K.

pneumoniae carbapenemase (KPC), imipenemase metallo-β-lactamase (IMP), Verona

integron-encoded metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM), Sao


Paulo metallo-β-lactamase (SPM), Guiana-extended-spectrum β-lactamase (GES) and

German imipenemase (GIM) in Acinetobacter spp.; KPC, GES, OXA-24/40-like, IMP, VIM,

NDM, SPM, and GIM in P. aeruginosa; and KPC, GES, OXA-48-like, IMP, VIM, and NDM in

Enterobacteriaceae.

Genes encoding KPC, GES, IMP, VIM, and NDM carbapenemases were sequenced. Among

GES subtypes, GES-2, -4, -5, -6, -11, -12, -14, -15, -16, -18, 20, and -24 were considered

carbapenemases. All experiments were conducted at a central laboratory (International Health

Management Associates, Inc. in Schaumburg, IL, USA), where the isolates were stored.

5.4.1.3.1.2 Minimum inhibitory concentration (MIC) data

Antimicrobial susceptibility data reported in the SIDERO studies were used. MICs were

determined by the broth microdilution method according to the CLSI guidelines. For MIC

determination, iron-depleted cation-adjusted Mueller–Hinton broth (ID-CAMHB) medium was

used for testing of cefiderocol and CAMHB was used for testing of ceftazidime-avibactam,

ceftolozane-tazobactam, meropenem, cefepime, and colistin.

5.4.1.3.1.3 Susceptibility criteria

Susceptibility to each antibacterial agent was determined according to the CLSI M100-S29.

For the purpose of comparison, breakpoint values of ceftazidime-avibactam and ceftolozane-

tazobactam for P. aeruginosa were also applied to isolates of A. baumannii complex for which

breakpoint values have not been defined by the CLSI (Table 34).

Table 34: Susceptibility breakpoints according to the CLSI (cefiderocol) and/or EUCAST (all

comparators)

The following tables (Table 35 - Table 38) summarize the county-by country variability in the

frequency of resistant strains of A. baumannii, P. aeruginosa, K. pneumoniae, and

Enterobacteriaceae.


Table 35: Percentage of susceptibility of MEM-NS A. baumannii complex by country

Table 36: Percentage of susceptibility of MEM-NS P. aeruginosa complex by country

Table 37: Percentage of susceptibility of MEM-NS K. pneumoniae by country

Table 38: Percentage of susceptibility of other MEM-NS Enterobacteriaceae by country

This analysis found the molecular diversity to be high in carbapenemases. Carbapenemase

detection rates, especially in P. aeruginosa and K. pneumoniae, greatly varied across

countries. The presence of metallo-carbapenemases, both NDM and VIM, is noteworthy in

some countries.

The results show that cefiderocol demonstrated potent in vitro activity against MEM-NS

strains, including isolates with reduced susceptibility to colistin, irrespective of the presence of

either serine-type or metallo-type carbapenemases. Of the antibacterials tested, only


cefiderocol was broadly active against all species of MEN-NS clinical isolates regardless of

the geographic origin.

5.4.1.4 2) SIDERO-CR-2014-2016 study (protocol S-649266-EF-115-N)

The SIDERO-CR-2014-2016 study including CR Enterobacteriaceae and MDR non-

fermenters (defined as resistant to carbapenems, fluoroquinolones, and aminoglycosides)

demonstrated the potent in vitro activity of cefiderocol with a MIC90 ranging between 0.25 and

8 µg/mL [30, 250]. For MIC of ≤ 4 µg/mL, cefiderocol showed activity against 96.2% of these

pathogens and demonstrated higher in vitro activity than other available treatments (Table 39)

[30, 250]. Cefiderocol inhibited the growth of 97.0% of CR Enterobacteriaceae, 99.2% MDR

P. aeruginosa, 90.9% MDR A. baumanii and 100% S. maltophila at a concentration of 4 mg/L

(Table 39) [30, 250].

Table 39: In vitro activity data for all tested clinical strains (SIDERO-CR 2014-2016) of cefiderocol

versus ceftazidime-avibactam, ceftolozane-tazobactam, and colistin



Colistina %

CarbNSb Enterobacteriaceae (1022)

97.0 77.0 1.7 77.8c

MDR P. aeruginosa (262)

99.2 36.3 24.1 99.6

MDR A. baumannii (368)

90.9 NA NA 94.6

S. maltophilia (217)

100 NA NA NA

CarbNS, carbapenem-non-susceptible; MDR, multi drug resistant; NA, susceptibility breakpoints not available

a Ratios (%) susceptible strains were calculated by using the following MIC criteria: Cefiderocol MIC ≤4 μg/mL,

ceftazidime/avibactam MIC ≤8 μg/mL, ceftolozane/tazobactam MIC ≤2 μg/mL for Enterobacteriaceae, ≤4 μg/mL for non-

fermenters, colistin MIC ≤2 μg/mL.

b CR strain was defined as meropenem MIC ≥2 μg/mL for Enterobacteriaceae, ≥4 μg/mL for non-fermenters

c Includes 39 Serratia species that are intrinsically resistant to colistin

Source: Hackel, 2018 [30]; Yamano [250]

In addition to demonstrating high activity of cefiderocol against different drug-resistant

species, the SIDERO-CR study showed antibacterial activity against isolates stratified per

resistance determinants detected through the PCR method [250]. This includes VIM-, NDM-,

KPC-, and OXA-producing Enterobacteriaceae, VIM-producing P. aeruginosa, MEPM-non-

susceptible but acquired β-lactamase negative P. aeruginosa, OXA-23 and OXA-24/40

carbapenemase-producing A. baumannii.


5.4.1.5 3) Independent international validation studies

5.4.1.5.1 Germany [259]

Collection I comprised 213 first isolates from patients collected during a multicenter

surveillance study conducted by the Paul-Ehrlich-Society in 2013, namely 146

Enterobacterales (including 17 ESBL-producing strains), 13 Acinetobacter baumannii group

isolates, and 54 Pseudomonas aeruginosa. Collection II included 59 carbapenemase

producing Enterobacterales from our stock collection. Minimum inhibitory concentrations

(MICs) of cefiderocol and comparative antibacterial agents were determined using the

microdilution method according to the standard ISO 20776-1. The provisional CLSI breakpoint

of cefiderocol for susceptibility is ≤4 mg/L.

Cefiderocol inhibited 99% of the collection I at ≤4 mg/L (Table 40). MIC50/90 values of

cefiderocol for Enterobacterales isolates were 0.12/1 mg/L. However, cefiderocol was more

active against ESBL-negative isolates than against ESBL-producing Enterobacterales

(isolates with MIC >1 mg/L: 4/129 [3.1%] ESBL-negative isolates vs 7/17 [41%] ESBL-

producing isolates). In contrast, cefiderocol inhibited all Acinetobacter isolates at 0.12 mg/L

and all P. aeruginosa isolates at 1 mg/L (Table 40). The highest cefiderocol MICs observed

for collection II strains were 16 mg/L. Cefiderocol inhibited all seven carbapenemase-

producing A. baumannii at 0.25 mg/L. MIC50/90 values for Enterobacterales (n=30) and P.

aeruginosa (n=22) were 1/4 mg/L and 0.5/2mg/L, respectively.

Table 40: MIC of cefiderocol and comparators in Germany


5.4.1.5.2 Greece [252]

A total of 471 (445 meropenem resistant and 26 meropenem intermediate) isolates, collected

from ICUs and wards of 18 Greek hospitals, were included [282 Enterobacteriaceae (244 K.

pneumoniae, 1 Klebsiella oxytoca, 14 Enterobacter cloacae, 11 Providencia stuartii, 7 E. coli,

4 Proteus mirabilis and 1 Serratia marcescens) and 189 non-fermentative Gram-negative

bacteria (107 A. baumannii and 82 P. aeruginosa). Table 41 shows the summary data of the

MIC range, MIC50 and MIC90 of the antibacterials for the tested bacterial isolates and their

respective resistance percentages.

Resistance to colistin was observed in 154 isolates [including: 91 K. pneumoniae isolates

(37.2% of all K. pneumoniae); 45 A. baumannii isolates (42.1% of all A. baumannii); 1 P.

aeruginosa isolate and 2 E. coli isolates]. The MIC range, MIC50 and MIC90 of cefiderocol did

not differ between colistin-resistant and colistin-susceptible A. baumannii isolates.

Table 41: MIC of cefiderocol and comparators in Greece

5.4.1.5.3 Italy [260]

42 MDR strains, previously characterized for their β-lactamases content, including 13

Klebsiella pneumoniae, 9 Escherichia coli, 5 Proteus mirabilis, 6 Pseudomonas aeruginosa, 6

Acinetobacter baumannii, 2 Enterobacter cloacae complex and 1 Aeromonas spp., were

tested for susceptibility to cefiderocol and comparators.

The cefiderocol MIC50 and MIC90 values (0.5 mg/L and 4 mg/L, respectively) were significantly

lower than comparators. In particular, cefiderocol showed a good in vitro activity (MIC≤4 mg/L)


against: i) 20 carbapenemase-producing Enterobacterales (8 KPC, 3 VIM, 1 NDM, 4 OXA-48,

2 OXA-232, 2 NMC-A/IMI); ii) 6 ESBL-producing Enterobacterales (TEM-52,TEM-92,

PER1,VEB-6 + TEM-52, CTX-M-15, CTX-M-65); iii) one CMY-producing P. mirabilis; iv) 6

carbapenemase-producing P. aeruginosa (3 VIM, 1 FIM, 1 GES, 1 IMP);v) 5 A. baumannii (2

OXA-58, 1 OXA-23, 1 OXA-24, 1 ISAba1-OXA-51).

Cefiderocol was less active against a FOX-7-producing K. pneumoniae (MIC, 8 mg/L), an

NDM5-producing E. coli (MIC, >64 mg/L), an OXA-23-producing A. baumannii (MIC, >64

mg/L) and a PER-producing Aeromonas spp. (MIC, >64 mg/L).

High cefiderocol MIC values were not associated with any specific β-lactamase class.

5.4.1.5.4 Spain [257]

231 clinical isolates of Enterobacteriaceae (121 ESBL-and/or carbapenemase-producing K.

pneumoniae, and 4 carbapenemase-producing E. cloacae), 80 A. baumannii, six P.

aeruginosa, and 20 S. maltophilia were tested. Cefiderocol showed a potent in vitro activity

against the isolates analyzed, with MIC50 and MIC90 values between 0.125-8 mg/L and 0.5-8

mg/L, respectively, and 98% of isolates were inhibited at ≤4 mg/L. Only five isolates showed

a MIC of cefiderocol >4 mg/L, three ST2/OXA-24/40-producing A. baumannii, oneST114/ VIM-

1-producing E. cloacae, and one ST114 E. cloacae producing VIM-1 plus OXA-48. All KPC-

3-producing K. pneumoniae were susceptible to cefiderocol, even those resistant to

ceftazidime/avibactam (Table 42).

Table 42: MIC of cefiderocol and comparators in Spain


5.4.1.5.5 United Kingdom and Ireland [253]

The test panel were 305 clinical Enterobacteriaceae submitted between 2008 -2016 and all

but 2 were from UK hospitals. The 2 non-UK isolates were from Ireland. The panel was

selected to represent diverse carbapenemase producers and those with carbapenem

resistance via combinations of porin loss with AmpC or ESBL activity. Carbapenemase genes

were identified by PCR or by whole genome sequencing.

Carbapenem resistance due to porin loss combined with ESBL or AmpC activity was inferred

from their previous susceptibility results and the absence of carbapenemases.

Comparator antibacterials comprised meropenem, ceftazidime, ceftazidime-avibactam,

cefepime, ceftolozane-tazobactam, aztreonam, colistin, amikacin, ciprofloxacin and

tigecycline. MICs were interpreted using CLSI guidelines where available, or EUCAST

breakpoints for ceftazidime-avibactam, tigecycline, and colistin.

Table 43: MIC of cefiderocol and comparators against in United Kingdom and Ireland


Table 44: Activity of antimicrobial agents tested against carbapenem-resistant P. aeruginosa

and S. maltophilia

5.4.1.6 4) Independent validation study by Swiss scientists based on world-wide

pathogens [258]

A total of 753 clinical multidrug-resistant isolates were evaluated in this study. They were

representative of the most widespread and broad-spectrum mechanisms of resistance

currently observed worldwide in Gram-negative bacteria. The strains were collected from

hospitals worldwide (42 countries) from 2000 to 2016, with a majority dating from the 2012–

2016 period. They were of various origins (not always recorded) but mostly from urines,

broncho-alveolar specimens, blood, pus, and stools (Table 45).


Table 45: MIC of cefiderocol and comparators for MDR-GN isolated

5.4.1.7 5) In vitro studies investigating resistance of pathogens against

cefiderocol [61, 62] [261]

Cefiderocol activity against strains with porin channel mutations and overexpression of efflux

pumps has been demonstrated in two in vitro studies [61, 62].

A study assessing contribution of active iron transporters and binding ability to PBPs of

cefiderocol to its antibacterial/bactericidal activity against K. pneumoniae and E. coli compared

to meropenem and ceftazidime, reported that neither porin mutations nor single iron transport

mutations result in clinically relevant increases of cefiderocol MICs, probably due to the active

siderophore transport system and β-lactamase stability [62].

Another in vitro study assessed contribution of chelating ability with iron (III) and the utilization

of iron transporters through the outer membrane to the in vitro activity of cefiderocol against

P. aeruginosa compared to other siderophore compounds (hydroxypyridone-substituted

siderophore monobactams BAL30072, MB-1 and SMC-3176) [61]. The results suggest that

cefiderocol is active against the mutants with multiple transporters with MIC of 2 µg/mL while

other siderophore beta-lactams demonstrated lower activity. Of note, cefiderocol antibacterial

activity was not affected by major efflux pump MexAB-OprM of P. aeruginosa, which is known

to confer multidrug resistance (MDR) [61].

In the latest update of resistance investigations of the SIDERO-WT collection, Ito et al.

reported overall low rates of resistance against cefiderocol (Ito et al., Poster presentation,


ASM Microbe 2019). The authors followed up with additional characterizations of the mutant

strains identified in the SIDERO-WT-2014 subsample (red box in Table 46 below).

Table 46: Number of cefiderocol non-susceptible isolated in global surveillance studies (MIC ≥8

μg/mL)

Among the 38 isolates tested, 25 strains were Acinetobacter baumannii possessing PER β-

lactamase isolated in Russia (18 isolates), Turkey (6 isolates) and Sweden (1 isolate), and 5

isolates were Klebsiella pneumoniae possessing NDM carbapenemase from Turkey. The

addition of avibactam resulted in a ≥4-fold decrease of cefiderocol MIC to ≤0.5 μg/mL in 33

isolates that did not harbor NDM. Against the 5 isolates containing NDM, the addition of either

DPA or avibactam did not decrease the MIC of cefiderocol, but the addition of both avibactam

and DPA showed ≥8-fold decrease of the MIC to cefiderocol to ≤0.5 μg/mL. In contrast,

meropenem MIC showed ≥64-fold decrease with the addition of DPA alone against these

NDM-producing isolates. Additional testing of a further collection of 46 PER-producing isolates

from IHMA confirmed that 43 had cefiderocol MIC of ≤4 μg/mL.

The authors concluded that the findings suggest that the high MICs observed were unlikely

due to the presence of PER or NDM alone.


5.4.1.8 Summary Analysis: Expected comparative susceptibility

To determine susceptibility of Gram-negative bacteria to cefiderocol, multinational surveillance

studies (SIDERO) were conducted over four consecutive years (2014 to 2018) using

systematically collected clinical isolates from approximately 100 clinical laboratories in North

American and European countries. A separate multinational surveillance study of Proteeae

clinical isolates was also conducted. The antibacterial activity of cefiderocol was determined

in iron-depleted cation-adjusted Mueller-Hinton broth medium (ID-CAMHB) medium, a method

approved by the Clinical and Laboratory Standards Institute (CLSI). Comparators were tested

in parallel using standard cation- adjusted Mueller-Hinton medium according to CLSI

recommendations.

In February 2020, EUCAST defined a new clinical breakpoint for cefiderocol of 2 μg/mL for P.

Aeruginosa and Enterobacterales. For A. baumanii and S. maltophilia, was proposed

insufficient evidence (IE) refering to PK-PD breakpoints of 2 μg/mL (table below), which were

used for this analysis. For the comparators, EUCAST breakpoint (version 9.0) were used in

the analysis. In the absence of species specific breakpoint, PK/PD breakpoint were applied.

For colistin, PK/PD breakpoint were not available so the analysis considered the

Pseudomonas breakpoint of 2 μg/mL as an arbitrary breakpoint for Stenotrophomonas sp. and

Burkholderia sp.

Table 47: EUCAST breakpoints for cefiderocol

Species Sensitive (≤) Resistant (>)

PK-PD breakpoints 2 μg/mL 2 μg/mL

Enterobacterales 2 μg/mL 2 μg/mL

Pseudomonas Aeruginosa 2 μg/mL 2 μg/mL

Acientobacter baumanii 2 μg/mL 2 μg/mL

Stenotrophomonas maltophilia 2 μg/mL 2 μg/mL

In total and for all infection sites, 20911 isolates were collected between 2013 and 2018 from

11 European countries. Out of the 20911 isolates, Enterobacterales represented 66.5 % of

the pathogens, Acinetobacter spp. 12.7%, Burkholderia sp 0.7 %, Pseudomonas aeruginosa

16.1% and Stenotrophomonas maltophilia 3.9%.

Susceptibility for cefiderocol and the comparators was estimated in different subgroups of

pathogens, suspected MDR/CR infections were defined as pathogens resistant to both

ciprofloxacin and cefepime simultaneously.

Theoretical success in suspected MDR/CR infections was estimated for each antibacterial

agent tested by combining the ECDC Epidemiological data of GN pathogen distribution in

each individual infection site with the susceptibility to each antibacterial agent.


Table 48 and Table 49 (A-D) below summarize the results of such analyses for four different

infection sites and the respective relevant comparators:

Table 48: Susceptibility to Cefiderocol and comparators in all sites of infections for MDR3

pathogens

Table 49- Theoretical success of antibacterial therapy in Gram‐negative 3MDR pathogens in gastrointestinal site of infections (A) Pneumonia; (B) cUTI; (C) BSI; (D) Gastrointestinal

(A)

(B)

(C)

(D)


Regardless of the infection sites, cefiderocol demonstrated the highest theoretical success

compared with meropenem, ceftolozane/tazobactam, ceftazidime/avibactam or colistin,for

pre-emptive therapy in suspected MDR/CR infections.

Table 50: Summary table Theoretical percentage of success for Gram‐negative antibacterial

therapy on aerobic Gram‐negative pathogens in different infection type


5.4.2 Individual study results (PK/PD data, study report S-649266-CPK-004-B)

This section summarizes the methodology, underlying assumptions, and main findings from

extensive population PK/PD modelling efforts for ceficerocol. The full study report of the

PK/PD population model (S-649266-CPK-004-B) is included in the submission.

5.4.2.1 Model description

A population pharmacokinetic (PK) analysis was performed to develop a model using a total

of 3427 plasma concentration data of cefiderocol from the single ascending dose

(SAD)/multiple dose (MAD) study (1203R2111), the renal impairment study (1222R2113), the

phase 2 APEKS-cUTI study (1409R2121), the phase 3 CREDIBLE-CR study (1424R2131),

and the phase 3 APEKS-NP study (1615R2132).

A 3-compartment model was used to describe the plasma concentrations of cefiderocol. The

covariates explored included creatinine clearance calculated by Cockcroft-Gault equation

(CrCL), body weight, age, albumin concentration, aspartate aminotransferase , alanine

aminotransferase, total bilirubin, sex, race, infection (no infection, complicated urinary tract

infection [cUTI] or acute uncomplicated pyelonephritis [AUP] in the phase 2 study, cUTI in the

CREDIBLE-CR study, bloodstream infections/sepsis [BSI/sepsis], either hospital-acquired

pneumonia [HAP]/ventilator-associated pneumonia [VAP]/healthcare-associated pneumonia

[HCAP] in the CREDIBLE-CR study, and HAP/VAP/HCAP in the APEKS-NP study), and

ventilation (with or without mechanical ventilation during PK sampling). CrCL was the most

significant covariate on cefiderocol total clearance (CL), as expected. Observed plasma

cefiderocol concentrations were adequately described by the developed final model.

5.4.2.2 Results

Individual maximum concentration (Cmax), daily area under the concentration-time curve

(AUC) at steady state, percentage of time for which free drug concentration in plasma exceeds

minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC), and the %fT>MIC

with MIC of 4 μg/mL (%fT>4) were predicted using Monte Carlo simulation of 1000 virtual

patients for each infection sites. The ELF concentrations of cefiderocol in patients with

pneumonia were predicted using a developed ELF model based on the ELF concentrations in

20 healthy subjects and 7 ventilated patients with pneumonia. The ELF compartment was

linked with plasma compartment in the population PK model. The

probabilityPTAPTAprobabilityPTA of target attainment for cefiderocol in ELF was also

estimated usingwithwithusingwith Monte-Carlo simulations. A thousand virtual patients with

pneumonia were generated for the simulations [251].


Probability of target attainment (PTA) were simulated to achieve 75%T>MIC for the different patient population in plasma and in ELF, depending

on the renal function and dose adjustment required.

Table 51: PTA per infectious disease renal function, and dose

Target

fT>MIC

PK variable Infection disease

Renal Function Regimena

MIC (µg/mL)

0.25 0.5 1 2 4 8 16

75% Plasma HAP/VAP/HCAP Augmented 2 g q6h 100 100 100 100 99.7 94.5 60.4

Normal 2 g q8h 100 100 100 99.9 98.9 87.1 43.4

Mild 2 g q8h 100 100 100 100 99.8 97.0 69.7

Moderate 1.5 g q8h 100 100 100 100 99.9 98.7 83.3

Severe 1 g q8h 100 100 100 100 100 99.9 90.7

ESRD 750 mg q12h 100 100 100 100 100 99.6 86.3

BSI/sepsis Augmented 2 g q6h 100 100 100 100 99.4 91.3 49.6

Normal 2 g q8h 100 100 100 99.9 97.3 80.6 32.6

Mild 2 g q8h 100 100 100 99.9 99.6 94.4 57.7

Moderate 1.5 g q8h 100 100 100 100 99.9 98.0 74.8

Severe 1 g q8h 100 100 100 100 100 99.8 84.8

ESRD 750 mg q12h 100 100 100 100 100 99.2 79.2

cUTI/AUP Augmented 2 g q6h 100 100 100 100 99.9 96.9 73.3

Normal 2 g q8h 100 100 100 100 99.6 93.6 56.3

Mild 2 g q8h 100 100 100 100 99.8 98.4 81.2

Moderate 1.5 g q8h 100 100 100 100 100 99.6 90.4

Severe 1 g q8h 100 100 100 100 100 100 95.9

ESRD 750 mg q12h 100 100 100 100 100 100 91.6

ELF HAP/VAP/HCAP Augmented 2 g q6h 100 100 100 99.8 92.1 55.9 11.0


Normal 2 g q8h 100 100 100 99.6 88.5 45.3 6.8

Mild 2 g q8h 100 100 100 99.8 94.1 62.1 16.2

Moderate 1.5 g q8h 100 100 100 100 96.5 67.6 19.3

Severe 1 g q8h 100 100 100 99.9 98.0 75.4 27.1

ESRD 750 mg q12h 100 100 100 99.9 94.7 64.7 21.9

Augmented: CrCL ≥ 120 mL/min (120 to < 150 = 50%; ≥ 150 = 50%). Normal: CrCL 90 to < 120 mL/min.

Mild: CrCL 60 to < 90 mL/min. Moderate: CrCL 30 to < 60 mL/min. Severe: CrCL 15 to < 30 mL/min. ESRD: CrCL 5 to < 15 mL/min.

PTA for 75% fT>MIC was above 97% for a MIC of 4 mg/L regardless of the site of infection or the renal function. In the ELF, PTA for 75% fT>MIC

was above 88% for a MIC of 4 mg/L confirming the adequacy of the dosing regimen in the different patient populations.


5.4.3 Retrospective analysis of cefiderocol and comparators by population

PK/PD simulation

A retrospective analysis was performed comparing the probability of target attainment

(PTA) for cefiderocol, ceftolozane/tazobactam and meropenem against

Enterobacterales and Pseudomonas aeruginosa in a representative patient population

at risk of MDR or carbapenem resistant infections. Published pharmacokinetic (PK)

models for meropenem and ceftolozane/tazobactam, and an existing model for

cefiderocol, were used with standard dosage regimens for simulating individual PK

data. The intial list of comparators included ceftazidime/avibactam and colistin, but this

proved not possible to include:

the model implemented for ceftazidime-avibactam could not be appropriately

validated.

the model for colistin, required information about the correlation matrix, and the

nature of the parameter values reported in the original colistin model article,

which was not made available by the original model’s authors.

PTA for clinically relevant pharmacokinetic/pharmacodynamic (PK/PD) targets was

calculated from steady state PK profiles for a range of minimum inhibitory

concentrations (MICs). The calculated PTAs in plasma for the 3 antimicrobials were

above 95% at their respective MIC corresponding to their EUCAST breakpoints

confirming published results. Cumulative fractions of response (CFRs) were also

calculated to estimate using European MIC distributions from the SIDERO surveillance

selected for being resistant to two antibiotic classes (quinolone and cephalosporins)

and thereby representative of a patient population at risk of MDR infections. CFR

analysis was performed on selected European isolates already resistant to cefepime

and ciprofloxacin. In this patient population infected with suspected MDR/CR

pathogens, CFRs were 97.4% and 99.8% for cefiderocol for Enterobacterales and

Pseudomonas spp. respectively. The cumulative fractional responses for cefiderocol

against Enterobacterales and Pseudomonas spp. are considerably higher than seen

for meropenem and ceftolozane-tazobactam. Despite the simulation of high dose,

extended infusion of meropenem CFRs were 91.2% for Enterobacterales but only


68.4% for Pseudomonas spp. The dose simulated for ceftolozane/tazobactam is also

a high dose applied for the treatment of nosocomial pneumonia however due to the

selected suspected MDR/CR isolates CFRs were only 67.2% for Enterobacterales and

55.2% for Pseudomonas spp.

Table 52. Estimated CFR for MIC distributions corresponding to Enterobacterales and Pseudomonas spp. More simulation results for corresponding PTA, MIC and T>MIC target values are shown in Appendix C. The applied MIC distributions can be seen in Appendix D of the study report.

Cefiderocol Meropenem Ceftolozane-tazobactam*

MIC distribution: Cumulative fraction of response, CFR (%) xxx

Enterobacterales 97.4 91.2 67.2

Pseudomonas spp. 99.8 68.4 55.2

Meaningful comparisons could be made between the performances of the models for

cefiderocol, meropenem and ceftolozane-tazobactam. The simulations showed a

superior performance of cefiderocol against Enterobacterales and Pseudomonas spp

in terms of cumulative fraction of response when compared with meropenem and

ceftolozane/tazobactam (Table 52). It should be noted, though, that the meropenem

model exhibited a very long terminal half-life for the drug in plasma, probably reflecting

that the experimental data originate from a patient population where the majority of the

patients had bloodstream infections.


5.4.4 Clinical study results (clinical outcomes)

Each section begins with a summary of the results for the respective primary endpoint, followed

by summaries of relevant secondary endpoints in the order shown below. Detailed results (e.g.,

stratifications by pathogen) are provided in 5.4.3 [262, 263]. The section on APEKS-cUTI

contains additional results from a network-meta-analysis.

The Table 53 below summarizes the endpoint analyses requested by EUnetHTA in the scoping

process. In the following sections, the results for each of these endpoints are presented, if

applicable.

EA: early assessment; EOT: end of treatment; TOC: test of cure; FUP: follow up; EOS: end of

study; NR: not relevant; NA: not applicable

Table 53: Endpoint Analysis as per EUnetHTA Request

Study Endpoint/Analysis Available

time points

Stratifi-

cation

by

infection

site

Stratification

by pathogen

Primary

endpoint?

APEKS-

cUTI

Clinical outcome EA, EOT,

TOC, FUP

NA

No. Pathogen

specific data

detailed

results on file

[262]

No

Composite

microbiological

eradication and

cure

EA, EOT,

TOC, and FUP

Yes (at TOC)

Microbiological

eradication

EA, EOT,

TOC, FUP

No

All-cause mortality

at day 14 and 28

NR No

Changes of MIC or

appearance of

resistant bacteria

At EOS


Network meta-

analysis (NMA)

Clinical Cure

and

microbiological

eradication at

TOC and FU

Not relevant

APEKS-NP Clinical outcome TOC NA

Main

pathogens

No

Microbiological

eradication

EA, EOT,

TOC, FUP

Main

pathogens

No

All-cause

mortality

Day 14, day

28

Yes Yes, day 14

ACM

CREDIBLE-

CR (only

descriptive

results)

Clinical outcome EOT, TOC, FU Yes Main

pathogens

and non-

fermenters

Yes, for

HAP/VAP/HCAP

and BSI/sepsis

Microbiological

eradication

EOT, TOC, FU Yes Yes, for cUTI

All-cause mortality

(part of safety

assessment in

study protocol)

Day 14, day

28, EOS

Yes No

Blue font: primary endpoint

5.4.4.1 APEKs-cUTI

APEKS-cUTI was a Phase 2, multicentre (multinational), double-blind, randomised, active-

controlled, parallel-group study including 452 patients diagnosed with complicated urinary tract

infection [51] Clinicaltrials.gov Record NCT02321800).


The Figure 29 below summarizes the trial design and displays relevant endpoints.

Figure 29: APEKS-cUTI study design and endpoints

5.4.4.1.1 APEKS-cUTI primary efficacy endpoint: composite clinical

and microbiological response at TOC in the mITT population

Primary efficacy endpoint analysis

In accordance to the FDA guidelines, the primary efficacy endpoint is the composite of clinical

outcome and microbiological outcome at TOC. The response rate for the primary efficacy

endpoint was 72.6% (183/252) of subjects in the cefiderocol group and 54.6% (65/119) of

subjects in the IPM/CS group.

In a post-hoc analysis, the adjusted treatment difference was 18.58% (95% CI; 8.23%, 28.92%)

in favor of cefiderocol (Figure 30) demonstrated superiority; it and met the criterion for

noninferiority at the prespecified 20% and 15% margins (the lower limit of the 95% CI was

8.23% and exceeded both -15% and -20%). In addition, as it exceeded zero, which is

consistent with the superiority of cefiderocol compared with IPM/CS this was further confirmed

to be statistically significant (p=0.0004). Similar results were observed in the sensitivity analysis

(composite clinical and microbiological response in ME population) [51, 236].


Table 54: Summary for Composite of Clinical and Microbiological Outcome by Time

Point (Microbiological Intent-to-Treat Population)

Figure 30: Primary efficacy results: Composite outcome at TOC in the MITT population

(Clinical and microbiological response)

[a]Treatment difference (cefiderocol minus

imipenem/cilastatin) is the adjusted estimate

of the difference in the responder rate

between the 2 treatment arms, calculated

using a stratified analysis with Cochran-

Mantel-Haenszel weights based on the

stratified factor at baseline (cUTI with or

without pyelonephritis vs acute

uncomplicated pyelonephritis). CI,

confidence interval; MITT, modified intent-to-

treat; TOC, test of cure. Source: Portsmouth,

2018 [51]; Data on file [236]


Treatment differences by clinical diagnosis were consistent with the treatment difference in the

mITT population, with cefiderocol demonstrating higher efficacy rates than IPM/CS in patients

with cUTI with or without pyelonephritis, and with acute uncomplicated pyelonephritis (Figure

31) [51, 236]. The treatment differences by gender and age were also consistent with the

treatment difference for the primary analysis (Figure 31) [51, 236].

Figure 31: Primary efficacy results: Composite outcome at TOC by predefined subgroups

aTreatment difference (cefiderocol minus imipenem/cilastatin) is the adjusted estimate of the

difference in the responder rate between the 2 treatment arms, calculated using a stratified

analysis with Cochran-Mantel-Haenszel weights based on the stratified factor at baseline (cUTI

with or without pyelonephritis vs acute uncomplicated pyelonephritis); bMITT population

included all patients who received at least one dose of study drug and had a qualifying baseline

Gram-negative uropathogen (≥1×10⁵ CFU/mL). CFU, colony forming units; CI, confidence

interval; cUTI, complicated urinary tract infection; MITT, modified intent-to-treat; NI, non-

inferiority; TOC, test of cure. Source: Portsmouth S, et al. Lancet Infect Dis 2018;18:1319–28.

Composite clinical and microbiological response at TOC across different pathogens

For E. coli and Klebsiella spp. pneumoniae. the most frequently observed pathogens, the

treatment difference between both arms was preserved. The composite of microbiological

eradication and clinical response was higher in the cefiderocol group and the treatment

difference was statistically significant with a treatment difference of 15.53% for E. coli and

25.91% for Klebsiella spp. (Table 55) [51, 236]. Other uropathogens occurred at a low

frequency (in less than 10 patients in at least 1 of the groups) and therefore a statistical


comparison could not be made for either clinical response or microbiological eradication [51,

236].

Table 55: Composite of Clinical Response and Microbiological Outcome per

Pathogen at TOC (microbiological ITT population)

Pathogen

Percent Response % (n/N) Treatment Difference (95%CI)

Cefiderocol

Imipenem/ Cilastatin

E. coli 74.0 (108/146)

58.4 (45/77)

15.53 (2.42-28.64) *

K. pneumoniae

73.9 (34/46)

48.0 (12/25)

25.91 (2.58-49.25) *

P. aeruginosa

46.7 (7/15)

50.0 (2/4)

-3.33 (NA)

P. mirabilis

69.2 (9/13)

0.0 (0/1) 69.23 (NA)

CI - confidence Interval; NA, not available; * significant difference

Additional detailed stratified results for the primary endpoint by uropathogen are

on file[262, 263].

5.4.4.1.2 APEKS-cUTI secondary endpoint: Clinical Outcome

Clinical Outcome per Subject at EA, EOT, TOC, and FUP

At TOC, clinical response was 89.7% (226/252) of subjects in the cefiderocol group and 87.4%

(104/119) of subjects in the IPM/CS group. At FUP, sustained clinical response was higher in

the cefiderocol group (81.3% [205/252] of subjects) than in the IPM/CS group (72.3% [86/119]

of subjects), with an adjusted treatment difference of 9.02% (95% CI; -0.37%, 18.41%) (Table

56).

Clinical response rates for the ME Population (Table 14.2.5.1.2 of the CSR) were similar to the

Micro-ITT Population, with sustained clinical response at FUP in the cefiderocol group (85.1%

[194/228]) higher than in the IPM/CS group (78.3% [83/106]). Results were otherwise similar

for both treatment groups and assessment time points for this population.


Table 56: Summary of Clinical Outcomes per Subject by Time Point

(Microbiological Intent-to-Treat Population)

Stratified analyses: Clinical Outcome by Baseline Uropathogens at EA, EOT, TOC, and FUP

The summary of clinical outcome per uropathogen by time point (4 major uropathogens: E.

coli, K. pneumoniae, P. aeruginosa, and P. mirabilis) for the Micro-ITT Population is shown in

Table 57. For each of the major pathogen cefiderocol demonstrated no significant treatment

difference in clinical outcome at any of the assessment time point. Additional detailed stratified

analyses per pathogen and time point are on file [262, 263].


Table 57: Summary of Clinical Outcome per Uropathogen (E. coli, K. pneumoniae,

P. aeruginosa, and P. mirabilis) by Time Point (Microbiological ITT Population)


5.4.4.1.3 APEKS-cUTI secondary endpoint: Microbiological outcome

The microbiological eradication rate in the mITT Population (Table 58) was statistically

significantly higher at TOC in the cefiderocol group (73.0% [184/252] of subjects) compared

with the IPM/CS group (56.3% [67/119] of subjects). The adjusted treatment difference of

17.25% (95% CI; 6.92%, 27.58%) in favor of the cefiderocol group was statistically significant

and clinically meaningful. Results for both treatment groups were similar at EA and at EOT.

The sustained microbiological eradication rate at FUP was also higher in the cefiderocol group

(57.1% [144/252] of subjects) compared with the IPM/CS group (43.7% [52/119] of subjects).

The adjusted treatment difference of 13.92% (95% CI; 3.21%, 24.63%) in favor of the

cefiderocol group was statistically significant and clinically meaningful.

Table 58: Summary of Microbiological Outcome per Subject by Time Point

(Microbiological ITT Population)


Results for both treatment groups showed no significant difference at EA and at EOT. The

sustained microbiological eradication rate at FUP was also statistically significantly higher in

the cefiderocol group (57.1% [144/252] of subjects) compared with the IPM/CS group (43.7%

[52/119] of subjects).

The adjusted treatment difference of 17.83% (95% CI; 7.42%, 28.24%) for the microbiological

eradication rate at TOC between the treatment groups in the ME Population (Table 14.2.2.1.2

of the CSR) was similar to the results in the Micro-ITT Population.

Microbiological Outcome per Uropathogen at EA, EOT, TOC, and FUP

The summary of microbiological outcome per uropathogen by time point (for the 4 most

frequent uropathogens E. coli, K. pneumoniae, P. aeruginosa, and Proteus mirabilis) for the

Micro-ITT Population is shown in Table 59.

Summaries of microbiological outcomes per uropathogen by time point for all uropathogens

and per uropathogen group by time point are on file[262, 263]. For the most frequently

isolatedisolated uropathogens, E. coli and K. pneumoniae, eradication at EA and EOT was not

different between the treatment groups. For E. coli at TOC and FUP an adjusted treatment

difference of 16.77% and 18.10%, respectively, was demonstrated, and this difference is

consistent with the microbiological responses in the overall population. For K. pneumoniae, an

adjusted treatment difference of 23.00% at TOC was observed, followed by a treatment

difference of 6.33% at FUP.

These results demonstrate the microbiological efficacy of cefiderocol, which is consistently

better than IPM/CS for these uropathogens.

Similar responses were seen in the ME Population for both pathogens; however, for K.

pneumoniae, the difference between the 2 treatment groups for sustained eradication at FUP

was minimal (3.13%) [237].


Table 59: Summary of Microbiological Outcome per Uropathogen (E. coli, K.

pneumoniae, P. aeruginosa, P. mirabilis) by Time Point (Microbiological ITT

Population)


5.4.4.1.4 APEKS-cUTI secondary endpoint: New Infection and

Superinfection during the Study

No new infections were noted. Superinfection, defined as an uropathogen emerging during

study drug therapy, was limited to a single occurrence of E. coli in 1 subject (Subject 143-002)

in the cefiderocol group. The subject had E. coli isolated from the urine at the EA visit (Table

14.2.4.1.1 of the CSR). Of note, this subject had P. aeruginosa alone isolated at baseline and

was treated for 10 days with cefiderocol. The E. coli superinfection was sensitive to

levofloxacin, cefepime, and IPM, and the MIC for cefiderocol was 0.12 μg/mL. Both E. coli and

P. aeruginosa were eradicated at TOC, and P. aeruginosa alone was isolated at FUP.

There were 8.3% (21/252) of subjects in the cefiderocol group and 15.1% (18/119) of subjects

in the IPM/CS group who had new uropathogens that emerged after the EOS drug therapy in

the mITT Population [262, 263]. Numbers of isolates for each pathogen identified and tested

for susceptibility were small (the largest number was for E. coli, with 8 isolates in the cefiderocol

group and 3 isolates in the IPM/CS group); hence no meaningful comparisons or conclusions

could be made.

In conclusion, the cUTI study demonstrated that in a hospitalized population of 448 patients,

with multiple comorbidities and difficult-to-treat infections caused by MDR pathogens sensitive

to imipenem, cefiderocol was non-inferior to a standard-of-care antibacterial comparator,

IPM/CS. Although the study was only designed to demonstrate non-inferiority, the findings of

a post-hoc analysis were consistent with superiority for cefiderocol. The adjusted treatment

difference favored cefiderocol and the lower limit of the 95 % confidence interval exceeded 0.

The absolute difference of 18.58% in the composite primary endpoint was supported across

all analyzed populations and clinical diagnostic groups with cUTI. The magnitude of the

observed treatment differences is considered clinically important. Sensitivity analyses also

showed that cefiderocol had better microbiological efficacy than IPM/CS in predefined

subgroups and in patients infected with E. coli and K. pneumoniae, the most prevalent

uropathogens.


5.4.4.2 APEKS-cUTI Network Meta-Analysis (NMA)

Feasibility for an NMA was conducted based on APEKS cUTI study (full detailes of the SLR

and feasibility assessment can be found in [227]). The patient populations and most

importantly, the pathogens included in the different trials were similar, enabling a small NMA

to be conducted based on data from a YHEC SLR and feasibility assessment. The following

analyses were conducted using a fixed effects model (frequentist analysis) as well as a

Bayesian analysis:

Microbiological eradication at TOC and at FU visit

Clinical cure at TOC visit and FU visits

Any adverse event

Any ‘drug related’ adverse event

It should be noted that several of the outcomes and timepoints were infeasible due to

insufficient reporting and 100% events (the equivalent of 0 events). Full report of the NMA

analysis are provided as an attachment [264].

Also, the Figure 32 below reflects the maximum network diagram, of which TANGO II study

was then removed because of significant differences the baseline patient population (patients

were included after CR confirmation), therefore preventing the inclusion of TANGO I and ZEUS

trials in the network:


Figure 32: Maximum Network Chart for Network Meta-analysis

The most extensive network could be constructed for the microbiological eradication secondary

outcome is displayed in Figure 33 below:

Figure 33: Network Diagram for Microbiological Eradication Secondary Outcome

Consistent with the clinical trials results, the results in Figure 34 show a trend favouring

cefiderocol, and there were significant differences in microbiological eradication rates at TOC

between cefiderocol and imipenem/cilastatin and BAT in the frequentist analysis, respectively.

This is due to superior results in the APEKS-cUTI for cefiderocol vs IPM-CIL (73% vs 56%)

compared to Vasquez for CZA vs IPM-CIL (67% vs 63%). The Bayesian analysis (on the right)

is consistent with frequentist analysis, showing the same trends but without reaching statistical

significant difference:

Legends:

BAT: best available therapy C_T: ceftazalone-tazobactam CZA: ceftaz idime-avibactam DOR: doripenem FDC: cefiderocol IPM_CIL: imipenem/cilastatin LVX: levofloxacin


Figure 34: Microbiological Eradication Rates at TOC - Frequentist Analysis

Figure 35: Microbiological Eradication Rates at TOC - Bayesian Analysis

Similar results and trends were obtained for the microbiological eradication at follow-up in a

smaller network.

Clinical cure endpoint was evaluated in a smaller network as shown in Figure 36 below.

Figure 36: Network Diagram for Clinical Cure Outcome

Legends:


Legends:


Legends:



The safety analysis based on “any adverse event” resulted in the largest network (Figure 37):

Figure 37: Clinical cure rates at TOC - Frequentist Analysis

Figure 38: Clinical Cure rate at TOC - Bayesian Analysis

Figure 39: Clinical cure rates at FU - Frequentist Analysis

The results did not show any statistically significant difference in clinical cure rates

at TOC between cefiderocol and comparators both frequentist (Figure 37) and

Bayesian analysis. However, in the analysis for clinical cure in the FU visit, show

Legends:


Legends:


Legends:



a trend favouring cefiderocol, and there were statistically significant differences

in clinical cure rate at FU between cefiderocol and imipenem/cilastatin in the

frequentist analysis (Figure 39). Again.this is due to the superior results in APEKS

cUTI for cefiderocol vs IPM-CIL (81% vs 72%) compared to Vasquez for CZA vs

IPM-CIL (74% vs 67%). The Bayesian analysis (Figure 38) is consistent with

frequentist analysis, showing the same trends but without reaching statistical

significant difference.


5.4.4.3 APEKs-NP clinical outcomes

The APEKS-NP study compared treatment with cefiderocol against high-dose, prolonged

infusion (HD) meropenem in patients with nosocomial pneumonia caused by suspected MDR

Gram-negative pathogens. 300 patients were randomized 1:1 to cefiderocol or HD

meropenem, a regimen only used in more difficult-to-treat pathogens which optimizes exposure

and efficacy for meropenem (Figure 40).

Figure 40: APEKS-NP study design

The dose of meropenem was increased from the labeled dose of 1 g to 2 g and extended to a

3-hour infusion to optimize the antibacterial activity of meropenem, at the request of regulators.

[265].

5.4.4.3.1 APEKS-NP primary efficacy endpoint: Day-14 ACM

Cefiderocol demonstrated noninferiority to high-dose extended infusion meropenem with

regard to all-cause mortality at Day 14. The all-cause mortality rate was 12.4% (18/145

subjects) for the cefiderocol group and 11.6% (17/146 subjects) for the HDhigh-doseHD

meropenem group, demonstrating the noninferiority of cefiderocol, as the upper limit of the

95% CI was < 12.5% (95% CI: −6.6, 8.2) (Figure 41).


Figure 41: All-cause Mortality (mITT)

[a] Treatment difference (cefiderocol minus

meropenem) is the adjusted estimate of the

difference in the all-cause mortality rate at Day

14 and Day 28 between the 2 treatment arms

based on Cochran-Mantel Haenszel weights

using APACHE II score (≤ 15 and ≥ 16) as the

stratification factor.; [b] The 95% CI (2-sided)

is based on a stratified analysis using

Cochran-Mantel Haenszel weights using

APACHE II score (≤ 15 and ≥ 16) as the

stratification factor. The CI was calculated

using a normal approximation to the difference

between 2 binomial proportions (Wald method). Source: Data on file [239]

Table 60: Day 14 All-cause Mortality (mITT and ME-PP Populations)

Population Cefiderocol n/N’ (%)

HD Meropenem n/N’ (%)

Total n/N’ (%)

Treatment Differencea

Difference (%) 95% CIb p-value

mITT N = 145 18/145 (12.4)

N = 147 17/146 (11.6)

N = 292 35/291 (12.0)

0.8 (−6.6, 8.2) 0.0020c

0.8321d

ME-PP N = 105 13/105 (12.4)

N = 101 13/100 (13.0)

N = 206 26/205 (12.7)

−0.3 (−9.4, 8.7) nc

mITT excl meropenem resistante

N = 145 9/91 (9.9)

N = 147 10/90 (11.1)

N = 292 19/181 (10.5)

−1.3 (−10.1, 7.5)

nc

APACHE II = Acute Physiology and Chronic Health Evaluation II; CI = confidence interval; CLSI = Clinical and Laboratory Standards Institute; Day 14 ACM = all-cause mortality at Day 14 since first infusion of study drug; excl = excluding; ME-PP = microbiologically-evaluable per-protocol; mITT = modified intent-to-treat; n = number of subjects who died; nc = not calculated; N = number of subjects in the analysis set; N’= number of subjects with known survival status [a] Treatment difference (cefiderocol minus meropenem) is the adjusted estimate of the difference in the all-cause mortality

rate at Day 14 and Day 28 between the 2 treatment arms based on Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor.

[b] The 95% CI (2-sided) is based on a stratified analysis using Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor. The CI was calculated using a normal approximation to the difference between 2 binomial proportions (Wald method).

[c] p-value for non-inferiority hypothesis. [d] p-value for the superiority hypothesis. [e] Meropenem-resistant subjects were those subjects whose baseline Gram-negative pathogens were resistant to

meropenem based on CLSI susceptibility results. Subjects who did not have any susceptibility results available at baseline based on CLSI were not included for this analysis.

Source: Tables 14.2.1.1.1, 14.2.1.1.3, and 14.2.1.1.4

The sensitivity analysis of Day 14 all-cause mortality using the ME-PP population is in support

of the noninferiority finding in the primary efficacy population (Table 60). In a supplementary

analysis of the primary endpoint, in which subjects who were resistant to HD meropenem were


excluded from the mITT population, Day 14 all-cause mortality was 9.9% in the cefiderocol

group and 11.1% in the HD meropenem group (Table 60).

Subgroup analyses revealed no statistically significant differences between the included

groups (Figure 42).

Figure 42: Primary efficacy results: Day 14 All-cause Mortality by Subgroups


5.4.4.3.2 Secondary efficacy endpoints

Rates of microbiological eradication and clinical cure at TOC confirmed the non-inferiority

between the treatments (Table 61). The microbiological eradication at TOC was 47.6%

(59/124) in the cefiderocol group and 48.0% (61/127) in the HD meropenem group, and the

clinical cure at TOC was 64.8% (94/145) in the cefiderocol group and 66.7% (98/147) in the

HD meropenem group.


Table 61: Secondary Endpoints (mITT Population)

Endpoint

Cefiderocol (N = 145) n/N’ (%)

HD Meropenem (N = 147) n/N’ (%)

Total (N = 292) n/N’ (%)

Treatment Comparison

Difference (%) 95% CI

Microbiological eradication at TOC

59/124 (47.6) 61/127 (48.0)

120/251 (47.8) -1.4 a (-13.5, 10.7) a

Clinical cure at TOC

94/145 (64.8) 98/147 (66.7)

192/292 (65.8) -2.0 a (-12.5, 8.5) a

Day 28 all-cause mortality

30/143 (21.0) 30/146 (20.5)

60/289 (20.8) 0.5b (-8.7, 9.8)b

EOS all-cause mortality

38/142 (26.8) 34/146 (23.3)

72/288 (25.0) 3.6b (-6.3, 13.4)b

APACHE II = Acute Physiology and Chronic Health Evaluation II; CI = confidence interval; EOS = end of study; mITT = modified intent=to-treat; TOC = test of cure [a] Treatment difference (cefiderocol minus meropenem) is the adjusted estimate of the difference in the eradication

rate or cure rate between the 2 treatment arms. The adjusted difference estimates and the 95% CIs (2-sided) were calculated using a stratified analysis with Cochran-Mantel-Haenszel weights based on the stratified factors at baseline, infection type (HABP/VABP/HCABP), and APACHE II score (≤ 15 and ≥ 16).

[b] Treatment difference (cefiderocol minus meropenem) is the adjusted estimate of the difference in the all-cause mortality rate at Day 28 or at the EOS visit between the 2 treatment arms based on Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor. The 95% CI (2-sided) is based on a stratified analysis using Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor. The CI is calculated using a normal approximation to the difference between 2 binomial proportions (Wald method).

Source: Tables 14.2.2.1.1, 14.2.3.1.1, 14.2.1.1.1, and 14.2.4.1.1

Cefiderocol has demonstrated similar all-cause mortality at Day 28, clinical and microbiological

outcomes to HD meropenem (Table 62) [239]. The microbiological eradication at TOC was

47.6% (59/124) in the cefiderocol group and 48.0% (61/127) in the HD meropenem group and

the clinical cure at TOC was 64.8% (94/145) in the cefiderocol group and 66.7% (98/147) in

the HD meropenem group [239]. All-cause mortality at Day 28 and at EOS was also similar

between the treatment groups [239].

Table 62: Secondary Endpoints (mITT Population)

Endpoint

Cefiderocol

(N = 145) n/N’ (%)

HD meropenem

(N = 147)

n/N’ (%)

Microbiological eradication at TOC 59/124 (47.6) 61/127 (48.0)

Clinical cure at TOC 94/145 (64.8) 98/147 (66.7)

Day 28 all-cause mortality 30/143 (21.0) 30/146 (20.5)

EOS all-cause mortality 38/142 (26.8) 34/146 (23.3)

EOS, end of study; TOC, test of cure



Efficacy data across different pathogens

A similar response between cefiderocol and HD meropenem was observed across different

pathogens (Table 63) [239].

Table 63: Clinical and microbiological outcome per baseline pathogen

Cefiderocol (n=145)

HD Meropenem (n=147)

Treatment comparison

Difference (%)

95% CI

Clinical cure at TOC (mITT)

K. pneumoniae 31/48 (64.6) 29/44 (65.9) −1.3 (−20.8, 18.1)

P. aeruginosa 16/24 (66.7) 17/24 (70.8) −4.2 (−30.4, 22.0)

A. baumannii 12/23 (52.2) 14/24 (58.3) −6.2 (−34.5, 22.2)

E. coli 12/19 (63.2) 13/22 (59.1) 4.1 (−25.8, 33.9)

Microbiological eradication at TOC (mITT)

K. pneumoniae 22/48 (45.8) 24/44 (54.5) −8.7 (−29.1, 11.7)

P. aeruginosa 9/24 (37.5) 11/24 (45.8) −8.3 (−36.1, 19.5)

A. baumannii 9/23 (39.1) 8/24 (33.3) 5.8 (−21.7, 33.2)

E. coli 10/19 (52.6) 11/22 (50.0) 2.6 (−28.0, 33.3) HD, high-dose; TOC, test of cure; Source: Data on file [239]

5.4.4.3.3 Efficacy data based on susceptibility to meropenem

In a subgroup analysis including a small sample of patients with meropenem-non-susceptible

Gram-negative pathogens (as per CLSI break point of 8mg/L), post hoc analyses of subjects

with values of > 16 μg/mL, > 32 μg/mL, and > 64 μg/mL, showed a trend of lower mortality in

the cefiderocol group than in the meropenem group at Day 14 and Day 28; however, the

sample sizes are too small to draw definitive conclusions (Figure 43) [239].


Figure 43: Day 14 and Day 28 all-cause mortality according to MIC for meropenem

HD, high dose; MIC, minimum inhibitory concentration; Source: Data on file [239]

Microbiological and clinical outcomes at TOC in the subgroup of meropenem-nonsusceptible

subjects are shown in Table 64. The meropenem–nonsusceptible subgroup includes

intermediate and resistant categories of susceptibility. At TOC, the microbiological eradication

rate was 40.0% (14/35) in the cefiderocol group and 33.3% (10/30) in the meropenem group,

and the clinical cure rate was 57.1% (20/35) in the cefiderocol group and 56.7% (17/30) in the

meropenem group.


Table 64: Microbiological and Clinical Outcome for the Meropenem-non-

susceptible Subgroup (mITT Population)

Meropenem-nonsusceptible Status = Yesa

Cefiderocol (N = 145) n/N’ (%)

HD Meropenem (N = 147) n/N’ (%)

Total (N = 292) n/N’ (%)

Treatment Comparisonb

Difference (%) 95% CI (N’ = 35) (N’ = 30) (N’ = 65)

Microbiological eradication at TOC

14 (40.0) 10 (33.3) 24 (36.9) 6.7 (-16.7, 30.1)

Clinical cure at TOC

20 (57.1) 17 (56.7) 37 (56.9) 0.5 (-23.7, 24.6)

CI = confidence interval; CLSI = Clinical and Laboratory Standards Institute; EOS = end of study; mITT = modified intent=to-treat; N’ = number of meropenem-nonsusceptible subjects; TOC = test of cure [a] The meropenem-nonsusceptible status for subjects was Yes if for any baseline Gram-negative pathogens

(including Stenotrophomonas maltophilia) the CLSI results were nonsusceptible to meropenem. Subjects who did not have any susceptibility results available at baseline based on CLSI were not included for this analysis.

[b] Treatment difference is cefiderocol minus meropenem. The 95% CIs (2-sided) of treatment difference were calculated using a normal approximation to the difference between the 2 binomial proportions (Wald method). The CIs for cure rates within a visit with less than 10 subjects in any treatment arm are not presented.

Source: Tables 14.2.2.1.4 and 14.2.3.1.4

When analyzing microbiological eradication rates based on different CLSI MIC for

meropenem in the non-susceptible group, data suggests that cefiderocol retains

microbiological eradication as MIC for meropenem increases, whereas for it HD

meropenem decreased (Figure 44).

Figure 44: Microbiological eradication by MIC at EOT

EOT, end of treatment; HD, high dose; MIC, minimum inhibitory concentration; Source: Data on file [239]


Feasibility for NMA in nosocomial pneumonia:

A feasibility assessment was carried out for an NMA for APEKS-NP trial. It proved

not to be possible to conduct an NMA, given that the comparator used in APEKS

NP trial (HD meropenem) was not used in other trials alone, and there was no

bridging study. Even though the molecule is the same, this higher dose and

prolonged infusion optimizes efficacy of meropenem. In addition, APEKS NP

included difficult to treat pathogens such as Acinetobacter baumannii, which are

not included in other clinical trials because they are not susceptible to the newer

drugs. For full information on the feasibility assessment please refer to [227].

5.4.4.4 Comparative analysis of estimated success rates considering the European pathogen epidemiology in the population with suspected MDR/CR infections

In the absence of antibiogram, cefiderocol provides the best predicted susceptibility rates and

estimated success rates considering the European pathogen epidemiology

When critically ill patients require immediate treatment in the absence of AST, the likelihood of

treatment success with cefiderocol and comparators can be predicted through a simple

effectiveness model, that projects the clinical trials outcomes in terms of microbiological

eradication and clinical cure for each of antimicrobials, for a scenario where an antimicrobial

prescription is required in the absence of an antibiogram for a suspected MDR pathogen. This

analysis is therefore based on epidemiology (pathogen prevalence estimates for the specific

site of infection, taken from eCDC) and pathogen susceptibility results (taken from the SIDERO

studies, when selecting pathogens already resistant to ciprofloxacin and cefepime), relying on

drug’s ability to achieve effective concentrations to the infections site. This weighed

susceptibility is then overlaid with the individual relevant antimicrobial outcomes in the clinical

trials for each infection site.


Results for cUTI and pneumonia are shown below [266-269].

Table 65: Susceptibility and effectiveness model predicting outcomes for

Cefiderocol versus comparators in UTI

UTI

Susceptibility

*EPI

Microbiological

eradication at TOC (m-

ITT) from clinical trials

Projected Microbiological

eradication at TOC in the

Suspected population

Clinical Cure at

TOC from

clinical trials

Projected Clinical

Cure at TOC in

the Suspected

antimicrobial

cefiderocol 94.28% 73.00%1 68.82% 89.70%1 84.57%

ceftolozane

/tazobactam 63.87% 80.40%2 51.35% 92.00%2 58.76%

ceftazidime

/avibactam 84.79% 77.40%3 65.63% 70.20%3 59.53%

Source: 1-APEKS cUTI trial; 2- EPAR for Zerbaxa [270] ; 3 RECAPTURE [271],

Results from this effectiveness model analysis showed that cefiderocol has a higher predicted

susceptibility rates in the European prevalent Gram-negative bacteria than comparators in

cUTI and higher projected treatment success rates both microbiological eradication and clinical

cure (Table 65). Given the higher susceptibility rates for cefiderocol, these results are generally

consistent with actual results from the APEKS cUTI trial, but not for comparators as the analysis

included pathogens for which they are not susceptible, situation that can occur in the need to

immediate treatment in the absence of an antibiogram.

Table 66: Susceptibility and effectiveness model predicting outcomes for

Cefiderocol versus comparators in Pneumonia

Pneumonia Susceptibility

*EPI

Microbiological

eradication at

TOC (m-ITT) from

clinical trials

Projected Microbiological

eradication at TOC in the

Suspected population

Clinical Cure at

TOC from

clinical trials

Projected

Clinical Cure

at TOC in the

Suspected

antimicrobial

cefiderocol 92.70% 47.60% 44.13% 64.8% 60.07%

meropenem

(MIC>8mg/mL) 58.29% 50.00%1 29.15% 65.1% 37.95%

ceftolozane/tazobactam 47.55% 73.10% 34.76% 54.4% 25.87%

ceftazidime/avibactam 65.27% 54.00% 35.25% 68.8% 44.91%


Sources for cefiderocol and comparator data: APEKS-NP (1- for meropenem only results of the

subgroup MIC>8mg/mL were considered); EPAR for Zerbaxa [270], Torres 2018 [272], Torres 2019

[273]

Furthermore, for pneumonia, results from this effectiveness model analysis showed that

cefiderocol has a higher predicted susceptibility and higher predicted treatment success rates

from both a clinical and microbiological perspective. These results are generally consistent with

actual results from the APEKS NP clinical trials, but not for comparators as the analysis

included pathogens for which they are not susceptible (Table 66). Even though a similar

breakpoint of 8mg/L was considered for both APEKS NP and susceptibility analysis in SIDERO

studies, the high dose, prolonged infusion meropenem regimen used in APEKS NP trial,

showed to be effective in pathogens with MICs up to 16mg/ml, reason why the results observed

in this effectiveness model and the clinical trial for the meropenem susceptible group are

different.

Such methodologies are required, when ethical considerations limit clinical trials design to

intendedly risk exposing patients to potentially ineffective drugs. Also, since NMAs are based

on the non-inferiority clinical trials results (which excludes non-susceptible pathogens) the

results obtained between the 2 methodologies are therefore understandably different, but

consistent:

the effectiveness model highlights the potential difference in

effectiveness between different drugs, obtained when antimicrobial

prescription is needed in the absence of antibiogram

the NMA reinforces the notion that similar results are obtained

between drugs when comparing effectiveness in similar patient

population with similar pathogen distribution (i.e. pathogen is

sensitive to both drugs, and both drugs reach the infection site in

effective concentrations, which can occur when antibiogram is

available and prescription is targeted).

Also to note that the results of this effectiveness model will vary according with the local

epidemiology, and changes in susceptibility patterns for each of the drugs.


5.4.4.5 CREDIBLE-CR

The CREDIBLE CR study was a small, descriptive, randomised, open label, descriptive study

conducted to evaluate efficacy in patients with confirmed CR infections for cefiderocol and

BAT, not designed or powered for statistical comparison between arms (Figure 45). The study

included 150 severely ill patients randomised 2:1 between the treatment groups, consistent

with compassionate use cases, with a range of infection sites including nosocomial pneumonia,

cUTI, BSI/sepsis. Many patients had end stage comorbidities and had failed multiple lines of

therapy.

This study, alongside with the compassionate use cases inform the efficacy of cefiderocol in

the population with confirmed CR infection.

Figure 45: CREDIBLE CR study design

5.4.4.5.1 Primary endpoint analysis

Primary endpoint for HAP/VAP/HCAP and BSI/sepsis: clinical cure rate

Primary endpoint for cUTI: microbiological outcome

Results of clinical cure and microbiological eradication were similar between arms in each point

in time, with the highest differences being observed in patients with cUTI and follow-up visit.

One should remeber that this is a descriptive study without any formal comparison, and

furthermore, the number of patients in each group is too small to derive any conclusions other

than that cefiderocol demonstrated activity, from both a clinical and microbiological outcomes,

in all 3 infection sites (Figure 46 and Figure 47) [242].


Figure 46: Clinical cure by Clinical Diagnosis and time point

BAT, best available therapy; BSI, bloodstream infection; cUTI, complicated urinary tract infection; EOT, end of

treatment; FU, follow-up; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; Micro-

ITT, microbiological intent-to-treat; TOC, time of cure; VAP, ventilator-associated pneumonia; Source: Data on

file [242]

Figure 47: Microbiological eradication by Clinical Diagnosis and time point

BAT, best available therapy; BSI, bloodstream infection; cUTI, complicated urinary tract infection; EOT, end of

treatment; FU, follow-up; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; Micro-

ITT, microbiological intent-to-treat; TOC, time of cure; VAP, ventilator-associated pneumonia; Source: Data on

file [242]


5.4.4.5.2 Efficacy data across different pathogens

Outcomes by pathogen were broadly similar between the treatment groups. Cefiderocol has

demonstrated efficacy across all main pathogens [242].

Table 67: Clinical cure and microbiological eradication by baseline CR-pathogen

CR Micro-ITT population Cefiderocol (n=80)

BAT (n=38)

Clinical cure 42/80 (52.5)

19/38 (50.0)

CR A. baumannii 16/37 (43.2)

9/17 (52.9)

CR P. aeruginosa 7/12 (58.3) 5/10 (50.0)

CR K. pneumoniae 18/27 (66.7)

6/12 (50.0)

Microbiological eradication 25/80 (31.3)

9/38 (23.7)

CR A. baumannii 10/37 (27.0)

5/17 (29.4)

CR P. aeruginosa 1/12 (8.3) 2/10 (20.0)

CR K. pneumoniae 13/27 (48.1)

3/12 (25.0)


Against the most difficult-to-treat pathogens with New Delhi metallo-β-lactamase (NDM),

metallo-betalactamases or porin channels mutations, cefiderocol showed to be an effective

treatment presenting similar or better clinical and microbiological outcomes than BAT. There

were eight NDM producing Enterobacteriaceae in the cefiderocol arm and four in the BAT arm.

Six out of eight patients in cefiderocol arms had a clinical cure and microbiological response.

Of the four in the BAT arm, none responded (Figure 48). There were 14 KPC producers in the

cefiderocol group and seven in the BAT group. The clinical and microbiological responses were

similar between treatment groups (Figure 48). Porin channel mutations were present in 15

pathogens in the cefiderocol group and 9 in the BAT group with similar clinical responses.

Microbiological eradication was demonstrated in seven out of 15 pathogens in cefiderocol arm

and one out of nine in BAT arm (Figure 48). In patients with infections caused by metallo-

betalactamase producing Gram-negative pathogens, cefiderocol demonstrated benefits for

both clinical cure and microbiological responses (Figure 49), but again, numbers are too small

to derive any conclusion.


Figure 48: Clinical and Microbiological Outcomes at TOC in Enterobacteriaceae by

Carbapenemase or Porin Channel Mutation (CR Micro-ITT Population)

*OMPK35/36-deficient. Only patients with molecular data are included.

Figure 49: Clinical and Microbiological Outcomes in Metallo Β-lactamase

Producing Gram-negative Pathogens (CR Micro-ITT Population)

5.4.4.5.3 CREDIBLE-CR all-cause Mortality Data

Mortality was evaluated as part of safety assessment in the study, however, as per EUnetHTA

request, it is presented within the efficacy outcomes.

An imbalance in mortality favouring the BAT arm was observed at all time points in the study.

Table 68 and Figure 50 includes a summary of death in all subjects and by infection type at

each time point. Twenty-eight-day mortality represents a fixed time point for all patients and is


a conventional endpoint to assess both safety and efficacy in antibacterial studies. The Day 28

mortality for all subjects (i.e., all infection sites combined) was 24.8% in the cefiderocol group

and 18.4% in the BAT group. This difference was observed in pneumonia and BSI patients,

but not in subjects with cUTI.

Through EOS (Day 49), mortality for all subjects (ie, all infection sites combined) was 33.7%

in the cefiderocol group and 18.4% in the BAT group.

Table 68: Summary for All-cause Mortality in the Study (Intent to treat Population)

Infection Site All-cause Mortality Rate

Cefiderocol (N = 101) n/N (%) 95% CI

BAT (N = 49) n/N (%) 95% CI

All Infection Sites Combined N' = 101 N' = 49

Day 14 19/101 (18.8) (11.7, 27.8) 6/49 (12.2) (4.6, 24.8)

Day 28 25/101 (24.8) (16.7, 34.3) 9/49 (18.4) (8.8, 32.0)

Through EOS 34/101 (33.7) (24.6, 43.8) 9/49 (18.4) (8.8, 32.0)

Figure 50: All-cause Mortality Rates by Type of Infection

BAT, best available therapy; BSI, bloodstream infection; cUTI, complicated urinary tract infection; HAP, hospital-

acquired pneumonia; HCAP, healthcare-associated pneumonia; VAP, ventilator-associated pneumonia;


The time stratification analysis of the mortality data show that the imbalance occurs outside

the treatment effective period: 4 deaths occurred in cefiderocol arm only at very early stages

of treatment (up to day 3 when there was an early assessment), and 9 occurred after after

TOC, which are more likely to be associated with the underlying condition of the patient


Considering the 2:1 randomization, there was no significant difference in mortality rates

between day 4 and 28 (Table 68).

For completion of mortality information, there were 7 subjects in the CREDIBLE-CR study who

died after study completion are provided on file [274]. There were 2 subjects treated with

cefiderocol (Subjects 2AA001 and 3HK002) and 5 subjects treated with best available therapy

(BAT; Subjects 3HN001, 3HJ001, 3HJ004, 3HM003, and 3FG010) who died after study

completion. Neither of the 2 cefiderocol-treated subjects, but 3 of the 5 subjects treated with

BAT (3HN001, 3HJ004, and 3FG010) had Acinetobacter baumannii as a causative pathogen

at baseline.

The population in the CREDIBLE-CR study was designed to be very heterogeneous as it was

a pathogen-focussed study which included subjects with many underlying conditions, different

infection sites and infections due to a variety of Gram-negative pathogens. The study was

relatively small (101 subjects treated with cefiderocol and 49 subjects treated with BAT) and

due to the heterogeneity of the population the treatment groups do not appear to be balanced

for baseline characteristics such as shock (which has a major impact on mortality) in the

subgroup of subjects with A. baumannii infections. It is likely that the mortality imbalance

observed is due to a variety of factors related to baseline imbalances. [275]

When considering baseline pathogens, mortality was lower in cefiderocol-treated subjects than

BAT-treated subjects for the Enterobacteriaceae and the higher mortality was seen for the non-

fermenters. Many subjects had co-infection with multiple non-fermenters (Table 69). The

difference seen in non-fermenters was mostly due to the difference seen with A. baumannii.

The mortality rate for subjects with P. aeruginosa alone without Acinetobacter spp. as a co-

pathogen was the same in each treatment group being 18.2% (2/11 subjects) for cefiderocol

and 18.2% (2/11 subjects) for BAT [50].


Table 69: Summary for all-cause mortality overall by pathogens subgroup

(Enterobactereacea and non-fermenters)

Source: Response to D90 [276]

In subjects with A. baumannii infection and a history of shock (both shock at baseline and a

history of shock within 31 days of baseline), mortality rates were much higher than in subjects

without a history of shock in both treatment groups [277]. The proportion of subjects with a

history of shock was higher for the cefiderocol group than for the BAT group and so given the

high mortality rates reported for subjects with shock, the increased incidence of a history of

shock in cefiderocol-treated subjects with A. baumannii may provide an explanation for some

of the difference in mortality rates between the treatment groups in the CREDIBLE-CR study

(Table 70).

Table 70: CREDIBLE-CR study: Mortality subgroup Analysis for Subjects with A.

baumannii (safety population)

Subgroup

Cefiderocol (N=39) BAT (N=17)

N’/N (%)

All-cause mortality n/N' (%) N’/N (%)

All-cause mortality n/N' (%)

Overall 39 19/39 (48.7) 17 3/17 (17.6)

Shock within 31 days of baseline

Yes 9/39 (23.1) 7/9 (77.8) 1/17 (5.9) 1/1 (100)

No 30/39 (76.9) 12/30 (40.0) 16/17 (94.1) 2/16 (12.5)

Shock ongoing at baseline

Yes 7/39 (17.9) 6/7 (85.7) 1/17 (5.9) 1/1 (100)

No 32/39 (82.1) 13/32 (40.6) 16/17 (94.1) 2/16 (12.5)

ICU at baseline

Yes 32/39 (82.1) 15/32 (46.9) 8/17 (47.1) 1/8 (12.5)

No 7/39 (17.9) 4/7 (57.1) 9/17 (52.9) 2/9 (22.2)

BAT = best available therapy; ICU = intensive care unit; N = number of subjects with A baumannii.; N’ = number of subjects in subgroup


5.4.4.5.4 Comparison of CREDIBLE-CR mortality with other studies

Whereas the mortality rate in the cefiderocol group was consistent with previous studies in

similar populations with high levels of A. baumannii infections ([142, 278, 279]), the mortality

rate in the BAT group was substantially lower than expected from previous studies (Figure 51)

[142, 244, 275, 278-283]. The reason for the lower than expected mortality in the BAT group

is not clear but is likely also due to a variety of factors related to baseline imbalances and other

anomalies (such as the low mortality associated with high APACHE II and SOFA scores). The

evidence suggests that the mortality rate in the BAT group was unexpectedly low for the

population randomised and that the mortality in the cefiderocol group was consistent with what

has been reported in previous studies.

Figure 51: Mortality rates comparison across studies

No other factors that indicated disease severity were identified that clearly contributed to the

mortality imbalance seen between treatments [275].

In conclusion, the difference in mortality between treatments in the CREDIBLE-CR study still

cannot be fully explained. However, there are plausible factors contributing to the mortality

difference in this pathogen-focussed study. The 2:1 randomisation, the small study size, and

the heterogeneity of the patient population, particularly the inclusion of multiple infection sites

and diverse comorbidities, means that it was difficult to ensure that treatment groups were

balanced for all baseline factors. Other than a history of shock, and possibly low WBC count,

no individual baseline characteristic has been identified which could clearly be linked to this


imbalance. A mortality imbalance was not observed in the APEKS-NP study overall, including

in the subset of subjects infected with A. baumannii [276]. The evidence suggests that the

mortality rate in the BAT group was unexpectedly low for the population randomised and that

the mortality in the cefiderocol group was consistent with what has been reported in previous

studies.

5.4.4.6 Compassionate Use

To date, over 200 patients were treated with cefiderocol, worldwide, within compassionate use

programme. Data for 74 patients who have completed therapy is available, of which only 3

positive outcomes are published to date [246-248]. This programme included patients with a

diversity of infections beyond those presented in the clinical trials, with a baseline patient

characteristics consistent with that of CREDIBLE CR as per previously detailed in section 5.3

5.4.4.6.1 Clinical efficacy and safety

Over 60% of the patients receiving cefiderocol survived when no other possible treatment

option were available to them [244]. Of these, 17 died due to their underlying infection, 6 died

for reasons other than the original bacterial infection, and other causes of death remained

unknown [244]. However, none of the observed deaths were considered to be related to

cefiderocol [245]. Cefiderocol has demonstrated a manageable safety profile with the longest

use being more than 90 days in a renal transplant patient where no apparent safety issues

were observed [244].

Table 71: Mortality and serious adverse events

Mortality, n (%) Cefiderocol (n=74)

Overall mortality 27 (36.5)

Overall mortality by pathogen

Acinetobacter baumannii 12/22 (54.5)

Klebsiella pneumoniae 2/7 (28.6)

Burkholderia cenocepacia 4/10 (40)

Pseudomonas aeruginosa 9/31 (29)

Abnormal LFTs 4 (5.4)

Multiple organ failure 6 (8.1)

Acute renal failure 3 (4.1)

Cardiac arrest 2 (2.7)

Sepsis or septic shock 5 (6.8) LFT, liver function test; SAE, serious adverse event; Source: NDA briefing document[244]; Data on file [245]


5.4.4.7 Published case reports

Case reports for three patients from the expanded access program have been

published so far.

A patient was treated successfully for endocarditis due to extensively drug

resistant (XDR) Pseudomonas aeruginosa.(Edgeworth et al., 2019)[246]

A patient with multiple comorbidities and a complicated intra-abdominal infection

(IAI) due to MDR Pseudomonas aeruginosa was released from hospital care

within six weeks of completion of cefiderocol treatment. (Stevens et al.,

2019)[247]

A patient with VAP and BSI caused by XDR Acinetobacter baumannii and

carbapenemase-producing Klebsiella pneumoniae had potentially serious organ

failure from older anti-infectives. Six weeks after cefiderocol administration, chest

X-rays showed complete resolution of infection (Trecarichi et al., 2019)[248]


5.4.5 Resistance against Cefiderocol

5.4.5.1 In vitro resistance development

Resistance development to Cefiderocol has been investigated using the standard

in vitro experiments to determine the frequency of spontaneous resistance and to

observe the adaptation of pathogens during serial passaging.

Frequency of spontaneous resistance: The frequency of spontaneous resistance

of E. coli, E. cloacae, K. pneumoniae, and P. aeruginosa (8 strains in total) was

determined in the presence of 10 × MIC of cefiderocol. If resistant mutants were

isolated, the in vitro activity of cefiderocol against the mutant strains was

determined and compared to the susceptibility of the parent strains. The

magnitude of the order of frequency of the resistance for cefiderocol was similar

to ceftazidime with a frequency of 10−7 to 10−8 except for P. aeruginosa for which

the frequency ranged from 10−6 to 10−8. Cefiderocol MIC increase was shown to

be associated with the mutation in the upstream region of pvdS (pyoverdine

synthesis gene) and fadD3 (fatty acyl-CoA synthetase) in P. aeruginosa, and

baeS, envZ, ompR (all are 2-component signal transduction gene), and exbD

(biopolymer transport gene) in K. pneumoniae.

Resistance acquisition assay by serial passage: Resistance acquisition was

evaluated for K. pneumoniae, and P. aeruginosa (5 strains in total) by a 10 times

serial passage in two different media. The MIC of cefiderocol increased in general

1 to 4-fold but for one strain up to 8-fold.

Resistance acquisition by using an in vitro pharmacodynamic model: To estimate

the risk of emergence of cefiderocol-resistant mutants during the treatment of

patients, in vitro PD models simulating the free concentration-time curves in

human plasma was used. The simulated concentration-time curves were

determined for a 2-g cefiderocol q8h administration with 3-hour infusion, 2-g/0.5

g CAZ/AVI q8h administration with 2-hour infusion, and 1-g MEPM q8h

administration with 1-hour infusion. Against all 3 strains, cefiderocol showed rapid

bacterial reduction within 4 hours. Regrowth was observed for one strain, but no

growth was observed with a MIC of ≥ 10 mg/L and no resistant colonies to

cefiderocol were detected at the 24- and 72-hour time points.


5.4.5.2 MIC shifts during therapy

During the clinical studies, 4-fold MIC increases have been observed with both cefiderocol and

the comparators. Table 72 is summarising the MIC shift observed:

Table 72: Summary of MIC shift

APEKS-cUTI APEKS-NP CREDIBLE CR

Cefidero

col

(N=252)

imipene

m/

cilastatin

(N=119)

Cefidero

col

(N=145)

HD

meropenem

(N=147)

Cefiderocol

(N=101)

BAT

(N=49)

Nb patients with 4-

fold MIC increase 7 3 9* 9 15** 5

% patients with 4-

fold MIC increase 2.8% 2.5% 6.2% 6.1% 14.8% 10.2%

*1 subject with postbaseline MIC>4 mg/L**only 3 with postbaseline MIC>4mg/L, in the APEKS-cUTI none of the strains had an

MIC>4 mg/L postbaseline.

In the 3 clinical studies, a similar percentage of subjects with 4-fold MIC increase was observed

in both the cefiderocol and the comparator treatment group. Only in 4 subjects the MIC

observed postbaseline was above the unbound concentration of cefiderocol in plasma of 4

mg/L. Molecular characterisation of the strains with increased MICs is not completed yet.

In conclusion, as for other antibacterial, in vitro resistance development was observed for

cefiderocol similar to ceftazidime. In clinical trials, MIC’s increase was also observed with the

same magnitude in both treatment gourps (ie cefiderocol and comparators). The HD

meropenem was not sufficient to fully repress increase in MICs during treatment of patient with

nosocomial pneumonia.


Table 73a: Methods of data collection and analysis of Mortality

Study

reference/ID

Endpoint definition Method of analysis

APEKS-NP All-cause mortality at Day 14 since first

infusion of study drug (ACM): All-cause

mortality rate at Day 14 since first infusion of

study drug will be calculated as the proportion

of patients who experienced mortality

regardless of the cause at or before Day 14

since first infusion.

ACM at Day 28: All-cause mortality rate at Day

28 since first infusion of study drug will be

calculated as the proportion of patients who

experienced mortality regardless of the cause

at or before Day 28 since first infusion.

.

ACM by treatment group will be calculated as the proportion of patients who experienced mortality

regardless of the cause at or before Day 14. The adjusted estimates of the difference in ACM at Day

14 between cefiderocol and meropenem will be presented along with 95% confidence intervals (CIs)

based on a stratified analysis using Cochran-Mantel-Haenszel (CMH) weights. The CI will be 2-sided.

Cochran-Mantel-Haenszel weights will be calculated with APACHE II score (≤ 15 and ≥ 16) as the

stratified factor.

Sensitivity analysis for missing Day 14 ACM status will be implemented as follows: subjects with

unknown mortality status at Day 14 in the cefiderocol group will be imputed as “Death” while any

subject with unknown mortality status at Day 14 in the Meropenem arm will be imputed as “Alive “.

The estimates of the difference in the ACM at Day 14 between cefiderocol and meropenem will be

presented along with 95% confidence intervals (CIs) (Wald method) if data warrant. If the number of

subjects within a subgroup is less than 10 in any treatment arm, only the difference in the ACM

between the two treatment arms (no CI) will be presented. The CI will be 2-sided. Similar analysis will

also be carried out for Day 28 all-cause mortality.

Analysis for Day 14 ACM will also be performed by excluding subjects who are meropenem resistant

in the mITT analysis population as a supplementary analysis. Subjects who are meropenem resistant

will be determined from central laboratory culture results

Analyses of ACM at Day 14 will be presented for the following subgroups:

Clinical diagnosis, Gender, Race, Age, Region and Baseline clinical characteristics.

ACM rate during treatment and follow-up

period (until EOS)

ACM rate during treatment and follow-up period (until EOS) will be calculated as the proportion of

patients who experienced mortality regardless of the cause at or before EOS since the first infusion.


If a subject discontinues from the study before this period and survival information was not available,

then the survival status for this endpoint for the subject will be unknown.

All-cause until EOS visit will be analysed in a similar way to the Primary Efficacy endpoint described

CREDIBLE-CR All-cause mortality at Day 14 and Day28 for

HAP/VAP/HCAP and BSI/sepsis.

Survival time (HAP/VAP/HCAP, BSI/sepsis)

All-cause mortality rate with 95% CI at Day 14, Day 28 and overall by treatment group will be

calculated as the proportion of subjects who experienced mortality regardless of the cause at or

before Day 14 and Day 28, respectively. In this analysis, deaths occurring after EOS will not be used

for analysis and any subject who does not have vital status information at Day 14 and 28 will not be

included in the analysis. This analysis will be performed for both CR MITT and ITT Population.

In addition, for CR MITT Population, subgroup analysis regarding all-cause mortality at Day 28 will be

performed. For the survival time up to End of Study (EOS), the survival curve using Kaplan-Meier

method by treatment group will be presented. For the subjects whose vital status is survival at EOS,

the subjects will be treated as right-censored at EOS. For the subjects whose vital status is not

collected or unknown, the subjects will be treated as right-censored at last visit day.

All-cause mortality rate at Day 14, Day 28 and overall including death after EOS will be calculated by

treatment group for ITT population.

EA: Early Assessment, EOT: End of Treatment, TOC: Test of Cure, FUP: Follow-up, MAX


Table 80b: Methods of data collection and analysis of Clinical outcomes

Study

reference/ID


APEKS-cUTI Clinical response at EA

Clinical Cure: Resolution or improvement of

baseline signs and symptoms of cUTI at EA or

return to pre-infection baseline if known.

Clinical Failure: No apparent response to

therapy, persistence of signs and/or symptoms

of cUTI infection beyond pre-infection baseline,

or reappearance of signs and/or symptoms, at

or before the EA.

Indeterminate: Lost to follow-up such that a

determination of clinical response (cure,

improvement, or failure) cannot be made.

Clinical response at EOT and TOC

Clinical Cure: Resolution or improvement of

baseline signs and symptoms of cUTI, or return

to pre-infection baseline if known, at EOT and

TOC.


therapy, persistence of signs and/or symptoms

of cUTI infection beyond pre-infection baseline,

or reappearance of signs and/or symptoms, at

or before the EOT and/or TOC visit.


determination of clinical response (success or

failure) cannot be made.

Subject reported symptoms identified at baseline will be assessed at EA, EOT, TOC, and FUP utilizing

a Structured Subject Interview (see Appendix 3 of the study protocol [237]) that will evaluate whether

the symptom is still present (and if so the degree of that symptom, i.e., mild, moderate, or severe) or

returned to baseline.

Clinical response will be determined by the investigator based upon resolution or improvement of

clinical signs and symptoms of cUTI prior to receiving any potentially effective antibacterial therapy

for cUTI and subject reported symptoms noted in the Structured Subject Interview. Baseline

symptoms associated with anatomic abnormalities that predisposes to cUTI do not need to be

resolved for a consideration of a successful responder.

For the primary analysis, the clinical response will be a dichotomy (cure or failure) based on the

clinical outcome as assessed by the investigator taking into consideration objective data

(temperature, WBC, urinalysis) and patient reported symptoms noted in the Structured Patient

Interview.

The clinical outcome of interest at EA, EOT, and TOC will be the proportion of subjects who have a

clinical outcome of cure. The outcome of interest at FUP will be the proportion of subjects with

sustained clinical cure.


Clinical response at FUP

Sustained Clinical Cure: All pre-therapy signs

and symptoms of cUTI show no evidence of

recurrence after administration of the last dose

of study drug.

Failure: Patients carried forward from TOC.

Relapse: Signs and/or symptoms of cUTI that

were absent at TOC reappear at the FUP.


determination of clinical response (success or

failure) cannot be made

APEKS-NP Clinical response

Clinical Cure: Resolution or substantial

improvement of baseline signs and symptoms

of pneumonia, including a reduction in

Sequential Organ Failure Assessment (SOFA)

and Clinical Pulmonary Infection (CPIS) scores,

and improvement or lack of progression of

chest radiographic abnormalities such that no

additional antibacterial therapy is required for

the treatment of current infection at the EA and

EOT visits, and no antibacterial therapy is

required for the treatment of the current

infection at the TOC.


therapy; persistence or worsening of baseline

signs and/or symptoms of pneumonia;

reappearance of signs and/or symptoms of

The clinical outcomes will be assessed by the investigator according to the described criteria at EA,

EOT and TOC.

The clinical response rate at Early Assessment, End of Treatment and Test of Cure will be calculated

as the proportion of subjects who have a clinical outcome of cure. The adjusted estimate of the

difference in the cure rate between the 2 treatment groups will be presented along with the adjusted

95% CIs based on the CMH weights: diagnosis and APACHE II score. In addition, the number and

proportion of subjects having clinical outcome as failure and indeterminate will be summarized by

treatment group.

Results will be presented per Infection site, Pathogen and Non-fermenters


pneumonia; development of new signs and/or

symptoms of pneumonia requiring antibacterial

therapy other than, or in addition to, study

treatment therapy; progression of chest

radiographic abnormalities; or death due to

pneumonia.


determination of clinical cure/failure cannot be

made.

APEKS-NP Sustained Clinical Cure: Continued resolution

or substantial improvement of baseline signs

and symptoms of pneumonia, such that no

antibacterial therapy has been required for the

treatment of pneumonia in a subject assessed

as cured at TOC.

Relapse: Recurrence of signs and/or

symptoms of pneumonia, appearance of new

signs and/or symptoms of pneumonia, or new

chest radiographic evidence of pneumonia in a

subject assessed as cured at TOC.

Clinical Failure: Clinical failure at TOC will be

carried forward regardless of lost to follow-up.

Indeterminate: Lost to follow-up, such that a

determination of clinical sustained cure/relapse

cannot be made, or subject received additional

antibacterial therapy for the treatment of the

current infection.

The clinical outcome at FU will be assessed by the investigator according to the

described criteria.

The cure rate at FU will be calculated as the proportion of subjects with clinical outcome of sustained

clinical cure. In addition, the number and proportion of subjects having clinical outcome as relapse,

clinical failure and indeterminate will be summarized by treatment group.

The same analysis method as described above for clinical outcome per subject at EA, EOT and TOC

will be performed for the clinical outcome per subject FU.

The outcome will be tabulated for each treatment group. The adjusted estimate of the difference in

the response rate between the 2 treatments arms along with the adjusted 95% CIs based on the CMH

weights will be presented.

CREDIBLE-CR HAP/VAP/HCAP: Efficacy Criteria for Infection Site Specific Clinical Outcomes assessed at EA, EOT, and TOC


● Clinical Cure: Resolution or

substantial improvement of baseline

signs and symptoms of pneumonia

including a reduction in SOFA and

CPIS scores, and improvement or lack

of progression of chest radiographic

abnormalities such that no additional

antibacterial therapy is required for the

treatment of the current infection.

● Clinical Failure: No apparent

response to therapy; persistence or

worsening of baseline signs and/or

symptoms of pneumonia;

reappearance of signs and/or

symptoms of pneumonia;

development of new signs and/or

symptoms of pneumonia requiring

antibacterial therapy other than, or in

addition to, study treatment therapy;

progression of chest radiographic

abnormalities; or death due to

pneumonia.

● Indeterminate: Lost to follow-up such

that a determination of clinical

cure/failure cannot be made.

cUTI



The clinical outcomes will be assessed by the investigator according to the described criteria

established for each infection site at EOT and TOC. In case treatment duration is extended beyond

14 days, an additional clinical outcome will be assessed on Day 14.

Sequential Organ Failure Assessment score (SOFA) and its change from baseline will be summarized

by treatment group per infection site at Baseline, EOT, TOC, and FU. Change from baseline will also

be summarized. In addition, SOFA score regardless of primary infection diagnosis will be analysed in

a similar manner.

For the HABP/VABP/HCABP subjects, CPIS at EOT, TOC, and FU will be summarized by treatment

group.


signs and symptoms of cUTI, or return

to pre-infection baseline if known,

such that no additional antibacterial

therapy is required for the treatment of

the current infection.




symptoms of cUTI; or reappearance of

signs and/or symptoms of cUTI;

development of new signs and/or

symptoms of cUTI requiring



or death due to cUTI.




BSI/Sepsis



signs and symptoms including a

reduction in SOFA score, such that no

additional antibacterial therapy is

required for the treatment of

BSI/sepsis. Patients with bacteraemia

must have eradication of bacteraemia

caused by the Gram-negative


pathogen.




symptoms, reappearance of signs

and/or symptoms; development of

new signs and/or symptoms requiring



or death due to BSI/sepsis.




CREDIBLE-CR HAP/VAP/HCAP:

● Sustained Clinical Cure: Continued

resolution or substantial improvement

of baseline signs and symptoms of

pneumonia, such that no additional


treatment of pneumonia in a patient

assessed as cured at TOC.

● Relapse: Recurrence of signs and/or

symptoms of pneumonia, appearance

of new signs and/or symptoms of

pneumonia, or new chest radiographic

evidence of pneumonia in a patient

Efficacy Criteria for Infection Site Specific Clinical Outcomes assessed at FUP will be determined

according to the described criteria above.


assessed as cured at TOC.



sustained cure/relapse cannot be

made, or patient received additional

antibacterial therapy for the treatment

of the current infection.

● Clinical Failure: Clinical failure at

TOC will be carried forward regardless

of lost to follow-up

cUTI


resolution or improvement of baseline

signs and symptoms of cUTI, or return

to pre-infection baseline if known, in a

patient assessed as cured at TOC.


symptoms of cUTI, or appearance of

new signs and/or symptoms of cUTI in

a patient assessed as cured at TOC.











BSI/Sepsis


resolution or substantial improvement

of baseline signs and symptoms

associated with reduction in SOFA

score, such that no additional


treatment of the patient’s original

BSI/sepsis in a patient assessed as

cured at TOC.


symptoms of BSI/sepsis, or

appearance of new signs and/or

symptoms of the patient’s original

BSI/sepsis in a patient assessed as

cured at TOC.












Table 80c: Methods of data collection and analysis of Composite microbiological eradication and cure

Study

reference/ID


APEKS-cUTI Clinical and microbiologic response:

Resolution or improvement of the symptoms of

cUTI present at trial entry (and no new

symptoms) and the demonstration that

bacterial pathogen found at trial entry is

reduced to fewer than 104 CFU/mL on urine

culture at the TOC (microbiological response).

Clinical or microbiologic failure: Symptoms

of cUTI present at trial entry have not

completely resolved or new symptoms have

developed, the subject has died, or the urine

culture taken at the TOC grows greater than or

equal to 104 CFU/mL of the original pathogen

identified at trial entry.

The primary composite efficacy endpoint is based on the outcome (response or failure) for both the

clinical and microbiologic response at TOC.

The composite outcome is a “response” if both the clinical and microbiologic outcome are responses.

Clinical resolution assessed by the investigator will be defined based in part on the graded response

to the structured subject interview about the current status of the subject’s symptoms that had been

recorded at the time of randomization, and the absence of any new symptoms related to the cUTI.

Definition of clinical and microbiological outcome based on possible combinations of microbiological

outcome and clinical outcome is presented below.

At EA, EOT and TOC:

Per Subject Microbiological

Outcome Clinical Outcome

Composite of Clinical and

Microbiological Outcome

Microbiological eradication Clinical cure Response

Microbiological eradication Clinical failure Failure

Microbiological eradication Indeterminate Indeterminate

Microbiological failure Clinical cure Failure

Microbiological failure Clinical failure Failure

Microbiological failure Indeterminate Failure

Indeterminate Clinical cure Indeterminate


Indeterminate Clinical failure Failure

Indeterminate Indeterminate Indeterminate

At FUP:





Sustained eradication Sustained clinical cure Response

Sustained eradication Clinical failure Failure

Sustained eradication Clinical relapse Failure

Sustained eradication Indeterminate Indeterminate

Microbiological failure Sustained clinical cure Failure

Microbiological failure Clinical failure Failure

Microbiological failure Clinical relapse Failure

Microbiological failure Indeterminate Failure

Indeterminate Sustained clinical cure Indeterminate


Indeterminate Clinical relapse Failure


CREDIBLE-CR The definition for composite of clinical and

microbiological outcome based on possible

combinations per subject microbiological

outcome and clinical outcome is shown in the

For the composite clinical and microbiological outcome, the outcomes will be summarized and the

response rate with 95% CI at EOT, TOC, and FU will be calculated per infection site by treatment

group as the proportion of subjects who have both clinical cure and microbiological eradication.


tables for EOT and TOC, and in separate tables

for FUP

Clinical and Microbiological Outcome: EOT and TOC





Eradication Clinical cure Response

Eradication Clinical failure Failure

Eradication Indeterminate Indeterminate

Persistence Clinical cure Failure

Persistence Clinical failure Failure

Persistence Indeterminate Failure

Indeterminate Clinical cure Indeterminate



Composite Outcome: Follow-up





Sustained eradication Sustained clinical cure Response

Sustained eradication Clinical failure Failure

Sustained eradication Clinical relapse Failure

Sustained eradication Indeterminate Indeterminate

Persistence Sustained clinical cure Failure

Persistence Clinical failure Failure

Persistence Clinical relapse Failure


Persistence Indeterminate Failure

Recurrence Sustained clinical cure Failure

Recurrence Clinical failure Failure

Recurrence Clinical relapse Failure

Recurrence Indeterminate Failure

Indeterminate Sustained clinical cure Indeterminate


Indeterminate Clinical relapse Failure




Table 80d: Methods of data collection and analysis of Microbiological outcomes

Study

reference/ID


APEKS-cUTI Eradication: A urine culture shows the

bacterial uropathogen(s) identified at baseline

at ≥ 105 CFU/mL are reduced to < 104

CFU/mL.

Persistence: A urine culture shows that the

original bacterial uropathogen(s) identified at

baseline at ≥ 105 CFU/mL grows ≥ 104

CFU/mL.

Indeterminate: No urine culture or a urine

culture that cannot be interpreted for any

reason.

An overall per subject microbiological outcome will be determined at EA, EOT, TOC,

and FUP. In addition, per pathogen microbiological outcomes will be determined for baseline

uropathogens. New pathogens that emerge after study therapy is started will also be assessed. Per

subject and per pathogen microbiological outcomes will be assessed only for Gram-negative

uropathogens which are identified with quantitative measurements by the local laboratory and

confirmed by the central microbiology laboratory. If the pathogen is not sent to central microbiology

laboratory, the outcome will be only assessed by the local laboratory.

For the subjects who have Gram-positive uropathogens at baseline, the Gram-positive uropathogens

will be shown in the listing of local microbiological test and not be considered in either per pathogen

microbiological outcome or per subject microbiological outcome.

Subjects who used non-study antibacterial drug therapy with Gram-negative coverage and thus may

have a potential effect on outcome evaluation in patients with cUTI were treated as microbiological

failure at all the following analysis visits after the use of the non-study antibacterial drug therapy

regardless of outcome above.

As shown below, subjects who experience eradication of all baseline Gram-negative uropathogen(s)

at EA, EOT, and TOC will be considered” microbiological eradication” and subjects who experience

persistence of any baseline Gram-negative uropathogen will be considered” microbiological failures”.

Subjects whose experiences are other than above will be considered” indeterminate”.


The microbiological response rate at EA, EOT and TOC will be calculated as the proportion of subjects

who experience eradication at EA, EOT and TOC respectively by treatment group. The adjusted

estimate of the difference in the response rate between the 2 treatment groups will be presented along

with the 95% CIs based on a stratified analysis using the CMH weights: infection diagnosis

(HABP/VABP/HCABP) and APACHE II score (≤ 15 and ≥ 16). In addition, the number and proportion

of subjects having microbiological outcome as persistence and indeterminate will be summarized by

treatment group.

APEKS-cUTI Sustained Eradication: A urine culture

obtained after documented eradication at

the TOC, up to and including the FUP, shows

that the bacterial uropathogen(s)

identified at baseline at ≥105 CFU/mL remain

<104 CFU/mL.

Assessment of baseline Gram-negative pathogens at FUP includes sustained eradication

At FU, the per subject microbiological outcome for subjects who experience sustained eradication of

all baseline Gram-negative pathogens will be considered as “sustained eradication” and subjects who

experience recurrence of any baseline Gram-negative pathogens will have a per subject

microbiological outcome of “recurrence”. Subjects who show persistence of any baseline Gram-


• Persistence: A urine culture obtained any time

after TOC, up to and including the FUP, grows

≥104 CFU/mL of the original uropathogen. If

there are no available culture results, the

outcomes for pathogens that persisted at TOC

are carried forward to the FUP.

• Recurrence: A urine culture obtained any time

after documented eradication at the TOC, up to

and including the FUP, grows ≥104 CFU/mL of

the original uropathogen.

negative pathogens will have a per subject microbiological outcome of “persistence”. Subjects whose

experiences are other than above at FU will be considered “indeterminate”.

APEKS-NP Eradication: Absence of the baseline Gram-

negative pathogen from an

appropriate clinical specimen. Presence of

colonizers or contaminants associated

with a baseline pathogen will be associated

with microbiological outcome of

eradication. If it is not possible to obtain an

appropriate clinical culture, and the

subject has a successful clinical outcome; the

response will be presumed as eradication.

The microbiological outcomes by baseline pathogens will be determined according to the described

criteria at EA, EOT and TOC.

Subjects who experience eradication of all baseline Gram-negative

pathogen(s) at EA, EOT and TOC their per subject microbiological outcome

will be considered “eradication” and subjects who experience persistence of any baseline

Gram-negative pathogens, per subject microbiological outcome will be considered

“persistent”.” Subjects whose experiences are other than the above will be considered

“indeterminate.”


Persistence: Continued presence of the

baseline Gram-negative pathogen from an

appropriate clinical specimen. Persistence at

End of Treatment or Test of Cure will be carried

forward.

Indeterminate: No culture obtained from an

appropriate clinical specimen or if the

microbiological outcome is eradication after

additional antibacterial therapy for the

treatment of the current infection.

The microbiological response rate at EA, EOT and TOC will be calculated as the

proportion of subjects who experience eradication at EA, EOT and TOC respectively by treatment

group. The adjusted estimate of the difference in the response rate between the 2 treatment groups

will be presented along with the 95% CIs based on a stratified analysis using the CMH weights:

infection diagnosis (HABP/VABP/HCABP) and

APACHE II score (≤ 15 and ≥ 16). In addition, the number and proportion of subjects having

microbiological outcome as persistence and indeterminate will be summarized by treatment group.

APEKS-NP Sustained Eradication: Absence of the

baseline Gram-negative pathogen from an

appropriate clinical specimen after TOC.

Presence of colonizers or contaminants

associated with a baseline pathogen will be

associated with microbiological outcome of

sustained eradication. If it is not possible to

obtain an appropriate clinical culture, and the

The microbiological outcomes by baseline pathogens will be determined according to the described

criteria at FU.

At FU, the per subject microbiological outcome for subjects who experience sustained eradication of

all baseline Gram-negative pathogens will be considered as “sustained eradication” and subjects who

experience recurrence of any baseline Gram-negative pathogens will have a per subject

microbiological outcome of “recurrence”. Subjects who show persistence of any baseline Gram-


subject has a successful clinical response after

TOC, the response will be presumed

eradication.

Recurrence: Recurrence of the baseline

Gram-negative pathogen from an appropriate

clinical specimen taken after TOC, and the

TOC culture was negative.

Persistence: Persistence of any baseline

Gram-negative pathogen from an appropriate

specimen.

Indeterminate: No culture obtained from an

appropriate clinical specimen or if the

microbiological outcome is eradication after the

subject received additional antibacterial

therapy for the treatment of the current

infection.

negative pathogens will have a per subject microbiological outcome of “persistence”. Subjects whose

experiences are other than above at FU will be considered “indeterminate”.

The microbiologic response rate at FU will be calculated as the proportion of subjects who experience

sustained eradication of all baseline Gram-negative pathogens after

documented eradication at the TOC.

The same analysis method as described above for microbiological outcome per subject at EA, EOT

and TOC will be performed for the microbiologic outcome per subject at FU. The outcome will be

tabulated for each treatment group. The adjusted estimate of the difference in the response rate

between the 2 treatments arms along with the adjusted 95% CIs based on the CMH weights will be

presented.

CREDIBLE-CR HAP/VAP/HCAP

● Eradication: Absence of the baseline

Gram-negative pathogen from an

appropriate clinical specimen. If it is

not possible to obtain an appropriate

clinical culture and the patient has a

The microbiological outcomes by baseline pathogen will be determined by the sponsor according to

the described criteria established for each infection site at EA, EOT, and TOC. In case treatment

duration is extended beyond 14 days, an additional microbiological outcome will be assessed on Day

14. An overall per-subject microbiological outcome will also be determined based on the individual

microbiological outcomes for each baseline pathogen. Emergent (i.e., non-baseline) pathogens are

considered separately, and do not affect the per-subject microbiological outcome.


successful clinical outcome, the

response will be presumed as

eradication.

● Persistence: Continued presence of

the baseline Gram-negative pathogen

from an appropriate clinical specimen.

● Indeterminate: No culture obtained

from an appropriate clinical specimen

or additional antibacterial therapy for

the treatment of the current infection.

cUTI

● Eradication: A urine culture shows

the baseline Gram-negative

uropathogen found at entry at ≥ 105

CFU/mL are reduced to < 104

CFU/mL.

● Persistence: A urine culture shows

that the baseline Gram-negative

uropathogen found at entry at ≥ 105

CFU/mL grows ≥ 104 CFU/mL.

● Indeterminate: No urine culture

obtained or additional antibacterial


infection.

BSI/Sepsis

● Eradication: Absence of the baseline

Gram-negative pathogen from a blood

Subjects who experience eradication of all baseline Gram-negative pathogens at EOT and TOC will

be considered “Eradication” and subjects who experience persistence of any baseline Gram-negative

pathogen will be considered “persistence.” Subjects whose experiences are other than above will be

considered “indeterminate.” At FU, subjects who experience sustained eradication of all baseline

Gram-negative pathogens after documented eradication at the TOC will be considered “sustained

eradication” and subjects who experience eradication at TOC, but recurrence of any baseline Gram-

negative pathogen will be considered as” recurrence”, and subjects who are considered as

“persistence” at TOC will be “persistence.” Subjects whose experiences are other than above will be

considered “indeterminate.” (see Table below)

Visit Per Subject Microbiological

Outcome Definition

EOT, TOC Eradication Eradication of all baseline Gram-negative

pathogens

Persistence Persistence of any baseline Gram-negative

pathogens

Indeterminate Other than those above

FU Sustained eradication Sustained eradication of all baseline Gram-

negative pathogens after documented

eradication at the TOC

Persistence Persistence of any baseline Gram- at the TOC

Recurrence Recurrence of any baseline Gram-negative

pathogens for subject’s eradication at the TOC

Indeterminate Other than those above

EOT = End of Treatment; FU = Follow-up; TOC = Test of Cure


culture and/or other primary source.

● Persistence: Continued presence of


from a blood culture or other primary

source.


or additional antibacterial therapy for

the treatment of the current infection.

HAP/VAP/HCAP

● Sustained Eradication: Absence of



after TOC. If it is not possible to obtain

an appropriate clinical culture and the

patient has a successful clinical

response after TOC, the response will

be presumed eradication.

● Recurrence: Recurrence of the

baseline Gram-negative pathogen


taken after TOC and the TOC culture

is negative.



or patient received additional



The microbiological outcomes by baseline pathogen will be determined according to the described

criteria established for each infection site at FUP.


● Persistence: Persistence at TOC will

be carried forward.

cUTI

● Sustained Eradication: A culture

taken any time after documented

eradication at TOC, and a urine

culture obtained at FUP shows that

the baseline uropathogen found at

entry at ≥105 CFU/mL remains < 104

CFU/mL.

● Recurrence: A culture taken any time

after documented eradication at TOC,

up to and including FUP that grows

the baseline uropathogen

≥ 104 CFU/mL

● Indeterminate: No urine culture or

patient received additional




be carried forward.

BSI/Sepsis

● Sustained Eradication: Absence of



source after TOC.

● Recurrence: Recurrence of the

baseline Gram-negative pathogen



source after TOC and the TOC culture

is negative.

● Indeterminate: No culture or patient

received additional antibacterial


infection.


be carried forward.

CREDIBLE-CR New Pathogens

● Superinfection: The identification


of a new pathogen from the original

infection site. This new pathogen

must be associated with new or

persisting signs and symptoms of

infection.

● New Infection: The identification from

an appropriate clinical specimen of a

new pathogen from an infection site

different from the original infection

site. This new pathogen must be

associated with new or persisting

signs and symptoms of infection.

New pathogens that emerge on or after Day 3 will be categorized as either superinfection or new

infection as follows: Superinfection and new infection will be listed by Gram-negative pathogen and

the others.



Table 80e: Methods of data collection and analysis of Susceptibility rates

Study

reference/ID


SIDERO-WT

SIDERO-CR

Minimum inhibitory concentrations (MICs) of

cefiderocol, cefepime, ceftazidime-avibactam,

ceftolozane-tazobactam, ciprofloxacin, colistin,

and meropenem, were determined by broth

microdilution.

The range and concentration of each antimicrobial agent tested is listed below:

SIDERO-WT

SIDERO-CR

Percent susceptibility (%) calculation Percent susceptibility (%) was calculated according to CLSI interpretive criteria where available, and

the FDA interpretive criteria for ceftazidime-avibactam. In the absence of any CLSI or FDA

breakpoints for colistin tested against Enterobacteriaceae, the EUCAST

susceptible breakpoint of ≤2 μg/mL was applied.


5.5 Individual study results (safety outcomes)

1. Describe the relevant endpoints, including the definition of the endpoint and methods of

analysis (Table 94).

Endpoints are described in Dossier Table 94.

2. For the technology, and the comparator, tabulate the total number of adverse events,

frequency of occurrence (as a %), absolute and relative risk and 95% CI reported in each of

the clinical studies. Categorise the adverse events by frequency, severity and system organ

class.

This section summarizes the safety outcomes in the overall sample, based on regulatory documents,

followed by the reporting of results of safety assessments in each clinical study.

5.5.1 Overall safety results: pooled analysis and individual studies: APEKS-cUTI,

APEKS-NP, and CREDIBLE CR

The cefiderocol clinical development program to date includes information from 6 completed clinical

pharmacology studies, a completed Phase 2 study, two Phase 3 studies and cases of compassionate

Table 81 summarises the dose and exposure of patients to cefiderocol within the clinical trials, where

nearly half the patients are from APEKS cUTI that per protocol design had a maximum treatment

duration of 14 days. As so, the vast majority of patients were treated with cefiderocol between 7 to 14

days for cUTI. APEKS NP and CREDIBLE presented longer treatment durations; 52 patients receivd

treatment with cefiderocol between 14 and 22 days (mostly coming from CREDIBLE CR study).

Table 81: Dose and Duration of Exposure to cefiderocol* (Number of Patients by Indication)

*

Source: EU Risk Managing Plan for Fetcroja [284]; cUTI dose was given over 1 hour; CREDIBLE-CR and APEKS NP dose was given over

3 hours

Duration

of

exposure

(days)

cUTI study (Dose

2g cefiderocol 3

times daily (every

8 hours)

for 7-14 days)

CREDIBLE-CR study

(Dose 2g cefiderocol 3

times daily (every 8 hours)

for 7-14 days (may be

extended up to 21 days))

APEKS NP Study

(Dose 2g cefiderocol 3

times daily (every 8

hours) for 7-14 days (may

be extended up to 21

days))

Total (Dose 2g

cefiderocol 3 times

daily)

<5 8 8 14 30

5 to <7 10 7 4 21

7 to ≤14 277 61 97 435

>14 to

≤21 5 16 31

52

>21 0 9 2 11


Table 82 summarizes treatment-related adverse events for each trial and for the total patient

population studied. An additional detailed summary of all treatment-emergent adverse events is on

file[262, 263].

Pooled adverse event analyses there overall less treatment emergent adverse events with cefiderocol

(344/549 [67.1%]) vs comparators (252/347 [72.6%]). The most common adverse reactions for

cefiderocol were diarrhoea (8.2%), constipation (4.6%), pyrexia (4.0%) and UTI (4.7%).

In the total sample, 56/549 (10.2%) patients treated with cefiderocol experienced treatment related

AEs and 45/347 (13.0%) patients treated with comparators.


Table 82: Subjects with Treatment Related Adverse Events by System Organ Class and Preferred Term (All Phase II/III Studies) Safety Population

cUTI Study CREDIBLE-CR Study APEKS NP Study All Studies System Organ Class - Preferred Term

Cefiderocol N=300 n (%)

Imipenem/Cilastatin N=148 n (%)


BAT N=49 n (%)


Meropenem N=150 n (%)


Comparator N=347 n (%)

Subjects with any Treatment Related AEs 27 (9.0) 17 (11.5) 15 (14.9) 11 (22.4) 14 (9.5) 17 (11.3) 56 (10.2) 45 (13.0) Blood and lymphatic system disorders 0 0 0 0 0 2 (1.3) 0 2 (0.6) - Disseminated intravascular coagulation 0 0 0 0 0 1 (0.7) 0 1 (0.3) - Thrombocytopenia 0 0 0 0 0 1 (0.7) 0 1 (0.3) Cardiac disorders 0 1 (0.7) 0 0 0 0 0 1 (0.3) - Tachycardia 0 1 (0.7) 0 0 0 0 0 1 (0.3) Ear and labyrinth disorders 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Ear discomfort 0 0 0 0 1 (0.7) 0 1 (0.2) 0 Gastrointestinal disorders 9 (3.0) 5 (3.4) 4 (4.0) 1 (2.0) 3 (2.0) 5 (3.3) 16 (2.9) 11 (3.2) - Diarrhoea 4 (1.3) 3 (2.0) 2 (2.0) 0 3 (2.0) 5 (3.3) 9 (1.6) 8 (2.3) - Nausea 3 (1.0) 1 (0.7) 0 0 0 0 3 (0.5) 1 (0.3) - Vomiting 1 (0.3) 1 (0.7) 0 1 (2.0) 0 0 1 (0.2) 2 (0.6) - Abdominal pain upper 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Ascites 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Constipation 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Dry mouth 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Stomatitis 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Upper gastrointestinal haemorrhage 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Lip oedema 0 1 (0.7) 0 0 0 0 0 1 (0.3) General disorders and administration site conditions

5 (1.7) 0 2 (2.0) 0 0 2 (1.3) 7 (1.3) 2 (0.6)

- Oedema peripheral 2 (0.7) 0 0 0 0 0 2 (0.4) 0






BAT N=49 n (%)





- Infusion site pain 2 (0.7) 0 0 0 0 0 2 (0.4) 0 - Feeling hot 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Oedema 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Pyrexia 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Infusion site erythema 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Hyperthermia 0 0 0 0 0 1 (0.7) 0 1 (0.3) - Multiple organ dysfunction syndrome 0 0 0 0 0 1 (0.7) 0 1 (0.3) Hepatobiliary disorders 0 1 (0.7) 0 0 1 (0.7) 1 (0.7) 1 (0.2) 2 (0.6) - Hepatic failure 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Hepatic function abnormal 0 1 (0.7) 0 0 0 0 0 1 (0.3) - Hepatocellular injury 0 0 0 0 0 1 (0.7) 0 1 (0.3) Immune system disorders 1 (0.3) 0 0 1 (2.0) 0 0 1 (0.2) 1 (0.3) - Drug hypersensitivity 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Anaphylactic reaction 0 0 0 1 (2.0) 0 0 0 1 (0.3) Infections and infestations 4 (1.3) 6 (4.1) 2 (2.0) 2 (4.1) 3 (2.0) 6 (4.0) 9 (1.6) 14 (4.0) - Clostridium difficile colitis 1 (0.3) 4 (2.7) 1 (1.0) 0 0 0 2 (0.4) 4 (1.2) - Oral candidiasis 1 (0.3) 0 0 0 1 (0.7) 0 2 (0.4) 0 - Candiduria 2 (0.7) 0 0 0 0 0 2 (0.4) 0 - Clostridium difficile infection 0 0 0 0 1 (0.7) 2 (1.3) 1 (0.2) 2 (0.6) - Pseudomembranous colitis 0 0 1 (1.0) 1 (2.0) 0 0 1 (0.2) 1 (0.3) - Sepsis 0 0 0 1 (2.0) 1 (0.7) 0 1 (0.2) 1 (0.3) - Fungal infection 0 1 (0.7) 0 0 0 0 0 1 (0.3) - Septic shock 0 0 0 1 (2.0) 0 0 0 1 (0.3) - Systemic candida 0 0 0 0 0 1 (0.7) 0 1 (0.3) - Vaginal infection 0 1 (0.7) 0 0 0 0 0 1 (0.3) - Urinary tract infection fungal 0 0 0 0 0 1 (0.7) 0 1 (0.3) - Pseudomonas infection 0 0 0 0 0 1 (0.7) 0 1 (0.3)






BAT N=49 n (%)





- Candida infection 0 0 0 0 0 1 (0.7) 0 1 (0.3) Investigations 5 (1.7) 2 (1.4) 8 (7.9) 2 (4.1) 4 (2.7) 4 (2.7) 17 (3.1) 8 (2.3) - Alanine aminotransferase increased 1 (0.3) 0 3 (3.0) 0 2 (1.4) 1 (0.7) 6 (1.1) 1 (0.3) - Gamma-glutamyltransferase increased 4 (1.3) 1 (0.7) 0 0 2 (1.4) 0 6 (1.1) 1 (0.3) - Aspartate aminotransferase increased 0 0 3 (3.0) 0 2 (1.4) 1 (0.7) 5 (0.9) 1 (0.3) - Transaminases increased 0 0 1 (1.0) 0 1 (0.7) 0 2 (0.4) 0 - Liver function test increased 0 0 2 (2.0) 0 0 0 2 (0.4) 0 - Hepatic enzyme increased 1 (0.3) 0 0 1 (2.0) 0 2 (1.3) 1 (0.2) 3 (0.9) - Blood creatinine increased 0 1 (0.7) 1 (1.0) 0 0 0 1 (0.2) 1 (0.3) - Blood pressure increased 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Blood creatine increased 0 0 0 1 (2.0) 0 0 0 1 (0.3) - Blood alkaline phosphatase increased 0 1 (0.7) 0 0 0 0 0 1 (0.3) Metabolism and nutrition disorders 0 0 1 (1.0) 1 (2.0) 0 0 1 (0.2) 1 (0.3) - Hypokalaemia 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Metabolic acidosis 0 0 0 1 (2.0) 0 0 0 1 (0.3) Musculoskeletal and connective tissue disorders 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Myalgia 1 (0.3) 0 0 0 0 0 1 (0.2) 0 Nervous system disorders 1 (0.3) 4 (2.7) 1 (1.0) 1 (2.0) 3 (2.0) 0 5 (0.9) 5 (1.4) - Dysgeusia 1 (0.3) 1 (0.7) 1 (1.0) 0 0 0 2 (0.4) 1 (0.3) - Headache 0 3 (2.0) 0 0 1 (0.7) 0 1 (0.2) 3 (0.9) - Dizziness 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Paraesthesia 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Status epilepticus 0 0 0 1 (2.0) 0 0 0 1 (0.3) Psychiatric disorders 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Confusional state 0 0 0 0 1 (0.7) 0 1 (0.2) 0 Renal and urinary disorders 0 0 0 5 (10.2) 0 0 0 5 (1.4) - Acute kidney injury 0 0 0 4 (8.2) 0 0 0 4 (1.2)






BAT N=49 n (%)





- Renal disorder 0 0 0 1 (2.0) 0 0 0 1 (0.3) Reproductive system and breast disorders 0 0 0 0 0 1 (0.7) 0 1 (0.3) - Vulvovaginal pruritus 0 0 0 0 0 1 (0.7) 0 1 (0.3) Respiratory, thoracic and mediastinal disorders 0 0 1 (1.0) 1 (2.0) 2 (1.4) 0 3 (0.5) 1 (0.3) - Pleural effusion 0 0 1 (1.0) 0 1 (0.7) 0 2 (0.4) 0 - Acute respiratory failure 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Asthma 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Respiratory arrest 0 0 0 1 (2.0) 0 0 0 1 (0.3) Skin and subcutaneous tissue disorders 3 (1.0) 0 2 (2.0) 0 2 (1.4) 1 (0.7) 7 (1.3) 1 (0.3) - Rash 0 0 1 (1.0) 0 1 (0.7) 0 2 (0.4) 0 - Pruritus 1 (0.3) 0 0 0 0 1 (0.7) 1 (0.2) 1 (0.3) - Drug eruption 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Erythema 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Palmar erythema 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Rash maculo-papular 1 (0.3) 0 0 0 0 0 1 (0.2) 0 Vascular disorders 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Hypertension 0 0 1 (1.0) 0 0 0 1 (0.2) 0

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BAT = best available therapy; INC = increase from baseline; PT-INR = prothrombin time-international normalized ratio;

ULN = upper limit of normal; Percentage is calculated using N’ as the denominator, where N’ is the number of subjects with valid postbaseline measurements.


5.5.2 Safety analyses by clinical trial

5.5.2.1 APEKS cUTI

Cefiderocol was generally safe and well-tolerated in the cUTI study, with a safety profile

consistent with other cephalosporin antibacterials. Adverse events (AEs) and serious adverse

events (SAEs) were comparable between the cefiderocol and imipenem groups. The safety

profile of cefiderocol supports its use in cUTI.

5.5.2.1.1 Extent of Exposure

Safety Analysis Population

Of 452 subjects randomized, 448 received at least 1 dose of the study drugs and were included

in the Safety Population (99.0% [300/303] of subjects in the cefiderocol group and 99.3%

[148/149] of subjects in the IPM/CS group) (Table 82). Of the subjects in the Safety Population,

93.4% (283/303) of randomized subjects in the cefiderocol group and 92.6% (138/149) of

randomized subjects in the IPM/CS group completed the study.

Subjects were excluded from the Safety Population for no study drug infusion (1.0% [3/303]

of subjects in the cefiderocol group and 0.7% [1/149] of subjects in the IPM/CS group). Study

blind was broken for 4 subjects. All four were unblinded before the database was locked to

evaluate potential suspected unexpected serious adverse reactions.

Duration of Study Treatment

The duration of treatment exposure in the Safety Population is shown in Table 83. Treatment

duration was similar between the treatment groups and consistent with the ITT and Micro-ITT

populations. A similar percentage of subjects received less than 5 days of treatment (2.7% in

both treatment groups). A median of 9.0 days of treatment for both groups suggests the

majority of subjects received an adequate duration of therapy, and no differences between the

treatment groups were observed.


Table 83: Summary of duration of exposure (safety population)

5.5.2.1.2 Brief Summary of Adverse Events

Incidence rates for AEs, treatment-related AEs, and SAEs were numerically lower in the

cefiderocol group compared with the IPM/CS group in the Safety Population (Table 84).

Adverse events and SAEs related to study drug are referred to as “treatment-related” in the

tables.

Table 84: Summary of treatment-emergent adverse events (safety population)

Safety Event Cefiderocol (N=300)

n (%)

Imipenem/cilastatin (N=148)

n (%)

Any AE 122 (41.0%) 76 (51.0%)

Any drug-related AEa 27 (8.7%) 17 (11.5%)

Discontinuation due to AEb 5 (1.7%) 3 (2.0%)

Any SAEs 14 (4.7%) 12 (8.1%)

Deathsc 1 (0.3%) 0 (0%)

[a] Considered treatment-related by the investigator; [b] SAEs for cefiderocol: C. difficile, hypersensitivity (itching), increased

hepatic enzymes, diarrhea; [c] Death due to cardiac arrest considered unrelated to study drug by investigator.

AE - adverse event; SAE - serious adverse event; Source: Portsmouth, 2018[51]


Discontinuations due to AEs were reported for 1.7% (5/300) of subjects in the cefiderocol

group compared with 2.0% (3/148) of subjects in the IPM/CS group.

One death due to cardiorespiratory arrest was observed in the cefiderocol treatment group;

however, this SAE was considered not related to the study drug by both the investigator and

the sponsor [51, 236].

5.5.2.1.3 Incidence of Adverse Events

Adverse events were most frequently reported in the gastrointestinal disorders SOC as shown

in Table 82. Of the AEs reported in at least 2% of subjects, diarrhea, hypertension,

constipation, infusion site pain, headache, nausea, hypokalemia, insomnia, renal cyst, infusion

site erythema, abdominal pain upper, cardiac failure, C. difficile colitis, and vaginal infection

were seen less frequently in the cefiderocol group than in the IPM/CS group (Table 82).

Cough and vomiting were reported more frequently in the cefiderocol group than in the IPM/CS

group. Cough was reported in 2.3% (7/300) of subjects in the cefiderocol group compared with

0.7% (1/148) of subjects in the IPM/CS group. Of note, cough was mild in severity in 5 of 7

subjects and moderate in 2 of 7 subjects in the cefiderocol group, and the single incidence of

cough in the IPM/CS group was mild. There were no reports of severe cough. Vomiting was

reported in 2.0% (6/300) of subjects in the cefiderocol group compared with 1.4% (2/148) of

subjects in the IPM/CS group (all mild in severity). There were no other notable differences

between the treatment groups.

The incidence rate of treatment-related AEs (considered treatment-related by the investigator)

was 9.0% (27/300) of subjects in the cefiderocol group and 11.5% (17/148) of subjects in the

IPM/CS group (Table 82).

5.5.2.1.4 Severity of Adverse Events

The percentage of subjects with mild AEs was approximately the same for each treatment:

25.7% (77/300) of subjects in the cefiderocol group and 24.3% (36/148) of subjects in the

IPM/CS group. However, a lower percentage of subjects in the cefiderocol group had

moderate AEs (13.0% [39/300] of subjects) compared with the IPM/CS group (23.6% [35/148]

of subjects) and severe AEs (2.0% [6/300] of subjects in the cefiderocol group compared with

3.4% [5/148] of subjects in the IPM/CS group) (Table 85).


Table 85: Number (%) of subjects with adverse events by maximum severity (safety population)

5.5.2.1.5 Relationship

9.0% (27/300) of subjects had AEs reported as related to treatment in the cefiderocol group

and 11.5% (17/148) of subjects in the IPM/CS group (Table 82).

5.5.2.1.6 Other Serious Adverse Events

Serious adverse events were reported in 4.7% (14/300) of subjects in the cefiderocol group

and 8.1% (12/148) of subjects in the IPM/CS group (Table 86). The most frequently reported

SAE was C. difficile colitis (0.7% [3/448] of subjects in the total population), with 0.3% (1/300)

of subjects in the cefiderocol group and 1.4% (2/148) of subjects in the IPM/CS group. The

SAEs of C. difficile colitis in 1 subject in the cefiderocol group (0.3% [1/300]) and in 1 of the 2

subjects in the IPM/CS group (0.7% [1/148]) were considered by the investigator to be

treatment related (Table 87).


Table 86: Number (percent) of subjects with serious adverse events (SAEs) by organ class and

preferred term (safety population)


Table 87: Number (%) of subjects with treatment-related serious adverse events (SAEs)

5.5.2.2 APEKS cUTI NMA safety analysis

The safety NMA analysis was only possible to be performed for All AEs and Treatment related

AEs. Results for both endpoints are presented in this section. Full information on the feasibility

assessment and NMA analysis can be found in [227] and [285].


Figure 52: Network Diagram for Safety Analysis

Results for both safety analysis were non-significant, except for the results observed in the

APEKS cUTI vs Imipenem/cilastatin in the frequentist analysis for all AEs (Figure 53 to Figure

55)

Figure 53: Safety Analysis for All Adverse Events - Frequentist Analysis

Figure 54: Network for safety analysis for Treatment related AEs

Figure 55: safety analysis for Treatment related AEs – Frequentist analysis

Legends:


Legends:



5.5.2.3 APEKs-NP: SAFETY

5.5.2.3.1 Extent of Exposure

Of the 300 randomised subjects, 298 received at least one dose of study drug and were

included in the safety population: 148 subjects in the cefiderocol group (2 g q8h, 3-hour

infusion, or equivalent renally adjusted dose) and 150 in the HD meropenem group (2 g q8h,

3-hour infusion, or equivalent renally adjusted dose). The median (range) duration of treatment

was 10.0 (2-22) days in the cefiderocol group and 8.5 (1-22) days in the HD meropenem group

[238]. Most subjects in both treatment groups had 7-14 days of exposure (65.5% [97/148] and

73.3% [110/150] in cefiderocol and HD meropenem groups, respectively).

Adverse events occurred in 87.8% (130/148) of subjects in the cefiderocol group and 86.0%

(129/150) of the HD meropenem group (Table 88). SAEs occurred in 36.5% (54/148) of

subjects in the cefiderocol group and 30.0% (45/150) in the meropenem group.

Adverse events leading to death occurred in 26.4% (39/148) of subjects in the cefiderocol

group and 23.3% (35/150) in the meropenem group. Treatment-related AEs, treatment-related

SAEs, discontinuations due to AEs, and discontinuations due to treatment-related AEs differed

between treatment groups by < 2%.

Table 88: Overview of Treatment-emergent Adverse Events (Safety Population)

Adverse Event Category

Cefiderocol

(N = 148)

HD Meropenem

(N = 150) Difference of

Proportion

(95% CI)

Subjects

n (%)

# of

events

Subjects

n (%)

# of

events

TEAEs 130 (87.8) 582 129 (86.0) 537 1.8 (-5.8, 9.5)

Treatment-related TEAEs 14 (9.5) 24 17 (11.3) 22 -1.9 (-8.8, 5.1)

TEAEs leading to death 39 (26.4) 49 35 (23.3) 50 3.0 (-6.8, 12.8)

Treatment-emergent SAEs 54 (36.5) 102 45 (30.0) 96 6.5 (-4.2, 17.2)

Treatment-related SAEs 3 (2.0) 6 5 (3.3) 6 -1.3 (-5.0, 2.4)

Discontinuation due to TEAEs 12 (8.1) 18 14 (9.3) 19 -1.2 (-7.6, 5.2)

Discontinuation due to

treatment-related TEAEs

2 (1.4) 4 2 (1.3) 3 0.0 (-2.6, 2.6)

CI = confidence interval; TEAEs = treatment emergent adverse events; SAEs = serious adverse events; Percentage was calculated using the number of subjects in the column heading as the denominator. Adverse events that started on or after the first dose date of the study drug and up to ‘End of Study’ were defined as treatment-emergent. Confidence intervals were calculated using the Wilson score method. Source: APEKS-NP Study Synopsis[238]


Adverse events with the highest frequency in the cefiderocol group (urinary tract infection

[15.5%], hypokalemia [10.8%], diarrhea [8.8%], and anemia [8.1%]) were also the most

frequent AEs in the high-dose meropenem group (hypokalemia [15.3%], urinary tract infection

[10.7%], diarrhea [8.7%], and anemia [8.0%]) [262, 263].

5.5.2.3.2 Overview of TEAEs

Most subjects in the cefiderocol group and meropenem group experienced at least 1 TEAE

(87.8% [130/148] and 86.0% [129/150], respectively) (Table 88). SAEs were reported in 36.5%

(54/148) in the cefiderocol group and 30.0% (45/150) in the meropenem group. Overall,

treatment-related TEAEs and SAEs, TEAEs leading to death and discontinuation were

reported with similar frequency in the two treatment groups.

5.5.2.3.3 Common TEAEs

The most commonly reported TEAEs (i.e. TEAEs reported in ≥5% of subjects in either

treatment group) are summarised by PT in Table 119-9. All TEAEs are reported by SOC and

PT in a safety data on file[262, 263]. The most commonly reported TEAEs were from the

following SOCs:

Infections and Infestations: in 40.5% (60/148) and 35.3% (53/150) of subjects in

the cefiderocol and meropenem groups, respectively

Metabolism and nutrition disorders: in 29.1% (43/148) and 31.3% (47/150) of

subjects in the cefiderocol and meropenem groups, respectively.

Specifically, the most common TEAEs were urinary tract infection in the cefiderocol group (in

15.5% [23/148] of subjects compared with 10.7% [16/150] in the meropenem group) and

hypokalaemia in the meropenem group (in 15.3% [23/150] of subjects compared with 10.8%

[16/148] in the cefiderocol group). Most TEAEs were reported with similar frequency in the two

treatment groups. TEAEs reported more frequently (>4% difference between treatment

groups) in the cefiderocol group than in the meropenem group were: urinary tract infection (in

15.5% [23/148] vs. 10.7% [16/150] of subjects) and hypomagnesaemia (in 5.4% [8/148] vs.

0.7% [1/150] of subjects). TEAEs reported less frequently in the cefiderocol group than in the

meropenem group (>4% difference between treatment groups) were: hypokalaemia (in 10.8%

[16/148] vs. 15.3% [23/150] of subjects), hepatic enzyme increased, hyponatraemia and

decubitus ulcer (each in 2.7% [4/148] vs. 6.7% [10/150] of subjects), and hypotension (in 1.4%

[2/148] vs. 6.7% [10/150] of subjects).


5.5.2.3.4 TEAEs by severity

Overall, the proportions of subjects experiencing mild, moderate or severe TEAEs was 23.5%

(70/298), 29.5% (88/298) and 33.9% (101/298), respectively. The incidence of severe TEAEs

was 37.8% (56/148) in the cefiderocol group compared with 30.0% (45/150) in the high-dose

meropenem group.

5.5.2.3.5 Severe TEAEs

The most common severe TEAEs were: cardiac arrest was reported in 4.7% (7/148) in the

cefiderocol group and 3.3% (5/150) in the high-dose meropenem group, and pneumonia, was

reported in 4.7% (7/148) and 2.0% (3/150), respectively; brain oedema was reported in 0.7%

(1/148) subjects in the cefiderocol group compared with 3.3% (5/150) in the meropenem

group.Treatment-related TEAEs

Treatment-related TEAEs are presented by SOC and PT in Table 86. Overall, the incidence

of treatment-related TEAEs was 9.5% (14/148) in the cefiderocol group and 11.3% (17/150)

in the meropenem group. The most common treatment-related TEAE was diarrhoea, reported

for 2.0% (3/148) subjects in the cefiderocol group compared with 3.3% (5/150) subjects in the

meropenem group.

All treatment-related TEAEs associated with increases in liver enzyme in the cefiderocol group

were transient and resolved or were resolving during the study. Overall, the majority of

treatment-related TEAEs were either mild (n=15) or moderate (n=20), while 11 were severe.

5.5.2.3.6 Deaths

The primary objective of this study was to compare all-cause mortality between the 2 groups

at Day 14 after start of study drug therapy in the mITT population. All-cause mortality rates for

the mITT population are reported in the efficacy section.

5.5.2.3.7 Other SAEs

All SAEs reported during the study are presented by SOC and PT on file [238]. Overall, the

frequency of SAEs was 36.5% (54/148) in the cefiderocol group compared with 30.0%

(45/150) in the meropenem group. Overall, the most common SAE was cardiac arrest,

reported in 4.7% (7/148) in the cefiderocol group compared with 3.3% (5/150) in the

meropenem group.

Overall, treatment-related SAEs were reported in 2.0% (3/148) in the cefiderocol group

compared with 3.3% (5/150) in the meropenem group [238].


Table 89 – Number (percent) of subjects with serious adverse events (SAEs) by organ class and preferred term (safety population)


5.5.2.3.8 TEAEs leading to study treatment discontinuation

All TEAEs leading to study treatment discontinuation are presented by SOC and PT in Table

119-13. TEAEs leading to study treatment discontinuation were reported for 8.1% (12/148) in

the cefiderocol group and 9.3% (14/150) in the meropenem group. Alanine aminotransferase

increased was the most frequently reported TEAE leading to discontinuation, in 2/148 (1.4%)

subjects in the cefiderocol group. Hepatic enzymes increased was reported in no subjects in

the cefiderocol group and 5/150 (3.3%) in the HD meropenem group. All other TEAEs leading

to discontinuation were reported at most in 1 subject in either treatment group.

5.5.2.3.9 Conclusions for APEKS-NP Study

Overall, the types and frequency of TEAEs for cefiderocol were generally similar to high-dose

meropenem and consistent with safety profile of cephalosporin class of antibacterials.


5.5.2.4 CREDIBLE-CR

ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS

5.5.2.4.1 Treatment-Emergent Adverse Events

Over 90% of the subjects in each treatment group had at least 1 adverse event (Table 90).

The incidence of treatment-related adverse events was 14.9% in the cefiderocol group and

22.4% in the BAT group. The incidence of adverse events with an outcome of death by the

end of the study was 33.7% in the cefiderocol group and 18.4% in the BAT group. Of note,

none of the deaths in the cefiderocol group were considered related to study treatment by

either the investigator or Shionogi. The percentage of reported serious adverse events was

49.5% in the cefiderocol group and 46.9% in the BAT group. Overall, 6 subjects experienced

treatment-related serious adverse events (1 in the cefiderocol group and 5 in the BAT group).

The percentage of discontinuations due to adverse events was 9.9% in the cefiderocol group

and 6.1% in the BAT group.

Table 90: Overview of Treatment-emergent Adverse Events (Safety Population)

Cefiderocol (N = 101)

BAT (N = 49)

Adverse Event Category Subjects n (%)

Events n'

Subjects n (%)

Events n'

AEs 92 (91.1) 634 47 (95.9) 311 Treatment-related AEs 15 (14.9) 27 11 (22.4) 16 Death 34 (33.7) 45 9 (18.4) 14 SAEs 50 (49.5) 92 23 (46.9) 36 Treatment-related SAEs 1 (1.0) 1 5 (10.2) 7 Discontinuation due to AEs 10 (9.9) 12 3 (6.1) 3 Discontinuation due to treatment-related AEs

3 (3.0) 3 2 (4.1) 2

AEs = adverse events; BAT = best available therapy; SAEs = serious adverse events

Percentage is calculated using the number of subjects in the column heading as the denominator. Adverse events that started

after the first dose of the study drug and up to End of Study visit are defined as treatment-emergent. One subject received

cefiderocol after completion of BAT; this subject is included under BAT in this table. Source: CREDIBLE-CR Final Study Summary

[243]

Treatment-emergent Adverse Events Reported in Either Treatment Group

The most frequently (> 10% of subjects in either arm) reported adverse events were diarrhea,

pyrexia, septic shock, and vomiting. Adverse events reported more frequently (> 5% difference

between the treatment groups) in the cefiderocol group than in the BAT group were diarrhea,

alanine aminotransferase increased, aspartate aminotransferase increased, pleural effusion,

and chest pain. Adverse events reported less frequently (> 5% difference between the

treatment groups) in the cefiderocol group than in the BAT group were hypokalemia,

hyperkalemia, rash, and depression.


Transient elevations in liver enzymes due to cefiderocol cannot be excluded; however, like

other cephalosporins, the elevations are reversible after discontinuing the study drug, and

none have resulted in serious hepatotoxicity.

All 6 chest pain cases were in the cefiderocol group and were reviewed. The majority of the

events of chest pain were considered to be noncardiovascular in nature and not related to

cefiderocol. Most of the remaining adverse events occurred at a low frequency, suggesting

manifestations of the subjects’ underlying disease. Overall, no safety signals related to

cefiderocol use were observed.

5.5.2.4.2 Treatment-related Adverse Events

Overall there were 15 (14.9%) of patients with treatment related AEs in the cefiderocol arm

and 11 (22.4%) in the BAT arm.

Diarrhea (2.0%), liver function test abnormal (2.0%), alanine aminotransferase increased

(3.0%), and aspartate aminotransferase increased (3.0%) were the most frequently reported

treatment-related treatment-emergent adverse events in the cefiderocol group, while acute

kidney injury (8.2%) was the most frequently reported treatment-related treatment-emergent

adverse event in the BAT group.

Only 1 (1%; increase in transaminases) in cefiderocol arm and 5 (10.2%) in the BAT arm were

considered serious (1 anaphilactic reaction; 1 septic shock; 1 metabolic acidosis; 1 status

epilepticus; 2 acute renal failure; and 1 respiratory arrest). The higher incidence of treatment-

related SAE in the BAT group was due to use of antibacterials with known renal toxicity in BAT

group. In the BAT group, 5 SAEs of renal impairment (acute kidney injury and renal disorder)

considered related to colistin and tobramycin were reported.

Table 91: Subjects with Treatment-related Adverse Events by Preferred Term (Safety Population)

Preferred Term

Cefiderocol (N = 101) n (%)

BAT (N = 49) n (%)

Subjects with treatment-related AEs 15 (14.9) 11 (22.4) Alanine aminotransferase increased 3 (3.0) 0 Aspartate aminotransferase increased 3 (3.0) 0 Diarrhoea 2 (2.0) 0 Liver function test abnormal 2 (2.0) 0

Ascites 1 (1.0) 0 Blood creatinine increased 1 (1.0) 0 Blood pressure increased 1 (1.0) 0 Clostridium difficile colitis 1 (1.0) 0 Drug eruption 1 (1.0) 0 Dysgeusia 1 (1.0) 0 Hypertension 1 (1.0) 0 Hypokalaemia 1 (1.0) 0 Oedema 1 (1.0) 0 Pleural effusion 1 (1.0) 0


Preferred Term


BAT (N = 49) n (%)

Pseudomembranous colitis 1 (1.0) 1 (2.0) Pyrexia 1 (1.0) 0 Rash 1 (1.0) 0 Transaminases increased 1 (1.0) 0 Upper gastrointestinal haemorrhage 1 (1.0) 0 Acute kidney injury 0 4 (8.2)

Anaphylactic reaction 0 1 (2.0) Blood creatine increased 0 1 (2.0) Hepatic enzyme increased 0 1 (2.0) Metabolic acidosis 0 1 (2.0) Renal disorder 0 1 (2.0) Respiratory arrest 0 1 (2.0) Sepsis 0 1 (2.0) Septic shock 0 1 (2.0) Status epilepticus 0 1 (2.0) Vomiting 0 1 (2.0)

AEs = adverse events; BAT = best available therapy

Percentage was calculated using the number of subjects in the column heading as the denominator. Adverse events that started

after the first dose of the study drug and up to End of Study visit were defined as treatment-emergent. Although a subject may

have had 2 or more adverse events, the subject was counted only once within a System Organ Class category. The same subject

may have contributed to 2 or more Preferred Terms in the same System Organ Class category. One subject received cefiderocol

after completion of BAT; this subject is included under BAT in this table. The most frequently reported treatment-related treatment-

emergent adverse events are shown in bold. Source: CREDIBLE-CR Final Study Summary [243]

5.5.2.4.3 Serious Adverse Events

Septic shock was the most frequently reported serious adverse event in both the cefiderocol

(11.9%; 12/101 subjects) and BAT (12.2%; 6/49 subjects) groups (Table 92).

Table 92: Subjects with Serious Adverse Events by System Organ Class and Preferred Term

(Safety Population)

System Organ Class Preferred Term


BAT (N = 49) n (%)

Subjects with SAEs 50 (49.5) 23 (46.9) Blood and lymphatic system disorders 1 (1.0) 1 (2.0) Anaemia 0 1 (2.0) Febrile neutropenia 1 (1.0) 0 Cardiac disorders 6 (5.9) 4 (8.2) Bradycardia 1 (1.0) 1 (2.0) Cardiac arrest 4 (4.0) 2 (4.1) Cardiac failure congestive 1 (1.0) 0 Myocardial infarction 1 (1.0) 0 Pulseless electrical activity 0 1 (2.0) Gastrointestinal disorders 5 (5.0) 0 Abdominal pain 1 (1.0) 0 Abdominal pain upper 1 (1.0) 0 Gastrointestinal haemorrhage 1 (1.0) 0 Intestinal ischaemia 1 (1.0) 0 Lower gastrointestinal haemorrhage 1 (1.0) 0 Pancreatitis 1 (1.0) 0 Small intestinal obstruction 1 (1.0) 0 General disorders and administration site conditions 7 (6.9) 3 (6.1) Chills 1 (1.0) 0 General physical health deterioration 0 1 (2.0) Multi-organ failure 2 (2.0) 2 (4.1) Pyrexia 3 (3.0) 0


System Organ Class Preferred Term


BAT (N = 49) n (%)

Sudden death 1 (1.0) 0 Hepatobiliary disorders 3 (3.0) 0 Chronic hepatic failure 1 (1.0) 0 Hepatic failure 1 (1.0) 0 Hepatitis 1 (1.0) 0 Immune system disorders 0 1 (2.0) Anaphylactic reaction 0 1 (2.0) Infections and infestations 29 (28.7) 11 (22.4) Bacteraemia 3 (3.0) 0 Bacterial infection 1 (1.0) 0 Device related infection 0 1 (2.0) Empyema 1 (1.0) 1 (2.0) Endocarditis 0 1 (2.0) Enterococcal bacteraemia 1 (1.0) 0 Enterococcal infection 2 (2.0) 0 Meningitis 0 1 (2.0) Necrotising fasciitis 0 1 (2.0) Osteomyelitis 1 (1.0) 0 Osteomyelitis acute 0 1 (2.0) Pneumonia 5 (5.0) 1 (2.0) Pneumonia bacterial 1 (1.0) 0 Renal abscess 1 (1.0) 0 Sepsis 3 (3.0) 0 Septic shock 12 (11.9) 6 (12.2)

Systemic candida 1 (1.0) 0 Urinary tract infection 1 (1.0) 0 Urosepsis 1 (1.0) 0 Investigations 5 (5.0) 3 (6.1) Liver function test abnormal 4 (4.0) 3 (6.1) Transaminases increased 1 (1.0) 0 Metabolism and nutrition disorders 3 (3.0) 1 (2.0) Hyponatraemia 1 (1.0) 0 Metabolic acidosis 2 (2.0) 1 (2.0) Neoplasms benign, malignant and unspecified (incl cysts and polyps)

1 (1.0) 0

Lung neoplasm malignant 1 (1.0) 0 Nervous system disorders 3 (3.0) 2 (4.1) Dizziness 1 (1.0) 0 Hypoaesthesia 1 (1.0) 0 Neurological decompensation 1 (1.0) 0 Paraesthesia 1 (1.0) 0 Quadriplegia 0 1 (2.0) Status epilepticus 0 1 (2.0) Renal and urinary disorders 6 (5.9) 2 (4.1) Acute kidney injury 3 (3.0) 2 (4.1) Anuria 1 (1.0) 0 Nephrolithiasis 1 (1.0) 0 Oliguria 2 (2.0) 0 Respiratory, thoracic and mediastinal disorders 7 (6.9) 2 (4.1) Acute respiratory failure 1 (1.0) 1 (2.0) Chronic obstructive pulmonary disease 1 (1.0) 0 Obstructive airways disorder 1 (1.0) 0 Pneumonia aspiration 2 (2.0) 0 Respiratory arrest 0 1 (2.0) Respiratory failure 2 (2.0) 0 Vascular disorders 2 (2.0) 2 (4.1) Hypotension 2 (2.0) 1 (2.0) Shock 1 (1.0) 1 (2.0)

BAT = best available therapy; SAEs = serious adverse events

Percentage was calculated using the number of subjects in the column heading as the denominator. Adverse events that started

after the first dose of the study drug and up to End of Study visit were defined as treatment-emergent. Although a subject may


have had 2 or more adverse events, the subject was counted only once within a System Organ Class category. The same subject

may have contributed to 2 or more Preferred Terms in the same System Organ Class category.

One subject received cefiderocol after completion of BAT; this subject is included under BAT in this table.

Source: CREDIBLE-CR Final Study Summary [243]

5.5.2.4.4 Adverse Events Leading to Death

Adverse events leading to death are summarized in the efficacy section (5.4.5 and the

summary study report [243]) There were 20.6% (21/102) of patients in the cefiderocol group

and 6.3% (3/48) of patients in the BAT group with deaths classified in the SOC of Infections

and Infestations. After reviewing the details for each individual patient, this imbalance in

mortality between the treatment groups was not considered a safety issue, considering the

complicated comorbidities and difficult-to-treat infections in this patient population. As per

request of EUnetHTA, mortality data is included in the efficacy section.

5.5.2.4.5 Discussion

Limitations to Detect Adverse Reactions in Clinical Trial Development Programmes

The limitations on adverse drug reactions (ADR) detection are based on the information in

Table 93 for patients with Gram-negative infections (including complicated urinary tract

infection) and considering patients with at least 7 days of treatment with cefiderocol. In addition

to the differences in adverse event reporting which occur in open label vs double-blind studies,

the study populations in the three studies are very different, with the cUTI study subjects more

clinically stable than those in the APEKS NP and CREDIBLE-CR studies.

Table 93: Limitations to detect adverse events in clinical trial programmes

Source: EU Risk Management Plan [284]


Table 94: Methods of data collection and analysis of AE, TEAE and SAE

Study

reference/ID


APEKs-cUTI

APEKs-NP

CREDIBLE-CR

Adverse Events (AE) or

Treatment-emergent Adverse

Events (TEAE)

An AE was defined as any

untoward medical occurrence in

a subject administered a

pharmaceutical product

(including investigational drug)

during a clinical investigation. An

AE could therefore be any

unfavourable and unintended

sign (including an abnormal

laboratory finding), symptom,

unplanned procedure, or disease

temporally associated with the

use of an investigational product,

whether considered related to

the investigational product.

The severity of an event was graded according to the

following definitions:

• Mild: A finding, or symptom was minor and did not

interfere with usual daily activities

• Moderate: The event was discomfort and caused

interference with usual daily activity or affected clinical

status

• Severe: The event caused interruption of the subject's

usual daily activities or had a clinically significant effect

The relationship of an event to the study drug was

determined according to the following criteria:

– Related: An AE that can be reasonably

explained that the study drug caused the AE.

For example, the occurrence of the AE cannot

be explained by other causative factors, but

can be explained by pharmacological effect of

the study drug, such as a similar event had

been reported previously, or

increasing/decreasing the dose affects the

occurrence or seriousness of the AE, etc.

Not Related: An AE that cannot be reasonably

explained that the study drug caused the AE

Unless otherwise noted, the summary of AEs will be

performed for events of treatment emergent.

An expected treatment-related AE was any AE that was

consistent with the current Investigator's Brochure for

cefiderocol.

Expectedness

A treatment-related AE is considered expected if it is

listed in Expected Adverse Reactions in Section

“Undesirable Effects” of “SUMMARY OF DATA AND

GUIDANCE FOR INVESTIGATORS” in the current

investigator's brochure for cefiderocol. The expected

adverse reactions of comparators will be those found in

the EMA SmPC. The expected adverse reactions of

linezolid will be those found in the local SmPC.

Expectedness will be assessed by the sponsor.

Clinical Laboratory Adverse Events


For any abnormal laboratory test results (haematology,

blood chemistry, or urinalysis) or other safety

assessments (e.g., physical examination, vital signs)

that are worsening from baseline or occur thereafter in

the course of the study, the investigator or sub-

investigator will consider whether these results are

clinically significant. Abnormal laboratory test results are

defined as values outside the reference range. Any test

results which are clinically significant at the discretion of

the investigator or sub investigator are to be recorded

as AEs. If an abnormal laboratory finding is associated

with disease or organ toxicity, the investigator should

report only the disease or organ toxicity as AEs. These

AEs should also be assessed as to whether they meet

the definition of seriousness and reported accordingly.

The investigator or sub-investigator will consider test

results to be clinically significant in the following

circumstances:

Test result leads to any of the outcomes

included in the definition of an SAE.

Test result leads to discontinuation from the

study.

Test result leads to a concomitant drug

treatment or other therapy.

Test result requiring additional diagnostic

testing or other medical intervention.

Test result meeting the management criteria

for liver function abnormalities identified in the

Appendix 6 of the statistical analysis plan

(SAP).

Liver Abnormalities

Management and Discontinuation Criteria for Abnormal

Liver Function tests have been designed to ensure

subject safety and evaluate liver event aetiology. The

investigator or sub-investigator must review study

subject laboratory results as they become available to

identify if any values meet the criteria in Appendix 6.

When any test result meets the management criteria for

liver function abnormalities, the results of further

assessments and required FUP.

Serious Adverse Events (SAE)

An SAE is defined by regulation

as any AE occurring at any dose

The severity of a SAE was graded to the listed criteria.


that results in any of the following

outcomes:

Death

Life-threatening

condition

Hospitalization or

prolongation of existing

hospitalization for

treatment

Persistent or significant

disability/incapacity

Congenital

anomaly/birth defect

Other medically

important condition


5.6 Conclusions

1. Provide a general interpretation of the evidence base considering the benefits

associated with the technology relative to those of the comparators.

Cefiderocol is an innovative siderophore cephalosporin antibacterial with a unique molecular

structure designed to provide high stability to carbapenemases and use bacteria’s own

mechanism of iron uptake. Both these attributes enable cefiderocol to overcome three main

mechanisms of beta-lactam bacterial resistance (degradation by β-lactamase enzymes, porin

channel mutations, and overexpression of efflux pumps), which is translated in a wide activity

spectrum against aerobic Gram-negative pathogens, including the MDR and WHO critically

important carbapenem resistant strains of Enterobactereacea, A. baumanii and P. aeruginosa,

as well as intrinsically CR S. maltophilia. MDR pathogens are difficult to treat, have limited

treatment options, and no existing treatment provides both comprehensive coverage and good

safety profile. Cefiderocol therefore constitutes an effective and safe treatment option for

patients with serious infections in the presence of world-wide growing resistances.

MDR infections, including those resistant to carbapenems, primarily occur in vulnerable

hospitalised patients. The treatment of MDR-GNB infections in critically ill patients presents

many challenges are associated with poorer outcomes including increased mortality,

increased length of stay and healthcare resource utilization, compared to non-resistant

pathogens. Since an effective treatment should be administered as soon as possible,

resistance to many antimicrobial classes almost invariably reduces the probability of adequate

empirical coverage, with possible unfavorable consequences in terms of increased mortality,

length of stay and healthcare reseource utilization.

In this light, readily available patient’s medical history and updated information about the local

microbiological epidemiology remain critical for defining the baseline risk of MDR-GNB

infections and firmly guiding empirical treatment choices, with the aim of avoiding both

undertreatment and overtreatment. Treatment of severe MDR-GNB infections in critically ill

patients requires a expert and complex clinical reasoning, taking into account the peculiar

characteristics of the target population, but also the need for adequate empirical coverage and

the more andmore specific enzyme-level activity of novel antimicrobials with respect to the

different resistance mechanisms of MDR-GNB.

Due to the urgent need to develop new treatments based on the underlying pathogens rather

than the infection site, the EMA label is expected to authorize cefiderocol to be used for

treatment of infections due to aerobic Gram-negative organisms in adults with limited

treatment options


Assessment of the effectiveness of cefiderocol is based on the integration of in vitro, PK/PD

and clinical data. Large susceptibility studies have confirmed cefiderocol wider Gram-negative

spectrum, and being a more potent antimicrobial agent than comparators. It’s very favourable

minimum inhibitory concentrations (MICs) have been shown to correlate well with in vivo

efficacy and randomized clinical trials in patients with cUTI, nosocomial pneumonia, and BSI

have provided confirmation of the efficacy and safety of cefiderocol in key target patient

populations. These reflect the label and are pathogen focused, not restricted to any specific

site of infection and supports the use of cefiderocol in two types of patients:



provides full cover against CR pathogens and potential resistant mechanisms, to

avoid the risk of rapid clinical deterioration (with the option to de-escalate to a more

targeted treatment when the pathogen and susceptibility profile is subsequently

confirmed).

Hospitalised patients where CR infection has been confirmed and cefiderocol is

best option based on pathogen susceptibility information and/or where other

treatment choices are inappropriate (efficacy, contra-indication or

tolerability).Conclusions based on the in-vitro surveillance, PK/PD data and clinical

data

Cefiderocol is a time-dependent cephalosporin. Preclinical studies showed that cefiderocol

has linear pharmacokinetics, primarily urinary excretion, an elimination half-life of 2–3 hours,

and a protein binding of 58% in human plasma. The probability of a target attainment at ≥75%

of the dosing interval during which the free drug concentration exceeds the minimum inhibitory

concentration (ƒT/MIC) for bacterial strains with an MIC of ≤4 μg/mL was greater than 90% at

the therapeutic dose of 2 g over 3-hour infusion every 8 hours in most patients.

Only renal function markers were found to be influential covariates for the pharmacokinetics

of cefiderocol for patients with altered renal function. Dose adjustment is recommended for

patients with impaired and augmented renal function.

The potent activity of cefiderocol was confirmed in an extensive series of in vitro studies,

against clinical isolates from surveillance studies, and in animal infection models. The

SIDERO-WT study showed ccefiderocol to have activity against 99.5% of Gram-negative

isolates at a MIC of 4 mg/L, while the SIDERO-CR study, which only includes CR isolates,

showed cefiderocol to have potent in vitro activity at a MIC of 4 mg/L against 96.2% of isolates

of carbapenem-non-susceptible pathogens including all of the WHO priority pathogens and

Stenotrophomonas maltophilia. In both studies, cefiderocol was found to give wider Gram-


negative coverage, and to be a more potent in vitro antibacterial agent than comparators. The

results confirm cefiderocol overcomes multiple mechanisms or resistance and to be stable

against the 4 known classes of β-lactamases, including serine carbapenemases, with potency

which is equal to or greater than comparators.

An improved in vitro potency in addition to a well-characterized favorable PK/PD profile are

crucial to achieve both adequate exposure to the antibacterial over the MIC for the pathogen,

and clinical cure in patients infected with drug-resistant pathogens [52]. Therefore, clinical

studies in antimicrobials, provide only supportive safety and efficacy evidence to the pivotal

in-vitro and PK/PD data. Furthermore, in the context of antibacterial resistance, the standard

clinical trial approach aiming at demonstrating superiority over existing treatments is not

feasible. Treatment options for MDR infections do not allow a superiority trial and it would be

unethical to wihthold effective treatment to pateints in such trials [52]. Hence, clinical trials

have an important role to confirm clinical efficacy, but a limited role in providing comparative

evidence outside the trial, as only pathogens that fall within the in-vitro spectrum of the tested

treatments and comparators are included in the study. This is particularly relevant for

antimicrobial treatment selection in the absence of antibiogram.

The clinical evidence to support the use of cefiderocol is based on 2 randomised, double

blinded clinical trials, and 1 descriptive open-label study. Data from an NMA, an effectiveness

model and compassionate use cases complement the body of confirmatory clinical data.

Low likelihood of in treatment development of resistance against cefiderocol was

demonstrated by the fact that only very few and moderate increases in the cefiderocol MIC

were seen over the treatment course, usually requiring more than 1 simultaneous mutation to

increase the MIC. Cefiderocol also presents low likelihood of generating cross resistance,

given that the main resistant pathway identified in in vitro studies was related with the

siderophore ion uptake.

5.6.1 Evidence to support use of cefiderocol in patients with infections by suspected MDR/CR pathogens:

SIDERO WT provides evidence to support the use of cefiderocol in the group of critically ill

patients with infections suspected to be caused by a MDR pathogen, who require immediate

treatment. These patients would benefit from the availability of an additional effective antibiotic

treatment providing full cover against carbapenem-resistant pathogens while pathogen

susceptibility is being confirmed.


The SIDERO-WT study tested the in-vitro antibacterial activity of cefiderocol against Gram-

negative bacteria [29]. A total of 30,459 clinical isolates of Gram-negative bacilli were

systematically collected from USA, Canada, and 11 European countries between 2014 and

2017. Cefiderocol demonstrated activity against 99.5% of Gram-negative isolates at a MIC of

4 mg/L. Isolates were less susceptible to the comparators including colistin (95.5%),

ceftazidime-avibacatam (90.2%) and ceftolozane-tazobactam (84.3%).

In a retrospective analysis comparing the probability of target attainment (PTA) for cefiderocol,

ceftolozane/tazobactam and meropenem against Enterobacterales and Pseudomonas

aeruginosa in a representative patient population at risk of MDR or carbapenem resistant

infections, the cumulative fractions of response (CFRs) calculated using European MIC

distributions from the SIDERO surveillance for cefiderocol against Enterobacterales and

Pseudomonas spp. are considerably higher than seen for meropenem and ceftolozane-

tazobactam.

In patients with infections suspected to be caused by MDR/CR pathogens, clinical trials

only provide limited comparative evidence regarding the efficacy of new antibacterials. This is

because trials must include only pathogens for which the tested agents and comparators are

effective, as it would be unethical to knowingly allow patients to have ineffective treatment. In

this setting, standard NMAs also provide little information, as they never account for pathogens

not susceptible to the treatment regimens included in the network. A comparison of efficacy

against all relevant comparators can only be obtained from in-vitro surveillance studies. Hence

approaches integrating all available evidence from in vitro, PK/PD and clinical data (such as

effectiveness models), are the necessary to predict susceptibility rates and clinical

effectiveness rates.

APEKS-cUTI compared cefiderocol with imipenem/cilastatin (IPM/CS) in cUTI caused by

Gram-negative MDR pathogens in hospitalized adults. The study was designed to

demonstrate non-inferiority, with the primary efficacy endpoint being the composite of clinical

response and microbiological response at TOC. 73% of patients in the cefiderocol group

achieved the primary endpoint, vs only 55 % of patients in the IPM/CS group, with an adjusted

treatment difference of 18.6% (95 % CI: 8.2, 28.9). A further post-hoc analysis confirmed

superiority in favour of cefiderocol.

Given the similarority of patients and pathogens included in across trials, a NMA was

conducted to compare the result of APEKS cUTI with relevant comparator studies. Results

showed no statistically significant difference between the APEKS cUTI result and results from


studies of ceftazidime/avibactam and ceftolozane/tazobactam conducted in a similar

population with a similar pathogen distribution.

The APEKS-NP study compared treatment with cefiderocol against high-dose and prolonged

infusion (HD) meropenem in patients with nosocomial pneumonia caused by MDR Gram-

negative pathogens. Cefiderocol met the primary endpoint of non-inferiority in ACM at day 14

versus HD meropenem (12.4% vs 11.6%; (95 % CI: -6.6, 8.2)). APEKS-NP used an improved

meropenem regimen (both high dose and prolonged infusion time) to optimize its exposure

and efficacy. This meant that a NMA was not possible because previously published

meropenem studies had used a lower dose of meropenem.

The results of the two randomized, double-blind APEKS trials combined provide highly reliable

and clinically relevant evidence to support the use of cefiderocol in patients with suspected

MDR pathogens with limited treatment options.

Furthermore, in an analysis incorporating European pathogen epidemiology and susceptibility

data, cefiderocol provides the best predicted susceptibility rates and estimated clinical and

microbiological success rates regardless of the infection site, in the absence of an antibiogram

for the critically ill patients with suspected MDR pathogen infection requiring immediate

treatment.

Combining these results and clinical data in an effectiveness model, show that cefiderocol has

a greater likelihood of achieving microbiological eradication and clinical cure, in the patients

with suspected MDR/CR infections than relevant comparators across for cUTI and

pneumonia. In the absence of antibiogram, cefiderocol provides an effective option for treating

critically ill, hospitalised patients where CR infection is suspected and time to effective

treatment must be as short as possible, increasing the likelihood of providing an initial

appropriate therapy and potentially avoiding worse morbidity and mortality outcomes

associated with delayed effective therapy.

5.6.2 Evidence to support use of cefiderocol in patients with infections by confirmed CR pathogens:

Data from the SIDERO-CR study indicate that cefiderocol maintains high activity in the

presence of beta-lactamases, carbapenemases, and strains with porin channel mutations or

efflux-pump overexpression. Patients with confirmed MDR/CR infections, for whom the

antibiogram indicates susceptibility for cefiderocol thus gain an additional treatment option

with equal or higher susceptibility than comparators.


In the SIDERO-CR-2014-2016 study [30], which was a global study of 52 countries, focusing

only on CR isolates, cefiderocol demonstrated potent in vitro activity at a MIC of 4 mg/L against

96.4% of isolates of carbapenem-nonsusceptible pathogens including all of the WHO priority

pathogens and Stenotrophomas maltophilia. Cefiderocol was found to provide a wider Gram-

negative coverage, and more potent in vitro antimicrobial activity than comparators including

ceftazidime/avibactam (39.8%), ceftolozane/tazobactam (37%), and colistin (91.5%).

Clinical trials can provide more reliable information regarding comparative efficacy when the

pathogens have confirmed or expected susceptibility to both drugs. This is consistent with

prescription based on AST results, which occurs in patients with confirmed CR infections. In

this setting, Network meta-analysis (NMA) if feasible provide additional reliable information of

comparative effectiveness.

Evidence of clinical efficacy of cefiderocol in patients with a confirmed CR infection comes

from three sources; the APEKS NP study, the CREDIBLE CR study and the cefiderocol

compassionate use programme:

In a small subgroup of patients participating in the APEKS-NP that was non-susceptible to

meropenem considering a breakpoint of 8mg/L (MIC), similar results in terms of mortality,

clinical and microbiological outcomes were achieved between arms. However, when looking

into the stratification for pathogens with MIC >16 mg/mL, patients on cefiderocol had reduced

mortality and higher clinical cure rates. The HD prolonged infusion meropenem regimen in this

trial, increased exposure in terms of time and concentration to the infection site, increasing

the likelihood of effectiveness, even on pathogens with MIC up to 16mg/mL.

The CREDIBLE CR study was a small, randomised, open label, descriptive, exploratory, study

conducted to evaluate efficacy in patients with confirmed CR infections given cefiderocol or

BAT. The study was not designed or powered for statistical comparison between arms. The

study included 150 severely ill patients, consistent with compassionate use cases, with a

range of infection sites including nosocomial pneumonia, cUTI, BSI/sepsis. Many patients had

end stage comorbidities and had failed multiple lines of therapy. Cefiderocol and BAT were

shown to be effective in terms of clinical and microbiological outcomes in these patients,

particularly for cefiderocol also showing clinical and microbiological efficacy regardless of

carbapenemases present in the pathogen causing the infection. However, there were marked

clinically relevant differences in some baseline characteristics and pathogen distribution of the

cefiderocol and BAT arms. An imbalance in mortality was observed in the cefiderocol arm


compared to BAT (18/49 vs 5/25), which was not considered to be related with safety signals.

No deaths were found to be causally associated with cefiderocol through assessment by the

investigator and two independent committees. No single factor that would explain the

imbalance was identified. Small patient numbers and multiple confounders preclude definitive

conclusions. Additional analyses revealed that mortality in the treatment arm was similar to

other studies in the context, while the BAT arm performed better than all reported studies,

particularly for non-fermenters. The reasons for this are not understood.

Compassionate use program: More than 200 patients were treated with cefiderocol within the

compassionate use programme around the world, demonstrating the unmet medical need.

Confirmed information on 74 patients who have completed treatment in the compassionate

use program showed that over 60% of the severely ill patients infected with CR Gram-negative

pathogens survived when no other treatment option was available to them.

The overall mortality across the compassionate use programs and CREDIBLE CR was similar,

36.5% and 33.7% respectively, supporting the notion that the population recruited into the

CREDIBLE-CR trial, included severely ill patients with a very poor prognosis, similar to those

applying for compassionate use and other similar studies reported on literature.

5.6.3 Quality of Life

Patients with these severe nosocomial infections are frequently treated in ICU units, often

unconscious, and on many occasions require ventilation (intubation), preventing investigation

of patient-reported outcomes. Because the most severely ill patients cannot complete

questionnaires, this can lead to systematic under-reporting QoL data of the most severe

courses of illness. The fact that these patients are hospitalised already has decrimental impact

on their quality of life. The ward in the hospital also impacts the patient’s quality of life (i.e

patients on ICU or isolation, are expected to have lower quality of life compared to general

ward), although this may be correlated with the severity of the infection and underlying

condition. All these factors make investigating quality of life in antimicrobial clinical trials

difficult and infrequent. The microbiological outcomes and mortality have thus been deemed

to be most relevant, also by regulators. No PROs are, therefore, reported in the dossier.

However, any therapy that resolves the infection and/or reduces length of hospitalization is

expected to improve patient’s quality of life.

5.6.4 Comparators

The in vitro data and combination of the in vitro, PK/PD, and clinical data show that cefiderocol

outperforms all relevant comparators with regard to the likelihood of obtaining microbiological


eradication in the population with suspected MDR/CR infections. While clinical evidence is

restricted to a limited number of comparators that were deemed to be relevant in the specific

context by regulators, an NMA in the cUTI indication and the additional in vitro data reveal

favourable outcomes of cefiderocol compared with all relevant available treatments (Table

95).

Table 95 - Comparator overview

Population Comparator Data source Result (cefiderocol vs. comparator)

Suspected MDR/CR

High dose Meropenem SIDERO WT surveillance

Broader coverage of Gram-negative, aerobic pathogens. Lower MIC value and preserved efficacy in the presence of carbapenemases.

APEKS-NP RCT

Non-inferior with regard to mortality (primary outcome) and all clinical and microbiological secondary outcomes.


Integrated epidemiology and in-vitro data analysis

Cefiderocol presents higher weighed susceptibility rates in cUTI, pneumonia, BSI, and gastrointestinal samples vs comparators


Effectiveness model integrating epidemiology, in-vitro data and clinical data

Cefiderocol presents higher likelihood of clinical and microbiological effectiveness in pneumonia and cUTI vs comparators.

Imipenem/Cilastatin APEKS-cUTI RCT

Non-inferior to comparator, but proven superiority in a post-hoc analysis, on the primary endpoint of combined microbiological eradication / clinical cure at TOC, and secondary endpoint microbiological eradication at TOC.

Ceftalozane-tazobactam, ceftazidime-avibactam, doripenem, imipenem/cilastatin

network meta-analysis for cUTI

In similar patient populations with similar pathogen distribution across different trials, and consistent with APEKS-cUTI there was statistical significant difference in microbiological eradication at TOC vs Imipenem/cilastatin, but in all other endpoints there was no statistically significant difference, including clinical cure rates and adverse events

Ceftolozane/tazobactam SIDERO WT surveillance

Lower MIC90 (0.25 vs. 8 for Pseudomonas, 0.25 vs. 32 for


Acinetobacter, 1 vs. 64 for Enterobacteriaceae)6 Higher % isolates susceptible to cefiderocol

Ceftazidime/avibactam SIDERO WT surveillance

Same MIC90 for Enterobacteriaceae (1 vs. 1), otherwise superiority of cefiderocol Higher % isolates susceptible to cefiderocol

Confirmed CR

Colistin-based (combination) regimens (most relevant for for A. Baumanii, S. maltophilia, pathogens with metallobeta-lactamases)


Higher % isolates susceptible to cefiderocol; Similar in-vitro efficacy. Colistin is known to have severe side effects, especially kidney toxicity. Resistances against colistin have been reported to increase in epidemiological studies.

Ceftolozane/tazobactam (most relevant for P. aeruginosa, except pathogens with metallobeta-lactamases)


Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)7

Ceftazidime/avibactam (most relevant for Enterobacterales, except pathogens with metallobeta-lactamases)


Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)

Best available therapy (BAT), predominantly (combination) regimens (most relevant for A. Baumanii, S. maltophilia, pathogens with metallobeta-lactamases)

CREDIBLE-CR Descriptive results only. Evidence of eradication of resistant pathogens. Numerical, non-significant disadvantage with regard to mortality for cefiderocol compared to BAT.

2. Provide a general interpretation of the evidence base considering the harms

associated with the technology relative to those of the comparators.

The presented data demonstrate that cefiderocol has a similar safety profile compared to other

cephalosporins.

Pre-clinical studies showed that single and multiple doses of cefiderocol tested were well

tolerated in both healthy subjects and those with renal impairment. Furthermore, neither QT

interval prolongation nor drug–drug interaction via organic anion transporters was

demonstrated in healthy subjects.

The clinical safety for cefiderocol was established in the three randomised clinical trials,

including 549 treated patients, and showed a similar profile compared to other cephalosporins.

6 Longshaw et al., 2019 ID Week 7 Sato et al. 2019 ID Week


Pooled adverse event analyses showed that there were overall less treatment emergent

adverse events with cefiderocol (344/549 [67.1%]) vs comparators (252/347 [72.6%]), as well

as less treatment related AEs, (56/549 [10.2%]) with cefiderocol vs compartors (45/347

[13.0%]).

The large APEKS trials with active comparators showed that TEAEs and treatment-related

TAEs were overall balanced between arms. In APEKS-NP, adverse events were experienced

by most subjects in both treatment groups with SAE rates being slightly higher in the

cefiderocol group (36.5%) than in in the meropenem group (30%). In the APEKS-cUTI trial,

serious adverse events (SAE) occurred less in cefiderocol-treated patients than in IPM/CS-

treated patients (5% vs 8%).

In the confirmed carbapenem-resistant CREDIBLE-CR trial, the cefiderocol group had lower

incidence of AEs and treatment-related AEs, but imbalance in mortality, SAEs and

discontinuation due to AEs, compared with BAT was observed. The incidence of treatment-

related AEs leading to discontinuation was similar between treatment groups. A blinded

adjudication committee concluded that none of the deaths was due to a drug-related AE.

The SPC details all potential risks associated with drug interactions or potential harms with

drug use in special categories of patients.


5.7 Strengths and limitations

1. Summarise the internal validity of the evidence base, considering the study quality, the

validity of the endpoints used as well as the overall level of evidence. Include a

statement about the consistency of the results in the evidence base.

5.7.1 Risk of bias assessment

Unlike therapeutic areas, in vitro studies are key sources of data to substantiate clinical use

of the antibacterials. Traditionally this falls outside the scope of bias assessment, as

theoretically the risk of bias is considered minimal. In this case, same isolates were tested for

all comparators, the methodology used was based on standard defined methods, and data

was reported. The manufacturer provided the study protocol, and several publications for this

assessment; thus, the possibility of selective outcome reporting is regarded as low.

In summary, robustness of the study is ensured through large number of isolate samples,

testing same sample for all comparators. The study shows high internal validity with low risk

of bias.

In addition to the in vitro and PK/PD data, the evidence base in the population with suspected

MDR/difficult-to-treat infections is amended by two RCTs, the APEKS cUTI and APEKS NP

trials. Both studies were multicentre, multinational, double-blind, randomized, active-controlled

studies.

APEKS-cUTI was a Multicentre, Double-blind, Randomized, Clinical Study to Assess the

Efficacy and Safety of Intravenous S-649266 (Cefiderocol) in Complicated Urinary Tract

Infections with or without Pyelonephritis or Acute Uncomplicated Pyelonephritis Caused by

Gram-Negative Pathogens in Hospitalized Adults in Comparison with Intravenous

Imipenem/Cilastatin. Randomization was stratified according to the patient’s clinical diagnosis,

(cUTI with or without pyelonephritis and AUP) and region (North America, European Union,

Russia, and Japan plus the rest of world). Randomization used a computer-generated

randomization list (IXRS® provider), an interactive web or voice response system

(IWRS/IVRS) was used to assign a total of 450 patients to identification numbers for which

treatment has already been randomly assigned. Patients and investigator, site personnel, the

sponsor, and the sponsor’s designees involved in blinded monitoring, data management, or

other aspects of the study were blinded to treatment assignment. The site pharmacist or

qualified designee who prepared the intravenous infusion solution was the only study site

personnel with the identification of the study drug assignments for that site. Generation of

randomization sequence and allocation concealment are considered adequate for this


study. Performance and detection bias were minimized through the described blinding and

alignment of infusion duration. mITT population proportions were comparable in both arms

with 252/300 for cefiderocol and 119/148 for IPM/CS thus reducing the likelihood of attrition

bias. The main study publication (Portsmouth et al 2018) reported primary outcome

(composite outcome at TOC) by predefined subgroups and microbiological and clinical

secondary outcomes at the predefined time points EA, EOT, TOC, FU as well as any AE,

treatment-related AEs, SAEs, AEs leading to discontinuation, deaths and AEs in at least 2%

of patients in either treatment group. The manufacturer provided the study protocol, SAP, CSR

and study synopsis for this assessment; thus, the possibility of selective outcome reporting

is regarded as low.

In summary, robustness of the study is ensured through randomization and stratification,

blinding and large number of patients. The study shows high internal validity with low risk of

bias at the study level.

APEKS-NP was a Phase 3, Multicentre, Randomized, Double-blind, Parallel-group, Clinical

Study of Cefiderocol Compared with Meropenem for the Treatment of Hospital-acquired

Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated

Bacterial Pneumonia Caused by Gram-negative Pathogens. Treatments were randomized to

subject identification numbers by the interactive response technology (IRT) provider in a 1:1

fashion to cefiderocol or meropenem. An IRT was used to assign a total of 300 subjects to

identification numbers for which treatment has already been randomly assigned.

Randomization was performed by the stratified randomization method using their infection

type (HABP, VABP, and HCABP) and APACHE II score (≤ 15 and ≥ 16) as allocation factors.

Linezolid infusion did not require blinding and was labelled with the study number, subject’s

identification number, and infusion rate and drug name. Patients and investigator, site

personnel, the sponsor, and the sponsor’s designees involved in blinded monitoring, data

management, or other aspects of the study were blinded to treatment assignment. The site

pharmacist or qualified designee who prepared the intravenous infusion solution was the only

study site personnel with the identification of the study drug assignments for that site.

Generation of randomization sequence and allocation concealment are considered

adequate for this study. Performance and detection bias were minimized through the

described blinding and alignment of infusion duration. mITT population proportions were

comparable in both arms with 145/148 for cefiderocol and 147/150 for high dose meropenem,

equally the microbiologically-evaluable Per-protocol (ME-PP) population was balanced (105

for cefiderocol and 101 for high dose meropenem), thus reducing the likelihood of attrition

bias. Results of the study have been presented in an international clinical conference, but

have not yet been published as a manuscript and no results have been posted at


clicnitrials.gov yet, however, the manufacturer provided the study protocol, SAP, and in the

absence of available CSR at the date of EUnetHTA submission, the manufacturer also

provided study synopsis and all the documentation submitted to EMA for this assessment thus

possibility of selective outcome reporting is regarded as low.

Thus, robustness of the study is ensured through randomization and stratification, blinding

and large number of patients. The study shows high internal validity with low risk of bias at

study level.

CREDIBLE-CR was a Multicentre, Randomized, Open-label Clinical Study of S-649266 or

Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-

resistant Gram-negative Pathogens.

The study is a small descriptive study, with no inferential analysis planned. The treatments

were randomized to subject identification numbers by the IXRS® provider in a 2:1 fashion, i.e.

to cefiderocol and BAT, respectively. An interactive web or voice response system

(IWRS/IVRS) was used to assign patients to identification numbers for which treatment has

already been randomly assigned. Randomization was performed by the stochastic

minimization method using the infection site (HAP/VAP/HCAP, cUTI, and BSI/sepsis),

APACHE II score (≤15 and ≥16), and region (N. America, S. America, Europe, and Asia-

Pacific) as allocation factors, but did not account for pathogen stratification or other clinically

relevant factors. To avoid deterministic allocation based on the ongoing allocation results,

probabilistic allocation was incorporated [Pocock SJ, Simon R. Sequential Treatment

Assignment with Balancing for Prognostic Factors in the Controlled Clinical Trial. Biometrics

1975; 31: 103-15.]. Planned proportions were approximately 50% with HAP/VAP/HCAP; cUTI

no more than 30% and the remainder of patients were enrolled under the BSI/sepsis

diagnosis. The randomization ratio of patients between treatment groups based on clinical

diagnosis was maintained through the allocation factor of clinical diagnosis at the time of

randomization. BAT was the standard of care for CR infections at each enrolling study site

and could include up to three antibiotics with Gram-negative coverage used in combination.

The comparator BAT could not be defined in the protocol and BAT was determined by the site

investigator based on the assessment of the patient’s clinical condition and had to be

determined by the investigator prior to randomization. The dosage of BAT was adjusted

according to the local country-specific label. De-escalation of BAT was allowed. Concomitant

antibiotics were allowed if the patients had a confirmed/suspected Gram-positive or anaerobic

co-infection (e.g., vancomycin, daptomycin, linezolid, clindamycin, or metronidazole).

Performance and detection bias cannot be ruled out due to the open-label design. mITT

population proportions were comparable in both arms and populations were balanced

reducing the likelihood of attrition bias. Results of the study have not been published yet and


no results have been posted at clinitrials.gov yet but have been presented to FDA for an

Advisory Committee Meeting and made publicly available in the briefing book. Furthermore,

the manufacturer provided the study protocol, SAP, results summary and in the absence of

available CSR at the date of EUnetHTA submission, the manufacturer also provided study

synopsis and all the documentation submitted to EMA, for this assessment thus possibility of

selective outcome reporting is regarded as low.

In summary, the CREDIBLE-CR study is a small open-label, randomized, multinational,

parallel-group, Phase 3 clinical trial designed as descriptive study. Through its open-label

design, small number of patients and non-inferential design, the study shows unclear internal

validity and high risk of bias at study level.

Table 96: Risk of bias on study level – Randomized trials with cefiderocol

Study

Ad

eq

uate

ge

nera

tio

n o

f

ran

do

miz

ati

on

seq

ue

nce

Ad

eq

uate

allo

cati

on

co

nc

ealm

en

t

Blinding

Rep

ort

ing

of

ind

ivid

ua

l

ou

tco

mes i

nd

ep

en

de

nt

of

resu

lts

No

oth

er

asp

ects

of

bia

s

Ris

k o

f b

ias o

n s

tud

y

level

Pati

en

t

Tre

ati

ng

Sta

ff

<yes/no/

unclear>

<yes/no/

unclear>

<yes/no/

unclear>

<yes/no/

unclear>

<yes/no/

unclear>

<yes/no/

unclear> <high/low>

RCTs

APEKS NP yes yes yes yes yes yes low

APEKS cUTI yes yes yes yes yes yes low

Descriptive Trial

CREDIBLE CR yes no no no yes* no+ high

*Results of the study have not been published yet and no results have been posted at clicnitrials.gov yet. The manufacturer

provided the study protocol, SAP, CSR and study synopsis for this assessment thus possibility of selective outcome reporting is

regarded as low. +Several unbalances detected after study conclusion


5.7.2 Discussion

Unlike other therapeutic areas, the evaluation of an antimicrobial relies on the combined

consideration of in vitro, PK/PD and clinical data. This is because of the primary importance

of confirming pathogen susceptibility, and theoretically, if the pathogen is susceptible to the

antimicrobial and it has adequate exposure in the infection site, the antibacterial therapy

should be effective. The main evidence supporting efficacy of cefiderocol against a wide range

of Gram-negative, aerobic pathogens thus comes from several large in-vitro surveillance

studies, which were further confirmed by independent national studies in five European

countries (Germany, Italy, Greece, Switzerland, UK). PK/PD studies showed that cefiderocol

could reach target tissues in adequate concentrations at the recommended dosing regimen.

Clinical trials served to confirm efficacy predicted based on the in vitro and PK/PD results.

In vitro testing was performed in iron-depleted broth, a standardized methodology that has

been independently validated and approved. In vitro testing results are critical for clinical

decision making, and the low MIC values reported from the studies together with the

favourable PK/PD data indicate that cefiderocol is likely to will demonstrate clinical activity

against the target Gram-negative, aerobic pathogens regardless of the infection site.

A clinical study in healthy volunteers [8] showed that the penetration ratio of cefiderocol into

ELF was comparable with that of ceftazidime in critically ill patients (0.229 based on free

plasma using a protein unbound fraction of 0.9).

The fraction of time during the dosing interval where free concentration exceeded the MIC

(fT>MIC) for a PD target was reported to be 75%. PK/PD modelling confirmed that with

probabilities of 97% in plasma and 88% in ELF free cefiderocol concentration of 4 mg/L could

be achieved using the recommended dosing regimen. Outcomes of the APEKS-NP trial, which

focused on pneumonia, lent further support to cefiderocol’s adequate penetration into lung

tissues.

In general, clinical trials can only provide very limited evidence regarding the efficacy of new

antibiotics in a real-world population of patients with suspected MDR/CR-resistant pathogens,

because trials must focus on pathogens for which the tested agents are effective; otherwise,

they would be un-ethical. Because trials thus focus on pathogens that fall within the in vitro

spectrum of the tested treatments and comparators, it is difficult to conduct network-meta-

analyses based on these trials. Since each trial excludes patients for which a poor outcome

for the candidate treatment is expected, meta-analysis will only provide answers about the

8 https://academic.oup.com/jac/article/74/7/1971/5435733

https://academic.oup.com/jac/article/74/7/1971/5435733


efficacy of the treatment in patients with susceptible pathogens, but it cannot tell which

treatment would have the best chances of success in an overall, un-tested population. Such

results can only be obtained from in vitro surveillance studies. This implies that the clinical trial

programs for antibiotics have an important role to confirm clinical efficacy, but a limited role in

providing comparative evidence.

Formal risk-of-bias assessments performed for this dossier showed that the internal validity of

the clinical trials differed in the two target populations:

In the population with infections that were suspected to be MDR/CR the

randomized and double-blinded APEKS trials provided strong evidence for non-

inferiority of cefiderocol compared to respective treatment options when the

pathogens are susceptible to both cefiderocol and comparator, and also confirmed

the potential benefit of a wider pathogen Gram-negative coverage vs comparators.

o The non-inferiority designs were necessary due to the fact that it would be

unethical to withhold effective treatments from the comparator group.

o The results are not only relevant for today’s use of antibiotics in the clinic, but

also for a future in which resistances are projected to increase further and there

will be many patients who would need new, effective treatment options, such

as cefiderocol. In such a future scenario, cefiderocol treatment would expected

to be superior compared to treatment with ineffective agents due to pan-

resistant pathogens.

The clinical results in the confirmed carbapenem-resistant populations show

lower levels of internal validity, while the compassionate use program illustrates

the relevance in the current treatment landscape.

o Patients with carbapenem non-susceptible pathogens in the APEKS-NP study

were treated as effectively with cefiderocol as with higher-dosage meropenem.

Due to the increase in dosage, meropenem maintained its efficacy in this group,

leading to similar treatment results in both groups. Numerical evidence showed

that cefiderocol maintained activity in high MIC (>16) to meropenem-non-

susceptible infections.

o The CREDIBLE-CR trial was a small, randomised, non-blinded, non-inferential,

exploratory descriptive study to start to gain experience in patients with

confirmed CR infections, severe often end-stage comorbidities, often after

failing multiple lines of therapy (i.e., salvage therapy context). No stratification

was made for pathogen or presence of terminal disease (e.g., disseminated


cancers, end-stage organ failure). Given the small number of patients included

in the trial, there are differences in the baseline characteristics of the treatment

arms (older, more severe renal impairment in cefiderocol arm).

o The 74 compassionate use studies included open-label treatment of patients

who had received other lines of treatment. The requests for cefiderocol

treatment indicate the urgent clinical need for additional treatment options.

Initial results from these cases confirm that cefiderocol shows clinical activity in

severely ill patients with very limited options.

2. Provide a brief statement of the relevance of the evidence base to the scope of the

assessment.

Overall, the level of evidence supporting cefiderocol treatment is higher in the suspected

resistant population than in the confirmed CR populations, due to the robustness of the APEKS

studies ensured through blinding, randomization, large number of patients, and adequate

control group. The systematic evaluations show high internal validity with low risk of bias at

study level and thus stronger confirmatory clinical results from the APEKS trials.

Population and Comparators: The presented results present the most relevant evidence base

for the assessment of cefiderocol. The most relevant comparators in line with current

regulatory recommendations were considered in in vitro studies and appropriate comparators

reflected in the comparator arms of the clinical trials. As with all antibiotic therapies for patients

with Gram-negative aerobic infections suspected to be MDR/CR/difficult-to-treat or confirmed

CR-resistant, the patient populations included in the trials had a high unmet medical need.

The trial populations in APEKS (cUTI and NP) trials and CREDIBLE-CR study represented

patients eligible for treatment also observed in clinical practice. Complicated urinary tract

infections, nosocomial pneumonia and sepsis are the most common infections observed with

Gram-negative aerobic MDR/CR/difficult-to-treat pathogens.

In line with ethical standards, most effective comparators (IMP/CS and HD meropenem) were

chosen for the APEKS studies. Following good stewardship practice and at request of EMA

BAT was decided to be appropriate to be administered in CREDIBLE-CR study.

Outcomes and timing: Standard outcomes for antibiotic treatment such as clinical and

microbiological outcomes as well as composite clinical and microbiological endpoints and

microbiological and clinical response per-pathogen and per-patient at different time points

(early assessment, end of treatment (EOT), test of cure (TOC), follow-up (FUP)) were


collected in the respective trials. Clinical endpoints were in line with site of infections and

severity of disease:

For cUTI the primary efficacy endpoint was the composite of clinical response and

microbiological response at the test of cure (TOC).

For nosocomial pneumonia (HAP/VAP/CAP) the primary outcome was all-cause

mortality at day 14.

For HAP/VAP/CAP and bloodstream infections/sepsis in CREDIBLE CR study primary

endpoint was clinical cure at TOC, for cUTI it was microbiological outcomes at TOC.

All of these endpoints are main outcomes routinely assessed for antimicrobial studies

according to current regulatory standards. All endpoints considered in the trials adequately

measure relevant outcomes and follow established practice. Quality of life could not be

assessed for the stated reasons.

A full clinical assessment of cefiderocol’s value needs to consider several important pieces of

contextual information:

Delays in appropriate antibiotic therapy lead to worse clinical outcomes. This means

that an additional treatment that can target pathogens with a high unmet need can lead

to more effective early treatment and improved clinical outcomes.

Resistance rates are increasing. A dramatic slump in the development of new antibiotic

treatments in the past two decades lead to lack of treatment options for current and

future resistances.

o New treatments that show non-inferiority with all available treatments can turn

out to become life-saving last-resort options in the future, when more and more

pathogens have become resistant to the existing options.

o In addition to the static assessment of the current treatment landscape, a

dynamic assessment that includes future trends is necessary to fully

understand the current and future benefit of new antibiotic treatments.

Overall, the evidence provided in this dossier supports the clinical benefit of cefiderocol as an

additional treatment option for patients with Gram-negative, aerobic infections with limited

treatment options. As is true for all antibiotics, clinical use of cefiderocol will be based on the


integration of in vitro susceptibility data, hospital-wide antibiograms, monitoring resistance

trends, and individual patient needs.

Within the expected pathogen based indication, it is proposed that cefiderocol offers most

value in two clinical scenarios:

Hospitalised patients with suspected MDR/CR infection who are at risk of rapid

deterioration and require antibiotic treatment that provides full cover against

carbapenem-resistant pathogens in the period while pathogen susceptibility is being

confirmed.

Hospitalised patients with a confirmed MDR/CR infection where existing treatment

options are inappropriate because of pathogen susceptibility, contraindications or poor

tolerability

Given the growing threat from MDR/CR infection and the limitations of currently available

treatment options both populations have a high unmet medical need. Advances in fast

diagnostics will allow clinicians to make decisions about effective treatment options earlier and

earlier. The recent advent of several new treatment options, together with such early

diagnostics holds promise to improve outcomes for critically ill patients and slow down the

further spread of resistant pathogens. Economic evaluations of antibiotics based on these

clinical data will need to take the full spectrum of benefits into account (e.g., enablement of

chemotherapy, high-risk surgeries).


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