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Neonatal SepsisMike Sharland, Sally Ellis and

Neonatal Sepsis team

Disease burden

• Maternal and child deaths have halved worldwide over the past two decades

• Neonatal mortality remains high with 2.9 million deaths estimated in newborns (<28 days) every year

• Nearly a quarter(23%) of deaths are due to infectious causes

Sepsis

Prematurity

Asphyxia

• To achieve the SDGs, a high proportion of neonatal deathsneeds to be prevented and the outcome of neonates withsepsis must significantly improved

Number of neonatal lives saved annually, and from asphyxia, sepsis and prematurity. Arnesen L, BMC

Public Health. 2016

• SBIs in neonates account for about 3% ofall disability-adjusted life years (DALY),and infection-attributable deathscontribute largely to the global burden ofdisease

• The first pooled estimate of incidencerisk in LMICs was 7.6%, with 6.9 millioncases of pSBI estimated among neonatesin 2012 (Seale AC, Lancet Infect Dis 2014)

• Overall, case-fatality risk associated withpSBI was 9.8%

Global burden of neonatal sepsis

Clinical diagnosis of Severe Bacterial Infections (SBIs) is often challenging in neonates, since symptoms and signs can be non-specific and difficult to detect

WHO Guidelines

• Hospitalised neonates and infants are at high-risk of developing MDR healthcare-associated infections

• Very high rates of AMR reported in both resource-rich and resource-poor countries

Pathogen

WHO Regions

EURO EMRO AFRO PAHO WPRO SEARO

A^ G^^ A G A G A G A G A G

E. coli 35.5% 86.5% -* - 7.1% 57.1% - - - - 3.1% 16.7%

K. pneumoniae - 73.8% - - 0% 45.5% - - - - 6.2% 31.2%

P. aeruginosa - 85.7% - - - - - - - - 85% 80.6%

S. aureus** 83% - - - - -

^A: ampicillin; ^^G: Gentamicin; *No regional data available; **Percentage of methicillin-susceptibility

Sensitivity to the individual components of WHO first-line neonatal sepsis regimen

• Pooled data demonstrate that over 40% of sepsis in neonates was due to pathogensthat were resistant to the currently recommended WHO regimen (ampicillin andgentamicin)

Global AMR in neonatal sepsis

• Based on the first estimate of neonatal deaths due to AMR, 214,000 neonatal sepsisdeaths due to MDR pathogens have been predicted every year globally (Laxminarayan R,2016)

• Limited data suggests high rates of MDRAMR in NNU globally but this is based ona Very low number of studies

• Clinical outcome data are crucial toclarify the relationship between AMR andempiric-prescribing regimens

• Very few data are currently available onthe impact of AMR on neonatal mortality

• Urgent need to identify new regimes totreat MDR neonatal sepsis

Global AMR in neonatal sepsis

Pathogens on WHO Priority pathogen list include carbapenem-resistant:• Acinetobacter baumannii• Pseudomonas aeruginosa• Enterobacteriaceae, ESBL-producing

• 14 779 neonates admitted to NICU

• 59·9% (8111) were low birthweight, and 44·2% (5989,) were preterm.

• 1980 episodes of sepsis in 1934 neonates = incidence of 14·3% (95% CI 13·8–14·9)

• culture-positive sepsis was 6·2% (5·8–6·6) of NICU admissions.

• Common isolates: Acinetobacter spp, Klebsiella spp, E coli, Pseudomonas spp,

• Most isolated pathogens showed a high degree of resistance, including to extended-spectrumcephalosporins and carbapenems

Neonatal sepsis on 3 hospitals in Delhi (DeNIS)

Antibiotics for use in children / neonates

New Antibiotics (2013)11 newly approved antibiotics, 31 clinical trials enrolling children in Europe BUT• trials often included adults and children but did not provide a subset analysis for children,

limiting the relevance of their findings. • prematurely terminated or apparently active but not yet recruiting patients• Among paediatric-specific studies,

• 18 evaluate safety and efficacy of new compounds, • 4 are pharmacokinetic studies, but only 2 focus on neonates.

• For most antibiotics, despite adult phase 3 studies being completed, with specific concerns for particular drugs already noted, it will take another 3–5 years before adequate prescribing information becomes available for paediatricians.

Old antibiotics – Limited data• Only 6 of the antibiotics identified in the ECCMID review of 33 antibiotics have a

licensed neonatal indication and of these 6, only tobramycin and fosfomycin have significant MDRGN activity.

• Colistin – 2 pharmacokinetic studies in neonates 1 in 1967 and second in 2016 each with less than 10 patients

NeoAMR Program

WP1: Pre-selection of potential agents Advisory Role for study conduct

WP6: Project Management

Target PopulationWP 2: Clinical Observational study of

neonatal sepsis in target settings

Bacterial EpidemiologyWP3: Microbiological study of neonatal

sepsis in target settings

Therapeutic Options

WP4: Pharmacokinetic study(ies)

WP4: PK /PD modelling

WP4: Formulation

WP5: Clinical

Trial(s)

• Empiric

treatment

• Confirmed

MDR

resistant

treatment

Aim: By 2023,

deliver one

combination

treatment for the

empiric

management and

one combination

treatment targeted

for MDR cases

Primary objectives: Develop 1-2 new treatments within the 6 years. 1. An empirical treatment for babies with possible serious bacterial infection in areas

where drug-resistant Gram-negative (ESBL) pathogens are suspected (cf. TPP1) 2. A treatment for babies where MDR Gram-negative pathogens have been confirmed (e.g.

carbapenem-resistant K. pneumoniae, or Acinetobacter spp), cf. TPP2.

Secondary Objectives 1. To develop a global network of neonatal centers and relevant partners to design and conduct

studies (optimal use of off-patent/new antibiotics, and other strategies, for the effective prevention and management of MDR/XDR neonatal sepsis)

2. To determine the current phenotypic and genotypic resistance profiles of invasive and colonizing GN isolates from Neonatal Units participating in the project

3. To design and conduct PK, observational and interventional studies (efficacy and safety of novel regimens vs existing therapies)

4. To develop a conservation strategy for novel treatment regimens

Neonatal Sepsis Program

NeoAMR - A global consortium to develop two new treatments for neonatal sepsis

Prospective cohort study of empirical antibiotic treatment in neonatal sepsis and clinical outcome

AimCollect Routine clinical data for 28 days on:• Patients with Significant sepsis (2

clinical signs / laboratory finding)• Patients with microbiologically

confirmed MDR gram negative organisms in blood or CSF

• Collect opportunistic pharmacokinetic samples (blood, CSF) from patients with confirmed MDRGN sepsis in selected sites

Primary Objective• To prospectively characterise mortality rates in infants in NNU treated for clinical sepsisTrial Design• Prospective, multinational, multicentre, observational cohort study of the inpatient

management of neonatal sepsis in approximately 20 sites. • Enroling 200 infants per site gives >80% power to detect differences in mortality of 50% in

5% blood culture positives vs 10% in 95% blood culture negatives, as observed in DENIS

Indication Empiric treatment of neonatal sepsis, including meningitis (premature and term, early and late onset)

Patient Population Neonates with pSBI in settings of high prevalence of resistance to first line WHO empiric therapy

Route of Administration i.v. (intravenous), 30-120 min infusions Dosing Schedule 2-4 x daily Efficacy Comparable clinical activity to ampicillin/gentamicin or

ceftriaxone/gentamicin in claimed indicationClinical activity in pathogens resistant to ampicillin/gentamicin or ceftriaxone/gentamicin

Treatment duration 5-28 daysSafety / Tolerability Low propensity for resistance development, large therapeutic window

concerning hepatotoxicity, nephro- and CNS-toxicity, no QT-prolongation

TPP1

TPP1 Candidates Potential Candidates Antibiotic Class Active against Form Comments

Fosfomycin(Infectopharm and ERN Laborotries plus others)

Antibiotic –prevents cell wall synthesis

Broad spectrum Gram Negative

iv and po

Neonatal indication in EuropeLimited use in Europe mainly UTINeed to be used in combinationUsed with care with renal impairment

Amikacin AminoclycosideBroad Spectrum gram negative including Acetinobacter

Iv or im

Neonatal indication in EuropeRenal toxicity and ototoxicity

Lead Candidates

Potential Candidates Antibiotic Class Active against Form Comments

Tobramycin Aminoglycoside Broad spectrum gram negative - Neonatal indication- Resistance levels not known

Plazomicin Aminoglycoside most KPC not active against NDM iv Phase 3 PL Vs Colistin + Meropenem or tigecyclinefor CRE BSI

Flomoxef (Shinoghi) Broad-Spectrum Oxa-Cephem

Broad spectrum gram +ve and –veE coli and Klebsiella sp. and stable against ESBL per SPC but to beconfirmed with current isolates

iv Off patent marketed in Japan, China, Korea and TaiwanNeonatal indication for septicaemia

Ceftazidime Avibactam(Allergan)

Cephlasporin / β-lactamase inhibitor

Active against KPCs and OXA-48 (not active against MBLs)

iv No clinical trials in ChildrenPhase 3:Ceftaz/Avi+metronidazole vs Meropenem cIAI and NP Ceftaz/Avi vs doripenem for cUTI

Temocillin (EumedicaPharmaceuticals)

β-lactamase-resistant penicillin

Gram -ve - ESBL & AmpC no Gram +ve or Pseudamonas

iv Phase 4: PK in Paediatrics (TEMOPEDI): - No neonatal data &-IV formulation only, no oral

Back-up Candidates

Fosfomycin

•orally absorbed & crosses the BBB with low rates of toxicity

• small molecule, renally excreted

•use has been very low internationally for the last 30 years, so global resistance rates remain low, but outbreaks of resistant clones have been reported.

•neonatal i.v. dose, including for preterm infants varies from 100 -400mg/kg/day divided into two to three doses

• Ideally combined with aminoglycosides to protect against the emergence of resistance on treatment

Country Brand name Children1-12 years(10-40kg)

Infants1-12 months(up to 10kg)

Neonates(pre-/full-term,0-1 months)

Austria FosfomycinSandozTM

4 - 8g(in 2-3 doses)

100-200/400*mg(in 2-3 doses)

100-200/400*mg(in 2-3 doses)

Germany InfectofosTM 100-200/300*mg(in 3 doses)

200-250mg(in 3 doses)

100mg(in 2 doses)

Spain SolufosTM 100-200/400§mg(in 2-3 doses)

not specified not specified

France FosfocineTM 100-200§# mg not specified not specified

Recommended total daily dosages for i.v. fosfomycin in children, infants and neonates with normal renal function for age.§General dosage for “children” (no sub-division for age is reported)*Maximum dosage for severe infections

ActivityVery broad activity against Gram-negative and Gram-positive organisms including:

• S. aureus & MRSA• extended-spectrum β-lactamase (ESBL) • E. coli and Klebsiella• moderate activity against carbapenem-resistant

Klebsiella.

Fosfomycin synopsis

Objectives

• assess the safety of IV fosfomycin with regard to possible elevation of sodium, calcium and creatinine at Day 2 and 7 in neonates

• estimate the PK of IV fosfomycin in neonates

• estimate the oral bioavailability of fosfomycin in neonates

Treatment

• Randomised to Amp/Gent (SoC) vs Amp/Gent plus a 7-day course of fosfomycin

• 48 hours (or more) IV fosfomycin, followed by up to 5 days of oral fosfomycin.

• Neonates will move to oral fosfomycin once they are tolerating oral feeds.

PK and Safety Sampling

• Two PK samples will be taken after the first IV and oral doses; the sampling times will be randomly allocated to one of three possible early and late time points

• Adverse events, blood sampling for electrolytes including sodium and kidney function at Day 2 and 7 to assess safety

• All SAEs reviewed by DSMB

Statistics

Sample size: 60 babies to get 45 with complete PK

Baseline Assessments including:Electrolytes, blood culture, Lumbar Puncture (if

indicated)

Randomisation

Standard of care aloneStandard of care + Fosfomycin

Early & Late PK sample after IV dose

Day 2: Electrolytes and CMP (48h) Electrolytes and CMP (48h)

Early and Late PK sample after IV dose

Day 7: Electrolytes

Start Ampicillin and GentamicinDay 1: Start Ampicillin and Gentamicin

Day 1 & 2: Start intravenous Fosfomycin

If tolerating oral meds / clinical improved:stop IV fosfomycin start Oral Fosfomycin Day 3-7

Day 7: Trough PK sample

Day 28: Follow-up

Day 7: Electrolytes

Day 28: Follow-up

MDR Gram-negative - Current - Standard of carePotential Candidates Antibiotic Class Activity Form Dose

ColistemethateColistin(Generic)

Polymixin Broad spectrum Gram Negative including CRE

iv 50000-75000IU/Kg/day in 3 divided doses(up to 75000-120000 IU/Kg/day has been used in 3 divided doses)

ONGOING CLINICAL TRIALS• NCT02806141: Safety and Efficacy RCT on aerosolized + i.v. vs i.v. Colistin alone in VAP due to PDR

Acinetobacter Baumannii in neonates

o Estimated Enrollment: 204o Study start date: September 2016o Estimated Study Completion Date: December 2018

PK STUDIESAxline SG, Pediatrics 1967• Single i.m. 5 mg/kg dose in premature infants• 8 premature infants enrolled• Results: serum half-life did not decline with increasing postnatal age

Nakwan N, Pediatr Infect Dis J 2016• Single i.v. dose of colistimethate sodium in critically ill neonates• Equivalent to 1.1 and 2.6 mg/kg/day of colistin base (approximately 33,000–78,000 IU/d of CMS).• Prospective, open-label study conducted in NICU• 7 neonates enrolled (5 VAP, 2 MDR-GN BSIs)• Results: currently recommended dosage resulted in undectable levels in virtually all

babies….and this is the dose being used in SA..

Indication Neonatal sepsis, where MDR Gram-negative pathogens have been demonstrated, including K. pneumoniae, P. aeruginosa or Acinetobacter spp. Including CROsNeonatal meningitis

Patient Population Hospitalized neonates with severe infections, failure on optimal current treatment and proven microbiology

Route of Administration i.v., 30-120 min infusions Dosing Schedule 2-4 x daily Efficacy Comparable clinical activity to existing options in claimed indication

Clinical activity in pathogens resistant to carbapenems

Treatment duration 5-28 daysSafety / Tolerability Low propensity for resistance development, large therapeutic window

concerning hepatotoxicity, nephro- and CNS-toxicity, no QT-prolongation

TPP2 - MDR Gram-negative pathogens

TPP2 Strategy

Short term Conduct opportunistic blood sampling in patients with confirmed multidrug resistant gram negative infections with CRO• Determining the feasibility of conducting neonatal PK in LMIC

setting with limited neonatal clinical trials experience as part of the observational study

Mid-term: • Design a randomised trial to evaluate optimally dosed polymyxin B compared to SOC (NeoPolyB) in neonates starting in Q4 2018.

Long term Evaluate the possibilities with partners to set up a master protocol / multi-arm stage study to evaluate pharmacokinetics of antibiotics or combinations of old and new antibiotics with activity against CRO/CRE. This could be established from 2019/2020.

TPP2 Lead Candidates

Potential Candidates Antibiotic Class Activity Form Comments

Polymixin B (Generic but limited use outside USA)

Polymixin Broad spectrum Gram Negative including CRE

iv Nephrotoxic – small therapeutic window

Plazomicin Aminoglycoside Active against most KPC not active against NDM

iv Phase 3 PL Vs Colistin + Meropenem or tigecyclinefor CRE BSI

Cefiderocol (S-649266) (Shionogi & Co. Ltd.)

Siderophore-β-lactam (cephalosporin)

Broad spectrum Gram-ve including CRE Acinetobacter & Pseudomonas aeruginosa,

iv Phase 3 (no CTs in children)

Biapenem/VaborbactamMeropenem/Vaborbactam (Carbavance, Rempex Pharmaceuticals Inc.)

Carbapenems + β-lactamase-inhibitor

Gram negative including Activity against KPC, CRE

iv Phase 1: currently recruiting children (0-18 yr) (NCT02687906)

Ceftazidime Avibactam(Allergan) Cephlasporin / β-lactamase inhibitor

Active against KPCs and OXA-48 (not active against MBLs)

iv Completed Phase 1Ceftaz/Avi+metronidazole vs Meropenem cIAI and NP Ceftaz/Avi vs doripenem for cUTI

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Thank YouSt Georges, University of London Prof. Mike Sharland, Prof Paul Heath, Julia Bielicki, Laura Folgori, Grace LiPENTA Foundation Prof Carlo Giaquinto, Laura Mangiarini, Davide Bilardi, Daniele DonaUniversity of Antwerp Prof Herman Goossens, Tomislav Kostanyev