treatment of multidrug-resistant gram negative infections · treatment of multidrug-resistant gram...

Treatment of multidrug-resistant Gram negative infections

Jesús Rodríguez BañoUnidad Clínica de Enfermedades Infecciosas y Microbiología

Hospital Universitario Virgen Macarena / Univ. de Sevilla / IBiSRed Española de Investigación en Patología Infecciosa (REIPI)

Treatment of multidrug-resistant Gram negative infectionsor a tale on personalised/precision medicine

Jesús Rodríguez BañoUnidad Clínica de Enfermedades Infecciosas y Microbiología

Hospital Universitario Virgen Macarena / Univ. de Sevilla / IBiSRed Española de Investigación en Patología Infecciosa (REIPI)

Conflicts of interest

• Horonaria for scientific coordination in research project byAstraZeneca

• Honoraria for educational accredited activities funded byMerck

Key aspects of therapy

Source control

ResuscitationAntimicrobials

Handle with care

• Best evidence from (mostly) clinical studies– RCT, cohorts– Not from in vivo/animal studies

• Three reasons to doubt of my conclusions– Many studies have important limitations, I will give my interpretation– I may be biased towards the results of our studies– Doubt is needed in science

FEP AZT AMC PTZ MER COL TIG FOS AG

Red: >75%ROrange: >25% or increasing

Lancet Infect Dis 2013

Carbapenems sales

Antimicrob Agents Chemother 2015

Candidates as carbapenems-spare regimens

Beta-lactams– BLBLI– Cephamycins– Temocillin– Cephalosporins– Pivmecillinam

Aminoglycosides, fluroquinolines, TMP/SMX Fosfomycin

Escherichia coli - ESBL Ampicillin R Amoxicillin/clavulanate S (MIC=4 mg/L) Piperacillin/tazobactam S (MIC=2 mg/L) Ceftazidime S (MIC=1 mg/L) Cefotaxime R Cefoxitine S Meropenem S Ertapenem S Ciprofloxacin R Cotrimoxazol R Gentamicin R Amikacin S Tigecycline S Fosfomycin S Colistin S

CTX-M-14

76 yo womanUrinary stones, diabetesNew fever flank painNo shockNormal renal function

Tamma & Rodríguez-Baño, CID 2017

Antimicrob Agents Chemother 2016

Conditions for BLBLI use in severe ESBL infections (so far)

EUCAST breakpoint Adequate dose

– Piperacillin/tazobactam, 4.5 g/8h (extended infusión better)– Amoxicillin/clavulanate, 2.2 g/8h

Less data for pneumonia and septic shock (but probably OK)

Next: MERINO trial

Tamma & Rodríguez-Baño, CID 2017

Tamma & Rodríguez-Baño, CID 2017

Conditions for cefepime/cephamycins use in ESBL

EUCAST breakpoints Adequate dose

– Cefepime 2 g/8h– Cephamycins – high range

Mostly non-severe infections or UTI

Escherichia coli - ESBL Ampicillin R Amoxicilin/clavulanate R Piperacillin/tazobactam R Ceftazidime R Cefotaxime R Cefoxitine R Meropenem S Ertapenem S Ciprofloxacin R Cotrimoxazol R Gentamicin R Amikacin S Tigecycline S Fosfomycin S Colistin S

CTX-M-15 + OXA-1

76 yo womanUrinary stones, diabetesNew fever flank painNo shockNormal renal function

Variables Points

Age >50 years 3

Klebsiella spp. 2

Source other then UTI 3

UF/RF underlying disease 4

Pitt score >3 3

Severe sepsis/shock 4

Inappropriate early targeted therapy 2

Mortality according to risk score <11: 5-6%>11: 35-46% (NPP: 94%)

Empirical therapy No. deaths/treated (%)

High-risk score (%)

Low-risk score (%)

Carbapenems 51/249 (20.4) 41/81 (50.6) 11/168 (6.5)

Other active drugs 16/87 (18.3) 14/28 (50) 2/59 (3.3)

Cephalosporin as only active drug 2/7 (28.6) 1/2 (50) 1/5 (20)

Aminoglycoside as only active drug 9/41 (21.9) 8/16 (50) 1/25 (4)

Fluoroquinolone as only active drug 2/19 (10.5) 2/2 (100) 0/17 (0)

TMP-SMX as only active drug 0/4 (0) 0/1 (0) 0/3 (0)

Tigecycline as only active drug 1/2 (50) 1/2 (50) 0

Others used as only active drug 2/10 (20) 2/4 (50) 0/6 (0)

Other combinations 0/4 (0) 0/1 (0) 0/3 (0)

Non-carbapenem, non-BLBI empirical therapy of ESBL-producing Enterobacteriaceae BSIPalacios-Baena et al, ECCMID 2017 and submitted (pending revised versión)

Adjusted HR (mortality) = 0.75 (95% CI: 0.38-1.48) p=0.42(reference: carbapenem)

My interpretation

Are your ESBL/AmpC-producers susceptible to aminoglycosides? Consider adding an aminoglycoside to standard empirical therapy in

severe infections/patients at high risk of these organisms Follow them and provide good target therapy

Clin Microbiol Infect 2017

Clin Microbiol Infect 2017

BMJ Open 2015

Fosfomycin as single drug for cUTIPress release by Zavante Therapeutics, May 2017

465 patients with cUTI including acute pyelonephritis randomised Arms

– Fosfomycin 6 g/8h, 1hour iv infusion – Piperacillin/tazobactam 4.5 g/8h, 1h IV infusion

7 days (14 if bacteremia); no oral relay Overall success rate: 64.7% (119/184) vs 54.5% (97/178) Non-inferiority demonstrated

K. pneumoniae BLEE Ampicillin R Amoxicillin/clavulante R Piperacillin/tazobactam R Ceftazidime R Cefoxitin R Temocillin R Meropenem S Ertapenem S Ciprofloxacin R Co-trimoxazole R Gentamicin R Amikacin S Tigecycline S Fosfomycin R Colistin S

CTX-M-15SHV-1OXA-1

76 yo womanNosocomial pneumoniaSeptic shock

JAC 2016

Ceftazidime-avibactam Best available therapy

Mosty Enterobacteriaceae (P. aeruginosa 4-10%)

J Antimicrob Chemother 2016

My interpretation

I would not use newer drug for ESBL/AmpC producers (not needed) I would wait to read and discuss the data on IV fosfomycin for cUTI

Carbapenem-resistant Enterobacteriaeae

• Carbapenemase-producers• Other mechanisms (permeability + ESBL or AmpC, etc)

• Best treatment unknown

Clin Microbiol Rev 2012

AGCarb

TIG

COLInactive

Comb(-carba)

Comb(+carba)

Ref Design Patients N Combination lowermortality

ZarcotouCMI 2011

Retrospectivecohort

BacteraeamiaKPC Kp

53 No

TumbarelloCID 2013

Retrospectivecohort

BacteraeamiaKPC Kp

124 Yes(MER + COL + TIG)

QureshiAAC 2013

Retrospectivecohort

BacteraeamiaKPC Kp

41 Yes

DaikosAAC 2014

Retrospectivecohort

BacteraeamiaKPC or VIM Kp

205 Yes

Gomez-SimmondsAAC 2016

Retrospectivecohort

BactereaemiaCR-Kp

141 No

Combination vs monotherapy for CPE BSI

aHR=

Clin Microbiol Infect 2011

AAC 2016

Beta-lactams for CPE?

• Aztreonam for MBL (if ESBL-neg)• Cephalosporins for OXA-48 (if ESBL-neg)

… should work but no clinical data!

Inhibition of beta-lactamases by new compounds

Ambler class Enzime Ceftolozane/tazobactam Ceftazidime/avibactam

A ESBLs Yes Yes

KPC No Yes

B MBL (NDM, VIM, IMP) No No

C AmpC Variable Yes

D OXA No Variable

Clin Infect Dis 2016

N=37. Mortality 24%10 microbiological failure 3 resistance

Antimicrob Agents Chemother 2017

8 vs 23, mortality 25% vs 52% (p=0.19)

Int J Infect Dis (in press)

King et al, Antimicrob Agents Chemother 2017 (in press)

N=60, mortality 32%

N=38, mortality 39%

KPC: 6/23 (26.0%) p=0.07OXA-48: 8/13 (61.5%)

Plazomicin

My interpretation for CRE/CPE

• Incorporate an active program to treat CPE/CRE as early as possible• I would like to know MICs and mechanisms of resistance…• Consider using the INCREMENT CPE score to classify• Low risk: monotherapy according to susceptibility/source

– UTI: aminoglycoside, fosfomycin, beta-lactam, colistin– IAI: tigecycline, colistin, beta-lactam

• High-risk: consider combination (according to susceptibility and source) including ceftazidime-avibactam if available

• Use optimised dosing and source control!!

(Some) pending questions

• Ceftazidime/avibactam better than combination of “oldies”?• Can we avoid development of R to ceftazidime/avibactam?• Will newer compounds (e.g., aztreonam/avibactam) add

anything?• Does carbapenemase-type makes a difference beyond

susceptibility?

• Therapy must be individualized (susceptibility, source, severity) (CII)• Combination therapy is recommended for invasive or severe infections by KPC-

producing K. pneumoniae (CII), and possibly for other CPE (CIII)• Combination therapy may not be needed in mild infections, cUTI, and early

source control with available fully active useful drugs (CIII)• Dosing of all administered drugs should be optimized

Spanish Guidelines: therapy for CPE

Rodríguez-Baño et al. Enferm Infecc Microbiol Clin 2015

ESCMID guidelines in preparation

Clin Infect Dis 2013

• Active against many CR isolates if porin loss (not carbapenemases)• N=35 (18 HAP/VAP); 6 BSI• 27 monotherapy. Dosing 1.5/8h (n=20), 3 g/8h (n=9) or adjusted• 9 failures

– 3 unrelated deaths; 4 MIC > 8mg/L; 2 MIC unknown– 7 pneumonia; 7 recived 1,5 g/8h or equivalent

Clin Infect Dis 2017

Carbapanem-R A. baumannii: we have a problem

• Concerns about colistin monotherapy– Garnacho-Montero CID 2013; Doi, SRCCM 2015

• Concerns about tigecycline (particularly if MIC >2)– Lee, JCMID 2013; Chang CCM 2015– High dose? De Pascale CCM 2014

• Combination not clearly better than monotherapy– López-Cortés, JAC 2014

RCT: colistin+ RMP vs colistin alone Durante-Mangoni et al, CID 2013

Pipeline…

• Inhibitors– Aztreonam/avibactam– Imipenemrelebactam– Meropenem/vaborbactam– Cefepime/AAI101

• Siderofores– Cefiderocol

• Aminoglycosides– Plazomicin

• Glycilcyclines– Eravacycline

Conclusions

• Therapy must be individualised– Susceptibility (EUCAST!!), source, shock… (scores?)

• Opportunity for active intervention / stewardship– Collaboration Microbiologists + Infectious Diseases– Early appropriate therapy - better outcomes– Avoid overuse of carbapenems, combinations and new drugs

• Opportunity for research - many questions to be answered

Ackowledgements• HUVM team

– Infectious Diseases: B Gutiérrez, P Retamar, LE López-Cortés, MD del Toro, J Gálvez, MA Muniain, J Sojo

– Microbiology: A Pascual, M de Cueto, L López-Cerero, F. Docobo– Pharmacy: V Merino– Research staff: I Morales, J Bravo, V Palomo, L Navarro, M Barrio, L Sadyrbaeva,

A Martín, A Serna, S Monteau

• Spanish Network for Research in Infectious Diseases (REIPI)• International groups and consortia (ESGBIS, INCREMENT, COMBACTE)