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