Fighting MDR Pathogens in the ICU Dr. Murat Akova Hacettepe University School of Medicine, Department of Infectious Diseases, Ankara, Turkey 1
50.000 deaths each year in US and Europe due to antimicrobial resistance 700.000 worldwide O Neill J. May 2016
If resistance continues by 2050 10 million death every year 2-3.5% reduction in GDP O Neill J. December 2014
O Neill J. December 2014
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ESKAPE vs ESCAPE E S C A P E E. faecium S. aureus C. difficile A. baumannii P. aeruginosa Enterobacteriaceae Resistant strains E. coli K. pneumoniae Proteus spp Peterson LR. Clin Infect Dis. 2009;49:992
ESKAPE Pathogen Predictors- Risk Profiling Risk factor VRE MRSA ESBL CRE Acinet. Pseud. Long-term care facility X X Recent antibiotics X X X X X X Dependent func. status X Foreign device X X X Recent surgery X Prior hospitalization X Elderly X X Comorbidity X X Immunosuppression X X X ICU stay X X Male sex X X 8 Pogue JM, et al. Clin Microbiol Infect 2015;21:302
Barriers for New Antibiotics Scientific - Hard to find new antibiotics, especially vs. Gram (-)s - Hard to find new classes of antibiotics - Superiority trials are not feasible Regulatory - Hard to get a licence from the FDA - Rules repeatedly changed Financial - Antibiotics not very profitable
New Antibiotic Development from an Economical Perspective
O Neill J. February 2015
Basic Principles of Antibiotic Therapy Timely Appropriate Apply PK/PD parameters De-escalate Stop as soon as possible Deresinski S. Clin Infect Dis 2007;45:S177 12 Opal SM, et al. JAMA 2009;302:2367
Epidemiology of ESBL-producing E. coli, 2011-2014 13
14 ECDC, January 30, 2017
15 ECDC, January 30, 2017
BL-BLIs for BSIs Caused by ESBL (+) Enterobacteriaceae (ESBL-E) INCREMENT Project Multinational retrospective cohort study Patients w monomicrobial BSI due to ESBL-E Patient cohorts Empirical therapy (ETC, n=365) Targeted therapy (TTC, n=601) Global cohort (GC, n=627) Gutierrez-Gutierrez B, et al. AAC 2016,60:4159 16
Results, INCREMENT Cure/improvement ETC TTC 30-day mortality ETC TTC BLBLI Carbapenem P 80.0% 90.2% 17.6% 9.8% 78.9% 85.5% 20.6% 13.9% 0.81 0.22 0.6 0.28 Gutierrez-Gutierrrez B, et al. AAC 2016,60:4159 17
Cure / Improvement at Day 14 with Empirical Therapy 18 Gutierrez-Gutierrez B, et al. AAC 2016,60:4159
Survival with Empirical Therapy 19 Gutierrez-Gutierrez B, et al. AAC 2016,60:4159
Conclusions, INCREMENT BLBLIs are not inferior to carbapenems for tx of BSI due to ESBL-E The isolate should be susceptible E. coli and others with various sources of infection Empirical decision should provide Evaluation of risk factors for ESBL Local epidemiology for susceptibility of ESBLproducers Gutierrez-Gutierrez B, et al. AAC 2016,60:4159
Carbapenemases in Enterobacteriaceae KPC NDM OXA-48 VIM Courtesy of DM Livermore
Epidemiology of KPC-Kp 22 Lee C-R, et al. Frontiers Microbiol 2016;7:895
KPC-producing K. pneumoniae Usually resistant To all beta-lactams, quinolones, aminoglycosides Except temocillin, in UTI infections May be sensitive Polymyxins, selected aminoglycosides, fosfomycin, tigecycline Usually sensitive Ceftazidime-avibactam, plazomicin 23
Caution for Fosfomycin 39.2% - 43.4% resistance reported from China among KPC-Kp Resistance associated with fosa3 gene mainly associated with bla CTX-M gene Also on bla KPC -harboring plasmids In China, 55.6% fosfo-r KPC-Kp are harboring fosa3 Lee C-R, et al. Frontiers Microbiol 2016;7:895 24
Caution for Tigecycline Low serum levels, not to be used for primary bacteremia Not effective as monotherapy for HAP/VAP Double dose in combination therapy Overproduction of efflux pumps are responsible for resistance Lee C-R, et al. Frontiers Microbiol 2016;7:895 25
Mortality Outcome of Patients with CP-Kp Bacteremia 50 40 * p=.018 * 30 20 * 10 0 Combination Comb. w carbapenem Comb. w/o carbapenem Monotherapy No active agent Daikos GL, et al. Antimicrob Agents Chemother 2014;58:2322 26
INCREMENT-CPE Mortality Score Severe sepsis or septic shock at presentation (5 points) Pitt bacteremia score >6, (4 points) Charlson index >2 (3 points) Source of BSI other than urinary or biliary tracts (3 points) Inappropriate empirical and early targeted therapy (2 points) Gutierrez-Gutierrez B, et al. Mayo Clin Proc 2016;91:1362 27
Final Score for 14-day All Cause Mortality 0-8 low (18% mortality) 9-13 intermediate (50%) 14-17 high (80%) Gutierrez-Gutierrez B, et al. Mayo Clin Proc 2016;91:1362 28
Combination Therapy for BSIs Due to Carbapenemase-producing Enterobacteriaceae An international retrospective cohort study 26 hospital, 11 countries Outcome variable 30-day mortality 437 patients, with BSIs due to CPE 85.8% K. pneumoniae and 75.2% KPC 343 had active antibiotic therapy Combination therapy decreased mortality only in high-risk patients (score 8-15) Gutierrez-Gutierrez B, et al. Submitted March 2017 29
Other Proposed and New Therapeutic Alternatives Double carbapenem + colistin therapy High dose tigecycline combinations Combinations including gentamicin New agents Ceftazidime avibactam Plazomicin Imipenem relebactam Meropenem varbobactam Meropenem RG6080 Cefiderocol Adapted from Viale P, et al. Curr Opinion Pharmacol 2015;24:30 30
Non-KPC Producers Metallo-beta-lactamases (VIM, IMP, NDM-1) Sensitive to aztreonam, but no other betalactams NDM-1 producers can benefit from carbapenems, despite high MICs OXA-48 Sensitive to broad-spectrum cephalosporins Aminoglycosides Carbapenems may not be a reliable option Lee C-R, et al. Frontiers Microbiol 2016;7:895 31
MDR P. aeruginosa Usually combination therapy is required Beta-lactam + aminoglycoside Beta-lactam + fluoroquinolone Colistin + carbapenem Ceftolozane-tazobactam Viale P, et al. Curr Opinion Pharmacol 2015;24:30 32
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Algorithm for A. baumannii Epidemics 34 Garnacho-Montero J, et al. Intensive Care Med 2015;41:2057
22 studies including 28 comparisons Although polymyxin monotherapy was inferior to combination therapy for mortality, the quality of evidence was low This can not be taken as a proof for the effectiveness of combination therapy 35
DALI: Defining Antibiotic Levels in ICU patients 384 patients in 68 hospitals in 10 countries 10 beta-lactams antibiotics including meropenem 248 patients treated for infection 16% did not achieve 50% f T>MIC 32% less likely to have (+) outcome (+) outcome was associated with increasing 50% and 100% f T>MIC 36 Roberts JA, et al. Clin Infect Dis 2014;58:1072
Achievement of PK/PD Targets in Critically Ill Patients % achievement Antibiotics 50% f T>MIC 100% f T>MIC 50% f T>4XMIC 100% f T>4XMIC Cefepime 6 g Ceftriaxone 2 g Piperacillin, 12 g Meropenem 3 g 78,6 50 78,6 71,4 97 93,9 93,9 87,9 80,6 48,9 67 30,3 95 68,8 69,7 41,6 37 Roberts JA, et al. Clin Infect Dis 2014;58:1072
High Intensity Meropenem Combinations with Polymyxin B: to Overcome CRAB Infections Time-kill experiments 3 polymyxin-b (P-B) susceptible CRAB strains Meropenem MICs 4,16,64 Drastic decline meropenem MICs w P-B Similar all 3 strains A hollow-fibre infection model to simulate humanized regimens Meropenem 2,4,6 and 8 g prolonged infusion q8h Complete eradication by 336 h (8g q8h) Lenhard JR, et al. JAC 2017;72:153 38
Conclusions Treatment MDR-GN infections is very challenging Early diagnosis is essential to avoid inappropriate therapy Molecular diagnostics may lead appropriate agents for treatment Combination therapy seems to be superior than monotherapy??? Meticulous infection control practices have utmost importance 39
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Thank you Ευχαριστώ 41