Carbapenem-resistant Gram-negative pathogens in a German university medical center: Prevalence, clinical implications and the role of novel β-lactam/β-lactamase inhibitor combinations.

Juri Katchanov,Eva-Maria Klupp,Camilla Rothe,Christina König,Holger Rohde,Florian P Maurer,Anna Both,Stefan Kluge,Lucia Asar,William M Shafer

doi:10.1371/journal.pone.0195757

Abstract

ObjectivesTo determine the spectrum of infections with multidrug-resistant Gram-negative bacteria (MDR-GNB) and the clinical impact of the newly available betalactam/betalactamase inhibitor combinations ceftolozane/tazobactam and ceftazidime/avibactam in a German academic tertiary care center.MethodsRetrospective analysis.ResultsBetween September 1, 2015 and August 31, 2016, 119 individual patients (0.22% of all hospital admissions) were colonized or infected with carbapenem-resistant MDR-GNB. The species distribution was Pseudomonas aeruginosa, n = 66; Enterobacteriaceae spp., n = 44; and Acinetobacter baumannii, n = 18. In 9 patients, carbapenem-resistant isolates belonging to more than one species were detected. Infection was diagnosed in 50 patients (total: 42.0%; nosocomial pneumonia: n = 23, 19.3%; bloodstream infection: n = 11, 9.2%). Antimicrobial treatment with broad-spectrum antibiotics prior to detection of a carbapenem-resistant isolate was documented in 105 patients (88.2%, prior administration of carbapenems: 62.2%). Nosocomial transmission was documented in 29 patients (24.4%). In 26 patients (21.8%), at least one carbapenem-susceptible, third-generation cephalosporin non-susceptible isolate was documented prior to detection of a carbapenem-resistant isolate belonging to the same species (median 38 days, IQR 23–78). 12 patients (10.1%) had documented previous contact to the healthcare system in a country with high burden of carbapenemase-producing strains. Genes encoding carbapenemases were detected in 60/102 patient isolates (58.8%; VIM-2, n = 25; OXA-48, n = 21; OXA-23-like, n = 10). Susceptibility to colistin was 94.3%. Ceftolozane/tazobactam and ceftazidime/avibactam were administered to 3 and 5 patients, respectively (in-hospital mortality: 66% and 100%). Development of drug-resistance under therapy was observed for both antimicrobials.Conclusionsi) The major predisposing factors for acquisition of carbapenem-resistant MDR-GNB were selective pressure due to preceding antimicrobial therapy and nosocomial transmission. ii) Colistin remains the backbone of antimicrobial chemotherapy for infections caused by carbapenem-resistant MDR-GNB. iii) Novel β-lactam/β-lactamase inhibitor combinations are of limited usefulness in our setting because of the high prevalence of Ambler class B carbapenemases and the emergence of nonsusceptibility under therapy.

Highlights

Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) represent an increasing global threat [1]
Antimicrobial treatment with broad-spectrum antibiotics prior to detection of a carbapenem-resistant isolate was documented in 105 patients (88.2%, prior administration of carbapenems: 62.2%)
Conclusions i) The major predisposing factors for acquisition of carbapenem-resistant MDR-GNB were selective pressure due to preceding antimicrobial therapy and nosocomial transmission. ii) Colistin remains the backbone of antimicrobial chemotherapy for infections caused by carbapenem-resistant MDR-GNB. iii) Novel β-lactam/β-lactamase inhibitor combinations are of limited usefulness in our setting because of the high prevalence of Ambler class B carbapenemases and the emergence of nonsusceptibility under therapy

Summary

Introduction

Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) represent an increasing global threat [1]. Therapeutic regimens for infections caused by carbapenem-resistant MDR-GNB are often based on colistin, aminoglycosides, tigecycline and/or fosfomycin and their overall benefit on patient outcome is limited [3]. Two novel β-lactam/β-lactamase inhibitor combinations, ceftolozane/tazobactam and ceftazidime/avibactam, have been approved by FDA and EMA for treatment of complicated urinary tract and intra-abdominal infections. In vitro and clinical trial data indicate substantial benefits of these antimicrobials, against Pseudomonas aeruginosa isolates with up-regulated efflux and derepressed AmpC, and against P. aeruginosa and Enterobacteriaceae strains carrying class A (including KPC), some class C and D β-lactamases, respectively [4,5]. Currently few data exist regarding the post-approval efficacy of ceftolozane/ tazobactam and ceftazidime/avibactam in Europe and first reports on a priori and acquired non-susceptibility, mainly from the United States, raise concerns about their limited usefulness in the target population [6,7]

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