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

Abstract

Objectives: To 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.

Methods: Retrospective analysis.

Results: Between 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.

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.

Fig 1. Distribution of MDR-GNB per hospital section.

Panel A: Departments, in which carbapenem-resistant MDR-GNB were isolated. Each affected patient was counted once per department. Panel B: Services that primarily cared for these patients. Each patient was counted once per service. A & E, accident and emergency; *excluding stem cell transplantation ward; **including hepatobiliary surgery.

Fig 2. Examples of strain typing results using pulse-field gel electrophoresis.

Panels A and B: Identical PFGE patterns generated from carbapenem-resistant MDR Acinetobacter baumannii (five individual patients A₁-A₅, panel A) and Klebsiella pneumoniae (five individual patients K₁-K₅, panel B) highly suggestive of nosocomial transmission. Panel C: Identical PFGE patterns of carbapenem-susceptible (P₁) and carbapenem-resistant (P₂) MDR Pseudomonas aeruginosa isolates from the same patient (blood culture and bronchioalveolar lavage, respectively) exemplifying acquisition of carbapenem-resistance under therapy. The time span between detection of the carbapenem-susceptible and carbapenem-resistant isolate was 21 days. Abbreviations: M, DNA Marker; C, unrelated clinical control isolate (same species, obtained outside the study period).

Fig 3

Colistin minimal inhibitory concentrations (MICs) for a) Klebsiella pneumoniae, b) Pseudomonas aeruginosa, and c) Acinetobacter baumannii isolates. Shown are non-duplicate isolates from individual patients. Dashed line: Clinical breakpoint according to EUCAST Breakpoint Table v.7.0 (MIC ≤ 2 mg/L, susceptible; MIC > 2 mg/L resistant).