Changing Epidemiology of Carbapenemases among Carbapenem-Resistant Enterobacterales from United States Hospitals and the Activity of Aztreonam-Avibactam Against Contemporary Enterobacterales (2019-2021)

Abstract

Background: As the frequency of metallo-β-lactamase (MBL)-producing Enterobacterales is increasing worldwide, effective antimicrobials to treat the infections caused by these organisms are urgently needed. Methods: The activity of aztreonam-Avibactam and comparators were evaluated against 27 834 Enterobacterales isolates collected from 74 US medical centers in 2019-2021. Isolates were susceptibility tested by broth microdilution. An aztreonam-Avibactam pharmacokinetic/pharmacodynamic breakpoint of ≤8mg/L was applied for comparison. Antimicrobial susceptibility and the frequency of key resistance phenotypes were assessed then stratified by year and infection type. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemase (CPE) genes by whole genome sequencing. Results: Aztreonam-Avibactam inhibited >99.9% of Enterobacterales at ≤8mg/L. Only 3 isolates (0.01%) had an aztreonam-Avibactam minimum inhibitory concentration (MIC) >8mg/L. The CRE rates were 0.8%, 0.9%, and 1.1% in 2019, 2020, and 2021, respectively; 99.6% (260 of 261) of CRE isolates were inhibited at an aztreonam-Avibactam MIC of ≤8mg/L. The CRE susceptibility to meropenem-vaborbactam decreased from 91.7% in 2019 to 83.1% in 2020 and 76.5% in 2021 (82.1% overall). The CRE, multidrug-resistant, and extensively drug-resistant phenotypes were markedly higher among isolates from pneumonia compared with other infections. The most common carbapenemase among CRE was Klebsiella pneumoniae carbapenemase (65.5% of CRE), followed by New Delhi metallo-β-lactamase (11.1%), oxacillinase (OXA)-48-like (4.6%), Serratia marcescens enzyme (2.3%), and imipenemase (1.5%). Among non-CPE-producing CRE isolates (n = 44; 16.9% of CRE), 97.7% were inhibited at ≤8mg/L aztreonam-Avibactam and 85.4% were meropenem-vaborbactam susceptible. Conclusions: The frequencies of MBL and OXA-48-Type producers increased markedly. Aztreonam-Avibactam demonstrated potent and consistent activity against Enterobacterales across infection types and over time.