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. 2023 Jan 31;10(2):ofad046.
doi: 10.1093/ofid/ofad046. eCollection 2023 Feb.

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

Helio S Sader  1 , Rodrigo E Mendes  1 , Cecilia G Carvalhaes  1 , John H Kimbrough  1 , Mariana Castanheira  1
Affiliations

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

Helio S Sader et al. Open Forum Infect Dis. .

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 ≤8 mg/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 ≤8 mg/L. Only 3 isolates (0.01%) had an aztreonam-avibactam minimum inhibitory concentration (MIC) >8 mg/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 ≤8 mg/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 ≤8 mg/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.

Keywords: CRE; beta-lactamase inhibitor; carbapenemase; metallo-beta-lactamase.

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Conflict of interest statement

Potential conflicts of interest. HSS, REM, CGC, JHK, and MC are employees of JMI Laboratories, which was paid consultant to AbbVie in connection with the development of this manuscript. JMI Laboratories was contracted to perform services in 2022 for AimMax Therapeutics, Amicrobe, Inc., Appili Therapeutics, Armata Pharmaceuticals, Astellas Pharma, Inc., Basilea Pharmaceutica AG, Becton, Dickinson and Company, bioMérieux, Biosergen AB, Bugworks, Cerba Research NV, Cidara Therapeutics, Cipla USA Inc., ContraFect Corporation, CorMedix Inc., Crestone, Inc., Curza Global, LLC, Diamond V, Discuva Ltd., Entasis Therapeutics, Enveda Biosciences, Evopoint Biosciences, Fedora Pharmaceuticals, Fox Chase Chemical Diversity Center, Genentech, Gilead Sciences, Inc., GSK plc, Institute for Clinical Pharmacodynamics, Iterum Therapeutics plc, Janssen Biopharma, Johnson & Johnson, Kaleido Biosciences, LifeMine Therapeutics, Medpace, Inc, Lysovant Sciences, Inc, Meiji Seika Pharma, Melinta Therapeutics, Menarini Group, Merck & Co., MicuRx Pharmaceutical Inc., Mundipharma International Ltd., Mutabilis, Nabriva Therapeutics, National Cancer Institute, National Institutes of Health, Ohio State University, Omnix Medical Ltd., Paratek Pharmaceuticals, Pfizer, PolyPid Ltd., PPD, Prokaryotics, Inc., Pulmocide Ltd, Qpex Biopharma, Revagenix, Roche Holding AG, Roivant Sciences, Scynexis, Inc., SeLux Diagnostics, Shionogi & Co., Ltd., Sinovent Pharmaceuticals, Inc., Spero Therapeutics, Sumitovant Biopharma, Inc., TenNor Therapeutics, Thermo Fisher Scientific, US Food and Drug Administration, VenatoRx Pharmaceuticals, Washington University, Watershed Medical, LLC, Wockhardt, Zoetis, Inc. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Carbapenem resistance rates stratified by species. C freundii, Citrobacter freundii; E cloacae, Enterobacter cloacae; E coli, Escherichia coli; K aerogenes, Klebsiella aerogenes; K pneumoniae, Klebsiella pneumoniae; K oxytoca, Klebsiella oxytoca; S marcescens, Serratia marcescens.
Figure 2.
Figure 2.
Frequencies of isolates producing Klebsiella pneumoniae carbapenemase (KPC), metallo-β-lactamase (MBL), and oxacillinase (OXA)-48 types of carbapenemases among carbapenem-resistant Enterobacterales (CRE) from US medical centers stratified by year (2019–2021). *Includes New Delhi metallo-β-lactamase (NDM) type (87.9%) and imipenemase (IMP) type (12.1%).
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