Pilot Program for Aztreonam-Avibactam Susceptibility Testing of Metallo-Beta-Lactamase-Producing Enterobacteriaceae

Abstract

Background: Carbapenemase-producing Enterobacteriaceae (CPE) are a major public health concern because they typically display multidrug resistance and they cause hard-to-treat infections. Organisms harboring metallo-β-lactamases (MBLs) pose a critical challenge in clinical practice because they confer resistance to nearly all β-lactams, including recently approved β-lactam combination agents. A promising new β-lactam-β-lactamase inhibitor combination for treating infections caused by MBL-producing CPE is aztreonam–avibactam. Although clinical trials using aztreonam–avibactam are ongoing, clinicians can administer this combination using 2 US Food and Drug Administration (FDA)–approved drugs: aztreonam and ceftazidime–avibactam. In 2019, the Centers for Disease Control and Prevention (CDC) initiated a pilot program in the Antibiotic Resistance Laboratory Network (AR Lab Network) to address the lack of commercially available antimicrobial susceptibility tests (ASTs) for aztreonam-avibactam by performing broth microdilution (BMD) for this drug combination. We describe the isolates submitted for aztreonam-avibactam AST during the AR Lab Network pilot in 2019. Methods: The AR Lab Network regional laboratories adopted the HP D300e Digital Dispenser to create customized BMD panels for aztreonam–avibactam ASTs. To qualify for aztreonam–avibactam AST, isolates had to be an Enterobacteriaceae displaying nonsusceptibility to all tested β-lactams (including either ceftazidime-avibactam or meropenem-vaborbactam) or confirmed to harbor at least 1 MBL gene (blaVIM, blaNDM, or blaIMP). Regional laboratories confirmed carbapenemase gene(s) using a molecular method. If an MBL gene was confirmed, aztreonam-–avibactam minimum inhibitory concentrations (MICs) were reported back to submitters within 3 working days of receipt. Findings were reported to CDC using a REDCap database. Results: From March through August 2019, aztreonam–avibactam AST was requested for 32 clinical isolates across 16 states. These isolates included 15 Escherichia coli, 12 Klebsiella pneumoniae, 4 Enterobacter cloacae complex, and 1 Proteus mirabilis. Molecular detection identified 27 blaNDM-positive isolates, 2 blaOXA-48-like-positive isolates, and 3 blaOXA-48/blaNDM-positive isolates. Aztreonam-avibactam results were reported for 30 isolates; 5 displayed elevated aztreonam-avibactam MICs of 8/4 µg/mL (n = 4) or 16/4 µg/mL (n = 1). Results for 2 isolates were not reported because the isolates were MBL negative. Aztreonam-avibactam MICs ranged from 0.06/4 µg/mL to 16/4 µg/mL. The MIC50/MIC90 were 0.5/4 µg/mL and 8/4 µg/mL. Conclusions: In the absence of effective FDA-approved treatments and lack of available AST for novel antibiotic combinations, CDC’s provision of AST for aztreonam-avibactam among MBL-producing CPE, offered through the AR Lab Network, helps fill a critical gap to inform patient treatment decisions. To date, our in vitro data suggest that aztreonam–avibactam could be a promising drug combination for use against infections caused by MBL-producing Enterobacteriaceae.

Funding: None

Disclosures: None