Validation of Aztreonam-Avibactam Susceptibility Testing Using Digitally Dispensed Custom Panels

Abstract

Aztreonam-avibactam is a combination antimicrobial agent with activity against carbapenemase-producing Enterobacteriaceae (CPE) with metallo-β-lactamases (MβLs). Although aztreonam-avibactam is not yet approved by the U.S. Food and Drug Administration (FDA), clinicians can administer this combination by using two FDA-approved drugs: aztreonam and ceftazidime-avibactam. This combination of drugs is recommended by multiple experts for treatment of serious infections caused by MβL-producing CPE. At present, in vitro antimicrobial susceptibility testing (AST) of aztreonam-avibactam is not commercially available; thus, most clinicians receive no laboratory-based guidance that can support consideration of aztreonam-avibactam for serious CPE infections. Here, we report our internal validation for aztreonam-avibactam AST by reference broth microdilution (BMD) according to Clinical and Laboratory Standards Institute (CLSI) guidelines. The validation was performed using custom frozen reference BMD panels prepared in-house at the Centers for Disease Control and Prevention (CDC). In addition, we took this opportunity to evaluate a new panel-making method using a digital dispenser, the Hewlett Packard (HP) D300e. Our studies demonstrate that the performance characteristics of digitally dispensed panels were equivalent to those of conventionally prepared frozen reference BMD panels for a number of drugs, including aztreonam-avibactam. We found the HP D300e digital dispenser to be easy to use and to provide the capacity to prepare complex drug panels. Our findings will help other clinical and public health laboratories implement susceptibility testing for aztreonam-avibactam.

Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales

“…As these agents are two separate FDA-approved agents, automated susceptibility testing for this combination is not available and testing for synergy poses a challenge for many institutional microbiology labs. 63 …”

Present and Future Perspectives on Therapeutic Options for Carbapenemase-Producing Enterobacterales Infections

“…AZT/AVI is a particular compound combining two FDA-approved agents: AZT and CAZ/AVI, that exerts activity on CPE and MBLs [ 153 ]. AZT is mainly resistant to the action of MBLs; however, aztreonam can be readily hydrolyzed by Ambler class A or class C β-lactamases [ 152 ].…”

“…Notably, avibactam can inhibit these secondary β-lactamases, which is why the AZT-AVI combination may be a valuable therapeutic strategy against MβL-producing organisms with secondary β-lactamases. The combination of AZT-AVI is currently being studied in clinical trials to investigate its efficacy on MβL-related CRE infections [ 153 ]. However, both components of the combination are FDA-approved: aztreonam and CAZ/AVI, respectively.…”

“…However, both components of the combination are FDA-approved: aztreonam and CAZ/AVI, respectively. Only by using these approved drugs can patients benefit from the AZT/AVI combination; this procedure was also recently included in the Sanford guide for antimicrobial therapy of CRE infections [ 153 ]. Although the use of AZT in conjunction with CAZ-AVI is permitted for clinical use, there are still many details to elucidate regarding in vitro antimicrobial susceptibility testing (AST) of this combination or AZT-AVI [ 153 , 154 ].…”

Synergistic Activity of Minocycline and Rifampin in Combination with Antifungal Drugs againstCandida auris

“…Manual synergy testing is an error-prone and time-consuming process, and automation allows for significantly higher throughput of the technique, thereby facilitating more rapid investigation of novel combinations. This use of the DDM for MIC and synergy testing of bacteria, first described in our laboratory (34, 35), has been adopted by the United States Centers for Disease Control and Prevention to test drug combinations against multidrug-resistant bacterial pathogens (36) and has the potential for similar use for fungal pathogens such as C. auris .…”