Abstract
ObjectivesTo assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing Enterobacterales (CPE) clinical isolates and 6 in vitro selected ATM-AVI-resistant CPE with CMY-16 Tyr150Ser and Asn346His mutants or transformants.MethodsMICs of imipenem, ceftazidime-avibact8am (CAZ-AVI), ATM-AVI, CAZ-AVI-AUR and ATM-AVI-AUR were determined via the broth microdilution method. Genetic background and carbapenemase genes were determined by PCR and Sanger sequencing.ResultsAUR alone showed little antibacterial activity with AUR MICs were greater than 64 μg/mL for all the 88 clinical CPE isolates. The addition of AUR (16 μg/mL) resulted in an 3-folding dilutions MIC reduction of ATM-AVI MIC50 (0.5 to 0.0625 μg/mL) and a 2-folding dilutions MIC reduction of MIC90 (1 to 0.25 μg/mL) against all 88 clinical CPE isolates, respectively. Notably, the reduced ATM-AVI MIC values were mainly found in MBL-producers, and the MIC50 and MIC90 reduced by 2-folding dilutions (0.25 to 0.0625 μg/mL) and 3-folding dilutions (2 to 0.25 μg/mL) respectively by AUR among the 51 MBL-producers. By contrast, the addition of AUR did not showed significant effects on ATM-AVI MIC50 (0.0625 μg/mL) and MIC90 (0.125 μg/mL) among single KPC-producers. Interestingly, the addition of AUR restored the ATM-AVI susceptibility against the 6 in vitro selected ATM-AVI-resistant CMY-16 Tyr150Ser and Asn346His mutants or transfromants, with the MICs reduced from ≥32 μg/mL (32->256 μg/mL) to ≤8 μg/mL (0.0625-8 μg/mL).ConclusionsOur results demonstrated that AUR potentiated the activities of CAZ-AVI and ATM-AVI against MBL-producing isolates in vitro. Importantly, AUR restored the ATM-AVI activity against ATM-AVI resistant mutant strains. As a clinically approved drug, AUR might be repurposed in combination with ATM-AVI to treat infections caused by highly resistant MBL-producing Enterobacterales.
Highlights
Carbapenem resistance in carbapenem-resistant Enterobacterales (CRE) is driven primarily by the acquisition of various carbapenemases that are able to degrade carbapenem antibiotics
Among the 88 non-duplicate clinical carbapenemase-producing Enterobacterales (CPE) isolates, K. pneumoniae was the most abundant species (n = 62), followed by E. coli (n = 18), Enterobacter cloacae (n = 4), Citrobacter freundii (n = 2) and K. aerogenes (n = 2). They were obtained from various clinical sources, and harbored different carbapenemase genes and from different sequences types (STs)
multilocus sequence typing (MLST) data showed that the 62 K. pneumoniae isolates belonged to 18 different ST types, with ST11 being the most common (30/62, 48.4%)
Summary
Carbapenem resistance in carbapenem-resistant Enterobacterales (CRE) is driven primarily by the acquisition of various carbapenemases that are able to degrade carbapenem antibiotics. The rapid worldwide emergence of MBLs in Enterobacterales is especially worrisome due to their broad, constant and efficient carbapenemase activity against almost all the b-lactam antibiotics (except for monobactam, e.g., aztreonam, ATM), potential for horizontal gene transfer, and the absence of clinically available inhibitors (Bush and Bradford, 2020). Novel agents such as the newer b-lactam-blactamase inhibitor combinations i.e., ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam, and imipenemrelebactam, offer safe and effective therapies for serious infections caused by some of the extended-spectrum blactamases, KPC, AmpC, and/or OXA-48 producers, none of them present in vitro activity against MBL-producing Enterobacterales (Yahav et al, 2021). A more recent study showed that AUR in combination with colistin was effective against colistin-resistent Gram-negtive bacteria both in vitro and in vivo (Feng et al, 2021)
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