Global & Disaster Medicine

A new study describes a novel combination therapy that could serve as a weapon against a growing antibiotic resistance threat.

Antimicrobial Agents and Chemotherapy

“….Ceftazidime/avibactam, which was approved in the United States in 2015, has been a valuable tool for treating certain multidrug-resistant gram-negative infections. It works by inhibiting class A and class C bacterial enzymes, such as extended-spectrum beta lactamases (ESBLs), Klebsiella pneumoniae producing carbapenemases (KPCs), and cephalosporinases, which confer resistance to beta-lactam antibiotics.

But ceftazidime/avibactam has a significant weakness: metallo-beta-lactamase enzymes, which have emerged as a significant global antibiotic resistance threat, particularly in Southeast Asia and parts of Europe. Aztreonam, on the other hand, is susceptible to the class A and C beta-lactamases but isn’t broken down by metallo-beta-lactamases.

What Bonomo and his team hypothesized was that if aztreonam were added to the ceftazidime/avibactam combination therapy, the duo would help free aztreonam to work against infection-causing bacteria by protecting it from the other beta-lactamase enzymes, like offensive lineman in football blocking for a running back…..”

Antimicrob Agents Chemother. 2017 Feb 6. pii: AAC.02243-16. doi: 10.1128/AAC.02243-16. [Epub ahead of print]
Can ceftazidime/avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?
Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, et al.

Abstract

Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram negative bacteria, we tested the effectiveness of the combination of ceftazidime/avibactam (CAZ/AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk-diffusion and agar based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ/AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ/AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ/AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥ 21 mm. All isolates demonstrated a reduction in CAZ/AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥ 4 log10 CFU decrease for all groups that had CAZ/AVI plus ATM (8 μg/ml) added, compared to the CAZ/AVI alone group. In the murine neutropenic thigh infection model, an almost 4 log10 reduction in CFUs was noted at 24 h for CAZ/AVI (32 mg/kg q8h) plus ATM (32 mg/kg q8h) vs. CAZ/AVI (32 mg/kg q8h) alone. The data presented herein, requires us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.


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