Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

Abstract

Based upon knowledge of the hydrolytic profile of major ␤-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-␤-lactamases (MBLs). Disk diffusion and agarbased 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 bla IMP , bla NDM , bla , bla CTX-M , bla AmpC , 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 Ն21 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 Ն4-log 10 -CFU decrease for all groups that had CAZ-AVI with ATM (8 g/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log 10 -CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.

Unusual Escherichia coli PBP 3 Insertion Sequence Identified from a Collection of Carbapenem-Resistant Enterobacteriaceae Tested In Vitro with a Combination of Ceftazidime-, Ceftaroline-, or Aztreonam-Avibactam

“…A combination of aztreonam with ceftazidime-avibactam was recently used successfully to treat a patient infected with an NDM-1-producing pathogen (23). However, the clinical use of ceftazidime-avibactam has been linked to the emergence of resistance due to mutations in the KPC-3 ⍀ loop in isolates that regained susceptibility to meropenem (24).…”

Novel Beta-Lactamase Inhibitors: Unlocking Their Potential in Therapy

“…This combination resulted in a reduction in carbapenem MIC for carbapenem-resistant Enterobacteriaceae including MBL-containing pathogens was reduced. [4, 11, 52] The hypothesis is that MBL producing pathogens, often concurrently produce extended spectrum or AmpC β-lactamases, which can be inhibited by avibactam while aztreonam intrinsically evades hydrolysis by MBLs and can thereby still exert an antimicrobial effect. [4, 52]…”

Fighting bacterial resistance: approaches, challenges, and opportunities in the search for new antibiotics.Part 1. Antibiotics used in clinical practice: mechanisms of action and the development of bacterial resistance

“…11) are the only group of β-lactam antibiotics that can effectively inhibit those enzymes [32,33]. Thus, the results published by Marshall et al [34] suggest the combination of ceftazidime-avibactam and aztreonam could be used to overcome resistance of bacteria producing metallo-β-lactamases.…”