Will ceftazidime/avibactam plus aztreonam be effective for NDM and OXA-48-Like producing organisms: Lessons learnt from in vitro study

Abstract

Introduction: Carbapenem resistance (CR) in Klebsiella pneumoniae is mainly mediated by bla NDM and bla OXA-48 carbapenemases. Newer Food and Drug Administration-approved antimicrobial ceftazidime/avibactam (C/A) has a potent activity against bla OXA-48-like producers. However, its activity is limited in organisms co-producing bla NDM and bla OXA-48-like. Addition of aztreonam (ATM) to C/A potentially expands the spectrum of coverage for carbapenemase co-producers. With this, we aimed to determine the synergistic activity of combination of C/A plus ATM against bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48-like producing CR Klebsiella pneumoniae (CRKp). Materials and Methods: A total of 12 isolates of CRKp-harbouring genes encoding bla NDM and bla OXA-48-like were tested. Minimum inhibitory concentrations (MICs) were determined for several antimicrobial agents, including C/A (0.5-8 μg/ml) by broth microdilution method. Checkerboard assay was performed for the combination of C/A plus ATM at varying concentrations. Fold differences in the MIC of C/A with and without addition of ATM were determined to infer synergistic effects. Results: MIC of C/A and ATM ranged from 0.5 to >8 μg/ml and 64 to 2048 μg/ml, respectively. Two isolates were susceptible to C/A with MIC of 0.5 and 1 μg/ml, while others were resistant with MIC of >8 μg/ml. Synergistic effects of >8-fold MIC difference in C/A MIC were noted with addition of ATM at 4 μg/ml. This was observed for all CRKp with profiles of bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48-like genes, which was a promising effect. Notably, all five of the colistin-resistant CRKp were inhibited with >8-fold MIC difference in the combination of C/A plus ATM at 4 μg/ml. Conclusion: With the increasing burden of CRKp, the use of C/A with ATM combination seems to be very promising, especially for bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48like carbapenemases.