Cross resistance to cefiderocol and ceftazidime-avibactam in KPC beta-lactamase mutants and inoculum effect

Clin Microbiol Infect. 2021 Apr 26:S1198-743X(21)00199-3. doi: 10.1016/j.cmi.2021.04.016. Online ahead of print.


OBJECTIVES: Ceftazidime-avibactam and cefiderocol are recently commercialized molecules active against highly drug-resistant bacteria, including carbapenem-resistant Enterobacteriaceae. Resistant mutants to ceftazidime-avibactam were described and notably in Klebsiella pneumoniae carbapenemase (KPC). Considering the structural similarities between ceftazidime and cefiderocol, we hypothesized that resistance to ceftazidime-avibactam in KPC-producing Enterobacterales may lead to cross-resistance to cefiderocol.

METHODS: Ceftazidime-avibactam resistant mutants from 3 clinical isolates of Enterobacterales carrying either blaKPC-2 or blaKPC-3 were selected in vitro. Mutants with increased MIC to ceftazidime-avibactam compared to ancestral allele were cloned in pBR322 plasmid and expressed in E. coli TOP10. We evaluated the impact of these mutations on cefiderocol MICs, MBCs and assessed the impact of bacterial inoculum on cefiderocol MICs.

RESULTS: We used 37 KPC mutants with increased ceftazidime-avibactam MIC. Of these, 6 were previously described in clinical isolates. Compared to the wild-type alleles, 4 to 32-fold-increase in the cefiderocol's MICs were observed for 75.6% (28/37) of tested mutants, reaching MIC up to 4 mg/L in E. coli TOP10 for KPC-31 (D179Y-H274Y mutations). MBCs and MICs of cefiderocol were similar, confirming the bactericidal activity of this drug. Finally, when using higher inocula (107 CFU/ml), a high increase in cefiderocol MIC was observed and all isolates were categorized as resistant.

CONCLUSION: We observed that most of the CZA resistant KPC variants have a possible impact on cefiderocol by increasing the cefiderocol MICs. In addition, cefiderocol is greatly impacted by inoculum effect, suggesting precautions should be taken when treating infections with a suspected high inoculum.

PMID:33915286 | DOI:10.1016/j.cmi.2021.04.016