Activity of cefiderocol and synergy of novel β-lactam-β-lactamase inhibitor-based combinations against metallo-β-lactamase-producing gram-negative bacilli: insights from a two-year study (2019–2020)

Abstract

This study was aimed at analyzing the prevalence of metallo-β-lactamase-producing Gram-negative bacilli (MBL-GNB) and evaluating both in vitro activity of cefiderocol and synergy of novel β-lactam-β-lactamase inhibitor-based combinations. Carbapenemase-producing Enterobacterales and meropenem-non-susceptible P. aeruginosa clinical strains were collected (2019-2020) and prevalence of MBL-producers investigated. Activity of cefiderocol was evaluated and synergistic effects of cefiderocol in combination with ceftazidime/avibactam vs aztreonam plus ceftazidime/avibactam vs meropenem/vaborbactam plus aztreonam were compared. Among carbapenemase-producing Enterobacterales, 87% (n = 307) produced KPC, 11.6% (n = 41) produced MBL, and 1.4% (n = 5) produced OXA-48-like. Among MBL-producing Enterobacterales, 78.1% (n = 32) and 21.9% (n = 9) were VIM- and NDM-producers, respectively. Among meropenem-non-susceptible P. aeruginosa, 1.9% (n = 8) produced VIM-type MBL. Cefiderocol resistance rate in VIM-producing Enterobacterales, VIM-producing P. aeruginosa, and NDM-producing Enterobacterales, was 6.2%, 12.5%, and 88.9%, respectively. Among MBL-producers tested, cefiderocol in combination with ceftazidime/avibactam showed a synergy rate of 20%, while for both aztreonam plus ceftazidime/avibactam and meropenem/vaborbactam plus aztreonam was 40%. Prevalence of MBL-producing Enterobacterales was remarkable. VIM-producing isolates were almost all susceptible to cefiderocol, while NDM-producers were often resistant. Meropenem/vaborbactam in combination with aztreonam showed similar synergistic activity to ceftazidime/avibactam plus aztreonam but the addition of aztreonam reduced MICs below the resistance breakpoint only for meropenem/vaborbactam.

Keywords:

• Cefiderocol
• metallo-β-lactamases
• meropenem/vaborbactam
• ceftazidime/avibactam
• synergistic activity
• aztreonam

Declarations

Authorship statement

Boattini M, Bianco G, Costa C and Cavallo R designed the study; Boattini M, Comini S, Bianco G, Casale R, and Iannaccone M acquired data; Boattini M, Comini S, and Bianco G analyzed and interpreted data; Boattini M wrote the paper; all authors revised the article critically and approved the final version.

Availability of data and material

The authors confirm that the data supporting the findings of this study are available within the article.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Code availability

Not applicable.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval

This study was conducted in accordance with the Declaration of Helsinki. Formal ethical approval was not required by our Center’s institutional review board.