Broad spectrum of β-lactamase coverage and potent antimicrobial activity of xeruborbactam in combination with meropenem against carbapenemase-producing Enterobacterales, including strains resistant to new β-lactam/β-lactamase inhibitor combinations

Abstract

Xeruborbactam is a broad-spectrum boronate-type β-lactamase inhibitor. We aimed to evaluate its activity in combination with meropenem and compare it with other β-lactam/β-lactamase inhibitor combinations against Enterobacterales. The following isolates were screened: (i) an isogenic collection of 94 Escherichia coli isolates producing β-lactamases under wild-type and low-permeability conditions, (ii) 300 genetically diverse clinical Enterobacterales isolates producing the three main carbapenemase types (KPC-like, OXA-48-like, and metallo-β-lactamases), and (iii) two collections of isolates producing mechanisms of resistance to β-lactam/β-lactamase inhibitor combinations, such as KPC variants or PBP3 insertions combined with metallo-β-lactamases (MBLs). The MICs of meropenem, meropenem/xeruborbactam, meropenem/vaborbactam, imipenem, imipenem/relebactam, cefepime, cefepime/taniborbactam, ceftazidime, ceftazidime/avibactam, aztreonam, and aztreonam/avibactam were determined by reference broth microdilution and interpreted following the European Committee on Antimicrobial Susceptibility Testing guidelines, using the breakpoint of the β-lactam alone for not yet approved combinations. Resistance mechanisms of all clinical isolates were analyzed by whole genome sequencing. Meropenem/xeruborbactam had the broadest spectrum against the isogenic collection, although higher MICs were noted for transformants producing IMP-23, SPM-1, and NDM enzymes (these latter only when produced under low-permeability conditions). Meropenem/xeruborbactam displayed the most potent activity against the collection of 300 clinical strains (MIC_50/90 ≤0.06/≤0.06 mg/L). Xeruborbactam restored meropenem activity against the strains carrying resistance mechanisms to β-lactam/β-lactamase inhibitor combinations, including strains producing KPC variants or MBLs in combination with additional chromosomal alterations (MIC range: ≤0.06-0.25 and ≤0.06-4 mg/L, respectively). Our findings highlight the potential of xeruborbactam in combination with meropenem as a promising treatment against carbapenemase-producing Enterobacterales, including strains with emerging resistance to other β-lactam/β-lactamase inhibitor combinations.

Keywords: Enterobacterales; beta-lactam; beta-lactamase; beta-lactamase inhibitor; carbapenemase; carbapenemase-producing Enterobacterales; xeruborbactam.

Fig 1

(A) Cumulative MIC values of all CPE isolates, (B) OXA-48-like-producing isolates, (C) KPC-producing isolates, (D) MBL-producing isolates. MBL-producing isolates are also divided into (E) VIM-producing isolates and (F) NDM-producing isolates. MEM: meropenem; M/X: meropenem/xeruborbactam; M/V: meropenem/vaborbactam; I/R: imipenem/relebactam; F/T: cefepime/taniborbactam; C/A: ceftazidime/avibactam; A/A: aztreonam/avibactam.