A multi-species outbreak of VIM-producing carbapenem-resistant bacteria in a burn unit and subsequent investigation of rapid development of cefiderocol resistance

Abstract

Carbapenem resistance due to metallo-β-lactamases (MBLs) such as the Verona integron-encoded metallo-β-lactamase (VIM) is particularly problematic due to the limited treatment options. We describe a case series of bacterial infections in a tertiary care hospital due to multi-species acquisition of a VIM gene along with our experience using novel β-lactam antibiotics and antibiotic combinations to treat these infections. Four patients were treated with the combination of ceftazidime-avibactam and aztreonam, with no resistance to the combination detected. However, cefiderocol-resistant Klebsiella pneumoniae isolates were detected in two out of the five patients who received cefiderocol within 3 weeks of having started the antibiotic. Strain pairs of sequential susceptible and resistant isolates from both patients were analyzed using whole-genome sequencing. This analysis revealed that the pairs of isolates independently acquired point mutations in both the cirA and fiu genes, which encode siderophore receptors. These point mutations were remade in a laboratory strain of K. pneumoniae and resulted in a significant increase in the MIC of cefiderocol, even in the absence of a beta-lactamase enzyme or a penicillin-binding protein 3 (PBP3) mutation. While newer β-lactam antibiotics remain an exciting addition to the antibiotic armamentarium, their use must be accompanied by diligent monitoring for the rapid development of resistance.

Keywords: VIM; burn unit; carbapenem resistance; cefiderocol; ceftazidime-avibactam and aztreonam.

Fig 1

Susceptibility pattern of initial VIM-CROs isolates from each patient. The susceptibility to the antibiotics listed is shown for the first VIM-CRO isolated from each patient. If a patient had multiple species of VIM-producing CROs isolated, then the first VIM-CRO isolates for each species is shown. Blue indicates susceptibility, yellow indicates intermediate susceptibility, and red indicates resistance to a given antibiotic. The gray boxes represent antibiotic susceptibility data that were unavailable. Amikacin susceptibility was determined prior to the 2023 CLSI update to amikacin breakpoints.

Fig 2

MIC values among VIM-CROs for select antibiotics. The range (min-max) of MICs (µg/mL) for all VIM-CRO isolates with antimicrobial susceptibility testing results available from all nine patients included in this study. MICs are shown for amikacin, aztreonam, cefiderocol, ceftazidime-avibactam, and meropenem. For A. baumannii, P. aeruginosa, and E. cloacae, MIC values are reflective of a single isolate each. For K. pneumoniae and S. marcescens, isolates are separated by culture source, either blood or tissue/wound. Results include multiple isolates from the same patient in some cases. S*- susceptible but determined by disk diffusion method. NT: not tested.

Fig 3

Siderophore receptor mutations identified in clinical isolates with cefiderocol resistance. The schematic shows the representative full-length protein products of cirA and fiu along with the truncated versions that result from the mutations found in each clinical isolate. Red lines indicate the missense region of the protein. Numbers above the line indicate the single nucleotide deletion present while numbers below each line indicate the amino acid where the missense mutation or termination of the protein occurs.