Search PubMed⌕ Search
Home/Archive/PubMed

PubMed · 42604655

Single unscreened carrier triggered ICU outbreak of a KPC-producing Klebsiella pneumoniae which acquired in vivo resistance to ceftazidime-avibactam, and cefiderocol.

Lydia Gálvez-Benítez·Ángel Rodríguez-Villodres·Guillermo Martín Gutiérrez·José Miguel Cisneros·José Antonio Lepe·José Manuel Ortiz de la Rosa
View original source ↗Export metadata ↓

Abstract

BACKGROUND: Carbapenemase-producing Enterobacterales are a major cause of healthcare-associated outbreaks in intensive care units (ICUs), where unrecognized carriers can drive silent transmission. We report an ICU outbreak caused by KPC-producing Klebsiella pneumoniae and the within-host emergence of resistance to ceftazidime-avibactam and cefiderocol in the index case. METHODS: Four ICU patients with five K. pneumoniae isolates identified between July and August 2023 were investigated. Phenotypic, genomic and functional analyses were performed to determine the clonal relatedness of the isolates and elucidate the mechanisms underlying resistance evolution. RESULTS: All isolates belonged to ST512, confirming dissemination of a single high-risk clone. The first isolate recovered from the index patient was susceptible to ceftazidime-avibactam and cefiderocol, but a later isolate obtained during ceftazidime-avibactam therapy acquired resistance to both agents. Genomic analysis revealed a novel KPC variant (KPC-270) carrying a 19-amino-acid duplication. When expressed in Escherichia coli, KPC-270 conferred ceftazidime-avibactam resistance, but it did not fully reproduce the meropenem or cefiderocol phenotype. Efflux inhibition substantially reduced meropenem and cefiderocol MICs in the resistant isolate, and avibactam partially restored cefiderocol activity, supporting multifactorial mechanism. CONCLUSION: This outbreak illustrates how unrecognized multidrug-resistant carriage in the index patient facilitated the nosocomial dissemination of a high-risk ST512 K. pneumoniae clone, followed by rapid resistance evolution during ceftazidime-avibactam therapy. Resistance was multifactorial, involving the novel KPC-270 variant and efflux activity contributing to ceftazidime-avibactam, meropenem and cefiderocol resistance.

Explore related subjects

CefiderocolCeftazidime/avibactamKlebsiella pneumoniaeJournal Article

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Lydia Gálvez-Benítez, Ángel Rodríguez-Villodres, Guillermo Martín Gutiérrez, José Miguel Cisneros, José Antonio Lepe, José Manuel Ortiz de la Rosa. 2026-08-16. Single unscreened carrier triggered ICU outbreak of a KPC-producing Klebsiella pneumoniae which acquired in vivo resistance to ceftazidime-avibactam, and cefiderocol.. https://doi.org/10.1016/j.ijid.2026.109066

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2026

Genetic characterization of carbapenem-resistant Klebsiella pneumoniae bloodstream isolates with reduced susceptibility to cefiderocol.

OBJECTIVES: To assess cefiderocol activity against carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream isolates collected before local clinical introduction and to characterize the distribution of borderline MIC elevation across major genomic backgrounds. METHODS: We retrospectively analyzed 389 episodes of K. pneumoniae bloodstream infection at a tertiary hospital in China during 2018-2024. All 83 carbapenem-resistant isolates underwent cefiderocol broth microdilution testing and whole-genome sequencing. For epidemiological analysis, reduced susceptibility was prespecified as an MIC of 4-16 mg/L and was not intended to replace clinical breakpoint interpretation. RESULTS: CRKP accounted for 21.3% of K. pneumoniae bloodstream infections and remained associated with in-hospital mortality after adjustment for infection severity and source. By CLSI criteria, 83.1% of isolates were cefiderocol susceptible; the MIC50 and MIC90 were 4 and 8 mg/L, respectively, and 41.0% met the reduced-susceptibility definition. ST11 predominated, with KL47 and KL64 as the main capsular loci. Cefiderocol MICs were higher among KL47/KL64 and virulence-plasmid-associated isolates than among comparator backgrounds. In multivariable analysis, bla NDM-1, bla SHV-12, and the aerobactin locus remained associated with reduced susceptibility, although the findings require cautious interpretation because of limited sample size and possible effects of clonal background. No inactivating mutations were identified in cirA, fepA, or fiu. CONCLUSIONS: Borderline cefiderocol MIC elevation was present before local drug exposure and was more frequent in locally prevalent ST11-KL47/KL64 and virulence-plasmid-associated CRKP. These findings provide a bloodstream-specific pre-introduction baseline and support prospective surveillance of numerical MIC distributions and associated genomic backgrounds.

Cefiderocol↗
PubMed2026

Contribution of the Arg-33-His replacement in the histidine kinase CpxA to carbapenem and cefiderocol resistance in Serratia marcescens.

OBJECTIVE: The Serratia marcescens ROT_R clinical isolate, which was resistant to almost all β-lactams, including cefiderocol (4 mg/L), was recovered from a neonate 2 months after the isolation of the S. marcescens ROT_S strain that was susceptible to extended-spectrum cephalosporins (ESCs). In this study, we attempted to decipher the mechanism of resistance displayed by the ROT_R isolate. METHODS: The genomes of ROT_S and ROT_R were sequenced using the Illumina and the Oxford Nanopore Technologies. Long and short reads were assembled together, giving rise to a circularized hybrid genome. RESULTS: Genomic comparison between ROT_S and ROT_R disclosed only one mutation (G98A) in the cpxA gene of ROT_R, which led to the Arg-33-His substitution in the histidine kinase of the two-component system CpxA/CpxR. The cpxA alleles of ROT_S and ROT_R were amplified and cloned, thus giving rise to the pCpxA_WT and pCpxA_R33H recombinant plasmids, respectively, which were subsequently introduced into the S. marcescens HatR recipient strain, which lacks functional CpxA. The S. marcescens HatR (pCpxA_R33H) recombinant clone, which produced the altered CpxA_R33H variant, differed from the S. marcescens HatR (pCpxA_WT) recombinant clone, which produced the wild-type CpxA, by enhanced MICs of carbapenems and ESCs, including cefiderocol (1 mg/L). CONCLUSIONS: This study demonstrates that CpxA alteration, such as Arg-33-His substitution, can contribute to cefiderocol resistance. Although it increases slightly the MIC of cefiderocol without resulting per se in clinical resistance, it can contribute, in combination with other additional mechanisms, to achieve a high level of resistance to this siderophore cephalosporin.

Cefiderocol↗
PubMed2026

Cefiderocol susceptibility rates in carbapenem-resistant Gram-negative bacteria in a comparative, multicenter surveillance study in China.

BACKGROUND: Cefiderocol is a siderophore cephalosporin with potent, broad spectrum of activity against carbapenem-resistant (CR) Gram-negative bacteria. The objective of this surveillance study was to assess cefiderocol susceptibility in molecularly characterized CR Gram-negative pathogens collected from hospitalized patients across China. METHODS: Susceptibility testing was performed by the broth microdilution method according to Clinical and Laboratory Standards Institute guidelines, using pre-prepared frozen 96-well microtiter Thermo Fisher plates. Susceptibilities to cefiderocol and most comparators were determined by Clinical and Laboratory Standards Institute breakpoints, to tigecycline by US Food and Drug Administration breakpoints, and to colistin by European Committee on Antimicrobial Susceptibility Testing criteria. Carbapenemases were identified by whole-genome sequencing and polymerase chain reaction. RESULTS: Of 149 CR Klebsiella pneumoniae, 95.3% were susceptible to cefiderocol (OXA-48-positive 100% [n = 15]; IMP-positive 100% [n = 9]; KPC-positive 95.4% [n = 108]; NDM-positive 88.2% [n = 17]) and against 103 NDM-positive CR Escherichia coli, cefiderocol susceptibility was 45.6%. Among comparator antibiotics, ceftazidime-avibactam was only active against K. pneumoniae carbapenemase-positive and OXA-48-positive K. pneumoniae isolates. Susceptibilities to tigecycline and colistin were between 22.2% and 97.1% and between 88.2% and 100% across CR Enterobacterales with different carbapenemases, respectively. High cefiderocol susceptibility rates were found for CR Pseudomonas aeruginosa (98.4%), CR Acinetobacter baumannii (99.6%), and Stenotrophomonas maltophilia (99.6%). Among comparator antibiotics, only colistin showed high activity against CR P. aeruginosa (99.2%) and CR A. baumannii (99.2%). CONCLUSIONS: Cefiderocol susceptibility rates were ≥88% against a collection of carbapenemase-positive CR Gram-negative isolates, except for lower susceptibility in NDM-positive CR E. coli isolates. Continuous monitoring of cefiderocol susceptibility is warranted.

Cefiderocol↗