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. 2025 Feb;44(2):343-353.
doi: 10.1007/s10096-024-05005-4. Epub 2024 Nov 30.

Ceftazidime-avibactam tolerance and persistence among difficult-to-treat KPC-producing Klebsiella pneumoniae clinical isolates from bloodstream infections

N Abichabki  1 , G G Gaspar  2   3 , L R Bortolato  1 , D A F S Lima  3 , L N Silva  3 , R H C Pocente  3 , J C Ferreira  1 , T C Ogasawara  1 , D Pereira  4 , R R Guerra  4 , C Wilhelm  4 , P Barth  4 , A F Martins  4 , A Barth  4 , G U L Braga  1 , E C P De Martinis  1 , J Bengtsson-Palme  5   6   7 , F Bellissimo-Rodrigues  2 , V R Bollela  2   3 , A L C Darini  1 , L N Andrade  8
Affiliations

Ceftazidime-avibactam tolerance and persistence among difficult-to-treat KPC-producing Klebsiella pneumoniae clinical isolates from bloodstream infections

N Abichabki et al. Eur J Clin Microbiol Infect Dis. 2025 Feb.

Abstract

Purpose: Tolerance and persistence occur "silently" in bacteria categorized as susceptible by antimicrobial susceptibility testing in clinical microbiology laboratories. They are different from resistance phenomena, not well-studied, and often remain unnoticeable. We aimed to investigate and characterize ceftazidime-avibactam (CZA) tolerance/persistence in 80 Klebsiella pneumoniae isolates from bloodstream infections.

Methods: We used the Tolerance Disk Test (TDtest) to detect CZA tolerance/persistence and investigate the avibactam (AVI) influence on them, and time-kill assays with minimal duration for killing (MDK) determination to characterize/differentiate CZA tolerance from persistence, for selected isolates. Whole genome sequencing was performed for 49/80 selected isolates to investigate genes related to beta-lactam tolerance/persistence and resistance as well as phylogeny studies.

Results: Tolerance/persistence to CZA was detected in 48/80 (60%) isolates, all extensively drug-resistant (XDR) or multidrug-resistant, carbapenem-resistant K. pneumoniae (CRKp), KPC producers, and previously categorized as susceptible (not resistant) to CZA. No heteroresistance was detected. CZA tolerance/persistence occurred due to ceftazidime tolerance/persistence and was not related to AVI in the CZA combination. 5/11 isolates were characterized as CZA-tolerant and 5/11 as CZA-persistent. The single (1/11) XDR and CRKp non-KPC producer was truly susceptible. All the CZA-tolerant/persistent isolates (ST11, ST258, ST340, ST437, ST16, ST17, and ST307) harbored the carbapenemase-encoding gene blaKPC-2. Mutation in only two genes (rpoS and degQ) related to beta-lactam tolerance/persistence was found in only 7/49 CZA-tolerant/persistent isolates, suggesting the presence of yet unknown beta-lactam tolerance/persistence genes.

Conclusion: Among the K. pneumoniae bloodstream isolates studied, 60%, previously categorized as susceptible to CZA, were, actually, tolerant/persistent to this antibiotic, all these KPC producers.

Keywords: Antibiotic resistant bacteria; Minimal duration for killing (MDK); Time-kill assays; Tolerance disk test (TDtest).

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Conflict of interest statement

Declarations. Ethical approval: This study was approved by the Ethics Committee of the Ribeirao Preto School of Pharmaceutical Sciences– University of São Paulo (CAAE: 57488422.0.0000.5403– Protocol CEP/FCFRP nº 5.443.849) and by the Ethics Committee of the University Hospital, Ribeirão Preto Medical School– University of São Paulo (CAAE: 57488422.0.3001.5440– Protocol CEP/HCFMRP n° 5.462.049). Competing interests: The authors declare no competing interests.

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