Ceftazidime-avibactam tolerance and persistence among difficult-to-treat KPC-producing Klebsiella pneumoniae clinical isolates from bloodstream infections
Journal article, 2024
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.
Tolerance disk test (TDtest)
Antibiotic resistant bacteria
Minimal duration for killing (MDK)
Time-kill assays
Author
N. Abichabki
University of Sao Paulo (USP)
G. G. Gaspar
University of Sao Paulo (USP)
L. R. Bortolato
University of Sao Paulo (USP)
D. A.F.S. Lima
University of Sao Paulo (USP)
L. N. Silva
University of Sao Paulo (USP)
R. H.C. Pocente
University of Sao Paulo (USP)
J. C. Ferreira
University of Sao Paulo (USP)
T. C. Ogasawara
University of Sao Paulo (USP)
D. Pereira
Universidade Federal do Rio Grande do Sul (UFRGS)
R. R. Guerra
Universidade Federal do Rio Grande do Sul (UFRGS)
C. Wilhelm
Universidade Federal do Rio Grande do Sul (UFRGS)
P. Barth
Universidade Federal do Rio Grande do Sul (UFRGS)
A. F. Martins
Universidade Federal do Rio Grande do Sul (UFRGS)
A. Barth
Universidade Federal do Rio Grande do Sul (UFRGS)
Gilberto U.L. Braga
University of Sao Paulo (USP)
E. C.P. De Martinis
University of Sao Paulo (USP)
Johan Bengtsson Palme
Chalmers, Life Sciences, Systems and Synthetic Biology
University of Gothenburg
CARe
F. Bellissimo-Rodrigues
University of Sao Paulo (USP)
V. R. Bollela
University of Sao Paulo (USP)
A. L.C. Darini
University of Sao Paulo (USP)
L. N. Andrade
University of Sao Paulo (USP)
European Journal of Clinical Microbiology and Infectious Diseases
0934-9723 (ISSN) 1435-4373 (eISSN)
Vol. In PressPredicting future pathogenicity and antibiotic resistance
Swedish Foundation for Strategic Research (SSF) (FFL21-0174), 2022-08-01 -- 2027-12-31.
Subject Categories
Infectious Medicine
Biological Sciences
DOI
10.1007/s10096-024-05005-4
PubMed
39614972