Colonization by ceftazidime/avibactam-resistant KPC-producing Klebsiella pneumoniae following therapy in critically ill patients

Paolo Gaibani; Federica Bovo; Linda Bussini; Michele Bartoletti; Tiziana Lazzarotto; Pierluigi Viale; Federico Pea; Simone Ambretti

doi:10.1016/j.cmi.2023.01.012

Colonization by ceftazidime/avibactam-resistant KPC-producing Klebsiella pneumoniae following therapy in critically ill patients

Clin Microbiol Infect. 2023 May;29(5):654.e1-654.e4. doi: 10.1016/j.cmi.2023.01.012. Epub 2023 Jan 27.

Authors

Paolo Gaibani¹, Federica Bovo², Linda Bussini³, Michele Bartoletti⁴, Tiziana Lazzarotto⁵, Pierluigi Viale⁴, Federico Pea⁶, Simone Ambretti²

Affiliations

¹ Microbiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. Electronic address: paolo.gaibani@unibo.it.
² Microbiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
³ Infectious Diseases Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy.
⁴ Infectious Diseases Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Italy.
⁵ Microbiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy.
⁶ Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Italy; SSD Clinical Pharmacology -Department of Integrated Management of Infectious Risk, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy.

PMID: 36716999
DOI: 10.1016/j.cmi.2023.01.012

Abstract

Objectives: Ceftazidime-avibactam (CAZ-AVI)-based treatments have been associated with the emergence of resistance in KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates after antimicrobial exposure. Here, we evaluated the CAZ-AVI resistance development in KPC-Kp isolated from patients treated with CAZ-AVI-based therapy.

Methods: We enrolled adult patients treated with CAZ-AVI-based regimens between January 2020 and January 2021. Carbapenemase-producing isolates collected from clinical samples and rectal swabs were evaluated for CAZ-AVI resistance development after antimicrobial exposure. KPC-Kp developing CAZ-AVI resistance and parental susceptible strains were genomically characterized. Whole genome sequencing was performed by using the Illumina iSeq100 platform and genomes were analyzed for antimicrobial-resistance genes, plasmid and porins sequences.

Results: We enrolled 90 patients treated with CAZ-AVI-based therapy and 62.2% (56/90) of them were colonized by KPC-producers before CAZ-AVI-based treatment and 6.6% acquired colonization during therapy. Six (6.6%) patients developed infections because of resistant KPC-Kp after CAZ-AVI exposure and 3 (3.3%) of them developed CAZ-AVI resistance in the rectum. Development of resistance among KPC in the rectum occurred after 32 (IQR, 9-35) days of therapy and after 30 (IQR, 22-40) days in clinical specimens. Genetic analysis demonstrated that the development of CAZ-AVI resistance was associated with mutated bla_KPC-3 (bla_KPC-31, bla_KPC-53, bla_KPC-89, and bla_KPC-130) and phylogenetic analysis demonstrated a close genomic relationship between KCP-Kp collected from rectum and clinical samples of the same patient.

Discussion: Antimicrobial exposure induce a higher incidence of CAZ-AVI resistance development in the blood and respiratory tract than in the rectum (6.7% vs. 3.3%) of CAZ-AVI-treated patients and genome analysis showed that resistance was associated with mutated bla_KPC-3 variants.

Keywords: Genomic characterization; KPC-Variants; Rectal colonization; Resistance development; βL-βLICs.

MeSH terms

Adult
Anti-Bacterial Agents / pharmacology
Anti-Bacterial Agents / therapeutic use
Bacterial Proteins / genetics
Ceftazidime* / pharmacology
Ceftazidime* / therapeutic use
Critical Illness
Drug Combinations
Humans
Klebsiella Infections* / drug therapy
Klebsiella Infections* / microbiology
Klebsiella pneumoniae
Microbial Sensitivity Tests
Phylogeny
beta-Lactamases / genetics

Substances

avibactam, ceftazidime drug combination
Ceftazidime
avibactam
Anti-Bacterial Agents
Drug Combinations
Bacterial Proteins
beta-Lactamases