In vitro activity and genomic characterization of KPC-producing Klebsiella pneumoniae clinical blood culture isolates resistant to ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam: an Italian nationwide multicentre observational study (2022-23)

Gabriele Bianco; Matteo Boattini; Laura Lupo; Simone Ambretti; Rita Greco; Linda Degl'Innocenti; Sofia Chiatamone Ranieri; Teresa Fasciana; Annarita Mazzariol; Davide Gibellini; Guido Antonelli; Federica Sacco; Angela Quirino; Claudio Farina; Bianca Paglietti; Sara Comini; Maura Fiamma; Francesco Broccolo; Rossana Cavallo; Cristina Costa; Paolo Gaibani

doi:10.1093/jac/dkae450

In vitro activity and genomic characterization of KPC-producing Klebsiella pneumoniae clinical blood culture isolates resistant to ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam: an Italian nationwide multicentre observational study (2022-23)

J Antimicrob Chemother. 2024 Dec 19:dkae450. doi: 10.1093/jac/dkae450. Online ahead of print.

Authors

Gabriele Bianco^{1

2}, Matteo Boattini^{2

3

4}, Laura Lupo⁵, Simone Ambretti^{6

7}, Rita Greco⁸, Linda Degl'Innocenti⁹, Sofia Chiatamone Ranieri¹⁰, Teresa Fasciana¹¹, Annarita Mazzariol^{12

13}, Davide Gibellini^{12

13}, Guido Antonelli^{14

15}, Federica Sacco¹⁵, Angela Quirino^{16

17}, Claudio Farina¹⁸, Bianca Paglietti¹⁹, Sara Comini^{3

20}, Maura Fiamma²¹, Francesco Broccolo¹, Rossana Cavallo^{2

3}, Cristina Costa^{2

3}, Paolo Gaibani^{12

13}

Affiliations

¹ Department of Experimental Medicine, University of Salento, Lecce, Italy.
² Microbiology and Virology Unit, University Hospital Città della Salute e della Scienza di Torino, Turin, Italy.
³ Department of Public Health and Paediatrics, University of Torino, Turin, Italy.
⁴ Lisbon Academic Medical Centre, Lisbon, Portugal.
⁵ Clinical Pathology and Microbiology Unit, Vito Fazzi Hospital, Lecce, Italy.
⁶ Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Via Massarenti, 9, Bologna 40138, Italy.
⁷ Microbiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy.
⁸ U.O.C. Microbiology and Virology, A.O.R.N. Sant'Anna e San Sebastiano, Caserta 81100, Italy.
⁹ U.O.S. Microbiology e Virology, Clinical Pathology Division A.O.R.N. A. Cardarelli, Naples 80131, Italy.
¹⁰ Pathology Unit, Department of Services, AUSL 04 Teramo, Teramo 64100, Italy.
¹¹ Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo 90127, Italy.
¹² Microbiology and Virology Unit, Department of Pathology, Azienda Ospedaliera Universitaria Integrata Di Verona, Verona, Italy.
¹³ Department of Diagnostic and Public Health, Microbiology Section, University of Verona, Verona, Italy.
¹⁴ Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy.
¹⁵ University Hospital Policlinico Umberto I, Sapienza University, Viale del Policlinico 155, Rome 00161, Italy.
¹⁶ Health Sciences Department, University "Magna Graecia" of Catanzaro, Catanzaro 88100, Italy.
¹⁷ Unit of Clinical Microbiology, Department of Health Sciences, University of Catanzaro "Magna Græcia", Catanzaro 88100, Italy.
¹⁸ Microbiology and Virology Laboratory, ASST "Papa Giovanni XXIII", Bergamo 24127, Italy.
¹⁹ Department of Biomedical Sciences, University of Sassari, Sassari 07100, Italy.
²⁰ Operative Unit of Clinical Pathology, Carlo Urbani Hospital, Ancona, Italy.
²¹ Operative Unit of Clinical Pathology, Ospedale "San Francesco", ASSL Nuoro, Sardinia 08100, Italy.

PMID: 39699187
DOI: 10.1093/jac/dkae450

Abstract

Objectives: To evaluate the in vitro activity of ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam and comparators against KPC-producing Klebsiella pneumoniae (KPC-Kp) clinical isolates collected from a multicentre study in Italy (2022-23) and genomic characterization of the molecular mechanisms causing resistance.

Methods: Consecutive KPC-Kp isolates from blood cultures (n = 264) were collected from 14 hospital centres in the period 2022-23. Antimicrobial susceptibility testing was performed using broth microdilution. WGS was used to investigate KPC-Kp strains resistant to the new approved β-lactam/β-lactam inhibitor combinations (BLICs).

Results: Overall, meropenem/vaborbactam (95.1% susceptible by EUCAST and 93.9% susceptible by CLSI; MIC50 = 0.5 mg/L; MIC90 = 4 mg/L) and imipenem/relebactam (97% susceptible by EUCAST and 92.8% susceptible by CLSI; MIC50 = 0.25 mg/L; MIC90 = 0.5 mg/L) showed similar activity, followed by ceftazidime/avibactam (93.9% susceptible by both EUCAST and CLSI; MIC50 = 2 mg/L; MIC90 = 8 mg/L). Ten out of 13 (76.9%) KPC-Kp resistant to ceftazidime/avibactam carried a blaKPC variant including blaKPC-31, blaKPC-205, blaKPC-203 and blaKPC-93. Among KPC-Kp resistant to meropenem/vaborbactam and imipenem/relebactam, 90.9% (10/11) and 80% (4/5) harboured a WT carbapenemase (i.e. blaKPC-2 or blaKPC-3), respectively. All strains resistant to meropenem/vaborbactam and/or imipenem/relebactam carried truncated OmpK35 and/or mutated (ins135GD) OmpK36.

Conclusions: New BLICs were shown to be the most widely active therapeutic option against KPC-Kp clinical isolates collected in Italy. Ceftazidime/avibactam resistance is mainly driven by the expression of KPC variants, whereas the loss of function of the OmpK35 and OmpK36 porins appears to play a key but not exclusive role in the development of meropenem/vaborbactam and/or imipenem/relebactam resistance.

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