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ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Antimicrobials, Resistance and Chemotherapy
Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1490372
Carbapenem treatment options for metallo-beta-lactamase: drug screening and dose optimization of meropenem-based combinations against NDM-or IMP-producing Klebsiella pneumoniae
Provisionally accepted
Haoyue Che 1,2 Bo Hu 1 Cui Xiaoming 1
Jiyong Yang 3 Jinru Zeng 4
Liuhan Dong 4 Rui Wang 4
Yun Cai 1*- 1 People's Liberation Army General Hospital, Beijing, China
- 2 Medical Support Center, Chinese PLA General Hospital, Beijing, China
- 3 Department of Clinical Laboratory, Chinese PLA General Hospital, Beijing, Beijing Municipality, China
- 4 Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
Background: The global dissemination of carbapenemase-producing Klebsiella pneumoniae (CPKP) has been occurring at an alarming pace, especially for the metallo-β-lactamase (MBL) group. Current clinical data suggest that carbapenem is still irreplaceable in terms of safety and efficacy. For MBL-producing Klebsiella pneumoniae (MBL-KP), how to use carbapenem judiciously in the context of advocating carbapenem-sparing strategies remains largely undetermined. Methods: Four strains carrying different MBLs (two IMPs and two NDMs) were collected. The genome sequence, drug resistance phenotype, and synergistic effect of different meropenem-based antimicrobial combinations were tested. Dynamics in vitro pharmacokinetic/pharmacodynamic (PK/PD) model was used to optimize the dosage. The selected combination regimens were verified in a murine model of peritoneal sepsis. Results: Meropenem in combination with fosfomycin or colistin was effective against MBL-KP strains. Meropenem in combination with colistin had a better bactericidal effect compared with fosfomycin, while such a combination was prone to cause colistin-dependent heterogeneous resistance, especially for IMP-KP. For NDM-KP extremely resistant to meropenem, ultra-high dose up to 2.75 g q6h meropenem in combination with fosfomycin or colistin was needed. For IMP-KP, high-dose meropenem monotherapy (2 g q8h) or low-dose meropenem (1 g q8h) in combination with fosfomycin were both feasible. Conclusions: Meropenem in combination with fosfomycin or colistin was an effective choice for MBL-KP. The combination regimen and dosage optimization should be assessed based on not only the type of enzyme but also the specific value of minimum inhibitory concentration (MIC).
Keywords: Meropenem, Fosfomycin, Colistin (CST), In vitro PK/PD model, MBL-KP
Received: 03 Sep 2024; Accepted: 26 Mar 2025.
Copyright: © 2025 Che, Hu, Xiaoming, Yang, Zeng, Dong, Wang and Cai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yun Cai, People's Liberation Army General Hospital, Beijing, China
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