Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Synergistic Activity of Temocillin and Fosfomycin Combination against KPC-Producing Klebsiella pneumoniae Clinical Isolates

Venera Costantino
ORCID logo ,
Luigi Principe
,
Jai Mehat
ORCID logo ,
Marina Busetti
ORCID logo ,
Roberto Luzzati
ORCID logo ,
Verena Zerbato
,
Antonietta Meliadò
,
Roberto La Ragione
,
Stefano Di Bella
* ORCID logo
Version 1 : Received: 6 March 2024 / Approved: 7 March 2024 / Online: 7 March 2024 (11:09:35 CET)

How to cite: Costantino, V.; Principe, L.; Mehat, J.; Busetti, M.; Luzzati, R.; Zerbato, V.; Meliadò, A.; La Ragione, R.; Di Bella, S. Synergistic Activity of Temocillin and Fosfomycin Combination against KPC-Producing Klebsiella pneumoniae Clinical Isolates. Preprints 2024, 2024030415. https://doi.org/10.20944/preprints202403.0415.v1 Costantino, V.; Principe, L.; Mehat, J.; Busetti, M.; Luzzati, R.; Zerbato, V.; Meliadò, A.; La Ragione, R.; Di Bella, S. Synergistic Activity of Temocillin and Fosfomycin Combination against KPC-Producing Klebsiella pneumoniae Clinical Isolates. Preprints 2024, 2024030415. https://doi.org/10.20944/preprints202403.0415.v1

Abstract

Infections caused by KPC-producing K. pneumoniae continue to pose a significant clinical challenge due to emerging resistance to new antimicrobials. We investigated the association between two drugs whose roles have been repurposed against multidrug-resistant bacteria: fosfomycin and temocillin. Temocillin exhibits unusual stability against KPC enzymes, while fosfomycin acts as a potent “synergizer”. We conducted in vitro antimicrobial activity studies on 100 clinical isolates of KPC-producing K. pneumoniae using a combination of fosfomycin and temocillin. The results demonstrated synergistic activity in 91% of the isolates. Subsequently, we assessed the effect on Galleria mellonella larvae using 5 different KPC-Kp isolates. The addition of fosfomycin to temocillin increased larvae survival from 73 to 97% (+Δ 32%; isolate 1), from 93 to 100% (+Δ 7%; isolate 2), from 63 to 86% (+Δ 36%; isolate 3), from 63 to 90% (+Δ 42%; isolate 4), and from 93 to 97% (+Δ 4%; isolate 10), respectively. Among the temocillin-resistant KPC-producing K. pneumoniae isolates (24 isolates), the addition of fosfomycin reduced temocillin MIC values below the resistance breakpoint in all isolated except one. Temocillin combined with fosfomycin emerges as a promising combination against KPC-producing K. pneumoniae, warranting further clinical evaluation.

Keywords

antibiotic; combination; fosfomycin; Galleria mellonella; in vivo; KPC-producing Klebsiella pneumoniae; resistance; synergism; temocillin; therapy

Subject

Medicine and Pharmacology, Epidemiology and Infectious Diseases

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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