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Antibiotics
Volume 13
Issue 6
10.3390/antibiotics13060526
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Article

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

by
Venera Costantino
1,
Luigi Principe
2,
Jai Mehat
3,
Marina Busetti
1,
Alessandra Piccirilli
4,
Mariagrazia Perilli
4,
Roberto Luzzati
5,
Verena Zerbato
6,
Antonietta Meliadò
2,
Roberto La Ragione
3,7 and
Stefano Di Bella
5,*
1
Microbiology Unit, Trieste University Hospital (ASUGI), 34128 Trieste, Italy
2
Clinical Microbiology and Virology Unit, Great Metropolitan Hospital “Bianchi-Melacrino-Morelli”, 89128 Reggio di Calabria, Italy
3
Department of Microbial Sciences, School of Biosciences, University of Surrey, Guildford GU2 7XH, UK
4
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy
5
Clinical Department of Medical, Surgical and Health Sciences, Trieste University, 34129 Trieste, Italy
6
Infectious Diseases Unit, Trieste University Hospital (ASUGI), 34125 Trieste, Italy
7
Department of Comparative Biomedical Sciences, School of Veterinary Medicine, University of Surrey, Guildford GU2 7XH, UK
*
Author to whom correspondence should be addressed.
Antibiotics 2024, 13(6), 526; https://doi.org/10.3390/antibiotics13060526
Submission received: 28 February 2024 / Revised: 8 April 2024 / Accepted: 3 June 2024 / Published: 4 June 2024
(This article belongs to the Special Issue Epidemiology and Mechanism of Bacterial Resistance to Antibiotics)
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Abstract

Infections caused by KPC-producing K. pneumoniae continue to pose a significant clinical challenge due to their 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 five genetically 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). 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 isolates 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 antibiotic; combination; fosfomycin; Galleria mellonella; in vivo; KPC-producing Klebsiella pneumoniae; resistance; synergism; temocillin; therapy
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MDPI and ACS Style

Costantino, V.; Principe, L.; Mehat, J.; Busetti, M.; Piccirilli, A.; Perilli, M.; Luzzati, R.; Zerbato, V.; Meliadò, A.; La Ragione, R.; et al. Synergistic Activity of Temocillin and Fosfomycin Combination against KPC-Producing Klebsiella pneumoniae Clinical Isolates. Antibiotics 2024, 13, 526. https://doi.org/10.3390/antibiotics13060526

AMA Style

Costantino V, Principe L, Mehat J, Busetti M, Piccirilli A, Perilli M, Luzzati R, Zerbato V, Meliadò A, La Ragione R, et al. Synergistic Activity of Temocillin and Fosfomycin Combination against KPC-Producing Klebsiella pneumoniae Clinical Isolates. Antibiotics. 2024; 13(6):526. https://doi.org/10.3390/antibiotics13060526

Chicago/Turabian Style

Costantino, Venera, Luigi Principe, Jai Mehat, Marina Busetti, Alessandra Piccirilli, Mariagrazia Perilli, Roberto Luzzati, Verena Zerbato, Antonietta Meliadò, Roberto La Ragione, and et al. 2024. "Synergistic Activity of Temocillin and Fosfomycin Combination against KPC-Producing Klebsiella pneumoniae Clinical Isolates" Antibiotics 13, no. 6: 526. https://doi.org/10.3390/antibiotics13060526

APA Style

Costantino, V., Principe, L., Mehat, J., Busetti, M., Piccirilli, A., Perilli, M., Luzzati, R., Zerbato, V., Meliadò, A., La Ragione, R., & Di Bella, S. (2024). Synergistic Activity of Temocillin and Fosfomycin Combination against KPC-Producing Klebsiella pneumoniae Clinical Isolates. Antibiotics, 13(6), 526. https://doi.org/10.3390/antibiotics13060526

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