Pharmacokinetic/pharmacodynamic analysis of ceftazidime/avibactam and fosfomycin combinations in an in vitro hollow fiber infection model against multidrug-resistant Escherichia coli

• Published in: Microbiology spectrum Vol. 12; no. 1; p. e0331823
• Main Authors: Kroemer, Niklas, Amann, Lisa F, Farooq, Aneeq, Pfaffendorf, Christoph, Martens, Miklas, Decousser, Jean-Winoc, Grégoire, Nicolas, Nordmann, Patrice, Wicha, Sebastian G
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 11.01.2024
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antimicrobial Chemotherapy; Azabicyclo Compounds; beta-Lactamases - genetics; Ceftazidime - pharmacology; Ceftazidime - therapeutic use; ceftazidime/avibactam; Drug Combinations; drug interactions; Escherichia coli - genetics; fosfomycin; Fosfomycin - pharmacology; hollow fiber infection model; Life Sciences; Microbial Sensitivity Tests; Pharmaceutical sciences; Pharmacology; PK/PD; Research Article; synergy; ceftazidime/avibactam; PK/PD; drug interactions; synergy; Escherichia coli; hollow fiber infection model; fosfomycin
• ISSN: 2165-0497; 2165-0497
• DOI: 10.1128/spectrum.03318-23

Mechanistic understanding of pharmacodynamic interactions is key for the development of rational antibiotic combination therapies to increase efficacy and suppress the development of resistances. Potent tools to provide those insights into pharmacodynamic drug interactions are semi-mechanistic modeling and simulation techniques. This study uses those techniques to provide a detailed understanding with regard to the direction and strength of the synergy of ceftazidime-avibactam and ceftazidime-fosfomycin in a clinical isolate expressing extended spectrum beta-lactamase (CTX-M-15 and TEM-4) and carbapenemase (OXA-244) genes. Enhanced killing effects in combination were identified as a driver of the synergy and were translated from static time-kill experiments into the dynamic hollow fiber infection model. These findings in combination with a suppression of the emergence of resistance in combination emphasize a potential clinical benefit with regard to increased efficacy or to allow for dose reductions with maintained effect sizes to avoid toxicity.