Activity of temocillin in a murine model of urinary tract infection due to Escherichia coli producing or not producing the ESBL CTX-M-15

• Published in: Journal of antimicrobial chemotherapy Vol. 70; no. 5; pp. 1466 - 1472
• Main Authors: Soubirou, J F, Rossi, B, Couffignal, C, Ruppé, E, Chau, F, Massias, L, Lepeule, R, Mentre, F, Fantin, B
• Format: Journal Article
• Language: English
• Published: England Oxford Publishing Limited (England) 01.05.2015
• Subjects: Animals; Anti-Bacterial Agents - administration & dosage; beta-Lactamases - secretion; Disease Models, Animal; E coli; Escherichia coli - enzymology; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; Female; Imipenem - administration & dosage; Mice, Inbred CBA; Microbial Sensitivity Tests; Penicillin; Penicillins - administration & dosage; Rodents; Treatment Outcome; Urinary tract diseases; Urinary Tract Infections - drug therapy; antibiotic pharmacodynamics; antibiotic resistance; imipenem
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dku542

Temocillin is a 6α-methoxy derivative of ticarcillin that is resilient to ESBLs. Prospective data about its in vivo activity remain scarce. Our aims were: (i) to evaluate the activity of temocillin in a urinary tract infection (UTI) model due to ESBL-producing Escherichia coli and compare it with that of imipenem; and (ii) to define in vivo susceptibility breakpoints. Mice were infected with a susceptible E. coli CFT073-RR or its transconjugant (CFT073-RR Tc) harbouring a blaCTX-M-15-carrying plasmid, using an ascending UTI model. Therapeutic regimens were chosen in order to reproduce percentage of time of free drug concentrations above MIC (fT>MIC) obtained in humans with standard regimens of temocillin (200 mg/kg every 2 h for 2 g every 12 h) or imipenem (100 mg/kg every 2 h for 1 g every 8 h). Additional regimens of temocillin (200 mg/kg every 4 and 6 h) with reduced fT>MIC were studied. MICs of temocillin and imipenem were 4/8 and 0.5/0.5 mg/L, for CFT073-RR and CFT073-RR Tc, respectively. In vivo, when given every 2 h (fT>MIC = 82% and 70%), temocillin was bactericidal and as effective as imipenem in kidneys against both strains without selecting resistant mutants. Temocillin remained active even when given every 4 h, generating an fT>MIC of 41% and 35%, which corresponded to a breakpoint of 16 mg/L in humans with the standard regimen. Our observations support the consideration of a standard regimen of temocillin as an alternative to carbapenems for the treatment of UTI due to CTX-M-producing E. coli strains with an MIC of 16 mg/L or less.