J F Soubirou1, B Rossi1, C Couffignal1, E Ruppé2, F Chau3, L Massias4, R Lepeule5, F Mentre1, B Fantin6. 1. INSERM, IAME, UMR 1137, F-75018 Paris, France Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France. 2. INSERM, IAME, UMR 1137, F-75018 Paris, France Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France AP-HP, Groupe Hospitalier Paris Nord Val de Seine, Laboratoire de Microbiologie, F-75018 Paris, France. 3. Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France. 4. INSERM, IAME, UMR 1137, F-75018 Paris, France AP-HP, Groupe Hospitalier Paris Nord Val de Seine, Laboratoire de Pharmacologie, F-75018 Paris, France. 5. AP-HP, Groupe Hospitalier Paris Nord Val de Seine, Service de médecine interne, F-92210 Clichy, France. 6. INSERM, IAME, UMR 1137, F-75018 Paris, France Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France AP-HP, Groupe Hospitalier Paris Nord Val de Seine, Service de médecine interne, F-92210 Clichy, France bruno.fantin@bjn.aphp.fr.
Abstract
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVES: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. METHODS: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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Yan Q Xiong; Angeles Estellés; L Li; W Abdelhady; R Gonzales; Arnold S Bayer; Edgar Tenorio; Anton Leighton; Stefan Ryser; Lawrence M Kauvar Journal: Antimicrob Agents Chemother Date: 2017-09-22 Impact factor: 5.191
Authors: Elise T Zeiser; Scott A Becka; Melissa D Barnes; Magdalena A Taracila; John J LiPuma; Krisztina M Papp-Wallace Journal: Antimicrob Agents Chemother Date: 2019-03-27 Impact factor: 5.191
Authors: B Rossi; J F Soubirou; F Chau; L Massias; S Dion; R Lepeule; B Fantin; A Lefort Journal: Antimicrob Agents Chemother Date: 2015-11-02 Impact factor: 5.191