title: Activity of temocillin in a murine model of urinary tract infection due to Escherichia coli producing or not producing the ESBL CTX-M-15.
abstract: OBJECTIVE
  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.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France.
authors.forename: J F
authors.initials: JF
authors.lastname: Soubirou
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Rossi
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Couffignal
authors.affiliation: 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.
authors.forename: E
authors.initials: E
authors.lastname: Ruppé
authors.affiliation: Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Chau
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France AP-HP, Groupe Hospitalier Paris Nord Val de Seine, Laboratoire de Pharmacologie, F-75018 Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Massias
authors.affiliation: AP-HP, Groupe Hospitalier Paris Nord Val de Seine, Service de médecine interne, F-92210 Clichy, France.
authors.forename: R
authors.initials: R
authors.lastname: Lepeule
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Mentre
authors.affiliation: 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.
authors.forename: B
authors.initials: B
authors.lastname: Fantin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D015378:Imipenem / Q000008:administration & dosage; D008808:Mice, Inbred CBA; D008826:Microbial Sensitivity Tests; D010406:Penicillins / Q000008:administration & dosage*; D016896:Treatment Outcome; D014552:Urinary Tract Infections / Q000188:drug therapy*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D010406:Penicillins; C031367:temocillin; D015378:Imipenem; C473109:beta-lactamase CTX-M-15; D001618:beta-Lactamases
keywords: antibiotic pharmacodynamics; antibiotic resistance; imipenem