title: Activity of temocillin in a lethal murine model of infection of intra-abdominal origin due to KPC-producing Escherichia coli.
abstract: Temocillin is a 6-α-methoxy derivative of ticarcillin that shows in vitro activity against Enterobacteriaceae producing Klebsiella pneumoniae carbapenemase (KPC). Our objective was to assess in vivo temocillin activity against KPC-producing Escherichia coli.
  
  
  
  Isogenic derivatives of the WT E. coli CFT073 producing KPC-2, KPC-3 or OXA-48 were constructed. An experimental murine model of intra-abdominal infection with sepsis was used. Mice were treated subcutaneously with temocillin 200 mg/kg every 2 h for 24 h, reproducing the duration of time that the free serum concentration of temocillin exceeded the MIC in humans with a regimen of 2 g every 12 h or 2 g every 8 h. Blood, peritoneal fluid (PF) and spleen were collected; 24 h survival and sterility rates were assessed.
  
  
  
  Temocillin MICs were 8, 16, 32, and 256 mg/L for the susceptible strain and KPC-2-, KPC-3-, and OXA-48-producing strains, respectively. In mice treated with temocillin, significant bacterial reduction was obtained in PF, blood, and spleen for the susceptible strain and KPC-2- and KPC-3-producing strains (P < 0.001) but not for the OXA-48-producing strain. Sterility rates in PF were 53%, 10%, 0% and 0% (P < 0.001) and sterility rates in blood were 77%, 40%, 3% and 0% (P < 0.001), while survival rates were 97%, 97%, 57%, 0% (P < 0.001) for mice infected with the susceptible strain and KPC-2-, KPC-3- and OXA-48-producing strains, respectively.
  
  
  
  In a lethal-infection model with bacteraemia from intra-abdominal origin, temocillin retained significant activity in PF, blood and spleen and prevented death in mice by effectively working against KPC-producing E. coli with temocillin MICs ≤16 mg/L.
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Alexandre
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: Chau
authors.affiliation: Université de Caen Basse-Normandie, EA 4655 (Équipe "Antibio-résistance"), F-14032 Caen, France CHU de Caen, Service de Microbiologie, F-14033 Caen, France.
authors.forename: F
authors.initials: F
authors.lastname: Guérin
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: 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.
authors.forename: A
authors.initials: A
authors.lastname: Lefort
authors.affiliation: Université de Caen Basse-Normandie, EA 4655 (Équipe "Antibio-résistance"), F-14032 Caen, France CHU de Caen, Service de Microbiologie, F-14033 Caen, France.
authors.forename: V
authors.initials: V
authors.lastname: Cattoir
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* / Q000493:pharmacokinetics; D001202:Ascitic Fluid / Q000737:chemistry; D016470:Bacteremia / Q000188:drug therapy*; D001426:Bacterial Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D007279:Injections, Subcutaneous; D059413:Intraabdominal Infections / Q000150:complications* / Q000188:drug therapy; D051379:Mice; D008826:Microbial Sensitivity Tests; D010406:Penicillins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010949:Plasma / Q000737:chemistry; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010406:Penicillins; C031367:temocillin; D001618:beta-Lactamases; C063912:carbapenemase