Activity of temocillin in a lethal murine model of infection of intra-abdominal origin due to KPC-producing Escherichia coli

Abstract

Objectives: Temocillin is a 6-a-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. Methods: 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 200mg/kg every 2 h for 24 h, reproducing the duration of time that the free serumconcentration 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. Results: Temocillin MICs were 8, 16, 32, and 256mg/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) formice infected with the susceptible strain and KPC-2-, KPC-3-and OXA-48-producing strains, respectively. Conclusions: In a lethal-infection model with bacteraemia from intra-abdominal origin, temocillin retained significant activity in PF, blood and spleen and prevented death inmice by effectivelyworking against KPC-producing E. coli with temocillin MICs ≤16 mg/L.