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J Antimicrob Chemother. 2015 May;70(5):1466-72. doi: 10.1093/jac/dku542. Epub 2015 Jan 5.

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

Author information

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.

KEYWORDS:

antibiotic pharmacodynamics; antibiotic resistance; imipenem

PMID:
25564564
DOI:
10.1093/jac/dku542
[Indexed for MEDLINE]

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