Affiliation:
1. INSERM UMR1137, IAME, Paris, France
2. AP-HP, Hôpital Beaujon, Service de Médecine Interne, Clichy, France
3. AP-HP, Hôpital Bichat, Laboratoire de Toxicologie-Pharmacocinétique, Service de Pharmacie, Paris, France
Abstract
ABSTRACT
We investigated the efficacies of cefotaxime (CTX) and amoxicillin (AMX)-clavulanate (CLA) (AMC) against extended-spectrum-β-lactamase (ESBL)-producing
Escherichia coli
in vitro
and in a murine model of urinary tract infection (UTI). MICs, the checkerboard dilution method, and time-kill curves were used to explore the
in vitro
synergism between cefotaxime and amoxicillin-clavulanate against two isogenic
E. coli
strains—CFT073-RR and its transconjugant, CFT073-RR Tc
bla
CTX-M-15
—harboring a
bla
CTX-M-15
plasmid and a
bla
OXA-1
plasmid. For
in vivo
experiments, mice were separately infected with each strain and treated with cefotaxime, amoxicillin, and clavulanate, alone or in combination, or imipenem, using therapeutic regimens reproducing time of free-drug concentrations above the MIC (
fT
≥MIC) values close to that obtained in humans. MICs of amoxicillin, cefotaxime, and imipenem were 4/>1,024, 0.125/1,024, and 0.5/0.5 mg/liter, for CFT073-RR and CFT073-RR Tc
bla
CTX-M-15
, respectively. The addition of 2 mg/liter of clavulanate (CLA) restored the susceptibility of CFT073-RR Tc
bla
CTX-M-15
to CTX (MICs of the CTX-CLA combination, 0.125 mg/liter). The checkerboard dilution method and time-kill curves confirmed an
in vitro
synergy between amoxicillin-clavulanate and cefotaxime against CFT073-RR Tc
bla
CTX-M-15
.
In vivo
, this antibiotic combination was similarly active against both strains and as effective as imipenem. In conclusion, the cefotaxime and amoxicillin-clavulanate combination appear to be an effective, easy, and already available alternative to carbapenems for the treatment of UTI due to CTX-M-producing
E. coli
strains.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology