Cefoxitin as an alternative to carbapenems in a murine model of urinary tract infection due to Escherichia coli harboring CTX-M-15-type extended-spectrum β-lactamase.
We investigated the efficiency of the cephamycin cefoxitin as an alternative to carbapenems for the treatment of urinary tract infections (UTIs) due to Escherichia coli producing CTX-M-type extended-spectrum β-lactamases. The susceptible, UTI-inducing E. coli CFT073-RR strain and its transconjugant CFT073-RR Tc (pbla(CTX-M-15)), harboring a bla(CTX-M-15) carrying-plasmid, were used for all experiments. MICs of cefoxitin (FOX), ceftriaxone (CRO), imipenem (IMP), and ertapenem (ETP) for CFT073-RR and CFT073-RR Tc (pbla(CTX-M-15)) were 4 and 4, 0.125 and 512, 0.5 and 0.5, and 0.016 and 0.032 μg/ml, respectively. Bactericidal activity was similarly achieved in vitro against the two strains after 3 h of exposure to concentrations of FOX, IMI, and ETP that were 2 times the MIC, whereas CRO was not bactericidal against CFT073-RR Tc (pbla(CTX-M-15)). The frequencies of spontaneous mutants of the 2 strains were not higher for FOX than for IMP or ETP. In the murine model of UTIs, mice infected for 5 days were treated over 24 h. Therapeutic regimens in mice (200 mg/kg of body weight every 3 h or 4 h for FOX, 70 mg/kg every 6 h for CRO, 100 mg/kg every 2 h for IMP, and 100 mg/kg every 4 h for ETP) were chosen in order to reproduce the percentage of time that free-drug concentrations above the MIC are obtained in humans with standard regimens. All antibiotic regimens produced a significant reduction in bacterial counts (greater than 2 log(10) CFU) in kidneys and bladders for both strains (P < 0.001) without selecting resistant mutants in vivo, but the reduction obtained with CRO against CFT073-RR Tc (pbla(CTX-M-15)) in kidneys was significantly lower than that obtained with FOX. In conclusion, FOX appears to be an effective therapeutic alternative to carbapenems for the treatment of UTIs due to CTX-M-producing E. coli.
Université Paris Diderot, Paris, France.
Raphaël
R
Lepeule
Etienne
E
Ruppé
Patrick
P
Le
Laurent
L
Massias
Françoise
F
Chau
Amandine
A
Nucci
Agnès
A
Lefort
Bruno
B
Fantin
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D058491:Bacterial Load / Q000187:drug effects; D015780:Carbapenems / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002440:Cefoxitin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002443:Ceftriaxone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003227:Conjugation, Genetic; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D000077727:Ertapenem; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics*; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D059645:Mutation Rate; D010957:Plasmids; D001743:Urinary Bladder / Q000187:drug effects / Q000382:microbiology; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*; D047090:beta-Lactams / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D047090:beta-Lactams; D002440:Cefoxitin; D015378:Imipenem; D002443:Ceftriaxone; C473109:beta-lactamase CTX-M-15; D001618:beta-Lactamases; D000077727:Ertapenem