title: Efficacy of amoxycillin-clavulanate in an experimental model of murine pneumonia caused by AmpC-non-hyperproducing clinical isolates of Escherichia coli resistant to cefoxitin.
abstract: The algorithms included in most automated systems used for antimicrobial susceptibility testing (e.g., Vitek 2) consider that Escherichia coli isolates resistant to cefoxitin are AmpC-hyperproducers and, consequently, resistant also to amoxycillin-clavulanate. However, a recent study revealed that 30% of E. coli clinical isolates resistant to cefoxitin remained susceptible in vitro to amoxycillin-clavulanate. The aim of the present study was to evaluate the in-vivo efficacy of amoxycillin-clavulanate in the treatment of an experimental model of pneumonia, using two clonally related isolates (with identical repetitive extragenic palindromic sequence (REP)-PCR patterns) of AmpC-non-hyperproducing and OmpF-lacking E. coli (Ec985 and Ec571) that were resistant to cefoxitin and susceptible to cefotaxime and amoxycillin-clavulanate. MICs were determined using a microdilution technique, and in-vitro bactericidal activity was tested using time-kill assays. The in-vivo efficacy of amoxycillin, amoxycillin-clavulanate and cefotaxime against both isolates was tested in a murine pneumonia model using immunocompetent C57BL/6 mice. Ec571 (a TEM-1/2 producer) was resistant to amoxycillin, whereas Ec985 (a TEM-1/2 non-producer) was susceptible. Amoxycillin, amoxycillin-clavulanate and cefotaxime were bactericidal for Ec985, and amoxycillin-clavulanate and cefotaxime were bactericidal for Ec571 at different concentrations and time-points, as determined using time-kill assays. Treatment with amoxycillin, amoxycillin-clavulanate and cefotaxime reduced the bacterial lung concentration of Ec985 compared with non-treated controls (p <0.05), whereas amoxycillin-clavulanate and cefotaxime showed efficacy against Ec571 when compared with the control and amoxycillin groups (p <0.05). Regardless of the exact underlying mechanism(s) of resistance, amoxycillin-clavulanate was effective in the experimental murine model in the treatment of pneumonia caused by AmpC-non-hyperproducing strains of E. coli resistant to cefoxitin.
authors.affiliation: Service of Infectious Diseases, Hospitales Universitarios Virgen del Rocío, Sevilla, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Docobo-Pérez
authors.forename: F
authors.initials: F
authors.lastname: Fernández-Cuenca
authors.forename: M E
authors.initials: ME
authors.lastname: Pachón-Ibáñez
authors.forename: A
authors.initials: A
authors.lastname: Pascual
authors.forename: C
authors.initials: C
authors.lastname: Pichardo
authors.forename: L
authors.initials: L
authors.lastname: Martínez-Martínez
authors.forename: J
authors.initials: J
authors.lastname: Pachón
mesh_terms: D000658:Amoxicillin / Q000097:blood / Q000627:therapeutic use; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002439:Cefotaxime / Q000097:blood / Q000627:therapeutic use; D002440:Cefoxitin / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D008168:Lung / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D018410:Pneumonia, Bacterial / Q000188:drug therapy*; D013047:Specific Pathogen-Free Organisms; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D065093:beta-Lactamase Inhibitors; D002440:Cefoxitin; D019980:Amoxicillin-Potassium Clavulanate Combination; D000658:Amoxicillin; C048795:AmpC beta-lactamases; D001618:beta-Lactamases; D002439:Cefotaxime