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: F Docobo-Pérez, F Fernández-Cuenca, M E Pachón-Ibáñez, A Pascual, C Pichardo, L Martínez-Martínez, J Pachón (Affiliation: Service of Infectious Diseases, Hospitales Universitarios Virgen del Rocío, Sevilla, Spain.)
• Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases (Clin Microbiol Infect) Vol. 14 Issue 6 Pg. 582-7 (Jun 2008) ISSN: 1469-0691 [Electronic] France
• PMID: 18294246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Bacterial Proteins
• Amoxicillin
• Cefoxitin
• Cefotaxime
• Amoxicillin-Potassium Clavulanate Combination
• AmpC beta-lactamases
• beta-Lactamases

Topics

• Amoxicillin (blood, therapeutic use)
• Amoxicillin-Potassium Clavulanate Combination (pharmacokinetics, therapeutic use)
• Animals
• Anti-Bacterial Agents (blood, therapeutic use)
• Bacterial Proteins (antagonists & inhibitors)
• Cefotaxime (blood, therapeutic use)
• Cefoxitin (pharmacology)
• Drug Therapy, Combination
• Escherichia coli (drug effects, enzymology)
• Escherichia coli Infections (drug therapy)
• Female
• Lung (microbiology)
• Mice
• Mice, Inbred C57BL
• Microbial Sensitivity Tests
• Pneumonia, Bacterial (drug therapy)
• Specific Pathogen-Free Organisms
• beta-Lactam Resistance
• beta-Lactamases (antagonists & inhibitors)