title: Comparative assessment of inoculum effects on the antimicrobial activity of amoxycillin-clavulanate and piperacillin-tazobactam with extended-spectrum beta-lactamase-producing and extended-spectrum beta-lactamase-non-producing Escherichia coli isolates.
abstract: A significant inoculum-size effect has been observed with piperacillin-tazobactam, and has been associated with beta-lactamase production in extended-spectrum beta-lactamase (ESBL) producers. This association has not been previously studied in the case of amoxycillin-clavulanate. Piperacillin-tazobactam and amoxycillin-clavulanate were compared, using high inocula of susceptible strains either harbouring ESBLs or not. Two non-ESBL-producing and 15 amoxycillin-clavulanate-susceptible and piperacillin-tazobactam-susceptible ESBL-producing Escherichia coli isolates, and their respective transconjugants, were tested in dilution susceptibility tests using standard and 100-fold higher inocula. Three ESBL-producing strains and E. coli ATCC 25922 were selected for time-kill studies using standard and high initial inocula. At high inocula, MICs of piperacillin increased >eight-fold for non-ESBL-producing strains, and MICs of piperacillin-tazobactam (8:1 ratio or with tazobactam fixed at 4 mg/L) increased>eight-fold for all ESBL-producing strains. However, amoxycillin MICs were not affected by a high inoculum with non-ESBL-producing strains, whereas the MICs of amoxycillin-clavulanate (2:1 and 4:1) increased <or=four-fold for ESBL producers, using the broth and agar dilution methods. In kinetic studies at a high inoculum, amoxycillin and amoxycillin-clavulanate were bactericidal against E. coli ATCC 25922, whereas piperacillin and piperacillin-tazobactam yielded decreases of <1 log(10) CFU/mL. Similarly, at a high inoculum, only amoxycillin-clavulanate was able to maintain bactericidal rates of killing over 24 h against the ESBL-positive E. coli isolates. The stability of amoxycillin-clavulanate and the contrasting results obtained with piperacillin-tazobactam against high inocula of ESBL-non-producing and ESBL-producing E. coli strains appear to be related to aspects other than the amount of beta-lactamase production.
authors.affiliation: Department of Microbiology, University Hospital Virgen Macarena, Seville, Spain. llopez@us.es
authors.forename: L
authors.initials: L
authors.lastname: López-Cerero
authors.forename: E
authors.initials: E
authors.lastname: Picón
authors.forename: C
authors.initials: C
authors.lastname: Morillo
authors.forename: J R
authors.initials: JR
authors.lastname: Hernández
authors.forename: F
authors.initials: F
authors.lastname: Docobo
authors.forename: J
authors.initials: J
authors.lastname: Pachón
authors.forename: J
authors.initials: J
authors.lastname: Rodríguez-Baño
authors.forename: A
authors.initials: A
authors.lastname: Pascual
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015169:Colony Count, Microbial; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology* / Q000302:isolation & purification; D004927:Escherichia coli Infections; D029968:Escherichia coli Proteins / Q000096:biosynthesis*; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods*; D050296:Microbial Viability; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010878:Piperacillin / Q000494:pharmacology; D000077725:Piperacillin, Tazobactam Drug Combination; D013997:Time Factors; D001618:beta-Lactamases / Q000096:biosynthesis*
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D000077725:Piperacillin, Tazobactam Drug Combination; D019980:Amoxicillin-Potassium Clavulanate Combination; D010397:Penicillanic Acid; D001618:beta-Lactamases; D010878:Piperacillin