title: Comparison of the minimum inhibitory, mutant prevention and minimum bactericidal concentrations of ciprofloxacin, levofloxacin and garenoxacin against enteric Gram-negative urinary tract infection pathogens.
abstract: Acute, uncomplicated urinary tract infections (UTIs) are among the most commonly encountered bacterial infections and management has been made more complicated in the last decade due to the trend toward increasing antimicrobial resistance to ampicillin and trimethoprim/sulfamethoxazole (TMP/SMX). Fluoroquinolones are suggested as alternative antimicrobials for the treatment of UTIs in communities for which TMP/SMX resistance is > or = 10%. The mutant-prevention concentration (MPC) is a novel susceptibility parameter designed to minimize the selection of first-step resistant mutants present in large, > or = 10(10) CFU/mL, heterogeneous bacterial populations and is a distinct measurement from minimum inhibitory concentration testing. We measured MPC results for 80 enteric Gram-negative and 20 Pseudomonas aeruginosa urinary isolates against ciprofloxacin, levofloxacin and garenoxacin. Ciprofloxacin, levofloxacin and garenoxacin MPC results for Escherichia coli, Citrobacter freundii, Enterobacter cloacae, Klebsiella pneumoniae and P. aeruginosa respectively were 0.5, 1, 1, 1 and 4 mg/L; 1, 2, 4, 2 and 16 mg/L; 1, 8, >8, 4 and > or = 32 mg/L. By comparison, minimum inhibitory concentration (MIC)90 results for the Enterobacteriaceae organisms ranged from < or = 0.06-4 mg/L for the three drugs and 1-4 mg/L against P. aeruginosa. Similarly, MBC90 results ranged from < or = 0.06-4 mg/L and 2-8 mg/L respectively. For ciprofloxacin against E. coli, E. cloacae and K. pneumoniae and for levofloxacin against E. coli, C. freundii and K. pneumoniae, MPC results were below susceptible breakpoints and within clinically achievable and sustainable drug concentrations for >24 hours of the dosing interval against. For garenoxacin, urine drug concentrations are expected to be in excess of MPC results for the entire length of the dosing interval for E. coli. Application of MPCs to fluoroquinolones and management of UTIs represents a situation where high levels of in vitro activity, based on low MICs, is reflected in correspondingly low MPC values for most of the organisms tested. Incorporation of MPC strategies into current fluoroquinolone dosing in UTI represents a realistic approach for preventing the further selection of resistant organisms associated with UTIs.
authors.affiliation: Department of Clinical Microbiology, Royal University Hospital, Saskatoon, Saskatchewan, Canada.
authors.forename: G T
authors.initials: GT
authors.lastname: Hansen
authors.forename: J M
authors.initials: JM
authors.lastname: Blondeau
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology*; D024841:Fluoroquinolones / Q000494:pharmacology*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000187:drug effects; D015242:Ofloxacin / Q000494:pharmacology*; D014552:Urinary Tract Infections / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D002939:Ciprofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; C419689:garenoxacin