title: Efficacies of moxifloxacin, ciprofloxacin, and vancomycin against experimental endocarditis due to methicillin-resistant Staphylococcus aureus expressing various degrees of ciprofloxacin resistance.
abstract: The new 8-methoxyquinolone moxifloxacin was tested against two ciprofloxacin-susceptible Staphylococcus aureus strains (strains P8 and COL) and two ciprofloxacin-resistant derivatives of strain P8 carrying a single grlA mutation (strain P8-4) and double grlA and gyrA mutations (strain P8-128). All strains were resistant to methicillin. The MICs of ciprofloxacin and moxifloxacin were 0.5 and 0.125 mg/liter, respectively, for P8; 0.25 and 0.125 mg/liter, respectively, for COL; 8 and 0.25 mg/liter, respectively, for P8-4; and >or=128 and 2 mg/liter, respectively, for P8-128. In vitro, the rate of spontaneous resistance of P8 and COL was 10(-7) on agar plates containing ciprofloxacin at two times the MIC, whereas it was <or=10(-10) on agar plates containing moxifloxacin at two times the MIC. Rats with experimental aortic endocarditis were treated with doses of drugs that simulate the kinetics in humans: moxifloxacin, 400 mg orally once a day; ciprofloxacin, 750 mg orally twice a day; or vancomycin, 1 g intravenously twice a day. Treatment was started either 12 or 24 h after infection and lasted for 3 days. Moxifloxacin treatment resulted in culture-negative vegetations in a total of 20 of 21 (95%) rats infected with P8, 10 of 11 (91%) rats infected with COL, and 19 of 24 (79%) rats infected with P8-4 (P < 0.05 compared to the results for the controls). In contrast, ciprofloxacin treatment sterilized zero of nine (0%) vegetations infected with first-level resistant mutant P8-4. Vancomycin sterilized only 8 of 15 (53%), 6 of 11 (54%), and 12 of 23 (52%) of the vegetations, respectively. No moxifloxacin-resistant derivative emerged among these organisms. However, moxifloxacin treatment of highly ciprofloxacin-resistant mutant P8-128 failed and selected for variants for which the MIC increased two times in 2 of 10 animals. Thus, while oral moxifloxacin might deserve consideration as treatment for staphylococcal infections in humans, caution related to its use against strains for which MICs are borderline is warranted.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
authors.forename: J M
authors.initials: JM
authors.lastname: Entenza
authors.forename: Y A
authors.initials: YA
authors.lastname: Que
authors.forename: J
authors.initials: J
authors.lastname: Vouillamoz
authors.forename: M P
authors.initials: MP
authors.lastname: Glauser
authors.forename: P
authors.initials: P
authors.lastname: Moreillon
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001372:Aza Compounds; D002939:Ciprofloxacin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D027081:DNA Gyrase / Q000235:genetics; D004352:Drug Resistance, Microbial; D004697:Endocarditis, Bacterial / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D024841:Fluoroquinolones; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D011804:Quinolines; D051381:Rats; D013154:Spleen / Q000382:microbiology; D013203:Staphylococcal Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics*; D014640:Vancomycin / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D002939:Ciprofloxacin; D014640:Vancomycin; D027081:DNA Gyrase; D000077266:Moxifloxacin