title: Prevention of the selection of resistant Staphylococcus aureus by moxifloxacin plus doxycycline in an in vitro dynamic model: an additive effect of the combination.
abstract: Twenty-four hour ratios of area under the curve (AUC(24)) to MIC of 200-240 h providing quinolone concentrations above the mutant prevention concentration (MPC) protected from enrichment of resistant Staphylococcus aureus in our recent study that simulated the pharmacokinetics of moxifloxacin, gatifloxacin, levofloxacin and ciprofloxacin. These protective AUC(24)/MICs might also be achieved by using antibiotic combinations, assuming additive effects of two anti-staphylococcal agents. To test this hypothesis, changes in S. aureus susceptibility were examined in a dynamic model that simulates 5-day treatment with moxifloxacin and doxycycline, alone and in combination at sub-optimal AUC(24)/MICs of each agent. Significant increases in MIC were observed with monotherapy where moxifloxacin or doxycycline concentrations fell into the mutant selection window (MSW) for more than 80% of the dosing interval (AUC(24)/MIC 60 h). Less pronounced changes in MIC occurred when the summed concentrations of moxifloxacin (AUC(24)/MIC 30 and 60 h) and doxycycline (AUC(24)/MIC 30 and 60 h) were inside the MSWs for the individual drugs for 30-50% of the dosing interval. No loss in susceptibility was found at moxifloxacin or doxycycline AUC(24)/MIC 170 h combined with the smaller AUC(24)/MIC (60 h) of the second compound. These data suggest that the total AUC(24)/MIC of 230 h might protect against S. aureus resistance. As this value is very close to that predicted in monotherapy with moxifloxacin (220 h), an additive protective effect of quinolone+doxycycline on the selection of resistant S. aureus is proposed. The use of drug combinations may be useful for restricting the enrichment of resistant mutants with agents whose clinically achievable AUC(24)/MICs do not provide concentrations above the MPC.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia. firsov@dol.ru
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Firsov
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Vostrov
authors.forename: Irene Yu
authors.initials: IY
authors.lastname: Lubenko
authors.forename: Yury A
authors.initials: YA
authors.lastname: Portnoy
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Zinner
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D019540:Area Under Curve; D001372:Aza Compounds / Q000378:metabolism / Q000494:pharmacology*; D004318:Doxycycline / Q000378:metabolism / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000378:metabolism / Q000494:pharmacology*; D024841:Fluoroquinolones; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology*; D012641:Selection, Genetic; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D004318:Doxycycline; D000077266:Moxifloxacin