title: Impact of antimicrobial dosing regimen on evolution of drug resistance in vivo: fluconazole and Candida albicans.
abstract: Numerous factors have been theorized to affect the development of antimicrobial resistance, including those specific to the host, the organism, the environment, the drug, and the drug prescriber. One variable under the control of the prescriber is the drug dosing regimen. Dosing regimens can vary in dose level, dosing interval, and treatment duration. The current studies examined the relationships between antimicrobial dosing regimens and resistance development by use of an in vivo model. A murine model of systemic Candida albicans infection was used to examine resistance emergence during exposure to the triazole antifungal fluconazole. Data from this experimental model demonstrated that the more frequently administered dosing prevented selection of the isogenic resistant cell populations. Conversely, dosing regimens producing prolonged sub-MIC effects appeared to contribute to the outgrowth of isogenic resistant strains. The association between dosing and resistance emergence observed in the current investigation is disparate from that described for antimicrobial compounds with cidal killing characteristics. The inhibitory or static antimicrobial activity of the triazole compounds may explain these differences.
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, WI 53792, USA. dra@medicine.wisc.edu
authors.forename: D
authors.initials: D
authors.lastname: Andes
authors.forename: A
authors.initials: A
authors.lastname: Forrest
authors.forename: A
authors.initials: A
authors.lastname: Lepak
authors.forename: J
authors.initials: J
authors.lastname: Nett
authors.forename: K
authors.initials: K
authors.lastname: Marchillo
authors.forename: L
authors.initials: L
authors.lastname: Lincoln
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D004334:Drug Administration Schedule; D025141:Drug Resistance, Fungal / Q000235:genetics*; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013047:Specific Pathogen-Free Organisms
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole