title: Disseminated Candidiasis caused by Candida albicans with amino acid substitutions in Fks1 at position Ser645 cannot be successfully treated with micafungin.
abstract: The clinical utility of the echinocandins is potentially compromised by the emergence of drug resistance. We investigated whether Candida albicans with amino acid substitutions at position Ser645 in Fks1 can be treated with either a conventional or an elevated dosage of micafungin. We studied Candida albicans (wild-type SC5314; MIC, 0.06 mg/liter) and four fks1 mutants (one FKS1/fks1 heterozygote mutant [MIC, 0.5 mg/liter] and three fks1/fks1 homozygous mutants [MICs for all, 2 mg/liter]) with a variety of amino acid substitutions at Ser645. The pharmacokinetic and pharmacodynamic relationships were characterized in a persistently neutropenic murine model of disseminated candidiasis. A mathematical model was fitted to all pharmacokinetic and pharmacodynamic data. This mathematical model was then used to "humanize" the murine pharmacokinetics, and the predicted antifungal effect was determined. The estimated maximal rate of growth and ultimate fungal densities in the kidney for each of the strains were similar. The administration of micafungin at 1 mg/kg of body weight to the wild type resulted in moderate antifungal activity, whereas the administration of 5 and 20 mg/kg resulted in rapid fungicidal activity. In contrast, the FKS1/fks heterozygote was killed only with 20 mg/kg, and the homozygous fks1 mutants failed to respond to any dosage. The bridging study revealed that human dosages of 100 and 400 mg/day were active only against the wild type, with no activity against either the heterozygote or the homozygote mutants. Ser645 Fks1 Candida albicans mutants cannot be treated with either conventional or elevated dosages of micafungin and should be deemed resistant.
authors.affiliation: The University of Manchester, Manchester Academic Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: J L
authors.initials: JL
authors.lastname: Slater
authors.forename: S J
authors.initials: SJ
authors.lastname: Howard
authors.forename: A
authors.initials: A
authors.lastname: Sharp
authors.forename: J
authors.initials: J
authors.lastname: Goodwin
authors.forename: L M
authors.initials: LM
authors.lastname: Gregson
authors.forename: A
authors.initials: A
authors.lastname: Alastruey-Izquierdo
authors.forename: M C
authors.initials: MC
authors.lastname: Arendrup
authors.forename: P A
authors.initials: PA
authors.lastname: Warn
authors.forename: D S
authors.initials: DS
authors.lastname: Perlin
authors.forename: W W
authors.initials: WW
authors.lastname: Hope
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D025141:Drug Resistance, Fungal / Q000235:genetics; D054714:Echinocandins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006801:Humans; D055666:Lipopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D000077551:Micafungin; D051379:Mice; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D000077551:Micafungin