title: Differential in vivo activities of anidulafungin, caspofungin, and micafungin against Candida glabrata isolates with and without FKS resistance mutations.
abstract: We recently observed that the micafungin MICs for some Candida glabrata fks hot spot mutant isolates are less elevated than those for the other echinocandins, suggesting that the efficacy of micafungin may be differentially dependent on such mutations. Three clinical C. glabrata isolates with or without (S3) fks hot spot mutations R83 (Fks2p-S663F) and RR24 (Fks1p-S629P) and low, medium, and high echinocandin MICs, respectively, were evaluated to assess the in vivo efficacy in an immunocompetent mouse model using three doses of each echinocandin. Drug concentrations were determined in plasma and kidneys by high-performance liquid chromatography (HPLC). A pharmacokinetic-pharmacodynamic mathematical model was used to define the area under the concentration-time curve (AUC) that produced half- and near-maximal activity. Micafungin was equally efficacious against the S3 and R83 isolates. The estimates for the AUCs of each echinocandin that induced half-maximal effect (E(50)s) were 194.2 and 53.99 mg · h/liter, respectively. In contrast, the maximum effect (E(max)) for caspofungin was higher against S3 than R83, but the estimates for E(50) were similar (187.1 and 203.5 mg · h/liter, respectively). Anidulafungin failed to induce a ≥1-log reduction for any of the isolates (AUC range, 139 to 557 mg · h/liter). None of the echinocandins were efficacious in mice challenged with the RR24 isolate despite lower virulence (reduced maximal growth, prolonged lag phase, and lower kidney burden). The AUC associated with half-maximal effect was higher than the average human exposure for all drug-dose-bug combinations except micafungin and the R83 isolate. In conclusion, differences in micafungin MICs are associated with differential antifungal activities in the animal model. This study may have implications for clinical practice and echinocandin breakpoint determination, and further studies are warranted.
authors.affiliation: Unit of Mycology and Parasitology, Statens Serum Institut, Copenhagen, Denmark. maca@ssi.dk
authors.forename: Maiken Cavling
authors.initials: MC
authors.lastname: Arendrup
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.forename: Rasmus Hare
authors.identifier: 0000-0002-9796-023X
authors.initials: RH
authors.lastname: Jensen
authors.forename: Susan Julie
authors.initials: SJ
authors.lastname: Howard
authors.forename: Joanne
authors.initials: J
authors.lastname: Goodwin
authors.forename: William
authors.initials: W
authors.lastname: Hope
mesh_terms: D000077612:Anidulafungin; D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D041221:Candida glabrata / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D002177:Candidiasis / Q000097:blood / Q000188:drug therapy / Q000382:microbiology; D000077336:Caspofungin; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal / Q000235:genetics*; D054714:Echinocandins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005800:Genes, Fungal; D005964:Glucosyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D055666:Lipopeptides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077551:Micafungin; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077612:Anidulafungin; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase; D000077336:Caspofungin; D000077551:Micafungin