Journal article
Optimizing Echinocandin dosing and susceptibility breakpoint determination via in vivo pharmacodynamic evaluation against Candida glabrata with and without fks mutations
Antimicrobial agents and chemotherapy, Vol.56(11), pp.5875-5882
11/2012
DOI: 10.1128/AAC.01102-12
PMCID: PMC3486567
PMID: 22948870
Abstract
Echinocandins are a preferred therapy for invasive candidiasis due to their potency and broad spectrum. Resistance, especially in Candida glabrata, is an emerging threat to their use. Pharmacodynamic (PD) studies examining reduced susceptibility secondary to fks mutations in C. glabrata are lacking. The current study explored PD targets for anidulafungin, caspofungin, and micafungin in an in vivo invasive candidiasis model against 11 C. glabrata isolates with known or putative fks mutations. The PD targets were compared to those of 8 wild-type (WT) isolates. The MIC ranges in the WT group were 0.03 to 0.25 mg/liter for anidulafungin, 0.03 to 0.25 mg/liter for caspofungin, and 0.01 to 0.06 mg/liter for micafungin. The MIC ranges for mutants were 0.06 to 4, 0.25 to 16, and 0.13 to 8 mg/liter for the same compounds, respectively. The mean free drug 24-h area under the concentration-time curve (AUCf)/MIC ratio associated with a stasis endpoint for the WT group was 13.2 for anidulafungin, 2.04 for caspofungin, and 6.78 for micafungin. Comparative values for mutants were 3.43, 2.67, and 0.90, respectively. Pharmacokinetic data from patients suggest that the C. glabrata PD targets needed for success in this model could be achieved based on MIC values of 0.25 mg/liter for anidulafungin, 2 mg/liter for caspofungin, and 0.5 mg/liter for micafungin. These values are higher than recently identified epidemiology cutoff values (ECVs). The results suggest that drug-specific MIC breakpoints could be increased for caspofungin and micafungin against C. glabrata and could include organisms with mutations in fks-1 and fks-2. While identification of genetic mutants is epidemiologically important, the phenotype (MIC) provides a better predictor of therapeutic efficacy.
Details
- Title: Subtitle
- Optimizing Echinocandin dosing and susceptibility breakpoint determination via in vivo pharmacodynamic evaluation against Candida glabrata with and without fks mutations
- Creators
- Alexander Lepak - University of Wisconsin, Madison, Wisconsin, USAMariana CastanheiraDaniel DiekemaMichael PfallerDavid Andes
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.56(11), pp.5875-5882
- Publisher
- United States
- DOI
- 10.1128/AAC.01102-12
- PMID
- 22948870
- PMCID
- PMC3486567
- ISSN
- 1098-6596
- eISSN
- 1098-6596
- Language
- English
- Date published
- 11/2012
- Academic Unit
- Infectious Diseases; Epidemiology; Pathology; Internal Medicine
- Record Identifier
- 9983986373502771
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