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Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance
Published on: December 28, 2017
Breakthrough invasive candidiasis in patients on micafungin
Christopher D Pfeiffer1, Guillermo Garcia-Effron, Aimee K Zaas
1Division of Infectious Diseases, Duke University Medical Center, Durham, NC 27710, USA. christopher.pfeiffer@duke.edu
Journal of Clinical Microbiology
|April 28, 2010
Summary
Breakthrough invasive candidiasis (IC) on micafungin is rare, often occurring in transplant patients with prolonged exposure. Echinocandin resistance mechanisms vary between Candida species, with FKS mutations common in C. glabrata.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Pharmacology
Background:
- Echinocandins are crucial antifungal agents for invasive candidiasis (IC).
- Candida species exhibit a bimodal wild-type minimum inhibitory concentration (MIC) distribution for echinocandins.
- Echinocandin resistance in Candida is generally infrequent.
Purpose of the Study:
- To characterize Candida isolates from breakthrough invasive candidiasis (IC) cases treated with micafungin.
- To identify resistance mechanisms, including FKS gene mutations, in breakthrough isolates.
- To evaluate the utility of caspofungin MIC testing in identifying resistant strains.
Main Methods:
- Collected and characterized Candida isolates from patients experiencing IC breakthrough during micafungin therapy.
- Determined MICs for micafungin and caspofungin.
- Sequenced hot-spot regions of the FKS genes in resistant isolates.
Main Results:
- Eleven of 12 breakthrough IC cases occurred in transplant recipients with median micafungin exposure of 33 days.
- FKS hot-spot mutations were identified in 5 Candida glabrata and 2 Candida tropicalis isolates.
- All FKS-mutated isolates and 4/5 Candida parapsilosis isolates exhibited elevated micafungin MICs (>2 µg/mL); caspofungin MICs identified all mutant strains.
- Candida parapsilosis isolates with wild-type FKS sequences showed elevated micafungin MICs, suggesting alternative resistance mechanisms.
Conclusions:
- Breakthrough IC on micafungin predominantly affects severely immunosuppressed patients with extensive prior exposure.
- Common resistance mechanisms include FKS mutations in C. glabrata and potentially other mechanisms in C. parapsilosis.
- Caspofungin MIC testing effectively identifies strains with FKS mutations conferring resistance.
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