Breakthrough Invasive 1 Candidiasis on Micafungin

PFEIFFER, CHRISTOPHER D.; GARCIA-EFFRON, GUILLERMO; ZAAS, AIMEE K.; PERFECT, JOHN R.; PERLIN, DAVID S.; ALEXANDER, BARBARA D.

JOURNAL OF CLINICAL MICROBIOLOGY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2010 vol. 48 p. 2373 - 2380

0095-1137

For Candida spp., a bimodal wild-type minimum inhibitory concentration (MIC) distribution for echinocandins exists, but resistance to echinocandins is rare. We characterized isolates from patients with invasive candidiasis (IC) breaking through ¡Ý3 doses of micafungin therapy during the first 28 months of its use at our center: MICs were determined and hot-spot regions within FKS genes were sequenced. Eleven of twelve breakthrough IC cases identified were in transplant recipients. Median duration of micafungin exposure prior to breakthrough was 33 days (range 5-165). Seventeen breakthrough isolates were recovered: FKS hot-spot mutations were found in 5 C. glabrata and 2 C. tropicalis isolates; of these, 5 (including all C. glabrata) had  micafungin MICs >2 ¦Ìg/ml but all demonstrated caspofungin MICs >2 ¦Ìg/ml. Five C. parapsilosis isolates had wild-type FKS sequences and caspofungin MICs 0.5-1 ¦Ìg/ml but 4/5 had micafungin MICs >2 ¦Ìg/ml. The remaining isolates retained echinocandin MICs ¡Ü2 ¦Ìg/ml and wild-type FKS gene sequences. Breakthrough IC on micafungin predominantly occurred in severely immunosuppressed patients with heavy prior micafungin exposure. The majority of cases were due to C. glabrata with an FKS mutation or wild-type C. parapsilosis with elevated micafungin MICs. MIC testing with caspofungin identified all mutant strains. Whether the naturally occurring polymorphism within the C. parapsilosis FKS1 gene responsible for the bimodal wild type MIC distribution is also responsible for micafungin MICs >2 ¦Ìg/ml and clinical breakthrough or an alternative mechanism contributes to the non-susceptible echinocandin MICs in C. parapsilosis requires further study.