Breakthrough Invasive Candidiasis on Micafungin

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

San Francisco (EEUU)

Congreso; 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009

American Society for Microbiology

Background:  For Candida spp., a bimodal wild-type minimum inhibitory concentration (MIC) distribution for the echinocandins exists, but resistance resulting from echinocandin exposure is rare.  We characterized isolates from patients with invasive candidiasis (IC) breaking through micafungin therapy during the first 16 months of its use at Duke Hospital (DH).   Methods:  Breakthrough IC was defined as isolation of Candida spp. from sterile sites after >/=3 doses of micafungin.  Candida spp. isolates were retrieved from frozen storage, MICs were determined using CLSI M27-A3 document, and hot-spot regions of FKS1 and FKS2 genes were sequenced.   Results:  Between 2/06 and 7/08, 358 patients received micafungin at DH.  12 cases of breakthrough IC were identified; 11 were transplant recipients (6 solid organ, 5 hematopoietic stem cell).  Median duration of micafungin exposure prior to breakthrough was 26 days (range 5-165); all patients had received 100 mg daily.  17 breakthrough isolates were recovered, including C. parapsilosis (6), C. glabrata (6), C. tropicalis (2), C. albicans (1), C. dublienensis (1), and C. krusei (1).  FKS hot-spot mutations were found in 5 C. glabrata and 1 C. tropicalis; of these, 4 were micafungin non-susceptible (MIC >2 ìg/ml).  Five C. parapsilosis isolates demonstrated non-susceptible micafungin MICs yet had wild-type FKS sequence.  The remaining isolates retained echinocandin susceptibility (MIC </=2 ìg/ml) and wild-type FKS genes.   Conclusions:  Breakthrough IC on micafungin predominantly occurred in transplant recipients with heavy prior micafungin exposure. The majority of cases were due to C. glabrata with FKS mutations or wild-type C. parapsilosis with elevated micafungin MICs.  Micafungin exposure may predispose to resistance in C. glabrata.  Naturally occurring polymorphisms within the C. parapsilosis FKS1 gene responsible for the bimodal wild type MIC distribution appear clinically significant.