Relationship between in Vitro Resistance, MTL Homozygosity and ERG11 Point Mutations in C. albicans Clinical Isolates in Lebanon. (c2007)

Abstract

The incidence of antifungal resistance is on the increase worldwide and novel drugs are constantly being developed to counter this trend. 125 clinical isolates consisting mainly of Candida albicans (116 samples) were collected from five Lebanese hospitals. The purpose of this study is to first: determine the degree of resistance of Lebanese isolates to four common azoles: Fluconazole (FL), Itraconazole (I'I), Ketoconazole (KE), and Voriconazole (VO), in addition to Amphotericin B (AP) and the newly released echinocandin, Caspofungin (CS) through the E-test method. Second determine any relationship between the allelic compositions of the mating type loci (MTLa, MTL a or MTLa/ a heterozygote) with drug resistance in C. albicans, and third, screen by RFLP for the presence of two common C. albicans ERG 11 point mutations and correlate with drug resistance. Results showed that resistance among C. albicans isolates was highest for IT: 12%, followed by VO: 7.7%, then KE: 6%, FL: 5%, and 0% for CS. Furthermore 11 isolates were heterozygous at the MTL locus (9.5%), 5 of which (45%) were resistant to at least one antifungal drug while only 14 of the 105 heterozygous strains (13%) exhibited similar resistance, indicating a possible relationship between MTL locus homozygosity and resistance. Moreover no relationship between the Dl16E mutation and drug resistance was found, and no homozygous E266D mutants exist In addition, the study revealed the existence of a novel mutation, G407R that occurred frequently and alongside the E266D mutation (70% of isolates assayed were homozygous for G407R and heterozygous for E266D). This mutation was found to be correlated with drug resistance since all the isolates that were resistant to at least one antifungal drug possessed the G407R mutation. Finally this mutation was found to dominate in sputum (41%) and stool isolates (15%). In conclusion resistance to common azoles in Lebanon is low and azole treatment should not be discontinued in favor of newer drugs such as Caspofungin, which should be used as a last resort.