antifungal Effect of Voriconazole on Intracellular Candida glabrata, Candida krusei, and Candida parapsilosis in Human Monocytes.
Background: Infections caused by Candida species other than C. albicans, especially C. glabrata (Cgl), C. krusei (Ckr) and C. parapsilosis (Cpa), have become increasingly common. Decreased susceptibility of these organisms to azoles has made these infections more difficult to treat. Activity of voriconazole (Vor) against intracellular C. albicans has been demonstrated, but its activity against intracellular Cgl, Ckr and Cpa needs to be studied. Consequently, we investigated intracellular killing of fluconazole-resistant (FluR) Cgl, Ckr and Cpa by Vor. Methods: Four strains of each species with Flu and Vor MICs ranging from 16 to 64 µg/ml and 0.25 to 2 µg/ml, respectively, were tested. Yeast were grown for 18 h, opsonized, washed, and resuspended in RPMI 1640 containing 15% FBS (RPMI+). Monolayers of human monocyte-derived macrophages (MDM) isolated from the blood of healthy volunteers were infected with yeast (MDM:yeast ratio = 100:1). Following phagocytosis (1 h), monolayers were washed with RPMI+. RPMI+ and Vor (0.1 to 5xMIC) were then added. MDM were lysed at 0 h or incubated at 37°C and lysed at 24 and 48 h, and viable yeast in the lysates were enumerated. Results: 1] inhibition and killing were concentration-dependent for all three species; 2] at 24 h killing of Cgl occurred at all concentrations except 0.1xMIC, while at 48 h there was killing only at 5xMIC (P<0.05); 3] for Ckr there was killing at all Vor concentrations at 24 and 48 h; 4] for Cpa at 24 h there was inhibition at 0.5xMIC, and killing at ³ 1xMIC. At 48 h there was inhibition at 0.5 and 1xMIC and killing at ³ 2.5xMIC (P<0.05); 5] in untreated controls the number of viable intracellular Ckr decreased by 0.38 log10 units in 48 h, while the number of Cgl and Cpa increased by 0.55 and 2.45 log10 units, respectively. Conclusions: 1] Cgl and Cpa but not Ckr grew in untreated MDM; 2] Vor activity was concentration-dependent; 3] at ³ 0.5xMIC Vor was inhibitory or fungicidal for all 3 candida species in MDM.
Full conference title:
43rd Interscience Conference on Antimicrobial Agents