Correlation between in vitro and in vivo antifungal activities in experimental fluconazole-resistant oropharyngeal and esophageal candidiasis

Oropharyngeal and esophageal candidiasis (OPEC) is a frequent opportunistic mycosis in immunocompromised patients. Azole-resistant OPEC is a refractor y form of this infection occurring particularly in human immunodeficiency v irus (HIV)-infected patients. The procedures developed by the Antifungal Su bcommittee of the National Committee for Clinical Laboratory Standards (NCC LS) are an important advance in standardization of in vitro antifungal susc eptibility methodology. In order to further understand the relationship bet ween NCCLS methodology and antifungal therapeutic response, we studied the potential correlation between in vitro susceptibility to fluconazole and in vivo response in a rabbit model of fluconazole-resistant OPEC MICs of fluc onazole were determined by NCCLS methods. Three fluconazole-susceptible (FS ) (MIC, less than or equal to 0.125 mu g/ml) and three fluconazole-resistan t (FR) (MIC, greater than or equal to 64 mu g/ml) isolates of Candida albic ans from prospectively monitored HIV-infected children with OPEC were studi ed, FR isolates were recovered from children with severe OPEC refractory to fluconazole, and FS isolates were recovered from those with mucosal candid iasis responsive to fluconazole. Fluconazole at 2 mg/kg of body weight/day was administered to infected animals for 7 days. The concentrations of fluc onazole in plasma were maintained above the MICs for FS isolates throughout the dosing interval. Fluconazole concentrations in the esophagus were grea ter than or equal to those in plasma. Rabbits infected with FS isolates and treated with fluconazole had significant reductions in oral mucosal quanti tative cultures (P < 0.001) and tissue burden of C, albicans in tongue, sof t palate, and esophagus (P < 0.001). In comparison, rabbits infected with F R isolates were unresponsive to fluconazole and had no reduction in oral mu cosal quantitative cultures or tissue burden of C. albicans versus untreate d controls. We conclude that there is a strong correlation between in vitro fluconazole susceptibility by NCCLS methods and in vivo response to flucon azole therapy of OPEC due to C. albicans.