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Journal of Clinical Microbiology, June 2000, p. 2369-2373, Vol. 38, No. 6
0095-1137/00/$04.00+0

Correlation between In Vitro and In Vivo Antifungal Activities in Experimental Fluconazole-Resistant Oropharyngeal and Esophageal Candidiasis

Thomas J. Walsh,1,* Corina E. Gonzalez,1 Steven Piscitelli,2 John D. Bacher,3 Joanne Peter,1 Richard Torres,1 Daiva Shetti,1 Victoria Katsov,1 Kristina Kligys,1 and Caron A. Lyman1

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute,1 Pharmacy Department, National Institutes of Health Warren Grant Magnuson Clinical Center,2 and Veterinary Resources Program, Nation Center for Research Resources, National Institutes of Health,3 Bethesda, Maryland 20892

Received 18 November 1999/Returned for modification 23 December 1999/Accepted 1 February 2000

Oropharyngeal and esophageal candidiasis (OPEC) is a frequent opportunistic mycosis in immunocompromised patients. Azole-resistant OPEC is a refractory form of this infection occurring particularly in human immunodeficiency virus (HIV)-infected patients. The procedures developed by the Antifungal Subcommittee of the National Committee for Clinical Laboratory Standards (NCCLS) are an important advance in standardization of in vitro antifungal susceptibility methodology. In order to further understand the relationship between 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 fluconazole were determined by NCCLS methods. Three fluconazole-susceptible (FS) (MIC, <= 0.125 µg/ml) and three fluconazole-resistant (FR) (MIC, >= 64 µg/ml) isolates of Candida albicans from prospectively monitored HIV-infected children with OPEC were studied. FR isolates were recovered from children with severe OPEC refractory to fluconazole, and FS isolates were recovered from those with mucosal candidiasis responsive to fluconazole. Fluconazole at 2 mg/kg of body weight/day was administered to infected animals for 7 days. The concentrations of fluconazole in plasma were maintained above the MICs for FS isolates throughout the dosing interval. Fluconazole concentrations in the esophagus were greater than or equal to those in plasma. Rabbits infected with FS isolates and treated with fluconazole had significant reductions in oral mucosal quantitative cultures (P < 0.001) and tissue burden of C. albicans in tongue, soft palate, and esophagus (P < 0.001). In comparison, rabbits infected with FR isolates were unresponsive to fluconazole and had no reduction in oral mucosal quantitative cultures or tissue burden of C. albicans versus untreated controls. We conclude that there is a strong correlation between in vitro fluconazole susceptibility by NCCLS methods and in vivo response to fluconazole therapy of OPEC due to C. albicans.

* Corresponding author. Mailing address: Bldg. 10, Rm. 13N-240, Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892. Phone: (301) 496-7103. Fax: (301) 402-0575. E-mail: walsht{at}mail.nih.gov.

Journal of Clinical Microbiology, June 2000, p. 2369-2373, Vol. 38, No. 6
0095-1137/00/$04.00+0


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