Correlation of Susceptibility Test Results in vitro with Response in vivo: Ketoconazole Therapy in a Systemic Candidiasis Model

Abstract

In a previous study with flucytosine (5-FC) susceptibility of 40 Candidaalbicans isolates in vitro proved statistically correlated with response in systemic murine candidiasis in vivo, although exceptions occurred with individual isolates. For the present analogous study with ketoconazole, 58 C. albicans isolates were used of which 38 were from the 5-FC study and 20 were added to equalize the numbers of serotype A (n = 30) and B (n = 28) and to make the range of susceptibility in vitro to ketoconazole continuous and wide. The widest range of ketoconazole susceptibility was noted for the minimal inhibitory concentrations on Kimmig and Casitone agars (0.015–256 μg/ml) and disk zone diameters on YNB agar (0–54 mm), whereas with disk tests on other media, the range of 50% inhibitory concentrations, relative inhibition factors and MICs on serum agar remained narrow and/or showed strong ties. The Spearman’s rank correlation between the in vitro activities determined with the various parameters showed wide variation consistent with p values from < 0.001 to > 0.05. The serotype B isolates generally were more susceptible than the A isolates (p < 0.02 for the majority of parameters). Evaluation of response in vivo was hampered by the low activity of ketoconazole on the murine infection with any of the isolates, the range of the ED_50’s being only 10- > 100 mg/kg. The serotype B infections exhibited significantly better response (p < 0.05) than the serotype A infections. The overall correlation (Spearman’s rank) of the susceptibility test results in vitro with the response in vivo was poor (p < 0.05 for almost all parameters) suggesting very limited if any precise predictive values of the susceptibility tests in vitro with ketoconazole against C. albicans. However, the narrow range of the ED₅₀ suggests relatively little variation in the response of the different isolates in vivo and similarly small variation was also noted in some of the tests in vitro.