Influence of albumin on itraconazole and ketoconazole antifungal activity: results of a dynamic in vitro study

The relevance of intense protein binding to the antifungal activity of azole compounds is still a matter of debate. The influence of albumin on the antimicrobial activity of ketoconazole and itraconazole, which exhibit very strong plasma protein binding (99 and 99.8%), was evaluated in vitro. Candida albicans was exposed to continuously changing azole concentrations corresponding to drug levels in serum following an oral dose of 200 mg. Total as well as free drug levels in serum were simulated. The incubation medium was free of proteins or contained 4% human serum albumin. Itraconazole levels reflecting free drug concentrations in humans did not reduce the growth rate of C. albicans, as compared with controls (difference in the log CFU per milliliter at 12 h, 0.03 +/- 0.09), whereas total drug levels were as active in the presence of 4% albumin (mean difference, -0.61) as in its absence (-0.75). The same was true for ketoconazole, except that free drug levels were also active (-1.21 versus -1.39 for total drug levels). This result was due to the higher ketoconazole levels in humans. Thus, in terms of routine susceptibility testing, in vitro total drug levels can be considered relevant.