Impact of tolerance to fluconazole on treatment response in Candida albicans bloodstream infection.

Background: Treatment of Candida albicans bloodstream infection with fluconazole is associated with significant mortality despite in vitro susceptibility to the drug.

Objectives: We sought to determine whether tolerance to fluconazole is predictive of treatment failure.

Methods: We reviewed patients with monomicrobial C albicans bloodstream infection who received primary monotherapy with fluconazole.

Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia.

Tolerance to antifungal drug concentrations above the minimal inhibitory concentration (MIC) is rarely quantified, and current clinical recommendations suggest it should be ignored. Here, we quantify antifungal tolerance in Candida albicans isolates as the fraction of growth above the MIC, and find that it is distinct from susceptibility/resistance. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, and correlates inversely with intracellular drug accumulation.