Studies of the paradoxical effect of caspofungin at high drug concentrations.

Turbid growth of some Candida albicans isolates occurs, paradoxically, in some high concentrations of caspofungin, above the minimum inhibitory concentration. We show that the resistant phenotype is first detectable after 24 h of drug exposure. Although other studies have suggested an association between some azole resistance mechanisms and caspofungin resistance, our studies with isolates susceptible and resistant to azoles (the latter including groups with defined resistance mechanisms and derived mutants) suggest a weak association at most with a paradoxical effect. The paradoxical growth is not related to mutations in resistance-associated regions of the (1,3)-beta-glucan synthase complex and is not related to an up-regulation of (1,3)-beta-glucan synthase activity in the presence of drug. Subculture of a minority of tubes above the minimum fungicidal concentration yielded a few viable cells, suggesting random distribution, in some strains, of a few cells with propensity to grow in the presence of drug. We postulate high drug concentrations derepress or activate an as-yet undefined resistance mechanism(s).