S. Maesaki et al., Synergic effects of tacrolimus and azole antifungal agents against azole-resistant Candida albicans strains, J ANTIMICRO, 42(6), 1998, pp. 747-753
We investigated the effects of combining tacrolimus and azole antifungal ag
ents in azole-resistant strains of Candida albicans by comparing the accumu
lation of [H-3]itraconazole. The CDR1-expressing resistant strain C26 accum
ulated less itraconazole than the CaMDR-expressing resistant strain C40 or
the azole-sensitive strain B2630. A CDR1-expressing Saccharomyces cerevisia
e mutant, DSY415, showed si marked reduction in the accumulation of both fl
uconazole and itraconazole. A CaMDR-expressing S. cerevisiae mutant, DSY416
, also showed lower accumulation of fluconazole, but not of itracconazole.
The addition of sodium azide, an electron-transport chain inhibitor, increa
sed the intracellular accumulation of itraconazole only in the C26 strain,
and not in the C40 or B2630 strains. Addition of tacrolimus, an inhibitor o
f multidrug resistance proteins, resulted ire the highest increase in itrac
onazole accumulation in the C26 strain. The combination of itraconazole and
tacrolimus was synergic in azole-resistant C. albicans strains. In the C26
strain, the MIC of itraconazole decreased from >8 to 0.5 mg/L when combine
d with tacrolimus. Our results showed that two multidrug resistance phenoty
pes (encoded by the CDR1 and CaMDR genes) in C. albicans have different sub
strate specificity for azole antifungal agents and that a combination of ta
crolimus and azole antifungal agents is effective against azole-resistant s
trains of C. albicans.