In vitro interaction of posaconazole with calcineurin inhibitors and sirolimus against zygomycetes.
OBJECTIVE
Zygomycosis is an uncommon but devastating disease with few therapeutic options. Calcineurin inhibitors and sirolimus (mTOR inhibitor), commonly used in transplant patients as immunosuppressives, have antifungal activity. They are known to demonstrate synergy with triazoles against certain fungi, though limited data exist about their activity against zygomycetes. Our aim was to study the in vitro interaction of posaconazole with calcineurin inhibitors and sirolimus against zygomycetes.


METHODS
Drug interactions were assessed with chequerboard dilution for posaconazole with calcineurin inhibitors and sirolimus according to the CLSI M38-A2 method for filamentous fungi. Twenty-eight clinical isolates were studied, including Rhizopus arrhizus, Rhizopus microsporus, Rhizomucor pusillus, Mucor sp., Cunninghamella bertholletiae, Myocladus corymbifera and Apophysomyces elegans. Combinations of posaconazole with tacrolimus, cyclosporin A or sirolimus were used. Experiments were performed in duplicate. Mean fractional inhibitory concentration indices were calculated.


RESULTS
Posaconazole with calcineurin inhibitors demonstrated consistent synergy against C. bertholletiae, M. corymbifera and A. elegans, whereas synergy or no interaction was primarily observed against R. arrhizus, R. microsporus, R. pusillus and Mucor. Antagonism was seen with the combination of posaconazole and sirolimus. Strain variability was noted among the same species.


CONCLUSIONS
The clinical significance of these findings is unclear, but further studies are warranted given the potential for concomitant use of these agents in transplant patients treated for zygomycosis.
Department of Medicine, Division of Infectious Diseases, Wayne State University, Detroit, MI, USA.
S
S
Narreddy
E
E
Manavathu
P H
PH
Chandrasekar
G J
GJ
Alangaden
S G
SG
Revankar
D000935:Antifungal Agents / Q000494:pharmacology*; D019703:Calcineurin / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D009090:Mucorales / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*
D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole; D016572:Cyclosporine; D019703:Calcineurin; D020123:Sirolimus; D016559:Tacrolimus