In Vitro Activities of Statins (Anti-Cholesterol Drugs) Alone and in Combination with Antifungal Drugs against Aspergillus Species.

S. KRISHNAN, P. H. CHANDRASEKAR, G. J. ALANGADEN, E. K. MANAVATHU;

Author address: 

Wayne State Univ., Detroit, MI.

Abstract: 

Background: Statins inhibit β -hydroxy-β -methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the synthesis of mevalonate from HMG-CoA. Since the HMG-CoA reductase catalyzed reaction is a key rate limiting step in the synthesis of sterols in fungi, we investigated the in vitro growth inhibitory activities of pravastatin (PVT), rosuvastatin (RVT), atorvastatin (AVT), fluvastatin (FVT) and simvastatin (SVT) against Aspergillus spp. alone and in combination with antifungal drugs. Methods: Conidial suspensions were prepared from 6-day old fungal cultures grown on Sabouraud dextrose agar, standardized (1 x 106/ml) by hemocytometer count and the MICs, MFCs and fungicidal activities of various compounds alone and in combination with other antifungal drugs were determined. The MICs and the MFCs were determined by the CLS M-38A protocol and the fungicidal activity was determined by time-kill study. Results: Only FVT showed good activity (MIC = 1 μg/ml) against Aspergillus spp. whereas the other statins had comparatively weak activity (MICs ≥ 32 μg/ml). The MFC for FVT was 4 μg/ml. FVT in combination with caspofungin (CFG) showed enhanced activity against Aspergillus spp. but it showed no specific interaction with voriconazole (VCZ) or amphotericin B (AMB). MIC and sub-MIC concentrations of FVT in combination with CFG showed >99.9% killing of Aspergillus spores whereas neither drug alone had significant fungicidal activity at MIC and sub-MIC. On the other hand, FVT alone and in combination with VCZ or AMB resulted in ≥ 99.99% killing after 24 h exposure indicating that FVT had no specific interaction with VCZ or AMB. Conclusions: Statins being inhibitors of HMG-CoA reductase possess antifungal activity against Aspergillus spp. with the best activity displayed by FVT. Enhanced activity was noted for FVT in combination with CFG but not with VCZ or AMB. CFG and FVT targeting different pathways could be responsible for the enhanced activity with this combination.
2006

abstract No: 

M-304

Full conference title: 

46th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 46th