Are Statins Applicable for the Prevention and Treatment of Zygomycosis?

Abstract

To the Editor—A recent article by Sun and Singh [1] summarized the antimicrobial and immunomodulatory attributes of statins. Among other things, they detailed the antifungal effects of statins on Zygomycetes, suggesting their possible application for protection against zygomycosis. Here, we should like to point out some aspects pertaining to this application that have previously been only partially discussed: the minimum inhibitory concentration (MIC) values of statins, their attainable serum concentrations, and their possible combinations with other antifungal agents. Published data on statins' antifungal activities against Zygomycetes are available only for lovastatin, simvastatin, rosuvastatin, and atorvastatin [2–4]. These statins displayed significant in vitro effects, completely blocking the growth of Zygomycetes at concentrations of 8–64 µg/mL, depending on the test method applied, the organisms involved, and the drugs studied [2–4]. Our investigations on the antifungal action of fluvastatin recently furnished similar results: MICs were found in the range of 3.125–100 µg/mL, depending on the sensitivity of the species investigat ed [5]. Atorvastatin seems less effective against Zygomycetes; it blocks sporangiospore germination at concentrations of 50–100 µg/mL (L.G., T.P., and Cs.V., unpublished data). The MICs of statins are much higher than the concentrations attainable in the human serum; the differences are about 1 order of magnitude (table 1) [6–11]. In consequence, the combined application of statins and antifungal agents may be of practical importance. In particular, drugs that can act synergistically with statins, allowing substantial decreases in their therapeutic concentration, should be investigated. Indeed, lovastatin and voriconazole have proved to be synergistically effective against Zygomycetes in a range of clinically achievable concentrations of both drugs [3]. Our in vitro studies have revealed that amphotericin B acts synergistically with atorvastatin and fluvastatin at concentrations that can be achieved in the plasma. Their MIC 50 values (with regard to the minimum statin concentration in the studied combinations) were 390 ng/mL amphotericin B with 6 ng/mL atorvastatin and 48 ng/mL amphotericin B with 6 ng/mL fluvastatin (L.G., I.Ny., T.P., and Cs.V., unpublished data). Another study has revealed a synergistic interaction between fluvastatin and a non-antifungal agent, suramin, on the growth of different Zygomycetes [5]. Theoretically, some of the examined statin concentrations can be reached in the human plasma via administration of high oral doses (eg, a daily dosage of 40–80 mg). Pharmacokinetic Properties of Statins The administration of statins together with antifungals that are predominantly metabolized by the same cytochrome P450 (CYP450) isoenzymes in the liver is contraindicated, because such drug interactions with the CYP system may cause serious adverse effects (eg, myopathy). Thus, even if combinations of lovastatin and voriconazole may well be effective against Zygomycetes in clinically available concentrations, their possible application would involve considerable risks, because both compounds are metabolized by CYP3A4. Table 1presents examples of statins and antifungal drugs that are metabolized by different CYPs and, in principle, might be coadministered more safely. The future testing of such combinations may hopefully lead to the establishment of new, safer therapy against zygomycosis. Financial support. This research was supported in part by South Transdanubian Regional Knowledge Centre (grants RET-08/2005 and OMFB-00846/2005). Potential conflicts of interest. I.Ny. is an employee of PannonPharma. Cs.V. has received research funding from PannonPharma. I.Ny., T.P., and Cs.V. are coinventors in a patent application of PannonPharma in connection with antifungal application of statins. L.G.: no conflicts.