In vitro interactions between primycin and different statins in their effects against some clinically important fungi

Abstract

The in vitro antifungal activities of primycin (PN) and various statins against some opportunistic pathogenic fungi were investigated. PN completely inhibited the growth of Candida albicans (MIC 64 mg ml) and Candida glabrata (MIC 32 mg ml ). The fungi exhibited different degrees of sensitivity to the statins; fluvastatin (FLV) and simvastatin (SIM) exerted potent antifungal activities against a wide variety of clinically important fungal pathogens. Atorvastatin, rosuvastatin and lovastatin (LOV) had a slight effect against all fungal isolates tested, whereas pravastatin was completely ineffective. The in vitro interactions between PN and the different statins were investigated using a standard chequerboard titration method. When PN was combined with FLV, LOV or SIM, both synergistic and additive effects were observed. The extent of inhibition was higher when these compounds were applied together, and the concentrations of PN and the given statin needed to block fungal growth completely could be decreased by several dilution steps. Similar interactions were observed when the variability of the within-species sensitivities was investigated.

Case–control study of statin prevention of mould infections

“…Statin activity against Aspergillus fumigatus , Aspergillus flavus , Aspergillus terreus and Aspergillus niger has been shown for FLV, ATO, SIM and LOV 9–11,13 . In particular, SIM and LOV have demonstrated fungicidal activity, 9 with synergy described with FLV and caspofungin 11 .…”

“…In vitro studies have demonstrated statin activity against a variety of pathogenic moulds including Zygomycetes and Aspergillus spp 5–13 . Statins are believed to inhibit HMG‐CoA reductase, an important step in ergosterol synthesis.…”

“…Synergy studies with various statins and primycin, a broad‐spectrum antimicrobial agent, have been conducted with Rhizopus oryzae . Primycin was found to have an additive effect in combination with ATO and a synergistic effect with LOV 13 . Suramin, an antiparasitic and antitumour medication, has been reported to provide synergy as well as antagonism in combination with FLV against different species of Zygomycetes 12 …”

Is there a role for statins in fungal infections?

“…The synergistic effect of statins together with different standard antifungal drugs has also been evaluated [30][31][32][33][34][35][36][37][38][39], and the MIC is then generally lowered, sometimes by as much as with a factor of 10. Two articles report on potent synergistic effects of statins in combination with the atypical drugs primycin [40] and suramin [41] against various moulds. Notably, several of the in vitro studies reported no significant effect of statins against Candida albicans or Aspergillus spp.…”

Novel applications of statins for bone regeneration

“…Moreover, several statins, especially simvastatin and fluvastatin, were seen to act synergistically with various antifungals, showing strong fungicidal effects in vitro [67,68]. …”