MycologyFluvastatin potentiates the activity of caspofungin against Aspergillus fumigatus in vitro☆
Introduction
Invasive aspergillosis is a life-threatening infection in immunocompromised patients especially following hematopoietic stem cell transplantation. Despite the availability of novel antifungal agents, the mortality rate from invasive aspergillosis still remains high, and innovative therapeutic approaches are worthy of pursuit (Lin et al., 2001). Combination therapy is one approach that could be used to improve the efficacy of antimicrobial therapy for difficult-to-treat infections (Marr et al., 2004, Wheat, 2003, Johnson et al., 2004). Previous in vitro and in vivo studies have suggested good outcomes when echinocandins were used in combination with triazoles or polyene for therapy of invasive aspergillosis (Kirkpatrick et al., 2002, Petraitis et al., 2003, Aliff et al., 2003, Kontoyiannis et al., 2003).
The anticholesterol agents, statins are competitive inhibitors of 3-methylglutaryl-CoA-reductase (HMG-CoA-reductase), which is the rate-limiting enzyme in cholesterol synthesis and a precursor in the fungal ergosterol pathway (Bard and Downing, 1981, Ferreira et al., 2005, Abeles, 1990, Wilding et al., 2000, Vanden Bossche, 1990).
Although statins are primarily designed for the treatment of various forms of hyperlipidemia, they do possess antifungal, antiinflammatory, and apoptotic properties as well (Miida et al., 2004). Fluvastatin (FST) and other statins have been reported to exhibit synergistic antifungal interaction with azoles against Saccharomyces cerevisiae, Candida spp. (including azole-resistant species), and Cryptococcus neoformans (Chin et al., 1997). Therefore, we examined the in vitro efficacy of statins alone and in combination with either caspofungin (CFG), voriconazole (VCZ), or amphotericin B (AMB) against Aspergillus fumigatus.
Section snippets
Antifungal drugs
VCZ, AMB, and CFG were obtained from Pfizer Pharmaceuticals, New York, NY; Sigma Chemical, St. Louis, MO; and Merck, Rahway, NJ, respectively. VCZ and AMB were dissolved in dimethylsulfoxide to make a stock solution of 1 g/L, and then stored as 0.25-mL aliquots at −20 °C. CFG was dissolved in sterile double-distilled water to a concentration of 10 g/L and was stored as 0.25-mL aliquots at −70 °C. Frozen stocks of the antifungal agents were thawed at room temperature and used within 24 h. The
Results
Among the statins tested, FST had a MIC of 2 mg/L against A. fumigatus, whereas the other statins had no meaningful activity with MIC >256 mg/L. The MFC for FST was 4 mg/L. All strains were highly susceptible to VCZ and AMB with an MIC range of 0.15 to 0.25 and 0.25 to 2 mg/L, respectively (Espinel-Ingroff et al., 2005). The MIC value for CFG was high in the range of 32 to >256 mg/L. However, the MEC values for CFG were in the range of 0.015 to 0.25 mg/L, which was about 8- to 16-fold lower
Discussion
In our current study, enhanced fungicidal activity was observed with the combination of FST and CFG. The concentration of FST used in FICI and kill–curve studies was within the range (0.5–1 mg/L) of serum concentrations of FST reported for humans (Tse et al., 1992) Extrapolating from our results, it could be postulated that the enhanced fungicidal activity observed with the combination of FST and CFG may be secondary to the drugs targeting different sites on the fungal cell. It is also
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2020, Pharmacology and TherapeuticsCitation Excerpt :In fact, fluvastatin appears to be the most effective antifungal statin with the broadest and most potent fungal inhibitory activity. The synthetic statins are active against a wide variety of fungal species (n = 24) in relatively lower concentrations than other statins (1–8 μg/mL in many cases) (Natesan, Chandrasekar, Alangaden, & Manavathu, 2008; Nyilasi, Kocsubé, Pesti, et al., 2010). These concentrations are achievable when statins are used clinically (Cabral et al., 2010; Schmidt, Dzogbeta, & Boyer, 2009).
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2011, Diagnostic Microbiology and Infectious DiseaseCitation Excerpt :The synergisms between FVS with antifungal agents have been reported by other studies: Chin et al. (1997) reported synergism between FVS plus fluconazole or ITZ against Candida spp. and Cryptococcus neoformans. Natesan et al. (2008) observed that FVS increased the effect of caspofungin but did not show synergistic interactions with VRZ or AMB against A. fumigatus. The combinations AMB + FVS, ITZ + FVS, and VRZ + FVS have not been tested against Fusarium species yet.
Antifungal activity of statins
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