View More View Less
  • 1 University of Szeged Department of Microbiology, Faculty of Science and Informatics Szeged Hungary
Restricted access

Cross Mark

The in vitro antifungal activity of different statins and the combinations of the two most effective ones (fluvastatin and rosuvastatin) with amphotericin B were investigated in this study on 6 fungal isolates representing 4 clinically important genera, namely Absidia, Rhizomucor, Rhizopus and Syncephalastrum . The antifungal effects of statins revealed substantial differences. The synthetic statins proved to be more effective than the fungal metabolites. All investigated strains proved to be sensitive to fluvastatin. Fluvastatin and rosuvastatin acted synergistically and additively with amphotericin B in inhibiting the fungal growth in clinically available concentration ranges. Results suggest that statins combined with amphotericin B have a therapeutic potential against fungal infections caused by Zygomycetes species.

  • Almyroudis, N. G., Sutton, D. A., Fothergill, A. W., Rinaldi, M. G., Kusne, S. (2007) In vitro susceptibilities of 217 clinical isolates of Zygomycetes to conventional and new antifungal agents. Antimicrob. Agents. Ch. 51 , 2587–2590.

    Kusne S. , 'In vitro susceptibilities of 217 clinical isolates of Zygomycetes to conventional and new antifungal agents ' (2007 ) 51 Antimicrob. Agents. Ch. : 2587 -2590.

    • Search Google Scholar
  • Bellosta, S., Paoletti, R., Corsini, A. (2004) Safety of statins: Focus on clinical pharmacokinetics and drug interactions. American Heart Association, Circulation 109 , III-50–III-57, DOI: 10.1161/01.CIR.0000131519.15067.1f

    Corsini A. , 'Safety of statins: Focus on clinical pharmacokinetics and drug interactions ' (2004 ) 109 American Heart Association, Circulation : III-50 -III-57.

    • Search Google Scholar
  • Buemi, M., Floccari, F., Nostro, L., Campo, S., Caccamo, C., Sturiale, A., Aloisi, C., Giacobbe, M. S., Frisina, N. (2007) Statins in the prevention of cardiovascular events in patients with renal failure. Cardiovasc. Haematol. Disord. Drug. Targets 7 , 7–13.

    Frisina N. , 'Statins in the prevention of cardiovascular events in patients with renal failure ' (2007 ) 7 Cardiovasc. Haematol. Disord. Drug. Targets : 7 -13.

    • Search Google Scholar
  • Chamilos, G., Lewis, R. E., Kontoyiannis, D. P. (2006) Lovastatin has significant activity against Zygomycetes and interacts synergistically with voriconazole. Antimicrob. Agents. Ch. 50 , 96–103.

    Kontoyiannis D. P. , 'Lovastatin has significant activity against Zygomycetes and interacts synergistically with voriconazole ' (2006 ) 50 Antimicrob. Agents. Ch. : 96 -103.

    • Search Google Scholar
  • Chayakulkeeree, M., Ghannoum, M. A., Perfect, J. R. (2006) Zygomycosis: the re-emerging fungal infection. Eur. J. Clin. Microbiol. Infect. Dis. 25 , 215–229.

    Perfect J. R. , 'Zygomycosis: the re-emerging fungal infection ' (2006 ) 25 Eur. J. Clin. Microbiol. Infect. Dis. : 215 -229.

    • Search Google Scholar
  • Cordle, A., Koenigsknecht-Talboo, J., Wilkinson, B., Limpert, A., Landreth, G. (2005) Mechanism of statin-mediated inhibition of small G-protein function. J. Biol. Chem. 280 , 34202–34209.

    Landreth G. , 'Mechanism of statin-mediated inhibition of small G-protein function ' (2005 ) 280 J. Biol. Chem. : 34202 -34209.

    • Search Google Scholar
  • Corsini, A., Bellosta, S., Baetta, R., Fumagallia, R., Paolettia, R., Berninib, F. (1999) New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacolo. Therapeut. 84 , 413–428.

    Berninib F. , 'New insights into the pharmacodynamic and pharmacokinetic properties of statins ' (1999 ) 84 Pharmacolo. Therapeut. : 413 -428.

    • Search Google Scholar
  • Corsini, A., Bellosta, A., Davidson, H. M. (2005) Pharmacokinetic interactions between statins and fibrates. Am. J. Cardiol. 96 , 44–49.

    Davidson H. M. , 'Pharmacokinetic interactions between statins and fibrates ' (2005 ) 96 Am. J. Cardiol. : 44 -49.

    • Search Google Scholar
  • Eliopoulos, G. M., Moellering, R. C. (1996) Antimicrobial combinations. In: Lorian, V. (ed.) Antibiotics in Laboratory Medicine . 4th edn. Williams and Wilkins, Baltimore, MD, pp. 330–396.

    Moellering R. C. , '', in Antibiotics in Laboratory Medicine , (1996 ) -.

  • Galgóczy, L., Papp, T., Lukács, Gy., Leiter, É., Pócsi, I., Vágvölgyi, Cs. (2007) Interactions between statins and Penicillium chrysogenum antifungal protein (PAF) to inhibit the germination of sporangiospores of different sensitive Zygomycetes . FEMS Microbiol. Lett. 270 , 109–115.

    Vágvölgyi Cs. , 'Interactions between statins and Penicillium chrysogenum antifungal protein (PAF) to inhibit the germination of sporangiospores of different sensitive Zygomycetes ' (2007 ) 270 FEMS Microbiol. Lett. : 109 -115.

    • Search Google Scholar
  • Galgóczy, L., Papp, T., Vágvölgyi, Cs. (2009) In vitro interaction between suramin and fluvastatin against clinically important Zygomycetes. Mycoses. 52 , 447–453.

    Vágvölgyi Cs. , 'In vitro interaction between suramin and fluvastatin against clinically important Zygomycetes ' (2009 ) 52 Mycoses. : 447 -453.

    • Search Google Scholar
  • Gallagher, C. G., Ashley, E. S. D., Drew, R. H., Perfect, J. R. (2003) Antifungal pharmacotherapy for invasive mould infections. Expt. Opin. Pharmacother. 4 , 147–164.

    Perfect J. R. , 'Antifungal pharmacotherapy for invasive mould infections ' (2003 ) 4 Expt. Opin. Pharmacother. : 147 -164.

    • Search Google Scholar
  • Ghittoni, R., Patrussi, L., Pirozzi, K., Pellegrini, M., Lazzerini, P. E., Capecchi, P. L., Pasini, F. L., Baldari, C. T. (2005) Simvastatin inhibits T cell activation by selectively impairing the function of Ras superfamily GTPases. The FASEB Journal 19 , 605–607.

    Baldari C. T. , 'Simvastatin inhibits T cell activation by selectively impairing the function of Ras superfamily GTPases ' (2005 ) 19 The FASEB Journal : 605 -607.

    • Search Google Scholar
  • Groll, A. H., Giri, N., Petraitis, V., Petraitiene, R., Candelario, M., Bacher, J. S., Piscitelli, S. C, Walsh, T. J. (2000) Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans . J. Infect. Dis. 182 , 274–282.

    Walsh T. J. , 'Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans ' (2000 ) 182 J. Infect. Dis. : 274 -282.

    • Search Google Scholar
  • Kajinami, K., Takekoshi, N., Saito, Y. (2003) Pitavastatin: Efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor. Cardiovasc. Drug. Rev. 21 , 199–215.

    Saito Y. , 'Pitavastatin: Efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor ' (2003 ) 21 Cardiovasc. Drug. Rev. : 199 -215.

    • Search Google Scholar
  • Larabi, M., Pages, N., Pons, F., Appel, M., Gulik, A., Schlatter, J., Bouvet, S., Barratt, G. (2004) Study of the toxicity of a new lipid complex formulation of amphotericin B. J. Antimicrob. Chemoth. 53 , 81–88.

    Barratt G. , 'Study of the toxicity of a new lipid complex formulation of amphotericin B ' (2004 ) 53 J. Antimicrob. Chemoth. : 81 -88.

    • Search Google Scholar
  • Liao, J. K. (2002) Isoprenoids as mediators of the biological effects of statins. J. Clin. Invest. 110 , 285–288.

    Liao J. K. , 'Isoprenoids as mediators of the biological effects of statins ' (2002 ) 110 J. Clin. Invest. : 285 -288.

    • Search Google Scholar
  • Liao, J. K., Laufs, U. (2005) Pleiotropic effects of statins. Annu. Rev. Pharmacol. Toxicol. 45 , 89–118.

    Laufs U. , 'Pleiotropic effects of statins ' (2005 ) 45 Annu. Rev. Pharmacol. Toxicol. : 89 -118.

    • Search Google Scholar
  • Lorenz, R. T., Parks, L. W. (1990) Effects of Lovastatin (Mevinolin) on sterol levels and on activity of azoles in Saccharomyces cerevisiae. Antimicrob. Agents Chemother. 34 , 1660–1665.

    Parks L. W. , 'Effects of Lovastatin (Mevinolin) on sterol levels and on activity of azoles in Saccharomyces cerevisiae ' (1990 ) 34 Antimicrob. Agents Chemother. : 1660 -1665.

    • Search Google Scholar
  • Lukács, Gy., Papp, T., Nyilasi, I., Nagy, E., Vágvölgyi, Cs. (2004) Differentiation of Rhizomucor species on the basis of their different sensitivities to lovastatin. J. Clin. Microbiol. 42 , 5400–5402.

    Vágvölgyi Cs. , 'Differentiation of Rhizomucor species on the basis of their different sensitivities to lovastatin ' (2004 ) 42 J. Clin. Microbiol. : 5400 -5402.

    • Search Google Scholar
  • Lukács, Gy., Papp, T., Somogyvári, F., Csernetics, Á., Nyilasi, I., Vágvölgyi, Cs. (2008) Cloning of the Rhizomucor miehei 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene and its heterologous expression in Mucor circinelloides . Anton. Leeuw. Int. J. G. 95 , 55–64.

    Vágvölgyi Cs. , 'Cloning of the Rhizomucor miehei 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene and its heterologous expression in Mucor circinelloides ' (2008 ) 95 Anton. Leeuw. Int. J. G. : 55 -64.

    • Search Google Scholar
  • Miida, T., Hirayama, S., Nakamura, Y. (2004) Cholesterol-independent effects of statins and new therapeutic strategies: ischemic stroke and dementia. J. Atheroscler. Thromb. 11 , 253–264.

    Nakamura Y. , 'Cholesterol-independent effects of statins and new therapeutic strategies: ischemic stroke and dementia ' (2004 ) 11 J. Atheroscler. Thromb. : 253 -264.

    • Search Google Scholar
  • Minassian, B., Huczko, E., Washo, T., Bonner, T., Fung-Tomc, J. (2003) In vitro activity of ravuconazole against Zygomycetes, Scedosporium and Fusarium isolates. Clin. Microbiol. Infect. 9 , 1250–1252.

    Fung-Tomc J. , 'In vitro activity of ravuconazole against Zygomycetes, Scedosporium and Fusarium isolates ' (2003 ) 9 Clin. Microbiol. Infect. : 1250 -1252.

    • Search Google Scholar
  • Moreno, A. B., del Pozo, A. M., Borja, M., San Segudo, B. (2003) Activity of the antifungal protein from Aspergillus giganteus against Botrytis cinerea . Phytopathology 93 , 1344–1353.

    San Segudo B. , 'Activity of the antifungal protein from Aspergillus giganteus against Botrytis cinerea ' (2003 ) 93 Phytopathology : 1344 -1353.

    • Search Google Scholar
  • National Committee for Clinical Laboratory Standards. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi. Approved standard. (2002) NCCLS document M38-A . NCLS, Wayne, Pennsylvania, USA.

    '', in NCCLS document M38-A , (2002 ) -.

  • Nucci, M. (2003) Emerging moulds: Fusarium , Scedosporium and Zygomycetes in transplant recipients. Curr. Opin. Infect. Dis. 16 , 607–612.

    Nucci M. , 'Emerging moulds: Fusarium, Scedosporium and Zygomycetes in transplant recipients ' (2003 ) 16 Curr. Opin. Infect. Dis. : 607 -612.

    • Search Google Scholar
  • Prabhu, R. M., Patel, R. (2004) Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment. Clin. Microbiol. Infect. 10(S1) , 31–47.

    Patel R. , 'Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment ' (2004 ) 10 Clin. Microbiol. Infect. : 31 -47.

    • Search Google Scholar
  • Ribes, J. A., Vanhover-Sams, C. L., Baker, D. J. (2000) Zygomycetes in human disease. Clin. Microbiol. Rev. 13 , 236–301.

    Baker D. J. , 'Zygomycetes in human disease ' (2000 ) 13 Clin. Microbiol. Rev. : 236 -301.

  • Rodriguez-Tudela, J. L., Arendrup, M. C., Arikan, S., Barchiesi, F., Bille, J., Chryssanthou, E., Cuenca-Estrella, M., Dannaoui, E., Denning, D. W., Donnelly, J. P., Fegeler, W., Lass-Flörl, C., Moore, C., Richardson, M., Gaustad, P., Schmalreck, A., Velegraki, A., Verweij, P. (2007) Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia forming moulds. EUCAST Discussion Document . European Committee on Antimicrobial Susceptibility Testing, Basel, Switzerland.

    Verweij P. , '', in EUCAST Discussion Document , (2007 ) -.

  • Rogers, T. R. (2008) Treatment of zygomycosis: current and new options. J. Antimicrob. Chemoth. 61(S1) , 35–39.

    Rogers T. R. , 'Treatment of zygomycosis: current and new options ' (2008 ) 61 J. Antimicrob. Chemoth. : 35 -39.

    • Search Google Scholar
  • Roze, L. V., Linz. J. E. (1998) Lovastatin triggers an apoptosis-like cell death process in the fungus Mucor racemosus . Fungal. Genet. Biol. 25 , 119–133.

    Linz J. E. , 'Lovastatin triggers an apoptosis-like cell death process in the fungus Mucor racemosus ' (1998 ) 25 Fungal. Genet. Biol. : 119 -133.

    • Search Google Scholar
  • Sabatelli, F., Patel, R., Mann, P. A., Mendrick, C. A., Norris, C. C., Hare, R., Loebenberg, D., Black, T. A., McNicholas, P. M. (2006) In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob. Agents Ch. 50 , 2009–2015.

    McNicholas P. M. , 'In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts ' (2006 ) 50 Antimicrob. Agents Ch. : 2009 -2015.

    • Search Google Scholar
  • Schachter, M. (2004) Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fund. Clin. Pharmacol. 19 , 117–125.

    Schachter M. , 'Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update ' (2004 ) 19 Fund. Clin. Pharmacol. : 117 -125.

    • Search Google Scholar
  • Sun, H.-Y., Singh, N. (2009) Antimicrobial and immunomodulatory attributes of statins: Relevance in solid-organ transplant recipients. Clin. Infect. Dis. 48 , 745–755.

    Singh N. , 'Antimicrobial and immunomodulatory attributes of statins: Relevance in solid-organ transplant recipients ' (2009 ) 48 Clin. Infect. Dis. : 745 -755.

    • Search Google Scholar
  • Takó, M., Csernetics, Á. (2005) Genotypic analysis of variability in zygomycetes. Acta Biol. Hung. 56 , 345–357.

    Csernetics , 'Genotypic analysis of variability in zygomycetes ' (2005 ) 56 Acta Biol. Hung. : 345 -357.

    • Search Google Scholar
  • Vazquez, J. A. (2007) Combination antifungal therapy: the new frontier. Future Microbiol. 2 , 115–139.

    Vazquez J. A. , 'Combination antifungal therapy: the new frontier ' (2007 ) 2 Future Microbiol. : 115 -139.

    • Search Google Scholar
  • Vicente, M. F., Basilio, A., Cabello, A., Pelaez, F. (2003) Microbial natural products as a source of antifungals. Clin. Microbiol. Infect. 9 , 15–32.

    Pelaez F. , 'Microbial natural products as a source of antifungals ' (2003 ) 9 Clin. Microbiol. Infect. : 15 -32.

    • Search Google Scholar
  • Walsh, T. J., Groll, A., Hiemenz, J., Fleming, R., Roilides, E., Anaissie, E. (2004) Infections due to emerging and uncommon medically important fungal pathogens. Clin. Microbiol. Infect. 10(S1) , 48–66.

    Anaissie E. , 'Infections due to emerging and uncommon medically important fungal pathogens ' (2004 ) 10 Clin. Microbiol. Infect. : 48 -66.

    • Search Google Scholar