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Effects of Antifungal Agents Alone and in Combination Against Candida glabrata Strains Susceptible or Resistant to Fluconazole

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Abstract

The rise of Candida spp. resistant to classic triazole antifungal agents has led to a search for new therapeutic options. Here, we evaluated combinations of antifungals in a checkerboard assay against two groups of Candida glabrata strains: one containing fluconazole-susceptible clinical isolates (FS) and another containing fluconazole-resistant laboratory derivative (FR). The most synergistic combination observed was amphotericin B + flucytosine (synergistic for 61.77 % of FS strains and 76.47 % of FR strains). The most antagonistic combination observed was ketoconazole + flucytosine (FS 61.77 % and FR 55.88 %). Surprisingly, most combinations evidenced indifferent interactions, and the best synergism appeared when amphotericin B and flucytosine were combined against both groups of isolates.

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References

  1. Arai R, Sugita T, Nishikawa A. Reassessment of the in vitro synergistic effect of fluconazole with the non-steroidal anti-inflammatory agent ibuprofen against Candida albicans. Mycoses. 2005;2005(48):38–41.

    Article  Google Scholar 

  2. Baltch AL, Bopp LH, Smith RP, Ritz WJ, Michelsen PB. AntiCandidal effects of voriconazole and caspofungin, singly and in combination, against Candida glabrata, extracellularly and intracellularly in granulocyte-macrophage colony stimulating factor (GM-CSF)-activated human monocytes. J Antimicrob Chemother. 2008;62:1285–90.

    Article  PubMed  CAS  Google Scholar 

  3. Barchiesi F, Gallo D, Caselli F, Di Francesco LF, Arzeni D, Giacometti A, Scalise G. In vitro interactions of itraconazole with flucytosine against clinical isolates of Cryptococcus neoformans. J Antimicrob Chemother. 1999;44:65–70.

    Article  PubMed  CAS  Google Scholar 

  4. Barchiesi F, Spreghini E, Maracci M, Fothergill AW, Badassarri I, Rinaldi MG, Scalise G. In vitro activities of voriconazole in combination with three other antifungal agents against Candida glabrata. Antimicrob Agents Chemother. 2004;48:3317–22.

    Article  PubMed  CAS  Google Scholar 

  5. Barchiesi F, Spreghini E, Fothergill AW, Arzeni D, Graganti G, Giannini D, Rinaldi MG, Scalise G. Caspofungin in combination with amphotericin B against Candida glabrata. Antimicrob Agents Chemother. 2005;49:2546–9.

    Article  PubMed  CAS  Google Scholar 

  6. Bennett JE, Izumikawa K, Marr KA. Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis. Antimicrob Agents Chemother. 2004;48:1773–7.

    Article  PubMed  CAS  Google Scholar 

  7. Block E, Bennett JE. The combined effect of 5-fluorocytosine and amphotericin B in the therapy of murine cryptococcosis. Proc Soc Exp Biol Med. 1973;142:476–80.

    PubMed  CAS  Google Scholar 

  8. Cantón E, Pemán J, Gobernado M, Viudes A, Ana Espinel-Ingroff A. Synergistic Activities of Fluconazole and Voriconazole with Terbinafine against Four Candida Species Determined by Checkerboard, Time-Kill, and Etest Methods. Antimicrob Agents Chemother. 2005;49:1593–6.

    Article  PubMed  Google Scholar 

  9. Clinical and Laboratory Standards Institute (CLSI). Reference method for broth dilution antifungal susceptibility testing yeasts 3rd ed. Approved standard M27-A3. 2008;Wayne, PA.

  10. Colombo AL, Nucci M, Park BJ, Nouer AS, Arthington-Skaggs B, Matta DA, Warnock D, Morgan J. The Brazilian Network Candidemia Study. Epidemiology of candidemia in Brazil: a nationwide sentinel surveillance of candidemia in eleven medical centers. J Clin Microbiol. 2006;44:2816–23.

    Article  PubMed  CAS  Google Scholar 

  11. Dumainn V, Eyrolle L, Baixench MT, Paugam A, Larousserie F, Padoin C, Tod M, Salmon D. Successful treatment of prosthetic knee Candida glabrata infection with caspofungin combined with flucytosine. Int J Antimicrob Chemother. 2008;31:398–9.

    Article  Google Scholar 

  12. Denning DW, Baily GG, Hood SV. Azole resistance in Candida. Eur J Clin Microbiol Infect Dis. 1997;16:261–80.

    Article  PubMed  CAS  Google Scholar 

  13. Fekete-Forgács K, Gyurc L, Lenkey B. Changes of virulence factors accompanying the phenomenon of induced fluconazole resistance in Candida albicans. Mycoses. 1999;43:273–9.

    Article  Google Scholar 

  14. Garcia-Effron G, Mellado E, Gomez-Lopez A, Alcazar-Fuolli L, Cuenca-Estrella M, Rodriguez-Tudela JL. Differences in interactions between azole drugs related to modifications in the 14-sterol demethylase gene (cyp51a) of Aspergillus fumigatus. Antimicrob Agents Chemother. 2005;49:2119–21.

    Article  PubMed  CAS  Google Scholar 

  15. Ghannoum MA, Isham N. Abstr. 29th Annu. Meet. Eur. Group Blood and Marrow Transplant. 2003; Abstr. 671.

  16. Hossain MA, Reyes GH, Long LA, Mukherjee PK, Ghannoum MA. Efficacy of caspofungin combined with amphotericin B against azole-resistant Candida albicans. J Antimicrob Chemother. 2003;51:1427–9.

    Article  PubMed  CAS  Google Scholar 

  17. Johnson MD, Macdougall C, Ostrosky L, Perfect JR, Rex JH. Combination antifungal therapy. Antimicrob Agents Chemother. 2004;48:693–715.

    Article  PubMed  CAS  Google Scholar 

  18. Lewis RE, Diekema DJ, Messes SA, Pfaller MA, Klepser ME. Comparison of Etest, chequerboard dilution and time-kill studies for the detection of synergy or antagonism between antifungal agents tested against Candida species. J Antimicrob Chemother. 2002;49:345–51.

    Article  PubMed  CAS  Google Scholar 

  19. Odds FC. Interactions among amphotericin b, 5-fluorocytosine, ketoconazole, and miconazole against pathogenic fungi in vitro. Antimicrob Agents Chemother. 1982;22:763–70.

    Article  PubMed  CAS  Google Scholar 

  20. Oz Y, Akşit F, Kiraz N, Kiremitçi A. In vitro activity of amphotericin B with fluconazole or voriconazole combinations against Candida albicans isolates. Mikrobiyol Bul. 2008;42:149–55.

    PubMed  CAS  Google Scholar 

  21. Pina-Vaz C, Sansonetty F, Rodrigues AG, Martinez-De-Oliveira J, Fonseca AF, Mårdh PA. Antifungal activity of ibuprofen alone and in combination with fluconazole against Candida species. J Med Microbiol. 2000;49:831–40.

    PubMed  CAS  Google Scholar 

  22. Pfaller MA, Messer SA, Boyken L, Hollis RJ, Rice C, Tendolkar S, Diekema DJ. In vitro activities of voriconazole, posaconazole, and fluconazole against 4,169 clinical isolates of Candida spp. and Cryptococcus neoformans collected during 2001 and 2002 in the ARTEMIS global antifungal surveillance program. Diagn Microbiol Infect Dis. 2004;48:201–5.

    Article  PubMed  CAS  Google Scholar 

  23. Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev. 2007;20:133–63.

    Article  PubMed  CAS  Google Scholar 

  24. Polak A. Combination therapy of experimental candidiasis, cryptococcosis, aspergillosis and wangiellosis in mice. Chemotherapy. 1987;33:381–95.

    Article  PubMed  CAS  Google Scholar 

  25. Sanguinetti M, Posteraro B, Fiori B, Ranno S, Torelli S, Fadda G. Mechanisms of azole resistance in clinical isolates of Candida glabrata collected during a hospital survey of antifungal resistance. Antimicrob Agents Chemother. 2005;49:668–79.

    Article  PubMed  CAS  Google Scholar 

  26. Scheid LA, Mario DAN, Kubiça TF, Santurio JM, Alves SH. In vitro activities of antifungal agents alone and in combination against fluconazole-susceptible and -resistant strains of Candida dubliniensis. Braz J Infect Dis. 2012;16(78):81.

    Google Scholar 

  27. Siau H, Kerridge D. The effect of antifungal drugs in combination on the growth of Candida glabrata in solid and liquid media. J Antimicrob Chemother. 1998;41:357–66.

    Article  PubMed  CAS  Google Scholar 

  28. Silva EG, Paula CR, Dias AL, Chan MR, Ruiz LD, Gambale V, Prates R, Ribeiro MS. Combination efficacy of voriconazole and amphotericin b in the experimental disease in immunodeficient mice caused by fluconazole-resistant Cryptococcus neoformans. Mycopathologia. 2010;24:31–6.

    Google Scholar 

  29. Tobudic S, Kratzer C, Lassnigg A, Graninger W, Prestrl E. In vitro activity of antifungal combinations against Candida albicans biofilms. J Antimicrob Chemother. 2010;65:271–4.

    Article  PubMed  CAS  Google Scholar 

  30. White DJ, Habib AR, Vanthuyne A, Langford S, Symonds M. Combined topical flucytosine and amphotericin B for refractory vaginal Candida glabrata infections. Sex Transm Inf. 2001;77:212–3.

    Article  CAS  Google Scholar 

  31. Vazquez JA. Combination antifungal therapy against Candida species: the new frontier—are we there yet? Med Mycol. 2003;41:355–68.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Débora Alves Nunes Mario.

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Alves, I.A., Bandeira, L.A., Mario, D.A.N. et al. Effects of Antifungal Agents Alone and in Combination Against Candida glabrata Strains Susceptible or Resistant to Fluconazole. Mycopathologia 174, 215–221 (2012). https://doi.org/10.1007/s11046-012-9538-7

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  • DOI: https://doi.org/10.1007/s11046-012-9538-7

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