Current Infectious Disease Reports

, Volume 9, Issue 6, pp 448–456

Combination antifungal therapy for the treatment of invasive yeast and mold infections



Combination antifungal therapy has been an area of great research and clinical interest since antifungals became available decades ago, in part driven by the severe morbidity and mortality associated with invasive fungal infections. Because of the availability of newer antifungal agents including echinocandins and expanded-spectrum triazoles, interest in combination antifungal therapy for invasive mold disease, especially invasive aspergillosis, has grown. This review examines combination antifungal therapy for the treatment of yeast and molds, including current studies evaluating combination antifungal therapy in three clinically important invasive fungal infections: candidiasis, cryptococcosis, and aspergillosis. This article focuses on recent clinical data and potential future clinical directions.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Codish SD, Tobias JS, Hannigan M: Combined amphotericin B-flucytosine therapy in aspergillus pneumonia. JAMA 1979, 241:2418–2419.PubMedCrossRefGoogle Scholar
  2. 2.
    Bennett JE, Dismukes WE, Duma RJ, et al.: A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 1979, 301:126–131.PubMedCrossRefGoogle Scholar
  3. 3.
    Dismukes WE, Cloud G, Gallis HA, et al.: Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N Engl J Med 1987, 317:334–341.PubMedCrossRefGoogle Scholar
  4. 4.
    van der Horst C, Saag MS, Cloud GA, et al.: Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med 1997, 337:15–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Lewis RE, Klepser ME, Pfaller MA: Combination systemic antifungal therapy for cryptococcosis, candidiasis, and aspergillosis. J Infect Dis Pharmacother 1999, 3:61–84.CrossRefGoogle Scholar
  6. 6.
    Johnson MD, MacDougall C, Ostrosky-Zeichner L, et al.: Combination antifungal therapy. Antimicrob Agents Chemother 2004, 48:693–715.PubMedCrossRefGoogle Scholar
  7. 7.
    Baddley JW, Pappas PG: Combination antifungal therapy: clinical potential. Drugs 2005, 65:1461–1480.PubMedCrossRefGoogle Scholar
  8. 8.
    Lewis RE, Kontoyiannis DP: Rationale for combination antifungal therapy. Pharmacotherapy 2001, 21(8 pt 2):149S–164S.PubMedCrossRefGoogle Scholar
  9. 9.
    Fridkin SK: The changing face of fungal infections in health care settings. Clin Infect Dis 2005, 41:1455–1460.PubMedCrossRefGoogle Scholar
  10. 10.
    Lewis RE, Diekema DJ, Messer SA, et al.: Comparison of Etest, checquerboard dilution and time-kill studies for the detection of synergy or antagonism between antifungal agents tested against Candida species. J Antimicrob Chemother 2002, 49:345–351.PubMedCrossRefGoogle Scholar
  11. 11.
    Ghannoum MA, Fu AY, Ibrahim AS, et al.: In vitro determination of optimal antifungal combinations against Cryptococcus neoformans and Candida albicans. Antimicrob Agents Chemother 1995, 39:2459–2465.PubMedGoogle Scholar
  12. 12.
    Keele DJ, DeLallo VC, Lewis RE, et al.: Evaluation of amphotericin B and flucytosine in combination against Candida albicans and Cryptococcus neoformans using time-kill methodology. Diagn Microbiol Infect Dis 2001, 14:121–126.CrossRefGoogle Scholar
  13. 13.
    Polak A: Synergism of polyene antibiotics with 5-fluorocytosine. Chemotherapy 1978, 24:2–16.PubMedGoogle Scholar
  14. 14.
    Odds FC: Interactions among amphotericin B, 5-flurocytosine, ketoconazole, and miconazole against pathogenic fungi in vitro. Antimicrob Agents Chemother 1982, 22:763–770.PubMedGoogle Scholar
  15. 15.
    Brajtburg J, Kobayashi D, Medoff G, et al.: Antifungal action of amphotericin B in combination with other polyene or imidazole antibiotics. J Infect Dis 1982, 146:138–146.PubMedGoogle Scholar
  16. 16.
    Roling E, Klepser ME, Wasson A, et al.: Antifungal activities of fluconazole and caspofungin (MK0991), and anidulafungin (LY303366) alone and in combination against Candida spp. and Cryptococcus neoformans. Diagn Microbiol Infect Dis 2002, 43:13–17.PubMedCrossRefGoogle Scholar
  17. 17.
    Thaler M, Bacher J, O’Leary T, et al.: Evaluation of single-drug and combination antifungal therapy in an experimental model of candidiasis in rabbits with prolonged neutropenia. J Infect Dis 1988, 158:80–88.PubMedGoogle Scholar
  18. 18.
    Sugar AM, Hitchcock CA, Troke PF, et al.: Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B. Antimicrob Agents Chemother 1995, 39:598–601.PubMedGoogle Scholar
  19. 19.
    Marine M, Serena C, Pastor FJ, et al.: Combined antifungal therapy in a murine infection by Candida. J Antimicrob Chemother 2006, 58:1295–1298.PubMedCrossRefGoogle Scholar
  20. 20.
    Pappas PG, Rex JH, Sobel JD, et al.: Guidelines for treatment of candidiasis. Clin Infect Dis 2004, 38:161–189.PubMedCrossRefGoogle Scholar
  21. 21.
    Abele-Horn M, Kopp A, Sternberg U, et al.: A randomized study comparing fluconazole with amphotericin B/5-flucytosine for the treatment of systemic Candida infections in intensive care patients. Infection 1996, 24:426–432.PubMedCrossRefGoogle Scholar
  22. 22.
    Rex JH, Pappas PG, Karchmer AW, et al.: A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 2003, 36:1221–1228.PubMedCrossRefGoogle Scholar
  23. 23.
    Ostrosky-Zeichner L, Kontoyiannis D, Raffalli J, et al.: International, open-label, noncomparative, clinical trial of micafungin alone and in combination for treatment of newly diagnosed and refractory candidemia. Eur J Clin Microbiol Infect Dis 2005, 24:662–664.CrossRefGoogle Scholar
  24. 24.
    Matthews RC, Rigg G, Hodgetts S, et al.: Preclinical assessment of the clinical efficacy of mycograb, a human recombinant antibody against fungal HSP90. Antimicrob Agents Chemother. 2003, 47:2208–2216.PubMedCrossRefGoogle Scholar
  25. 25.
    Pachl J, Svoboda P, Jacobs F, et al.: A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin Infect Dis 2006, 42:1404–1413.PubMedCrossRefGoogle Scholar
  26. 26.
    Barchiesi F, Gallo D, Caselli F, et al.: In vitro interactions of itraconazole with flucytosine against clinical isolates of Cryptococcus neoformans. J Antimicrob Chemother 1999, 44:65–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Barchiesi F, Schimizzi AM, Caselli F, et al.: Interactions between triazoles and amphotericin B against Cryptococcus neoformans. Antimicrob Agents Chemother 2000, 44:2435–2441.PubMedCrossRefGoogle Scholar
  28. 28.
    Graybill JR, Williams M, Van Cutsem E, et al.: Combination therapy of experimental histoplasmosis and cryptococcosis with amphotericin B and ketoconazole. Rev Infect Dis 1980, 2:551–558.PubMedGoogle Scholar
  29. 29.
    Franzot SP, Casadevall A: Pneumocandin L-743, 872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro. Antimicrob Agents Chemother 1997, 41:331–336.PubMedGoogle Scholar
  30. 30.
    Bava AJ, Negroni R: Comparative study of six antifungal treatments in an experimental model of murine cryptococcosis. Eur J Epidemiol 1992, 8:422–426.PubMedCrossRefGoogle Scholar
  31. 31.
    Polak, A, Scholer HJ, Wall M: Combination therapy of experimental candidiasis, cryptococcosis, and aspergillosis in mice. Chemotherapy 1982, 28:461–479.PubMedCrossRefGoogle Scholar
  32. 32.
    Ding JC, Bauer M, Diamond DM, et al.: Effect of severity of meningitis on fungicidal activity of flucytosine combined with fluconazole in a murine model of cryptococcal meningitis. Antimicrob Agents Chemother 1997, 41:1589–1593.PubMedGoogle Scholar
  33. 33.
    Larsen RA, Bauer M, Thomas AM, et al.: Amphotericin B combined with fluconazole is better than all other combinations for cryptococcal meningitis [abstract 17]. Presented at the Focus on Fungal Infections 12 Meeting. Phoenix, AR; March 20–22, 2002.Google Scholar
  34. 34.
    Saag MS, Graybill RJ, Larsen RA, et al.: Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000, 30:710–718.PubMedCrossRefGoogle Scholar
  35. 35.
    Larsen RA, Leal ME, Chan LS: Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS: a randomized trial. Ann Intern Med 1990, 113:183–187.PubMedGoogle Scholar
  36. 36.
    Saag MS, Powderly WG, Cloud GA, et al.: Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med 1992, 326:83–89.PubMedCrossRefGoogle Scholar
  37. 37.
    Saag MS, Cloud GA, Graybill JR, et al.: A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. The National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1999, 28:291–296.PubMedCrossRefGoogle Scholar
  38. 38.
    Larsen RA, Bozzette SA, Jones BE, et al.: Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1994, 19:741–745.PubMedGoogle Scholar
  39. 39.
    Brouwer AE, Rajanuwong A, Chierakul W, et al.: Combination therapies for HIV associated cryptococcal meningitis: a randomized trial. Lancet 2004, 363:1764–1767.PubMedCrossRefGoogle Scholar
  40. 40.
    Pappas PG, Larsen RA, Chenkostad P, et al.: Combination amphotericin B plus fluconazole versus amphotericin B alone for treatment of acute cryptococcal meningitis [abstract]. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL; September 17–20, 2007.Google Scholar
  41. 41.
    Herbrecht R, Denning DW, Patterson TF, et al.: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. New Engl J Med 2002, 347:408–415.PubMedCrossRefGoogle Scholar
  42. 42.
    Walsh TJ, Raad I, Patterson TG, et al.: Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 2007, 44:2–12.PubMedCrossRefGoogle Scholar
  43. 43.
    Maertens J, Raad I, Petrikkos G, et al.: Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients reftactory to on intolerant of conventional antifungal therapy. Clin Infect Dis 2004, 39:1563–1571.PubMedCrossRefGoogle Scholar
  44. 44.
    Denning DW, Marr Ka, Lau WM, et al.: Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect 2006, 53:337–349.PubMedCrossRefGoogle Scholar
  45. 45.
    Denning DW, Hanson LA, Perlman AM, et al.: In vitro susceptibility and synergy studies of Aspergillus species to conventional and new agents. Diagn Microbiol Infect Dis 1992, 15:21–34.PubMedCrossRefGoogle Scholar
  46. 46.
    Meletiadis J, Petraitis V, Petratiene R, et al.: Triazole-polyene antagonism in experimental pulmonary aspergillosis: in vitro and in vivo correlation. J Infect Dis 2006, 194:1008–1018.PubMedCrossRefGoogle Scholar
  47. 47.
    Arikan S, Lozano-Chiu M, Paetznik V, et al.: In vitro synergy of caspofungin and amphotericin B against Aspergillus and Fusarium spp. Antimicrob Agents Chemother 2002, 46:245–247.PubMedCrossRefGoogle Scholar
  48. 48.
    Perea SG, Gonzalez G, Fothergill AW, et al.: In vitro interaction of caspofungin acetate with voriconazole against clinical isolates of Aspergillus spp. Antimicrob Agents Chemother 2002, 46:3039–3041.PubMedCrossRefGoogle Scholar
  49. 49.
    Polak A: Combination therapy with antifungal drugs. Mycoses 1988, 31(Suppl 2):45S–53S.Google Scholar
  50. 50.
    Clemons KV, Espiritu M, Parmar R, et al.: Comparative efficacies of conventional amphotericin b, liposomal amphotericin b (AmBisome), caspofungin, micafungin, and voriconazole alone and in combination against murine cental nervous system aspergillosis. Antimicrob Agents Chemother 2005, 49:4867–4875.PubMedCrossRefGoogle Scholar
  51. 51.
    Petraitis V, Petraitiene R, Sarafandi AA, et al.: Combination therapy in treatment of experimental pulmonary aspergillosis: synergistic interaction between an antifungal triazole and an echinocandin. Journal Infect Dis 2003, 187:1834–1843.CrossRefGoogle Scholar
  52. 52.
    Kirkpatrick WR, Perea S, Coco BJ, et al.: Efficacy of caspofungin alone and in combination with voriconazole in a guinea pig model of invasive aspergillosis. Antimicrob Agents Chemother 2002, 46:2564–2568.PubMedCrossRefGoogle Scholar
  53. 53.
    Petraitis V, Petraitiene R, Legit RJ, et al.: Combination antifungal therapy with FK463 plus amphotericin B in treatment of experimental pulmonary aspergillosis [abstract 2003]. Presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco; September 26–29, 1999.Google Scholar
  54. 54.
    Stevens DA, Kan VL, Judson MA, et al.: Practice guidelines for disease caused by Aspergillus. Clin Infect Dis 2000, 30:696–709.PubMedCrossRefGoogle Scholar
  55. 55.
    Aliff TB, Maslak PG, Jurcic JG, et al.: Refractory aspergillus pneumonia in patients with acute leukemia. Cancer 2003, 97:1025–1032.PubMedCrossRefGoogle Scholar
  56. 56.
    Kontoyiannis DP, Hachen R, Lewis RE, et al.: Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies. Cancer 2003, 98:292–299.PubMedCrossRefGoogle Scholar
  57. 57.
    Marr KA, Boeckth M, Carter RA, et al.: Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004, 39:797–802.PubMedCrossRefGoogle Scholar
  58. 58.
    Singh N, Limaye AP, Forrest G, et al.: Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation 2006, 81:320–326.PubMedCrossRefGoogle Scholar
  59. 59.
    Steinbach WJ, Stevens DA, Denning DW: Combination and sequential antifungal therapy for invasive aspergillosis: review of published in vitro and in vivo interactions and 6281 clinical cases from 1966 to 2001. Clin Infect Dis 2002, 37(Suppl 3):188S–224S.Google Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  1. 1.Department of Medicine, Division of Infectious DiseasesUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations