Combination Therapy for Invasive Fungal Infections

  • 6 Accesses


Purpose of the Review

The purpose of this review is to summarize and evaluate relevant literature on combination antifungal therapy for invasive fungal infections (IFIs).

Recent Findings

Cryptococcal meningitis has the largest body and highest quality in support of combination therapy with amphotericin B and flucytosine. More recent data in treatment of invasive aspergillosis suggest combination therapy with voriconazole and echinocandins may be effective in select patients. Quality studies are needed to define combination therapy in rare mold infections.


Multiple strategies have been employed to optimize treatment of the growing incidence of IFIs. With exceptions as noted above, justification for the use of combination antifungal therapy is most often based on uncontrolled and/or underpowered studies, in vitro data, and case reports.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.


    Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

    1. 1.

      Webb BJ, Ferraro JP, Rea S, Kaufusi S, Goodman BE, Spalding J. Epidemiology and clinical features of invasive fungal infection in a US Health Care Network. Open Forum Infect Dis. 2018;5(8):ofy187.

    2. 2.

      Maertens J, Glasmacher A, Herbrecht R, Thiebaut A, Cordonnier C, Segal BH, et al. Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis. Cancer. 2006;107(12):2888–97.

    3. 3.

      Campitelli M, Zeineddine N, Samaha G, Maslak S. Combination antifungal therapy: a review of current data. J Clin Med Res. 2017;9(6):451–6.

    4. 4.

      Scorzoni L, de Paula ESAC, Marcos CM, Assato PA, de Melo WC, de Oliveira HC, et al. Antifungal therapy: new advances in the understanding and treatment of mycosis. Front Microbiol. 2017;8:36.

    5. 5.

      Chen X, Ren B, Chen M, Liu MX, Ren W, Wang QX, et al. ASDCD: antifungal synergistic drug combination database. PLoS One. 2014;9(1):e86499.

    6. 6.

      Johnson MD, MacDougall C, Ostrosky-Zeichner L, Perfect JR, Rex JH. Combination antifungal therapy. Antimicrob Agents Chemother. 2004;48(3):693–715.

    7. 7.

      Lewis RE, Kontoyiannis DP. Micafungin in combination with voriconazole in Aspergillus species: a pharmacodynamic approach for detection of combined antifungal activity in vitro. J Antimicrob Chemother. 2005;56(5):887–92.

    8. 8.

      Doern CD. When does 2 plus 2 equal 5? A review of antimicrobial synergy testing. J Clin Microbiol. 2014;52(12):4124–8.

    9. 9.

      Siopi M, Siafakas N, Vourli S, Mouton JW, Zerva L, Meletiadis J. Dose optimization of voriconazole/anidulafungin combination against Aspergillus fumigatus using an in vitro pharmacokinetic/pharmacodynamic model and response surface analysis: clinical implications for azole-resistant aspergillosis. J Antimicrob Chemother. 2016;71(11):3135–47.

    10. 10.

      Shanks N, Greek R, Greek J. Are animal models predictive for humans? Philos Ethics Humanit Med. 2009;4:2.

    11. 11.

      Euser AM, Zoccali C, Jager KJ, Dekker FW. Cohort studies: prospective versus retrospective. Nephron Clin Pract. 2009;113(3):c214–7.

    12. 12.

      Jones CW, Platts-Mills TF. Understanding commonly encountered limitations in clinical research: an emergency medicine resident's perspective. Ann Emerg Med. 2012;59(5):425–31 e11.

    13. 13.

      Pappas PG. Antifungal clinical trials and guidelines: what we know and do not know. Cold Spring Harb Perspect Med. 2014;4(11):a019745.

    14. 14.

      Baddley JW, Andes DR, Marr KA, Kontoyiannis DP, Alexander BD, Kauffman CA, et al. Factors associated with mortality in transplant patients with invasive aspergillosis. Clin Infect Dis. 2010;50(12):1559–67.

    15. 15.

      •• Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1–e60. update of theAspergillustreatment guidelines containing recommendations for combination therapy.

    16. 16.

      • Maertens JA, Raad MKA II, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760–9. 3 trial establishing isavuconazoles efficacy in treatingAspergillus.

    17. 17.

      Zhang M, Su X, Sun WK, Chen F, Xu XY, Shi Y. Efficacy of the combination of voriconazole and caspofungin in experimental pulmonary aspergillosis by different Aspergillus species. Mycopathologia. 2014;177(1–2):11–8.

    18. 18.

      Katragkou A, McCarthy M, Meletiadis J, Petraitis V, Moradi PW, Strauss GE, et al. In vitro combination of isavuconazole with micafungin or amphotericin B deoxycholate against medically important molds. Antimicrob Agents Chemother. 2014;58(11):6934–7.

    19. 19.

      Petraitis V, Petraitiene R, McCarthy MW, Kovanda LL, Zaw MH, Hussain K, et al. Combination therapy with isavuconazole and micafungin for treatment of experimental invasive pulmonary Aspergillosis. Antimicrob Agents Chemother. 2017;61(9).

    20. 20.

      Panackal AA, Parisini E, Proschan M. Salvage combination antifungal therapy for acute invasive aspergillosis may improve outcomes: a systematic review and meta-analysis. Int J Infect Dis. 2014;28:80–94.

    21. 21.

      Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015;162(2):81–9.

    22. 22.

      Panackal AA. Combination antifungal therapy for invasive Aspergillosis revisited. Med Mycol Open Access. 2016;2(2):12.

    23. 23.

      Schaffner A, Frick PG. The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis. J Infect Dis. 1985;151(5):902–10.

    24. 24.

      Siopi M, Siafakas N, Vourli S, Zerva L, Meletiadis J. Optimization of polyene-azole combination therapy against aspergillosis using an in vitro pharmacokinetic-pharmacodynamic model. Antimicrob Agents Chemother. 2015;59(7):3973–83.

    25. 25.

      Arikan S, Lozano-Chiu M, Paetznick V, Rex JH. In vitro synergy of caspofungin and amphotericin B against Aspergillus and Fusarium spp. Antimicrob Agents Chemother. 2002;46(1):245–7.

    26. 26.

      Olson JA, George A, Constable D, Smith P, Proffitt RT, Adler-Moore JP. Liposomal amphotericin B and echinocandins as monotherapy or sequential or concomitant therapy in murine disseminated and pulmonary Aspergillus fumigatus infections. Antimicrob Agents Chemother. 2010;54(9):3884–94.

    27. 27.

      •• Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1–50. update to the Candidiasis treatment guidelines.

    28. 28.

      Chaturvedi V, Ramani R, Andes D, Diekema DJ, Pfaller MA, Ghannoum MA, et al. Multilaboratory testing of two-drug combinations of antifungals against Candida albicans, Candida glabrata, and Candida parapsilosis. Antimicrob Agents Chemother. 2011;55(4):1543–8.

    29. 29.

      Rex JH, Pappas PG, Karchmer AW, Sobel J, Edwards JE, Hadley S, 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(10):1221–8.

    30. 30.

      Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother. 2000;46(2):171–9.

    31. 31.

      Groll AH, Giri N, Petraitis V, Petraitiene R, Candelario M, Bacher JS, et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis. 2000;182(1):274–82.

    32. 32.

      Chen YL, Lehman VN, Averette AF, Perfect JR, Heitman J. Posaconazole exhibits in vitro and in vivo synergistic antifungal activity with caspofungin or FK506 against Candida albicans. PLoS One. 2013;8(3):e57672.

    33. 33.

      Steinbach WJ, Perfect JR, Cabell CH, Fowler VG, Corey GR, Li JS, et al. A meta-analysis of medical versus surgical therapy for Candida endocarditis. J Inf Secur. 2005;51(3):230–47.

    34. 34.

      Liu S, Hou Y, Chen X, Gao Y, Li H, Sun S. Combination of fluconazole with non-antifungal agents: a promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery. Int J Antimicrob Agents. 2014;43(5):395–402.

    35. 35.

      Cui J, Ren B, Tong Y, Dai H, Zhang L. Synergistic combinations of antifungals and anti-virulence agents to fight against Candida albicans. Virulence. 2015;6(4):362–71.

    36. 36.

      Lu M, Yang X, Yu C, Gong Y, Yuan L, Hao L, et al. Linezolid in combination with azoles induced synergistic effects against Candida albicans and protected Galleria mellonella against experimental candidiasis. Front Microbiol. 2018;9:3142.

    37. 37.

      Nussbaum JC, Jackson A, Namarika D, Phulusa J, Kenala J, Kanyemba C, et al. Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi. Clin Infect Dis. 2010;50(3):338–44.

    38. 38.

      • Molloy SF, Kanyama C, Heyderman RS, Loyse A, Kouanfack C, Chanda D, et al. Antifungal combinations for treatment of cryptococcal meningitis in Africa. N Engl J Med. 2018;378(11):1004–17. randomized trial evaluating alternative combination therapy in a resource limited area for cryptococcal meningitis.

    39. 39.

      Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2010;50(3):291–322.

    40. 40.

      Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. A randomized trial. Ann Intern Med. 1990;113(3):183–7.

    41. 41.

      Day JN, Chau TTH, Wolbers M, Mai PP, Dung NT, Mai NH, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368(14):1291–302.

    42. 42.

      van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, 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(1):15–21.

    43. 43.

      Brouwer AE, Rajanuwong A, Chierakul W, Griffin GE, Larsen RA, White NJ, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet. 2004;363(9423):1764–7.

    44. 44.

      Rossato L, Loreto ES, Venturini TP, Azevedo MI, Al-Hatmi AMS, Santurio JM, et al. In vitro evaluation of antifungal combination against Cryptococcus neoformans. Diagn Microbiol Infect Dis. 2019;94(2):155–6.

    45. 45.

      Jackson AT, Nussbaum JC, Phulusa J, Namarika D, Chikasema M, Kanyemba C, et al. A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis. AIDS. 2012;26(11):1363–70.

    46. 46.

      Jarvis JN, Meintjes G, Rebe K, Williams GN, Bicanic T, Williams A, et al. Adjunctive interferon-gamma immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial. AIDS. 2012;26(9):1105–13.

    47. 47.

      • Rhein J, Huppler Hullsiek K, Tugume L, Nuwagira E, Mpoza E, Evans EE, et al. Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial. Lancet Infect Dis. 2019;19(8):843–51. trial evaluating sertraline as a potential adjunctive agent to be used in cryptococcal meningitis.

    48. 48.

      Gebremariam T, Wiederhold NP, Alqarihi A, Uppuluri P, Azie N, Edwards JE Jr, et al. Monotherapy or combination therapy of isavuconazole and micafungin for treating murine mucormycosis. J Antimicrob Chemother. 2017;72(2):462–6.

    49. 49.

      Lewis RE, Kontoyiannis DP. Epidemiology and treatment of mucormycosis. Future Microbiol. 2013;8(9):1163–75.

    50. 50.

      Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR 3rd, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16(7):828–37.

    51. 51.

      van Burik JA, Hare RS, Solomon HF, Corrado ML, Kontoyiannis DP. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis. 2006;42(7):e61–5.

    52. 52.

      Ibrahim AS, Gebremariam T, Schwartz JA, Edwards JE Jr, Spellberg B. Posaconazole mono- or combination therapy for treatment of murine zygomycosis. Antimicrob Agents Chemother. 2009;53(2):772–5.

    53. 53.

      Ibrahim AS, Gebremariam T, Husseiny MI, Stevens DA, Fu Y, Edwards JE Jr, et al. Comparison of lipid amphotericin B preparations in treating murine zygomycosis. Antimicrob Agents Chemother. 2008;52(4):1573–6.

    54. 54.

      Reed C, Bryant R, Ibrahim AS, Edwards J Jr, Filler SG, Goldberg R, et al. Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis. 2008;47(3):364–71.

    55. 55.

      Spellberg B, Ibrahim AS, Chin-Hong PV, Kontoyiannis DP, Morris MI, Perfect JR, et al. The Deferasirox-AmBisome therapy for mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial. J Antimicrob Chemother. 2012;67(3):715–22.

    56. 56.

      Troke P, Aguirrebengoa K, Arteaga C, Ellis D, Heath CH, Lutsar I, et al. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother. 2008;52(5):1743–50.

    57. 57.

      McCarthy MW, Katragkou A, Iosifidis E, Roilides E, Walsh TJ. Recent advances in the treatment of scedosporiosis and fusariosis. J Fungi (Basel). 2018;4(2).

    58. 58.

      Cuenca-Estrella M, Alastruey-Izquierdo A, Alcazar-Fuoli L, Bernal-Martinez L, Gomez-Lopez A, Buitrago MJ, et al. In vitro activities of 35 double combinations of antifungal agents against Scedosporium apiospermum and Scedosporium prolificans. Antimicrob Agents Chemother. 2008;52(3):1136–9.

    59. 59.

      Martin-Vicente A, Guarro J, Capilla J. Does a triple combination have better activity than double combinations against multiresistant fungi? Experimental in vitro evaluation. Int J Antimicrob Agents. 2017;49(4):422–6.

    60. 60.

      Johnson MD, Perfect JR. Use of antifungal combination therapy: agents, order, and timing. Curr Fungal Infect Rep. 2010;4(2):87–95.

    Download references

    Author information

    Correspondence to Spencer J. Livengood.

    Ethics declarations

    Conflict of Interest

    John Perfect reports grants and being a member of the advisory board for Merck; grants from Astellas, serving on the advisory board for F2G, serving on the advisory board, and consulting for Scynexis; grants from Pfizer; grants from Amplyx, serving on the advisory board and consulting for Ampili; and grants from Minnetronix, serving on the advisory board for Matinas outside the submitted work. Richard Drew reports expenses for CME presentation from American Society of Microbiology, consultant fees from Paratek, and publication royalties from UpToDate. Spencer Livengood declares no conflicts of interest relevant to this manuscript.

    Human and Animal Rights and Informed Consent

    This article does not contain any studies with human or animal subjects performed by any of the authors.

    Additional information

    Publisher’s Note

    Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

    This article is part of the Topical Collection on Pharmacology and Pharmacodynamics of Antifungal Agents

    Rights and permissions

    Reprints and Permissions

    About this article

    Verify currency and authenticity via CrossMark

    Cite this article

    Livengood, S.J., Drew, R.H. & Perfect, J.R. Combination Therapy for Invasive Fungal Infections. Curr Fungal Infect Rep (2020) doi:10.1007/s12281-020-00369-4

    Download citation


    • Combination antifungals
    • Invasive fungal infections
    • Antifungal synergy
    • Aspergillosis
    • Cryptococcus
    • Candidiasis