Advertisement

Combination Therapy for Invasive Fungal Infections

  • Spencer J. LivengoodEmail author
  • Richard H. Drew
  • John R. Perfect
Pharmacology and Pharmacodynamics of Antifungal Agents (J Amsden, Section Editor)
  • 10 Downloads
Part of the following topical collections:
  1. Topical Collection on Pharmacology and Pharmacodynamics of Antifungal Agents

Abstract

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.

Summary

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.

Keywords

Combination antifungals Invasive fungal infections Antifungal synergy Aspergillosis Cryptococcus Candidiasis 

Notes

Compliance with Ethical Standards

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.

References

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.  https://doi.org/10.1093/ofid/ofy187.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1002/cncr.22348.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.14740/jocmr2992w.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.3389/fmicb.2017.00036.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1371/journal.pone.0086499.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Johnson MD, MacDougall C, Ostrosky-Zeichner L, Perfect JR, Rex JH. Combination antifungal therapy. Antimicrob Agents Chemother. 2004;48(3):693–715.  https://doi.org/10.1128/aac.48.3.693-715.2004.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1093/jac/dki343.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1128/JCM.01121-14.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1093/jac/dkw276.CrossRefPubMedGoogle Scholar
  10. 10.
    Shanks N, Greek R, Greek J. Are animal models predictive for humans? Philos Ethics Humanit Med. 2009;4:2.  https://doi.org/10.1186/1747-5341-4-2.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Euser AM, Zoccali C, Jager KJ, Dekker FW. Cohort studies: prospective versus retrospective. Nephron Clin Pract. 2009;113(3):c214–7.  https://doi.org/10.1159/000235241.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1016/j.annemergmed.2011.05.024.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1101/cshperspect.a019745.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1086/652768.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1093/cid/ciw326New update of theAspergillustreatment guidelines containing recommendations for combination therapy.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1016/S0140-6736(15)01159-9Phase 3 trial establishing isavuconazoles efficacy in treatingAspergillus.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1007/s11046-013-9719-z.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1128/AAC.03261-14.CrossRefPubMedPubMedCentralGoogle Scholar
  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).  https://doi.org/10.1128/AAC.00305-17.
  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.  https://doi.org/10.1016/j.ijid.2014.07.007.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.7326/M13-2508.CrossRefPubMedGoogle Scholar
  22. 22.
    Panackal AA. Combination antifungal therapy for invasive Aspergillosis revisited. Med Mycol Open Access. 2016;2(2):12.Google Scholar
  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.  https://doi.org/10.1093/infdis/151.5.902.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1128/AAC.05035-14.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1128/aac.46.1.245-247.2002.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1128/AAC.01554-09.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1093/cid/civ933New update to the Candidiasis treatment guidelines.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1128/AAC.01510-09.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1086/374850.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1093/jac/46.2.171.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1086/315643.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1371/journal.pone.0057672.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1016/j.jinf.2004.10.016.CrossRefGoogle Scholar
  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.  https://doi.org/10.1016/j.ijantimicag.2013.12.009.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1080/21505594.2015.1039885.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.3389/fmicb.2018.03142.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1086/649861.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1056/NEJMoa1710922Large randomized trial evaluating alternative combination therapy in a resource limited area for cryptococcal meningitis. CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1086/649858.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.7326/0003-4819-113-3-183.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1056/NEJMoa1110404.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1056/nejm199707033370103.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1016/S0140-6736(04)16301-0.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1016/j.diagmicrobio.2018.12.003.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1097/QAD.0b013e328354b419.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1097/QAD.0b013e3283536a93.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1016/S1473-3099(19)30127-6First trial evaluating sertraline as a potential adjunctive agent to be used in cryptococcal meningitis.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1093/jac/dkw433.CrossRefPubMedGoogle Scholar
  49. 49.
    Lewis RE, Kontoyiannis DP. Epidemiology and treatment of mucormycosis. Future Microbiol. 2013;8(9):1163–75.  https://doi.org/10.2217/fmb.13.78.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1016/S1473-3099(16)00071-2.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1086/500212.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1128/AAC.01124-08.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1128/AAC.01488-07.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1086/589857.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1093/jac/dkr375.CrossRefPubMedGoogle Scholar
  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.  https://doi.org/10.1128/AAC.01388-07.CrossRefPubMedPubMedCentralGoogle Scholar
  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).  https://doi.org/10.3390/jof4020073.CrossRefGoogle Scholar
  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.  https://doi.org/10.1128/AAC.01160-07.CrossRefPubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1016/j.ijantimicag.2016.12.015.CrossRefPubMedGoogle Scholar
  60. 60.
    Johnson MD, Perfect JR. Use of antifungal combination therapy: agents, order, and timing. Curr Fungal Infect Rep. 2010;4(2):87–95.  https://doi.org/10.1007/s12281-010-0018-6.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Spencer J. Livengood
    • 1
    • 2
    Email author
  • Richard H. Drew
    • 1
    • 2
  • John R. Perfect
    • 1
  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.Campbell University College of Pharmacy & Health SciencesBuies CreekUSA

Personalised recommendations