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Combination antifungal therapy: what can and should we expect?

Bone Marrow Transplantation volume 40, pages 297–306 (2007)Cite this article

Abstract

Invasive fungal infections are associated with significant morbidity and mortality among immunocompromised patients. Recent advances in antifungal development have afforded us more pharmacologic compounds to choose from when managing these fungal infections. The role of combination antifungal therapy has been well established for fungal infections such as cryptococcal meningitis. The availability of new antifungals, increased incidence of mould infections and high mortality among certain affected populations, such as hematopoietic stem cell transplant recipients, has stimulated interest in the clinical use of combination antifungal therapy. In this paper, we review supporting evidence for the use of combination antifungals in the treatment of cryptococcal meningitis, invasive candidiasis, invasive aspergillosis and zygomycosis. Several controlled clinical trials have demonstrated benefits of combination antifungal approaches for patients with cryptococcal meningitis and invasive candidiasis, but variable effects when using different agents in combination have been reported. Randomized prospective studies of combination antifungal therapy in mould infections are lacking but some series provide supportive evidence for this approach. We also describe limitations of the data and these study designs, including the fact that we still need randomized controlled multicenter studies of combination antifungal therapy for mould infections. Trials in this area should be performed with efficiency and economics in mind, and could potentially use surrogate markers as end points. Therefore, we suggest future investigations of combination antifungal therapy should include a randomized, comparative trial of primary therapy for invasive aspergillosis.

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References

  1. Marr KA, Carter RA, Boeckh M, Martin P, Corey L . Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002; 100: 4358–4366.

    Article  CAS  Google Scholar 

  2. Lin SJ, Schranz J, Teutsch SM . Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 2001; 32: 358–366.

    Article  CAS  Google Scholar 

  3. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–415.

    Article  CAS  Google Scholar 

  4. Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005; 41: 634–653.

    Article  Google Scholar 

  5. Morrell M, Fraser VJ, Kollef MH . Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005; 49: 3640–3645.

    Article  CAS  Google Scholar 

  6. Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 2006; 43: 25–31.

    Article  CAS  Google Scholar 

  7. Segal BH, Kwon-Chung J, Walsh TJ, Klein BS, Battiwalla M, Almyroudis NG et al. Immunotherapy for fungal infections. Clin Infect Dis 2006; 42: 507–515.

    Article  CAS  Google Scholar 

  8. Singh N, Lortholary O, Alexander BD, Gupta KL, John GT, Pursell K et al. An immune reconstitution syndrome-like illness associated with cryptococcus neoformans infection in organ transplant recipients. Clin Infect Dis 2005; 40: 1756–1761.

    Article  CAS  Google Scholar 

  9. York J, Bodi I, Reeves I, Riordan-Eva P, Easterbrook PJ . Raised intracranial pressure complicating cryptococcal meningitis: immune reconstitution inflammatory syndrome or recurrent cryptococcal disease? J Infect 2005; 51: 165–171.

    Article  Google Scholar 

  10. Maiolino A, Biasoli I, Lima J, Portugal AC, Pulcheri W, Nucci M . Engraftment syndrome following autologous hematopoietic stem cell transplantation: definition of diagnostic criteria. Bone Marrow Transplant 2003; 31: 393–397.

    Article  CAS  Google Scholar 

  11. Kishi Y, Kami M, Miyakoshi S, Kanda Y, Murashige N, Teshima T et al. Early immune reaction after reduced-intensity cord-blood transplantation for adult patients. Transplantation 2005; 80: 34–40.

    Article  Google Scholar 

  12. Shankar G, Cohen DA . Idiopathic pneumonia syndrome after bone marrow transplantation: the role of pre-transplant radiation conditioning and local cytokine dysregulation in promoting lung inflammation and fibrosis. Int J Exp Pathol 2001; 82: 101–113.

    Article  CAS  Google Scholar 

  13. Hirsch HH, Kaufmann G, Sendi P, Battegay M . Immune reconstitution in HIV-infected patients. Clin Infect Dis 2004; 38: 1159–1166.

    Article  Google Scholar 

  14. Smith J, Safdar N, Knasinski V, Simmons W, Bhavnani SM, Ambrose PG et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006; 50: 1570–1572.

    Article  CAS  Google Scholar 

  15. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356: 348–359.

    Article  CAS  Google Scholar 

  16. Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356: 335–347.

    Article  CAS  Google Scholar 

  17. Lewis RE . Decision making in antifungal monotherapy versus combination therapy. Pharmacotherapy 2006; 26: 61S–67S.

    Article  CAS  Google Scholar 

  18. Kontoyiannis DP, Lewis RE . Combination chemotherapy for invasive fungal infections: what laboratory and clinical studies tell us so far. Drug Resist Updat 2003; 6: 257–269.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Clemons KV, Stevens DA . Animal models testing monotherapy versus combination antifungal therapy: lessons learned and future directions. Curr Opin Infect Dis 2006; 19: 360–364.

    Article  CAS  Google Scholar 

  21. Bennett JE, Dismukes WE, Duma RJ, Medoff G, Sande MA, Gallis H 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.

    Article  CAS  Google Scholar 

  22. Dismukes WE, Cloud G, Gallis HA, Kerkering TM, Medoff G, Craven PC 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.

    Article  CAS  Google Scholar 

  23. 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. N Engl J Med 1997; 337: 15–21.

    Article  CAS  Google Scholar 

  24. Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG et al. Practice guidelines for the management of cryptococcal disease. Infectious diseases society of America. Clin Infect Dis 2000; 30: 710–718.

    Article  CAS  Google Scholar 

  25. 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: 1764–1767.

    Article  CAS  Google Scholar 

  26. Larsen RA, Bauer M, Thomas AM, Graybill JR . Amphotericin B and fluconazole, a potent combination therapy for cryptococcal meningitis. Antimicrob Agents Chemother 2004; 48: 985–991.

    Article  CAS  Google Scholar 

  27. Barchiesi F, Schimizzi AM, Caselli F, Novelli A, Fallani S, Giannini D et al. Interactions between triazoles and amphotericin B against Cryptococcus neoformans. Antimicrob Agents Chemother 2000; 44: 2435–2441.

    Article  CAS  Google Scholar 

  28. Larsen RA, Bozzette SA, Jones BE, Haghighat D, Leal MA, Forthal D et al. Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1994; 19: 741–745.

    Article  CAS  Google Scholar 

  29. Mayanja-Kizza H, Oishi K, Mitarai S, Yamashita H, Nalongo K, Watanabe K et al. Combination therapy with fluconazole and flucytosine for cryptococcal meningitis in Ugandan patients with AIDS. Clin Infect Dis 1998; 26: 1362–1366.

    Article  CAS  Google Scholar 

  30. Pappas PG, Bustamante B, Ticona E, Hamill RJ, Johnson PC, Reboli A et al. Recombinant interferon- gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J Infect Dis 2004; 189: 2185–2191.

    Article  CAS  Google Scholar 

  31. Rex JH, Pappas PG, Karchmer AW, Sobel J, Edwards J, 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: 1221–1228.

    Article  CAS  Google Scholar 

  32. Rex JH, Walsh TJ, Sobel JD, Filler SG, Pappas PG, Dismukes WE et al. Practice guidelines for the treatment of candidiasis. Infectious diseases society of America. Clin Infect Dis 2000; 30: 662–678.

    Article  CAS  Google Scholar 

  33. Pachl J, Svoboda P, Jacobs F, Vandewoude K, van der Hoven B, Spronk P 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.

    Article  CAS  Google Scholar 

  34. Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002; 347: 2020–2029.

    Article  CAS  Google Scholar 

  35. Ostrosky-Zeichner L, Kontoyiannis D, Raffalli J, Mullane KM, Vazquez J, Anaissie EJ 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: 654–661.

    Article  CAS  Google Scholar 

  36. Rex JH, Bennett JE, Sugar AM, Pappas PG, van der Horst CM, Edwards JE et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. N Engl J Med 1994; 331: 1325–1330.

    Article  CAS  Google Scholar 

  37. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L . Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004; 39: 797–802.

    Article  CAS  Google Scholar 

  38. Kontoyiannis DP, Hachem R, Lewis RE, Rivero GA, Torres HA, Thornby J 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.

    Article  CAS  Google Scholar 

  39. Singh N, Limaye AP, Forrest G, Safdar N, Munoz P, Pursell K 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.

    Article  CAS  Google Scholar 

  40. Caillot D, Thiebaut A, Herbrecht R, Pigneux A, Alfandari S, Attal M et al. Liposomal amphotericin B standard dose in combination with caspofungin versus liposomal amphotericin B high dose regimen for the treatment of invasive aspergillosis in immunocompromised patients: randomized pilot study (combistrat trial). Program and Abstracts of the 16th Congress of the International Society for Human and Animal Mycology. International Society for Human and Animal Mycology: Paris, France, 2006. Abstract O-0017.

    Google Scholar 

  41. 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: e61–e65.

    Article  CAS  Google Scholar 

  42. Powers JH . Considerations in clinical trials of combination antifungal therapy. Clin Infect Dis 2004; 39 (Suppl 35): S228–S235.

    Article  Google Scholar 

  43. Wenzel R, Del FA, Kibbler C, Rogers T, Rotstein C, Mauskopf J et al. Economic evaluation of voriconazole compared with conventional amphotericin B for the primary treatment of aspergillosis in immunocompromised patients. J Antimicrob Chemother 2005; 55: 352–361.

    Article  CAS  Google Scholar 

  44. Maertens J, Verhaegen J, Lagrou K, Van EJ, Boogaerts M . Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 2001; 97: 1604–1610.

    Article  CAS  Google Scholar 

  45. Maertens J, Van EJ, Verhaegen J, Verbeken E, Verschakelen J, Boogaerts M . Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients. J Infect Dis 2002; 186: 1297–1306.

    Article  CAS  Google Scholar 

  46. Kawazu M, Kanda Y, Nannya Y, Aoki K, Kurokawa M, Chiba S et al. Prospective comparison of the diagnostic potential of real-time PCR, double-sandwich enzyme-linked immunosorbent assay for galactomannan, and a (1-->3)-beta-D-glucan test in weekly screening for invasive aspergillosis in patients with hematological disorders. J Clin Microbiol 2004; 42: 2733–2741.

    Article  CAS  Google Scholar 

  47. Busca A, Locatelli F, Barbui A, Limerutti G, Serra R, Libertucci D et al. Usefulness of sequential Aspergillus galactomannan antigen detection combined with early radiologic evaluation for diagnosis of invasive pulmonary aspergillosis in patients undergoing allogeneic stem cell transplantation. Transplantation Proc 2006; 38: 1610–1613.

    Article  CAS  Google Scholar 

  48. Adam O, Auperin A, Wilquin F, Bourhis JH, Gachot B, Chachaty E . Treatment with piperacillin-tazobactam and false-positive Aspergillus galactomannan antigen test results for patients with hematological malignancies. Clin Infect Dis 2004; 38: 917–920.

    Article  Google Scholar 

  49. Aubry A, Porcher R, Bottero J, Touratier S, Leblanc T, Brethon B et al. Occurrence and kinetics of false-positive Aspergillus galactomannan test results following treatment with beta-lactam antibiotics in patients with hematological disorders. J Clin Microbiol 2006; 44: 389–394.

    Article  CAS  Google Scholar 

  50. Musher B, Fredricks D, Leisenring W, Balajee SA, Smith C, Marr KA . Aspergillus galactomannan enzyme immunoassay and quantitative PCR for diagnosis of invasive aspergillosis with bronchoalveolar lavage fluid. J Clin Microbiol 2004; 42: 5517–5522.

    Article  CAS  Google Scholar 

  51. Sanguinetti M, Posteraro B, Pagano L, Pagliari G, Fianchi L, Mele L et al. Comparison of real-time PCR, conventional PCR, and galactomannan antigen detection by enzyme-linked immunosorbent assay using bronchoalveolar lavage fluid samples from hematology patients for diagnosis of invasive pulmonary aspergillosis. J Clin Microbiol 2003; 41: 3922–3925.

    Article  CAS  Google Scholar 

  52. Becker MJ, Lugtenburg EJ, Cornelissen JJ, Van Der SC, Hoogsteden HC, De MS . Galactomannan detection in computerized tomography-based broncho-alveolar lavage fluid and serum in haematological patients at risk for invasive pulmonary aspergillosis. Br J Haematol 2003; 121: 448–457.

    Article  CAS  Google Scholar 

  53. Salonen J, Lehtonen OP, Terasjarvi MR, Nikoskelainen J . Aspergillus antigen in serum, urine and bronchoalveolar lavage specimens of neutropenic patients in relation to clinical outcome. Scand J Infect Dis 2000; 32: 485–490.

    Article  CAS  Google Scholar 

  54. Buchheidt D, Baust C, Skladny H, Baldus M, Brauninger S, Hehlmann R . Clinical evaluation of a polymerase chain reaction assay to detect Aspergillus species in bronchoalveolar lavage samples of neutropenic patients. Br J Haematol 2002; 116: 803–811.

    Article  CAS  Google Scholar 

  55. Miyazaki T, Kohno S, Mitsutake K, Maesaki S, Tanaka K, Ishikawa N et al. Plasma (1-->3)-beta-D-glucan and fungal antigenemia in patients with candidemia, aspergillosis, and cryptococcosis. J Clin Microbiol 1995; 33: 3115–3118.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Mitsutake K, Miyazaki T, Tashiro T, Yamamoto Y, Kakeya H, Otsubo T et al. Enolase antigen, mannan antigen, Cand-Tec antigen, and beta-glucan in patients with candidemia. J Clin Microbiol 1996; 34: 1918–1921.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chryssanthou E, Klingspor L, Tollemar J, Petrini B, Larsson L, Christensson B et al. PCR and other non-culture methods for diagnosis of invasive Candida infections in allogeneic bone marrow and solid organ transplant recipients. Mycoses 1999; 42: 239–247.

    Article  CAS  Google Scholar 

  58. Bretagne S, Costa JM, Bart-Delabesse E, Dhedin N, Rieux C, Cordonnier C . Comparison of serum galactomannan antigen detection and competitive polymerase chain reaction for diagnosing invasive aspergillosis. Clin Infect Dis 1998; 26: 1407–1412.

    Article  CAS  Google Scholar 

  59. Hebart H, Loffler J, Meisner C, Serey F, Schmidt D, Bohme A et al. Early detection of Aspergillus infection after allogeneic stem cell transplantation by polymerase chain reaction screening. J Infect Dis 2000; 181: 1713–1719.

    Article  CAS  Google Scholar 

  60. Hebart H, Loffler J, Reitze H, Engel A, Schumacher U, Klingebiel T et al. Prospective screening by a panfungal polymerase chain reaction assay in patients at risk for fungal infections: implications for the management of febrile neutropenia. Br J Haematol 2000; 111: 635–640.

    Article  CAS  Google Scholar 

  61. van Burik JA, Myerson D, Schreckhise RW, Bowden RA . Panfungal PCR assay for detection of fungal infection in human blood specimens. J Clin Microbiol 1998; 36: 1169–1175.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Johnson MD, Dodds Ashley ES, Kaye KS, Ely T, Perfect JR . Impact of voriconazole on antifungal expenditures at a tertiary care medical center. Program and Abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology: Washington, DC, 2003. Abstract M-986.

    Google Scholar 

  63. Meletiadis J, Petraitis V, Petraitiene R, Lin P, Stergiopoulou T, Kelaher AM et al. Triazole-polyene antagonism in experimental invasive pulmonary aspergillosis: in vitro and in vivo correlation. J Infect Dis 2006; 194: 1008–1018.

    Article  CAS  Google Scholar 

  64. Kujath P, Lerch K, Kochendorfer P, Boos C . Comparative study of the efficacy of fluconazole versus amphotericin B/flucytosine in surgical patients with systemic mycoses. Infection 1993; 21: 376–382.

    Article  CAS  Google Scholar 

  65. Denning DW, Marr KA, Lau WM, Facklam DP, Ratanatharathorn V, Becker C 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.

    Article  Google Scholar 

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  1. Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, USA

    M D Johnson & J R Perfect

  2. Campbell University School of Pharmacy, Buies Creek, NC, USA

    M D Johnson

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Johnson, M., Perfect, J. Combination antifungal therapy: what can and should we expect?. Bone Marrow Transplant 40, 297–306 (2007). https://doi.org/10.1038/sj.bmt.1705687

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