Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients

Gary M Cox, MD
John R Perfect, MD
Section Editor
John G Bartlett, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Cryptococcus neoformans meningoencephalitis is one of the leading opportunistic infections seen in patients with untreated AIDS [1]. Management of these severely immunocompromised patients includes antifungal therapy combined with antiretroviral therapy (ART), with careful monitoring for complications related to the invasive fungal infection and the inflammatory syndromes secondary to immune recovery [2].

This topic is devoted to the treatment of the HIV-infected host with C. neoformans meningitis. The epidemiology, clinical manifestations, diagnosis, treatment and management of complications of disease are discussed elsewhere. C. neoformans infection outside the central nervous system, C. neoformans infection in HIV seronegative patients, and Cryptococcus gattii infection are also discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients" and "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Immune reconstitution inflammatory syndrome" and "Clinical management and monitoring during antifungal therapy of the HIV-infected patient with cryptococcal meningoencephalitis" and "Cryptococcus neoformans infection outside the central nervous system" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative patients" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in HIV seronegative patients" and "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Clinical features and diagnosis" and "Cryptococcus gattii infection: Treatment".)


The primary antifungal agents used for the treatment of cryptococcal meningoencephalitis include intravenous amphotericin B deoxycholate or its lipid formulations, oral flucytosine, and oral fluconazole. For most patients, liposomal preparations of amphotericin B are preferred to minimize the risk of toxicity and improve the ability to give an uninterrupted induction period of treatment. Echinocandin antifungals do not have significant activity against C. neoformans and should not be used to treat this infection [3]. (See "Pharmacology of azoles" and "Pharmacology of amphotericin B".)

Combination therapy with amphotericin B and flucytosine is fungicidal (inhibition leads to cell death), while fluconazole alone is only fungistatic (ie, inhibits without killing). Importantly, the use of a fungicidal regimen during the initial phase of therapy has been associated with better clinical outcomes [4]. (See 'Induction and consolidation therapy' below.)


The HIV-infected patient with advanced immunosuppression (CD4 cell count <50 cells/microL) is at risk for severe cryptococcal meningoencephalitis, which is uniformly fatal within approximately two weeks if untreated [5]. Common presenting symptoms include fever, headache, photophobia, nausea, and vomiting; patients with fulminant disease may present with coma. Predictors of poor outcome include high cerebrospinal fluid (CSF) cryptococcal antigen levels (titer >1:1024), low body weight, poor CSF inflammatory response (<20 cells/ul of CSF), and altered mental status on presentation [6]. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients", section on 'Clinical manifestations'.)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Feb 26, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Bamba S, Lortholary O, Sawadogo A, et al. Decreasing incidence of cryptococcal meningitis in West Africa in the era of highly active antiretroviral therapy. AIDS 2012; 26:1039.
  2. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 2010; 50:291.
  3. Spanakis EK, Aperis G, Mylonakis E. New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage. Clin Infect Dis 2006; 43:1060.
  4. Bicanic T, Harrison T, Niepieklo A, et al. Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis 2006; 43:1069.
  5. French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 2002; 16:1031.
  6. Anekthananon T, Manosuthi W, Chetchotisakd P, et al. Predictors of poor clinical outcome of cryptococcal meningitis in HIV-infected patients. Int J STD AIDS 2011; 22:665.
  7. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguideline s/adult_oi.pdf (Accessed on November 04, 2015).
  8. Day JN, Chau TT, Wolbers M, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med 2013; 368:1291.
  9. van der Horst CM, 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.
  10. Bicanic T, Muzoora C, Brouwer AE, et al. Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin Infect Dis 2009; 49:702.
  11. Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med 1992; 326:83.
  12. Perfect JR. Efficiently killing a sugar-coated yeast. N Engl J Med 2013; 368:1354.
  13. Saag MS, Cloud GA, Graybill JR, et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1999; 28:291.
  14. Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004; 363:1764.
  15. Milefchik E, Leal MA, Haubrich R, et al. Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis. Med Mycol 2008; 46:393.
  16. Dromer F, Bernede-Bauduin C, Guillemot D, et al. Major role for amphotericin B-flucytosine combination in severe cryptococcosis. PLoS One 2008; 3:e2870.
  17. Loyse A, Wilson D, Meintjes G, et al. Comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis 2012; 54:121.
  18. Pappas PG, Chetchotisakd P, Larsen RA, et al. A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis 2009; 48:1775.
  19. Jackson AT, Nussbaum JC, Phulusa J, 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; 26:1363.
  20. Bicanic T, Wood R, Meintjes G, et al. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis 2008; 47:123.
  21. Bozzette SA, Larsen RA, Chiu J, et al. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med 1991; 324:580.
  22. Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group. N Engl J Med 1992; 326:793.
  23. Diamond RD, Bennett JE. A subcutaneous reservoir for intrathecal therapy of fungal meningitis. N Engl J Med 1973; 288:186.
  24. Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis. N Engl J Med 2016; 374:542.
  25. Hamill RJ, Sobel JD, El-Sadr W, et al. Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety. Clin Infect Dis 2010; 51:225.
  26. Messori A, Fadda V, Maratea D, et al. Nephrotoxicity of different formulations of amphotericin B: summarizing evidence by network meta-analysis. Clin Infect Dis 2013; 57:1783.
  27. Bratton EW, El Husseini N, Chastain CA, et al. Approaches to antifungal therapies and their effectiveness among patients with cryptococcosis. Antimicrob Agents Chemother 2013; 57:2485.
  28. World Health Organization. Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents, and children. http://whqlibdoc.who.int/publications/2011/9789241502979_eng.pdf?ua=1 (Accessed on March 03, 2014).
  29. Sharkey PK, Graybill JR, Johnson ES, et al. Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1996; 22:315.
  30. Leenders AC, Reiss P, Portegies P, et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 1997; 11:1463.
  31. 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.
  32. Mayanja-Kizza H, Oishi K, Mitarai S, et al. Combination therapy with fluconazole and flucytosine for cryptococcal meningitis in Ugandan patients with AIDS. Clin Infect Dis 1998; 26:1362.
  33. Vibhagool A, Sungkanuparph S, Mootsikapun P, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study. Clin Infect Dis 2003; 36:1329.
  34. Mussini C, Pezzotti P, Miró JM, et al. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study. Clin Infect Dis 2004; 38:565.
  35. Kirk O, Reiss P, Uberti-Foppa C, et al. Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Ann Intern Med 2002; 137:239.
  36. Chang LW, Phipps WT, Kennedy GE, Rutherford GW. Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. Cochrane Database Syst Rev 2005; :CD004773.
  37. Parkes-Ratanshi R, Kamali A, Wakeham K, et al. Successful primary prevention of cryptococcal disease using fluconazole prophylaxis in HIV-infected patient Ugandan adults. Presented at the 16th Annual Conference on Retroviruses and Opportunistic Infections, Montreal, Canada February 8-11th, 2009; abstract #32.
  38. Meya DB, Manabe YC, Castelnuovo B, et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings. Clin Infect Dis 2010; 51:448.
  39. Micol R, Lortholary O, Sar B, et al. Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients. J Acquir Immune Defic Syndr 2007; 45:555.
  40. Longley N, Jarvis JN, Meintjes G, et al. Cryptococcal Antigen Screening in Patients Initiating ART in South Africa: A Prospective Cohort Study. Clin Infect Dis 2016; 62:581.
  41. Mfinanga S, Chanda D, Kivuyo SL, et al. Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet 2015; 385:2173.
  42. McKenney J, Bauman S, Neary B, et al. Prevalence, correlates, and outcomes of cryptococcal antigen positivity among patients with AIDS, United States, 1986-2012. Clin Infect Dis 2015; 60:959.
  43. Manabe YC, Moore RD. Cryptococcal Antigen Screening and Preemptive Treatment in a US Cohort of Patients With AIDS. Clin Infect Dis 2015; 61:1632.
  44. Jarvis JN, Lawn SD, Vogt M, et al. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clin Infect Dis 2009; 48:856.
  45. Rajasingham R, Meya DB, Boulware DR. Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care. J Acquir Immune Defic Syndr 2012; 59:e85.
  46. Jarvis JN, Harrison TS, Lawn SD, et al. Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa. PLoS One 2013; 8:e69288.