Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Clinical management and monitoring during antifungal therapy of the HIV-infected patient with cryptococcal meningoencephalitis

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


Cryptococcal meningoencephalitis is a serious opportunistic infection that is seen among patients with untreated AIDS [1]. The initial preferred approach to the patient with cryptococcal meningoencephalitis includes combination antifungal therapy with amphotericin B plus flucytosine (for the induction phase of therapy) followed by fluconazole (for the consolidation phase). During therapy, patients should be monitored for recurrence of clinical symptoms that may suggest increased intracranial pressure, relapse of infection (from lack of adherence or drug resistance), adverse events related to antifungal therapy, and immune recovery syndromes secondary to antiretroviral therapy (ART).

This topic is devoted to clinical monitoring of the HIV-infected host with cryptococcal meningitis. The epidemiology, clinical manifestations, diagnosis, and treatment of disease are found elsewhere. (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 "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients".)


Amphotericin B — Infusion-related reactions, particularly nausea, vomiting, chills, and rigors, are common with intravenous (IV) amphotericin B deoxycholate administration, and usually occur either during infusion (within 15 minutes to 3 hours following initiation) or immediately following administration of the dose. Patients with infusion-related reactions may be pretreated with acetaminophen, diphenhydramine, or corticosteroids administered approximately 30 minutes before infusion [2]. (See "Pharmacology of amphotericin B", section on 'Infusion-related reactions'.)

Amphotericin B is associated with renal insufficiency, hypocalcemia, hypophosphatemia, and hypokalemia. Thus, patients treated with amphotericin B should have daily monitoring of serum creatinine and electrolytes. Many patients require significant amounts of potassium and/or magnesium supplementation during therapy and hydration with normal saline during amphotericin B infusions. (See "Pharmacology of amphotericin B", section on 'Adverse effects'.)

A lipid-based formulation of amphotericin B should be used for patients who develop renal insufficiency (eg, plasma creatinine concentration exceeds 2.5 mg/dL) while receiving amphotericin B deoxycholate, or if there are concerns about having to interrupt induction therapy due to toxicity. If this is not possible, the dose of amphotericin B deoxycholate can be reduced by 50 percent or given every other day. It is critical that there is no interruption of the combination regimen during the two-week induction period. (See "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients", section on 'Approach to antifungal treatment'.)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Feb 22, 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 ©2016 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. 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/lvguidelines/adult_oi.pdf (Accessed on October 16, 2014).
  3. Vermes A, Guchelaar HJ, Dankert J. Prediction of flucytosine-induced thrombocytopenia using creatinine clearance. Chemotherapy 2000; 46:335.
  4. 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.
  5. Powderly WG, Cloud GA, Dismukes WE, Saag MS. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis 1994; 18:789.
  6. Aller AI, Martin-Mazuelos E, Lozano F, et al. Correlation of fluconazole MICs with clinical outcome in cryptococcal infection. Antimicrob Agents Chemother 2000; 44:1544.
  7. 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.
  8. 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.
  9. Tang LM. Ventriculoperitoneal shunt in cryptococcal meningitis with hydrocephalus. Surg Neurol 1990; 33:314.
  10. Bach MC, Tally PW, Godofsky EW. Use of cerebrospinal fluid shunts in patients having acquired immunodeficiency syndrome with cryptococcal meningitis and uncontrollable intracranial hypertension. Neurosurgery 1997; 41:1280.
  11. Claus JJ, Portegies P. Reversible blindness in AIDS-related cryptococcal meningitis. Clin Neurol Neurosurg 1998; 100:51.
  12. Fessler RD, Sobel J, Guyot L, et al. Management of elevated intracranial pressure in patients with Cryptococcal meningitis. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17:137.
  13. Mylonakis E, Merriman NA, Rich JD, et al. Use of cerebrospinal fluid shunt for the management of elevated intracranial pressure in a patient with active AIDS-related cryptococcal meningitis. Diagn Microbiol Infect Dis 1999; 34:111.
  14. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000; 30:47.
  15. Rolfes MA, Hullsiek KH, Rhein J, et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis 2014; 59:1607.
  16. Pappas PG. Managing cryptococcal meningitis is about handling the pressure. Clin Infect Dis 2005; 40:480.
  17. Loyse A, Wainwright H, Jarvis JN, et al. Histopathology of the arachnoid granulations and brain in HIV-associated cryptococcal meningitis: correlation with cerebrospinal fluid pressure. AIDS 2010; 24:405.
  18. Shoham S, Cover C, Donegan N, et al. Cryptococcus neoformans meningitis at 2 hospitals in Washington, D.C.: adherence of health care providers to published practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2005; 40:477.
  19. Kambugu A, Meya DB, Rhein J, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis 2008; 46:1694.
  20. Rex JH, Larsen RA, Dismukes WE, et al. Catastrophic visual loss due to Cryptococcus neoformans meningitis. Medicine (Baltimore) 1993; 72:207.
  21. Newton PN, Thai le H, Tip NQ, et al. A randomized, double-blind, placebo-controlled trial of acetazolamide for the treatment of elevated intracranial pressure in cryptococcal meningitis. Clin Infect Dis 2002; 35:769.
  22. Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis. N Engl J Med 2016; 374:542.
  23. Pitisuttithum P, Negroni R, Graybill JR, et al. Activity of posaconazole in the treatment of central nervous system fungal infections. J Antimicrob Chemother 2005; 56:745.
  24. Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis 2003; 36:1122.
  25. Pappas PG, Bustamante B, Ticona E, et al. Recombinant interferon- gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J Infect Dis 2004; 189:2185.
  26. Jarvis JN, Meintjes G, Rebe K, et al. Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial. AIDS 2012; 26:1105.
  27. DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy. Ann Intern Med 2000; 133:447.
  28. French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med 2000; 1:107.
  29. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 2002; 81:213.
  30. Michelet C, Arvieux C, François C, et al. Opportunistic infections occurring during highly active antiretroviral treatment. AIDS 1998; 12:1815.
  31. Hirsch HH, Kaufmann G, Sendi P, Battegay M. Immune reconstitution in HIV-infected patients. Clin Infect Dis 2004; 38:1159.
  32. Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother 2006; 57:167.
  33. Murdoch DM, Venter WD, Feldman C, Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 2008; 22:601.
  34. Müller M, Wandel S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 2010; 10:251.
  35. Lortholary O, Fontanet A, Mémain N, et al. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 2005; 19:1043.
  36. Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr 2009; 51:130.
  37. Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One 2009; 4:e5575.
  38. Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 2010; 10:791.
  39. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004; 351:1741.
  40. Sitapati AM, Kao CL, Cachay ER, et al. Treatment of HIV-related inflammatory cerebral cryptococcoma with adalimumab. Clin Infect Dis 2010; 50:e7.
  41. Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis 2010; 50:1532.
  42. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014; 370:2487.
  43. Bisson GP, Molefi M, Bellamy S, et al. Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis. Clin Infect Dis 2013; 56:1165.