New Approaches to the Diagnosis and Treatment of Cryptococcal Meningitis

Azure T. Makadzange; Grace McHugh

doi:10.1055/s-0034-1372342

Seminars in Neurology, Inhaltsverzeichnis

Semin Neurol 2014; 34(01): 047-060
DOI: 10.1055/s-0034-1372342

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

New Approaches to the Diagnosis and Treatment of Cryptococcal Meningitis

Authors

Azure T. Makadzange

¹Department of Ragon Institute of MGH, MIT and Harvard, Medicine Harvard Medical School, Boston, Massachusetts

²Department of Medicine, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe
Grace McHugh

³Department of Medicine, Parirenyatwa Hospital Family Care Centre, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe

Abstract

Cryptococcal meningitis remains one of the leading causes of morbidity and mortality among immunosuppressed individuals, particularly those with advanced acquired immunodeficiency syndrome. The greatest burden of disease is in sub-Saharan Africa and Asia where there is limited access to diagnostics and treatment for the disease. The authors review the available tools for diagnosing cryptococcal meningitis and review treatment for cryptococcal meningitis, highlighting the evidence behind current treatment guidelines.

Keywords

cryptococcal meningitis - human immunodeficiency virus - acquired immunodeficiency syndrome - sub-Saharan Africa

Volltext

Referenzen

References
1 Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009; 23 (4) 525-530
2 Hakim JG, Gangaidzo IT, Heyderman RS , et al. Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS 2000; 14 (10) 1401-1407
3 Scarborough M, Gordon SB, Whitty CJ , et al. Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med 2007; 357 (24) 2441-2450
4 Mwaba P, Mwansa J, Chintu C , et al. Clinical presentation, natural history, and cumulative death rates of 230 adults with primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions. Postgrad Med J 2001; 77 (914) 769-773
5 French N, Gray K, Watera C , et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 2002; 16 (7) 1031-1038
6 Bennett JE, Kwon-Chung KJ, Howard DH. Epidemiologic differences among serotypes of Cryptococcus neoformans . Am J Epidemiol 1977; 105 (6) 582-586
7 Grover N, Nawange SR, Naidu J, Singh SM, Sharma A. Ecological niche of Cryptococcus neoformans var. grubii and Cryptococcus gattii in decaying wood of trunk hollows of living trees in Jabalpur City of Central India. Mycopathologia 2007; 164 (4) 159-170
8 Kielstein P, Hotzel H, Schmalreck A, Khaschabi D, Glawischnig W. Occurrence of Cryptococcus spp. in excreta of pigeons and pet birds. Mycoses 2000; 43 (1-2) 7-15
9 Kwon-Chung KJ, Bennett JE. Epidemiologic differences between the two varieties of Cryptococcus neoformans . Am J Epidemiol 1984; 120 (1) 123-130
10 Ellis DH. Cryptococcus neoformans var. gattii in Australia. J Clin Microbiol 1987; 25 (2) 430-431
11 Ellis DH, Pfeiffer TJ. Natural habitat of Cryptococcus neoformans var. gattii . J Clin Microbiol 1990; 28 (7) 1642-1644
12 Galanis E, Macdougall L, Kidd S, Morshed M ; British Columbia Cryptococcus gattii Working Group. Epidemiology of Cryptococcus gattii, British Columbia, Canada, 1999-2007. Emerg Infect Dis 2010; 16 (2) 251-257 . Erratum in: Emerg Infect Dis 2010;16(4):750. Kidd, Sarah [added]; Morshed, Mohammad [added]; British Columbia Cryptococcus gattii Working Group [added]. Emerg Infect Dis 2011;17(9):1784
13 Gluck JL, Myers JP, Pass LM. Cryptococcemia due to Cryptococcus albidus . South Med J 1987; 80 (4) 511-513
14 Melo JC, Srinivasan S, Scott ML, Raff MJ. Cryptococcus albidus meningitis. J Infect 1980; 2 (1) 79-82
15 Kamalam A, Yesudian P, Thambiah AS. Cutaneous infection by Cryptococcus laurentii . Br J Dermatol 1977; 97 (2) 221-223
16 Lynch III JP, Schaberg DR, Kissner DG, Kauffman CA. Cryptococcus laurentii lung abscess. Am Rev Respir Dis 1981; 123 (1) 135-138
17 Binder L, Csillag A, Toth G. Diffuse infiltration of the lungs associated with Cryptocococcus luteolus . Lancet 1956; 270 (6931) 1043-1045
18 Hajjeh RA, Conn LA, Stephens DS , et al; Cryptococcal Active Surveillance Group. Cryptococcosis: population-based multistate active surveillance and risk factors in human immunodeficiency virus-infected persons. J Infect Dis 1999; 179 (2) 449-454
19 Dromer F, Mathoulin-Pélissier S, Fontanet A, Ronin O, Dupont B, Lortholary O ; French Cryptococcosis Study Group. Epidemiology of HIV-associated cryptococcosis in France (1985-2001): comparison of the pre- and post-HAART eras. AIDS 2004; 18 (3) 555-562
20 Bratton EW, El Husseini N, Chastain CA , et al. Comparison and temporal trends of three groups with cryptococcosis: HIV-infected, solid organ transplant, and HIV-negative/non-transplant. PLoS ONE 2012; 7 (8) e43582
21 Pyrgos V, Seitz AE, Steiner CA, Prevots DR, Williamson PR. Epidemiology of cryptococcal meningitis in the US: 1997-2009. PLoS ONE 2013; 8 (2) e56269
22 McCarthy KM, Morgan J, Wannemuehler KA , et al. Population-based surveillance for cryptococcosis in an antiretroviral-naive South African province with a high HIV seroprevalence. AIDS 2006; 20 (17) 2199-2206
23 Meiring ST, Quan VC, Cohen C , et al; Group for Enteric, Respiratory and Meningeal disease Surveillance in South Africa (GERMS-SA). A comparison of cases of paediatric-onset and adult-onset cryptococcosis detected through population-based surveillance, 2005-2007. AIDS 2012; 26 (18) 2307-2314
24 Ganiem AR, Parwati I, Wisaksana R , et al. The effect of HIV infection on adult meningitis in Indonesia: a prospective cohort study. AIDS 2009; 23 (17) 2309-2316
25 Jarvis JN, Boulle A, Loyse A , et al. High ongoing burden of cryptococcal disease in Africa despite antiretroviral roll out. AIDS 2009; 23 (9) 1182-1183
26 Bamba S, Lortholary O, Sawadogo A, Millogo A, Guiguemdé RT, Bretagne S. Decreasing incidence of cryptococcal meningitis in West Africa in the era of highly active antiretroviral therapy. AIDS 2012; 26 (8) 1039-1041
27 Goldman DL, Khine H, Abadi J , et al. Serologic evidence for Cryptococcus neoformans infection in early childhood. Pediatrics 2001; 107 (5) E66
28 Abadi J, Pirofski La. Antibodies reactive with the cryptococcal capsular polysaccharide glucuronoxylomannan are present in sera from children with and without human immunodeficiency virus infection. J Infect Dis 1999; 180 (3) 915-919
29 Davis J, Zheng WY, Glatman-Freedman A , et al. Serologic evidence for regional differences in pediatric cryptococcal infection. Pediatr Infect Dis J 2007; 26 (6) 549-551
30 Byrnes III EJ, Li W, Lewit Y , et al. First reported case of Cryptococcus gattii in the Southeastern USA: implications for travel-associated acquisition of an emerging pathogen. PLoS ONE 2009; 4 (6) e5851
31 Lindberg J, Hagen F, Laursen A, Stenderup J, Boekhout T. Cryptococcus gattii risk for tourists visiting Vancouver Island, Canada. Emerg Infect Dis 2007; 13 (1) 178-179
32 Shao X, Mednick A, Alvarez M, van Rooijen N, Casadevall A, Goldman DL. An innate immune system cell is a major determinant of species-related susceptibility differences to fungal pneumonia. J Immunol 2005; 175 (5) 3244-3251
33 Huffnagle GB, Yates JL, Lipscomb MF. T cell-mediated immunity in the lung: a Cryptococcus neoformans pulmonary infection model using SCID and athymic nude mice. Infect Immun 1991; 59 (4) 1423-1433
34 Kawakami K, Qureshi MH, Zhang T, Okamura H, Kurimoto M, Saito A. IL-18 protects mice against pulmonary and disseminated infection with Cryptococcus neoformans by inducing IFN-gamma production. J Immunol 1997; 159 (11) 5528-5534
35 Miyagi K, Kawakami K, Kinjo Y , et al. CpG oligodeoxynucleotides promote the host protective response against infection with Cryptococcus neoformans through induction of interferon-gamma production by CD4+ T cells. Clin Exp Immunol 2005; 140 (2) 220-229
36 Jarvis JN, Casazza JP, Stone HH , et al. The phenotype of the Cryptococcus-specific CD4+ memory T-cell response is associated with disease severity and outcome in HIV-associated cryptococcal meningitis. J Infect Dis 2013; 207 (12) 1817-1828
37 Lortholary O, Improvisi L, Rayhane N , et al. Cytokine profiles of AIDS patients are similar to those of mice with disseminated Cryptococcus neoformans infection. Infect Immun 1999; 67 (12) 6314-6320
38 Garcia-Hermoso D, Janbon G, Dromer F. Epidemiological evidence for dormant Cryptococcus neoformans infection. J Clin Microbiol 1999; 37 (10) 3204-3209
39 Saha DC, Goldman DL, Shao X , et al. Serologic evidence for reactivation of cryptococcosis in solid-organ transplant recipients. Clin Vaccine Immunol 2007; 14 (12) 1550-1554
40 Ieong MH, Reardon CC, Levitz SM, Kornfeld H. Human immunodeficiency virus type 1 infection of alveolar macrophages impairs their innate fungicidal activity. Am J Respir Crit Care Med 2000; 162 (3 Pt 1) 966-970
41 Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med 1989; 321 (12) 794-799
42 Moosa MY, Coovadia YM. Cryptococcal meningitis in Durban, South Africa: a comparison of clinical features, laboratory findings, and outcome for human immunodeficiency virus (HIV)-positive and HIV-negative patients. Clin Infect Dis 1997; 24 (2) 131-134
43 Heyderman RS, Gangaidzo IT, Hakim JG , et al. Cryptococcal meningitis in human immunodeficiency virus-infected patients in Harare, Zimbabwe. Clin Infect Dis 1998; 26 (2) 284-289
44 Lee SC, Dickson DW, Casadevall A. Pathology of cryptococcal meningoencephalitis: analysis of 27 patients with pathogenetic implications. Hum Pathol 1996; 27 (8) 839-847
45 Graybill JR, Sobel J, Saag M , et al; The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis 2000; 30 (1) 47-54
46 Johnston SR, Corbett EL, Foster O, Ash S, Cohen J. Raised intracranial pressure and visual complications in AIDS patients with cryptococcal meningitis. J Infect 1992; 24 (2) 185-189
47 Crump JR, Elner SG, Elner VM, Kauffman CA. Cryptococcal endophthalmitis: case report and review. Clin Infect Dis 1992; 14 (5) 1069-1073
48 Saha DC, Xess I, Jain N. Evaluation of conventional & serological methods for rapid diagnosis of cryptococcosis. Indian J Med Res 2008; 127 (5) 483-488
49 Thiruchelvan N, Wuu KY, Arseculeratne SN, Ashraful-Haq J. A pseudo-cryptococcal artefact derived from leucocytes in wet India ink mounts of centrifuged cerebrospinal fluid. J Clin Pathol 1998; 51 (3) 246-248
50 Lee SC, Casadevall A, Dickson DW. Immunohistochemical localization of capsular polysaccharide antigen in the central nervous system cells in cryptococcal meningoencephalitis. Am J Pathol 1996; 148 (4) 1267-1274
51 Butler WT, Alling DW, Spickard A, Utz JP. Diagnostic and prognostic value of clinical and laboratory findings in cryptococcal meningitis, a follow-up study of forty patients. N Engl J Med 1964; 270: 59-67
52 Bloomfield N, Gordon MA, Elmendorf Jr DF. Detection of Cryptococcus neoformans antigen in body fluids by latex particle agglutination. Proc Soc Exp Biol Med 1963; 114 (1) 64-67
53 Bennett JE, Hasenclever HF, Tynes BS. Detection of cryptococcal polysaccharide in serum and spinal fluid: value in diagnosis and prognosis. Trans Assoc Am Physicians 1964; 77: 145-150
54 Tanner DC, Weinstein MP, Fedorciw B, Joho KL, Thorpe JJ, Reller L. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol 1994; 32 (7) 1680-1684
55 Hamilton JR, Noble A, Denning DW, Stevens DA. Performance of cryptococcus antigen latex agglutination kits on serum and cerebrospinal fluid specimens of AIDS patients before and after pronase treatment. J Clin Microbiol 1991; 29 (2) 333-339
56 Gade W, Hinnefeld SW, Babcock LS , et al. Comparison of the PREMIER cryptococcal antigen enzyme immunoassay and the latex agglutination assay for detection of cryptococcal antigens. J Clin Microbiol 1991; 29 (8) 1616-1619
57 Binnicker MJ, Jespersen DJ, Bestrom JE, Rollins LO. Comparison of four assays for the detection of cryptococcal antigen. Clin Vaccine Immunol 2012; 19 (12) 1988-1990
58 Lindsley MD, Mekha N, Baggett HC , et al. Evaluation of a newly developed lateral flow immunoassay for the diagnosis of cryptococcosis. Clin Infect Dis 2011; 53 (4) 321-325
59 Jarvis JN, Percival A, Bauman S , et al. Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis. Clin Infect Dis 2011; 53 (10) 1019-1023
60 Gates-Hollingsworth MA, Kozel TR. Serotype sensitivity of a lateral flow immunoassay for cryptococcal antigen. Clin Vaccine Immunol 2013; 20 (4) 634-635
61 Hansen J, Slechta ES, Gates-Hollingsworth MA , et al. Large-scale evaluation of the immuno-mycologics lateral flow and enzyme-linked immunoassays for detection of cryptococcal antigen in serum and cerebrospinal fluid. Clin Vaccine Immunol 2013; 20 (1) 52-55
62 Lawn SD, Wood R. Point-of-care urine antigen screening tests for tuberculosis and cryptococcosis: potential for mortality reduction in antiretroviral treatment programs in Africa. Clin Infect Dis 2012; 54 (5) 739-740
63 Bennett JE, Dismukes WE, Duma RJ , et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N Engl J Med 1979; 301 (3) 126-131
64 Hospenthal DR, Bennett JE. Flucytosine monotherapy for cryptococcosis. Clin Infect Dis 1998; 27 (2) 260-264
65 Spickard A, Butler WT, Andriole V, Utz JP. The improved prognosis of cryptococcal meningitis with amphotericin B therapy. Ann Intern Med 1963; 58: 66-83
66 Rothe C, Sloan DJ, Goodson P , et al. A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800. mg oral fluconazole in Blantyre, Malawi. PLoS ONE 2013; 8 (6) e67311
67 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 (3) 291-322
68 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 (1) 123-130
69 Miller RP, Bates JH. Amphotericin B toxicity. A follow-up report of 53 patients. Ann Intern Med 1969; 71 (6) 1089-1095
70 Bozzette SA, Larsen RA, Chiu J , et al; California Collaborative Treatment Group. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. N Engl J Med 1991; 324 (9) 580-584
71 Kirk O, Reiss P, Uberti-Foppa C , et al; European HIV Cohorts. Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Ann Intern Med 2002; 137 (4) 239-250
72 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 (10) 1329-1331
73 Haddow LJ, Colebunders R, Meintjes G , et al; International Network for the Study of HIV-associated IRIS (INSHI). Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 2010; 10 (11) 791-802
74 Boulware DR, Meya DB, Bergemann TL , et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med 2010; 7 (12) e1000384
75 Shelburne SA, Visnegarwala F, Darcourt J , et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005; 19 (4) 399-406
76 Skiest DJ, Hester LJ, Hardy RD. Cryptococcal immune reconstitution inflammatory syndrome: report of four cases in three patients and review of the literature. J Infect 2005; 51 (5) e289-e297
77 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 (5) e5575
78 Havlir DV, Kendall MA, Ive P , et al; AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011; 365 (16) 1482-1491
79 Blanc FX, Sok T, Laureillard D , et al; CAMELIA (ANRS 1295–CIPRA KH001) Study Team. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011; 365 (16) 1471-1481
80 Abdool Karim SS, Naidoo K, Grobler A , et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011; 365 (16) 1492-1501
81 Török ME, Yen NT, Chau TT , et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)—associated tuberculous meningitis. Clin Infect Dis 2011; 52 (11) 1374-1383
82 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 (11) 1532-1538
83 Boulware D et al. ART initiation within the first 2 weeks of cryptococcal meningitis is associated with higher mortality: a multisite randomized trial. 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta, GA. Oral abstract 144
84 Pongsai P, Atamasirikul K, Sungkanuparph S. The role of serum cryptococcal antigen screening for the early diagnosis of cryptococcosis in HIV-infected patients with different ranges of CD4 cell counts. J Infect 2010; 60 (6) 474-477
85 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 (4) 448-455
86 Jarvis JN, Lawn SD, Vogt M, Bangani N, Wood R, Harrison TS. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clin Infect Dis 2009; 48 (7) 856-862
87 Meyer AC, Kendi CK, Penner JA , et al. The impact of routine cryptococcal antigen screening on survival among HIV-infected individuals with advanced immunosuppression in Kenya. Trop Med Int Health 2013; 18 (4) 495-503
88 Meyer AC, Jacobson M. Asymptomatic cryptococcemia in resource-limited settings. Curr HIV/AIDS Rep 2013; 10 (3) 254-263
89 World Health Organization. Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. http://www.who.int/hiv/pub/cryptococcal_disease2011/ . 2011. Accessed November 20, 2013
90 Govender NP, Meintjes G, Bicanic T , et al. Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV infected persons: 2013 update. S Afr J HIV Med 2013; 14 (2) 76-86
91 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/adult_oi.pdf . 2013. Accessed November 20, 2013
92 van der Horst CM, Saag MS, Cloud GA , et al; National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 1997; 337 (1) 15-21
93 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 (2) 225-232
94 Brouwer AE, Rajanuwong A, Chierakul W , et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004; 363 (9423) 1764-1767
95 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 (12) 1775-1783
96 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 (1) 121-128
97 Day JN, Chau TT, Wolbers M , et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med 2013; 368 (14) 1291-1302
98 Bicanic T, Meintjes G, Wood R , et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis 2007; 45 (1) 76-80
99 Muzoora CK, Kabanda T, Ortu G , et al. Short course amphotericin B with high dose fluconazole for HIV-associated cryptococcal meningitis. J Infect 2012; 64 (1) 76-81
100 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 (11) 1363-1370
101 Nussbaum JC, Jackson A, Namarika D , 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) 338-344
102 Longley N, Muzoora C, Taseera K , et al. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin Infect Dis 2008; 47 (12) 1556-1561