Treatment of Cryptococcal Meningitis Associated with the Acquired Immunodeficiency Syndrome
Charles M. van der Horst, M.D., Michael S. Saag, M.D., Gretchen A. Cloud, M.S., Richard J. Hamill, M.D., J. Richard Graybill, M.D., Jack D. Sobel, M.D., Philip C. Johnson, M.D., Carmelita U. Tuazon, M.D., Thomas Kerkering, M.D., Bruce L. Moskovitz, M.D., William G. Powderly, M.D., William E. Dismukes, M.D., for The National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group
Background Treatment with low-dose amphotericin B (0.4 mg perkilogram of body weight per day) or oral azole therapy in patientswith the acquired immunodeficiency syndrome (AIDS) and cryptococcalmeningitis has been associated with high mortality and low ratesof cerebrospinal fluid sterilization.
Methods In a double-blind multicenter trial we randomly assignedpatients with a first episode of AIDS-associated cryptococcalmeningitis to treatment with higher-dose amphotericin B (0.7mg per kilogram per day) with or without flucytosine (100 mgper kilogram per day) for two weeks (step one), followed byeight weeks of treatment with itraconazole (400 mg per day)or fluconazole (400 mg per day) (step two). Treatment was consideredsuccessful if cerebrospinal fluid cultures were negative at2 and 10 weeks or if the patient was clinically stable at 2weeks and asymptomatic at 10 weeks.
Results At two weeks, the cerebrospinal fluid cultures werenegative in 60 percent of the 202 patients receiving amphotericinB plus flucytosine and in 51 percent of the 179 receiving amphotericinB alone (P = 0.06). Elevated intracranial pressure was associatedwith death in 13 of 14 patients during step one. The clinicaloutcome did not differ significantly between the two groups.Seventy-two percent of the 151 fluconazole recipients and 60percent of the 155 itraconazole recipients had negative culturesat 10 weeks (95 percent confidence interval for the differencein percentages, -100 to 21). The proportion of patients whohad clinical responses was similar with fluconazole (68 percent)and itraconazole (70 percent). Overall mortality was 5.5 percentin the first two weeks and 3.9 percent in the next eight weeks,with no significant difference between the groups. In a multivariateanalysis, the addition of flucytosine during the initial twoweeks and treatment with fluconazole for the next eight weekswere independently associated with cerebrospinal fluid sterilization.
Conclusions For the initial treatment of AIDS-associated cryptococcalmeningitis, the use of higher-dose amphotericin B plus flucytosineis associated with an increased rate of cerebrospinal fluidsterilization and decreased mortality at two weeks, as comparedwith regimens used in previous studies. Although consolidationtherapy with fluconazole is associated with a higher rate ofcerebrospinal fluid sterilization, itraconazole may be a suitablealternative for patients unable to take fluconazole.
Source Information
From the Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill (C.M.H.); the Division of Infectious Diseases, Department of Medicine (M.S.S., W.E.D.), and the Biostatistics Unit, Comprehensive Cancer Center (G.A.C.), University of Alabama School of Medicine at Birmingham, Birmingham; the Section of Infectious Diseases, Veterans Affairs Medical Center and Baylor College of Medicine, Houston (R.J.H.); the University of Texas Health Sciences Center, San Antonio (J.R.G.); the Division of Infectious Diseases, Wayne State University, Detroit (J.D.S.); the Department of Medicine, University of Texas–Houston Medical Center, Houston (P.C.J.); the Department of Medicine, George Washington University, Washington, D.C. (C.U.T.); the Division of Infectious Diseases, Medical College of Virginia, Richmond (T.K.); the Janssen Research Foundation, Titusville, N.J. (B.L.M.); and the Division of Infectious Diseases, Washington University School of Medicine, St. Louis (W.G.P.). Presented in part at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 17–20, 1995.
Address reprint requests to Dr. van der Horst at the Division of Infectious Diseases, C.B.# 7030, University of North Carolina, Chapel Hill, NC 27599-7030.
ESPOSITO, V., VIGLIETTI, R., GARGIULO, M., PARRELLA, R., ONOFRIO, M., SANGIOVANNI, V., AMBROSINO, D., CHIRIANNI, A.
(2009). Successful Treatment of Cryptococcal Meningitis with a Combination of Liposomal Amphotericin B, Flucytosine and Posaconazole: Two Case Reports. In Vivo
23: 465-468
[Abstract][Full Text]
Karam, G. H.
(2009). Infections in AIDS Patients and Other Immunocompromised Hosts. ACCP Crit Care Med Brd Rev
20: 13-40
[Full Text]
Karam, G. H.
(2009). Nervous System Infections and Catheter Infections. ACCP Crit Care Med Brd Rev
20: 41-74
[Full Text]
Manosuthi, W., Sungkanuparph, S., Chottanapund, S., Tansuphaswadikul, S., Chimsuntorn, S., Limpanadusadee, P., Pappas, P. G
(2008). Temporary external lumbar drainage for reducing elevated intracranial pressure in HIV-infected patients with cryptococcal meningitis. Int J STD AIDS
19: 268-271
[Abstract][Full Text]
Davaro, R. E., Thirumalai, A.
(2007). Life-Threatening Complications of HIV Infection. J Intensive Care Med
22: 73-81
[Abstract]
Brouwer, A. E., van Kan, H. J. M., Johnson, E., Rajanuwong, A., Teparrukkul, P., Wuthiekanun, V., Chierakul, W., Day, N., Harrison, T. S.
(2007). Oral versus Intravenous Flucytosine in Patients with Human Immunodeficiency Virus-Associated Cryptococcal Meningitis. Antimicrob. Agents Chemother.
51: 1038-1042
[Abstract][Full Text]
Wormley, F. L. Jr., Perfect, J. R., Steele, C., Cox, G. M.
(2007). Protection against Cryptococcosis by Using a Murine Gamma Interferon-Producing Cryptococcus neoformans Strain. Infect. Immun.
75: 1453-1462
[Abstract][Full Text]
Beenhouwer, D. O., Yoo, E. M., Lai, C.-W., Rocha, M. A., Morrison, S. L.
(2007). Human Immunoglobulin G2 (IgG2) and IgG4, but Not IgG1 or IgG3, Protect Mice against Cryptococcus neoformans Infection. Infect. Immun.
75: 1424-1435
[Abstract][Full Text]
Schwarz, P., Janbon, G., Dromer, F., Lortholary, O., Dannaoui, E.
(2007). Combination of Amphotericin B with Flucytosine Is Active In Vitro against Flucytosine-Resistant Isolates of Cryptococcus neoformans. Antimicrob. Agents Chemother.
51: 383-385
[Abstract][Full Text]
Larsen, R. A., Bauer, M., Brouwer, A. E., Sanchez, A., Thomas, A. M., Rajanuwong, A., Chierakul, W., Peacock, S. J., Day, N., White, N. J., Rinaldi, M. G., Harrison, T. S.
(2007). In Vitro-Clinical Correlations for Amphotericin B Susceptibility in AIDS-Associated Cryptococcal Meningitis. Antimicrob. Agents Chemother.
51: 343-345
[Abstract][Full Text]
Lui, G., Lee, N., Ip, M., Choi, K.W., Tso, Y.K., Lam, E., Chau, S., Lai, R., Cockram, C.S.
(2006). Cryptococcosis in apparently immunocompetent patients. QJM
99: 143-151
[Abstract][Full Text]
Duffalo, M. L.
(2006). Fungal Opportunistic Infections in HIV Disease. Journal of Pharmacy Practice
19: 17-30
[Abstract]
Schwarz, P., Dromer, F., Lortholary, O., Dannaoui, E.
(2006). Efficacy of Amphotericin B in Combination with Flucytosine against Flucytosine-Susceptible or Flucytosine-Resistant Isolates of Cryptococcus neoformans during Disseminated Murine Cryptococcosis. Antimicrob. Agents Chemother.
50: 113-120
[Abstract][Full Text]
Pitisuttithum, P., Negroni, R., Graybill, J. R., Bustamante, B., Pappas, P., Chapman, S., Hare, R. S., Hardalo, C. J.
(2005). Activity of posaconazole in the treatment of central nervous system fungal infections. J Antimicrob Chemother
56: 745-755
[Abstract][Full Text]
Ioannidis, J. P. A.
(2005). Contradicted and Initially Stronger Effects in Highly Cited Clinical Research. JAMA
294: 218-228
[Abstract][Full Text]
Mylonakis, E., Moreno, R., El Khoury, J. B., Idnurm, A., Heitman, J., Calderwood, S. B., Ausubel, F. M., Diener, A.
(2005). Galleria mellonella as a Model System To Study Cryptococcus neoformans Pathogenesis. Infect. Immun.
73: 3842-3850
[Abstract][Full Text]
Michalik, D. E., Greene, G., Yang, F.
(2005). Diagnosis Disseminated Cryptococcosis. CLIN PEDIATR
44: 460-462
Bicanic, T., Harrison, T. S.
(2005). Cryptococcal meningitis. Br Med Bull
72: 99-118
[Abstract][Full Text]
Larsen, R. A., Pappas, P. G., Perfect, J., Aberg, J. A., Casadevall, A., Cloud, G. A., James, R., Filler, S., Dismukes, W. E.
(2005). Phase I Evaluation of the Safety and Pharmacokinetics of Murine-Derived Anticryptococcal Antibody 18B7 in Subjects with Treated Cryptococcal Meningitis. Antimicrob. Agents Chemother.
49: 952-958
[Abstract][Full Text]
Siddiqui, A. A., Brouwer, A. E., Wuthiekanun, V., Jaffar, S., Shattock, R., Irving, D., Sheldon, J., Chierakul, W., Peacock, S., Day, N., White, N. J., Harrison, T. S.
(2005). IFN-{gamma} at the Site of Infection Determines Rate of Clearance of Infection in Cryptococcal Meningitis. J. Immunol.
174: 1746-1750
[Abstract][Full Text]
Mukherjee, P. K., Sheehan, D. J., Hitchcock, C. A., Ghannoum, M. A.
(2005). Combination Treatment of Invasive Fungal Infections. Clin. Microbiol. Rev.
18: 163-194
[Abstract][Full Text]
Somchit, N, Norshahida, A R, Hasiah, A H, Zuraini, A, Sulaiman, M R, Noordin, M M
(2004). Hepatotoxicity induced by antifungal drugs itraconazole and fluconazole in rats: a comparative in vivo study. Hum Exp Toxicol
23: 519-525
[Abstract]
Cuenca-Estrella, M.
(2004). Combinations of antifungal agents in therapy-what value are they?. J Antimicrob Chemother
54: 854-869
[Abstract][Full Text]
Johnson, M. D., MacDougall, C., Ostrosky-Zeichner, L., Perfect, J. R., Rex, J. H.
(2004). Combination Antifungal Therapy. Antimicrob. Agents Chemother.
48: 693-715
[Full Text]
Larsen, R. A., Bauer, M., Thomas, A. M., Graybill, J. R.
(2004). Amphotericin B and Fluconazole, a Potent Combination Therapy for Cryptococcal Meningitis. Antimicrob. Agents Chemother.
48: 985-991
[Abstract][Full Text]
Woyke, T., Berens, M. E., Hoelzinger, D. B., Pettit, G. R., Winkelmann, G., Pettit, R. K.
(2004). Differential Gene Expression in Auristatin PHE-Treated Cryptococcus neoformans. Antimicrob. Agents Chemother.
48: 561-567
[Abstract][Full Text]
Schwarz, P., Dromer, F., Lortholary, O., Dannaoui, E.
(2003). In Vitro Interaction of Flucytosine with Conventional and New Antifungals against Cryptococcus neoformans Clinical Isolates. Antimicrob. Agents Chemother.
47: 3361-3364
[Abstract][Full Text]
Ette, E. I., Williams, P. J., Kim, Y. H., Lane, J. R., Liu, M.-J., Capparelli, E. V.
(2003). Model Appropriateness and Population Pharmacokinetic Modeling. J Clin Pharmacol
43: 610-623
[Abstract][Full Text]
Imbert, F., Jardin, M., Fernandez, C., Gantier, J. C., Dromer, F., Baron, G., Mentre, F., van Beijsterveldt, L., Singlas, E., Gimenez, F.
(2003). Effect of Efflux Inhibition on Brain Uptake of Itraconazole in Mice Infected with Cryptococcus neoformans. Drug Metab. Dispos.
31: 319-325
[Abstract][Full Text]
Johnson, M. D., Hamilton, C. D., Drew, R. H., Sanders, L. L., Pennick, G. J., Perfect, J. R.
(2003). A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution. J Antimicrob Chemother
51: 453-457
[Abstract][Full Text]
Beenhouwer, D. O., May, R. J., Valadon, P., Scharff, M. D.
(2002). High Affinity Mimotope of the Polysaccharide Capsule of Cryptococcus neoformans Identified from an Evolutionary Phage Peptide Library. J. Immunol.
169: 6992-6999
[Abstract][Full Text]
Woyke, T., Roberson, R. W., Pettit, G. R., Winkelmann, G., Pettit, R. K.
(2002). Effect of Auristatin PHE on Microtubule Integrity and Nuclear Localization in Cryptococcus neoformans. Antimicrob. Agents Chemother.
46: 3802-3808
[Abstract][Full Text]
Troncoso, A., Fumagalli, J., Shinzato, R., Gulotta, H., Toller, M., Bava, J.
(2002). CNS Cryptococcoma in an HIV-Positive Patient. J Int Assoc Physicians AIDS Care (Chic Ill)
1: 131-133
[Abstract]
Mwaba, P, Mwansa, J, Chintu, C, Pobee, J, Scarborough, M, Portsmouth, S, Zumla, A
(2001). 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.
77: 769-773
[Abstract][Full Text]
Cruz, M. C., Goldstein, A. L., Blankenship, J., Del Poeta, M., Perfect, J. R., McCusker, J. H., Bennani, Y. L., Cardenas, M. E., Heitman, J.
(2001). Rapamycin and Less Immunosuppressive Analogs Are Toxic to Candida albicans and Cryptococcus neoformans via FKBP12-Dependent Inhibition of TOR. Antimicrob. Agents Chemother.
45: 3162-3170
[Abstract][Full Text]
Beenhouwer, D. O., Shapiro, S., Feldmesser, M., Casadevall, A., Scharff, M. D.
(2001). Both Th1 and Th2 Cytokines Affect the Ability of Monoclonal Antibodies To Protect Mice against Cryptococcus neoformans. Infect. Immun.
69: 6445-6455
[Abstract][Full Text]
Purdy, B. D.
(2000). Management and Prevention of Opportunistic Infections in the HIV-Infected Patient. Journal of Pharmacy Practice
13: 475-498
[Abstract]
Vermes, A., Guchelaar, H.-J., Dankert, J.
(2000). Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother
46: 171-179
[Abstract][Full Text]
Cabre, P, Smadja, D, Cabié, A, Newton, C R J C
(2000). NEUROLOGICAL ASPECTS OF TROPICAL DISEASE: HTLV-1 and HIV infections of the central nervous system in tropical areas. J. Neurol. Neurosurg. Psychiatry
68: 550-557
[Full Text]
Clayette, P., Martin, M., Beringue, V., Dereuddre-Bosquet, N., Adjou, K. T., Seman, M., Dormont, D.
(2000). Effects of MS-8209, an Amphotericin B Derivative, on Tumor Necrosis Factor Alpha Synthesis and Human Immunodeficiency Virus Replication in Macrophages. Antimicrob. Agents Chemother.
44: 405-407
[Abstract][Full Text]
Rodero, L., Cordoba, S., Cahn, P., Hochenfellner, F., Davel, G., Canteros, C., Kaufman, S., Guelfand, L.
(2000). In vitro susceptibility studies of Cryptococcus neoformans isolated from patients with no clinical response to amphotericin B therapy. J Antimicrob Chemother
45: 239-242
[Abstract][Full Text]
Andriole, V. T.
(1999). Current and future antifungal therapy: new targets for antifungal agents. J Antimicrob Chemother
44: 151-162
[Abstract][Full Text]
Lortholary, O., Nicolas, M., Soreda, S., Improvisi, L., Ronin, O., Petitjean, O., Dupont, B., Tod, M., Dromer, F.
(1999). Fluconazole, with or without dexamethasone for experimental cryptococcosis: impact of treatment timing. J Antimicrob Chemother
43: 817-824
[Abstract][Full Text]
Limousin, P., Brown, R. G., Jahanshahi, M., Asselman, P., Quinn, N. P., Thomas, D., Obeso, J. A., Rothwell, J. C.
(1999). The effects of posteroventral pallidotomy on the preparation and execution of voluntary hand and arm movements in Parkinson's disease. Brain
122: 315-327
[Abstract][Full Text]
Pfaller, M. A., Zhang, J., Messer, S. A., Brandt, M. E., Hajjeh, R. A., Jessup, C. J., Tumberland, M., Mbidde, E. K., Ghannoum, M. A.
(1999). In Vitro Activities of Voriconazole, Fluconazole, and Itraconazole against 566 Clinical Isolates of Cryptococcus neoformans from the United States and Africa. Antimicrob. Agents Chemother.
43: 169-171
[Abstract][Full Text]
Klepser, M. E., Pfaller, M. A.
(1998). Variation in Electrophoretic Karyotype and Antifungal Susceptibility of Clinical Isolates of Cryptococcus neoformans at a University-Affiliated Teaching Hospital from 1987 to 1994. J. Clin. Microbiol.
36: 3653-3656
[Abstract][Full Text]
Schell, W. A., De Almeida, G. M. D., Dodge, R. K., Okonogi, K., Perfect, J. R.
(1998). In Vitro and In Vivo Efficacy of the Triazole TAK-187 against Cryptococcus neoformans. Antimicrob. Agents Chemother.
42: 2630-2632
[Abstract][Full Text]
(1998). Antiretroviral Therapy and Medical Management of Pediatric HIV Infection. Pediatrics
102: 1005-1062
[Full Text]
Lewis, R. E., Lund, B. C., Klepser, M. E., Ernst, E. J., Pfaller, M. A.
(1998). Assessment of Antifungal Activities of Fluconazole and Amphotericin B Administered Alone and in Combination against Candida albicans by Using a Dynamic In Vitro Mycotic Infection Model. Antimicrob. Agents Chemother.
42: 1382-1386
[Abstract][Full Text]
Lodge, J. K., Jackson-Machelski, E., Higgins, M., McWherter, C. A., Sikorski, J. A., Devadas, B., Gordon, J. I.
(1998). Genetic and Biochemical Studies Establish That the Fungicidal Effect of a Fully Depeptidized Inhibitor of Cryptococcus neoformans Myristoyl-CoA:Protein N-Myristoyltransferase (Nmt) Is Nmt-dependent. J. Biol. Chem.
273: 12482-12491
[Abstract][Full Text]
Larsen, R. A., Zingman, B. S., Saag, M. S., Cloud, G. A., van der Horst, C.
(1997). Treatment of Cryptococcal Meningitis. NEJM
337: 1557-1558
[Full Text]
(1997). Cryptococcal Meningitis. AIDS Clin Care
1997: 7-7
[Full Text]
A correction has been published: N Engl J Med 1997;337(21):1557.
Previous
