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Cryptococcosis
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Epidemiology

The majority of HIV-associated cryptococcal infections are caused by Cryptococcus neoformans; rarely, infection because of Cryptococcus neoformans var. gattii is recognized in the United States. Before the advent of potent ART, approximately 5%-8% of HIV-infected patients in developed countries acquired disseminated cryptococcosis (591Aberg JA, Powderly WG. Cryptococcosis. In: Dolin R, Masur H, Saag MS, eds. AIDS Therapy. New York, NY: Churcill Livingstone 2002:498-510.). The incidence has declined substantially since then (592Mirza S, Phelan M, Rimland D, et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992-2000. Clin Infect Dis 2003;36:789-94.). The majority of cases are observed among patients who have CD4+ counts of <50 cells/µL.

Clinical Manifestations

Among patients with HIV infection, cryptococcosis most commonly occurs as a subacute meningitis or meningoencephalitis with fever, malaise, and headache (591Aberg JA, Powderly WG. Cryptococcosis. In: Dolin R, Masur H, Saag MS, eds. AIDS Therapy. New York, NY: Churcill Livingstone 2002:498-510.). Classic meningeal symptoms and signs, such as neck stiffness and photophobia, occur in only one fourth to one third of patients. Encephalopathic symptoms, including lethargy, altered mentation, personality changes, and memory loss, usually resulting from elevated intracranial pressure, occurs in small groups of patients.

Analysis of CSF usually demonstrates a mildly elevated serum protein; glucose ranging from low to normal; a pleocytosis consisting mostly of lymphocytes, although some patients have no cells; and a positive Gram or India ink stain for numerous yeasts. The opening pressure in the CSF is usually elevated, with pressures >20 cm H2O occurring in up to 75% of patients. When cryptococcosis occurs in the HIV-infected patient, disseminated disease is common. Virtually any organ can be involved, and skin lesions mimicking molluscum contagiosum are frequently observed. In addition, isolated pulmonary infection is evident; symptoms and signs include cough and dyspnea in association with an abnormal chest radiograph.

Diagnosis

Cryptococcal antigen is almost invariably detected in CSF at high titer in patients with meningitis or meningoencephalitis. The serum cryptococcal antigen is also almost always positive in cases of CNS disease and in other instances of disseminated infection. As such, testing for serum cryptococcal antigen is a useful initial screening tool in diagnosing cryptococcosis in HIV-infected patients (593Powderly 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;18:789-92.). Up to 75% of patients with HIV-associated cryptococcal meningitis have routine blood cultures positive for C. neoformans.

Preventing Exposure

HIV-infected persons cannot completely avoid exposure to C. neoformans. Limited epidemiologic evidence suggests that specific activities, including exposure to bird droppings, lead to an increased risk for infection.

Preventing Disease

Because the incidence of cryptococcal disease is low, routine testing of asymptomatic persons for serum cryptococcal antigen is not recommended (DIII).

Prospective, controlled trials indicate that fluconazole and itraconazole can reduce the frequency of primary cryptococcal disease among patients who have CD4+ counts <50 cells/µL (579Powderly WG, Finkelstein D, Feinberg J, et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. N Engl J Med 1995;332:700-5., 594McKinsey DS, Wheat LJ, Cloud GA, et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999;28:1049-56.). However, the majority of HIV specialists recommend that antifungal prophylaxis not be used routinely to prevent cryptococcosis because of the relative infrequency of cryptococcal disease, lack of survival benefits associated with prophylaxis, possibility of drug interactions, potential antifungal drug resistance, and cost (DIII). The need for primary prophylaxis or suppressive therapy for other fungal infections (e.g., candidiasis, histoplasmosis, or coccidioidomycosis) should be considered when making decisions concerning primary prophylaxis for cryptococcosis.

Treatment of Disease

The recommended initial standard treatment is amphotericin B deoxycholate, at a dose of 0.7 mg/kg daily, combined with flucytosine, at a dose of 100 mg/kg daily in four divided doses, for ≥2 weeks for those with normal renal function (AI). Renal function should be monitored closely and the flucytosine dose adjusted appropriately for patients with renal impairment. The addition of flucytosine to amphotericin B during acute treatment is associated with more rapid sterilization of CSF (595Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000;30:710-8., 596van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 1997;337:15-21.). The combination of amphotericin B deoxycholate with fluconazole, 400 mg daily (BII), is inferior to amphotericin B combined with flucytosine for clearing Cryptococcus from CSF but is more effective than amphotericin B alone (BII) (597Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004;363:1764-7.).

Lipid formulations of amphotericin B also are effective and should be considered for patients who experience renal dysfunction during therapy or have a likelihood of having renal failure. The optimal dose of lipid formulations of amphotericin B has not been determined. An unpublished study demonstrated that liposomal amphotericin B (AmBisome®) at a dose of 6 mg/kg daily had an improved outcome over 3 mg/kg daily (598Larsen RA, Bozzette SA, Jones BE, et al. Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1994; 19:741-5.). The noncomparative CLEAR study used a mean dose of amphotericin B lipid complex (ABLC) of 4.4 mg/kg daily to treat cryptococcosis (599Baddour LM, Perfect JR, Ostrosky-Zeichner L. Successful use of amphotericin B lipid complex in the treatment of cryptococcosis. Clin Infect Dis 2005;40(Suppl 6):S409-13.). In an Australian study, a 3-week course of liposomal amphotericin B (AmBisome®) at 4 mg/kg daily resulted in more rapid sterilization of CSF than amphotericin B deoxycholate at 0.7 mg/kg daily (600Leenders 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;11:1463-71.). On the basis of these data, a dose of 4-6 mg/kg daily for lipid formulations of amphotercin B is recommended (AII).

Fluconazole (400-800 mg daily) combined with flucytosine is an alternative to amphotericin B plus flucytosine (598Larsen RA, Bozzette SA, Jones BE, et al. Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1994; 19:741-5.), but is inferior to amphotericin B (601Bicanic 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;45:76-80.) and is recommended only for persons who are unable to tolerate or unresponsive to standard treatment (CII).

After at least a 2-week period of successful induction therapy, defined as substantial clinical improvement and a negative CSF culture after repeat lumbar puncture, amphotericin B and flucytosine may be discontinued and follow-up therapy initiated with fluconazole 400 mg daily (AI). This therapy should continue for 8 weeks (AI) (595Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000;30:710-8., 596van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 1997;337:15-21., 602Saag MS, Cloud GA, Graybill JR, et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis 1999;28:291-6.). Itraconazole is an acceptable though less effective alternative (BI) (602). Limited data are available for the newer triazoles, voriconazole and posaconazole, as either primary or follow-up therapy for patients with cryptococcosis. Voriconazole should be used cautiously with HIV PIs and efavirenz.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Increased ICP can cause clinical deterioration despite a microbiologic response and is more likely if the CSF opening pressure is >20 cm H2O (596van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 1997;337:15-21., 603Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis 2000;30:47-54.). In one large clinical trial, 93% of deaths that occurred within the first 2 weeks of therapy and 40% of deaths that occurred within weeks 3-10 were associated with increased ICP (603Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis 2000;30:47-54.).

At time of diagnosis, all patients with cryptococcal meningitis should have their opening pressure measured in the lateral decubitus position with good manometrics assured; normal values are <25 cm H2O. Patients with confusion, blurred vision, papilledema, lower extremity clonus, or other neurologic signs of increased ICP should be managed using measures to decrease ICP. Daily lumbar punctures are usually recommended for initial management. One approach is to remove a volume (typically 20-30 mL) of CSF that halves the opening pressure (604Fessler 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;17:137-42.). CSF shunting should be considered for patients in whom daily lumbar punctures are no longer tolerated or whose signs and symptoms of cerebral edema are not being relieved (BIII). Corticosteroids, mannitol, and acetazolamide are not recommended (DIII).

After the initial 2 weeks of treatment, a repeat lumbar puncture should be performed to ensure the organism has been cleared from the CSF, even among those who have improved after the initial 2 weeks of treatment. Positive CSF cultures after 2 weeks of therapy are predictive of future relapse and typically less favorable clinical outcomes. If new symptoms or clinical findings occur later, a repeat lumbar puncture, with measurement of opening pressure and CSF culture, should be performed.

Patients treated with amphotericin B should be monitored for dose-dependent nephrotoxicity and electrolyte disturbances. Preinfusion administration of 500 mL of normal saline appears to reduce the risk for nephrotoxicity during treatment. Infusion-related adverse reactions may be ameliorated by pretreatment with acetaminophen and diphenhydramine; in rare cases, glucocorticosteroids administered approximately 30 minutes before the infusion might be required (CIII).

Patients receiving flucytosine should have flucytosine blood levels monitored to prevent bone marrow suppression and gastrointestinal toxicity; peak serum levels, which occur 2 hours after an oral dose, should not exceed 75 µg/mL. Persons treated with fluconazole should be monitored for hepatotoxicity.

An estimated 30% of patients with cryptococcal meningitis and HIV infection experience IRIS after initiation or reinitiation of ART (605Shelburne SA, Darcourt J, White AC, et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 2005; 40:1049-52.). Patients who have cryptococcal IRIS are more likely to be antiretroviral naïve and have higher HIV RNA levels. Appropriate management of IRIS is to continue ART and antifungal therapy (AII). In patients with severely symptomatic IRIS, short-course glucocorticosteroids are recommended by certain specialists (BIII). Delaying the initiation of potent ART might be prudent, at least until the completion of induction therapy (the first 2 weeks) for severe cryptococcosis, especially if patients have elevated ICP (CIII).

Management of Treatment Failure

Treatment failure is defined as either the lack of clinical improvement after 2 weeks of appropriate therapy, including management of increased ICP, or relapse after an initial clinical response, defined as either a positive CSF culture and/or a rising CSF cryptococcal antigen titer with an associated compatible clinical picture. Although fluconazole resistance has been reported with C. neoformans, it is rare in the United States (606Brandt ME, Pfaller M, Hajjeh R, et al. Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. Antimicrob Agents Chemother 2001;45:3065-9.). At this time, susceptibility testing is not recommended routinely (DII).

The optimal therapy for patients with treatment failure has not been established. For those initially treated with fluconazole, therapy should be changed to amphotericin B, with or without flucytosine, and continued until a clinical response occurs (BIII). Liposomal amphotericin B (4-6 mg/kg/day) might have improved efficacy over the deoxycholate formulation (600Leenders 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;11:1463-71., 607Chen SC. Cryptococcosis in Australasia and the treatment of cryptococcal and other fungal infections with liposomal amphotericin B. J Antimicrob Chemother 2002;49(Suppl 1):57-61.) and should be considered in treatment failures (AII). Higher doses of fluconazole in combination with flucytosine also might be useful (BIII). Caspofungin and other echinocandins have no in vitro activity against Cryptococcus spp. and no role in the clinical management of these patients. The newer triazoles, posaconazole and voriconazole, have activity against Cryptococcus spp. in vitro and might have a role in therapy.

Preventing Recurrence

Patients who have completed the initial 10 weeks of therapy for acute cryptococcosis should be administered chronic maintenance therapy with fluconazole 200 mg daily, either lifelong or until immune reconstitution occurs as a consequence of ART (AI). Itraconazole is inferior to fluconazole for preventing relapse of cryptococcal disease (BI) (608Larsen RA. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis 1999;28:297-8., 609Powderly 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. N Engl J Med 1992;326:793-8.).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

The risk for recurrence of cryptococcosis appears low when patients have successfully completed a course of initial therapy, remain asymptomatic with regard to signs and symptoms of cryptococcosis, and have a sustained increase (i.e., >6 months) in their CD4+ counts to ≥200 cells/µL after ART. The numbers of such patients who have been evaluated remain limited. In a European study, none of 39 subjects whose antifungal therapy was discontinued had a recurrence of cryptococcosis. The median CD4+ count of this cohort was 239 cells/µL, the median HIV RNA concentration was <500 copies/mL, and the median time on potent ART was 25 months (610Kirk 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;137:239-50.). A prospective randomized study of 60 patients in Thailand documented no cases of recurrence after 48 weeks when the CD4+ count was >100 cells/µL and HIV RNA was undetectable for 3 months (611Vibhagool 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;36:1329-31.). On the basis of two published studies and inference from data regarding safety of discontinuing secondary prophylaxis for other OIs during advanced HIV disease, discontinuing chronic maintenance therapy among such patients who have successfully completed a course of intial therapy when the CD4+ count is consistently >200 cells/µL is reasonable (BII) (612Mussini C, Pezzotti P, Miro 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;38:565-71.). Certain HIV specialists would perform a lumbar puncture to determine if the CSF is culture negative and antigen negative before stopping therapy even if patients are asymptomatic (CIII). Maintenance therapy should be reinitiated if the CD4+ count decreases to <200 cells/µL (AIII).

Special Considerations During Pregnancy

The diagnosis and treatment of cryptococcal infections during pregnancy is similar to that in nonpregnant adults with the following considerations regarding the use of antifungal during pregnancy. Because of their risk for teratogenicity, azole antifungals should be avoided during the first trimester of pregnancy (EII). Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia.

Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Cryptococcal meningitis
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Preferred induction therapy
transparent gifgrey bulletAmphotericin B deoxycholate 0.7 mg/kg IV daily plus flucytosine 100 mg/kg PO daily in 4 divided doses for at least 2 weeks (AI); or
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transparent gifgrey bulletLipid formulation amphotericin B 4-6 mg/kg IV daily (consider for persons who have renal dysfunction on therapy or have high likelihood of renal failure) plus flucytosine 100 mg/kg PO daily in 4 divided doses for at least 2 weeks (AII)
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Preferred consolidation therapy (after at least 2 weeks of successful induction - defined as significant clinical improvement & negative CSF culture)
transparent gifgrey bulletFluconazole 400 mg PO daily for 8 weeks (AI)
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Preferred maintenance therapy
transparent gifgrey bulletFluconazole 200 mg PO daily (AI) lifelong or until CD4+ count ≥200 cells/µL for >6 months as a result of ART (BII)
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Alternative induction therapy
transparent gifgrey bulletAmphotericin B (deoxycholate or lipid formulation, dose as preferred therapy) plus fluconazole 400 mg PO or IV daily (BII)
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transparent gifgrey bulletAmphotericin B (deoxycholate or lipid formulation, dose as preferred therapy) alone (BII)
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transparent gifgrey bulletFluconazole 400-800 mg/day (PO or IV) plus flucytosine 100 mg/kg PO daily in 4 divided doses for 4-6 weeks (CII) - for persons unable to tolerate or unresponsive to amphotericin B
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Alternative consolidation therapy
transparent gifgrey bulletItraconazole 200 mg PO bid for 8 weeks (BI), or until CD4+ count ≥200 cells/µL for >6 months as a result of ART (BII).
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Alternative maintenance therapy
transparent gifgrey bulletItraconazole 200 mg PO daily lifelong unless immune reconstitution as a result of potent ART - for patients intolerant of or who failed fluconazole (BI)
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Addition of flucytosine to amphotericin B has been associated with more rapid sterilization of CSF and decreased risk for subsequent relapse

Patients receiving flucytosine should have blood levels monitored; peak level 2 hours after dose should not exceed 75 µg/mL. Dosage should be adjusted in patients with renal insufficiency.

Opening pressure should always be measured when a lumbar puncture (LP) is performed (AII). Repeated LPs or CSF shunting are essential to effectively manage increased intracranial pressure (BIII).

References

579. Powderly WG, Finkelstein D, Feinberg J, et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. N Engl J Med 1995;332:700-5.
591. Aberg JA, Powderly WG. Cryptococcosis. In: Dolin R, Masur H, Saag MS, eds. AIDS Therapy. New York, NY: Churcill Livingstone 2002:498-510.
592. Mirza S, Phelan M, Rimland D, et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992-2000. Clin Infect Dis 2003;36:789-94.
593. 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;18:789-92.
594. McKinsey DS, Wheat LJ, Cloud GA, et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999;28:1049-56.
595. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000;30:710-8.
596. van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 1997;337:15-21.
597. Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004;363:1764-7.
598. 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; 19:741-5.
599. Baddour LM, Perfect JR, Ostrosky-Zeichner L. Successful use of amphotericin B lipid complex in the treatment of cryptococcosis. Clin Infect Dis 2005;40(Suppl 6):S409-13.
600. 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;11:1463-71.
601. 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;45:76-80.
602. Saag MS, Cloud GA, Graybill JR, et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis 1999;28:291-6.
603. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis 2000;30:47-54.
604. 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;17:137-42.
605. Shelburne SA, Darcourt J, White AC, et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 2005; 40:1049-52.
606. Brandt ME, Pfaller M, Hajjeh R, et al. Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. Antimicrob Agents Chemother 2001;45:3065-9.
607. Chen SC. Cryptococcosis in Australasia and the treatment of cryptococcal and other fungal infections with liposomal amphotericin B. J Antimicrob Chemother 2002;49(Suppl 1):57-61.
608. Larsen RA. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis 1999;28:297-8.
609. 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. N Engl J Med 1992;326:793-8.
610. 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;137:239-50.
611. 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;36:1329-31.
612. Mussini C, Pezzotti P, Miro 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;38:565-71.
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