Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Cryptococcosis   Epidemiology      Virtually all HIV-1--associated cryptococcal infections are caused by Cryptococcus neoformans var neoformans. Before the advent of ART, approximately 5%--8% of HIV-1--infected patients in developed countries acquired disseminated cryptococcosis. The incidence has declined substantially with use of effective ART. The majority of cases of infection are observed among patients who have CD4+ T lymphocyte counts of <50 cells/µL. Clinical Manifestations Cryptococcosis among patients with AIDS most commonly occurs as a subacute meningitis or meningoencephalitis with fever, malaise, and headache . Classic meningeal symptoms and signs (e.g., neck stiffness or photophobia) occur in approximately one fourth to one third of patients. Certain patients might present with encephalopathic symptoms (e.g., lethargy, altered mentation, personality changes, and memory loss). Analysis of the CSF usually indicates a mildly elevated serum protein, normal or slightly low glucose, and a few lymphocytes and numerous organisms. The opening pressure in the CSF is elevated (with pressures >200 mm of water) in up to 75% of patients. Disseminated disease is a common manifestation, with or without concurrent meningitis. Approximately half of patients with disseminated disease have evidence of pulmonary rather than meningeal involvement. Symptoms and signs of pulmonary infection include cough or dyspnea and abnormal chest radiographs. Skin lesions might be observed. Diagnosis Cryptococcal antigen is almost invariably detected in the CSF at high titer in patients with meningitis or meningoencephalitis. Up to 75% of patients with HIV-1--associated cryptococcal meningitis have positive blood cultures; if disseminated or other organ disease is suspected in the absence of meningitis, a fungal blood culture is also diagnostically helpful. The serum cryptococcal antigen is also usually positive and detection of cryptococcal antigen in serum might be useful in initial diagnosis . Treatment Recommendations Untreated cryptococcal meningitis is fatal. The recommended initial treatment for acute disease is amphotericin B, usually combined with flucytosine, for a 2-week duration followed by fluconazole alone for an additional 8 weeks (AI). This approach is associated with a mortality of <10% and a mycologic response of approximately 70%  The addition of flucytosine to amphotericin B during acute treatment does not improve immediate outcome but is well tolerated for 2 weeks and decreases the risk for relapse . Lipid formulations of amphotericin B appear effective. The optimal dose of lipid formulations of amphotericin B has not been determined, but AmBisome has been effective at doses of 4 mg/kg body weight/daily  (AI). After a 2-week period of successful induction therapy, consolidation therapy should be initiated with fluconazole administered for 8 weeks or until CSF cultures are sterile  (AI). Itraconazole is an acceptable though less effective alternative  (BI). Combination therapy with fluconazole (400--800 mg/daily) and flucytosine is effective for treating AIDS-associated cryptococcal meningitis . However, because of the toxicity of this regimen (especially myelotoxicity and gastrointestinal toxicity), it is recommended only as an alternative option for persons unable to tolerate or unresponsive to standard treatment (BII). Increased intracranial pressure might cause clinical deterioration despite a microbiologic response, probably reflects cerebral edema, and is more likely if the CSF opening pressure is >200 mm H2O.  In one large clinical trial, 93% of deaths occurring within the first 2 weeks of therapy and 40% of deaths occurring within weeks 3--10 were associated with increased intracranial pressure . The opening pressure should always be measured when a lumbar puncture is performed . The principal initial intervention for reducing symptomatic elevated intracranial pressure is repeated daily lumbar punctures (AII). CSF shunting should be considered for patients in whom daily lumbar punctures are no longer being tolerated or whose signs and symptoms of cerebral edema are not being relieved (BIII). Whether reducing opening pressure leads to a reduction in the mortality and morbidity associated with cerebral edema is unknown. No role exists for acetazolamide to reduce intracranial pressure (DIII). Monitoring and Adverse Events A repeat lumbar puncture to ensure clearance of the organism is not required for those with cryptococcal meningitis and improvement in clinical signs and symptoms after initiation of treatment. If new symptoms or clinical findings occur after 2 weeks of treatment, a repeat lumbar puncture should be performed. Serum cryptococcal antigen is not helpful in management because changes in titer do not correlate with clinical response .  Serial measurement of CSF cryptococcal antigen might be more useful but requires repeated lumbar punctures and is not routinely recommended for monitoring response. Patients treated with amphotericin B should be monitored for dose-dependent nephrotoxicity and electrolyte disturbances. Supplemental colloidal fluids might reduce the risk for nephrotoxicity during treatment (CIII). Infusion-related adverse reactions (e.g., fever, chills, renal tubular acidosis, hypokalemia, orthostatic hypotension, tachycardia, nausea, headache, vomiting, anemia, anorexia, and phlebitis) might be ameliorated by pretreatment with acetaminophen, diphenhydramine, or corticosteroids administered approximately 30 minutes before the infusion (CIII). Lipid formulations of amphotericin B are less toxic. Azotemic patients receiving flucytosine should have their blood levels monitored to prevent bone marrow suppression and gastrointestinal toxicity; peak serum levels (2 hours after an oral dose) should be <100 mg/mL. Persons treated with fluconazole should be monitored for hepatotoxicity, although this toxicity is rare. Management of Treatment Failure Treatment failure is defined as clinical deterioration despite appropriate therapy (assuming increased intracranial pressure is being adequately treated as described previously), the lack of improvement in signs and symptoms after 2 weeks of appropriate therapy, or relapse after an initial clinical response.  A repeat lumbar puncture should be performed (if a shunt is not already in place) to ascertain whether or not intracranial pressure has increased. Although fluconazole resistance has been reported with C. neoformans, it is rare. Susceptibility testing is not routinely recommended, and susceptibility techniques have not been standardized for this purpose. The optimal therapy for those with treatment failure is not known. Those who have failed on fluconazole should be treated with amphotericin B with or without flucytosine as indicated previously, and therapy should be continued until a clinical response occurs (BIII). Higher doses of fluconazole in combination with flucytosine also might be useful (BIII). Unlike caspofungin, voriconazole has activity against Cryptococcus spp. in vitro and might be an alternative. Prevention of Recurrence Patients who have completed initial therapy for cryptococcosis should be administered lifelong suppressive treatment (i.e., secondary prophylaxis or chronic maintenance therapy) (AI), unless immune reconstitution occurs as a consequence of ART. Fluconazole (AI) is superior to itraconazole (BI) for preventing relapse of cryptococcal disease and is the preferred drug . Adult and adolescent patients appear at low risk for recurrence of cryptococcosis when they 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+ T lymphocyte counts to >100--200 cells/µL after ART. The numbers of such patients who have been evaluated remain limited. On the basis of these observations and inference from more extensive data regarding safety of discontinuing secondary prophylaxis for other opportunistic infections during advanced HIV-1 disease, discontinuing chronic maintenance therapy among such patients is a reasonable consideration (CIII). 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; other specialists do not believe this is necessary. Maintenance therapy should be re-initiated if the CD4+ T lymphocyte count decreases to <100--200 cells/µL (AIII). Special Considerations During Pregnancy Diagnosis and treatment for cryptococcosis among HIV-1--infected pregnant women are the same as for nonpregnant women. Considerations about the use of amphotericin B, fluconazole, and itraconazole are the same as those for mucocutaneous and invasive candidiasis (i.e., amphotericin B should be used in the first trimester to avoid the potential for teratogenicity with fluconazole or itraconazole). Flucytosine is teratogenic in rats at high doses, but not at doses similar to human exposure (363). No reports exist about its use in the first trimester of pregnancy in humans. Flucytosine might be metabolized to 5-fluoruracil. It should be used in pregnancy only if clearly indicated.