Cryptococcosis Treatment & Management

Infection categories

These include (1) pulmonary cryptococcosis in immunocompetent hosts, (2) pulmonary cryptococcosis in immunosuppressed hosts, (3) CNS cryptococcosis, and (4) disseminated nonpulmonary non-CNS cryptococcosis. Although pulmonary cryptococcosis resolves without specific therapy in most immunocompetent patients, patients with infections who fall under the remaining 3 categories require antifungal therapy.

In patients who are co-infected with HIV and C neoformans, the therapeutic goal may differ from that in patients with cryptococcal infection uncomplicated by HIV infection. For cryptococcal infections in patients with concomitant HIV infection who have a CD4 count of less than 200 cells/μL, the therapeutic goal is to control the acute infection, followed by life-long suppression of C neoformans. For patients infected with HIV who have successfully completed an initial course of therapy, remain free of symptoms of cryptococcal disease, and reconstitute their CD4 count to more than 200 CD4 cells/μL for more than 6 months, some authorities suggest that suppressive therapy may be discontinued. However, if the patient’s CD4 count falls to less than 200 cells/μL, suppressive therapy should be reinstituted. ^[4]

For patients with cryptococcal disease not complicated by HIV infection, the therapeutic goal is to achieve a permanent cure of the fungal infection so that no chronic suppressive therapy is necessary.

Patients with AIDS

Patients who have AIDS and cryptococcal meningitis account for more than 80% of the patients with cryptococcosis. Many authorities now recommend an initial aggressive treatment course.

Initially, administer amphotericin B at 0.7-1 mg/kg/d for 2 weeks, with or without 2 weeks of flucytosine at 100 mg/kg/d in 4 divided doses, followed by fluconazole at 400 mg/d for a minimum of 8-10 weeks. The addition of flucytosine to amphotericin B results in quicker clearance of viable yeast from the cerebrospinal fluid (CSF) than is seen with amphotericin B alone or amphotericin B plus fluconazole. However, patients may be treated successfully without the addition of flucytosine (and its potential toxicity). The toxic potential of flucytosine increases in patients who have renal disfunction from any cause. In a 2016 study of patients with AIDS-associated cryptococcal meningitis, the addition of dexamethasone did not reduce mortality, was associated with more adverse events and disability, and resulted in slower clearance of Cryptococcus from the spinal fluid. ^[18]

Alternative initial therapies include lipid formulations of amphotericin B in doses of 4-6 mg/kg per day for 3 weeks. Fluconazole in doses ranging from 400-800 mg per day plus flucytosine is another option in patients unable to tolerate amphotericin B. However, the combination of fluconazole plus flucytosine is clinically inferior to amphotericin B–based therapy.

Initial therapy should be considered successful only after CSF culture is negative for cryptococcal organisms and the patient has had significant clinical improvement.

Guidelines from 2000 recommended that initial therapy be followed with maintenance therapy using fluconazole at 200 mg/d for life. ^[3] In a study of patients in the maintenance phase of treatment, itraconazole was inferior to fluconazole. The same study showed no clear benefits were evident when flucytosine was added to the 2-week initial course of amphotericin B. Guidelines published in 2002 support discontinuation of suppressive therapy for cryptococcal disease if CD4 counts remain greater than 200 cells/µL but reinstitution if the CD4 counts fall to fewer than 200 cells/µL. ^[4] Guidelines published in 2010 support discontinuation of suppressive therapy when the CD4 count exceeds 100 cells/µL and the HIV viral load is undetectable or very low for more than 3 months. However, reinstitution of maintenance therapy should be considered if the CD4 cell count falls to less than 100 cells/µL. ^[5]

Although the two newer triazoles, posaconazole and voriconazole, show in vitro activity against C neoformans, clinical data remain limited.

In patients who require life-long suppressive therapy, oral fluconazole was superior to therapy with weekly amphotericin B given as 1 mg/kg intravenously 1-3 times per week.

CSF pressure should be monitored during the initial phase of therapy, and CSF pressures should be reduced by therapeutic CSF removal when the opening pressure exceeds 250 mm H₂ O. Following removal of CSF, the closing pressure should be less than 200 mm H₂ O or at least 50% of the elevated opening pressure.

Repeat lumbar puncture was once recommended in all patients 2 weeks after the initiation of therapy to ensure that CSF cultures were negative. However, forgoing further spinal taps in patients who have normal neurologic function and no other evidence of inadequately treated cryptococcal infection is now considered acceptable by some authorities.

Alternative initial therapy of fluconazole plus flucytosine for 6 weeks, followed by life-long fluconazole maintenance therapy, has been proposed. However, pilot studies have indicated that initial therapy with fluconazole and flucytosine is not as reliably effective as therapy that includes amphotericin B during the initial phase. ^[30] Furthermore, the combination of flucytosine plus fluconazole has significant toxicity.

In patients with HIV infection who are not already on antiretroviral therapy, initiating treatment for cryptococcal meningitis prior to initiating antiretroviral therapy can reduce the risk of immune reconstitution inflammatory syndrome (IRIS). ^[31] Once cryptococcal antigen has been significantly reduced, antiretroviral therapy can be initiated while the therapy for cryptococcal infection continues. However, newer data demonstrate improved clinical outcomes when highly active antiretroviral therapy (HAART) is initiated within 6 months of the diagnosis of cryptococcal meningitis. ^[32]

A study of 27 HIV-infected adult patients with cryptococcal meningitis found no significant difference in the rate of clearance of fungus from the CSF whether antiretroviral therapy was initiated at 7 or 28 days after the start of amphotericin B treatment; however, the risk of cryptococcal meningitis IRIS was significantly higher in the early antiretroviral therapy group. Seven of 13 subjects (54%) in the 7-day arm experienced IRIS, as compared with 0 of 14 in the delayed-intervention arm. ^[33]

World Health Organization (WHO) guidelines recommend all HIV patients with CD4 count ≤100 cells/µL to screen for cryptococcal antigen to identify patients with cryptococcal disease who could benefit from preemptive fluconazole prior to the onset of meningitis. Cryptococcal antigen maybe detected several weeks before development of cryptococcal meningitis. ^[34] Providing preemptive fluconazole for antigenemia prior to the development of meningitis has been found to be lifesaving and cost effective. We can consider screening for cryptococcal antigenemia at a higher CD4 threshold of ≤200 cells/µL. ^{[35, 36, 37, 38]}

Patients without AIDS

Initial therapy should be amphotericin B (0.7-1 mg/kg/day) alone or in combination with flucytosine (100 mg/kg/day in 4 divided doses). Amphotericin B can be administered alone for 6-10 weeks or in conjunction with flucytosine for 2 weeks, followed by fluconazole for a minimum of 10 weeks.

Base therapy duration on CSF examination results.

Consider examining the patient's CSF weekly until culture conversion is documented and cultures remain negative for 4 weeks. In most cases, 6-10 weeks of therapy with amphotericin B is adequate.

At the end of therapy, most patients have a normal CSF glucose and cell count, but protein abnormalities may persist for years. Thus, an elevated CSF protein as the only residual abnormality should not dictate prolonging therapy.

In some patients, positive CSF cultures may persist or recur during active antifungal therapy. This requires extending therapy until CSF cultures remain negative.

The prostate may represent a sequestered focus of infection in men with recurrent disease. Fluconazole enters the prostate tissues well and may be useful in eradicating a prostatic focus of infection.

In contrast to patients with HIV, patients without HIV have been shown to have better outcomes in terms of functional recovery and survival when corticosteroids were used as an adjunct in the management of cryptococcal CNS infections. ^[39]

Pulmonary cryptococcosis

Most of these patients do not have concomitant immunosuppression or immunodeficiency; therefore, their condition may resolve without antifungal therapy.

Observing the patient and not administering antifungal therapy can be done as long as the CSF chemistry parameters are normal; the CSF culture, India ink preparation, and serology results are negative; urine culture results are negative; the pulmonary lesion is small and stable or shrinking; and the patient has no predisposing conditions for disseminated disease.

Immunocompetent patients with endobronchial Cryptococcus colonization who have no evidence of tissue invasion do not need antifungal therapy. Therapy would need to be reconsidered should the patient become immunosuppressed.

For mild-to-moderate cryptococcal pulmonary disease, the National Institute of Allergy and Infectious Diseases Mycoses Study Group (NIAID-MSG) recommends fluconazole for 6-12 months, itraconazole for 6-12 months, or amphotericin B (see "Study Shows Promise of Fluconazole for Treatment of AIDS-Related Cryptococcal Meningitis").

For severe pulmonary disease, the NIAID-MSG recommends the following treatment for CNS disease: amphotericin B (0.7-1 mg/kg/d) plus flucytosine (100 mg/kg/d) for 6-10 weeks. Alternatively, amphotericin B plus flucytosine in the above doses can be administered for 2 weeks, followed by fluconazole at 400 mg/kg/d for at least 10 weeks. Some physicians recommend further consolidation therapy for 6-12 months.

Treatment of extraneural nonpulmonary disease

For patients without AIDS, treat cryptococcal lesions of the skin, bones, or other organs with amphotericin B plus flucytosine or with amphotericin B alone. All patients with evidence of cryptococcal infection should undergo lumbar puncture to ensure the absence of CNS infection.

Surgical therapy is unnecessary in most cases.

Cryptococcoma

Cryptococcoma is a lesion within the brain parenchyma caused by cryptococcal infection; C gattii is more commonly involved than C neoformans.

Patients with cryptococcoma may have single or multiple lesions and are usually immunocompetent.

Therapy is the same as for cryptococcal meningitis. During early therapy, lesions may actually enlarge or new lesions may appear as a result of the inflammatory response associated with treatment. In most cases lesion enlargement does not represent failure of therapy; they usually shrink over time with continued treatment.

Glucocorticoids are recommended among patients with cryptococcomas with mass effect, the acute respiratory distress syndrome, or IRIS. ^[40]  

Surgical resection of lesions is usually not required but depends on the location of the lesions and any neurologic symptoms. Following induction therapy, prolonged treatment with fluconazole 400 mg per day or more for 1-2 years may be necessary.

Patients should be monitored with MRI or CT scans to ensure the lesions are shrinking.

Medications

The drug of choice (DOC) for initial therapy in disseminated or CNS cryptococcosis is amphotericin B. Amphotericin B may be used alone or in combination with flucytosine. Amphotericin B has a rapid onset of action and often leads to clinical improvement more rapidly than either intravenous or oral fluconazole. Because amphotericin B is nephrotoxic, monitor renal function carefully throughout its administration. Amphotericin B administered as a continuous infusion over 24 hours appears to have significantly less nephrotoxicity than the same doses administered over a 6- to 8-hour period. Lipid formulations (eg, lipid complexes), liposome-associated amphotericin B, or amphotericin B colloidal dispersion may be used in patients who do not respond to amphotericin B desoxycholate or who cannot tolerate its adverse effects, including nephrotoxicity.

Other preparations of amphotericin B include liposomal amphotericin B (AmBisome), amphotericin B lipid complex (Abelcet), amphotericin B cholesteryl complex (Amphotec), and amphotericin B colloidal dispersion (Amphocin). It remains unclear if these alternative forms of amphotericin B are superior to standard nonlipid amphotericin B, and they all cost much more. The lipid preparations may have an advantage in sparing renal function, but they may be associated with higher relapse rates than amphotericin B desoxycholate. Amphotericin B–associated elevations in serum creatinine and BUN levels usually return to normal after therapy is completed. Administering amphotericin B as a continuous drip over 24 hours reduces the frequency and severity of renal toxicity ^[41] and may even allow for daily doses to be increased up to 2 mg/kg/day. ^[42]

Flucytosine is unreliable if used alone, and resistance develops rapidly; in cryptococcal disease, administer this drug in conjunction with amphotericin B. Data on the use of fluconazole plus flucytosine are limited, but this combination appears to be less effective than amphotericin B plus flucytosine. If flucytosine is used with amphotericin B, serum concentrations of flucytosine should be kept in the range of 25-100 mcg/mL to reduce the risk of gastrointestinal toxicity and bone marrow suppression. The latter may preclude its use in patients with AIDS and cryptococcal disease.

Do not use ketoconazole or itraconazole in the initial treatment of disseminated or CNS cryptococcal disease. These azoles do not cross the blood-brain barrier adequately, and their onset of action is slower than amphotericin B.

Fluconazole is a bis -triazole with a triazole group substituted for the imidazole group. Because of the triazole substitution, fluconazole is water soluble and easily absorbed from the gut. Intravenous fluconazole can be used in early disease when gastrointestinal absorption is uncertain and then changed to oral fluconazole in the same dose for 10 weeks or more. The significance of fluconazole MIC and outcome in cryptococcal infections is unclear, as in vitro fluconazole resistance may not reflect fluconazole failure. Current recommendations continue to support fluconazole use, irrespective of MICs, guided by the clinical response. ^[43]  

Data regarding relapse with fluconazole are limited. Intravenous fluconazole may be administered to patients with cryptococcal meningitis, but its onset of action can be prolonged compared with that of amphotericin B. However, in patients with AIDS and cryptococcal meningitis, oral fluconazole provides excellent long-term therapy once amphotericin B has controlled the acute meningitis. Furthermore, fluconazole enters the prostate better than amphotericin B and can eradicate cryptococcal infection at this site. Control of prostatic foci of cryptococcal yeast is important because relapses may occur if this site is not adequately treated. C neoformans was found to be susceptible to a newer azole group of drugs, including posaconazole, voriconazole, and isavuconazole. ^[44] Isavuconazole has shown good efficacy in the management of C neoformans and C gattii infections. ^{[45, 46]} Isavuconazole was shown to have antifungal activity as both primary and salvage therapy in cryptococcosis and has a potential role for isavuconazole in the treatment of CNScryptococcosis. ^[47]

Physicians should inform women of childbearing age of the risk of fluconazole teratogenicity. In one study, authors reported good clinical outcomes using amphotericin B without high dose fluconazole in the first trimester in cryptococcal meningitis with pregnant women. ^[48]

Presently available echinocandins are not active against Cryptococcus species and should not be used.

Newer medications

Histone deacetylase inhibitors, when used in conjunction with triazoles, have been shown to have synergistic effect in in vitro trials. Hydroxylamines and aminothiazoles are two new classes of compounds with anticryptococcal activity in in vitro studies. ^[46]

Sertraline was shown to have in vitro fungicidal activity against Cryptococcus neoformans, synergistic to fluconazole in multiple studies. ^{[49, 50, 51, 52, 53, 54]}  Sertraline was also effective in in vivo experimental infected mice models. The inhibitory effect of sertraline was potent in the brain of Cryptococcus-infected mice with similar efficacy to fluconazole. ^{[50, 51, 52]}  However, sertraline did not reduce mortality and should not be used in HIV-associated cryptococcal meningitis patients. ^[54]  

On occasion, patients with cryptococcosis develop complete obstruction of the ventricles and require a CSF shunt to relieve intracranial pressure.

Consultation with infectious disease specialists can help in the treatment of patients with invasive cryptococcal infections that require antifungal therapy with either amphotericin B or fluconazole.