Cryptococcosis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The choice of treatment depends on the sites of involvement, the patient’s immune status, and disease severity. Determination of disease severity is based on clinical judgement.

Treatment of cryptococcal meningitis and other forms of extrapulmonary cryptococcosis is usually initiated with an amphotericin-B formulation in combination with oral flucytosine.[20] Amphotericin-B deoxycholate has been the preferred formulation, but lipid formulations of amphotericin-B are now known to be effective for disseminated cryptococcosis and are currently recommended, particularly in patients with, or at risk of, clinically significant renal dysfunction.[20][54] The addition of flucytosine to amphotericin-B during acute treatment may lead to more rapid clearing of cerebrospinal fluid (CSF) cryptococcosis.

Fluconazole is used for maintenance and consolidation therapy in HIV-infected patients with cryptococcal meningoencephalitis and may also be used as monotherapy for patients with milder forms of infection not involving the central nervous system (CNS).[20][55][56]

Azole antifungals and flucytosine should be avoided during the first trimester of pregnancy because of the risk of teratogenicity, and should only be used during pregnancy if the benefits outweigh the risks.[20][57] Consideration of flucytosine use should be limited to the third trimester.[20] Breast-feeding should not be undertaken if azole antifungals are used for treatment in the postpartum period.

Most cases of cryptococcosis during pregnancy reported in the literature have been treated by amphotericin-B, with good outcomes for both the mother and infant.[20][28]

HIV-negative: immunocompetent with mild-moderate focal pulmonary non-CNS disease, or asymptomatic with low serum CrAg titers (no CNS disease)

As few studies have been conducted to evaluate outcomes among HIV-negative patients with pulmonary and other non-CNS cryptococcosis, specific treatment and the optimal duration of treatment have not been fully elucidated for these patients.[32][58] Patients may have a positive lung culture or be asymptomatic with low serum cryptococcal polysaccharide antigen (CrAg) titers (i.e., <1:320 on lateral flow assay [LFA]).[20][52]

Antifungal therapy

Oral fluconazole is the first-choice antifungal treatment in these patients.[32][52][58] The duration of therapy is based on disease resolution, but it is normally 6 to 12 months for those with symptoms and 3 to 6 months for asymptomatic patients. Follow-up for 1 year is recommended because pulmonary cryptococcosis may disseminate.[52] If fluconazole is not an option, oral itraconazole can be given for 6 to 12 months, and if azole therapy is contraindicated (e.g., pregnancy), intravenous amphotericin-B deoxycholate is recommended.[52][58] The toxicity of the latter should always be considered.[58] Liposomal amphotericin-B or amphotericin-B lipid complex can be used as an alternative to amphotericin-B deoxycholate in patients at risk of renal dysfunction.[58]
Fluconazole is usually well tolerated. The most common adverse effects are nausea, abdominal pain, and skin rash. Although fluconazole resistance has been reported with Cryptococcus neoformans, it is rare in the US, and susceptibility testing is not routinely recommended unless there is relapse or treatment failure.[20][55][58][59] Fluconazole treatment longer than 6 months is recommended in patients with documented Cryptococcus var. gattii infection, because of the slightly reduced susceptibility to fluconazole with C neoformans.[52]

HIV-negative: immunocompromised, or severe pulmonary or extrapulmonary non-CNS disease, or asymptomatic with high serum CrAg titers (no CNS disease), or CNS disease

Immunocompromised patients, those with severe pulmonary and severe extrapulmonary non-CNS disease, and asymptomatic patients with high serum CrAg titers (i.e., ≥1:640 by LFA or >1:160 by latex agglutination) should be treated in the same way as HIV-negative patients with CNS disease, due to the high risk of developing disseminated or CNS infection.[20][32][58] A reduction in the dose of prednisone (or its equivalent) to 10 mg/day in patients receiving long-term corticosteroid therapy may result in improved outcomes with antifungal therapy.[58]

Antifungal induction therapy

The first-choice induction regimen is 2 weeks of intravenous liposomal amphotericin-B or amphotericin-B lipid complex plus oral flucytosine.[32][52][56][58] Amphotericin-B deoxycholate can be used as an alternative formulation if risk of renal dysfunction is low or if cost is prohibitive.[20][54]
Flucytosine has been shown to be a strong independent predictor of CSF sterilization at 2 weeks in both HIV-positive and total patient populations.[12][55] However, reduced platelet or neutrophil counts preclude the use of flucytosine.[52] If induction therapy does not include flucytosine, consider monotherapy with liposomal amphotericin-B, amphotericin-B lipid complex, or amphotericin-B deoxycholate for at least 4 to 6 weeks.[58]
Side effects associated with amphotericin-B include elevation of serum creatinine, hypokalemia, hypomagnesemia, renal tubular acidosis, hematologic sequelae, nausea, vomiting, chills, fever, and rigors.[1][58] Renal function should be monitored frequently in patients receiving prolonged (>2 weeks) courses of amphotericin-B and flucytosine therapy, and appropriate dose adjustment (preferably through monitoring serum flucytosine levels measured 2 hours postdose after 3 to 5 doses have been administered with optimal levels of 25-100 mg/L) should be undertaken to prevent bone marrow suppression and gastrointestinal toxicity.[20] If flucytosine levels are not available, frequent (i.e., at least twice weekly) blood counts can be performed to detect for cytopenia.[20]
Preinfusion administration of 1000 mL of normal saline may reduce the risk of nephrotoxicity, and pretreatment with acetaminophen, diphenhydramine, or hydrocortisone administered approximately 30 minutes before amphotericin-B infusion may reduce infusion-related adverse reactions.[20][60] These practices are; however, supported by limited evidence. Amphotericin-B-associated rigors can be prevented and treated with meperidine given during infusion.[20]
Repeat lumbar puncture after the first 2 weeks of treatment to assess CSF sterilization is advocated by US guidelines and some experts.[20][58] Patients with positive CSF cultures after 2 weeks of therapy and no clinical improvement should be continued on amphotericin-B until CSF cultures are negative.[20][52][58] Lipid formulations of amphotericin-B are better tolerated and more efficacious than the deoxycholate formulation, and should be considered when initial treatment with other regimens fails.[20] Patients with positive cultures but signs of clinical improvement should go on to receive consolidation therapy.[20]

Antifungal consolidation therapy

Consolidation therapy is with oral fluconazole.[32][58] The rationale for this approach is rapid control of infection with the most fungicidal regimen, followed by less toxic oral therapy for continued treatment and prevention of relapse, also minimizing the dose-dependent toxicity of amphotericin-B.[20][23]
The recommended consolidation phase of treatment is an 8-week course of fluconazole.[58] After 8 weeks, the patient should be switched to low-dose fluconazole for long-term maintenance therapy.[58]
Patients with positive CSF cultures but who have clinically improved after 2 weeks of induction therapy should receive a higher dose of fluconazole for consolidation therapy, and have repeat lumbar puncture in another 2 weeks.[20] Alternatively, nonhospitalized patients can receive flucytosine plus fluconazole for an additional 2 weeks before starting single-drug consolidation therapy.[20] The duration of consolidation therapy should be 8 weeks from the point at which CSF cultures are negative.[20][23]

Antifungal maintenance therapy

Following successful induction and consolidation therapy (i.e., clinical improvement and negative CSF culture after repeat lumbar puncture) antifungal maintenance therapy with oral fluconazole should be continued for at least 6 to 12 months.[58]

HIV-positive: mild-moderate focal pulmonary non-CNS disease, or asymptomatic with low serum CrAg titers (no CNS disease)

All HIV-positive patients, including those who are asymptomatic, require treatment due to the high risk of disseminated or CNS infection.[58][61] Patients may have a positive lung culture or CrAg.[52] For patients with mild to moderate symptoms and focal pulmonary infiltrates, and those who are asymptomatic with low serum CrAg titers (i.e., <1:320 on LFA), treatment with an antifungal plus an antiretroviral is appropriate.[20] All patients should have their CSF sampled to rule out CNS disease.[20]

Antifungal therapy

Oral fluconazole is generally the first-choice antifungal treatment in these patients. World Health Organization (WHO) guidelines recommend oral fluconazole treatment for 2 weeks at a higher dose then 8 weeks at a lower dose, followed by maintenance therapy.[23] Conversely, US guidelines recommend 10 weeks of oral fluconazole treatment at a higher dose followed by a lower dose for a total of 6 months, without any additional maintenance therapy.[20]
Fluconazole may be discontinued depending on the response to antiretroviral treatment (i.e., CD4 cell counts ≥100 cells/mm³, undetectable viral loads on antiretroviral treatment, minimum of 1 year of azole antifungal chronic maintenance therapy after successful treatment of cryptococcosis).[20]

Antiretroviral therapy (ART)

The optimum time to start ART in patients with non-CNS disease is not clear. US guidelines suggest delaying initiation of ART for 2 weeks after starting antifungal therapy.[20]

HIV-positive: severe pulmonary or extrapulmonary non-CNS disease, or asymptomatic with high serum CrAg titers (no CNS disease), or CNS disease

Asymptomatic patients with high serum CrAg titers (i.e., ≥1:640 by LFA or >1:160 by latex agglutination) should receive the same treatment as patients with CNS disease, due to increased risk for mortality and CNS involvement.[20]

Antifungal induction therapy

According to US guidelines, the first-choice induction regimen is 2 weeks of intravenous liposomal amphotericin-B plus oral flucytosine.[20] Amphotericin-B deoxycholate can be used as an alternative formulation if risk of renal dysfunction is low or if cost is prohibitive.[20][54]
For patients with HIV, especially in resource-limited settings, the WHO recommends an induction regimen that consists of a single high dose of liposomal amphotericin-B combined plus 14 days of flucytosine and fluconazole.[23] An alternative regimen recommended by the WHO (where liposomal amphotericin-B is not available) is 1 week of amphotericin-B deoxycholate and flucytosine, followed by 1 week of fluconazole.[23][62] [ ] [ ]
Alternative induction regimens recommended by US guidelines and the WHO are 2 weeks of intravenous or oral fluconazole plus oral flucytosine, 2 weeks of intravenous amphotericin-B deoxycholate plus oral or intravenous fluconazole, or 2 weeks of liposomal amphotericin-B plus fluconazole.[20][23] Other options included in US guidelines are amphotericin-B lipid complex plus flucytosine; liposomal amphotericin-B alone; amphotericin-B deoxycholate alone; liposomal amphotericin-B plus flucytosine followed by fluconazole; and fluconazole alone.[20] Fluconazole is markedly inferior to amphotericin-B in HIV-related cryptococcal meningitis and is associated with 30% higher 10-week mortality.[63]
WHO guidelines note that flucytosine-containing regimens are superior and should be used where possible.[23] Flucytosine has been shown to be a strong independent predictor of CSF sterilization at 2 weeks in both HIV-positive and total patient populations.[12][55] However, reduced platelet or neutrophil counts preclude the use of flucytosine.[52]
Side effects associated with amphotericin-B include elevation of serum creatinine, hypokalemia, hypomagnesemia, renal tubular acidosis, hematologic sequelae, nausea, vomiting, chills, fever, and rigors.[1][58] Renal function should be monitored frequently in patients receiving prolonged (>2 weeks) courses of amphotericin-B and flucytosine therapy, and appropriate dose adjustment (preferably through monitoring serum flucytosine levels measured 2 hours postdose after 3 to 5 doses have been administered with optimal levels of 25-100 mg/L) should be undertaken to prevent bone marrow suppression and gastrointestinal toxicity.[20][58] If flucytosine levels are not available, frequent (i.e., at least twice weekly) blood counts can be performed to detect cytopenia.[20]
Preinfusion administration of 1000 mL of normal saline may reduce the risk of nephrotoxicity, and pretreatment with acetaminophen, diphenhydramine, or hydrocortisone administered approximately 30 minutes before amphotericin-B infusion may reduce infusion-related adverse reactions.[20][60] These practices are; however, supported by limited evidence. Amphotericin-B-associated rigors can be prevented and treated with meperidine given during infusion.[20]
Fluconazole doses may need to be adjusted in patients on concomitant rifampin.
Repeat lumbar puncture after the first 2 weeks of treatment to assess CSF sterilization is advocated by US guidelines and some experts.[20][58] Patients with positive CSF cultures after 2 weeks of therapy and no clinical improvement should be continued on amphotericin-B until CSF cultures are negative.[20][58] Lipid formulations of amphotericin-B are better tolerated and more efficacious than the deoxycholate formulation, and should be considered when initial treatment with other regimens fails.[20] Patients with positive cultures but signs of clinical improvement should go on to receive consolidation therapy.[20]

Antifungal consolidation therapy

Consolidation therapy is with oral fluconazole.[20][23] The rationale for this approach is rapid control of infection with the most fungicidal regimen, followed by less toxic oral therapy for continued treatment and prevention of relapse, also minimizing the dose-dependent toxicity of amphotericin-B.[20][23]
The recommended consolidation phase of treatment is an 8-week course of fluconazole.[20][23] After 8 weeks, the patient should be switched to low-dose fluconazole for long-term maintenance therapy.[20][23]
Patients with positive CSF cultures but who have improved clinically after 2 weeks of induction therapy should receive a higher dose (1200 mg/day) of fluconazole for consolidation therapy, and have repeat lumbar puncture in another 2 weeks.[20] Alternatively, nonhospitalized patients can receive flucytosine plus fluconazole for an additional 2 weeks before starting single-drug consolidation therapy.[20] The duration of consolidation therapy should be 8 weeks from the point at which CSF cultures are negative.[20][23]

Antiretroviral therapy (ART)

For patients with cryptococcal meningitis, immediate initiation of ART is not recommended as there is an increased risk of mortality, thought to be caused by immune reconstitution inflammatory syndrome.[64][65]
WHO and US guidelines recommend that ART should be started 4 to 6 weeks after initiation of antifungal treatment.[20][23]
For non-CNS cryptococcosis, ART may be delayed for 2 weeks after starting antifungal treatment.[20]

Antifungal maintenance therapy

Following successful induction and consolidation therapy (i.e., clinical improvement and negative CSF culture after repeat lumbar puncture) antifungal maintenance therapy with oral fluconazole should be continued for at least 1 year.[20][23]
Antifungal maintenance therapy can be discontinued if CD4 cell count is ≥100 cells/mm³, with undetectable viral loads on antiretroviral therapy, with the patient having received a minimum of 1 year of azole antifungal chronic maintenance therapy after successful treatment of cryptococcosis. Maintenance therapy should be reinitiated if the CD4 count falls to <100 cells/mm³.[20]

Management of elevated intracranial pressure (ICP)

Elevated ICP, defined as an opening pressure of >20 cm H₂O, measured with the patient in the lateral decubitus position, occurs in up to 80% of patients with HIV-associated cryptococcal meningitis and when uncontrolled is associated with a poorer clinical response.[23][49][50][51] Managing raised intracranial pressure is critical, involving therapeutic lumbar punctures to normalize pressures and, where necessary, surgical interventions for persistent elevation.[32] Therapeutic lumbar puncture can be used to reduce elevated ICP and has been associated with 69% relative improvement in survival, regardless of initial ICP.[66]

Normal baseline opening pressure (≤20 cm H₂O)

The WHO recommends that all patients with HIV-associated cryptococcal meningitis should have an initial diagnostic lumbar puncture, and an early repeat lumbar puncture with measurement of CSF opening pressure to assess for raised ICP regardless of the presence of symptoms or signs of raised ICP. More than one repeat lumbar puncture may be considered, such as a third lumbar puncture on day 3.[23]
Monitoring serum or CSF CrAg is not recommended. If new symptoms or clinical findings occur, a repeat lumbar puncture with measurement of opening lumbar pressure and CSF culture is recommended.[20]

Elevated baseline opening pressure (>20 cm H₂O)

Elevated ICP should be reduced in all patients with confusion, blurred vision, papilledema, lower-extremity clonus, or other neurologic signs of increased ICP.[20]
The principal intervention for the reduction of elevated ICP is percutaneous lumbar drainage.[23] Focal neurologic deficits are uncommon in cryptococcosis and should prompt radiographic imaging of the brain to rule out the presence of a space-occupying lesion. Lumbar drainage sufficient to achieve a closing pressure of <20 cm H₂O or 50% of the initial opening pressure should be undertaken.[20] Patients should initially undergo daily lumbar punctures to maintain stable opening pressures within the normal range, and to improve symptoms and signs.[32]
If elevated ICP or signs and symptoms of cerebral edema persist after repeated lumbar puncture, a lumbar drain or ventriculoperitoneal shunt should be considered.[20][32][58]
Corticosteroids are not recommended for managing elevated ICP in HIV-positive patients.[20] In HIV-negative patients, as evidence of benefit has not yet been established, corticosteroids should also not be used. Acetazolamide, diuretic therapy, and mannitol have not been shown to provide any benefit and are not recommended.[20][52]

Treatment failure and persistent lesions

Treatment failure is defined as the lack of clinical improvement after 2 weeks of therapy (including management of increased ICP, with continued positive cultures) or relapse after initial clinical response (i.e., recurrence of symptoms with a positive CSF culture after ≥4 weeks of treatment).[20] Most clinical failures are a result of inadequate induction therapy, drug interactions, or development of immune reconstitution inflammatory syndrome.[20] Fluconazole resistance with Cryptococcus neoformans is rare; therefore, susceptibility testing is not routinely recommended for initial management.[20][59] However, fluconazole resistance is common among relapse cases.[67] Cryptococcal isolates that are checked for persistence or relapse should also be checked for susceptibility. Strains with minimum inhibitory concentrations against fluconazole ≥16 micrograms/mL may be considered resistant.[20]

Treatment-failure patients who are initially treated with fluconazole should have their therapy changed to amphotericin-B, with or without flucytosine, until clinical response is achieved.[20] Patients initially treated with an amphotericin-B formulation should continue this treatment until there is a clinical response.[20] Lipid formulations of amphotericin-B are better tolerated and more efficacious than the deoxycholate formulation, and should be considered when initial treatment with other regimens fails.[20] Higher doses of fluconazole with flucytosine may also be useful.[20] Echinocandins are not recommended as they have no activity against Cryptococcus.[20]

Surgery should be considered for patients with persistent or refractory pulmonary, bone, or CNS lesions.[52][58]

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