Cryptococcosis

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

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

HIV-negative

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

1st line – antifungal therapy

Back

1st line –

antifungal therapy

Patients may have a positive lung culture or be asymptomatic with low serum cryptococcal polysaccharide antigen (CrAg) titres (i.e., <1:320 on lateral flow assay).[20][52]

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. If this is not an option, itraconazole can be given for 6 to 12 months, and if azole therapy is contraindicated (e.g., pregnancy), intravenous amphotericin-B deoxycholate is recommended.[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. Although fluconazole resistance has been reported with Cryptococcus neoformans, it is rare in some countries, such as the US, and susceptibility testing is not routinely recommended unless there is relapse or treatment failure.[20][55][58][59]

Azole antifungals should be avoided during the first trimester of pregnancy, because of the risk of teratogenicity, and should be used during pregnancy only if the benefits outweigh the risks.[20][57] Breastfeeding should not be undertaken if azole antifungals are used for treatment in the postnatal period.

In the case of treatment failure (lack of clinical improvement after 2 weeks of therapy or relapse after initial clinical response), all patients initially treated with fluconazole (or itraconazole) should have their therapy changed to intravenous amphotericin-B, with or without oral flucytosine, until clinical response is achieved.[20] Flucytosine should be avoided during the first and second trimesters of pregnancy because of the risk of teratogenicity, and should only be used during pregnancy if the benefits outweigh the risks.[20][57] 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]

Primary options

fluconazole: 400-800 mg orally once daily

Secondary options

itraconazole: 400 mg/day orally given in 1-2 divided doses

Tertiary options

amphotericin B liposomal: 3-4 mg/kg intravenously once daily

amphotericin B lipid complex: 5 mg/kg intravenously once daily

amphotericin B deoxycholate: 0.7 to 1 mg/kg intravenously once daily

amphotericin B liposomal: 3-4 mg/kg intravenously once daily

amphotericin B lipid complex: 5 mg/kg intravenously once daily

amphotericin B deoxycholate: 0.7 to 1 mg/kg intravenously once daily

-- AND --

flucytosine: 25 mg/kg orally four times daily

Consider – surgery

Back

Consider –

surgery

Additional treatment recommended for SOME patients in selected patient group

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

immunocompromised, or severe pulmonary or extrapulmonary non-CNS disease, or asymptomatic with high serum CrAg titres (no CNS disease), or CNS disease

1st line – antifungal induction therapy

Back

1st line –

antifungal induction therapy

Immunocompromised patients, those with severe pulmonary and severe extrapulmonary non-central nervous system (CNS) disease, and asymptomatic patients with high serum cryptococcal polysaccharide antigen (CrAg) titres (i.e., ≥1:640 by lateral flow assay 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]

First-choice induction regimen is 2 weeks of 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 cerebrospinal fluid (CSF) sterilisation 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]

Other regimens for induction therapy are available and are included in US guidelines for HIV-positive patients.[20] These regimens would not typically be recommended in HIV-negative patients due to lack of clinical trial data in this population; however, they may be considered by some providers on a case-by-case basis.

Renal function should be monitored if >2-week course of amphotericin-B and flucytosine, with appropriate dose adjustment (monitor serum flucytosine 2 hours post-dose after 3 to 5 doses have been administered, optimal levels: 25-100 mg/L).[20] If flucytosine levels are not available, frequent (i.e., at least twice weekly) blood counts can be performed to detect for cytopenia.[20] Hepatotoxicity and gastrointestinal toxicities should also be monitored in patients receiving flucytosine.[20]

Preinfusion administration of 1000 mL of normal saline may reduce the risk of nephrotoxicity associated with amphotericin-B.[20] Also, pretreatment with paracetamol, diphenhydramine, or hydrocortisone administered approximately 30 minutes before amphotericin-B infusion may reduce infusion-related adverse reactions.[20] These practices are; however, supported by limited evidence. Amphotericin-B-associated rigors can be prevented and treated with pethidine given during infusion.[20]

Repeat lumbar puncture after the first 2 weeks of treatment to assess CSF sterilisation 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]

Azole antifungals and flucytosine should be avoided during the first trimester of pregnancy, due to teratogenicity risk, and should be used during pregnancy only if the benefits outweigh the risks.[20][57] Consideration of flucytosine use should be limited to the third trimester.[20] Breastfeeding should not be undertaken if azole antifungals are used in the postnatal period.

Reduction in prednisolone dose (or its equivalent) to 10 mg/day in patients receiving long-term corticosteroid therapy may improve outcomes.[58]

Primary options

amphotericin B liposomal: 3-4 mg/kg intravenously once daily

amphotericin B lipid complex: 5 mg/kg intravenously once daily

amphotericin B deoxycholate: 0.7 to 1 mg/kg intravenously once daily

-- AND --

flucytosine: 25 mg/kg orally four times daily

Secondary options

amphotericin B liposomal: 3-4 mg/kg intravenously once daily

amphotericin B lipid complex: 5 mg/kg intravenously once daily

amphotericin B deoxycholate: 0.7 to 1 mg/kg intravenously once daily

Plus – antifungal consolidation therapy

Back

Plus –

antifungal consolidation therapy

Treatment recommended for ALL patients in selected patient group

Consolidation therapy is with oral fluconazole.[32][58]

The recommended consolidation phase of treatment is 8 weeks.[58] After 8 weeks, the patient should be switched to low-dose fluconazole for long-term maintenance therapy.[58]

Patients with positive cerebrospinal fluid (CSF) cultures but who have clinically improved 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, non-hospitalised 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]

Primary options

fluconazole: clinically stable and negative CSF cultures: 400 mg orally once daily; positive CSF cultures: 800 mg orally once daily, may increase to 1200 mg once daily after 2 weeks if CSF remains positive and patient is clinically stable

Secondary options

fluconazole: 1200 mg orally once daily

and

flucytosine: 25 mg/kg orally four times daily

Plus – antifungal maintenance therapy

Back

Plus –

antifungal maintenance therapy

Treatment recommended for ALL patients in selected patient group

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

A reduction in the dose of prednisolone (or its equivalent) to 10 mg/day in patients receiving long-term corticosteroid therapy may result in improved outcomes with antifungal therapy.[58]

As azole antifungals should be avoided during the first trimester of pregnancy, because of the risk of teratogenicity, and be used during pregnancy only if the benefits outweigh the risks, maintenance therapy with fluconazole should not be initiated until after delivery.[20][57] Breastfeeding should not be undertaken if azole antifungals are used for treatment in the postnatal period.

Primary options

fluconazole: 200 mg orally once daily

Consider – lumbar drainage

Back

Consider –

lumbar drainage

Additional treatment recommended for SOME patients in selected patient group

Elevated intracranial pressure (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 cryptococcal meningitis and when uncontrolled is associated with a poorer clinical response.[23][49][50][51]

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]

Elevated ICP should be reduced in all patients with confusion, blurred vision, papilloedema, lower extremity clonus, or other neurological signs of increased ICP.[20]

The principal intervention for the reduction of elevated ICP is percutaneous lumbar drainage.[12][25] Focal neurological deficits are uncommon in cryptococcosis and should prompt radiographical 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] Initially undergo daily lumbar punctures to maintain stable opening pressures within the normal range, and to improve symptoms and signs.

If elevated ICP or signs and symptoms of cerebral oedema persist after repeated lumbar puncture, a lumbar drain or ventriculoperitoneal shunt should be considered.[20][58]

Consider – surgery

Back

Consider –

surgery

Additional treatment recommended for SOME patients in selected patient group

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

HIV-positive

mild-moderate focal pulmonary non-CNS disease, or asymptomatic with low serum CrAg titres (no CNS disease)

1st line – antifungal therapy

Back

1st line –

antifungal therapy

All HIV-positive patients, including those who are asymptomatic, require treatment, owing to the high risk of disseminated or central nervous system (CNS) infection.[58][61] Patients may have a positive lung culture or serum cryptococcal polysaccharide antigen (CrAg). For patients with mild to moderate symptoms and focal pulmonary infiltrates, and those who are asymptomatic with low serum CrAg titres (i.e., <1:320 on lateral flow assay), treatment with an antifungal plus an antiretroviral is appropriate.[20] All patients should have their cerebrospinal fluid sampled to rule out CNS disease.[20]

Oral fluconazole is generally the first-choice antifungal treatment in these patients. World Health Organization guidelines recommend that localised non-meningeal disease is treated with fluconazole for 2 weeks at a higher dose then for 8 weeks at a lower dose, then this is 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 (ART; i.e., CD4 cell counts ≥100 cells/mm³, undetectable viral loads on ART, minimum of 1 year of azole antifungal chronic maintenance therapy after successful treatment of cryptococcosis).[20]

If azole therapy is contraindicated (e.g., pregnancy), amphotericin-B with or without flucytosine is recommended.

In the case of treatment failure (lack of clinical improvement after 2 weeks of therapy or relapse after initial clinical response), all patients initially treated with fluconazole monotherapy should have their therapy changed to intravenous amphotericin-B, with or without oral flucytosine, until clinical response is achieved.[20] Flucytosine should be avoided during the first and second trimesters of pregnancy because of the risk of teratogenicity, and should only be used during pregnancy if the benefits outweigh the risks.[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]

Primary options

fluconazole: 400-800 mg orally once daily

Secondary options

amphotericin B liposomal: 3-4 mg/kg intravenously once daily

amphotericin B lipid complex: 5 mg/kg intravenously once daily

amphotericin B deoxycholate: 0.7 to 1 mg/kg intravenously once daily

amphotericin B liposomal: 3-4 mg/kg intravenously once daily

amphotericin B lipid complex: 5 mg/kg intravenously once daily

amphotericin B deoxycholate: 0.7 to 1 mg/kg intravenously once daily

-- AND --

flucytosine: 25 mg/kg orally four times daily

Plus – antiretroviral therapy

Back

Plus –

antiretroviral therapy

Treatment recommended for ALL patients in selected patient group

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

Consider – surgery

Back

Consider –

surgery

Additional treatment recommended for SOME patients in selected patient group

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

severe pulmonary or extrapulmonary non-CNS disease, or asymptomatic with high serum CrAg titres (no CNS disease), or CNS disease

1st line – antifungal induction therapy

Back

1st line –

antifungal induction therapy

All HIV-positive patients, including those who are asymptomatic, require treatment, owing to the high risk of disseminated or central nervous system (CNS) infection.[58][61] Asymptomatic patients with high serum cryptococcal polysaccharide antigen (CrAg) titres (i.e., ≥1:640 by lateral flow assay 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]

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 World Health Organization (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]

Renal function should be monitored if a >2-week course of amphotericin-B and flucytosine with appropriate dose adjustment (monitor serum flucytosine 2 hours post-dose after 3 to 5 doses have been administered, optimal levels: 25-100 mg/mL).[20] If flucytosine levels are not available, frequent (i.e., at least twice weekly) blood counts can be performed to detect for cytopenia.[20] Hepatotoxicity and gastrointestinal toxicities should also be monitored in patients receiving flucytosine.[20]

Fluconazole doses may need to be adjusted in patients on concomitant rifampicin.

Repeat lumbar puncture after the first 2 weeks of treatment to assess CSF sterilisation is advocated by US guidelines and some experts.[20] 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]

Azole antifungals and flucytosine should be avoided during the first trimester of pregnancy, due to teratogenicity risk, and should be used during pregnancy only if benefits outweigh risks.[20][57] Consideration of flucytosine use should be limited to the third trimester.[20] Breastfeeding should not be undertaken if azole antifungals are used in the postnatal period.

It should be noted that fluconazole is markedly inferior to amphotericin-B in HIV-related cryptococcal meningitis and is associated with 30% higher 10-week mortality.[63]

Primary options

amphotericin B liposomal: 3-4 mg/kg intravenously once daily for 2 weeks

amphotericin B deoxycholate: 0.7 to 1 mg/kg intravenously once daily for 2 weeks

-- AND --

flucytosine: 25 mg/kg orally four times daily for 2 weeks

amphotericin B liposomal: 10 mg/kg intravenously as a single dose

-- AND --

flucytosine: 25 mg/kg orally four times daily for 2 weeks

and

fluconazole: 1200 mg orally/intravenously once daily for 2 weeks

Secondary options

amphotericin B lipid complex: 5 mg/kg intravenously once daily for 2 weeks

and

flucytosine: 25 mg/kg orally four times daily for 2 weeks

amphotericin B liposomal: 3-4 mg/kg intravenously once daily for 2 weeks

and

fluconazole: 800-1200 mg orally/intravenously once daily for 2 weeks

and

flucytosine: 25 mg/kg orally four times daily for 2 weeks

amphotericin B deoxycholate: 0.7 to 1 mg/kg intravenously once daily for 2 weeks

and

fluconazole: 800-1200 mg orally/intravenously once daily for 2 weeks

amphotericin B liposomal: 3-4 mg/kg intravenously once daily for 2 weeks

amphotericin B deoxycholate: 0.7 to 1 mg/kg intravenously once daily for 2 weeks

amphotericin B liposomal: 3-4 mg/kg intravenously once daily for 1 week

and

flucytosine: 25 mg/kg orally four times daily for 1 week

and

fluconazole: 1200 mg orally/intravenously once daily for 1 week (after 1-week course of amphotericin B liposomal and flucytosine)

fluconazole: 1200 mg orally/intravenously once daily for 2 weeks

amphotericin B deoxycholate: 1 mg/kg intravenously once daily for 1 week

and

flucytosine: 25 mg/kg orally four times daily for 1 week

and

fluconazole: 1200 mg orally/intravenously once daily for 1 week (after 1-week course of amphotericin B deoxycholate and flucytosine

Plus – antiretroviral therapy

Back

Plus –

antiretroviral therapy

Treatment recommended for ALL patients in selected patient group

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

Plus – antifungal consolidation therapy

Back

Plus –

antifungal consolidation therapy

Treatment recommended for ALL patients in selected patient group

Consolidation therapy is with oral fluconazole.[58]

The recommended consolidation phase of treatment is 8 weeks.[58] After 8 weeks, the patient should be switched to low-dose fluconazole for long-term maintenance therapy.[58]

Primary options

Secondary options

fluconazole: 1200 mg orally once daily

and

flucytosine: 25 mg/kg orally four times daily

Plus – antifungal maintenance therapy

Back

Plus –

antifungal maintenance therapy

Treatment recommended for ALL patients in selected patient group

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]

Primary options

fluconazole: 200 mg orally once daily

Consider – lumbar drainage

Back

Consider –

lumbar drainage

Additional treatment recommended for SOME patients in selected patient group

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]

Elevated ICP should be reduced in all patients with confusion, blurred vision, papilloedema, lower extremity clonus, or other neurological signs of increased ICP.[20]

The principal intervention for the reduction of elevated ICP is percutaneous lumbar drainage.[23] Focal neurological deficits are uncommon in cryptococcosis and should prompt radiographical imaging of the brain to rule out the presence of a space-occupying lesion. Lumbar drainage sufficient to achieving 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 oedema persist, a lumbar drain or ventriculoperitoneal shunt should be considered.[20][32][58]

Consider – surgery

Back

Consider –

surgery

Additional treatment recommended for SOME patients in selected patient group

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

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Cryptococcosis

Treatment algorithm

HIV-negative

antifungal therapy

Primary options

Secondary options

Tertiary options

surgery

antifungal induction therapy

Primary options

Secondary options

antifungal consolidation therapy

Primary options

Secondary options

antifungal maintenance therapy

Primary options

lumbar drainage

surgery

HIV-positive

antifungal therapy

Primary options

Secondary options

antiretroviral therapy

surgery

antifungal induction therapy

Primary options

Secondary options

antiretroviral therapy

antifungal consolidation therapy

Primary options

Secondary options

antifungal maintenance therapy

Primary options

lumbar drainage

surgery