Treatment algorithm

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

without HIV

1st line – antifungal therapy

Back
ONGOING
|
without HIV
|
mild-moderate focal pulmonary disease
1st line – 

antifungal therapy

There are no randomised studies for treatment of pulmonary cryptococcosis.[35] Treatment options are based on US and global guidelines.[35][60][67]

Oral fluconazole is the first-choice antifungal treatment for mild-moderate focal pulmonary disease due to Cryptococcus neoformans and single, small cryptococcomas caused by Cryptococcus var. gattii.[35][60][67]​​​​​ The duration of therapy is normally 6-12 months and is guided by symptom resolution.[35][60][67] Follow-up for 1 year is recommended because pulmonary cryptococcosis may disseminate.[60] Fluconazole is recommended in both non-transplant recipients and transplant recipients.[67]

If fluconazole is not an option, itraconazole, voriconazole, or posaconazole can be given for 6-12 months.[60][67] If azole antifungal therapy is contraindicated, discuss treatment options with an infectious diseases specialist.[67]

Fluconazole is usually well tolerated. Although fluconazole resistance has been reported with C 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.​[64][67][68]

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.​[66]​ If azole antifungal therapy is contraindicated, discuss treatment options with an infectious diseases specialist. In pregnant patients with no evidence of central nervous system (CNS) disease or disseminated infection, and no significant symptoms, careful monitoring and deferral of antifungal therapy until after pregnancy may be considered.[67] Breastfeeding should not be undertaken if azole antifungals are used for treatment in the postnatal period.

Immunosuppressed patients with pulmonary cryptococcosis should have a lumbar puncture to exclude asymptomatic CNS disease. Lumbar puncture should be considered for immunocompetent patients.[67]

Primary options

fluconazole: 400 mg orally once daily

Secondary options

itraconazole: 200 mg orally twice daily

OR

voriconazole: 200 mg orally twice daily

OR

posaconazole: 400 mg orally (suspension) twice daily

Consider – surgery

Back
ONGOING
|
without HIV
|
mild-moderate focal pulmonary disease
Consider – 

surgery

Additional treatment recommended for SOME patients in selected patient group

Surgery should be considered for patients with persistent or refractory pulmonary lesions, and may aid diagnosis of persistent radiographical abnormalities.[60][67]

1st line – antifungal induction therapy

Back
ONGOING
|
without HIV
|
non-organ transplant recipient: CNS disease or severe pulmonary disease or high serum CrAg titre
1st line – 

antifungal induction therapy

Cryptococcal polysaccharide antigen (CrAg) titre of ≥1:512 indicates a high fungal burden and warrants intensive treatment.[67] Patients with cryptococcal meningitis without HIV or a history of solid organ transplantation are a heterogeneous population, including healthy immunocompetent people as well as people with other immune compromise (e.g., cancer, cirrhosis, connective tissue disease, and long-term corticosteroid use).[35][67]​ Treatment regimens and duration are tailored to individual needs.​[35][67]​​​​​

US guidelines recommend induction therapy with amphotericin-B deoxycholate plus flucytosine.[67] Induction therapy is usually given for at least 4 weeks. The induction period may be shortened to 2 weeks in patients who were diagnosed early, have an excellent response to induction therapy, and have no uncontrolled comorbid disease or immune compromise.[67] A total of 6 weeks of induction therapy may be given to patients with neurological complications.[67] Lumbar puncture is performed after 2 weeks of treatment; patients with persistently positive cerebrospinal fluid (CSF) may require a longer induction period.[67] Induction regimens for Cryptococcus var. gattii disease are the same as for C neoformans.[67]

Lipid or liposomal formulations of amphotericin-B are used if the patient cannot tolerate amphotericin-B deoxycholate.[67] Lipid or liposomal amphotericin-B formulations may be used for the second 2 weeks of the induction period if toxicity occurs with amphotericin-B deoxycholate.[67]

Flucytosine has been shown to be a strong independent predictor of CSF sterilisation at 2 weeks in people with central nervous system disease.​[64]​ However, reduced platelet or neutrophil counts preclude the use of flucytosine.[60] If induction therapy does not include flucytosine, consider monotherapy with liposomal amphotericin-B, amphotericin-B lipid complex, or amphotericin-B deoxycholate for at least 4-6 weeks.[67]

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 3-5 doses have been administered, optimal levels: 25-100 mg/L). If flucytosine levels are not available, frequent (i.e., at least twice weekly) blood counts can be performed to detect cytopenia. Hepatotoxicity and gastrointestinal toxicities should also be monitored in patients receiving flucytosine.​[20]

Lipid or liposomal formulations of amphotericin-B are preferred to amphotericin-B deoxycholate, where available, because they are effective for cryptococcosis and have lower toxicity.[62]​ Amphotericin-B deoxycholate is associated with renal impairment, renal tubular acidosis, hypokalaemia, hypomagnesaemia, and anaemia.[63]

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.​[66]​ Consideration of flucytosine use should be limited to the third trimester.

Primary options

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

or

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

or

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

OR

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

OR

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

Plus – antifungal consolidation therapy

Back
ONGOING
|
without HIV
|
non-organ transplant recipient: CNS disease or severe pulmonary disease or high serum CrAg titre
Plus – 

antifungal consolidation therapy

Treatment recommended for ALL patients in selected patient group

Consolidation therapy is with oral fluconazole.​[35][67]​​​ Consolidation regimens for Cryptococcus var. gattii disease are the same as for C neoformans.[67]

The recommended consolidation phase of treatment is 8 weeks.[67] After 8 weeks, the patient should be switched to low-dose fluconazole for long-term maintenance therapy.[67]

Azole antifungals should be avoided during the first trimester of pregnancy due to teratogenicity risk, and should only be used during pregnancy if benefits outweigh risks.[66]​ If azole antifungal therapy is contraindicated, discuss treatment options with an infectious diseases specialist. Breastfeeding should not be undertaken if azole antifungals are used in the postnatal period.

Primary options

fluconazole: 400-800 mg orally once daily

More

Plus – antifungal maintenance therapy

Back
ONGOING
|
without HIV
|
non-organ transplant recipient: CNS disease or severe pulmonary disease or high serum CrAg titre
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 6-12 months.[67]​ Maintenance regimens for Cryptococcus var. gattii disease are the same as for C neoformans.[67]

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.​[66]​ 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
ONGOING
|
without HIV
|
non-organ transplant recipient: CNS disease or severe pulmonary disease or high serum CrAg titre
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]​​[51][52][53]​ Data for management of raised ICP in people without HIV who have cryptococcal meningitis are lacking; management recommendations are extrapolated from treatment of people with HIV.[67]

Therapeutic lumbar puncture can be used to reduce elevated ICP and has been associated with 69% relative improvement in survival, regardless of initial ICP.[75]

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] Patients should 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][67]

Consider – surgery

Back
ONGOING
|
without HIV
|
non-organ transplant recipient: CNS disease or severe pulmonary disease or high serum CrAg titre
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.[60][67]

1st line – antifungal induction therapy

Back
ONGOING
|
without HIV
|
solid-organ transplant recipient: CNS disease or severe pulmonary disease or disseminated disease
1st line – 

antifungal induction therapy

Induction treatment is with liposomal amphotericin-B or amphotericin-B lipid complex plus flucytosine for at least 2 weeks.[67]​ Induction regimens for Cryptococcus var. gattii disease are the same as for C neoformans.[67]

Amphotericin-B deoxycholate is not recommended as first-line therapy due to the increased frequency of renal impairment in transplant recipients and the associated risk of nephrotoxicity.[67] Amphotericin-B deoxycholate is associated with renal impairment, renal tubular acidosis, hypokalaemia, hypomagnesaemia, and anaemia.[63]

Flucytosine has been shown to be a strong independent predictor of cerebrospinal fluid (CSF) sterilisation at 2 weeks in people with central nervous system disease.[64]​ However, reduced platelet or neutrophil counts preclude the use of flucytosine.[60]​ If induction therapy does not include flucytosine, consider monotherapy with liposomal amphotericin-B or amphotericin-B lipid complex for at least 4-6 weeks.[67]

Antifungal drug doses should be carefully monitored and drug-drug interactions with immunosuppressants considered.[67]

Patients with a positive initial CSF culture should have a repeat lumbar puncture after 2 weeks, or sooner if there are concerns about treatment failure or raised intracranial pressure.[67] The median time to negative CSF culture after starting treatment is 10 days.[69]

Flucytosine should be avoided during the first trimester of pregnancy due to teratogenicity risk, and should only be used during pregnancy if benefits outweigh risks.[66]​ Consideration of flucytosine use should be limited to the third trimester.

Primary options

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

or

amphotericin B lipid complex: 5 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

OR

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

Plus – antifungal consolidation therapy

Back
ONGOING
|
without HIV
|
solid-organ transplant recipient: CNS disease or severe pulmonary disease or disseminated disease
Plus – 

antifungal consolidation therapy

Treatment recommended for ALL patients in selected patient group

Induction therapy is followed by consolidation therapy with fluconazole for 8 weeks.[67]​ Consolidation regimens for Cryptococcus var. gattii disease are the same as for C neoformans.[67]

Azole antifungals 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.[66]​ If azole antifungal therapy is contraindicated, discuss treatment options with an infectious diseases specialist. Breastfeeding should not be undertaken if azole antifungals are used for treatment in the postnatal period.

Primary options

fluconazole: 400-800 mg orally once daily

Plus – antifungal maintenance therapy

Back
ONGOING
|
without HIV
|
solid-organ transplant recipient: CNS disease or severe pulmonary disease or disseminated disease
Plus – 

antifungal maintenance therapy

Treatment recommended for ALL patients in selected patient group

Fluconazole maintenance therapy is given for at least 6-12 months.[67] Maintenance regimens for Cryptococcus var. gattii disease are the same as for C neoformans.[67]

As azole antifungals should be avoided during the first trimester of pregnancy because of the risk of teratogenicity, and only be used during pregnancy if the benefits outweigh the risks, maintenance therapy with fluconazole should not be initiated until after delivery.[66] Breastfeeding should not be undertaken if azole antifungals are used for treatment in the postnatal period.

Primary options

fluconazole: 200-400 mg orally once daily

Plus – review immunosuppressive drugs

Back
ONGOING
|
without HIV
|
solid-organ transplant recipient: CNS disease or severe pulmonary disease or disseminated disease
Plus – 

review immunosuppressive drugs

Treatment recommended for ALL patients in selected patient group

Review the patient's immunosuppressive drugs. Immunosuppressants should be reduced step-wise or sequentially; consider reducing the corticosteroid dose first.[67] Abrupt withdrawal may precipitate immune reconstitution inflammatory syndrome or organ rejection.[67]

Consider – lumbar drainage

Back
ONGOING
|
without HIV
|
solid-organ transplant recipient: CNS disease or severe pulmonary disease or disseminated disease
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]​​[51][52][53]​ Data for management of raised ICP in people without HIV who have cryptococcal meningitis are lacking; management recommendations are extrapolated from treatment of people with HIV.[67]

Therapeutic lumbar puncture can be used to reduce elevated ICP and has been associated with 69% relative improvement in survival, regardless of initial ICP.[75]

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] Patients should 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][67]

Consider – surgery

Back
ONGOING
|
without HIV
|
solid-organ transplant recipient: CNS disease or severe pulmonary disease or disseminated disease
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.[60][67]

with HIV

1st line – antifungal therapy

Back
ONGOING
|
with HIV
|
isolated asymptomatic antigenaemia with low serum CrAg titres
1st line – 

antifungal therapy

All people with HIV, including those who are asymptomatic, require treatment due to the high risk of disseminated or central nervous system (CNS) infection.[67][70]

Asymptomatic patients with normal cerebrospinal fluid (CSF) and low serum cryptococcal polysaccharide antigen (CrAg) titres (i.e., <1:640 by lateral flow assay [LFA] and <1:160 by enzyme immunoassay [EIA] or latex agglutination) should be treated with an antifungal for a total of 6 months combined with antiretroviral therapy (ART).[20]

Oral fluconazole is generally the first-choice antifungal treatment in these patients. Higher doses are used for the first 12 weeks of treatment.[20]

Whether to sample CSF in fully asymptomatic patients with isolated cryptococcal antigenaemia is guided by CrAg titre and the risk of cryptococcal disease (e.g., patients with advanced immunosuppression not taking ART would be at higher risk). Patients at lower risk who are asymptomatic with a serum CrAg titre ≤1:80 by LFA (or <1:20 with EIA or latex agglutination) may be treated without lumbar puncture. All symptomatic patients should have CSF sampling to exclude CNS disease.[20]

Azole antifungals 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][66]​ Breastfeeding should not be undertaken if azole antifungals are used for treatment in the postnatal period. If azole therapy is contraindicated (e.g., pregnancy), amphotericin-B with or without flucytosine is recommended.

Lipid or liposomal formulations of amphotericin-B are preferred to amphotericin-B deoxycholate, where available, because they are effective for cryptococcosis and have lower toxicity.[20][62]​ Amphotericin-B deoxycholate is associated with renal impairment, renal tubular acidosis, hypokalaemia, hypomagnesaemia, and anaemia.[63]

Primary options

fluconazole: 800-1200 mg orally once daily for 2 weeks, followed by 400-800 mg once daily for 10 weeks, then 200 mg once daily for a total of 6 months

Secondary options

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

OR

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

OR

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

OR

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

or

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

or

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

-- AND --

flucytosine: 25 mg/kg orally four times daily

Plus – antiretroviral therapy (ART)

Back
ONGOING
|
with HIV
|
isolated asymptomatic antigenaemia with low serum CrAg titres
Plus – 

antiretroviral therapy (ART)

Treatment recommended for ALL patients in selected patient group

Antifungal therapy should be combined with ART. The optimum time to begin 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]

See HIV in adults.

1st line – antifungal therapy

Back
ONGOING
|
with HIV
|
non-CNS focal pulmonary infiltrates with mild symptoms and negative serum CrAg
1st line – 

antifungal therapy

For patients with mild symptoms and focal pulmonary infiltrates, treatment with an antifungal plus antiretroviral therapy (ART) is appropriate.[20] All patients should have their cerebrospinal fluid sampled to rule out central nervous system (CNS) disease.[20]

Oral fluconazole is the first-choice antifungal treatment in these patients. US guidelines recommend oral fluconazole treatment at the same dose for 6-12 months, with duration guided by symptom resolution.[20] Other guidelines may differ. For example, World Health Organization (WHO) 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]

Fluconazole may be discontinued depending on the response to ART (i.e., CD4 cell counts ≥100 cells/microlitre, undetectable viral loads on ART, minimum of 1 year of azole antifungal chronic maintenance therapy after successful treatment of cryptococcosis).[20]

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][66]​ Breastfeeding should not be undertaken if azole antifungals are used for treatment in the postnatal period. 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 or liposomal formulations of amphotericin-B are preferred to amphotericin-B deoxycholate, where available, because they are effective for cryptococcosis and have lower toxicity.[20][62]​ Amphotericin-B deoxycholate is associated with renal impairment, renal tubular acidosis, hypokalaemia, hypomagnesaemia, and anaemia.[63]

Primary options

fluconazole: 400 mg orally once daily for 6-12 months

Secondary options

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

OR

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

OR

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

OR

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

or

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

or

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

-- AND --

flucytosine: 25 mg/kg orally four times daily

Plus – antiretroviral therapy (ART)

Back
ONGOING
|
with HIV
|
non-CNS focal pulmonary infiltrates with mild symptoms and negative serum CrAg
Plus – 

antiretroviral therapy (ART)

Treatment recommended for ALL patients in selected patient group

Antifungal therapy should be combined with ART. The optimum time to begin 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]

See HIV in adults.

Consider – surgery

Back
ONGOING
|
with HIV
|
non-CNS focal pulmonary infiltrates with mild symptoms and negative serum CrAg
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.[60][67]

1st line – antifungal induction therapy

Back
ONGOING
|
with HIV
|
CNS and/or disseminated disease; non-CNS extrapulmonary disease, diffuse pulmonary disease, or non-CNS symptoms with normal CSF and high serum CrAg titres
1st line – 

antifungal induction therapy

All people with HIV require treatment due to the high risk of disseminated or central nervous system (CNS) infection.[67][70]​​ Asymptomatic patients with high serum cryptococcal polysaccharide antigen (CrAg) titres (i.e., ≥1:640 by lateral flow assay or >1:160 by enzyme immunoassay or 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][62]

Alternative induction regimens recommended by US guidelines are 2 weeks of intravenous amphotericin-B lipid complex plus oral flucytosine, or 1 week of amphotericin-B deoxycholate plus oral flucytosine followed by 1 week of oral fluconazole.[20]

For patients 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 with 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]​​[71] [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] ​​ 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 cerebrospinal fluid (CSF) sterilisation at 2 weeks in both people with HIV and total patient populations.[12][64]​​ Reduced platelet or neutrophil counts preclude the use of flucytosine.[60]

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 3-5 doses have been administered, optimal levels: 25-100 mg/mL). If flucytosine levels are not available, frequent (i.e., at least twice weekly) blood counts can be performed to detect cytopenia. Hepatotoxicity and gastrointestinal toxicities should also be monitored in patients receiving flucytosine.[20]

Lumbar puncture is typically performed on days 0, 3, 7, and 14, depending on opening pressure. 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][67]​​ 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][66]​​ 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.

Lipid or liposomal formulations of amphotericin-B are preferred to amphotericin-B deoxycholate, where available, because they are effective for cryptococcosis and have lower toxicity.[20][62]​ Amphotericin-B deoxycholate is associated with renal impairment, renal tubular acidosis, hypokalaemia, hypomagnesaemia, and anaemia.[63]

Primary options

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

and

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

OR

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

More

-- AND --

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

and

fluconazole: 1200 mg orally 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

OR

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 once daily for 1 week (after 1-week course of amphotericin B deoxycholate and flucytosine)

Tertiary options

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

OR

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

and

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

OR

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

and

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

OR

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

and

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

Plus – antiretroviral therapy (ART)

Back
ONGOING
|
with HIV
|
CNS and/or disseminated disease; non-CNS extrapulmonary disease, diffuse pulmonary disease, or non-CNS symptoms with normal CSF and high serum CrAg titres
Plus – 

antiretroviral therapy (ART)

Treatment recommended for ALL patients in selected patient group

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.[73][74]​ World Health Organization and US guidelines recommend that ART should be started 4-6 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]

See HIV in adults.

Plus – antifungal consolidation therapy

Back
ONGOING
|
with HIV
|
CNS and/or disseminated disease; non-CNS extrapulmonary disease, diffuse pulmonary disease, or non-CNS symptoms with normal CSF and high serum CrAg titres
Plus – 

antifungal consolidation therapy

Treatment recommended for ALL patients in selected patient group

Consolidation therapy is with oral fluconazole.[20][23] Itraconazole is an alternative option for patients who cannot tolerate fluconazole, or if fluconazole is unavailable.[20]

The recommended consolidation phase of treatment is at least 8 weeks.[20][23] After at least 8 weeks, the patient should be switched to low-dose fluconazole for long-term maintenance therapy.[20][23]

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 at least 8 weeks from the point at which CSF cultures are negative.[20][23]​​​

Primary options

fluconazole: clinically stable and positive CSF cultures: 800 mg orally once daily; clinically stable and negative CSF cultures: 400 mg orally once daily

More

Secondary options

fluconazole: 1200 mg orally once daily

and

flucytosine: 25 mg/kg orally four times daily

OR

itraconazole: 200 mg orally twice daily

Plus – antifungal maintenance therapy

Back
ONGOING
|
with HIV
|
CNS and/or disseminated disease; non-CNS extrapulmonary disease, diffuse pulmonary disease, or non-CNS symptoms with normal CSF and high serum CrAg titres
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 fluconazole can be continued for at least 1 year.[20][23]​​​

Itraconazole is an alternative option for patients who cannot tolerate fluconazole, or if fluconazole is unavailable.[20]

Maintenance therapy can be discontinued if CD4 cell count is ≥100 cells/microlitre, with undetectable viral loads on antiretroviral therapy (ART), 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 re-initiated if the CD4 count falls to <100 cells/microlitre.[20]

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][66]​ Breastfeeding should not be undertaken if azole antifungals are used for treatment in the postnatal period.

Primary options

fluconazole: 200 mg orally once daily

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Secondary options

itraconazole: 200 mg orally twice daily

Consider – lumbar drainage

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ONGOING
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with HIV
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CNS and/or disseminated disease; non-CNS extrapulmonary disease, diffuse pulmonary disease, or non-CNS symptoms with normal CSF and high serum CrAg titres
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][51][52][53]

Therapeutic lumbar puncture can be used to reduce elevated ICP and has been associated with 69% relative improvement in survival, regardless of initial ICP.[75]

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.[35]

If elevated ICP or signs and symptoms of cerebral oedema persist, a lumbar drain or ventriculoperitoneal shunt should be considered.[20][35]​​​​​​[63][67]

Consider – surgery

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ONGOING
|
with HIV
|
CNS and/or disseminated disease; non-CNS extrapulmonary disease, diffuse pulmonary disease, or non-CNS symptoms with normal CSF and high serum CrAg titres
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.[60][67]

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