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

ACUTE

cryptococcal meningitis

1st line – antifungal induction therapy

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ACUTE
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cryptococcal meningitis
1st line – 

antifungal induction therapy

Treatment is started as soon as the diagnosis is made, because untreated disease is uniformly fatal.

Initial induction combination therapy with an amphotericin-B formulation and flucytosine is recommended in both HIV- and non-HIV-associated infection. The preferred regimen recommended by US guidelines for patients with HIV is 2 weeks of intravenous liposomal amphotericin-B plus oral flucytosine.[67] Amphotericin-B deoxycholate can be used as an alternative formulation if risk of renal dysfunction is low or if cost is prohibitive.

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.[66]

Where liposomal amphotericin-B is not available, the WHO recommends 1 week of amphotericin-B deoxycholate and flucytosine, followed by 1 week of fluconazole.[66] 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 fluconazole, or 2 weeks of liposomal amphotericin-B plus oral fluconazole.[66][67]​ Other options included in US guidelines are amphotericin-B lipid complex plus flucytosine; amphotericin-B deoxycholate plus flucytosine followed by fluconazole; amphotericin-B deoxycholate plus flucytosine.[67] 

Lipid formulations of amphotericin-B may be preferred for patients with, or at risk of, clinically significant renal dysfunction.[67][92] Renal and haematological profiles must be monitored closely (especially in HIV-related nephropathy). Renal impairment may be reduced by saline and fluid loading, provided that there are no contraindications.[114]

Potassium and magnesium must be monitored and replaced if necessary.

A fall in haemoglobin of around 20% occurs within 2 weeks of starting amphotericin-B, and transfusion may be required.[115] Thrombophlebitis is common.

Some experts recommend measurement of serum peak concentrations of flucytosine 2 hours after dosing after 3-5 doses have been administered, with optimal concentrations being 25-100 mg/L.[67]

The combination of amphotericin-B and flucytosine, compared with amphotericin-B alone, was associated with improved survival in cryptococcal meningitis; however, there was no survival benefit from combining amphotericin-B and fluconazole.[93] WHO guidelines note that flucytosine-containing regimens are superior and should be used where possible.[66]

Treatment of cryptococcal meningitis in HIV-infected patients is complicated by the development of immune reconstitution inflammatory syndrome in nearly 1 in 8 patients.[19]

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 on day 1

-- 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 liposomal: 3-4 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

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

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 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)

Consider – antiretroviral therapy (ART)

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ACUTE
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cryptococcal meningitis
Consider – 

antiretroviral therapy (ART)

Additional treatment recommended for SOME patients in selected patient group

For patients with HIV infection, immediate initiation of ART is not recommended as there is an increased risk of mortality, thought to be caused by immune reconstitution inflammatory syndrome.[98][99]​ World Health Organization (WHO) and US guidelines recommend that ART should be started 4-6 weeks after initiation of antifungal treatment.[66][67]

Consider – therapeutic drainage of cerebrospinal fluid (CSF)

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ACUTE
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cryptococcal meningitis
Consider – 

therapeutic drainage of cerebrospinal fluid (CSF)

Additional treatment recommended for SOME patients in selected patient group

The management of patients with raised intracranial pressure is an important aspect of the management of cryptococcal meningitis.[100]

Current guidelines recommend therapeutic drainage of CSF if the CSF opening pressure is >25 cm H₂O.[66] The aim is to reduce the CSF closing pressure to <20 cm H₂O or 50% of the opening pressure, by serial daily lumbar punctures with withdrawal of large volumes of CSF (up to 30 mL/day; pressure checked after removal of each 10 mL of CSF).

If serial lumbar punctures over a number of days fail to control elevated intracranial pressure, a temporary lumbar drain or ventriculoperitoneal shunt may be considered.[101]

Medical approaches including the use of corticosteroids, acetazolamide, or mannitol are not recommended.

Plus – antifungal consolidation therapy

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ACUTE
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cryptococcal meningitis
Plus – 

antifungal consolidation therapy

Treatment recommended for ALL patients in selected patient group

Consolidation therapy is with fluconazole.[66][67] Less toxic oral therapy facilitates continued treatment and prevention of relapse, while minimising the dose-dependent toxicity of amphotericin-B.

The optimal consolidation phase of treatment is an 8-week course of oral fluconazole.[66][67]

US guidelines advise that patients with positive 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.[67] Alternatively, non-hospitalised patients can receive flucytosine plus fluconazole for an additional 2 weeks before starting single-drug consolidation therapy.[67] The duration of consolidation therapy should be 8 weeks from the point at which CSF cultures are negative.[67]

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

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ACUTE
|
cryptococcal meningitis
Plus – 

antifungal maintenance therapy

Treatment recommended for ALL patients in selected patient group

After the 8-week consolidation phase, the patient should be switched to low-dose fluconazole for long-term maintenance therapy.[66][67]

In patients with HIV-associated cryptococcal meningitis, maintenance therapy should be continued for at least 1 year. Treatment may be stopped in asymptomatic patients once the patient's CD4 count is 100 cells/microlitre or above and the viral RNA is undetectable on antiretroviral therapy (ART).[67]

It is unclear how long patients with non-HIV-associated cryptococcal meningitis should receive maintenance therapy. In the absence of data, most patients, depending on response to antifungal treatment and reversibility of immunosuppression, are maintained on fluconazole for 6 to 12 months.

Primary options

fluconazole: 200 mg orally once daily

histoplasmal meningitis

1st line – liposomal amphotericin-B

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ACUTE
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histoplasmal meningitis
1st line – 

liposomal amphotericin-B

May be isolated or as a component of disseminated histoplasmosis.

Initial therapy is with liposomal amphotericin-B for 4 to 6 weeks.[67]

Electrolytes are monitored (replace as required) and also renal function; however, nephrotoxicity is less with liposomal formulation compared with deoxycholate formulation.

Saline and fluid loading equivalent to 1 L normal saline may reduce nephrotoxicity.

Primary options

amphotericin B liposomal: 5 mg/kg/day intravenously for 4-6 weeks

Plus – maintenance therapy with azole antifungal

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ACUTE
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histoplasmal meningitis
Plus – 

maintenance therapy with azole antifungal

Treatment recommended for ALL patients in selected patient group

May be isolated or as a component of disseminated histoplasmosis.

Maintenance therapy is with itraconazole. Voriconazole may be given to people who are intolerant to itraconazole and are only moderately unwell. Fluconazole may be given if there is intolerance to both itraconazole and voriconazole.[67]

Given for at least 1 year and until resolution of cerebrospinal fluid (CSF) abnormalities and of CSF antigen (and serum and urine antigen if initially positive).

Itraconazole can be safely discontinued in people with HIV after at least 1 year if all of the following apply: HIV viral load is undetectable on stable antiretroviral therapy (ART), CD4 count is ≥150 cells/microlitre for at least 6 months in response to ART, fungal blood cultures are negative, and serum or urine Histoplasma antigen is below the level of quantification.[67]

Random itraconazole concentrations and trough voriconazole concentrations should be measured during treatment to reduce severity and frequency of adverse effects.[67]​ Drug levels of itraconazole are usually monitored to also ensure adequate drug absorption and assess adherence. Low levels may prompt a dose increase, a switch to liquid formulation, or switch to an alternative azole antifungal.[27]

Primary options

itraconazole: 200 mg orally twice to three times daily

Secondary options

voriconazole: 400 mg orally twice daily initially on day 1, followed by 200 mg twice daily

Tertiary options

fluconazole: 800 mg orally once daily

coccidioidal meningitis

1st line – azole antifungal therapy

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ACUTE
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coccidioidal meningitis
1st line – 

azole antifungal therapy

First-line therapy is usually fluconazole.[67][104]​​

Itraconazole is an acceptable alternative.[67]​ Alternative oral agents for patients intolerant or unresponsive to fluconazole or itraconazole are posaconazole, voriconazole, and isavuconazole.[67][105][106][107]

Patients who respond to azole antifungal therapy should continue this treatment indefinitely.[67]​ 

Primary options

fluconazole: 800-1200 mg orally/intravenously once daily

OR

itraconazole: 200 mg orally two to four times daily

Secondary options

posaconazole: 300 mg orally (delayed-release tablet) twice daily on day 1, followed by 300 mg once daily

OR

voriconazole: 200-400 mg orally twice daily

OR

isavuconazole: 200 mg orally three times daily for 6 doses, followed by 200 mg once daily

Consider – intravenous liposomal amphotericin-B

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ACUTE
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coccidioidal meningitis
Consider – 

intravenous liposomal amphotericin-B

Additional treatment recommended for SOME patients in selected patient group

Consultation with a specialist is required prior to administration. Intravenous amphotericin-B on its own is ineffective as treatment for coccidioidal meningitis. However, it can be used as an adjunct to oral azole antifungal therapy in patients who are critically unwell or have evidence of widespread extrameningeal dissemination.[67][108]

Primary options

amphotericin B liposomal: 3-5 mg/kg intravenously every 24 hours

Consider – ventricular shunt replacement

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ACUTE
|
coccidioidal meningitis
Consider – 

ventricular shunt replacement

Additional treatment recommended for SOME patients in selected patient group

Patients with hydrocephalus usually require ventricular shunt placement.

2nd line – intrathecal amphotericin-B

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ACUTE
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coccidioidal meningitis
2nd line – 

intrathecal amphotericin-B

Patients who do not respond to azole therapy may be treated with intrathecal amphotericin-B which should be used in consultation with a specialist and administered by a clinician experienced in this drug delivery technique.[67]

Primary options

amphotericin B deoxycholate: consult specialist for guidance on intrathecal dose

Consider – ventricular shunt replacement

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ACUTE
|
coccidioidal meningitis
Consider – 

ventricular shunt replacement

Additional treatment recommended for SOME patients in selected patient group

Patients with hydrocephalus usually require ventricular shunt placement.

candidal meningitis

1st line – amphotericin-B + flucytosine

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ACUTE
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candidal meningitis
1st line – 

amphotericin-B + flucytosine

Treatment should be started immediately after diagnosis, or empirically pending diagnostic test results in severely ill patients where candidal meningitis is suspected.

Flucytosine achieves good levels in the cerebrospinal fluid, and is additive with amphotericin-B against Candida species in vitro and in experimental infection. Liposomal amphotericin-B is preferred in patients with renal impairment.

Flucytosine's toxic effects on bone marrow and liver must be carefully monitored, preferably with frequent serum flucytosine levels.[70]

Renal and haematological profiles of patients receiving amphotericin-B must be monitored closely. Renal impairment may be reduced by saline and fluid loading, provided no contraindication.[114] Electrolytes (potassium and magnesium) need monitoring and replacement if necessary.

A fall in haemoglobin of around 20% occurs within 2 weeks of starting amphotericin-B.[115]

Transfusion may be required in those with low baseline haemoglobin. Thrombophlebitis is common.

Primary options

amphotericin B deoxycholate: 0.7 to 1 mg/kg/day intravenously for 2-6 weeks

or

amphotericin B liposomal: 4-6 mg/kg/day intravenously for 2-6 weeks

-- AND --

flucytosine: 50-100 mg/kg/day orally given in divided doses every 6 hours for 2-6 weeks

Consider – removal of prosthesis

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ACUTE
|
candidal meningitis
Consider – 

removal of prosthesis

Additional treatment recommended for SOME patients in selected patient group

In neurosurgical patients with candidaemia, prosthetic devices and infected intravascular catheters should be removed, if at all possible.

Plus – maintenance therapy with fluconazole or voriconazole

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ACUTE
|
candidal meningitis
Plus – 

maintenance therapy with fluconazole or voriconazole

Treatment recommended for ALL patients in selected patient group

Continuation of treatment with fluconazole may be considered, especially in patients with ongoing immunosuppression, or in patients who have responded to amphotericin-B and flucytosine but have developed drug-related toxicity. Maintenance therapy has been used in HIV-infected patients.

Voriconazole is an alternative for fluconazole-resistant isolates.

Due to the high risk of relapse, therapy should be continued for a minimum of 4 weeks after the resolution of all signs and symptoms associated with the infection. All cerebrospinal fluid analysis and radiological findings should also normalise prior to stopping antifungal therapy.

Primary options

fluconazole: 800 mg orally once daily

Secondary options

voriconazole: 200 mg orally twice daily

Exserohilum rostratum meningitis

1st line – antifungal therapy

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ACUTE
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Exserohilum rostratum meningitis
1st line – 

antifungal therapy

Before the 2012 outbreak from contaminated methylprednisolone in the US, human infections with E rostratumwere exceedingly rare. Little is known about its management, especially when the central nervous system (CNS) is involved.

For patients with E rostratum meningitis, a minimum of 3 months of antifungal therapy is recommended, with up to 1 year of treatment recommended for patients with severe CNS involvement (e.g., arachnoiditis).[109]

However, despite an optimum course of therapy, relapse of E rostratum meningitis has been reported after resolution of symptoms and normalisation of CSF white blood cell count.[110]

Prolonged or lifelong antifungal therapy may be required with relapsing fungal meningitis, depending on the nature of infection, the frequency of relapsing meningitis after cessation of antifungal therapy, the severity of CNS involvement, and the underlying immune status of the individual.

Treatment should be undertaken in consultation with an infectious diseases specialist.[109]

Aspergillus meningitis

1st line – voriconazole or amphotericin-B

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Aspergillus meningitis
1st line – 

voriconazole or amphotericin-B

Voriconazole is considered the primary treatment choice; lipid formulations of amphotericin-B are reserved for those intolerant or refractory to voriconazole.[111] Long-term treatment is usually required depending on clinical response and immune status.

Primary options

voriconazole: 6 mg/kg intravenously every 12 hours on day 1, followed by 4 mg/kg intravenously every 12 hours, switch to oral therapy when clinical improvement; 200 mg orally twice daily

Secondary options

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

Plus – debridement of paranasal sinuses

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ACUTE
|
Aspergillus meningitis
Plus – 

debridement of paranasal sinuses

Treatment recommended for ALL patients in selected patient group

Aggressive surgical debridement of paranasal fungal infection is a key to successful outcome of medical therapy.

mucormycosal meningitis

1st line – antifungal therapy

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ACUTE
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mucormycosal meningitis
1st line – 

antifungal therapy

Liposomal amphotericin-B is the first-line agent in central nervous system (CNS) mucormycosis.[46] Isavuconazole and posaconazole may be considered as second-line agents.[46][112][113]

Aggressive surgical debridement of paranasal fungal infection is key to the successful outcome of medical therapy.[46]

Primary options

amphotericin B liposomal: 5-10 mg/kg intravenously every 24 hours

Secondary options

isavuconazole: 200 mg intravenously/orally every 8 hours for 6 doses, followed by 200 mg every 24 hours

OR

posaconazole: 300 mg intravenously every 12 hours on day 1, followed by 300 mg every 24 hours; 300 mg orally (delayed-release tablet) twice daily on day 1, followed by 300 mg once daily

Plus – debridement of paranasal sinuses

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ACUTE
|
mucormycosal meningitis
Plus – 

debridement of paranasal sinuses

Treatment recommended for ALL patients in selected patient group

Aggressive surgical debridement of paranasal fungal infection is a key to successful outcome of medical therapy.[46]

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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

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