Approach

The aims of treatment are resolution of signs and symptoms of infection and sterilisation of the cerebrospinal fluid (CSF). Not all fungal meningitis is curable; coccidioidal meningitis requires lifelong therapy.[69] Aggressive therapy with antifungal agents is the mainstay of treatment.

Patients who are already diagnosed with HIV and on antiretroviral therapy (ART) should continue their treatment, but should be aware of the potential risk of immune reconstitution inflammatory syndrome.

Cryptococcal meningitis

Initial induction combination therapy with an amphotericin-B formulation and flucytosine is recommended in both HIV- and non-HIV-associated infection.[67] The preferred regimen 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 with 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

Guideline recommendations include 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] 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]

Consolidation and maintenance therapy

Fluconazole is recommended.[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] After 8 weeks, 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 begins after the 8-week consolidation phase and 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 ART.[67] Fluconazole is superior to itraconazole therapy for maintenance.[94][95]​ 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. There have been reports of fluconazole-resistant Cryptococcus neoformans in some geographical areas.[96][97]

Immune reconstitution inflammatory syndrome

Treatment of cryptococcal meningitis in HIV-infected patients is complicated by the development of immune reconstitution inflammatory syndrome (IRIS) in nearly 1 in 8 patients.[19] 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 IRIS.[98][99]

WHO and US guidelines recommend that ART should be started 4-6 weeks after initiation of antifungal treatment.[66][67]

Management of the raised CSF pressure

Important as it complicates the clinical course of more than 80% of patients with HIV-associated cryptococcal meningitis.[66] Raised intracranial pressure, if not aggressively managed, results in a poor prognosis.[100]

Guidelines advocate therapeutic drainage of CSF if the CSF opening pressure is more than 25 cm H₂O.[66]​ The aim is to reduce the CSF closing pressure to less than 20 cm H₂O or to 50% of the opening pressure, by serial daily lumbar punctures with withdrawal of large volumes of CSF (up to 30 mL/day). If serial lumbar punctures over a number of days fail to control the raised 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.

Histoplasmal meningitis

May occur as an isolated entity or as part of progressive disseminated histoplasmosis (PDH). An aggressive approach to treatment is warranted given the poor response to therapy compared with other types of histoplasmosis.

Liposomal amphotericin-B is given for 4 to 6 weeks, followed by itraconazole for at least 1 year and until resolution of CSF abnormalities. 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] 

Liposomal amphotericin-B appeared to be more effective than amphotericin-B deoxycholate in HIV-infected patients with PDH, and achieves higher concentrations in brain tissue than amphotericin-B lipid complex.[102][103] Combination antifungal therapy is not recommended. There is currently insufficient evidence to advocate azole antifungal therapy alone for central nervous system (CNS) histoplasmosis.

Itraconazole can be safely discontinued in people with HIV after at least 1 year if all of the following apply:[67]

  • HIV viral load is undetectable on stable ART

  • CD4 count is 150 cells/microlitre or above for at least 6 months in response to ART

  • Fungal blood cultures are negative, and

  • Serum or urine Histoplasma antigen below the level of quantification.

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]

Coccidioidal meningitis

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]​​ 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. Consultation with a specialist is required prior to the administration of intravenous amphotericin-B.[67][108]

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

Coccidioidal meningitis cure is currently not possible, necessitating lifelong therapy.[67]

Candidal meningitis

Owing to the high morbidity and mortality associated with candidal meningitis, aggressive therapy is warranted. The Infectious Diseases Society of America recommends initial therapy with amphotericin-B deoxycholate plus flucytosine.[70] Liposomal amphotericin-B can be used in case of renal impairment. Flucytosine has excellent penetration of the blood-brain barrier and achieves good CSF levels.

Following initial treatment (2 to 6 weeks) with amphotericin-B and flucytosine, continuation and/or maintenance therapy 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 serious drug-related toxicity).[70] Voriconazole is an alternative for fluconazole-resistant isolates.

Because of the high risk of relapse, therapy should be continued for a minimum of 4 weeks after the resolution of signs and symptoms. CSF analysis and radiological findings should also normalise prior to stopping. Prosthetic devices should be removed, if at all possible, in neurosurgical patients with candidal meningitis. Infected intravascular catheters should be removed, if possible, in patients with candidaemia.

Exserohilum rostratum meningitis

Before the 2012 outbreak from contaminated methylprednisolone in the US, human infections with E rostratum were exceedingly rare. Little is known about its management, especially when the CNS is involved. Treatment should be undertaken in consultation with an infectious diseases specialist.[109]

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

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. 

Aspergillus meningitis

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

Mucormycosis meningitis

Liposomal amphotericin-B is the first-line agent in 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]

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