Cryptococcus gattii infection: Treatment

INTRODUCTION — Cryptococcus gattii has emerged as an important fungal pathogen. Infection manifests most often as potentially fatal meningoencephalitis and/or pulmonary disease. The emergence of clusters of cryptococcosis due to C. gattii in British Columbia, Canada, in 1999, with subsequent spread to the United States Pacific Northwest, has challenged our understanding of this disease [1-3]. C. gattii infection had previously been detected infrequently and was thought to be largely restricted to tropical and subtropical regions, including Australia and Papua New Guinea. It is now clear that sporadic cases occur in various regions around the world.

The antifungal treatment and other aspects of management of C. gattii infection will be reviewed here. The microbiology, epidemiology, pathogenesis, clinical manifestations, and diagnosis of C. gattii infection are discussed separately; Cryptococcus neoformans infection is also reviewed elsewhere. (See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Clinical features and diagnosis" and "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV" and "Cryptococcus neoformans infection outside the central nervous system" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV".)

ANTIFUNGAL SUSCEPTIBILITIES — At present, there are no guidelines with interpretative clinical minimum inhibitory concentration (MIC) breakpoints to recognize antifungal susceptibility or resistance in C. gattii. However, there are now epidemiologic cut-off values (ECVs) for selected antifungal drugs for certain genotypes of C. gattii, which assist with categorizing strains as wild type or non-wild type [4]. These are based on MIC distributions of wild-type strains of C. gattii using both Clinical and Laboratory Standards Institute methodology and the commercial Sensititre YeastOne system (TREK Diagnostics) [5-7]. Thus, MICs may help guide clinicians in the management of C. gattii infection [8].

Many studies have documented low antifungal MICs against C. gattii and C. neoformans that have not increased over time [9-13]. However, in some regions, concern has arisen over whether C. gattii may be less susceptible than C. neoformans to some antifungal agents. A group in Brazil reported significantly higher geometric mean MICs for fluconazole, voriconazole, amphotericin B, and flucytosine against C. gattii compared with C. neoformans [14]. In a study from Spain, fluconazole, voriconazole, and posaconazole MICs were significantly higher against C. gattii than against C. neoformans [15], whilst in Taiwan, C. gattii has been reported to be less susceptible to flucytosine and amphotericin B [16]. In a study from India, 4 of 20 C. gattii isolates were reported to have high MICs to fluconazole [17].

In vitro susceptibility to azoles appears to vary among C. gattii genotypes, with several studies showing that C. gattii genotype VGII has higher fluconazole MICs than other genotypes [6,18-22], including one study of 90 clinical and environmental isolates of C. gattii from the Pacific Northwest of North America [23]. Although the clinical implications of higher fluconazole MICs have not been determined, there is major interest in this issue since C. gattii genotype VGII is the genotype associated with the ongoing outbreak of C. gattii infection in the Pacific Northwest of North America (table 1). (See "Microbiology and epidemiology of Cryptococcus neoformans infection".)

Genotype VGII isolates with relatively low susceptibilities to fluconazole have been found to have sustained susceptibility to voriconazole and posaconazole [6,7,21]. Clinical experience suggests that these azoles may have improved activity when used during the consolidation/maintenance phase of therapy in which the goal is to administer oral azole therapy for months to eradicate the organism [24,25]. (See 'Treatment' below.)

Since increased MICs have been observed with some C. gattii isolates, we suggest that susceptibility testing be performed in regions where genotype VGII isolates are prevalent, such as the United States Pacific Northwest and British Columbia, Canada. Because susceptibility testing is useful in monitoring resistance trends, it may also be performed in other regions.

Antifungal susceptibility testing is discussed in greater detail separately. (See "Antifungal susceptibility testing".)

TREATMENT — Management of C. gattii infection is based largely upon expert opinion. There are no randomized trial data regarding therapy of C. gattii infection, and optimal management strategies are not yet defined. An observational study has provided some insights regarding the treatment of C. gattii infection [26]. Because there are far more data for C. neoformans than C. gattii, the treatment recommendations for C. gattii infection have been extrapolated largely from data involving C. neoformans infection. The Infectious Diseases Society of America (IDSA) treatment guidelines outline similar treatment principles for C. gattii infection and C. neoformans infection [8]. Our recommendations are generally in keeping with those of the IDSA in that an induction course of antifungal treatment is followed by consolidation/suppressive therapy to prevent relapse of infection. In two series of C. gattii infections, treatment regimens were concordant with the IDSA guidelines in over 77 percent of cases [26,27].

Yet for C. gattii infection, clinical experience indicates that the choice of regimen and the duration of therapy are guided more by the site(s) of infection, including the presence or absence of cryptococcomas, than by the immune status of the host. There are no data to indicate that treatment of immunocompromised patients should differ from that of immunocompetent patients. In this regard, our recommendations for the treatment of C. gattii infection differ from the IDSA guidelines, in which the treatment of C. neoformans infection varies depending upon the immune status of the host [8].

Central nervous system disease

Meningoencephalitis — The following discussion involves the therapy for C. gattii meningoencephalitis, which may or may not be accompanied by the presence of cerebral cryptococcomas. Cryptococcomas may warrant additional therapy, and their treatment is discussed below. (See 'Cerebral cryptococcomas' below.)

Because one of the critical determinants of outcome of cryptococcal meningoencephalitis is control of intracranial pressure (ICP), ICP should always be measured as part of the lumbar puncture procedure. Elevated ICP should always be managed aggressively. This includes repeated lumbar puncture or, in some cases, a lumbar drain, ventriculostomy, or a ventriculoperitoneal shunt [8,24,28,29]. (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Approach to diagnosis' and 'Monitoring during therapy' below and "Lumbar puncture: Technique, contraindications, and complications in adults".)

Induction therapy — For all patients with C. gattii central nervous system (CNS) infection, we recommend induction therapy with an amphotericin B formulation plus flucytosine (25 mg/kg orally four times daily, adjusted for renal dysfunction) for four to six weeks [8,26,30]. These recommendations are based upon collective clinical experience (see "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Complications'). Amphotericin B deoxycholate (0.7 to 1.0 mg/kg intravenously [IV] once daily) is often used, but, if there is nephrotoxicity, lipid-based amphotericin B formulations such as liposomal amphotericin B (3 to 4 mg/kg IV daily) or amphotericin B lipid complex (5 mg/kg IV daily) appear to be equally effective and can be used [8]. The shorter induction course of four weeks should be reserved for patients without neurologic complications who have had a clear clinical response and who have had clearance of C. gattii from cerebrospinal fluid (CSF) cultures after two weeks of therapy. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV", section on 'Duration of preferred regimen'.)

We repeat a lumbar puncture after two weeks of induction therapy, when feasible, to assess the response to therapy; lumbar puncture may have to be repeated sooner for management of increased ICP or for concern about possible microbiologic failure. Patients whose CSF cultures remain positive should continue the induction regimen with serial lumbar punctures every two weeks until the CSF becomes sterile. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV", section on 'Patients without neurologic complications'.)

The largest study to evaluate the treatment of C. gattii infection was an observational study that included 86 patients in Australia who were followed for at least 12 months [26]. Of 73 patients with CNS disease, 64 patients (88 percent) received induction therapy with amphotericin B, 78 percent with concomitant flucytosine, for a median of six weeks (range 2 to 16 weeks). The median total duration of antifungal therapy (including azole therapy, most commonly with fluconazole) was 18 months (range 8 to 60 months). Among the patients who received amphotericin B, 80 percent had a complete or partial clinical response at 12 months. In contrast, among nine patients who received fluconazole induction therapy, seven (78 percent) required reinduction therapy with amphotericin B plus flucytosine for clinical failure. Of the 64 patients who received amphotericin B as part of the induction regimen, all received amphotericin B deoxycholate initially, but 31 (48 percent) were switched to liposomal amphotericin B after a median of eight days due to renal impairment. In the outbreak in British Columbia, Canada, the median duration of therapy for patients with CNS disease was 12.3 months; approximately 55 percent of patients were deemed to have achieved a complete or partial response at 12 months [27].

Observational data indicate that C. gattii infection can be eradicated with appropriate antifungal therapy of adequate duration. In the study described above and in a previous report, there were no late relapses (at five to seven years) [26,31].

Consolidation and maintenance therapy — The consolidation regimen of choice to prevent relapse is fluconazole rather than another azole [8]. Fluconazole should be given at a dose of 400 mg orally daily for eight weeks followed by maintenance dosing of 200 mg orally daily for approximately 12 months to eradicate infection. The total duration of antifungal therapy, however, depends upon the clinical and mycologic response, with many clinicians extending the duration of maintenance therapy beyond 12 months for cure. As noted above, among 73 patients with C. gattii CNS disease, the median total duration of antifungal therapy was 18 months (range 8 to 60 months) [26]. There were no instances of relapse.

HIV-infected patients require immune reconstitution and a suppressed viral load before discontinuing maintenance therapy. Maintenance therapy can be discontinued in those who have a CD4 cell count >100 cells/microL, who have an undetectable viral load on antiretroviral therapy for greater than three months, and who have received a minimum of one year of azole maintenance therapy [8,32].

Although itraconazole, voriconazole, and posaconazole have shown greater in vitro activity against C. gattii than fluconazole in some studies, clinical experience with these agents as alternatives to fluconazole for consolidation and/or maintenance therapy of C. gattii meningitis is limited [8]. Isavuconazole also has low minimum inhibitory concentrations (MICs) against C. gattii [23], but data on the efficacy of this agent are also limited. Clinicians treating patients from areas of VGII endemicity, particularly VGIIb and VGIIc endemicity (eg, the Pacific Northwest region of the United States for both genotypes and British Columbia, Canada, for VGIIb) should be guided in their choice of an azole by susceptibility testing results. (See 'Antifungal susceptibilities' above and "Antifungal susceptibility testing".)

Cerebral cryptococcomas — Intracerebral C. gattii infection has been associated with substantial neurologic sequelae, need for frequent neurosurgical intervention, and a delayed or poor response to therapy, typically attributed to the presence of cerebral cryptococcomas [33,34]. As a result, more intensive and prolonged therapy generally is required for cerebral cryptococcomas. In such patients, we suggest continuing induction therapy with amphotericin B plus flucytosine for at least six weeks [8,26]. Consolidation therapy for cerebral cryptococcoma consists of fluconazole (400 to 800 mg orally daily) for 6 to 18 months. (See 'Consolidation and maintenance therapy' above.)

Aggressive management of raised intracranial pressure and hydrocephalus (if present) is required, including drainage and/or insertion of a CSF shunting device [24]. (See 'Monitoring during therapy' below.)

Experience indicates that management of CNS infection can be guided by the findings on the brain computed tomography (CT) scan at presentation, since this has been shown to correlate with outcome [34]. Surgical resection should be considered for large, accessible CNS cryptococcomas with surrounding edema, with or without mass effect, to improve the response to antifungal therapy [8,35]. Surgery should also be considered if there is compression of vital structures or failure to reduce the size of a cryptococcoma after four weeks of therapy. Multiple mass lesions may require prolonged (>6 weeks) induction and consolidation (>12 months) therapy. Imaging findings are discussed separately. (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Brain imaging'.)

Adjunctive glucocorticoid therapy has been associated with good outcomes, especially if there is surrounding edema and/or accompanying neurologic deficits [36,37] and is recommended if both are present [8]. When glucocorticoids are necessary, we typically use prednisone 0.5 to 1 mg/kg once daily [8]. Glucocorticoids may be tapered over two to six weeks, depending on clinical circumstances.

Recombinant interferon-gamma has been tried as an adjunctive treatment modality in patients who have cryptococcomas and/or severe meningitis and who are unresponsive to prolonged courses of multiple antifungal drugs [38]. Its efficacy is uncertain and we therefore do not recommend its use.

Reimaging is indicated when relapse is suspected and may reveal new lesions, enlargement of lesions, and/or increased perilesional edema despite appropriate antifungal therapy. In cases with mycologic cure, these features appear to be due to inflammation and/or an immune reconstitution inflammatory syndrome (IRIS)-like disease, potentially warranting glucocorticoid administration (see 'IRIS-like syndrome' below). It is important to note that reliance on imaging to guide the duration of therapy can be misleading since intracerebral cryptococcomas may persist for prolonged periods (ie, more than one to two years), even with appropriate antifungal therapy [30].

Isolated pulmonary disease — In patients who are found to have pulmonary disease, a lumbar puncture is necessary to evaluate for CNS involvement because the presence or absence of CNS disease will affect the choice of therapy. In the non-outbreak setting, CNS involvement is common. For immunocompetent patients with a single small pulmonary cryptococcoma and no involvement of other sites, we suggest fluconazole alone rather than an amphotericin B formulation plus flucytosine; as for C. neoformans infection, fluconazole should be given at a dose of 400 mg orally daily for 6 to 12 months [8].

Immunocompetent patients with large and/or multiple pulmonary cryptococcomas and immunocompromised patients should be treated with a similar antifungal approach as that used for CNS cryptococcosis. Such patients should receive a four- to six-week course of induction therapy with an amphotericin B formulation plus flucytosine (25 mg/kg orally four times daily, adjusted for renal dysfunction), followed by consolidation therapy with fluconazole 400 mg orally daily for eight weeks, then maintenance therapy with 200 mg orally daily for 4 to 16 months. Issues regarding reduced in vitro susceptibility of fluconazole against some C. gattii genotypes are discussed above. (See 'Consolidation and maintenance therapy' above.)

Large pulmonary cryptococcomas may cause local complications and may require surgical resection, with resultant morbidity. Although there are few data to guide surgical management of lung cryptococcomas, complications such as respiratory obstruction or uncontrolled hemorrhage are clear indications for surgical intervention. Occasional patients with very large lesions fail to respond to appropriate antifungal therapy and have improved only after surgical resection or debulking of gelatinous cryptococcal material. Patients who undergo surgical resection generally require a shorter duration of maintenance therapy than those who do not. Among patients with C. gattii infection in British Columbia, Canada, the estimated median time to resolution of lung cryptococcomas was 2.8 years [27].

There are few data regarding the optimal therapy of isolated pulmonary cryptococcosis; in retrospective reviews, most patients have received either fluconazole or an induction course of amphotericin B plus flucytosine, followed by fluconazole, with relatively good outcomes reported for both regimens [8,26,39-42]. In an observational study that included 86 patients with C. gattii infection in Australia who were followed for at least 12 months, 7 of 10 patients with pulmonary involvement received amphotericin B induction therapy (6 with concomitant flucytosine) for a median of two weeks (range one to eight weeks) [26]. The total median duration of therapy including azole therapy was 41 weeks (range 24 to 208 weeks), with a complete or partial clinical response observed in 78 percent. No patients relapsed, although four required >12 months of therapy to achieve cure. Of patients studied in the British Columbia outbreak, patients with isolated lung infection had a median duration of 7.2 months with a complete or partial clinical response observed in 66.2 percent.

For both CNS and lung disease, further research is needed to prospectively evaluate treatment outcomes of C. gattii infections.

The management of cryptococcal infection outside the CNS is discussed in greater detail separately. (See "Cryptococcus neoformans infection outside the central nervous system".)

IRIS-like syndrome — Immune reconstitution inflammatory syndrome-like disease has been described uncommonly in the treatment of C. gattii infection in immunocompetent patients [30,36,37]. However, an observational study identified an IRIS-like syndrome in 9.4 percent of patients with C. gattii infection [26]. Risk factors included female sex, initial presentation with brain, or brain, meningeal, and lung involvement, and a higher median CD4 count; enlarging or new brain lesions were the predominant presenting feature. Based upon reported cases and the study described above, the IRIS-like syndrome can develop from four weeks to as long as 12 months after initiating antifungal drugs. (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'IRIS-like syndrome'.)

Glucocorticoids have been used successfully to control symptoms and the size of mass lesions [26] but are accompanied by immunosuppression and other adverse effects (see "Glucocorticoid effects on the immune system"). Those with minor manifestations of an IRIS-like syndrome can be managed with supportive care (in addition to continuation of antifungal therapy); symptoms frequently resolve spontaneously within weeks. In the setting of CNS inflammation with increased intracranial pressure, oral glucocorticoids (prednisone 0.5 to 1 mg/kg once daily) may be used, although no trials have been performed to prove the benefit of this approach [8]. For severe cases, dexamethasone can be used instead of prednisone. Glucocorticoids are generally tapered over two to six weeks, depending on the clinical circumstances. Cerebral imaging abnormalities return to pre-IRIS appearances within four to six months, and prognosis is generally good [26].

IRIS is discussed in greater detail separately. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Immune reconstitution inflammatory syndrome' and "Immune reconstitution inflammatory syndrome".)

MONITORING DURING THERAPY — It is important to monitor patients during therapy to evaluate the response to therapy, to detect drug toxicities, and to ensure that intracranial pressure is well controlled. An overview of these issues is provided below. A more detailed discussion of monitoring during therapy in HIV-infected patients is presented separately; many of the principles apply to HIV-negative patients with C. gattii infection. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV".)

●Regular monitoring of renal function, serum electrolytes, and complete blood count with differential is essential in patients receiving amphotericin B and flucytosine. We typically monitor these tests daily in hospitalized patients and at least weekly following hospital discharge. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV" and "Pharmacology of amphotericin B" and "Amphotericin B nephrotoxicity" and "Pharmacology of flucytosine (5-FC)".)

●Serial monitoring of liver enzymes (eg, at least weekly) is recommended for all patients receiving azole therapy. (See "Pharmacology of azoles", section on 'Hepatotoxicity'.)

●Careful attention to serum levels of flucytosine is warranted to avoid bone marrow toxicity, particularly in patients with renal dysfunction, in whom bone marrow toxicity is more likely to occur. Measurement of serum flucytosine concentrations, when available, is recommended after three to five doses of therapy and should be obtained two hours after a dose has been administered [8]. The peak concentration should be between 30 and 80 mcg/mL; concentrations >100 mcg/mL should be avoided. Serum drug concentrations should be repeated if renal function worsens or if leukopenia or thrombocytopenia occurs. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV", section on 'Induction antifungal therapy'.)

●Although cryptococcal antigen testing is useful for diagnosis, it has little role for monitoring the response to therapy. (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Cryptococcal antigen'.)

●We repeat a lumbar puncture after two weeks of induction therapy, when feasible, to assess the response to therapy; lumbar puncture may have to be repeated sooner for management of increased intracranial pressure or for concern about possible microbiologic failure. Patients whose cerebrospinal fluid (CSF) cultures remain positive should continue the induction regimen with serial lumbar punctures every two weeks until the CSF becomes sterile. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV", section on 'Monitoring for toxicity'.)

●Patients with meningoencephalitis and significantly raised intracranial pressure (ICP; ≥25 cm H₂0) require monitoring of ICP and reduction of ICP with serial lumbar punctures and, in some cases, with a lumbar drain, ventriculostomy, or ventriculoperitoneal shunt [8]. If ICP is extremely high, it should be reduced by 50 percent or to a normal pressure of ≤20 cm H₂0. (See "Initial therapy and prognosis of community-acquired bacterial meningitis in adults", section on 'Reduction of intracranial pressure' and "Evaluation and management of elevated intracranial pressure in adults" and "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Monitoring of intracranial pressure'.)

The adverse effects associated with antifungal therapy of C. gattii infection are summarized below. (See 'Adverse effects' below.)

ADVERSE EFFECTS

Amphotericin B — Amphotericin B deoxycholate is frequently associated with electrolyte disturbances, renal insufficiency, anemia, and infusion reactions, such as drug fever and rigors. The symptoms of an infusion reaction can be minimized or prevented by premedication with acetaminophen (usual adult dose, 650 to 1000 mg orally) and/or diphenhydramine (usual adult dose, 25 to 50 mg orally or intravenously). The risk of renal dysfunction may be reduced with infusion of 500 mL normal saline before and during administration. (See "Pharmacology of amphotericin B", section on 'Infusion-related reactions' and "Amphotericin B nephrotoxicity".)

The lipid formulations of amphotericin B (eg, liposomal amphotericin B, amphotericin B lipid complex) are associated with a lower incidence of renal dysfunction than amphotericin B deoxycholate. (See "Pharmacology of amphotericin B", section on 'Lipid-based amphotericin B formulations'.)

Flucytosine — Flucytosine is associated with bone marrow suppression, including anemia, leukopenia, and thrombocytopenia, as well as transaminitis. Flucytosine can also cause gastrointestinal intolerance. Bone marrow toxicity is more likely to occur in those with renal dysfunction and elevated serum levels. Flucytosine can also cause gastrointestinal intolerance. (See 'Monitoring during therapy' above and "Pharmacology of flucytosine (5-FC)" and "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV", section on 'Monitoring for drug toxicity'.)

Fluconazole — Fluconazole is generally well tolerated; patients occasionally develop rash or abnormal aminotransferases. Alopecia and chapped lips have been reported following long courses of high-dose fluconazole, but they are reversible after drug discontinuation. (See "Pharmacology of azoles", section on 'Adverse effects'.)

PROGNOSIS — Outcomes of C. gattii infection have varied by geographic region, with mortality rates of 41 percent reported in Papua New Guinea, compared with 0 to 20 percent in Australia, and 9 to 23 percent in the Pacific Northwest region of North America [3,8,27,30,31,33,34,43-46]. Further study is necessary to understand the factors causing these differences.

Prognostic determinants of mortality and patient outcomes have been best studied in immunocompromised patients with C. neoformans infection but are not well defined for C. gattii infection. In a study of C. gattii cases in British Columbia, Canada, C. gattii–related mortality was associated with age >50 years and immunocompromise [27]. In a single study of endemic C. gattii infection in Australia, an initial cerebrospinal fluid cryptococcal antigen titer ≥256 independently predicted death and/or neurologic sequelae [30]. The generalizability of these observations is uncertain.

The prognosis of C. neoformans meningoencephalitis and disseminated infection in HIV-seronegative patients is discussed separately.

SUMMARY AND RECOMMENDATIONS

●Cryptococcus gattii is an important fungal pathogen that is endemic in certain regions, including Australia and Papua New Guinea. Since the late 1990s, it has been causing an ongoing outbreak in British Columbia, Canada, and in the United States Pacific Northwest. Infection manifests most often as potentially fatal meningoencephalitis and/or pulmonary disease. (See 'Introduction' above.)

●Antifungal therapy approaches to C. gattii infections are influenced largely by the site and extent of infection. This contrasts with treatment recommendations for C. neoformans infection, in which the approach varies depending upon the immune status of the host. (See 'Treatment' above.)

●For patients with C. gattii meningoencephalitis, we recommend induction therapy with an amphotericin B formulation (amphotericin B deoxycholate 0.7 mg/kg intravenously [IV] daily or liposomal amphotericin B 3 to 5 mg/kg IV daily) plus flucytosine (25 mg/kg orally four times daily, adjusted for renal dysfunction) (Grade 1B). We continue the induction regimen for four to six weeks. (See 'Induction therapy' above.)

●Following completion of the induction regimen for patients with meningoencephalitis, we suggest consolidation therapy with fluconazole 400 mg orally daily for eight weeks followed by maintenance dosing of 200 mg orally daily for approximately 12 months (Grade 2C). The total duration of antifungal therapy depends upon the clinical and mycologic response, with many clinicians extending the duration of maintenance therapy beyond 12 months. (See 'Consolidation and maintenance therapy' above.)

●The appropriate duration of maintenance therapy for HIV-infected patients with meningoencephalitis is discussed separately.

●For patients with cerebral cryptococcomas, we favor continuing induction therapy with amphotericin B plus flucytosine for at least six weeks. For consolidation and maintenance therapy, we favor fluconazole (400 to 800 mg orally daily) for 6 to 18 months. In some cases, surgical resection and/or glucocorticoids are necessary. (See 'Cerebral cryptococcomas' above.)

●Aggressive management of raised intracranial pressure and hydrocephalus is required, including drainage and/or insertion of a cerebrospinal fluid shunting device and, sometimes, administration of glucocorticoids. (See 'Cerebral cryptococcomas' above and 'Monitoring during therapy' above.)

●For patients with a single small pulmonary cryptococcoma due to C. gattii and no involvement of other sites, we suggest monotherapy with fluconazole (400 mg orally daily) (Grade 2B). Treatment should be continued for 6 to 12 months. (See 'Isolated pulmonary disease' above.)

●For patients with large and/or multiple pulmonary cryptococcomas and for immunocompromised patients, we suggest a similar antifungal approach as that used for central nervous system cryptococcosis. (See 'Isolated pulmonary disease' above and 'Induction therapy' above.)

●Differential in vitro susceptibility to azoles has been reported among C. gattii, most notably, reduced susceptibility to fluconazole in isolates of the C. gattii genotype VII, which is the genotype associated with the ongoing outbreak in the Pacific Northwest region of North America. Clinicians treating patients from areas of VGII endemicity should select an azole as directed by susceptibility testing results. (See 'Antifungal susceptibilities' above and 'Consolidation and maintenance therapy' above.)

●It is important to monitor patients during therapy to evaluate the response to therapy, to detect drug toxicities, and to ensure that intracranial pressure is well controlled. (See 'Monitoring during therapy' above.)