Cryptococcus gattii infection: Treatment
Authors:
Sharon Chen, PhD, MBBS, FRACP, FRCPA
Kieren A Marr, MD
Tania C Sorrell, MD
Section Editor:
Carol A Kauffman, MD
Deputy Editor:
Jennifer Mitty, MD, MPH
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2018. | This topic last updated: Jul 12, 2017.
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 HIV-infected patients" and "Clinical manifestations and
diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative
patients" and "Cryptococcus neoformans infection outside the central nervous
system"and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated
infection in HIV seronegative patients".)
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. Only C. neoformans has been included in the Clinical Laboratory
Standard Institutes (CLSI) guidelines for testing of yeasts [4]. Clinical breakpoints and
epidemiologic cut-off values based on MIC distributions of wild-type strains of C. gattii are being
studied using both CLSI methodology and the commercial Sensititre YeastOne system (TREK
Diagnostics) [5-7].
Despite these limitations, MICs, most commonly determined by broth microdilution, have been
reported for C. gattii and may provide help to 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 [9-11]. 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 [12]. In a study
from Spain, fluconazole, voriconazole, and posaconazole MICs were significantly higher
against C. gattii than against C. neoformans [13], whilst in Taiwan, C. gattii has been reported to
be less susceptible to flucytosine and amphotericin B [14].
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 [6,1519], including one study of 90 clinical and environmental isolates of C. gattii from the Pacific
Northwest of North America [20]. 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 [6,7,18]. 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 [21,22]. (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 [23]. 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. neoformansinfection. The Infectious Diseases Society of America (IDSA)
treatment guidelines outline similar treatment principles for C. gattiiinfection 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 [23,24].
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. When elevated, ICP should be reduced by repeated lumbar puncture or, in
some cases, by a lumbar drain, ventriculostomy, or a ventriculoperitoneal shunt [8,21,25,26].
Symptomatic hydrocephalus visible on imaging requires antifungal therapy plus early relief of
ICP by shunting. (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on
'Approach to diagnosis' and 'Monitoring during therapy' below and "Lumbar puncture:
Technique, indications, 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 [8,23,27]. 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/kgIV 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 HIV seronegative patients", 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 intracranial pressure 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 HIV seronegative patients",
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 [23]. 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
[24].
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) [23,28].
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) [23]. 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 [8,29].
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 [20], but data on the efficacy of this agent remain sparse. 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
[30,31]. 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 [8,23]. 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/orinsertion of a CSF shunting device [21]. (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 [31]. 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 [8,32]. 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/oraccompanying neurologic deficits [33,34] 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/orsevere meningitis and who are unresponsive to prolonged
courses of multiple antifungal drugs [35]. 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 [27].
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. gattiigenotypes
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 [24].
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 [8,23,36-39]. 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) [23]. 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
[27,33,34]. However, an observational study identified an IRIS-like syndrome in 9.4 percent of
patients with C. gattii infection [23]. 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
[23] 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 [23].
IRIS is discussed in greater detail separately. (See "Clinical management and monitoring during
antifungal therapy of the HIV-infected patient with cryptococcal meningoencephalitis", 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 of the HIV-infected patient with
cryptococcal meningoencephalitis".)
●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 of the HIVinfected patient with cryptococcal meningoencephalitis" and "Pharmacology of
amphotericin B" and "Amphotericin B nephrotoxicity" and "Pharmacology of flucytosine (5FC)".)
●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 days 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 HIV seronegative patients", 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 HIV seronegative patients", 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 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 of the HIV-infected patient with cryptococcal meningoencephalitis", 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 of the HIV-infected patient with
cryptococcal meningoencephalitis", 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 [3,8,24,27,28,30,31,40-43].
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 [24]. In a single study of
endemic C. gattiiinfection in Australia, an initial cerebrospinal fluid cryptococcal antigen titer
≥256 independently predicted death and/or neurologic sequelae [27]. The generalizability of
these observations is uncertain.
The prognosis of C. neoformans meningoencephalitis and disseminated infection in HIVseronegative 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) plusflucytosine (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.)
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