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Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV

Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV
Literature review current through: Jan 2024.
This topic last updated: Jul 19, 2022.

INTRODUCTION — Most patients with cryptococcal meningoencephalitis are immunocompromised. The most common forms of immunosuppression other than human immunodeficiency virus (HIV) include glucocorticoid therapy, biologic modifiers, the use of some tyrosine kinase inhibitors (eg, ibrutinib), solid organ transplantation, cancer (particularly hematologic malignancy), and conditions such as sarcoidosis and hepatic failure. For many patients in these risk groups, the clinical presentation is variable. Some patients have symptoms for up to several months prior to diagnosis, whereas others present with an acute illness of only a few days. Typically, headache, lethargy, personality changes, and memory loss develop over two to four weeks. Patients may also present with disseminated disease to other body sites.

Issues related to treatment of Cryptococcus neoformans in patients without HIV will be reviewed here. Other topic reviews related to cryptococcal disease include:

(See "Microbiology and epidemiology of Cryptococcus neoformans infection".)

(See "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV".)

(See "Cryptococcus neoformans infection outside the central nervous system".)

(See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV".)

(See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention".)

(See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV".)

(See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis".)

(See "Cryptococcus gattii infection: Clinical features and diagnosis".)

(See "Cryptococcus gattii infection: Treatment".)

GENERAL PRINCIPLES — Patients with cryptococcal meningoencephalitis require a prolonged course of antifungal therapy (induction, consolidation, and maintenance phases) [1,2]. Additional therapeutic interventions include managing intracranial pressure, reducing immunosuppressive therapy, and controlling immune reconstitution inflammatory syndromes (IRIS). (See 'Control of intracranial pressure' below and 'Modulating immunosuppression' below and 'Immune reconstitution inflammatory syndrome' below.)

Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated disease (eg, involvement of at least two noncontiguous sites) should be treated with the same antifungal regimens as those used to treat central nervous system disease, even in the setting of normal findings on cerebrospinal fluid examination. (See "Cryptococcus neoformans infection outside the central nervous system".)

ANTIFUNGAL THERAPY — Antifungal agents used for the treatment of cryptococcal meningoencephalitis typically include amphotericin B, flucytosine, and fluconazole. The drug-drug interactions (eg, azoles and calcineurin inhibitors or sirolimus) and the adverse effects associated with these agents must be assessed carefully in the setting of cryptococcal infections. Refer to the Lexicomp drug information topics within UpToDate and the discussion of patient monitoring below for specific information. (See 'Monitoring for toxicity' below.)

Induction antifungal therapy — The preferred antifungal regimen for induction therapy for patients without HIV are largely extrapolated from larger studies of patients with HIV infection. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention".)

Preferred regimen — For nonpregnant adults, we suggest that induction therapy consist of a lipid formulation of amphotericin B plus flucytosine:

Either liposomal amphotericin B (3 to 4 mg/kg intravenously [IV] per day) or amphotericin B lipid complex (5 mg/kg IV per day) can be used.

Flucytosine should be administered as 100 mg/kg/day orally in four divided doses (adjusted for renal function). (See "Pharmacology of flucytosine (5-FC)", section on 'Dosing'.)

This regimen should be administered for at least two weeks. However, for some patients the duration should be extended for four to six weeks. (See 'Duration of preferred regimen' below.)

Specific treatment considerations for pregnant women, children, and those with cryptococcomas, and information regarding patient monitoring, are discussed below. (See 'Special populations' below and 'Monitoring for toxicity' below.)

Rationale — There are no controlled treatment trial data on lipid formulations and flucytosine together for the treatment of cryptococcal meningitis. Thus, the rationale for this approach is as follows:

Use of liposomal preparations – Lipid formulations of amphotericin B, rather than amphotericin B deoxycholate, are preferred as first-line therapy in organ transplant recipients due to the frequency of reduced renal function in such patients (approximately 25 percent have creatinine >2 mg/dL) and the risk of nephrotoxicity associated with concurrent use of amphotericin B deoxycholate and calcineurin inhibitors. In a prospective cohort study of 75 solid organ transplant recipients with central nervous system (CNS) cryptococcosis who were treated with amphotericin B, those who received a lipid formulation had a lower 90-day mortality on multivariate analysis than those who received the deoxycholate formulation (odds ratio 0.11, 95% CI 0.02-0.57) [3]. In addition, amphotericin B lipid complex has been used successfully for cryptococcal meningoencephalitis in salvage regimens and is also acceptable for patients with amphotericin B deoxycholate toxicity [4].

There are fewer data regarding the use of lipid formulations of amphotericin B preparations in nontransplant patients. The 2010 Infectious Disease Society of America (IDSA) guidelines suggest that induction therapy for nontransplant patients without HIV and with cryptococcal meningoencephalitis consists of amphotericin B deoxycholate (0.7 to 1 mg/kg IV daily) plus flucytosine (100 mg/kg/day orally in four divided doses). However, lipid formulations of amphotericin B with flucytosine have become the favored induction regimen for such patients in resource-available health care systems to minimize the risk of toxicity and reduce treatment interruptions, since it is critically important to complete an uninterrupted induction regimen to optimize clinical outcomes [5].

Combination therapy with flucytosine – Flucytosine is used as an adjunct to amphotericin B for the first two weeks of therapy because the combination of agents provides greater early fungicidal activity than amphotericin B alone [6-9]. The absence of flucytosine is associated with lack of cerebrospinal fluid (CSF) sterilization at week two and treatment failure [10,11]. Combination therapy with amphotericin B plus flucytosine also results in lower mortality compared with amphotericin B monotherapy or combination therapy with amphotericin B plus fluconazole [8,9].

Most of the data regarding the use of flucytosine are from studies of patients with HIV. In the cohort study of solid organ transplant recipients described above, there was no difference in mortality between patients who received lipid formulations of amphotericin B with or without flucytosine [3]. However, the number of patients who received flucytosine may have been inadequate to provide meaningful results.

Duration of preferred regimen — The minimum duration of induction therapy with amphotericin B and flucytosine is two weeks. However, the ultimate duration depends upon the presence of serious neurologic complications (eg, persistent headaches, seizures, ocular and auditory manifestations), radiographic evidence of brain parenchymal involvement (eg, cryptococcomas), the patient's underlying condition, and the response to therapy. (See 'Patients without neurologic complications' below and 'Patients with neurologic complications' below and 'Patients with cryptococcomas' below.)

After induction therapy is completed, patients should be transitioned to consolidation therapy, then a maintenance regimen. (See 'Consolidation and maintenance therapy' below.)

Patients without neurologic complications

Immunocompromised hosts – For immunocompromised hosts without neurologic complications or parenchymal involvement, a repeat lumbar puncture (LP) is typically performed after two weeks of induction therapy, and the response to therapy is assessed by the presence or absence of fungal growth [8,12]. Serial evaluation of CSF or serum cryptococcal antigen (CrAg) is not appropriate for evaluating response to therapy as CrAg does not correlate with CSF sterilization at two weeks or outcome at 180 days [2,13,14].

However, it can take several weeks for culture results to be finalized, and this delay makes decision-making difficult when determining the ultimate duration of treatment. Thus, we use certain prognostic factors to dictate the treatment approach while awaiting culture results.

We transition patients to consolidation therapy pending the results of the two-week CSF cultures if the cultures are anticipated to be negative based upon a clear clinical response to treatment and favorable baseline CSF studies, such as a CrAg titer ≤1:160 [1].

This approach has generally been used for organ transplant recipients. In a small prospective study of CNS cryptococcosis in transplant patients, the median time to CSF sterilization was 10 days (mean, 16 days) [14]. Guidelines have typically favored a four-week induction course for nontransplant patients without HIV because they tend to have a worse clinical outcome [1,15,16] (see 'Prognosis' below); however, we feel a two-week induction course is reasonable for such patients who have had a rapid response.

For all others, we continue the induction regimen pending the results of the cultures. If the cultures are negative at two weeks, the patient can then be transitioned to consolidation therapy. Although laboratories often keep cultures for three to four weeks to detect fungal growth, most persistently positive cryptococcal cultures grow within two weeks in patients who are on therapy.

Patients whose CSF cultures return positive should reinitiate (or continue) the induction regimen with serial lumbar punctures every two weeks until the CSF becomes sterile.

Immunocompetent hosts – On occasion, cryptococcal meningoencephalitis can occur in patients with no apparent underlying condition [17]. Immunocompetent hosts who have severe symptoms at presentation should be managed the same way as those who are immunocompromised, as described above.

However, certain immunocompetent hosts may transition to consolidation therapy without a repeat LP at two weeks. Such patients include those who were without severe symptoms at baseline, were diagnosed early, did not develop new symptoms, and demonstrated a clear clinical response after two weeks of combination antifungal therapy. In this setting, it is reasonable to administer a two-week induction course, and then transition to consolidation therapy with fluconazole at a high dose (800 mg [12 mg/kg] per day orally) for eight weeks [1]. (See 'Consolidation and maintenance therapy' below.)

Patients with neurologic complications — For individuals who have or develop neurologic complications on treatment, induction therapy should be extended for at least six weeks (or four weeks after the culture is negative) [18]. The management of patients with cryptococcomas is described below. (See 'Patients with cryptococcomas' below.)

Alternative regimens — Alternative regimens are used when patients cannot tolerate flucytosine and/or amphotericin B, or when a specific agent is not available.

If flucytosine is not available or tolerated, we typically administer amphotericin B with fluconazole (800 mg [12 mg/kg] per day orally) for two weeks of induction therapy.

Other options include extending the duration of amphotericin B so that patients receive at least four to six weeks of induction therapy [1], or, in cases with a high fungal burden of disease (or relapse), administering higher doses of liposomal amphotericin B (6 mg/kg/day). However, these alternative approaches are not ideal. As an example, extending the duration of amphotericin B is more likely to be associated with toxicity compared with using combination therapy. In addition, a randomized controlled trial that compared doses of 3 mg/kg and 6 mg/kg of liposomal amphotericin B in patients with acquired immunodeficiency syndrome (AIDS) found that the higher dose was safe, but not more efficacious than the lower dose [19].

If lipid formulations of amphotericin B are not available, amphotericin B deoxycholate (0.7 mg/kg/day) should be used. This agent is known to be effective for the treatment of cryptococcal disease and is generally well tolerated for two weeks when administered with adjunctive saline infusions [6,7,20]. (See "Pharmacology of amphotericin B", section on 'Amphotericin B deoxycholate'.)

If no amphotericin B formulations are tolerated or available, fluconazole (800 to 1200 mg orally per day) plus flucytosine (100 mg/kg orally per day in four divided doses) can be administered for the two-week induction period. This regimen can also be continued until two-week CSF culture returns negative and/or up to 10 weeks in severe cases [1,21-23]. Liver function tests should be monitored closely when this combination is used. (See 'Monitoring for toxicity' below.)

If flucytosine cannot be given, higher doses of fluconazole (eg, 1200 mg orally per day in patients with normal renal function) can be administered for at least 10 weeks or until CSF culture results are negative, followed by maintenance therapy with fluconazole (200 to 400 mg orally daily). However, fluconazole monotherapy for induction therapy is generally not recommended.

Consolidation and maintenance therapy — Following induction therapy, consolidation therapy with fluconazole 800 mg (or 12 mg/kg in children) orally daily should be administered for eight weeks.

Consolidation therapy should then be followed by maintenance therapy with fluconazole (200 to 400 mg orally daily) [1]. Maintenance azole therapy is generally given for one year after diagnosis. Longer therapy may be warranted for those receiving very high doses of immunosuppressive agents (eg, those receiving >40 mg/day of prednisone or persistently using biologic modifiers such as alemtuzumab); for such patients, the duration of maintenance therapy is determined on a case-by-case basis. Maintenance therapy may also need to be extended for those who have radiographic evidence of cryptococcomas. (See 'Patients with cryptococcomas' below.)

Prior to the use of fluconazole for maintenance therapy, the rate of relapse of cryptococcal meningoencephalitis in patients without HIV ranged from 15 to 25 percent; most relapses occurred within six months [18]. The use of consolidation and maintenance therapy has been associated with a very low relapse rate. As an example, in a prospective study of 79 solid organ transplant recipients in whom maintenance therapy was employed for a median of 183 days, the risk of relapse was 1.3 percent [14].

Special populations

Pregnant women — For pregnant women, it is reasonable to administer induction therapy for four weeks. Antifungal treatment should be continued throughout pregnancy. Immunologic alterations associated with pregnancy may increase the severity of cryptococcosis in pregnant women, and the mortality rate can approach 25 percent [24]. In addition, immune reconstitution inflammatory syndrome (IRIS) can occur in the postpartum period [25,26]. Indeed, nearly half of the cryptococcal cases reported in pregnancy presented with symptomatic disease in the third trimester or postpartum period [24]. (See 'Immune reconstitution inflammatory syndrome' below and "Immune reconstitution inflammatory syndrome".)

The specific regimen should be tailored to the stage of pregnancy.

Initial treatment of pregnant women with CNS or disseminated disease consists of amphotericin B deoxycholate (0.7 to 1.0 mg/kg IV daily) or a lipid formulation of amphotericin B (liposomal amphotericin B [3 to 4 mg/kg IV daily] or amphotericin B lipid complex [5 mg/kg IV daily]) [1].

There are no prospective data to guide which preparation should be used in this setting, and experience is limited. We would favor conventional amphotericin B, but if nephrotoxicity or other toxicities become an issue, clinicians should feel comfortable using a lipid formulation of amphotericin B instead. Although there is much more experience with amphotericin B deoxycholate, and the deoxycholate formulation is known to be well distributed in the placenta [27], the liposomal preparations appear safe in pregnancy, and there is some anecdotal experience treating cryptococcal meningoencephalitis with this agent during pregnancy [28].

Flucytosine should not be used during the first trimester of pregnancy. If the patient presents during the second or third trimester, the use of flucytosine should be determined on a case-by-case basis. Although this agent has been used to treat cryptococcosis in the second and third trimesters and has not been associated with adverse outcomes, the literature is limited to case series [29]. (See "Pharmacology of flucytosine (5-FC)", section on 'Pregnancy'.)

For consolidation therapy, it is appropriate to administer fluconazole during the second and third trimesters to ensure continuous antifungal therapy. However, fluconazole should be avoided during the first trimester since it has been associated with congenital anomalies [30,31]. The only alternative for continuous antifungal therapy during pregnancy is amphotericin B. A more detailed discussion of the use of azoles during pregnancy is found elsewhere. (See "Pharmacology of azoles", section on 'Pregnancy'.)

Children — Cryptococcosis has been reported in children with primary immunodeficiencies such as hyper-immunoglobulin M syndrome and severe combined immunodeficiency syndrome. It can also occur in children with HIV, connective tissue diseases, and in solid organ transplant recipients. Cryptococcosis has also been described in children with no recognized immunodeficiency.

Treatment of children with CNS or disseminated disease consists of an amphotericin B formulation (amphotericin B deoxycholate [1.0 mg/kg IV daily], liposomal amphotericin B [5 to 7.7 mg/kg/day], or amphotericin B lipid complex [5 mg/kg/day]) plus flucytosine (100 mg/kg orally per day in four divided doses) for two weeks, followed by fluconazole (10 to 12 mg/kg orally per day) for a minimum of eight weeks [1]. Amphotericin B plus fluconazole can be administered for the induction phase if flucytosine cannot be used [32].

Flucytosine can cause myelosuppression; monitoring of flucytosine levels and blood counts should be performed [33]. The American Academy of Pediatrics suggests that flucytosine peak concentrations (two hours after a dose) should be maintained between 40 and 60 mcg/mL [32].

Literature concerning pediatric cryptococcosis is limited to small series, and treatment recommendations are based on extrapolation of studies in adults. The dose of amphotericin B deoxycholate ranges from 0.5 to 1 mg/kg IV daily; children generally tolerate this agent better than adults and a dose of 1 mg/kg per day is commonly used [34]. Successful treatment of Cryptococcus in children using liposomal amphotericin B has been reported at daily doses of 5 to 7.5 mg/kg daily [35,36]. Fluconazole dosing is higher in children than adults as the volume of distribution is larger and the clearance is more rapid [37,38].

Patients with cryptococcomas — Cerebral cryptococcomas can cause significant morbidity, are difficult to treat, and require prolonged antifungal therapy [39,40]. They are more common in the setting of Cryptococcus gattii infection than C. neoformans infection [39,41,42]. The management of cryptococcomas associated with C. gattii infection is discussed separately. (See "Cryptococcus gattii infection: Treatment", section on 'Cerebral cryptococcomas'.)

There are no prospective studies evaluating management of cerebral cryptococcomas; the approach to therapy is extrapolated from observational studies, literature addressing management of cryptococcal meningitis, and expert opinion [17,40,43,44].

Antifungal therapy – Induction therapy for cerebral cryptococcomas should consist of a lipid formulation of amphotericin B (liposomal amphotericin B [3 to 4 mg/kg IV daily] or amphotericin B lipid complex [5 mg/kg IV daily]) plus flucytosine (100 mg/kg per day orally in four divided doses) for at least six weeks [1]. Consolidation and maintenance therapy for cerebral cryptococcoma consists of fluconazole (400 to 800 mg orally daily) for 18 months.

The duration of therapy depends on the clinical and radiographic response. Some brain lesions persist radiographically for long periods and/or develop surrounding edema during effective antifungal therapy, presumably because of an immunological response associated with control of infection [45]. Prolonged therapy and repeated induction courses may be warranted in some cases, even when fluconazole is used for consolidation [17].

Patients who do not respond to therapy should undergo biopsy or aspiration if the diagnosis was not confirmed initially, since severely immunosuppressed patients may have masses due to causes other than Cryptococcus. (See "Approach to the patient with HIV and central nervous system lesions".)

Adjunctive therapies – Glucocorticoids may be administered in the setting of mass effect and surrounding edema, especially if there are neurologic deficits. If glucocorticoids are used, the doses should be tapered gradually to prevent "a rebound" IRIS. (See 'Immune reconstitution inflammatory syndrome' below.)

Surgical removal (open or stereotactic guided) may be necessary for large (≥3 cm) lesions and lesions with mass effect with substantial surrounding edema. Surgery may also be needed in the setting of optic nerve involvement and in cases unresponsive to prolonged or repeated induction antifungal therapy [40,45,46]. Shunting is indicated for symptomatic hydrocephalus with dilated cerebral ventricles [47]. All surgical specimens, particularly enlarging lesions not explained by IRIS, should be submitted for histopathologic examination.

Monitoring for toxicity — It is important to monitor for signs of toxicity throughout the duration of antifungal therapy. The type of monitoring depends upon which agents are used.

Amphotericin B – Although the lipid formulations of amphotericin B are less toxic than conventional amphotericin B, monitoring for toxicity should mirror that used for amphotericin B deoxycholate, with daily monitoring of blood counts and chemistries. In patients who develop renal dysfunction despite appropriate hydration, transitioning off or interrupting polyene therapy becomes a bedside decision. In general, the risks and benefits of switching to an alternative regimen should be considered when creatinine levels rise above 3 mg/dL in a patient with initial normal kidney function. (See 'Alternative regimens' above.)

Flucytosine – Careful attention to serum flucytosine (5-FC) levels is also warranted to avoid bone marrow toxicity, particularly in patients with renal dysfunction. Measurement of serum 5-FC concentrations is recommended, when available, after three to five doses, and should be obtained two hours after a dose has been administered [1]. Guidelines for the treatment of cryptococcal infections recommend peak concentrations between 30 and 80 mcg/mL; concentrations >100 mcg/mL should be avoided [1]. Serum drug concentrations should be repeated if renal function worsens, or if leukopenia or thrombocytopenia occur. With decreasing renal function (often due to amphotericin B), toxicity is more common and patients must be monitored carefully. If amphotericin B-induced nephrotoxicity occurs, the dose of 5-FC should be reduced. (See "Pharmacology of flucytosine (5-FC)", section on 'Serum concentration monitoring'.)

All patients receiving 5-FC should undergo regular monitoring of complete blood counts (CBC). In settings in which serum 5-FC concentrations are not available, CBC monitoring two to three times per week provides an indirect method of screening for excessive dosing. An otherwise unexplained reduction in the neutrophil or platelet count may reflect 5-FC toxicity, and either the drug should be stopped or the dose reduced.

Fluconazole – Fluconazole is generally well tolerated; patients occasionally may develop rash or abnormal aminotransferases. Aminotransferase levels and symptoms should be monitored in patients on long-term therapy. The risk of drug-induced liver injury increases with high doses (eg, >800 mg daily). (See "Pharmacology of azoles", section on 'Fluconazole'.)

Additional discussions of how to prevent and manage toxicities associated with amphotericin B and 5-FC are found elsewhere. (See "Pharmacology of amphotericin B" and "Amphotericin B nephrotoxicity" and "Pharmacology of flucytosine (5-FC)".)

CONTROL OF INTRACRANIAL PRESSURE — Control of intracranial pressure is one of the most critical determinants of outcome for cryptococcal meningoencephalitis [18,48]. The intracranial pressure should be measured at the time of initial lumbar puncture. If the pressure is ≥25 cm of cerebrospinal fluid (CSF) and there are symptoms of increased intracranial pressure during induction therapy, CSF drainage should be performed to reduce the pressure by 50 percent (if extremely high) or to a normal pressure of ≤20 cm [1].

Therapeutic lumbar drainage should be repeated daily in the setting of clinical symptoms and persistent pressure elevations ≥25 cm of CSF until stabilized for >2 days. Temporary percutaneous lumbar drains or ventriculostomy may be appropriate for patients who require repeated lumbar punctures [47,49]. Ventriculoperitoneal shunting may be warranted if the patient is receiving appropriate antifungal therapy and more conservative measures to control increased intracranial pressure have failed [47,50,51]. In one series of 27 patients with obstructive hydrocephalus and cryptococcal meningoencephalitis, 63 percent had good outcomes following permanent shunt placement; outcomes were worse in those with Glasgow coma score <9 [51].

Mannitol and acetazolamide are not appropriate agents for control of elevated intracranial pressure in the setting of cryptococcal meningoencephalitis [52]. In addition, there is no benefit of administering glucocorticoids, except in the setting of an immune reconstitution inflammatory syndrome (IRIS) [48]. (See 'Immune reconstitution inflammatory syndrome' below.)

This approach to managing increased intracranial pressure is extrapolated from literature describing patients with HIV with cryptococcal meningoencephalitis. Among 55 patients with CSF pressure >35 cm, increased incidence of papilledema (29 percent) and impaired mentation (18 percent) were observed [48]. Among 12 patients who died in the first two weeks of therapy, 91 percent had baseline intracranial pressure ≥25 cm. Among the 161 patients treated by CSF lumbar drainage to reduce the pressure, there were fewer cases of clinical failure and patients reported relief of severe headache; recurrence of elevated pressure was associated with worsening symptoms.

MODULATING IMMUNOSUPPRESSION — Reducing immunosuppressive therapy may be beneficial for control of cryptococcal infection. As an example, tyrosine kinase inhibitors, such as ibrutinib, should be stopped until infection is shown to be controlled. However, in some patients, the benefit of reducing immunosuppressive therapy must be balanced with the potential for organ rejection and immune reconstitution [53]. (See 'Immune reconstitution inflammatory syndrome' below.)

The optimal approach to management of the immunosuppressive regimen in organ transplant recipients with cryptococcosis is uncertain. Reducing immunosuppressants over time in a step-wise fashion following initiation of antifungal therapy is appropriate [54]. It may be helpful to reduce corticosteroids before calcineurin inhibitors, since the latter class has direct anticryptococcal activity in vitro [55,56].

When making changes to an immunosuppressive regimen, the drug-drug interactions and adverse effects associated with these agents, particularly calcineurin inhibitors or sirolimus, must be considered carefully in the setting of cryptococcal infections. Detailed information on drug interactions can be found in the drug interaction program within UpToDate and within the individual topic reviews. (See "Pharmacology of cyclosporine and tacrolimus".)

PERSISTENT/WORSENING SYMPTOMS — For patients with persistent or worsening symptoms, distinguishing between persistent or relapsed cryptococcal infection, immune reconstitution inflammatory syndrome (IRIS), and other infections or complications can be difficult [54,57]. (See 'Persistent or relapsed infection' below and 'Immune reconstitution inflammatory syndrome' below.)

Clinical manifestations, inflammatory cerebrospinal fluid (CSF) values, positive India ink exams, and positive cryptococcal antigen titer may be present in both IRIS and cryptococcal infection. The most important distinguishing feature is that patients with active infection have positive CSF cultures, whereas patients with IRIS have sterile CSF cultures. In a study where polymerase chain reaction (PCR) testing using a Biofire Film Array Meningitis/Encephalitis Panel was performed on eight patients with HIV and symptomatic recurrence of cryptococcal meningitis, a positive PCR was associated with relapse/persistence while a negative PCR was associated with no growth, suggesting that the symptoms might be an IRIS [58].

Persistent or relapsed infection — Persistent infection refers to persistently positive CSF cultures after four weeks of appropriate antifungal therapy. Relapse of infection refers to resolution of infection followed by subsequent recurrence as demonstrated by both recovery of viable cryptococci from a sterile site and recrudescence of signs and symptoms at a previous site of disease. Most cases are attributable to inadequate primary therapy (dose and/or duration) or insufficient adherence to consolidation or maintenance fluconazole therapy.

Risk factors for relapse include [59]:

Low initial CSF white blood cell counts

Persistently low CSF glucose concentration after four weeks of therapy

Treatment with prednisone (≥20 mg) or equivalent that continues after completion of antifungal therapy

Initial management of persistent or relapsed infection should include evaluation of immunosuppressive therapy and management of increased intracranial pressure. (See 'Control of intracranial pressure' above and 'Modulating immunosuppression' above.)

Repeat induction phase therapy should be reinstituted for a longer course (4 to 10 weeks) and a repeat lumbar puncture should be performed after two weeks of therapy. The amphotericin B dose may also be increased; liposomal amphotericin B has been used at 6 mg/kg intravenously (IV) daily for treating cryptococcal meningitis [19]; for amphotericin B deoxycholate, the upper limit of the dosing range is 1 mg/kg IV daily.

The fungal isolates of patients who relapsed should be evaluated for changes in the minimum inhibitory concentration (MIC) from the original isolate; a ≥3-dilution difference suggests development of drug resistance. A fluconazole MIC of ≥16 mcg/mL or a flucytosine MIC of ≥32 mcg/mL has typically been considered resistant and alternative agents should be considered [60]. However, there are no validated MIC breakpoints for drug susceptibility in cryptococcosis, and on a practical basis, only isolates with extremely high MICs for fluconazole and flucytosine (ie, ≥64 mcg/mL) should probably be considered resistant. For these strains with very high MICs to azoles, increasing the dose of the azole alone is unlikely to be successful. In such cases, amphotericin B deoxycholate (1 mg/kg IV daily) or lipid formulations of amphotericin B (5 to 6 mg/kg IV daily) should be administered until CSF, blood, and/or other sites are sterile.

After induction therapy, pending in vitro susceptibility testing, salvage consolidation therapy with fluconazole (800 to 1200 mg orally daily) should be reinstituted if the isolate is shown to be susceptible. If the organism is not responding to fluconazole but has a low MIC to voriconazole (≤1 mcg/mL), then voriconazole can be administered (loading doses of 6 mg/kg IV twice daily or 400 mg orally twice daily on the first day, then 200 to 300 mg orally twice daily for 10 to 12 weeks). Posaconazole (loading dose of 300 mg orally twice daily on the first day, followed by 300 mg orally once daily thereafter) is an alternative but achieves poor levels in the CSF. Isavuconazole (200 mg three times daily for two days followed by 200 mg once daily) has also been reported to have antifungal activity in patients with cryptococcosis but achieves minimal levels in the CSF [61].

There are limited data regarding voriconazole, posaconazole, or isavuconazole for the treatment of cryptococcal meningoencephalitis [61-63]. Voriconazole and posaconazole have been used with variable success as salvage therapy for patients with HIV in open compassionate treatment trials. As an example, in those trials, 18 patients with refractory disease were treated with voriconazole; 39 percent were treated successfully and 55 percent had stabilization of disease [62]. Among 29 patients with refractory disease treated with posaconazole, 48 percent were treated successfully and 20 percent had stabilization of disease [63]. In one study that included nine patients with cryptococcosis who were treated with isavuconazole, six (67 percent) had a successful response [61].

The use of interferon-gamma as adjunctive therapy during primary (not salvage) treatment has been evaluated; its efficacy was encouraging but not definitive [64,65]. It may be a reasonable consideration for use in truly refractory cases with persistent positive cultures.

Immune reconstitution inflammatory syndrome — Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical worsening of an infectious process following restitution of immune function. Onset of IRIS in solid organ transplant recipients has been described at a mean of six weeks after initiation of antifungal therapy [53]. Manifestations may include fever, lymphadenitis, and signs and symptoms of meningitis. Acute respiratory distress syndrome can also be a manifestation of IRIS in immunocompromised individuals. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

Distinguishing between IRIS, relapse or progression of cryptococcal infection, and other infections or complications can be difficult in severely immunocompromised individuals [54,57]. Clinical manifestations, inflammatory CSF values, positive India ink exams, and positive cryptococcal antigen titer may be present in both IRIS and cryptococcal infection. The most important distinguishing feature is that patients with active infection have positive CSF cultures, whereas patients with IRIS have sterile CSF cultures. Some studies suggest that PCR positivity in CSF may help predict positive cultures [58].

Patients with IRIS should continue antifungal therapy. Those with minor manifestations can be managed with supportive care; symptoms frequently resolve spontaneously in days to weeks.

In the setting of central nervous system (CNS) inflammation with increased intracranial pressure and severe symptoms, glucocorticoids may be used. Glucocorticoids should be administered with concomitant antifungal therapy.

There are limited data to suggest a specific dosing regimen. Some providers administer dexamethasone, starting at a dose of approximately 0.3 mg/kg/day IV (20 to 24 mg IV for most normal and overweight patients) during week 1, and then tapering the dose over the course of six weeks (eg, 0.2 mg/kg/day IV during week 2; followed by oral administration of 0.1 mg/kg/day during week 3; 3 mg/day during week 4; 2 mg/day during week 5; and 1 mg/day during week 6) [66]. However, other clinicians empirically use prednisone, starting at approximately 1 mg/kg/day (60 to 80 mg/day for most normal and overweight patients) and then tapering over four to six weeks.

IRIS occurs most commonly in patients with HIV with initiation of antiretroviral therapy, although it has also been described in solid organ transplant recipients [41,53,67-69]. In one study of 89 solid organ transplant recipients with cryptococcosis, 14 percent developed signs and symptoms suggestive of IRIS [69]. CNS disease and discontinuation of a calcineurin inhibitor were independently associated with IRIS. Among patients with CNS disease, those with neuroimaging abnormalities were more likely to develop IRIS. (See "Immune reconstitution inflammatory syndrome".)

In patients with no obvious underlying immune deficiencies, worsening of symptoms can also occur, despite mycologic control of the infection [41,70,71]. Investigators have labelled this aggravated immune response "post-infectious inflammatory response syndrome" (PIIRS) [72]. Patients with PIIRS respond to systemic courses of steroids just as patients with IRIS do.

These episodes of clinical worsening appear very similar to immune reconstitution syndromes, but because there was no obvious underlying immune defect that was "reconstituted," investigators have been trying to identify the pathophysiology involved in these cases. In one study that evaluated a select group of apparently immunocompetent patients, investigators found that clinical deterioration appeared to occur as a result of dissociation between macrophages and T cells, leading to persistent inflammation due to failure of the macrophages to clear antigen [73]. A subsequent study described six cases of cryptococcal spinal arachnoiditis, which developed in previously healthy individuals with cryptococcal meningoencephalitis [70]. These patients had negative cultures, elevated CSF inflammatory markers (SCD27 and SCD21), and an elevated neuronal damage marker, neurofilament light chain; corticosteroid therapy significantly improved symptoms

PROGNOSIS — The most important prognostic factors are the nature of the underlying immunosuppression and/or the concurrent disease. As an example, relapse rates among solid organ transplant recipients are very low [14]; in contrast, the mortality rate in those with cirrhosis is extremely high [71]. In addition, patients with cryptococcal meningoencephalitis and an underlying malignancy have a shorter median survival rate than those with HIV infection (two versus nine months) [74]. The prognosis among patients with malignancy and liver disease is also worse than those with immunosuppression due to glucocorticoid therapy [17] or anti-granulocyte-macrophage colony stimulating factor auto-antibodies [75]. Other factors conferring poor prognosis include: positive India ink examination of the cerebrospinal fluid (CSF); CSF white blood cell count <20/microL; initial CSF or serum cryptococcal antigen titer >1:32; and/or high opening pressure on lumbar puncture [59].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cryptococcosis".)

SUMMARY AND RECOMMENDATIONS

Risk factors for cryptococcal disease − Most patients with cryptococcal meningoencephalitis are immunocompromised. The most common forms of immunosuppression other than HIV include glucocorticoid therapy, biologic modifiers, the use of some tyrosine kinase inhibitors (eg, ibrutinib), solid organ transplantation, cancer (particularly hematologic malignancy), and conditions such as sarcoidosis and hepatic failure. (See 'Introduction' above.)

General principles − Treatment of cryptococcal meningoencephalitis consists of antifungal therapy (induction, consolidation, and maintenance phases), managing intracranial pressure, and reducing immunosuppressive therapy. (See 'General Principles' above.)

Preferred antifungal therapy − For nonpregnant adults with meningoencephalitis, or severe pulmonary or disseminated disease:

We suggest combination therapy with amphotericin B plus flucytosine during the induction phase of treatment (Grade 2B). We prefer a lipid formulation rather than amphotericin B deoxycholate to reduce toxicity and minimize the risk of treatment interruptions. Liposomal amphotericin B (3 to 4 mg/kg intravenously [IV] per day) or amphotericin B lipid complex (5 mg/kg IV per day) can be used. (See 'Preferred regimen' above.)

The minimum duration of induction therapy with amphotericin B and flucytosine is two weeks. However, the ultimate duration depends upon the presence of serious neurologic complications (eg, persistent headaches, seizures, ocular and auditory manifestations), radiographic evidence of brain parenchymal involvement (eg, cryptococcomas), the patient's underlying condition, and the response to therapy (eg, clinical improvement, and, in some cases, the presence or absence of fungal growth on a lumbar puncture performed at two weeks). (See 'Duration of preferred regimen' above.)

Following induction therapy, we recommend consolidation therapy with fluconazole (Grade 1B). Fluconazole 800 mg (or 12 mg/kg in children) orally daily should be administered for eight weeks, followed by maintenance therapy with fluconazole (200 to 400 mg orally daily) [1]. Maintenance azole therapy is generally given for one year after diagnosis. (See 'Consolidation and maintenance therapy' above.)

Special populations − There are special considerations regarding the choice of agent and duration of treatment for patients who cannot tolerate first-line agents, as well as for pregnant women, children, and those who present with cryptococcomas. (See 'Alternative regimens' above and 'Special populations' above.)

Control of intracranial pressure − Control of intracranial pressure is one of the most critical determinants of outcome for cryptococcal meningoencephalitis. The intracranial pressure should be measured at the time of initial lumbar puncture. If the pressure is ≥25 cm of cerebrospinal fluid (CSF) and there are symptoms of increased intracranial pressure during induction therapy, CSF drainage should be performed to reduce the pressure by 50 percent or to a normal pressure of ≤20 cm. (See 'Control of intracranial pressure' above.)

Modulating immunosuppression − Reduction in immunosuppressive therapy may be beneficial for control of cryptococcal infection, although this must be balanced with the potential for organ rejection and immune reconstitution. (See 'Modulating immunosuppression' above.)

Evaluation of persistent or worsening symptoms − For patients with persistent or worsening symptoms, distinguishing between persistent or relapsed cryptococcal infection, immune reconstitution inflammatory syndrome (IRIS), and other infections or complications can be difficult. The most important distinguishing feature is that patients with active infection have positive CSF cultures, whereas patients with IRIS have sterile CSF cultures. (See 'Persistent/worsening symptoms' above.)

Managing persistent or relapsed infection − Initial management of persistent or relapsed infection should include evaluation of immunosuppressive therapy and management of increased intracranial pressure. Repeat induction phase therapy should be reinstituted for a longer course (4 to 10 weeks) and a surveillance lumbar puncture should be performed after two weeks of therapy. Salvage consolidation therapy depends upon in vitro susceptibility testing. (See 'Persistent or relapsed infection' above.)

Managing IRIS − Patients with IRIS should continue antifungal therapy. Those with minor manifestations can be managed with supportive care; symptoms frequently resolve spontaneously in days to weeks. In the setting of central nervous system inflammation with increased intracranial pressure and severe symptoms, oral glucocorticoids may be used. (See 'Immune reconstitution inflammatory syndrome' above.)

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Topic 2443 Version 35.0

References

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