Updated: May 11, 2021
Author: Pradeep Kumar Mada, MD, MRCP(UK); Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD 


Practice Essentials

Infection with the encapsulated yeast Cryptococcus neoformans can result in harmless colonization of the airways, but it can also lead to meningitis or disseminated disease, especially in persons with defective cell-mediated immunity. Cryptococcosis represents a major life-threatening fungal infection in patients with severe HIV infection and may also complicate organ transplantation, reticuloendothelial malignancy, corticosteroid treatment, or sarcoidosis. 

Axial T2-weighted magnetic resonance image shows c Axial T2-weighted magnetic resonance image shows clustered hyperintensities in the left caudate; these are consistent with enlarged Virchow-Robin spaces caused by small cryptococcomas.

Signs and symptoms

The presentation in cryptococcosis varies with the site of infection and the patient’s immune status. Signs and symptoms of pulmonary cryptococcosis in immunocompetent patients are as follows:

  • Cough (54%)

  • Cough with the production of scant mucoid sputum (32%)

  • Pleuritic chest pain (46%)

  • Low-grade fever, dyspnea, weight loss, and malaise (less common)

HIV-infected patients with pulmonary cryptococcosis may present with the following:

  • Fever (84%)

  • Cough (63%)

  • Dyspnea (50%)

  • Headache (41%)

  • Weight loss (47%)

Other possible findings in pulmonary infection are as follows:

  • Pleuritic pain

  • Hemoptysis

  • Rales or pleural rub

  • Acute respiratory distress syndrome (ARDS)

Meningitis and meningoencephalitis, the most common manifestations of CNS cryptococcosis, are usually subacute or chronic in nature. HIV-infected patients may have minimal or nonspecific symptoms. Common symptoms are as follows:

  • Headache

  • Confusion

  • Lethargy

  • Obtundation

  • Coma

  • Normal or mildly elevated temperature

  • Nausea and vomiting (with increased intracranial pressure)

  • Fever and stiff neck (with an aggressive inflammatory response; less common)

  • Blurred vision, photophobia, and diplopia

  • Hearing defects, seizures, ataxia, aphasia, and choreoathetoid movements

After lung and CNS infection, the next most commonly involved organs in disseminated cryptococcosis include the skin, the prostate, and the medullary cavity of bones. Cutaneous manifestations (10-15% of cases) are as follows:

  • Papules, pustules, nodules, ulcers, or draining sinuses

  • Umbilicated papules in patients with AIDS

  • Cellulitis with necrotizing vasculitis in organ transplant recipients[1, 2]

Other less common forms of cryptococcosis include the following:

  • Optic neuritis or endophthalmitis

  • Myocarditis

  • Chorioretinitis

  • Hepatitis

  • Peritonitis

  • Renal abscess

  • Myositis

  • Adrenal involvement


The workup in patients with suspected cryptococcosis includes the following:

  • Cutaneous lesions: Biopsy with fungal stains and cultures

  • Blood: Fungal culture, cryptococcal serology, and cryptococcal antigen testing

  • Cerebrospinal fluid: India ink smear, fungal culture, and cryptococcal antigen testing

  • Urine and sputum cultures, even if renal or pulmonary disease is not clinically evident

  • In AIDS patients with cryptococcal pneumonia, culture of bronchoalveolar lavage washings

With possible CNS cryptococcosis, especially in patients who present with focal neurologic deficits or a history compatible with slowly progressive meningitis, consider obtaining a computed tomography or magnetic resonance imaging scan of the brain prior to performing a lumbar puncture. If a mass lesion is identified, do not perform a lumbar puncture to obtain spinal fluid; rather, consult a neurosurgeon for an alternative procedure.

With pulmonary cryptococcosis, radiographic findings in patients who are asymptomatic and immunocompetent may include the following:

  • Patchy pneumonitis

  • Granulomas ranging from 2-7 cm

  • Miliary disease similar to that in tuberculosis


Pulmonary cryptococcosis resolves without specific therapy in most immunocompetent patients. Antifungal therapy is necessary for the following:

  • Pulmonary cryptococcosis in immunosuppressed hosts

  • CNS cryptococcosis

  • Disseminated nonpulmonary non-CNS cryptococcosis

Treatment for cryptococcal meningitis in patients with AIDS is as follows:

  • Amphotericin B deoxycholate, 0.7-1 mg/kg/day for 2 weeks, with or without

  • Flucytosine, 100 mg/kg/day in 4 divided doses for 2 weeks

  • Flucytosine speeds clearance of viable yeast from CSF but is potentially toxic, especially in patients with renal dysfunction

  • After 2 weeks, fluconazole at 400 mg/day for a minimum of 8-10 weeks

Alternative initial therapies include the following:

  • Liposomal amphotericin B 3-4 mg/kg/day for at least 2 weeks in patients at risk for renal dysfunction; in patients who have failed therapy or have a high fungal burden of disease, liposomal amphotericin B 6 mg/kg/day IV has been given safely
  • In patients intolerant of amphotericin B products, fluconazole 800-1200 mg/day plus flucytosine 100 mg/kg/day for at least 6 weeks can be used. Initial therapy should be considered successful only after CSF culture is negative for cryptococcal organisms and the patient has had significant clinical improvement.

Initial therapy should be considered successful only after CSF culture is negative for cryptococcal organisms and the patient has had significant clinical improvement.

Guidelines published in 2000 recommended maintenance therapy with fluconazole at 200 mg/day for life.[3] Guidelines published in 2002 supported discontinuation of suppressive therapy if CD4 counts remained greater than 200 cells/µL but reinstitution if the CD4 counts fall to fewer than 200 cells/µL.[4] Guidelines published in 2010 support discontinuation of suppressive therapy when the CD4 count exceeds 100 cells/µL and HIV viral load is undetectable or very low for more than 3 months. However, reinstitution of maintenance therapy should be considered if the CD4 cell count falls to less than 100 cells/µL.[5]

Control of CSF pressure is critical to the patient’s survival. An initial opening pressure of 250 mm H2O or greater must be reduced and kept around 200 H2O throughout therapy. In some patients, this may require daily spinal taps or a spinal fluid drain until pressures are controlled.  In rare cases, control of elevated CSF pressures may require a ventriculoperitoneal shunt. Failure to control CSF pressure may result in blindness, permanent neurologic deficits, or death.

  • Monitor CSF pressure during the initial phase of therapy
  • If the opening pressure exceeds 250 mm H 2O, remove CSF to reduce the closing pressure to below 200 mm H 2O or at least 50% of the elevated opening pressure
  • Mannitol has no proven value in reducing pressure in cryptococcal meningitis. Acetazolamide or corticosteroids to control CSF pressure unassociated with immune reconstitution inflammatory syndrome (IRIS) should also be avoided.
  • In severe IRIS complicating therapy of HIV-associated cryptococcal meningitis, prednisone 0.5-1.0 mg/kg/day or dexamethasone can be used to control signs or symptoms of severe CNS disease.

IRIS may occur in patients with AIDS or other severe immunosuppressive conditions. In patients with AIDS who are not on antiretroviral therapy but who develop cryptococcal meningitis, initiation of antiretrovirals early in the administration of anticryptococcal therapy may result in a rapid worsening of the patient’s condition. This worsening is believed to result from sudden enhancement in the patient’s immune response to the infection, leading to worsening signs and symptoms or even death.

In patients without AIDS, treatment of cryptococcal meningitis is as follows:

  • Amphotericin B (0.7-1 mg/kg/day) alone for 6-10 weeks or in combination with flucytosine (100 mg/kg/day in 4 divided doses) for 2 weeks, followed by fluconazole for a minimum of 10 weeks

  • Base therapy duration on CSF examination results

  • Consider weekly CSF examination until culture conversion is documented and cultures remain negative for 4 weeks

  • CSF protein abnormalities may persist for years despite successful therapy; thus, an elevated CSF protein as the only residual abnormality should not dictate prolonging therapy

Pulmonary cryptococcosis can be treated with observation only, if the following criteria are met:

  • CSF chemistry parameters are normal

  • CSF culture, CSF cryptococcal antigen, India ink preparation, and serology results are negative

  • Urine culture results are negative

  • The pulmonary lesion is small and stable or shrinking

  • The patient has no predisposing conditions for disseminated disease

Antifungal treatment for cryptococcal pulmonary disease is as follows:

  • Mild-to-moderate disease: Fluconazole for 6-12 months, itraconazole for 6-12 months, or amphotericin B

  • Severe disease: Amphotericin B (0.7-1 mg/kg/day) plus flucytosine (100 mg/kg/day) for 6-10 weeks, or for 2 weeks followed by fluconazole at 400 mg/kg/day for at least 10 weeks, possibly followed by further consolidation therapy for 6-12 months



Cryptococcus neoformans is an encapsulated yeast. In 1894, Busse, a pathologist, first described the yeast in a paper he presented to the Greifswald Medical Society. Busse isolated the yeast from the tibia of a 31-year-old woman, noted its resistance to sodium hydroxide, and published the case report that same year.[6] The following year, a surgeon named Buschke reported the same isolate from the same patient, thus establishing the early eponym of Busse-Buschke disease.[7] This single case served to identify a new yeast and to prove its pathogenic potential.

Since the initial reports, researchers have identified the diverse spectrum of host responses to cryptococcal infection. The responses range from a harmless colonization of the airways and asymptomatic infection in laboratory workers (resulting in only a positive skin test finding) to meningitis or disseminated disease. Although virulence in animals and, possibly, humans varies among strains of cryptococci, virulence probably plays a relatively small role in the outcome of an infection. The crucial factor is the immune status of the host.

The most serious infections usually develop in patients with defective cell-mediated immunity. For example, patients with AIDS, patients undergoing organ transplantation, patients with reticuloendothelial malignancy, patients undergoing corticosteroid treatment (but not those with neutropenia or immunoglobulin deficiency), and patients with sarcoidosis develop the most serious cryptococcal infections.

With the global emergence of AIDS, the incidence of cryptococcosis is increasing and now represents a major life-threatening fungal infection in these patients.


Although the genus Cryptococcus contains more than 50 species, only C neoformans and Cryptococcus gattii are considered principal pathogens in humans. Previously, C neoformans was defined as having two varieties—var neoformans and var gattii. However, based on the elucidation of the genomic sequences, C neoformans and C gattii are now considered two distinct species. These two species have 5 serotypes based on antigenic specificity of the capsular polysaccharide; these include serotypes A, D, and AD (C neoformans) and serotypes B and C (C gattii).

C neoformans is the most common species in the United States and other temperate climates throughout the world and is found in aged pigeon droppings. Until recently, C gattii was found principally in tropical and subtropical climates. C gattii is not associated with birds but grows in the litter around certain species of eucalyptus trees (ie, Eucalyptus camaldulensis, Eucalyptus tereticornis). A 2016 epidemiological study performed in Bogota, Columbia, showed that Cneoformans also has a predilection for eucalyptus tree species, similar to Cgattii.[8]

Worldwide, C neoformans serotype A causes most cryptococcal infections in immunocompromised patients, including patients infected with HIV. For unknown reasons, Cgattii rarely infects persons with HIV infection and other immunosuppressed patients. Patients infected with C gattii are usually immunocompetent, respond slowly to treatment, and are at risk for developing intracerebral mass lesions (eg, cryptococcomas). A 2016 epidemiological study revealed that Cryptococcus tetragattii (AFLP7/VGIV), one of the five recognized genotypes of Cgattii sensu lato, is associated with a higher prevalence of cryptococcal meningitis among HIV-infected patients in Zimbabwe.[9]

C neoformans reproduces by budding and forms round yeastlike cells that are 3-6 µm in diameter. Within the host and in certain culture media, a large polysaccharide capsule surrounds each cell. C neoformans forms smooth, convex, yellow or tan colonies on solid media at 20-37°C (68-98.6°F). This fungus is identified based on its microscopic appearance, biochemical test results, and ability to grow at 37°C (98.6°F); most nonpathogenic Cryptococcus strains do not grow at this temperature. In addition, C neoformans does not assimilate lactose and nitrates or produce pseudomycelia on cornmeal or rice-Tween agar.

Most strains of C neoformans can use creatinine as a nitrogen source, which may partially explain the growth of the organism in creatinine-rich avian feces. Another useful biochemical characteristic of C neoformans, which distinguishes it from nonpathogenic strains, is its ability to produce melanin. The fungal enzyme phenol oxidase acts on certain substrates (eg, dihydroxyphenylalanine, caffeic acid) to produce melanin.

C gattii contains genotypes VGI and the more commonly identified VGIIa and VDIIb. Cryptococcus species can reproduce via same-sex mating, and VGIIa may have arisen from the same-sex mating of VGIIb and another strain that has yet to be identified.

In 1976, Kwon-Chung described the perfect (ie, sexual, teleomorphic) form of C neoformans, which was named Filobasidiella neoformans. Prior to the identification of F neoformans, which is mycelial, C neoformans was considered a monomorphic yeast. F neoformans results from the mating of suitable strains of serotypes A and D. The perfect state of C gattii is Filobasidiella bacillispora and results from the mating of serotypes B and C. Some strains of A and D can mate with strains of B and C.


C neoformans is distributed worldwide. Most cases of cryptococcosis involve serotypes A and D. Serotypes B and C, C gattii, are most common in tropical and subtropical areas and can be isolated from certain species of eucalyptus trees and the air beneath them. C neoformans, which is recovered from aged pigeon feces, bird nests, and guano, is invariably serotype A or D. Although serotypes A and D exist in high concentrations in the pigeon feces, the fungus does not infect the birds. In moist or desiccated pigeon excreta, C neoformans may remain viable for 2 years or longer. The pigeon fanciers are known to have higher anti–C. neoformans antibodies titers than normal population.[10]  In saprobic environments, C neoformans grows unencapsulated; however, unencapsulated strains regain their virulence following reacquisition of their polysaccharide capsule. C gattii usually causes disease in patients with intact cell-mediated immunity.

Naturally occurring cryptococcosis occurs in both animals and humans, but neither animal-to-human transmission nor person-to-person respiratory transmission via the respiratory route has been documented. Transmission via organ transplantation has been reported when infected donor organs were used. C neoformans causes the vast majority of cryptococcal infections in immunosuppressed hosts, including patients with AIDS, whereas C gattii causes 70%-80% of cryptococcal infections among immunocompetent hosts. AIDS, decompensated liver cirrhosis, cellular mediated immunity suppressive regimens, and autoimmune disorders have been established as possible risk factors in the causation of invasive C neoformans disease.[11]

Although C neoformans is found worldwide, C gattii is usually identified in subtropical areas such as Australia, South America, Southeast Asia, and Central and sub-Saharan Africa. In the United States, C gattii is found in Southern California and more recently in the states of Washington and Oregon.

As noted above, C gattii may be found in association with several different trees, such as river red gum trees (E camaldulensis) and forest red gum trees (E tereticornis). Infection is acquired by inhalation of air-borne propagules that infect the lungs and may result in fungemia, leading to CNS involvement.

In 1999, C gattii emerged on Vancouver Island, British Columbia, Canada. Infections were reported among residents and visitors to the island, as well as among domesticated and wild animals. Disease has been most often identified in cats, dogs and ferrets. Marine mammals have also been infected. Vectors can disperse the spores from an endemic area to a previously unaffected area. This may have been the route of spread in the case of Vancouver Island. Since 2003, cryptococcal disease has become a provincially notifiable infection in British Columbia. Isolates have been identified in coastal Douglas fir and coastal western hemlock bioclimatic zones. C gattii has been identified subsequently in the states of Washington and Oregon.

The incidence of infection related to age, race, or occupation does not significantly differ. Cryptococcal antibodies acquisition begins at as early as one year of age. At the age of 5 years, 70% of children react with C. neoformans antigen.[12]  Healthy persons with a history of exposure to pigeons or bird feces and laboratory workers exposed to an aerosol of the organism have a higher rate of positive delayed hypersensitivity skin reactions to cryptococcal antigen or cryptococci. Occasionally, laboratory accidents result in transmission of C neoformans, but pulmonary and disseminated disease is rare in this setting. Accidental cutaneous inoculation with C neoformans causes localized cutaneous disease.

A report from British Columbia, Canada indicates that risk factors for infection by C gattii include steroid use and underlying pulmonary disease.[13] The authors also report a predilection for individuals older than 50 years, current smokers, and those with immunosuppression due to HIV or invasive malignancy.

The advent and increased use of anti-TNF and anti-CD 54 has posed an increased risk of contracting cryptococcosis, along with an increased risk of delayed diagnosis.[14, 15]


Of the more than 50 species that comprise the genus Cryptococcus, human disease is primarily associated with C neoformans and C gattii. Animal models provide much of the understanding of the pathogenesis and the host defense mechanisms involved in cryptococcal infections. Cryptococcosis is acquired in two routes; after exposure to C. neoformans in immunocompromised, causing rapidly progressive cryptococcosis; the second is with a phase of latency followed by reactivation and dissemination. The concept of latency has been validated in C. neoformans.[16]  The organism is primarily transmitted via the respiratory route, but not directly from human to human.

Following inhalation, the yeast spores are deposited into the pulmonary alveoli, where they must survive the neutral-to-alkaline pH and physiologic concentrations of carbon dioxide before they are phagocytized by alveolar macrophages. Glucosylceramide synthase (GCS) has been identified as an essential factor in the survival of C neoformans in this extracellular environment.[17] Although GCS is a critical factor in extracellular survival of the yeast, the yeast no longer requires GCS to survive the intracellular, more acidic, environment within the macrophage once it is phagocytized by alveolar macrophages.

Unencapsulated yeast are readily phagocytosed and destroyed, whereas encapsulated organisms are more resistant to phagocytosis. The cryptococcal polysaccharide capsule has antiphagocytic properties and may be immunosuppressive. The antiphagocytic properties of the capsule block recognition of the yeast by phagocytes and inhibit leukocyte migration into the area of fungal replication.

The host response to cryptococcal infection includes both cellular and humoral components. Animal models demonstrate that natural killer cells participate in the early killing of cryptococci and, possibly, antibody-dependent cell-mediated killing. In vitro monocyte-derived macrophages, natural killer cells, and T lymphocytes can inhibit or kill cryptococci. A successful host response includes an increase in helper T-cell activity, skin test conversion, and a reduction in the number of viable organisms in the tissues. In addition to cellular mechanisms, anticryptococcal antibodies and soluble anticryptococcal factors have been described. Antibodies to cryptococcal antigens play a critical role in enhancing the macrophage- and lymphocyte-mediated immune response to the organism. Researchers have used monoclonal antibodies to capsular polysaccharide to passively immunize mice against C neoformans.

C neoformans infection is usually characterized by little or no necrosis or organ dysfunction until late in the disease. Organ damage may be accelerated in persons with heavy infections. The lack of identifiable endotoxins or exotoxins may be partly responsible for the absence of extensive necrosis early in cryptococcal infections. Organ damage is primarily due to tissue distortion secondary to the expanding fungal burden. Extensive inflammation or fibrosis is rare. The characteristic lesion of C neoformans consists of a cystic cluster of yeast with no well-defined inflammatory response. Well-formed granulomas are generally absent.

C neoformans can cause an asymptomatic pulmonary infection followed later by the development of meningitis, which is often the first indication of disease. If limited to the lungs, C neoformans infection may cause pneumonia, poorly defined mass lesions, pulmonary nodules, and, rarely, pleural effusion. Although immune defects are common in patients with meningitis or disseminated infection, patients with disease that is confined to the lungs are usually immunocompetent.



United States

Prior to 1946, only 200 patients with cryptococcal disease had been reported in the medical literature. The development and use of corticosteroids and improvement in patient survival with some malignancies increased the reported incidence of cryptococcal disease. Since the mid 1980s, most cryptococcal disease has occurred in patients with AIDS. A study published in March 2005 that reviewed data from 1981-2000, the first 2 decades of the AIDS epidemic, showed that the annual incidence per million person-years was 19 cases in men and 2.6 cases in women. The highest incidence occurred from 1981-1992; afterward, the incidence began to decline. In women, the peak incidence occurred in 1997. The overall incidence in cryptococcal disease decreased and preceded the availability of of highly active antiretroviral therapy for AIDS.

Approximately 7%-15% of patients with AIDS develop cryptococcal infections. In 1993, the US Centers for Disease Control and Prevention reported that 6% of 274,150 patients with AIDS developed cryptococcal disease. Furthermore, patients with AIDS-associated cryptococcal infections now account for 80%-90% of all patients with cryptococcosis.


C neoformans has a worldwide distribution and, similar to in the United States, preferentially infects immunosuppressed individuals, especially those with AIDS. Cryptococcal meningitis associated with HIV infection is responsible for more than 600,000 deaths per year worldwide.[18] In sub-Saharan Africa, 15%-30% of all patients with AIDS develop cryptococcal disease. However, in some areas, such as Zimbabwe, 88% of patients with AIDS have cryptococcal infection as their AIDS-defining illness. Most case reports of C gattii have been from Australia, with a few case reports from the southern California coast and tropical regions of Central and South America. As mentioned above, some recent cases have been reported from Vancouver, British Columbia, Canada and the states of Washington and Oregon, United States.

An outbreak of  a hypervirulent strain of C gattii has been linked to climate changes in the northwestern United States and British Columbia.[19]


Prior to the use of amphotericin B (Throughout this article, the term amphotericin B refers to amphotericin B desoxycholate.), cryptococcal meningitis and disseminated disease were invariably fatal; however, with the availability of amphotericin B, lipid preparations of amphotericin B, flucytosine, fluconazole, and other azoles, the mortality rate of cryptococcal disease dramatically decreased. In 1995, Speed and Dunt reported a 14% mortality rate among patients with cryptococcal disease who were treated with amphotericin B plus flucytosine and a 28% mortality rate among patients treated with other regimens.[20]


No clear racial predilection has been reported for either cryptococcal infection or disease. No occupational predilection has been defined.


In most studies, cryptococcal disease is reportedly more common in men than in women.


In a 1972 review, Lewis and Rabinovich reported that almost two thirds of patients with cryptococcal disease were older than 40 years[21] ; furthermore, in patients aged 50 years and older, cryptococcal disease was more than 3 times as common in men as in women. However, the pandemic of AIDS has led to a simultaneous and dramatic rise in the incidence of cryptococcal disease and a reduction in the average age of affected patients.




The principal site or sites of infection (ie, pulmonary, CNS, disseminated disease) dictate the medical history of patients with symptomatic cryptococcal disease. Factors that are especially important include the presence of coexisting conditions associated with immunosuppression (eg, steroid use, malignant disease, transplantation) or HIV infection. Other key factors in the history often relate to organ-specific problems (eg, cough, headaches, focal neurological defects, skin rashes).

Cryptococcus has become an increasingly common infection among patients who have received solid organ transplants and is now among the 3 most common invasive fungal infections in the posttransplant period. Cryptococcus infections in solid organ transplant recipients usually occur 1-2 years after transplantation. However, a study identified a subset of patients who developed invasive cryptococcal disease within the first 30 days.[22] In 2 patients, invasive cryptococcal disease occurred in the first posttransplant day. The source of these infections are most likely unrecognized pretransplant infections or donor-derived infections. Most of the patients in this report were liver transplant recipients.

Pulmonary cryptococcosis

The pattern of cryptococcal pulmonary disease varies greatly, ranging from asymptomatic saprophytic airway colonization to acute respiratory distress syndrome, which affects immunocompromised hosts (eg, patients with AIDS, organ transplant recipients). On occasion, cryptococcal pulmonary disease may even manifest as a slowly progressive mass that may compress thoracic structures such as the vena cava.

A patient with pulmonary cryptococcosis may present with mild-to-moderate symptoms, including fever, malaise, cough with scant sputum, pleuritic pain, and hemoptysis (rare). Unusual findings include rales or pleural rub. Pleural effusions may be present but are uncommon.

Cavitation and hilar lymphadenopathy are uncommon.

Calcification and pulmonary fibrosis or stranding are usually absent.

Although chronic infection can occur, immunocompetent patients usually have spontaneous regression of both clinical and radiological manifestations.

Among patients who are HIV positive and have a pulmonary cryptococcal infection, 5%-25% present with cough and dyspnea.

Adult respiratory distress syndrome may ensue.

Pulmonary disease is more likely to progress in immunocompromised patients and to require antifungal therapy.

Pulmonary disease may occur in the absence of extrapulmonary disease. Conversely, extrapulmonary disease (eg, meningitis) may develop in the absence of identifiable pulmonary pathology.

CNS cryptococcosis

Meningitis and meningoencephalitis are the most common manifestations of CNS cryptococcosis and are usually subacute or chronic in nature.

This form of infection is invariably fatal without appropriate therapy; death may occur from 2 weeks to several years after symptom onset.

The clinical presentation and course of cryptococcal meningitis vary, relating in part to underlying medical conditions (eg, diabetes, sarcoidosis, glucocorticoid use) and the immune status of the host.

The most common symptoms are headache and altered mental status, including personality changes, confusion, lethargy, obtundation, and coma.

Nausea and vomiting are common and are often associated with increased intracranial pressure, whereas fever and stiff neck, symptoms associated with a more aggressive inflammatory response, are less common.

Some patients who are HIV positive may have minimal or nonspecific symptoms at presentation. Patients are often afebrile or have a mildly elevated temperature.

Symptoms such as blurred vision, photophobia, and diplopia may result from arachnoiditis, papilledema, optic nerve neuritis, or chorioretinitis.

Other findings include hearing defects, seizures, ataxia, aphasia, and choreoathetoid movements.

Dementia is a potential sequela and may indicate the presence of hydrocephalus as a late complication.

Cryptococcosis in other sites

After lung and CNS infection, the next most commonly involved organs in disseminated cryptococcosis include the skin, prostate, and the medullary cavity of bones.

Cutaneous manifestations occur in 10%-15% of cases and usually take the form of papules, pustules, nodules, ulcers, or draining sinuses.

Umbilicated papules in patients with AIDS may resemble molluscum contagiosum.

Cellulitis with necrotizing vasculitis is reported in patients who undergo organ transplantation.[1, 2]

Bone lesions develop in 5%-10% of patients and are usually osteolytic or resemble cold abscesses. These lesions may be confused with tuberculosis or neoplasm.

Cryptococcal spp. have diameter of around 20 µm which limit their passage through the intestinal wall.[23]  Cryptococcus neoformans has also been isolated though less commonly than candidal spp in spontaneous peritonitis cases in cirrhosis patients.[24, 25]  

Other less common forms of cryptococcosis include the following:

  • Myocarditis

  • Chorioretinitis

  • Hepatitis

  • Renal abscess

  • Prostatitis (Prostatic foci of cryptococci may persist after therapy for CNS disease and may act as a reservoir for relapse in men with AIDS.)

  • Myositis

  • Adrenal involvement


The physical findings of patients with cryptococcal infection primarily depend on the patient’s immune status prior to infection and the site or sites involved. Because the inflammatory responses to encapsulated cryptococci are blunted, tissues may be extensively involved before the patient presents for medical care. Furthermore, the limited inflammatory response associated with the encapsulated yeast can result in mild clinical findings, further complicating diagnosis.

Pulmonary cryptococcosis

Although C neoformans most often infects patients via the pulmonary route, less than 15% of patients present with a clinical picture of pneumonia. On occasion, isolation of Cryptococcus from sputum may represent colonization rather than true infection, especially in patients with chronic obstructive pulmonary disease (COPD) or bronchiectasis.

One third of immunocompetent patients who develop pulmonary infection are asymptomatic or have symptoms so mild that they do not seek medical care.

When symptoms develop in immunocompetent hosts, they include cough (54%), cough with the production of scant mucoid sputum (32%), and pleuritic chest pain (46%). Low-grade fever, dyspnea, weight loss, and malaise may also be present.

Night sweats, as observed in tuberculosis, are uncommon in cryptococcal pulmonary disease but may occur with disseminated or CNS disease.

In immunocompromised patients who do not have HIV infection, cryptococcal pulmonary infection is associated with an accelerated course, often with early dissemination. As many as 83% of these patients present with constitutional symptoms (eg, fever, malaise).[26]

Patients co-infected with HIV and Cryptococcus present with fever (84%), cough (63%), dyspnea (50%), headache (41%), and weight loss (47%). Often, patients with co-infection have cryptococcal antigens and cultures that are positive in cerebrospinal fluid (CSF), blood, and urine. Any part of a lung may be involved, and infiltrates may be bilateral, unilateral, multilobar, or lobar.

CNS cryptococcosis

Although C neoformans enters the body via the lungs, the CNS is the main site of clinically evident infection in both immunocompetent and immunocompromised hosts. Following pulmonary infection, cryptococci disseminate widely and may infect any organ. The organs most often involved include the CNS, bones, prostate, eyes, and skin. Prior to the discovery of amphotericin B in 1955, 80% of patients with CNS involvement died within 2 years of diagnosis.

Cryptococcal CNS infections usually involve both the brain and meninges, causing diffuse disease. Immunocompetent hosts may present with either meningitis or focal cryptococcomas. Meningitis manifests with diffuse nonfocal findings (eg, altered mental status, vomiting), whereas cryptococcomas often manifest with focal neurologic defects.

Cryptococcal skin infection

Approximately 10%-15% of patients infected with C neoformans develop skin involvement. In immunocompetent hosts, the skin may be the only site of infection; however, immunosuppressed patients, especially those with AIDS, have skin involvement that must be considered evidence of disseminated disease.

Cutaneous lesions include nodules, ulcers, papules, and vasculitic lesions.

Cryptococcal osteomyelitis

Bone involvement is documented in 5%-10% of patients with cryptococcal infection.

Bone lesions are usually osteolytic and may be misinterpreted as neoplastic lesions or osseous tuberculosis.

Other sites of cryptococcal infection

The eyes and prostate are often involved. Eye involvement often manifests as vision loss caused by optic neuritis or endophthalmitis. Rapid diagnosis and treatment are essential to preserve the patient's sight.

In men, eradication of cryptococci from the prostate is often difficult, and prostatic foci of infection can act as a reservoir for relapse of systemic infections.

Other considerations

A CT scan or MRI in patients with cryptococcal infection may reveal diffuse atrophy or cerebral edema with focal, homogenous, or contrast-enhanced areas. These findings may help distinguish cryptococcal infection from other causes of intracranial mass lesions and infections. However, scans are not diagnostic in and of themselves.

Early cryptococcal meningitis may resemble other mycoses, syphilis, tuberculosis, or meningeal metastases. Do not confuse this condition with chronic meningitis caused by other infections or by noninfectious causes (eg, sarcoidosis, chronic benign lymphocytic meningitis).

Pulmonary findings may be indistinguishable from those in patients with acute pneumonia caused by Pneumocystis jiroveci (previously Pneumocystiscarinii), Mycobacterium tuberculous, Histoplasma capsulatum, or other organisms.

Cutaneous lesions are nonspecific and may be mistaken for a large variety of lesions related to other causes, including acne, syphilis, lipoma, tuberculosis, molluscum contagiosum, or basal cell carcinoma.

Bone lesions may be mistaken for tubercular cold abscess or neoplasm.


Infection with either C neoformans or Cgattii causes cryptococcal disease. The most common pathogen of the genus Cryptococcus in immunocompromised patients is C neoformans. Both C neoformans and Cgattii cause disease in immunocompetent patients. Most patients with disease due to C gattii have been reported to be immunocompetent.



Diagnostic Considerations

The following are other causes of intracranial mass lesions and infections:

  • Pyogenic abscess

  • Nocardial abscess

  • Aspergillus abscess

  • Hemorrhages

  • Lymphomas

  • Other neoplasms

  • Mycoses

  • Meningeal metastases

  • Chronic, benign lymphocytic meningitis

  • Mycobacterium tuberculous infection

  • Histoplasma capsulatum infection

  • Acne

Differential Diagnoses



Laboratory Studies

Cutaneous lesions should be biopsied and evaluated with fungal stains and cultures.

Blood and CSF should be cultured for fungi and submitted for cryptococcal antigen testing.

Even with widespread disease, the routine laboratory tests (eg, leukocyte count, hematocrit, sedimentation rate) may yield normal results.

Evaluation of spinal fluid is essential in diagnosing CNS disease. Opening pressures should be measured at each spinal tap; elevated pressures (≥250 mm H2 O) portend a poor prognosis. Opening pressures in excess of 250 mm H2 O require drainage of CSF to reduce the pressure to 200 mm H2 O or lower. Prior to removal of CSF, CT scanning or MRI should be performed to exclude masses that could result in herniation.

CSF glucose concentrations are usually depressed, while CSF protein concentrations are usually elevated. Leukocyte counts in the CSF are 20/µL or higher, with a lymphocyte predominance. The CSF can be normal at times, as in patients with AIDS who are unable to mount an adequate inflammatory response or in persons with early infection. However, these patients often have positive results on India ink preparation and CSF cryptococcal antigen testing.

Serologic testing of blood and CSF should be done whenever cryptococcal CNS infection is considered.

Antigen tests are frequently out of reach in impoverished countries due to cost. As a result, cryptococcosis often goes undiagnosed in these areas. In 2009, a lateral flow assay (LFA) for diagnosing cryptococcosis was developed. A study of HIV-infected patients in Thailand compared LFA results with culture and enzyme immunoassay (EIA). Results showed a high level of agreement between LFA and EIA testing, which suggests LFA may be potentially useful as a point-of-care assay in resource-poor areas.[27]  More recently, another study was performed at a French university hospital center to evaluate the efficacy of the LFA diagnostic technique. The study revealed an excellent negative predictive value of the cryptococcal antigen LFA. This, in concert with the rapid and ease of performing the test, suggests that it can be used as an alternative in the diagnosis of cryptococcal infection.[28]

Culturing for Cryptococcus may be appropriate, even when the CSF profile is unremarkable. In patients with an indolent waxing and waning course, CSF abnormalities may persist, indicating continued disease activity. A 2016 study has established the effectiveness of an economical and easy-to-use PCR method that uses restriction digest in delineating the two species, which would be helpful in administering appropriate management.[29]

Smear and culture

An India ink preparation is commonly used with CSF to identify the organism and to support a presumptive diagnosis. If performed correctly, 25%-50% of patients with cryptococcal meningitis show cryptococci.

Diagnosis depends on detecting the organism with culture; therefore, always confirm positive smears with cultures.

Culture centrifuged CSF specimens on 3 or more occasions to increase the yield.

Obtain urine and sputum cultures, even if renal or pulmonary disease is not clinically evident.

In patients with AIDS and with cryptococcal pneumonia, the culture sensitivity of bronchoalveolar lavage washings is better than that of transbronchial biopsy specimens.

Positive blood culture results indicate extensive infection, and the organism may be observed within peripheral leukocytes or bone marrow macrophages in these patients. Use the lysis-centrifugation method of blood culture, which is the most sensitive and rapid.

Whenever cryptococcosis occurs at any site, carefully search for lesions elsewhere, both inside and outside the CNS.

Pathogenic C neoformans can be primarily isolated by streaking clinical specimens on Sabouraud dextrose agar, with or without antibiotics for bacterial growth suppression. C neoformans grows at 37°C (98.6°F), assimilates inositol, produces urease, and does not produce mycelia on cornmeal agar. C neoformans also produces melanin when incubated on agar that contains seeds from the common weed Guizotia abyssinica.

Imaging Studies

When the clinical presentation is not that of acute pyogenic meningitis, consider obtaining a CT or MRI of the brain prior to performing a lumbar puncture. This is especially important in patients who present with focal neurologic deficits or a history compatible with slowly progressive meningitis. If a mass lesion is identified, do not perform a lumbar puncture to obtain spinal fluid; rather, consult a neurosurgeon for an alternative procedure. 

Axial T2-weighted magnetic resonance image shows c Axial T2-weighted magnetic resonance image shows clustered hyperintensities in the left caudate; these are consistent with enlarged Virchow-Robin spaces caused by small cryptococcomas.

In patients who are asymptomatic and immunocompetent, radiographic findings can include patchy pneumonitis, granulomas ranging from 2-7 cm, or miliary disease similar to that observed in persons with tuberculosis.


Because of the neurotropism of C neoformans, perform a lumbar puncture in all patients with known or suspected cryptococcal disease. Most patients do not present with a clinical picture of an acute pyogenic meningitis; thus, the patient may undergo CT scan or MRI prior to a lumbar puncture. This procedure allows the physician to detect a mass lesion that may increase the risk of CNS herniation following a lumbar puncture. Both CT scanning and MRI can also reveal the presence of hydrocephalus caused by basilar meningitis. Once invasive cryptococcal disease is confirmed, initiate effective antifungal therapy.

Histologic Findings

In spinal fluid, urine, and tissue, pathogenic strains of C neoformans grow as round-to-oval yeast, surrounded by a polysaccharide capsule composed of mannose, xylose, and glucuronic acid. The yeast may be single or may have a single budding daughter cell. Cell size varies widely and ranges from 3.5-8 µm in diameter. Rarely, pseudohyphae develop.

India ink, which outlines the organisms by negative contrast, helps to identify the yeast cells in fluids or macerated tissue samples. In fixed tissue, the capsule of C neoformans may also be stained with mucicarmine, which preferentially stains mucopolysaccharides. Tissue sections can be stained with the Fontana-Masson stain to detect melanin precursors in the yeast cell wall. The presence of melanin or melanin precursors is useful in differentiating C neoformans from other yeasts.



Medical Care

Infection categories

These include (1) pulmonary cryptococcosis in immunocompetent hosts, (2) pulmonary cryptococcosis in immunosuppressed hosts, (3) CNS cryptococcosis, and (4) disseminated nonpulmonary non-CNS cryptococcosis. Although pulmonary cryptococcosis resolves without specific therapy in most immunocompetent patients, patients with infections who fall under the remaining 3 categories require antifungal therapy.

In patients who are co-infected with HIV and C neoformans, the therapeutic goal may differ from that in patients with cryptococcal infection uncomplicated by HIV infection. For cryptococcal infections in patients with concomitant HIV infection who have a CD4 count of less than 200 cells/μL, the therapeutic goal is to control the acute infection, followed by life-long suppression of C neoformans. For patients infected with HIV who have successfully completed an initial course of therapy, remain free of symptoms of cryptococcal disease, and reconstitute their CD4 count to more than 200 CD4 cells/μL for more than 6 months, some authorities suggest that suppressive therapy may be discontinued. However, if the patient’s CD4 count falls to less than 200 cells/μL, suppressive therapy should be reinstituted.[4]

For patients with cryptococcal disease not complicated by HIV infection, the therapeutic goal is to achieve a permanent cure of the fungal infection so that no chronic suppressive therapy is necessary.

Patients with AIDS

Patients who have AIDS and cryptococcal meningitis account for more than 80% of the patients with cryptococcosis. Many authorities now recommend an initial aggressive treatment course.

Initially, administer amphotericin B at 0.7-1 mg/kg/d for 2 weeks, with or without 2 weeks of flucytosine at 100 mg/kg/d in 4 divided doses, followed by fluconazole at 400 mg/d for a minimum of 8-10 weeks. The addition of flucytosine to amphotericin B results in quicker clearance of viable yeast from the cerebrospinal fluid (CSF) than is seen with amphotericin B alone or amphotericin B plus fluconazole. However, patients may be treated successfully without the addition of flucytosine (and its potential toxicity). The toxic potential of flucytosine increases in patients who have renal disfunction from any cause. In a 2016 study of patients with AIDS-associated cryptococcal meningitis, the addition of dexamethasone did not reduce mortality, was associated with more adverse events and disability, and resulted in slower clearance of Cryptococcus from the spinal fluid.[18]

Alternative initial therapies include lipid formulations of amphotericin B in doses of 4-6 mg/kg per day for 3 weeks. Fluconazole in doses ranging from 400-800 mg per day plus flucytosine is another option in patients unable to tolerate amphotericin B. However, the combination of fluconazole plus flucytosine is clinically inferior to amphotericin B–based therapy.

Initial therapy should be considered successful only after CSF culture is negative for cryptococcal organisms and the patient has had significant clinical improvement.

Guidelines from 2000 recommended that initial therapy be followed with maintenance therapy using fluconazole at 200 mg/d for life.[3] In a study of patients in the maintenance phase of treatment, itraconazole was inferior to fluconazole. The same study showed no clear benefits were evident when flucytosine was added to the 2-week initial course of amphotericin B. Guidelines published in 2002 support discontinuation of suppressive therapy for cryptococcal disease if CD4 counts remain greater than 200 cells/µL but reinstitution if the CD4 counts fall to fewer than 200 cells/µL.[4] Guidelines published in 2010 support discontinuation of suppressive therapy when the CD4 count exceeds 100 cells/µL and the HIV viral load is undetectable or very low for more than 3 months. However, reinstitution of maintenance therapy should be considered if the CD4 cell count falls to less than 100 cells/µL.[5]

Although the two newer triazoles, posaconazole and voriconazole, show in vitro activity against C neoformans, clinical data remain limited.

In patients who require life-long suppressive therapy, oral fluconazole was superior to therapy with weekly amphotericin B given as 1 mg/kg intravenously 1-3 times per week.

CSF pressure should be monitored during the initial phase of therapy, and CSF pressures should be reduced by therapeutic CSF removal when the opening pressure exceeds 250 mm H2 O. Following removal of CSF, the closing pressure should be less than 200 mm H2 O or at least 50% of the elevated opening pressure.

Repeat lumbar puncture was once recommended in all patients 2 weeks after the initiation of therapy to ensure that CSF cultures were negative. However, forgoing further spinal taps in patients who have normal neurologic function and no other evidence of inadequately treated cryptococcal infection is now considered acceptable by some authorities.

Alternative initial therapy of fluconazole plus flucytosine for 6 weeks, followed by life-long fluconazole maintenance therapy, has been proposed. However, pilot studies have indicated that initial therapy with fluconazole and flucytosine is not as reliably effective as therapy that includes amphotericin B during the initial phase.[30] Furthermore, the combination of flucytosine plus fluconazole has significant toxicity.

In patients with HIV infection who are not already on antiretroviral therapy, initiating treatment for cryptococcal meningitis prior to initiating antiretroviral therapy can reduce the risk of immune reconstitution inflammatory syndrome (IRIS).[31] Once cryptococcal antigen has been significantly reduced, antiretroviral therapy can be initiated while the therapy for cryptococcal infection continues. However, newer data demonstrate improved clinical outcomes when highly active antiretroviral therapy (HAART) is initiated within 6 months of the diagnosis of cryptococcal meningitis.[32]

A study of 27 HIV-infected adult patients with cryptococcal meningitis found no significant difference in the rate of clearance of fungus from the CSF whether antiretroviral therapy was initiated at 7 or 28 days after the start of amphotericin B treatment; however, the risk of cryptococcal meningitis IRIS was significantly higher in the early antiretroviral therapy group. Seven of 13 subjects (54%) in the 7-day arm experienced IRIS, as compared with 0 of 14 in the delayed-intervention arm.[33]

World Health Organization (WHO) guidelines recommend all HIV patients with CD4 count ≤100 cells/µL to screen for cryptococcal antigen to identify patients with cryptococcal disease who could benefit from preemptive fluconazole prior to the onset of meningitis. Cryptococcal antigen maybe detected several weeks before development of cryptococcal meningitis.[34] Providing preemptive fluconazole for antigenemia prior to the development of meningitis has been found to be lifesaving and cost effective. We can consider screening for cryptococcal antigenemia at a higher CD4 threshold of ≤200 cells/µL.[35, 36, 37, 38]

Patients without AIDS

Initial therapy should be amphotericin B (0.7-1 mg/kg/day) alone or in combination with flucytosine (100 mg/kg/day in 4 divided doses). Amphotericin B can be administered alone for 6-10 weeks or in conjunction with flucytosine for 2 weeks, followed by fluconazole for a minimum of 10 weeks.

Base therapy duration on CSF examination results.

Consider examining the patient's CSF weekly until culture conversion is documented and cultures remain negative for 4 weeks. In most cases, 6-10 weeks of therapy with amphotericin B is adequate.

At the end of therapy, most patients have a normal CSF glucose and cell count, but protein abnormalities may persist for years. Thus, an elevated CSF protein as the only residual abnormality should not dictate prolonging therapy.

In some patients, positive CSF cultures may persist or recur during active antifungal therapy. This requires extending therapy until CSF cultures remain negative.

The prostate may represent a sequestered focus of infection in men with recurrent disease. Fluconazole enters the prostate tissues well and may be useful in eradicating a prostatic focus of infection.

In contrast to patients with HIV, patients without HIV have been shown to have better outcomes in terms of functional recovery and survival when corticosteroids were used as an adjunct in the management of cryptococcal CNS infections.[39]

Pulmonary cryptococcosis

Most of these patients do not have concomitant immunosuppression or immunodeficiency; therefore, their condition may resolve without antifungal therapy.

Observing the patient and not administering antifungal therapy can be done as long as the CSF chemistry parameters are normal; the CSF culture, India ink preparation, and serology results are negative; urine culture results are negative; the pulmonary lesion is small and stable or shrinking; and the patient has no predisposing conditions for disseminated disease.

Immunocompetent patients with endobronchial Cryptococcus colonization who have no evidence of tissue invasion do not need antifungal therapy. Therapy would need to be reconsidered should the patient become immunosuppressed.

For mild-to-moderate cryptococcal pulmonary disease, the National Institute of Allergy and Infectious Diseases Mycoses Study Group (NIAID-MSG) recommends fluconazole for 6-12 months, itraconazole for 6-12 months, or amphotericin B (see "Study Shows Promise of Fluconazole for Treatment of AIDS-Related Cryptococcal Meningitis").

For severe pulmonary disease, the NIAID-MSG recommends the following treatment for CNS disease: amphotericin B (0.7-1 mg/kg/d) plus flucytosine (100 mg/kg/d) for 6-10 weeks. Alternatively, amphotericin B plus flucytosine in the above doses can be administered for 2 weeks, followed by fluconazole at 400 mg/kg/d for at least 10 weeks. Some physicians recommend further consolidation therapy for 6-12 months.

Treatment of extraneural nonpulmonary disease

For patients without AIDS, treat cryptococcal lesions of the skin, bones, or other organs with amphotericin B plus flucytosine or with amphotericin B alone. All patients with evidence of cryptococcal infection should undergo lumbar puncture to ensure the absence of CNS infection.

Surgical therapy is unnecessary in most cases.


Cryptococcoma is a lesion within the brain parenchyma caused by cryptococcal infection; C gattii is more commonly involved than C neoformans.

Patients with cryptococcoma may have single or multiple lesions and are usually immunocompetent.

Therapy is the same as for cryptococcal meningitis. During early therapy, lesions may actually enlarge or new lesions may appear as a result of the inflammatory response associated with treatment. In most cases lesion enlargement does not represent failure of therapy; they usually shrink over time with continued treatment.

Glucocorticoids are recommended among patients with cryptococcomas with mass effect, the acute respiratory distress syndrome, or IRIS.[40]  

Surgical resection of lesions is usually not required but depends on the location of the lesions and any neurologic symptoms. Following induction therapy, prolonged treatment with fluconazole 400 mg per day or more for 1-2 years may be necessary.

Patients should be monitored with MRI or CT scans to ensure the lesions are shrinking.


The drug of choice (DOC) for initial therapy in disseminated or CNS cryptococcosis is amphotericin B. Amphotericin B may be used alone or in combination with flucytosine. Amphotericin B has a rapid onset of action and often leads to clinical improvement more rapidly than either intravenous or oral fluconazole. Because amphotericin B is nephrotoxic, monitor renal function carefully throughout its administration. Amphotericin B administered as a continuous infusion over 24 hours appears to have significantly less nephrotoxicity than the same doses administered over a 6- to 8-hour period. Lipid formulations (eg, lipid complexes), liposome-associated amphotericin B, or amphotericin B colloidal dispersion may be used in patients who do not respond to amphotericin B desoxycholate or who cannot tolerate its adverse effects, including nephrotoxicity.

Other preparations of amphotericin B include liposomal amphotericin B (AmBisome), amphotericin B lipid complex (Abelcet), amphotericin B cholesteryl complex (Amphotec), and amphotericin B colloidal dispersion (Amphocin). It remains unclear if these alternative forms of amphotericin B are superior to standard nonlipid amphotericin B, and they all cost much more. The lipid preparations may have an advantage in sparing renal function, but they may be associated with higher relapse rates than amphotericin B desoxycholate. Amphotericin B–associated elevations in serum creatinine and BUN levels usually return to normal after therapy is completed. Administering amphotericin B as a continuous drip over 24 hours reduces the frequency and severity of renal toxicity[41] and may even allow for daily doses to be increased up to 2 mg/kg/day.[42]

Flucytosine is unreliable if used alone, and resistance develops rapidly; in cryptococcal disease, administer this drug in conjunction with amphotericin B. Data on the use of fluconazole plus flucytosine are limited, but this combination appears to be less effective than amphotericin B plus flucytosine. If flucytosine is used with amphotericin B, serum concentrations of flucytosine should be kept in the range of 25-100 mcg/mL to reduce the risk of gastrointestinal toxicity and bone marrow suppression. The latter may preclude its use in patients with AIDS and cryptococcal disease.

Do not use ketoconazole or itraconazole in the initial treatment of disseminated or CNS cryptococcal disease. These azoles do not cross the blood-brain barrier adequately, and their onset of action is slower than amphotericin B.

Fluconazole is a bis -triazole with a triazole group substituted for the imidazole group. Because of the triazole substitution, fluconazole is water soluble and easily absorbed from the gut. Intravenous fluconazole can be used in early disease when gastrointestinal absorption is uncertain and then changed to oral fluconazole in the same dose for 10 weeks or more. The significance of fluconazole MIC and outcome in cryptococcal infections is unclear, as in vitro fluconazole resistance may not reflect fluconazole failure. Current recommendations continue to support fluconazole use, irrespective of MICs, guided by the clinical response.[43]  

Data regarding relapse with fluconazole are limited. Intravenous fluconazole may be administered to patients with cryptococcal meningitis, but its onset of action can be prolonged compared with that of amphotericin B. However, in patients with AIDS and cryptococcal meningitis, oral fluconazole provides excellent long-term therapy once amphotericin B has controlled the acute meningitis. Furthermore, fluconazole enters the prostate better than amphotericin B and can eradicate cryptococcal infection at this site. Control of prostatic foci of cryptococcal yeast is important because relapses may occur if this site is not adequately treated. C neoformans was found to be susceptible to a newer azole group of drugs, including posaconazole, voriconazole, and isavuconazole.[44] Isavuconazole has shown good efficacy in the management of C neoformans and C gattii infections.[45, 46] Isavuconazole was shown to have antifungal activity as both primary and salvage therapy in cryptococcosis and has a potential role for isavuconazole in the treatment of CNScryptococcosis.[47]

Physicians should inform women of childbearing age of the risk of fluconazole teratogenicity. In one study, authors reported good clinical outcomes using amphotericin B without high dose fluconazole in the first trimester in cryptococcal meningitis with pregnant women.[48]

Presently available echinocandins are not active against Cryptococcus species and should not be used.

Newer medications

Histone deacetylase inhibitors, when used in conjunction with triazoles, have been shown to have synergistic effect in in vitro trials. Hydroxylamines and aminothiazoles are two new classes of compounds with anticryptococcal activity in in vitro studies.[46]

Sertraline was shown to have in vitro fungicidal activity against Cryptococcus neoformans, synergistic to fluconazole in multiple studies.[49, 50, 51, 52, 53, 54]  Sertraline was also effective in in vivo experimental infected mice models. The inhibitory effect of sertraline was potent in the brain of Cryptococcus-infected mice with similar efficacy to fluconazole.[50, 51, 52]  However, sertraline did not reduce mortality and should not be used in HIV-associated cryptococcal meningitis patients.[54]  

Surgical Care

On occasion, patients with cryptococcosis develop complete obstruction of the ventricles and require a CSF shunt to relieve intracranial pressure.


Consultation with infectious disease specialists can help in the treatment of patients with invasive cryptococcal infections that require antifungal therapy with either amphotericin B or fluconazole.



Medication Summary

The goal of pharmacotherapy is either to terminate the infection when possible or to control the infection and to reduce morbidity when cure is not possible.

Antifungal agents

Class Summary

The mechanism of action of antifungal agents differs by agent and may involve an alteration of RNA or DNA, allow for an intracellular accumulation of peroxide that is toxic to the fungal cells, or allow for intracellular potassium to be lost while intracellular sodium levels increase.

Amphotericin B (Amphocin, Fungizone)

Because of its rapid onset of action, this is the DOC for cryptococcal meningitis. Antifungal activity results from its ability to insert itself into fungal cytoplasmic membrane at sites that contain ergosterol or other sterols. Aggregates accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium). At low concentrations, main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity; however, at higher concentrations, pores of 40-105 nm are produced in cytoplasmic membrane, leading to large losses of ions and other molecules. A second effect is its ability to cause auto-oxidation of cytoplasmic membrane and release of lethal free radicals. Main fungicidal activity may reside in its ability to cause auto-oxidation of cell membranes.

If therapy is supplemented by oral flucytosine, therapy can be used until the patient is afebrile and alert and spinal fluid cultures are negative for 2 wk; then, patient can be placed on fluconazole.

Flucytosine (Ancobon)

Metabolized to fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against some Candida and Cryptococcus species and generally used in combination with amphotericin B. Always use with another active antifungal agent (eg, amphotericin B).

Fluconazole (Diflucan)

An antifungal agent active against many yeast and dimorphic fungi. In general, has poor activity against molds and filamentous fungi. Selectively inhibits fungal cytochrome P-450 and sterol C-14-alpha demethylation.



Further Outpatient Care

Following control of acute life-threatening cryptococcal infection, consider continuing outpatient therapy with intravenous amphotericin B, oral fluconazole, or oral itraconazole (if no evidence of CNS disease is present). Itraconazole does not cross the blood-brain barrier well; therefore, do not use it as initial therapy in patients with cryptococcal disease or in patients with known or suspected CNS involvement.

Following initial therapy with amphotericin B, maintenance therapy with itraconazole is still less effective than with fluconazole. An oral solution of itraconazole is available and has improved bioavailability compared with the capsules.

Further Inpatient Care

Provide immediate care of invasive cryptococcal infections in the hospital.

Because cryptococcal infections may have a rapid onset, administer amphotericin B desoxycholate with or without the addition of flucytosine to patients with CNS involvement, disseminated disease, or invasive pulmonary disease.

Carefully perform a lumbar puncture in patients who do not have symptomatic CNS disease but who do have invasive pulmonary or disseminated disease.

Measure opening and closing pressures and send CSF for an India ink preparation, stains, and cultures for fungi, mycobacteria, and cryptococcal antigen. In addition, obtain spinal fluid cell counts and CSF glucose and protein concentrations.

After the patient demonstrates significant improvement, consider switching to intravenous or oral fluconazole. Amphotericin B lipid complex is an alternative to amphotericin B desoxycholate in patients with cryptococcal meningitis who do not respond to or tolerate amphotericin B desoxycholate.

Inpatient & Outpatient Medications

Amphotericin B desoxycholate is the DOC for initial therapy of cryptococcal infection. This drug has a faster onset of action than fluconazole (even when fluconazole is administered intravenously) and crosses the blood-brain barrier more reliably than the azoles (eg, itraconazole, ketoconazole).

Lipid preparations of amphotericin B are very expensive and, although less nephrotoxic, are not more effective. Further, giving the daily dose of amphotericin B desoxycholate as a continuous infusion over 24 hours instead of 4-8 hours significantly reduces its nephrotoxicity.


Once stable, patients with cryptococcal meningitis or disseminated cryptococcal disease can be considered for transfer to a facility where they can receive their therapy closer to their families.

If a patient's condition continues to deteriorate while on appropriate medical therapy, consider transferring the patient to a facility with neurosurgical and infectious disease support. Some patients may benefit from a reduction in intracranial pressure by placement of a shunt or other device.


The principal vector of C neoformans is the pigeon, Columba livia. Pigeons contaminate their roosts with their excreta, which provides the high-nitrogen, high-salt, alkaline environment conducive to the growth of C neoformans. Because of their high regular temperature (42°C [107.6°F]), pigeons are rarely infected themselves; however, cryptococci do survive gut transport through the pigeon's intestines. Pigeon excreta contaminated with cryptococci may remain infectious for up to 2 years; thus, the principal method of prevention of infection with C neoformans is to avoid contact with areas inhabited by pigeons.

Unlike C neoformans, Cgattii is not associated with pigeon excreta. The distribution of Cgattii is tropical and subtropical and is associated with exposure to the river red gum tree (ie, E camaldulensis) and the forest red gum tree (ie, E tereticornis). During the flowering seasons, from November to February, the organism contaminates the air surrounding these tree species. Preventing exposure to an environment containing flowering eucalyptus trees may reduce the likelihood of infection; however, epidemiologic evidence indicates that eucalyptus trees are not the sole source of environmental exposure.


In patients with AIDS and other causes of immunosuppression who are infected with C neoformans, cure is often impossible, and patients require life-long suppressive therapy.

In immunocompromised patients, the overall mortality rate following treatment of cryptococcal meningitis is approximately 25%-30%. Of those who survive, 40% have significant neurological deficits, including loss of vision, decreased mental function, hydrocephalus, and cranial nerve palsies. Relapse occurs in 20%-25% of patients.


With early diagnosis, infections from cryptococcal organisms, including CNS and disseminated infections, are usually amenable to therapy. In patients with no demonstrable immunosuppression, amphotericin B therapy, with or without flucytosine, is effective in controlling or terminating infection in 70%-75% of patients.

Patient Education

Presently, patients with AIDS or HIV infection constitute the population at greatest risk for cryptococcal disease.

Alert patients with HIV infection or AIDS to seek early medical attention if they begin to experience severe or persistent headaches or other neurological symptoms. If cryptococcal CNS infection is present, early diagnosis may reduce the risk of death or permanent morbidity.

For patient education resources, see the Brain and Nervous System Center. Also, see the patient education article Brain Infection.


Questions & Answers


What is cryptococcosis?

What are the signs and symptoms of pulmonary cryptococcosis?

What are the signs and symptoms of pulmonary cryptococcosis in patients with HIV infection?

Which physical findings are characteristic of pulmonary cryptococcosis?

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How is cryptococcoma treated?

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Which medications are contraindicated in the treatment of disseminated or CNS cryptococcosis?

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Which medications in the drug class Antifungal agents are used in the treatment of Cryptococcosis?


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