eMedicine Specialties > Infectious Diseases > Fungal Infections

Cryptococcosis: Treatment & Medication

Author: John W King, MD, Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center
Coauthor(s): Meredith L DeWitt, MD, Fellow, Department of Internal Medicine, Section of Infectious Diseases, Louisiana State University Health Sciences Center
Contributor Information and Disclosures

Updated: Oct 30, 2009

Treatment

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.6
    • 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 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.
    • 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.7 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.6
    • 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.8 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).9 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.10
  • 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.
  • 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
    • 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.
    • 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.
  • Medications
    • 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 toxicity11 and may even allow for daily doses to be increased up to 2 mg/kg/day.12
    • 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.
    • 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.
    • Presently available echinocandins are not active against Cryptococcus species and should not be used.

Surgical Care

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

Consultations

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

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

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.

Adult

Patients with AIDS: 0.7-1 mg/kg/d of amphotericin B given IV plus oral flucytosine 100 mg/kg/d for 2 wk, followed by fluconazole 400 mg/d for at least 10 wk; the patient is then treated with fluconazole 200 mg/d for life
Immunocompetent patients with cryptococcal CNS disease: 0.7-1 mg/kg/d plus flucytosine 100 mg/kg/d for 6-10 wk; alternatively, same doses of amphotericin B and flucytosine for 2 wk, followed by fluconazole 400 mg/d for at least 10 wk (some continue 6-12 mo)

Pediatric

0.7-1 mg/kg IV

Antineoplastic agents may enhance potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity increased with cyclosporine or aminoglycosides.

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hypokalemia and total body depletion of potassium can occur in patients with normal renal function; adjust doses to prevent associated renal failure; mild-to-moderate elevations of serum creatinine levels are common and reversible; renal dysfunction is dose dependent; monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; if therapy is interrupted for >7 days, resume therapy at 0.25 mg/kg; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients who are neutropenic and receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion)


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).

Adult

100-150 mg/kg/d PO divided qid
Combination with amphotericin B: 100 mg/kg/d PO or 25-37.5 mg/kg PO q6h

Pediatric

50-100 mg/kg/d PO divided qid

Synergistic with amphotericin B and fluconazole against C neoformans; cytosine may inactivate flucytosine

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Can cause leukopenia and thrombocytopenia, usually at levels of 125 mcg/mL or higher; nausea and vomiting, skin rashes, and photosensitivity can occur; adjust dose in renal impairment; do not use as monotherapy


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.

Adult

Oropharyngeal candidiasis loading dose: 200 mg PO/IV, then 100 mg PO/IV qd for at least 14 d
Cryptococcal infection loading dose: 400 mg PO/IV, then 200-400 mg PO/IV qd
Resistant infections: 800-1600 mg/d has been used by some investigators
Combination with amphotericin B: 400 mg/d PO/IV for 10 wk

Pediatric

Therapeutic dose: 12 mg/kg/d PO/IV; not to exceed 600 mg/d
Suppressive dose: 3-6 mg/kg/d PO/IV
Premature neonates: 3-6 mg/kg/d PO/IV q72h
Combination with amphotericin B: 6 mg/kg/d

Levels may increase with hydrochlorothiazides; levels may decrease with long-term coadministration of rifampin; may increase concentrations of theophylline, phenytoin, tolbutamide, cyclosporine, glyburide, and glipizide; effects of anticoagulants may increase with coadministration

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Ensure that patients receiving warfarin undergo frequent PT assays to prevent bleeding caused by a prolonged PT; ensure that patients on phenytoin have serum levels checked to prevent toxicity caused by a fluconazole-associated reduction in phenytoin metabolism; monitor closely if rashes develop and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) with underlying medical conditions (eg, AIDS) or a malignancy and while taking multiple concomitant medications; not recommended for nursing mothers; convenience and efficacy of single-dose regimen for treatment of vaginal yeast infections should be weighed against difficulties resulting from higher prevalence of adverse reactions reported with oral fluconazole versus intravaginal agents

More on Cryptococcosis

Overview: Cryptococcosis
Differential Diagnoses & Workup: Cryptococcosis
Treatment & Medication: Cryptococcosis
Follow-up: Cryptococcosis
References
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Further Reading

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Keywords

cryptococcosis, Busse-Buschke disease, European blastomycosis, torulosis, Cryptococcus neoformans, Cryptococcus gattii, cryptococcal infection, yeast infection, cryptococci, fungal infection, cryptococcoma, meningitis, cryptococcal meningitis, cryptococcal lung infection

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Contributor Information and Disclosures

Author

John W King, MD, Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center
John W King, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Association of Subspecialty Professors, Infectious Diseases Society of America, and Sigma Xi
Disclosure: emedicine $50.00 author of chapter

Coauthor(s)

Meredith L DeWitt, MD, Fellow, Department of Internal Medicine, Section of Infectious Diseases, Louisiana State University Health Sciences Center
Meredith L DeWitt, MD is a member of the following medical societies: Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Medical Editor

Jeffrey D Band, MD, Clinical Professor of Medicine, Wayne State University School of Medicine; Director, Division of Infectious Diseases and International Medicine, William Beaumont Hospital Corporation
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

John W King, MD, Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center
John W King, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Association of Subspecialty Professors, Infectious Diseases Society of America, and Sigma Xi
Disclosure: emedicine $50.00 author of chapter

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

 
 
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