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Guideline Summary
Guideline Title
Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America.
Bibliographic Source(s)
Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322. [191 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, Sobel JD, Dismukes WE. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000 Apr;30(4):710-8. [37 references]

Scope

Disease/Condition(s)

Cryptococcal disease (Cryptococcus neoformans and Cryptococcus gattii infection)

Guideline Category
Evaluation
Management
Treatment
Clinical Specialty
Family Practice
Infectious Diseases
Internal Medicine
Intended Users
Advanced Practice Nurses
Health Care Providers
Nurses
Physician Assistants
Physicians
Guideline Objective(s)

To update and review the choice of treatment and management for disease caused by Cryptococcus neoformans and Cryptococcus gattii infection depending on:

  • Anatomic sites of infection
  • Host's immune status (organ transplant recipients, human immunodeficiency virus [HIV]–infected individuals, non-HIV infected and non-transplant hosts)
Target Population

Patients with cryptococcal disease (Cryptococcus neoformans and Cryptococcus gattii infection)

Interventions and Practices Considered
  1. Pharmacotherapy
    • Amphotericin B (AmB) deoxycholate
    • Lipid formulation of amphotericin B including liposomal AmB and AmB lipid complex (ABLC)
    • Fluconazole
    • Voriconazole
    • Posaconazole
    • Itraconazole
    • Flucytosine
    • Highly active antiretroviral therapy (HAART), in human immunodeficiency (HIV)-infected individuals
  2. Management of specific patient populations (HIV-infected individuals, organ transplant recipients, non-HIV, non-transplant hosts)
  3. Management of complications in patients with cryptococcus
    • Relapse (induction therapy, in vitro susceptibility)
    • Elevated cerebrospinal fluid (CSF) pressure (lumbar puncture, CSF drainage, temporary percutaneous lumbar drains, ventriculostomy)
    • Lumbar puncture
    • Radiographic imaging before lumbar puncture to identify mass lesions that may contraindicate lumbar puncture
    • Ventriculoperitoneal shunt
    • Immune reconstitution inflammatory syndrome (corticosteroids [not recommended for HIV-infected patients], nonsteroidal anti-inflammatory drugs, thalidomide)
    • Cerebral cryptococcomas (induction therapy, consolidation and maintenance therapy, corticosteroids, surgery)
  4. Nonmeningeal cryptococcus
    • Pulmonary, immunosuppressed (induction therapy, lumbar puncture, corticosteroids, fluconazole, surgery)
    • Pulmonary, nonimmunosuppressed (fluconazole, voriconazole, posaconazole, itraconazole, lumbar puncture, corticosteroids, surgery)
  5. Nonmeningeal, non-pulmonary cryptococcus (fluconazole)
  6. Treatment of special clinical situations
    • Pregnant women
    • Children
    • Cryptococcus in resource limited healthcare environment
  7. Cryptococcus gattii infection (AmB, fluconazole, flucytosine, surgery)
Major Outcomes Considered
  • Resolution of symptoms (such as cough, shortness of breath, sputum production, chest pain, and fever)
  • Resolution or stabilization of abnormalities (such as infiltrates, nodules, or masses) on chest radiograph
  • Resolution of central nervous system (CNS) abnormalities (such as fever, headache, altered mental status, ocular signs, intracranial pressure, and meningeal signs)
  • Resolution of lesions
  • Morbidity and mortality

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Literature Review and Analysis

For the 2010 update, the Expert Panel completed the review and analysis of data published since 1999. Computerized literature searches of the PubMed database were performed. The searches of the English language literature from 1999 through 2009 used the terms, "cryptococcal," "cryptococcosis," "Cryptococcus," "meningeal," "pulmonary," "pregnancy," "children," "cerebrospinal fluid," "intracranial," "cerebral," "immunosuppressed," "HIV," "transplant," and "Immune Reconstitution Inflammatory Syndrome" and focused on human studies. Data published up to December 2009 were considered during final preparation of the manuscript. Relevant studies included randomized clinical trials, open-label clinical trials, retrospective case series, cohort studies, case reports, reports of in vitro studies, and animal model experiments. Abstracts from international meetings were also included. Because of the limited nature of the data in many areas, the Expert Panel made a decision to also retain high quality reviews or background papers. Expert Panel members were assigned sections of the guideline and reviewed the relevant literature.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Quality of Evidence

  1. Evidence from at least one properly randomized, controlled trial
  2. Evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from >1 center), from multiple time-series studies, or from dramatic results of uncontrolled experiments
  3. Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees
Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence

In evaluating the evidence regarding the management of cryptococcal disease, the Expert Panel followed a process used in the development of other Infectious Diseases Society of America (IDSA) guidelines. This included a systematic weighting of the quality of the evidence and the grade of recommendation.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

The Infectious Diseases Society of America (IDSA) Standards and Practice Guidelines Committee (SPGC) convened experts in the management of patients with cryptococcal disease.

The Expert Panel met on 3 occasions via teleconference and once in person to complete the work of the guideline. The purpose of the teleconferences was to discuss the questions to be addressed, make writing assignments, and discuss recommendations.

Rating Scheme for the Strength of the Recommendations

Strength of Recommendation

  1. Good evidence to support a recommendation for or against use
  2. Moderate evidence to support a recommendation for or against use
  3. Poor evidence to support a recommendation for or against use
Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

All members of the Expert Panel participated in the preparation and review of the draft guideline. Feedback from external peer reviews was obtained. The guidelines were reviewed and approved by the Standards and Practice Guidelines Committee (SPGC) and the Board of Directors prior to dissemination.

Recommendations

Major Recommendations

Quality of evidence (I–III) and strength of recommendation (A–C) ratings are defined at the end of the "Major Recommendations" field.

HIV-Infected Individuals

Primary Therapy: Induction and Consolidation

  1. Amphotericin B (AmB) deoxycholate (AmBd) (0.7–1.0 mg/kg per day intravenously [IV]) plus flucytosine (100 mg/kg per day orally in 4 divided doses; IV formulations may be used in severe cases and in those without oral intake where the preparation is available) for at least 2 weeks, followed by fluconazole (400 mg [6 mg/kg] per day orally) for a minimum of 8 weeks (A-I). Lipid formulations of AmB (LFAmB), including liposomal AmB (3–4 mg/kg per day IV) and AmB lipid complex (ABLC) (5 mg/kg per day IV) for at least 2 weeks, could be substituted for AmBd among patients with or predisposed to renal dysfunction (B-II).

Primary Therapy: Alternative Regimens for Induction and Consolidation (listed in order of highest recommendation top to bottom)

  1. AmBd (0.7–1.0 mg/kg per day IV), liposomal AmB (3–4 mg/kg per day IV), or ABLC (5 mg/kg per day IV) for 4–6 weeks (A-II). Liposomal AmB has been given safely at 6 mg/kg per day IV in cryptococcal meningoencephalitis and could be considered in the event of treatment failure or high–fungal burden disease.
  2. AmBd (0.7 mg/kg per day IV) plus fluconazole (800 mg per day orally) for 2 weeks, followed by fluconazole (800 mg per day orally) for a minimum of 8 weeks (B-I).
  3. Fluconazole (≥800 mg per day orally; 1200 mg per day is favored) plus flucytosine (100 mg/kg per day orally) for 6 weeks (B-II).
  4. Fluconazole (800–2000 mg per day orally) for 10–12 weeks; a dosage of ≥1200 mg per day is encouraged if fluconazole alone is used (B-II).
  5. Itraconazole (200 mg twice per day orally) for 10–12 weeks (C-II), although use of this agent is discouraged.

Maintenance (Suppressive) and Prophylactic Therapy

  1. Fluconazole (200 mg per day orally) (A-I).
  2. Itraconazole (200 mg twice per day orally; drug-level monitoring strongly advised) (C-I).
  3. AmBd (1 mg/kg per week IV); this is less effective than azoles and is associated with IV catheter–related infections; use for azole-intolerant individuals (C-I).
  4. Initiate highly active antiretroviral therapy (HAART) 2–10 weeks after commencement of initial antifungal treatment (B-III).
  5. Consider discontinuing suppressive therapy during HAART in patients with a CD4 cell count >100 cells/µL and an undetectable or very low HIV RNA level sustained for ≥3 months (minimum of 12 months of antifungal therapy) (BII); consider reinstitution of maintenance therapy if the CD4 cell count decreases to <100 cells/µL (B-III).
  6. For asymptomatic antigenemia, perform lumbar puncture and blood culture; if results are positive, treat as symptomatic meningoencephalitis and/or disseminated disease. Without evidence of meningoencephalitis, treat with fluconazole (400 mg per day orally) until immune reconstitution (see above for maintenance therapy) (B-III).
  7. Primary antifungal prophylaxis for cryptococcosis is not routinely recommended in HIV-infected patients in the United States and Europe, but areas with limited HAART availability, high levels of antiretroviral drug resistance, and a high burden of disease might consider it or a preemptive strategy with serum cryptococcal antigen testing for asymptomatic antigenemia (see above) (B-I).

Organ Transplant Recipients

  1. For central nervous system (CNS) disease, liposomal AmB (3–4 mg/kg per day IV) or ABLC (5 mg/kg per day IV) plus flucytosine (100 mg/kg per day in 4 divided doses) for at least 2 weeks for the induction regimen, followed by fluconazole (400–800 mg [6–12 mg/kg] per day orally) for 8 weeks and by fluconazole (200–400 mg per day orally) for 6–12 months (B-II). If induction therapy does not include flucytosine, consider LFAmB for at least 4–6 weeks of induction therapy, and liposomal AmB (6 mg/kg per day) might be considered in high-fungal burden disease or relapse (B-III).
  2. For mild-to-moderate non-CNS disease, fluconazole (400 mg [6 mg/kg] per day) for 6–12 months (B-III).
  3. For moderately severe–to-severe non-CNS or disseminated disease (ie, >1 noncontiguous site) without CNS involvement, treat the same as CNS disease (B-III).
  4. In the absence of any clinical evidence of extrapulmonary or disseminated cryptococcosis, severe pulmonary disease is treated the same as CNS disease (B-III). For mild-to-moderate symptoms without diffuse pulmonary infiltrates, use fluconazole (400 mg [6 mg/kg] per day) for 6–12 months (B-III).
  5. Fluconazole maintenance therapy should be continued for at least 6–12 months (B-III).
  6. Immunosuppressive management should include sequential or step-wise reduction of immunosuppressants, with consideration of lowering the corticosteroid dose first (B-III).
  7. Because of the risk of nephrotoxicity, AmBd should be used with caution in transplant recipients and is not recommended as first-line therapy in this patient population (C-III). If used, the tolerated dosage is uncertain, but 0.7 mg/kg per day is suggested with frequent renal function monitoring. In fact, this population will frequently have reduced renal function, and all antifungal dosages will need to be carefully monitored.

Non–HIV-Infected, Nontransplant Hosts

  1. AmBd (0.7–1.0 mg/kg per day IV) plus flucytosine (100 mg/kg per day orally in 4 divided doses) for at least 4 weeks for induction therapy. The 4-week induction therapy is reserved for persons with meningoencephalitis without neurological complications and cerebrospinal fluid (CSF) yeast culture results that are negative after 2 weeks of treatment. For AmBd toxicity issues, LFAmB may be substituted in the second 2 weeks. In patients with neurological complications, consider extending induction therapy for a total of 6 weeks, and LFAmB may be given for the last 4 weeks of the prolonged induction period. Then, start consolidation with fluconazole (400 mg per day) for 8 weeks (B-II).
  2. If patient is AmBd intolerant, substitute liposomal AmB (3–4 mg/kg per day IV) or ABLC (5 mg/kg per day IV) (B-III).
  3. If flucytosine is not given or treatment is interrupted, consider lengthening AmBd or LFAmB induction therapy for at least 2 weeks (B-III).
  4. In patients at low risk for therapeutic failure (i.e., they have an early diagnosis by history, no uncontrolled underlying disease or immunocompromised state, and excellent clinical response to initial 2-week antifungal combination course), consider induction therapy with combination of AmBd plus flucytosine for only 2 weeks, followed by consolidation with fluconazole (800 mg [12 mg/kg] per day orally) for 8 weeks (B-III).
  5. After induction and consolidation therapy, use maintenance therapy with fluconazole (200 mg [3 mg/kg] per day orally) for 6–12 months (B-III).

Management of Complications in Patients with Cryptococcosis

Persistence

  1. Check that adequate measures have been taken to improve immune status (e.g., decrease immunosuppressants and introduce HAART) and optimize management of increased intracranial pressure (B-III).
  2. Reinstitute induction phase of primary therapy for longer course (4–10 weeks) (B-III).
  3. Consider increasing the dose if the initial dosage of induction therapy was ≤0.7 mg/kg IV of AmBd per day or ≤3 mg/kg of LFAmB per day (B-III), up to 1 mg/kg IV of AmBd per day or 6 mg/kg of liposomal AmB per day (B-III); in general, combination therapy is recommended (B-III).
  4. If the patient is polyene intolerant, consider fluconazole (≥800 mg per day orally) plus flucytosine (100 mg/kg per day orally in 4 divided doses) (B-III).
  5. If patient is flucytosine intolerant, consider AmBd (0.7 mg/kg per day IV) plus fluconazole (800 mg [12 mg/kg] per day orally) (B-III).
  6. Use of intrathecal or intraventricular AmBd is generally discouraged and is rarely necessary (C-III).
  7. Ideally, persistent and relapse isolates should be checked for changes in the minimum inhibitory concentration (MIC) from the original isolate; a ≥3-dilution difference suggests development of direct drug resistance. Otherwise, an MIC of the persistent or relapse isolate ≥16 μg/mL for fluconazole or ≥32 μg/mL for flucytosine may be considered resistant, and alternative agents should be considered (B-III).
  8. In azole-exposed patients, increasing the dose of the azole alone is unlikely to be successful and is not recommended (C-III).
  9. Adjunctive immunological therapy with recombinant interferon (IFN)-gamma at a dosage of 100 µg/m2 for adults who weigh ≥50 kg (for those who weigh <50 kg, consider 50 µg/m2) 3 times per week for 10 weeks can be considered for refractory infection, with the concomitant use of a specific antifungal drug (B-III).

Relapse

  1. Restart induction phase therapy (see "Persistence," above) (B-III).
  2. Determine susceptibility of the relapse isolate (see "Persistence," above) (B-III).
  3. After induction therapy and in vitro susceptibility testing, consider salvage consolidation therapy with either fluconazole (800–1200 mg per day orally), voriconazole (200–400 mg twice per day orally), or posaconazole (200 mg orally 4 times per day or 400 mg twice per day orally) for 10–12 weeks (BIII); if there are compliance issues and a susceptible isolate, prior suppressive doses of fluconazole may be reinstituted (BIII).

Elevated CSF Pressure

  1. Identify CSF pressure at baseline. A prompt baseline lumbar puncture is strongly encouraged, but in the presence of focal neurologic signs or impaired mentation, it should be delayed pending the results of a computed tomography (CT) or magnetic resonance imaging (MRI) scan (B-II).
  2. If the CSF pressure is ≥25 cm of CSF and there are symptoms of increased intracranial pressure during induction therapy, relieve by CSF drainage (by lumbar puncture, reduce the opening pressure by 50% if it is extremely high or to a normal pressure of ≤20 cm of CSF) (B-II).
  3. If there is persistent pressure elevation ≥25 cm of CSF and symptoms, repeat lumbar puncture daily until the CSF pressure and symptoms have been stabilized for >2 days and consider temporary percutaneous lumbar drains or ventriculostomy for persons who require repeated daily lumbar punctures (B-III).
  4. Permanent ventriculoperitoneal (VP) shunts should be placed only if the patient is receiving or has received appropriate antifungal therapy and if more conservative measures to control increased intracranial pressure have failed. If the patient is receiving an appropriate antifungal regimen, VP shunts can be placed during active infection and without complete sterilization of CNS, if clinically necessary (B-III).

Other Medications for Intracranial Pressure

  1. Mannitol has no proven benefit and is not routinely recommended (A-III).
  2. Acetazolamide and corticosteroids (unless part of IRIS treatment) should be avoided to control increased intracranial pressure (A-II).

Recurrence of Signs and Symptoms

  1. For recurrence of signs and symptoms, reinstitute drainage procedures (B-II).
  2. For patients with recurrence, measurement of opening pressure with lumbar puncture after a 2-week course of treatment may be useful in evaluation of persistent or new CNS symptoms (B-III).

Long-term Elevated Intracranial Pressure

  1. If the CSF pressure remains elevated and if symptoms persist for an extended period of time in spite of frequent lumbar drainage, consider insertion of a VP shunt (A-II).

IRIS

  1. No need to alter direct antifungal therapy (B-III).
  2. No definitive specific treatment recommendation for minor IRIS manifestations is necessary, because they will resolve spontaneously in days to weeks (B-III).
  3. For major complications, such as CNS inflammation with increased intracranial pressure, consider corticosteroids (0.5–1.0 mg/kg per day of prednisone equivalent) and possibly dexamethasone at higher doses for severe CNS signs and symptoms. Length and dose of the corticosteroid taper are empirically chosen and require careful following of the patient, but a 2–6-week course is a reasonable starting point. The course should be given with a concomitant antifungal regimen (B-III).
  4. Nonsteroidal anti-inflammatory drugs and thalidomide have been used but with too little experience to make a recommendation (C-III).

Cerebral Cyptococcomas

  1. Induction therapy with AmBd (0.7–1 mg/kg per day IV), liposomal AmB (3–4 mg/kg per day IV), or ABLC (5 mg/kg per day IV) plus flucytosine (100 mg/kg per day orally in 4 divided doses) for at least 6 weeks (B-III).
  2. Consolidation and maintenance therapy with fluconazole (400–800 mg per day orally) for 6–18 months (B-III).
  3. Adjunctive therapies include the following:
    1. Corticosteroids for mass effect and surrounding edema (B-III).
    2. Surgery: for large (≥3-cm lesion), accessible lesions with mass effect, consider open or stereotactic-guided debulkment and/or removal; also, enlarging lesions not explained by immune reconstitution inflammatory syndrome (IRIS), should be submitted for further tissue diagnosis (B-II).

Treatment Strategies for Patients with Nonmeningeal Cryptococcosis

Pulmonary (Immunosuppressed)

  1. In immunosuppressed patients with pulmonary cryptococcosis, meningitis should be ruled out by lumbar puncture; the presence of CNS disease alters the dose and duration of induction therapy and the need for intracranial pressure monitoring (B-II).
  2. Pneumonia associated with CNS or documented dissemination and/or severe pneumonia (acute respiratory distress syndrome [ARDS]) is treated like CNS disease (B-III).
  3. Corticosteroid treatment may be considered if ARDS is present in the context of IRIS (B-III).
  4. For mild-to-moderate symptoms, absence of diffuse pulmonary infiltrates, absence of severe immunosuppression, and negative results of a diagnostic evaluation for dissemination, use fluconazole (400 mg [6 mg/kg] per day orally) for 6–12 months (B-III).
  5. In HIV-infected patients who are receiving HAART with a CD4 cell count >100 cells/μL and a cryptococcal antigen titer that is ≤1:512 and/or not increasing, consider stopping maintenance fluconazole after 1 year of treatment (B-II).
  6. Surgery should be considered for either diagnosis or persistent radiographic abnormalities and symptoms not responding to antifungal therapy (B-III).

Pulmonary (Nonimmunosuppressed)

  1. For mild-to-moderate symptoms, administer fluconazole (400 mg per day orally) for 6–12 months; persistently positive serum cryptococcal antigen titers are not criteria for continuance of therapy (B-II).
  2. For severe disease, treat similarly to CNS disease (B-III).
  3. Itraconazole (200 mg twice per day orally), voriconazole (200 mg twice per day orally), and posaconazole (400 mg twice per day orally) are acceptable alternatives if fluconazole is unavailable or contraindicated (B-II).
  4. Surgery should be considered for either diagnosis or persistent radiographic abnormalities and symptoms not responding to antifungal therapy (B-III).
  5. In nonimmunocompromised patients with pulmonary cryptococcosis, consider a lumbar puncture to rule out asymptomatic CNS involvement. However, for normal hosts with asymptomatic pulmonary nodule or infiltrate, no CNS symptoms, and negative or very low serum cryptococcal antigen, a lumbar puncture can be avoided (B-II).
  6. ARDS in the context of an inflammatory syndrome response may require corticosteroid treatment (B-III).

Nonmeningeal, Nonpulmonary Cryptococcosis

  1. For cryptococcemia or dissemination (involvement of at least 2 noncontiguous sites or evidence of high fungal burden based on cryptococcal antigen titer ≥1:512), treat as CNS disease (B-III).
  2. If CNS disease is ruled out, fungemia is not present, infection occurs at single site, and there are no immunosuppressive risk factors, consider fluconazole (400 mg [6 mg/kg] per day orally) for 6–12 months (B-III).

Treatment in Special Clinical Situations (Pregnant Women, Children, Persons in a Resource-Limited Environment, and Cryptococcus gattii–infected Persons)

Pregnant Women with Cryptococcosis

  1. For disseminated and CNS disease, use AmBd or LFAmB, with or without flucytosine (B-II). Flucytosine is a category C drug for pregnancy, and therefore, its use must be considered in relationship to benefit versus risk.
  2. Start fluconazole (pregnancy category C) after delivery; avoid fluconazole exposure during the first trimester; and during the last 2 trimesters, judge the use of fluconazole with the need for continuous antifungal drug exposure during pregnancy (B-III).
  3. For limited and stable pulmonary cryptococcosis, perform close follow-up and administer fluconazole after delivery (B-III).
  4. Watch for IRIS in the postpartum period (B-III).

Children with Cryptococcosis

  1. Induction and consolidation therapy for CNS and disseminated disease is AmBd (1 mg/kg per day IV) plus flucytosine (100 mg/kg per day orally in 4 divided doses) for 2 weeks (for the non–HIV-infected, non-transplant population, follow the treatment length schedule for adults), followed by fluconazole (10–12 mg/kg per day orally) for 8 weeks; for AmB-intolerant patients, either liposomal AmB (5 mg/kg per day) or ABLC (5 mg/kg per day) (A-II).
  2. Maintenance therapy is fluconazole (6 mg/kg per day orally) (A-II).
  3. Discontinuation of maintenance therapy in children receiving HAART is poorly studied and must be individualized (C-III).
  4. For cryptococcal pneumonia, use fluconazole (6–12 mg/kg per day orally) for 6–12 months (B-II).

Cryptococcosis in a Resource-limited Health Care Environment

  1. For CNS and/or disseminated disease where flucytosine is not available, induction therapy is AmBd (1 mg/kg per day IV) for 2 weeks or AmBd (0.7 mg/kg per day IV) plus fluconazole (800 mg per day orally) for 2 weeks, followed by consolidation therapy with fluconazole (800 mg per day orally) for 8 weeks (A-I).
  2. Maintenance therapy is fluconazole (200–400 mg per day orally) until immune reconstitution (A-I).
  3. With CNS and/or disseminated disease where polyene is not available, induction therapy is fluconazole (≥800 mg per day orally; 1200 mg per day is favored) for at least 10 weeks or until CSF culture results are negative, followed by maintenance therapy with fluconazole (200–400 mg per day orally) (B-II).
  4. With CNS and/or disseminated disease when polyene is not available but flucytosine is available, induction therapy is fluconazole (≥800 mg per day orally; 1200 mg per day is favored) plus flucytosine (100 mg/kg per day orally) for 2–10 weeks, followed by maintenance therapy with fluconazole (200–400 mg per day orally) (B-II).
  5. With use of primary fluconazole therapy for induction, both primary or secondary drug resistance of the isolate may be an issue, and minimum inhibitory concentration (MIC) testing is advised (B-III).
  6. For azole-resistant strains, administer AmBd (1 mg/kg per day IV) until CSF, blood, and/or other sites are sterile (B-III).

C. gattii Infection

  1. For CNS and disseminated disease due to C. gattii, induction, consolidation, and suppressive treatment are the same as for Cryptococcus neoformans (A-II).
  2. More diagnostic focus by radiology and follow-up examinations are needed for cryptococcomas/hydrocephalus due to C. gattii than that due to C. neoformans, but the management principles are the same (B-II).
  3. Pulmonary cryptococcosis (same as C. neoformans): single, small cryptococcoma suggests fluconazole (400 mg per day orally); for very large and multiple cryptococcomas, consider a combination of AmBd and flucytosine therapy for 4–6 weeks, followed by fluconazole for 6–18 months, depending on whether surgery was performed (B-III).
  4. Consider surgery if there is compression of vital structures, failure to reduce size of cryptococcoma after 4 weeks of therapy, or failure to thrive (B-III).
  5. Recombinant IFN-gamma use remains uncertain (C-III).

Definitions:

Quality of Evidence

  1. Evidence from at least one properly designed randomized, controlled trial
  2. Evidence from at least one well-designed clinical trial without randomization, from cohort or case-control analytic studies (preferably from >1 center), from multiple time-series studies, or from dramatic results of uncontrolled experiments
  3. Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees

Strength of Recommendation

  1. Good evidence to support a recommendation for or against use
  2. Moderate evidence to support a recommendation for or against use
  3. Poor evidence to support a recommendation
Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Early, appropriate treatment of non-central nervous system (CNS) pulmonary and extrapulmonary cryptococcosis reduces morbidity and prevents progression to a potentially life-threatening central nervous system disease.

Potential Harms
  • Drug-related toxicities and development of adverse drug-drug interactions are the principal potential harms of therapeutic intervention.
  • Patients receiving amphotericin B (AmB) had more frequent adverse events and associated bacterial infections, including bacteremia.
  • Because of the risk of nephrotoxicity, amphotericin B should be used with caution in transplant recipients and is not recommended as first-line therapy in this patient population.

Qualifying Statements

Qualifying Statements

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Audit Criteria/Indicators
Mobile Device Resources
Pocket Guide/Reference Cards
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322. [191 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2000 Apr (revised 2010 Jan)
Guideline Developer(s)
Infectious Diseases Society of America - Medical Specialty Society
Source(s) of Funding

Infectious Diseases Society of America (IDSA)

Guideline Committee

Infectious Diseases Society of America (IDSA) Standards and Practice Guidelines Committee

Composition of Group That Authored the Guideline

Authors: John R. Perfect, Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina; William E. Dismukes, Division of Infectious Diseases, University of Alabama at Birmingham; Francoise Dromer, Institut Pasteur, Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moleculaire, Paris, France; David L. Goldman, Department of Pediatric Infectious Diseases, Albert Einstein College of Medicine, Bronx, New York; John R. Graybill, Division of Infectious Diseases, University of Texas San Antonio, Audie L. Murphy Veterans Affairs Hospital, San Antonio; Richard J. Hamill, Division of Infectious Diseases, Veterans Affairs (VA) Medical Center, Houston, Texas; Thomas S. Harrison, Department of Infectious Diseases, St. George's Hospital Medical School, London, United Kingdom; Robert A. Larsen, Departments of Medicine and Infectious Diseases, University of Southern California School of Medicine, Los Angeles; Olivier Lortholary, Institute Pasteur, Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moleculaire, and Université Paris-Descartes, Service des Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants Malades, Centre d’Infectiologie Necker-Pasteur, Paris, France; Minh-Hong Nguyen, Division of Infectious Diseases, University of Pittsburgh College of Medicine, and Infectious Diseases Section, VA Medical Center, Pittsburgh, Pennsylvania; Peter G. Pappas, Division of Infectious Diseases, University of Alabama at Birmingham; William G. Powderly, University College, Dublin, Ireland; Nina Singh, Wayne State University, Harper Hospital, Detroit, Michigan; Jack D. Sobel, Wayne State University, Harper Hospital, Detroit, Michigan; Tania C. Sorrell, Centre for Infectious Diseases and Microbiology, University of Sydney at Westmead, Sydney, Australia

Financial Disclosures/Conflicts of Interest

Guidelines and Conflicts of Interest

All members of the Expert Panel complied with the Infectious Diseases Society of America (IDSA) policy on conflicts of interest, which requires disclosure of any financial or other interest that might be construed as constituting an actual, potential, or apparent conflict. Members of the Expert Panel were provided the IDSA's conflict of interest disclosure statement and were asked to identify ties to companies developing products that might be affected by promulgation of the guideline. Information was requested regarding employment, consultancies, stock ownership, honoraria, research funding, expert testimony, and membership on company advisory committees. The Expert Panel made decisions on a case-by-case basis as to whether an individual's role should be limited as a result of a conflict.

Potential Conflicts of Interest

J.R.G. has served as a research consultant for Schering-Plough.

P.G.P. has received grant support from Schering-Plough, Pfizer, Merck, and Astellas; has served as an ad hoc consultant to Pfizer; and has served as a speaker to Pfizer and Astellas.

J.R.P. has received grant support from Merck, Astellas, Pfizer, Schering-Plough, and Enzon; has received honoraria from Merck, Astellas, Pfizer, Schering-Plough, and Enzon; and has served as a consultant to Merck, Astellas, Pfizer, Schering-Plough, and Enzon.

T.C.S. has received grant support from Pfizer, Merck, and Gilead and has served on advisory boards for Pfizer, Merck, Gilead, and Schering-Plough.

O.L. serves on speaker bureaus for Merck, Schering-Plough, Pfizer, and Gilead Sciences.

All other authors: no conflicts.

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, Sobel JD, Dismukes WE. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000 Apr;30(4):710-8. [37 references]

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the Infectious Diseases Society of America (IDSA) Web site External Web Site Policy.

Print copies: Available from Dr. John R. Perfect, Div Infectious Diseases, Duke University Medical Center, Hanes House, Rm 163, Trent Dr, Box 102359, Durham, NC 27710; email: perfe001@mc.duke.edu.

Availability of Companion Documents

The following are available:

  • Cryptococcosis management. Pocket guide. Infectious Diseases Society of America (IDSA); 2010. 14 p. Electronic copies: Available from the IDSA Web site External Web Site Policy.
  • Cryptococcosis management. PDA version. Infectious Diseases Society of America (IDSA); 2010. 14 p. Electronic copies: Available from the IDSA Web site External Web Site Policy.

In addition, performance measures are available in the original guideline document External Web Site Policy.

Patient Resources

None available

NGC Status

This summary was completed by ECRI on May 1, 2001. The information was verified by the guideline developer as of June 29, 2001. This NGC summary was updated by ECRI Institute on November 9, 2010. The updated information was verified by the guideline developer on December 6, 2010.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

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