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"Practice Guidelines for the Management of Cryptococcal Disease"

current
Published: Clinical Infectious Diseases ; 2010 ; 50 : 291 -322

Abstract

Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)–infected individuals, (2) organ transplant recipients, and (3) non–HIV‐infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource‐limited environments, and those with Cryptococcus gattii infection.  

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*Every 12 to 18 months following publication, IDSA reviews its guidelines to determine whether an update is required. This guideline was last reviewed and deemed current as of 04/2013.

Recommendations

 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)

2. 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.

3. 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).

4. 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).

5. 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).

6. 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

7. Fluconazole (200 mg per day orally) (A-I).

8. Itraconazole (200 mg twice per day orally; drug-level monitoring strongly advised) (C-I).

9. 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).

10. Initiate HAART 2–10 weeks after commencement of initial antifungal treatment (B-III).

11. 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) (B-II); consider reinstitution of maintenance therapy if the CD4 cell count decreases to <100 cells/µL (B-III).

12. 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).

13. 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

14. 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).

15. For mild-to-moderate non-CNS disease, fluconazole (400 mg [6 mg/kg] per day) for 6–12 months (B-III).

16. 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).

17. 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).

18. Fluconazole maintenance therapy should be continued for at least 6–12 months (B-III).

19. Immunosuppressive management should include sequential or step-wise reduction of immunosuppressants, with consideration of lowering the corticosteroid dose first (B-III).

20. 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

21. 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).

22. 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).

23. If flucytosine is not given or treatment is interrupted, consider lengthening AmBd or LFAmB induction therapy for at least 2 weeks (B-III).

24. In patients at low risk for therapeutic failure (ie, 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).

25. 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

26. Check that adequate measures have been taken to improve immune status (eg, decrease immunosuppressants and introduce HAART) and optimize management of increased intracranial pressure (B-III).

27. Reinstitute induction phase of primary therapy for longer course (4–10 weeks) (B-III).

28. 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).

29. 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).

30. 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).

31. Use of intrathecal or intraventricular AmBd is generally discouraged and is rarely necessary (C-III).

32. 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).

33. In azole-exposed patients, increasing the dose of the azole alone is unlikely to be successful and is not recommended (C-III).

34. Adjunctive immunological therapy with recombinant interferon (IFN)-γ 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

35. Restart induction phase therapy (see “Persistence,” above) (B-III).

36. Determine susceptibility of the relapse isolate (see “Persistence,” above) (B-III).

37. 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 (B-III); if there are compliance issues and a susceptible isolate, prior suppressive doses of fluconazole may be reinstituted (B-III).

Elevated CSF pressure

38. 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).

39. 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).

40. 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).

41. 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

42. Mannitol has no proven benefit and is not routinely recommended (A-III).

43. Acetazolamide and corticosteroids (unless part of IRIS treatment) should be avoided to control increased intracranial pressure (A-II).

Recurrence of signs and symptoms

44. For recurrence of signs and symptoms, reinstitute drainage procedures (B-II).

45. 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

46. 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

47. No need to alter direct antifungal therapy (B-III).

48. No definitive specific treatment recommendation for minor IRIS manifestations is necessary, because they will resolve spontaneously in days to weeks (B-III).

49. 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).

50. Nonsteroidal anti-inflammatory drugs and thalidomide have been used but with too little experience to make a recommendation (C-III).

Cerebral cyptococcomas

51. 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).

52. Consolidation and maintenance therapy with fluconazole (400–800 mg per day orally) for 6–18 months (B-III).

53. Adjunctive therapies include the following:

A. Corticosteroids for mass effect and surrounding edema (B-III).

A. Corticosteroids for mass effect and surrounding edema (B-III).

B. 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 IRIS should be submitted for further tissue diagnosis (B-II).

Treatment Strategies for Patients with Nonmeningeal Cryptococcosis

Pulmonary (immunosuppressed)

54. 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).

55. Pneumonia associated with CNS or documented dissemination and/or severe pneumonia (acute respiratory distress syndrome [ARDS]) is treated like CNS disease (B-III).

56. Corticosteroid treatment may be considered if ARDS is present in the context of IRIS (B-III).

57. 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).

58. 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).

59. Surgery should be considered for either diagnosis or persistent radiographic abnormalities and symptoms not responding to antifungal therapy (B-III).

Pulmonary (nonimmunosuppressed)

60. 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).

61. For severe disease, treat similarly to CNS disease (B-III).

62. 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).

63. Surgery should be considered for either diagnosis or persistent radiographic abnormalities and symptoms not responding to antifungal therapy (B-III).

64. 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).

65. ARDS in the context of an inflammatory syndrome response may require corticosteroid treatment (B-III).

Nonmeningeal, nonpulmonary cryptococcosis

66. 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).

67. 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 C. gattii–Infected Persons)

Pregnant women with cryptococcosis

68. 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.

69. 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).

70. For limited and stable pulmonary cryptococcosis, perform close follow-up and administer fluconazole after delivery (B-III).

71. Watch for IRIS in the postpartum period (B-III).

Children with cryptococcosis

72. 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).

73. Maintenance therapy is fluconazole (6 mg/kg per day orally) (A-II).

74. Discontinuation of maintenance therapy in children receiving HAART is poorly studied and must be individualized (C-III).

75. 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

76. 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).

77. Maintenance therapy is fluconazole (200–400 mg per day orally) until immune reconstitution (A-I).

78. 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).

79. 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).

80. With use of primary fluconazole therapy for induction, both primary or secondary drug resistance of the isolate may be an issue, and MIC testing is advised (B-III).

81. 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

For CNS and disseminated disease due to C. gattii, induction, consolidation, and suppressive treatment are the same as for C. neoformans (A-II).

83. 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).

84. 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).

85. 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).

86. Recombinant IFN-γ use remains uncertain (C-III).

 

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