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Preferred antifungal regimens for severe cryptococcal disease in nonpregnant patients with or without HIV[1-3]

Preferred antifungal regimens for severe cryptococcal disease in nonpregnant patients with or without HIV[1-3]
  Preferred regimens Duration Additional considerations for patients with CNS disease
Induction therapy* When resources allow:
  • Liposomal amphotericin B (3 to 4 mg/kg IV once daily) plus flucytosine (100 mg/kg per day orally in 4 divided doses)
  • or
  • Amphotericin B lipid complex (5 mg/kg IV once daily) plus flucytosine (100 mg/kg per day orally in 4 divided doses).

Persons with HIV if resources are limited:

  • Liposomal amphotericin B (10 mg/kg IV single dose) plus the combination of flucytosine (100 mg/kg per day orally in 4 divided doses) and fluconazole (1200 mg orally once daily) for the duration of induction therapy.
 No cryptococcomas present:
  • Minimum 2 weeks

Cryptococcomas present:

  • Non-CNS disease with small cryptococcomas (<2 cm): Minimum 2 weeks
  • CNS involvement or presence of large pulmonary cryptococcomas: Minimum 4 to 6 weeks

For all patients, the duration should be extended if clinical improvement is not observed and/or if clinical laboratory parameters have not yet been achieved (eg, persistent culture positivity in patients with CNS disease).
  • In most cases, an LP should be repeated after 2 weeks of induction therapy to confirm CSF sterilization.
  • However, if a regimen that includes less than 2 weeks of amphotericin is used, we prefer to do a repeat LP earlier in the course (7 to 14 days) so we can better identify those at risk for treatment failure.Δ
  • During 2-week induction therapy, clinical response should be assessed daily (in a hospital setting if possible).
  • Persons with HIV who are not receiving ART should initiate treatment for HIV. However, for those with CNS disease, initiation of ART should be delayed several weeks after induction therapy has been started to minimize the risk of developing an immune reconstitution inflammatory syndrome (IRIS). Refer to the UpToDate topic on the treatment of patients with cryptococcal meningitis for a detailed discussion of when to initiate HIV therapy.
Consolidation therapy◊ Fluconazole (400 to 800 mg orally once daily) Minimum duration of 8 weeks§
  • Patients who have had a clear response to therapy can transition to fluconazole pending the results of the repeat CSF culture.
  • We generally initiate consolidation therapy with fluconazole 800 mg/day, with adjustment for kidney function, especially in resource-limited settings.
  • In resource-available settings, the dose can then be reduced to 400 mg/day to complete the 8-week consolidation phase if all of the following criteria are met:
    • The patient received induction therapy with amphotericin B plus flucytosine for 2 weeks.
    • CSF cultures obtained after 2 weeks of induction therapy are negative.
    • ART has been started, if applicable.
Maintenance therapy◊ Fluconazole (200 mg orally once daily) Minimum duration of 1 year
  • For persons with HIV, the minimum duration of maintenance therapy should be at least 1 year. After that, maintenance therapy can be discontinued in individuals on ART who have a CD4 cell count ≥100 cells/microL and have achieved an undetectable viral load on ART for more than 3 months.
  • If viral load testing is not available, maintenance therapy should be continued until CD4 is ≥200 cells/microL.
This table should be used in conjunction with the UpToDate topics on treatment of severe cryptococcal disease (CNS disease, pulmonary disease in immunocompromised patients and those with large [>2 cm] or multiple lesions, and those with disseminated infection). The doses listed above are for patients with normal kidney function. Dose modifications for patients with reduced kidney function can be found in the drug information topics within UpToDate. Pregnant persons should be managed in conjunction with an infectious diseases specialist, since flucytosine and azoles can be teratogenic during pregnancy, particularly in the first trimester. If there is concern for treatment failure, azole resistance may be a factor if the MIC >16 mcg/mL or if there is a 3-fold rise in MIC of serial isolate to fluconazole.

ART: antiretroviral therapy; CNS: central nervous system; CSF: cerebrospinal fluid; HIV: human immunodeficiency virus; IV: intravenous; LP: lumbar puncture; MIC: minimum inhibitory concentration.

* Alternative induction regimens are discussed in detail in the topics on treatment of cryptococcal meningitis. Regimen selection depends in part upon the availability of antifungal agents; only some have been studies in persons with HIV. Possible regimens include:

  • If liposomal amphotericin B and amphotericin B lipid complex are not available:
    • Amphotericin B deoxycholate (0.7 to 1 mg/kg IV once daily) plus flucytosine (100 mg/kg per day orally in 4 divided doses). In resource-limited settings, the 1 mg/kg dose daily of amphotericin B has been best studied. However, in resource-abundant countries, we favor the 0.7 mg/kg dose daily to reduce the risk of nephrotoxicity.
    • Amphotericin B deoxycholate (1 mg/kg IV once daily) plus flucytosine (100 mg/kg per day orally in 4 divided doses) for 7 days, followed by fluconazole monotherapy (1200 mg orally once daily) for the remainder of the duration of induction therapy.
  • If flucytosine is not available: Amphotericin B (any formulation) plus fluconazole (800 to 1200 mg orally once daily). Liposomal amphotericin B or Amphotericin B lipid complex is preferred.
  • If amphotericin B is not available: Fluconazole (800 to 1200 mg orally once daily) plus flucytosine (100 mg/kg per day orally in 4 divided doses). For persons with HIV, we prefer the 1200 mg dose of fluconazole.
  • If amphotericin B and flucytosine are not available: Oral fluconazole alone (1200 mg orally once daily); however, this regimen is not as effective as others.

¶ This regimen has not been studied in persons without HIV, and if used, very close follow-up is required.

Δ The World Health Organization (WHO) states that in low- and middle-income countries, a routine LP is not indicated after 2 weeks of induction therapy to confirm CSF sterilization if the patient has had a clear clinical response to treatment. However, we still consider it when feasible.

◊ Alternative regimens for consolidation and maintenance therapy include: Voriconazole (200 mg orally twice daily), posaconazole (300 mg orally once daily), isavuconazole (200 mg orally once daily [equivalent to isavuconazole sulfate 372 mg orally once daily]), or itraconazole (200 mg orally twice daily). We generally prefer voriconazole, posaconazole, or isavuconazole rather than itraconazole. Although itraconazole has traditionally been considered the alternative azole of choice, it has variable bioavailability. Drug levels should be monitored for voriconazole, posaconazole, and itraconazole. Refer to the UpToDate topic on pharmacology of azoles.

§ For persons with HIV, we typically extend the duration of consolidation therapy for those with a slow clinical response to therapy or who do not have sterile CSF at 2 weeks and in patients whose ART is delayed for >10 weeks after diagnosis.

References:
  1. Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: Cryptococcosis. National Institutes of Health, Centers for Disease Control and Prevention, HIV Medicine Association, and Infectious Diseases Society of America. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis?view=full (Accessed on December 06, 2023).
  2. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. World Health Organization. https://www.who.int/publications/i/item/9789240052178 (Accessed on July 08, 2022).
  3. Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: An initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis 2024; 24:e495.
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