Preferred antifungal regimens for cryptococcal meningoencephalitis in nonpregnant patients with HIV^*^[1,2]

	Preferred regimens	Alternative regimens^¶	Comments
Regimens for induction therapy^Δ	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) for a minimum of 2 weeks or Amphotericin B lipid complex (5 mg/kg IV once daily) plus flucytosine (100 mg/kg per day orally in 4 divided doses) for a minimum of 2 weeks If resources are limited: Liposomal amphotericin B (10 mg/kg IV single dose) plus the combination of flucytosine (100 mg/kg/day orally in 4 divided doses) and fluconazole (1200 mg orally once daily) for a minimum of 2 weeks If resources are limited and liposomal amphotericin B is not available: 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 a minimum of 7 days	Amphotericin B deoxycholate (0.7 to 1 mg/kg IV once daily)^§ plus flucytosine (100 mg/kg per day orally in 4 divided doses) for a minimum of 2 weeks or Fluconazole (1200 mg orally once daily) plus flucytosine (100 mg/kg orally in 4 divided doses) for a minimum of 2 weeks or Amphotericin B^§ plus fluconazole (800 to 1200 mg orally once daily) for a minimum of 2 weeks^¥	An LP should be repeated after 2 weeks of induction therapy to confirm CSF sterilization. If a shortened course of polyene therapy 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.^‡ During 2-week induction therapy, clinical response should be assessed daily (in a hospital setting if possible).
Consolidation therapy	Fluconazole (400 to 800 mg orally or IV once daily) for a minimum of 8 weeks	Itraconazole (200 mg orally twice daily) for a minimum 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 the 800 mg/day dosing of fluconazole with adjustment for renal function. 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.
Maintenance therapy	Fluconazole (200 mg orally once daily) for a minimum of 1 year	Itraconazole (200 mg orally once daily) for a minimum of 1 year^†	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 cryptococcal meningitis in persons with HIV. The doses listed above are for patients with normal kidney function. Dose modifications for patients with reduced kidney function can be found in the Lexicomp drug information topics within UpToDate. Pregnant persons should be managed in conjunction with an infectious diseases specialist, since flucytosine and azoles may be teratogenic during pregnancy, particularly in the first trimester.

IV: intravenous; LP: lumbar puncture; CSF: cerebrospinal fluid; ART: antiretroviral therapy.

* In addition to antifungal therapy, patients who are not receiving ART should initiate treatment for HIV. However, 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 treatment of patients with cryptococcal meningitis for a detailed discussion of when to initiate HIV therapy.

¶ Selection among alternative regimens depends on why a preferred regimen cannot be used. Refer to the UpToDate topic on treatment of patients with cryptococcal meningitis for a detailed discussion.

Δ The duration should be extended if clinical improvement is not observed and/or if CSF sterilization has not yet been achieved.

§ Lipid formulations of amphotericin B are favored to minimize the risk of toxicity and reduce treatment interruptions. However, amphotericin B deoxycholate remains an effective regimen if lipid formations are not available. When amphotericin B deoxycholate is used, the dose is 0.7 to 1 mg/kg IV once daily. In resource-limited settings, we use the 1 mg/kg/dose, as it has been best studied. However, in resource-available countries, we favor the 0.7 mg/kg dose to reduce the risk of nephrotoxicity.

¥ If it is not feasible to administer amphotericin B for 2 weeks, amphotericin B can be given for 1 week with fluconazole (1200 mg orally once daily), followed by 1 week of fluconazole (1200 mg orally once daily) alone.

‡ The World Health Organization 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.

† Levels should be monitored during the course of therapy. Refer to the UpToDate topic on pharmacology of azoles.

References:

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. Available at: https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis?view=full (Accessed on December 06, 2023).
World Health Organization. Diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. https://www.who.int/publications/i/item/9789240052178 (Accessed on July 08, 2022).

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Preferred antifungal regimens for cryptococcal meningoencephalitis in nonpregnant patients with HIV*[1,2]

Preferred antifungal regimens for cryptococcal meningoencephalitis in nonpregnant patients with HIV^*^[1,2]