Guideline sources The following summarized guidelines for the evaluation and management of cryptococcal meningitis (CM) are prepared by our editorial team based on guidelines from the Infectious Diseases Society of America (IDSA/CDC/NIH/HIVMA 2023), the World Health Organization (WHO 2022), and the Infectious Diseases Society of America (IDSA 2010). 1 2 3 Guidelines 1. Screening and diagnosis Indications for screening: As per CDC 2023 guidelines: Obtain routine surveillance testing for serum cryptococcal antigen in patients with newly diagnosed human immunodeficiency virus with no overt clinical signs of meningitis, if the CD4 counts are 100 cells/mm , especially if 50 cells/mm . B Obtain prompt CSF evaluation for CNS infection in patients with a positive test (BIII), particularly when the serum cryptococcal antigen lateral flow assay titer is 1:160. B https://web.pathway.md/diseases/rec8qZXQuHUGCY1CX 1/8 6/23/23, 3:37 AM Cryptococcal meningitis Pathway As per WHO 2022 guidelines, consider screening for plasma, serum or whole-blood cryptococcal antigen as the optimal approach for guiding resources in a public health approach and as the preferred approach for identifying infection when managing 10 years old patients presenting with advanced human immunodeficiency virus disease. E Show 2 more 2. Diagnostic investigations Antigen testing: Obtain rapid serum, plasma or whole-blood cryptococcal antigen testing as the preferred diagnostic approach if both access to a cryptococcal antigen assay and rapid results (< 24 hours) are available in settings without immediate access to lumbar puncture or when lumbar puncture is clinically contraindicated. B Consider referring for further investigation and treatment promptly if a cryptococcal antigen assay is not available and/or rapid access to results is not ensured in settings without immediate access to lumbar puncture or when lumbar puncture is clinically contraindicated. B 3. Diagnostic procedures Lumbar puncture: As per WHO 2022 guidelines, perform s prompt lumbar puncture with measurement of CSF opening pressure and rapid cryptococcal antigen assay as the preferred diagnostic approach in adult, adolescent B and pediatric patients with human immunodeficiency virus suspected of having a first episode of CM. B Show 2 more As per IDSA 2010 guidelines, consider performing a prompt baseline lumbar puncture to assess CSF pressure at baseline. C Show 2 more 4. Medical management Antifungal therapy, induction, HIV-positive: As per IDSA/HIVMA/CDC/NIH 2023 guidelines, initiate IV amphotericin B in combination with oral flucytosine as induction therapy in patients with CM. A Show 5 more As per WHO 2022 guidelines, administer a single high-dose (10 mg/kg) of liposomal amphotericin B and initiate flucytosine (100 mg/kg/day divided into 4 doses per day) and fluconazole (1,200 mg/daily in adult patients and 12 mg/kg/day in pediatric and adolescent patients up to a maximum of 800 mg daily) for 14 days as the first-line induction regimen for the treatment of patients with CM. B Show 5 more https://web.pathway.md/diseases/rec8qZXQuHUGCY1CX 2/8 6/23/23, 3:37 AM Cryptococcal meningitis Pathway As per IDSA 2010 guidelines, initiate amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day PO in 4 divided doses (consider initiating IV formulations in severe cases and in patients without oral intake where the preparation is available) for at least 2 weeks as first-line induction therapy in human immunodeficiency virus-infected patients with CM. A Show 2 more Antifungal therapy, induction (organ transplant recipients): initiate liposomal amphotericin B (3-4 mg/kg/day IV) or amphotericin B lipid complex (5 mg/kg/day IV) plus flucytosine (100 mg/kg/day in 4 divided doses) for at least 2 weeks as induction therapy in organ transplant recipients with CM. B Show 2 more Antifungal therapy, induction (HIV-negative, non-transplant recipients): initiate amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day PO in 4 divided doses for at least 4 weeks as induction therapy in human immunodeficiency virus-negative, non-transplant patients with CM. B Show 6 more Antifungal therapy, consolidation, HIV-positive: As per IDSA/HIVMA/CDC/NIH 2023 guidelines, initiate fluconazole 800 mg/day as consolidation therapy. A Show 7 more As per WHO 2022 guidelines, initiate fluconazole (800 mg/day for adult patients and 6-12 mg/kg/day for pediatric and adolescent patients up to a maximum of 800 mg/day) for the consolidation phase (for 8 weeks following the induction phase). B As per IDSA 2010 guidelines: Initiate fluconazole 400 mg (6 mg/kg) per day PO for a minimum of 8 weeks following an induction therapy with amphotericin B and flucytosine as first-line consolidation therapy in human immunodeficiency virus-infected patients with CM. A Initiate fluconazole 800 mg/day PO for a minimum of 8 weeks following an induction therapy with amphotericin B and fluconazole as consolidation therapy in human immunodeficiency virus-infected patients with CM. B Antifungal therapy, consolidation (organ transplant recipients): initiate fluconazole 400-800 mg (6-12 mg/kg) per day PO for 8 weeks following an induction therapy with liposomal amphotericin B or amphotericin B lipid complex plus flucytosine as consolidation therapy in organ transplant recipients with CM. B Antifungal therapy, consolidation (HIV-negative, non-transplant recipients): Initiate fluconazole 400 mg/day for 8 weeks following an induction therapy with amphotericin B and flucytosine as consolidation therapy in human immunodeficiency virus-negative, non- transplant patients with CM. B Initiate fluconazole 800 mg (12 mg/kg) per day PO for 8 weeks following a 2-week induction therapy with amphotericin B and flucytosine as consolidation therapy in patients at low risk for therapeutic failure (an early diagnosis by history, no uncontrolled underlying disease or https://web.pathway.md/diseases/rec8qZXQuHUGCY1CX 3/8 6/23/23, 3:37 AM Cryptococcal meningitis Pathway immunocompromised state and excellent clinical response to initial 2-week antifungal combination course). B Antifungal therapy, maintenance, HIV-positive: As per IDSA/HIVMA/CDC/NIH 2023 guidelines, initiate fluconazole 200 mg/day as maintenance therapy and continue until at least 1 year from initiation of antifungal therapy. A Show 4 more As per WHO 2022 guidelines, initiate fluconazole (200 mg/day for adult patients and 6 mg/kg/day for adolescent and pediatric patients) for the maintenance phase until immune reconstitution (CD4 > 200 cells/mm ) and suppression of viral loads on ART. A As per IDSA 2010 guidelines, initiate the following regimens as maintenance therapy in human immunodeficiency virus-infected patients with CM: fluconazole 200 mg/day PO A traconazole 200 mg BID PO with drug-level monitoring B amphotericin B deoxycholate 1 mg/kg/week IV in azole-intolerant patients, as it is less effective than azoles and is associated with IV catheter-related infections. B Antifungal therapy, maintenance (organ transplant recipients): Continue fluconazole 200-400 mg/day PO for at least 6-12 months as maintenance therapy in organ transplant recipients with CM. B Reduce immunosuppressants sequentially or in a stepwise manner, with consideration of lowering the corticosteroid dose first. B Antifungal therapy, maintenance (HIV-negative, non-transplant recipients): initiate fluconazole 200 mg (3 mg/kg) per day PO for 6-12 months as maintenance therapy in human immunodeficiency virus-negative, non-transplant patients with CM. B Antiretroviral therapy: As per CDC 2023 guidelines, defer initiation of ART 4-6 weeks after antifungal agents are started. A As per WHO 2022 guidelines, do not initiate immediate ART in adult, (Strong recommendation; low-certainty evidence) adolescent and pediatric patients with human immunodeficiency virus and CM because of the risk of increased mortality and defer it 4-6 weeks from the initiation of antifungal treatment. D As per IDSA 2010 guidelines: Initiate HAART 2-10 weeks after commencement of initial antifungal treatment. B Consider discontinuing suppressive therapy during HAART in patients with a CD4 cell count > 100 cells/ L and an undetectable or very low human immunodeficiency virus RNA level sustained for 3 months, minimum of 12 months of antifungal therapy. C Consider resuming maintenance therapy if the CD4 cell count decreases to < 100 cells/ L. C Diuretics and corticosteroids: As per CDC 2023 guidelines: https://web.pathway.md/diseases/rec8qZXQuHUGCY1CX 4/8 6/23/23, 3:37 AM Cryptococcal meningitis Pathway Do not use mannitol or corticosteroids for elevated ICP because of the ineffectiveness. D Do not use acetazolamide for elevated ICP because it is ineffective and may exacerbate hyperchloremic acidosis from amphotericin B. D Do not use corticosteroids during induction therapy for ICP control in patients with human immunodeficiency virus-associated CM unless for immune reconstitution inflammatory syndrome. D As per WHO 2022 guidelines, do not use adjunctive corticosteroids routinely during the induction phase in treating adult, adolescent D and pediatric patients with human immunodeficiency virus-associated CM. D As per IDSA 2010 guidelines: Do not use routine mannitol for ICP. D Avoid using acetazolamide and corticosteroids (unless part of immune reconstitution inflammatory syndrome treatment) to control increased ICP. D Management of medication adverse effects: consider administering acetaminophen 650 mg and diphenhydramine 25-50 mg or hydrocortisone 50-100 mg 30 minutes before the infusion of amphotericin to reduce the severity of infusion reactions in patients with severe amphotericin infusion-related adverse reactions. C Show 4 more Management of treatment failure: As per CDC 2023 guidelines, switch to amphotericin B, with or without flucytosine, in patients not responding to induction with fluconazole monotherapy. B Show 4 more As per IDSA 2010 guidelines, take adequate measures to improve immune status (such as decrease immunosuppressants and introduce HAART) and optimize management of increased ICP. B Show 8 more Management of relapse: As per CDC 2023 guidelines, confirm CSF culture sterility at the completion of re-induction therapy for treatment failure or relapse. B Show 2 more As per IDSA 2010 guidelines, restart induction phase therapy as in patients with persistence disease. B Show 2 more 5. Therapeutic procedures CSF drainage: As per CDC 2023 guidelines, take measures to decrease ICP in all patients with confusion, blurred vision, papilledema, lower extremity clonus, or other neurologic signs indicative of increased ICP. Perform drainage of CSF via lumbar puncture for initial management. B https://web.pathway.md/diseases/rec8qZXQuHUGCY1CX 5/8 6/23/23, 3:37 AM Cryptococcal meningitis Pathway Show 4 more As per IDSA 2010 guidelines, perform CSF drainage by lumbar puncture to relieve ICP (reduce the opening pressure by 50% if it is extremely high or to a normal pressure of 20 cm of CSF) if the CSF pressure is 25 cm and there are symptoms of increased ICP during induction therapy. B Show 2 more Ventriculoperitoneal shunting: consider placing permanent ventriculoperitoneal shunts only if the patient is receiving or has received appropriate antifungal therapy and if more conservative measures to control increased ICP have failed. C Show 2 more 6. Specific circumstances Pediatric patients: initiate amphotericin B deoxycholate 1 mg/kg/day IV plus flucytosine 100 mg/kg/day PO in 4 divided doses for 2 weeks (follow the treatment length schedule for adults in non-human immunodeficiency virus-infected, non-transplant patients) followed by fluconazole 10- 12 mg/kg/day PO for 8 weeks as induction and consolidation therapy in pediatric patients with CNS disease. B Show 2 more Pregnant patients: As per CDC 2023 guidelines, consider using flucytosine during pregnancy only when the benefits outweigh the risks to the fetus and only in the third trimester. B Show 2 more As per IDSA 2010 guidelines, initiate amphotericin B deoxycholate or lipid formulations of amphotericin B with or without flucytosine in pregnant patients with CNS disease. B Consider using flucytosine in a relationship to benefit versus risk because it is a category C drug for pregnancy. Show 2 more Patients with immune reconstitution inflammatory syndrome: Do not alter direct antifungal therapy in patients with immune reconstitution inflammatory syndrome. D Show 3 more Do not alter direct antifungal therapy in patients with immune reconstitution inflammatory syndrome. D Show 3 more Patients with cerebral cyptococcomas: initiate amphotericin B deoxycholate 0.7-1 mg/kg/day IV, liposomal amphotericin B 3-4 mg/kg/day IV or amphotericin B lipid complex 5 mg/kg/day IV plus flucytosine 100 mg/kg/day PO in 4 divided doses for at least 6 weeks as induction therapy in patients with cerebral cyptococcomas. B Show 4 more https://web.pathway.md/diseases/rec8qZXQuHUGCY1CX 6/8 6/23/23, 3:37 AM Cryptococcal meningitis Pathway Patients with Cryptococcus gattii infection: Initiate the same induction, consolidation and suppressive therapy in patients with CNS disease due to Cryptococcus gattii as for Cryptococcus neoformans. B Pay more diagnostic attention by radiology and follow-up examinations for cryptococcomas/hydrocephalus due to Cryptococcus gattii than that due to Cryptococcus neoformans, but recognize that the management principles are the same. B Resource-limited healthcare environments: As per CDC 2023 guidelines, prefer 1-week amphotericin B deoxycholate with flucytosine regimen followed by high-dose fluconazole as induction and consolidation therapy in resource- limited settings. B As per IDSA 2010 guidelines, initiate amphotericin B deoxycholate 1 mg/kg/day IV for 2 weeks or amphotericin deoxycholate 0.7 mg/kg/day IV plus fluconazole 800 mg/day PO for 2 weeks followed by consolidation therapy with fluconazole 800 mg/day PO for 8 weeks as induction and consolidation therapy in patients with CNS disease in areas where flucytosine is not available. A Show 5 more 7. Preventative measures Primary prophylaxis, HIV-positive: As per IDSA/HIVMA/CDC/NIH 2023 guidelines, do not initiate primary prophylaxis in human immunodeficiency virus-positive patients in the United States in the absence of a positive serum cryptococcal antigen test because of the relative infrequency of cryptococcal disease, lack of survival benefit associated with prophylaxis, possibility of drug-drug interactions, potential development of antifungal drug resistance, and costs. D Show 4 more As per WHO 2022 guidelines: Initiate fluconazole primary prophylaxis in adult and adolescent patients with human immunodeficiency virus having a CD4 cell count < 100 cells/mm when cryptococcal antigen screening is not available. B Consider initiating fluconazole primary prophylaxis at a higher CD4 cell count threshold of < 200 cells/mm . C As per IDSA 2010 guidelines, do not initiate routine primary antifungal prophylaxis for cryptococcosis in patients with human immunodeficiency virus in the United States and Europe. D Show 2 more 8. Follow-up and surveillance https://web.pathway.md/diseases/rec8qZXQuHUGCY1CX 7/8 6/23/23, 3:37 AM Cryptococcal meningitis Pathway Assessment of treatment response: do not monitor serum or CSF cryptococcal antigen titers for determination of initial response to therapy. D References 1. Perfect JR, Dismukes WE, Dromer F et al. 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. Open 2. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Department of Health and Human Services. 2023. Open 3. No authors listed. Guidelines for Diagnosing, Preventing and Managing Cryptococcal Disease Among Adults, Adolescents and Children Living with HIV. Geneva: World Health Organization; 2022. Open 4. Saag MS, Graybill RJ, Larsen RA et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. 2000 Apr;30 4 710 8. Open 5. Joseph N Jarvis, David S Lawrence, David B Meya et al. Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis. N Engl J Med. 2022 Mar 24;386 12 1109 1120. Open https://web.pathway.md/diseases/rec8qZXQuHUGCY1CX 8/8