Disease caused by Cryptococcus neoformans

Diagnosis and treatment

Cryptococcal meningitis is the most frequent manifestation of cryptococcosis. Cryptococcal infection can also cause a pneumonitis which may be difficult to distinguish from Pneumocystis pneumonia. Infection may also involve other organs or may be disseminated

Primary prophylaxis: not recommended systematically in the European context

Positive microscopy, OR detection of antigen in serum or CSF OR culture from CSF, blood or urine. Serum cryptococcal antigen should be performed in all newly HIV-diagnosed persons with CD4 counts < 100 cells/μL. See Pre-emptive therapy below

Notes on treatment:
Treat cryptococcal meningitis and disseminated cryptococcosis for 14 days (induction therapy), then 8 weeks (consolidation therapy), then secondary prophylaxis for at least 12 months. Stop secondary prophylaxis if CD4 count > 100 cells/μL and HIV-VL undetectable over 3 months. See also Anti-infective/ART interaction table for treatment optimization

  Drug / Dose Comments
Pre-emptive therapy fluconazole
800 mg qd po for 2 weeks
followed by 400 mg qd po for 8 weeks

In case of:

  • positive cryptococcal serum antigen
  • asymptomatic individual with CD4 < 100 cells/μL
  • cryptococcal meningitis, pulmonary or other site infection ruled out
Induction therapy 

amphotericin B
3 mg/kg qd iv
+ flucytosine
25 mg/kg qid po

14 days

  • Perform repeated lumbar puncture (LP), until opening pressure is < 20 cm H20:
  • If CSF culture is sterile, switch to oral regimen
  • Repeated LPs or CSF shunting are essential to effectively manage increased intracranial pressure which is associated with better survival
  • Corticosteroids have no effect in reducing increased intracranial pressure, could be detrimental and are contraindicated
  • Flucytosine dosage must be adapted to renal function
  • Defer start of ART for at least 4 weeks, since early initiation of ART has been associated with decreased survival. Where very close monitoring and optimal treatment are available, earlier ART start can be considered in selected, low-risk cases
  • Due to substantial nephrotoxicity amphotericin B deoxycholate should only be used if liposomal amphotericin B is not available
  • Flucytosine may not be available in all European countries. Consider replacing it by fluconazole 800 mg qd during the induction phase

amphotericin B deoxycholate
0.7 mg/kg qd iv
+ flucytosine
25 mg/kg qid po

single-dose liposomal amphotericin B
10 mg/kg IV single-dose
+ flucytosine
25 mg/kg qid po for 2 weeks
+ fluconazole
1200 mg/die for 2 weeks

  • Preferred WHO-2022 regimen in resource limited settings
  • In resource-limited settings, alternative induction regimens may include:
    • i) one week of amphotericin B + flucytosine followed by one week of fluconazole 1200 mg qd (the 2018 WHO-recommended treatment) or
    • ii) two weeks of fluconazole 1200 mg qd plus flucytosine
Consolidation therapy fluconazole
400 mg qd po (single loading dose of 800 mg on 1st day)
8 weeks
See Drug-drug interactions between ARVs and Non-ARVs

Secondary Prophylaxis / Maintenance Therapy

  • At least 12 months
  • Consider to stop: if CD4 count >100 cells/μL and HIV-VL undetectable over 3 months
Drug / Dose Comments
200 mg qd po
See Drug-drug interactions between ARVs and Non-ARVs