Cryptococcosis

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

Diagnosis:
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 

liposomal
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

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

OR
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
fluconazole
200 mg qd po		 See Drug-drug interactions between ARVs and Non-ARVs