Cryptococcosis

Disease caused by Cryptococcus neoformans

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: One large RCT in Africa (the REALITY trial [5]) showed that an enhanced infection prophylaxis in severely immunosuppressed persons (< 50 CD4 cells/μL) including INH 12 weeks, fluconazole 100 mg/day for 12 weeks, azithromycin 500 mg/day for 5 days and albendazole 400 mg single dose may decrease overall opportunistic infections (including cryptococcal meningitis) and mortality. Due to the different epidemiology of opportunistic infections in Africa and in Europe these results may not be extrapolated to European countries
  • 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 diagnosed PLWH with CD4 counts < 100 cells/μL. See Pre-emptive therapy below
    Treatment (Cryptococcal meningitis and disseminated cryptococcosis). 14 days induction therapy, then 8 weeks consolidation therapy, then secondary prophylaxis for at least 12 months. Stop, if CD4 count > 100 cells/μL and HIV-VL undetectable over 3 months
  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 cART for at least 4 weeks, since early initiation of cART is associated with decreased survival
  • 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
  • In resource-limited settings, a large RCT suggested that one week of amphotericin B + flucytosine or two weeks of fluconazole 1200 mg qd plus flucytosine may be acceptable induction regimens [6]

OR amphotericin B deoxycholate
0.7 mg/kg qd iv

+ flucytosine
25 mg/kg qid po
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