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 Test for serum cryptococcal antigen all persons with<100 cells/µL	fluconazole 800 mg qd po for 2 weeks followed by 400 mg qd po for 8 weeks	In case of: positive cryptococcal serum antigen AND asymptomatic individual with CD4 < 100 cells/μL AND cryptococcal meningitis, pulmonary or other site infection ruled out after thorough investigation No evidence from clinical trials is available to guide optimal ART initiation in this context. Consider initiation of ART according to general recommendations, see When to start ART Consider different doses/duration of fluconazole pre-emptive therapy in resource-limited settings, see also global guidelines
Induction therapy	liposomal amphotericin B 3 mg/kg qd iv + flucytosine 25 mg/kg qid po Preferred regimen in high-resource settings	2 weeks Principles of management: Perform repeated lumbar puncture (LP), until opening pressure is < 20 cm H₂0 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 If after 2 weeks of induction therapy CSF cultures are negative, switch to consolidation therapy. If CSF cultures remain positive and there is no clinical improvement, extend induction therapy until negative results. Flucytosine dosage must be adjusted on renal function, monitor for cytopenia Defer start of ART for 4-6 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
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 regimen in resource-limited settings	Alternative regimens: - If liposomal amphotericin B is not available, alternative regimens include: Amphotericin B deoxycholate 0.7 mg/kg qd iv + flucytosine 25 mg/kg qid po for two weeks (beware of nephrotoxicity of this regimen) Fluconazole 1200 mg qd plus flucytosine 25mg/kg qid for two weeks - Flucytosine may not be available in all European countries. If flucytosine is not available, alternative regimens may include: • Liposomal amphotericin B + fluconazole 800-1200 mg qd for 2 weeks
Consolidation therapy	fluconazole 400 mg qd po (single loading dose of 800 mg on 1^st day)	8 weeks See Drug-drug interactions between ARVs and Non-ARVs

Drug / Dose

Comments

Pre-emptive therapy

Test for serum cryptococcal antigen all persons with<100 cells/µL

fluconazole
800 mg qd po for 2 weeks
followed by 400 mg qd po for 8 weeks

In case of:

positive cryptococcal serum antigen AND
asymptomatic individual with CD4 < 100 cells/μL AND
cryptococcal meningitis, pulmonary or other site infection ruled out after thorough investigation

No evidence from clinical trials is available to guide optimal ART initiation in this context. Consider initiation of ART according to general recommendations, see When to start ART

Consider different doses/duration of fluconazole pre-emptive therapy in resource-limited settings, see also global guidelines

Induction therapy

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

Preferred regimen in high-resource settings

2 weeks

Principles of management:

Perform repeated lumbar puncture (LP), until opening pressure is < 20 cm H₂0
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
If after 2 weeks of induction therapy CSF cultures are negative, switch to consolidation therapy. If CSF cultures remain positive and there is no clinical improvement, extend induction therapy until negative results.
Flucytosine dosage must be adjusted on renal function, monitor for cytopenia
Defer start of ART for 4-6 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

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 regimen in resource-limited settings

Alternative regimens:

- If liposomal amphotericin B is not available, alternative regimens include:

Amphotericin B deoxycholate 0.7 mg/kg qd iv + flucytosine 25 mg/kg qid po for two weeks (beware of nephrotoxicity of this regimen)
Fluconazole 1200 mg qd plus flucytosine 25mg/kg qid for two weeks

- Flucytosine may not be available in all European countries. If flucytosine is not available, alternative regimens may include:

• Liposomal amphotericin B + fluconazole 800-1200 mg qd for 2 weeks

Consolidation therapy

fluconazole
400 mg qd po (single loading dose of 800 mg on 1^st 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

Drug / Dose

Comments

fluconazole
200 mg qd po

See Drug-drug interactions between ARVs and Non-ARVs