Cryptococcal Meningitis

CNS

Patient + scenario modifiers

Patient

Clinical scenario / source

Annotations only — chart still shows the full chemistry of each drug.

1. Clinical Syndrome

Subacute meningoencephalitis caused by Cryptococcus neoformans (or C. gattii in immunocompetent hosts). Classic presentation: HEADACHE, fever, altered mental status evolving over days–weeks; often elevated opening pressure on LP. CSF CrAg highly sensitive/specific; serum CrAg lateral flow assay used for screening in advanced HIV.

2. Pathogens

Consider the patient: HIV with CD4 <100 (most common host), solid organ transplant (esp. liver, kidney), hematologic malignancy / lymphoma, anti-TNF biologics, prolonged high-dose steroids, cirrhosis. C. gattii: immunocompetent hosts in Pacific Northwest / Vancouver Island endemic regions.

Consider the case: Opening pressure management is as important as antifungal therapy — mortality tracks ICP. ALWAYS measure opening pressure. Serum CrAg precedes clinical disease in HIV; many programs screen at CD4 <100.

Common

- Cryptococcus neoformans
  Most common; var. grubii (serotype A) globally; var. neoformans (serotype D) Europe.

3. Empiric Therapy

Tier	First choice	Alternatives	Duration	Comments
Acute / severe	3–4 mg/kg · q24h · IV · ≥2 weeks INDUCTION phase. Higher-dose 5 mg/kg in resource-limited settings or severe disease. 25 mg/kg · PO q6h · PO · ≥2 weeks Combo with amphotericin — synergistic. Adjust for renal function. Therapeutic drug monitoring (peak 30–80 mg/L).	3–4 mg/kg · q24h · IV · ≥4 weeks Monotherapy if flucytosine unavailable / contraindicated — extend induction to ≥4 weeks before consolidation. 1200 mg · PO daily · PO · 2 weeks Combo with amphotericin if flucytosine unavailable (WHO short-course regimen alternative).	≥2 weeks induction; transition to consolidation when stable + CSF culture clear	INDUCTION × ≥2 weeks (longer if monotherapy or persistent CSF positivity). Confirm CSF culture clearance before consolidation transition.
Admitted to ward	400–800 mg (6–12 mg/kg) · PO daily · PO · ≥8 weeks CONSOLIDATION phase. Use 800 mg daily in HIV per IDSA.	200 mg · PO BID · PO · ≥8 weeks Alternative for fluconazole-resistant or intolerant cases. 200 mg · PO BID · PO · ≥8 weeks Inferior to fluconazole — only if fluconazole contraindicated.	≥8 weeks consolidation	CONSOLIDATION × ≥8 weeks after successful induction. Begins after CSF culture clearance.
Chronic outpatient	200 mg · PO daily · PO · ≥1 year MAINTENANCE / chronic suppression. HIV: continue until CD4 >100 (ideally >200) × 3 months on suppressive ART AND ≥1 year total therapy.	—	≥1 year (HIV: until CD4 immune reconstitution criteria met)	MAINTENANCE phase — secondary prophylaxis. HIV: continue ≥1 year and until CD4 >100 (preferably >200) × ≥3 months on suppressive ART. SOT: per program protocol, often 6–12 months.

4. Directed Therapy

Opening pressure management is critical — mortality tracks ICP:

Measure opening pressure on EVERY LP
If ≥25 cmH2O: drain CSF to <20 cmH2O OR 50% of opening pressure (whichever lower) — don't remove >30 mL per LP without imaging
Repeat LPs daily until pressure <20 cmH2O sustained
Persistent ICP → consider lumbar drain or VP shunt
AVOID corticosteroids except for documented mass effect from cryptococcoma (worse outcomes in CryptoDex trial)
AVOID acetazolamide / mannitol — no role; can worsen outcomes

Repeat LP at 2 weeks to confirm CSF culture clearance — guides transition to consolidation.

Phase transitions (IDSA 2010 / WHO 2022):

Induction × ≥2 weeks (LiAmB + flucytosine)
→ Consolidation × ≥8 weeks (high-dose fluconazole)
→ Maintenance × ≥1 year (low-dose fluconazole; HIV: until CD4 >100 × ≥3 months on ART)

Ophthalmologic exam for papilledema, optic nerve involvement.

5. Monitoring

Resolution: clinical improvement (headache, mental status), CSF culture clearance at 2 weeks, opening pressure normalization.

Toxicity (induction):

Liposomal amphotericin B: BMP daily (Cr, K, Mg — replete aggressively); pre-medicate for rigors with acetaminophen + diphenhydramine
Flucytosine: BMP, CBC daily (cytopenia, transaminitis); peak level 30–80 mg/L; reduce dose for renal impairment

Toxicity (consolidation/maintenance):

Fluconazole: LFTs; QTc; CYP interactions (warfarin, tacrolimus, sirolimus)

Pearls

3-PHASE THERAPY:

Induction × ≥2 weeks: LiAmB 3–4 mg/kg + flucytosine 25 mg/kg PO q6h
Consolidation × ≥8 weeks: fluconazole 400–800 mg PO daily
Maintenance × ≥1 year: fluconazole 200 mg PO daily

OPENING PRESSURE MANAGEMENT is co-equal with antifungals — serial LPs / drain / shunt; mortality follows ICP.

HIV: DELAY ART 4–6 WEEKS after antifungal start (COAT trial — early ART caused worse mortality).

No corticosteroids for crypto meningitis (CryptoDex trial showed worse outcomes) — except for mass effect from cryptococcoma.

C. gattii (Pacific Northwest) more virulent in immunocompetent hosts; may form cryptococcomas requiring longer therapy.

Symptomatic relapse: re-induction with LiAmB + flucytosine; check fluconazole adherence + level; consider resistance testing.

Serum CrAg screening in advanced HIV (CD4 <100) — pre-emptive fluconazole 400–800 mg if asymptomatic CrAg+ without meningeal signs.

References

IDSA Cryptococcus Guidelines (2010)
WHO Guidelines for the Diagnosis, Prevention and Management of Cryptococcal Disease in HIV-Infected Adults, Adolescents and Children (2022)
COAT Trial — Boulware et al., NEJM (2014)
CryptoDex Trial — Beardsley et al., NEJM (2016)