A 28-year-old woman with HIV infection (CD4 count 45 cells/μL, viral load 180,000 copies/mL) presents with headache, fever, and meningeal signs. CSF analysis shows elevated protein (120 mg/dL), low glucose (35 mg/dL), and India ink stain is positive for Cryptococcus neoformans. What is the drug of choice for induction therapy of cryptococcal meningitis?

## Induction Therapy for Cryptococcal Meningitis **Key Point:** Amphotericin B deoxycholate (AmB-d) combined with flucytosine is the gold-standard induction regimen for cryptococcal meningitis (CM) in HIV patients with CD4 < 100 cells/μL, regardless of disease severity. ### Induction Phase (2 Weeks) **Amphotericin B deoxycholate:** - **Dose:** 0.7–1.0 mg/kg IV daily - **Mechanism:** Binds ergosterol in fungal cell membrane; fungicidal - **CSF penetration:** ~20% (adequate for meningitis) - **Monitoring:** Renal function, electrolytes, CBC (baseline and 2–3 times weekly) **Flucytosine (5-FC):** - **Dose:** 100 mg/kg/day in 4 divided doses (25 mg/kg QID) - **Mechanism:** Converted to 5-fluorouracil; inhibits fungal DNA/RNA synthesis - **CSF penetration:** ~80% (excellent) - **Synergy:** Reduces mortality by ~15% when combined with AmB-d vs. AmB-d alone - **Monitoring:** Serum levels (target 25–100 μg/mL), CBC (flucytosine is myelosuppressive) ### Consolidation Phase (8 Weeks) - **Fluconazole:** 400 mg daily (oral or IV) - Transition after 2 weeks of induction if clinical improvement and CSF sterilization ### Maintenance Phase (Until CD4 > 200 for ≥ 3 months) - **Fluconazole:** 200 mg daily ### Comparison of Antifungal Agents | Agent | Role | Limitation | | --- | --- | --- | | **Amphotericin B-d** | Induction (first-line) | Nephrotoxicity, infusion reactions, electrolyte wasting | | **Amphotericin B liposomal** | Induction (if renal impairment) | Cost-prohibitive in resource-limited settings | | **Flucytosine** | Adjunct to AmB-d | Myelosuppression, resistance if used alone | | **Fluconazole** | Consolidation/maintenance | Inadequate for induction monotherapy; resistance if CD4 < 50 | | **Itraconazole** | Not recommended | Poor CSF penetration, variable bioavailability | | **Voriconazole** | Not recommended | No proven benefit over fluconazole; higher toxicity | **High-Yield:** The combination of AmB-d + 5-FC for 2 weeks followed by fluconazole consolidation reduces mortality to ~25% at 10 weeks (vs. ~40% with AmB-d alone or fluconazole monotherapy). **Clinical Pearl:** Flucytosine levels must be monitored to avoid toxicity; peak levels should be 25–100 μg/mL. Baseline and weekly CBC is essential due to myelosuppression risk. **Mnemonic — CM Management:** **AFFC** = **A**mphotericin B + **F**lucytosine (Induction), then **F**luconazole (Consolidation/maintenance). **Warning:** Fluconazole monotherapy is inadequate for induction in CM with CD4 < 100; it has been associated with higher mortality and should only be used in resource-constrained settings as a last resort, or after AmB-d induction is complete. [cite:Harrison 21e Ch 197; WHO Guidelines on Treatment of Cryptococcal Meningitis in HIV-Infected Patients]