What is the recommended treatment for Candida auris central nervous system (CNS) infection using Flucytosine (Flocytosin)?

Treatment of Candida auris CNS Infection with Flucytosine

For Candida auris CNS infections, initiate combination therapy with liposomal amphotericin B (3-5 mg/kg daily) plus flucytosine (25 mg/kg orally four times daily), continuing for several weeks until clinical and CSF improvement, followed by step-down therapy with high-dose fluconazole (400-800 mg daily) if susceptible. 1, 2

Initial Combination Therapy

Flucytosine must always be combined with amphotericin B—never use it as monotherapy due to rapid resistance emergence. 2 The rationale for this combination is compelling:

• Flucytosine achieves excellent CSF penetration, making it ideal for CNS infections 1
• In vitro synergism exists between amphotericin B and flucytosine against Candida species, including C. auris 1, 3
• Liposomal amphotericin B is preferred over conventional amphotericin B deoxycholate due to decreased nephrotoxicity risk while maintaining superior brain tissue penetration 1

Dosing and Monitoring Requirements

Standard flucytosine dosing is 25 mg/kg orally four times daily for patients with normal renal function 1, 2:

• Mandatory renal dose adjustment is required as flucytosine is primarily renally excreted 2
• Therapeutic drug monitoring is essential, targeting serum levels of 40-60 mg/mL to minimize concentration-dependent toxicity 2
• Monitor for bone marrow suppression, particularly when combined with amphotericin B 1

Critical Limitation: Oral-Only Formulation

A major pitfall is that flucytosine is only available as an oral formulation in the United States, limiting use in patients unable to take oral medications 2. For such patients, consider:

• Alternative combination regimens with echinocandins plus amphotericin B
• Nasogastric/orogastric tube administration if feasible
• Intraventricular antifungal administration for refractory cases 4

Device Management

Remove all infected CNS devices (ventriculoperitoneal shunts, ventriculostomy drains, stimulators) whenever possible 1, 5:

• Device removal combined with systemic antifungal therapy is strongly recommended 1
• Successful treatment of C. auris ventriculitis has been documented with device removal plus liposomal amphotericin B and flucytosine 5
• For devices that cannot be removed, consider intraventricular antifungal administration 1, 4

Treatment Duration and Step-Down Therapy

Continue initial combination therapy for several weeks until the patient demonstrates clinical improvement and CSF normalization 1:

• Transition to fluconazole (400-800 mg daily) as step-down therapy after initial response, provided the isolate is fluconazole-susceptible 1
• Total therapy duration continues until complete resolution of all signs, symptoms, CSF abnormalities, and radiologic abnormalities 1
• This typically requires at least 6 weeks of total antifungal therapy 1

C. auris-Specific Considerations

While IDSA guidelines do not specifically address C. auris CNS infections, the combination of liposomal amphotericin B plus flucytosine remains the recommended approach 2:

• Flucytosine shows broad activity against most Candida species, with C. auris generally susceptible 2, 3
• In vitro studies demonstrate no antagonism between flucytosine and amphotericin B, micafungin, or voriconazole against C. auris 3
• Case reports document successful treatment of C. auris CNS infections with this combination 5

Alternative Strategies for Refractory Cases

If systemic therapy with amphotericin B and flucytosine fails:

• Intraventricular caspofungin (10 mg daily) has been used successfully in combination with systemic voriconazole for multidrug-resistant C. auris shunt infection 4
• Triple combination therapy with anidulafungin, amphotericin B, and flucytosine has been reported for severe C. auris infections 6
• Anidulafungin combined with flucytosine shows synergistic activity (FICI 0.36-1.02) against both resistant and susceptible C. auris isolates 7

Key Pitfalls to Avoid

• Never use flucytosine monotherapy—resistance develops rapidly 2
• Do not forget renal dose adjustment—flucytosine toxicity is concentration-dependent 2
• Do not rely on echinocandins alone for CNS infections—poor CNS penetration with documented breakthrough infections 1
• Do not assume oral flucytosine is feasible—have a backup plan for patients who cannot take oral medications 2