What is the recommended treatment for Central Nervous System (CNS) aspergillosis?

CNS Aspergillosis Treatment

Voriconazole is the first-line treatment for CNS aspergillosis, with surgical resection strongly recommended as an adjunct whenever feasible to improve survival. 1, 2

Primary Treatment Regimen

Voriconazole should be initiated immediately using the following dosing protocol 1, 3:

• Loading dose: 6 mg/kg IV every 12 hours for the first 24 hours 1, 3
• Maintenance dose: 4 mg/kg IV every 12 hours for minimum 7 days 1, 3
• Oral transition: 200-300 mg PO every 12 hours once clinically improved and able to tolerate oral intake 1, 3

Therapeutic drug monitoring is mandatory for voriconazole due to variable pharmacokinetics and narrow therapeutic window, ensuring adequate CNS penetration 2, 4

Alternative Primary Therapy

Liposomal amphotericin B (L-AMB) at 3-5 mg/kg/day IV is the preferred alternative when voriconazole is contraindicated or not tolerated 1, 2, 4

Other salvage options include 1:

• Amphotericin B lipid complex (ABLC) 5 mg/kg/day IV 1
• Posaconazole (oral suspension 200 mg TID; tablet 300 mg BID day 1, then 300 mg daily; IV 300 mg BID day 1, then 300 mg daily) 1
• Itraconazole suspension 200 mg PO every 12 hours 1

Surgical Management

Neurosurgical resection is strongly recommended as an adjunct to antifungal therapy and is associated with significantly improved survival (p=0.02) 1, 5

Surgical interventions include 1, 5:

• Craniotomy with abscess resection 5
• Abscess drainage 5
• Debridement of infected tissue 1

Surgery should be performed whenever feasible to prevent neurological deficits and remove infected cerebral tissue 1, 5, 6

Treatment Duration and Monitoring

Long-term therapy measured in months is required for CNS aspergillosis 2, 7

• Continue treatment throughout the immunosuppression period 2, 4
• Treat until complete resolution or stabilization of clinical and radiographic findings 2, 4
• Median duration in clinical studies: 10 days IV followed by 76 days oral therapy 1, 3
• Real-world data suggests median treatment duration of 14 months may be necessary 7

Evidence Supporting Voriconazole

Voriconazole demonstrates superior outcomes compared to amphotericin B in CNS aspergillosis 1, 3, 5:

• Complete or partial responses achieved in 35% of patients with CNS aspergillosis treated with voriconazole 1, 5
• 31% survival rate with median observation time of 390 days 5
• When combined with neurosurgery, 22% of hematopoietic stem cell transplant patients survived (median 203 days) 5
• Voriconazole penetrates well into the CNS, unlike other antifungal agents 1, 5, 6

Critical Pitfalls and Considerations

CNS aspergillosis carries the highest mortality among all patterns of invasive aspergillosis 1

Monitor for drug interactions with anticonvulsant therapy, as voriconazole has significant interactions with phenytoin and other anticonvulsants commonly used in CNS infections 1, 2

Dose adjustments may be necessary 3:

• Increase voriconazole dose when co-administered with phenytoin or efavirenz 3
• For inadequate response, increase oral maintenance dose from 200 mg to 300 mg every 12 hours 3
• Reduce dose in patients with hepatic impairment 3

Consider the route of CNS infection when planning treatment 1, 8, 6:

• Hematogenous dissemination from pulmonary focus (most common) 8, 6
• Direct extension from paranasal sinus infection 1, 8, 6
• Direct inoculation through trauma or neurosurgery 8, 6

Aggressive management of underlying immunosuppression is critical for favorable outcomes 1