Objective: In 2012, 35 patients in Southwest Virginia, USA were diagnosed with fungal meningitis after receiving an epidural corticosteroid injection from a contaminated lot. Most patients received either amphotericin or voriconazole for the course of therapy. Two patients, however, had treatment failures and considerable tolerance concerns with available therapies. Emergency use was obtained from the US Food and Drug Administration for Isavuconazole, an investigational triazole in Phase 3 clinical trials.
Methods: Both patients received Isavuconazole orally, after failing other regimens. Clinical signs and symptoms and serial analyses of CSF samples for infection markers (WBC and protein) were used to guide therapy. Serum and CSF specimens were saved from multiple time points for drug level analysis by Astellas Pharma US,Inc.
Results: Patient 1, 45 years old, was diagnosed with fungal meningitis/arachnoiditis complicated by spinal hardware. Therapy failed with both liposomal amphotericin and voriconazole due to lack of improvement and poor tolerance of adverse effects. Itraconazole failure was determined by progression of disease based on CSF analysis despite therapeutic drug levels. Isavuconazole was initiated at the manufacturer recommended standard dose (200mg Q24H). After disease progression on CSF analysis, the dose was increased to 600mg Q24H with subsequent improvement. Facial numbness developed after a month at this dose, and resolved rapidly when the dose was decreased to 400mg Q24H. Dosing was further decreased to 300mg and 200mg Q24H after continued improvement was demonstrated on CSF analysis. Patient 1 had an 18 month total course of therapy, of which 9 months were Isavuconazole. Patient 2, 82 years old, was diagnosed with fungal meningitis/arachnoiditis and began therapy on voriconazole, but was switched to amphotericin following clinical progression of disease. Isavuconazole was initiated at the standard dosage following months of poor amphotericin tolerance. Patient 2 had a 17 month total course of therapy, of which the final 4 months were Isavuconazole. Table 1 demonstrates serum and CSF levels chronologically for both patients at all doses.
Conclusions: Isavuconazole was an effective therapy in the treatment of fungal meningitis associated with contaminated epidural steroid injections. Despite low CSF levels compared to serum level, patients experienced resolution of infection with no evidence of recrudescence. Both patients successfully finished therapy and have follow-up CSF analyses at 1, 3, and 6 months post treatment. Isavuconazole was well tolerated at recommended dosing; adverse effects were experienced at 3x the standard dose.