Isavuconazole is Effective for the Treatment of Experimental Cryptococcal Meningitis

L. K. Najvar 1,2, N. P. Wiederhold1, R. Bocanegra1,2, M. Olivo1,2, W. R. Kirkpatrick1,2, T. F. Patterson1,2; 1UTHSCSA, San Antonio, TX, 2STVHCS, San Antonio, TX

Abstract: 

Background: Cryptococcal meningitis (CM) remains a significant cause of morbidity and mortality in HIV/AIDS patients and other highly immunocompromised groups, including solid organ transplant recipients. Mortality secondary to CM remains unacceptably high even with appropriate antifungal therapy. Isavuconazole (ISA) is an investigational triazole with potent in vitro activity against many fungi, including Cryptococcus spp., and has been shown to be efficacious in different animal models of invasive mycoses, including invasive candidiasis, invasive aspergillosis, and mucormycosis. Our objective was to evaluate the in vivo effectiveness of ISA for the treatment of CM. Methods: ICR mice were inoculated intracranially with C. neoformans USC 1597 (ISA MIC < 0.03 μg/mL, fluconazole [FLU] MIC 0.5 μg/mL). Treatment with oral ISA (120 & 240 mg/kg BID for clinically achievable concentrations), oral FLU (20 & 40 mg/kg BID as a positive control), or placebo control began 1 day later. In the fungal burden arm (N = 10 mice/group), treatment continued for 7 days, and brain tissue was collected on day 8. In the survival arm (N = 10 mice/group) treatment continued until day 10 after which mice were monitored off therapy until day 30. Fungal burden was assessed by colony-forming units per gram of tissue (CFU/g). Survival was assessed by Kaplan-Meier analysis and differences in brain tissue fungal burden were assessed for significance by ANOVA. Results: Treatment with ISA resulted in a marked survival benefit. Median survival was significantly improved with both doses of ISA (28 days & >30 days) compared to control (15 days; p = 0.0002). Percent survival was also significantly improved with ISA 240 mg/kg compared to control (70% vs. 0%; p = 0.0031). Similar results were also observed with FLU (>30 days & 60% survival with both doses). Each dose of ISA and FLU also significantly reduced brain tissue fungal burden (ISA 2.87 & 1.60 log CFU/g; FLU 2.10 & 2.11 log CFU/g) compared to control (6.58 log CFU/g; p < 0.0001). Conclusions: ISA was effective as treatment in this murine model of CM. Both significant improvements in survival and reductions in fungal burden were observed with this investigational triazole. These data demonstrate the potential utility of ISA in the treatment of CM.

2014

abstract No: 

M-427

Full conference title: 

54th Interscience Conference of Antimicrobial Agents and Chemotherapy
    • ICAAC 54th (2014)