• Fungal Infections
• Infectious Disease Clinical Trials

• Fungal Infections
• Infectious Disease
• Infectious Disease Clinical Trials

Isavuconazole treatment in patients with Cryptococcus spp infection resulted in an overall response in 6 of 9 patients, some of whom were refractory to prior therapies. F. Queiroz-Telles, MD, PhD, Federal University of Paraná, Curitiba, Brazil, presented data from the Isavuconazole in the Treatment of Renally Impaired Aspergillosis and Rare Fungi study [VICAL; NCT00634049].

Cryptococcosis causes substantial morbidity and mortality in immunocompromised patients; about 650 000 annual deaths worldwide are attributed to Cryptococcus gattii and Cryptococcus neoformans infection [Perfect JR et al. Clin Infect Dis 2010; Harrison TS. AIDS 2009]. Isavuconazole, a broad-spectrum, triazole antifungal agent, has demonstrated antifungal activity against Aspergillus spp, Candida spp, Cryptococcus spp, and Mucorales both in vitro and in animal models [Lepak A et al. Antimicrob Agents Chemother 2013; Lepak A et al. Antimicrob Agents Chemother 2013; Luo G et al. Antimicrob Agents Chemother 2014; Najvar L et al. ICAAC 2014 M-427]. Isavuconazole penetrates the central nervous system (CNS) [Majithiya J et al. J Antimicrob Chemother 2009], an important characteristic for the potential treatment of Cryptococcus spp that frequently infect the CNS [Chang YC et al. Infect Immun 2004]. The purpose of the VICAL trial was to determine the safety and efficacy of isavuconazole treatment in patients with invasive fungal disease (IFD); this analysis specifically evaluated the effect of isavuconazole treatment on Cryptococcus spp infections.

The phase 3, multicenter, open-label VICAL trial assigned 149 patients with IFD to receive isavuconazole (IV or oral) TID for 2 days followed by daily administration (IV or oral) for up to 180 days. Patients age ≥ 18 years were eligible if they had proven or probable IFD according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC-MSG) criteria. The primary end point was complete or partial resolution of clinical symptoms resulting from treatment with isavuconazole in patients with IFD, and the secondary end points included all-cause mortality, safety, and tolerability.

In this analysis, 9 patients with cryptococcosis were treated with isavuconazole, 4 of whom were infected with C. neoformans and 3 with C. gattii. The mean duration of treatment for C. gattii was 179 days and for C. neoformans was 96 days. Three patients had isolated pulmonary disease, and 2 had CNS disease. The other 4 patients had both CNS and pulmonary disease; 2 had additional blood, bone, and tissue disease.

Treatment with isavuconazole resulted in an overall response in 6 out of 9 patients, with 2 patients experiencing a complete response, 4 having a partial response, 2 remaining stable, and 1 experiencing progression of cryptococcosis (Table 1). In addition, a patient infected with C. gattii, in whom previous antifungal treatment failed, experienced a partial response.

Treatment-emergent adverse events included infections such as herpes zoster, bacteremia, septic shock, staphylococcal pneumonia, upper respiratory tract infection, sinusitis, and urinary tract infection, as well as gastrointestinal disorders such as constipation, nausea, and vomiting. All-cause mortality was 11% (1 patient out of 9) at days 42 and 84. Death occurred in a patient who had disseminated infection with C. neoformans and was intolerant to previous treatment with fluconazole and liposomal amphotericin.

In conclusion, these data suggest that isavuconazole treatment was effective in a small population of patients with Cryptococcus spp infections. Further studies are warranted to evaluate isavuconazole in a larger population.

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