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Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Murine infections with most Coccidioides spp. strains are lethal by 3 weeks, limiting the study of immune responses. Coccidioides posadasii, strain 1038 (Cp1038), while slowly lethal, resulted in protracted survival of C57BL/6 (B6) mice. In resistant (B6D2)F1/J mice, lung fungal burdens stabilized by week 4 without progression through week 16, better modeling human coccidioidal infections after their immunologic control. Immunodeficient tumor necrosis factor (Tnf) α knockout (KO) and interferon (Ifn) γ receptor 1 (Ifn-γr1) KO mice survived a median of 22.5 and 34 days, compared with 70 days in B6 mice (P = .001 and P < .01, respectively), though 14-day lung fungal burden studies showed little difference between Ifn-γr1 KO and B6 mice. B6 mice showed peak concentrations of key inflammatory lung cytokines, including interleukin 6, 23, and 17A, Tnf-α, and Ifn-γ, only after 4 weeks of infection. The slower progression in B6 and the acquired fungal burden stability in B6D2 mice after Cp1038 infection greatly increases the array of possible immunologic studies., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Canine coccidioidomycosis, a systemic fungal infection endemic to arid and semiarid regions of North, Central, and South America, is commonly diagnosed in dogs living in or traveling through lower Sonoran life zones in the states of California and Arizona. Canine and human cases have geographic overlap. Similarities between clinical coccidioidomycosis in dogs and humans include asymptomatic infection, primary respiratory disease and disseminated disease. Differences include a high rate of dissemination in dogs, differences in predilection of dissemination sites, and a granulomatous or diffuse meningoencephalopathic form in the canine central nervous system (CNS) without the obstructive component seen in humans. Dogs presenting with CNS coccidioidomycosis most commonly experience seizures. Prior disease history and serology are unreliable indicators of CNS coccidioidomycosis. Magnetic resonance imaging (MRI) is advantageous for diagnosis of CNS coccidioidomycosis in dogs. Long-term administration of antifungal medication is promoted for treatment of both primary and disseminated coccidioidomycosis in dogs. Supportive treatment addressing pain, fever, inappetance, coughing, and other clinical signs improves patient care. Glucocorticoids and or anticonvulsants are also recommended for canine disseminated CNS disease. Protracted treatment times, lack of owner compliance, failure of the disease to respond to the first antifungal drug selected, and high cost are challenges of successfully treating dogs.

Nikkomycin Z (NikZ) is a chitin synthase inhibitor with activity against Coccidioides species that is being developed as a first-in-class orphan product for treatment of coccidioidomycosis. It has previously been shown to reduce lethal respiratory infections in mice to undetectable levels when treatment is begun 48 hours after infection. The studies described here focus on bracketing NikZ doses for phase 2 and 3 clinical trials, using an established mouse respiratory infection as a model and starting treatment 120 hours after infection. A dose of 80 mg/kg/day, divided into 2 doses, nearly eradicated infection, and larger doses did not improve fungal clearance. Increasing the duration of treatment from 1 week to 3 weeks resulted in a greater percentage of culture-negative mice. Comparative data show that plasma levels of NikZ that nearly eradicate Coccidioides in mice are achievable in patients and provide a plausibly effective dose range for initial phase 2 clinical studies., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Nikkomycin Z (NikZ) is a chitin synthase inhibitor with antifungal efficacy against Coccidioides spp. and other endemic fungi. Dogs suffer a rate and range of natural coccidioidomycosis similar to humans and were considered an excellent model for initially testing NikZ against naturally acquired disease. Twelve dogs with coccidioidal pneumonia that had been present for an average of three months were treated with 250 mg (5-15 kg) or 500 mg (> 15-30 kg) twice daily for 60 days. Nine dogs completed the course of treatment and seven dogs had improvement in disease based on radiographs, clinicopathological parameters, physical examination findings, and subjective assessment by owners; three dogs had resolution or near resolution of disease. Based on this small study, NikZ shows efficacy to treat naturally acquired coccidioidomycosis and merits further development for trials in humans.