Efficacy of nikkomycin Z in murine CNS coccidioidomycosis: modelling sustained-release dosing

Abstract

Objectives Meningitis is the most feared coccidioidomycosis complication. Nikkomycin Z (nikZ) is a chitin synthase inhibitor. A concern is short half-life, necessitating multiple dose/day regimens. We simulated extended release, providing nikZ in drinking water. Extended release would enhance convenience, and adherence, for patients. Methods Coccidioides posadasii was injected intracerebrally into mice. Twelve day treatments began on Day 3. Fluconazole was given 100 mg/kg once daily (gavage); designed doses of nikZ 30, 100 or 300 mg/kg/day in drinking water. On Day 30 post-treatment, survivors were euthanized, brain cfu quantitated and cfu in other organs assessed. Results nikZ was stable in drinking water. Survival was 11%, 50%, 70%, 90% and 100% in untreated controls, fluconazole and nikZ 30, 100 and 300 mg/kg/day, respectively ; nikZ 300 mg/kg/day was superior (P ≤ 0.01) to fluconazole. Brains were sterilized in 0%, 20%, 86%, 89% and 80% of mice, respectively; nikZ 100 or 300 mg/kg/day was superior (P ≤ 0.01) to fluconazole. Clearance of infection in other organs was similar. All decreased drinking after infection, causing nikZ mice to ingest less than the desired dose in early therapy; despite this, they recovered sufficiently to resume pre-infection drinking and designed drug intakes. Thus, when sickest, even less than the designed dose was sufficient to enable recovery. Conclusions This efficacy supports the development of sustained-release nikZ. Decreased intake wouldn’t be a factor in humans, receiving drug via extended-release pill or continuous IV infusion. In prior studies (twice daily nikZ) of murine coccidioidal meningitis, results were inferior, suggesting sustained release may provide both convenience and superior outcomes.

Continuous dosing of nikkomycin Z against systemic candidiasis, in vivo and in vitro correlates

“…Taken together, the findings might suggest NIKZ may be particularly useful in renal fungal infections. Studies in other models have also indicated NIKZ efficacy in other organs, including lung and brain 5,6,28,36 …”

“…Studies in other models have also indicated NIKZ efficacy in other organs, including lung and brain. 5,6,28,36 A second possible factor relates to candidal physiology and the mechanism of action of NIKZ. Mycelial formation is one virulence factor for C. albicans, and occurs in tissue.…”

Diagnosis and Treatment of Pulmonary Coccidioidomycosis and Paracoccidioidomycosis

“…Promising results were observed in a phase II study of dogs with CM. However, well-designed clinical trials are not available to confirm its effectiveness and safety profile in patients with CM [ 72 , 73 , 74 , 75 ].…”

Coccidioidomycosis Osteoarticular Dissemination

“…The few existing murine studies on the dissemination of coccidioidomycosis have focused on the spleen, lungs, liver, kidneys, and brain. These include studies of the immune response to systemic C. immitis infection of the lungs, spleen, and liver [67], C. immitis tissue invasiveness in lungs, liver, spleen, and kidneys [68] as well as the drug efficacy against disseminated coccidioidomycosis in lungs, spleen, liver and CNS [69][70][71]. To our knowledge, no investigation using rodent animal models has been performed to study the dissemination of coccidioidomycosis to bones and joints.…”