{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T14:24:22Z","timestamp":1763389462081,"version":"3.37.3"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T00:00:00Z","timestamp":1626393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Valley Fever Americas Foundation of Bakersfield"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Coccidioides posadasii was injected intracerebrally into mice. Twelve day treatments began on Day 3. Fluconazole was given 100\u200amg\/kg once daily (gavage); designed doses of nikZ 30, 100 or 300\u2009mg\/kg\/day in drinking water. On Day 30 post-treatment, survivors were euthanized, brain cfu quantitated and cfu in other organs assessed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>nikZ was stable in drinking water. Survival was 11%, 50%, 70%, 90% and 100% in untreated controls, fluconazole and nikZ 30, 100 and 300\u2009mg\/kg\/day, respectively ; nikZ 300\u2009mg\/kg\/day was superior (P\u2009\u2264\u20090.01) to fluconazole. Brains were sterilized in 0%, 20%, 86%, 89% and 80% of mice, respectively; nikZ 100 or 300\u2009mg\/kg\/day was superior (P\u2009\u2264\u20090.01) 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This efficacy supports the development of sustained-release nikZ. Decreased intake wouldn\u2019t 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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkab223","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T19:11:59Z","timestamp":1623438719000},"page":"2629-2635","source":"Crossref","is-referenced-by-count":14,"title":["Efficacy of nikkomycin Z in murine CNS coccidioidomycosis: modelling sustained-release dosing"],"prefix":"10.1093","volume":"76","author":[{"given":"Gabriele","family":"Sass","sequence":"first","affiliation":[{"name":"California Institute for Medical Research, San Jose, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J","family":"Larwood","sequence":"additional","affiliation":[{"name":"California Institute for Medical Research, San Jose, CA, USA"},{"name":"Valley Fever Solutions, Tucson, AZ, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marife","family":"Martinez","sequence":"additional","affiliation":[{"name":"California Institute for Medical Research, San Jose, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6490-0804","authenticated-orcid":false,"given":"Pallabi","family":"Shrestha","sequence":"additional","affiliation":[{"name":"California Institute for Medical Research, San Jose, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A","family":"Stevens","sequence":"additional","affiliation":[{"name":"California Institute for Medical Research, San Jose, CA, USA"},{"name":"Division of Infectious Diseases and Geographic Medicine, Stanford University Medical School, Stanford, CA, 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