{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T09:54:25Z","timestamp":1775901265278,"version":"3.50.1"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T00:00:00Z","timestamp":1659657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Crestone, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Listeriosis is an orphan disease, which is nevertheless fatal in immunocompromised people. CRS0540 is a novel PolC DNA polymerase inhibitor that has demonstrated good in vitro and in vivo activity against Listeria monocytogenes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Rodent-to-human allometry projection-based human population pharmacokinetics of CRS0540 were used for all studies. CRS0540 pharmacokinetics\/pharmacodynamics studies in an intracellular hollow-fibre system model of disseminated listeriosis (HFS-Lister) examined the effect of eight treatment doses, administered daily over 7\u2005days, in duplicate units. Total bacterial burden versus AUC\/MIC exposures on each day were modelled using the inhibitory sigmoid Emax model, while CRS0540-resistant bacterial burden was modelled using a quadratic function. Ten thousand-subject Monte Carlo simulations were used to predict an optimal clinical dose for treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The mean CRS0540 intracellular\/extracellular AUC0\u201324 ratio was 34.07 (standard error: 15.70) as measured in the HFS-Lister. CRS0540 demonstrated exposure-dependent bactericidal activity in the HFS-Lister, with the highest exposure killing approximately 5.0\u2005log10\u2005cfu\/mL. The free drug AUC0\u201324\/MIC associated with 80% of maximal kill (EC80) was 36.4. Resistance emergence versus AUC\/MIC was described by a quadratic function, with resistance amplification at an AUC\/MIC of 54.8 and resistance suppression at an AUC\/MIC of 119. Monte Carlo simulations demonstrated that for the EC80 target, IV CRS0540 doses of 100\u2005mg\/kg achieved PTAs of &amp;gt;90% at MICs up to 1.0\u2005mg\/L.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>CRS0540 is a promising orphan drug candidate for listeriosis. Future PK\/PD studies comparing it with penicillin, the standard of care, could lead to this drug as a new treatment in immunocompromised patients.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkac269","type":"journal-article","created":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T07:30:33Z","timestamp":1659684633000},"page":"2876-2885","source":"Crossref","is-referenced-by-count":4,"title":["Potency of the novel PolC DNA polymerase inhibitor CRS0540 in a disseminated <i>Listeria monocytogenes<\/i> intracellular hollow-fibre model"],"prefix":"10.1093","volume":"77","author":[{"given":"Swati","family":"Patel","sequence":"first","affiliation":[{"name":"Hollow Fiber System & Experimental Therapeutics Laboratories, Praedicare Inc. , Dallas, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moti","family":"Chapagain","sequence":"additional","affiliation":[{"name":"Hollow Fiber System & Experimental Therapeutics Laboratories, Praedicare Inc. , Dallas, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clifford","family":"Mason","sequence":"additional","affiliation":[{"name":"Crestone, Inc. , Boulder, CO , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Gingrich","sequence":"additional","affiliation":[{"name":"Crestone, Inc. , Boulder, CO , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shruti","family":"Athale","sequence":"additional","affiliation":[{"name":"Hollow Fiber System & Experimental Therapeutics Laboratories, Praedicare Inc. , Dallas, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy","family":"Ribble","sequence":"additional","affiliation":[{"name":"Crestone, Inc. , Boulder, CO , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Hoang","sequence":"additional","affiliation":[{"name":"Crestone, Inc. , Boulder, CO , 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