{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:03:16Z","timestamp":1777611796733,"version":"3.51.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The emergence and spread of antimicrobial resistance in <jats:italic>Neisseria gonorrhoeae<\/jats:italic> is seriously threatening the treatment and control of gonorrhea globally. Novel treatment options are essential, coupled with appropriate methods to pharmacodynamically examine the efficacy and resistance emergence of these novel drugs. Herein, we used our dynamic <jats:italic>in vitro<\/jats:italic> hollow fiber infection model (HFIM) to evaluate protein-unbound lefamulin, a semisynthetic pleuromutilin, against <jats:italic>N. gonorrhoeae<\/jats:italic>. Dose\u2013range and dose\u2013fractionation experiments with <jats:italic>N. gonorrhoeae<\/jats:italic> reference strains: WHO F (susceptible to all relevant antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone resistance), and WHO V (high-level azithromycin resistant, and highest gonococcal MIC of lefamulin (2\u00a0mg\/l) reported), were performed to examine lefamulin gonococcal killing and resistance development during treatment. The dose\u2013range experiments, simulating a single oral dose of lefamulin based on human plasma concentrations, indicated that \u22651.2\u00a0g, \u22652.8\u00a0g, and \u22659.6\u00a0g of lefamulin were required to eradicate WHO F, X, and V, respectively. Dose\u2013fractionation experiments, based on human lefamulin plasma concentrations, showed that WHO X was eradicated with \u22652.8\u00a0g per day when administered as q12\u00a0h (1.4\u00a0g twice a day) and with \u22653.6\u00a0g per day when administered as q8 h (1.2\u00a0g thrice a day), both for 7\u00a0days. However, when simulating the treatment with 5\u201310 times higher concentrations of free lefamulin in relevant gonorrhea tissues (based on urogenital tissues in a rat model), 600\u00a0mg every 12\u00a0h for 5\u00a0days (approved oral treatment for community-acquired bacterial pneumonia) eradicated all strains, and no lefamulin resistance emerged in the successful treatment arms. In many arms failing single or multiple dose treatments for WHO X, lefamulin-resistant mutants (MIC = 2\u00a0mg\/l), containing an A132V amino acid substitution in ribosomal protein L3, were selected. Nevertheless, these lefamulin-resistant mutants demonstrated an impaired biofitness. In conclusion, a clinical study is warranted to elucidate the clinical potential of lefamulin as a treatment option for uncomplicated gonorrhea (as well as several other bacterial STIs).<\/jats:p>","DOI":"10.3389\/fphar.2022.1035841","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T05:27:58Z","timestamp":1668403678000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Pharmacodynamic evaluation of lefamulin in the treatment of gonorrhea using a hollow fiber infection model simulating Neisseria gonorrhoeae infections"],"prefix":"10.3389","volume":"13","author":[{"given":"Susanne","family":"Jacobsson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Golparian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joakim","family":"Oxelbark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang W.","family":"Wicha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renata Maria Augusto","family":"da Costa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois","family":"Franceschi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Brown","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnold","family":"Louie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven P.","family":"Gelone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Drusano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magnus","family":"Unemo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1001\/jama.2019.15468","article-title":"Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: The LEAP 2 randomized clinical trial","volume":"322","author":"Alexander","year":"2019","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","first-page":"4304","DOI":"10.1128\/JCM.05341-11","article-title":"Differing Neisseria gonorrhoeae bacterial loads in the pharynx and rectum in men who have sex with men: Implications for gonococcal detection, transmission, and control","volume":"49","author":"Bissessor","year":"2011","journal-title":"J. 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