{"id":176,"date":"2023-06-25T10:02:58","date_gmt":"2023-06-25T09:02:58","guid":{"rendered":"https:\/\/microregistrar.com\/?p=176"},"modified":"2023-06-25T10:02:58","modified_gmt":"2023-06-25T09:02:58","slug":"lefamulin","status":"publish","type":"post","link":"https:\/\/microregistrar.com\/?p=176","title":{"rendered":"Lefamulin"},"content":{"rendered":"\n<h3 class=\"wp-block-heading\"><strong>Nature of the antibiotic<\/strong><\/h3>\n\n\n\n<p>Semi-synthetic, pleuromutilin class.<br>Molecular weight \u2013 567.79 gm\/mole<\/p>\n\n\n\n<h2 class=\"wp-block-heading\">Pleuromutilins<\/h2>\n\n\n\n<p>Pleuromutilins (produced by Pleurotus sp.), discovered in the 1950s, have a&nbsp;tricyclic mutilin core.<br>Tiamulin \u2013 the first member of this group, was approved for veterinary use in 1979.<br>Retapamulin \u2013 topical pleuromutilin was approved for human use in 2007.<\/p>\n\n\n\n<figure class=\"wp-block-image\"><img decoding=\"async\" src=\"https:\/\/microregistrar.com\/wp-content\/uploads\/2021\/07\/220px-Pleuromutilin.svg_.png\" alt=\"\" class=\"wp-image-6468\"\/><\/figure>\n\n\n\n<h3 class=\"wp-block-heading\">Mechanism of action<\/h3>\n\n\n\n<p><strong>It inhibits protein synthesis by preventing the binding of tRNA for peptide transfer.<\/strong><\/p>\n\n\n\n<p>It interacts with the A- and P-sites of the peptidyl transferase centre in domain V of the 23s rRNA of the<br>50S subunit. It interacts by hydrogen bonds, hydrophobic interactions, and Van der Waals forces.<\/p>\n\n\n\n<figure class=\"wp-block-image\"><img decoding=\"async\" src=\"https:\/\/microregistrar.com\/wp-content\/uploads\/2021\/07\/image-6.jpeg\" alt=\"Amino acids attached to the tRNA on P site(' ) is forming a link with the amino acid ( O)attached \nto the tRNA on A site (chain elongation process of the protein synthesis) \ntRNA is leaving \ne site after the \namino acid(O) \nincorporation in \nthe peptide \nchain \nmRNA \nProtein (peptide) \nchain \nE \nP \nAmino \nacid \nAminoacyl \n-tRNA \n50S ribosomal \nsubunit \n30S ribosomal \nsubunit \nOnce the link between 'and O \nhas been established the current A site will become the NEW P site. The tRNA with 'will leave. \nA new tRNA with another amino acid \u2022 will attach to the NEW A site \"\/><\/figure>\n\n\n\n<h3 class=\"wp-block-heading\">Mechanism of resistance<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Protection or modification of the ribosomal target: by ABC-F proteins such as vga (A, B, E), lsa(E), sal(A), Cfr methyl transferase,<\/li>\n\n\n\n<li>Mutations of ribosomal proteins L3 and L4<\/li>\n<\/ul>\n\n\n\n<p>There is potential for cross-resistance with chloramphenicol, lincosamides, oxazolidinones, and<br>streptogramin A.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\">PK\/PD<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Best PK-PD index \u2013 The 24\u202fh free-drug AUC to minimal inhibitory concentration (MIC) ratio.<\/li>\n\n\n\n<li>oral bioavailability \u2013 25%<\/li>\n\n\n\n<li>Food (esp high fat, high calorie) reduce bioavailability \u2013 tablets should be taken 1 hour before or 2 hours after food.<\/li>\n\n\n\n<li>Plasma protein binding &gt;\/= 95%<\/li>\n\n\n\n<li>T1\/2 (in patients with community-acquired bacterial pneumonia patients \u2013 8 hours.<\/li>\n\n\n\n<li>Lefamulin is primarily metabolized by CYP3A4.<\/li>\n\n\n\n<li>Hepatic impairment: IV \u2013 dose reduction in severe liver derangement (Child-Pugh C); PO \u2013 not recommended in moderate-severe (Child-Pugh B and C).<\/li>\n\n\n\n<li>Excretion \u2013 mainly in faeces (&gt;705), and urine (approx 15%)<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Use<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>FDA approval in 2019 to treat adults with community-acquired bacterial pneumonia (caused by Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumonia).<\/li>\n\n\n\n<li><strong>Other potential use<\/strong>s&nbsp;(<a href=\"https:\/\/www.nabriva.com\/pipeline-research\">trial, as per the manufacturer Nabriva<\/a>) \u2013 Acute bacterial skin and skin structure infections (ABSSSI), sexually transmitted infections (STIs), ventilator-associated bacterial pneumonia (VABP), hospital-acquired bacterial pneumonia (HABP), osteomyelitis, and prosthetic joint infections.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Adverse effect<\/h3>\n\n\n\n<p>Gastrointestinal adverse effects (diarrhoea, nausea, vomiting), administration site reactions, hepatic enzyme elevation, hypokalemia, insomnia, headache, QT Prolongation.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\">Caution\/contraindication<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Avoid use in patients with known QT prolongation, ventricular arrhythmias including torsades de pointes, and patients receiving drugs that prolong the QT interval.<\/li>\n\n\n\n<li>May cause fetal harm (Females of reproductive age may need effective contraception).<\/li>\n\n\n\n<li>C difficile-associated diarrhoea.<\/li>\n\n\n\n<li>Avoid in hypersensitivity to lefamulin\/Pleuromutilin.<\/li>\n\n\n\n<li>Avoid concurrent use with strong or moderate CYP3A inducers or P-gp inducers.<\/li>\n\n\n\n<li>Avoid concurrent use of Lefamulin tablets with strong CYP3A inhibitors or P-gp inhibitors.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Spectrum<\/h3>\n\n\n\n<p>Gram-positive: Methicillin sensitive Staph aureus (Not MRSA \u2013 not evaluated), Streptococcus pneumonia.<br>Gram-negative: H influenzae<br>Atypicals: Mycoplasma pneumonia, Chlamydophila pneumonia, Legionella pneumophila.<br><br>It is not active against Enterobacteriaceae and Pseudomonas aeruginosa.<br>The safety and efficacy have not been assessed in the trial for \u2013 group A Streptococcus, group B Streptococcus, alpha haemolytic Streptococcus, MRSA.<br>It is bacteriostatic against MSSA and group A Streptococcus; bacteriocidal against S. pneumoniae, H. influenzae and M. pneumoniae.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\">Papers\/ref:<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><a href=\"https:\/\/www.nature.com\/articles\/srep39004\">https:\/\/www.nature.com\/articles\/srep39004<\/a><\/li>\n\n\n\n<li><a href=\"https:\/\/academic.oup.com\/cid\/article\/69\/11\/1856\/5306243?searchresult=1\">https:\/\/academic.oup.com\/cid\/article\/69\/11\/1856\/5306243?searchresult=1<\/a><\/li>\n\n\n\n<li><a href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02559310?cond=lefamulin&amp;draw=2&amp;rank=2\">LEAP \u2013&nbsp;Study to Compare Lefamulin to Moxifloxacin (With or Without Linezolid) for the Treatment of Adults With Pneumonia<\/a><\/li>\n\n\n\n<li><a href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02813694\">LEAP2 \u2013&nbsp;Study to Compare Lefamulin to Moxifloxacin for the Treatment of Adults With Pneumonia<\/a><\/li>\n\n\n\n<li><a href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02557789?cond=lefamulin&amp;draw=2&amp;rank=3\">Bioavailability and Pharmacokinetics of Lefamulin When Administered to Fed and Fasted Healthy Subjects<\/a><\/li>\n<\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Nature of the antibiotic Semi-synthetic, pleuromutilin class.Molecular weight \u2013 567.79 gm\/mole Pleuromutilins Pleuromutilins (produced by Pleurotus sp.), discovered in the [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":177,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center 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