{"id":201,"date":"2023-06-25T11:13:20","date_gmt":"2023-06-25T10:13:20","guid":{"rendered":"https:\/\/microregistrar.com\/?p=201"},"modified":"2023-06-25T11:13:21","modified_gmt":"2023-06-25T10:13:21","slug":"daptomycin","status":"publish","type":"post","link":"https:\/\/microregistrar.com\/?p=201","title":{"rendered":"Daptomycin"},"content":{"rendered":"\n<p>Class:&nbsp;Cyclic lipopeptide<br>Source:&nbsp;Streptomyces roseosporus<br>Discovered: 1980s; approved for use in 2003 (FDA)<br>Molecular weight: 1620 DA.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Mechanism of action:<\/strong><\/h3>\n\n\n\n<p>The Daptomycin (DAP) combines with Calcium ions to form a positively charged complex that attaches to the bacterial cell membrane (preferably at the nascent septa). This attachment depends upon the presence of phospholipid phosphatidylglycerol (PG). After attachment, DAP forms oligomers and moves to encroach on the inner side of the membrane. This process requires the presence of cardiolipin inside the cell membrane. The DAP oligomer for pores leads to the movement of ions and depolarization of the cell membrane. This process leads to cell death.<\/p>\n\n\n\n<figure class=\"wp-block-image\"><img decoding=\"async\" src=\"https:\/\/microregistrar.com\/wp-content\/uploads\/2021\/07\/image-4.jpeg\" alt=\"Leakage of ion due to daptomycin, leading to the depolarisation of the cell membrane \nDaptomycin \nOligomerisation \nCell membrane \nChannel \nformation \" class=\"wp-image-6442\"\/><\/figure>\n\n\n\n<p>Another theory suggests that DAP attachment leads to a\u00a0lipid-extracting effect.\u00a0Lipid-peptide aggregates exude from the cell membrane disrupting the cell membrane structure. [<a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4966536\/\">Tran, 2015<\/a>]<\/p>\n\n\n\n<p><strong>Immunomodulatory effect:<\/strong><\/p>\n\n\n\n<p>Daptomycin causes limited\/no bacterial cell lysis. It also impairs cell division. This process leads to a milder inflammatory response\u2014suppression of cytokine response and other proinflammatory responses like macrophage stimulation.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Mechanism of resistance:<\/strong><\/h3>\n\n\n\n<p><em>The emergence of resistance has been associated with the use of lower doses (&lt;\/=6mg\/kg\/day) and high-inoculum infections (endocarditis, abscess) [Tran,2015].\u00a0Phenotypic changes seen in the non-susceptible bacteria are \u2013\u00a0thickened cell wall, aberrant septal placement, increase in relative cell surface positive charge and reduction of the ability of DAP to depolarize the cell membrane. The mechanisms involved are \u2013<\/em><\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>generating a positive charge on the cell membrane to repulse daptomycin<\/li>\n\n\n\n<li>cell envelop stress response \u2013 decrease in PG content of cell membrane, thickening of the cell wall, aberrant septum formation, diverting the daptomycin from its preferred site of action<\/li>\n\n\n\n<li>Increasing the fluidity of the cell membrane<\/li>\n<\/ul>\n\n\n\n<p>See full details here \u2013 including the genes involved in the development of resistance-<\/p>\n\n\n\n<figure class=\"wp-block-table\"><table><tbody><tr><td><strong>Mutation in the&nbsp;<em>mprF<\/em>&nbsp;gene<\/strong><\/td><td>generating positively charged cell membrane phosphatidylglycerol (PG) through lysinylation (L-PG) and translocating the L-PG from the inner to the outer side of the cell membrane. This result in a positive charged outer side of the cell membrane, which repulses the calcium-DAP complex (Bayer 2013).<\/td><\/tr><tr><td><strong>Activation of&nbsp;<\/strong><strong><em>liaFSR&nbsp;<\/em><\/strong><strong>regulatory system<\/strong><\/td><td>This is a cell envelope stress response \u2013 decrease in the PG content of the cell membrane. It also causes thickening of the cell wall and aberrant septum placement. Cross-resistance has been noted with vancomycin and bacitracin. This system may play a role in diverting the DAP from the preferred septal target to other areas of the cell membrane.<\/td><\/tr><tr><td><strong>Overexpression&nbsp;of the&nbsp;dlt&nbsp;operon<\/strong><\/td><td>positively charged amino acid D-alanine is incorporated into&nbsp;teichoic acids in the cell wall, causing positive surface charge and repulsion of DAP.<\/td><\/tr><tr><td><strong>Altered PG\/cardiolipin metabolism<\/strong><\/td><td><strong><em>cls<\/em><\/strong>&nbsp;genes mutation- decreases the level of cardiolipin in the cell membrane&nbsp;<strong><em>pgsA&nbsp;<\/em><\/strong>gene mutation<em>&nbsp;\u2013&nbsp;<\/em>encode for a transferase responsible for PG synthesis. Decreased level of PG in the cell membrane.&nbsp;<strong><em>GdpD<\/em><\/strong>&nbsp;mutation \u2013 potentiate liaFSR mediated resistance in Enterococci.<\/td><\/tr><tr><td><strong>Increase the thickness of the cell wall; altered homeostasis<\/strong><\/td><td>This mechanism is responsible for vancomycin-intermediate Staph aureus (VISA), often responsible for daptomycin resistance as well.&nbsp;<strong><em>TagA<\/em><\/strong>&nbsp;mediated \u2013 responsible for the synthesis of teichoic acid.&nbsp;<strong><em>RpoB<\/em><\/strong>&nbsp;mutation \u2013 also plays a part in hVISA.&nbsp;<strong><em>yycFG<\/em>&nbsp;[<em>walKR<\/em>]<\/strong>&nbsp;and&nbsp;<strong><em>vraSR<\/em><\/strong><em>&nbsp;mutation \u2013 thickening of the cell wall, altered homeostasis.<\/em><\/td><\/tr><tr><td><strong>Increase fluidity of the cell membrane<\/strong><\/td><td>e.g. altered&nbsp;staphyloxanthin (carotenoid pigment) in Staph aureus may alter the fluidity resulting in resistance.<\/td><\/tr><tr><td><strong>Loss of&nbsp;an 81&nbsp;kDa&nbsp;membrane protein<\/strong><\/td><td>which acts as a chaperone for&nbsp;daptomycin&nbsp;interaction. (Kaatz&nbsp;2006<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<p><strong>Daptomycin tolerance:<\/strong><\/p>\n\n\n\n<p>Daptomycin tolerance has been noted in-<br>Staph aureus \u2013 due to pitA mutation.<br>Enterococcus \u2013 due to&nbsp;liaF (a part of liaFSR) mutation.<\/p>\n\n\n\n<p><strong>Synergy\/Combination therapy:<\/strong><\/p>\n\n\n\n<p>Daptomycin resistance increases the susceptibility of many organisms to other antibiotics- especially cell wall active antibiotics (see-saw effect). The combination may prevent the development of resistance to daptomycin as well.<br>The mechanism of synergy is not well understood. Beta-lactams may modulate the surface charge of the bacteria to make to susceptible to DAP. It is also reported to be specific for those beta-lactams which use PBP1 and are restricted to a specific genetic mutation in Enterococci (liaFSR).<\/p>\n\n\n\n<p>Following combinations were reported beneficial \u2013<\/p>\n\n\n\n<figure class=\"wp-block-table\"><table><tbody><tr><td>Strep mitis<\/td><td>Daptomycin -gentamicin<\/td><\/tr><tr><td>Staph aureus<\/td><td>Daptomycin-oxacillin\/cloxacillin (MSSA) Daptomycin- gentamicin Daptomycin-Clarithromycin (MRSA) Daptomycin \u2013 rifampicin (MSSA) Daptomycin \u2013 cotrimoxazole Daptomycin- ceftaroline (MRSA) daptomycin -vancomycin (biofilm-forming MRSA) Daptomycin \u2013 fosfomycin \u2013&nbsp;temporary prevention of development of resistance ~7 days.<\/td><\/tr><tr><td>Enterococcus<\/td><td>Daptomycin \u2013 ampicillin (even in DAP R strains,&nbsp;liaFSR+ ), Daptomycin- ceftaroline (VRE), Daptomycin- gentamicin daptomycin-ceftobiprole (VRE) Daptomycin \u2013 ceftriaxone Synergy has been seen with Ertapenem and cefepime as well.<\/td><\/tr><tr><td>Acinetobacter baumannii&nbsp;<\/td><td>Daptomycin \u2013 colistin<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<p><strong>Antagonism<\/strong>&nbsp;(in-vitro) has been reported with the following combination (<a rel=\"noreferrer noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4468720\/\" target=\"_blank\">Hindler 2015<\/a>, Luther 2015)<\/p>\n\n\n\n<figure class=\"wp-block-table\"><table><tbody><tr><td>DAP \u2013 Linezolid<\/td><td>MRSA<\/td><\/tr><tr><td>DAP- Tigecycline<\/td><td>Enterococcus<\/td><\/tr><tr><td>Dap- Rifampicin<\/td><td>Enterococcus<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>PK\/PD<\/strong><\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>IV, Intraperitoneal (Off-label).<\/li>\n\n\n\n<li>Dose based on actual body weight (for comparison to IBW see Ng et al \u2013&nbsp;<a href=\"https:\/\/aac.asm.org\/content\/58\/1\/88\">https:\/\/aac.asm.org\/content\/58\/1\/88<\/a>).<\/li>\n\n\n\n<li>Pregnancy \u2013 category B, no controlled trial (<a href=\"https:\/\/accpjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/phar.1649#:~:text=Daptomycin%20is%20Pregnancy%20Category%20B,may%20be%20safe%20to%20use.\">BookStaver, 2015<\/a>)<\/li>\n\n\n\n<li>AUC\/MIC and Cmax\/MIC correlate with efficacy<\/li>\n\n\n\n<li>Post antibiotic effect \u2013 Staph aureus and Enterococcus (6 hours)<\/li>\n\n\n\n<li>Protein binding \u2013 High (>90%) &amp; reversible.<\/li>\n\n\n\n<li>The volume of distribution \u2013 1L\/kg, small, does not cross cell membrane (restricted to plasma, extracellular fluid).<\/li>\n\n\n\n<li>Excretion \u2013 Kidney.<\/li>\n\n\n\n<li>No interaction with the CYP450 system.<\/li>\n\n\n\n<li>T1\/2 \u2013 8-9 hours.<\/li>\n\n\n\n<li>DAP has no activity in the pulmonary tissue as it is inactivated by the surfactant.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Caution and monitoring:<\/strong><\/h3>\n\n\n\n<p><strong>Check creatinine kinase<\/strong>\u00a0at baseline and weekly [more frequently in patients, who are at a higher risk of myopathy \u2013 renal impairment, dialysis, CK>5 times the upper limit of normal (if prescription deemed necessary) and on drugs which can increase CK (e.g \u00a0HMG-CoA reductase inhibitors, fibrates and ciclosporin etc.; prescription only if benefit >risk)]. If muscle pain develops, CK should be monitored every 2 days and stopped if CK >5 times the UNL.<\/p>\n\n\n\n<p>Should not be prescribed in&nbsp;<strong>children &lt;1 year<\/strong>&nbsp;\u2013 potential&nbsp;muscular, neuromuscular, and\/or nervous systems&nbsp;adverse effects.<\/p>\n\n\n\n<p><strong>Eosinophilic pneumonia<\/strong>&nbsp;\u2013 the patient may develop eosinophilic pneumonia (Fever, dyspnoea, hypoxia, pulmonary infiltrate, organising pneumonia) \u2013 usually 2 weeks after treatment. DAP should be stopped. Treatment is systemic steroid. Other causes of pneumonia should be excluded.<\/p>\n\n\n\n<p><strong>Peripheral neuropathy<\/strong>&nbsp;\u2013 Patients developing signs and symptoms of peripheral neuropathy should stop DAP.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Adverse effects:&nbsp;<\/strong><\/h3>\n\n\n\n<p>Common adverse effects:<\/p>\n\n\n\n<p>Fungal\/Candida infection, UTI, anaemia, anxiety, insomnia, hypo-\/hyper-tension, GI adverse effects, increased liver enzyme, rash, limb pain, increase in CK, infusion site reaction, fever, asthenia.<\/p>\n\n\n\n<p>Serious adverse effects:<\/p>\n\n\n\n<p>Hypersensitivity reaction, angioedema, rhabdomyolysis, eosinophilic pneumonia, DRESS syndrome.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Indication:<\/strong><\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Complicated skin and soft-tissue infections (cSSTI) \u2013 adults and children > 1-year-old.<\/li>\n\n\n\n<li>Adult patients with right-sided infective endocarditis (RIE) due to&nbsp;Staphylococcus aureus.<\/li>\n\n\n\n<li>Staphylococcus aureus&nbsp;bacteraemia associated with RIE or cSSTI \u2013 Adults.<\/li>\n\n\n\n<li>Staphylococcus aureus&nbsp;bacteraemia associated with cSSTI \u2013 Children &gt; 1-year-old.<\/li>\n<\/ul>\n\n\n\n<p>[<a href=\"https:\/\/www.medicines.org.uk\/emc\/product\/177\/smpc%5d\">https:\/\/www.medicines.org.uk\/emc\/product\/177\/smpc]<\/a><\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Spectrum:<\/strong><\/h3>\n\n\n\n<p>It is active on gram-positive bacteria only. No meaningful activity against gram-negative.&nbsp;It also has activity against biofilms of Staph aureus (with rifampicin) and Borrelia burgdorferi (with doxycycline\/cefuroxime).<\/p>\n\n\n\n<figure class=\"wp-block-table\"><table><tbody><tr><td>Staph aureus (MSSA, MRSA, VRSA<\/td><td>Susceptible<\/td><td>MIC\/resistance may be seen in VISA\/hVISA<\/td><\/tr><tr><td>Coagulase-negative Staphylococcus<\/td><td>Susceptible<\/td><td>&nbsp;<\/td><\/tr><tr><td>Streptococcus \u2013 Group A, B, C, G, Strep milleri<\/td><td>Susceptible<\/td><td>penicillin is four times more potent<\/td><\/tr><tr><td>Strep pneumoniae<\/td><td>Susceptible<\/td><td>&nbsp;<\/td><\/tr><tr><td>Viridans Streptococcus<\/td><td>Susceptible<\/td><td>penicillin is four times more potent<\/td><\/tr><tr><td>Enterococcus<\/td><td>Susceptible<\/td><td>Resistance increasing. 10% E faecium resistant, VRE may have high MIC<\/td><\/tr><tr><td>Anaerobic gram-positive organism<\/td><td>Susceptible<\/td><td>&nbsp;<\/td><\/tr><tr><td>Corynebacterium<\/td><td>Susceptible<\/td><td>&nbsp;<\/td><\/tr><tr><td>Listeria<\/td><td>High MIC<\/td><td>&nbsp;<\/td><\/tr><tr><td>Lactobacillus<\/td><td>High MIC<\/td><td>&nbsp;<\/td><\/tr><tr><td>Pediococcus, Leuconostoc<\/td><td>Susceptible<\/td><td>&nbsp;<\/td><\/tr><tr><td>Actinomyces<\/td><td>High MIC<\/td><td>&nbsp;<\/td><\/tr><\/tbody><\/table><\/figure>\n","protected":false},"excerpt":{"rendered":"<p>Class:&nbsp;Cyclic lipopeptideSource:&nbsp;Streptomyces roseosporusDiscovered: 1980s; approved for use in 2003 (FDA)Molecular weight: 1620 DA. Mechanism of action: The Daptomycin (DAP) combines [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":197,"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 center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ngg_post_thumbnail":0,"footnotes":""},"categories":[9],"tags":[28,46],"class_list":["post-201","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-antibiotic","tag-antibiotic","tag-daptomycin"],"_links":{"self":[{"href":"https:\/\/microregistrar.com\/index.php?rest_route=\/wp\/v2\/posts\/201","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/microregistrar.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/microregistrar.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/microregistrar.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/microregistrar.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=201"}],"version-history":[{"count":1,"href":"https:\/\/microregistrar.com\/index.php?rest_route=\/wp\/v2\/posts\/201\/revisions"}],"predecessor-version":[{"id":202,"href":"https:\/\/microregistrar.com\/index.php?rest_route=\/wp\/v2\/posts\/201\/revisions\/202"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/microregistrar.com\/index.php?rest_route=\/wp\/v2\/media\/197"}],"wp:attachment":[{"href":"https:\/\/microregistrar.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=201"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/microregistrar.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=201"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/microregistrar.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=201"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}