{"id":240,"date":"2019-10-09T10:12:28","date_gmt":"2019-10-09T04:42:28","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=240"},"modified":"2019-10-09T10:12:28","modified_gmt":"2019-10-09T04:42:28","slug":"beta-lactamase-inhibitors","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/beta-lactamase-inhibitors\/","title":{"rendered":"Beta-Lactamase Inhibitors"},"content":{"rendered":"\n<p><strong>Beta-lactamases<\/strong><\/p>\n\n\n\n<ul><li>act by breaking the\u00a0beta-lactam\u00a0ring that allows\u00a0penicillin-like antibiotics to work. <\/li><li>Although \u03b2-lactamase inhibitors have little antibiotic activity of their own,\u00a0they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.<\/li><\/ul>\n\n\n\n<ul><li><strong>Beta-lactamase\nproducing bacteria<\/strong><\/li><\/ul>\n\n\n\n<ul><li><a href=\"https:\/\/en.wikipedia.org\/wiki\/Staphylococcus\"><em>S<\/em><\/a><em>taphylococcus<\/em><ul><li><em>MRSA<\/em>(Methicillin-resistant Staphylococcus aureus)<\/li><\/ul><\/li><li><em>Enterobacteriaceae<\/em>:<ul><li><em>Klebsiella pneumoniae, Citrobacter, Proteus vulgaris, Salmonella, Shigella, Escherichia coli<\/em><\/li><\/ul><\/li><li><em>Haemophilus influenzae<\/em><\/li><li><em>Neisseria gonorrhoeae<\/em><\/li><li><em>Pseudomonas aeruginosa<\/em><\/li><li><em>Mycobacterium tuberculosis<\/em><\/li><\/ul>\n\n\n\n<p><strong>Medical uses<\/strong><\/p>\n\n\n\n<ul><li>the most important use of beta-lactamase inhibitors is in the <strong>treatment of infections known or believed to be caused by\u00a0gram-negative bacteria<\/strong>, as <strong>beta-lactamase production is an important contributor<\/strong> to beta-lactam <strong>resistance<\/strong> in these pathogens. <\/li><li>In contrast, most <strong>beta-lactam resistance in\u00a0gram-positive bacteria<\/strong>\u00a0is due to <strong>variations in\u00a0penicillin-binding proteins<\/strong>\u00a0that lead to reduced binding to the beta-lactam.<\/li><li>The gram-positive pathogen\u00a0<em>Staphylococcus aureus<\/em>\u00a0produces beta-lactamases, but beta-lactamase inhibitors play a lesser role in the treatment of these infections because the most resistant strains (methicillin-resistant\u00a0<em>Staphylococcus aureus<\/em>) also use variant penicillin-binding proteins. <\/li><\/ul>\n\n\n\n<p><strong>Mechanism of action<\/strong><\/p>\n\n\n\n<p>Currently, available beta-lactamase inhibitors are\neffective against <\/p>\n\n\n\n<p><strong>Based on their catalytic\nactivities, \u03b2-lactamases are classified as <\/strong><\/p>\n\n\n\n<ul><li><strong>serine \u03b2-lactamases (SBLs, Ambler class A, C, and D) and <\/strong><\/li><li><strong>Metallo-\u03b2-lactamases (MBLs, Ambler class B)<\/strong><\/li><li><strong>Ambler Class A beta-lactamases<\/strong> (tazobactam, clavulanate, and sulbactam) or against <\/li><li><strong>Ambler Class A, C and some Class D beta-<\/strong>lactamases (avibactam). <\/li><li>Unlike the case of beta-lactam antibiotics, <strong>the inhibitors act as\u00a0suicide substrates\u00a0(tazobactam and sulbactam) which ultimately leads to the degradation of the beta-lactamase<\/strong><\/li><li><strong>Avibactam<\/strong>, on the other hand, does not contain a beta-lactam ring <strong>(non-beta-lactam beta-lactamase inhibitor)<\/strong> and instead binds\u00a0reversibly.<\/li><li><strong>Ambler Class B beta-lactams cleave beta-lactams by a mechanism similar to that of\u00a0metalloproteases<\/strong>. As no covalent intermediate is formed, the <strong>mechanism of action of marketed beta-lactamase inhibitors is not applicable. <\/strong>Thus the spread of bacterial strains expressing Metallo beta-lactamases such as the\u00a0<strong>New Delhi Metallo-beta-lactamase 1<\/strong>\u00a0has engendered considerable concern. <\/li><\/ul>\n\n\n\n<p><strong>Commonly used agents<\/strong><\/p>\n\n\n\n<ul><li>Currently\nmarketed \u03b2-lactamase inhibitors are <strong>not\nsold as individual drugs.<\/strong> <\/li><li>Instead,\nthey are <strong>co-formulated with a \u03b2-lactam\nantibiotic with a similar serum half-life<\/strong>. <\/li><li>This\nis <strong>done not only for dosing convenience\nbut also to minimize resistance development<\/strong> that might occur as a result of\nvarying exposure to one or the other drug. <\/li><li>The\nmain classes of \u03b2-lactam antibiotics used to treat gram-negative bacterial\ninfections include (in approximate order of intrinsic resistance to cleavage by\n\u03b2-lactamases) penicillins (especially aminopenicillins and ureidopenicillins),\n3rd generation cephalosporins, and carbapenems. <\/li><li>Individual\n\u03b2-lactamase variants may target one or many of these drug classes, and only a\nsubset will be inhibited by a given \u03b2-lactamase inhibitor.<\/li><li>\u03b2-lactamase\ninhibitors expand the useful spectrum of these \u03b2-lactam antibiotics by\ninhibiting the \u03b2-lactamase enzymes produced by bacteria to deactivate them. <\/li><\/ul>\n\n\n\n<p><strong>\u03b2-lactamase inhibitors with the \u03b2-lactam core:<\/strong><\/p>\n\n\n\n<ul><li>Clavulanic acid\u00a0or clavulanate, usually combined with\u00a0amoxicillin\u00a0(Augmentin) or\u00a0ticarcillin\u00a0(Timentin)<ul><li>Sulbactam, usually combined with\u00a0ampicillin\u00a0or\u00a0Cefoperazone\u00a0<\/li><\/ul><ul><li>Tazobactam, usually combined with\u00a0piperacillin <\/li><\/ul><ul><li>Ceftolozane plus tazobactam (Zerbaxa) \u00e0 novel <strong>fifth-generation cephalosporin antibiotic ceftolozane and the established \u03b2-lactamase inhibitor tazobactam<\/strong><\/li><\/ul><\/li><\/ul>\n\n\n\n<ul><li><strong>Non-\u03b2-lactam \u03b2-lactamase inhibitors:<\/strong><ul><li><strong>Avibactam, approved in combination with\u00a0ceftazidime<\/strong>\u00a0(Avycaz), currently undergoing clinical trials for combination with\u00a0ceftaroline \u00e0 complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI)<\/li><\/ul><ul><li>\u00a0<\/li><\/ul><ul><li><strong>Relebactam<\/strong>\u00a0(previously known as MK-7655) is undergoing Phase III clinical trials as a treatment for pneumonia and bacterial infections (as of March 1, 2016). <\/li><\/ul><ul><li>Vaborbactam plus meropenem -&gt; complicated UTI  -&gt;  as an injectable solution with each vial containing 1 g of meropenem and 1 g of tazobactam<\/li><\/ul><\/li><\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Beta-lactamases act by breaking the\u00a0beta-lactam\u00a0ring that allows\u00a0penicillin-like antibiotics to work. Although \u03b2-lactamase inhibitors have little antibiotic activity of their own,\u00a0they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against. Beta-lactamase producing bacteria Staphylococcus MRSA(Methicillin-resistant Staphylococcus aureus) Enterobacteriaceae: Klebsiella pneumoniae, Citrobacter, Proteus vulgaris, Salmonella, Shigella, Escherichia coli[&#8230;]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/240"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=240"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/240\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=240"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=240"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=240"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}