AntibioticsSOMC230course - Beta Lactam Antibiotics...

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1 Beta Lactam Antibiotics Mechanism of Action: 1.) B-lactam ring structural analog of D-ala-D-ala substrate of enzymes (penicillin binding proteins = PBPs; family of enzymes involved in cell wall synthesis) used in cell wall synth. 2.) B-lactams are suicide inhibitors of PBPs. (suicide inhibitor = once enzyme binds B-lactam ring in its active site, the drug becomes covalently attached to the enzyme resulting in permanent inactivation) a.) PBP-1 = transpeptidase (inhib-->lysis), b.) PBP-2 = shape (inhib-->round cells), c.) PBP-3 = septum formation (inhib-->long cells); 3.) Not bacteriocidal in slow growing or dormant bacteria (eg. endocarditis, osteomyelitis) & bacteria that downregulate autolysin activity (enterococci). Bacterial susceptibility to B-lactams: 1.) Gram (+): susceptibility determined by affinity of drug for its target PBPs & whether organism produces B-lactamase that can degrade drug before it reaches its target 2.) Gram (-): In addition to the above, drugs must cross OM to gain access to cell wall; do so via outer membrane (OM) channels called porins. Notes: 1.) Events that B-lactams mediate are lethal 2.) Bactericidal against growing bacteria with active autolysis 3.) B-lactam ring must be intact Penicillin: 4 member B-lactam ring attached to a 5-member ring R group will determine spectrum of activity Metabolism: 1.) Short half-life 2.) Excreted unchanged in kidney (glomerular filtration & tubular secretion) 3.) Probenecid extend half-life (blocks tubular secretion) 4.) Nafcillin/Oxacillin ureidopenicillins ( piperacillin mezclocillin ) - hepatic excretion Bioavailability: 1.) IV, IM, or Oral 2.) Effective: >4x MIC for 60-80% of day, a.) Only amoxicillin absorbs w/ food, b.) PCNs distributed to most tissues ( NOT CNS, prostate, eye), can cross inflamed meninges, high CSF levels induce seizures Side Effects: 1.) Allergic rxns (cross reactivity from b-lactam ring byproducts, i.e., cross allergencity btwn PCNs), 2.) Neutropenia due to arres of meta-meylocytes when given high doses 3.) Methicillin -> allergic interstitial nephritis 4.) Nafcillin Oxacillin –> hepatitis 5.) Carboxycillin & ticercillin (are disodium salts) -> large salt load Penicillin (classes of): Natural: PCN G, PCN VK Uses: 1.) Susceptible gram (+) such as a.) B-hemolytic strep b.)Treponema pallidum 2.) First line for: Comments: 1.) Naturally occurring 2.) Rapid metab/excretion (IV t 1/2 = 30 min) 3.) Trick to prolong blood levels: use IM administration a.) Procaine can be administered w/ PCN G or b.) Benzathine PCN can be injected Penicillinase-stable : methicillin, nafcillin, dicloxacillin, oxacillin Uses: 1.) Made to resist inactivation by penicillinase (a B-lacatamase) from S. aureus (MSSA) a.) Use for Tx of MSSA b.) NOT active against MRSA c.) NOT active against Listeria or Enterococci d.) NOT active against Gram (-) bacteria e.) Less active than PCN agains Gram (+)’s that do not produce B-lactamases.
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This note was uploaded on 09/14/2011 for the course PHARM TBL taught by Professor Staff during the Spring '11 term at UCSD.

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AntibioticsSOMC230course - Beta Lactam Antibiotics...

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