Lecture 12 Penicillins and Cephalosporins Dolly Mehta Ph D Knowledge Objectives 1 Know the components of bacterial cell wall and basic processes of cell wall synthesis and maintenance 2 Know the mechanism of antimicrobial activity for penicillins cephalosporins bacitracin vancomycin aztreonam imipenem clavulanic acid sulbactam 3 Know the classification of penicillins and cephalosporins according to their chemical structure and their antimicrobial spectrum Know lactamase resistant sensitive drugs 4 Know the most common adverse effects of the these drugs 5 Know the mechanisms of bacterial resistance for these drugs 6 Know the most common applications of these antibiotics for the treatment of disease Which drugs are broad spectrum and which have specific or unique uses Drug List Other lactams Penicillins clavulanic acid sulbactam imipenem aztreonam penicillin G penicillin V Other Drugs nafcillin methicillin oxacillin cloxacillin dicloxacillin flucloxacillin vancomycin bacitracin ampicillin amoxacillin carbenicillin ticarcillin azocillin mezlocillin pipericillin Cephalosporins cephalothin cefazolin cefalexin cefuroxime cefamandole cefoxitin cefaclor moxalactam cefaperazone ceftazidime ceftriaxone 1 Dolly Mehta 5 0236 dmehta uic edu Antimicrobial Therapy Cell Wall Protein syn Cell memb Nucleic acid syn 2 1 Bacterial Cell Wall Components Peptidoglycan N acetylmuramic acid NAMA M N acetylglucosamine NAG G Penta peptide Glycine 3 M M G G M M M G G G M M M G G G M M G 4 2 Gram Proteoglycan PG 15 50 nm thick M b Membrane Gram LPS Lipopolysacharides and proteins PG 2 nm thick Membrane periplasm 5 6 3 Biosynthesis of Peptidoglycan 30 enzymes Three stages 1 Precursor formation Cytoplasm 2 Binding with phospho C55 lipid carrier to form long polymer Cell membrane 3 Cross linking in cell wall 7 L alanine CYTO M UDP racemase D alanine synthetase h M UDP UMP P C55 lipid G UDP UDP M P P C55 G M P P C55 G M P P C55 MEMB P P P C55 lipid G M WALL transglycolase G M G M G M G transpeptidase 8 4 Lactam antibiotics Penicillin G and V Nafcillin Ampicillin Extended spectrum penicillin Cephalosporins Clavulanate Carbapenems 9 Penicillin Lactam antibiotics Drug of choice for a large number of diseases Discovered by Alexander Flemming 1928 Produced by penicillium 10 5 O S R C 2 CH NH CH B O C C A N 1 CH R decides Penicillin subtype Antibacterial activity CH3 CH3 COOH A Thiazolidine ring B lactum ring 1 penicillnase 2 amidase resistance to lactamase stability for stomach acids 11 Mechanism Inhibits cross linking of peptidoglycan transpeptidase M G M G M G M G M G M G M M G M G M G 12 6 lactum moeity of penicillins binds covalently irreversibly with penicillin binding proteins PBPs at serine residue lactamase PBP PBP 13 lactum antibodies Acylation of PBPs I hibiti off PBP Inhibition PBPs Structural irregularities Cell lysis 14 7 PBPs belong to the family of acyl serine transferases high molecular weight HMW PBPs low molecular weight LMW PBPs lactamases 15 PBPs HMW 16 8 LMW 17 Class A B lactamase 18 9 PBP s 40kD 91kD Number of PBPs varies within bacterial strain i e S aureus has 4 PBPs whereas E coli has 7 1 2 3 Apparent pp molecular weight 91000 66000 60000 Binding g of penicillin total 8 1 0 7 1 9 230 20 50 4 5 6 49000 42000 40000 4 0 64 7 20 6 110 1800 570 Protein Molecules cell 19 Affinity of PBPs to antibiotics is variable Penicillin lytic as well as non lytic Lytic PBP1 Non lytic PBP2 3 affect holin like proteins in bacterial cell memb which alter membrane potential 20 10 Mechanisms of Resistance A Elaboration of altered PBPs a decreased affinity for lactams a1 formed by homologous recombination between PBPs of different bact sp a2 by transposans from unknown org b structural differences in PBPs 21 B Inability of agent to penetrate to site of action b1 Gram bact outer layer of LPS Small hydrophilic antibiotics can pass through channels porins i e amoxicillin ampicillin Penicillin G P aeruginosa resistant to most antibiotics lacks porins 22 11 C Increased expression of efflux pumps i e E coli 23 D Production of lactamase Hydrolyse lactam ring of penicillin s d1 lactamases lactamases class A D A D Class A extended spectrum lactamase degrade penicillin some cephalosporin s and carbapenems Class B Zn dependent destroy all lactums except aztreonam Class C cephalosporin s Class D cloxacillin 24 12 d2 Site of liberation Gram lactamase is secreted extracellularly in large amts Gram lactamase is located in the periplasmic space small amounts Primary mechanism of acquired resistance d3 Other factors surviving bacterial cell biofilms produce bacteria in prosthetics 25 26 13 Classification Spectrum Natural Penicillins Penicillin V and G phenoxymethyl penicillin Gram cocci hydrolyzed by penicillinase so ineffective against most strains of S aureus lacatamse resistant Penicillin methicillin discontinued in US nafcillin isoxazoyl penicillin Less active agnst bacteria sensitive to Penicillin G First choice for S aureus and S epidermidis Aminopenicillins or modern spectrum Ampicillin amoxicillin Gram e g Hemophillus influenzae E Coli Neissaria sp Administered with b lactamse inhibitor such as clavanate to prevent hydrolysis CH2OCH2 OCH3 OCH3 Carboxypenicillin Cabbenicillin discontinued in US Ticarcillin Gram e g pseudomonas sp enterobacter sp Inferior to ampicillin G cocci against Gram Ureidopenicillins extended penicillin Mezlocillin Azliocillin discontinued in US Piperacillin Pseudomonas sp 10 times more effective than carboxypenicillin R1 CH2 NH2 CH COOR 27 General features of the Penicillins Distribution widely distributed throughout body fluids but conc varies in diff tissues therapeutic concentrations is achieved readily in tissues and in secretions such as joint fluid pleural fluid pericardial fluid and bile Do not penetrate phagocytic cells very low conc in prostatic fluids brain tissue and intracular fluid 1 in CSF when meninges are normal 5 g when inflamed meningis Active transport process pumps penicillin s from CSF to the bloodstream This mechanism is blocked by Probenecid 28 14 Excretion Predominantly eliminated rapidly by glomerular filtration Short half life 30 90 min in body So higher urine concentrations 29 Specific Agents Penicillin V Penicillin G Stability Low acid stability gastric juices at pH 2 degrades it rapidly rapidl Food interference 30 min before meal More acid stable Absorption Oral dose Rapidly absorbed and max conc 30 60 min in blood should be used only when proven efficacious Peak value 0
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