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 cyclosporin aztreonam imipenem 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 clavulanic acid sulbactam imipenem aztreonam Penicillins penicillin G penicillin V nafcillin methicillin oxacillin cloxacillin dicloxacillin flucloxacillin Other Drugs vancomycin bacitracin ampicillin amoxacillin carbenicillin ticarcillin azocillin mezlocillin pipericillin Cephalosporins cephalothin cefazolin cefalexin cefuroxime cefamandole cefoxitin cefaclor moxalactam cefaperazone ceftazidime ceftriaxone 1 Antimicrobial Therapy Dolly Mehta 5 0236 dmehta uic edu Cell Wall Protein syn Cell memb Nucleic acid syn 2 Bacterial Cell Wall Components M G M G M G Peptidoglycan N acetylmuramic acid NAMA M M G M M N acetylglucosamine NAG G G G M M G G M M G Penta peptide Glycine 3 4 1 Biosynthesis of Peptidoglycan CYTO Gram 30 enzymes M UDP M UDP Proteoglycan PG 15 50 nm thick Membrane UMP Gram P C55 lipid Lipopolysachrides and proteins G UDP UDP M P P C55 G M P P C55 G M P P C55 MEMB PG 2 nm thick P Membrane P P C55 lipid G M periplasm 5 WALL transglycolase G M G M G M G 6 transpeptidase Cycloserine Seromycin D 4 amino 3 isoxazolidone V Absorption Distribution and excretion I structural analog of D Ala acts as a competitive inhibitor Orally absorbed 70 90 Peak concentrations in plasma are reached within 3 4 after single dose distributed throughout body fluids CSF conc plasma Metabolism slow only 50 excreted UNCHANGED in urine in Ist 12 hrs renal patients accumulate to toxic conc removed by dialysis II stable in alkaline solution rapidly destroyed in neutral or acid pH III Mechanism III M h i cycloserine M UDP IV Therapeutic Use Effective agnst M tuberculosis 5 20 g ml used WHEN PRIMARY Anti Tuberculosis agents such as Isoniazid rifampin failed 7 VI Untoward Effects CNS headache tremor confusion etc symtoms disappear after drug is withdrawn Large dose or concomitatnt use of alchohol seizures CONTRAINDICATED Epileptic patients Caution patients with history of depression or suicidal attempts 8 2 Vancomycin IV Absorption Distribution and excretion Oral absorption poor slow IV is preferred NEVER IM A single 1 g IV 15 30 ug ml in plasma after 1 2 hr half life 6 hrs appears in body fluids and CSF 90 excreted by glomerular filtration accumulates if renal function is impaired can be cleared by hemodialysis I Complex tricyclic glycopeptide antibiotic II Mechanism Inhibits polymerization or transglycolase reaction G M n G M P P C55 G M G M n P P C55 III Antibacterial activity Gram Gram are resistant because D ala D ala target is substituted with D ala D ser or D ala D lactate 9 V Untoward Effects Hypersensitive Reacn skin rashes and anaphylaxis Chills rash Rapid administration causes flushing tachycardia hypotension erythematous or urticarial reac auditory impairment ototoxicity and nephrotoxicity caution with the use of aminoglycosides cause red neck or red man syndrome by 10 directly inducing toxicity in mast cells Penicillin Lactam antibiotics Bacitracin I Mechanism P P C55 lipid Drug of choice for a large number of diseases P C55 lipid II Antibacterial Activity Gram cocci and bacilli However bact strain such as Enterobacteriaceae Pseudomonas Candida spp and Nocardia are resistant Discovered by Alexander Flemming 1928 Produced by penicillium III Use Restricted to topical use such as for skin and eye infections 11 12 3 Mechanism O S R C 2 NH CH B O C CH3 C CH A N 1 CH Inhibits cross linking of peptidoglycan CH3 COOH M G M G M G M G M G M G M A Thiazolidine ring R decides B lactum ring 1 penicillnase 2 amidase Penicillin subtype Antibacterial activity M G M G M G resistance to lactamase stability for stomach acids 13 14 PBPs lactum moeity of penicillins binds covalently irreversibly with penicillin binding proteins PBPs at serine residue PBPs belong to the family of acyl serine transferases high molecular weight HMW PBPs low molecular weight LMW PBPs lactamases HMW lactamase PBP PBP 15 16 4 LMW lactamase Class A B 17 18 PBP s 40kD 91kD lactum antibodies Number of PBPs varies within bacterial strain i e S aureus has 4 PBPs whereas E coli has 7 Acylation of PBPs Inhibition of PBPs 1 Apparent molecular weight 91000 Binding of penicillin total 8 1 2 66000 0 7 20 3 60000 1 9 50 4 49000 4 0 110 5 6 42000 40000 64 7 20 6 1800 570 Protein Structural irregularities Cell lysis 19 Molecules cell 230 20 5 III Mechanisms of Resistance 3 Affinity of PBPs to antibiotics is variable A Elaboration of altered PBPs Penicillin lytic as well as non lytic a decreased affinity for lactams a1 formed by homologous recombination between PBPs of different bact sp Lytic PBP1 Non lytic PBP2 3 affect holin like proteins in bacterial cell memb which alter membrane potential a2 by transposans from unknown org B Structural differences in PBPs 21 22 C Increased expression of efflux pumps i e E coli 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 i e amoxicillin ampicillin Penicillin G P aeruginosa resistant to most antibiotics lacks porins 23 24 6 D Production of lactamase d2 Site of liberation Hydrolyse lactam ring of penicillin s Gram lactamase is secreted extracellularly in large amts d1 lactamases class A D Gram lactamase is located in the periplasmic space small amounts Class A extended spectrum lactamase degrade penicillin some cephalosporin s p p p and carbapenems Primary mechanism of acquired resistance Class B Zn dependent destroy all lactums except aztreonam Class C cephalosporin s Class D cloxacillin d3 Other factors surviving bacterial cell biofilms produce bacteria in prosthetics 25 27 26 Classification Spectrum Natural Penicillins Penicillin V and G phenoxymethyl penicillin Gram cocci hydrolyzed by penicillinase so ineffective against most
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