-1-Lecture 12: Penicillins and CephalosporinsDolly Mehta, Ph.D.Knowledge Objectives1. Know the components of bacterial cell wall, and basic processes of cell wall synthesis andmaintenance.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 ofdisease. Which drugs are broad spectrum, and which have specific or unique uses.Drug ListPenicillinspenicillin Gpenicillin Vnafcillinmethicillinoxacillincloxacillin dicloxacillinflucloxacillinampicillinamoxacillincarbenicillin ticarcillinazocillinmezlocillinpipericillinCephalosporinscephalothincefazolincefalexincefuroximecefamandolecefoxitincefaclormoxalactamcefaperazoneceftazidimeceftriaxoneOther $$$$-lactamsclavulanic acidsulbactamimipenemaztreonamOther Drugsvancomycinbacitracin1Dolly [email protected] TherapyCell Wall Cell memb Protein syn Nucleic acid syn 2Bacterial Cell Wall ComponentsPeptidoglycanMN acetylmuramic acid (NAMA) GN acetylglucosamine (NAG)Penta peptide Glycine 3M G M G M GM G M G M GMM G M G M G42Proteoglycan (PG) (15-50 nm thick)MembraneGram +PG (2 nm thick)MembraneLipopolysachrides and proteinsperiplasmGram -5Biosynthesis of Peptidoglycan30 enzymesMUDPUDPMUMPGUDPUDPCYTOP-C55 lipidP-P-C55MP-P-C55MGMEMBWALLP-P-C55MGGMM G M G M GP-P-C55 lipidtransglycolaseP6transpeptidaseGI. structural analog of D-Ala (acts as a competitive inhibitor) Cycloserine (Seromycin) D-4-amino-3-isoxazolidoneIIIMh icycloserineII. stable in alkaline solution rapidly destroyed in neutral or acid pHIV. Therapeutic Use: Effective agnst M. tuberculosis (5-20 μg/ml)used WHEN PRIMARY Anti-Tuberculosis agents (such as Isoniazid, rifampin) failedIII. Mechanism:MUDPcycloserine7V. Absorption, Distribution and excretionOrally absorbed 70-90%Peak concentrations in plasma are reached within 3-4 after single dosedistributed throughout body fluids (CSF conc. = plasma)Metabolism slow, only 50% excreted UNCHANGED in urinein Ist 12 hrs renal patients: accumulate to toxic conc, removed by dialysisVI. Untoward EffectsCNS: headache, tremor, confusion etc(symtoms disappear after drug is withdrawn)Large dose or concomitatnt use of alchoholÆseizuresCONTRAINDICATED: Epileptic patientsCaution: patients with history of depression or suicidal attempts83VancomycinI. Complex tricyclic glycopeptide antibioticII. Mechanism: Inhibits polymerization or transglycolase reaction P-P-C55MGMGMG()n+MG()nIII. Antibacterial activity:Gram (+) Gram(–) are resistant because D-ala-D-ala (target) is substituted with D-ala-D-ser or D-ala-D-lactateP-P-C559IV. Absorption, Distribution and excretion: Oral absorption poor; slow IV is preferred, NEVER IMA single 1 g IV Æ 15-30 ug/ml in plasma after 1-2 hr; half life~ 6 hrsappears in body fluids and CSF90% excreted by glomerular filtration ; accumulates if renal function is impaired (can be cleared by hemodialysis)V. Untoward Effects:Hypersensitive Reacn(skin rashes, and anaphylaxis, Chills, rash)Rapid administrationcauses flushing, tachycardia, hypotension, erythematous or urticarial reac auditory impairment (ototoxicity) and nephrotoxicity; Æcaution with the use of aminoglycosidescause “red-neck” or “red-man”syndrome bydirectly inducing toxicity in mast cells10II. Antibacterial Activity: Gram (+) cocci and bacilli. However, bact strain such as Enterobacteriaceae, Pseudomonas, BacitracinI. Mechanism:P-P-C55 lipidP-C55 lipidCandida spp and Nocardia are resistant III. Use: Restricted to topical use such as for skin and eye infections 11Penicillin: β-Lactam antibioticsDrug of choice for a large number of diseasesDiscovered by Alexander Flemming 1928. Produced bypenicilliumProduced by penicillium124CCH COOHCH3CH3SCHNCHC=ONHCR=OBA12AB β-lactum ringThiazolidine ring1 penicillnase2 amidaseR decides:stability for stomach acidsAntibacterial activityPenicillin subtyperesistance to β-lactamase13Mechanism:MGMGMGM G M G M GMInhibits cross linking of peptidoglycanMGMGMGM G M G M GM14β-lactum moeity of penicillins binds covalently (irreversibly) with penicillin-binding proteins (PBPs) at serine residuePBPs:belong to the family of acyl serine transferaseshigh-molecular-weight (HMW) PBPslow-molecular-weight (LMW) PBPsPBPPBPβ-lactamaseß-lactamases 15PBPsHMWHMW165LMW17Class A-B β-lactamase18β-lactum antibodiesAcylation of PBPsInhibition of PBPs Structural irregularitiesCell lysis19PBP’s (40kD-91kD):Number of PBPs varies within bacterial strain. i.e. S aureus has 4 PBPs whereas E coli has 7ProteinApparent molecular weightBinding of penicillin( % total )Molecules/cell1910008.12301910008.12302 66000 0.7 203 60000 1.9 504 49000 4.0 1105 42000 64.7 18006 40000 20.6 5702063. Affinity of PBPs to antibiotics is variablePenicillin (lytic as well as non-lytic)Lytic PBP1; Non-lytic (PBP2/3) (affect holin-like proteins in bacterial cell memb which alter membrane potential)21III. Mechanisms of Resistance:A. Elaboration of altered PBPsa) decreased affinity for β-lactamsa1. formed by homologous recombination between PBPs of different bact sp.a2. by transposans from unknown orgB. Structural differences in PBPs22B. Inability of agent to penetrate to site of actionb1. Gram (-) bact outer layer of LPSSmall hydrophilic antibiotics can pass through channels porinsi e amoxicillin ampicillin>Penicillin Gi.e. amoxicillin, ampicillin>Penicillin GP aeruginosa resistant to most antibiotics lacks porins23C. Increased expression of efflux pumps i.e E. coli247D. Production of β-lactamased1. β-lactamases class A-D:Class A (extended spectrum β-lactamase): degrade penicillin, some cephalosporin's and Hydrolyse β lactam ring of penicillin's p, ppcarbapenemsClass B (Zn-dependent): destroy all β-lactums except aztreonamClass C: cephalosporin'sClass D: cloxacillin25Gram (+), β lactamase is secreted extracellularly in large amtsGram (-), β lactamase is located in the periplasmic space, small amounts. d2. Site of liberationPrimary mechanism of acquired resistance!d3. Other factors: surviving bacterial cell, biofilms produce bacteria in prosthetics2627Classification Spectrum Natural
View Full Document
Unlocking...