Beta-lactams

INHIBITORS OF CELL WALL SYNTHESIS; Penicillins and Cephalosporins: 

INHIBITORS OF CELL WALL SYNTHESIS; Penicillins and Cephalosporins 한림대학교 의과대학 약리학교실 이종호

INHIBITORS OF CELL WALL SYNTHESIS; Penicillins and Cephalosporins: 

INHIBITORS OF CELL WALL SYNTHESIS; Penicillins and Cephalosporins 학습목적 Penicillin 계 약물의 작용기전, 부작용 및 임상적 이용을 기술한다.

INHIBITORS OF CELL WALL SYNTHESIS; Penicillins and Cephalosporins: 

INHIBITORS OF CELL WALL SYNTHESIS; Penicillins and Cephalosporins 학습목표 1. b -lactam 항생제의 작용기전을 설명한다. 2. b -lactam 항생제에 대해 저항성이 생기는 기전을 설명한다. 3. Penicillin 제제의 종류, 항균범위와 임상응용을 기술한다. 4. Cephalosporin 을 세대별로 구분하고 항균범위와 임상 응용을 기술한다. 5. Penicillin 에 대한 과민 반응의 발생기전, 증상, 검사방법과 치료방법을 설명한다 .

Classification I; Bacterial Targets for Antibiotics: 

Classification I; Bacterial Targets for Antibiotics

Slide 5: 

Classification of Antibiotics

Slide 6: 

Classification of Antibiotics

Bacterial Cell Walls: 

Bacterial Cell Walls Gram (+) Gram (-)

Slide 8: 

Teichoic acid From: Goodman and Gilman, 9th ed.

Stages of Peptidoglycan Synthesis: 

Stages of Peptidoglycan Synthesis

Peptidoglycan synthesis: 

Peptidoglycan synthesis Cytoplasm Cell wall Bactoprenol sugar amino acid Cell Membrane

Stages of Peptidoglycan Synthesis & Inhibitors : 

Stages of Peptidoglycan Synthesis & Inhibitors

Stages of Peptidoglycan Synthesis & Inhibitors : 

Stages of Peptidoglycan Synthesis & Inhibitors

Cycloserine: 

Cycloserine Alanine (ala) analog Inhibits conversion of L-ala to D-ala Inhibits formation of D-ala-D-ala

Cycloserine: 

Cycloserine Cytoplasm sugar amino acid Analog of alanine X X X X

Stages of Peptidoglycan Synthesis & Inhibitors : 

Stages of Peptidoglycan Synthesis & Inhibitors

Bacitracin: 

Bacitracin Inhibits dephosphorylation in cycling of the lipid carrier(bactoprenol) that transfers peptidoglycan subunits to the growing cell wall

Bacitracin: 

Bacitracin Cell membrane Batoprenol P P

Stages of Peptidoglycan Synthesis & Inhibitors : 

Stages of Peptidoglycan Synthesis & Inhibitors

Vancomycin: 

Vancomycin Binds to D-ala-D-ala Inhibits cross-linking

Vancomycin: 

Vancomycin Cell wall

Beta-lactam antibiotics: 

Beta-lactam antibiotics Penicillins Cephalosporins Monobactams Carbapenems Bind and inhibit penicillin binding proteins(PBPs) Stop cross-linking

Beta-lactams: 

Beta-lactams Cell wall Penicillin binding protein

Slide 23: 

STAPHYLOCOCCUS STAPHYLOCOCCUS ON PENICILLINS

Slide 24: 

Bactericidal Bacteriostatic Penicillins Erythromycin Cephalosporins Clindamycin Aztreonam Imipenem Tetracycline Vancomycin Sulfonamides Aminoglycosides Quinolones Metronidazole Chloramphenicol 살균 및 정균 항생제

INHIBITORS OF CELL WALL SYNTHESIS: 

INHIBITORS OF CELL WALL SYNTHESIS PENICILLINS CEPHALOSPORINS OTHER b -LACTAM ANTIBIOTICS VANCOMYCIN

INHIBITORS OF CELL WALL SYNTHESIS: 

INHIBITORS OF CELL WALL SYNTHESIS PENICILLINS CEPHALOSPORINS OTHER b -LACTAM ANTIBIOTICS VANCOMYCIN

History of Penicillins: 

History of Penicillins 1929; Discovery of penicillin by Alexander Fleming 1940; Produce significant quantities of penicillins by Chain and Florey Penicillium notatum

Characteristics of the b-Lactam Ring: 

Characteristics of the b -Lactam Ring Bind and inhibits transpeptidease Substrate for b -lactamases An unstable structure Acid labile Breakdown products; Immunogenic

Slide 29: 

PENICILLINS

Classification of Penicillins: 

Classification of Penicillins The prototype Penicillin G Acid resistant Penicillin V Penicillinase resistant Methicillin, Oxacillin “ Broad Spectrum ” Amoxicillin, Ampicillin “ Antipseudomonas ” Azlocillin, Piperacillin Combinations Augmentin, Timentin (+ b -lactamase inhibitor)

Mechanism of Action of Penicillins: 

Mechanism of Action of Penicillins

Slide 32: 

Teichoic acid From: Goodman and Gilman, 9th ed. Crosslinks

Penicillin Binding Proteins Identification by gel electrophoresis: 

Penicillin Binding Proteins Identification by gel electrophoresis

Transpeptidease Inhibition : 

Transpeptidease Inhibition C N C COOH CH3 CH N C O C O R’ ( D-alanyl-D-alanine-peptidoglycan)

Transpeptidease Reaction : 

Transpeptidease Reaction

MECHANISM OF ACTION OF PENICILLIN. INHIBITION OF FINAL STAGE OF CROSS-LINKING: 

G M G M G M G M G M G M G M G M 5 amino acid stem Nascent peptide bridge MECHANISM OF ACTION OF PENICILLIN. INHIBITION OF FINAL STAGE OF CROSS-LINKING

Slide 37: 

G M G M G M G M G M G M G M G M Transpeptidation Enzyme inhibited by penicillin MECHANISM OF ACTION OF PENICILLIN. INHIBITION OF FINAL STAGE OF CROSS-LINKING

Slide 38: 

G M G M G M G M G M G M G M G M MECHANISM OF ACTION OF PENICILLIN. INHIBITION OF FINAL STAGE OF CROSS-LINKING

Slide 39: 

G M G M G M G M G M G M G M G M MECHANISM OF ACTION OF PENICILLIN. INHIBITION OF FINAL STAGE OF CROSS-LINKING

Resistance to Penicillins: 

Resistance to Penicillins

The Mechanism of Antibiotic Resistance: 

The Mechanism of Antibiotic Resistance Altered expression of proteins in drug resistant organisms Modification of target sites Decreased accumulation Enzymic inactivation

The Resistance Mechanisms to b-lactams: 

The Resistance Mechanisms to b -lactams

RESISTANCE TO ANTIBIOTICS- PENICILLIN: 

RESISTANCE TO ANTIBIOTICS- PENICILLIN NH O COOH CH 3 CH 3 NH O COOH CH3 CH3 + H 2 0 b - LACTAM RING PENICILLOIC ACID OH N N H Hydrolysis of b -lactam bond b -LACTAMASE

Clinical Uses of Penicillins: 

Clinical Uses of Penicillins

PENICILLINS : 

PENICILLINS Natural Penicillins Penicillin G Benzathine PN G Procaine PN G Penicillin V Streptococcus Neisseria meningitidis Spirochetes Penicillinase-resistant Methicillin Oxacillin Nafcillin Cloxacillin Dicloxacillin Staphylococcus aureus (penicillinase 생성균) Aminopenicillin Ampicillin Amoxicillin Heamophilus influenzae Proteus mirabilis E. coli Neisseria Carboxypenicillins Carbenicillin Ticarcillin ampicillin 감수성균 Pseudomonas Enterobacter Proteus Ureidopenicillins Piperacillin Azlocillin Mezlocillin Pseudomonas Enterobacter Klebsiella

PENICILLINS : 

PENICILLINS Natural Penicillins Penicillin G Benzathine PN G Procaine PN G Penicillin V Streptococcus Neisseria meningitidis Spirochetes Penicillinase-resistant Methicillin Oxacillin Nafcillin Cloxacillin Dicloxacillin Staphylococcus aureus (penicillinase 생성균) Aminopenicillin Ampicillin Amoxicillin Heamophilus influenzae Proteus mirabilis E. coli Neisseria Carboxypenicillins Carbenicillin Ticarcillin ampicillin 감수성균 Pseudomonas Enterobacter Proteus Ureidopenicillins Piperacillin Azlocillin Mezlocillin Pseudomonas Enterobacter Klebsiella

PENICILLINS : 

PENICILLINS Natural Penicillins Penicillin G Benzathine PN G Procaine PN G Penicillin V Streptococcus Neisseria meningitidis Spirochetes Penicillinase-resistant Methicillin Oxacillin Nafcillin Cloxacillin Dicloxacillin Staphylococcus aureus (penicillinase 생성균) Aminopenicillins Ampicillin Amoxicillin Heamophilus influenzae Proteus mirabilis E. coli Neisseria Carboxypenicillins Carbenicillin Ticarcillin ampicillin 감수성균 Pseudomonas Enterobacter Proteus Ureidopenicillins Piperacillin Azlocillin Mezlocillin Pseudomonas Enterobacter Klebsiella

PENICILLINS : 

PENICILLINS Natural Penicillins Penicillin G Benzathine PN G Procaine PN G Penicillin V Streptococcus Neisseria meningitidis Spirochetes Penicillinase-resistant Methicillin Oxacillin Nafcillin Cloxacillin Dicloxacillin Staphylococcus aureus (penicillinase 생성균) Aminopenicillins Ampicillin Amoxicillin Heamophilus influenzae Proteus mirabilis E. coli Neisseria Carboxypenicillins Carbenicillin Ticarcillin Pseudomonas Enterobacter Proteus Ureidopenicillins Piperacillin Azlocillin Mezlocillin Pseudomonas Enterobacter Klebsiella

PENICILLINS : 

PENICILLINS Natural Penicillins Penicillin G Benzathine PN G Procaine PN G Penicillin V Streptococcus Neisseria meningitidis Spirochetes Penicillinase-resistant Methicillin Oxacillin Nafcillin Cloxacillin Dicloxacillin Staphylococcus aureus (penicillinase 생성균) Aminopenicillins Ampicillin Amoxicillin Heamophilus influenzae Proteus mirabilis E. coli Neisseria Carboxypenicillins Carbenicillin Ticarcillin Pseudomonas Enterobacter Proteus Ureidopenicillins Piperacillin Azlocillin Mezlocillin Pseudomonas Enterobacter Klebsiella

Adverse Reactions to Penicillins: 

Adverse Reactions to Penicillins Little direct tissue toxicity Hypersensitivity 5% of population Anaphylactic shock (0.05%) Serum sickness type (rare) Skin rashes Desensitization can be accomplished with gradually increasing doses of penicillin

The Antigenic Determinant for Hypersensitivity: 

The Antigenic Determinant for Hypersensitivity Penicilloic acid and products of alkaline hydrolysis bound to host protein

INHIBITORS OF CELL WALL SYNTHESIS: 

INHIBITORS OF CELL WALL SYNTHESIS PENICILLINS CEPHALOSPORINS OTHER b -LACTAM ANTIBIOTICS VANCOMYCIN

Cephalosporins are Structurally Similar to Penicillins : 

Cephalosporins are Structurally Similar to Penicillins

Characteristics of Cephalosporins: 

Characteristics of Cephalosporins Inhibits synthesis of the bacterial cell wall Absorption, distribution, elimination - similar to penicillins Adverse reactions: Hypersensitivity; similar to penicillins Thrombophlebitis after intravenous injection Renal toxicity; interstitial nephritis Incidence of resistance is lower than penicillins

Generations of Cephalosporins: 

Generations of Cephalosporins FIRST GENERATION Cephalothin, Cephalexin, Cephradine SECOND GENERATION Cefaclor, Cefuroxime THIRD GENERATION Cefotaxime, Ceftriaxone FOURTH GENERATION Cefepime, Cefpirome

Some Uses for Cephalosporins: 

Some Uses for Cephalosporins Hospital-acquired pneumonias - Cefotaxime Meningitis - Cefotaxime, Ceftriaxone Sepsis (initial Rx) - 3 rd and 4 th generation cephalosporins Gonorrhea Acute urinary tract infections (UTI) From: The Medical Letter, 1999

INHIBITORS OF CELL WALL SYNTHESIS: 

INHIBITORS OF CELL WALL SYNTHESIS PENICILLINS CEPHALOSPORINS OTHER b -LACTAM ANTIBIOTICS MONOBACTAMS BETA-LACTAMASE INHIBITORS CARBAPENEMS VANCOMYCIN

Monobactam : 

Monobactam Aztreonam Narrow spectrum – Gram(-) rods Highly resistant to b -lactamases Few serious adverse reactions Alternative to aminoglycosides and 3rd generation cephalosporins

AZTREONAM: 

AZTREONAM b - lactam ring

PENICILLIN BINDING PROTEINS: Mechanism of action of Aztreonam: 

PENICILLIN BINDING PROTEINS : Mechanism of action of Aztreonam Site of action of Aztreonam

β-lactamase inhibitor : 

β-lactamase inhibitor Clavulanic acid, sulbactam, tazobactam Ampicillin, amoxicillin, ticarcillin, piperacill 등과 병용요법 β-lactamase 형성 세균에 유효 E. coli, Klebsiella spp., H. influenza, Moraxella catarrhalis, Providencia spp., Bacteroides spp, Staphylococcus spp. Enterobacter, Pseudomonas, Acinetobacter

β-lactamase inhibitor: 

β-lactamase inhibitor

CARBAPENEM: 

CARBAPENEM Imipenem-Cilastatin IMIPENEM is a carbapenem that binds to PBP-2  cell lysis CILASTATIN is a peptidase inhibitor that blocks renal degradation of Imipenem Broad spectrum Good coverage of hospital-acquired Gram(-) organisms including anaerobes Allergic reactions

IMIPENEM-CILASTATIN (Primaxin): 

IMIPENEM-CILASTATIN (Primaxin  ) b - lactam ring

Penicillin Binding Proteins Mechanism of action of Imipenem: 

Penicillin Binding Proteins Mechanism of action of Imipenem Site of action of Imipenem

INHIBITORS OF CELL WALL SYNTHESIS: 

INHIBITORS OF CELL WALL SYNTHESIS PENICILLINS CEPHALOSPORINS OTHER b -LACTAM ANTIBIOTICS VANCOMYCIN

Structure and Mechanism of Action of Vancomycin : 

Structure and Mechanism of Action of Vancomycin

VANCOMYCIN: 

VANCOMYCIN Prevents polymerization of peptidoglycan Narrow spectrum – Gram (+) cocci, Staph. & Strep., Enterococcus, Clostridium sp. 2 nd line therapy for Gram (+) cocci Adverse reactions Ototoxicity “ Red neck ” syndrome Clinical Uses Methicillin-resistant Staphylococcus (MRSA) Pseudomembranous colitis by Clostridium difficile (alternate to Metronidazole)

Slide 69: 

Vancomycin Resistance

Vancomycin Resistance: 

Vancomycin Resistance

Classification I; Bacterial Targets for Antibiotics: 

Classification I; Bacterial Targets for Antibiotics