1. Cell Wall Synthesis Inhibitors By S.Bohlooli, PhD

2. Inhibitors of Cell Wall Synthesis Penicillins Penicillins Cephalosporins Cephalosporins Monobactams Monobactams Carbapenems Carbapenems Glycopeptides Other Cell Wall- or Membrane-Active Agents

3. Chemical Structure

5. Penicillins In 1928, Alexander Fleming was researching vaccines and noticed a culture of staphlococci had undergone lysis from contamination with a mold In 1928, Alexander Fleming was researching vaccines and noticed a culture of staphlococci had undergone lysis from contamination with a mold Fleming finally isolated the mold, Penicillium notatum, and found that the fluid beneath it possessed antibacterial properties Fleming finally isolated the mold, Penicillium notatum, and found that the fluid beneath it possessed antibacterial properties Basic structure consists of thiazolidine ring connected to  -lactam ring, to which is attached a side chain Basic structure consists of thiazolidine ring connected to  -lactam ring, to which is attached a side chain

6. Structure of penicillins and products of their enzymatic hydrolysis.

7. Chemical structure,major variants

9. Cell envelope of a gram-negative bacterium

11. Biosynthesis of cell wall peptidoglycan

12. Mechanism of Action Interferes with last step of bacterial cell wall synthesis, causing cell lysis Interferes with last step of bacterial cell wall synthesis, causing cell lysis Bactericidal Bactericidal Only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall Only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall Inactive against mycobacteria, fungi, viruses Inactive against mycobacteria, fungi, viruses

13. Mechanism of Action way of being bactericide Penicillin binding proteins Penicillin binding proteins Enzymes involved in forming cross linkages between peptidoglycan chains inactivated by penicillin Enzymes involved in forming cross linkages between peptidoglycan chains inactivated by penicillin Inhibition of transpeptidase Inhibition of transpeptidase Hinders last step in formation of cross links needed for cell wall integrity Hinders last step in formation of cross links needed for cell wall integrity Autolysins Autolysins Normally degrade cell wall, but penicillin prevents new synthesis Normally degrade cell wall, but penicillin prevents new synthesis

14. Antibacterial Spectrum Natural penicillins Natural penicillins Antistaphylococcal penicillins Antistaphylococcal penicillins Extended spectrum penicillins Extended spectrum penicillins Antipseudomonal penicillins Antipseudomonal penicillins

15. Natural Penicillins Penicillin G (Benzylpenicillin) Penicillin G (Benzylpenicillin) Gram +/- cocci, Gram + bacilli, spirochetes, anaerobes Gram +/- cocci, Gram + bacilli, spirochetes, anaerobes Susceptible to inactivation by  -lactamase Susceptible to inactivation by  -lactamase Penicillin V Penicillin V Similar spectrum Similar spectrum More acid stable than Pen G More acid stable than Pen G Higher minimum inhibitory concentration Higher minimum inhibitory concentration

16. Bacteria Susceptible to Penicillin Strep pneumonia Strep pneumonia Major cause of bacterial pneumonia in all ages Major cause of bacterial pneumonia in all ages Gonorrhea Gonorrhea Neisseria gonorrhea and meningitidis Neisseria gonorrhea and meningitidis Syphilis Syphilis Treponema pallidum Treponema pallidum

17. Antistaphylococcal penicillins Methicillin Methicillin Nafcillin Nafcillin Oxacillin Oxacillin Dicloxacillin Dicloxacillin All are penicillinase-resistant penicillins used in penicillinase-producing staphylococci All are penicillinase-resistant penicillins used in penicillinase-producing staphylococci  Methicillin-resistant staph aureus

18. Extended Spectrum Penicillins Ampicillin Ampicillin Amoxicillin Amoxicillin Activity against haemophilus influenza, proteus mirabilis, E. coli, and neisseria species Activity against haemophilus influenza, proteus mirabilis, E. coli, and neisseria species Resistance due to plasmid mediated penicillinase Resistance due to plasmid mediated penicillinase May use clavulanic acid or sulbactam to extend the antibacterial activity May use clavulanic acid or sulbactam to extend the antibacterial activity

19. Antipseudomonas Penicillins Carbenicillin Carbenicillin Ticarcillin Ticarcillin Piperacillin Piperacillin Azlocillin Azlocillin Mezlocillin Mezlocillin Effective against pseudomonas aeroginosa and other gram negatives Effective against pseudomonas aeroginosa and other gram negatives

20. Penicillins and Aminoglycosides Synergistic Synergistic Inactivate each other if placed in same IV fluid bag because of positively charged aminoglycosides and negative penicillins Inactivate each other if placed in same IV fluid bag because of positively charged aminoglycosides and negative penicillins

21. Specific Indications for Penicillin Narrow-spectrum bactericidal Narrow-spectrum bactericidal Most Gm+ cocci and rods and anaerobes Most Gm+ cocci and rods and anaerobes Intravenous: Pen G (potassium or sodium) Intravenous: Pen G (potassium or sodium) Intramuscular: Benzathine or procaine Pen G Intramuscular: Benzathine or procaine Pen G Oral: Pen V Oral: Pen V Pen V, G well distributed in soft tissues Pen V, G well distributed in soft tissues Bone level is fraction of plasma concentration Bone level is fraction of plasma concentration Excreted primarily via kidneys Excreted primarily via kidneys

22. Bacterial Resistance   -lactamase activity Hydrolyzes cyclic amide bond of  -lactam ring Hydrolyzes cyclic amide bond of  -lactam ring Usually acquired by transfer of plasmids Usually acquired by transfer of plasmids 2. Decreased permeability to drug 3. Altered penicillin binding proteins May require greater antibiotic concentrations May require greater antibiotic concentrations 4. Efflux

23.  -lactamase Inhibitors Clavulanic acid: product of streptomyces clavuligerus Clavulanic acid: product of streptomyces clavuligerus Irreversibly binds  -lactamases and inactivates them Irreversibly binds  -lactamases and inactivates them Augmentin: amoxicillin + clavulanic acid Augmentin: amoxicillin + clavulanic acid Timentin: ticarcillin + clavulanic acid Timentin: ticarcillin + clavulanic acid Unasyn: ampicillin + sulbactam Unasyn: ampicillin + sulbactam

25. Pharmacokinetics Administration Administration Oral, IV, IM Oral, IV, IM Absorption Absorption Amoxicillin most completely absorbed Amoxicillin most completely absorbed Pen G absorption impeded by food in stomach Pen G absorption impeded by food in stomach Administered at least 1–2 hours before or after a meal. Distribution Distribution All cross placenta All cross placenta Minimal penetration into bone and CSF Minimal penetration into bone and CSF

27. Pharmacokinetics (con’t) Metabolism Metabolism Minimal, except in renal failure Minimal, except in renal failure Excretion Excretion Kidney Kidney Adjust dose in renal compromise Adjust dose in renal compromise Probenecid inhibits penicillin secretion Probenecid inhibits penicillin secretion

28. Adverse Reactions Hypersensitivity- 1-10% patients treated Hypersensitivity- 1-10% patients treated Penicilloic acid- hapten for immune reaction Penicilloic acid- hapten for immune reaction Urticaria to angioedema to anaphylaxis Urticaria to angioedema to anaphylaxis  -lactam cross reactivity  -lactam cross reactivity Diarrhea- disruption of flora- ampicillin Diarrhea- disruption of flora- ampicillin Nephritis- methicillin Nephritis- methicillin Neurotoxicity- intrathecal or seizure disorders Neurotoxicity- intrathecal or seizure disorders Platelet dysfunction- carbenicillin, ticarcillin Platelet dysfunction- carbenicillin, ticarcillin Cation toxicity- watch sodium (congenstive heart failure) and potassium (cardiac toxicity esp in renal failure pts) Cation toxicity- watch sodium (congenstive heart failure) and potassium (cardiac toxicity esp in renal failure pts) Skin rashes-ampicillin and amoxicillin

29. Allergic Reactions Acute (< 30 min) Acute (< 30 min) Urticaria, angioedema, bronchoconstriction, GI, shock Urticaria, angioedema, bronchoconstriction, GI, shock Accelerated (30 min-48 hrs) Accelerated (30 min-48 hrs) Urticaria, pruritis, wheezing, mild laryngeal edema, local inflammatory reactions Urticaria, pruritis, wheezing, mild laryngeal edema, local inflammatory reactions Delayed (> 2 days) Delayed (> 2 days) Skin rash Skin rash Oral glossitis, flurred tongue, black and brown tongue, cheilosis, severe stomatitis with loss buccal mucosa Oral glossitis, flurred tongue, black and brown tongue, cheilosis, severe stomatitis with loss buccal mucosa

30. Allergic Reactions Mild: Diphenhydramine 25-50 mg IV/IM/PO Mild: Diphenhydramine 25-50 mg IV/IM/PO Severe: Epinephrine 0.03-0.05 mg Severe: Epinephrine 0.03-0.05 mg Skin tests: benzylpenicilloyl-polylysine Skin tests: benzylpenicilloyl-polylysine

31. Cephalosporins Cephalosporium acremonium, first source, isolated in 1948 Cephalosporium acremonium, first source, isolated in 1948  -lactam antibiotics  -lactam antibiotics Related to penicillins structurally and functionally Related to penicillins structurally and functionally More resistant to  -lactamases More resistant to  -lactamases

37. Antibacterial Spectrum First generation First generation Second generation Second generation Third generation Third generation Fourth generation Fourth generation Increased generation number, increased gram negative bacterial susceptibility, increased  - lactamase resistance, decreased efficacy against gram + Increased generation number, increased gram negative bacterial susceptibility, increased  - lactamase resistance, decreased efficacy against gram +

38. First Generation Gram + cocci, gram - bacilli, oral anaerobes Gram + cocci, gram - bacilli, oral anaerobes Staphylococcus aureus, Proteus mirabilis, E. coli, Klebsiella pneumonia Staphylococcus aureus, Proteus mirabilis, E. coli, Klebsiella pneumonia Cefazolin, Cephalothin (parenteral) Cefazolin, Cephalothin (parenteral) Cephalexin, Cefadroxil, Cephradine (oral) Cephalexin, Cefadroxil, Cephradine (oral)

39. Second Generation Less active against G+, more G- Less active against G+, more G- Haemophilus influenzae, Enterobacter aerogenes, Neisseria Haemophilus influenzae, Enterobacter aerogenes, Neisseria Cefaclor, Cefuroxime axetil (Oral) Cefaclor, Cefuroxime axetil (Oral) Cefamandole, Cefonicid, Cefuroxime, Cefotetan, Ceforanide (Parenteral) Cefamandole, Cefonicid, Cefuroxime, Cefotetan, Ceforanide (Parenteral) Cefoxitin- Bacteroides fragilis Cefoxitin- Bacteroides fragilis Used with aminoglycosides for G - bacilli Used with aminoglycosides for G - bacilli

40. Third Generation More Gm – bacilli, Serratia marcescens More Gm – bacilli, Serratia marcescens Cefixime (Oral) Cefixime (Oral) Cefotaxime Cefotaxime Ceftizoxime Ceftizoxime Ceftazidime Ceftazidime Cefoperazone Cefoperazone Ceftriaxone Ceftriaxone Cefpodoxime Cefpodoxime

41. Fourth Generation Similar spectrum to third generation Similar spectrum to third generation More resistance to  -lactamases More resistance to  -lactamases Cefepime hydrochloride Cefepime hydrochloride

42. Cephalosporins Active Against Methicillin-Resistant Staphylococci Ceftaroline fosamil Ceftobiprole medocaril Binding to penicillin-binding protein 2a

43. Resistance Similar to penicillins Similar to penicillins Limited cross resistance with penicillin, except with staph and strep pneumonia Limited cross resistance with penicillin, except with staph and strep pneumonia

44. Pharmacokinetics Administration Administration Distribution Distribution Distributed well through body fluids Distributed well through body fluids Only third generation well into CSF Only third generation well into CSF Excretion Excretion Renal elimination Renal elimination Cefoperazone and ceftriaxone excreted through bile and feces Cefoperazone and ceftriaxone excreted through bile and feces

45. General Therapeutic Uses Acute respiratory infection Acute respiratory infection First and second generation First and second generation Gonorrhea and H. influenza Gonorrhea and H. influenza Ceftriaxone Ceftriaxone Enterobacter, Serratia, E.Coli, Providencia, Salmonella Enterobacter, Serratia, E.Coli, Providencia, Salmonella Third generation Third generation Gram negative meningitis and septicemia Gram negative meningitis and septicemia Third generation Third generation

46. Adverse Effects Allergy- 15% cross sensitivity with Pen allergy Allergy- 15% cross sensitivity with Pen allergy 1-2% without Pen allergy 1-2% without Pen allergy Disulfiram-like effect Disulfiram-like effect Cefamandole, cefoperazone when ingested with alcohol block second step in oxidation and aldehyde accumulation Cefamandole, cefoperazone when ingested with alcohol block second step in oxidation and aldehyde accumulation Bleeding Bleeding Cefamandole, cefoperazone- anti-vitamin K effects Cefamandole, cefoperazone- anti-vitamin K effects Renal, hepatic dysfunction Renal, hepatic dysfunction

47. Carbapenems Synthetic  -lactam antibiotics Synthetic  -lactam antibiotics Differ from penicillin in sulfur atom of thiazolidine ring Differ from penicillin in sulfur atom of thiazolidine ring Imipenem Imipenem Combined with cilastin- broadest spectrum  - lactam antibiotic available against penicillinase- producing Gram + and -, anaerobes, and pseudomonas Combined with cilastin- broadest spectrum  - lactam antibiotic available against penicillinase- producing Gram + and -, anaerobes, and pseudomonas Resists  -lactamase hydrolysis Resists  -lactamase hydrolysis Meropenem, Meropenem, doripenem, ertapenem Greater activity against gram-negative aerobes

48. Carbapenems Intravenous use Intravenous use Penetrates well into CNS Penetrates well into CNS Excreted by kidneys Excreted by kidneys Toxic metabolite may cause nephrotoxicity Toxic metabolite may cause nephrotoxicity Administered with cilastin to prevent cleavage and toxic metabolite formation Administered with cilastin to prevent cleavage and toxic metabolite formation Nausea, vomiting, diarrhea, seizures, eosinophilia, and neutropenia Nausea, vomiting, diarrhea, seizures, eosinophilia, and neutropenia

49. Monobactams Narrow spectrum- enterobacteriaceae, pseudomonas; no gram + or anaerobic activity Narrow spectrum- enterobacteriaceae, pseudomonas; no gram + or anaerobic activity Resistant to  -lactamase Resistant to  -lactamase Aztreonam IV or IM Aztreonam IV or IM Phlebitis, skin rash, abnormal liver function tests Phlebitis, skin rash, abnormal liver function tests Little cross reactivity with penicillin Little cross reactivity with penicillin

50. Vancomycin It binds firmly to the D-Ala-D-Ala terminus and inhibits transglycosylase. It binds firmly to the D-Ala-D-Ala terminus and inhibits transglycosylase. Narrow-spectrum against methicillin-resistant staphylococci and pseudomembranous colitis caused by clostridium difficile Narrow-spectrum against methicillin-resistant staphylococci and pseudomembranous colitis caused by clostridium difficile Prophylaxis for subacute bacterial endocarditis in penicillin allergic patients for high risk surgery Prophylaxis for subacute bacterial endocarditis in penicillin allergic patients for high risk surgery Oral route only for P. colitis Oral route only for P. colitis IV for systemic infections IV for systemic infections

51. Vancomycin Minimal resistant bacteria, but not vancomycin resistant enterococci (VRE) Minimal resistant bacteria, but not vancomycin resistant enterococci (VRE) Renal elimination Renal elimination Fever, chills, phlebitis at infusion site, rash with chronic administration, ototoxicity (cochlear damage above 80  g/ml), nephrotoxicity Fever, chills, phlebitis at infusion site, rash with chronic administration, ototoxicity (cochlear damage above 80  g/ml), nephrotoxicity Slow IV administration- fast causes histamine release (“red man syndrome”), hypotension Slow IV administration- fast causes histamine release (“red man syndrome”), hypotension

52. Newer glycopeptide antibiotics Teicoplanin It can be given intramuscularly Dalbavancin Derived from teicoplanin Effectrive on methicillin-resistant and vancomycin- intermediate S aureus Telavancin Derived from vancomycin active versus gram-positive bacteria including strains with reduced susceptibility to vancomycin

53. Other Cell Wall- or Membrane-Active Agents Daptomycin Novel cyclic lipopeptide Similar to that of vancomycin Active against vancomycin-resistant strains of enterococci and S aureus Fosfomycin Analog of phosphoenolpyruvate Active against both gram-positive and gram-negative Cycloserine Bacitracin

54. Mechanism of action of daptomycin

55. Bacitracin Bacitracin inhibits cell wall synthesis by interfering with dephosphorlyation in cycling of the lipid carrier Bacitracin inhibits cell wall synthesis by interfering with dephosphorlyation in cycling of the lipid carrier Effective against Gram positive microorganisms Effective against Gram positive microorganisms Topical application due to nephrotoxicity Topical application due to nephrotoxicity Often used for traumatic abrasions Often used for traumatic abrasions