Penicillin

A presentation about natural and semisynthetic penicillins

1. By: Dr. Shruthi Rammohan PG in Pharmacology RRMCH

2. Penicillin Learning Objectives: History Classification (Natural Penicillins ) Structure and Properties Mechanism of Action Antibacterial Spectrum Uses Adverse Effects

3. History Who discovered Penicillin? Alexander Fleming (1881-1955)

4. History Scottish biologist and pharmacologist After World War I  elected Professor of Bacteriology at the University of London in 1928 Accidentally discovered Penicillin while studying properties of Staphylococci Described the mould as being from the genus Penicillium Named the substance released as Penicillin PENICILLIN WAS BORN 7 TH MARCH, 1929

5. History Mass production of the new drug for use in World War II Penicillin saved many lives during the war that may have been lost due to infected wounds Penicillin was also said to treat diphtheria, gangrene, pneumonia, syphilis and tuberculosis Penicillin- first antibiotic to be used clinically Fleming received the Nobel Prize in 1945

6. Classification

7. Semisynthetic Penicillins Acid Labile Penicillin- G (Benzyl Penicillin) Procaine penicillin- G Benzathine penicillin- G Penicillin- V ( Phenoxymethyl penicillin) Acid Resistant Penicillinase Resistant β - Lactamase inhibitors Natural Extended Spectrum Originally obtained from fungus Penicillium nonatum Present source from Penicillium chrysogenum

8. Preparations Sodium Penicillin G (crystalline penicillin) 0.5 – 5 MU i.m ./ i.v . 6-12 hourly Dry powder to be dissolved in sterile water Repository Penicillin G Injections - Insoluble salts given deep i.m ONLY 1. Procaine Penicillin G 0.5 – 1 MU i.m . 12-24 hourly 2. Fortified Procaine Penicillin G 3 lac U Procaine Pen + 1 lac U Sod. Pen G 3. Benzathine Penicillin G 0.6 – 2.4 MU i.m . every 2-4 weeks

9. Structure Penicillin Nucleus β - Lactam Ring Thiazolidine Ring Side Chain

10. Side chain can be split off by amidase Other side chains can be attached Beta- lactamases breakdown β – lactam ring

11. Water soluble Acid Labile Thermolabile A - Rapid and complete absorption ( i.m .) D - Distributed extracellularly E - Rapid renal excretion Tubular secretion * What happens if PROBENECID is given along with Penicillin?  Tubular secretion is blocked by probenecid , therefore higher and longer lasting plasma concentrations of penicillin

12. Mechanism of Action Interferes with bacterial cell wall synthesis PEPTIDOGLYCAN LAYER N- ACETYL MURAMIC ACID (NAM) N- ACETYL GLUCOSAMINE (NAG) AMINO ACID CHAINS

13. β - Lactam Antibiotic (Penicillin) TRANSPEPTIDASE CROSS-LINKING PENICILLIN BINDING PROTEINS (PBPs) (ANIMATION)

14. β - Lactam Antibiotic (Penicillin) PENICILLIN BINDING PROTEINS (PBPs) X - Inhibition of cross-linking (ANIMATION)

15. Mechanism of Action Cross-linking is blocked by: X - cleavage of terminal D- alanine X - transpeptidation of 5- glycine chain residues Inhibiting cell wall synthesis DAMAGES cell High osmotic pressure inside cell and low osmotic pressure outside causes cell to BURST due to a weak and unstable cell wall Bactericidal Autolysins released from penicillin-PBP complex to digest remaining cell wall remnants

16. Antibacterial Spectrum Narrow spectrum Gram positive bacteria Cocci - Streptococci, Pneumococci Bacilli- B. anthracis , C. diphtheriae , Clostridia and Listeria species Limited gram negative bacteria Cocci - Gonocci , Meningococci Actinomyces Spirochetes Treponema Leptospira

17. Uses Streptococcal Infections: Pharyngitis , Otitis Media, Scarlet Fever Rheumatic Fever Subacute Bacterial Endocarditis Pneumococcal Infections: Lobar Pneumonia Meningococcal Infections: Meningitis Gonococcal Infections: Ophthalmia Neonatorum Syphilis Leptospirosis

18. Diphtheria Tetanus Anthrax Actinomycosis Rat bite fever Prophylaxis Rheumatic Fever Bacterial Endocarditis Agranulocytosis

19. Uses Penicillin G- DRUG OF CHOICE IN: Subacute Bacterial Endocarditis Sodium PnG 10-20 MU i.v daily + Gentamicin for 2-6 weeks Ophthalmia Neonatorum Saline irrigation Sodium PnG 10,000-20,000 U/ mL 1 drop in each eye every 1-3hours

20. Syphilis Early/Latent Syphilis Procaine Pn 1.2 MU i.m . daily for 10 days OR Benzathine Pn 2.4 MU i.m . weekly for 4 weeks Late Syphilis Benzathine Pn 2.4 MU weekly for 4 weeks Cardiovascular/ Neurosyphilis Sodium PnG 5 MU i.m . 6 hourly for 2 weeks Leptospirosis Sodium PnG 1.5 MU i.v . 6 hourly for 7 days

21. Diphtheria Tetanus and Gas gangrene Anthrax Actinomycosis Rat bite fever Prophylaxis Rheumatic Fever Benzathine Pn 1.2 MU every 4 weeks until 18 years of age or 5 years after attack (whichever is more)

22. Adverse Effects Hypersensitivity- rash, itching, urticaria , fever wheezing, angioneurotic edema, serum sickness, exfoliative dermatitis (less common) Anaphylaxis (rare, but fatal)

23. Adverse Effects Hypersensitivity- *Commonly seen after PARENTERAL administration *Incidence highest with PROCAINE pn *History of penicillin allergy should be elicited *Scratch test or Intradermal Test dose - negative test does not rule out delayed hypersensitivity reactions!

24. Adverse Effects Superinfections Rare with PnG Bowel, respiratory and cutaneous microflora can undergo changes Jarisch - Herxheimer Reaction Shivering, fever, myalgia , exacerbation of lesions, vascular collapse Seen in syphilitic patients injected with Penicillin Due to sudden release of spirochetal lytic products Symptomatic treatment with aspirin and sedation

25. Adverse Effects Local irritation Pain at injection site Thrombophlebitis Neurotoxicity Mental confusion, muscular twitching, convulsions, coma Bleeding Due to interference of platelet function Intrathecal PnG injections (not recommended) Arachnoiditis , degenerative changes in spinal cord Accidental IV procaine penicillin injection CNS stimulation, hallucinations, convulsions

26. Phenoxymethyl Penicillin Penicillin V Acid stable Given orally Plasma t½ = 30-60 min Antibacterial spectrum- same as PnG Not used for serious infections (preferred only when oral drug is to be selected) Dose- 250-500mg 6 hourly

27. Semisynthetic Penicillins

28. Learning Objectives: Classification ( Semisynthetic Penicillins ) Structure and Properties Penicillinase - resistant penicillins Extended spectrum penicillins β - Lactamase inhibitors Bacterial Resistance

29. Why Semisynthetics ? Penicillin G has… Poor oral efficacy Susceptibility to penicillinase Not stable in gastric acid; rapidly broken down in stomach Narrow spectrum of activity Hypersensitivity reactions

30. Semisynthetic Penicillins Acid Labile Penicillin- G (Benzyl Penicillin) Procaine penicillin- G Benzathine penicillin- G Penicillin- V ( Phenoxymethyl penicillin) Acid Resistant Penicillinase Resistant β - Lactamase inhibitors Natural Extended Spectrum

31. Semisynthetic Penicillins Penicillinase Resistant β - Lactamase inhibitors Extended Spectrum Methicillin Cloxacillin Dicloxacillin Ampicillin Bacampicillin Amoxicillin Carbenicillin Piperacillin Mezlocillin Clavulanic acid Sulbactam Tazobactam Aminopenicillins Carboxypenicillins Ureidopenicillins

32. Structural Difference Semisynthetic Pns - produced by chemically combining specific side chains to 6-aminopenicillanic acid 6- aminopenicillanic acid

33. Penicillinase Resistant: Methicillin Cloxacillin Dicloxacillin Side chains protect β – Lactam ring from penicillinase (staphylococcal) Partially protects bacteria from β – Lactam ring. Oxacillin Flucloxacillin Nafcillin

34. Methicillin : Highly penicillinase resistant Acid Labile… should be administered parenterally Narrow spectrum- was used to treat certain Gram positive bacteria Induces penicillinase production Adverse effects- interstitial nephritis, hematuria , albuminuria Not in use due to resistance Replaced by other drugs in same group

35. MRSA: Methicillin Resistant Staphylococcus Aureus Insensitive to penicillinase - resistant penicillins , other β – lactams as well as other antibiotics Evolved from horizontal gene transfer  altered PBPs  do not bind to penicillins Drugs to be used in MRSA: Vancomycin Linezolid Ciprofloxacin

36. Cloxacillin / Dicloxacillin Highly penicillinase resistant Acid stable… can be given orally Used against staphylococcal infection EXCEPT MRSA Mostly binds to plasma proteins Dose: 0.25 – 0.5g every 6 hours Oxacillin / Floxacillin Similar to cloxacillin Nafcillin Given parenterally Other side effects- oral thrush, agranulocytosis , neutropenia

37. Extended Spectrum: AMINO- Ampicillin Bacampacillin Amoxacillin CARBOXY- Carbenicillin UREIDO- Piperacillin Mezlocillin Amino substitution in side chain Carboxylic acid group in side chain Cyclic ureas in side chain

38. AMPICILLIN AMOXICILLIN BACAMPACILLIN Acid Stable Incomplete oral absorption Food interference t½ = 1 hour Spectrum similar to PnG + S. viridans , enterococci and Listeria Partially excreted in bile and reabsorbed Enterohepatic circulation Primary excretion via kidney Acid Stable Not a prodrug Better oral absorption No food interference t½ = 1 hour Spectrum similar to ampicillin + more active against penicillin resistant S. pneumoniae Similar to ampicillin Acid Stable Ester prodrug of ampicillin Complete GIT absorption t½ ≈ 1 hour Spectrum similar to ampicillin Similar to ampicillin

39. AMPICILLIN AMOXICILLIN BACAMPACILLIN Uses: UTI Respiratory tract -Bronchitis - Otitis media -Sinusitis Meningitis Gonorrhea (Single dose 3.5g + 1g of probenecid ) Cholecystitis SABE (2g i.v . 6 th hourly with gentamicin ) H. pylori Septicemia ANUG Uses same as ampicillin Preferred over ampicillin in many cases - Bronchitis - UTI - SABE - Gonorrhea Uses same as ampicillin

40. AMPICILLIN AMOXICILLIN BACAMPACILLIN Ampicillin + Cloxacillin Post operative infections Not synergistic Irrational and harmful Adverse Effects: Diarrhea Rashes - HIV - EB virus infection - Lymphatic leukemia Dose 0.5 - 2g 6 th hourly (oral/ i.m / i.v ) Coamoxiclav Lower incidence of diarrhea 0.25 – 1g TID (oral/ i.m /slow i.v ) Less incidence of diarrhea 400 – 800mg BD (oral)

41. Other prodrugs of ampicillin Talampicillin Pivampicillin Hetacillin

42. Carbenicillin : Has activity against Pseudomonas and Proteus Acid Labile… should be administered parenterally t½= 1 hour Excreted rapidly in urine Uses - serious Pseudomonas or Proteus infections Can be combined with Gentamicin BUT SHOULD NOT BE MIXED IN THE SAME SYRINGE Dose- 1-2g i.m or 1-5g i.v every 4-6 hours Adverse effects - fluid retention & CHF in patients with borderline renal and cardiac function, bleeding

43. Other carboxypenicillins Ticarcillin Temocillin

44. Piperacillin : Has more activity against Pseudomonas and Klebsiella , Enterobacteriaceae and Bacteroides Acid Labile… should be administered parenterally t½= 1 hour Excreted rapidly in urine Uses - serious Pseudomonas or Klebsiella infections like UTI Concurrent use of Gentamicin or tobramycin is advised Dose- 100-150mg/kg/day i.m / i.v in 3 divided doses Adverse effects - diarrhea, nausea, headache

45. Other ureidopenicillins Mezlocillin Azlocillin

46. β - Lactamase Inhibitors: Clavulanic Acid Sulbactam Tazobactam

47. CLAVULANIC ACID SULBACTAM TAZOBACTAM Streptomyces clavuligerus β - Lactam ring present but no antibacterial activity Inhibits a wide variety of β - Lactamases Inhibition increases with time “progressive” “Suicide” inhibitor Pharmacokinetics Rapid oral absorption t½= 1 hour Eiminated by glomerular filtration Combined with Amox Related chemically to clavulanic acid Some antibacterial activity present; too weak Irreversible β - Lactamase inhibitor Less potent than clavulanic acid; same inhibition with higher dose Inconsistent oral absorption Combined with Ampicillin Similar to sulbactam Antipseudomonal Broadens spectrum of Piperacillin Combined with Piperacillin

48. CLAVULANIC ACID SULBACTAM TAZOBACTAM COAMOXICLAV Combined with Amox Does not potentiate action of amox Uses: Skin, intra-abdominal, gynecological, urinary tract, biliary tract and resp tract infections Dose: 250mg + 125mg tab 500mg + 125mg tab 1g + 0.2g vial deep i.m / i.v Adverse Effects: Poor GI tolerance Candida infections Combined with Ampicillin Uses: PPNG gonorrhea Intra-abdominal infections Gynecological Skin/soft tissue infections Dose: 1g + 0.5g vial (1-2 vials Deep i.m / i.v 6-8 th hourly Adverse Effects: Pain at site of injection Thrombophlebitis Diarrhea Combined with Piperacillin Combined with ceftriaxone also Dose: 4g + 0.5g iv over 30min, 8 th hourly

49. Bacterial Resistance: Primarily due to production of penicillinase Mechanisms of resistance: Transformation Plasmid donor via Conjugation Bacteria resistant to penicillins Staphylococci S. pneumoniae Strains of Gonococci- PnG Strains of E. coli Penicillinase used to destroy PnG in blood samples

50. Bacterial Resistance: https://www.youtube.com/watch?v=qBdYnRhdWcQ

51. THANK YOU!