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Penicillin
Penicillin and its derivatives were the first widely used antibiotics. Alexander Fleming discovered penicillin in 1928. It was mass produced during World War II and saved many lives. There are natural and semisynthetic penicillins. Semisynthetics were developed to overcome limitations of natural penicillins like poor oral absorption. They include penicillinase-resistant drugs like methicillin, extended-spectrum drugs like ampicillin, and beta-lactamase inhibitor combinations. Semisynthetics have variable spectra, stability, absorption and uses against different bacteria. Common adverse effects include diarrhea, rash and hypersensitivity reactions.
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Penicillin
- 1. By: Dr. ShruthiRammohan 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 discoveredPenicillin? Alexander Fleming (1881-1955)
- 4. History Scottish biologistand 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 7TH MARCH, 1929
- 5. History Mass productionof 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
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- 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 PenicillinG (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 chaincan 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 PENICILLINBINDING PROTEINS (PBPs) (ANIMATION)
- 14. β- Lactam Antibiotic (Penicillin) PENICILLINBINDING 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 Narrowspectrum ◦ 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- DRUGOF 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/LatentSyphilis 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 Tetanusand 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- *Commonlyseen 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 Localirritation ◦ 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 PenicillinV 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
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- 28. Learning Objectives: Classification(Semisynthetic Penicillins) Structure and Properties Penicillinase- resistant penicillins Extended spectrum penicillins β-Lactamase inhibitors Bacterial Resistance
- 29. Why Semisynthetics? Penicillin Ghas… 1. Poor oral efficacy 2. Susceptibility to penicillinase 3. Not stable in gastric acid; rapidly broken down in stomach 4. Narrow spectrum of activity 5. 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 SemisyntheticPns - produced by chemically combining specific side chains to 6-aminopenicillanic acid 6- aminopenicillanic acid
- 34. Penicillinase Resistant: Methicillin Cloxacillin Dicloxacillin • Side chains protect β– Lactam ring from penicillinase (staphylococcal) • Partially protects bacteria from β– Lactam ring. Oxacillin Flucloxacillin Nafcillin
- 35. Methicillin: Highly penicillinaseresistant 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
- 36. MRSA: Methicillin Resistant StaphylococcusAureus 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
- 37. Cloxacillin/Dicloxacillin Highly penicillinaseresistant 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
- 38. 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
- 39. 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
- 40. 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. 6th 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
- 41. 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 6th 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)
- 42. Other prodrugsof ampicillin ◦ Talampicillin ◦ Pivampicillin ◦ Hetacillin
- 43. Carbenicillin: Has activityagainst 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
- 44. Other carboxypenicillins ◦Ticarcillin ◦ Temocillin
- 45. Piperacillin: Has moreactivity 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
- 46. Other ureidopenicillins ◦Mezlocillin ◦ Azlocillin
- 47. β- Lactamase Inhibitors: Clavulanic Acid Sulbactam Tazobactam
- 48. 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
- 49. CLAVULANIC ACID SULBACTAMTAZOBACTAM 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 6-8th hourly Adverse Effects: • Pain at site of injection • Thrombophlebitis • Diarrhea • Combined with Piperacillin • Combined with ceftriaxone also Dose: 4g + 0.5g iv over 30min, 8th hourly
- 50. Bacterial Resistance: Primarilydue 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
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