Successfully reported this slideshow.

Beta lactam antibiotics

55

Share

Upcoming SlideShare
Penicillin
Penicillin
Loading in …3
×
1 of 37
1 of 37

More Related Content

More from Mahatma Gandhi Medical College & Hospital

Related Books

Free with a 14 day trial from Scribd

See all

Related Audiobooks

Free with a 14 day trial from Scribd

See all

Beta lactam antibiotics

  1. 1. BETA LACTAM ANTIBIOTICS: THE PENICILLIN STORY Dr. K. Manimekalai (Professor and Head) Dept. of Pharmacology
  2. 2. LEARNING OBJECTIVES • What are beta lactam antibiotics? • How was penicillin discovered? • How does penicillin act and against which organisms? • What are the methods by which bacteria became resistant to penicillins? • What are the different classes of penicillins? • How are they used and what are the safety precautions during their use? • What are beta lactamase inhibitors?
  3. 3. BETA LACTAMS • Penicillins, Cephalosporins, Monobactams, Carbapenems. • Common structure (BETA LACTAM RING) fused with a THIAZOLIDINE ring and a side chain • Both rings constitute Penicillin nucleus = 6 - AMINO PENICILLINIC ACID • Nucleus + side chain ~ Antibacterial activity • Side chain ~ Stability against degradation by gastric juice and PENICILLINASE (BETA LACTAMASE)
  4. 4. DISCOVERY OF PENICILLIN • In 1928, Alexander Fleming observed that a mould contaminating one of his cultures of Staphylococcus caused the bacteria in its vicinity to undergo lysis. • Broth in which the fungus was grown was inhibitory for many micro-organisms. • Because the mould belonged to the genus Penicillium, Fleming named the antibacterial substance Penicillin.
  5. 5. DISCOVERY OF PENICILLIN • A decade later, penicillin was developed as a systemic therapeutic agent by Florey, Chain, and Abraham • By May 1940, a crude preparation produced dramatic therapeutic effects in mice with streptococcal infection. • By 1941, therapeutic trials in several patients with staphylococcal and streptococcal infections refractory to all other therapy • Effective procedure developed for mass synthesis of penicillins by the late 40s
  6. 6. MOA • Peptidoglycan cell wall • Penicillin binding proteins (PBPs) • CELL WALL SYNTHESIS (Transpeptidation, Carboxypeptidation, Endopeptidation) • Activation of autolysins • Bactericidal effect • CWD bacteria bursts bcos interior is hyperosmotic.
  7. 7. CLASSIFICATION • NATURAL PENICILLINS Penicillin G (Benzyl penicillin) Procaine penicillin G Benzathine penicillin G Penicillins other than natural are semisynthetic • ACID RESISTANT PENICILLINS Penicillin V (Phenoxymethyl penicillin) • PENICILLINASE RESISTANT PENICILLINS Methicillin, Nafcillin, Cloxacillin, Flucloxacillin
  8. 8. CLASSIFICATION • EXTENDED SPECTRUM PENICILLINS Aminopenicillins – Ampicillin, Amoxicillin Carboxypenicillins – Carbenicillin, Ticarcillin Ureidopenicillins – Piperacillin, Mezlocillin Amidinopenicillins - Mecillinam • PENICILLINS WITH BETA LACTAMASE INHIBITORS Amoxycillin – Clavulanic acid Ampicillin – Sulbactam Piperacillin - Tazobactam
  9. 9. ANTIMICROBIAL SPECTRUM NATURAL PENICILLINS • Narrow spectrum • Cocci – Strep-, Pneumo- (G+), Nisseria- (G-) • Bacilli – B.anthracis, Corynebacterium diphtheriae, Clostridia, Listeria, Treponema PENICILLINASE RESISTANT PENICILLINS • Beta lactamase producing Staph (Now >> MRSA infections)
  10. 10. RESISTANCE • Natural resistance as target enzymes and PBPs are deep seated (G-) • Acquired resistance
  11. 11. RESISTANCE MECHANISMS • MODIFICATION OF PBPs (MRSA, Streptococcus pneumoniae, Enterococcus) • ↓ PERMEABILITY TO REACH PBPs (Pseudomonas) • ACTIVATION OF EFFLUX MECHANISMS (Salmonella, Pseudomonas)
  12. 12. PENICILLIN G PK • A - Acid labile (Poor oral absorption) IM Sod. PnG absorption rapid and complete • D – CSF, serous cavities poor, except when inflamed, 60% plasma protein binding • E – Renal Caution in elderly, renal failure Q. What happens when PROBENECID and PENICILLIN are given concurrently?
  13. 13. PENICILLIN G PREPARATIONS AND DOSE • UNITAGE: 1U of Crystalline sodium Benzyl Penicillin = 0.6µg of the standard preparation or, 1g = 1.6 Million U (MU) • Inj Sod PnG (Crystalline penicillin) 0.5-5 MU IM/IV q6h – 12h • Repository PnG inj to be administered deep IM ONLY (NEVER IV) Inj Procaine PnG 0.5-1 MU IM q12-24h Inj Fortified Procaine PnG (Procaine PnG + Sod. PnG) Inj Benzathine PnG – 0.6 – 2.4 MU IM/2-4 WKS (sustained release for prophylaxis)
  14. 14. PENICILLIN G USES • Streptococcal infections – URTI, Otitis media, Rheumatic fever, SABE (with Gentamicin) • Pneumococcal infections – ONLY if organism is sensitive • Meningococcal infections – IV >> doses • Gonorrhoea – Ophthalmia neonatorum due to sensitive N. gonorrhoae
  15. 15. PENICILLIN G • Syphilis – Benzathine PnG 2.4 MU IM /WK X 2-3 WKS or, Procaine PnG 1.2 MU IM/DAY X 10 DAYS • Diphtheria - Procaine PnG 1.2 MU IM/DAY X 10 DAYS (ADJUVANT) • Tetanus and Gas gangrene (ADJUVANT) • Anthrax, Trench mouth, Rat bite fever, Actinomycosis (craniofacial/thoracic/abdominal abscess)
  16. 16. PENICILLIN G • PROPHYLACTIC USES – Rheumatic fever SABE (during dental extraction, endoscopy, catheterisation, surgical procedures likely to cause bacteremia) Gonorrhoea Syphilis Surgical site infections
  17. 17. PENICILLIN G ADRs • Local irritation & Direct toxicity - Inj site pain - Thrombophlebitis of injected Vv - CNS toxicity - Platelet malfunction (Bleeding) - Microembolism • Hypersensitivity
  18. 18. PENICILLIN G - Rash, itching, urticaria, fever, wheezing, angioneurotic edema, serum sickness, exfoliative dermatitis - ANAPHYLAXIS - Partial cross sensitivity Q. How will you manage anaphylaxis caused by penicillin? • Superinfections • Jarisch-Herxheimer reaction Precautions – Elicit H/O penicillin allergy, scratch test or intradermal test (2-10 U)
  19. 19. SEMISYNTHETIC PENICILLINS The major drawbacks of benzyl penicillin are: • Inactivation by the gastric acid. • Short duration of action. • Poor penetration into the CSF. • Narrow spectrum of activity. • Development of resistant organisms, especially staphylococci; and • Possibility of anaphylaxis.
  20. 20. • (Penicillin V) • Spectrum is like that of benzyl penicillin. • Penicillin V may be employed in less serious infections due to pneumococci and streptococci.
  21. 21. METHICILLIN • As several strains of staphylococci have developed resistance to methicillin, it is now rarely used except for laboratory testing for MRSA. • The term methicillin resistant staphylococcus aureus (MRSA) is used to refer to beta-lactam- antibiotic-resistant (i.e., penicillinase producing) staphylococci.
  22. 22. • CLOXACILLIN: Acid resistant. • DICLOXACILLIN: Highly (95%) protein. • AMPICILLIN: Ampicillin is water soluble and acid resistant. • It is highly effective against various Gram- negative bacteria. • The Gram-positive cocci are less sensitive to ampicillin. • ADVERSE REACTIONS: • Skin rashes are more common.
  23. 23. THERAPEUTIC USES: • Urinary tract infections. • Respiratory tract infections • Meningitis and subacute bacterial endocarditis. • Biliary tract and intestinal infections.
  24. 24. • Miscellaneous: • Management of intestinal malabsorption and is preferred in the treatment of whooping cough. • The other drugs useful in whooping cough are azithromycin (the drug of choice), erythromycin and co-trimoxazole.
  25. 25. • TALAMPICILLIN: is a prodrug. • AMOXICILLIN: • Advantages: a) Almost completely absorbed b) Absorption is not influenced by food. c) Less protein bound and the urinary excretion is higher than that of ampicillin. d) The incidence of diarrhoea is less However, much more expensive. Preferred for preventing the carrier state in typhoid fever.
  26. 26. EXTENDED SPECTRUM PENICILLINS Carboxypenicillins and the ureido penicillins They are acid labile and susceptible to beta lactamase. They are highly active against anaerobes. They are most useful in infections caused by P. aeruginosa and other Gram negative rods. They are much less active than penicillin G against Gram positive organisms and are not reliable for treating staphylococcal infections.
  27. 27. • The CNS penetration of the carboxy and the ureido-penicillins is about 10% of their serum levels, and hence they are not recommended for the treatment of meningeal infections. • They act synergistically with aminoglycoside antibiotics, particularly against P.aeruginosa and the Enterobacteriaceae. • They may inactivate the aminoglycoside antibiotics in vitro when mixed together in the same bottle.
  28. 28. CARBENICILLIN • Its important advantage over ampicillin is that it is effective against all strains of Proteus and P. aeruginosa. • The drug can cause CHF because of its large sodium content, and bleeding due to abnormal platelet aggregation.
  29. 29. TICARCILLIN • Analogue of Carbenicillin is twice as active against P. aeruginosa. • Anaerobes Bacteroides fragilis. • Usually combined with clavulanic acid to increase effective blood levels. • It can be combined with amino glycosides. • Because of its high sodium content, it may cause sodium overload in patients with cardiac or renal damage.
  30. 30. PIPERACILLIN • Gram negative bacilli, particularly P. aeruginosa • Eliminated in the urine adjustment of its dose in the presence of renal damage. • Piperacillin crosses the BBB and may be useful in neonatal meningitis. • Less likely to cause sodium overload. • Azlocillin and mezlocillin have similar indications as piperacillin.
  31. 31. Amidinopenicillins MECILLINAM • Mecillinam has no therapeutic activity against Gram positive organisms but is highly effective against Gram negative organisms • Poorly absorbed orally and is given IM. • Used in UTI and in typhoid fever, but do not appear to be superior to the other commonly used drugs.
  32. 32. BETA LACTAMASE INHIBITORS CLAVULANIC ACID: • It is well absorbed on oral administration but has only a weak antibacterial activity. • It is a potent and irreversible inhibitor of many beta lactamases and protects beta lactam antibiotics from inactivation, when combined with them.
  33. 33. • Combined with amoxicillin, it widens the antibacterial spectrum of the latter to include beta lactamase producing strains of staph. aureus, H. influenzae, N. gonorrhoea, E. coli, Proteus, Klebsiella, M. catarrhalis and Bacterodies species. • Used in combination with amoxicillin or ticarcillin.
  34. 34. SULBACTAM • It is combined with ampicillin. • Tazobactam is a penicillanic-acid-sulfone • It is combined with piperacillin. • These combinations are expensive and are not cost-effective for routine infections • Should be reserved for infection due to beta lactamase producing organisms.
  35. 35. • The beta lactamases produced by Ps. Aeruginosa and by Enterobacter species are resistant to clavulanic acid and sulbactam. • Further, MRSA are not susceptible to antimicrobials containing clavulanic acid or sulbactam.
  36. 36. SUMMARY • Penicillins - beta lactam antibiotics • Discovered by Alexander Fleming • MOA by inhibition of cell wall synthesis by inhibiting PBPs and autolysin activation • Classified into natural and semisynthetic • Spectrum narrow, mainly G+ cocci, bactericidal, but semisynthetic penicillins have broader spectrum • Natural penicillins injectible only and used in coccal infections, syphilis, prophylaxis of Rheumatic fever, SABE
  37. 37. THANK YOU

×