Beta latam antibiotics
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Penicillin works by binding to penicillin binding proteins and disrupting the cross-linking process in bacterial cell walls. This prevents cell wall synthesis and causes bacterial lysis. However, bacteria have developed resistance through mechanisms like beta-lactamases, which are enzymes that break down the beta-lactam ring structure of penicillin. To address this, beta-lactamase inhibitors like clavulanic acid were developed that bind irreversibly to beta-lactamases and protect the antibiotic from destruction.
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Beta latam antibiotics
- 3. Gram positive vs. Gram negative bacteria Source: Google Images
- 4. Cell Wall Source: Google Images
- 5. Structure of Peptidoglycan layer •Peptidoglycan is a carbohydrate composed of alternating units of NAMA and NAGA. •The NAMA units have a peptide side chain which can be cross linked from the L-Lys residue to the terminal D-Ala-D- Ala link on a neighboring NAMA unit. Source: Google Images
- 6. Transpeptidase Enzyme •The cross linking reaction is catalyzed by a class of transpeptidases known as penicillin binding proteins •A critical part of the process is the recognition of the D-Ala-D-Ala sequence of the NAMA peptide side chain by the PBP. Interfering with this recognition disrupts the cell wall synthesis. •β-lactams mimic the structure of the D-Ala-D-Ala link and bind to the active site of PBPs, disrupting the cross- linking process. Source: Google Images
- 8. Beta-Lactam Antibiotics β-lactam ring •Contains a beta-lactam ring in their molecular structures. •Nitrogen is attached to the beta carbon relative to the carbonyl ring and hence the name.
- 9. Classification •Penicillins •Cephalosporins •Other β-Lactam drugs --Cephamycins --Carbapenems --Oxacephalosporins --β-Lactamase inhibitors --Monolactams
- 10. Semisynthetic Penicillins 1.Acid resistant alternative to PnG Penicillin V (phenoxymethy peniciillin) 2. Penicillinase resistant penicillins methicillin and cloxacillin 3.Extended specturm penicillins A)Aminopenicillins: ampicillin, bacampicillin, amoxicillin B)Carboxypenicillins: carbenicillin, ticarcillin C)Ureidopeniciilins: pipercillin and mezlocillin 4. Beta lactamase inhibitors Clavulanic acid, sulbactam and tazobactam
- 12. Discovery of Penicillin(First beta- lactam drug) •Discovered in 1928. • While working in his lab, trying to kill a deadly bacteria,he noticed a blue mold growing on the dish •Learned that it was the mold Penicillum Notatum. •Penicillin is found in this mold. •Noticed that the bacteria around the mold was dissolving. Source: Google Images
- 13. How it is was Developed • For 9 years, nobody could purify the Penicillum Notatum to get the pure penicillin. Finally, in 1938, a team of Oxford University Scientists, headed by Howard Florey and Ernst B. Chain helped to develop penicillin. Source: Google Images
- 15. Penicillin
- 17. How do they work? 1. The β-lactam binds to Penicillin Binding Protein (PBP) 2. PBP is unable to crosslink peptidoglycan chains 3. The bacteria is unable to synthesize a stable cell wall 4. The bacteria is lysed
- 18. • Narrow spectrum • Steptococci, staph. Aureus, niesseria gonoarrhoeae, n.meningitiidis, B anthracis, corynebacterium diphtheriiae, clostridia, actinomyces israeli are sensitive to PnG • Mycobacteriuim tuvberculosis, chlamydeiase,rickettsiae, protozoa, fungi and viruses are totally insensitive to PnG • Rapid absorption and complete, peak plasma level in 30 min, • Reach most body fluids except CSF • 60% Protein bound, little metabolized because of rapid excretion mainly glomerular filteration and secretion • Tubular secretion can be blocked by using probenecid. PENICILLIN G
- 19. USES • Streptococcal infections • Penumococcal infections • Meningococcal infections • Gonorrhoea • Syphilis • Dyptheria • Tetanus and gas gangrene • Drug of choice for rare diseases like anthrax, actinomycetes, trench mouth, rat bite fever and those caused by listeria monocyotogenes Prophylactic uses • Rheumatic fever • Bacteria endocarditis • Agranulocytosis patients
- 20. Adverse effects of penicillin G • PnG is one of the most nontoxic antibiotic up to 20 MU has been injected in a day without any organ toxicity • Pain at i.m injection site, • Nauseas on oral ingestion • Thrombophlebitis of injected vein • Mental confusion • Muscular wasting/ twitching • Convulsion and coma
- 21. • Bleeding. • Arachnoiditis and degenerative changes in spinal cord. • Hallucinations and convulsion . • hypersensitivity • Allergy • Rashes, itching, urticarial and fever • Wheezing, angioneurotic edema, serum sickness • Exofoliative dermatitis • Anaphylaxis is rare Adverse effects of penicillin G
- 22. Preparation of penicillin G • Sod.penicillin G (crystalline penicillin) –i.m/i.v • Repository penicillin G injections: insoluble salts of PnG, Must be deep i.m They release slowly at the site of injection e.g: Procaine penicillin G (Inj) Benzathine penicillin G (Inj)
- 23. Penicillin V (Phenoxymethylpenicillin) EFFECTIVE AGAINST: • Gram positive + Less effective against Gram negative bacteria TREATMENT FOR: • Tonsillitis • Anthrax • Rheumatic fever • Streptococcal skin infections CHARACTERISTICS: • Narrow spectrum • Should be given orally • Prone to beta-lactamase
- 25. Ampicillin EFFECTIVE AGAINST: • Gram positive + Gram negative bacteria TREATMENT FOR: • Ear infection • Sinusitis • Urinary tract infections • Meningitis CHARACTERISTICS: • Broad spectrum • Can be given orally and parenterally • Prone to beta-lactamase Ampicillin Sulbactam + ll Unasyn
- 26. Amoxicillin EFFECTIVE AGAINST: • Gram positive + Gram negative bacteria TREATMENT FOR: • Skin infection • Sinusitis • Urinary tract infections • Streptococcal pharyngitis CHARACTERISTICS: • Broad spectrum • Can be given orally and parenterally • Prone to beta-lactamase SIDE-EFFECTS: • Rash, diarrhea, vomiting, nausea, edema, stomatitis, and easy fatigue. Amoxicillin Clavulanic Acid + ll Augmentin
- 28. Methicillin EFFECTIVE AGAINST: • Gram positive bacteria TREATMENT FOR: Nosocomial infection CHARACTERISTICS: • Very narrow Spectrum • Should be given parenterally SIDE-EFFECT: • Interstitial nephritis
- 29. Oxacillin EFFECTIVE AGAINST: • Gram positive bacteria TREATMENT AGAINST: • penicillin-resistant Staphylococcus aureus CHARACTERISTICS: • Very narrow Spectrum • Should be given parenterally SIDE-EFFECT: • Hypersensitivity and local reactions • In high doses, renal, hepatic, or nervous system effects can occur
- 30. Flucloxacillin EFFECTIVE AGAINST: • Gram positive bacteria + Staphylococci that produce beta- lactamase CHARACTERISTICS: • Very narrow Spectrum • Should be given orally SIDE-EFFECT: • Allergic reaction • Diarrhoea, nausea, rash, urticaria pain and inflammation at injection site
- 32. Piperacillin EFFECTIVE AGAINST: • Gram positive +Gram negative CHARACTERISTICS: • Extended Spectrum • Should be given by intravenous or intramuscular injection SIDE-EFFECT: • Hypersensitivity • Gastrointestinal • Renal • Nervous system *Piperacillin+Tazobactam=Zosyn
- 33. Carbenicillin EFFECTIVE AGAINST: • Gram negative + Limited Gram positive TREATMENT FOR: • Urinary tract infections CHARACTERISTICS: • Highly soluble in water and acid- labile SIDE-EFFECT: • High doses can cause bleeding • Hypokalemia
- 34. BETA-LACTAMASE INHIBITORS • Resemble β-lactam antibiotic structure • Bind to β-lactamase and protect the antibiotic from destruction • Most successful when they bind the β-lactamase irreversibly • Three important in medicine: » Clavulanic Acid » Sulbactam » Tazobactam
- 36. Resistance-The Global Battle.!!! What is Resistance? •Drug resistance refers to unresponsiveness of a microorganism to an antimicrobial agent. •Drug resistance are of two types: ---Natural Resistance ---Acquired Resistance
- 37. Porins Altered penicillin binding proteins b-lactamases MECHANISMS OF RESISTANCE
- 39. CHALLENGES OF b-LACTAMASES 1940 : Introduction of penicillins 1940 : First description of b-lactamases published 1944 : Strains of staphylococcus aureus producing b-lactamase 1960s : Clinical use of expanded spectrum penicillins - such as ampicillin and carbenicillin 1970s : plasmid mediated b-lactamases assumed prominence in enterobacteriaceae and gram-negative bacteria 1980-90 : Development of broad-spectrum cephalosporins, cephamycins, monobactams and carbapenems 1990 : Increased resistance among gram-negative bacteria with inducible chromosomally-mediated b lactamases JAC (1993); suppl A: 1-8
- 40. Beta–lactamases
- 41. Beta-Lactamase Enzyme Functional Classification Group 1 (Cephalosporinases*) Group 2 (Penicillinases, Cephalosporinases) Group 3 (Metalloenzymes*) Group 4 (Penicillinases*) * Not inhibited by Clavulanic Acid
- 42. Beta-Lactamase Enzyme Molecular Classification Serine Based Class A Class C Class D Metallo B-lactamases Class B
- 43. BETA-LACTAMASE INHIBITORS • Resemble β-lactam antibiotic structure • Bind to β-lactamase and protect the antibiotic from destruction • Most successful when they bind the β-lactamase irreversibly • Three important in medicine: » Clavulanic Acid » Sulbactam » Tazobactam
Editor's Notes
- Adding the oxygen decreases the nucleophilicity of the carbonyl group, making penicillin V acid stable and orally viable
- Ampicillin is active against Gram-(+) bacteria including Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus (but not methicillin-resistant strains), and some Enterococci Ampicillin is relatively non-toxic. Its most common side effects include rash, diarrhea, nausea and vomiting.[4] In very rare cases it causes severe side effects such as anaphylaxis and Clostridium difficile diarrhea.
- Side effects are similar to those for other β-lactam antibiotics, including nausea, vomiting, rashes, and antibiotic-associated colitis. Loose bowel movements (diarrhea) may also occur. Rarer side effects include mental changes, lightheadedness, insomnia, confusion, anxiety, sensitivity to lights and sounds, and unclear thinking.
- Dicloxacillin is insensitive to beta-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of theisoxazolyl group on the side chain of the penicillin nucleus facilitates the β-lactamase resistance, since they are relatively intolerant of side-chain steric hindrance. Thus, it is able to bind to penicillin-binding proteins (PBPs) and inhibit peptidoglycan crosslinking, but is not bound by or inactivated by β-lactamases.