Chapter-Beta lactamase inhibitors

Dear students, you can watch the Complete chapter of antibiotics in these videos as per PCI syllabus
1)Antibiotics-History & Introduction
https://www.youtube.com/watch?v=xdKch...
2)Easy Learning Of Chapter - β-Lactam antibiotics-Cephalosporin
https://www.youtube.com/watch?v=D7b5g...
3)Learn Complete Topic -β-Lactam antibiotics(Penicillin) in Medicinal Chemistry
https://www.youtube.com/watch?v=qXQ3S...

1. Easy Learning Of Chapter β- Lactamase Inhibitors Medicinal Chemistry B.Pharm 6 th Semester & Pharm. D 3 rd Year Chapter Content -History & Classification -SAR & Synthesis -Use & Adverse Effects According to PCI Syllabus Especially For OU,JNTU,UPTU Students

2. β- lactamase Inhibitors β-lactamases are a family of enzymes produced by many gram-positive and gram-negative bacteria that inactivate β-lactam antibiotics by opening the β-lactam ring. Different β-lactamases differ in their substrate affinities. Three inhibitors of this enzyme: Clavulanic Acid Acid Sulbactam Tazobactam

3. Beta Lactam Ring Beta Lactam Ring Ring Open Loss of Activity

4. Clavulanic Acid -Obtained from Streptomyces clavuligerus , it has a β-lactam ring but no antibacterial activity of its own. -It inhibits a wide variety (class II to class V) of β-lactamases (but not class I cephalosporinase) produced by both gram-positive and gram-negative bacteria. -Clavulanic acid is a ‘progressive’ inhibitor :binding with β-lactamase is reversible initially, but becomes covalent later—inhibition increasing with time. -Called a ‘suicide’ inhibitor, it gets inactivated after binding to the enzyme. -It permeates the outer layers of the cell wall of gram negative bacteria and inhibits the periplasmically located β-lactamase.

5. Addition of clavulanic acid re-establishes the activity of amoxicillin against β-lactamase producing resistant Staph. Aureus , H. influenzae, N. gonorrhoeae, E. coli, Proteus, Klebsiella, Salmonella and Shigella. Bact. fragilis are not responsive to amoxicillin alone, but are inhibited by the combination. Amoxicillin sensitive strains are not affected by the addition of clavulanic acid.

6. Coamoxiclav is indicated for:  Skin and soft tissue infections, intra-abdominal and gynecological sepsis, urinary, biliary and respiratory tract infections: especially when empiric antibiotic. therapy is to be given for hospital acquired infections. Gonorrhea (including PPNG) single dose amoxicillin 3 g + clavulanic acid 0.5 g +probenecid 1 g is highly curative. Adverse effects of Clavulanic acid : They are the same as for amoxicillin alone; g.i. tolerance is poorer—especially in children. Candida stomatitis/ vaginitis Rashes Hepatic injury in some case with the combination.

7. Sulbactam It is a semisynthetic β-lactamase inhibitor, related chemically as well as in activity to clavulanic acid. It is also a progressive inhibitor, highly active against class II to V but poorly active against class I β-lactamase. On weight basis, it is 2–3 times less potent than clavulanic acid for most types of the enzyme, but the same level of inhibition can be obtained at the higher concentrations achieved clinically. Oral absorption of sulbactam is inconsistent. Therefore, it is preferably given parenterally.

8. It has been combined with ampicillin for use against β-lactamase producing resistant strains. Absorption of its complex salt with ampicillin— sultamicillin tosylate is better, which is given orally. Main Adverse Effects :  Pain At Site Of Injection  Thrombophlebitis Of Injected Vein  Rash  Diarrhoea

9. Tazobactam similar to sulbactam. Its pharmacokinetics matches with piperacillin with which it has been combined for use in severe infections like peritonitis, pelvic/urinary/respiratory infections caused by β- lactamase producing bacilli. However, the combination is not active against piperacillin-resistant Pseudomonas, because tazobactam (like clavulanic acid and sulbactam) does not inhibit inducible chromosomal β-lactamase produced by Enterobacteriaceae. It is also of no help against Pseudomonas that develop resistance by losing permeability to piperacillin. Dose: 0.5 combined with piperacillin 4 g injected i.v. over 30 min 8 hourly.

10. Other β -Lactam antibiotics Carbapenems and monobactams were developed to deal with β- lactamase-producing Gram-negative organisms resistant to penicillin’s. Carbapenems Monobactams Imipenem Aztreonam

11. Carbapenems Imipenem : Acts in the same way as the other β-lactams. It has a very broad spectrum of antimicrobial activity, being active against many aerobic and anaerobic Gram-positive and Gram-negative organisms. However, many of the ‘methicillin-resistant’ staphylococci are less susceptible, and resistant strains of P.aeruginosa have emerged during therapy. Resistance to imipenem was low, but is increasing as some organisms now have chromosomal genes that code for imipenem- hydrolysing β- lactamases. It is sometimes given together with cilastatin , which inhibits its inactivation by renal enzymes.

12. -Meropenem is similar but is not metabolized by the kidney. -Ertapenem has a broad spectrum of antibacterial actions but is licensed only for a limited range of indications. Most carbapenems are not orally active, and are used only in special situations. Unwanted effects : Similar to other β- lactams  Nausea and vomiting being the most frequently seen.  Neurotoxicity can occur with high plasma concentrations.

13. The main monobactam is aztreonam, which is resistant to most β- lactamases. It is given by injection . Plasma half-life 2 h. Aztreonam has an unusual spectrum of activity and is effective only against Gram-negative aerobic bacilli such as pseudomonas species, Neisseria meningitidis and Haemophilus influenzae. It has no action against Gram-positive organisms or anaerobes.

14. Adverse effects : Similar to those of other β-lactam antibiotics  but this agent does not necessarily cross-react immunologically with penicillin and its products, and so does not usually cause allergic reactions in penicillin sensitive individuals.