PENICILLINS CEPHALOSPORINS & OTHER β -LACTUM ANTIBIOTICS

1. PENICILLINS CEPHALOSPORINS & OTHER β-LACTUM ANTIBIOTICS Dr. Rajendra Nath Professor

2. PENICILLINS CEPHALOSPORINS & OTHER β-LACTUM ANTIBIOTICS • Useful & frequently prescribed AM agents . • Share a common structure & mech. of action i.e. – inhibition of synth. of the bact. peptidoglycan cell wall .

3. PENICILLINS CEPHALOSPORINS & OTHER β-LACTUM ANTIBIOTICS • β- lactums - include Cephalosporin antibiotics which are classified by generations .

4. PENICILLINS CEPHALOSPORINS & OTHER β-LACTUM ANTIBIOTICS • β- lactamase inhibitors e.g.- Clavulanate , Sulbactum etc. are used to extend the spectrum of Penicil. against β- lactamase prod. organisms.

5. PENICILLINS CEPHALOSPORINS & OTHER β-LACTUM ANTIBIOTICS • Otherβ- lactums include – - Carbapenems including Meropenem & Imipenem which have broadest AM spect. of any antibiotics . • Monobactums – e.g.- Aztreonam has G-ve spect. resembling that of Amino -glycosides .

6. PENICILLINS CEPHALOSPORINS & OTHER β-LACTUM ANTIBIOTICS Bact. resist. against the β- lactum antb.s continues to ↑at high rate. Mech. - - by β –lactamase that destroy the antb - alteration in or acquisition of novel penicil. binding proteins ( PBPs) . - Decreased entry & / or efflux of antb.s .

7. PENICILLINS -One of the most important gp of antibiotics. - However numerous other AM agents have been prod. since the first penicil. become available. • These are still used widely & many of these are currently the DOC for a large no. of infectious diseases .

8. PENICILLINS - In 1928 in laboratory of St mary’s hosp. London , A. Fleming observed that a mold contaminating one of the bact. cultures caused the bact. in its vicinity to undergo lysis. Because the the mold belonged to the genus Penicillium , Fleming named the antb.

9. PENICILLINS substance as Penicillin . Chemistry : Basic struct. consists of 1. Thiazolidine ring (A) connected to 2. β- lactum ring (B) to which attach 3. Side chain (R) .

10. PENICILLINS O S CH3 R C NH CH CH C 2BA CH3 O = C N CH COOH Amidase1 Penicillin Penicillinase site of action

11. PENICILLINS • Thiazolidine ring • β- lactam ring 1. Site of action of penicillinase 2. Site of action of amidase

12. PENICILLINS • The penicillin nucleus itself is the chief struct. requirement for biologic. activity . Metabolic transformation/ chem. alteration of this portion of the mol. causes loss of all sig. AB activity • Side chain determine many of the AB & pharmacol. character of a particular

13. PENICILLINS type of Penicillin. • Penicil. G ( benzyl penicil. ) has the greatest AM activity of these & is the only natural penicil. used clinically. Semi-synthetic Penicillins : It has been discovered that 6- amino- penicillanic acid could be obtained from

14. PENICILLINS cultures of P. chrysojenum lead to the dev. of the semi-synth. Penicil.s .by adding different side chains in this . -6-aminopenicillanic acid is now prod. in large quantities with the aid of the amidase from P. chrysojenum .

15. PENICILLINS Unitage of Penicillin : - one Int. unit ≡ 0.6 μg of the cryst. sod. salt of Penicil. G. -1mg of pure Penicil. G≡ 1667 units. Mech. of Penicillins : -The cell walls of bact. are essential for their normal growth & development.

16. PENICILLINS • Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mech. stability . • Cell wall is 50-100 mols thick in G+ve & ½ molecule thick in G-ve bacteria . • Peptidog. is composed of glycan chains having linear strands of two

17. PENICILLINS alternating amino sugar (N-acetyl – glucosamine & N- acetyl muramic acid) & they are cross-linked by peptide chain . Biosynth. of Peptidoglycan : involves three stages

18. PENICILLINS Final stage involves completion of the cross link .This accomplished by a transpeptidation react. that occurs outside the cell memb.( with the help of Transpeptidase enz. which is memb. bound ). These enz.s & related proteins are now called as Penicillin Binding Proteins ( PBPs).

19. PENICILLINS It is this last step in peptidoglycan synth. that is inhibited by the β- lactum antb.s & glycopeptide antb.s (e.g.Vancomyc.)

20. PENICILLINS • Main target for the action of penicil.s & cephalosporins are these Penicil.BindingProteins (PBPs) .All bact. have such entities e.g.- E .coli

22. PENICILLINS

23. PENICILLINS has 7 & S. aureus has 4 PBPs . The PBPs vary in their affinity for diff. β – lactum antb.s , although interact. become covalent . - ↓ of transpept.( PBP-I) causes formation of spheroplast & rapid lysis. - ↓ of PBP-II & III ( Carboxypeptidase & endopeptidase enz.s) cause delayed lysis or production

24. PENICILLINS of spherical cells & large filamentous form of bacterium. Penicil.↓ synth. of cell wall & thereby expose the org.s to the lethal external environment which is not matching with internal osmotic –pressure & bact . swells & lysis occurs .

25. PENICILLINS Death of the bact. also occurs due to activation of autolysing enz.s called autolysins or murein -hydrolase . -Lethality of penicil. involve both lysis or nonlytic mech.

26. PENICILLINS Mech. of bact . Resist. to penicillin ( & Cephalosporins ) : 1.Micro-org may be intrinsically resist. because of structural diff. in the PBPs that are the targets of these drugs (A sensitive strain may acquire resist. of this type by the dev. of high mol.

27. PENICILLINS wt. PBPs that have ↓ affinity for the antb. e.g.- Penicil. resistance in Streptococcus gp. emerged as a result of replacement of its PBPs with resist. PBPs from S. pneumoniae.

28. PENICILLINS 2. Other way of bact. resist. is caused by the inability of the agent to penetrate to its site of action e.g.- G-ve bact.

29. PENICILLINS - in G+ve bact . the peptidoglycan polymer is very near the cell surface , some G+ve bact. have polysacch. capsule that are external to the cell wall but they are not the barrier to the diffusion of β- lactums .

30. PENICILLINS • In G-ve bact. the inner memb. is analog. to the cytoplasmic memb. of G+ve bact. & is covered by outer memb. of Lipopolysaccharide & capsule ,it functions as a impermeab. barrier for some antb.s

31. PENICILLINS Some small hydrophilic antb.s diffuse through aqueous channels in the out. memb. that are formed by protein called porins . -Broad spect. Penicil.s e.g. – Ampicill. & Amoxycill. & most of the Cephalo- sporins diff. through the pores in the

32. PENICILLINS E.coli outer memb. more rapidly than can Penicill. G ( the no. & size of the pores vary e.g.- Pseudomonas aeru. lack the classical high permeability porins .) 3. Active efflux pumps serve as another mech. of resist. removing the antb.s

33. PENICILLINS

34. PENICILLINS from its site of action before it can act e.g.-β- lactum resist. in P.aerug. ,E.coli & N. gonorrheae . 4.Bact. can also destroy β- lactum antb. enzymatically by β- lactamases which inactivates certain of these antb.s .

35. PENICILLINS -diff. micro-orgs elaborate a no. of distinct β- lactamase which often are described as Penicillinases or Cepha - linases . These are grouped into 4 clases ( A-D) . • Class Aβ- lactamases include the extend. spect. β –lactamases which

36. PENICILLINS degrade Penicil.s , some Cephalospor. and in some instances ,Carbapenems. -Class B: β-lactamases are Zn++ dep. enz. that destroy all β- lactams except Aztreonam . - Class C: β- lactamases are active against Cephalosporins.

37. PENICILLINS -Class D : include Cloxacillin deg. enz.s • G+ve bact. prod. & secrt. a large amount of β- lactmases . Most of these are Penicillinases . The information for Staphylococcal penicillinase is encoded In a plasmid & this may be transferred by bacteriophage to other bact.

38. PENICILLINS • In G-ve bact. β-lactamases are found in relatively small amounts . they are encoded either in chromos. or in plasmids & may be constitutive or inducible . • The plasmids can be transferred between bact. by conjugation .

39. PENICILLINS • Other factors : micro-org.s adhering to implanted prosthetic devices ( e.g.- catheters , artific. Joints , prosth. heart valves etc.) prod. biofilms & are much less sens. to antb.s . • The presence of proteins & other

40. PENICILLINS constituents of pus, low pH or low oxyg. tension does not appreciably ↓ the ability of β-lactum antb.s to kill bact. However bact. that survive inside visible cells of the host gener. are protected from the action of the β- lactum antb.s .

41. PENICILLINS Classification : According to their spectrum of AM act. I Narrow spectrum A. Penicillinase sensitive i) Penicillin G ( parenteral ) – highly active against sensitive strains of G+ve cocci hydrolyzed by

42. PENICILLINS penicillinase , not effective against most strains of S. aureus e.g.- -Crystalline or Benzyl Penicil. or Penicil. G. - Procaine Penicil. - Benzathine Penicil. ii) Phenoxy methyl Penicil. or Penicil. V

43. PENICILLINS ( orally active ) B. Penicillinase resist. Penicil. -e.g.- Methicillin , Naficillin , Cloxacillin Oxacillin , Flucloxacillin etc. have less potent AM activity against micro-org. sensitive to Penicil. G . but agent of first choice for

44. PENICILLINS penicillinase prod. S. aureus & S. epid -ermidis . C. Penicillinase inhibitors . e.g.- Clavulanic acid ( comb. with Amoxycil.) - Sulbactum ( + Ampicillin ) - Tazobactum ( + Piperacillin)

45. PENICILLINS They are given with broad spectrum antb.s to prevent hydrolysis by broad spect. β- lactamases ( in G-ve bact. e.g. E.coli .) II Broad spect. Penicillins : A. Carboxypenicil. e.g.- Carbenicillin Carbenicil. Indanyl ,Ticarcillin .

46. PENICILLINS their AM activity is extended to include Pseudomonas , Enterobacter & Proteus gp. (inferior to Ampicil.against G+ve cocci & L.monocytogenes & less active than Piperacil. against Pseudomonas.& also known as anti- Pseudomonal penicillins )

47. PENICILLINS B. Aminopenicillins : e.g.- Ampicillin , Amoxycillin, etc.. They are also effective against G- ve org.s e.g. – H. influenzae , E. coli , Proteus mira - bilis . etc. . But they are sensitive to penicillinase enzyme. (They are used now with β- lactamase inhib.s e.g. Clavulanic acid which further extends their spectrum )

48. PENICILLINS C. Uriedopenicillins ( extended spect. penicil.) : e.g.- Azlocillin , Mezlocillin & Piperacillin . Excellent activity against Pseudomonas ,Klebsiella & other G-ve org.s

49. PENICILLINS Pharmacological propert. in general: - Following abs. of orally administered penicil. these agents are distributed widely through out the body. - Therapeutic conc. attain readily in tissues & in secret. e.g. joint fluid , pleural fluid ,pericardial fluid & bile

50. PENICILLINS -Low conc. in prostatic fluid ,brain tissue ,intra-ocular fluid & in CSF (conc of penicil. is < 1% of those in plasma , but in inflammed meninges conc. may ↑ upto 5% of plasma ) . - Eliminated rapidly by glomerular filtr. & renal tubular secrt. (t½ -30-90 min.)