Cephalosporins

1. Cephalosporins

2. Cephalosporin antibiotics • derived from “cephalosporin C” • obtained from fungus Cephalosporium acremonium • Cephalosporin nucleus Consists of dihydrothiazine ring fused to a β–lactam ring • 7-aminocephalosporanic acid

3. 7-aminocephalosporanic acid has been modified by addition of different side chains to create a whole family of cephalosporin antibiotics. • these have been conventionally divided into 5 generations

4. Mechanism of action • All cephalosporins are bactericidal. • MOA same as penicillin- Inhibit cell wall synthesisin a manner similar to penicillins • Bind to different proteins than those which bind penicillin. PBP-1 &PBP-3 • This explains diffenece in spectrum, potency & lack of resistance.

5. Inhibition of transpeptidation • Imperfect cell wall • Osmotic drive • Activation of autolysin enzymes • Lysis of bacteria • BACTERICIDAL

6. CLASSIFICATION • Based on • antimicrobial spectrum • Chronological sequence of development • Divided into generations.

7. First-generation agents • Cephalexin (O) • Cefadroxil (O) • Cefazolin (i.m, i.v) • Cefalothin (withdrawn)

8. Exhibit good activity against gram-positive bacteriabut modest activity against gram negative organisms. • Most gram-positive cocci • Strepto, • Pneumo, • Methicillin sens. Staph. are susceptible to first-generation cephalosporins • Modest activity against E. coli, K. pneumoniae & Proteus mirabilis Most oral cavity anaerobes are sensitive.  However, the Bacteroidesfragilis group is resistant.

9. Second-generation agents • Cefaclor (O) • Ceforanide • Cefuroxime acetil (O) • Cefuroxime (i.m , i.v) • Cefoprozil • Cefamandole (Banned) • Cefoxitin (Banned) • Cefotetan (Banned)

10. Exhibit somewhat increased activity against gram negative organisms, • but much less active than third generation agents. • Less active against gram positive cocci & bacilli compared to first gen. drugs. • Use declined • Clinically replaced by 3rd & 4th generation drugs .

11. Third-generation agents • Cefotaxime • Ceftriaxone • Cefdinir • Cefibuten • Cefpodoxime • Ceftizoxime • Ceftazidime • Cefoperazone (withdrawn)

12. Highly augmented activity against gram-negative organisms • Less active than first generation agents against gram positive cocci & anaerobes. • All are highly resistant to β-lactamases from gram negative bacteria. • Some inhibit psuedomonas as well; ceftazidime, cefoperazone(withdrawn)

13. Some members of this group have enhanced ability to cross the blood-brainbarrier eg. Ceftriaxone and are effective in treating meningitis caused by pneumococci, meningococci, H. influenzae and susceptible gram negative rods.

14. Fourth-generation agents • Cefpirome P/E (im/iv) • Cefepime P/E (iv) • Cefozopran P/E

15. Highly active against G –ve organisms • Similar to third gen drugs for g +ve bacteria • The fourth generation drugs comparable to third generation but more resistant to hydrolysis by β-lactamases. • Effective against bacterial infections resistant to earlier drugs

16. Fifth-generation agents • Ceftobiprole • Ceftaroline • Active against, g +ve cocci especially MRSA • penicillin resistant S. pneumoniae • and enterococci

17. Resistance • Impermeability to the antibiotic. • to reach its site of action • Alteration in PBPs -antibiotics bind with low affinity • Elaboration of β-lactamases; that can hydrolyze the β-lactam ring and inactivate the cephalosporin (most prevalent mech)

18. Adverse reactions • Pain after im injection • Thrombophlebitis of injected vein. • Diarrhoea more common with • oralCeferadine • P/ECefoperazone (Banned)

19. Hypersensitivityreactions • Identical to penicillins, incidence is lower. • shared β-lactam structure • Allergic to penicillins- allergic to cephalosporins. CROSS-REACTIVITY. • Rashes, frequent, anaphylaxis, angioedema, asthma, urticaria have also occurred.

20. Cephalosporins potentially nephrotoxicdrugs • Cephaloridine(withdrawn) RTN • Cephalothin (withdrawn) Acute tubular necrosis • Serious bleeding • Cefoperazone(Banned), • Moxalactam(Banned). • Due to hypoprothrombinemia.

21. Intolerance to alcohol Disulfiram like reaction • Cefamandole (Banned) • Cefotetan (Banned) • Moxalactam (Banned) • Cefoperazone (Banned)

22. Therapeutic Uses • Extensively used & therapeutically important antibiotics • Effective therapeutic & prophylactic agents

23. First Gen agents • Excellent for skin & soft tissue infections • Surgical prophylaxis first generation drugs are the preferred for prophylaxis in procedures in which skin flora are likely pathogens.

24. Second Gen agents • Displaced by third generation agents for Gram negative infections • Oral-RTI (replaced by augmentin)

25. Third Gen agents • With/without aminoglycosides DOC- severe G -ve infections caused by • Kleibsiella • Enterobacter • Proteus • Providencia • Serratia & haemophillus species.

26. Ceftriaxone is the therapy of choice for all forms of Gonorrhea • 250 mg i.m as single dose • i.v ceftriaxone for enteric fever • Cefotaxime & ceftriaxone • Community aquired pneumonia

27. Cefotaxime/ceftriaxone are used for initial treatment of meningitis because of their • antimicrobial activity, • good penetration into CSF • & record of clinical success • They are DOC - Meningitis due to • H. influenzae • Sensitive S. pneumonae • N. meningitidis • G-ve enteric bacteria • Ceftazidime + aminoglycosides • Psuedomonas meningitisDOC

28. Fourth Generation Agents • Same as third generation drugs • Indicated for hospital acquired infections resistant to commonly used antibiotics

29. Other β -lactam antibiotics

30. Other β -lactam antibiotics • Newer classes of β-lactam antibiotics are the • Monobactams • Carbapenems • Carbacephems • Important therapeutic agents with a β-lactam structure & are neither penicillins nor cephalosporins

31. Monobactams Aztreonam • Isolated from chromobacterium violaceum • Only monobactam currently in clinical use • β - lactam ring, lacking the thiazolidine ring. - a monobactam

32. Antimicrobial activity differs from those of other β -lactam antibiotics & more closely resembles that of an aminoglycoside • Primarily affects : • Aerobic gram negative microorganisms • gram positive bacteria & anaerobic organisms are resistant • Preferred-all sorts of gram negative infections in patients with renalimpairment where aminoglycosides are to be avoided.

33. Stable to most β-lactamases elaborated by gram negative bacteria. • i.m / i.v • Therapeutic conc. inCSF in the presence of inflammed meninges, Alternative to cephalosporins for therapy of meningitis caused by G-ve bacilli

34. Carbapenems • β-lactam antibiotic • Broader spectrum of activity : than most other β-lactams . • gram-negative rods • gram-positive bacteria • and anaerobes.

35. Carbapenems • Imipenem • Meropenem • Ertapenem

36. Imipenem • Derived from compound produced by Streptomycescattleya • Mechanism same as penicillins • Bactericidal • Resistant to hydrolysis by β-lactamase • Marketed in combination with cilastin • Inhibits degradation – by renal dipeptidase • Without cilastin renal dehydropeptidases inactivate the drug which results in low urinary tract concentrations.

37. Adverse effects • Nausea ,vomiting • Seizures • Patients allergic to other β-lactam antibiotics may have hypersenstivity reactions when given imipenem

38. Meropenem • Therapeutic equivalence with imipenem • Coadministration with cilastin not required • Meropenem is less seizure producing compared to imipenem.

39. Ertapenem • Differs from imipenam & meropenem largerserum half life, OD. • Co-administration with cilastin not required • less seizure producing compared to imipenem.

40. All are parenteral • i.v, im painful • Imipenem 6 hrly • Meropenam 8 hrly • All are resistant to β – lactamases • All bactericidal • MOA same • Patients allergic to other β-lactam antibiotics may have hypersenstivity reactions when given imipenem/carbapenems.

41. Therapeutic uses • Urinary tract infections • Lower respiratory tract infections • Intra-abdominal & gynaecological infections • Skin, bone, joint, & soft tissue infections • Especially cephalosporin/ penicillin resistant nosocomial bacteria.

42. Carbacephems Loracarbef • Synthetic β-lactam antibiotic • Similar to cefaclor • Antibacterial activity resembles II generation cephalosporins.