4. cephalosporins

1. CEPHALOSPORINS

2. INTRODUCTION Antibacterial agents which inhibit bacterial cell wall synthesis Discovered from a fungal colony Cephalosporium acremonium in Sardinian sewer water (1948) Cephalosporin C identified in 1961 These are β - lactam antibiotics that are closely related both structurally and functionally to the pencillins Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid

3. Why Cephalosporins? Broad spectrum of activity Stability to -lactamase Oral and parenteral preparations Widely accepted Treats ‘day to day’ as well as ‘serious infections’ High safety profile

4. Cephalosporins -Limitations Emerging resistance patterns Some III & IV generation cephalosporins were available only as parenteral formulations Pharmacoeconomics

5. Dihidrothiazine ring PK Β - lactam ring Side chain Spect

6. Mechanism of action Identical to pencillins, i.e., Binding to cephalosporin binding proteins (PBP) Inhibition of transpeptidation process Activation of autolysin enzyme

7. Mechanism of action

8. Resistance Bacteria produce -lactamase : -lactamases are either constitutive, or more commonly, are acquired by the transfer of plasmids. Altered PBPs : Modified PBPs have a low affinity for -lactam antibiotics. Decreased concentration of antibiotics in target site : altered porin (either in the number or function); increased active efflux system.

9. Classification Have been classified as first, second, third and fourth generation, based on their bacterial spectrum and resistance to β - lactamases Note : Cephalosporins are ineffective against MRSA, L. monocytogenes , Clostredium dificile and the enterococci

10. Generation Parenteral Agents Oral Agents First-generation(1960s) Cefazolin, Cephalothin Cefadroxil, cephalexin ,cephradine Second-generation (1970s) Cefotetan, cefoxitin, cefuroxime Cefaclor, cefprozil, cefuroxime axetil Third-generation (1980s) Cefotaxime, ceftazidime , ceftizoxime , ceftriaxone Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, cefixime Fourth-generation (1997-98) Cefepime, cefpirome Classification

11. First Generation Cephalosporins Pharmacokinetics: Oral cephalosporins are generally well absorbed IM injection of cephalothin is very painful and hence given by IV route Except for cefazolin , which is 80-90% protein bound, others exhibit a poor protein binding Good distribution to most tissues except in CSF Metabolism is not a major elimination path Primarily excreted through kidney Probenecid increases plasma half life All are sensitive to β - lactamase enzyme degradation

12. Antimicrobial spectrum

13. Gram-positive bacteria Streptococcus pyogenes , Some viridans streptococci, Some Staphylococcus aureus , Some Streptococcus pneumoniae Gram-negative bacteria Some Escherichia coli, Some Klebsiella pneumonia, Some Proteus mirabilis Antimicrobial spectrum Cocci > Bacilli > Bacilli > Cocci + - + -

14. Uses UTI’s Minor staphylococcal infections Cellulitis or soft tissue abscess Ineffective in meningitis (do not cross BBB) Cefazolin is drug of choice for surgical prophylaxis before cardiac surgery and before orthopedic prosthesis procedures (has better penetration to tissues)

15. Second Generation Cephalosporins Pharmacokinetics: Cefaclor and cefuroxime can be given orally and have good bioavailability Cefuroxime axetil is an ester prodrug formulation in which the ester is hydrolyzed during drug passage through the intestinal mucosa The free cefuroxime then enters the systemic circulation Only cefuroxime crosses BBB among 2 nd gen Only cefoxitin is 80-90% protein bound; others have poor protein binding

16. More stable to β -lactamase degradation than 1 st gen Their IM injections are painful and hence preferably given administered by IV route These are excreted unchanged through kidney Probenecid increases plasma half life Second Generation Cephalosporins

17. The second-generation cephalosporins have a greater Gram-negative spectrum while retaining some activity against Gram-positive cocci. Antimicrobial spectrum

18. Gram-positive bacteria True cephalosporins have activity equivalent to first-generation agents. Cefoxitin and cefotetan have little activity Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, Neisseria spp. Anaerobic bacteria Cefoxitin and cefotetan have moderate anaerobic activity. Antimicrobial spectrum Cocci Bacilli > Bacilli, Cocci Anaerobes - - +

19. Uses Cefaclor : URTI’s Cefuroxime : commonly acquired pneumonia, gonorrhoea and meningitis Cefoxitin & cefotetan : peritonitis and diverticulitis and some gynecological infections (anaerobic infection)

20. Third Generation Cephalosporins Pharmacokinetics: All these drugs distribute very well into body compartments Adequate levels in the CSF regardless of inflammation, are achieved only with these 3 rd gen Thus these are used to treat meningitis Ceftriaxone differs from others by its long plasma half life(7-8hrs) and high protein bound (90%)- OD Metabolism is not major path for elimination Cefotaxime is metabolized to active metabolite – desacetyl cefotaxime

21. Cefoperazone and ceftriaxone are excreted through bile, so no dose adjustment requied for renal insufficiency Urinary excretion is the major elimination route Probenecid may increase the plasma half life All are highly resistant to degradation by β - lactamases from gram-negative bacteria Third Generation Cephalosporins

22. Antimicrobial spectrum

23. Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptococcus pneumoniae, Modest activity against Staphylococcus aureus Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Some Enterobacteriaceae. Anaerobic bacteria Atypical bacteria Spirochetes Borrelia burgorferi Antimicrobial spectrum - Cocci , Bacilli > Bacilli , Cocci anaerobic org. +

24. Ceftriaxone: Very effective in treating meningitis caused by N. meningitidis, Pneumococci, H. influenza and susceptible enteric gram-negative rods but not by Listeria monocytogenes A single IM dose of 250mg is effective in gonorrhoae and chancroid Excellent for treatment of community acquired pneumonia caused by pneumococc i, H. influenzae and staph aureus Lyme disease caused by Borrelia burgdorferi Also efficacious in treating complicated UTI’s, abdominal sepsis and septicaemias Also used to treat multi drug resistant typhoid fever (doses are high)

25. Cefotaxime: Like ceftriaxone, has been utilized effectively for treating meningitis and community acquired pneumonia A single 0.5-1g IM dose is effective in treating gonorrhoea Has been used in respiratory, genitourinary, abdominal infections, septicaemia, anaerobic and hospital acquired infections

26. Cefoperazone: More active than cefotaxime against pseudomonas (but less active than ceftadizime) Good for Salmonella typhi and B. fragilis also Used for pseudomonal UTI’s, bactreamia , and infections in immunocompromised patients Other uses like meningitis, gonorrhoae and septicaemia are common to other drugs of this series

27. Ceftazidime: Has excellent activity against pseudomonas (better than cefoperazone) and other gram-negative bacilli Ceftadizime+aminoglycosides is the treatment of choice for pseudomonal meningitis Also useful for nosocomial infections also

28. Ceftizoxime: More active agaist B. fragilis than cefotaxime, otherwise similar

29. Cefixime: Orally administered (200-400mg BD) Cefixime is used to treat respiratory, urinary, biliary infections In a single 400mg oral dose it provides effective treatment of uncomplicated gonorrhoea Not effective against Staph. aureus and Pseudomonas Cefpodoxime: Is similar to cefixime but it is active against Staph. aureus also

30. Zwitterionic compounds Enhanced ability to cross the outer membrane of Gram negative bacteria Given by IM /IV Plasma half life is 2hrs Protein binding is only 20% Widely distributed in tissues and body fluids Accumulates well in CSF Fourth Generation Cephalosporins Oximinocephalosporins

31. Fourth Generation Cephalosporins It is eliminated 85-90% through kidney Pharmacokinetics of cefpirone is identical to cefepime expect that its protein binding is only 10% Good affinity for the transpeptidase enzyme Low affinity for some β -lactamases Active vs. Gram +ve cocci and a broad array of Gram -ve bacteria Active vs. P. Aeruginosa

32. Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptococcus pneumoniae. Modest activity against Staphylococcus aureus Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Many other Enterobacteriaceae, Pseudomonas aeroginosa. Anaerobic bacteria Atypical bacteria Antimicrobial spectrum Cocci , Bacilli > Cocci . Noanaerobic , No Bacilli - + +

33. IV Gen. Uses Hospital acquired pneumonia Bactreamia and septicaemia Also useful in UTI’s, RTI’s and as empiric therapy for febrile neutropinic patients

34. Adverse effects Pain after IM inj. ( cephalothin ) Diarrhoea ( cephradine and cefoperazone ) Hypersensitivity reactions Nephrotoxicity ( cephaloridine , cephalothin and few other) Bleeding ( cefoperazone , ceftriaxone )(N-methyl thiotetrazole side chain at R2 position Disulfiram like reaction ( cefoperazone )