b - Lactamase Inhibitors

1. b-Lactamase Inhibitors Clavulanic acid (Beecham 1976)(from Streptomycesclavuligerus) • Weak, unimportant antibacterial activity • Powerful irreversible inhibitor of b-lactamases - suicide substrate • Used as a sentry drug for ampicillin • Augmentin = amoxicillin+ clavulanic acid • Allows less amoxicillin per dose and an increased activity spectrum • Timentin = ticarcillin + clavulanic acid

3. b-Lactamase Inhibitors Augmentin = Amoxicillin + Clavulanic Acid

4. Sulbactam Tazobactam b-Lactamase Inhibitors Penicillanic acid sulfone derivatives • Suicide substrates for b-lactamase enzymes • Sulbactam has a broader spectrum of activity vsb-lactamases than clavulanic acid, but is less potent • Unasyn = ampicillin + sulbactam • Tazobactam has a broader spectrum of activity vsb-lactamases than clavulanic acid, and has similar potency • Tazocin or Zosyn = piperacillin + tazobactam

5. The aminopenicillins + b-lactamase inhibitor combinations include ampicillin-sulbactam (parenteral) and amoxicillin-clavulanate (oral)

6. Problem 3 - Range of Activity Examples of Broad Spectrum Penicillins Class 2 - CO2H at the a-position (carboxypenicillins) Examples R = H CARBENICILLIN R = Ph CARFECILLIN • Carfecillin = prodrug for carbenicillin • Active over a wider range of Gram -ve bacteria than ampicillin • Active vs. Pseudomonas aeruginosa • Resistant to most b-lactamases • Less active vs Gram + bacteria (note the hydrophilic group) • Acid sensitive and must be injected • Stereochemistry at the a-position is important • CO2H at the a-position is ionised at blood pH

7. TICARCILLIN Problem 3 - Range of Activity Examples of Broad Spectrum Penicillins Class 2 - CO2H at a-position (carboxypenicillins) Examples • Administered by injection • Identical antibacterial spectrum to carbenicillin • Smaller doses required compared to carbenicillin • More effective against P. aeruginosa • Fewer side effects • Can be administered with clavulanic acid

8. Class 3 - Urea group at the a-position (ureidopenicillins) Examples Azlocillin Mezlocillin Piperacillin Problem 3 - Range of Activity Examples of Broad Spectrum Penicillins • Administered by injection • Generally more active than carboxypenicillins vs. streptococci and Haemophilus species • Generally have similar activity vs Gram - aerobic rods • Generally more active vs other Gram - bacteria • Azlocillin is effective vsP. aeruginosa • Piperacillin can be administered alongside tazobactam

9. The Extended Spectrum Penicillins include Piperacillin and Ticarcillin (parenteral) as well as Carbenicillin (oral)

10. Extended-Spectrum Penicillin + b-Lactamase Inhibitor Combinations include:Piperacillin-tazobactam as well as ticarcillin-clavulanate (both pairs are parenteral)

11. CEPHALOSPORINS

12. 1. Introduction • Antibacterial agents which inhibit bacterial cell wall synthesis • Discovered from a fungal colony in Sardinian sewer water (1948) • Cephalosporin C identified in 1961

13. Giussepe Brotzu noticed that the substance cultured from the sewer water had activity against Salmonella typhi, the active cause of typhoid fever Typhoid fever is transmitted human to human by contact with contaminated feces.

14. 6. Mechanism of Action • The acetoxy group acts as a good leaving group and aids the mechanism

15. The Cephalosporins

16. 8. First Generation Cephalosporins Cephalothin • First generation cephalosporin • More active than penicillin G vs. some Gram - bacteria • Less likely to cause allergic reactions • Useful vs. penicillinase producing strains of S. aureus • Not active vs. Pseudonomasaeruginosa • Poorly absorbed from GIT • Administered by injection • Metabolised to give a free 3-hydroxymethyl group (deacetylation) • Metabolite is less active

17. Metabolism 8. First Generation Cephalosporins Cephalothin - drug metabolism Less active OH is a poorer leaving group • Strategy • Replace the acetoxy group with a metabolically stable leaving group

18. 8. First Generation Cephalosporins Cephaloridine • The pyridine ring is stable to metabolism • The pyridine ring is a good leaving group (neutralisation of charge) • Exists as a zwitterion and is soluble in water • Poorly absorbed through the gut wall • Administered by injection

19. 8. First Generation Cephalosporins Cefalexin • The methyl group at position 3 is not a good leaving group • The methyl group is bad for activity but aids oral absorption - mechanism unknown • Cefalexin can be administered orally • A hydrophilic amino group at the a-carbon of the side chain helps to compensate for the loss of activity due to the methyl group

20. First Generation Cephalosporins Cefazolin Cefadroxil Cefalexin

21. First Generation Cephalosporins include Cefazolin (parenteral) as well as cefadroxil and cefalexin (oral).

22. 9. Second Generation Cephalosporins 9.1 Cephamycins Cephamycin C • Isolated from a culture of Streptomyces clavuligerus • First b-lactam to be isolated from a bacterial source • Modifications carried out on the 7-acylamino side chain

23. 9. Second Generation Cephalosporins 9.1 Cephamycins Cefoxitin • Broader spectrum of activity than most first generation cephalosporins • Greater resistance to b-lactamase enzymes • The 7-methoxy group may act as a steric shield • The urethane group is stable to metabolism compared to the ester • Introducing a methoxy group to the equivalent position of penicillins (position 6) eliminates activity.

24. 9. Second Generation Cephalosporins 9.2 Oximinocephalosporins Cefuroxime • Much greater stability against some b-lactamases • Resistant to esterases due to the urethane group • Wide spectrum of activity • Useful against organisms that have gained resistance to penicillin • Not active against P. aeruginosa • Used clinically against respiratory infections

25. Second generation • The second-generation cephalosporins have a greater Gram-negative spectrum while retaining some activity against Gram-positive cocci. They are also more resistant to beta-lactamase. • Cefaclor (Ceclor, Distaclor, Keflor, Raniclor) • Cefonicid (Monocid) • Cefprozil (cefproxil; Cefzil) • Cefuroxime (Zinnat, Zinacef, Ceftin, Biofuroksym) • Cefuzonam

26. Forms of Cefuroxime (2nd generation cephalosporin) Cefuroxime axetil (CEFTIN) Cefuroxime sodium (ZINACEF)

27. More second generation cephalosporins: Loracarbef (Lorabid)

28. The Second-generation cephalosporins include Cefotetan, cefoxitin, and cefuroxime (all parenteral) as well as Cefaclor, cefprozil, cefuroxime axetil, and loracarbef (all oral).

29. R Aminothiazole ring 10. Third Generation CephalosporinsOximinocephalosporins • Aminothiazole ring enhances penetration of cephalosporins across the outer membrane of Gram - bacteria • May also increase affinity for the transpeptidase enzyme • Good activity against Gram - bacteria • Variable activity against Gram + cocci • Variable activity vs. P. aeruginosa • Lack activity vs MRSA • Generally reserved for troublesome infections

30. Ceftriazone (Rocephin) is a popular third generation cephalosporin It is the drug of choice for bacterial meningitis

31. 10. Third Generation CephalosporinsOximinocephalosporins Ceftazidime • Injectable cephalosporin • Excellent activity vs. P. aeruginosa and other Gram - bacteria • Can cross the blood brain barrier • Used to treat meningitis

32. The Third-generation Cephalosporins include Cefotaxime, ceftazidime, ceftizoxime, and ceftriaxone (all parenteral) as well as Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, and cefixime (all oral).

33. R 11. Fourth Generation CephalosporinsOximinocephalosporins • Zwitterionic compounds • Enhanced ability to cross the outer membrane of Gram negative bacteria • Good affinity for the transpeptidase enzyme • Low affinity for some b-lactamases • Active vs. Gram + cocci and a broad array of Gram - bacteria • Active vs. P. aeruginosa

34. Fourth Generation Cephalosporins include cefepime (parenteral).

35. Newer b-Lactam Antibiotics Thienamycin (Merck 1976)(from Streptomyces cattleya) • Potent and wide range of activity vs Gram + and Gram - bacteria • Active vs. Pseudomonas aeruginosa • Low toxicity • High resistance to b-lactamases • Poor stability in solution (ten times less stable than Pen G)

36. Imipenem Meropenem Ertapenem(2002) Newer b-Lactam Antibiotics Thienamycinanalogues used in the clinic

37. Primaxin = Imipenem + Cilastatin Cilastatin is an inhibitor of a human enzyme, renal dehydropeptidase, which degrades carbapenems

38. Meropenem, Merrem, AstraZeneca Ertapenem, Invanz, Merck

39. The Carbapenems include Imipenem/cilstatin, Meropenem, and Ertapenem (all parenteral)

40. Newer b-Lactam Antibiotics Clinically useful monobactam Aztreonam • Administered by intravenous injection • Can be used for patients with allergies to penicillins • and cephalosporins • No activity vs. Gram + or anaerobic bacteria • Active vs. Gram - aerobic bacteria

41. The Monobactams include only Aztreonam, which is parenteral

42. Vancomycin

43. Mechanism of Action of Vancomycin Vancomycin binds to the D-alanyl-D-alanine dipeptide on the peptide side chain of newly synthesized peptidoglycan subunits, preventing them from being incorporated into the cell wall by penicillin-binding proteins (PBPs). In many vancomycin-resistant strains of enterococci, the D-alanyl-D-alanine dipeptide is replaced with D-alanyl-D-lactate, which is not recognized by vancomycin. Thus, the peptidoglycan subunit is appropriately incorporated into the cell wall.

44. Vancomycin Animation

46. Antimicrobial Activity of Vancomycin

47. Daptomycin • Daptomycin is a lipopeptide antibiotic • Approved for use in 2003 • Lipid portion inserts into the bacterial cytoplasmic membrane where it forms an ion-conducting channel.

48. Link

49. Antimicrobial Activity of Daptomycin

50. Rifamycins • Rifampin is the oldest and most widely used of the rifamycins • Rifampin is also the most potent inducer of the cytochrome P450 system • Therefore, Rifabutin is favored over rifampin in individual who are simultaneously being treated for tuberculosis and HIV infection, since it will not result in oxidation of the antiviral drugs the patient is taking • Rifaximin is a poorly absorbed rifamycin that is used for treatment of travelers’ diarrhea.