1. b-Lactamase Inhibitors
Clavulanic acid (Beecham 1976)(from Streptomyces clavuligerus)
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. Augmentin = Amoxicillin + Clavulanic Acid
b-Lactamase Inhibitors
Augmentin = Amoxicillin + Clavulanic Acid

4. b-Lactamase Inhibitors
Penicillanic acid sulfone derivatives
Sulbactam
Tazobactam
Suicide substrates for b-lactamase enzymes
Sulbactam has a broader spectrum of activity vs b-lactamases than clavulanic acid, but is less potent
Unasyn = ampicillin + sulbactam
Tazobactam has a broader spectrum of activity vs b-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)
Gram-positive bacteria
Some Staphylococcus aureus, Streptococcus pyogenes, Viridans streptococci, Some Streptoocus pneumoniae, Some enterococci Listeria monocytogenes
Gram-negative bacteria
Neisseria spp. Haemophilus influenzae, Many Enterobacteriaceae
Anaerobic bacteria
Clostridia spp. (except C. difficile), Actinomyces israellii, Bacteroides spp.
Spirochetes
Borrelia burgdorferi

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. Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins
Class 2 - CO2H at a-position (carboxypenicillins)
Examples
TICARCILLIN
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. Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins
Class 3 - Urea group at the a-position (ureidopenicillins)
Examples
Azlocillin
Mezlocillin
Piperacillin
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 vs P. aeruginosa
Piperacillin can be administered alongside tazobactam

9. The Extended Spectrum Penicillins include Piperacillin and Ticarcillin (parenteral) as well as Carbenicillin (oral)
Gram-positive bacteria
Streptococcus pyogenes, Viridans streptococci, Some Streptococcus pneumoniae, Some enterococci
Gram-negative bacteria
Neisseria meningitidis, Some Haemophilus influenzae, Some Enterobacteriaceae, Pseudomonas aeruginosa
Anaerobic bacteria
Clostridia spp. (except C. difficile), Some Bacteroides spp.

10. Extended-Spectrum Penicillin + b-Lactamase Inhibitor Combinations include:Piperacillin-tazobactam as well as ticarcillin-clavulanate (both pairs are parenteral)
Gram-positive bacteria
Some Staphylococcus aureus, Streptocosoccus pyogenes, Viridans streptococci, Some Streptococcus pneumoniae, Some enterococci Listeria monocytogenes
Gram-negative bacteria
Neisseria spp. Haemophilus influenzae, Most Enterobacteriaceae, Pseudomonas aeruginosa
Anaerobic bacteria
Clostridia spp. (except C. difficile), Bacteroides spp.

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 Generation Parenteral Agents Oral Agents
First-generation
Cefazolin
Cefadroxil, cephalexin
Second-generation
Cefotetan, cefoxitin, cefuroxime
Cefaclor, cefprozil, cefuroxime axetil, loracarbef
Third-generation
Cefotaxime, ceftazidime, ceftizoxime, ceftriaxone
Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, cefixime
Fourth-generation
Cefepime

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. Pseudonomas aeruginosa
Poorly absorbed from GIT
Administered by injection
Metabolised to give a free 3-hydroxymethyl group (deacetylation)
Metabolite is less active

17. 8. First Generation Cephalosporins
Cephalothin - drug metabolism
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).
Gram-positive bacteria
Streptococcus pyogenes, Some virdans streptococci, Some Staphylococcus aureus, Some Streptococcus pneumoniae
Gram-negative bacteria
Some Eschericia coli, Some Klebsiella pneumoniae, Some Proteus mirabilis

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).
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.

29. 10. Third Generation Cephalosporins Oximinocephalosporins
Aminothiazole
ring
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. It is the drug of choice for bacterial meningitis
Ceftriazone (Rocephin) is a popular third generation cephalosporin
It is the drug of choice for bacterial meningitis

31. 10. Third Generation Cephalosporins Oximinocephalosporins
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).
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

33. 11. Fourth Generation Cephalosporins Oximinocephalosporins
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).
Gram-positive bacteria
Streptococcus pyogenes, Viridans streptococci, Many Streptocossus pneumoniae. Modest activity against Staphylococcus aureus
Gram-negative bacteria
Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Many other Enterobacteriaceae, Pseudomonas aeruginosa.
Anaerobic bacteria
Atypical bacteria

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

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)
Gram-positive bacteria
Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Modest activity against Staphylococcus aureus, Some enterococci, Listeria monocytogenes
Gram-negative bacteria
Haemophilus influenzae, Neisseria spp., Enterobacteriaceae, Pseudomonas aeruginosa
Anaerobic bacteria
Bacteroides fragilis, Most other anaerobes.

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
Gram-positive bacteria
Gram-negative bacteria
Haemophilus influenzae, Neisseria spp. Most Enterobacteriaceae, Many Pseudomonas aeruginosa.
Anaerobic bacteria
Atypical bacteria

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
Gram-positive bacteria
Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Some enterococci.
Gram-negative bacteria
Anaerobic bacteria
Clostridium spp. Other Gram-positive anaerobes.
Atypical bacteria

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
Gram-positive bacteria
Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci.
Gram-negative bacteria
Anaerobic bacteria
Some Clostridium spp.
Atypical

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.

51. The Rifamycins include Rifampin, Rifabutin, Rifapentine, and Rifaximin, all of which can be administered orally. Rifampin can also be administered parenterally.
Gram-positive bacteria
Staphylococci
Gram-negative bacteria
Haemophilus influenzae, Neisseria meningitidis
Anaerobic bacteria
Mycobacteria
Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacteriumleprae.

52. Aminoglycosides
The structure of the aminoglycoside amikacin. Features of aminoglycosides include amino sugars bound by glycosidic linkages to a relatively conserved six-membered ring that itself contains amino group substituents.

53. Bacterial resistance to aminoglycosides occurs via one of three mechanisms that prevent the normal binding of the antibiotic to its ribosomal target:
Efflux pumps prevent accumulation of the aminoglycoside in the cytosol of the bacterium.
Modification of the aminoglycoside prevents binding to the ribosome.
Mutations within the ribosome prevent aminoglycoside binding.

54. The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as Neomycin (oral).
Gram-positive bacteria
Used synergistically against some: Staphylococci, Streptococci, Enterococci, and Listeria monocytogenes
Gram-negative bacteria
Haemophilus influenzae, Enterobacteiaceae, Pseudomonas aeruginosa
Anaerobic bacteria
Atypical bacteria
Mycobacteria
Mycobacterium tuberculosis, Mycobacterium avium complex.

55. Macrolides and Ketolides
The structures of erythromycin and telithromycin Circled substituents and distinguish telithromycin from the macrolides. Substituent allows telithromycin to bind to a second site on the bacterial ribosome.

56. The macrolide group consists of Erythromycin, Clarithromycin, and Azithromycin (all oral, with erythromycin and azithromycin also being available parenterally).
Gram-positive bacteria
Some Streptococcus pyogenes. Some viridans streptococci, Some Streptococcus pneumoniae. Some Staphylococcus aureus.
Gram-negative bacteria
Neiseria spp. Some Haemophilus influenzae. Bordetella pertussis
Anaerobic bacteria
Atypical bacteria
Chlamydia spp. Mycoplasma spp. Legionella pneumophila, Some Rickettsia spp.
Mycobacteria
Mycobacterium avium complex, Mycobacterium leprae.
Spirochetes
Treponema pallidum, Borrelia burgdorferi.

57. The related ketolide class consists of Telithromycin (oral).
Gram-positive bacteria
Streptococcus pyogenes, Streptococcus pneumoniae, Some Staphylococcus aureus
Gram-negative bacteria
Some Haemophilus influenzae, Bordetella pertussis
Anaerobic bacteria
Atypical bacteria
Chlamydia spp. Mycoplasma spp. Legionella pneumophila

58. The Tetracycline Antibiotics
The structure of tetracycline

59. The Tetracycline Class of Antibiotics consists of Doxycycline and Tigecycline (parenteral) as well as Tetracycline, Doxycycline and Minocycline (oral)
Gram-positive bacteria
Some Streptococcus pneumoniae
Gram-negative bacteria
Haemophilus influenzae, Neisseria meningitidis
Anaerobic bacteria
Some Clostridia spp. Borrelia burgdorferi, Treponema pallidum
Atypical bacteria
Rickettsia spp. Chlamydia spp.

60. Tigecycline

61. The antimicrobial activity of Tigecycline (parenteral)
Gram-positive bacteria
Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci, Listeria monocytogenes
Gram-negative bacteria
Haemophilus influenzae, Neisseria spp. Enterobacteriaceae
Anaerobic bacteria
Bacteroides fragilis, Many other anaerobes
Atypical bacteria
Mycoplasma spp.

62. Chloramphenicol

63. The Antimicrobial Activity of Chloramphenicol
Gram-positive bacteria
Streptococcus pyogenes, Viridans group streptococci. Some Streptococcus pneumoniae
Gram-negative bacteria
Haemophilus influenzae, Neisseria spp. Salmonella spp. Shigella spp.
Anaerobic bacteria
Bacteroides fragilis. Some Clostridia spp. Other anaerobic Gram-positive and Gram negative bacteria
Atypical bacteria
Rickettsia spp. Chlamydia trachomatis, Mycoplasma spp.

64. Clindamycin

65. The Antimicrobial Activity of Clindamycin (both oral and parenteral)
Gram-positive bacteria
Some Streptococcus pyogenes, Some viridans group streptococci. Some Streptococcus pneumoniae, Some Staphylococcus aureus
Gram-negative bacteria
Anaerobic bacteria
Some Bacteroides fragilis, Some Clostridium spp. Most other anaerobes.
Atypical bacteria

66. Streptogramins

67. The Antimicrobial Activity of Quinupristin/Dalfopristin (parenteral)
Gram-positive bacteria
Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococcus aureus, Some enterococci.
Gram-negative bacteria
Anaerobic bacteria
Atypical bacteria

68. The structure of Linezolide
The Oxazolidinones
The structure of Linezolide

69. The Antimicrobial Activity of Linezolid (both oral and parenteral)
Gram-positive bacteria
Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci.
Gram-negative bacteria
Anaerobic bacteria
Atypical bacteria