1. Vancomycin
Vancomycin is called a ‘glycopeptide’, meaning that it is a cyclic peptide, with sugar residues attached to it.

2. Vancomycin Mechanism of Action
Bacterial Cell Wall Synthesis (review)
Penicillin Mechanism of Action (review)
Vancomycin Mechanism of Action
Link

3. 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.

4. Vancomycin Uses
Vancomycin is used to treat aerobic Gram + bacteria, including MRSA and strains of penicillin-resistant Streptococcus pneumoniae
Vancomycin is administered intravenously
Vancomycin can also be used to treat anearobic Gram + bacteria, including Clostridium difficile (in the case of a GI infection, Vancomycin can be administered orally).
Vancomycin cannot be used to treat Gram – bacteria, since the large size of the vancomycin molecule prohibits its passing of the outer membrane.

5. Vancomycin Resistance
Some Enterococci have developed resistance to vancomycin (Enterococcus faecium and Enterococcus faecalis).
These bacteria are called Vancomycin Resistant Enterococci (VRE)

6. The mechanism of resistance involves the transformation of the D-Ala-D-Ala linkage in the peptide side chain into D-Ala-D-Lac (i.e. replacement of the NH2 group by an OH group)
This terminal linkage is still recognized by the essential PBP’s (so the cell wall can still be constructed), but is not recognized by vancomycin (thus resulting in resistance).

7. 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

8. Daptomycin Daptomycin is called a lipopeptide antibiotic
Approved for use in 2003
Lipid portion inserts into the bacterial cytoplasmic membrane where it forms an ion-conducting channel.
Marketed under the trade name Cubicin

9. Step 1: Daptomycin binds to the cytoplasmic membrane in a calcium-dependent manner
Step 2: Daptomycin oligomerizes, disrupting the membrane
Step 3: The release of intracellular ions and rapid death
Link

10. Uses of Daptomycin
Daptomycin is active against many aerobic Gram-positive bacteria
Includes activity against MRSA, penicillin-resistant Streptococcus pneumoniae, and some vancomycin-resistant Enterococci (VRE)
Daptomycin is not active against Gram negative strains, since it cannot penetrate the outer membrane.

11. Primarily been used to treat skin and soft tissue infections
Poor activity in the lung.

12. 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

13. Rifamycins
Rifampin is the oldest and most widely used of the rifamycins
Rifampin is also the most potent inducer of the cytochrome P450 system

14. Therefore, Rifabutin (brand name Mycobutin) is favored over rifampin in individuals 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

15. Rifaximin is a poorly absorbed rifamycin that is used for treatment of travelers’ diarrhea.

16. Mechanism of Action of Rifampin
Rifampin inhibits transcription by inactivating bacterial RNA polymerase

17. Resistance develops relatively easily, and can result from one of a number of single mutations in the baqcterial gene that encodes RNA polymerase.
Therefore, Rifampin is rarely used as monotherapy (i.e. not used as a single agent) but usually combined with other antibiotics

18. Uses of Rifampin
Used, in combination with other drugs, to treat Mycobacterium tuberculosis
Used to treat some Staphylococcal infections.

19. 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.

20. 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.

21. Aminoglycoside Mechanism of Action
Aminoglycosides bind to the 30S subunit of the bacterial ribosome, thereby inhibiting bacterial protein synthesis (translation)
Link

22. Uses of Aminoglycoside Antibiotics
Unlike vancomycin, the aminoglycosides have excellent activity against Gram – aerobic bacteria
Their extensive positive charge enables them to bind to and penetrate the negatively charged outer membrane and get into the periplasm
They are further transported into the cytoplasm by a bacterial transport system.

23. Lipopolysaccharide is Part of the Outer Membrane of Gram Negative Bacteria

26. Bacterial lipopolysaccharides are toxic to animals
Bacterial lipopolysaccharides are toxic to animals. When injected in small amounts LPS or endotoxin activates several host responses that lead to fever, inflammation and shock.

27. Endotoxins may play a role in infection by any Gram-negative bacterium
Endotoxins may play a role in infection by any Gram-negative bacterium. The toxic component of endotoxin (LPS) is Lipid A. The O-specific polysaccharide may provide for adherence or resistance to phagocytosis, in the same manner as fimbriae and capsules.

28. The O polysaccharide (also referred to as the O antigen) also accounts for multiple antigenic types (serotypes) among Gram-negative bacterial pathogens.
Thus, E. coli O157 (the Jack-in-the-Box and Stock Pavillion E. coli) is #157 of the different antigenic types of E. coli and may be identified on this basis.

29. 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.

30. The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as Neomycin (oral).

31. 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.

32. Macrolides and Ketolides
The structures of erythromycin and telithromycin Circled substituents and distinguish telithromycin from the macrolides.

33. Substituent allows telithromycin to bind to a second site on the bacterial ribosome.

35. Mechanism of Action of Macrolide Antibiotics
Macrolides bind tightly to the 50S subunit of the bacterial ribosome, thus blocking the exit of the newly synthesized peptide
Thus, they are interfering with bacterial translation
Link

36. Uses of Macrolide Antibiotics
Active against a broad range of bacteria
Effective against some stphylococci and streptococci, but not usually used for MRSA or penicillin-resistant streptococci
Most aerobic Gram- bacteria are resistant
Active against many atypical bacteria and some mycobacteria and spirochetes

37. The macrolide group consists of Erythromycin, Clarithromycin, and Azithromycin (all oral, with erythromycin and azithromycin also being available parenterally).
Clariithromycin
Erythromycin

38. Azithromycin
Link

39. 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.

40. Uses of Telithromycin (a ketolide)
Telithromycin is approved for use against bacterial respiratory infections
Active against most strains of Streptococcus pneumoniae, including penicillin- and macrolide-resistant strains
Also active against more strains of Staphylococci
Only available in oral formulation

41. Telithromycin

42. 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

43. The Tetracycline Antibiotics
The structure of tetracycline

44. Tetracycline Antibiotics
Tigecycline
Doxycycline

45. Mechanism of Action of the Tetracycline Antibiotics
The tetracyclines bind to the 30S subunit of the bacterial ribosome and prevent binding by tRNA molecules loaded with amino acids.

46. Uses of the Tetracycline Antibiotics
Main use is against atypical bacteria, including reckettsiae, chlamydiae, and mycoplasmas
Also active agains some aerobic Gram-positive pathogens and some aerobic Gram-negative bacteria

47. 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.

48. Tigecycline

49. 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.

50. Chloramphenicol

51. Mechanism of Action of Chloroamphenicol
Binds to the 50S subunit of the bacterial ribosome, where it blocks binding of tRNA

52. Uses of Chloramphenicol
Severe toxicity limits utility
The most serious side effect of chloramphenicol treatment is aplastic anaemia (a condition where bone marrow does not produce sufficient new cells to replenish blood cells)
This effect is rare and is generally fatal: there is no treatment and there is no way of predicting who may or may not get this side effect.
The effect usually occurs weeks or months after chloramphenicol treatment has been stopped.

53. Uses of Chloramphenicol
However, despite its toxicity, chloramphenicol has a wide spectrum of activity, that includes many aerobic Gram-positive, Gram-negative, anaerobic, and atypical bacteria

54. 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.

55. Clindamycin

56. Mechanism of Action of Clindamycin
Clindamycin binds to the 50S subunit of the ribosome to inhibit protein synthesis

58. Uses of Clindamycin
Clindamycin is a member of the lincosamide series of antibiotics
Main utility is in treatment of Gram-positive bacteria and anaerobic bacteria
Active against staphylococcus, including some strains of MRSA
Not useful against Gram-negative bacteria

59. Toxicity of Clindamycin
Clindamycin kills many components of the gastrointestinal flora, leaving only Clostridium difficile
This can result in overgrowth by C. difficile, which is resistant

60. 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

61. Streptogramins

62. Mechanism of Action of Streptogramins
Dalfopristin inhibits the early phase of protein synthesis in the bacterial ribosome and quinupristin inhibits the late phase of protein synthesis. The combination of the two components acts synergistically and is more effective in vitro than each component alone.
Link

63. Uses of the Streptogramins
Have activity against Gram positive aerobic bacteria
Including MRSA, penicillin-resistant Streptococcus pneumoniae and some VRE (active against vancomycin resistant Enterococcus faecelis, but not Enterococcus faecium)
The Quinupristin/Dalfopristin mixture is marketed as Synercid

64. 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

65. The structure of Linezolide
The Oxazolidinones
The structure of Linezolide

66. Binds to the 50S subunit and prevents association of this unit with the 30S subunit.

67. Mechanism of Action of the Oxazolidinones
Binds to the 50S subunit and prevents association of this unit with the 30S subunit.

68. Uses of the Oxazolidinones
Has excellent activity against most aerobic Gram-positive bacteria, including MRSA and VRE.
Only oxazolidonone on the market now is Linezolid, which is both oral and intravenous.

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

70. The Sulfa Drugs
Most commonly used sulfa drug is a mixture of the sulfa drug Sulfamethoxazole and Trimethoprim
These two drugs work in synergy, with the combination being superior to either drug alone.
Sulfamethoxazole
Trimethoprim

71. This combination is known as co-trimoxazole, TMP-sulfa, or TMP-SMX

72. Mechanism of Activity of Sulfa Drugs
Trimethoprim-sulfamethoxazole works by preventing the synthesis of tetrahydrofolate (THF), an essential cofactor for the metabolic pathways that generate deoxynucleotides, the building blocks of DNA.

73. Tetrahydrofolic Acid Biosynthetic Pathway
In the first step of the pathway, the sulfonamides are mistaken for the natural substrate, p-aminobenzoic acid (PABA) and the drug acts as a competitive inhibitor of this enzyme
In a later step, the trimethoprim acts as a structural analog of dihydrofolate and therefore inhibits dihydrofolate reductase

75. Structural Resemblance of Sulfamethoxazole and p-Aminobenzoic Acid

76. Another sulfa drug is Dapsone, which is used to treat Mycobacterium leprae

77. Structural Comparison of Two Sulfa Drugs

78. The Antimicrobial Activity of the Sulfa Drugs
Gram-positive bacteria
Some Sreptococcus pneumoniae, Some Staphylococci, Listeria monocytogenes
Gram-negative bacteria
Some Haemophilus influenzae, Some Enterobacteriaceae
Anaerobic bacteria
Atypical bacteria
Mycobacteria (Dapsone)
Mycobacterium leprae

79. The Fluoroquinolones

80. Fluoroquinolones

81. Mechanism of Action: Quinolones
Quinolone antibiotics inhibit bacterial DNA gyrase (Gram negative bacteria) or Topoisomerase IV (Gram positive bacteria)

82. Uses of the Quinolone Antibiotics
Urinary Tract Infections: fluoroquinolones are more effective than trimethoprim-sulfamethoxazole
Prostatitis
Respiratory tract infections
Gastrointestinal and Abdominal Infections

83. Antimicrobial Activity of the Quinolones (oral)
Gram-positive bacteria
Some Staphylococcus aureus, Streptococcus pyogenes, Virdans group streptococci, Streptococcus pneumoniae
Gram-negative bacteria
Neisseria spp. Haemophilus influenzae
Many Enterobacteriaceae, Some Pseudomonas aeruginosa
Anaerobic bacteria
Some clostridia spp, Some Bacteroides spp.
Atypical bacteria
Chlamydia and Chlamydophilia, Mycoplasma pneumoniae, Legionella spp
Mycobacteria
Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacterium leprae

84. Metronidazole (Flagyl)
Metronidazole is used in the treatment of infections caused by anaerobic bacteria

85. Metronidazole Mechanism of Action
Metronidazole is a prodrug. It is converted in anaerobic organisms by the redox enzyme pyruvate-ferredoxin oxidoreductase. The nitro group of metronidazole is chemically reduced by ferredoxin (or a ferredoxin-linked metabolic process) and the products are responsible for disrupting the DNA helical structure, thus inhibiting nucleic acid synthesis.

86. Mechanism of Action of Metronidazole
Metronidazole is selectively taken up by anaerobic bacteria and sensitive protozoal organisms because of the ability of these organisms to reduce metronidazole to its active form intracellularly.

87. Systemic metronidazole is indicated for the treatment of:
Vaginitis due to Trichomonas vaginalis (protozoal) infection in both symptomatic patients as well as their asymptomatic sexual contacts;
Pelvic inflammatory disease in conjunction with other antibiotics such as ofloxacin, levofloxacin, or ceftriaxone
Protozoal infections due to Entamoeba histolytica (Amoebic dysentery or Hepatic abscesses), and Giardia lamblia (Giardiasis) should be treated alone or in conjunction with iodoquinol or diloxanide furoate
Anaerobic bacterial infections such as Bacteroides fragilis, spp, Fusobacterium spp, Clostridium spp, Peptostreptococcus spp, Prevotella spp, or any other anaerobes in intraabdominal abscess, peritonitis, empyema, pneumonia, aspiration pneumonia, lung abscess, diabetic foot ulcer, meningitis and brain abscess, bone and joint infections, septicemia, endometritis, tubo-ovarian abscess, or endocarditis
Pseudomembranous colitis due to Clostridium difficile
Helicobacter pylori eradication therapy, as part of a multi-drug regimen in peptic ulcer disease
Prophylaxis for those undergoing potentially contaminated colorectal surgery and may be combined with neomycin

88. Antimicrobial Activity of Metronidazole (both oral and intravenous)
Gram-positive bacteria
Gram-negative bacteria
Anaerobic bacteria
Bacteroides fragilis, Clostridium spp. Most other anaerobes
Atypical bacteria

89. Antimicobacterial Agents
Mycobacterial infections are very slow progressing
Many antibiotics have poor activity against slow growing infections
Mycobacteria must be treated for a long time, and therefore, may readily develop resistance to a single antibiotic
Typically, several antibiotic agents are used simultaneously

90. Antimycobacterial Agents
Pyrazinamide
Rifampin
Ethambutol

91. Mycobacterial Infections

92. Mycolic Acids provide protection
Mycolic acids are long fatty acids found in the cell walls of the mycolata taxon, a group of bacteria that includes Mycobacterium tuberculosis, the causative agent of the disease tuberculosis. They form the major component of the cell wall of mycolata species.
The presence of mycolic acids gives M. tuberculosis many characteristics that defy medical treatment. They lend the organism increased resistance to chemical damage and dehydration, and prevent the effective activity of hydrophobic antibiotics. In addition, the mycolic acids allow the bacterium to grow readily inside macrophages, effectively hiding it from the host's immune system.

94. Mechanism of Action of Anti-Mycobacterial Antibiotics
Rifampin is an inhibitor of RNA polymerase

95. Isoniazide inhibits the synthesis of mycolic acid

96. Pyrazinoic acid inhibits the enzyme fatty acid synthetase I, which is required by the bacterium to synthesise fatty acids.

97. Ethambutol disrupts the formation of the cell wall