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Vancomycin

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Title: Vancomycin


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)
  • http//student.ccbcmd.edu/courses/bio141/lecguide/
    unit2/control/ppgsynanim.html

Penicillin Mechanism of Action (review) http//stu
dent.ccbcmd.edu/courses/bio141/lecguide/unit2/cont
rol/penres.html
  • http//student.ccbcmd.edu/courses/bio141/lecguide/
    unit2/control/vanres.html
  • 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 PBPs (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)
  • http//www.microbelibrary.org/microbelibrary/files
    /ccImages/Articleimages/kaiser/mechanisms/altribo_
    antibiot.html
  • http//www.microbelibrary.org/microbelibrary/files
    /ccImages/Articleimages/kaiser/mechanisms/altribo_
    antibiot.html
  • Link
  • 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
24
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25
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26
  • 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. 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.
34
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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
  • http//www.microbelibrary.org/microbelibrary/files
    /ccImages/Articleimages/kaiser/mechanisms/altribo_
    antibiot.html
  • http//www.microbelibrary.org/microbelibrary/files
    /ccImages/Articleimages/kaiser/mechanisms/altribo_
    antibiot.html
  • Link
  • 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
Tetracycline
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.
  • http//student.ccbcmd.edu/courses/bio141/lecguide/
    unit2/control/tetres.html

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

57
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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/Dalfopr
istin (parenteral)
Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococcus aureus, Some enterococci.
Gram-negative bacteria
Anaerobic bacteria
Atypical bacteria
65
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.
  • http//student.ccbcmd.edu/courses/bio141/lecguide/
    unit6/genetics/protsyn/translation/oxazolres_anim.
    html

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

74
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75
Structural Resemblance of Sulfamethoxazole and
p-Aminobenzoic Acid
Sulfamethoxazole
p-Aminobenzoic Acid
76
Another sulfa drug is Dapsone, which is used to
treat Mycobacterium leprae
Dapsone
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)
  • http//can-r.ca/images/Flash/fluoroquinolones.swf

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
http//www.nature.com/nrmicro/animation/imp_animat
ion/index.html http//web.uct.ac.za/depts/mmi/lst
eyn/cellwall.html
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.

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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

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