Definitions

1
Definitions

• Bacteremia Presence of bacteria in the blood
• Under normal circumstances, the blood is a
  sterile environment

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Systemic Inflammatory Response Syndrome (SIRS)

• An inflammatory response, to a wide variety of
  clinical insults, characterized by two or more of
  the following
• Temperature greater than 38 oC (100.4 oF)
• Heart rate greater than 90 beats per min
• Respiratory rate greater than 20 breaths per min
• White blood cell count greater than 12,000/mL

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Sepsis
Sepsis is a systemic inflammatory response to a
documented infection In addition to preceding
criteria, at least one of the following must be
present Alteration in mental state Hypoxemia
(lower pressure of oxygen in blood) Elevated
plasma lactate
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Lipopolysaccharide is Part of the Outer Membrane
of Gram Negative Bacteria
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• 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.

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• 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.

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• 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.

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Allergic Responses to Antibiotics

• Uticaria A skin rash involving dark red itchy
  bumps.

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Allergic Responses

• Anaphylaxis A severe, life-threatening allergic
  response, having many potential manifestations,
  including loss of consciousness, labored
  breathing, swelling of the tongue, low blood
  pressure, etc.

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Shock

• Shock is characterized by low blood pressure
  (hypotension) and tachycardia
• Septic shock is a result of the infection itself
  (bacteremia, sepsis).
• Anaphylactic shock is an allergic response to a
  foreign agent (antibiotic, bee sting, etc.)

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Vancomycin
Carbohydrate
Peptide Linkages
Vancomycin is called a glycopeptide, meaning
that it is a cyclic peptide, with sugar residues
attached to it.
14
Discovery
Vancomycin was discovered in a soil sample sent
to the pharmaceutical company Eli Lilly by a
missionary in Borneo in the 1950s.
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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

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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.
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Vancomycin Uses

• Vancomycin is used to treat aerobic Gram
  bacteria, including MRSA and strains of
  penicillin-resistant Streptococcus pneumoniae
• Vancomycin is most often 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.

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Vancomycin Resistance

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

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• 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 amide NH by an O)
• 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).

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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
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Daptomycin
Lipophilic Tail

• 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

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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
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Uses of Daptomycin (Cubicin)

• 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.

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• Primarily been used to treat skin and soft tissue
  infections (complicated skin and skin structure
  infections, including MRSA).
• Also approved for S. aureus bloodstream
  infections (bacteremia), including those with
  right-sided infective endocarditis
• Poor activity in the lung, thus not used for
  pneumonia

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• Cubicin (Daptomycin) is administered
  intravenously.
• It is not orally bioavailable.

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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
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Rifamycins

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

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The Rifamycins
Rifampicin (Rifampin)
Rifabutin (Mycobutin)
Rifaximin (Xifaxan (US), Spiraxin (EU))
Rifapentine (Priftin)
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• 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.

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

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Mechanism of Action of Rifampin

• Rifampin inhibits transcription by inactivating
  bacterial RNA polymerase

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• 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

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Uses of Rifampin

• Used, in combination with other drugs, to treat
  Mycobacterium tuberculosis
• Used to treat some Staphylococcal infections.
• Rifampin and the other rifamycins are orally
  bioavailable.

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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.
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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.
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Aminoglycoside Mechanism of Action

• Aminoglycosides bind to the 30S subunit of the
  bacterial ribosome, thereby inhibiting bacterial
  protein synthesis (translation)
• Link
• LINK
• Link

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The ribosome target of aminoglycosides is a
combination of RNA (below) and proteins
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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.

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• 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.

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The Aminoglycosides include Streptomycin,
Gentamicin, Tobramycin, and Amikacin (all
parenteral), as well as Neomycin (topical, oral).
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Aminoglycosides
Streptomycin
Streptomycin was the first aminoglycoside to be
discovered (1944) and it still valuable (in
combination with other antibacterial agents) in
the treatment of multidrug resistant tuberculosis
(although not a first line drug for tuberculosis)
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Aminoglycosides
Gentamicin

• Gentamicin is most commonly used of the
  aminoglycosides
• Active against aerobic Gram-negative infections
  (and sometimes Gram positive)
• Can be used synergistically, together with a cell
  wall targeting agent (e.g. a penicillin)
• Available in parenteral, opthalmic, and topical
  formulations

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Aminoglycosides
Tobramycin

• Tobramycin has better activity against
  Pseudomonas aeruginosa than does gentamicin
• Tobramycin may be given either intramuscularly or
  intravenously
• It is also administered by inhaler, particularly
  useful for individuals with cystic fibrosis
  (frequently contract P. aeruginosa infections)

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Amikacin

• Amikacin has the broadest antimicrobial spectrum
  of the aminoglycosides
• It is more resistant to aminoglycoside-inactivatin
  g enzymes than the other aminoglycosides
• It is often used in hospitals where gentamicin-
  and tobramycin-resistant microorganisms are
  prevalent

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Neomycin

• Neomycin is widely used for topical
  administration
• Like other aminoglycosides, it is not absorbed
  well orally, and is used to prepare the bowel for
  surgery.

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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.
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Macrolides and Ketolides
The structures of erythromycin and telithromycin
Circled substituents and distinguish
telithromycin from the macrolides.
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Chemical Definitions
Ester Linkage
Cladinose Sugar

• Macrolide macrocyclic lactone (cyclic ester)
• Macrolide antibiotics usually have ring sizes of
  14, 15, or 16 atoms

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

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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

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The macrolide group consists of Erythromycin,
Clarithromycin, and Azithromycin (all oral, with
erythromycin and azithromycin also being
available parenterally).
Clariithromycin
Erythromycin
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Erythromycin reactions under acidic conditions
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Clarithromycin substitutes a methoxy group for
the hydroxy and improves acid stability
Methoxy group
Hydroxy group
Clariithromycin (14 membered ring)
Erythromycin (14 membered ring)
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Insertion of N into the ring
Azithromycin (15 membered ring)
Link
LInk
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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.
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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

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Cladinose sugar replaced by ketone
Telithromycin A ketolide (14 membered ring)
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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
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The Tetracycline Antibiotics
The structure of tetracycline
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Tetracycline Antibiotics
Tetracycline
Tigecycline
Doxycycline
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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.
• LINK

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Uses of the Tetracycline Antibiotics

• Main use is against atypical bacteria, including
  rickettsia, chlamydia, and mycoplasmas
• Also active against some aerobic Gram-positive
  pathogens and some aerobic Gram-negative bacteria

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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.
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Tigecycline
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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.
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Chloramphenicol
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Mechanism of Action of Chloroamphenicol

• Binds to the 50S subunit of the bacterial
  ribosome, where it blocks binding of tRNA

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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.

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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

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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.
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Clindamycin
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Mechanism of Action of Clindamycin

• Clindamycin binds to the 50S subunit of the
  ribosome to inhibit protein synthesis

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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

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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

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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
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Streptogramins
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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

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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

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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
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The Oxazolidinones
The structure of Linezolide
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• Binds to the 50S subunit and prevents association
  of this unit with the 30S subunit.

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Mechanism of Action of the Oxazolidinones

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

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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.

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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
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The Sulfa Drugs

• LINK
• 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
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• This combination is known as co-trimoxazole,
  TMP-sulfa, or TMP-SMX

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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.

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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

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The Target of Trimethoprim is Dihydrofolate
Reductase (DHFR)
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Inhibitors of Dihydrofolate Reductase (DHFR)
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Structural Resemblance of Sulfamethoxazole and
p-Aminobenzoic Acid
Sulfamethoxazole
p-Aminobenzoic Acid
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Another sulfa drug is Dapsone, which is used to
treat Mycobacterium leprae
Dapsone
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Structural Comparison of Two Sulfa Drugs
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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
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The Fluoroquinolones
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Fluoroquinolones
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Mechanism of Action Quinolones

• Quinolone antibiotics inhibit bacterial DNA
  gyrase (Gram negative bacteria) or Topoisomerase
  IV (Gram positive bacteria)
• Link
• LINK
• LINK

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Uses of the Quinolone Antibiotics

• Urinary Tract Infections fluoroquinolones are
  more effective than trimethoprim-sulfamethoxazole
  
• Prostatitis
• Respiratory tract infections
• Gastrointestinal and Abdominal Infections

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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
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Metronidazole (Flagyl)
Metronidazole is used in the treatment of
infections caused by anaerobic bacteria
111
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.
112
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.

113

• 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

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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
115
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

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Antimycobacterial Agents
Pyrazinamide
Rifampin
Ethambutol
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Mycobacterial Infections
http//www.nature.com/nrmicro/animation/imp_animat
ion/index.html http//web.uct.ac.za/depts/mmi/lst
eyn/cellwall.html
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Mycolic Acids provide protection

• Mycolic acids are long fatty acids found in the
  cell envelope 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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Mycobacterium Cell Wall
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Mechanism of Action of Anti-Mycobacterial
Antibiotics

• Rifampin is an inhibitor of RNA polymerase

122

• Isoniazide inhibits the synthesis of mycolic acid

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Mechanism of Action of Isoniazid
isoniazid
NADH
Isoniazid is a produg, that is activated by a
mycobacterial peroxidase, called KatG to form a
reactive free radical, which, in turn, reacts
with NADH to form a covalent adduct. The
reactive (isoniazid-derived) species is probably
an acyl radical (shown)
124
Mechanism of Action of Isoniazid
This isoniazid-NADP adduct then forms a complex
with bacterial enoyl reductase (InhA),an enzyme
responsible for reducing double bonds during
fatty acid synthesis
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• Pyrazinoic acid inhibits the enzyme fatty acid
  synthetase I (FAS I), which is required by the
  bacterium to synthesise fatty acids.

127

• Ethambutol disrupts the formation of the cell
  envelope by interfering with the enzyme that
  forms the arabinogalactan polysaccharide (called
  arabinogalactan transferase)

128
Arabinogalactan
D-Galactose

• Arabinogalactan is a biopolymer consisting of
  arabinose and galactose monosaccharides

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Arabinogalactan-mycolic acid adduct
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Targets of First Line anti-TB Drugs
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Overview of anti-mycobacterial drugs
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Antimicrobial Resistance

• LINK

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Assigned Reading

• Antibiotic Basics for Clinicians, by Alan R.
  Hauser, pp. 3399
• Kirkpatrick Peter Raja Aarti LaBonte Jason
  Lebbos John Daptomycin. Nature reviews. Drug
  discovery (2003), 2(12), 943-4.
• Ammerlaan, H. S. M. Bonten, M. J. M.
  Daptomycin graduation day. Clinical
  Microbiology and Infection (2006), 12(Suppl.
  8), 22-28.
• Baltz, Richard H. Miao, Vivian Wrigley, Stephen
  K. Natural products to drugs Daptomycin and
  related lipopeptide antibiotics. Natural
  Product Reports (2005), 22(6), 717-741. pp.
  717-722, 725-726.
• Baltz Richard H Daptomycin mechanisms of action
  and resistance, and biosynthetic engineering.
  Current opinion in chemical biology (2009),
  13(2), 144-51. Journal code 9811312.
• Clay Kimberly D Hanson John S Pope Scott D
  Rissmiller Richard W Purdum Preston P 3rd Banks
  Peter M Brief communication severe
  hepatotoxicity of telithromycin three case
  reports and literature review. Annals of
  internal medicine (2006), 144(6), 415-20.
• Zeitlinger, Markus Wagner, Claudia Christina
  Heinisch, Birgit. Ketolides - the modern
  relatives of macrolides the pharmacokinetic
  perspective. Clinical Pharmacokinetics
  (2009), 48(1), 23-38.
• Vicens, Quentin Westhof, Eric. RNA as a drug
  target The case of aminoglycosides.
  ChemBioChem (2003), 4(10), 1018-1023.
• Wilson, Daniel N. Nierhaus, Knud H. The
  oxazolidinone class of drugs find their
  orientation on the ribosome. Molecular Cell
  (2007), 26(4), 460-462.
• Marchese, A. Schito, G. C. The oxazolidinones
  as a new family of antimicrobial agent.
  Clinical Microbiology and Infection (2001),
  7(Suppl. 4), 66-74.
• Asaka, Toshifumi Manaka, Akira Sugiyama,
  Hiroyuki. Recent developments in macrolide
  antimicrobial research. Current Topics in
  Medicinal Chemistry (Sharjah, United Arab
  Emirates) (2003), 3(9), 961-989. READ ONLY
  PP. 961-966 AND 981-983
• Zhanel, George G. Homenuik, Kristen Nichol,
  Kim Noreddin, Ayman Vercaigne, Lavern Embil,
  John Gin, Alfred Karlowsky, James A. Hoban,
  Daryl J. The glycylcyclines a comparative
  review with the tetracyclines. Drugs (2004),
  64(1), 63-88. Read pp. 64-72

139
Homework Questions

1. To which site on the ribosome do the
   aminoglycoside antibiotics bind?
2. A high level of aminoglycoside resistance is
   known to result from the A1408G mutation in
   bacterial ribosomes. A potential solution would
   be to design aminoglycosides that can bind more
   tightly to this mutation. Why cant this be
   achieved?
3. Discuss the advantages and the disadvantages of
   using RNA as a drug target.
4. The activity o f daptomycin is highly dependent
   on which alkaline earth metal? What is the
   function of this metal in the mechanism of action
   (MOA) of daptomycin?
5. At which ribosomal site do the oxazolidinones
   bind? What accounts for their side effects in
   patients undertaking prolonged treatment with
   these drugs?
6. Why is azithromycin currently considered one of
   the best of the macrolides?
7. Explain how tetracyclines gain access to the
   cytoplasm of Gram-negative bacteria.