CEPHALOSPORINS

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CEPHALOSPORINS
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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

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6. Mechanism of Action

• The acetoxy group acts as a good leaving group
  and aids the mechanism

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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
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8. First Generation Cephalosporins
Cephalothin

• First generation cephalosporin
• More active than penicillin G vs. some Gram -ve
  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

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8. First Generation Cephalosporins
Cephalothin - drug metabolism
Less active OH is a poorer leaving group

• Strategy
• Replace the acetoxy group with a metabolically
  stable leaving group

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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

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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

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First Generation Cephalosporins
Cefazolin
Cefadroxil
Cefalexin
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First Generation Cephalosporins include Cefazolin
(parenteral) as well as cefadroxil and cephalexin
(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
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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

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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.

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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

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• 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

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Forms of Cefuroxime (2nd generation
cephalosporin)
Cefuroxime (ZINACEF)
Cefuroxime axetil (CEFTIN)
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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.
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10. Third Generation Cephalosporins
Oximinocephalosporins

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

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10. Third Generation Cephalosporins
Oximinocephalosporins
Ceftazidime

• Injectable cephalosporin
• Excellent activity vs. P. aeruginosa and other
  Gram -ve bacteria
• Can cross the blood brain barrier
• Used to treat meningitis

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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
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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 ve cocci and a broad array of
  Gram -ve bacteria
• Active vs. P. aeruginosa

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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
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Newer b-Lactam Antibiotics
Thienamycin (Merck 1976)(from Streptomyces
cattleya)

• Potent and wide range of activity vs Gram ve and
  Gram -ve bacteria
• Active vs. Pseudomonas aeruginosa
• Low toxicity
• High resistance to b-lactamases
• Poor stability in solution (ten times less stable
  than Pen G)

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Newer b-Lactam Antibiotics
Thienamycin analogues used in the clinic
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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.
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Newer b-Lactam Antibiotics
Clinically useful monobactam

• Administered by intravenous injection
• Can be used for patients with allergies to
  penicillins
• and cephalosporins
• No activity vs. Gram ve or anaerobic bacteria
• Active vs. Gram -ve aerobic bacteria

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

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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 administered intraveneously
• 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)
• 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).

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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

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

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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
• Therefore, Rifabutin 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
• 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
• 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.

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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)
• 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

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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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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. 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. 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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• 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 (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. 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
• 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

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

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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

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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
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.
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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
  gastrointestinalo flora, leaving only Clostridium
  difficile
• This can result in overgrowth by C. difficile,
  which is resistant

71
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.

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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

75
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
77
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

78
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.

79
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
80
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.
• This combination is known as co-trimoxazole,
  TMP-sulfa, or TMP-SMX

Sulfamethoxazole
Trimethoprim
81
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.

82
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

83
Structural Resemblance of Sulfamethoxazole and
p-Aminobenzoic Acid
Sulfamethoxazole
p-Aminobenzoic Acid
84
Another sulfa drug is Dapsone, which is used to
treat Mycobacterium leprae
Dapsone
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Structural Comparison of Two Sulfa Drugs
86
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
88
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

89
Uses of the Quinolone Antibiotics

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

90
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
91
Metronidazole (Flagyl)
Metronidazole is used in the treatment of
infections caused by anaerobic bacteria
92
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.
93
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.

94

• 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
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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 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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Mechanism of Action of Anti-Mycobacterial
Antibiotics

• Rifampin is an inhibitor of RNA polymerase
• Isoniazide inhibits the synthesis of mycolic acid
• Pyrazinoic acid inhibits the enzyme fatty acid
  synthetase I, which is required by the bacterium
  to synthesise fatty acids.
• Ethambutol disrupts the formation of the cell wall

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