b-Lactamase Inhibitors

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b-Lactamase Inhibitors
Clavulanic acid (Beecham 1976)(from Streptomyces
clavuligerus)

• Weak, unimportant antibacterial activity
• Powerful irreversible inhibitor of b-lactamases -
  suicide substrate
• Used as a sentry drug for ampicillin
• Augmentin amoxicillin clavulanic acid
• Allows less amoxicillin per dose and an increased
  activity spectrum
• Timentin ticarcillin clavulanic acid

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b-Lactamase Inhibitors
Augmentin Amoxicillin Clavulanic Acid
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b-Lactamase Inhibitors
Penicillanic acid sulfone derivatives

• Suicide substrates for b-lactamase enzymes
• Sulbactam has a broader spectrum of activity vs
  b-lactamases than clavulanic acid, but is less
  potent
• Unasyn ampicillin sulbactam
• Tazobactam has a broader spectrum of activity vs
  b-lactamases than clavulanic acid, and has
  similar potency
• Tazocin or Zosyn piperacillin tazobactam

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The aminopenicillins b-lactamase inhibitor
combinations include ampicillin-sulbactam
(parenteral) and amoxicillin-clavulanate (oral)
Gram-positive bacteria Some Staphylococcus aureus, Streptococcus pyogenes, Viridans streptococci, Some Streptoocus pneumoniae, Some enterococci Listeria monocytogenes
Gram-negative bacteria Neisseria spp. Haemophilus influenzae, Many Enterobacteriaceae
Anaerobic bacteria Clostridia spp. (except C. difficile), Actinomyces israellii, Bacteroides spp.
Spirochetes Borrelia burgdorferi
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Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins
Class 2 - CO2H at the a-position
(carboxypenicillins)
Examples
R H CARBENICILLIN R Ph CARFECILLIN

• Carfecillin prodrug for carbenicillin
• Active over a wider range of Gram -ve bacteria
  than ampicillin
• Active vs. Pseudomonas aeruginosa
• Resistant to most b-lactamases
• Less active vs Gram bacteria (note the
  hydrophilic group)
• Acid sensitive and must be injected
• Stereochemistry at the a-position is important
• CO2H at the a-position is ionised at blood pH

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Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins
Class 2 - CO2H at a-position (carboxypenicillins)
Examples

• Administered by injection
• Identical antibacterial spectrum to carbenicillin
• Smaller doses required compared to carbenicillin
• More effective against P. aeruginosa
• Fewer side effects
• Can be administered with clavulanic acid

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Problem 3 - Range of Activity
Examples of Broad Spectrum Penicillins

• Administered by injection
• Generally more active than carboxypenicillins vs.
  streptococci and Haemophilus species
• Generally have similar activity vs Gram -
  aerobic rods
• Generally more active vs other Gram - bacteria
• Azlocillin is effective vs P. aeruginosa
• Piperacillin can be administered alongside
  tazobactam

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The Extended Spectrum Penicillins include
Piperacillin and Ticarcillin (parenteral) as well
as Carbenicillin (oral)
Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Some Streptococcus pneumoniae, Some enterococci
Gram-negative bacteria Neisseria meningitidis, Some Haemophilus influenzae, Some Enterobacteriaceae, Pseudomonas aeruginosa
Anaerobic bacteria Clostridia spp. (except C. difficile), Some Bacteroides spp.
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Extended-Spectrum Penicillin b-Lactamase
Inhibitor Combinations includePiperacillin-tazoba
ctam as well as ticarcillin-clavulanate (both
pairs are parenteral)
Gram-positive bacteria Some Staphylococcus aureus, Streptocosoccus pyogenes, Viridans streptococci, Some Streptococcus pneumoniae, Some enterococci Listeria monocytogenes
Gram-negative bacteria Neisseria spp. Haemophilus influenzae, Most Enterobacteriaceae, Pseudomonas aeruginosa
Anaerobic bacteria Clostridia spp. (except C. difficile), Bacteroides spp.
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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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Giussepe Brotzu noticed that the substance
cultured from the sewer water had activity
against Salmonella typhi, the active cause of
typhoid fever Typhoid fever is transmitted human
to human by contact with contaminated feces.
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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 -
  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 cefalexin
(oral).
Gram-positive bacteria Streptococcus pyogenes, Some virdans streptococci, Some Staphylococcus aureus, Some Streptococcus pneumoniae
Gram-negative bacteria Some Eschericia coli, Some Klebsiella pneumoniae, Some Proteus mirabilis
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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 axetil (CEFTIN)
Cefuroxime sodium (ZINACEF)
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More second generation cephalosporins Loracarbef
(Lorabid)
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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
  - bacteria
• May also increase affinity for the
  transpeptidase enzyme
• Good activity against Gram - bacteria
• Variable activity against Gram cocci
• Variable activity vs. P. aeruginosa
• Lack activity vs MRSA
• Generally reserved for troublesome infections

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

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

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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 cocci and a broad array of Gram
  - 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 and
  Gram - bacteria
• Active vs. Pseudomonas aeruginosa
• Low toxicity
• High resistance to b-lactamases
• Poor stability in solution (ten times less stable
  than Pen G)

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Newer b-Lactam Antibiotics
Thienamycin analogues used in the clinic
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Primaxin Imipenem Cilastatin Cilastatin is
an inhibitor of a human enzyme, renal
dehydropeptidase, which degrades carbapenems
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Meropenem, Merrem, AstraZeneca
Ertapenem, Invanz, Merck
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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
Aztreonam

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

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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
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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.
43

• http//student.ccbcmd.edu/courses/bio141/lecguide/
  unit2/control/vanres.html
• LINK

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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 a lipopeptide antibiotic
• Approved for use in 2003
• Lipid portion inserts into the bacterial
  cytoplasmic membrane where it forms an
  ion-conducting channel.

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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
  individual who are simultaneously being treated
  for tuberculosis and HIV infection, since it will
  not result in oxidation of the antiviral drugs
  the patient is taking
• Rifaximin is a poorly absorbed rifamycin that is
  used for treatment of travelers diarrhea.

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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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• 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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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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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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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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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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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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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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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