Download Lec. 5 - Overview of.. - College of Pharmacy at Howard University

Howard University College of Pharmacy
Pharmacy Biomedical Preview 2014
Paula Ingram Darasaw
1
Lecture Objectives

Discuss the structure
and mechanism of
action of various
antibiotic classes:
 Cell wall inhibitors
 Sulfonamides
 Macrolides
 Tetracyclines
 Fluoroquinolones
 Metronidazole
Understand the
principles of
antimicrobial resistance
and the pharmacist’s
role in combating it
 Discuss counseling
points and other
important tips to provide
to patients when
administering
antimicrobial therapy

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Beta-lactams
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Beta-lactams
Penicillins
 Cephalosporins
 Carbapenums
 Monobactams

http://www.life.umd.edu/classroom/bsci424/Images/PathogenImages/Bet
aLactam.gif
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Structure and Reactivity
Beta-lactam nucleus is responsible for
antimicrobial activity
 Degradation of beta-lactam ring (by betalactamases) or other means results in a
loss of function

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Bacterial Cell Wall Review

Bacteria constantly remodel their
peptidoglycan cell walls
○ Simultaneously building and breaking
down the wall at different portions as the
cell grows and divides

Transpeptidase cross-links the oligopeptide
side-chains
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Peptidoglycan Structure
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Mechanism of Action
Beta-lactams irreversibly bind to specific
sites on transpeptidase (penicillinbinding proteins), disabling the enzyme’s
ability to cross-link peptidoglycan.
 This weakens the cell wall, and causes
the bacteria to rupture from osmotic
pressure

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Mechanism of Action
http://www.antibioticslist.com/images/design/penicillin_img.gif
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Penicillins

Discovered as natural products from the
mold Penicillium rubrum
 Alexander Fleming

Among the earliest and still most widely
used antibiotics
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Penicillin Structure
www.microbiologyprocesses.blogspot.com
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Penicillins
 Penicillin
G
 Penicillin V
 Oxacillin
 Dicloxacillin
 Nafcillin
 Amoxicillin
 Ampicillin
 Methicillin*
 Piperacillin
 Ticarcillin
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Patient Counseling Tip
 Take
penicillin-VK with food to reduce
the GI side effects (diarrhea, nausea)
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Cephalosporins
 Originally
isolated from the fungus
Acremonium sp.
 Widely used in the prophylaxis and
treatment of infections
 5 generations—some variance in
antimicrobial coverage and side
effects between them
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Cephalosporin Structure
http://withfriendship.com/images/h/39377/Cephalosporin-picture.gif
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Cephalosporins
1st
2nd
3rd
Generation
• Cefazolin
• Cephalexin
Generation
• Cefuroxime
• Cefoxitin
Generation
• Ceftriaxone
• Cefdinir
4th Generation
• Cefipime
5th Generation
• Ceftobiprole
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Patient Counseling Tip
 Patients
who are allergic to penicillins
may also be allergic to
cephalosporins. Use caution when
administering to these patients or
avoid altogether
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Carbapenems
Developed from thienamycin, a natural
product from the bacteria Streptomyces
cattleya
 Very broad spectrum of activity
 Only available in IV formulations

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Carbapenem Structure
http://upload.wikimedia.org/wikipedia/commons/thumb/a/af/Carba
penems_structure.svg/500px-Carbapenems_structure.svg.png
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Carbapenems
Ertapenem
Imipenem/cilastatin
Meropenem
Doripenem
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Patient Counseling Tip
 Some
carbapenems increase the risk
of seizures. Use extreme caution and
monitoring when administering them
to patients who have a history of
seizures or are currently taking antiepileptic medication
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Monobactams




Unique among beta-lactams in that the
principle structure consists of only one ring
(the beta-lactam)
Only available agent in the US is aztreonam
Structure is a modified derivative of the
bacteria Chromobacterium violaceum
One of only a few antibiotics that are available
via the inhalation route
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Aztreonam Structure
http://upload.wikimedia.org/wikipedia/commons/thumb/4/4d/Aztreonam_str
ucture.svg/500px-Aztreonam_structure.svg.png
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Patient Counseling Tip
 There
is no documented crosssensitivity between aztreonam and
penicillins. If a patient is allergic to
penicillin, aztreonam can still be
considered for use. However, caution
and monitoring is recommended
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Beta-lactamase Inhibitors

Clavulanic
acid

Sulbactam
Tazobactam
Sometimes given with
penicillins to
counteract bacterial
resistance
Inhibit the bacterial
enzyme betalatamase, which
breaks open the betalactam ring—thus
rendering the
antibiotic ineffective
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Vancomycin
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Vancomycin
Originally isolated from the soil
bacterium Amycolatopsis orientalis
 Has a spectrum limited to gram positive
organisms

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Vancomycin Structure
http://upload.wikimedia.org/wikipedia/commons/thumb/f/f4/Vancomy
cin.svg/500px-Vancomycin.svg.png
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Vancomycin Mechanism of Action
Inhibits proper cell wall synthesis in gram
positive bacteria
 Binds to terminal D-Ala-D-Ala residues on
the oligopeptides protruding from the
NAG/NAM backbone

 This prevents cross-linking (similar to beta-
lactams, but by a different mechanism)
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Vancomycin Mechanism of Action
http://upload.wikimedia.org/wikipedia/commons/thumb/5/5f/Vancomycin_resist
ance.svg/800px-Vancomycin_resistance.svg.png
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Patient Counseling Tip
 Infusion
of vancomycin at rates above
1 gram/hour can lead to an immune
reaction known as “Red Man
Syndrome”
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Summary
http://e-learning.perubatan.org/index.php?topic=622.0
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Sulfonamides
The first antimicrobial drugs
discovered—launched the antibiotic
revolution in medicine
 Have a broad antibiotic spectrum
 The sulfonamide moiety is found in
many other areas of medicine

34
Sulfonamide Structure
http://upload.wikimedia.org/wikipedia/commons/5/59/Sulfona
mide.png
http://upload.wikimedia.org/wikipedia/commons/8/8b/Sulfam
ethoxazole.png
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Sulfonamide Mechanism of
Action
Structural
analogs of
PABA
PABA is
necessary
for Folic acid
synthesis
Folic acid is
necessary
for DNA
synthesis
Bacteria are
unable to
replicate
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Sulfonamide Mechanism of
Action
http://upload.wikimedia.org/wikipedia/commons/thumb/0/09/Sulfa_fo
late.svg/1000px-Sulfa_folate.svg.png
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Sulfonamide Antibiotics
Sulfamethoxazole
 Sulfacetamide
 Sulfadiazine
 Silver Sulfadiazine
 Mafenide

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Patient Counseling Tip
 Drink
a full glass of water when taking
each dose of a sulfonamide
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Macrolides
Derived from secondary metabolites
(polyketides) of bacteria and fungi
 Broad spectrum of antimicrobial activity
 Activity stems from macrocytic lactone
(macrolide) ring

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Macrolide Structure
http://upload.wikimedia.org/wikipedia/commons/thumb/6/6
5/Erythromycin_A.svg/500px-Erythromycin_A.svg.png
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Macrolide Mechanism of Action
Reversibly bind to the P-site on the 50s
ribosomal subunit of susceptible bacteria
 This inhibits the action of peptidyl
transferase, which is responsible for
elongation of the growing peptide chain
 Bacteria is unable therefore unable to
synthesize protein, and will eventually die

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Macrolide Mechanism of Action
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Macrolides
Erythromycin
 Clarithromycin
 Azithromycin
 Telithromycin*

○ a ketolide
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Clindamycin



A lincosamide
antibiotic
Structurally
dissimilar to
macrolides
Similar MOA (binds
to 50s subunit) as
macrolides
http://www.chemicalbook.com/CAS%5CGIF%5C1832
3-44-9.gif
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Patient Counseling Tip
 Macrolides
interact with many other
medications. Review the patient’s full
medication list before use—
particularly if the patient is using
drugs that affect heart rate
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Tetracyclines
Originally isolated from the
Streptomyces genus of bacteria
 Have a broad antimicrobial spectrum
 Commonly used in acne, UTI, and
atypical infections

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Tetracycline Structure
http://upload.wikimedia.org/wikipedia/commons/8/84/Tetracyclines.png
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Tetracycline Mechanism of Action

Bind to the 30s ribosomal subunit in
susceptible bacteria
 Distinguish from macrolides, which bind to the
50s subunit

Specifically block the A-site so that the
incoming aminoacyl-tRNA cannot bind
 Distinguish from macrolides, which block the P-
site

This stops the addition of new amino acids
to the growing protein chain—inability to
synthesize new proteins results in bacterial
death
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Tetracycline Mechanism of Action
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Tetracyclines
Tetracycline (naturally occurring)
 Demeclocycline (naturally occurring)
 Doxycycline
 Minocycline
 Tigecycline*

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Patient Counseling Tip
 Do
not take tetracyclines with dairy
products, multivitamins, or antacids
 Take 2 hours before or 4 hours after
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Fluoroquinolones
 Fully
synthetic, broad range
antibiotics
 Widely used as eye/ear drops, as well
as oral and IV formulation
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Fluoroquinolone Structure
http://upload.wikimedia.org/wikipedia/commons/thumb/1/17/Quino
lone.svg/500px-Quinolone.svg.png
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Fluoroquinolone Mechanism of
Action
Bind to and inhibit DNA gyrase in gram
negative bacteria and Topoisomerase in
gram positive bacteria
 These enzymes aid in the process of
unwinding/rewinding DNA during
replication
 Inhibiting their action disrupts DNA
replication, causing cell death

58
Fluoroquinolone Mechanism of
Action
http://www.seminfect.be/D-Low-28-06-01/img039.gif
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Fluoroquinolones
Ciprofloxacin
 Ofloxacin
 Levofloxacin

Moxifloxacin
 Gatifloxacin
 Gemifloxacin

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Patient Counseling Tip
 Do
not take fluoroquinolones with
dairy products, multivitamins, or
antacids
 Take 2 hours before or 4 hours after
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Metronidazole
Used in the treatment only of
ANAEROBIC bacterial infections
 Also used to treat infections from
protozoa and amoebas

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Metronidazole Structure
http://upload.wikimedia.org/wikipedia/commons/thumb/f/f1/Metronidazole.svg/500px
-Metronidazole.svg.png
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Metronidazole Mechanism of
Action
Metronidazole is taken
into the bacterial cell and
reduced by ferredoxin
 The reduced form of
metronidazole is a toxic
free-radical
 This free-radical
covalently binds to and
deactivates many
bacterial enzymes-disrupting vital functions

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Patient Counseling Tip
 Do
not consume any alcohol during
course of therapy or for 3 days
afterwards
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Antimicrobial Overview
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Antibiotic Resistance
Bacteria grow and divide very rapidly,
and as a result have quickly developed
resistance to many antibiotics
 Regardless of the antibiotic or bacteria,
resistance to antibiotics occurs through
five main mechanisms

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Antibiotic Resistance
 Drug
inactivation/modification
 Altered target site
 Altered metabolic pathway
 Decrease drug permeability
 Efflux pump
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Pharmacist’s Role
Help ensure proper use, selection, and
duration of antibiotics
 Counsel patients on potential side effects
and drug interactions with antibiotic use
 Counsel patients on importance of taking
ALL of their antibiotic regimen
 Others?

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References
1.
2.
3.
Petri WA. Chapter 52. Sulfonamides, Trimethoprim-Sulfamethoxazole,
Quinolones, and Agents for Urinary Tract Infections. In: Chabner BA,
Brunton LL, Knollman BC, eds. Goodman & Gilman’s The Pharmacological
Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011.
http://www.accesspharmacy.com/content.aspx?aID=16677067. Accessed
June 28 2012
Petri WA. Chapter 53. Penicillins, Cephalosporins, and other beta-lactam
antibiotics. In: Chabner BA, Brunton LL, Knollman BC, eds. Goodman &
Gilman’s The Pharmacological Basis of Therapeutics. 12nd ed. New York:
McGraw-Hill; 2011.
http://www.accesspharmacy.com/content.aspx?aID=16677067. Accessed
June 28 2012
Petri WA. Chapter 55. Protein Synthesis Inhibitors and Miscellaneous
Antimicrobial agents. In: Chabner BA, Brunton LL, Knollman BC, eds.
Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12nd ed.
New York: McGraw-Hill; 2011.
http://www.accesspharmacy.com/content.aspx?aID=16677067. Accessed
June 28 2012
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Questions
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