Download Overview of Antimicrobial Agents

Chijioke Onejeme
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
3
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

5
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
6
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)
13
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
16
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
17
Carbapenems
Developed from thienamycin, a natural
product from the bacteria Streptomyces
cattleya
 Very broad spectrum of activity
 Only available in IV formulations

18
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
22
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
30
Patient Counseling Tip
 Infusion
of vancomycin at rates above
1 gram/hour can lead to an immune
reaction known as “Red Man
Syndrome”
31
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
36
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
39
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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

41
Macrolide Structure
http://upload.wikimedia.org/wikipedia/commons/thumb/6/6
5/Erythromycin_A.svg/500px-Erythromycin_A.svg.png
42
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

43
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
47
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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

49
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
51
Tetracycline Mechanism of Action
52
Tetracyclines
Tetracycline (naturally occuring)
 Demeclocycline (naturally occuring)
 Doxycycline
 Minocycline
 Tigecycline*

53
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
56
Fluoroquinolone Structure
http://upload.wikimedia.org/wikipedia/commons/thumb/1/17/Quino
lone.svg/500px-Quinolone.svg.png
57
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

63
Metronidazole Structure
http://upload.wikimedia.org/wikipedia/commons/thumb/f/f1/Metronidazole.svg/500px
-Metronidazole.svg.png
64
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

65
Patient Counseling Tip
 Do
not consume any alcohol during
course of therapy or for 3 days
afterwards
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Antimicrobial Overview
67
68
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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