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(1) Chemotherapeutic drugs Antimicrobials.ppt
1. Chemotherapeutic drugs
(the part of antimicrobial agents)
a. Principles of Anti-microbial Therapy
b. Cell Wall Inhibitors, Penicillin
c. Cell Wall Synthesis Inhibitors, Cephalosporins
d. Cell Wall Synthesis Inhibitors, others
e. Protein Synthesis Inhibitors:
e. Quinolone & Sulfonamides
f. Antimycobacterials
g. Anti-fungal agents
h. Antiparasitic Drugs
i. Antiviral Agents
3. Anti-infective Therapy
• Modern age
– Discovery of sulfanilamide in 1936
– Commercial introduction of penicillin in 1941
Antimicrobial Therapy
– Original antimicrobials: derived from
microorganisms
– Newer agents: chemically synthesized
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4. Factors Leading to Infection
• Age: young and elderly
• Increased exposure to pathogenic
organisms
• Disruption of the normal barriers (↓
immunity) & Inadequate immunological
defenses
• Impaired circulation (e.g. diabetes)
• Poor nutritional status
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6. Overuse
• Overuse of antimicrobial agents can lead
to the development of severely resistant
organisms.
– Promoted the development of organisms
that are not affected by any of the available
therapies
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7. Classifications
• Antibacterial agents are classified based
on the following factors:
– Bactericidal or bacteriostatic
– Site of action
– Narrow or broad spectrum
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10. New antibacterial agents approved in the USA, 1983–2009 (as reported by the
Infectious Diseases Society of America's Antimicrobial Availability Task Force).
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11. Fungi & fungal infections
• Contracted
– Air
– Skin to skin
• Opportunistic organisms: i.e. due to normal
flora being killed off:
– Antibiotics
– Corticosteroid therapy
– Anticancer agents
– Suppressed immune system
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12. Fungal (mycotic) Infections
• Three general types:
– Cutaneous
– Subcutaneous
– Systemic (can be life threatening)
• Treatment
– Antibiotic therapy will not work.
– Requires prolonged treatment
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13. Antiviral Agents
• Viruses cause many infectious disorders:
– Acute: common cold
– Chronic: Herpes
– Slow growing: AIDS
• Available vaccines
– Polio, rabies, and smallpox
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14. Antiviral Agents: Key
Characteristics
• Inhibit viral replication by interfering with:
– Viral nucleic acid synthesis and/or regulation
– Ability of virus to bind to cells
• Interferon: stimulates immune system
7 - 14
16. Selection of Antimicrobial Agents
• Requires knowledge of
1) the organism's identity
2) the organism's susceptibility to a particular agent
3) the site of the infection
4) patient factors
5) the safety of the agent
6) the cost of therapy.
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17. Empiric therapy: immediate administration of
drug(s) prior to bacterial identification and
susceptibility testing.
•Broad-spectrum therapy may be needed:
– initially for serious infections when the identity
of the organism is unknown or
– the site makes a polymicrobial infection likely.
Pathogen-directed therapy: drug administration
after bacterial identification according to
susceptibility testing
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18. Bacteriostatic vs. Bactericidal drugs
• Bacteriostatic drugs arrest the growth and replication
of bacteria.
• Bactericidal drugs kill bacteria at drug serum levels
achievable in the patient.
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20. Minimum inhibitory concentration (MIC)
(for bacteriostatic agents)
• MIC: the lowest concentration of antibiotic that
inhibits bacterial growth.
• To provide effective antimicrobial therapy, the
clinically obtainable antibiotic concentration in body
fluids should be greater than the MIC.
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21. Minimum bactericidal concentration (MBC)
(for bactericidal agents)
• MBC: determines the minimum concentration of
antibiotic that kills the bacteria under investigation.
• The tubes that show no growth in the MIC assay are
subcultured into antibiotic-free media.
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22. Effect of the site of infection on therapy
• The blood-brain barrier
• The penetration and concentration of an antibacterial agent in
the CSF is particularly influenced by the following:
1. Lipid solubility of the drug:
– quinolones and metronidazole VS –latam antibiotics
2. Molecular weight of the drug:
– high molecular weight (for example, vancomycin) penetrates poorly.
• Protein binding of the drug
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23. Patient factors
• Attention must be paid to the condition of the
patient. For example:
– the status of the patient's immune system
– Kidneys
– Liver
– circulation
– age
• In women:
– pregnancy
– breastfeeding
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24. A. Immune system: and bacteriostatic antimicrobials
• Immunosuppression due to:
– Alcoholism
– Diabetes
– infection with the HIV
– Malnutrition
– advanced age
– immunosuppressive drugs.
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25. B. Renal dysfunction:
• Poor kidney function
causes accumulation
of antibiotics in the
body.
– Adjusting the dose or
the dosage schedule.
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26. C. Hepatic dysfunction: Erythromycin & Tetracycline
D. Poor perfusion: Diabetes
E. Age: Renal or hepatic elimination processes
F. Pregnancy: All antibiotics cross the placenta.
C.
C. Tetracyclines:
Tetracyclines: tooth dysplasia and inhibition of bone
growth
D.Some anthelmintics
anthelmintics are embryotoxic and teratogenic.
E.
E. Aminoglycosides
Aminoglycosides are ototoxic to the fetus.
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27. • Lactation: the concentration of an antibiotic in
breast milk is usually low, the total dose to the infant
may be enough to cause problems
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28. Safety of the agent
• Many of the antibiotics are safe due to selective
toxicity.
• Others are very toxic (for example, chloramphenicol)
– reserved for life-threatening infections
– Less selectivity
Cost of therapy
• Often, several drugs may show similar efficacy
in treating an infection but vary widely in cost.
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29. Route of Administration
1. Oral route:
– mild infections and can be treated on an outpatient basis.
– In patients requiring a course of intravenous therapy initially, the
switch to oral agents occurs as soon as possible.
2. Parenteral:
– Antimicrobials that are poorly absorbed from the GI tract
– Treatment of patients with serious infections
– Patient is not capable of swallowing.
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30. Combinations of Antimicrobial Drugs
A. It is advisable to treat patients with the single agent
that is most specific for the infecting organism.
– This strategy:
1. reduces the possibility of superinfection
2. decreases the emergence of resistant organisms
3. minimizes toxicity.
B. Combinations therapy may be advisable in certain
situations. For example, the treatment of tuberculosis
benefits from drug combinations.
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31. Drug Resistance
• Bacteria are said to be resistant to an antibiotic if the
maximal level of that antibiotic that can be tolerated
by the host does not halt their growth.
• Some organisms are inherently resistant to an
antibiotic.
– For example, gram-negative organisms are
inherently resistant to vancomycin.
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33. Complications of Antimicrobial Therapy
A. Hypersensitivity
– Hypersensitivity reactions to antimicrobial drugs or
their metabolic products frequently occur.
– For example, Penicillins.
B. Direct toxicity
– High serum levels of certain antibiotics may cause
toxicity by directly affecting cellular processes in the
host.
– For example, aminoglycosides can cause ototoxicity by
interfering with membrane function in the hair cells of
the organ of Corti.
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34. C. Super-infections
• With
– broad-spectrum antimicrobials
– combinations of agents
• May result in alterations of the normal microbial
flora permitting the overgrowth of opportunistic
organisms, especially fungi or resistant bacteria.
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39. I. Overview
• The cell wall is composed of a polymer called peptidoglycan that consists
of glycan units joined to each other by peptide cross-links.
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40. • To be maximally effective, inhibitors of cell wall synthesis
require actively proliferating microorganisms.
• The most important members of this group of drugs are:
1. -lactam antibiotics (named after the -lactam ring that
is essential to their activity)
2. vancomycin.
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41. A. Mechanism of action
• The penicillins interfere with the last step of bacterial cell wall
synthesis (transpeptidation or cross-linkage), resulting in
exposure of the osmotically less stable membrane.
• Cell lysis can then occur
- These drugs are bactericidal.
- Penicillins are only effective against:
– rapidly growing organisms
– synthesize a peptidoglycan cell wall.
II. Penicillins
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42. 1. Penicillin-binding proteins (PBP):
– bacterial enzymes involved in the synthesis of the cell wall and in the
maintenance of the morphologic features of the bacterium
– Alterations in some of these target molecules provide the organism
with resistance to the penicillins.
2. Inhibition of transpeptidase:
– Some PBPs catalyze formation of the cross-linkages between
peptidoglycan chains
– Penicillins inhibit this transpeptidase-catalyzed reaction
3. Production of autolysins:
– degradative enzymes
– participate in the normal remodeling of the bacterial cell wall.
Penicillins
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43. 1. Alter the affinity of transpeptidases for binding to
penicillin
2. enzymatically cleave the beta-lactam ring and
prevent binding to transpeptidase
3. active transport out of cell (efflux pumps)
4. poor penetration into cell (intrinsic resistance)
Penicillins
Mechanisms of resistance
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44. Pharmacokinetics of Penicillins
A. absorbance- administered orally, intramuscularly, or
intravenously
B. fate after absorption
– after oral dose, widely distributed in tissues and secretions
– do not penetrate living cells, and poor penetration into
prostatic fluid, brain tissue, or intraocular fluid
– food interferes with absorption
C. excretion
– rapid elimination through kidney – urine concentrations
high
– found in breast milk
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45. Pharmacology of Select Penicillins
1. antimicrobial activity
antimicrobial activity
a) both share antimicrobial spectra for aerobic G+
organisms but penicillin G is more active against
Neisseria sp. and anaerobes
b) 90% of staphylococci are resistant, most
gonococci are too
A. the naturals - penicillin G and penicillin V
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46. 3. Fate after absorption
– 60% of penicillin G is
bound to albumin
– significant amounts are
found in liver, bile,
kidney, semen, joint
fluid, lymph, and
intestine
– penetration into CSF is
poor unless there is
inflammation
4. Excretion
– eliminated rapidly (i.e.,
30 minutes) from the
body by kidneys
– in neonates and infants,
clearance is much less
because renal function
hasn’t been fully
established
– in patients with renal
failure, liver will
inactivate penicillin G at
the rate of 10% per hour
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47. therapeutic uses:
a. Streptococcus pneumoniae infections (pneumonia and
meningitis
b. Streptococcus pyogenes infections (pharyngitis, Scarlet
Fever, toxic shock, necrotizing fascititis, arthritis,
meningitis, etc); also given prophylactically
c. viridans streptococcal endocarditis (also given
prophylactically)
d. anaerobes except Bacteroides fragilis group
e. meningococcal infections
f. syphilis and other diseases caused by spirochetes
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48. B. Antistaphylococcal penicillins: Isoxazolyl penicillins
oxacillin, cloxacillin, dicloxacillin, nafcillin
1.
1. Antimicrobial activity
Antimicrobial activity
– these drugs were made to resist
staphylococcal penicillinases
– activity against staph not
guaranteed with rise of MRSA
2.
2. Absorption
Absorption
– oxacillin, cloxacillin, and
dicloxacillin are pharmacologically
similar
– stable in gastric acid and readily
absorbed after oral administration
– can also be administered
parenterally for serious cases of
staphylococcal disease
– food interferes with absorption
– nafcillin is inactivated by acid pH so
its given parenterally
3. excretion
3. excretion
– rapidly excreted by kidneys
– significant hepatic elimination into
bile
4. therapeutic uses
4. therapeutic uses
– community acquired MSSA
infections
– not effective against enterococci or
Listeria
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49. C. Extended-spectrum penicillins:
Aminopenicillins – ampicillin and amoxicillin
1.
1. Antimicrobial activity
Antimicrobial activity
a. broad spectrum
b. do not work against
beta-lactamase
producers (i.e.
Pseudomonas, Proteus,
Klebsiella, etc)
c. beta-lactamase
inhibitors (clavulanate,
sulbactam) extend the
spectrum somewhat
2.
2. Absorption
Absorption
a. both are acid resistant
but more amoxicillin is
absorbed by the
intestinal tract than
ampicillin after an oral
dosage
b. food interferes with
absorption of ampicillin
but not amoxicillin
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51. 3. fate after absorption
20% bound to plasma
proteins
4. excretion
a. both are excreted from
the kidneys
5. therapeutic uses
5. therapeutic uses
a. upper respiratory tract
infections
b. otitis media
c. uncomplicated urinary
tract infections
d. acute bacterial
meningitis in children
e. typhoid fever
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52. D. Antipseudomonal penicillins: Carbenicillin, a
carboxypenicillin (ticarcillin) and a ureidopenicillin
(piperacillin)
1. Antimicrobial activity
1. Antimicrobial activity
a. ticarcillin is an anti-
pseudomonal drug
b. piperacillin plus
tazobactam (a beta-
lactamase inhibitor) has
the broadest spectrum of
all penicillins
2. Absorption
2. Absorption – given
parenterally
3. Fate after absorption
3. Fate after absorption –
same as other penicillins
4. Excretion
4. Excretion – kidneys
5. Therapeutic uses
5. Therapeutic uses
a. for immunocompromised
patients with serious G-
infections
b. bacteremias, UTI,
pneumonias
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54. Toxicity/Contraindications
A. hypersensitivity reactions (uncommon)
1. in order of decreasing frequency: maculopapular
rash, urticarial rash, fever, bronchospasm,
vasculitis, serum sickness, exfoliative dermatitis,
Stevens-Johnson syndrome, anaphylaxis
3. rashes will disappear when drug is withdrawn, can
use antihistamines or glucocorticoids
4. for patients with allergies, use a different drug or
try to desensitize
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55. B. other adverse reactions
1. pain and sterile inflammatory reactions at sites of IM
injections
2. large doses (>20 million IU/day) given to patients with
renal failure can cause lethargy, confusion, twitching,
and seizures
3. dizziness, tinnitus, headache, hallucinations are side
effects sometimes seen with penicillin G procaine
injections for venereal disease due to sudden release
of procaine
4. pseudomembranous colitis due to Clostridium difficle
overgrowth
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56. -Lactamase Inhibitors
• -Lactamase inhibitors:
1. clavulanic acid
2. Sulbactam
3. Tazobactam
• contain a -lactam ring
• do not have significant
antibacterial activity.
• Instead, they bind to and
inactivate -lactamases,
thereby protecting the
antibiotics that are
normally substrates for
these enzymes.
• The -lactamase
inhibitors are therefore
formulated in
combination with -
lactamase sensitive
antibiotics.
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