Chapter 21: Antimicrobial Medications

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Chapter 21AntimicrobialMedications
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Important Point
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Antimicrobial Chemotherapeutics

• The prognosis for people with common diseases
  such as bacterial pneumonia and severe
  staphylococcal infection was grim before the
  discovery and widespread availability of
  penicillin in the 1940s.
• Physicians were able to identify the cause of
  the disease, but they were generally unable to
  recommend treatments other than bed rest.
• Early history of Antimicrobial Chemotherapeutic
  Agents
• 1910 Salvarsan (an arsenic compound) by Paul
  Ehlrich
• 1928 Penicillin (a mold product--first
  antibiotic discovered) by Alexander Fleming
• 1932 Sulfanilamide (sulfa drug) by Gerhard
  Domagk
• 1941 Purification of Penicillin by Ernst Chain
  and Howard Florey
• post-WWII Widespread availability Penicillin G

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Antibiotic Discovery
It is easy to identify antibiotic-producing
microorganism, the hard part is finding
antibiotics that are sufficiently Selectively
Toxic.
Selective Toxicity means that the agent is more
toxic against bacteria than against, e.g., humans.
Post-microbe modified antibiotics are called
Semisynthetic antibiotics.
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Antimicrobal Chemotherapy Terms
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Distinguishing Antibiotics

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

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Distinguishing Antibiotics

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

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Antibiotics Sources
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Distinguishing Antibiotics

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

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Family Tree of Penicillins
Antibiotics are chemotherapeutic antimicrobials
that are isolated from microorganisms.
Compare Synthetic drug.
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Some Penicillin Derivatives
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Methicillin-Induced Lysis
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Vancomycin
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Cell-Wall Synthesis Inhibitors
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Distinguishing Antibiotics

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

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Therapeutic Index

• It is relatively trivial to identify antibiotics.
• The trick is to identify antibiotics that are
  selectively toxicharming the pathogen but not
  the host.
• We employ a concept called the Therapeutic Index
  as a measure of the degree of selective toxicity.
• The therapeutic index is the ratio of the toxic
  dosage to the therapeutic dosage.
• That is, (Lowest dose toxic to patient) ? (Dose
  normally used for therapy).
• The greater the ratio (or difference) of these
  two numbers, the easier it is to find a dosage
  that kills the pathogen without harming the host.

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Therapeutic Index
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Therapeutic Index
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Distinguishing Antibiotics
Bacteriostatic agents inhibit growth but dont
kill. They rely on body defenses to clear the
infection.

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostatic versus bactericidal.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

Removal of agent results in return of growth of
any remaining bacteria.
Bactericidal agents are preferable particularly
if the body otherwise has trouble clearing the
bacteria.
Bactericidal agents outright kill bacteria.
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Distinguishing Antibiotics

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

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Spectrum of Activity
Narrow-Spectrum Antimicrobial
Wide-Spectrum Antimicrobial
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Spectrum of Activity
Broad-spectrum antibiotics are useful if one must
begin treatment before identifying either a
pathogen or its antibiotic susceptibility.
However, broad-spectrum antibiotics are more
likely to destroy normal flora, resulting in
superinfections.
Wide-Spectrum Antimicrobial
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Distinguishing Antibiotics
Penetration of the antibiotic to infected tissues
is kind of important, and antibiotics differ in
where and to what degree they penetrate.

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

Anitibiotics differ in terms of how the body
modifies or destroys them, e.g., liver vs.
kidneys.
Ultimately, antibiotics are not retained within
the body indefinitely, and the dosage and rate of
administration allows a balance of uptake and
excretion.
Concentrations at the site of action should
remain high throughout the treatment period,
though not so high that the host is poisoned.
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Fluctuation of Antibiotic Levels with Time
Time of ingestion of dose 3.
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Distinguishing Antibiotics

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

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Finding Targets
Drug-Finding Ability as Function of Host-Pathogen
Similarity
Too Biochemically similar as fellow Eukaryotes
Bacteria
Too-Few Genes share host Metabolism
Fungi, Helminths, Protists
Number Drug Targets or Drugs with High
Chemotherapeutic Index
Different domain from Us!
Viruses, Cancer
Basically they are Us!
Biochemical Differences from Mammalian Host
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Targets of Antibacterial Drugs
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Targets of Antibacterial Drugs
Yes, do know the five indicated sites of action.
No, do not memorize the specific antibiotics from
this figure.
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Ribosomal Targets
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Tetracyclines
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Tetracycline
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Distinguishing Antibiotics

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

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Combination of Drugs

• For antibiotics A and B used in combination
• Actual killing rate A B ? Additive
• Actual killing rate gt A B ? Synergistic
• Actual killing rate lt A B ? Antagonistic
• Typically bacteriostatic agents are antagonistic
  to bactericidal agents.
• Bacteriocidal agents can be synergistic (think of
  the latter as one antibiotic weakens more
  bacteria than it kills, making the not-killed
  bacteria more susceptible to additional insult by
  the second antibiotic).
• Additive means that the two (or more) antibiotics
  neither hinder nor help each others ability to
  kill.
• Also relevant to rates of mutation to resistance.

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Combination of Drugs

• For antibiotics A and B used in combination
• Actual killing rate A B ? Additive
• Actual killing rate gt A B ? Synergistic
• Actual killing rate lt A B ? Antagonistic
• Typically bacteriostatic agents are antagonistic
  to bactericidal agents.
• Bacteriocidal agents can be synergistic (think of
  the latter as one antibiotic weakens more
  bacteria than it kills, making the not-killed
  bacteria more susceptible to additional insult by
  the second antibiotic).
• Additive means that the two (or more) antibiotics
  neither hinder nor help each others ability to
  kill.
• Also relevant to rates of mutation to resistance.

Synergistic means greater than the sum of the
parts.
Antagonistic means less than the sum of the parts.
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Mutation to Resistance
The number of resistant bacteria is dependent on
the rate of mutation to resistance.
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Rational for Combining Drugs
What you want is a rate of mutation to multiple
drug resistance that is less than than the
reciprocal of the pathogen population size (and
then some accounting for lack of environmental
homogeneity).
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Consequence of Not Combining
If this were cancer than each bump would
represent the end of remission.
In a homogeneous population this would be the
last cancer cell / virus / pathogen alive.
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Consequence of Not Combining
So, hence, multi-drug anti-cancer chemotherapy or
combination therapy against HIV or TB.
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Not Maintaining Course
Obviously this is not what you want to happen.
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Distinguishing Antibiotics

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

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Acquired Antibiotic Resistance
Innate or Intrinsic Resistance means that the
antibiotic targets simply are missing from a
bacterium, e.g., lack of cell wall penicillin
resistance.
Alternatively there exist a number of
non-intrinsic (acquired) mechanisms that can lead
to antibiotic resistance.
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Acquired Antibiotic Resistance
Acquired resistance can occur by alteration of
target by chromosomal mutation.
Or acquisition on plasmid encoding resistance
genes.
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Resistance in Simpler Terms
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Chromosomal vs. R Plasmid Encoded
R plasmid
R plasmid
Chromosomal mutation
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Distinguishing Antibiotics

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

And lets not forget that killed cells can
release toxic substances such as endotoxin, e.g.,
leading to septic shock.
Toxic interaction with host metabolism/tissues.
All else held constant it makes sense to use a
drug with a high-therapeutic index versus one
with a lower one.
Allergic reactions, e.g., penicillin.
Killing of normal flora.
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Distinguishing Antibiotics

• Antibiotics (as well as synthetic antimicrobials)
  differ in terms of
• The organism they are or were isolated from.
• Their chemical structure.
• Their (chemo)Therapeutic index.
• Bacteriostasis versus bacteriostatic.
• Their spectrum of activity.
• Their pharmacokinetics (tissue distribution,
  metabolism, and excretion).
• Their site of action in bacterial cells.
• Interaction with other chemotherapeutics.
• Potential for evolution to resistance.
• Mechanism of toxicity to the host.
• Cost.

Obviously all else held constant it makes better
sense to prescribe inexpensive drugs rather than
expensive ones.
Sometimes, especially when dealing with otherwise
antibiotic-resistant pathogens one has no choice,
however.
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