INTRODUCTION TO
ANTIMICROBIAL
CHEMOTHERAPEUTICS
September 2013
Selective Toxicity
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The selective toxicity of antibiotics means that they
must be highly effective against the pathogen
microorganisms but have minimal or no toxicity to
humans.
In practice, this is expressed by a drug's therapeutic
index (TI) - the ratio of the toxic dose (to the patient) to
the therapeutic dose (to eliminate the infection).
The larger the index, the safer is the drug (antibiotic) for
human use.
Selective Toxicity
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The selective toxicity of antibiotics is brought about by
finding vulnerable targets for the drug in the target
microorganism that do not exist in the animal (eucaryote)
that is given the drug.
Most antibiotics in clinical usage are directed against;
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bacterial cell wall synthesis,
bacterial protein synthesis, or
bacterial nucleic acid synthesis, which are unique in some ways
to bacteria.
Selective Toxicity
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For example, the beta lactam antibiotics (penicillin and
its relatives) inhibit peptidoglycan synthesis in the cell
wall.
Humans have neither a cell wall nor peptidoglycan and
so are unaffected by the action of the drug.
Other antibiotics, including streptomycin and the
tetracyclines, target bacterial protein synthesis because
bacterial ribosomes (termed 70S ribosomes) are
different from the ribosomes (80S) of humans and other
eucaryotic organisms.
Selective Toxicity
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Antibiotics such as the flouroqinolones (e.g.
ciprofloxacin) inhibit procaryotic (not eucaryotic) DNA
replication, and rifamycins inhibit bacterial (not
eucaryotic) DNA transcription.
From a patient point of view, the most important property
of an antimicrobial agent is its selective toxicity, i.e.,
that the agent acts in some way that inhibits or kills
bacterial pathogens but has little or no toxic effect on the
patient.
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Antibiotics may have a cidal (killing) effect or a static
(inhibitory) effect on a range of microbes.
The range of bacteria or other microorganisms that is
affected by a certain antibiotic is expressed as its
spectrum of action.
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Antibiotics effective against procaryotes that kill or inhibit
a wide range of Gram-positive and Gram-negative
bacteria are said to be broad spectrum.
If effective mainly against Gram-positive or Gramnegative bacteria, they are narrow spectrum.
If effective against a single organism or disease, they are
referred to as limited spectrum.
• Effect of different dose
schedules on shape of
concentration-time
curve.
• The total AUC for the
fractionated dose in
curve B is determined
by adding AUC0-8h,
AUC8-16h and AUC1624h, which adds up to
the same AUC0-24h in
curve A.
• The time that the drug
concentration exceeds
MIC in curve B is also
determined by adding
up T1>MIC, T2>MIC,
and T3>MIC, which
results in a fraction
greater than that for
curve A.