Pharmacodynamics of Antibiotics

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Pharmacodynamics of Antibiotics

• Hail M. Al-Abdely, MD

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Concepts

• Pharmacokinetics
• describe how drugs behave in the human host
• Pharmacodynamics
• the relationship between drug concentration and
  antimicrobial effect. Time course of
  antimicrobial activity

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Concepts

• Minimum Inhibitory Concentration (MIC)
• The lowest concentration of an antibiotic that
  inhibits bacterial growth after 16-20 hrs
  incubation.
• Minimum Bacteriocidal Concentrations.
• The lowest concentration of an antibiotic
  required to kill 99.9 bacterial growth after
  16-20 hrs exposure.
• C-p
• Peak antibiotic concentration
• Area under the curve (AUC)
• Amount of antibiotic delivered over a specific
  time.

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Antimicrobial-micro-organism interaction

• Antibiotic must reach the binding site of the
  microbe to interfere with the life cycle.
• Antibiotic must occupy sufficient number of
  active sites.
• Antibiotic must reside on the active site for
  sufficient time. Antibiotics are not contact
  poisons.

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Static versus Cidal
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Questions

• Can this antibiotic inhibit/kill these bacteria?
• Can this antibiotic reach the site of bacterial
  replication?
• What concentration of this antibiotic is needed
  to inhibit/kill bacteria?
• Will the antibiotic kill better or faster if we
  increase its concentration?
• Do we need to keep the antibiotic concentration
  always high throughout the day?

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Can this antibiotic inhibit/kill these bacteria?

• In vitro susceptibility testing
• Mixing bacteria with antibiotic at different
  concentrations and observing for bacterial
  growth.

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What concentration of this antibiotic is needed
to inhibit/kill bacteria?

• In vitro offers some help
• Concentrations have to be above the MIC.
• How much above the MIC?
• How long above the MIC?

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Patterns of Microbial Killing

• Concentration dependent
• Higher concentration greater killing
• Aminoglycosides, Flouroquinolones, Ketolides,
  metronidazole, Ampho B.
• Time-dependent killing
• Minimal concentration-dependent killing (4x MIC)
• More exposure more killing
• Beta lactams, glycopeptides, clindamycin,
  macrolides, tetracyclines, bactrim

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Persistent Effects

• Persistent suppression of bacterial growth
  following antimicrobial exposure.
• Moderate to prolonged against all GM positives
  (In vitro)
• Moderate to prolonged against GM negatives for
  protein and nucleic acid synthesis inhibitors.
• Minimal or non against GM negatives for beta
  lactams (except carabapenems against P.
  aeruginosa)

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Persistent Effects

• Post-antibiotic sub-MIC effect.
• Prolonged drug level at sub-MIC augment the
  post-antibiotic effect.
• Post-antibiotic leukocyte killing enhancement.
• Augmentation of intracellular killing by
  leukocytes.
• The longest PAE with antibiotics exhibiting this
  characteristic.

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Patterns of Antimicrobial Activity

• Concentration dependent with moderate to
  prolonged persistent effects
• Goal of dosing
• Maximize concentrations
• PK parameter determining efficacy
• Peak level and AUC
• Examples
• Aminoglycosides, Flouroquinolones, Ketolides,
  metronidazole, Ampho B.

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Patterns of Antimicrobial Activity

• Time-dependent killing and minimal to moderate
  persistent effects
• Goal of dosing
• Maximize duration of exposure
• PK parameter determining efficacy
• Time above the MIC
• Examples
• Beta lactam, macrolides, clindamycin,
  flucytosine, linezolid.

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Patterns of Antimicrobial Activity

• Time-dependent killing and prolonged persistent
  effects
• Goal of dosing
• Optimize amount of drug
• PK parameter determining efficacy
• AUC
• Examples
• Azithromycin, vancomycin, tetracyclines,
  fluconazole.

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PK/PD patterns
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Ceftazidime effect on K. pneumoniae thigh
infection in neutropenic mice
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Temafloxacin effect on S. pneumoniae thigh
infection in neutropenic mice
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Ceftazidime
Temafloxacin
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Survival of Animals infected with S. pneumoniae
treated with cephalosporin and penicillin
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Survival of Animals infected with GN bacilli
treated with Fluoroquinolones
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Human Data
Percentage bacteriologic cure for ß-lactam agents
against Streptococcus pneumoniae (black circle)
and Haemophilus influenzae (white circle) in
children with acute otitis media
Craig WA, Andes W.. Pediatr Infect Dis J
199615255-9.
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Beta lactams
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Aminoglycosides
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Fluoroquinolones
AUC
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Glycopeptides
AUC
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Effects of PD on breakpoints Recommended for many
antibiotics for S. pneumoniae