a)    Interpret the three pharmacodynamic (PD) profiles, labelled Scenario 1, Scenario 2 and Scenario 3, shown below. (40% marks)

b)    For each PD profile, describe how you would optimise the dose and/or frequency of antibiotic if prescribing:

i)    a beta lactam

ii)    an aminoglycoside

(60% marks)

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College Answer

a)

Comments:
Scenario 1

  • Drug concentration does not reach MIC
  • Ineffective dose

Scenario 2.

  • Drug concentration is well above MIC.
  • Repeat dose maintains the concentration above MIC but increases the AUC: MIC ratio.

Scenario 3

  • Peak drug concentration is well above MIC
  • Significant period of interval between doses where drug level is below MIC

b)
Methods to optimise:

(i) Beta Lactam agents:

Scenario 1

  • Increase dose
  • More frequent dosing
  • Consider continuous infusion after an appropriate loading dose

Scenario 2

  • Decrease dose
  • Less frequent dosing intervals
  • Continuous infusion

Scenario 3

  • More frequent dosing interval
  • Continuous infusion

(ii)    Aminoglycosides

Scenario 1

  • Increase dose

Scenario 2

  • Prolong dosing interval
  • Therapeutic drug monitoring to avoid drug toxicity

Scenario 3

  • No change
  • Could consider higher dose.

Discussion

Obviously, in Scenario 1 the antibiotics will never be effective as the MIC is never achieved, and in Scenario 2 the antibiotics will kill the bugs shortly before they kill the patient with toxicity. In Scenario 3, one might argue that nothing needs to change for antibiotics with concentration-dependent killing; whereas those with time-dependent killing should probably be dosed more regularly (or given as an infusion).

This would work best as a table:

Drug profile Time-dependent killers Concentration-dependent killers
MIC not achieved Increase dose
Decrease dosing interval
Increase dose
Dose accumulation Decrease dose
Increase dosing interval
Increase dosing interval
MIC achieved but prolonged sub-MIC time Decrease dose AND increase dosing frequency Do nothing (fine like this)

In regard to the college answers, one might add that "continuous infusion" is the correct answer to any sort of dose adjustment problem when it comes to time-dependent killers, and "therapeutic drug monitoring" can never be a wrong answer in a dose adjustment question. Kill characteristics of antibiotic agents are discussed elsewhere.