Question 19
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)
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.