L16 Antimicrobial PKPD and TDM

Question 1

Pharmacodynamics is the study of actions or effects (beneficial/ toxic) of drugs on the body or microorganism.

List 3 important examples.

Answer 1

1. Synergism and antagonism
2. Killing characteristics
   - time-dependent killing
   - concentration-dependent killing
   - time above AUC
3. Post antibiotic effect

Question 2

Example of synergism (1) and antagonism (2).

Answer 2

Synergism
- ampicillin given with gentamicin for enterococcal infections - ampicillin acts on cell wall to enable gentamicin to gain entry to cell

Antagonism
- Bacteriostatic agent like tetracycline will inhibit the bactericidal activity of beta-lactam

Question 3

What does it mean by time-dependent killing (time above MIC) in pharmacodynamics?
How can we increase the extent of killing using these Abx?

Answer 3

• Antibiotic only kills the bacteria when its concentration is above the MIC (minimal inhibitory concentration) of the organism
• increase in concentration does not lead to increased killing
• duration of exposure determines the extent of killing (maximise time, more frequent dose)

Question 4

Example of Abx with time-dependent killing characteristics?

Answer 4

Beta lactams

• do not increase in concentration, but increase time above MIC by more frequent dosage (continous infusion)

Question 5

What does it mean by concentration-dependent killing (concentration above MIC) in pharmacodynamics?

How can we increase the extent of killing using these Abx?

Answer 5

• Antibiotic kills the organism when its concentration is well above the MIC of the organism
• the greater the peak, the greater the killing
• Direct relationship between antibiotic concentration and bactericidal effect (maximize concentration, infrequent dosing)

Question 6

Example of Abx with concentration-dependent killing characteristics?

Answer 6

Aminoglycosides e.g. gentamicin, tobramycin, amikacin, plazomicin, streptomycin, neomycin

> One daily dosage is enough

Question 7

What does it mean by Area under curve above MIC in pharmacodynamics?

Example of Abx with this characteristic? (2)

Answer 7

• Combination of both time-dependenet and concentration-dependent killing
• Vancomycin
• Fluoroquinolones (e.g. Ciprofloxacin, norfloxacin, and ofloxacin, levofloxacin, and moxifloxacin)

Question 8

What is PAE post-antibiotic effect?

Answer 8

Persistent suppresion after antibiotic exposure, even when concentration falls below MIC.

Question 9

When is Therapeutic drug monitoring (TDM) indicated?

Answer 9

In drugs with narrow theraeutic window

• e.g. vancomycin, aminoglycosides > minimize toxicity risk
• Acute care patients for longer term care and treatment
• Trough level correspond to toxicity
  (Trough level = lowest [ ] reached by drug before next does is administered)
• Peak level correspond to clinical outcome

Question 10

Case
- patient given 3 doses of gentamicin

Trough level is normal
Peak level exceeded (post-dose rr)

What should be done?

Answer 10

Gentamicin - aminoglycosides (concentration-dependent)

> decrease dosage is the solution

Question 11

Trough levels relate to?

Peak levels relate to?

Answer 11

Trough levels: accumulation (frequency)

Peak levels: therapeutic outcome (dosage)

Question 12

Gentamicin

Trough level low, Peak level low ?

Answer 12

• increase frequency and increase dosage

Question 13

Gentamicin

Trough level high, Peak level low?

Answer 13

Wrong specimens, repeat specimen

Question 14

Gentamicin

Trough level high, Peak level normal?

Answer 14

Reduce frequency, no need to decrease dosage

Question 15

Which of the following has a high-risk of unpredictable drug concentration in target sides due to altered Vd and clearance?

A. Obesity
B. Critical care patients like sepsis and burns
C. Extreme ages
D. Extracorporeal membrane oxygenation (ECMO)
E.. Renal replacement therapy (RRT)

Answer 15

all of the above