Look at the diagram below, representing antibiotic drug concentration against time. Curves D and E represent concentrations after regular bolus administration of the same dose of an antibiotic to the same patient at different points of time

a) What pharmacokinetic changes are demonstrated in D and E?

b) List the clinical conditions that could explain the difference between E and D.

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College Answer

a)
PK changes – Increased plasma concentrations with E relative to D for the same dose indicating reduced clearance and increased half-life.

b)
Hepatic dysfunction
Renal dysfunction

Discussion

The question itself is reasonably straightforward to answer. The drug is clearly accumulating; its concentration is increasing.

Pharmacokinetics of antibiotic dosing and the challanges of antibiotic dosing in renal failure are discussed in greater detail elsewhere. More detail regarding pharmacokinetics in the context of continuous renal replaceemnt therapy can be found in the Required Reading section for the renal failure and dialysis SAQs.

In brief, the following factors influence antibiotic clearance in critical illness:

Factors which decrease the antibiotic peak dose:

  • Poor gut absorption
  • Increased volume of distribution
  • Poor penetration to the site of action

Factors which increase the antibiotic peak dose:

  • Decreased protein binding
  • Diminished clearance mechanisms

Factors which increase the antibiotic half-life

  • Decreased renal clearance
  • Decreased hepatic clearance
  • Decreased overall metabolism (eg. hypothermia)

Factors which decrease the antibiotic half-life

  • Renal replacement therapy
  • Increased hepatic clearance, eg. enzymes induced by drug interactions

References

Oh's Intensive Care Manual: Chapter 72  (pp. 738)  Principles  of  antibiotic  use  by Jeffrey  Lipman

Roberts, Jason A., and Jeffrey Lipman. "Pharmacokinetic issues for antibiotics in the critically ill patient." Critical care medicine 37.3 (2009): 840-851.

Craig, William A. "Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid." Infectious disease clinics of North America 17.3 (2003): 479-501.

Craig, William A. "Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men." Clinical infectious diseases (1998): 1-10.