The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents

Adv Drug Deliv Rev. 2014 Nov 20:77:3-11. doi: 10.1016/j.addr.2014.07.006. Epub 2014 Jul 15.


Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leading to underdosing are predominant. Yet, since prediction of serum concentrations remains difficult, therapeutic drug monitoring for individual fine-tuning of antimicrobial therapy seems the way forward.

Keywords: Acute kidney injury; Antimicrobial agents; Hepatic failure; Intensive care unit; Organ failure; Pharmacodynamics; Pharmacokinetics; Sepsis.

Publication types

  • Review

MeSH terms

  • Acute Kidney Injury / physiopathology*
  • Anti-Infective Agents / administration & dosage
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacokinetics*
  • Critical Illness
  • Drug Monitoring / methods
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Multiple Organ Failure / etiology
  • Multiple Organ Failure / physiopathology
  • Sepsis / drug therapy*
  • Sepsis / physiopathology
  • Tissue Distribution


  • Anti-Infective Agents