CHAPTER 61: Principles of Antimicrobial Therapy and the Clinical Pharmacology of Antimicrobial Drugs

KEY POINTS

• The altered pharmacokinetics of critically ill patients can greatly impact antimicrobial exposures. Recognizing these changes and optimizing antimicrobial administration to make certain appropriate pharmacodynamic targets are reached is crucial in ensuring successful outcomes.

• Understanding the impact of the MIC of the pathogen on overall free-drug exposures is important to be able to reach required pharmacodynamic targets of efficacy. Ultimately, organisms with high MICs will require a larger free-drug exposure compared with organisms with lower MICs.

• Patients with augmented renal function will exhibit enhanced clearance of antimicrobials, particularly β-lactams, and are at risk for subtherapeutic exposures. Therefore, these patients often require higher doses and more frequent administration of the antimicrobial.

• Antimicrobial stewardship focused on disease state management and selecting the appropriate antimicrobial therapy for the infecting pathogen is essential in preventing poor outcomes. In addition to poor outcomes, failure to treat infections appropriately can lead to the emergence of resistant organisms that become increasingly difficult to treat.

• Given the vast majority of antimicrobials are renally cleared, concentrations of antimicrobials are affected by continuous renal replacement therapy and therefore dosing should be modified accordingly to obtain adequate target exposures.

INTRODUCTION

Ensuring adequate antimicrobial treatment to critically ill patients remains a significant challenge. Physiological changes within the patient and resistant pathogens make it increasingly difficult to successfully treat infections. Optimizing the way antimicrobials are administered and understanding the principles of pharmacokinetics and pharmacodynamics can significantly change the outcomes of a patient’s clinical course. In addition, optimizing regimens can help minimize the development of resistance. Herein the various classes of antimicrobials used within the ICU and optimization strategies are described.

PHARMACOKINETICS AND PHARMACODYNAMICS IN CRITICALLY ILL PATIENTS

The major changes in pharmacokinetic parameters of critically ill patients include alterations in volume of distribution (V_d) and clearance (Cl).^1,2 Subsequently, these alterations affect the concentrations of antimicrobials in the body and the extent to which they are cleared. The V_d is the volume in which the total amount of drug would have to be evenly distributed in to equal the same concentration as in the plasma. The toxins produced by various bacteria often lead to endothelial damage and result in increased capillary permeability. This leads to the phenomenon of “third spacing” where fluid shifts into the interstitial space from the intravascular space. These fluid shifts will increase the V_d of hydrophilic antimicrobials. Generally speaking, hydrophilic antimicrobials have a low V_d and therefore are greatly affected by these fluid shifts. Since lipophilic antimicrobials have a larger V_d, they typically distribute further into tissues and are less affected by these fluid shifts. Patients in the ICU often have hypotension as a result of septic shock, which requires the administration of fluid boluses. Additionally, heart failure and renal failure lead to more edematous states where patients can retain large amounts of fluid. These ...