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KEY POINTS
The altered and variable 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 minimum inhibitory concentration (MIC) of the pathogen on overall free-drug exposures is important to be able to reach the 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.
Due to the vast degree of pharmacokinetic variability, critically ill patients are likely to benefit from individualized dosing with therapeutic drug monitoring to help ensure efficacy and safety of the antimicrobials they receive.
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 many antimicrobials are renally cleared, concentrations of antimicrobials are affected by renal replacement therapies, and therefore dosing should be modified accordingly to obtain adequate target exposures.
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Early effective antimicrobial therapy is essential for critically ill patients with infections. Due to higher rates of resistance and difficulties obtaining appropriate drug concentrations, antimicrobial treatment in this population can be a significant challenge. Optimizing the administration of antimicrobials and understanding the principles of pharmacokinetics and pharmacodynamics can improve the likelihood of favorable clinical outcomes. In addition, optimizing regimens may help mitigate the development of resistance. Herein the various classes of antimicrobials used within the ICU and optimization strategies are described (Table 63-1).
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PHARMACOKINETICS AND PHARMACODYNAMICS IN CRITICALLY ILL PATIENTS
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The physiological disturbances in critically ill patients lead to changes in pharmacokinetic parameters of antimicrobials such as volume of distribution (Vd) and clearance (CL).1,2 The pharmacokinetics of antimicrobials are the concentrations of drugs in the body and the extent to which the drugs are cleared. The Vd is the volume in which the total amount of drug would have to be evenly distributed into equal the same concentration as in the plasma. A consequence of the inflammatory state of critical illness is endothelial damage which results in increased capillary permeability. In patients with infections, the toxins produced by various bacteria can also contribute to this damage. This leads to the phenomenon of “third spacing” where fluid shifts into the interstitial space from the intravascular space. These fluid shifts increase the Vd of hydrophilic antimicrobials. In general, hydrophilic antimicrobials have a low Vd and therefore are greatly affected by these fluid ...