A Guide to Understanding Antimicrobial Drug Dosing in Critically Ill Patients on Renal Replacement Therapy

Abstract

A careful management of antimicrobials is essential in the critically ill with acute kidney injury, especially if renal replacement therapy is required. Acute kidney injury may lead per se to clinically significant modifications of drugs' pharmacokinetic parameters, and the need for renal replacement therapy represents a further variable that should be considered to avoid inappropriate antimicrobial therapy. The most important pharmacokinetic parameters, useful to determine the significance of extracorporeal removal of a given drug, are molecular weight, protein binding, and distribution volume. In many cases, the extracorporeal removal of antimicrobials can be relevant, with a consistent risk of underdosing-related treatment failure and/or potential onset of bacterial resistance. It should also be taken into account that renal replacement therapies are often not standardized in critically ill patients, and their impact on plasma drug concentrations may substantially vary in relation to membrane characteristics, treatment modality, and delivered dialysis dose. Thus, in this clinical scenario, the knowledge of the pharmacokinetic and pharmacodynamic properties of different antimicrobial classes is crucial to tailor maintenance dose and/or time interval according to clinical needs. Finally, especially for antimicrobials known for a tight therapeutic range, therapeutic drug monitoring is strongly suggested to guide dosing adjustment in complex clinical settings, such as septic patients with acute kidney injury undergoing renal replacement therapy.

Keywords: CRRT; acute kidney injury; antimicrobials; continuous renal replacement therapy; convection; diffusion; extracorporeal clearance; pharmacodynamics; pharmacokinetics; renal replacement therapy.

FIG 1

Proposed methods to calculate solutes’ extracorporeal clearance (CL_EC) with different renal replacement therapy (RRT) modalities.

FIG 2

The extracorporeal fractional clearance (CL_EC/CL_TB [percentage]) of a given antimicrobial during renal replacement therapy derives from the ratio of extracorporeal clearance (CL_EC) to total body clearance (CL_TB) (shown here as “ECCl/TBCl”) and indicates the relative contribution of CL_EC to CL_TB. As displayed above, the variability of V and f (here “Vd” and “F_F”) results in a substantially different impact of CRRT on CL_TB of antimicrobials, while an MW up to 1,000 to 1,500 Da (e.g., vancomycin or colistin) does not represent per se a limit to extracorporeal removal across the membranes commonly used in CRRT. MW, molecular weight; V, distribution volume.