Pharmacological principles of antibiotic prescription in the critically ill

Abstract

The goal of antimicrobial prescription is to achieve effective drug concentrations. Standard antimicrobial dosing regimens are based on research performed often decades ago and for the most part with patients who were not critically ill. More recent insights into antibiotic activity (e.g. the importance of high peak/MIC ratios for aminoglycosides and time above MIC for beta-lactam antibiotics), drug pharmacokinetics (e.g. increased volume of distribution and altered clearances) and the pathogenesis of sepsis (e.g. third space losses and altered creatinine clearances) have made re-evaluation of dosing regimens necessary for the critically ill. The inflammatory response associated with sepsis results in a rapid decrease in serum albumin levels, large fluid shifts and third space losses, initially with a high cardiac output. In turn these changes result in increased creatinine clearance and increased renal drug clearance. Unless these effects are offset by ensuing renal and/or hepatic impairment, with subsequent drug accumulation, antibiotic levels may be too low for optimal efficacy. The institution of continuous renal replacement therapy separately affects antibiotic clearances, and therefore dosing, even further. This article reviews relevant literature and offers principles for more effective and appropriate antibiotic dosing in the critically ill, based on the pharmacokinetic and pharmacodynamic principles of the main antibiotic groups (aminoglyosides, glycopeptides, beta-lactams, carbapenems and quinolones) and knowledge of the pathophysiology of the inflammatory response syndrome. Finally it also provides some guidance on the basic principles of drug prescription for patients receiving continuous renal replacement therapy.