Unbound serum polymyxin B in patients with sepsis: Detection approaches and limited sampling strategy for clinical practice and research

Abstract

Polymyxins are increasingly used to treat multidrug resistant bacteria in critically ill patients, however these drugs have a narrow therapeutic window. Highly variable antibiotic pharmacokinetics in critically ill patients puts them at high risks of toxicity and underdosing, therefore robust tools suitable for therapeutic drug monitoring and pharmacokinetic studies are in great demand. It is now recognized that only antibiotics not bound to serum proteins possess antimicrobial effects and free drug concentration is the most appropriate pharmacokinetic target. However, data on unbound polymyxin B (PMB) determination is very limited, especially in different cohorts of critically ill patients. Performance of rapid equilibrium dialysis and ultrafiltration in unbound PMB measurement, as well as different approaches to predict free PMB exposure based on a single measurement were explored in present study. In comparison to ultrafiltration rapid equilibrium dialysis demonstrated a lower degree of non-specific binding, which makes the latter a more reliable tool. Overall, unbound drug determination is a costly and labor-intensive procedure, hence different limited sampling strategies were proposed for further clinical application. Although pooled sample analysis is commonly used for this purpose, the results showed inconsistency between observed and predicted values. An alternative approach using 1–3 sampling points and Bayesian estimation is proposed.