Adequate posology of antimicrobial therapy in the septic critically ill in continuous veno-venous hemofiltration: a single centre prospective observational study.

Abstract

Background: Determining the optimal antibiotic (ATB) dosage in septic critically ill patients on continuous renal replacement therapy (CRRT) is still challenging. CRRT further disrupts antibiotic PK, already altered by sepsis-induced fluid shifts, volume of distribution (VD) changes and half-life modifications.

Materials and methods: Our multi-disciplinary team-comprising an intensivist, nephrologist and clinical pharmacologist-conducted a prospective observational cohort study to evaluate the extent of ATB removal by CRRT and to assess the pharmacokinetic/pharmacodynamic (PK/PD) parameters of the most commonly used antibiotics for treating severe infections.

Results: A total of 135 ATB therapeutic drug monitoring (TDM) assessments were conducted, measuring total drug concentrations (C) in both plasma (P) and ultrafiltrate in 85 septic patients undergoing CRRT. A high sieving coefficient (∼75%) was recorded for all antibiotics, with CRRT-related drug loss described by the following equations: (i) [CUF-ATB](trough level) = 0.77 × [CP-ATB](trough level) + 0.93 ng/mL; (ii) [CUF-ATB](peak) = 0.77 × [CP-ATB](peak) + 3.1 ng/mL. The VD exhibited wide variability, with values exceeding those reported in the literature. Lower ATB molecular weight and steric hindrance were associated with a higher elimination rate constant (Kemin⁻¹). ATB TDM consistently correlated with AUC and AUC/MIC, ensuring effective bactericidal activity.

Conclusions: Despite its limitations, our study suggests to carry out a loading dose for the main antibiotics and consider the daily drug loss, as identified by the linear regression equation, along with daily TDM to guide further dosing adjustments.