A Simulation Study Reveals Lack of Pharmacokinetic/Pharmacodynamic Target Attainment in De-escalated Antibiotic Therapy in Critically Ill Patients

Mieke Carlier, Jason A. Roberts, Veronique Stove, Alain G. Verstraete, Jeffrey Lipman, Jan J. De Waele

De-escalation of empirical antibiotic therapy is often included in antimicrobial stewardship programs in critically ill patients, but differences in target attainment when switching antibiotics are rarely considered. The primary objective of this study was to compare the fractional target attainment of contemporary dosing of empirical broad-spectrum β-lactam antibiotics and narrower spectrum antibiotics for a number pathogens for which de-escalation may be considered. The secondary objective was to determine whether alternative dosing strategies improve target attainment. We performed a simulation study using published population pharmacokinetic (PK) studies in critically ill patients for a number of broad-spectrum β-lactam antibiotics and narrower spectrum antibiotics. Simulations were undertaken using a dataset obtained from critically ill patients with sepsis without absolute renal failure (n=49). The probability of target attainment of antibiotic therapy for different micro-organisms for which de-escalation is applied was analyzed. EUCAST MIC distribution data were used to calculate fractional target attainment. The probability to achieve therapeutic exposure was lower for the narrower spectrum antibiotics in conventional dosing compared to the broad spectrum alternatives, which could drastically be improved when higher dosages and different modes of administrations are used. For a selection of microorganisms the probability to achieve therapeutic exposure was overall lower for the narrower spectrum antibiotics using conventional dosing compared to the broad-spectrum antibiotics.