Use of pharmacodynamic principles to inform β-lactam dosing: "S" does not always mean success.

Dose optimization is one of the key strategies for enhancing antimicrobial stewardship. There have been tremendous strides in our understanding of antibiotic exposure-response relationships over the past 25 years. For many antibiotics, the "pharmacodynamic" or the exposure variable associated with outcome has been identified. With advances in mathematical modeling, it is possible to apply our understanding of antimicrobial pharmacodynamics (PD) into clinical practice and design empirical regimens that have a high probability of achieving the PD target linked to effect. By optimizing antibiotic doses to achieve PD targets predictive of efficacy, clinicians can improve care and minimize drug toxicity. For β-lactams, the PD parameter most predictive of maximal bactericidal activity is the duration of time free drug concentrations remain above the minimum inhibitory concentration (MIC) during the dosing interval (fT > MIC). Unfortunately, the conventional intermittent β-lactam dosing schemes often used in practice have suboptimal PD profiles. Prolonging the infusion time of β-lactams is one method to maximize the probability of achieving concentrations in excess of the MIC for the majority of the dosing interval, especially against pathogens with elevated MIC values. Prolonged infusions of intravenous β-lactams are not only associated with improved probability of target attainment (PTA) profiles but offer possible cost savings and greater potential for reducing emergence of resistance relative to intermittent infusions.