Use of pharmacodynamic principles to inform β‐lactam dosing: “S” does not always mean success

Abstract

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 b-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 b-lactam dosing schemes often used in practice have suboptimal PD profiles. Prolonging the infusion time of b-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 b-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. Journal of Hospital Medicine 2011;6:S16-S23. V C

Characterization of the Population Pharmacokinetics of Ampicillin in Neonates Using an Opportunistic Study Design

“…The PD target most correlated to maximal bactericidal activity for beta-lactams is the time in which free drug concentrations remain above the MIC (TϾMIC) (17). The total, rather than free, drug concentration was used in this study due to low protein binding of ampicillin (ϳ10%) reported in neonates (18).…”

Ertapenem Pharmacokinetics and Pharmacodynamics during Continuous Ambulatory Peritoneal Dialysis

“…Adequate antibiotic concentrations at the site of infection are critical to ensure the highest probability of favorable clinical and microbiological responses (16,17). Significant advances have been made in identifying the exposure target associated with the maximal response for many classes of antibiotics (2,7,9,16,17).…”

“…Significant advances have been made in identifying the exposure target associated with the maximal response for many classes of antibiotics (2,7,9,16,17). For carbapenem antibiotics such as ertapenem, studies have demonstrated that the microbiological response is optimized when concentrations exceed the MIC for 30 to 40% of the dosing interval (7,9,22,29).…”

“…For carbapenem antibiotics such as ertapenem, studies have demonstrated that the microbiological response is optimized when concentrations exceed the MIC for 30 to 40% of the dosing interval (7,9,22,29). To translate this knowledge into clinical practice, mathematical modeling techniques (i.e., population PK modeling and Monte Carlo simulation) can be used to predict whether the dosing regimen will actually achieve the exposure target associated with success in both the serum and at the site of infection (16,17). Because of their versatility, these techniques have become the standard methodology for assessing the clinical viability of both experimental and approved antimicrobials (16,17).…”

Bacterial sepsis

“…These recommendations are derived from animal experiments; clinical investigations underscore the fact that in sepsis patients, an fT>MIC of 100% elicits a more effective anti-infective effect, and is thus relevant for outcome [190,[201][202][203]. Especially on the basis of striving to achieve adequate tissue concentrations even in deep-lying compartments (pneumonia; bone infections; infections of the central nervous system, CNS)-frequently in the context of disturbed microcirculation in sepsis patients [204][205][206] and also wishing to avoid development of resistance [207,208]-many experts recommend aiming for a concentration of β-lactam antibiotics in the primary compartment (serum/plasma) that exceeds the MIC by 4-times (up to 6-times) for 60-100% of the dosing interval [209]. In addition to individual dosing of antibiotics, the current DGI guideline [124] names therapeutic drug monitoring (TDM) as a possibility for treatment management and reduction of undesirable side effects of antibiotics.…”