Refining Vancomycin Protein Binding Estimates: Identification of Clinical Factors That Influence Protein Binding

Abstract

. Validation of our model was performed in 13 patients, and the predictive performance was highly favorable (R 2 was 0.9, and bias and precision were 0.18 and 0.18, respectively). Prediction models such as ours can be utilized in future pharmacokinetics and pharmacodynamics studies evaluating the exposure-response profile and to determine the pharmacodynamic target of interest as it relates to the free concentration.Antimicrobial pharmacodynamics describes the relationship between drug exposure and antimicrobial activity. The past 25 years have witnessed tremendous advances in understanding the relationship between antimicrobial pharmacodynamics and microbiological response, and the pharmacodynamic targets associated with maximal effect have been identified for many antimicrobials (8,9,14,16). For vancomycin, the ratio of the area under the serum drug concentration-versus-time curve (AUC) and the MIC, or the AUC/MIC ratio, appears to be the best predictor of response based in part on data from animal models, in vitro studies, and limited human studies (22,27). Collectively, these data suggest that microbiological success is optimized when the vancomycin total drug AUC/MIC ratio exceeds 400 (22,26). In clinical practice, since it is not practical to obtain serial vancomycin concentrations within a dosing interval to estimate the AUC, many clinicians use vancomycin trough concentrations as a surrogate for the AUC when optimizing the vancomycin dosing regimen.One commonality of these vancomycin pharmacodynamic studies is that they examined total vancomycin concentrations (total [vanco]) rather than free or unbound drug (22,27). While these studies demonstrated a positive correlation between the total vancomycin AUC/MIC ratio and response, there are data that indicate only free drug or unbound drug is pharmacologically active and is most predictive of the response (3,5,10,11,15,19,21,24,33). We are not aware of any studies that have assessed whether free vancomycin concentrations (f[vanco]) are predictive of outcomes.In the absence of pharmacodynamic studies that delineate the relationship between drug exposure and response, it is common practice to multiply the total drug exposure by the extent of protein binding to determine the amount of free drug necessary for response. In order to do this, it is critical to have a reasonable point estimate of the extent of protein binding. While it is assumed that vancomycin is approximately 50% bound (25), protein binding for the agent has not been well characterized in the literature, and estimates have varied considerably (1,2,12,18,23,31,35). In particular, a recent analysis reported a range of percent protein binding to be 12% to 100% in 15 hospitalized adults (4).Given the variability surrounding the extent of vancomycin protein binding, the purpose of this study was 2-fold: (i) to determine the extent to which vancomycin is protein bound in the blood and (ii) to identify factors that modulate vancomycin protein binding to create and validate a prediction tool for estimat...

Comparative In Vivo Efficacies of Epithelial Lining Fluid Exposures of Tedizolid, Linezolid, and Vancomycin for Methicillin-Resistant Staphylococcus aureus in a Mouse Pneumonia Model

“…As such, additional treatment options appear necessary as MRSA isolates with reduced VAN susceptibilities (MIC, 2 g/ml) are becoming more prevalent and may contribute to poorer clinical outcomes (22,32,41). In addition to reductions in potency, the relatively low penetration (ϳ50%) of vancomycin into ELF has also been suggested as a reason for the compound's diminished clinical efficacy (6,22,30,35).…”

Quantification of isoniazid, pyrazinamide and ethambutol in serum using liquid chromatography-tandem mass spectrometry

“…In this experiment, calibration curve samples were freshly prepared and processed within 30 minutes to minimise alterations to isoniazid other than the reversible protein binding under investigation. This period is comparable to other studies on protein binding [26,27]. Inert type 1 borosilicate glass inserts were used to minimise any adsorption of ethambutol to glass inserts.…”

“…All the calibration curves showed a significant goodness of fit. All obtained results met the acceptance criteria set by the FDA [27]. These criteria were < 20% bias and <20% coefficient of variation (CV) for LLOQ QC samples and <15% bias STURKENBOOM MGG J. APPL.…”

Antimicrobial Distribution From Local Delivery Depends on Dose

“…Gd-DTPA does not bind to protein, does not enter cells, and has no antimicrobial activity. While Gd-DTPA will not affect the cells that it comes near, the effects of protein binding and intracellular transport on the respective concentrations observed are likely to be minimal because the amount of antimicrobial that is lost to protein binding and intracellular uptake is small compared to the total amount of antimicrobial present [5]. Third, the imaging intervals were too long to detect the maximum volume of distribution for the 4-and 1-g formulations.…”