Pharmacodynamics of Vancomycin at Simulated Epithelial Lining Fluid Concentrations against Methicillin-Resistant Staphylococcus aureus (MRSA): Implications for Dosing in MRSA Pneumonia

Abstract

Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resistant

Quantifying Subpopulation Synergy for Antibiotic Combinations via Mechanism-Based Modeling and a Sequential Dosing Design

“…Time-kill experiments were performed as described previously (19)(20)(21). In brief, fresh bacterial colonies were grown on Luria-Bertani agar for approximately 20 h prior to each experiment.…”

“…For all arms, serial viable counts were quantified over 48 h as described previously (19)(20)(21). For sequential combinations, additional viable counts were assessed before centrifugation and ϳ5 min after resuspension of the bacterial pellets.…”

Evaluation of Once-Daily Vancomycin against Methicillin-Resistant Staphylococcus aureus in a Hollow-Fiber Infection Model

“…Although vancomycin is classified as an AUC/MIC ratio-driven antimicrobial, the data that support this were derived from multiple-dailydosing regimens (4,5,7,9,12,13,20,21). To our knowledge, this is the first contemporary dose fractionation study designed to evaluate whether killing by vancomycin is driven by the AUC/ MIC ratio.…”

“…Data suggest that killing by vancomycin is concentration dependent, and a near-maximal bactericidal effect is achieved against MRSA when the ratio of the area under the total vancomycin concentration-time curve (AUC) to the MIC exceeds 400 (22). While an AUC/MIC ratio of 400 is a well-recognized pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin, this target has been determined using multiple daily doses, which has resulted in the default stance of using multiple-daily-dosing regimens in clinical practice (4,5,7,9,12,13,20,21). The possibility of once-daily administration is appealing from a PK/PD perspective, as it affords the ability to achieve more robust AUCs in a defined interval (i.e., during the first 6 to 12 h) while minimizing trough concentrations, which predicts nephrotoxicity (10).…”

Dose optimization of ceftriaxone-vancomycin combination using fractional inhibitory concentration kinetics in resistant bacteria

“…Higher the sigmoidicity factor, lesser is the predictability of PD effect with respect to PK/PD index. The concentration-effect relationships were incorporated in the bacterial model (equation 1) to predict the bacterial count from PK/PD model [26][27][28][29] (equation 3). In the constructed model, the antibacterial effect of FDC of ceftriaxone/vancomycin is hypothesized as a combination of bacterial growth inhibition (k growth ) and bacterial killing enhancement (k death ) ( Figure 2).…”