. 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...

e While extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50% fT>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50% fT>MIC for MICs of >8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximize fT>MIC in certain hospitalized populations. P iperacillin-tazobactam (TZP) is a combination of an extended-spectrum ␤-lactam antibiotic and a ␤-lactamase inhibitor and is frequently used for nosocomial infections (3, 21). For ␤-lactam antibiotics, the pharmacodynamic index that best links drug exposure with the observed antibacterial effect is the fraction of the dosing interval in which free drug concentrations are above the MIC (9). Near-maximal effect is generally observed when free concentrations exceed the MIC for at least 50% of the dosing interval (fTϾMIC 50%) (12). Although TZP is frequently administered as a rapid infusion, extended infusions of TZP are increasingly used in clinical practice because they facilitate the extension of the fTϾMIC.Although the method is more commonplace than rapid infusions, the impact of prolonging the infusion time of TZP on its pharmacokinetic (PK) profile has not been widely assessed. Here, we describe the population pharmacokinetics for both piperacillin and tazobactam among hospitalized patients receiving an extended infusion regimen. The goal was to identify the model that best explained the observed clearance of both piperacillin and tazobactam. When modeling piperacillin, it is important to consider linear, Michalis-Menten (MM), and parallel first-order/MM models. Piperacillin is cleared via a combination of renal tubular secretion and glomerular filtration (25). Whil...

Although vancomycin is often regarded as an agent that concentrates poorly in the lower respiratory tract, as determined from concentrations in epithelial lining fluid (ELF), few data are available. This study sought to determine the profile of vancomycin exposure in the ELF relative to plasma. Population modeling and Monte Carlo simulation were employed to estimate the penetration of vancomycin into ELF. Plasma and ELF pharmacokinetic (PK) data were obtained from 10 healthy volunteers. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and firstorder elimination and transfer using the big nonparametric adaptive grid (BigNPAG) program. Monte Carlo simulation with 9,999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the area under the concentration-time curve (AUC) in ELF (AUC ELF ) and plasma (AUC plasma ) after a single simulated 1,000-mg dose. The mean (standard deviation) AUC ELF /AUC plasma penetration ratio was 0.675 (0.677), and the 25th, 50th, and 75th percentile penetration ratios were 0.265, 0.474, and 0.842, respectively. Our results indicate that vancomycin penetrates ELF at approximately 50% of plasma levels. To properly judge the adequacy of current doses and schedules employed in practice, future studies are needed to delineate the PK/PD (pharmacodynamics) target for vancomycin in ELF. If the PK/PD target in ELF is found to be consistent with the currently proposed target of an AUC/MIC of >400, suboptimal probability of target attainment would be expected when vancomycin is utilized for pneumonias due to MRSA (methicillin-resistant Staphylococcus aureus) with MICs in excess of 1 mg/liter.Ventilator-associated pneumonia (VAP) continues to be a major source of morbidity and mortality among intensive care unit (ICU) patients (1, 17). In many institutions, methicillin-resistant Staphylococcus aureus (MRSA) accounts for Ͼ25% of all VAPs (1, 8). Because MRSA has become such a likely culprit, vancomycin is recommended as firstline empirical therapy for patients with suspected or documented VAP (1, 20). However, several trials have demonstrated suboptimal therapeutic outcomes with this agent against MRSA (7,19,21).The low therapeutic success rates have been associated with a number of factors, including MIC creep, agr phenotype, and emergence of MRSA strains with heteroresistance to vancomycin (20). Poor penetration of vancomycin into the site of infection, as determined from concentrations in epithelial lining fluid (ELF), is also considered a major contributing factor of failure (1,20). Although low concentration in the lungs is often cited as an attributable factor, the penetration of vancomycin into the ELF remains poorly defined, and the available data on its penetration have notable limitations (3, 6, 9).The intent of this study was to determine the pharmacokinetics of vancomycin in plasma and ELF among healthy subjects. Population pharmacokinetic (PK) modeling and Monte Carlo simulati...

No abstract

While the potential exists for serotonin toxicity to occur with concomitant use of linezolid and serotonergic agents, the risk appears to be low. Based on the large database of Phase III and IV studies included in our analysis, we did not find enough evidence to conclude that linezolid-induced serotonin toxicity was different from that of comparators.

Despite emerging evidence that dysfunction in the accessory gene regulator (agr) locus is associated with deleterious outcomes among patients treated with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) infections, factors predictive of agr dysfunction have not been evaluated. This study describes the epidemiology of agr dysfunction, identifies predictors of agr dysfunction in MRSA isolates among those with MRSA bloodstream infections, and describes the relationship between agr dysfunction and other microbiologic phenotypes. A cross-sectional study of patients with MRSA bloodstream infections at two institutions in upstate New York was performed. Clinical data on demographics, comorbidities, disease severity, hospitalization history, and antibiotic history were collected. Microbiologic phenotypes, including agr dysfunction, MIC values by broth microdilution (BMD) and Etest, and vancomycin heteroresistance (hVISA) were tested. Multivariable analyses were performed to identify factors predictive of agr dysfunction. Among 200 patients with an MRSA bloodstream infection, the proportion of strains with agr dysfunction was 31.5%. The distribution of MICs determined by both BMD and Etest were equivalent across agr groups, and there was no association between agr dysfunction and the presence of hVISA. Severity of illness, comorbidities, and hospitalization history were comparable between agr groups. In the multivariate analysis, prior antibiotic exposure was the only factor of variables studied found to be predictive of agr dysfunction. This relationship was predominantly driven by prior beta-lactam and fluoroquinolone administration in the bivariate analysis. Identifying these institution-specific risk factors can be used to develop a process to assess the risk of agr dysfunction and guide empirical antibiotic therapy decisions.The accessory gene regulator (agr) is a quorum-sensing operon which coordinates the expression of secreted and cellassociated virulence factors, and it controls several metabolic pathways in Staphylococcus aureus in a growth phase-related fashion (7,30). In vitro studies show that alterations in agr function result in several phenotypic changes in S. aureus, including diminished autolysis (21), attenuated vancomycin activity (20,22,29), vancomycin heteroresistance (22), and an increased proclivity for the development of intermediate resistance to vancomycin (7,22,29,30). There is also increasing clinical evidence showing that alterations in agr in S. aureus are a key risk factor for poor outcomes in patients with S. aureus bacteremia (7,25).Despite the poor outcomes associated with agr dysfunction, factors predictive of agr dysfunction have not been well described, and scant literature exists describing the relationship between agr dysfunction and other reduced vancomycin susceptibility phenotypes. This study describes the epidemiology of agr dysfunction, determines predictors of agr dysfunction in methicillin-resistant Staphylococcus aureus (MRSA) isolates among those with MRS...

No 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