Evaluation of a Two-Compartment Bayesian Forecasting Program for Predicting Vancomycin Concentrations

This study evaluated the predictive performance of a Bayesian PK estimation method (ADAPT V) to estimate the 24-h vancomycin area under the curve (AUC) with limited pharmacokinetic (PK) sampling in adult obese patients receiving vancomycin for suspected or confirmed Gram-positive infections. This was an Albany Medical Center Institutional Review Board-approved prospective evaluation of 12 patients. Patients had a median (95% confidence interval) age of 61 years (39 to 71 years), a median creatinine clearance of 86 ml/min (75 to 120 ml/min), and a median body mass index of 45 kg/m 2 (40 to 52 kg/m 2 ). For each patient, five PK concentrations were measured, and four different vancomycin population PK models were used as Bayesian priors to estimate the vancomycin AUC (AUC FULL ). Using each PK model as a prior, data-depleted PK subsets were used to estimate the 24-h AUC (i.e., peak and trough data [AUC PT ], midpoint and trough data [AUC MT ], and trough-only data [AUC T ]). The 24-h AUC derived from the full data set (AUC FULL ) was compared to the AUC derived from data-depleted subsets (AUC PT , AUC MT , and AUC T ) for each model. For the four sets of analyses, AUC FULL estimates ranged from 437 to 489 mg·h/liter. The AUC PT provided the best approximation of the AUC FULL ; AUC MT and AUC T tended to overestimate AUC FULL . Further prospective studies are needed to evaluate the impact of AUC monitoring in clinical practice, but the findings from this study suggest that the vancomycin AUC can be estimated with good precision and accuracy with limited PK sampling using Bayesian PK estimation software.

Section: Methodsmentioning

confidence: 99%

Pilot Study of a Bayesian Approach To Estimate Vancomycin Exposure in Obese Patients with Limited Pharmacokinetic Sampling

Carreno

Lomaestro

Tietjan

et al. 2017

“…Vancomycin AUC values were estimated with ADAPT 5 software (University of Southern California, Los Angeles, CA, USA). Using data from a previously published 2-compartment VAN model, the mean parameter vector and full covariance matrix were embedded into the PRIOR subroutine of ADAPT 5 (14,15). For each individual patient, the pharmacokinetic parameter values were estimated using the maximum a posteriori probability (MAP) procedure.…”

Section: Methodsmentioning

confidence: 99%

Vancomycin 24-Hour Area under the Curve/Minimum Bactericidal Concentration Ratio as a Novel Predictor of Mortality in Methicillin-Resistant Staphylococcus aureus Bacteremia

Britt

Patel

Horvat

et al. 2016

T he incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections in health care and community settings has increased in recent years (1). Vancomycin (VAN) has been a mainstay in the armamentarium against MRSA for nearly half a century, but changes in susceptibility patterns have presented new treatment challenges (2). The gradual reduction in susceptibility of MRSA isolates to VAN occurring over the last 2 decades has been associated with increased treatment failure and mortality (3, 4). While the relationship between VAN MIC and clinical outcomes in MRSA bacteremia (MRSA-B) is well established, the importance of VAN minimum bactericidal concentration (MBC) is less clear (5).Multiple studies have highlighted the importance of bactericidal therapy in treating S. aureus bacteremia (SAB). Previous research has demonstrated that in vitro 24-h bactericidal activity by VAN is associated with a decrease in the duration of MRSA-B clinically compared to in vitro bacteriostatic activity (6). Additionally, decreased in vitro VAN killing activity over 72 h also has been associated with an increase in 30-day mortality in patients with MRSA-B treated with VAN (7). Sakoulas et al. reported an association between elevated VAN MIC and treatment failure but also noted that reduced bactericidal activity had a similar effect (8).Lastly, multiple studies have demonstrated improved clinical outcomes with ␤-lactam therapy compared to those with VAN for methicillin-susceptible SAB, which may be partially attributed to the superior killing activity of ␤-lactams compared to that of VAN (9,10). Thus, there is evidence to suggest that VAN bactericidal activity plays an influential role in clinical outcomes of SAB, including MRSA-B.Consensus recommendations support a VAN area under the curve (AUC)/MIC ratio of Ն400 as a pharmacodynamic predictor of therapeutic effectiveness for MRSA infections (11). An AUC/ MIC ratio of Ն421 also has been associated with clinical success in MRSA-B (12). Due to the trend toward improved outcomes with increased bactericidal activity of VAN, we hypothesized that VAN exposure as a function of MBC rather than MIC may be a more important predictor of VAN effectiveness in the treatment of MRSA-B. Therefore, the objectives of this study were to (i) evaluate the association between pharmacodynamic parameters (VAN AUC 24 /MIC ratio determined by broth microdilution [MIC BMD ], VAN AUC 24 /MIC ratio determined by Etest [MIC Etest ], and VAN AUC 24 /MBC ratio) and 30-day mortality and (ii) quantify the VAN AUC 24 /MBC threshold associated with an increased probability of mortality in a cohort of hospitalized patients with MRSA-B.

“…Recently, there have been several reports in which Bayesian methods have been used to adjust vancomycin regimens by using either a one-or a two-compartment model (3,22,24 (24) are that different parameters were determined. In this study we used klo, whereas Rodvold et al (24) used clearance.…”

mentioning

confidence: 99%

Application of a Bayesian method to monitor and adjust vancomycin dosage regimens

Hurst

Yoshinaga

Mitani

et al. 1990

A Bayesian method for monitoring vancomycin concentrations and adjusting regimens in patients with unstable renal function by using a two-compartment population model was evaluated with a personal computer. The population model was derived from data from 12 cardiac outpatients who received single doses of vancomycin. The performance of the method was then tested in 27 acutely ill patients who received multiple doses of vancomycin. Significant renal impairment was observed in 15 patients. Renal function changed in 15 patients. The vancomycin concentrations in the patients with changing renal function were not at steady state during the observation times. Two concentrations in serum (peak and then trough, or trough and then peak) were fitted along with the population model to individualize the parameter values for each patient. All the subsequent concentrations in serum for each patient were then predicted by using the parameter values for each patient. Future concentrations of 118 serum samples were predicted. The mean absolute prediction error was 3.6 ± 4.5 ,Lg/ml, and the mean prediction error was -0.7 ± 5.3 ,Ig/ml. These results confirm that a two-compartment pharmacokinetic model can be sufficiently individualized with the knowledge of just two concentrations of drug in patient serum; it is possible to predict closely subsequent concentrations in serum, and dosing regimens for individual patients can be well adjusted to achieve the chosen therapeutic goals.Three favorable characteristics of vancomycin are the bactericidal effect, the sustained concentrations in serum achieved compared with those achieved with beta-lactam antibiotics, and the rare development of bacterial resistance (4). These traits, along with the current rise in methicillinresistant staphylococcal infections and the increasing use of prosthetic devices requiring antibiotic prophylaxis (1), have stimulated new interest in vancomycin use. In addition, the availability of more precise methods of measuring vancomycin concentrations in serum and the availability of sophisticated computer software for analyzing drug concentrationin-serum data (7, 14) now make it possible to individualize vancomycin dosage regimens that are more clinically effective, safe, and cost-effective. These factors have led to a growing demand to monitor vancomycin therapy and to interpret the meaning of its concentrations in serum.The (2,4,11,17,18,21). The controversy stems from the fact that the concentration-time profile of vancomycin in serum is not described by a monoexponential decay, as reflected by the one-compartment pharmacokinetic model used in many earlier clinical studies (3,10,18). At least two compartments are required to describe vancomycin pharmacokinetics adequately: a central serum compartment and a peripheral compartment (nonserum) (5,13,16