Predictability of Vancomycin Trough Concentrations Using Seven Approaches for Estimating Pharmacokinetic Parameters

John E. Murphy; David E. Gillespie; Carol V. Bateman

Disclosures

Am J Health Syst Pharm. 2006;63(23):2365-2370. 

In This Article

Abstract and Introduction

Abstract

Purpose. Seven methods for estimating vancomycin pharmacokinetic parameters were studied to determine which method best predicted measured concentrations for patients at a community teaching hospital.
Methods. Data from adult patients who were given vancomycin and had at least one steady-state trough concentration measured were retrospectively reviewed. Data analyzed included laboratory test values, concomitant medications, weight, height, sex, age, laboratory cultures, medical procedures performed, vancomycin dose and interval, measured vancomycin concentrations, and time of measurement. Relevant data were used in seven predictor methods that estimate volume of distribution, vancomycin clearance, and elimination rate constant to determine which yielded the best predictions of actual measured concentrations in the patient population.
Results. Data from 189 patients were included in the analyses. The coefficients of determination for the methods ranged from 0.114 to 0.234. Bias ranged from −5.90 to 0.69 mg/L, and precision ranged from 6.05 to 8.08. The Matzke method had the best combination of the least bias and best precision. Predictions were within 2.5 and 5 mg/L of measured concentrations 18.0—43.9% and 43.4—66.1% of the time, respectively. The percentage of predictions within 25% and 50% of measured concentrations ranged from 7.9% to 31.2% and from 18.0% to 48.1%, respectively. Ten (5.3%) patients had trough concentrations exceeding 20 mg/L, and 11 (5.8%) had trough concentrations of ≤3 mg/L.
Conclusion. The seven methods studied for estimating vancomycin pharmacokinetic parameters varied widely in predicting vancomycin trough concentrations compared with measured serum concentrations and were not sufficiently reliable to replace therapeutic monitoring of vancomycin serum concentrations.

Introduction

Vancomycin is a tricyclic glycopeptide antibiotic that is largely excreted unchanged in the urine.[1] Because of this, patients with reduced renal function have decreased clearances of vancomycin and need reduced doses or increased dosing intervals. Common adverse reactions to vancomycin include hypotension, flushing, erythematous rash, and chills.[2] More worrisome but much less common reactions include ototoxicity and nephrotoxicity, which are weakly associated with peak vancomycin concentrations above 45 mg/L, though patients developing ototoxicity or nephrotoxicity with vancomycin were often also taking concomitant medications that can cause these adverse effects.[3,4,5] Unfortunately, the studies did not account for underlying diseases or conditions that could cause hearing loss or renal damage.

Patients’ medical problems and interpatient variation in pharmacokinetic parameters due to other causes necessitate the use of doseprediction methods that lead to desirable vancomycin serum concentrations. [6] Over the years of vancomycin use, dosing and monitoring approaches have been developed and evaluated, with some methods working better than others at predicting desired concentrations.

Some controversy surrounds the relationship between vancomycin concentration and therapeutic response. [4] There is also considerable controversy over the use of drug concentration measurements to guide vancomycin dosing decisions.[5,6,7] In the past, it was fairly routine to measure both peak and trough concentrations; now, many clinicians monitor only the trough concentration or do not monitor drug concentrations at all.

Using vancomycin concentrations to monitor patients’ therapeutic response is not typically suggested if the duration of therapy is expected to be less than 72 hours or for patients receiving oral vancomycin. Drug monitoring is more commonly recommended for patients receiving other nephrotoxic drugs, burned patients, patients with central nervous system infections or endocarditis, i.v. drug abusers, patients with sepsis, and patients with rapidly changing renal function.[8]

There are a variety of methods to facilitate the dosing of vancomycin. These methods were designed to help clinicians treat their patients effectively while avoiding toxicities. For example, some methods have the potential for reducing drug therapy costs when longer intervals or smaller doses can be used. Four initial dosing approaches for vancomycin include (1) information found in the package insert, (2) the Nielsen method,[9] (3) the Rotschafer method,[10] and (4) the Lake method.[11] These methods can be used to quickly start a patient on vancomycin. Initial doses and dosing intervals can then be individualized for patients by using measured concentrations when deemed necessary.

A number of predictor methods to determine dosing regimens based on estimations of a patient’s pharmacokinetic parameters for vancomycin have been developed. Some of the more commonly cited predictors are the Birt,[8] Matzke,[12] Burton,[13] and Rodvold[14] methods. Depending on the specific patient population, one method may be better than another for estimating that population’s vancomycin concentrations. Some of the calculation challenges associated with these predictors include selecting the best dosing weight and estimating vancomycin clearance from creatinine clearance (CLcr) (also estimated), especially in the presence of diminished renal function. Determining the appropriate weight to estimate CLcr and volume of distribution is increasingly important in the United States, as the population becomes increasingly obese.

Knowing how dosing methods perform for a given patient population can be helpful. One study evaluating the utility of three methods found that the Lake—Peterson method typically provided the best vancomycin dosing estimates for individuals with a CLcr above 15 mL/min, while the Matzke method was best for CLcr of ≤15 mL/min.[15]

Because vancomycin pharmacokinetic parameters can vary widely among individuals, it may be necessary to develop institution-specific, population-based dosing methods and monitoring approaches. Many clinicians now measure a single trough concentration to monitor therapeutic response, which does not allow the pharmacokinetic parameters (i.e., vancomycin clearance [CLvanco], volume of distribution [V], and elimination rate constant [k]) for individuals to be determined. Thus, use of previously developed nomograms and dosing approaches could be helpful if they consistently produced concentrations in desired ranges.

The purpose of this study was to determine whether any of seven methods for estimating the vancomycin pharmacokinetic parameters (V, CLvanco, and k) accurately predicted measured concentrations for patients at a 421-bed community teaching hospital in South Carolina.

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