Multicenter Evaluation of Vancomycin Dosing: Emphasis on Obesity
Article Outline
Abstract
Background
There is a paucity of data available regarding the dosing of antimicrobials in obesity. However, data are available demonstrating that vancomycin should be dosed on the basis of actual body weight.
Methods
This study was conducted at 2 tertiary care medical centers that did not have pharmacy-guided vancomycin dosing programs or other institutional vancomycin dosing policies or protocols. Patients who received vancomycin between July 1, 2003, and June 30, 2006, were stratified by body mass index and randomly selected from the computer-generated queries. Patients ≥18 years of age with a creatinine clearance of at least 60 mL/min who received vancomycin for at least 36 hours were included.
Results
Data were collected on a random sampling of 421 patients, stratified by body mass index, who met the inclusion criteria. Most patients in each body mass index category received a fixed dose of vancomycin 2 g daily divided into 2 doses (underweight 82%, normal weight 90%, overweight 86%, and obese 91%). Adequate initial dosing (≥10 mg/kg/dose) was achieved for 100% of underweight, 99% of normal weight, 93.9% of overweight, and 27.7% of obese patients (P < .0001). Ninety-seven percent of underweight, 46% of normal weight, 1% of overweight, and 0.6% of obese patients received ≥15 mg/kg/dose recommended by several Infectious Diseases Society of America guidelines. Pharmacists also failed to correct inadequate dosing because only 3.3% of patients receiving less than 10 mg/kg/dose had their regimen changed in the first 24 hours of therapy.
Conclusion
In this multicenter pilot study, obese patients routinely received inadequate empiric vancomycin using a lenient assessment of dosing. Greater efforts should be undertaken to ensure patients receive weight-based dosing because inadequate dosing can lead to subtherapeutic concentrations and potentially worse clinical outcomes.
Keywords: Dosing, Obesity, Vancomycin
Approximately one third of Americans are obese, which is defined as a body mass index (BMI) of at least 30 kg/m2, and 4.8% of Americans are extremely obese (BMI ≥ 40 kg/m2).1 There is little information available regarding the pharmacokinetics, pharmacodynamics, and optimal dosing of most antimicrobials for obese patients.2 However, multiple pharmacokinetic studies have demonstrated that actual body weight is the preferred method to dose vancomycin in obese patients.3, 4, 5 As a result, several consensus guidelines written or endorsed by the Infectious Diseases Society of America recommend weight-based dosing for vancomycin.6, 7, 8, 9
Despite the aforementioned literature, many studies continue to use a flat dosing regimen of vancomycin 1 g every 12 hours to evaluate new agents for the treatment of gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA).10, 11, 12, 13, 14, 15 The use of flat dosing regimens in clinical trials may teach clinicians that weight-based dosing is not important. However, recent literature has created an increased awareness of S. aureus isolates that are heterogeneously resistant to vancomycin.16, 17 The development of heterogeneous vancomycin-intermediate S. aureus is associated with low vancomycin concentrations, making the appropriate empiric dosing of vancomycin critical if clinicians want to have vancomycin available as an option for the treatment of MRSA in the future.
Materials and Methods
Selection and Description of Participants
This study was conducted at 2 tertiary care medical centers that did not have pharmacy-guided vancomycin dosing programs or other institutional vancomycin dosing policies or protocols. After institutional review board approval by both institutions and Texas Tech University Health Sciences Center, subjects were identified through a retrospective search of pharmacy prescription files to include all patients who received vancomycin between July 1, 2003, and June 30, 2006. BMI was calculated as weight (kilograms) divided by height squared (meters squared).18 Patients were divided into cohorts on the basis of their BMI: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (≥30 kg/m2). A sample of patients in each BMI cohort were randomly selected by a computer-based random number generator. The electronic medical record of selected patients was reviewed for demographic characteristics and information regarding the initial vancomycin regimen, serum creatinine, whether the dose was appropriately weight-based, and whether the dose was changed within 24 hours (if initially inappropriate). The site of infection and vancomycin drug concentrations were not evaluated, because the primary focus of this study was to characterize the adequacy of recommended empiric weight-based vancomycin dosing practices. Patients ≥18 years of age were included if they received at least 1 dose of vancomycin during an inpatient stay at either medical center and vancomycin was continued for at least 36 hours. Patients were excluded if their creatinine clearance was less than 60 mL/min as assessed by the Cockcroft and Gault equation. If a patient received more than 1 course of vancomycin therapy during the same hospitalization, only the first course was included in the analysis.
Study End Points
The primary end point was to determine the frequency of adequate empiric vancomycin dosing, defined for the purposes of this study as ≥10 mg/kg per dose for each of the BMI cohorts. This dose is lower than the 15 mg/kg per dose recommended in several Infectious Diseases Society of America guidelines but was chosen to allow for dose rounding to the nearest vial size. Secondary end points included the percentage of patients receiving initial empiric doses of ≥15 mg/kg/dose, ≥20 mg/kg/dose, and ≥20 mg/kg/d for each of the BMI cohorts. The frequency of adequate empiric dosing was also assessed for the 3 classes of obesity (class I: 30.0-34.9 kg/m2; class II: 35.0-39.9 kg/m2; and class III: ≥40 kg/m2). The percentage of inadequate doses (<10 mg/kg/dose) changed within 24 hours of initiation was assessed to determine whether pharmacists or physicians changed inadequate doses in a timely manner.
Statistical Analysis
The data were analyzed using SAS software version 9.13 (SAS Inc, Cary, NC). A statistically significant difference between the appropriate weight-based dosing of vancomycin in underweight, normal weight, overweight, and obese patients was determined using the Cochran-Armitage test. Continuous variables were assessed using analysis of variance. Because this was a pilot study, a power analysis was not performed. A priori, it was decided to review the charts of more than 50 patients per hospital per cohort. A smaller sample size was accepted for the underweight population because this was not a primary focus.
Results
Data were collected on a random sampling of 421 patients, stratified by BMI, who met the inclusion criteria. Baseline characteristics were similar except for expected differences in weight and BMI. The average age was 56.6 ± 13.9 years, 78.4% were male, and the average creatinine clearance was 102 ± 35.8 mL/min. The mean initial dose (milligrams/dose) and total daily dose (milligrams/dose) were similar in all groups (Table 1). The majority of patients included in the study received a fixed dose of vancomycin 2 g daily divided into 2 doses (underweight 82%, normal weight 90%, overweight 86%, obese 91%). A significant association (P < .0001) was observed between increasing BMI group and the average initial vancomycin dose (milligrams/kilogram/dose).
Table. Results
| BMI < 18.5 kg/m2 | BMI 18.5-24.9 kg/m2 | BMI 25.0-29.9 kg/m2 | BMI ≥ 30.0 kg/m2 | |
|---|---|---|---|---|
| Dosing characteristic | (n = 67) | (n = 100) | (n = 99) | (n = 155) |
| Initial dose (mg/dose), mean (SD) | 1009.0 ±132.3 | 1000.0±35.5 | 1000.0±123.7 | 1014.5±128.2 |
| Total daily dose (mg/d), mean (SD) | 1853.7±464.0 | 1900±309.8 | 1929.3±384.7 | 1983.9±334.3 |
| Initial dose (mg/kg/dose), mean (SD) | 20.6±4.7 | 14.9±2.1 | 12.2±2.0 | 9.2±1.9 |
| Weight-based dose (%) | ||||
| ≥10 mg/kg/dose | 100 | 99 | 93.9 | 27.7 |
| ≥15 mg/kg/dose | 97 | 46 | 1 | 0.6 |
| ≥20 mg/kg/dose | 44.8 | 0 | 1 | 0 |
| ≥20 mg/kg/d | 91 | 92 | 84.8 | 27.1 |
| Initial dose < 10 mg/kg/dose changed within 24 h (%) | Not applicable | 0(0/1) | 0(0/6) | 3.5(4/113) |
Adequate initial dosing (≥10 mg/kg/dose) was achieved for 100% of underweight, 99% of normal weight, 93.9% of overweight, and 27.7% of obese patients (P < .0001). This trend was also observed when evaluating the frequency of adequate initial dosing in the previously defined obesity subgroups (class I = 43.4%, class II = 16.3%, class III = 0%). Ninety-seven percent of underweight, 46% of normal weight, 1% of overweight, and 0.6% of obese patients received ≥15 mg/kg/dose recommended by several Infectious Diseases Society of America guidelines.
None of the normal weight and overweight patients with initial doses less than 10 mg/kg/dose had their doses corrected within 24 hours. Only 3.5% of obese patients who received less than 10 mg/kg/dose had their doses corrected.
Discussion
Our multicenter pilot study observed that obese patients are more likely to receive inadequate empiric dosing compared with other BMI groups. When evaluating patients by the 15 mg/kg/dose recommended by several Infectious Diseases Society of America guidelines, less than half of normal weight patients and only 2 patients in the overweight and obese groups received adequate doses.6, 7, 8, 9
Previous pharmacokinetic studies have established total body weight as the preferred method to calculate vancomycin dosing. Blouin and colleagues4 evaluated vancomycin pharmacokinetics in 4 normal weight and 6 morbidly obese subjects. They observed that similar milligram per kilogram doses of vancomycin based on actual body weight were required to produce an average steady-state concentration of 15 μg/mL for normal weight (23.4 ± 1.5 mg/kg) and obese (24.0 ± 3.4 mg/kg) subjects. Vance-Bryan et al3 evaluated 95 nonobese and 135 obese patients and found that actual body weight was a more accurate predictor of vancomycin pharmacokinetic parameters when compared with lean body weight. Bauer and colleagues5 concluded that a 30 mg/kg/d dose based on total body weight is needed for obese patients. These investigators also suggested that shorter dosing intervals may be needed to achieve goal vancomycin trough concentrations.
Vancomycin does not have a pharmacodynamic end point that has been validated in a prospective study. Two retrospective studies suggest an area under the curve to minimum inhibitory concentration (MIC) ratio of more than 400 is associated with improved clinical outcomes.19, 20 A recent study calculated area under the curve values of 318 ± 111 μg/h/mL for patients receiving low-dose vancomycin (mean trough concentration = 9.4 μg/mL) and 418 ± 152 for patients receiving high-dose vancomycin (mean trough concentration 20.4 μg/mL).21 A Monte Carlo simulation using these pharmacokinetic data demonstrated that the high-dose regimen had a 20% higher probability of achieving the pharmacodynamic target for MRSA isolates with a vancomycin MIC of 1 μg/mL, whereas pharmacodynamic target attainment rates for higher or lower MIC values were not significantly affected by dosing strategy.22 Optimizing vancomycin dosing is important because 70% of MRSA isolates in a recent study had a vancomycin MIC of 1 μg/mL.23 These data are not specific to obese patients, but the pharmacodynamic principles should transcend BMI classes.
Our findings should be considered a pilot study focused on characterizing the empiric dosing of vancomycin across BMI cohorts. It did not include data regarding infection type, serum vancomycin concentrations, MICs, and clinical outcomes. However, clinicians do not have MIC or pharmacokinetic data and may not be certain of the infection source when initiating therapy. We acknowledge that 1 g every 12 hours may be acceptable for some disease states, such as cellulitis, but the association of low vancomycin concentrations and the development of heterogeneous vancomycin-intermediate S. aureus is still worrisome in these populations.16, 17 Therefore, these observations were not deemed necessary for this pilot study. In addition, clinical outcomes were not evaluated because some patients receiving empiric therapy may not ultimately have an infection with a gram-positive pathogen. Others might correctly state that the pharmacodynamic target for vancomycin has not been prospectively defined. Although this is true, there are substantial data that vancomycin concentrations are affected by weight and that vancomycin should be dosed on the basis of actual body weight.2, 3, 4, 5 If 1 g administered intravenously every 12 hours is satisfactory for the “average” patient, it should be understood that obese patients will require higher doses. Our results highlight the fact that obese patients can be routinely underdosed as a result of the widespread practice of prescribing fixed-dose vancomycin.
It is equally important to note that pharmacists routinely failed to correct inadequate dosing in a timely period in this study. This result highlights that weight-based dosing recommendations for vancomycin are not routinely implemented in clinical practice by multiple disciplines. Therefore, all health care professionals involved in the use of medications for obese patients should be vigilant in using a weight-based approach to drug dosing when appropriate. Neither study institution has a pharmacist-guided vancomycin or aminoglycoside dosing program, which may decrease the frequency of inadequate initial dosing.
In this multicenter pilot study, obese patients were routinely underdosed using a lenient assessment of dosing. More than half of normal weight patients and 99% of overweight patients did not receive the 15 mg/kg/dose recommended in several Infectious Diseases Society of America guidelines. Greater efforts should be undertaken to ensure that patients receive weight-based dosing because inadequate dosing can lead to subtherapeutic concentrations and worse clinical outcomes.
Acknowledgment
We thank Travis Cooper, PharmD, BCPS, for critical review of this article.
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This project was supported by Grant Number KL2RR024983, titled “North and Central Texas Clinical and Translational Science Initiative” (Milton Packer, MD, PI) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp.
PII: S0002-9343(08)00230-1
doi:10.1016/j.amjmed.2008.01.046
© 2008 Elsevier Inc. All rights reserved.
