Altered vancomycin pharmacokinetics in obese and morbidly obese patients: what we have learned over the past 30 years

J Antimicrob Chemother 2012; 67: 1305 1310 doi:10.1093/jac/dks066 Advance Access publication 1 March 2012 Altered vancomycin pharmacokinetics in obese and morbidly obese patients: what we have learned over the past 30 years Edward Grace* Presbyterian College School of Pharmacy, 307 North Broad Street, Clinton, SC 29325, USA *Tel: +1-864-938-3856; Fax: +1-864-938-3903; E-mail: eegrace@presby.edu Vancomycin was the first glycopeptide antibiotic introduced into clinical practice. Despite the numerous benefits of vancomycin, clinicians have struggled to dose vancomycin successfully in obese patients to achieve a therapeutic concentration for optimal bacterial killing. Owing to the hydrophilicity of vancomycin and the increase in both adipose tissue and muscle mass associated with obesity, the volume of distribution of vancomycin in obese patients is likely to be altered compared with non-obese patients. In addition to an increase in body mass, obesity is associated with an increase in certain circulating proteins, which results in altered free serum vancomycin concentration. Another alteration that occurs in obesity is increased blood flow secondary to increased cardiac output and blood volume, resulting in increased vancomycin clearance in obese patients. Vancomycin pharmacokinetics in the obese population remain an area of much debate, one that requires continued research given the rising number of obese patients in both the USA and worldwide. Keywords: antibiotics, volume of distribution, glycopeptides, overweight Introduction Vancomycin was the first glycopeptide antibiotic introduced into clinical practice. First discovered in the early 1950s and produced by Streptomyces orientalis, vancomycin exhibits bactericidal killing by inhibiting Gram-positive bacterial cell wall synthesis. 1 It binds a D-alanyl-D-alanine precursor that is essential for peptidoglycan cross-linking in most Gram-positive bacterial cell walls. The spectrum of activity of vancomycin includes most Gram-positive organisms, most notably methicillin-resistant Staphylococcus aureus (MRSA). However, despite the numerous benefits of vancomycin, clinicians have struggled to consistently dose vancomycin in a manner that achieves a therapeutic serum vancomycin concentration (SVC) and an AUC to MIC ratio that is optimal for bacterial killing, while minimizing adverse effects. Several studies have addressed the population pharmacokinetic parameters of vancomycin in non-obese patients and have produced numerous nomograms for dosing vancomycin. 2 5 Despite the wide use of vancomycin, very few studies to date have focused on its pharmacokinetics in the obese population. Obesity was once viewed as a minor factor in dosing medications due to the small portion of obese patients in the population. Obesity now plays a major role in drug pharmacokinetics because of the increased incidence of obesity worldwide. The WHO estimated in 2008 that 1.5 billion adults 20 years of age and older were overweight, of whom 200 million adult men and nearly 300 million women met the clinical criteria for obesity. 6 Based on 2005 data, the WHO estimates that 60% of the world s population will be classified as either overweight or obese by the year 2030. 7 The National Health and Examination Survey (NHANES) reported in 2010 that all states in the USA had a prevalence of obesity of.20%; 36 states had a prevalence of 25%, with 12 of these states having a prevalence of 30%. 8 Based on 2005 data from the European HAPIEE (Health, Alcohol and Psychosocial factors in Eastern Europe) study, the highest incidences of obesity were found in regions of Italy, Spain, Portugal, Poland, the Czech Republic, Romania and Albania. In many European countries included in the study, the incidence of obesity was greater in females than in males which accounted for 25% of the overall incidence of obesity in the given countries. 9 Clinical obesity can be defined using various techniques previously published in the literature. The most commonly utilized methods to define obesity in pharmacokinetic studies are the body mass index (BMI), body fat content as a percentage of actual body weight, and total body weight (TBW) as a percentage of ideal body weight (IBW). Other more recently 10 13 defined methods utilize parameters such as the biomechanical lean body weight and predicted normal body weight (PNWT). 14,15 Despite the possible benefits of these newer methods, clinical trials that have been conducted to validate them have been limited. 16 The WHO classification of obesity is based on the BMI scale and is divided into three classes: obese class I (BMI 30.00 34.99 kg/m 2 ), obese class II (BMI 35.00 39.99 kg/m 2 ) and obese class III, which is also synonymous with the term morbid obesity (BMI 40.00 kg/m 2 ). 17 Obesity can be defined as body fat content of 25% 30% of TBW (a TBW:IBW ratio of 1.25 1.3: 1.0), while morbidly obese has # The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com 1305

been defined as TBW exceeding 200% of IBW (TBW:IBW ratio of 2:1). 18 Despite the general agreement on the definition of obesity among healthcare professionals, some researchers have utilized variations of the above-mentioned criteria to define obesity and morbid obesity in various clinical trials. Pathophysiology of obesity related to vancomycin pharmacokinetics Obesity is often attributed to an increase in body mass due solely to an increase in adipose tissue deposition; however, obesity involves numerous physiological changes, including an increase in muscle mass and connective tissue. 19 Owing to the hydrophilicity of vancomycin and the increase in both adipose tissue and muscle mass associated with obesity, the volume of distribution (V) of vancomycin in obese patients is likely to be larger than that of normal weight patients. The disconnect between TBW, IBW, adjusted body weight (AdBW) and V is likely due to water accounting for 30% of the content of adipose tissue; thus, hydrophilic drugs such as vancomycin are able to penetrate and distribute, to some degree, in adipose tissue, thus increasing the V. In addition to an increase in body mass, obesity is associated with an increase in certain circulating proteins that bind to various medications, affecting the free drug concentration in the blood. In the initial study to examine the extent of vancomycin binding to circulating serum proteins, Krogstad et al. 1 showed that vancomycin protein binding ranged from 44% to 82% (average of 55%) in healthy adults. In addition, vancomycin binding to serum proteins in the studied concentration range of 10 100 mg/l was not shown to be concentration dependent. 1 In another study, vancomycin protein binding ranged from 27% to 62% in patients with MRSA infections. 18 In that study, SVC correlated with a 1 -acid glycoprotein (AAG) levels, which was increased in patients with documented MRSA infection. There was no correlation, however, between SVC and serum albumin levels, which were lower in MRSA patients compared with controls. 20 Like patients with MRSA infection, morbidly obese patients have been shown to have increased AAG, thus possibly increasing the percentage of protein-bound vancomycin and decreasing the percentage of free vancomycin, which is thought to be the active form of vancomycin, in serum. 20 22 Conversely, other studies have shown that obese patients have increased cholesterol, triglycerides and free fatty acids; this binding may displace or prevent antibiotics from binding to the serum proteins, thus increasing free antibiotic concentration in the serum. 23 25 The extent of vancomycin binding to AAG and albumin in the serum remains unclear, and thus the question remains whether circulating protein levels play a major role in vancomycin pharmacokinetics. Another alteration that occurs in obesity is increased blood flow secondary to increased cardiac output and blood volume. 26 28 Due to the hydrophilicity of vancomycin, this increase in blood flow and blood volume may play a role in increased V of vancomycin. Chagnac et al. 29 observed that overweight and obese patients had an increased glomerular filtration rate and increased renal plasma flow. Renal hyperfiltration occurs through renal vasodilation, which is a compensatory mechanism to overcome the increased tubular reabsorption of sodium. The compensatory vasodilation of the afferent arterioles results in increased hydrostatic pressure in the glomerulus, which can lead to renal hypertrophy similar to that seen in diabetes patients. 30 This renal hypertrophy due to obesity has been associated with a larger kidney size than that in non-obese patients. 31 In addition to hypertrophy of nephrons, the increase in hydrostatic pressure within the glomerulus may cause the observed increase in renal function and glomerular filtration rate noted in obese patients. Effects of obesity on vancomycin pharmacokinetics Altered V in obese patients Several factors associated with obesity may alter the V of vancomycin, thus affecting the loading dose and dosing interval recommended to achieve a therapeutic serum level. In a study utilizing single-dose kinetics of vancomycin in healthy patients under a two-compartment model, the V of vancomycin ranged from 0.49 to 1.25 L/kg TBW. 1 The first study to analyse the effects of obesity on vancomycin pharmacokinetics was conducted by Blouin et al. 32 in 1982. This was an uncontrolled study of six morbidly obese patients and four normal-weight patients. The morbidly obese patients were defined as subjects.90% above IBW, while the normal patients were defined as,15% over their IBW. The range of TBW in the morbidly obese patients ranged from 96.5% to 197.7% above IBW. All subjects in both groups had normal renal function with creatinine clearance (CL CR ).90 ml/min per 1.73 m 2. Vancomycin was dosed based on the previously published nomogram by Moellering et al., 33 which targeted a mean SVC of 15 mg/l. Analysis revealed that the V of vancomycin in morbidly obese patients was significantly higher than that in normal-weight patients. In addition, the V of vancomycin in morbidly obese patients correlated better with TBW (0.26+0.03 L/kg TBW) than with IBW (0.68+0.07 L/kg IBW). In a subsequent study, which further examined the effects of obesity on vancomycin V, 230 adult subjects with normal renal function (serum creatinine 1.5 mg/dl) were enrolled. 34 Obese subjects (defined as.20% above IBW) accounted for 47% (107 subjects) of all the subjects in the study. The subjects received 10 15 mg/kg TBW of vancomycin with a dosing interval as previously described by Rodvold et al. 3 A two-compartment model was utilized in the analysis. Both TBW and percentage over lean body weight (LBW) were found to be significant and independent predictors of V (r 2 ¼0.814+0.13, P¼0.0001, and r 2 ¼0.536+0.094, P¼0.0001, respectively). In addition, age was found to be an independent predictor of V (r 2 ¼0.219+0.075, P¼0.04). The authors concluded that the vancomycin pharmacokinetic parameter most affected by body weight was V. Ducharme et al. 35 studied the effects of obesity on vancomycin V in 1085 sets of vancomycin serum peaks and troughs obtained from 704 patients. Patients were excluded if their serum creatinine was,0.7 mg/dl. Obese patients were defined as patients with a TBW:IBW ratio of.1.30. Multivariate analysis of variance indicated that gender, age and weight were significant and independent factors affecting V. In obese subjects, V was represented by 0.89 L/kg IBW or 0.56 L/kg TBW, while other studies, such as that by Thomson et al., 36 reported a higher V that ranged from 1.4 to 1.7 L/kg 1306

JAC Table 1. Volume of distribution (V) reported by various studies Study Number of subjects Patient type (normal weight or obese) Definition of obese/morbidly obese Pharmacokinetic compartment model Weight correlated with V ss Relationship of weight to V ss Regression coefficient Krogstad 4 normal NA three-compartment TBW 0.49 1.25 L/kg NA et al. 1 Blouin et al. 32 6 obese.190% of IBW three-compartment TBW 0.26 L/kg r 2 ¼0.943, P,0.005 IBW 0.68 L/kg 4 normal IBW/TBW 0.39 L/kg Vance-Bryan 107 obese.120% of LBW two-compartment TBW 0.81 L/kg r 2 ¼0.58 et al. 34 113 normal NR NR Ducharme 108 obese.130% of IBW one-compartment IBW 0.89 L/kg et al. 35 596 normal IBW 0.65 L/kg Bauer et al. 5 24 obese.190% of IBW one-compartment TBW 0.32 L/kg r 2 ¼0.490, P,0.01 24 normal IBW 0.64 L/kg V ss, V at steady state; NA, not applicable; NR, not reported. TBW. In the study by Thomson et al., in which obese patients represented 19% of the total study population, replacing TBW with IBW or LBW did not improve the fit of the population model. Based on the results of studies that have examined vancomycin pharmacokinetics, it is likely that variation in age, sex, muscle mass and protein binding play a role in determining the V of vancomycin. A summary of the studies conducted in obese and morbidly obese patients with regard to vancomycin V can be found in Table 1. Altered vancomycin protein binding In a study that aimed to determine the effects of obesity on the extent of drug protein binding and changes in serum protein concentrations, Blouin et al. 23 found that albumin and total protein concentrations were unaltered in obese patients; however, concentrations of AAG were higher in obese patients. In addition, a later study showed that the mean albumin level in infected patients was significantly lower than that in healthy adults. 20 In comparison, the mean AAG level in the MRSA-infected patients was 2.5 times greater than that in healthy subjects (1.51 and 0.59 g/l, respectively). There was no correlation between the vancomycin binding percentage and serum albumin level; however, a strong correlation did exist between AAG level and the percentage of vancomycin protein binding (r¼0.63, P, 0.001). Obesity has been associated with increases in the levels of cholesterol and triglycerides, which may displace drugs from the serum proteins, thus increasing the free concentration of drugs, including vancomycin; thus, the exact effect of obesity on vancomycin protein binding remains unknown. 21,23 Based on published data regarding obese and morbidly obese patients, vancomycin protein binding in serum increases with increased AAG levels, and thus the vancomycin free-fraction is decreased. Often a change in the free fraction of a drug does not translate into a decrease in the free concentration of the drug, as renal function, among other factors, compensates for the lower free fraction of the drug, thus maintaining the same free concentration in the serum. In the case of vancomycin, a decrease in the free fraction of vancomycin may result in a decrease in the free concentration of vancomycin, as vancomycin clearance (CL VAN ) has been shown to increase with obesity, thus aiding in the decrease of free vancomycin concentration in the serum. 32 The decrease of free vancomycin concentration in serum would likely result in fewer clinical cures. The predicted decrease in free vancomycin concentration due to the decrease in total vancomycin concentration in obesity secondary to increased CL VAN is supported by the linear relationship between total SVC and free vancomycin concentration. Ackerman et al. 37 showed that the free vancomycin concentration can be calculated from the total SVC with the following equation: unbound vancomycin concentration¼[0.597- (total SVC)] 20.362. In one recent study, supporting the concept of increased serum protein concentrations resulting in decreased free vancomycin concentration, Butterfield et al. 38 suggested that patients with higher total serum protein may require higher doses of vancomycin due to the reduced free fraction of vancomycin in serum to achieve the same free vancomycin exposure as patients with lower total protein. Additional studies are still needed to examine vancomycin free concentrations compared with the total SVC in obese and morbidly obese patients, which can aid clinicians in determining whether obese and morbidly obese patients require both higher doses and higher SVC compared with non-obese patients. Altered renal CL VAN in obesity Obesity is associated with various physiological changes, which include increased kidney mass, increased renal blood flow, increased CL CR and increased CL VAN, resulting in lower than predicted SVCs compared with normal-weight patients. In the previously mentioned study by Blouin et al., 32 the mean total CL VAN for morbidly obese patients was 1.112+0.160 ml/min per kg TBW 1307

Table 2. CL VAN in obese patients reported in published studies Study Number of patients Type of patients Definition of obese CL CR method used Type of weight Relationship of weight to used Ratio of CL CR to CL VAN CL VAN Blouin et al. 32 6 obese TBW.190% of IBW 24 h creatinine TBW CL VAN ¼1.353(CL CR ) 76.23 2.897 ml/min/kg TBW 4 normal 24 h creatinine TBW 1.085 ml/min/kg TBW Vance-Bryan 107 obese TBW.120% of LBW Cockcroft Gault TBW NR 0.61 0.85 ml/min/kg TBW et al. 34 113 normal Cockcroft Gault TBW NR 1.04 1.10 ml/min/kg TBW Ducharme 108 obese TBW.130% of IBW Cockcroft Gault IBW a CL VAN ¼1.20(CL CR ) NR et al. 35 596 normal Cockcroft Gault TBW/IBW b NR Bauer et al. 5 24 obese.190% of IBW Salazar Corcoran TBW NR 1.2 ml/min/kg TBW 24 normal 85% 115% of IBW Cockcroft Gault TBW NR 1.1 ml/min/kg TBW Demirovic et al. 13 54 obese BMI 40.0 kg/m 2 Cockcroft Gault LBW a NR NR NA, not applicable; NR, not reported. a Use of fat-free mass [IBW+0.4(TBW2IBW)] in the Cockcroft Gault equation resulted in a better correlation between CL CR and CL VAN. b TBW or IBW can be used interchangeably based on the results of the study. or 2.897+0.611 ml/min per kg IBW, whereas normal-weight patients had a mean total CL VAN of 1.085+0.071 ml/min per kg (IBW or TBW). TBW correlated best with total CL VAN for all subjects (r¼0.981, P, 0.001). There was a significant difference in mean total CL VAN between normal-weight and morbidly obese patients, as CL VAN was approximately 2.5-fold greater in obese patients compared with normal-weight patients (187.50 and 80.78 ml/min, respectively). Vancomycin pharmacokinetics were examined in 24 morbidly obese patients, with obesity defined as TBW.190% of IBW. 39 Unlike other studies to date, in this study estimated CL CR was calculated using the Salazar Corcoran method for morbidly obese patients. 40 Similar to the results of Blouin et al., 32 CL VAN was 2.5-fold greater in morbidly obese patients compared with matched normal-weight patients (mean CL VAN was 197 and 77 ml/min, respectively). Similar results were observed with regard to the good correlation between TBW and CL VAN in morbidly obese patients with normal renal function (r¼0.948, P,0.0001), and the poor correlation between IBW and CL VAN (r¼0.204). 36 Vance-Bryan et al. 34 examined the effect of obesity on vancomycin pharmacokinetics using a Bayesian model in 135 obese patients (defined as individuals.20% over their LBW). As in other studies, the investigators compared the correlations of CL VAN with both LBW and TBW, and concluded that TBW correlated better with CL VAN than did both IBW and LBW. In contrast to the other studies, Vance-Bryan et al. found that CL VAN decreased in relation to weight as the TBW:LBW ratio increased. The majority of vancomycin pharmacokinetic studies to date have tested various dosing weights, including IBW, TBW and AdBW, as part of the Cockcroft Gault method, in estimating CL CR and CL VAN. 41 The results of such studies using the Cockcroft Gault method have shown conflicting data as some studies have shown that the use of IBW is preferred over the use of TBW, whereas other studies have shown otherwise. For example, in a study examining the accuracy of estimating CL CR in obese patients using various dosing weights and estimation equations, such as the Cockcroft Gault equation, the Modification of Diet in Renal Disease (MDRD) and the Salazar Corcoran methods, only the Cockcroft Gault equation using LBW and fat-free weight correlated with the measured CL CR in obese patients. 13 However, a subsequent study by Murphy et al. 42 compared seven previously published methods for estimating vancomycin pharmacokinetics using various dosing weights, including TBW, AdBW and IBW. Among the methods that were compared were methods previously published by Matzke et al., 2 Rodvold et al., 3 Birt and Chandler, 43 Burton et al., 44 Ambrose and Winter 4 and Bauer. 5 Among the 189 included patients, 116 were.20% over their IBW. In a study of patients who were.120% of their IBW, the Ambrose method using TBW had the highest coefficient of determination compared with the other methods. Of note, AdBW was used to calculate the CL CR using the Cockcroft Gault equation while TBW was used to estimate CL VAN based on the calculated CL CR. Table 2 summarizes the findings of various vancomycin pharmacokinetic studies with regard to estimating CL CR and CL VAN. In the previously mentioned study by Ducharme et al., 35 which examined the relationship of age, gender and obesity with vancomycin pharmacokinetics, the ratio of CL VAN to the estimated CL CR (applying the Cockcroft Gault equation using IBW) averaged 1.20 in obese patients. In another study, the ratio of CL VAN to estimated CL CR (applying the Cockcroft Gault equation using TBW) was better reflected by a factor of 0.9. 45 Both ratios observed in these studies were significantly greater than the ratio of 0.65 that was observed in studies with healthy adults. 46 Conclusions Vancomycin pharmacokinetics in the obese population remains an area of much debate, one that requires continued research given the rising number of obese patients in both the USA and worldwide. Based on published data, vancomycin pharmacokinetics are altered in the obese population with regard to the 1308

JAC extent of serum protein binding and renal clearance, which in turn affect vancomycin V, CL VAN and the free fraction in serum. Vancomycin V is greater in obese patients than in non-obese patients, as shown in several published studies. It is evident that the V of vancomycin in obese patients correlates best with TBW and not IBW. In addition, CL VAN is altered in obesity, as reflected in numerous published studies previously mentioned. Most published data to date support the use of the Cockcroft Gault equation with TBW to calculate CL VAN in non-obese patients; however, further studies are needed to determine the best combination of equations to estimate CL CR in the obese and morbidly obese populations. In addition to V and CL VAN, the relationship of SVC to serum AAG and albumin levels needs to be further researched to determine more accurately the free concentration of vancomycin in serum of obese and morbidly obese patients. Transparency declarations None to declare. 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