Simplified Estimation of Aminoglycoside Pharmacokinetics in Underweight and Obese Adult Patients

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 2011, p. 4006 4011 Vol. 55, No. 9 0066-4804/11/$12.00 doi:10.1128/aac.00174-11 Copyright 2011, American Society for Microbiology. All Rights Reserved. Simplified Estimation of Aminoglycoside Pharmacokinetics in Underweight and Obese Adult Patients Manjunath P. Pai, 1 * Anne N. Nafziger, 2 and Joseph S. Bertino, Jr. 2 Albany College of Pharmacy and Health Sciences, Albany, New York, 1 and Bertino Consulting, Schenectady, New York 2 Received 9 February 2011/Returned for modification 28 April 2011/Accepted 4 June 2011 Aminoglycosides are an important class of agents that are used in combination antimicrobial regimens to treat bacterial pathogens. Dosing of aminoglycosides is typically based on total body weight. However, the most appropriate alternative body size descriptor for dosing aminoglycosides at the extremes of weight (underweight and obese) is not known. Also, the predictive performance of newer formulas to assess kidney function, such as the modification of diet in renal disease (MDRD) and chronic kidney disease-epidemiology (CKD-EPI) equations compared to the Cockcroft-Gault equation to predict aminoglycoside clearance, is not known. We sought to examine dosing of aminoglycosides across the extremes of weight using a variety of formulas to assess kidney function. Pharmacokinetic data were obtained from a set of prospectively collected data (1982 to 2003) of 2,073 (53.5% male) adult patients that included 497 tobramycin- and 1,576 gentamicin-treated cases. The median (minimum, maximum) age, weight, and body mass index were 66 (18, 98) years, 70.0 (29.7, 206.7) kg, and 24.4 (11.3, 73.8) kg/m 2, respectively. The percentage of underweight, normal-weight, overweight, and obese cases based on the World Health Organization classification were 8.8%, 45.5%, 26.5%, and 19.2%, respectively. The aminoglycoside volume of distribution was normalized to several alternative body size descriptors. Only lean body weight estimated by the method of S. Janmahasatian et al. (Clin. Pharmacokinet. 44:1051 1065, 2005) normalized the volume of distribution for both tobramycin and gentamicin across all weight strata, with the estimate being approximately 0.45 liter/kg. Aminoglycoside dosing can be simplified across all weight strata with the use of lean body weight. The CKD-EPI equation best predicts aminoglycoside clearance. Aminoglycosides are an important class of agents that have been used in antimicrobial combination regimens against Gram-negative and Gram-positive bacterial pathogens for over 50 years (5, 12). Despite concerns of the ototoxic and nephrotoxic potential of aminoglycosides, their use has been sustained by the continued emergence of antimicrobial resistance among Gram-negative bacteria (5, 11). Aminoglycoside dosing to treat infections follows two basic strategies, namely, by traditional dosing or, alternatively, as an extended-interval aminoglycoside dosing (EIAD) (33). Both dosing approaches follow a weight-based approach. In patients with normal kidney function, traditional dosing includes use of 1 to 2 mg/kg of body weight dosed multiple times per day on the basis of renal function, while EIAD utilizes 5 to 10 mg/kg every 24 h (19, 25). Therapeutic drug monitoring to individualize drug dosing should be used with either dosing approach to increase the probability of achieving specific target concentrations and reduce the risk of toxicity, especially among the critically ill (18, 31). Traditional doses typically target a maximum concentration in plasma (C max ) of between 4 and 10 mg/liter and a detectable minimum concentration in plasma (C min ) of 0.3 mg/liter to 2 mg/liter, while EIAD targets a C max of 16 to 20 mg/liter and an undetectable C min ( 0.3 mg/liter). The ability to achieve these C max and C min targets after the first dose is * Corresponding author. Mailing address: Albany College of Pharmacy, 106 New Scotland Ave., O Brien Room 204, Albany, NY 12208. Phone: (518) 694-7146. Fax: (518) 694-7062. E-mail: amit.pai@acphs.edu. Supplemental material for this article may be found at http://aac.asm.org/. Published ahead of print on 13 June 2011. largely based on the size of the dose, the dosing interval, and an estimate of the individual patient s kidney function (19). Kidney function is currently estimated for drug dosing using equations that require stable serum creatinine values (28, 30). The Cockcroft-Gault (CG) equation incorporates age, weight, sex, and serum creatinine level to determine the estimated creatinine clearance (ecl CR ; in ml/min) (4). Creatinine clearance (CL CR ) serves as a surrogate estimate of the glomerular filtration rate (GFR) but typically overestimates GFR due to tubular secretion of creatinine (35). Two newer equations, the four-variable modification of diet in renal disease (MDRD) and the chronic kidney disease-epidemiology (CKD-EPI) methods, have been introduced as improved mathematical functions that provide an estimated GFR (egfr; in ml/min/ 1.73 m 2 ) (15, 16). The MDRD and the CKD-EPI equations incorporate age, sex, race, and serum creatinine level to determine an egfr that is normalized to body surface area (BSA) (15, 16). The MDRD equation is used to classify chronic kidney disease into stages but has recently been advocated to aid adjustment of drug dosing (20). The predictive value of the MDRD and CKD-EPI equations to estimate aminoglycoside dosing has not been evaluated across a large patient population. Consequently, the relative precision of the Cockcroft- Gault, MDRD, and CKD-EPI equations to aid aminoglycoside dosing is not known. As noted above, the Cockcroft-Gault equation includes weight as a parameter, while the MDRD and CKD-EPI equations do not. This exclusion is relevant because significant changes have occurred to the clinical weight spectrum in United States since the introduction of aminoglycosides. The average weights for U.S. adult males and females were 75.6 kg and 63.7 kg, respectively, in 1960, compared to 86.8 kg and 74.7 4006

VOL. 55, 2011 AMINOGLYCOSIDE DOSING IN OBESITY 4007 kg, respectively, in 2002 (21). One of every three Americans is obese, as defined by a body mass index (BMI) of 30 kg/m 2, and the percentages of overweight and obese adults continue to increase (8). Surveys within our local health care institutions indicate that normal-weight patients represent only one-third of the hospitalized population. As a result, selection of the right weight parameter to dose drugs like aminoglycosides is important. Basing the dose and dosing interval of aminoglycosides on total body weight (TBW) assumes that aminoglycoside clearance (CL) and volume of distribution increase in proportion to TBW. Given that this is not the case, alternative body size descriptors (ABSDs) have been utilized to improve aminoglycoside dosing (19). Ideal body weight (IBW) serves as an example of an ABSD that has been repeatedly mischaracterized as lean body weight (LBW) in the literature and is used to dose aminoglycosides (7, 14, 24). IBW is an innately flawed ABSD developed as a general rule of thumb and was never intended to support drug dosing (24). Newer, more scientifically based equations that better predict LBW have been developed and shown to improve the scaling of pharmacokinetic parameters across a large weight spectrum (10, 22). Hence, the current analysis was performed to (i) compare LBW, TBW, and IBW as weight standards to index aminoglycoside volume of distribution at steady state (V ss ) and (ii) compare the Cockcroft-Gault ecl CR using LBW, TBW, or IBW and the MDRD and CKD-EPI equations as surrogate estimates of measured aminoglycoside clearance. The overall goal of this work is to identify a simplified approach to aminoglycoside dosing for patients across the weight spectrum. (This work was presented in part at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, 12 to 15 September 2010.) MATERIALS AND METHODS Data source. Data were obtained from a set of prospectively collected data. Briefly, all data were collected by the Clinical Pharmacy Service (CPS) of Bassett Healthcare (31) between May 1982 through December 2003. The adults ( 18 years of age) included in the study were admitted to the medical or surgical service, were treated with gentamicin or tobramycin, and received individualized pharmacokinetic monitoring. Only data for patients with stable kidney function were included in the data set. Data for patients with a diagnosis of cystic fibrosis were not included in the database of prospectively collected data. The initial dosing regimens were selected by the patient s physician, with dose modification recommendations made by the CPS if estimated C min s exceeded 2 mg/liter or C max s were below 5 mg/liter. Pharmacokinetic sampling, assay, and analysis. Aminoglycosides were typically infused over 30 min, with the actual infusion durations recorded by CPS. Blood sampling was conducted such that the first sample was collected at least 30 min after the end of infusion. Two to three additional blood samples were collected over the dosing interval. Serum was analyzed for gentamicin or tobramycin using a fluorescence polarization immunoassay technique (TDx; Abbott Diagnostics, Chicago, IL) with a between-run coefficient of variation that was 5% across the measurement range. Data were fitted to a one-compartment model by the method of Sawchuk and Zaske in order to estimate V ss and CL (26). Weight parameter estimation. The measured initial patient weight was defined as TBW. IBW (kg) and LBW (kg) were estimated using the equations presented below and were based on patient sex (7, 13, 24). Several equations exist to estimate LBW; the rationale for use of the equations developed in the year 2005 (LBW 2005 ) have been described previously (22). For simplicity, LBW 2005 is referred to as LBW in this report, unless distinctly specified otherwise. The equations are as follows: IBW-male 50 2.3 (height per inch over 60 in.) IBW-female 45.5 2.3 (height per inch over 60 in.) LBW 2005 -male (9,270 TBW)/(6,680 216 BMI) LBW 2005 -female (9,270 TBW)/(8,780 244 BMI) ecl CR and egfr estimation. ecl CR was calculated using the CG equation by replacing the weight (Wt) parameter with TBW (CG_TBW), IBW (CG_IBW), or LBW (CG_LBW) (4). The initial serum creatinine concentration (Scr; in mg/dl) was used and was not rounded up to 1.0 mg/dl for values of 1.0 mg/dl. A factor of 0.85 was not multiplied to account for differences between the sexes when LBW 2005 was used because a 10 to 20% difference in the estimate of LBW between the sexes is accounted for by the equations. No black patients were in the patient population, and so corrections for black race in the MDRD and CKD-EPI equations are not included below (15, 16). The Cockcroft-Gault (CG) equation for calculation of ecl CR is (140 age) (TBW, IBW, or LBW) 0.85 (if female) ecl CR (72 Scr) In this equation, the 0.85 factor was not used with LBW, as noted above. The MDRD equation for egfr (ml/min/1.73 m 2 )is egfr 175 Scr 1.154 age 0.203 0.742 (if female) The respective CKD-EPI equations for egfr (ml/min/1.73 m 2 ) for females with an Scr of 0.7, females with an Scr of 0.7, males with an Scr of 0.9, and males with an Scr of 0.9 are egfr 144 (Scr/0.7) 0.329 (0.993) age egfr 144 (Scr/0.7) 1.209 (0.993) age egfr 141 (Scr/0.9) 0.411 (0.993) age egfr 144 (Scr/0.9) 1.209 (0.993) age Given that MDRD and CK-EPI equations are normalized to BSA, Mosteller s adaptation (BSA_M) was used to transform these values from ml/min/1.73 m 2 to ml/min and are denoted MDRD_BSA_M and CKD-EPI_BSA_M, respectively (17). BSA_M is calculated as follows: BSA_M [(TBW height)/3,600] 0.5 where TBW is in kg and height is in cm. Data analysis. All data were analyzed using the STATA program (version 11; StataCorp, College Station, TX). The patients were categorized by the World Health Organization (WHO) classification into four BMI groups: underweight (BMI 18.5 kg/m 2 ), normal weight (BMI 18.5 to 24.99 kg/m 2 ), overweight (BMI 25 to 29.99 kg/m 2 ), and obese (BMI 30 kg/m 2 ) (36). Absolute gentamicin and tobramycin V ss and V ss indexed to TBW, IBW, and LBW were compared between groups using analysis of variance with post hoc comparisons by the Bonferroni test. Ordinary least-squares regression was used to compare ecl CR (CG_TBW, CG_IBW, or CG_LBW) and egfr (MDRD, MDRD_ BSA_M, CKD-EPI, or CKD-EPI_BSA_M) as predictors of gentamicin and tobramycin CLs. The latter approach was also used to compare the predictive value of ecl CR and egfr above and below 60-ml/min or 60-ml/min/1.73 m 2 stratification breakpoints. The rationales for use of these breakpoints include the known bias of MDRD for egfr values greater than 60 ml/min/1.73 m 2 as well as recent FDA draft guidance that supports consideration of these breakpoints (9, 16). Finally, the slope and intercepts derived through these regression analyses were compared to identify potential differences between ecl CR or egfr as measures of aminoglycoside CL. RESULTS Population demographics. The study population consisted of 2,073 cases. Most of the cases (90.4%) were derived from individual patients; however, data from 100 patients were characterized as multiple cases. Table 1 includes the demographic characteristics of the study population by aminoglycoside administered. There were 497 cases treated with tobramycin and 1,576 cases treated with gentamicin. More males than females were in the sample, but the distribution of males to females did

4008 PAI ET AL. ANTIMICROB. AGENTS CHEMOTHER. Variable TABLE 1. Demographic characteristics of study population by aminoglycoside received No. (%) of subjects Mean SD (minimum, maximum) No. (%) of subjects Mean SD (minimum, maximum) Age (yr) 497 62.2 17.3 (18, 98) 1,576 61.5 17.5 (18, 97) Male 283 (56.9) 826 (52.4) Female 214 (43.1) 750 (47.6) TBW (kg) 497 70.8 17.5 (30.2, 136) 1,576 72.9 20.4 (29.7, 206.7) Ht (cm) 496 168.3 9.9 (136.4, 192.7) 1,535 168.5 10.2 (136.6, 202.7) BMI (kg/m 2 ) 496 24.9 5.8 (11.5, 51.3) 1,535 25.7 6.7 (11.3, 73.8) Underweight 46 16.5 1.61 (11.5, 18.49) 133 16.6 1.58 (11.3, 18.49) Normal wt 249 22.0 1.70 (18.5, 24.98) 676 22.0 1.79 (18.5, 24.99) Overweight 110 27.2 1.48 (25.0, 29.8) 428 27.2 1.39 (25.0, 29.99) Obese 91 34.4 3.99 (30.1, 51.3) 298 35.8 6.69 (30.0, 73.8) Scr (mg/dl) 497 1.04 0.49 (0.2, 3.5) 1,576 1.10 0.46 (0.2, 3.6) ICU a 154 (31.0) 433 (27.5) Dose (mg) 497 123.1 41.2 (35, 400) 1,576 105.6 35.5 (20, 320) Dose (mg/kg) 497 1.76 0.48 (0.73, 3.99) 1,576 1.49 0.44 (0.42, 3.65) a ICU, intensive care unit. not differ by the aminoglycoside used. Variable ranges for the population were 18 to 98 years for age, 30.2 to 206.7 kg for weight, and 0.2 to 3.8 mg/dl for Scr. The TBW and BMI of patients were statistically (P 0.05) higher in the gentamicin group than the tobramycin group, but these differences are considered clinically insignificant. The percentages of patients by WHO classification were 8.8% underweight, 45.5% normal weight, 26.5% overweight, and 19.2% obese. Aminoglycoside doses were consistent with traditional doses, given that only eight cases had a measured C max of 16 g/ml (data not shown). Prediction of aminoglycoside volume of distribution. The mean standard deviation (SD) absolute tobramycin V ss values by BMI were 18.8 5.1 liters for underweight, 22.2 7.7 liters for normal weight, 25.2 6.9 liters for overweight, and 27.2 8.0 liters for obese. Similarly, the absolute gentamicin V ss values were 18.9 6.0 liters for underweight, 21.7 7.4 liters for normal weight, 24.8 8.9 liters for overweight, and 27.3 10.5 liters for obese. Table 2 includes tobramycin and gentamicin V ss s indexed to TBW, IBW, or LBW. As tabulated, the estimate of V ss s indexed to LBW remained relatively constant across weight strata. In contrast, V ss s indexed to TBW or IBW were statistically different between the obese and normal-weight groups. Figure 1 demonstrates a similar distribution of V ss s indexed to LBW compared to V ss s indexed to TBW or IBW across BMI groups. The ability to achieve a relatively constant V ss when it was indexed to LBW compared to TBW or IBW across a BMI range of 11.3 to 73.8 kg/m 2 is further illustrated in Fig. 2. The geometric mean estimate for weight-indexed aminoglycoside V ss was 0.452 (95% confidence interval [CI], 0.446, 0.459) liter/kg (LBW) for the study population. Prediction of aminoglycoside clearance. The median CLs were 65.0 (minimum, maximum, 6.90, 235) ml/min for tobramycin and 70.0 (minimum, maximum, 12.0, 263) ml/min for gentamicin. Table 3 includes a comparison of the linear regression models of ecl CR compared to the tobramycin or gentamicin CL. The models are further stratified by an ecl CR below, above, or equal to 60 ml/min. Use of TBW, IBW, or LBW yielded a comparable degree of precision (R 2 0.40 to 0.44) when it was incorporated in the CG equation as an estimate of the tobramycin CL. Poor precision for estimation of gentamicin CL was noted with these equations. Table 3 demonstrates that regardless of weight descriptor (TBW, IBW, or LBW), the slope increases while the intercept decreases with ecl CR values of 60 ml/min compared to those of 60 TABLE 2. Comparison of volume of distribution indexed to TBW, IBW, and LBW values for tobramycin and gentamicin by four body mass index classes V ss (liter/kg) a BMI class TBW IBW LBW TBW IBW LBW Total 0.34 0.11 0.38 0.14 0.48 0.16 0.33 0.11 0.37 0.14 0.48 0.16 Underweight 0.41 0.11 b 0.31 0.09 b 0.51 0.15 0.40 0.12 b 0.31 0.10 0.51 0.17 Normal wt 0.35 0.11 0.35 0.11 0.47 0.15 0.35 0.11 0.35 0.12 0.48 0.16 Overweight 0.33 0.10 0.41 0.13 c 0.48 0.16 0.32 0.10 c 0.39 0.13 0.46 0.15 Obese 0.30 0.11 c 0.48 0.18 c 0.51 0.17 0.27 0.10 c 0.45 0.17 c 0.47 0.17 a Data represent arithmetic means SDs. b P 0.008, compared to all BMI classes. c P 0.008, compared to normal-weight subjects.

VOL. 55, 2011 AMINOGLYCOSIDE DOSING IN OBESITY 4009 TABLE 3. Comparison of linear regression models of CL CR using CG equation with TBW, IBW, or LBW as predictors of aminoglycoside CL Aminoglycoside, model, and GFR Coefficient Mean CL (ml/min) a R 2 Constant CG_TBW 0.50 (0.44, 0.55) 31.2 (26.2, 36.3) 0.40 60 ml/min 0.78 (0.53, 1.01) 13.5 (3.08, 24.0) 0.19 60 ml/min 0.38 (0.31, 0.46) 45.7 (37.0, 54.3) 0.22 CG_IBW 0.53 (0.47, 0.58) 32.5 (27.9, 37.2) 0.43 60 ml/min 0.89 (0.67, 1.12) 11.4 (1.64, 21.1) 0.22 60 ml/min 0.36 (0.28, 0.45) 53.2 (44.4, 62.1) 0.21 CG_LBW 0.69 (0.62, 0.76) 29.0 (24.1, 33.8) 0.44 60 ml/min 1.18 (0.98, 1.38) 7.2 ( 1.15, 15.6) 0.32 60 ml/min 0.48 (0.36, 0.61) 50.5 (38.5, 62.5) 0.21 FIG. 1. Box plots of V ss indexed to TBW, IBW, and LBW over body mass index category. ml/min. Furthermore, the slope approaches unity (approximately 1) with ecl CR values of 60 ml/min. Table 4 includes a comparison of the linear regression models of egfr compared to the tobramycin or gentamicin CL. These models are also stratified around 60 ml/min or 60 ml/min/1.73 m 2. The CKD-EPI equation yielded the highest overall precision as an estimate of tobramycin and gentamicin CLs. More importantly, regression of aminoglycoside CL to egfr by CKD-EPI yielded a slope that was close to unity and a nonsignificant intercept (i.e., intercept 0). This relationship was maintained regardless of egfr stratification when the tobramycin CL was evaluated. An intercept was noted when egfrs were compared by use of CKD-EPI and gentamicin CL. This intercept was roughly 50% lower than the intercepts obtained by all functions evaluated in this investigation. The precision of the CKD-EPI equation was consistent for underweight (R 2 0.41) and obese (R 2 0.41) patients. The MDRD equation was a less precise estimate of aminoglycoside CL. However, when the subsets of cases with egfrs of 60 ml/min/1.73 m 2 were compared, the MDRD and CKD-EPI FIG. 2. Linear fit with 95% confidence interval plots of V ss indexed to TBW, IBW, and LBW over body mass index. CG_TBW 0.47 (0.43, 0.50) 37.8 (34.6, 40.9) 0.30 60 ml/min 1.0 (0.85, 1.2) 9.82 (3.00, 16.6) 0.21 60 ml/min 0.31 (0.26, 0.37) 56.9 (51.1, 62.7) 0.12 CG_IBW 0.59 (0.55, 0.63) 34.8 (31.4, 38.2) 0.31 60 ml/min 1.15 (1.01, 1.29) 6.9 (0.74, 13.01) 0.26 60 ml/min 0.32 (0.25, 0.40) 63.5 (56.2, 70.7) 0.08 CG_LBW 0.73 (0.68, 0.78) 32.5 (29.1, 35.8) 0.34 60 ml/min 1.20 (1.07, 1.33) 11.8 (6.31, 17.3) 0.26 60 ml/min 0.35 (0.24, 0.45) 69.0 (59.3, 78.7) 0.06 a Values in parentheses are 95% CIs. equations were comparable predictors of aminoglycoside CL. Transformation of egfr to individualized estimates of BSA lowered the precision of the CKD-EPI and MDRD equations as estimates of aminoglycoside CL (Table 4). Bland-Altman TABLE 4. Comparison of linear regression models of glomerular filtration rate using the MDRD and CKD-EPI equations, including those normalized to BSA_M, as predictors of aminoglycoside CL Aminoglycoside, model, and GFR Coefficient Mean CL (ml/min) a R 2 Constant MDRD 0.39 (0.34, 0.44) 38.2 (33.0, 43.3) 0.31 60 ml/min/1.73 m 2 0.90 (0.67, 1.13) 3.10 ( 7.18, 13.4) 0.31 60 ml/min/1.73 m 2 0.27 (0.21, 0.33) 55.1 (47.7, 62.4) 0.16 MDRD_BSA_M 0.44 (0.38, 0.49) 32.9 (27.6, 38.1) 0.35 60 ml/min 0.91 (0.63, 1.19) 2.58 ( 10.2, 15.3) 0.24 60 ml/min 0.33 (0.27, 0.40) 46.9 (39.2, 54.6) 0.21 CKD-EPI 0.86 (0.79, 0.94) 5.43 ( 0.81, 11.7) 0.50 60 ml/min/1.73 m 2 0.87 (0.65, 1.09) 5.65 ( 4.18, 15.5) 0.29 60 ml/min/1.73 m 2 0.89 (0.75, 1.02) 3.16 ( 9.91, 16.2) 0.31 CKD-EPI_BSA_M 0.79 (0.71, 0.86) 9.20 (2.91, 15.5) 0.47 60 ml/min 0.83 (0.57, 1.08) 7.21 ( 3.94, 18.4) 0.23 60 ml/min 0.77 (0.64, 0.90) 10.6 ( 1.71, 22.9) 0.28 MDRD 0.52 (0.47, 0.57) 35.0 (31.0, 39.0) 0.23 60 ml/min/1.73 m 2 1.0 (0.82, 1.18) 4.77 ( 3.39, 12.9) 0.19 60 ml/min/1.73 m 2 0.27 (0.20, 0.34) 62.2 (55.7, 68.7) 0.05 MDRD_BSA_M 0.50 (0.46, 0.54) 34.4 (30.6, 38.2) 0.25 60 ml/min 1.04 (0.87, 1.23) 2.61 ( 5.47, 10.7) 0.23 60 ml/min 0.32 (0.26, 0.38) 55.1 (48.9, 61.3) 0.09 CKD-EPI 0.84 (0.78, 0.89) 14.1 (9.9, 18.3) 0.37 60 ml/min/1.73 m 2 1.00 (0.83, 1.17) 6.28 ( 1.33, 13.9) 0.20 60 ml/min/1.73 m 2 0.75 (0.65, 0.85) 22.0 (12.9, 31.3) 0.16 CKD-EPI_BSA_M 0.72 (0.67, 0.76) 19.7 (15.7, 23.7) 0.36 60 ml/min 1.00 (0.85, 1.17) 5.43 ( 1.61, 12.5) 0.25 60 ml/min 0.61 (0.52, 0.69) 30.6 (22.7, 38.5) 0.16 a Values in parentheses are 95% CIs.

4010 PAI ET AL. ANTIMICROB. AGENTS CHEMOTHER. plots of the relationships between ecl CR and egfr to aminoglycoside CL are provided in the supplemental material. DISCUSSION Aminoglycoside dosing is currently based on weight, and the dosing interval is adjusted in patients with reduced kidney function (19). The FDA-approved product labels for gentamicin and tobramycin include dosing approaches that are discordant with current traditional dosing and EIAD approaches (3, 19, 27). However, both product labels recognize the importance of LBW rather than TBW as the weight parameter for aminoglycoside dosing. Although LBW is difficult to optimally define, LBW refers to the total weight of organs, bones, and muscles (i.e., all weight other than fat). Minimally put, LBW is approximately representative of the fat-free weight (10). LBW is influenced by age, sex, and body size (height and weight) (10). Several methods have been devised to estimate LBW and are based on sex, height, and weight. The exception to this rule is IBW, which includes only height and sex as estimation parameters (10). IBW was never intended for pharmacologic use, and its misuse is perpetuated in pharmacokinetic definitions of obesity and dosing recommendations (7, 10, 23, 24). The reliance of IBW on height leads to a distribution of IBW values that mimic population height distributions and that have limited variance. As a result, when LBW estimates are based on IBW, an obese male has the same LBW as a malnourished male of equal height, a result that is clearly not reasonable. Pharmacokinetic studies of aminoglycosides observe this fundamental failure of IBW as a basis for dosing for obese patients (2, 32). Studies attempt to resolve the innate weakness of IBW through a correction factor that multiplies the difference in excess weight: (TBW IBW) IBW. This new ABSD, referred to as adjusted body weight (ABW), includes aminoglycoside-specific correction factors of 0.42 (amikacin), 0.45 (gentamicin), and 0.37 (tobramycin) (2). Numerous clinical pharmacokinetic textbooks and the tobramycin product label have simplified this correction factor to 0.40 (27), despite the knowledge that the aminoglycoside dosing correction factor can range from 0.14 to 0.98. Ultimately, the need for selection of one of three potential weight parameters (TBW, IBW, or ABW) is confusing and a potential source of error. This fundamental error has also been applied to other agents and should not be perpetuated (34, 37). The selection of an ABSD for a mg/kg dose has also confused the debate over selection of a weight parameter when kidney function is estimated using the CG equation (4). The CG equation is based on TBW and is derived from a sample of 249 men (4). The factor to adjust for female sex (0.85) was arbitrary and is based on the assumption that women have 10 to 20% lower LBWs than men (4, 20). The CG equation also overestimates the measured CL CR in underweight individuals (14). In contrast, when the CG equation is used, the use of IBW underestimates CL CR while the use of TBW overestimates CL CR in comparison to the measured CL CR in obese individuals (6). The shortcomings of the CG equation compared to the MDRD equation have been reviewed and continue to be debated (20, 28, 30). The current investigation was conducted to address two fundamental discrepancies in the dosing of aminoglycosides across the adult clinical weight spectrum: (i) what weight parameter should be used to dose aminoglycosides? and (ii) what estimate of kidney function best predicts the dosing interval? Our data demonstrate that indexing V ss to TBW and IBW leads to an unstable population estimate as one considers treating an individual who weighs between 29.7 and 206.7 kg or has a BMI between 11.3 and 73.8 kg/m 2. In contrast, use of LBW 2005 yields a stable geometric mean population estimate of V ss (0.45 liter/kg). Hence, average LBW-based gentamicin or tobramycin doses of 9, 4.5, and 2.25 mg/kg are theoretically more likely to achieve respective target C max values of approximately 20, 10, and 5 mg/liter, respectively. This compares with the current dosing approach with 7, 3 to 4, and 1 to 2 mg/kg, which may not achieve the target C max if the right dosing weight is not selected. Hence, validation of LBW as the basis of initial aminoglycoside dosing, regardless of weight classification, will improve achievement of the pharmacodynamic target. This is especially true when EIAD is considered, as this investigation included only eight cases with a measured C max of 16 g/ml. Therapeutic drug monitoring can then be utilized to optimize the dose. Although LBW is identified as the best parameter for selection of an initial dose, it did not improve the estimate of aminoglycoside CL when the CG equation was used. Overall, this investigation demonstrates that egfr better predicts aminoglycoside CL than ecl CR. This finding is consistent with the elimination pathway of aminoglycosides (38). Aminoglycosides undergo glomerular filtration but have not been demonstrated to undergo tubular secretion. CL CR is a function of both glomerular filtration and tubular secretion (35). Several studies have verified that measured GFR closely correlates with aminoglycoside CL (38). Zarowitz and colleagues compared gentamicin and tobramycin clearance to inulin clearance (GFR) and the CL CR measured at 24 h among critically ill patients (38). This publication included subject-specific data that permitted reanalysis and direct comparison with our results. The linear regression of aminoglycoside CL to CL CR yielded a mean coefficient and constant of 0.47 (95% CI, 0.31, 0.63) and 14.1 (95% CI, 3.19, 31.4), respectively (R 2 0.85). In contrast, the linear regression of aminoglycoside CL to GFR yielded a mean coefficient and constant of 1.05 (95% CI, 0.82, 1.27) and 1.97 (95% CI, 16.0, 12.1), respectively (R 2 0.92). A slope near unity and a higher R 2 demonstrate the clear dominance of GFR as an estimate of gentamicin and tobramycin CL (and vice versa). Accordingly, these results firmly support the function of egfr as a more precise estimate of aminoglycoside CL. This is most apparent with the CKD-EPI equation, where a slope near unity and nonsignificant intercept are noted when regression is against tobramycin CL. The superiority of egfr over ecl CR has practical relevance since many health care institutions automatically calculate egfr using the MDRD function (30). The National Kidney Disease Education Program currently advocates the use of the MDRD equation to stage chronic kidney disease (CKD) and recommends use of either egfr or ecl CR for drug dosing (20). The current demonstration that the MDRD and CKD-EPI equations provide comparable precision in patients with CKD implies that no major modifications in reporting of egfr are needed. However, given the known bias of the MDRD equation for egfr values of 60 ml/

VOL. 55, 2011 AMINOGLYCOSIDE DOSING IN OBESITY 4011 min/1.73 m 2, the CKD-EPI equation should be utilized to define dose modification across the egfr range in patients with and without CKD. One key issue not addressed is the potential effect of race or ethnicity on egfr (29). Because all our patients were nonblack/non-african-american, our analysis has no correction for race/ethnicity, which is found in the MDRD and CKD-EPI equations. The MDRD equation forces a 21.2% higher egfr in African-Americans, and the CKD-EPI equation forces a 15.9% higher egfr in black patients (15, 16). Although the term black is used synonymously with African-American in the previous sentence (consistent with the terminology used in the published papers), the interpretation of this term is not intuitive. As an example, correction for black race or African- American ethnicity overestimates GFR in black South Africans and Ghanaians (29). Additional race and ethnicity factors were recently introduced to improve race/ethnicity-specific egfr estimates (29). The controversy that exists regarding race/ethnicity-specific modification of egfr remains to be addressed and is beyond the scope of this paper. In conclusion, the current investigation demonstrates that LBW estimated using LBW 2005 is the most appropriate scale to index aminoglycoside V ss. Improved prediction of aminoglycoside CL using equations of egfr rather than ecl CR was shown. Our findings should aid development of improved dosing guidelines for this class of agents as well as analogous compounds like the neoglycosides (1). However, our results should not be extrapolated to special populations such as patients with cystic fibrosis, burns, or rapidly changing kidney function without further study. 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