Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients

Bauer, Larry A.; Edwards, William; Dellinger, E. Patchen; Simonowitz, David

doi:10.1007/bf00542215

Cited by 157 publications

(128 citation statements)

References 18 publications

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“…The descriptor was derived as a tool to normalize V, where some proportion (termed a correction factor) of excess weight above IBW was added to IBW. The mean correction factor (CF) was estimated at 0.45 for gentamicin, 0.37 for tobramycin and 0.42 for amikacin [41]. Because of the variability in the constant CF, it would seem prudent to estimate a population value on a case by case basis.…”

Section: Adjusted Body Weightmentioning

confidence: 99%

“…ABW was the first size descriptor specifically developed for use in pharmacokinetic experiments, and was presented in 1983 as part of a noncompartmental analysis of aminoglycoside dosing [41]. The descriptor was derived as a tool to normalize V, where some proportion (termed a correction factor) of excess weight above IBW was added to IBW.…”

Section: Adjusted Body Weightmentioning

confidence: 99%

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What is the best size descriptor to use for pharmacokinetic studies in the obese?

Green

Duffull

2004

Brit J Clinical Pharma

312

244

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The prevalence of obesity in the western world is dramatically rising, with many of these individuals requiring therapeutic intervention for a variety of disease states. Despite the growing prevalence of obesity there is a paucity of information describing how doses should be adjusted, or indeed whether they need to be adjusted, in the clinical setting. This review is aimed at identifying which descriptors of body size provide the most information about the relationship between dose and concentration in the obese. The size descriptors, weight, lean body weight, ideal body weight, body surface area, body mass index, fat-free mass, percent ideal body weight, adjusted body weight and predicted normal body weight were considered as potential size descriptors. We conducted an extensive review of the literature to identify studies that have assessed the quantitative relationship between the parameters clearance (CL) and volume of distribution ( V ) and these descriptors of body size. Surprisingly few studies have addressed the relationship between obesity and CL or V in a quantitative manner. Despite the lack of studies there were consistent findings: (i) most studies found total body weight to be the best descriptor of V . A further analysis of the studies that have addressed V found that total body weight or another descriptor that incorporated fat mass was the preferred descriptor for drugs that have high lipophilicity; (ii) in contrast, CL was best described by lean body mass and no apparent relationship between lipophilicity or clearance mechanism and preference for body size descriptor was found. In conclusion, no single descriptor described the influence of body size on both CL and V equally well. For drugs that are dosed chronically, and therefore CL is of primary concern, dosing for obese patients should not be based on their total weight. If a weight-based dose individualization is required then we would suggest that chronic drug dosing in the obese subject should be based on lean body weight, at least until a more robust size descriptor becomes available.

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Section: Adjusted Body Weightmentioning

confidence: 99%

Section: Adjusted Body Weightmentioning

confidence: 99%

What is the best size descriptor to use for pharmacokinetic studies in the obese?

Green

Duffull

2004

Brit J Clinical Pharma

312

244

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“…Past investigators have utilized dosing weight correction factors (DWCFs) to normalize predictions of V ss in morbidly obese subjects by using 40% excess body weight (EBW [TBW Ϫ IBW]) added to IBW (2,3,6,21). Guidelines outlining aminoglycoside pharmacokinetic dosing parameters have not been formulated for moderately overweight patients (TBW/ IBW ratio, 1.25 to 2.00) or underweight patients (TBW/IBW ratio, Ͻ1).…”

mentioning

confidence: 99%

Aminoglycoside dosing weight correction factors for patients of various body sizes

Traynor

Nafziger

Bertino

1995

Antimicrob Agents Chemother

112

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Prior investigations have suggested the use of a dosing weight correction factor of ideal body weight (IBW) plus 40% excess body weight (EBW, where EBW ‫؍‬ total body weight [TBW] ؊ IBW) to determine the weight to use for aminoglycoside dosing in morbidly obese (TBW/IBW ratio, >2) patients. Little data are available to provide dosing information for underweight or moderately obese patients. We investigated aminoglycoside pharmacokinetics in 1,708 patients receiving gentamicin and tobramycin. Patients were stratified into underaverage-weight or overweight weight categories based on both TBW/IBW ratio and body mass index (weight/ height 2 ratio), which has been shown to correlate with physiologic estimates of body fat. Regression analyses revealed that the TBW/IBW ratio predicts the volume of distribution. Dosing weight correction factors to give equivalent predicted peak aminoglycoside concentrations with a 2-mg/kg loading dose are 1.13 times the TBW for underweight patients and 0.43 times the EBW plus IBW for overweight patients. There were no large differences between the dosing weight correction factors derived from IBW-and body mass index-based classification systems. These data generate useful aminoglycoside dosing weight equations for both underweight and overweight patients.Ascertainment of accurate pharmacokinetic parameters for aminoglycoside dosing remains critical, as the serum drug concentration relates directly to both therapeutic response and toxic effect. Both maximum 1-h postinfusion peak and overall mean peak serum drug concentrations have been identified as significant predictors of therapeutic success for treatment of gram-negative bacteremia and pneumonia (16,17). Moore et al. demonstrated a linear dose-response effect correlating the ratio of peak serum aminoglycoside concentration/MIC to clinical response in treatment of a broad array of documented gram-negative infections (15). Deziel-Evans et al. also noted that this ratio served as an accurate determinant of response in patients treated with aminoglycosides (10). Conversely, inadequate serum drug concentrations may result in treatment failure (16,17). In addition, the narrow therapeutic effect/toxicity ratio for aminoglycosides mandates accuracy in predicting dosing parameters when attempting to reduce the risk of nephrotoxicity (4).The physiologically linked variable volume of distribution at steady state (V ss ) is an important determinant of serum drug concentration. However, V ss remains a poorly predicted pharmacokinetic parameter affecting aminoglycoside dosing in morbidly obese patients (TBW/IBW ratio Ͼ2, where TBW is total body weight and IBW is ideal body weight). This is due, in part, to the variable penetration of these highly polar polycationic compounds into adipose tissue. Additional factors influencing estimations of V ss in the population include increased projections of lean body mass and blood volume, as well as organ hypertrophy (2, 12).Past investigators have utilized dosing weight correction factors (DWCFs) to normali...

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“…This phenomenon is magnified for lipophilic medications, which tend to more readily distribute than hydrophilic drugs. Previous work has identified larger V d in obese patients for most classes of antimicrobial agents, including penicillins, cephalosporins, carbapenems, aminoglycosides, vancomycin, and others [16][17][18][19][20][21][22][23][24][25]. The extent to which a medication is protein-bound also affects V d , and obesity has been shown to alter lipoproteins and alpha1-acid glycoprotein [2].…”

Section: Discussionmentioning

confidence: 99%

Obesity Is Not Associated with Antimicrobial Treatment Failure for Intra-Abdominal Infection

Dietch

Duane

Cook

et al. 2016

Surgical Infections

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Background: Obesity and commonly associated comorbidities are known risk factors for the development of infections. However, the intensity and duration of antimicrobial treatment are rarely conditioned on body mass index (BMI). In particular, the influence of obesity on failure of antimicrobial treatment for intra-abdominal infection (IAI) remains unknown. We hypothesized that obesity is associated with recurrent infectious complications in patients treated for IAI. Methods: Five hundred eighteen patients randomized to treatment in the Surgical Infection Society Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial were evaluated. Patients were stratified by obese (BMI ‡30) versus non-obese (BMI ‡30) status. Descriptive comparisons were performed using Chi-square test, Fisher exact test, or Wilcoxon rank-sum tests as appropriate. Multivariable logistic regression using a priori selected variables was performed to assess the independent association between obesity and treatment failure in patients with IAI. Results: Overall, 198 (38.3%) of patients were obese (BMI ‡30) versus 319 (61.7%) who were non-obese. Mean antibiotic d and total hospital d were similar between both groups. Unadjusted outcomes of surgical site infection (9.1% vs. 6.9%, p = 0.36), recurrent intra-abdominal infection (16.2% vs. 13.8, p = 0.46), death (1.0% vs. 0.9%, p = 1.0), and a composite of all complications (25.3% vs. 19.8%, p = 0.14) were also similar between both groups. After controlling for appropriate demographics, comorbidities, severity of illness, treatment group, and duration of antimicrobial therapy, obesity was not independently associated with treatment failure (c-statistic: 0.64). Conclusions: Obesity is not associated with antimicrobial treatment failure among patients with IAI. These results suggest that obesity may not independently influence the need for longer duration of antimicrobial therapy in treatment of IAI versus non-obese patients.

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Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients

Cited by 157 publications

References 18 publications

What is the best size descriptor to use for pharmacokinetic studies in the obese?

What is the best size descriptor to use for pharmacokinetic studies in the obese?

Aminoglycoside dosing weight correction factors for patients of various body sizes

Obesity Is Not Associated with Antimicrobial Treatment Failure for Intra-Abdominal Infection

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