A Controlled Investigation of the Pharmacokinetics of Gentamicin and Tobramycin in Obese Subjects

Schwartz, Stanley N.; Pazin, George J.; Lyon, James A.; Ho, Monto; Pasculle, A. William

doi:10.1093/infdis/138.4.499

Cited by 113 publications

(54 citation statements)

References 18 publications

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“…Table 2 illustrates the V sst , relative V ss per kilogram of TBW, total body clearance, and calculated creatinine clearance for the patient groups by both methods of categorization. Our finding of an inverse relation between adiposity and relative V ss per kilogram of TBW for both methods of weight categorization confirms that of other investigators (3,7,21,23). Significant differences between classification groups were found for V sst and V ss .…”

supporting

confidence: 92%

“…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%

“…Table 3 demonstrates DWCFs obtained for the six patient groups when equivalent predicted peak serum aminoglycoside concentrations were determined for a 2-mg/kg loading dose by using V sst of the two average-weight groups as the references for the TBW/IBW ratio and BMI weight categorization methods, respectively. Incorporation of the DWCF into aminoglycoside pharmacokinetics mitigates variability in serum drug concentration obtained after dosing based upon either TBW or (3,21,23). In studying aminoglycoside pharmacokinetics in underweight patients whose TBW equals 85% of IBW, Tointon et al found the mean relative V ss per kilogram of TBW to be significantly larger than that of controls (23).…”

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confidence: 99%

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Aminoglycoside dosing weight correction factors for patients of various body sizes

Traynor

Nafziger

Bertino

1995

Antimicrob Agents Chemother

113

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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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confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Aminoglycoside dosing weight correction factors for patients of various body sizes

Traynor

Nafziger

Bertino

1995

Antimicrob Agents Chemother

113

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“…No statistically significant difference in the volume of distribu tion of gentamicin in l/kg of total body weight (gV d) was observed in paraplegic subjects as compared to tetraplegic subjects. Since a significant distribution of gentamicin to adipose tissue has been demonstrated in normal subjects (Schwartz et al, 1978), a greater gV d might be expected in tetraplegic subjects. Our data, however, contradict this and suggest that additional factors unique to the pathophysiology of SCI are operative.…”

Section: Discussionmentioning

confidence: 98%

Gentamicin disposition kinetics in humans with spinal cord injury

Segal¹,

Gray

Gordon

et al. 1985

Spinal Cord

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SummaryThe disposition kinetics of gentamicin, an aminoglycoside antibiotic, were studied in seven tetraplegic and six paraplegic volunteers. The volume of distribution of gentamicin in 1/ kg of body weight varied in a statistically significant way from values of this parameter measured in normal subjects. The elimination of gentamicin in spinal man proceeded in a log-linear fashion accurately characterized by a one compartment open-model with a half-life of approximately 2 hours.The clinical significance of altered disposition kinetics and an increased intersubject variability in gentamicin disposition in spinal man as compared to normal subjects is unknown. The existence of these observed differences in pharmacokinetic para meters, however, emphasizes the need to define individual pharmacokinetic profiles and individualize dosing regimens in spinal man. The data presented are supportive of the hypothesis that spinal man constitutes a discreet therapeutic population.

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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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A Controlled Investigation of the Pharmacokinetics of Gentamicin and Tobramycin in Obese Subjects

Cited by 113 publications

References 18 publications

Aminoglycoside dosing weight correction factors for patients of various body sizes

Aminoglycoside dosing weight correction factors for patients of various body sizes

Gentamicin disposition kinetics in humans with spinal cord injury

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

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