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Effects of body weight and composition on gentamicin volume of distribution

University of British Columbia

Gentamicin is an aminoglycoside antibiotic that possesses bactericidal activity against many gram-positive and gram-negative organisms. Clinically, it is used most often to treat life-threatening infections due to Pseudomonas, Proteus, and the Klebsiella-Enterobacter group. A relationship between gentamicin serum concentrations and clinical response has been demonstrated. Toxicities, notably ototoxicity and nephrotoxicity, are also associated with serum concentrations. Gentamicin is given intermittently either intramuscularly or intravenously resulting in peak and trough concentrations. The therapeutic range is defined as peak concentrations between 4-15mg/L (depending in part on the site of infection and the susceptibility of the infecting organism), and trough concentrations less than 2mg/L (to minimize toxicity). Gentamicin distributes into a space similar to the extracellular fluid volume (ECFV). Pathophysiologic changes which alter the extracellular fluid compartment also alter gentamicin volume of distribution (Vd). One intrinsic factor known to alter gentamicin Vd is obesity. Leanness is also thought to alter gentamicin Vd but its effect has not been quantitated. The objectives of this study were to: 1) accurately describe a Vd in "normal" patients, that is, those with no factors known to alter gentamicin volume of distribution; 2) determine if there is a continuous linear relationship between gentamicin volume of distribution (L/kg) and percent body fat; 3) determine if that relationship is associated with changes in ECFV; and 4) develop a formula for predicting Vd in a similar patient population. Twenty patients with no extrinsic factors known to alter gentamicin Vd participated in the study. Five blood samples were drawn around one steady state dose of gentamicin. A one-compartment model was used to calculate Vd. Tritiated water and anthropometric measurements were conducted simultaneously to provide estimates of body composition. Together these values were used to examine the relationship between gentamicin Vd and body composition. We have described a Vd for gentamicin that is larger but no less variable than is currently used to determine initial dosage regimens. This volume may be larger either due to the selection of patients or method of serum gentamicin analysis. This larger volume should be used to calculate empiric dosage regimens for similarly selected patients to decrease the risk of treatment failure. We were not able to describe a linear relationship between percent body fat and gentamicin volume of distribution. We have postulated several reasons as to why this relationship could not be detected; 1) the sample size may not have been large enough, 2) the relationship is not important in patients who are not at extremes of weight, or 3) the variations caused by changes in body composition were not as significant as other factors that may cause fluid alterations in hospitalized patients. There was a strong correlation between gentamicin Vd and total body water noted. Having eliminated all patients in whom the relationship between total body water and ECFV could not be assumed to be normal and constant, we have indirectly demonstrated a strong relationship between ECFV and gentamicin Vd. This relationship still leaves variability in gentamicin's distribution characteristics to be explained. The predictive formula is based on measurements of height, weight, and a larger Vd [L/kg(ideal body weight)] than has previously been used. The predictive formula recommended for clinical use in adults is Vd=0.30L/kg (Dosing Weight). Dosing weight equals ideal body weight (IBW) when actual body weight (ABW) is ≤ IBW, or 0.4(ABW-IBW)+IBW, when ABW is > IBW. The consequences of estimating a larger Vd are that patients empirically would receive larger doses than are currently being administered, thus more patients should obtain therapeutic serum concentrations within the first 24 hours of therapy. This information will be useful in our attempts to optimize gentamicin therapy.

Text

2010-08-25

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http://hdl.handle.net/2429/27801

Pharmaceutical Sciences

University of British Columbia

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