The present study characterized the single-dose pharmacokinetics of daptomycin dosed as 4 mg/kg of total body weight (TBW) in seven morbidly obese and seven age-, sex-, race-, and serum creatinine-matched healthy subjects. The glomerular filtration rate (GFR) was measured for both groups following a single bolus injection of [ 125 I]sodium iothalamate. Noncompartmental analysis was used to determine the pharmacokinetic parameters, and these values were normalized against TBW, ideal body weight (IBW), and fat-free weight (FFW) for comparison of the two groups. All subjects enrolled in this study were female, and the mean (؎standard deviation) body mass index was 46.2 ؎ 5.5 kg/m 2 or 21.8 ؎ 1.9 kg/m 2 for the morbidly obese or normal-weight group, respectively. The maximum plasma concentration and area under the concentration-time curve from dosing to 24 h were approximately 60% higher (P < 0.05) in the morbidly obese group than in the normalweight group, and these were a function of the higher total dose received in the morbidly obese group. No differences in daptomycin volume of distribution (V), total clearance, renal clearance, or protein binding were noted between the two groups. Of TBW, FFW, or IBW, TBW provided the best correlation to V. In contrast, TBW overestimated GFR through creatinine clearance calculations using the Cockcroft-Gault equation. Use of IBW in the Cockcroft-Gault equation or use of the four-variable modification of diet in renal disease equation best estimated GFR in morbidly obese subjects. Further studies of daptomycin pharmacokinetics in morbidly obese patients with acute bacterial infections and impaired renal function are necessary to better predict appropriate dosage intervals.

The present study assessed potential subclinical markers of amphotericin B (AmB)-related nephrotoxicity and infusion-related reactions (IRR). Subjects were pretreated with diphenhydramine and acetaminophen and received a 500-ml bolus infusion of 0.9% sodium chloride prior to each effective renal plasma flow (ERPF) assessment. ERPF was measured before and after administration of a single 0.25-mg/kg intravenous AmB dose using technetium-99m mercaptoacetyltriglycine. Blood was collected before and 3 h after AmB infusion for tumor necrosis factor alpha (TNF-␣) and interleukin-1␤ (IL-1␤) plasma concentrations. Overnight 12-h urine collections were performed before administration of AmB and for 2 nights after administration of AmB and analyzed for ␣ and glutathione-S-transferases (GST␣ and GST, respectively) and N-acetyl-␤-D-glucosaminidase (NAG). Six men and six women with mean ؎ standard deviation (SD) ages of 24.8 ؎ 5.3 and 28.0 ؎ 8.5 years, respectively, were studied. Baseline serum creatinine values were within the normal range and were unaltered after administration of AmB. The mean ؎ SD decrease in ERPF after administration of AmB was significant (P < 0.05) in males (15.7 ؎ 8.1%) but not females (9.5 ؎ 14.0%). The GST and GST␣ indices increased significantly (P < 0.05) by two to fourfold and returned to baseline in males but were unaltered in females. NAG indices were unaffected by AmB. Six patients experienced an IRR that was associated with increased TNF-␣ (P < 0.05) but not IL-1␤ (P ‫؍‬ 0.09). These results suggest a potential sex-related difference in AmB-induced nephrotoxicity and provide a rationale for use of ERPF, urine GST, and TNF-␣ as subclinical markers of polyene-induced toxicity.Conventional amphotericin B desoxycholate (AmB) is an intravenously administered antifungal agent associated with a number of adverse drug reactions that include infusion-related reactions (IRR) and nephrotoxicity (12). The IRR consist of fever, chills, hypotension, tachypnea, nausea, and vomiting and occur in 50% to 70% of patients who receive this drug (12). These IRR are associated with the acute release of tumor necrosis factor alpha (TNF-␣) and interleukin-1␤ (IL-1␤) (1). An assessment of the expression of these cytokines has been performed in patients who have received AmB for the management of a documented fungal infection. However, TNF-␣ and IL-1␤ are proinflammatory cytokines that increase in concentration during an acute infection. Consequently, the direct effect of AmB on these cytokines and IRR in the absence of an acute infection in humans has not been characterized.Nephrotoxicity is a serious, dose-limiting adverse event associated with the use of AmB (19). AmB-induced nephrotoxicity manifests itself as both glomerular and tubular dysfunction. The exact mechanisms involved in AmB-induced nephrotoxicity have not been elucidated (19). However, the short-term physiological effects of AmB include a reduction in the effective renal plasma flow (ERPF) and the glomerular filtration rate. Serum creatinine is the most...

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