Comparative pharmacokinetics of oral ceftibuten, cefixime, cefaclor, and cefuroxime axetil in healthy volunteers.

STUDY OBJECTIVE: To compare the pharmacokinetics of ceftibuten, cefixime, ceturoxime axetil, and cefaclor after oral administration. DESIGN: Randomized, four-period, crossover study. SETTING: Hospital-based clinical research center. SUBJECTS: Healthy adult men and women volunteers. INTERVENTIONS: Single 400-mg doses of cefixime and ceftibuten, and 500-mg doses of cefuroxime axetil and cefaclor. MEASUREMENTS AND MAIN RESULTS: Serum concentrations were determined by high-performance liquid chromatography methods. The mean oral clearances of cefixime, cefuroxime axetil, and cefaclor were similar, ranging from 20.4-27.0 L/hour; clearance of ceftibuten was approximately 4-fold less, 5.45 L/hour. The serum half-lives of ceftibuten (2.35 hrs) and cefixime (2.38 hrs) were prolonged compared with those of cefuroxime axetil (1.30 hrs) and cefaclor (0.693 hr). These agents also differed in terms of time to maximum concentration, time to peak plasma level, area under the curve, and apparent volume of distribution, the last reflecting differences in biovailability. CONCLUSION: Ceftibuten had a relatively high time to maximum concentration and long half-life, resulting in a 3.5-fold higher area under the curve than cefixime, cefuroxime axetil, and cefaclor. These pharmacokinetic data can be used as a basis to compare the four oral cephalosporins; however, comparative susceptibility data must also be considered.

Effect of concomitant administration of piperacillin on the dispositions of isepamicin and gentamicin in patients with end-stage renal disease.

Piperacillin inactivation of the aminoglycosides isepamicin and gentamicin in 12 chronic hemodialysis patients was assessed. Six subjects each received isepamicin (7.5 mg/kg of body weight) or gentamicin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Isepamicin and gentamicin concentrations in plasma and urine were monitored over 48 h after each dose and analyzed by high-performance liquid chromatography and fluorescence polarization immunoassay, respectively. The pharmacokinetics of isepamicin were not significantly altered during combination treatment with piperacillin. The total body clearance (3.79 +/- 0.71 versus 3.94 +/- 1.05 ml/min), the steady-state volume of distribution (0.19 +/- 0.04 versus 0.18 +/- 0.03 liter/kg), and the terminal elimination half-life (47.91 +/- 7.20 versus 45.08 +/- 10.34 h) were not significantly altered in the presence of piperacillin. In contrast, the terminal elimination half-life (47.68 +/- 20.58 versus 35.67 +/- 11.18 h) of gentamicin was significantly reduced when gentamicin was given with piperacillin. The total body clearance (4.26 +/- 3.07 versus 4.89 +/- 1.94 ml/min) and the steady-state volume of distribution (0.19 +/- 0.04 versus 0.20 +/- 0.04 liter/kg) of gentamicin were not significantly altered during combination therapy; however, the nonrenal clearance of gentamicin administered in combination with piperacillin (3.56 +/- 0.38 ml/min) increased significantly compared with that of gentamicin (2.03 +/- 0.50 ml/min) given alone. The results of this study suggest that no additional dosage adjustment of isepamicin during concomitant therapy with piperacillin in hemodialysis patients is necessary. However, this does not preclude the need for appropriately ex vivo-handled specimens for monitoring isepamicin concentrations in plasma to ensure therapeutic efficacy and prevent toxicity. Furthermore, additional dosage adjustments may be necessary when gentamicin is used concomitantly with piperacillin, on the basis of the significant in vivo inactivation that takes place in end-stage renal disease patients.

Isepamicin disposition in subjects with various degrees of renal function.

The disposition of isepamicin, an investigational aminoglycoside antibiotic, was evaluated in 30 subjects with various degrees of renal function. The subjects were divided into five groups: those with normal renal function (creatinine clearance [CLCR], greater than 80 ml/min/1.73 m2), those with mild renal insufficiency (CLCR, 50 to 80 ml/min/1.73 m2), those with moderate renal insufficiency (CLCR, 30 to 49 ml/min/1.73 m2), those with severe renal insufficiency (CLCR, 5 to 29 ml/min/1.73 m2), and those maintained on hemodialysis (CLCR, less than 5 ml/min/1.73 m2). Subjects on hemodialysis were studied both during hemodialysis and during an interdialytic period. The volumes of distribution of isepamicin were not significantly different among the five groups of patients. The total body clearance (CLP) and renal clearance (CLR) of isepamicin significantly decreased as CLCR decreased. The CLP of isepamicin and CLCR were significantly related [(COP = 0.391.[CLCR] + 1.83; r2 = 0.878)]. Nonrenal clearance of isepamicin did not differ between groups. Hemodialysis augmented the CLP of isepamicin by approximately 25-fold. The amount of isepamicin recovered in the dialysate was 60.6 +/- 15.8% of the dose administered. The maximal rebound of the isepamicin concentration in plasma after cessation of hemodialysis was observed at 0.78 +/- 0.7 h. Concentrations in plasma increased 32.7 +/- 22.9% over that measured at the end of hemodialysis. These data indicate that dosage adjustments are necessary in subjects with decreased renal function.