Disposition of cefmetazole in healthy volunteers and patients with impaired renal function.

The disposition of cefmetazole was studied in 25 subjects with various degrees of renal function after a 1,000-mg, constant-rate, 30-min intravenous infusion of cefmetazole sodium. In six subjects with creatinine clearance (CLCR) of greater than 90 ml/min per 1.73 m2 (group 1), the terminal elimination half-life (t1/2 beta) was 1.31 +/- 0.54 h (mean +/- standard deviation), cefmetazole total body clearance (CLP) was 132.8 +/- 25.1 ml/min per 1.73 m2, and volume of distribution at steady state was 0.165 +/- 0.025 liter/kg. The fraction of dose excreted unchanged in the urine was 84.0% +/- 26.1%. Subjects with CLCRS of 40 to 69 (group 2, n = 6) and 10 to 39 (group 3, n = 6) ml/min per 1.73 m2 demonstrated prolongation of the t1/2 beta (3.62 +/- 1.06 and 5.93 +/- 1.81 h, respectively) and significant reductions in cefmetazole CLP (52.8 +/- 14.3 and 30.2 +/- 10.2 ml/min per 1.73 m2, respectively), compared with group 1. In seven subjects on chronic hemodialysis (group 4) studied during an interdialytic period, the cefmetazole t1/2 beta was increased to 24.10 +/- 8.12 h and the CLP was reduced to 6.8 +/- 2.1 ml/min per 1.73 m2. Cefmetazole CLP correlated positively with CLCR (r = 0.951, P less than 0.001): CLP = (1.181 . CLCR) -- 0.287. The disposition of cefmetazole was also assessed in six group 4 subjects during an intradialytic period. The t1/2 beta during hemodialysis (2.09 +/- 0.69 h) was significantly shorter than that observed during the interdialytic period. The hemodialysis clearance of cefmetazole was 86.1 +/- 20.1 ml/min, and the fraction of cefmetazole removed during hemodialysis was 59.8% +/- 5.9%. It is recommended that patients with renal insufficiency received standard doses of cefmetazole at extended intervals and patients on maintenance hemodialysis received standard doses after hemodialysis.

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

The effect of piperacillin administration on the dispositions of netilmicin and tobramycin was assessed in 12 chronic hemodialysis patients. Six subjects each received netilmicin (2 mg/kg) or tobramycin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Subjects also received a single dose of piperacillin (4 g) on a separate occasion. The serum concentration-versus-time profiles of netilmicin and tobramycin were biexponential. The terminal elimination half-life (t1/2 beta) of tobramycin was markedly reduced (59.62 +/- 25.18 [mean +/- standard deviation] versus 24.71 +/- 5.41 h) and total body clearance (CLP) was significantly increased in the presence of piperacillin (3.45 +/- 1.61 versus 7.16 +/- 1.64 ml/min). In contrast, the t1/2 beta (41.80 +/- 13.24 versus 40.07 +/- 10.37 h) and CLP (5.11 +/- 2.15 versus 5.55 +/- 2.32 ml/min) of netilmicin were not significantly altered when netilmicin was administered in combination with piperacillin. No change in the central or steady-state volume of distribution of netilmicin or tobramycin was observed. The disposition of piperacillin in hemodialysis patients was not altered in the presence of either aminoglycoside antibiotic. Although no adjustment in netilmicin dosing is required, tobramycin should be administered more frequently when given concomitantly with piperacillin to hemodialysis patients to avoid prolonged periods of subtherapeutic concentrations.

Steady-state pharmacokinetics of intravenous and oral ciprofloxacin in elderly patients.

The steady-state pharmacokinetics of ciprofloxacin were evaluated in nine elderly patients with lower respiratory tract infections after an intravenous dosage regimen of 200 mg every 12 h (n = 9) and an oral dosage regimen of 750 mg every 12 h (n = 6). Ciprofloxacin concentrations in serum and urine were measured by high-performance liquid chromatography. The peak concentration in serum, total body clearance (CLs), steady-state volume of distribution (Vss), and terminal elimination half-life after intravenous dosing were 3.5 +/- 0.8 micrograms/ml, 4.38 +/- 1.80 ml/min per kg, 1.6 +/- 0.6 liters/kg, and 5.8 +/- 2.4 h, respectively. The peak concentration in serum, time to peak concentration in serum, absorption lag time, and absolute bioavailability (F) after oral dosing were 7.6 +/- 2.2 micrograms/ml, 1.9 +/- 1.0 h, 0.4 +/- 0.5 h, and 7.7 +/- 24.2%, respectively. The elevated drug concentrations in serum samples from the elderly after oral dosing, compared with data obtained from younger subjects, appear to be a function of reduced CLs, renal clearance, and Vss. The increased F observed in some patients may be due to the effect of concomitant or proximate administration of tube feedings, medications which may alter gastric motility or acidity, or decreased first-pass metabolism. The results demonstrate that factors related to age and declining renal function, rather than infectious disease state, may be primary in determining alterations in pharmacokinetic parameters in the elderly. In elderly patients with normal renal function for their age, no dosage adjustment for intravenous or oral ciprofloxacin is necessary.