This open-label, randomized, three-way crossover study of 28 healthy premenopausal women was conducted to compare the impact of concomitant rifabutin and rifampicin on the safety, pharmacokinetics, and pharmacodynamics of the oral contraceptives ethinylestradiol and norethindrone (Ortho-Novum 1/35; Ortho Pharmaceutical, Raritan, NJ). Each participant received oral contraceptives daily for 21 days for the first control cycle, then was randomized to one of two sequences to receive oral contraceptives with concomitant rifampicin and rifabutin at equal doses of 300 mg/day for 10 days. Ethinylestradiol, norethindrone, follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, rifampicin, and rifabutin (and metabolite) were measured in plasma over the same time frames in all three cycles. Safety was assessed from before the beginning to the end of each cycle. Twenty-two subjects completed all three cycles. Compared with the control cycle, rifabutin and rifampicin significantly altered the disposition of the oral contraceptive. Area under the concentration-time curve from 0 to 24 hours (AUC0-24) and maximum plasma concentration (Cmax) of ethinylestradiol decreased by 64% and 42%, respectively, after coadministration with rifampicin and by 35% and 20%, respectively, after coadministration with rifabutin. The AUC0-24 of norethindrone decreased by 60% and 20% after coadministration with rifampicin and rifabutin, respectively. Unlike progesterone levels, FSH and LH levels increased during coadministration with rifampicin and rifabutin. The incidence of spotting was significantly higher after coadministration with rifampicin (36.4%) and rifabutin (21.7%) than during the control cycle (3.7%). Although both rifampicin and rifabutin affected the pharmacokinetics of ethinylestradiol and norethindrone, the magnitude of this effect was more pronounced with rifampicin. Likewise, the fact that the highest incidence of spotting occurred with rifampicin was consistent with higher metabolic induction by rifampicin. Despite the fact that there was no change in progesterone levels, it is recommended that patients be advised to use additional contraceptive methods while receiving rifabutin or rifampicin with oral contraceptives to prevent inadvertent pregnancy.

We compared the pharmacokinetics and the serum bactericidal activities of cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin. Fifteen healthy volunteers received 1 g of cefpirome, ceftazidime, and ceftriaxone intravenously, 500 mg of imipenem-cilastatin intravenously, and 500 mg of ciprofloxacin orally. High-performance liquid chromatographic assays were used to quantitate unchanged antibiotic in plasma and urine. Serum bactericidal activities were determined against six clinical isolates each of Staphylococcus aureus, Enterobacter cloacae, and Pseudomonas aeruginosa by using a modified microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977). Overall, cefpirome exhibited pharmacokinetics similar to those of ceftazidime: half-life (t,/2), 1.95 h; concentration at 1 h (Clh), 47 to 49 ig/ml for both antibiotics. Ceftriaxone displayed the longest tV2 (7.65 h) and the highest Clh (137.8 iLg/ml), while we observed the shortest t1/2 (1.05 h) and the lowest Clh (19.85 Fg/ml) with imipenem. At

The pharmacokinetics of ciprofloxacin and its metabolite 1 (desethyleneciprofloxacin) were studied in 17 obese men (mean age, 29.2 +/- 7.5 years; mean weight, 110.7 +/- 20.2 kg; mean body mass index, 36.4 +/- 3.9 kg/m2) and 11 control subjects (men of normal weight; mean age, 25.0 +/- 5.1 years; mean weight, 71.8 +/- 9.9 kg; mean body mass index, 23.3 +/- 2.4 kg/m2). Each subject received a single 400 mg intravenous dose of ciprofloxacin infused over 1 hour. Ciprofloxacin total clearance was significantly increased in obese subjects compared with control subjects (897.44 +/- 159.57 versus 744.44 +/- 120.51 ml/min, respectively; p < 0.05). Ciprofloxacin renal clearance in obese subjects (637.58 +/- 128.89 ml/min) was 29% higher than in control subjects (495.47 +/- 137.85 ml/min; p < 0.05). The elimination half-life values of ciprofloxacin and desethyleneciprofloxacin were not statistically different between groups. Ciprofloxacin steady-state volume of distribution (Vss) was significantly larger in obese group (269.17 +/- 51.64 versus 219.03 +/- 35.80 L; p < 0.01) compared with the control group, and when it was normalized by total body weight, obese subjects exhibited lower Vss/kg than control subjects (2.46 +/- 0.42 versus 3.06 +/- 0.31 L/kg; p < 0.001). These findings indicate that ciprofloxacin is distributed less to adipose tissue than to other tissues, but partial distribution to adipose tissue does occur. To normalize the volume of distribution of obese subjects to that of normal weight subjects, 45% of excess weight (total body weight minus ideal body weight) must be added to the ideal body weights of obese subjects.

The pharmacokinetics and suction-induced blister fluid penetration of cefdinir following single oral administrations of 200, 300, 400, and 600 mg were studied in 16 healthy young male volunteers according to a Latin square design. Plasma, blister, and urine samples were assayed by high-pressure liquid chromatography. We observed a nonlinear relationship (P ‫؍‬ 0.02) between the dose and the maximum concentration in plasma as well as between the dose and the area under the concentration-time curve (AUC) in plasma (P < 0.001), which may be indicative of a limited absorption process. This resulted in a lower AUC value than expected as well as a smaller fraction of cefdinir excreted unchanged at a dose of 600 mg. Renal clearance decreased with increasing doses (P < 0.006; analysis of variance with the Latin square design and Games-Howell procedure). Maximal cefdinir concentrations in blister fluid were delayed compared with concentrations in plasma. Blister fluid penetration measured by the ratio of the AUC in blister fluid to the AUC in plasma was extensive (92.4 to 108.4%). Cefdinir concentrations in blister fluid remained equal to or higher than the concentrations in plasma from 6 to 12 h following cefdinir administration. On the basis of the concentrations in blister fluid and the in vitro MIC data, we estimated that cefdinir at 200 to 400 mg administered twice daily would be adequate to treat uncomplicated skin infections caused by Streptococcus pyogenes. Seven volunteers experienced episodes of light-to-moderate diarrhea. These adverse events occurred irrespective of dose.