Pharmacokinetics of meropenem in patients with cystic fibrosis.

The pharmacokinetics of meropenem were studied after single i.v. infusions of 15 mg meropenem/kg body weight in eight subjects with cystic fibrosis (CF) and eight healthy volunteers matched for age, sex, and weight. Significantly shorter terminal half-lives (mean, 0.74 h vs. 0.99 h) and mean residence times (mean, 1.09 h vs. 1.39 h) were noted in CF subjects. Plasma and renal clearances tended to be higher and distribution volumes smaller among the patients, but differences were not statistically significant. The results are consistent with the findings for many other beta-lactam agents used in CF patients. Assuming a MIC90 of 4 mg/l for meropenem against Pseudomonas aeruginosa, the time above the MIC was less than 3.3 h in six of the eight CF patients. This finding should be kept in mind when designing treatment regimens with meropenem in CF subjects.

Increased oral bioavailability of ciprofloxacin in cystic fibrosis patients.

The altered pharmacokinetic properties of, e.g., aminoglycosides in cystic fibrosis patients have to be considered when pulmonary exacerbations are treated. Since reported data on ciprofloxacin, a fluorinated quinolone, are conflicting, we compared intravenous and oral administration in cystic fibrosis patients when treating them for mild symptoms of pulmonary infection. All of the patients were colonized with Pseudomonas species. Ciprofloxacin was administered orally (15 mg/kg of body weight) or intravenously (6 mg/kg) twice a day for at least 10 days during separate treatment periods. Five healthy volunteers received single intravenous and oral doses. Pharmacokinetic evaluations were performed at first dose and at steady state. The results showed that cystic fibrosis patients have increased oral bioavailability of ciprofloxacin (80% in cystic fibrosis patients versus 57% in volunteers) and increased total clearance (688 ml/min in CF patients versus 528 ml/min in volunteers). Our data indicate that the pharmacokinetic properties of ciprofloxacin are altered in cystic fibrosis patients with mild symptoms of pulmonary exacerbations and that the changes most probably are due to cystic fibrosis per se or to the impact of chronic infection.

Pharmacokinetics of meropenem in subjects with various degrees of renal impairment.

Five healthy volunteers and 18 patients with various degrees of renal impairment received 500 mg of meropenem intravenously as a 30-min infusion. Five dialysis patients were dosed 2 h prior to hemodialysis, and four of them were also dosed between hemodialysis treatments. Plasma and urine samples were collected for up to 48 h and 12 h, respectively. Concentrations of meropenem and its open ring metabolite ICI 213,689 were determined by high-performance liquid chromatography and radioimmunoassay, respectively. The subjects were divided into four groups with glomerular filtration rates (GFR) of greater than 80, 30 to 80, 5 to 29, or less than 5 ml/min. There were linear correlations between the GFR and the rates for total plasma clearance as well as renal clearance of meropenem (group mean values for total clearance of 186, 74, 53, and 19 ml/min/1.73 m2, respectively). In subjects with normal renal function, nonrenal clearance accounted for approximately 20% of total elimination, increasing to about 50% in patients with GFR between 5 and 29 ml/min/1.73 m2. The terminal half-life of meropenem increased from 0.9 h in the healthy volunteers to 6.8 h in patients with end-stage renal disease. The half-life of ICI 213,689 was 2.31 h in the healthy volunteers and increased to 23.6 h in patients with GFR of 5 to 29 ml/min. In patients with end-stage renal disease, half-lives could not be measured, as concentrations were hardly declining during the 48-h observation period. The area under the concentration-time curve for meropenem increased more than 10-fold. Both meropenem and its open ring metabolite were readily dialyzable, with dialysis clearances of 79 and 81 ml/min/1.73 m2, respectively.

Efficacy and tolerance of roxithromycin in comparison with erythromycin stearate in patients with lower respiratory tract infections.

The efficacy and tolerance of roxithromycin 150 mg b.i.d. were compared with those of erythromycin stearate 500 mg b.i.d. in patients with lower respiratory tract infections. Out of 86 patients recruited for the study, 79 were evaluable for tolerance and 76 for efficacy. These patients were evenly distributed among the 3 investigational clinics, with 26, 25 and 28 patients, respectively. The diagnosis of lower respiratory tract infections was based on clinical, laboratory, radiological and/or physical findings and, when available, bacteriological and serological findings. The duration of treatment was 10 days, with follow-up at post-treatment visits directly after treatment and 6 weeks thereafter. The clinical outcome was satisfactory with no significant difference between the drugs. More patients reporting adverse events were on erythromycin than on roxithromycin (51.3% vs 17.5%; p = 0.003). The results suggest that roxithromycin is as effective as erythromycin stearate in the treatment of lower respiratory tract infections and causes fewer adverse effects.