Cephalosporin therapeutics in cystic fibrosis.

Cephalosporins modified at the C-3 and C-7 positions of the cephem-nucleus have high antimicrobial activity and are safe. With evolution through first, second, and third generations, they have gained increasing gram-negative activity, but often at the expense of potency against gram-positive organisms. All third-generation cephalosporins have some intrinsic anti-Pseudomonas activity, indicating their potential benefit in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Rational therapy in this clinical setting requires recognition of the pharmacodynamic and pharmacokinetic idiosyncrasies intrinsic to this patient population. When these priorities are recognized, only two of the available agents, cefsulodin and ceftazidime, appear to be of any therapeutic value. Both agents have been evaluated extensively in the treatment of acute pulmonary exacerbation in cystic fibrosis, and both have been found to be safe and effective.

Pharmacokinetic determination of ranitidine pharmacodynamics in pediatric ulcer disease.

The pharmacokinetics and pharmacodynamics of ranitidine were evaluated during three methods of administration in 12 children ranging in age from 3.5 to 16 years with documented gastric or duodenal ulcer disease. First, a continuous intravenous infusion of ranitidine was administered to determine the serum concentration necessary to suppress gastric acid secretion by at least 90%. From these data a therapeutic dose of ranitidine was calculated and administered on separate days via the intravenous bolus and oral routes. Half-life, volume of distribution, and clearance values for ranitidine were the same after intravenous bolus and oral doses (1.8 vs 2.0 hours, 2.3 vs 2.5 L/kg, and 794.7 vs 788.0 ml/min/1.73 m2, respectively). The bioavailability of ranitidine given orally averaged 48%. Serum ranitidine concentrations necessary to inhibit gastric acid secretion by at least 90% ranged between 40 and 60 ng/ml for all children studied. No adverse clinical or biochemical effects were observed in any child during the 6 weeks of orally administered treatment. Endoscopic reevaluation after 6 weeks indicated complete healing of initial ulcers.

Dosing implications of rapid elimination of trimethoprim-sulfamethoxazole in patients with cystic fibrosis.

The first-dose and steady-state pharmacokinetics of trimethoprim and sulfamethoxazole were determined in 14 patients with cystic fibrosis. When pharmacokinetic data from the first dose were compared with those at steady state, both TMP and SMZ showed expected accumulations in serum concentrations and decreases in total body clearance. The area under the SMZ serum concentration-time curve was significantly greater at steady state, suggesting drug accumulation during long-term therapy. When pharmacokinetic characteristics for TMP and SMZ obtained in patients with cystic fibrosis were compared with those reported for normal adults, the patients were found to have shorter elimination half-lives and greater plasma clearances. In addition, the apparent volume of distribution for TMP was smaller for patients with cystic fibrosis than for normal adults, consistent with their reduced mass of adipose tissue. Our data support the need for increased dosing or decreased dosing intervals when administering TMP-SMZ to patients with cystic fibrosis.