Randomized double-blind evaluation of ceftazidime dose ranging in hospitalized patients with cystic fibrosis

Abstract

Eighty-five patients with cystic fibrosis who were experiencing an acute infectious exacerbation of their disease were randomized in double-blind fashion to receive either 50 or 75 mg of ceftazidime per kg (body weight) per dose administered intravenously every 8 h for 14 days. Three patients were dropped from the study within 4 days of enrollment for reasons unrelated to drug administration. The total daily dose of ceftazidime administered was restricted by protocol design and was independent of the body weight of the patient. Thus, for datum analysis, patients were separated into three ceftazidime dosage groups (denoted as range of milligrams per kilogram per dose): group 1, 22 to 44.5; group 2, 46.3 to 56.6; and group 3, 66.7 to 80.6. Ceftazidime monotherapy had no effect on sputum colony counts for any Pseudomonas cepacia isolate. In contrast, a substantial reduction in Pseudomonas aeruginosa sputum colony counts was observed, and from 19 to 31% of isolates were suppressed _i10 CFU/mi after 14 days of therapy. Bacterial resistance in vitro was not observed, although a trend for increasing ceftazidime MICs was observed for group 1 patients (P < 0.05). Overall, clinical response appeared independent of drug dose, and no relationship could be identified between the reduction in P. aeruginosa sputum colony counts and clinical outcome. Adverse effects of ceftazidime were mild and transient, necessitating drug discontinuation in one patient. These data suggest that the clinical response to ceftazidime in patients with cystic fibrosis may be maximal with 50 mg/kg per dose (150 mg/kg per day) up to a total daily dose of 6 g.Ceftazidime, an aminothiazolyl expanded-spectrum cephalosporin, demonstrates potent in vitro activity against Pseudomonas aeruginosa and Pseudomonas cepacia sputum isolates obtained from patients with cystic fibrosis (CF) (1, 7). Pharmacologic evaluations of ceftazidime in these patients have demonstrated altered biodisposition characteristics (8) similar to those observed for other antimicrobial agents in patients with CF (9, 12, 16). Our previous experience assessing the sputum penetration characteristics of ceftazidime in patients with CF revealed sputum drug concentrations which equalled or only marginally exceeded the MIC for pseudomonal isolates (2). Despite these potential pharmacologic limitations, numerous studies have documented the clinical efficacy of ceftazidime monotherapy in the treatment of acute pulmonary exacerbations experienced by patients with CF (2, 3, 6, 11). These data combined suggest that an increased total daily dose of ceftazidime might improve bacteriologic or patient clinical response. To evaluate this hypothesis, we undertook a randomized double-blind evaluation of the efficacy and tolerability of ceftazidime monotherapy administered in varying dosages to patients with CF who were experiencing an acute pulmonary exacerbation of their disease.(Portions of this work were presented at the 25th Interscience Conference on Antimicrobial Agents and Chemotherapy, Minneapoli...

Susceptibility of Pseudomonas aeruginosa to Cefepime versus Ceftazidime in Patients with Cystic Fibrosis

“…This is similar to the results of a recent study, which found nonmucoid strains to be more resistant than mucoid strains to seven antimicrobial agents. 20 Similar observations have been noted for aminoglycosides and ciprofloxacin. 21,22 In contrast, one study found mucoid isolates to have higher MICs than nonmucoid isolates with ceftazidime, piperacillin, and amikacin.…”

Population Pharmacokinetic Comparison and Pharmacodynamic Breakpoints of Ceftazidime in Cystic Fibrosis Patients and Healthy Volunteers

“…Optimal treatment of infections by P. aeruginosa (28) is crucially important, as it is almost impossible to eradicate chronic lung infections by this pathogen in CF patients. Ceftazidime is still the cephalosporin with the best activity against P. aeruginosa (45) and is a valuable treatment option in antipseudomonal therapy in CF patients (6,12,61,69).…”

Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus

“…A theoretical calculation of the dosing of ceftazidime demonstrates that the previously recommended doses of <200 mg . kg -1 [97] may still be too low for treating CF patients [70] when given intermittently. Meropenem was given at a dose of 40 mg .…”

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