Tobramycin once- vs thrice-daily for elective intravenous antipseudomonal therapy in pediatric cystic fibrosis patients. Once-daily tobramycin in the treatment of adult patients with cystic fibrosis. Efficacy, tolerance, and pharmacokinetics of once daily tobramycin for pseudomonas exacerbations in cystic fibrosis. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis--the TOPIC study: a randomised controlled trial.
We hypothesized that a single intravenous (iv) tobramycine infusion (treatment B) would have equivalent anti-infectious efficacy in chronic Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) as the commonly performed treatment of three doses (treatment A) . Toxicity and practicability may even be improved in the single-dose regimen.
                This was a randomized crossover study comparing outcome after 14 and 35 days. The primary end-point was a decrease in the leukocyte count, and the secondary end-points were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunoglobulin G, C-reactive protein) in serum. 30 patients (20 female, mean age 11.2 years, mean age range 1.7-18.1 years) received elective 14-day courses of treatments A or B, followed by the alternative treatment after a mean interval of 37 (+/- 21) weeks.
                With the exception of PA density, there were no significant differences between both treatment strategies after 14 days of treatment. After 35 days of treatment, there were no significant changes in the leukocyte count and inflammation markers. Both treatment strategies reduced the bacterial load in the airways, as reflected by a decreased PA density in sputum. Nephrotoxicity was equal in both groups, with a transient slight elevation of urinary N-acetyl-beta-glucosaminidase concentrations. Standard audiometry tests revealed no evidence of a hearing impairment in any patient following therapy. Mean body weight increased during the study period by 0.5 kg. Forced expiratory volume increased by approximately 5% of the predicted volume, forced vital capacity increased by 2% of predicted capacity, and forced mid expiratory flow rate increased by 7% (A) or 4% (B) of the predicted normal value, although these changes were not statistically significant.
                We conclude that tobramycin given in a daily single dose (with the advantage of being more practical in a home environment) has an efficacy equal to that of three daily doses in terms of elective antipseudomonal therapy in clinically stable patients with CF. The aim of this study was to test the equivalence of once- and thrice-daily dosing with tobramycin by comparing efficacy and safety in adult patients with cystic fibrosis. Sixty adult patients with an acute respiratory exacerbation were randomized to receive either 10 mg x kg(-1) tobramycin once-daily or 3.3 mg x kg(-1) tobramycin thrice-daily. Primary efficacy and safety endpoints were defined as changes in respiratory function and changes in renal function and hearing. Both groups showed a significant increase in respiratory function without a clinically significant change in renal function. For changes in forced vital capacity % predicted and serum potassium and magnesium levels, equivalence was demonstrated. For the variables forced expiratory volume in one second and forced mid-expiratory flow % pred and serum creatinine levels, there was insufficient power to demonstrate equivalence. One patient in each group showed bilateral impairment in pure tone audiogram after treatment. This study demonstrated significant clinical improvement with both once- and thrice-daily tobramycin dosing. Equivalence between the two regimens was shown for some, but not all primary endpoints. Once-daily dosing should be used with careful monitoring of safety and efficacy until large multicentre studies confirm these encouraging results. To compare once daily with thrice daily tobramycin for treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis.
                22 patients with cystic fibrosis, mean (SD) age 11 (3.4) years (range 5.6-19.3), with pulmonary pseudomonas exacerbations were randomly assigned to receive a 14 day course of tobramycin (15 mg/kg/day) either in three infusions (group A) (n = 10) or a single daily infusion (group B) (n = 12), combined with ceftazidime (200 mg/kg/day as three intravenous injections). Efficacy was assessed by comparison of pulmonary, nutritional, and inflammatory indices on days 1 and 14. Cochlear and renal tolerance were assessed on days 1 and 14. Tobramycin concentration was measured in serum and sputum 1, 2, 3, 4, 8, and 24 hours after the start of the infusion. Analysis was by non-parametric Wilcoxon test.
                Variables improving (p < 0.05) in both groups A and B were, respectively: weight/height (+4% and +3.1%), plasma prealbumin (+66 and +63 mg/l), forced vital capacity (FVC) (+14% and +11%), forced expiratory volume in one second (+15% and +14%), and forced expiratory flow between 25% and 75% of FVC (+13% and +21%). Improvement was not significantly different between groups. Renal and cochlear indices remained within the normal range. Serum peak concentration of tobramycin on day 1 was 13.2 (7.1) mg/l in group A and 42.5 (11.2) mg/l in group B (p < 0.001); serum trough was 1.1 (0.8) mg/l in group A and 0.3 (0.2) mg/l in group B (p < 0.01). Tobramycin concentrations in sputum were two to three times higher in group B than group A.
                Once daily tobramycin combined with three injections of ceftazidime is safe and effective for the treatment of pseudomonas exacerbations in cystic fibrosis patients. Intravenous tobramycin (three-times daily) is widely used for pulmonary exacerbations in patients with cystic fibrosis who have chronic Pseudomonas aeruginosa infection. We undertook a double-blind, randomised controlled trial to assess the safety and efficacy of once versus three-times daily tobramycin in these patients.
                244 patients from 21 cystic-fibrosis centres in the UK were randomly assigned to once or three-times daily tobramycin (with ceftazidime) for 14 days. Treatment was given as 30-min infusions of tobramycin in 0.9% saline. Primary outcome measure was change in forced expiratory volume in 1s (FEV1), over the 14 days of treatment, expressed as a percentage of the predicted normal value for age, sex, and height. We also measured the change in FEV1 expressed as a percentage of baseline. Secondary outcomes included change in serum creatinine. The study was powered for equivalence, and primary analysis was per protocol.
                219 patients (107 once daily, 112 three-times daily) completed the study per protocol. None was lost to follow-up, although 20 discontinued intervention. Of 122 patients assigned to once daily treatment, three did not receive the study regimen. The mean change in FEV1 (% predicted) over 14 days was similar on the two regimens (10.4% [once daily] vs 10.0% [three-times daily]; adjusted mean difference 0.4% [95% CI -3.3 to 4.1]). Mean% change in FEV1 from baseline was also similar in both treatments (21.9% vs 22.1%; -0.1% [-8.0 to 7.9]). There was no significant difference in% change in creatinine from baseline (-1.5% [once daily] vs 1.7% [three-times daily]). However, in children, once daily treatment was significantly less nephrotoxic than was thrice daily (mean% change in creatine -4.5% [once daily] vs 3.7% [thrice daily]; adjusted mean difference -8.0%, 95% CI -15.7 to -0.4). No patients developed hearing loss during the study, although two reported acute dizziness and were withdrawn from the study.
                Intravenous tobramycin has equal efficacy if given once or three-times daily (with ceftazidime) for pulmonary exacerbations of cystic fibrosis. The once daily regimen might be less nephrotoxic in children.