The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison (original) (raw)
Related papers
Antimicrobial Agents and Chemotherapy, 2000
Once-daily administration of aminoglycosides is routinely used in many institutions. However, comparative efficacy data for patients with cystic fibrosis (CF) are lacking. The purpose of the present study was to compare the predicted pharmacodynamic activity of tobramycin at 10 mg/kg of body weight/day administered every 24 h (q24h), q12h, and q8h. Pharmacokinetic (PK) data were derived from analysis of data on the drug concentration in sera from 60 adult CF patients. Individual maximum a posteriori probability Bayesian PK parameter values were used to construct serum concentration-versus-time curves and to determine various indices (peak concentration/MIC ratio [peak/MIC], area under the concentration-time curve/MIC ratio [AUC/MIC], and time that the concentration was less than the MIC [T<MIC]) for the three regimens described above. MICs of 1, 2, and 4 g/ml for Pseudomonas aeruginosa were assumed in the simulations. Irrespective of the MIC, significantly lower peak/MIC but shorter T<MIC were noted when regimens of q8h versus q12h (P < 0.001), q8h versus q24h (P < 0.001), and q12h versus q24h (P < 0.001) were compared. This analysis suggests that the potential benefit of achieving a greater peak/MIC with once-daily aminoglycoside administration may be offset by the significantly greater T<MIC in CF patients compared with that achieved with multiple-dailydosing regimens. Clinical trials are necessary to determine if once daily aminoglycoside administration is efficacious in the CF population before its routine use can be recommended.
Journal of Chemotherapy, 2016
The optimal dosing of intravenous tobramycin for treatment of pulmonary exacerbations in paediatric cystic fibrosis (CF) patients has not been completely delineated. We performed a retrospective study evaluating the pharmacokinetics and pharmacodynamics of once daily dosing (ODD) of IV tobramycin compared to twice daily dosing (TDD). Fifty-nine and 44 patients were included in the ODD and TDD groups, respectively. Once daily dosing achieved higher C max as compared to TDD (29.5+11.0 vs 19.0+4.9, Pv0.001), lower 24 hours AUC (92.8+28.7 vs 128.5+34.6, Pv0.001), and greater time less than the MIC (13.4 + 1.7 vs 3.9 + 3.1 hours, Pv0.001). Twice daily dosing failed to achieve goal C max :MIC for MICs w1.0 mg/l. Twice daily dosing may be a viable alternative to ODD in treating organisms with MICs j1.0 mg/l; however, with MICs w1.0 mg/l, ODD is likely necessary to achieve goal C max :MIC ratios.
Once-daily tobramycin in the treatment of adult patients with cystic fibrosis
European Respiratory Journal, 2002
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?kg-1 tobramycin once-daily or 3.3 mg?kg-1 tobramycin thricedaily. 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 thricedaily 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.
Minimisation of aminoglycoside toxicity in patients with cystic fibrosis
Thorax, 1996
Background -There is evidence that administration of higher doses of aminoglycosides given less frequently improves the bactericidal effect and reduces the potential to cause side effects. To investigate this, a prospectively randomised open label therapeutic trial was undertaken in stratified groups of patients with cystic fibrosis to examine the efficacy and toxic potential of an aminoglycoside dosing regimen designed to generate high peak drug concentrations at 12 hourly intervals compared with conventional dosing at eight hourly intervals. Methods -Patients in group A received tobramycin eight hourly using a dose aimed at generating a peak concentration of 10 mgIl with trough concentrations below 2 mglI, and those in group B received the total daily dose required to achieve eight hourly target concentrations administered as two equal 12 hourly doses. Clinical outcomes measured and assessed included vestibular symptoms, hearing and renal function, length of hospital stay, readmission rate, and mortality. Results -Twenty nine patients were recruited during a six month period, 20 to group A and nine to group B. The average peak tobramycin level was higher in group B (12.5 (2.2) mgIl) than in group A (7.9 (1.9) mgIl), whilst the average trough level was higher in group A (0-8 (0.3) mgIl) than in group B (0-5 (0.2) mg/l). There was a difference in the number ofototoxic events between patients in group A (seven of 18, 38c9%) and group B (none of eight), but no difference was found in other outcome measures assessed. Conclusions -These results suggest that 12 hourly high peak aminoglycoside dosing may be less toxic than equivalent eight hourly dosing, without any apparent difference in efficacy.
Journal of Antimicrobial Chemotherapy, 2015
We evaluated the pharmacokinetics, safety and tolerability of two different continuous treatment regimens of tobramycin inhalation solution (TIS) in 29 cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. Patients and methods: In this randomized, multicentre, open-label, two-period crossover study, TIS (300 mg/5 mL) was administered via PARI eFlow w rapid once daily and twice daily each for 8 weeks. Serum pharmacokinetics of these two regimens was analysed. Tobramycin levels were determined before the morning dose and at 30, 60 and 90 min after the end of nebulization in the middle and at the end of each 8 week cycle. At these timepoints, trough and peak serum tobramycin concentrations (C max , mg/L) as well as the area under the curve for 0-90 min of tobramycin (AUC 0-90min) were assessed in order to evaluate the risk of systemic toxicity. Safety parameters and forced expiratory volume in 1 s (FEV 1) were assessed. Results: For once-daily treatment, tobramycin levels were 10% higher after 8 weeks compared with 4 weeks (AUC 0-90min ratio ¼ 1.096, 90% CI ¼ 0.860-1.396, P ¼ 0.5237). For twice-daily treatment, tobramycin levels after 8 weeks showed a 40% decrease compared with 4 weeks (AUC 0-90min ratio ¼ 0.608, 90% CI ¼ 0.461-0.802, P ¼ 0.0055). The AUC 0-90min ratio at 8 weeks (once daily versus twice daily) did not differ significantly (AUC 0-90min ratio¼0.749, 90% CI¼0.514-1.092, P¼0.2009). The mean FEV 1 did not differ markedly compared between treatment periods or with baseline. No audiological or nephrotoxic side effects were noted.
Extended-Interval Aminoglycoside Use in Cystic Fibrosis Exacerbation in Children and Young Adults
Global pediatric health, 2016
This is a prospective quality improvement project for patients with cystic fibrosis who are 5 years of age and older who were admitted for intravenous antibiotic administration as part of treatment of cystic fibrosis exacerbation. The goal of this project was to compare the pharmacokinetics of once-daily versus thrice-daily aminoglycoside use when treating cystic fibrosis exacerbation in different age groups. Of the total of 119 patient encounters, 82.4% were started on once-daily dosing, and the remainder were started on thrice-daily dosing. Patients with pharmacokinetics allowing the continuation of once-daily dosing differed from patients who required a switch to thrice-daily dosing in terms of baseline forced expiratory volume in 1 second, forced expiratory flow from 25% to 75% of vital capacity, age, and body mass index (BMI) but were similar in BMI percentiles. The once-daily dosing group had higher mean 18-hour level, higher mean half-life, higher mean area under the curve, and lower mean elimination constant. This study showed that aminoglycoside clearance is higher in younger children.