***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: BACKGROUND 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 , r and omised controlled trial to assess the safety and efficacy of once versus three-times daily tobramycin in these patients . METHODS 244 patients from 21 cystic-fibrosis centres in the UK were r and omly 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 . FINDINGS 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 No patients developed hearing loss during the study , although two reported acute dizziness and were withdrawn from the study . INTERPRETATION 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 Purpose : 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 . Methods : This was a r and omized 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 . Results : 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-β-glucosaminidase concentrations . St and ard 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 . Conclusion : 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 clinical ly stable patients with CF 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 prospect ively r and omised 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 design ed 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 aim ed at generating a peak concentration of 10 mg/l with trough concentrations below 2 mg/l , 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 ) mg/l ) than in group A ( 7.9 ( 1.9 ) mg/l ) , whilst the average trough level was higher in group A ( 0.8 ( 0.3 ) mg/l ) than in group B ( 0.5 ( 0.2 ) mg/l ) . There was a difference in the number of ototoxic events between patients in group A ( seven of 18 , 38.9 % ) 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 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 r and omized to receive either 10 mg·kg−1 tobramycin once-daily or 3.3 mg·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 clinical ly 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 OBJECTIVES Once-daily administration of aminoglycosides in cystic fibrosis ( CF ) patients is considered equally efficacious and potentially less nephrotoxic than dosing three times a day . However , the choice of the most suitable PK/PD index ( C(max)/MIC versus AUC(24)/MIC ) to ensure optimum clinical outcome in this patient population is not clear . PATIENTS AND METHODS In a single-centre , open , r and omized , controlled , non-blinded study 33 adult CF patients ( 20 females , 19 - 37 years ) were treated with intravenous tobramycin ( 10 mg/kg/day ) for 14 days given either as single dose once a day ( Q24 ; 17 patients ) or divided into three equal doses every 8 h ( Q8 ; 16 patients ) . Tobramycin serum concentrations and MICs for Pseudomonas aeruginosa were determined on days 1 and 14 . The clinical outcome parameter , correlated to PK/PD indices , was the percentage predicted forced expiratory volume in 1 s ( FEV(1)% pred . ) . RESULTS FEV(1)% pred . improved significantly for both treatments . There was a log-linear relationship between C(max)/MIC and FEV(1)% pred . and AUC/MIC and FEV(1)% pred . for both treatments . For equal values of AUC24/MIC , however , Q24 treatment provided better improvement in lung function than Q8 dosing , whereas C(max)/MIC did not show any dosing interval dependence . A statistically significant increase was observed for MIC ( day 1 ) versus MIC ( day 14 ) for Q24 treatment , however , no such difference was observed for Q8 treatment . CONCLUSIONS The most important PK/PD parameter for clinical outcome in CF patients was C(max)/MIC . Outcome prediction of AUC(24)/MIC was dependent on the regimen . The increase of P. aeruginosa resistance after once-daily administration is linked to a long dosing interval . More and larger studies are needed to optimize the dosing regimen for maximum clinical outcome with minimum resistance development Aminoglycosides are often prescribed as part of the treatment regimen for acute pulmonary exacerbations due to their potent activity and low potential for development of resistance . Preliminary evidence from r and omized controlled trials in patients with cystic fibrosis ( CF ) suggests that once-daily administration of aminoglycosides results in similar efficacy and a low risk for toxicity compared with traditional dosing . The pharmacokinetics of aminoglycosides administered once daily in CF patients are currently not well described . In this study we compare the distribution and elimination patterns of traditional dosing ( 3.3 mg/kg q8h ) versus once-daily dosing ( 10 mg/kg q24h ) of tobramycin in six adult patients with CF . The pharmacokinetics of tobramycin administered either once daily or every 8 h were best described by a two-compartment model . No statistically significant differences in any of the pharmacokinetic parameter values between regimens were noted . The distribution phase half-lives of 32 and 24 min following the q8h and q24h regimens were longer than expected . The use of a one-compartment model requires clinical peak levels to be drawn 2 h after initiation of either a 30 min infusion for multiple daily dosing or a 60 min infusion with once-daily dosing , to ensure completion of the distribution phase . Our data indicate that a dose of 10 mg/kg/day provides post-distributional phase peak concentrations that achieve the desired goal for susceptible organisms ( > 20 mg/L ) and AUC(24 ) values at the upper end of the desired range ( 70 - 100 mg.h/L ) ABSTRACT We undertook assessment of hearing in patients with cystic fibrosis who were taking part in a large r and omized controlled trial of once- versus three-times-daily tobramycin for pulmonary exacerbations of cystic fibrosis ( the TOPIC study ) . All patients were eligible to have st and ard pure tone audiometry performed across the frequency range of 0.25 to 8 kHz .  High-frequency pure tone audiometry  over 10 to 16 kHz was also performed with a subset of patients . Audiometry was undertaken at the start of tobramycin treatment , at the end of a 14-day course of treatment , and at follow-up 6 to 8 weeks later . We enrolled 244 patients , of whom 219 ( 125 children and 94 adults ) completed treatment . Nineteen patients were excluded from analysis due to abnormal baseline audiometry . Complete pre- and posttreatment st and ard audiological data were obtained for 168/219 patients . We found no significant differences in hearing thresholds when they were assessed at the baseline , at the end of treatment , and at follow-up 6 to 8 weeks later were compared . In addition , no significant differences in hearing thresholds were detected between treatment regimens . Similar results were obtained for the subset of 63/168 patients who underwent high-frequency audiometry . We conclude that for a single 14-day course of tobramycin treatment in patients with cystic fibrosis with no preexisiting auditory deficit , no measurable effect on hearing was apparent with either once- or three-times-daily treatment . Estimation of the cumulative cochleotoxic risk in cystic fibrosis patients due to repeated aminoglycoside therapy , as evidence d by the patients excluded from this study due to hearing loss , also requires further characterization Our objective was to compare the efficacy , safety , and microbiology of once-daily intravenous ( IV ) tobramycin with conventional 8-hourly tobramycin/ceftazidime IV therapy for acute Pseudomonas aeruginosa ( PA ) pulmonary exacerbations in cystic fibrosis ( CF ) . CF patients with PA-indu 
    Output:
    
Once and three times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis .
There is evidence of less nephrotoxicity in children