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New clinical evidence from the European tobramycin trial in cystic fibrosis
Journal of Cystic Fibrosis 1 (2002) S199–S202
New clinical evidence from the European tobramycin trial in cystic fibrosis M.E. Hodson*, C.G. Gallagher1 Department of Cystic Fibrosis, The Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK
Abstract The major cause of morbidity and mortality in patients with cystic fibrosis (CF) is respiratory disease (Penketh et al., Thorax 1987; 42: 526–532, w1x). Recent studies in the USA have shown that intermittent administration of inhaled tobramycin is beneficial to patients with CF who are chronically infected with Pseudomonas aeruginosa (Ramsey et al., N Engl J Med 1999; 340: 23–30, ,w3x; Ramsey et al., Proceedings of the 12th Annual North American Cystic Fibrosis Conference, 1998, Montreal, Canada; Ramsey et al., Abstract from 23rd European Cystic Fibrosis Conference, 1999, the Hague, Netherlands, , w4x). In Europe, the use of nebulised colistin in patients chronically infected with P. aeruginosa is widespread. A recently published study compared the efficacy and safety of tobramycin nebuliser solution (TNS) and nebulised colistin in CF patients , w6x. One hundred and fifteen patients were randomised to receive either TNS or colistin in a multi-centre open-labelled study that assessed change from baseline in FEV1 and sputum P. aeruginosa density. TNS produced a mean 6.7% improvement in lung function (Ps0.006), whilst there was no significant improvement in the colistin-treated patients. The TNS-treated patients had a significantly greater improvement in lung function than those treated with colistin (Ps0.008). The safety profile of both treatments was good. We conclude that patients treated with TNS for 1 month experience improved lung function compared with patients treated with colistin. 䊚 2002 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. Keywords: TOBI; Tobramycin; Airways reactivity; Cystic fibrosis; Pseudomonas aeruginosa
1. Introduction Endobronchial infection with P. aeruginosa is frequently found in patients with CF. It is associated with a progressive decline in lung function, patients losing an average of 2% of their lung function per year. The aim is to stabilise lung function in these chronically infected patients, and if possible, to improve it w5x. Tobramycin nebuliser solution (TNS), or TOBI䉸, is a preservative-free formulation for nebulisation recently licensed in the USA and Europe. Placebo-controlled studies have demonstrated significant improvement in lung function within 14 days of commencing treatment w2x. A recently published study compared TNS over a 28-day period with nebulised colistin w6x, which is widely prescribed in Europe. This paper provides a *Corresponding author. Tel.: q44-171-351-8041; fax: q44-171351-8052. E-mail address: [email protected] (M.E. Hodson). 1 On behalf of the investigators.
summary of the methods and main conclusions of that study. 2. Methods Patients were enrolled from 16 CF centres in the UK and Ireland. The criteria for inclusion included: age 16 years or over, CF diagnosed by sweat sodium, or genetic studies. Patients were excluded if an anti-pseudomonal antibiotic was given by any route within 14 days prior to drug administration, if they were known to be hypersensitive to aminoglycosides or colistin, if they had significant haemoptysis, if they were pregnant, if they had evidence of impaired renal function, or if they were colonised by Burkholderia cepacia. The study had the approval of the North Thames Multicentre Research Ethics Committee and local ethics committees, and the patients’ written consent was obtained. The study design is shown in Fig. 1. There was a 2-week run-in period and then patients were
1569-1993/02/$ - see front matter 䊚 2002 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. PII: S 1 5 6 9 - 1 9 9 3 Ž 0 2 . 0 0 0 0 4 - 8
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M.E. Hodson, C.G. Gallagher / Journal of Cystic Fibrosis 1 (2002) S199–S202
Fig. 1. Study design.
randomised to two parallel treatment groups. Randomisation was stratified by age and centre. Patients received either TNS 300 mg 5 mly1 or colistin sulfomethate sodium (Colomycin) 80 mg dissolved in 3 ml preservative-free normal saline. Study medication was delivered by inhalation twice daily for 4 weeks. TNS was administered using the PARI LC PLUS nebuliser (Pari Medical Limited) and CR50 compressor (Medic-Aid). Colistin was administered using the Ventstream nebuliser (Medic-Aid) and the CR50 compressor. Clinical evaluations were performed and sputum samples obtained for microscopy at screening (week y2), baseline (week 0) and week 4. Lung function was also measured. The primary endpoint was mean change in lung function, as measured by the mean relative percent change in FEV1% predicted, calculated from the following formula: FEV1% predictedweek 4yFEV1% predictedweek FEV1% predictedweek 0
0
Patients were asked to report any adverse event occurring during the study period. Airway reactivity was assessed by measuring FEV1 before and 30 min after the first and last dose of study medication. Routine haematological and biochemical screening was performed. The target size was 60 patients per group to yield an 80% coverage, with a probability of 95% confidence limits, with a length of 6.5% on either side of the observed mean relative change in FEV1% predicted for the tobramycin group from the US study. An intent-totreat analysis was conducted. Change in bacterial sputum density was performed on patients with sputum samples obtained at week 0 and week 4. Demographics and baseline characteristics were compared using either Student’s t-test or the chi-square (x2) test. The changes in FEV1 were compared using Wilcoxon signed rank tests. Changes in sputum bacterial density were analysed using Student’s t-test, and airway reactivity by a paired t-test. 3. Results One hundred and fifteen patients were enrolled at week 0; 53 were randomised to TNS and 62 to colistin.
There were no notable differences in baseline characteristics in terms of gender, age, DNase use or nebulised antibiotics use within 6 months of commencing the study. There was also no significant difference in the percentage predicted FEV1, percentage predicted FVC or sputum bacterial density. The mean initial FEV1 was 55.4% predicted in the TNS group and 59.4% predicted in the colistin group. The study was completed by 50 patients in the TNS group and 58 in the colistin-treated group. In the TNS group, 92% of patients had previously received aerosol antibiotics, all but three of whom received colistin. In the colistin group, 83% of patients had previously received aerosol antibiotics, all but four of whom received colistin. In patients receiving colistin, 37 had received 1 megaunit twice daily, and nine had received 2 megaunits twice daily. Three patients withdrew from the study in the TNS arm: one with a respiratory exacerbation possibly related to the drug, one with a respiratory exacerbation thought to be unrelated to the drug, and one with a drop in FEV1 related to the study drug. In the colistin arm, four patients withdrew: two with respiratory exacerbation thought to be unrelated to the drug, one died with pancreatic carcinoma and one was lost to follow-up. The change in lung function following 4 weeks of nebulised antibiotic therapy is shown in Table 1. There was a 6.7% improvement in the percentage predicted FEV1 in the TNS-treated group (Ps0.006). There was a non-significant improvement in the colistin group of 0.37%. The improvement in the TNS-treated group was significantly greater than in the colistin group (Ps0.008). The greatest improvement was seen in the Table 1 Change in lung function following 4 weeks of nebulised antibiotic therapy Assessment
FEV1% predicted, % change from baseline TNS
Colistin
ITT population: No. patients at week 4 Mean (S.D.) P-value (within)a
50 6.70 (15.11) 0.006
59 0.37 (18.78) 0.473
6–12 age group: No. patients at week 4 Mean (S.D.) P-value (within)a
10 6.56 (18.92) 0.375
11 y8.11 (18.38) 0.206
13–17 age group: No. patients at week 4 Mean (S.D.) P-value (within)a 18q age group: No. patients at week 4 Mean (S.D.) P-value (within)a a
11 14.4 -0.001 28 1.77 (10.80) 0.723
14 6.0 0.426 34 0.79 (14.75) 0.808
Within group—Wilcoxon signed rank test.
P-value 0.008
M.E. Hodson, C.G. Gallagher / Journal of Cystic Fibrosis 1 (2002) S199–S202
younger patients. At week 4, more TNS-treated patients (21 out of 53, 40%) than colistin-treated patients (10 out of 62, 16%) were clinically assessed to have improved. Similarly, more patients in the TNS group (25%) than in the colistin group (13%) rated themselves as having improved. There was no significant difference in adverse events between the two groups, with 65% of TNS-treated patients and 50% of colistin-treated patients reporting at least one adverse event. The highest incidence was related to events of the respiratory system and the body as a whole. Pharyngitis was more common in the TNStreated group. Airway reactivity was defined as a loss of 10% of FEV1 30 min after nebulisation of the drug, and was recorded in 11% of TNS-treated patients and 18% of colistin-treated patients.
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placebo plus standard therapy. TNS was administered in cycles of 28 days on the drug followed by 28 days off the drug. At week 20, the TNS patients had an average 10% increase in FEV1 compared with a 2% decline observed in those receiving placebo (P-0.001). TNS also reduced the use of other anti-pseudomonal drugs, with patients 36% less likely to require intravenous pseudomonal antibiotics. There was also a reduction in hospitalisation. Three hundred and ninety-six patients were then followed for a total of 96 weeks, and these patients were also shown to continue to benefit from treatment. There is, therefore, evidence of long-term benefit from treatment with TNS. The present study indicates a significant improvement in lung function for patients treated for 1 month with nebulised tobramycin compared with colistin, but both treatments were well tolerated.
4. Discussion Acknowledgments Patients treated with TNS showed a significant improvement in lung function and a significant decrease in P. aeruginosa sputum density over a 1-month observation period. Patients treated with nebulised colistin showed a significant decrease in sputum P. aeruginosa density, but no significant improvement in lung function. The study was of short duration, but previous inhaled antibiotic studies have shown improvement in lung function in less than 1 month. It was not possible to design a double-blind study, as colistin required reconstitution with saline and has a tendency to foam. The PARI LC PLUS was chosen for the administration of TNS, as this is the approved nebuliser, and the colistintreated patients used the VENTSTREAM, which a pretrial survey identified as the most commonly chosen nebuliser in clinical practise. The use of inhaled antibiotics has been more widespread in Europe, where many patients have received colistin, than in North America. Most patients would have received nebulised colistin prior to this study. As there is a widespread use of intravenous tobramycin in Europe, most patients would also have received intravenous tobramycin, but very few patients would have received intravenous colistin. The lack of improvement in FEV1 observed with colistin is consistent with previous data. In a placebocontrolled study of 40 Danish patients given nebulised colistin, 1 megaunit twice daily or placebo for 30 days, both groups showed a decline in lung function; however, there was significantly less decline in the colistin-treated arm compared with placebo w7x. Two multi-centre, randomised, double-blind, placebo-controlled trials of TNS were conducted in the USA with a total of 520 patients. These studies compared TNS plus standard therapy with
Acknowledgements to co-authors: Dr David Adeboyeku, Royal Brompton Hospital, London; Dr Eileen Redmond, Dr Mary Mitchell, Royal Belfast Hospital for Sick Children, Belfast; Dr Peter Greally, National Children’s Hospital, Dublin; Dr Stuart Elborn, Belfast City Hospital, Belfast; Dr Anne Thomson, John Radcliffe Hospital, Oxford; Dr Peter Weller, Birmingham Children’s Hospital, Birmingham; Dr Chris J. Taylor, Dr O. Pirzada, The Sheffield Children’s Hospital, Sheffield; Dr Steve Conway, Dr Christine Etherington, Seacroft Hospital and St James’ University Hospital, Leeds; Dr Maurice Soper, Dr Dennis Corbett, Royal Manchester Children’s Hospital, Manchester; Dr Robert Dinwiddie, Dr Steve Cunningham, Great Ormond Street Hospital for Children, London; Dr Diana Bilton, Papworth Hospital, Cambridge; Dr Kevin Webb, Wythenshawe Hospital, Manchester; Dr David Stableforth, Birmingham Heartlands Hospital, Birmingham; and Dr Mary Carroll, Southampton General Hospital, Southampton. References w1x Penketh ARL, Wise A, Mearns MB, Hodson ME, Batten JC. Cystic fibrosis in adolescents and adults. Thorax 1987;42:526 – 32. w2x Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999;340:23 –30. w3x Ramsey BW, et al. Long-term efficacy and safety of inhaled tobramycin (TOBI) in patients with cystic fibrosis. Proceedings of the 12th Annual North American Cystic Fibrosis Conference 1998, Montreal, Canada. 1998. w4x Ramsey BW, et al. Survival and lung function during two
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M.E. Hodson, C.G. Gallagher / Journal of Cystic Fibrosis 1 (2002) S199–S202
years of treatment with intermittent tobramycin solution forinhalation in CF patients. Abstract from 23rd European Cystic Fibrosis Conference 1999, The Hague, Netherlands. 1999. w5x Frederiksen B, Koch C, Hoiby N. Antibiotic treatment of initial colonisation with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol 1997;23:330 –5.
w6x Hodson ME, Gallagher CG, Govan JRW. A randomised trial of nebulized tobramycin or colistin in cystic fibrosis. European Respiratory Journal 2002;20:658 –64. w7x Jensen T, Pedersen SS, Garne S, Heilmann C, Hoiby N, Koch C. Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung function. J Antimicrob Chemother 1987;19:831 –8.
New clinical evidence from the European tobramycin trial in cystic fibrosis M.E. Hodson*, C.G. Gallagher1 Department of Cystic Fibrosis, The Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK
Abstract The major cause of morbidity and mortality in patients with cystic fibrosis (CF) is respiratory disease (Penketh et al., Thorax 1987; 42: 526–532, w1x). Recent studies in the USA have shown that intermittent administration of inhaled tobramycin is beneficial to patients with CF who are chronically infected with Pseudomonas aeruginosa (Ramsey et al., N Engl J Med 1999; 340: 23–30, ,w3x; Ramsey et al., Proceedings of the 12th Annual North American Cystic Fibrosis Conference, 1998, Montreal, Canada; Ramsey et al., Abstract from 23rd European Cystic Fibrosis Conference, 1999, the Hague, Netherlands, , w4x). In Europe, the use of nebulised colistin in patients chronically infected with P. aeruginosa is widespread. A recently published study compared the efficacy and safety of tobramycin nebuliser solution (TNS) and nebulised colistin in CF patients , w6x. One hundred and fifteen patients were randomised to receive either TNS or colistin in a multi-centre open-labelled study that assessed change from baseline in FEV1 and sputum P. aeruginosa density. TNS produced a mean 6.7% improvement in lung function (Ps0.006), whilst there was no significant improvement in the colistin-treated patients. The TNS-treated patients had a significantly greater improvement in lung function than those treated with colistin (Ps0.008). The safety profile of both treatments was good. We conclude that patients treated with TNS for 1 month experience improved lung function compared with patients treated with colistin. 䊚 2002 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. Keywords: TOBI; Tobramycin; Airways reactivity; Cystic fibrosis; Pseudomonas aeruginosa
1. Introduction Endobronchial infection with P. aeruginosa is frequently found in patients with CF. It is associated with a progressive decline in lung function, patients losing an average of 2% of their lung function per year. The aim is to stabilise lung function in these chronically infected patients, and if possible, to improve it w5x. Tobramycin nebuliser solution (TNS), or TOBI䉸, is a preservative-free formulation for nebulisation recently licensed in the USA and Europe. Placebo-controlled studies have demonstrated significant improvement in lung function within 14 days of commencing treatment w2x. A recently published study compared TNS over a 28-day period with nebulised colistin w6x, which is widely prescribed in Europe. This paper provides a *Corresponding author. Tel.: q44-171-351-8041; fax: q44-171351-8052. E-mail address: [email protected] (M.E. Hodson). 1 On behalf of the investigators.
summary of the methods and main conclusions of that study. 2. Methods Patients were enrolled from 16 CF centres in the UK and Ireland. The criteria for inclusion included: age 16 years or over, CF diagnosed by sweat sodium, or genetic studies. Patients were excluded if an anti-pseudomonal antibiotic was given by any route within 14 days prior to drug administration, if they were known to be hypersensitive to aminoglycosides or colistin, if they had significant haemoptysis, if they were pregnant, if they had evidence of impaired renal function, or if they were colonised by Burkholderia cepacia. The study had the approval of the North Thames Multicentre Research Ethics Committee and local ethics committees, and the patients’ written consent was obtained. The study design is shown in Fig. 1. There was a 2-week run-in period and then patients were
1569-1993/02/$ - see front matter 䊚 2002 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. PII: S 1 5 6 9 - 1 9 9 3 Ž 0 2 . 0 0 0 0 4 - 8
S200
M.E. Hodson, C.G. Gallagher / Journal of Cystic Fibrosis 1 (2002) S199–S202
Fig. 1. Study design.
randomised to two parallel treatment groups. Randomisation was stratified by age and centre. Patients received either TNS 300 mg 5 mly1 or colistin sulfomethate sodium (Colomycin) 80 mg dissolved in 3 ml preservative-free normal saline. Study medication was delivered by inhalation twice daily for 4 weeks. TNS was administered using the PARI LC PLUS nebuliser (Pari Medical Limited) and CR50 compressor (Medic-Aid). Colistin was administered using the Ventstream nebuliser (Medic-Aid) and the CR50 compressor. Clinical evaluations were performed and sputum samples obtained for microscopy at screening (week y2), baseline (week 0) and week 4. Lung function was also measured. The primary endpoint was mean change in lung function, as measured by the mean relative percent change in FEV1% predicted, calculated from the following formula: FEV1% predictedweek 4yFEV1% predictedweek FEV1% predictedweek 0
0
Patients were asked to report any adverse event occurring during the study period. Airway reactivity was assessed by measuring FEV1 before and 30 min after the first and last dose of study medication. Routine haematological and biochemical screening was performed. The target size was 60 patients per group to yield an 80% coverage, with a probability of 95% confidence limits, with a length of 6.5% on either side of the observed mean relative change in FEV1% predicted for the tobramycin group from the US study. An intent-totreat analysis was conducted. Change in bacterial sputum density was performed on patients with sputum samples obtained at week 0 and week 4. Demographics and baseline characteristics were compared using either Student’s t-test or the chi-square (x2) test. The changes in FEV1 were compared using Wilcoxon signed rank tests. Changes in sputum bacterial density were analysed using Student’s t-test, and airway reactivity by a paired t-test. 3. Results One hundred and fifteen patients were enrolled at week 0; 53 were randomised to TNS and 62 to colistin.
There were no notable differences in baseline characteristics in terms of gender, age, DNase use or nebulised antibiotics use within 6 months of commencing the study. There was also no significant difference in the percentage predicted FEV1, percentage predicted FVC or sputum bacterial density. The mean initial FEV1 was 55.4% predicted in the TNS group and 59.4% predicted in the colistin group. The study was completed by 50 patients in the TNS group and 58 in the colistin-treated group. In the TNS group, 92% of patients had previously received aerosol antibiotics, all but three of whom received colistin. In the colistin group, 83% of patients had previously received aerosol antibiotics, all but four of whom received colistin. In patients receiving colistin, 37 had received 1 megaunit twice daily, and nine had received 2 megaunits twice daily. Three patients withdrew from the study in the TNS arm: one with a respiratory exacerbation possibly related to the drug, one with a respiratory exacerbation thought to be unrelated to the drug, and one with a drop in FEV1 related to the study drug. In the colistin arm, four patients withdrew: two with respiratory exacerbation thought to be unrelated to the drug, one died with pancreatic carcinoma and one was lost to follow-up. The change in lung function following 4 weeks of nebulised antibiotic therapy is shown in Table 1. There was a 6.7% improvement in the percentage predicted FEV1 in the TNS-treated group (Ps0.006). There was a non-significant improvement in the colistin group of 0.37%. The improvement in the TNS-treated group was significantly greater than in the colistin group (Ps0.008). The greatest improvement was seen in the Table 1 Change in lung function following 4 weeks of nebulised antibiotic therapy Assessment
FEV1% predicted, % change from baseline TNS
Colistin
ITT population: No. patients at week 4 Mean (S.D.) P-value (within)a
50 6.70 (15.11) 0.006
59 0.37 (18.78) 0.473
6–12 age group: No. patients at week 4 Mean (S.D.) P-value (within)a
10 6.56 (18.92) 0.375
11 y8.11 (18.38) 0.206
13–17 age group: No. patients at week 4 Mean (S.D.) P-value (within)a 18q age group: No. patients at week 4 Mean (S.D.) P-value (within)a a
11 14.4 -0.001 28 1.77 (10.80) 0.723
14 6.0 0.426 34 0.79 (14.75) 0.808
Within group—Wilcoxon signed rank test.
P-value 0.008
M.E. Hodson, C.G. Gallagher / Journal of Cystic Fibrosis 1 (2002) S199–S202
younger patients. At week 4, more TNS-treated patients (21 out of 53, 40%) than colistin-treated patients (10 out of 62, 16%) were clinically assessed to have improved. Similarly, more patients in the TNS group (25%) than in the colistin group (13%) rated themselves as having improved. There was no significant difference in adverse events between the two groups, with 65% of TNS-treated patients and 50% of colistin-treated patients reporting at least one adverse event. The highest incidence was related to events of the respiratory system and the body as a whole. Pharyngitis was more common in the TNStreated group. Airway reactivity was defined as a loss of 10% of FEV1 30 min after nebulisation of the drug, and was recorded in 11% of TNS-treated patients and 18% of colistin-treated patients.
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placebo plus standard therapy. TNS was administered in cycles of 28 days on the drug followed by 28 days off the drug. At week 20, the TNS patients had an average 10% increase in FEV1 compared with a 2% decline observed in those receiving placebo (P-0.001). TNS also reduced the use of other anti-pseudomonal drugs, with patients 36% less likely to require intravenous pseudomonal antibiotics. There was also a reduction in hospitalisation. Three hundred and ninety-six patients were then followed for a total of 96 weeks, and these patients were also shown to continue to benefit from treatment. There is, therefore, evidence of long-term benefit from treatment with TNS. The present study indicates a significant improvement in lung function for patients treated for 1 month with nebulised tobramycin compared with colistin, but both treatments were well tolerated.
4. Discussion Acknowledgments Patients treated with TNS showed a significant improvement in lung function and a significant decrease in P. aeruginosa sputum density over a 1-month observation period. Patients treated with nebulised colistin showed a significant decrease in sputum P. aeruginosa density, but no significant improvement in lung function. The study was of short duration, but previous inhaled antibiotic studies have shown improvement in lung function in less than 1 month. It was not possible to design a double-blind study, as colistin required reconstitution with saline and has a tendency to foam. The PARI LC PLUS was chosen for the administration of TNS, as this is the approved nebuliser, and the colistintreated patients used the VENTSTREAM, which a pretrial survey identified as the most commonly chosen nebuliser in clinical practise. The use of inhaled antibiotics has been more widespread in Europe, where many patients have received colistin, than in North America. Most patients would have received nebulised colistin prior to this study. As there is a widespread use of intravenous tobramycin in Europe, most patients would also have received intravenous tobramycin, but very few patients would have received intravenous colistin. The lack of improvement in FEV1 observed with colistin is consistent with previous data. In a placebocontrolled study of 40 Danish patients given nebulised colistin, 1 megaunit twice daily or placebo for 30 days, both groups showed a decline in lung function; however, there was significantly less decline in the colistin-treated arm compared with placebo w7x. Two multi-centre, randomised, double-blind, placebo-controlled trials of TNS were conducted in the USA with a total of 520 patients. These studies compared TNS plus standard therapy with
Acknowledgements to co-authors: Dr David Adeboyeku, Royal Brompton Hospital, London; Dr Eileen Redmond, Dr Mary Mitchell, Royal Belfast Hospital for Sick Children, Belfast; Dr Peter Greally, National Children’s Hospital, Dublin; Dr Stuart Elborn, Belfast City Hospital, Belfast; Dr Anne Thomson, John Radcliffe Hospital, Oxford; Dr Peter Weller, Birmingham Children’s Hospital, Birmingham; Dr Chris J. Taylor, Dr O. Pirzada, The Sheffield Children’s Hospital, Sheffield; Dr Steve Conway, Dr Christine Etherington, Seacroft Hospital and St James’ University Hospital, Leeds; Dr Maurice Soper, Dr Dennis Corbett, Royal Manchester Children’s Hospital, Manchester; Dr Robert Dinwiddie, Dr Steve Cunningham, Great Ormond Street Hospital for Children, London; Dr Diana Bilton, Papworth Hospital, Cambridge; Dr Kevin Webb, Wythenshawe Hospital, Manchester; Dr David Stableforth, Birmingham Heartlands Hospital, Birmingham; and Dr Mary Carroll, Southampton General Hospital, Southampton. References w1x Penketh ARL, Wise A, Mearns MB, Hodson ME, Batten JC. Cystic fibrosis in adolescents and adults. Thorax 1987;42:526 – 32. w2x Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999;340:23 –30. w3x Ramsey BW, et al. Long-term efficacy and safety of inhaled tobramycin (TOBI) in patients with cystic fibrosis. Proceedings of the 12th Annual North American Cystic Fibrosis Conference 1998, Montreal, Canada. 1998. w4x Ramsey BW, et al. Survival and lung function during two
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M.E. Hodson, C.G. Gallagher / Journal of Cystic Fibrosis 1 (2002) S199–S202
years of treatment with intermittent tobramycin solution forinhalation in CF patients. Abstract from 23rd European Cystic Fibrosis Conference 1999, The Hague, Netherlands. 1999. w5x Frederiksen B, Koch C, Hoiby N. Antibiotic treatment of initial colonisation with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol 1997;23:330 –5.
w6x Hodson ME, Gallagher CG, Govan JRW. A randomised trial of nebulized tobramycin or colistin in cystic fibrosis. European Respiratory Journal 2002;20:658 –64. w7x Jensen T, Pedersen SS, Garne S, Heilmann C, Hoiby N, Koch C. Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung function. J Antimicrob Chemother 1987;19:831 –8.