You are here

Applying clinical outcome variables to appropriate aerosolized antibiotics for the treatment of patients with cystic fibrosis

Respiratory Medicine, pages S18 - S23

Summary

Commercial availability of more than one inhaled antibiotic for the management of chronic Pseudomonas aeruginosa lung infections in persons with cystic fibrosis creates a welcome question: Can different inhaled therapies be combined to improve patient outcomes? Although clinicians intuit that antibiotic alternation might extend the duration of benefit, prospective clinical trials will be unable to test this hypothesis. Rather, endpoints acceptable for demonstrating the efficacy of a chronic pulmonary therapy (lung function improvement/stabilization, reduction in exacerbation risk, improvement in quality of life) can test only whether the benefit amplitude is increased during fixed treatment periods. Reduction in pulmonary exacerbation risk appears to be best suited for this task, although lack of consensus on an objective definition of exacerbation independent of the decision to treat is a shortcoming. The broader clinical question of whether a patient has become refractory to a chronic therapy over time would be better addressed with a carefully conducted withdrawal study.

Keywords: Cystic fibrosis, Aerosolized antibiotics, Antibiotic alternation, Combination inhaled antibiotic therapy, Monotherapy, Refractoriness, Endpoints, Continuous inhaled antibiotic therapy, Intermittent inhaled antibiotic therapy.

References

  • 1 BW Ramsey, MS Pepe, JM Quan, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med. 1999;340(1):23-30 Crossref
  • 2 TD Murphy, RD Anbar, LA Lester, et al. Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease. Pediatr Pulmonol. 2004;38(4):314-320 Crossref
  • 3 A Chuchalin, E Csiszér, K Gyurkovics, et al. A formulation of aerosolized tobramycin (Bramitob) in the treatment of patients with cystic fibrosis and Pseudomonas aeruginosa infection: a double-blind, placebo-controlled, multicenter study. Paediatr Drugs. 2007;9(Suppl 1):21-31 Crossref
  • 4 KS McCoy, AL Quittner, CM Oermann, RL Gibson, GZ Retsch-Bogart, AB Montgomery. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008;178(9):921-928 Crossref
  • 5 GZ Retsch-Bogart, AL Quittner, RL Gibson, et al. Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. Chest. 2009;135(5):1223-1232 Crossref
  • 6 MW Konstan, DE Geller, P Minic, F Brockhaus, J Zhang, G Angyalosi. Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial. Pediatr Pulmonol. 2011;46(3):230-238 Crossref
  • 7 CE Wainwright, AL Quittner, DE Geller, et al. Aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis, mild lung impairment, and P. aeruginosa. J Cyst Fibros. 2011;10(4):234-242 Crossref
  • 8 DE Geller, PA Flume, D Staab, R Fischer, JS Loutit, DJ Conrad, Mpex 204 Study Group. Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa. Am J Respir Crit Care Med. 2011;183(11):1510-1516 Crossref
  • 9 ME Hodson, CG Gallagher, JR Govan. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J. 2002;20(3):658-664 Crossref
  • 10 CM Oermann, B Assael, C Nakamura, et al. Aztreonam for inhalation solution (AZLI) vs. tobramycin inhalation solution (TIS), a 6-month comparative trial in cystic fibrosis patients with Pseudomonas aeruginosa. Pediatr Pulmonol. 2010;45(Suppl 33):327
  • 11 AL Quittner, AC Modi, C Wainwright, K Otto, J Kirihara, AB Montgomery. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618 Crossref
  • 12 RB Moss. Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest. 2002;121(1):55-63 Crossref
  • 13 MW Konstan, PA Flume, M Kappler, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros. 2011;10(1):54-61 Crossref
  • 14 CM Oermann, GZ Retsch-Bogart, AL Quittner, et al. An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis. Pediatr Pulmonol. 2010;45(11):1121-1134 Crossref
  • 15 CM Oermann, KS McCoy, GZ Retsch-Bogart, RL Gibson, M McKevitt, AB Montgomery. Pseudomonas aeruginosa antibiotic susceptibility during long-term use of aztreonam for inhalation solution (AZLI). J Antimicrob Chemother. 2011 Jul 22; [Epub ahead of print].
  • 16 JL Burns, JM Van Dalfsen, RM Shawar, et al. Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis. J Infect Dis. 1999;179(5):1190-1196 Crossref
  • 17 JJ LiPuma. Microbiological and immunologic considerations with aerosolized drug delivery. Chest. 2001;120(3 Suppl):118S-123S Crossref
  • 18 Data on file, Novartis Pharmaceuticals Corporation.
  • 19 AL Smith, BW Ramsey, DL Hedges, et al. Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis. Pediatr Pulmonol. 1989;7(4):265-271 Crossref
  • 20 BW Ramsey, HL Dorkin, JD Eisenberg, et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993;328(24):1740-1746 Crossref
  • 21 IB MacLusky, R Gold, M Corey, H Levison. Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Pediatr Pulmonol. 1989;7(1):42-48 Crossref
  • 22 N Mayer-Hamblett, JF Lymp, U Kahn, RA Kronmal. Optimal spirometry endpoints for randomized controlled trials in cystic fibrosis: percent predicted or liters?. Pediatr Pulmonol. 2008;43(Suppl 31):359
  • 23 PB Davis. The decline and fall of pulmonary function in cystic fibrosis: new models, new lessons. J Pediatr. 1997;131:789-790 Crossref
  • 24 MD Schluchter, MW Konstan, PB Davis. Jointly modeling the relationship between survival and pulmonary function in cystic fibrosis Patients. Statistics Med. 2002;21:1271-1287 Crossref
  • 25 MW Konstan, PJ Byard, CL Hoppel, PB Davis. Effect of highdose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995;332:848-854 Crossref
  • 26 LC Lands, R Milner, AM Cantin, D Manson, M Corey. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. J Pediatr. 2007;151:249-254 Crossref
  • 27 MW Konstan, MD Schluchter, W Xue, PB Davis. Clinical use of ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis. Am J Respir Crit Care Med. 2007;176:1084-1089 Crossref
  • 28 CL Ren, DJ Pasta, L Rasouliyan, et al. Relationship between inhaled cortiocsteroids theraepy and rate of lung function decline in children with cystic fibrosis. J Pediatr. 2008;153:746-751
  • 29 MW Konstan, JS Wagener, A Yegin, SJ Millar, DJ Pasta, DR VanDevanter. Design and powering of cystic fibrosis clinical trials using rate of FEV1 decline as an efficacy endpoint. J Cyst Fibros. 2010;9:332-338 Crossref
  • 30 TA Lieu, GT Ray, G Farmer, GF Shay. The cost of medical care for patients with cystic fibrosis in a health maintenance organization. Pediatrics. 1999;103:e72 Crossref
  • 31 L Ouyang, SD Grosse, DD Amendah, MS Schechter. Healthcare expenditures for privately insured people with cystic fibrosis. Pediatr Pulmonol. 2009;44:989-996 Crossref
  • 32 T Ferkol, M Rosenfeld, CE Milla. Cystic fibrosis pulmonary exacerbations. J Pediatr. 2006;148:259-264 Crossref
  • 33 M Robinson, PT Bye. Mucociliary clearance in cystic fibrosis. Pediatr Pulmonol. 2002;33(4):293-306 Crossref
  • 34 SH Donaldson, TE Corcoran, BL Laube, WD Bennett. Mucociliary clearance as an outcome measure for cystic fibrosis clinical research. Proc Am Thorac Soc. 2007;4(4):399-405
  • 35 R Kraemer, A Blum, A Schibler, RA Ammann, S Gallati. Ventilation inhomogeneities in relation to standard lung function in patients with cystic fibrosis. Am J Respir Crit Care Med. 2005;171(4):371-378 Crossref
  • 36 PM Gustafsson, P Aurora, A Lindblad. Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis. Eur Respir J. 2003;22(6):972-979 Crossref
  • 37 E Kieninger, F Singer, O Fuchs, et al. Long-term course of lung clearance index between infancy and school-age in cystic fibrosis subjects. J Cyst Fibros. 2011 Aug 9; [Epub ahead of print].
  • 38 AS Brody, HA Tiddens, RG Castile, et al. Computed tomography in the evaluation of cystic fibrosis lung disease. Am J Respir Crit Care Med. 2005;172(10):1246-1252 Crossref
  • 39 SZ Nasr, E Sakmar, E Christodoulou, BP Eckhardt, DS Streetman, PJ Strouse. The use of high resolution computerized tomography (HRCT) of the chest in evaluating the effect of tobramycin solution for inhalation in cystic fibrosis lung disease. Pediatr Pulmonol. 2010;45(5):440-449
  • 40 SD Sagel, JF Chmiel, MW Konstan. Sputum biomarkers of inflammation in cystic fibrosis lung disease. Proc Am Thorac Soc. 2007;4(4):406-417
  • 41 N Mayer-Hamblett, ML Aitken, FJ Accurso, et al. Association between pulmonary function and sputum biomarkers in cystic fibrosis. Am J Respir Crit Care Med. 2007;175(8):822-828 Crossref

Footnotes

a Case Western Reserve University School of Medicine, Cleveland, OH, USA

b Klinikum der Ruhr-Universitat, D-44791 Bochum, Germany

c Departments of Medicine and Pediatrics, Medical University of South Carolina, Charleston, SC, USA

* Corresponding author. Donald R. VanDevanter, PhD, 12520 33rd Street Ct E, Edgewood, WA 98372, USA. Tel.: +1 253 370 5859