You are here

Aerosolized antibiotic therapy for chronic cystic fibrosis airway infections: continuous or intermittent?

Respiratory Medicine, pages S9 - S17

Summary

The use of inhaled therapies for chronic respiratory infections in cystic fibrosis represents a substantive treatment burden to patients. In this paper, we review the evidence supporting two commonly used inhaled antibiotic regimens for chronic respiratory infections – continuous vs. intermittent (28 days on followed by 28 days off) therapy. We included trials of good methodological quality and excluded those in which the primary intent was eradication. In total, we included 13 trials (5 of intermittent therapy and 8 of continuous therapy) and summarized their main findings, placing particular emphasis on change in FEV1, emergence of resistance and patient adherence. What is evident from our review is that both continuous and intermittent inhaled therapies work. Although an intermittent regimen would be intuitively “better” in terms of cost savings and patient tolerability, there is currently a lack of head-to-head trials that compare the same drugs (and dosages) using the two different regimens to make such a recommendation based on robust clinical evidence.

Keywords: Cystic fibrosis, Aerosolized antibiotics, Continuous therapy, Intermittent therapy, Randomized, controlled trials (RCTs), FEV1.

References

  • 1 DH Andersen. Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathologic study. Am J Dis Child. 1938;56(2):344-399 Crossref
  • 2 PA Lewis, S Morison, JA Dodge, et al. Survival estimates for adults with cystic fibrosis born in the United Kingdom between 1947 and 1967. The UK Cystic Fibrosis Survey Management Committee. Thorax. 1999;54(5):420-422 Crossref
  • 3 Cystic Fibrosis Trust. UK Cystic Fibrosis Registry Annual Data Report 2009 (Cystic Fibrosis Trust, Bromley, Kent, UK, 2011)
  • 4 JA Dodge, PA Lewis, M Stanton, J Wilsher. Cystic fibrosis mortality and survival in the UK: 1947-2003. Eur Respir J. 2007;29(3):522-526 Crossref
  • 5 Cystic Fibrosis Foundation. US Cystic Fibrosis Foundation Annual Registry Report 2009 (Cystic Fibrosis Foundation, Bethesda, MD, 2010)
  • 6 P Lebecque, T Leal, K Zylberberg, G Reychler, X Bossuyt, V Godding. Towards zero prevalence of chronic Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cyst Fibros. 2006;5(4):237-244 Crossref
  • 7 TW Lee, KG Brownlee, M Denton, JM Littlewood, SP Conway. Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a regional pediatric cystic fibrosis center. Pediatr Pulmonol. 2004;37(2):104-110 Crossref
  • 8 CR Hansen, T Pressler, N Hoiby. Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience. J Cyst Fibros. 2008;7(6):523-530 Crossref
  • 9 JM Littlewood, MG Miller, AT Ghoneim, CH Ramsden. Nebulised colomycin for early pseudomonas colonisation in cystic fibrosis. Lancet. 1985;1(8433):865 Crossref
  • 10 T Jensen, SS Pedersen, S Garne, C Heilmann, N Høiby, C Koch. Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. J Antimicrob Chemother. 1987;19(6):831-838
  • 11 T Schulin. In vitro activity of the aerosolized agents colistin and tobramycin and five intravenous agents against Pseudomonas aeruginosa isolated from cystic fibrosis patients in southwestern Germany. J Antimicrob Chemother. 2002;49(2):403-406 Crossref
  • 12 BW Ramsey, MS Pepe, JM Quan, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340(1):23-30 Crossref
  • 13 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
  • 14 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
  • 15 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
  • 16 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
  • 17 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
  • 18 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
  • 19 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
  • 20 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
  • 21 WH Nikolaizik, D Vietzke, F Ratjen. A pilot study to compare tobramycin 80 mg injectable preparation with 300 mg solution for inhalation in cystic fibrosis patients. Can Respir J. 2008;15(5):259-262
  • 22 G Ryan, M Singh, K Dwan. Inhaled antibiotics for long-term therapy in cystic fibrosis. Cochrane Database Syst Rev. 2011;(3):CD001021
  • 23 ME Hodson, AR Penketh, JC Batten. Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis. Lancet. 1981;2(8256):1137-1139 Crossref
  • 24 G Nolan, P Moivor, H Levison, PC Fleming, M Corey, R Gold. Antibiotic prophylaxis in cystic fibrosis: inhaled cephaloridine as an adjunct to oral cloxacillin. J Pediatr. 1982;101(4):626-630 Crossref
  • 25 P Kun, LI Landau, PD Phelan. Nebulized gentamicin in children and adolescents with cystic fibrosis. Aust Paediatr J. 1984;20(1):43-45 Crossref
  • 26 I Nathanson, GJA Cropp, P Li, P Neter. Effectiveness of aerosolized gentamicin in cystic fibrosis. Cystic Fibrosis Club Abstracts. 1985;26:145
  • 27 RJ Stead, ME Hodson, JC Batten. Inhaled ceftazidime compared with gentamicin and carbenicillin in older patients with cystic fibrosis infected with Pseudomonas aeruginosa. Br J Dis Chest. 1987;81(3):272-279 Crossref
  • 28 Day AJ, Williams J, Mckeown C, et al. Evaluation of inhaled colomycin in children with cystic fibrosis. In: Proceedings of the 10th International Cystic Fibrosis Congress; March 5-10, 1988; Sydney, Australia. Excerpta Medica Asia Pacific Congress Series 1988;74:106. Poster R9c03.
  • 29 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
  • 30 SA McColley, B Trapnell, D Kissner, et al. Fosfomycin/tobramycin for inhalation (FTI): microbiological results of a phase 2 placebo-controlled trial in patients with cystic fibrosis and Pseudomonas aeruginosa. Pediatr Pulmonol. 2010;45:338 Abstract 38.
  • 31 DE Geller, PA Flume, D Staab, R Fischer, JS Loutit, DJ Conrad, Mpex204 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
  • 32 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
  • 33 G Lenoir, YG Antypkin, A Miano, et al. Efficacy, safety, and local pharmacokinetics of highly concentrated nebulized tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Paediatr Drugs. 2007;9(Suppl 1):11-20 Crossref
  • 34 MJ Ledson, MJ Gallagher, M Robinson, et al. A randomized double-blinded placebo-controlled crossover trial of nebulized taurolidine in adult cystic fibrosis patients infected with Burkholderia cepacia. J Aeroso Med. 2002;15(1):51-57 Crossref
  • 35 E Kerem, J Reisman, M Corey, GJ Canny, H Levison. Prediction of mortality in patients with cystic fibrosis. N Engl J Med. 1992;326(18):1187-1191 Crossref
  • 36 AL Quittner, A Buu, MA Messer, AC Modi, M Watrous. Development and validation of The Cystic Fibrosis Questionnaire in the United States: a health-related quality-of-life measure for cystic fibrosis. Chest. 2005;128(4):2347-2354 Crossref
  • 37 IM Hoffmann, BK Rubin, SS Iskandar, MS Schechter, SK Nagaraj, MM Bitzan. Acute renal failure in cystic fibrosis: association with inhaled tobramycin therapy. Pediatr Pulmonol. 2002;34(5):375-377 Crossref
  • 38 D Dulon, H Hiel, C Aurousseau, JP Erre, JM Aran. Pharmacokinetics of gentamicin in the sensory hair cells of the organ of Corti: rapid uptake and long term persistence. C R Acad Sci III. 1993;316(7):682-687
  • 39 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
  • 40 BA Briesacher, AL Quittner, L Saiman, P Sacco, H Fouayzi, LM Quittell. Adherence with tobramycin inhaled solution and health care utilization. BMC Pulm Med. 2011;11:5 Crossref
  • 41 J LeLorier, S Perreault, H Birnbaum, P Greenberg, O Sheehy. Savings in direct medical costs from the use of tobramycin solution for inhalation in patients with cystic fibrosis. Clin Ther. 2000;22(1):140-151 Crossref
  • 42 DE Geller, MW Konstan, J Smith, SB Noonberg, C Conrad. Novel tobramycin inhalation powder in cystic fibrosis subjects: pharmacokinetics and safety. Pediatr Pulmonol. 2007;42(4):307-313 Crossref
  • 43 JJ LiPuma. Microbiological and immunological considerations with aerosolized drug delivery. Chest. 2001;120(3 Suppl):118S-123S Crossref
  • 44 AL Smith, SB Fiel, N Mayer-Hamblett, B Ramsey, JL Burns. Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest. 2003;123(5):1495-1502 Crossref
  • 45 SD Aaron, K Vandemheen, W Ferris, et al. Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, doubleblind, controlled clinical trial. Lancet. 2005;366(9484):463-471 Crossref
  • 46 DR VanDevanter, M Ballmann, PA Flume. Applying clinical outcome variables to appropriate aerosolized antibiotics for the treatment of patients with cystic fibrosis. Respir Med. 2011;105(Suppl 2):S18-S23 Crossref

Footnotes

a Division of Child Health, School of Clinical Sciences, Queens Medical Center, Nottingham, UK

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

c Medical University of South Carolina, Charleston, SC, USA

d Division of Human Development (Child Health), School of Clinical Sciences, Queens Medical Centre, Nottingham, UK

* Corresponding author. Alan Smyth, Professor of Child Health, Division of Child Health, School of Clinical Sciences, University of Nottingham, NG7 2UH, UK