The Approach to Pseudomonas aeruginosa in Cystic Fibrosis

ABSTRACT

Pseudomonas aeruginosa continues to be the most common pathogen in cystic fibrosis (CF) lung disease, and chronic infection with mucoid strains is associated with an accelerated decline in lung function. Although multiple factors can potentially explain the susceptibility of CF airways to this organism, their individual relevance is still largely unclear. Prevention of infection remains an important task, and hygiene measures have been successful in reducing cross-infection, but the universal presence of the organism creates an ongoing challenge, and vaccination strategies have not been highly successful to date. Over the last decade treatment strategies have shifted from controlling chronic infection to attempting to eradicate P. aeruginosa in the early stages of infection. Multiple strategies have been shown to be efficacious, but the optimal form and duration of therapy have yet to be defined. Inhaled antibiotics are a key component of maintenance therapy for chronic infection, and the spectrum of available compounds is rapidly expanding. Pulmonary exacerbations can be reduced with this strategy but usually require intravenous antibiotic therapy once they occur. Nonantibiotic approaches to address P. aeruginosa infection are currently being developed and may expand the therapeutic repertoire in the future.

KEYWORDS

Cystic fibrosis - Pseudomonas aeruginosa - antibiotic therapy - eradication

REFERENCES

• 1 Ratjen F, Döring G. Cystic fibrosis.  Lancet. 2003;  361 681-689
• 2 Li Z, Kosorok M R, Farrell P M et al.. Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis.  JAMA. 2005;  293 581-588
• 3 Cystic Fibrosis Foundation .Patient Registry 2007 Annual Data Report. Bethesda, MD; Cystic Fibrosis Foundation 2008
• 4 Smith J J, Travis S M, Greenberg E P, Welsh M J. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid.  Cell. 1996;  85 229-236
• 5 Pier G B, Grout M, Zaidi T S et al.. Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections.  Science. 1996;  271 64-67
• 6 Noone P G, Leigh M W, Sannuti A et al.. Primary ciliary dyskinesia: diagnostic and phenotypic features.  Am J Respir Crit Care Med. 2004;  169 459-467
• 7 Gibson R L, Burns J L, Ramsey B W. Pathophysiology and management of pulmonary infections in cystic fibrosis.  Am J Respir Crit Care Med. 2003;  168 918-951
• 8 Burns J L, Gibson R L, McNamara S et al.. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis.  J Infect Dis. 2001;  183 444-452
• 9 Fegan M, Francis P, Hayward A C, Davis G H, Fuerst J A. Phenotypic conversion of Pseudomonas aeruginosa in cystic fibrosis.  J Clin Microbiol. 1990;  28 1143-1146
• 10 Levy H, Kalish L A, Cannon C L et al.. Predictors of mucoid Pseudomonas colonization in cystic fibrosis patients.  Pediatr Pulmonol. 2008;  43 463-471
• 11 Konstan M W, Morgan W J, Butler S M Scientific Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis et al. Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis.  J Pediatr. 2007;  151 134-139, 139, e1
• 12 Courtney J M, Bradley J, Mccaughan J et al.. Predictors of mortality in adults with cystic fibrosis.  Pediatr Pulmonol. 2007;  42 525-532
• 13 Henry R L, Mellis C M, Petrovic L. Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis.  Pediatr Pulmonol. 1992;  12 158-161
• 14 Nixon G M, Armstrong D S, Carzino R et al.. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis.  J Pediatr. 2001;  138 699-704
• 15 Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson R L. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis.  Pediatr Pulmonol. 2002;  34 91-100
• 16 Schelstraete P, Van Daele S, De Boeck K et al.. Pseudomonas aeruginosa in the home environment of newly infected cystic fibrosis patients.  Eur Respir J. 2008;  31 822-829
• 17 Green S K, Schroth M N, Cho J J, Kominos S K, Vitanza-jack V B. Agricultural plants and soil as a reservoir for Pseudomonas aeruginosa .  Appl Microbiol. 1974;  28 987-991
• 18 Regnath T, Kreutzberger M, Illing S, Oehme R, Liesenfeld O. Prevalence of Pseudomonas aeruginosa in households of patients with cystic fibrosis.  Int J Hyg Environ Health. 2004;  207 585-588
• 19 Barben J, Hafen G, Schmid J. Swiss Paediatric Respiratory Research Group . Pseudomonas aeruginosa in public swimming pools and bathroom water of patients with cystic fibrosis.  J Cyst Fibros. 2005;  4 227-231
• 20 Whitby J L, Rampling A. Pseudomonas aeruginosa contamination in domestic and hospital environments.  Lancet. 1972;  1 15-17
• 21 Döring G, Jansen S, Noll H et al.. Distribution and transmission of Pseudomonas aeruginosa and Burkholderia cepacia in a hospital ward.  Pediatr Pulmonol. 1996;  21 90-100
• 22 Zimakoff J, Høiby N, Rosendal K, Guilbert J P. Epidemiology of Pseudomonas aeruginosa infection and the role of contamination of the environment in a cystic fibrosis clinic.  J Hosp Infect. 1983;  4 31-40
• 23 Festini F, Taccetti G, Mannini C et al.. Patient risk of contact with respiratory pathogens from inanimate surfaces in a cystic fibrosis outpatient clinic: a prospective study over a four-year period.  Pediatr Pulmonol. 2007;  42 779-784
• 24 Speert D P, Campbell M E. Hospital epidemiology of Pseudomonas aeruginosa from patients with cystic fibrosis.  J Hosp Infect. 1987;  9 11-21
• 25 Grothues D, Koopmann U, von der Hardt H, Tümmler B. Genome fingerprinting of Pseudomonas aeruginosa indicates colonization of cystic fibrosis siblings with closely related strains.  J Clin Microbiol. 1988;  26 1973-1977
• 26 Ojeniyi B, Frederiksen B, Hoiby N. Pseudomonas aeruginosa cross-infection among patients with cystic fibrosis during a winter camp.  Pediatr Pulmonol. 2000;  29 177-181
• 27 Brimicombe R W, Dijkshoorn L, van der Reijden T J et al.. Transmission of Pseudomonas aeruginosa in children with cystic fibrosis attending summer camps in the Netherlands.  J Cyst Fibros. 2008;  7 30-36
• 28 Jones A M, Govan J RW, Doherty C J et al.. Spread of a multiresistant strain of Pseudomonas aeruginosa in an adult cystic fibrosis clinic.  Lancet. 2001;  358 557-558
• 29 Griffiths A L, Jamsen K, Carlin J B et al.. Effects of segregation on an epidemic Pseudomonas aeruginosa strain in a cystic fibrosis clinic.  Am J Respir Crit Care Med. 2005;  171 1020-1025
• 30 Saiman L, Siegel J. Cystic Fibrosis Foundation Consensus Conference on Infection Control Participants . Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission.  Am J Infect Control. 2003;  31(3, Suppl) S1-S62
• 31 Lang A B, Rüdeberg A, Schöni M H, Que J U, Fürer E, Schaad U B. Vaccination of cystic fibrosis patients against Pseudomonas aeruginosa reduces the proportion of patients infected and delays time to infection.  Pediatr Infect Dis J. 2004;  23 504-510
• 32 Döring G, Meisner C, Stern M. for the Flagella Vaccine Trial Study Group . A double-blind randomized placebo-controlled phase III study of a Pseudomonas aeruginosa flagella vaccine in cystic fibrosis patients.  Proc Natl Acad Sci U S A. 2007;  104 11020-11025
• 33 Johansen H K, Gøtsche P C. Vaccines for preventing infection with Pseudomonas aeruginosa in cystic fibrosis.  Cochrane Database Syst Rev. 2008;  (4) CD001399
• 34 Steinkamp G, Tümmler B, Malottke R, von der Hardt H. Treatment of Pseudomonas aeruginosa colonisation in cystic fibrosis.  Arch Dis Child. 1989;  64 1022-1028
• 35 Littlewood J M, Miller M G, Ghoneim A T, Ramsden C H. Nebulised colomycin for early Pseudomonas colonisation in cystic fibrosis.  Lancet. 1985;  1 865
• 36 Valerius N H, Koch C, Høiby N. Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment.  Lancet. 1991;  338 725-726
• 37 Frederiksen B, Koch C, Høiby N. Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis.  Pediatr Pulmonol. 1997;  23 330-335
• 38 Taccetti G, Campana S, Festini F, Mascherini M, Döring G. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients.  Eur Respir J. 2005;  26 458-461
• 39 Lee T WR, Brownlee K G, Denton M, Littlewood J M, Conway S P. Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a regional pediatric cystic fibrosis center.  Pediatr Pulmonol. 2004;  37 104-110
• 40 Hansen C R, Pressler T, Høiby N. Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience.  J Cyst Fibros. 2008;  7 523-530
• 41 Wiesemann H G, Steinkamp G, Ratjen F et al.. Placebo-controlled, double-blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis.  Pediatr Pulmonol. 1998;  25 88-92
• 42 Ratjen F, Döring G, Nikolaizik W H. Effect of inhaled tobramycin on early Pseudomonas aeruginosa colonisation in patients with cystic fibrosis.  Lancet. 2001;  358 983-984
• 43 Ratjen F, Walter H, Haug M, Meisner C, Grasemann H, Döring G. Diagnostic value of serum antibodies in early Pseudomonas aeruginosa infection in cystic fibrosis patients.  Pediatr Pulmonol. 2007;  42 249-255
• 44 Rosenfeld M, Emerson J, Accurso F et al.. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis.  Pediatr Pulmonol. 1999;  28 321-328
• 45 Gibson R L, Emerson J, McNamara S Cystic Fibrosis Therapeutics Development Network Study Group et al. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis.  Am J Respir Crit Care Med. 2003;  167 841-849
• 46 Gibson R L, Emerson J, Mayer-Hamblett N et al.. Duration of treatment effect after tobramycin solution for inhalation in young children with cystic fibrosis.  Pediatr Pulmonol. 2007;  42 610-623
• 47 Ratjen F, Munck A, Kho P. Short and long-term efficacy of inhaled tobramycin in early P. aeruginosa infection: The ELITE study [abstract].  Pediatr Pulmonol. 2008;  S31 319-320
• 48 United States National Institutes of Health .Comparison of two treatment regimens to reduce PA infection in children with cystic fibrosis (EPIC). http://clinicaltrials.gov/ct2/show/NCT00097773?term=epic&rank=25 Accessed March 30, 2009
• 49 Pritt B, O’Brien L, Winn W. Mucoid Pseudomonas in cystic fibrosis.  Am J Clin Pathol. 2007;  128 32-34
• 50 May T B, Shinabarger D, Maharaj R et al.. Alginate synthesis by Pseudomonas aeruginosa: a key pathogenic factor in chronic pulmonary infections of cystic fibrosis patients.  Clin Microbiol Rev. 1991;  4 191-206
• 51 Pier G B, Coleman F, Grout M, Franklin M, Ohman D E. Role of alginate O acetylation in resistance of mucoid Pseudomonas aeruginosa to opsonic phagocytosis.  Infect Immun. 2001;  69 1885-1901
• 52 Murray T S, Egan M, Kazmierczak B I. Pseudomonas aeruginosa chronic colonization in cystic fibrosis patients.  Curr Opin Pediatr. 2007;  19 83-88
• 53 Singh P K, Schaefer A L, Parsek M R, Moninger T O, Welsh M J, Greenberg E P. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms.  Nature. 2000;  407 762-764
• 54 Ratjen F. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis.  Curr Opin Pulm Med. 2006;  12 428-432
• 55 Levy J. Antibiotic activity in sputum.  J Pediatr. 1986;  108(5 Pt 2) 841-846
• 56 Oliver A, Cantón R, Campo P, Baquero F, Blázquez J. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection.  Science. 2000;  288 1251-1254
• 57 Steinkamp G, Tümmler B, Gappa M et al.. Long-term tobramycin aerosol therapy in cystic fibrosis.  Pediatr Pulmonol. 1989;  6 91-98
• 58 MacLusky I B, Gold R, Corey M, Levison H. Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa .  Pediatr Pulmonol. 1989;  7 42-48
• 59 Ramsey B W, Pepe M S, Quan J M Cystic Fibrosis Inhaled Tobramycin Study Group et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.  N Engl J Med. 1999;  340 23-30
• 60 Murphy T D, Anbar R D, Lester L A et al.. Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease.  Pediatr Pulmonol. 2004;  38 314-320
• 61 Flume P A, O'sullivan B P, Robinson K A Cystic Fibrosis Foundation, Pulmonary Therapies Committee et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health.  Am J Respir Crit Care Med. 2007;  176 957-969
• 62 Jensen T, Pedersen S S, Garne S, Heilmann C, Høiby N, Koch C. Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection.  J Antimicrob Chemother. 1987;  19 831-838
• 63 Hodson M E, Gallagher C G, Govan J RW. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis.  Eur Respir J. 2002;  20 658-664
• 64 McCoy K S, Quittner A L, Oermann C M, Gibson R L, Retsch-Bogart G Z, Montgomery A B. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis.  Am J Respir Crit Care Med. 2008;  178 921-928
• 65 United States National Institutes of Health .International safety and efficacy study of aztreonam lysinate for inhalation (AI) in cystic fibrosis patients. http://www.clinicaltrials.gov/ct2/show/NCT00112359?cond=%22Cystic+Fibrosis%22&rank=12 Accessed March 30, 2009
• 66 United States National Institutes of Health .Aztreonam for inhalation solution versus tobramycin nebuliser solution in patients with cystic fibrosis and P. aeruginosa, followed by an open-label, single arm extension. http://www.clinicaltrials.gov/ct2/show/NCT00757237?cond=%22Cystic+Fibrosis%22&rank=110 Accessed March 30, 2009
• 67 United States National Institutes of Health .Multidose safety and tolerability study of (Arikace™) for inhalation in cystic fibrosis patients. http://www.clinicaltrials.gov/ct2/show/NCT00558844?cond=%22Cystic+Fibrosis%22&rank=8 Accessed March 30, 2009
• 68 United States National Institutes of Health .Multidose safety and tolerability study of dose escalation of liposomal amikacin for inhalation (ARIKACE™). http://www.clinicaltrials.gov/ct2/show/NCT00777296?cond=%22Cystic+Fibrosis%22&rank=194 Accessed March 30, 2009
• 69 United States National Institutes of Health .Study to evaluate the safety and efficacy of ciprofloxacin (inhaled) in patients with cystic fibrosis. http://www.clinicaltrials.gov/ct2/show/NCT00645788?cond=%22Cystic+Fibrosis%22&rank=71 Accessed March 30, 2009
• 70 United States National Institutes of Health .Safety, pharmacokinetic and pharmacodynamic study of MP-376 in patients with cystic fibrosis. http://www.clinicaltrials.gov/ct2/show/NCT00503490?cond=%22Cystic+Fibrosis%22&rank=223 Accessed March 30, 2009
• 71 United States National Institutes of Health .Safety, tolerability and efficacy of MP-376 given for 28 days to cystic fibrosis (CF) patients. http://www.clinicaltrials.gov/ct2/show/NCT00677365?cond=%22Cystic+Fibrosis%22&rank=228 Accessed March 30, 2009
• 72 United States National Institutes of Health .Study evaluating fosfomycin/tobramycin for inhalation in cystic fibrosis patients with Pseudomonas aeruginosa lung infection. http://www.clinicaltrials.gov/ct2/show/NCT00794586?cond=%22Cystic+Fibrosis%22&rank=95 Accessed March 30, 2009
• 73 United States National Institutes of Health .Safety of tobramycin inhalation powder (TIP) vs tobramycin solution for inhalation in patients with cystic fibrosis. http://www.clinicaltrials.gov/ct2/show/NCT00388505?cond=%22Cystic+Fibrosis%22&rank=147 Accessed March 30, 2009
• 74 Labro M T. Anti-inflammatory activity of macrolides: a new therapeutic potential?.  J Antimicrob Chemother. 1998;  41(Suppl B) 37-46
• 75 Tateda K, Ishii Y, Matsumoto T et al.. Direct evidence for antipseudomonal activity of macrolides: exposure-dependent bactericidal activity and inhibition of protein synthesis by erythromycin, clarithromycin, and azithromycin.  Antimicrob Agents Chemother. 1996;  40 2271-2275
• 76 Saiman L, Marshall B C, Mayer-Hamblett N Macrolide Study Group et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.  JAMA. 2003;  290 1749-1756
• 77 Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial.  Thorax. 2002;  57 212-216
• 78 Clement A, Tamalet A, Leroux E, Ravilly S, Fauroux B, Jais J-P. Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial.  Thorax. 2006;  61 895-902
• 79 Elborn J S, Prescott R J, Stack B HR et al.. Elective versus symptomatic antibiotic treatment in cystic fibrosis patients with chronic Pseudomonas infection of the lungs.  Thorax. 2000;  55 355-358
• 80 Bradley J, McAlister O, Elborn S. Pulmonary function, inflammation, exercise capacity and quality of life in cystic fibrosis.  Eur Respir J. 2001;  17 712-715
• 81 Ramsey B W. Management of pulmonary disease in patients with cystic fibrosis.  N Engl J Med. 1996;  335 179-188
• 82 Balfour-Lynn I M, Elborn J S. Respiratory disease: infection. In: Hodson M, Geddes D, Bush A Cystic Fibrosis. 3rd ed. London; Hodder Arnold 2007: 138
• 83 Fuchs H J, Borowitz D S, Christiansen D H The Pulmozyme Study Group et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis.  N Engl J Med. 1994;  331 637-642
• 84 Michel B C. Antibacterial therapy in cystic fibrosis: a review of the literature published between 1980 and February 1987.  Chest. 1988;  94(2, Suppl) 129S-140S
• 85 Gold R, Carpenter S, Heurter H, Corey M, Levison H. Randomized trial of ceftazidime versus placebo in the management of acute respiratory exacerbations in patients with cystic fibrosis.  J Pediatr. 1987;  111(6 Pt 1) 907-913
• 86 Regelmann W E, Elliott G R, Warwick W J, Clawson C C. Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and chest physiotherapy alone.  Am Rev Respir Dis. 1990;  141(4 Pt 1) 914-921
• 87 Smith A L, Fiel S B, Mayer-Hamblett N, Ramsey B, Burns J L. Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis.  Chest. 2003;  123 1495-1502
• 88 Foweraker J E, Laughton C R, Brown D FJ, Bilton D. Phenotypic variability of Pseudomonas aeruginosa in sputa from patients with acute infective exacerbation of cystic fibrosis and its impact on the validity of antimicrobial susceptibility testing.  J Antimicrob Chemother. 2005;  55 921-927
• 89 Keays T, Ferris W, Vandemheen K L et al.. A retrospective analysis of biofilm antibiotic susceptibility testing: a better predictor of clinical response in cystic fibrosis exacerbations.  J Cyst Fibros. 2009;  8 122-127
• 90 United States National Institutes of Health .Use of a biofilm antimicrobial susceptibility assay to guide antibiotic therapy. http://www.clinicaltrials.gov/ct2/show/NCT00786513?cond=%22Cystic+Fibrosis%22&rank=214 Accessed March 30, 2009
• 91 Smyth A, Tan K HV, Hyman-Taylor P TOPIC Study Group et al. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis—the TOPIC study: a randomised controlled trial.  Lancet. 2005;  365 573-578
• 92 Lam W, Tjon J, Seto W et al.. Pharmacokinetic modelling of a once-daily dosing regimen for intravenous tobramycin in paediatric cystic fibrosis patients.  J Antimicrob Chemother. 2007;  59 1135-1140
• 93 Elborn J S, Prescott R J, Stack B HR et al.. Elective versus symptomatic antibiotic treatment in cystic fibrosis patients with chronic Pseudomonas infection of the lungs.  Thorax. 2000;  55(5) 355-358
• 94 Hodson M E, Roberts C M, Butland R JA, Smith M J, Batten J C. Oral ciprofloxacin compared with conventional intravenous treatment for Pseudomonas aeruginosa infection in adults with cystic fibrosis.  Lancet. 1987;  1 235-237
• 95 Jensen T, Pedersen S S, Høiby N, Koch C. Efficacy of oral fluoroquinolones versus conventional intravenous antipseudomonal chemotherapy in treatment of cystic fibrosis.  Eur J Clin Microbiol. 1987;  6 618-622