1,812
Views
97
CrossRef citations to date
0
Altmetric
Review

Pseudomonas aeruginosa infection in cystic fibrosis: pathophysiological mechanisms and therapeutic approaches

, , , , , , , , , , , , , , , , , , , , , , & show all
Pages 685-697 | Received 13 Jan 2016, Accepted 08 Apr 2016, Published online: 13 May 2016

References

  • Sadikot RT, Blackwell TS, Christman JW, et al. Pathogen-host interactions in Pseudomonas aeruginosa pneumonia. Am J Respir Crit Care Med. 2005;171(11):1209–1223.
  • Aujoulat F, Roger F, Bourdier A, et al. From environment to man: genome evolution and adaptation of human opportunistic bacterial pathogens. Genes (Basel). 2012;3(2):191–232.
  • Schwartz T, Volkmann H, Kirchen S, et al. Real-time PCR detection of Pseudomonas aeruginosa in clinical and municipal wastewater and genotyping of the ciprofloxacin-resistant isolates. FEMS Microbiol Ecol. 2006;57(1):158–167.
  • Frimmersdorf E, Horatzek S, Pelnikevich A, et al. How Pseudomonas aeruginosa adapts to various environments: a metabolomic approach. Environ Microbiol. 2010;12(6):1734–1747.
  • Stover CK, Pham XQ, Erwin AL, et al. Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen. Nature. 2000;406(6799):959–964.
  • Burns JL, Gibson RL, McNamara S, et al. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J Infect Dis. 2001;183(3):444–452.
  • Rosenfeld M, Gibson RL, McNamara S, et al. Early pulmonary infection, inflammation, and clinical outcomes in infants with cystic fibrosis. Pediatr Pulmonol. 2001;32(5):356–366.
  • Armstrong DS, Grimwood K, Carlin JB, et al. Bronchoalveolar lavage or oropharyngeal cultures to identify lower respiratory pathogens in infants with cystic fibrosis. Pediatr Pulmonol. 1996;21(5):267–275.
  • Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev. 2014;11:Cd004197.
  • UK Cystic Fibrosis Registry. Annual data report 2013: Cystic Fibrosis Trust; 2014. Available from: http://www.cysticfibrosis.org.uk/media/598466/annual-data-report-2013-jul14.pdf.
  • Cystic Fibrosis Foundation Patient Registry. 2013 annual data report to the center directors. Bethesda, Maryland; 2014. Available from: https://www.cff.org/2013_CFF_Annual_Data_Report_to_the_Center_Directors.pdf.
  • Konstan MW, Morgan WJ, Butler SM, 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(2):134–139, 9.e1.
  • Emerson J, Rosenfeld M, McNamara S, et al. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34(2):91–100.
  • Nixon GM, Armstrong DS, Carzino R, et al. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr. 2001;138(5):699–704.
  • Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168(8):918–951.
  • Matsui H, Grubb BR, Tarran R, et al. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell. 1998;95(7):1005–1015.
  • Tarran R, Button B, Picher M, et al. Normal and cystic fibrosis airway surface liquid homeostasis. The effects of phasic shear stress and viral infections. J Biol Chem. 2005;280(42):35751–35759.
  • Matsui H, Wagner VE, Hill DB, et al. A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms. Proc Natl Acad Sci U S A. 2006;103(48):18131–18136.
  • Stoltz DA, Meyerholz DK, Pezzulo AA, et al. Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth. Sci Transl Med. 2010;2(29):29ra31.
  • Keiser NW, Birket SE, Evans IA, et al. Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs. Am J Respir Cell Mol Biol. 2015;52(6):683–694.
  • Pezzulo AA, Tang XX, Hoegger MJ, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature. 2012;487(7405):109–113.
  • Abou Alaiwa MH, Reznikov LR, Gansemer ND, et al. pH modulates the activity and synergism of the airway surface liquid antimicrobials beta-defensin-3 and LL-37. Proc Natl Acad Sci U S A. 2014;111(52):18703–18708.
  • Abou Alaiwa MH, Beer AM, Pezzulo AA, et al. Neonates with cystic fibrosis have a reduced nasal liquid pH; a small pilot study. J Cyst Fibros. 2014;13(4):373–377.
  • McShane D, Davies JC, Davies MG, et al. Airway surface pH in subjects with cystic fibrosis. Eur Respir J. 2003;21(1):37–42.
  • Schroeder TH, Lee MM, Yacono PW, et al. CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-kappa B translocation. Proc Natl Acad Sci U S A. 2002;99(10):6907–6912.
  • Pier GB, Grout M, Zaidi TS, et al. Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science. 1996;271(5245):64–67.
  • Krivan HC, Roberts DD, Ginsburg V. Many pulmonary pathogenic bacteria bind specifically to the carbohydrate sequence GalNAc beta 1-4Gal found in some glycolipids. Proc Natl Acad Sci U S A. 1988;85(16):6157–6161.
  • Saiman L, Prince A. Pseudomonas aeruginosa pili bind to asialoGM1 which is increased on the surface of cystic fibrosis epithelial cells. J Clin Invest. 1993;92(4):1875–1880.
  • Davies JC, Stern M, Dewar A, et al. CFTR gene transfer reduces the binding of Pseudomonas aeruginosa to cystic fibrosis respiratory epithelium. Am J Respir Cell Mol Biol. 1997;16(6):657–663.
  • Baltimore RS, Christie CD, Smith GJ. Immunohistopathologic localization of Pseudomonas aeruginosa in lungs from patients with cystic fibrosis. Implications for the pathogenesis of progressive lung deterioration. Am Rev Respir Dis. 1989;140(6):1650–1661.
  • Worlitzsch D, Tarran R, Ulrich M, et al. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest. 2002;109(3):317–325.
  • Jelsbak L, Johansen HK, Frost AL, et al. Molecular epidemiology and dynamics of Pseudomonas aeruginosa populations in lungs of cystic fibrosis patients. Infect Immun. 2007;75(5):2214–2224.
  • Kidd TJ, Ramsay KA, Vidmar S, et al. Pseudomonas aeruginosa genotypes acquired by children with cystic fibrosis by age 5-years. Journal of Cystic Fibrosis. 2015;14(3):361–369.
  • Cramer N, Wiehlmann L, Ciofu O, et al. Molecular epidemiology of chronic Pseudomonas aeruginosa airway infections in cystic fibrosis. PLoS One. 2012;7(11):e50731.
  • Goeminne PC, Nawrot TS, De Boeck K, et al. Proximity to blue spaces and risk of infection with Pseudomonas aeruginosa in cystic fibrosis: a case-control analysis. J Cyst Fibros. 2015;14(6):741–747.
  • Psoter KJ, Der AJ, Wakefield J, et al. Association of meteorological and geographical factors and risk of initial Pseudomonas aeruginosa acquisition in young children with cystic fibrosis. Epidemiol Infect. 2016;144(5):1075–1083.
  • Cheng K, Smyth RL, Govan JR, et al. Spread of beta-lactam-resistant Pseudomonas aeruginosa in a cystic fibrosis clinic. Lancet. 1996;348(9028):639–642.
  • Jones AM, Govan JR, Doherty CJ, et al. Spread of a multiresistant strain of Pseudomonas aeruginosa in an adult cystic fibrosis clinic. Lancet. 2001;358(9281):557–558.
  • Armstrong DS, Nixon GM, Carzino R, et al. Detection of a widespread clone of Pseudomonas aeruginosa in a pediatric cystic fibrosis clinic. Am J Respir Crit Care Med. 2002;166(7):983–987.
  • Zimakoff J, Hoiby N, Rosendal K, et al. Epidemiology of Pseudomonas aeruginosa infection and the role of contamination of the environment in a cystic fibrosis clinic. J Hosp Infect. 1983;4(1):31–40.
  • Scott FW, Pitt TL. Identification and characterization of transmissible Pseudomonas aeruginosa strains in cystic fibrosis patients in England and Wales. J Med Microbiol. 2004;53(Pt 7):609–615.
  • Aaron SD, Vandemheen KL, Ramotar K, et al. Infection with transmissible strains of Pseudomonas aeruginosa and clinical outcomes in adults with cystic fibrosis. Jama. 2010;304(19):2145–2153.
  • Jones AM, Govan JR, Doherty CJ, et al. Identification of airborne dissemination of epidemic multiresistant strains of Pseudomonas aeruginosa at a CF centre during a cross infection outbreak. Thorax. 2003;58(6):525–527.
  • Panagea S, Winstanley C, Walshaw MJ, et al. Environmental contamination with an epidemic strain of Pseudomonas aeruginosa in a Liverpool cystic fibrosis centre, and study of its survival on dry surfaces. J Hosp Infect. 2005;59(2):102–107.
  • Knibbs LD, Johnson GR, Kidd TJ, et al. Viability of Pseudomonas aeruginosa in cough aerosols generated by persons with cystic fibrosis. Thorax. 2014;69(8):740–745.
  • Li Z, Kosorok MR, Farrell PM, et al. Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis. Jama. 2005;293(5):581–588.
  • Mainz JG, Naehrlich L, Schien M, et al. Concordant genotype of upper and lower airways P. aeruginosa and S. aureus isolates in cystic fibrosis. Thorax. 2009;64(6):535–540.
  • Hansen SK, Rau MH, Johansen HK, et al. Evolution and diversification of Pseudomonas aeruginosa in the paranasal sinuses of cystic fibrosis children have implications for chronic lung infection. ISME J. 2012;6(1):31–45.
  • Aanaes K. Bacterial sinusitis can be a focus for initial lung colonisation and chronic lung infection in patients with cystic fibrosis. J Cyst Fibros. 2013;12(Suppl 2):S1–S20.
  • Rivas Caldas R, Le Gall F, Revert K, et al. Pseudomonas aeruginosa and periodontal pathogens in the oral cavity and lungs of cystic fibrosis patients: a case-control study. J Clin Microbiol. 2015;53(6):1898–1907.
  • Rivas Caldas R, Boisramé S. Upper aero-digestive contamination by Pseudomonas aeruginosa and implications in cystic fibrosis. Journal of Cystic Fibrosis. 2015;14(1):6–15.
  • Mainz JG, Hentschel J, Schien C, et al. Sinonasal persistence of Pseudomonas aeruginosa after lung transplantation. J Cyst Fibros. 2012;11(2):158–161.
  • Pier GB. Pseudomonas aeruginosa lipopolysaccharide: a major virulence factor, initiator of inflammation and target for effective immunity. Int J Med Microbiol. 2007;297(5):277–295.
  • Ernst RK, Yi EC, Guo L, et al. Specific lipopolysaccharide found in cystic fibrosis airway Pseudomonas aeruginosa. Science. 1999;286(5444):1561–1565.
  • Feldman M, Bryan R, Rajan S, et al. Role of flagella in pathogenesis of Pseudomonas aeruginosa pulmonary infection. Infect Immun. 1998;66(1):43–51.
  • O’Toole GA, Kolter R. Flagellar and twitching motility are necessary for Pseudomonas aeruginosa biofilm development. Mol Microbiol. 1998;30(2):295–304.
  • Hayashi F, Smith KD, Ozinsky A, et al. The innate immune response to bacterial flagellin is mediated by toll-like receptor 5. Nature. 2001;410(6832):1099–1103.
  • Wolfgang MC, Jyot J, Goodman AL, et al. Pseudomonas aeruginosa regulates flagellin expression as part of a global response to airway fluid from cystic fibrosis patients. Proc Natl Acad Sci U S A. 2004;101(17):6664–6668.
  • Bleves S, Viarre V, Salacha R, et al. Protein secretion systems in Pseudomonas aeruginosa: a wealth of pathogenic weapons. Int J Med Microbiol. 2010;300(8):534–543.
  • Bainbridge T, Fick RB Jr. Functional importance of cystic fibrosis immunoglobulin G fragments generated by Pseudomonas aeruginosa elastase. J Lab Clin Med. 1989;114(6):728–733.
  • Mariencheck WI, Alcorn JF, Palmer SM, et al. Pseudomonas aeruginosa elastase degrades surfactant proteins A and D. Am J Respir Cell Mol Biol. 2003;28(4):528–537.
  • Kurahashi K, Kajikawa O, Sawa T, et al. Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia. J Clin Invest. 1999;104(6):743–750.
  • Rada B, Leto TL. Pyocyanin effects on respiratory epithelium: relevance in Pseudomonas aeruginosa airway infections. Trends Microbiol. 2013;21(2):73–81.
  • Nair C, Shoemark A, Chan M, et al. Cyanide levels found in infected cystic fibrosis sputum inhibit airway ciliary function. Eur Respir J. 2014;44(5):1253–1261.
  • Wilson R, Pitt T, Taylor G, et al. Pyocyanin and 1-hydroxyphenazine produced by Pseudomonas aeruginosa inhibit the beating of human respiratory cilia in vitro. J Clin Invest. 1987;79(1):221–229.
  • Filloux A. Protein secretion systems in Pseudomonas aeruginosa: an essay on diversity, evolution, and function. Front Microbiol. 2011;2:155.
  • Kulasekara BR, Kulasekara HD, Wolfgang MC, et al. Acquisition and evolution of the exoU locus in Pseudomonas aeruginosa. J Bacteriol. 2006;188(11):4037–4050.
  • Wolfgang MC, Kulasekara BR, Liang X, et al. Conservation of genome content and virulence determinants among clinical and environmental isolates of Pseudomonas aeruginosa. Proc Natl Acad Sci U S A. 2003;100(14):8484–8489.
  • Wareham DW, Curtis MA. A genotypic and phenotypic comparison of type III secretion profiles of Pseudomonas aeruginosa cystic fibrosis and bacteremia isolates. Int J Med Microbiol. 2007;297(4):227–234.
  • Hauser AR. The type III secretion system of Pseudomonas aeruginosa: infection by injection. Nat Rev Microbiol. 2009;7(9):654–665.
  • Mougous JD, Cuff ME, Raunser S, et al. A virulence locus of Pseudomonas aeruginosa encodes a protein secretion apparatus. Science. 2006;312(5779):1526–1530.
  • Mayer-Hamblett N, Rosenfeld M, Gibson RL, et al. Pseudomonas aeruginosa in vitro phenotypes distinguish cystic fibrosis infection stages and outcomes. Am J Respir Crit Care Med. 2014;190(3):289–297.
  • Martin DW, Schurr MJ, Mudd MH, et al. Mechanism of conversion to mucoidy in Pseudomonas aeruginosa infecting cystic fibrosis patients. Proc Natl Acad Sci U S A. 1993;90(18):8377–8381.
  • Mathee K, Ciofu O, Sternberg C, et al. Mucoid conversion of Pseudomonas aeruginosa by hydrogen peroxide: a mechanism for virulence activation in the cystic fibrosis lung. Microbiology. 1999;145(Pt 6):1349–1357.
  • Hentzer M, Teitzel GM, Balzer GJ, et al. Alginate overproduction affects Pseudomonas aeruginosa biofilm structure and function. J Bacteriol. 2001;183(18):5395–5401.
  • Singh PK, Schaefer AL, Parsek MR, et al. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature. 2000;407(6805):762–764.
  • Bjarnsholt T, Jensen PO, Fiandaca MJ, et al. Pseudomonas aeruginosa biofilms in the respiratory tract of cystic fibrosis patients. Pediatr Pulmonol. 2009;44(6):547–558.
  • Lopez-Causape C, Rojo-Molinero E, Macia MD, et al. The problems of antibiotic resistance in cystic fibrosis and solutions. Expert Rev Respir Med. 2015;9(1):73–88.
  • Hoiby N, Bjarnsholt T, Givskov M, et al. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents. 2010;35(4):322–332.
  • Costerton JW, Lewandowski Z, Caldwell DE, et al. Microbial biofilms. Annu Rev Microbiol. 1995;49:711–745.
  • Moscoso JA, Mikkelsen H, Heeb S, et al. The Pseudomonas aeruginosa sensor RetS switches type III and type VI secretion via c-di-GMP signalling. Environ Microbiol. 2011;13(12):3128–3138.
  • Yang L, Haagensen JA, Jelsbak L, et al. In situ growth rates and biofilm development of Pseudomonas aeruginosa populations in chronic lung infections. J Bacteriol. 2008;190(8):2767–2776.
  • Yoon SS, Hennigan RF, Hilliard GM, et al. Pseudomonas aeruginosa anaerobic respiration in biofilms: relationships to cystic fibrosis pathogenesis. Dev Cell. 2002;3(4):593–603.
  • Gambello MJ, Iglewski BH. Cloning and characterization of the Pseudomonas aeruginosa lasR gene, a transcriptional activator of elastase expression. J Bacteriol. 1991;173(9):3000–3009.
  • Pearson JP, Gray KM, Passador L, et al. Structure of the autoinducer required for expression of Pseudomonas aeruginosa virulence genes. Proc Natl Acad Sci U S A. 1994;91(1):197–201.
  • Passador L, Cook JM, Gambello MJ, et al. Expression of Pseudomonas aeruginosa virulence genes requires cell-to-cell communication. Science. 1993;260(5111):1127–1130.
  • Ochsner UA, Koch AK, Fiechter A, et al. Isolation and characterization of a regulatory gene affecting rhamnolipid biosurfactant synthesis in Pseudomonas aeruginosa. J Bacteriol. 1994;176(7):2044–2054.
  • Pesci EC, Pearson JP, Seed PC, et al. Regulation of las and rhl quorum sensing in Pseudomonas aeruginosa. J Bacteriol. 1997;179(10):3127–3132.
  • Storey DG, Ujack EE, Rabin HR, et al. Pseudomonas aeruginosa lasR transcription correlates with the transcription of lasA, lasB, and toxA in chronic lung infections associated with cystic fibrosis. Infect Immun. 1998;66(6):2521–2528.
  • Erickson DL. Pseudomonas aeruginosa quorum-sensing systems may control virulence factor expression in the lungs of patients with cystic fibrosis. Infect Immun. 2002;70(4):1783–1790.
  • Whiteley M, Lee KM, Greenberg EP. Identification of genes controlled by quorum sensing in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A. 1999;96(24):13904–13909.
  • Smith RP. aeruginosa quorum-sensing systems and virulence. Curr Opin Microbiol. 2003;6(1):56–60.
  • Williams P, Camara M. Quorum sensing and environmental adaptation in Pseudomonas aeruginosa: a tale of regulatory networks and multifunctional signal molecules. Curr Opin Microbiol. 2009;12(2):182–191.
  • Smith RS, Iglewski BH. P. aeruginosa quorum-sensing systems and virulence. Curr Opin Microbiol. 2003;6(1):56–60.
  • Pesci EC, Milbank JB, Pearson JP, et al. Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa. Proc Natl Acad Sci U S A. 1999;96(20):11229–11234.
  • Smith EE, Buckley DG, Wu Z, et al. Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients. Proc Natl Acad Sci U S A. 2006;103(22):8487–8492.
  • Hoffman LR, Kulasekara HD, Emerson J, et al. Pseudomonas aeruginosa lasR mutants are associated with cystic fibrosis lung disease progression. J Cyst Fibros. 2009;8(1):66–70.
  • Bjarnsholt T, Jensen PO, Jakobsen TH, et al. Quorum sensing and virulence of Pseudomonas aeruginosa during lung infection of cystic fibrosis patients. PLoS One. 2010;5(4):e10115.
  • Ryall B, Carrara M, Zlosnik JE, et al. The mucoid switch in Pseudomonas aeruginosa represses quorum sensing systems and leads to complex changes to stationary phase virulence factor regulation. PLoS One. 2014;9(5):e96166.
  • Zhao WH, Hu ZQ. Beta-lactamases identified in clinical isolates of Pseudomonas aeruginosa. Crit Rev Microbiol. 2010;36(3):245–258.
  • Poole K. Pseudomonas aeruginosa: resistance to the max. Front Microbiol. 2011;2:65.
  • Rodriguez-Martinez JM, Poirel L, Nordmann P. Molecular epidemiology and mechanisms of carbapenem resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2009;53(11):4783–4788.
  • Armstrong DS, Hook SM, Jamsen KM, et al. Lower airway inflammation in infants with cystic fibrosis detected by newborn screening. Pediatr Pulmonol. 2005;40(6):500–510.
  • Dhooghe B, Noel S, Huaux F, et al. Lung inflammation in cystic fibrosis: pathogenesis and novel therapies. Clin Biochem. 2014;47(7–8):539–546.
  • Painter RG, Valentine VG, Lanson NA Jr., et al. CFTR expression in human neutrophils and the phagolysosomal chlorination defect in cystic fibrosis. Biochemistry. 2006;45(34):10260–10269.
  • Young RL, Malcolm KC, Kret JE, et al. Neutrophil extracellular trap (NET)-mediated killing of Pseudomonas aeruginosa: evidence of acquired resistance within the CF airway, independent of CFTR. PLoS One. 2011;6(9):e23637.
  • Hartl D, Latzin P, Hordijk P, et al. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med. 2007;13(12):1423–1430.
  • Cohen-Cymberknoh M, Kerem E, Ferkol T, et al. Airway inflammation in cystic fibrosis: molecular mechanisms and clinical implications. Thorax. 2013;68(12):1157–1162.
  • Pernet E, Guillemot L, Burgel PR, et al. Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity. Nat Commun. 2014;5:5105.
  • Kessler E, Safrin M, Olson JC, et al. Secreted LasA of Pseudomonas aeruginosa is a staphylolytic protease. J Biol Chem. 1993;268(10):7503–7508.
  • Kaur J, Pethani BP, Kumar S, et al. Pseudomonas aeruginosa inhibits the growth of Scedosporium aurantiacum, an opportunistic fungal pathogen isolated from the lungs of cystic fibrosis patients. Front Microbiol. 2015;6:866.
  • Smith K, Rajendran R, Kerr S, et al. Aspergillus fumigatus enhances elastase production in Pseudomonas aeruginosa co-cultures. Med Mycol. 2015;53(7):645–655.
  • Lopez-Medina E, Fan D, Coughlin LA, et al. Candida albicans inhibits Pseudomonas aeruginosa virulence through suppression of pyochelin and pyoverdine biosynthesis. PLoS Pathog. 2015;11(8):e1005129.
  • Chattoraj SS, Ganesan S, Jones AM, et al. Rhinovirus infection liberates planktonic bacteria from biofilm and increases chemokine responses in cystic fibrosis airway epithelial cells. Thorax. 2011;66(4):333–339.
  • Wainwright CE, Vidmar S, Armstrong DS, et al. Effect of bronchoalveolar lavage-directed therapy on Pseudomonas aeruginosa infection and structural lung injury in children with cystic fibrosis: a randomized trial. JAMA. 2011;306(2):163–171.
  • Muhlebach MS, Miller MB, Moore C, et al. Are lower airway or throat cultures predictive of sinus bacteriology in cystic fibrosis? Pediatr Pulmonol. 2006;41(5):445–451.
  • Douglas TA, Brennan S, Berry L, et al. Value of serology in predicting Pseudomonas aeruginosa infection in young children with cystic fibrosis. Thorax. 2010;65(11):985–990.
  • Kappler M, Nagel F, Feilcke M, et al. Predictive values of antibodies against Pseudomonas aeruginosa in patients with cystic fibrosis one year after early eradication treatment. J Cyst Fibros. 2014;13(5):534–541.
  • Pabary R, Huang J, Kumar S, et al. Does mass spectrometric breath analysis detect Pseudomonas aeruginosa in cystic fibrosis? Eur Respir J. 2016;47(3):994–997.
  • Gilchrist FJ, Bright-Thomas RJ, Jones AM, et al. Hydrogen cyanide concentrations in the breath of adult cystic fibrosis patients with and without Pseudomonas aeruginosa infection. J Breath Res. 2013;7(2):026010.
  • Vogelberg C, Hirsch T, Rosen-Wolff A, et al. Pseudomonas aeruginosa and Burkholderia cepacia cannot be detected by PCR in the breath condensate of patients with cystic fibrosis. Pediatr Pulmonol. 2003;36(4):348–352.
  • Strittmatter N, Rebec M, Jones EA, et al. Characterization and identification of clinically relevant microorganisms using rapid evaporative ionization mass spectrometry. Anal Chem. 2014;86(13):6555–6562.
  • Ashish A, Shaw M, Winstanley C, et al. Halting the spread of epidemic Pseudomonas aeruginosa in an adult cystic fibrosis centre: a prospective cohort study. JRSM Short Rep. 2013;4(1):1.
  • Zhao J, Schloss PD, Kalikin LM, et al. Decade-long bacterial community dynamics in cystic fibrosis airways. Proc Natl Acad Sci U S A. 2012;109(15):5809–5814.
  • Boutin S, Graeber SY, Weitnauer M, et al. Comparison of microbiomes from different niches of upper and lower airways in children and adolescents with cystic fibrosis. PLoS One. 2015;10(1):e0116029.
  • Mogayzel PJ Jr., Naureckas ET, Robinson KA, et al. Cystic fibrosis foundation pulmonary guideline. Pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. Ann Am Thorac Soc. 2014;11(10):1640–1650.
  • Ratjen F, Munck A, Kho P, et al. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax. 2010;65(4):286–291.
  • Tramper-Stranders GA, Wolfs TF, Van Haren Noman S, et al. Controlled trial of cycled antibiotic prophylaxis to prevent initial Pseudomonas aeruginosa infection in children with cystic fibrosis. Thorax. 2010;65(10):915–920.
  • Waters V, Stanojevic S, Atenafu EG, et al. Effect of pulmonary exacerbations on long-term lung function decline in cystic fibrosis. Eur Respir J. 2012;40(1):61–66.
  • De Boer K, Vandemheen KL, Tullis E, et al. Exacerbation frequency and clinical outcomes in adult patients with cystic fibrosis. Thorax. 2011;66(8):680–685.
  • Sanders DB, Bittner RC, Rosenfeld M, et al. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med. 2010;182(5):627–632.
  • Waters V, Atenafu EG, Salazar JG, et al. Chronic Stenotrophomonas maltophilia infection and exacerbation outcomes in cystic fibrosis. J Cyst Fibros. 2012;11(1):8–13.
  • Aaron SD, Vandemheen KL, Ferris W, et al. Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial. Lancet. 2005;366(9484):463–471.
  • Lee TWR, Brownlee KG, Conway SP, et al. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. Journal of Cystic Fibrosis. 2003;2(1):29–34.
  • Equi A, Balfour-Lynn IM, Bush A, et al. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002;360(9338):978–984.
  • Smyth AR, Cifelli PM, Ortori CA, et al. Garlic as an inhibitor of Pseudomonas aeruginosa quorum sensing in cystic fibrosis–a pilot randomized controlled trial. Pediatr Pulmonol. 2010;45(4):356–362.
  • Barraud N, Hassett DJ, Hwang SH, et al. Involvement of nitric oxide in biofilm dispersal of Pseudomonas aeruginosa. J Bacteriol. 2006;188(21):7344–7353.
  • Barraud N, Kardak BG, Yepuri NR, et al. Cephalosporin-3ʹ-diazeniumdiolates: targeted NO-donor prodrugs for dispersing bacterial biofilms. Angew Chem Int Ed Engl. 2012;51(36):9057–9060.
  • Wright A, Hawkins CH, Anggard EE, et al. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol. 2009;34(4):349–357.
  • Pabary R, Singh C, Morales S, et al. Anti-pseudomonal bacteriophage reduces infective burden and inflammatory response in murine lung. Antimicrob Agents Chemother. 2015;60(2):744–751.
  • Debarbieux L, Leduc D, Maura D, et al. Bacteriophages can treat and prevent Pseudomonas aeruginosa lung infections. J Infect Dis. 2010;201(7):1096–1104.
  • Secher T, Fas S, Fauconnier L, et al. The anti-Pseudomonas aeruginosa antibody Panobacumab is efficacious on acute pneumonia in neutropenic mice and has additive effects with meropenem. PLoS One. 2013;8(9):e73396.
  • Johansen HK, Gotzsche PC. Vaccines for preventing infection with Pseudomonas aeruginosa in cystic fibrosis. Cochrane Database Syst Rev. 2013;6:Cd001399.
  • Heltshe SL, Mayer-Hamblett N, Burns JL, et al. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis. 2015;60(5):703–712.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.