New anti-pseudomonal agents for cystic fibrosis- still needed in the era of small molecule CFTR modulators?

References

• UK Cystic Fibrosis Registry Annual Data Report 2016. [cited Jul 25] https://www.cysticfibrosis.org.uk/~/media/documents/the-work-we-do/uk-cf-registry/uk-cf-registry-annual-data-report-2016.ashx?la+en
   Google Scholar
• Fajac I, Viel M, Gaitch N, et al. Combination of ENaC and CFTR mutations may predispose to cystic fibrosis-like disease. Eur Respir J. 2009 Sep;34(3):772–773.
   PubMed Web of Science ®Google Scholar
• Horisberger JD. ENaC-CFTR interactions: the role of electrical coupling of ion fluxes explored in an epithelial cell model. Pflugers Arch. 2003 Jan;445(4):522–528.
   PubMed Web of Science ®Google Scholar
• Matsui H, Grubb BR, Tarran R, et al. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airway disease. Cell. 1998 Dec 23;1998(95):1005–1015.
   Google Scholar
• Pezzulo AA, Tang XX, Hoegger MJ, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature. 2012 Jul 4;487(7405):109–113.
   PubMed Web of Science ®Google Scholar
• Schultz A, Puvvadi R, Borisov SM, et al. Airway surface liquid pH is not acidic in children with cystic fibrosis. Nat Commun. 2017 Nov 10;8(1):1409.
   PubMedGoogle Scholar
• Kostikas K, Papatheodorou G, Ganas K, et al. pH in expired breath condensate of patients with inflammatory airway diseases. Am J Respir Crit Care Med. 2002 May 15;165(10):1364–1370.
   PubMed Web of Science ®Google Scholar
• Kodric M, Shah AN, Fabbri LM, et al. An investigation of airway acidification in asthma using induced sputum: a study of feasibility and correlation. Am J Respir Crit Care Med. 2007 May 01;175(9):905–910.
   PubMed Web of Science ®Google Scholar
• Saiman L, Siegel J. Infection control in cystic fibrosis. Clin Microbiol Rev. 2004;17(1):57–71.
   PubMed Web of Science ®Google Scholar
• Saiman L, Siegel JD, LiPuma JJ, et al. Infection prevention and control guideline for cystic fibrosis: 2013 update. Infect Control Hosp Epidemiol. 2014 Aug;35(Suppl 1):S1–S67.
   PubMed Web of Science ®Google Scholar
• Giron RM, Maiz L, Barrio I, et al. [Nontuberculous mycobacterial infection in patients with cystic fibrosis: a multicenter prevalence study]. Arch Bronconeumol. 2008 Dec;44(12):679–684.
   PubMed Web of Science ®Google Scholar
• Seddon P, Fidler K, Raman S, et al. Prevalence of nontuberculous mycobacteria in cystic fibrosis clinics, United Kingdom, 2009. Emerg Infect Dis. 2013;19(7):1128–1130.
   PubMed Web of Science ®Google Scholar
• Adjemian J, Olivier KN, Prevots DR. Nontuberculous mycobacteria among patients with cystic fibrosis in the United States: screening practices and environmental risk. Am J Respir Crit Care Med. 2014 Sep 1;190(5):581–586.
   PubMed Web of Science ®Google Scholar
• Qvist T, Gilljam M, Jonsson B, et al. Epidemiology of nontuberculous mycobacteria among patients with cystic fibrosis in Scandinavia. J Cyst Fibros. 2015 Jan;14(1):46–52.
   PubMed Web of Science ®Google Scholar
• Bar-On O, Mussaffi H, Mei-Zahav M, et al. Increasing nontuberculous mycobacteria infection in cystic fibrosis. J Cyst Fibros. 2015 Jan;14(1):53–62.
   PubMed Web of Science ®Google Scholar
• Surette MG. The cystic fibrosis lung microbiome. Ann Am Thorac Soc. 2014 Jan;11(Suppl 1):S61–S5.
   PubMedGoogle Scholar
• Dickson RP, Erb-Downward JR, Martinez FJ, et al. The microbiome and the respiratory tract. Annu Rev Physiol. 2016;78:481–504.
   PubMed Web of Science ®Google Scholar
• Huang YJ, LiPuma JJ. The microbiome in cystic fibrosis. Clin Chest Med. 2016 Mar;37(1):59–67.
   PubMed Web of Science ®Google Scholar
• Johansen HK, Hoiby N. Seasonal onset of initial colonisation and chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis in Denmark. Thorax. 1992 Feb;47(2):109–111.
   PubMed Web of Science ®Google Scholar
• Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev. 2014 Nov;10(11):CD004197.
   Google Scholar
• Schuster M, Greenberg EP. A network of networks: quorum-sensing gene regulation in Pseudomonas aeruginosa. Int J Med Microbiol. 2006 Apr;296(2–3):73–81.
   PubMed Web of Science ®Google Scholar
• Hauser AR, Jain M, Bar-Meir M, et al. Clinical significance of microbial infection and adaptation in cystic fibrosis. Clin Microbiol Rev. 2011 Jan;24(1):29–70.
   PubMed Web of Science ®Google Scholar
• Dufour DLV, Levesque CM. Bacterial biofilm: structure, function, and antimicrobial resistance. Endodontic Topics. 2012;22:2–16.
   Google Scholar
• Ryder C, Byrd M, Wozniak DJ. Role of polysaccharides in Pseudomonas aeruginosa biofilm development. Curr Opin Microbiol. 2007 Dec;10(6):644–648.
   PubMed Web of Science ®Google Scholar
• Singh PK, Schaefer AL, Parsek MR, et al. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature. 2000 Oct 12;407(6805):762–764.
   PubMed Web of Science ®Google Scholar
• 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 Aug;34(2):91–100.
   PubMed Web of Science ®Google Scholar
• Robinson TE, Leung AN, Chen X, et al. Cystic fibrosis HRCT scores correlate strongly with Pseudomonas infection. Pediatr Pulmonol. 2009 Nov;44(11):1107–1117.
   PubMed Web of Science ®Google Scholar
• Aaron SV, Ramotar KL, Giesbrecht-Lewis K, et al. Infection with transmissible strains of pseudomonas aeruginosa and clinical outcomes in adults with cystic fibrosis. J Am Microbiol Assoc. 2010 Nov 17;304(19):2145–3153.
   PubMed Web of Science ®Google Scholar
• Torpedo-Cf NIHR. 2018 [2018 Feb 25]; The TORPEDO-CF trial is funded by NIHR. The information contained in this website is for general information about the TORPEDO-CF trial and is provided by The University of Liverpool Clinical Trials Research Centre.]. Available from: http://www.torpedo-cf.org.uk/
   Google Scholar
• Ahmed B, Bush A, Davies JC. How to use: bacterial cultures in diagnosing lower respiratory tract infections in cystic fibrosis. Arch Dis Child Educ Pract Ed. 2014 Oct;99(5):181–187.
   PubMed Web of Science ®Google Scholar
• Pabary R, Huang J, Kumar S, et al. Selective ion-flow mass spectrometry (SIFT-MS) analysis of exhaled breath as a non-invasive determinant of Pseudomonas aeruginosa infection in CF patients. J Cystic Fibrosis. 2014;13(2):S34.
   Google Scholar
• Robinson M, Bye PTB. Mucociliary clearance in cystic fibrosis. Pediatr Pulmonol. 2002 Apr;33(4):293–306.
   PubMed Web of Science ®Google Scholar
• Flume PA, Mogayzel PJ Jr., Robinson KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009 Nov 1;180(9):802–808.
   PubMed Web of Science ®Google Scholar
• Hoiby N. Recent advances in the treatment of Pseudomonas aeruginosa infections in cystic fibrosis. BMC Med. 2011 Apr 4;9:32.
   PubMed Web of Science ®Google Scholar
• Aloush V, Navon-Venezia S, Seigman-Igra Y, et al. Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrob Agents Chemother. 2006 Jan;50(1):43–48.
   PubMed Web of Science ®Google Scholar
• Smith AL, Fiel SB, Mayer-Hamblett N, et al. Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest. 2003;123:1495–1502.
   PubMed Web of Science ®Google Scholar
• Barraud N, Hassett DJ, Hwang S-H, et al. Involvement of nitric oxide in biofilm dispersal of Pseudomonas aeruginosa. J Bacteriol. 2006 Nov;188(21):7344–7353.
   PubMed Web of Science ®Google Scholar
• Howlin RP, Cathie K, Hall-Stoodley L, et al. Low-dose nitric oxide as targeted anti-biofilm adjunctive therapy to treat chronic pseudomonas aeruginosa infection in cystic fibrosis. Mol Ther. 2017 Sep 6;25(9):2104–2116.
   PubMed Web of Science ®Google Scholar
• Yepuri NR, Barraud N, Mohammadi NS, et al. Synthesis of cephalosporin-3ʹ-diazeniumdiolates: biofilm dispersing NO-donor prodrugs activated by beta-lactamase. Chem Commun. 2013 May 25;49(42):4791–4793.
   PubMed Web of Science ®Google Scholar
• Kutty SK, Barraud N, Ho KK, et al. Hybrids of acylated homoserine lactone and nitric oxide donors as inhibitors of quorum sensing and virulence factors in Pseudomonas aeruginosa. Org Biomol Chem. 2015 Oct 14;13(38):9850–9861.
   PubMed Web of Science ®Google Scholar
• Tateda K, Comte R, Pechere JC, et al. Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2001 Jun;45(6):1930–1933.
   PubMed Web of Science ®Google Scholar
• Bjarnsholt T, Jensen PO, Rasmussen TB, et al. Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiology. 2005 Dec;151(Pt 12):3873–3880.
   PubMedGoogle Scholar
• Persson T, Hansen TH, Rasmussen TB, et al. Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic. Org Biomol Chem. 2005 Jan 21;3(2):253–262.
   PubMed Web of Science ®Google Scholar
• 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 Apr;45(4):356–362.
   PubMed Web of Science ®Google Scholar
• Khan S, Tondervik A, Sletta H, et al. Overcoming drug resistance with alginate oligosaccharides able to potentiate the action of selected antibiotics. Antimicrob Agents Chemother. 2012 Oct;56(10):5134–5141.
   PubMed Web of Science ®Google Scholar
• Tosco A, De Gregorio F, Esposito S, et al. A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR. Cell Death Differ. 2016 Aug;23(8):1380–1393.
   PubMed Web of Science ®Google Scholar
• Ferrari E, Monzani R, Villella VR, et al. Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation. Cell Death Dis. 2017 Jan 12;8(1):e2544.
   PubMedGoogle Scholar
• Brussow H. What is needed for phage therapy to become a reality in Western medicine? Virology. 2012 Dec 20;434(2):138–142.
   PubMed Web of Science ®Google Scholar
• Wright A, Hawkins CH, Anggard EE, et al. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiot ic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol. 2009;34:349–357.
   PubMed Web of Science ®Google Scholar
• Pabary R, Singh C, Morales S, et al. Antipseudomonal bacteriophage reduces infective burden and inflammatory response in murine lung. Antimicrob Agents Chemother. 2016 Feb;60(2):744–751.
   PubMed Web of Science ®Google Scholar
• Martin I, Davies JC, Morales S, et al. WS07.4 Combined killing effects of lytic bacteriophages and antibiotics in biofilm-grown Pseudomonas aeruginosa from CF airway cultures. J Cystic Fibrosis. 2017;16:S12–S13.
   Google Scholar
• Johansen HK, Gotzsche PC. Vaccines for preventing infection with Pseudomonas aeruginosa in cystic fibrosis. Cochrane Database Syst Rev. 2015 Aug;23(8):CD001399.
   Google Scholar
• Thomsen K, Christophersen L, Bjarnsholt T, et al. Anti-Pseudomonas aeruginosa IgY antibodies augment bacterial clearance in a murine pneumonia model. J Cyst Fibros. 2016 Mar;15(2):171–178.
   PubMed Web of Science ®Google Scholar
• Milla CE, Chmiel JF, Accurso FJ, et al. Anti-PcrV antibody in –cystic fibrosis: a novel approach targeting Pseudomonas aeruginosa airway infection. Pediatr Pulmonol. 2014 Jul;49(7):650–658.
   PubMed Web of Science ®Google Scholar
• Jain R, Beckett VV, Konstan MW, et al. KB001-A Study Group. KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa. J Cyst Fibros. 2018 Jul;17(4):484–491.
   PubMed Web of Science ®Google Scholar
• Lu Q, Rouby JJ, Laterre PF, et al. Pharmacokinetics and safety of panobacumab: specific adjunctive immunotherapy in critical patients with nosocomial Pseudomonas aeruginosa O11 pneumonia. J Antimicrob Chemother. 2011 May;66(5):1110–1116.
   PubMed Web of Science ®Google Scholar
• Galietta LJ. Managing the underlying cause of cystic fibrosis: a future role for potentiators and correctors. Paediatric Drugs. 2013 Oct;15(5):393–402.
   PubMed Web of Science ®Google Scholar
• Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011 Nov 3;365(18):1663–1672.
   PubMed Web of Science ®Google Scholar
• Fidler MC, Beusmans J, Panorchan P, et al. Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor. J Cyst Fibros. 2017 Jan;16(1):41–44.
   PubMed Web of Science ®Google Scholar
• Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med. 2016;4(2):107–115.
   PubMed Web of Science ®Google Scholar
• Brewington JJ, McPhail GL, Clancy JP. Lumacaftor alone and combined with ivacaftor: preclinical and clinical trial experience of F508del CFTR correction. Expert Rev Respir Med. 2016;10(1):5–17.
   PubMed Web of Science ®Google Scholar
• Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del CFTR. N Engl J Med. 2015 Jul 16;373(3):220–231.
   PubMed Web of Science ®Google Scholar
• Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017 Nov 23;377(21):2024–2035.
   PubMed Web of Science ®Google Scholar
• Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017 Nov 23;377(21):2013–2023.
   PubMed Web of Science ®Google Scholar
• Tullis E, Colombo C, Davies JC, et al. Preliminary safety and efficacy of triple combination cftr modulator regimens in cystic fibrosis. Pediatr Pulmonol. 2017;52(S47):#246.
   Google Scholar
• Drug Development Pipeline. 2018 [cited 2018 Feb 25]; Available from: https://www.cff.org/Trials/Pipeline
   Google Scholar
• Sawicki GS, McKone EF, Pasta DJ, et al. Sustained benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data. Am J Respir Crit Care Med. 2015 Oct 1;192(7):836–842.
   PubMed Web of Science ®Google Scholar
• A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Ivacaftor in Subjects With Cystic Fibrosis Who Are Less Than 24 Months of Age and Have a CFTR Gating Mutation. 2017 [cited 2018 Feb 25];
   Google Scholar
• Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014 Jul 15;190(2):175–184.
   PubMed Web of Science ®Google Scholar
• 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 Mar 1;60(5):703–712.
   PubMed Web of Science ®Google Scholar
• Hubert D, Dehillotte C, Munck A, et al. Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2 years of treatment with ivacaftor in a real-world setting. J Cyst Fibros. 2018 Jan;17(1):89–95.
   PubMed Web of Science ®Google Scholar
• Hoffman L, Pope C, Jorth P, et al. Short-term and long-term effects of ivacaftor treatment on sputum microbiota in cf patients with the G551d Cftr mutation. Am J Respir Crit Care Med. 2016;193:A2885.
   Google Scholar
• Hisert KB, Heltshe SL, Pope C, et al. Restoring cystic fibrosis transmembrane conductance regulator function reduces airway bacteria and inflammation in people with cystic fibrosis and chronic lung infections. Am J Respir Crit Care Med. 2017 Jun 15;195(12):1617–1628.
   PubMed Web of Science ®Google Scholar
• Strang A, Fischer AJ, Chidekel A. Pseudomonas eradication and clinical effectivness of Ivacaftor in four hispanic patients with S549N. Pediatr Pulmonol. 2017 Jul;52(7):E37–E39.
   PubMed Web of Science ®Google Scholar
• Reznikov LR, Abou Alaiwa MH, Dohrn CL, et al. Antibacterial properties of the CFTR potentiator ivacaftor. J Cyst Fibros. 2014 Sep;13(5):515–519.
   PubMed Web of Science ®Google Scholar
• Schneider EK, Azad MA, Han ML, et al. An “unlikely” pair: the antimicrobial synergy of polymyxin B in combination with the cystic fibrosis transmembrane conductance regulator drugs KALYDECO and ORKAMBI. ACS Infect Dis. 2016 Jul 8;2(7):478–488.
   PubMed Web of Science ®Google Scholar
• Cho DY, Lim DJ, Mackey C, et al. l-Methionine anti-biofilm activity against Pseudomonas aeruginosa is enhanced by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor. Int Forum Allergy Rhinol. 2018 Feb7;5(8):577–583.
   Web of Science ®Google Scholar
• Barnaby R, Koeppen K, Nymon A, et al. Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol. 2017 Nov 16;314(3):432–438.
   PubMed Web of Science ®Google Scholar
• Pohl K, Hayes E, Keenan J, et al. A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy. Blood. 2014 Aug 14;124(7):999–1009.
   PubMed Web of Science ®Google Scholar
• McCarron A, Donnelley M, Parsons D. Airway disease phenotypes in animal models of cystic fibrosis. Respir Res. 2018 Apr 2;19(1):54.
   PubMedGoogle Scholar
• Sun X, Sui H, Fisher JT, et al. Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis. J Clin Invest. 2010 Sep;120(9):3149–3160.
   PubMed Web of Science ®Google Scholar
• Tuggle KL, Birket SE, Cui X, et al. Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats. PloS One. 2014;9(3):e91253.
   PubMed Web of Science ®Google Scholar
• Bratcher PE, Rowe SM, Reeves G, et al. Alterations in blood leukocytes of G551D-bearing cystic fibrosis patients undergoing treatment with ivacaftor. J Cystic Fibrosis: off J Eur Cystic Fibrosis Soc. 2016 Jan;15(1):67–73.
   PubMed Web of Science ®Google Scholar