Targeting the Pseudomonas aeruginosa biofilm to combat infections in patients with cystic fibrosis

Drugs of the Future

Volumn 35, Issue 12, 2010, Pages 1007-1014

  Smyth, Alan R ^a   Hurley, M N ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLCYSTEINE; ALGINIC ACID; ANTIBIOTIC AGENT; AVIBACTAM; AZITHROMYCIN; CEFTAZIDIME; CEFTOBIPROLE; CIPROFLOXACIN; CXA 101; DORIPENEM; GALLIUM NITRATE; GENTAMICIN; LCR 35; LECTIN; LEVOFLOXACIN; MC 02595; MEROPENEM; PROBIOTIC AGENT; TIGECYCLINE; TOBRAMYCIN; TRIMETHOPRIM; UNCLASSIFIED DRUG;

ANTIBIOTIC SENSITIVITY; BACTERIAL CELL; BACTERIAL LOAD; BACTERIOPHAGE; BACTERIUM ISOLATE; BIOFILM; BROTH DILUTION; CONTROLLED STUDY; CYSTIC FIBROSIS; DISEASE ASSOCIATION; DRUG EFFICACY; DRUG POTENTIATION; DRUG TOLERANCE; ENCAPSULATION; EXTRACELLULAR MATRIX; HUMAN; HYDROLYSIS; IRON CHELATION; LACTOBACILLUS RHAMNOSUS; LECTIN BINDING; LUNG INFECTION; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PSEUDOMONAS AERUGINOSA; PSEUDOMONAS INFECTION; QUORUM SENSING; REVIEW; TREATMENT RESPONSE; URINARY TRACT INFECTION;

EID: 79956209908     PISSN: 03778282     EISSN: None     Source Type: Journal    
DOI: 10.1358/dof.2010.035.012.1537937     Document Type: Review

References (99)

1. Sadikot, R.T., Blackwell, T.S., Christman, J.W., Prince, A.S. Pathogen-host interactions in Pseudomonas aeruginosa pneumonia. Am J Respir Crit Care Med 2005, 171(11): 1209-23.
2. Costerton, J.W., Lewandowski, Z., DeBeer, D., Caldwell, D., Korber, D., James, G. Biofilms, the customized microniche. J Bacteriol 1994, 176(8): 2137-42.
3. UK Cystic Fibrosis Trust. UK Cystic Fibrosis Registry 2008 Annual Report: UK Cystic Fibrosis Trust; 2009.
4. 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(2): 91-100.
5. Mouton, J.W., den Hollander, J.G., Horrevorts, A.M. Emergence of antibiotic resistance amongst Pseudomonas aeruginosa isolates from patients with cystic fibrosis. J Antimicrob Chemother 1993, 31(6): 919-26.
6. Oliver, A., Canton, R., Campo, P., Baquero, F., Blazquez, J. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science 2000, 288(5469): 1251-3.
7. Fothergill, J.L., Mowat, E., Ledson, M.J., Walshaw, M.J., Winstanley, C. Fluctuations in phenotypes and genotypes within populations of Pseudomonas aeruginosa in the cystic fibrosis lung during pulmonary exacerbations. J Med Microbiol 2010, 59(Pt. 4): 472-81.
8. Aaron, S.D., Ferris, W., Ramotar, K., Vandemheen, K., Chan, F., Saginur, R. Single and combination antibiotic susceptibilities of planktonic, adherent, and biofilm-grown Pseudomonas aeruginosa isolates cultured from sputa of adults with cystic fibrosis. J Clin Microbiol 2002, 40(11): 4172-9.
9. Singh, P., Schaefer, A., Parsek, M., Moninger, T., Welsh, M., Greenberg, E. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 2000, 407(6805): 762-4.
10. Bjarnsholt, T., Jensen, P.O., Fiandaca, M.J. et al. Pseudomonas aeruginosa biofilms in the respiratory tract of cystic fibrosis patients. Pediatr Pulmonol 2009, 44(6): 547-58.
11. Aaron, S.D., Vandemheen, K.L., 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): 463-71.
12. Drumm, M.L., Konstan, M.W., Schluchter, M.D. et al. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 2005, 353(14): 1443-53.
13. Cox, M.J., Allgaier, M., Taylor, B. et al. Airway microbiota and pathogen abundance in age-stratified cystic fibrosis patients. PLoS ONE 2010, 5(6): e11044.
14. Rogers, G.B., Skelton, S., Serisier, D.J., van der Gast, C.J., Bruce, K.D. Determining cystic fibrosis-affected lung microbiology: Comparison of spontaneous and serially induced sputum samples by use of terminal restriction fragment length polymorphism profiling. J Clin Microbiol 2010, 48(1): 78-86.
15. Yang, L., Haagensen, J.A.J., Jelsbak, L., Johansen, H.K., Sternberg, C., Hoiby, N., Molin, S. In situ growth rates and biofilm development of Pseudomonas aeruginosa populations in chronic lung infections. J Bacteriol 2008, 190(8): 2767-76.
16. Høiby, N., Bjarnsholt, T., Givskov, M., Molin, S., Ciofu, O. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents 2010, 35(4): 322-32.
17. Cernohorská, L., Votava, M. Antibiotic synergy against biofilm-forming Pseudomonas aeruginosa. Folia Microbiol (Praha) 2008, 53(1): 57-60.
18. Mah, T.-F.C., O'Toole, G.A. Mechanisms of biofilm resistance to antimicrobial agents. Trends in Microbiology 2001, 9(1): 34-9.
19. Costerton, J.W., Lewandowski, Z., Caldwell, D.E., Korber, D.R., Lappin-Scott, H.M. Microbial biofilms. Annu Rev Microbiol 1995, 49: 711-45.
20. Lewis, K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol 2007, 5(1): 48-56.
21. European Medicines Agency, European Centre for Disease Prevention and Control. Joint technical report: The bacterial challenge - time to react. September 2009.
22. Hurley, M., Forrester, D., Smyth, A. Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis. Cochrane Database Syst Rev 2010, 10: CD 008037.
23. Diggle, S., Stacey, R., Dodd, C., Cámara, M., Williams, P., Winzer, K. The galactophilic lectin, leca, contributes to biofilm development in Pseudomonas aeruginosa. Environ Microbiol 2006, 8(6): 1095-104.
24. Tielker, D., Hacker, S., Loris, R., et al. Pseudomonas aeruginosa lectin lecb is located in the outer membrane and is involved in biofilm formation. Microbiology 2005, 151(Pt. 5): 1313-23.
25. Branda, S.S., Vik, S., Friedman, L., Kolter, R. Biofilms: The matrix revisited. Trends Microbiol 2005, 13(1): 20-6.
26. Allesen-Holm, M., Barken, K., Yang, L. et al. A characterization of DNA release in Pseudomonas aeruginosa cultures and biofilms. Mol Microbiol 2006, 59(4): 1114-28.
27. Hentzer, M., Teitzel, G., Balzer, G., Heydorn, A., Molin, S., Givskov, M., Parsek, M. Alginate overproduction affects Pseudomonas aeruginosa biofilm structure and function. J Bacteriol 2001, 183(18): 5395-401.
28. Karatan, E., Watnick, P. Signals, regulatory networks, and materials that build and break bacterial biofilms. Microbiol Mol Biol Rev 2009, 73(2): 310-47.
29. Jensen, P., Bjarnsholt, T., Phipps, R. et al. Rapid necrotic killing of polymorphonuclear leukocytes is caused by quorum-sensing-controlled production of rhamnolipid by Pseudomonas aeruginosa. Microbiology 2007, 153(Pt. 5): 1329-38.
30. Alibert-Franco, S., Pradines, B., Mahamoud, A., Davin-Regli, A., Pagès, J. Efflux mechanism, an attractive target to combat multidrug resistant Plasmodium falciparum and Pseudomonas aeruginosa. Curr Med Chem 2009, 16(3): 301-17.
31. Bester, E., Wolfaardt, G., Joubert, L., Garny, K., Saftic, S. Planktonic-cell yield of a pseudomonad biofilm. Appl Environ Microbiol 2005, 71(12): 7792-8.
32. Cystic Fibrosis Trust. Antibiotic treatment for cystic fibrosis - Report of the UK Cystic Fibrosis Trust Antibiotic Working Group. 2009.
33. Høiby, N., Krogh Johansen, H., Moser, C., Song, Z., Ciofu, O., Kharazmi, A. Pseudomonas aeruginosa and the in vitro and in vivo biofilm mode of growth. Microbes Infect 2001, 3(1): 23-35.
34. Dales, L., Ferris, W., Vandemheen, K., Aaron, S.D. Combination antibiotic susceptibility of biofilm-grown Burkholderia cepacia and Pseudomonas aeruginosa isolated from patients with pulmonary exacerbations of cystic fibrosis. Eur J Clin Microbiol Infect Dis 2009, 28(10): 1275-9.
35. Blumer, J.L., Saiman, L., Konstan, M.W., Melnick, D. The efficacy and safety of meropenem and tobramycin vs ceftazidime and tobramycin in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Chest 2005, 128(4): 2336-46.
36. Hill, D., Rose, B., Pajkos, A. et al. Antibiotic susceptabilities of Pseudomonas aeruginosa isolates derived from patients with cystic fibrosis under aerobic, anaerobic, and biofilm conditions. J Clin Microbiol 2005, 43(10): 5085-90.
37. Use of a biofilm antimicrobial susceptibility assay to guide antibiotic therapy (NCT00786513). ClinicalTrials.gov Web site, December 1, 2010.
38. Pritt, B., O'Brien, L., Winn, W. Mucoid pseudomonas in cystic fibrosis. Am J Clin Pathol 2007, 128(1): 32-4.
39. Bragonzi, A., Worlitzsch, D., Pier, G. et al. Nonmucoid Pseudomonas aeruginosa expresses alginate in the lungs of patients with cystic fibrosis and in a mouse model. J Infect Dis 2005, 192(3): 410-9.
40. Stapper, A.P., Narasimhan, G., Ohman, D.E. et al. Alginate production affects Pseudomonas aeruginosa biofilm development and architecture, but is not essential for biofilm formation. J Med Microbiol 2004, 53(7): 679-90.
41. Boyd, A., Chakrabarty, A.M. Role of alginate lyase in cell detachment of Pseudomonas aeruginosa. Appl Environ Microbiol 1994, 60(7): 2355-9.
42. Hatch, R.A., Schiller, N.L. Alginate lyase promotes diffusion of aminoglycosides through the extracellular polysaccharide of mucoid Pseudomonas aeruginosa. Antimicrob Agents Chemother 1998, 42(4): 974-7.
43. Alkawash, M., Soothill, J., Schiller, N. Alginate lyase enhances antibiotic killing of mucoid Pseudomonas aeruginosa in biofilms. APMIS 2006, 114(2): 131-8.
44. Glonti, T., Chanishvili, N., Taylor, P. Bacteriophage-derived enzyme that depolymerizes the alginic acid capsule associated with cystic fibrosis isolates of Pseudomonas aeruginosa. J Appl Microbiol 2010, 108(2): 695-702.
45. Safety and efficacy of inhaled oligog cf-5/20 for the treatment cystic fibrosis (NCT00970346). ClinialTrials.gov Web site, December 1, 2010.
46. Dzieglewska, H., Onsoyen, E., Myrvold, R. (AlgiPharma AS). Use of alginate oligomers in combating biofilms. CA 2706637, WO 2009068841.
47. De Kievit, T., Gillis, R., Marx, S., Brown, C., Iglewski, B. Quorum-sensing genes in Pseudomonas aeruginosa biofilms: Their role and expression patterns. Appl Environ Microbiol 2001, 67(4): 1865-73.
48. Morici, L., Carterson, A., Wagner, V. et al. Pseudomonas aeruginosa algr represses the rhl quorum-sensing system in a biofilm-specific manner. J Bacteriol 2007, 189(21): 7752-64.
49. Laux, D., Corson, J., Givskov, M. et al. Lysophosphatidic acid inhibition of the accumulation of Pseudomonas aeruginosa pao1 alginate, pyoverdin, elastase and lasa. Microbiology 2002, 148(Pt 6): 1709-23.
50. Dubern, J., Diggle, S. Quorum sensing by 2-alkyl-4-quinolones in Pseudomonas aeruginosa and other bacterial species. Mol Biosyst 2008, 4(9): 882-8.
51. Kohler, T., Guanella, R., Carlet, J., van Delden, C. Quorum sensing-dependent virulence during Pseudomonas aeruginosa colonisation and pneumonia in mechanically ventilated patients. Thorax 2010, 65(8): 703-10.
52. Rumbaugh, K., Diggle, S., Watters, C., Ross-Gillespie, A., Griffin, A., West, S. Quorum sensing and the social evolution of bacterial virulence. Curr Biol 2009, 19(4): 341-5.
53. Hentzer, M., Riedel, K., Rasmussen, T. et al. Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology 2002, 148(Pt. 1): 87-102.
54. Bjarnsholt, T., Jensen, P., Rasmussen, T. et al. Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiology 2005, 151(Pt. 12): 3873-80.
55. Hurley, M., Camara, M., Williams, P., Smyth, A. Commercial garlic preparations inhibit quorum sensing lasb and pqsa gene expression in Pseudomonas aeruginosa clinical strains. J Cystic Fibrosis 2010, 9(Suppl. 1): S21.
56. Smyth, A.R., Cifelli, P.M., Ortori, C.A. et al. Garlic as an inhibitor of Pseudomonas aeruginosa quorum sensing in cystic fibrosis - A pilot randomized controlled trial. Pediatr Pulmonol 2010, 45(4): 356-62.
57. Mewe, M., Tielker, D., Schönberg, R., Schachner, M., Jaeger, K., Schumacher, U. Pseudomonas aeruginosa lectins i and ii and their interaction with human airway cilia. J Laryngol Otol 2005, 119(8): 595-9.
58. Adam, E., Mitchell, B., Schumacher, D., Grant, G., Schumacher, U. Pseudomonas aeruginosa ii lectin stops human ciliary beating: Therapeutic implications of fucose. Am J Respir Crit Care Med 1997, 155(6): 2102-4.
59. Johansson, E., Crusz, S., Kolomiets, E. et al. Inhibition and dispersion of Pseudomonas aeruginosa biofilms by glycopeptide dendrimers targeting the fucose-specific lectin lecb. Chem Biol 2008, 15(12): 1249-57.
60. Chemani, C., Imberty, A., de Bentzmann, S., Pierre, M., Wimmerova, M., Guery, B.P., Faure, K. Role of leca and lecb lectins in Pseudomonas aeruginosa-induced lung injury and effect of carbohydrate ligands. Infect Immun 2009, 77(5): 2065-75.
61. Borlee, B.R., Goldman, A.D., Murakami, K., Samudrala, R., Wozniak, D.J., Parsek, M.R. Pseudomonas aeruginosa uses a cyclic-di-gmp-regulated adhesin to reinforce the biofilm extracellular matrix. Mol Microbiol 2010, 75(4): 827-42.
62. Hauber, H., Schulz, M., Pforte, A., Mack, D., Zabel, P., Schumacher, U. Inhalation with fucose and galactose for treatment of Pseudomonas aeruginosa in cystic fibrosis patients. Int J Med Sci 2008, 5(6): 371-6.
63. Jones, A.P., Wallis, C. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev 2010, 3: CD001127.
64. Wark, P., McDonald, V.M. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst Rev 2009, (2): CD001506.
65. Bilton, D. Phase iii study of inhaled dry powder mannitol (bronchitol) in cystic fibrosis - Results from the 6 and 12 month open label phase. J Cystic Fibrosis 2010, 9(Suppl. 1): S21.
66. Zhao, T., Liu, Y. N-Acetylcysteine inhibit biofilms produced by Pseudomonas aeruginosa. BMC Microbiol 2010, 10: 140.
67. Nash, E.F., Stephenson, A., Ratjen, F., Tullis, E. Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis. Cochrane Database Syst Rev 2009, (1): CD007168.
68. Van Daele, S. The effect of inhaled N-acetylcysteine compared to normal saline on sputum rheology and lung function (NCT 00996424). Clinical Trials.gov Web site, December 1, 2010.
69. Parkins, M.D., Elborn, J.S. Newer antibacterial agents and their potential role in cystic fibrosis pulmonary exacerbation management. J Antimicrob Chemother 2010, 65(9): 1853-61.
70. Zamorano, L., Juan, C., Fernández-Olmos, A., Ge, Y., Cantón, R., Oliver, A. Activity of the new cephalosporin cxa-101 (fr264205) against pseudomonas aeruginosa isolates from chronically infected cystic fibrosis patients. Clin Microbiol Infect 2009, Epub ahead of print.
71. Aendekerk, S., Diggle, S., Song, Z., Høiby, N., Cornelis, P., Williams, P., Cámara, M. The mexghi-opmd multidrug efflux pump controls growth, antibiotic susceptibility and virulence in Pseudomonas aeruginosa via 4- quinolone-dependent cell-to-cell communication. Microbiology 2005, 151(Pt. 4): 1113-25.
72. Lomovskaya, O., Warren, M.S., Lee, A. et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: Novel agents for combination therapy. Antimicrob Agents Chemother 2001, 45(1): 105-16.
73. Gentile, A., Saechao, B., Myers, M., Lomovskaya, O., Griffith, D. Pharmacodynamics of levofloxacin (lvx) with or without the broad spectrum efflux pump inhibitor (epi), mc-02,595 (595), in a neutropenic mouse thigh infection model due to strains of P. aeruginosa (pa) overexpressing efflux pumps. 46th Intersci Conf Antimicrob Agents Chemother (ICAAC) (Sept 27-30, San Francisco) 2006, Abst A-15.
74. Liu, Y., Yang, L., Molin, S. Synergistic activities of an efflux pump inhibitor and iron chelators against Pseudomonas aeruginosa growth and biofilm formation. Antimicrob Agents Chemother 2010, 54(9): 3960-3.
75. Banin, E., Lozinski, P., Brady, K.M. et al. The potential of desferrioxamine-gallium as an anti-Pseudomonas therapeutic agent. Proc Natl Acad Sci U S A 2008, 105(43): 16761-6.
76. Halwani, M., Yebio, B., Suntres, Z.E., Alipour, M., Azghani, A.O., Omri, A. Co-encapsulation of gallium with gentamicin in liposomes enhances antimicrobial activity of gentamicin against Pseudomonas aeruginosa. J Antimicrob Chemother 2008, 62(6): 1291-7.
77. A pharmacokinetic and safety study of iv gallium nitrate (ganite) in cystic fibrosis patients (NCT01093521). ClinicalTrials.gov Web site, December 1, 2010.
78. Sahm, D., Pillar, C., Brown, N., Alluru, V., Miossec, C., Levasseur, P. Activity of ceftazidime/NXL104 and select comparators against geographically diverse clinical isolates of Pseudomonas aeruginosa. 49th Intersci Conf Antimicrob Agents Chemother (ICAAC) (Sept 12-15, San Francisco) 2009, Abst E-194.
79. Comparative study of NXL104/ceftazidime versus comparator in adults with complicated urinary tract infections (NCT00690378). ClinicalTrials. gov Web site, December 1, 2010.
80. Piddock, L.J.V., Garvey, M.I., Rahman, M.M., Gibbons, S. Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria. J Antimicrob Chemother 2010, 65(6): 1215-23.
81. Hoffmann, N., Lee, B., Hentzer, M. et al. Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in cftr(-/-) mice. Antimicrob Agents Chemother 2007, 51(10): 3677-87.
82. Southern, K.W., Barker, P.M., Solis, A. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2004, (2): CD002203.
83. Saiman, L., Marshall, B.C., Mayer-Hamblett, N. et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: A randomized controlled trial. JAMA 2003, 290(13): 1749-56.
84. Equi, A., Balfour-Lynn, I.M., Bush, A., Rosenthal, M. Long term azithromycin in children with cystic fibrosis: A randomised, placebo-controlled crossover trial. Lancet 2002, 360(9338): 978-84.
85. 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(3): 212-6.
86. Saiman, L., Anstead, M., Mayer-Hamblett, N. et al. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: A randomized controlled trial. JAMA 2010, 303(17): 1707-15.
87. Tang, B.C., Dawson, M., Lai, S.K. et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci U S A 2009, 106(46): 19268-73.
88. Alipour, M., Suntres, Z.E., Lafrenie, R.M., Omri, A. Attenuation of Pseudomonas aeruginosa virulence factors and biofilms by co-encapsulation of bismuth-ethanedithiol with tobramycin in liposomes. J Antimicrob Chemother 2010, 65(4): 684-93.
89. Nicolosi, D., Scalia, M., Nicolosi, V.M., Pignatello, R. Encapsulation in fusogenic liposomes broadens the spectrum of action of vancomycin against Gram-negative bacteria. Int J Antimicrob Agents 2010, 35(6): 553-8.
90. Tsifansky, M., Yeo, Y., Evgenov, O., Bellas, E., Benjamin, J., Kohane, D. Microparticles for inhalational delivery of antipseudomonal antibiotics. The AAPS J 2008, 10(2): 254-60.
91. Yang, Y., Tsifansky, M., Wu, C.-J., Yang, H.I., Schmidt, G., Yeo, Y. Inhalable antibiotic delivery using a dry powder co-delivering recombinant deoxyribonuclease and ciprofloxacin for treatment of cystic fibrosis. Pharm Res 2010, 27(1): 151-60.
92. Dupont, L., Clancy, J., Minic, P., et al. Evaluation of two phase II blinded and placebo-controlled studies of nebulized liposomal amikacin (Arikace™) in the treatment of cystic fibrosis patients with Pseudomonas aeruginosa lung infection. Am J Respir Crit Care Med 2010, 181 (1, Meeting Abstracts): A1836.
93. Forestier, C., Guelon, D., Cluytens, V., Gillart, T., Sirot, J., De Champs, C. Oral probiotic and prevention of Pseudomonas aeruginosa infections: A randomized, double-blind, placebo-controlled pilot study in intensive care unit patients. Critical Care 2008, 12(3): R69.
94. Pedersen, S.S., Koch, C., Heiby, N., Rosendal, K. An epidemic spread of multiresistant Pseudomonas aeruginosa in a cystic fibrosis centre. J Antimicrob Chemother 1986, 17(4): 505-16.
95. Donlan, R.M. Preventing biofilms of clinically relevant organisms using bacteriophage. Trends Microbiol 2009, 17(2): 66-72.
96. Hagens, S., Habel, A., von Ahsen, U., von Gabain, A., Blasi, U. Therapy of experimental Pseudomonas infections with a nonreplicating genetically modified phage. Antimicrob Agents Chemother 2004, 48(10): 3817-22.
97. Wright, A., Hawkins, C.H., Änggard, E.E., Harper, D.R. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa. Clin Otolaryngol 2009, 34(4): 349-57.
98. Experimental phage therapy of bacterial infections (NCT00945087). ClinicalTrials.gov Web site, December 1, 2010.
99. Sable, C. Prospective multicenter doubleblind randomized study of NXL104/ceftazidime + metronidazole vs. meropenem in treatment of complicated intra-abdominal infections (NCT00752219). ClinicalTrials.gov Web site, December 1, 2010.