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Review article: Biomedical intelligence

Vol. 147 No. 4748 (2017)

Multidrug resistant (or antimicrobial-resistant) pathogens - alternatives to new antibiotics?

  • Anne-Sophie Brunel
  • Benoit Guery
DOI
https://doi.org/10.4414/smw.2017.14553
Cite this as:
Swiss Med Wkly. 2017;147:w14553
Published
22.11.2017

Summary

For the last few decades, multidrug resistance has become an increasing concern for both Gram-positive and Gram-negative bacteria. The number of new molecules has dramatically decreased and antibiotic resistance is now a priority in the international community. Facing this new threat, a large number of new as well as “old” solutions are now being discussed in the medical community to propose an alternative to antibiotic treatments. A first option is to potentiate the effect of existing molecules through combinations to circumvent the individual molecule resistance. The second option is to neutralise either the infectious agent itself or its by-products using specific antibodies. A third option is to use the pathogen signaling mechanism and inhibit the production of virulence factor through quorum sensing inhibition. A fourth pathway would be to interact with the patient’s microbiota using either probiotics or faecal transplantation to modulate the innate immune response and improve response to the infectious challenge, but also to act directly against colonisation by resistant bacteria by replacing the flora with susceptible strains. The last option is to target the bacteria using phage therapy. Phages are natural viruses that specifically infect target bacteria independently of any antibiotic-susceptibility profile. In this review, we will discuss each of these options and provide the scientific rationale and the available clinical data. In the majority of cases, these treatments represent an interesting approach but not the ultimate solution to multiresistance. Well-performed clinical trials are still missing and the major priority remains to promote good use and appropriate stewardship of antibiotics to decrease resistance.

References

  1. Grundmann H, Glasner C, Albiger B, Aanensen DM, Tomlinson CT, Andrasević AT, et al.; European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) Working Group. Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study. Lancet Infect Dis. 2017;17(2):153–63. doi:.https://doi.org/10.1016/S1473-3099(16)30257-2
  2. Denis B, Lafaurie M, Donay JL, Fontaine JP, Oksenhendler E, Raffoux E, et al. Prevalence, risk factors, and impact on clinical outcome of extended-spectrum beta-lactamase-producing Escherichia coli bacteraemia: a five-year study. Int J Infect Dis. 2015;39:1–6. doi:.https://doi.org/10.1016/j.ijid.2015.07.010
  3. Karanika S, Karantanos T, Arvanitis M, Grigoras C, Mylonakis E. Fecal Colonization With Extended-spectrum Beta-lactamase-Producing Enterobacteriaceae and Risk Factors Among Healthy Individuals: A Systematic Review and Metaanalysis. Clin Infect Dis. 2016;63(3):310–8. doi:.https://doi.org/10.1093/cid/ciw283
  4. Bassetti M, Poulakou G, Ruppe E, Bouza E, Van Hal SJ, Brink A. Antimicrobial resistance in the next 30 years, humankind, bugs and drugs: a visionary approach. Intensive Care Med. 2017;43(10):1464–75. doi:.https://doi.org/10.1007/s00134-017-4878-x
  5. Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother. 2014;15(10):1351–70. doi:.https://doi.org/10.1517/14656566.2014.914172
  6. Falagas ME, Kasiakou SK, Saravolatz LD. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005;40(9):1333–41. doi:. Corrected in: Clin Infect Dis. 2006;42(12):1819.https://doi.org/10.1086/429323
  7. Michalopoulos AS, Tsiodras S, Rellos K, Mentzelopoulos S, Falagas ME. Colistin treatment in patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria: the renaissance of an old antibiotic. Clin Microbiol Infect. 2005;11(2):115–21. doi:.https://doi.org/10.1111/j.1469-0691.2004.01043.x
  8. Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. Int J Infect Dis. 2011;15(11):e732–9. doi:.https://doi.org/10.1016/j.ijid.2011.07.007
  9. Linden PK, Kusne S, Coley K, Fontes P, Kramer DJ, Paterson D. Use of parenteral colistin for the treatment of serious infection due to antimicrobial-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2003;37(11):e154–60. doi:.https://doi.org/10.1086/379611
  10. Linden PK, Paterson DL. Parenteral and inhaled colistin for treatment of ventilator-associated pneumonia. Clin Infect Dis. 2006;43(Suppl 2):S89–94. doi:.https://doi.org/10.1086/504485
  11. Falagas ME, Rafailidis PI, Ioannidou E, Alexiou VG, Matthaiou DK, Karageorgopoulos DE, et al. Colistin therapy for microbiologically documented multidrug-resistant Gram-negative bacterial infections: a retrospective cohort study of 258 patients. Int J Antimicrob Agents. 2010;35(2):194–9. doi:.https://doi.org/10.1016/j.ijantimicag.2009.10.005
  12. Michalopoulos A, Kasiakou SK, Mastora Z, Rellos K, Kapaskelis AM, Falagas ME. Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis. Crit Care. 2005;9(1):R53–9. doi:.https://doi.org/10.1186/cc3020
  13. Falagas ME, Bliziotis IA, Kasiakou SK, Samonis G, Athanassopoulou P, Michalopoulos A. Outcome of infections due to pandrug-resistant (PDR) Gram-negative bacteria. BMC Infect Dis. 2005;5(1):24. doi:.https://doi.org/10.1186/1471-2334-5-24
  14. Tascini C, Ferranti S, Messina F, Menichetti F. In vitro and in vivo synergistic activity of colistin, rifampin, and amikacin against a multiresistant Pseudomonas aeruginosa isolate. Clin Microbiol Infect. 2000;6(12):690–1. doi:.https://doi.org/10.1046/j.1469-0691.2000.00169.x
  15. Tascini C, Gemignani G, Ferranti S, Tagliaferri E, Leonildi A, Lucarini A, et al. Microbiological activity and clinical efficacy of a colistin and rifampin combination in multidrug-resistant Pseudomonas aeruginosa infections. J Chemother. 2004;16(3):282–7. doi:.https://doi.org/10.1179/joc.2004.16.3.282
  16. Olaitan AO, Morand S, Rolain J-M. Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. Front Microbiol. 2014;5:643. doi:.https://doi.org/10.3389/fmicb.2014.00643
  17. Zusman O, Altunin S, Koppel F, Dishon Benattar Y, Gedik H, Paul M. Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(1):29–39. doi:.https://doi.org/10.1093/jac/dkw377
  18. Dickstein Y, Leibovici L, Yahav D, Eliakim-Raz N, Daikos GL, Skiada A, et al.; AIDA consortium. Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol. BMJ Open. 2016;6(4):e009956–10. doi:.https://doi.org/10.1136/bmjopen-2015-009956
  19. Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin. Clin Microbiol Rev. 2016;29(2):321–47. doi:.https://doi.org/10.1128/CMR.00068-15
  20. Bassetti M, Giacobbe DR, Giamarellou H, Viscoli C, Daikos GL, Dimopoulos G, et al.; Critically Ill Patients Study Group of the European Society of Clinical Microbiology and Infectious Disease (ESCMID); Hellenic Society of Chemotherapy (HSC) and Società Italiana di Terapia Antinfettiva (SITA). Management of KPC-producing Klebsiella pneumoniae infections. Clin Microbiol Infect. 2017;S1198-743X(17)30499-8.
  21. Falagas ME, Kastoris AC, Karageorgopoulos DE, Rafailidis PI. Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents. 2009;34(2):111–20. doi:.https://doi.org/10.1016/j.ijantimicag.2009.03.009
  22. Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M, et al. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Agents. 2014;43(1):52–9. doi:.https://doi.org/10.1016/j.ijantimicag.2013.09.010
  23. Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M, et al.; ISGRI-SITA (Italian Study Group on Resistant Infections of the Società Italiana Terapia Antinfettiva). Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother. 2015;70(7):2133–43. doi:.https://doi.org/10.1093/jac/dkv086
  24. Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014;58(4):2322–8. doi:.https://doi.org/10.1128/AAC.02166-13
  25. Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect. 2014;20(9):862–72. doi:.https://doi.org/10.1111/1469-0691.12697
  26. Giannella M, Trecarichi EM, Giacobbe DR, De FG, Bassetti M, Bartoloni A, et al.; Italian Study Group on Resistant Infections of the Società Italiana Terapia Antinfettiva (ISGRI-SITA). Effect of combination therapy containing a high dose carbapenem on mortality in patients with carbapenem-resistant klebsiella pneumoniae bloodstream infection. Int J Antimicrob Agents. 2017;S0924-8579(17)30311-4.
  27. Munita JM, Aitken SL, Miller WR, Pérez F, Rosa R, Shimose LA, et al. Multicenter Evaluation of Ceftolozane/Tazobactam for Serious Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa. Clin Infect Dis. 2017;65(1):158–61. doi:.https://doi.org/10.1093/cid/cix014
  28. Temkin E, Torre-Cisneros J, Beovic B, Benito N, Giannella M, Gilarranz R, et al. Ceftazidime-avibactam as salvage therapy for infections caused by carbapenem-resistant organisms: a case series from the compassionate-use program. Antimicrob Agents Chemother. 2017; 61: e01964–16.
  29. Bassetti M, Carnelutti A, Peghin M. Patient specific risk stratification for antimicrobial resistance and possible treatment strategies in gram-negative bacterial infections. Expert Rev Anti Infect Ther. 2017;15(1):55–65. doi:.https://doi.org/10.1080/14787210.2017.1251840
  30. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012;55(7):943–50. doi:.https://doi.org/10.1093/cid/cis588
  31. Gutiérrez-Gutiérrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Paño-Pardo JR, et al.; REIPI/ESGBIS/INCREMENT Investigators. Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis. 2017;17(7):726–34. doi:.https://doi.org/10.1016/S1473-3099(17)30228-1
  32. Ersoy SC, Heithoff DM, Barnes L, 5th, Tripp GK, House JK, Marth JD, et al. Correcting a Fundamental Flaw in the Paradigm for Antimicrobial Susceptibility Testing. EBioMedicine. 2017;20(C):173–81. doi:.https://doi.org/10.1016/j.ebiom.2017.05.026
  33. Whang DW, Miller LG, Partain NM, McKinnell JA. Systematic review and meta-analysis of linezolid and daptomycin for treatment of vancomycin-resistant enterococcal bloodstream infections. Antimicrob Agents Chemother. 2013;57(10):5013–8. doi:.https://doi.org/10.1128/AAC.00714-13
  34. Balli EP, Venetis CA, Miyakis S. Systematic review and meta-analysis of linezolid versus daptomycin for treatment of vancomycin-resistant enterococcal bacteremia. Antimicrob Agents Chemother. 2014;58(2):734–9. doi:.https://doi.org/10.1128/AAC.01289-13
  35. Chuang Y-C, Wang J-T, Lin H-Y, Chang S-C. Daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bacteremia: systematic review and meta-analysis. BMC Infect Dis. 2014;14(1):687. doi:.https://doi.org/10.1186/s12879-014-0687-9
  36. McKinnell JA, Arias CA. Editorial Commentary: Linezolid vs Daptomycin for Vancomycin-Resistant Enterococci: The Evidence Gap Between Trials and Clinical Experience. Clin Infect Dis. 2015;61(6):879–82. doi:.https://doi.org/10.1093/cid/civ449
  37. Britt NS, Potter EM, Patel N, Steed ME. Comparison of the Effectiveness and Safety of Linezolid and Daptomycin in Vancomycin-Resistant Enterococcal Bloodstream Infection: A National Cohort Study of Veterans Affairs Patients. Clin Infect Dis. 2015;61(6):871–8. doi:.https://doi.org/10.1093/cid/civ444
  38. Chuang YC, Lin HY, Chen PY, Lin CY, Wang JT, Chang SC. Daptomycin versus linezolid for the treatment of vancomycin-resistant enterococcal bacteraemia: implications of daptomycin dose. Clin Microbiol Infect. 2016;22(10):890.e1–7. doi:.https://doi.org/10.1016/j.cmi.2016.07.018
  39. Britt NS, Potter EM, Patel N, Steed ME. Comparative Effectiveness and Safety of Standard-, Medium-, and High-Dose Daptomycin Strategies for the Treatment of Vancomycin-Resistant Enterococcal Bacteremia Among Veterans Affairs Patients. Clin Infect Dis. 2017;64(5):605–13.
  40. Arias CA, Torres HA, Singh KV, Panesso D, Moore J, Wanger A, et al. Failure of daptomycin monotherapy for endocarditis caused by an Enterococcus faecium strain with vancomycin-resistant and vancomycin-susceptible subpopulations and evidence of in vivo loss of the vanA gene cluster. Clin Infect Dis. 2007;45(10):1343–6. doi:.https://doi.org/10.1086/522656
  41. Britt NS, Potter EM, Patel N, Steed ME. Comparative Effectiveness and Safety of Standard-, Medium-, and High-Dose Daptomycin Strategies for the Treatment of Vancomycin-Resistant Enterococcal Bacteremia Among Veterans Affairs Patients. Clin Infect Dis. 2017;64(5):605–13.
  42. Chuang Y-C, Lin H-Y, Chen P-Y, Lin C-Y, Wang J-T, Chen Y-C, et al. Effect of Daptomycin Dose on the Outcome of Vancomycin-Resistant, Daptomycin-Susceptible Enterococcus faecium Bacteremia. Clin Infect Dis. 2017;64(8):1026–34. doi:.https://doi.org/10.1093/cid/cix024
  43. Kelesidis T, Humphries R, Uslan DZ, Pegues DA. Daptomycin nonsusceptible enterococci: an emerging challenge for clinicians. Clin Infect Dis. 2011;52(2):228–34. doi:.https://doi.org/10.1093/cid/ciq113
  44. Munita JM, Murray BE, Arias CA. Daptomycin for the treatment of bacteraemia due to vancomycin-resistant enterococci. Int J Antimicrob Agents. 2014;44(5):387–95. doi:.https://doi.org/10.1016/j.ijantimicag.2014.08.002
  45. Sakoulas G, Bayer AS, Pogliano J, Tsuji BT, Yang S-J, Mishra NN, et al. Ampicillin enhances daptomycin- and cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother. 2012;56(2):838–44. doi:.https://doi.org/10.1128/AAC.05551-11
  46. Sakoulas G, Rose W, Nonejuie P, Olson J, Pogliano J, Humphries R, et al. Ceftaroline restores daptomycin activity against daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother. 2014;58(3):1494–500. doi:.https://doi.org/10.1128/AAC.02274-13
  47. Arias CA, Contreras GA, Murray BE. Management of multidrug-resistant enterococcal infections. Clin Microbiol Infect. 2010;16(6):555–62. doi:.https://doi.org/10.1111/j.1469-0691.2010.03214.x
  48. Egli A, Schmid H, Kuenzli E, Widmer AF, Battegay M, Plagge H, et al. Association of daptomycin use with resistance development in Enterococcus faecium bacteraemia-a 7-year individual and population-based analysis. Clin Microbiol Infect. 2017;23(2):118.e1–7. doi:.https://doi.org/10.1016/j.cmi.2016.10.003
  49. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18–55.
  50. Mehta S, Singh C, Plata KB, Chanda PK, Paul A, Riosa S, et al. β-Lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant Staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives. Antimicrob Agents Chemother. 2012;56(12):6192–200. doi:.https://doi.org/10.1128/AAC.01525-12
  51. Dhand A, Bayer AS, Pogliano J, Yang S-J, Bolaris M, Nizet V, et al. Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding. Clin Infect Dis. 2011;53(2):158–63. doi:.https://doi.org/10.1093/cid/cir340
  52. Sakoulas G, Okumura CY, Thienphrapa W, Olson J, Nonejuie P, Dam Q, et al. Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus. J Mol Med (Berl). 2014;92(2):139–49. doi:.https://doi.org/10.1007/s00109-013-1100-7
  53. Rose WE, Schulz LT, Andes D, Striker R, Berti AD, Hutson PR, et al. Addition of ceftaroline to daptomycin after emergence of daptomycin-nonsusceptible Staphylococcus aureus during therapy improves antibacterial activity. Antimicrob Agents Chemother. 2012;56(10):5296–302. doi:.https://doi.org/10.1128/AAC.00797-12
  54. Sakoulas G, Moise PA, Casapao AM, Nonejuie P, Olson J, Okumura CYM, et al. Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline. Clin Ther. 2014;36(10):1317–33. doi:.https://doi.org/10.1016/j.clinthera.2014.05.061
  55. Nigo M, Diaz L, Carvajal LP, Tran TT, Rios R, Panesso D, et al. Ceftaroline-Resistant, Daptomycin-Tolerant, and Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus Causing Infective Endocarditis. Antimicrob Agents Chemother. 2017;61(3):e01235-16. doi:.https://doi.org/10.1128/AAC.01235-16
  56. Dilworth TJ, Sliwinski J, Ryan K, Dodd M, Mercier R-C. Evaluation of vancomycin in combination with piperacillin-tazobactam or oxacillin against clinical methicillin-resistant Staphylococcus aureus Isolates and vancomycin-intermediate S. aureus isolates in vitro. Antimicrob Agents Chemother. 2014;58(2):1028–33. doi:.https://doi.org/10.1128/AAC.01888-13
  57. Werth BJ, Vidaillac C, Murray KP, Newton KL, Sakoulas G, Nonejuie P, et al. Novel combinations of vancomycin plus ceftaroline or oxacillin against methicillin-resistant vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA. Antimicrob Agents Chemother. 2013;57(5):2376–9. doi:.https://doi.org/10.1128/AAC.02354-12
  58. Barber KE, Rybak MJ, Sakoulas G. Vancomycin plus ceftaroline shows potent in vitro synergy and was successfully utilized to clear persistent daptomycin-non-susceptible MRSA bacteraemia. J Antimicrob Chemother. 2015;70(1):311–3. doi:.https://doi.org/10.1093/jac/dku322
  59. Shaw E, Miró JM, Puig-Asensio M, Pigrau C, Barcenilla F, Murillas J, et al.; Spanish Network for Research in Infectious Diseases (REIPI RD12/0015); Instituto de Salud Carlos III, Madrid, Spain; GEIH (Hospital Infection Study Group). Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial. BMJ Open. 2015;5(3):e006723. doi:.https://doi.org/10.1136/bmjopen-2014-006723
  60. Chen L-Y, Huang C-H, Kuo S-C, Hsiao C-Y, Lin M-L, Wang F-D, et al. High-dose daptomycin and fosfomycin treatment of a patient with endocarditis caused by daptomycin-nonsusceptible Staphylococcus aureus: case report. BMC Infect Dis. 2011;11(1):152. doi:.https://doi.org/10.1186/1471-2334-11-152
  61. Miró JM, Entenza JM, Del Río A, Velasco M, Castañeda X, Garcia de la Mària C, et al.; Hospital Clinic Experimental Endocarditis Study Group. High-dose daptomycin plus fosfomycin is safe and effective in treating methicillin-susceptible and methicillin-resistant Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 2012;56(8):4511–5. doi:.https://doi.org/10.1128/AAC.06449-11
  62. Miró JM, García-de-la-Mària C, Armero Y, Soy D, Moreno A, del Río A, et al.; Hospital Clinic Experimental Endocarditis Study Group. Addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2009;53(10):4172–7. doi:.https://doi.org/10.1128/AAC.00051-09
  63. Davis JS, Sud A, O’Sullivan MVN, Robinson JO, Ferguson PE, Foo H, et al.; Combination Antibiotics for MEthicillin Resistant Staphylococcus aureus (CAMERA) study group; Combination Antibiotics for MEthicillin Resistant Staphylococcus aureus (CAMERA) study group. Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial. Clin Infect Dis. 2016;62(2):173–80. doi:.https://doi.org/10.1093/cid/civ808
  64. Tong SYC, Nelson J, Paterson DL, Fowler VG, Jr, Howden BP, Cheng AC, et al.; CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research Network. CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: study protocol for a randomised controlled trial. Trials. 2016;17(1):170. doi:.https://doi.org/10.1186/s13063-016-1295-3
  65. Poulakou G, Matthaiou DK, Bassetti M, Erdem H, Dimopoulos G, Curcio DJ, et al.; ESGCIP Investigators. “Salvage treatment” for infections by extensively- and pan-drug-resistant pathogens is common and often sub-optimal. Intensive Care Med. 2017;43(8):1164–6. doi:.https://doi.org/10.1007/s00134-017-4796-y
  66. Behring E, Kitasato S. Ueber das Zustandekommen der Diphtherie-Immunität und der Tetanus-Immunität bei Thieren. Dtsch Med Wochenschr. 1890;16(49):1113–4. doi:.https://doi.org/10.1055/s-0029-1207589
  67. Casadevall A, Scharff MD. Return to the past: the case for antibody-based therapies in infectious diseases. Clin Infect Dis. 1995;21(1):150–61. doi:.https://doi.org/10.1093/clinids/21.1.150
  68. Cavaillon J-M, Eisen D, Annane D. Is boosting the immune system in sepsis appropriate? Crit Care. 2014;18(2):216. doi:.https://doi.org/10.1186/cc13787
  69. Kreymann KG, de Heer G, Nierhaus A, Kluge S. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med. 2007;35(12):2677–85.
  70. Turgeon AF, Hutton B, Fergusson DA, McIntyre L, Tinmouth AA, Cameron DW, et al. Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med. 2007;146(3):193–203. doi:.https://doi.org/10.7326/0003-4819-146-3-200702060-00009
  71. Alejandria MM, Lansang MAD, Dans LF, Mantaring JB, 3rd. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013;273(9):CD001090.
  72. Cavazzuti I, Serafini G, Busani S, Rinaldi L, Biagioni E, Buoncristiano M, et al. Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock. Intensive Care Med. 2014;40(12):1888–96. doi:.https://doi.org/10.1007/s00134-014-3474-6
  73. Ziegler EJ, Fisher CJ, Jr, Sprung CL, Straube RC, Sadoff JC, Foulke GE, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med. 1991;324(7):429–36. doi:.https://doi.org/10.1056/NEJM199102143240701
  74. McCloskey RV, Straube RC, Sanders C, Smith SM, Smith CR ; CHESS Trial Study Group. Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1994;121(1):1–5. doi:.https://doi.org/10.7326/0003-4819-121-1-199407010-00001
  75. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987;330(6149):662–4. doi:.https://doi.org/10.1038/330662a0
  76. Arndt P, Abraham E. Immunological therapy of sepsis: experimental therapies. Intensive Care Med. 2001;27(0, Suppl 1):S104–15. doi:.https://doi.org/10.1007/s001340000574
  77. Lorente JA, Marshall JC. Neutralization of tumor necrosis factor in preclinical models of sepsis. Shock. 2005;24(Suppl 1):107–19. doi:.https://doi.org/10.1097/01.shk.0000191343.21228.78
  78. Fisher CJ, Jr, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271(23):1836–43. doi:.https://doi.org/10.1001/jama.1994.03510470040032
  79. Opal SM, Fisher CJ, Jr, Dhainaut JF, Vincent J-L, Brase R, Lowry SF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med. 1997;25(7):1115–24. doi:.https://doi.org/10.1097/00003246-199707000-00010
  80. Opal SM, Laterre P-F, Francois B, LaRosa SP, Angus DC, Mira J-P, et al.; ACCESS Study Group. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013;309(11):1154–62. doi:.https://doi.org/10.1001/jama.2013.2194
  81. Chang K, Svabek C, Vazquez-Guillamet C, Sato B, Rasche D, Wilson S, et al. Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit Care. 2014;18(1):R3. doi:.https://doi.org/10.1186/cc13176
  82. Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol. 2010;88(2):233–40. doi:.https://doi.org/10.1189/jlb.0110037
  83. Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN, Hültner L, et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med. 2000;6(2):164–70. doi:.https://doi.org/10.1038/72262
  84. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA. 2004;101(1):296–301. doi:.https://doi.org/10.1073/pnas.2434651100
  85. Weisman LE, Fischer GW, Thackray HM, Johnson KE, Schuman RF, Mandy GT, et al. Safety and pharmacokinetics of a chimerized anti-lipoteichoic acid monoclonal antibody in healthy adults. Int Immunopharmacol. 2009;9(5):639–44. doi:.https://doi.org/10.1016/j.intimp.2009.02.008
  86. Weisman LE, Thackray HM, Garcia-Prats JA, Nesin M, Schneider JH, Fretz J, et al. Phase 1/2 double-blind, placebo-controlled, dose escalation, safety, and pharmacokinetic study of pagibaximab (BSYX-A110), an antistaphylococcal monoclonal antibody for the prevention of staphylococcal bloodstream infections, in very-low-birth-weight neonates. Antimicrob Agents Chemother. 2009;53(7):2879–86. doi:.https://doi.org/10.1128/AAC.01565-08
  87. Weisman LE, Thackray HM, Steinhorn RH, Walsh WF, Lassiter HA, Dhanireddy R, et al. A randomized study of a monoclonal antibody (pagibaximab) to prevent staphylococcal sepsis. Pediatrics. 2011;128(2):271–9. doi:.https://doi.org/10.1542/peds.2010-3081
  88. Hetherington S, Texter M, Wenzel E, Patti JM, Reynolds L, Shamp T, et al. Phase I dose escalation study to evaluate the safety and pharmacokinetic profile of tefibazumab in subjects with end-stage renal disease requiring hemodialysis. Antimicrob Agents Chemother. 2006;50(10):3499–500. doi:.https://doi.org/10.1128/AAC.00407-06
  89. Weems JJ, Jr, Steinberg JP, Filler S, Baddley JW, Corey GR, Sampathkumar P, et al. Phase II, randomized, double-blind, multicenter study comparing the safety and pharmacokinetics of tefibazumab to placebo for treatment of Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2006;50(8):2751–5. doi:.https://doi.org/10.1128/AAC.00096-06
  90. Benjamin DK, Schelonka R, White R, Holley HP, Bifano E, Cummings J, et al.; S. aureus prevention investigators. A blinded, randomized, multicenter study of an intravenous Staphylococcus aureus immune globulin. J Perinatol. 2006;26(5):290–5. doi:.https://doi.org/10.1038/sj.jp.7211496
  91. Rupp ME, Holley HP, Jr, Lutz J, Dicpinigaitis PV, Woods CW, Levine DP, et al. Phase II, randomized, multicenter, double-blind, placebo-controlled trial of a polyclonal anti-Staphylococcus aureus capsular polysaccharide immune globulin in treatment of Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2007;51(12):4249–54. doi:.https://doi.org/10.1128/AAC.00570-07
  92. Landrum ML, Lalani T, Niknian M, Maguire JD, Hospenthal DR, Fattom A, et al. Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults. Hum Vaccin Immunother. 2017;13(4):791–801. doi:.https://doi.org/10.1080/21645515.2016.1248326
  93. Adhikari RP, Kort T, Shulenin S, Kanipakala T, Ganjbaksh N, Roghmann M-C, et al. Antibodies to S. aureus LukS-PV Attenuated Subunit Vaccine Neutralize a Broad Spectrum of Canonical and Non-Canonical Bicomponent Leukotoxin Pairs. PLoS One. 2015;10(9):e0137874. doi:. PLoS One. 2015;10(11) e0143493. https://doi.org/10.1371/journal.pone.0143493https://doi.org/10.1371/journal.pone.0137874
  94. Bagnoli F, Fontana MR, Soldaini E, Mishra RPN, Fiaschi L, Cartocci E, et al. Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus. Proc Natl Acad Sci USA. 2015;112(12):3680–5.
  95. Tkaczyk C, Hua L, Varkey R, Shi Y, Dettinger L, Woods R, et al. Identification of anti-alpha toxin monoclonal antibodies that reduce the severity of Staphylococcus aureus dermonecrosis and exhibit a correlation between affinity and potency. Clin Vaccine Immunol. 2012;19(3):377–85. doi:.https://doi.org/10.1128/CVI.05589-11
  96. Ragle BE, Bubeck Wardenburg J. Anti-alpha-hemolysin monoclonal antibodies mediate protection against Staphylococcus aureus pneumonia. Infect Immun. 2009;77(7):2712–8. doi:.https://doi.org/10.1128/IAI.00115-09
  97. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis. 2010;51(S1, Suppl 1):S81–7. doi:.https://doi.org/10.1086/653053
  98. Kipnis E, Sawa T, Wiener-Kronish J. Targeting mechanisms of Pseudomonas aeruginosa pathogenesis. Med Mal Infect. 2006;36(2):78–91. doi:.https://doi.org/10.1016/j.medmal.2005.10.007
  99. Hauser AR. The type III secretion system of Pseudomonas aeruginosa: infection by injection. Nat Rev Microbiol. 2009;7(9):654–65. doi:.https://doi.org/10.1038/nrmicro2199
  100. Hueck CJ. Type III protein secretion systems in bacterial pathogens of animals and plants. Microbiol Mol Biol Rev. 1998;62(2):379–433.
  101. Cornelis GR, Van Gijsegem F. Assembly and function of type III secretory systems. Annu Rev Microbiol. 2000;54(1):735–74. doi:.https://doi.org/10.1146/annurev.micro.54.1.735
  102. Sawa T, Yahr TL, Ohara M, Kurahashi K, Gropper MA, Wiener-Kronish JP, et al. Active and passive immunization with the Pseudomonas V antigen protects against type III intoxication and lung injury. Nat Med. 1999;5(4):392–8. doi:.https://doi.org/10.1038/7391
  103. Neely AN, Holder IA, Wiener-Kronish JP, Sawa T. Passive anti-PcrV treatment protects burned mice against Pseudomonas aeruginosa challenge. Burns. 2005;31(2):153–8. doi:.https://doi.org/10.1016/j.burns.2004.09.002
  104. Kurahashi K, Kajikawa O, Sawa T, Ohara M, Gropper MA, Frank DW, et al. Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia. J Clin Invest. 1999;104(6):743–50. doi:.https://doi.org/10.1172/JCI7124
  105. Allewelt M, Coleman FT, Grout M, Priebe GP, Pier GB. Acquisition of expression of the Pseudomonas aeruginosa ExoU cytotoxin leads to increased bacterial virulence in a murine model of acute pneumonia and systemic spread. Infect Immun. 2000;68(7):3998–4004. doi:.https://doi.org/10.1128/IAI.68.7.3998-4004.2000
  106. Ader F, Le Berre R, Faure K, Gosset P, Epaulard O, Toussaint B, et al. Alveolar response to Pseudomonas aeruginosa: role of the type III secretion system. Infect Immun. 2005;73(7):4263–71. doi:.https://doi.org/10.1128/IAI.73.7.4263-4271.2005
  107. Hauser AR, Cobb E, Bodi M, Mariscal D, Vallés J, Engel JN, et al. Type III protein secretion is associated with poor clinical outcomes in patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Crit Care Med. 2002;30(3):521–8. doi:.https://doi.org/10.1097/00003246-200203000-00005
  108. Sawa T, Shimizu M, Moriyama K, Wiener-Kronish JP. Association between Pseudomonas aeruginosa type III secretion, antibiotic resistance, and clinical outcome: a review. Crit Care. 2014;18(6):668. doi:.https://doi.org/10.1186/s13054-014-0668-9
  109. François B, Luyt C-E, Dugard A, Wolff M, Diehl J-L, Jaber S, et al. Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Pseudomonas aeruginosa: a randomized,double-blind, placebo-controlled trial. Crit Care Med. 2012;40(8):2320–6. doi:.https://doi.org/10.1097/CCM.0b013e31825334f6
  110. Song Y, Baer M, Srinivasan R, Lima J, Yarranton G, Bebbington C, et al. PcrV antibody-antibiotic combination improves survival in Pseudomonas aeruginosa-infected mice. Eur J Clin Microbiol Infect Dis. 2012;31(8):1837–45. doi:.https://doi.org/10.1007/s10096-011-1509-2
  111. Al-Hamad A, Burnie J, Upton M. Enhancement of antibiotic susceptibility of Stenotrophomonas maltophilia using a polyclonal antibody developed against an ABC multidrug efflux pump. Can J Microbiol. 2011;57(10):820–8. doi:.https://doi.org/10.1139/w11-076
  112. Lindorfer MA, Nardin A, Foley PL, Solga MD, Bankovich AJ, Martin EN, et al. Targeting of Pseudomonas aeruginosa in the bloodstream with bispecific monoclonal antibodies. J Immunol. 2001;167(4):2240–9. doi:.https://doi.org/10.4049/jimmunol.167.4.2240
  113. Mohamed N, Clagett M, Li J, Jones S, Pincus S, D’Alia G, et al. A high-affinity monoclonal antibody to anthrax protective antigen passively protects rabbits before and after aerosolized Bacillus anthracis spore challenge. Infect Immun. 2005;73(2):795–802. doi:.https://doi.org/10.1128/IAI.73.2.795-802.2005
  114. Gyimesi E, Bankovich AJ, Schuman TA, Goldberg JB, Lindorfer MA, Taylor RP. Staphylococcus aureus bound to complement receptor 1 on human erythrocytes by bispecific monoclonal antibodies is phagocytosed by acceptor macrophages. Immunol Lett. 2004;95(2):185–92. doi:.https://doi.org/10.1016/j.imlet.2004.07.007
  115. Matthews RC, Rigg G, Hodgetts S, Carter T, Chapman C, Gregory C, et al. Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90. Antimicrob Agents Chemother. 2003;47(7):2208–16. doi:.https://doi.org/10.1128/AAC.47.7.2208-2216.2003
  116. Nooney L, Matthews RC, Burnie JP. Evaluation of Mycograb, amphotericin B, caspofungin, and fluconazole in combination against Cryptococcus neoformans by checkerboard and time-kill methodologies. Diagn Microbiol Infect Dis. 2005;51(1):19–29. doi:.https://doi.org/10.1016/j.diagmicrobio.2004.08.013
  117. Pachl J, Svoboda P, Jacobs F, Vandewoude K, van der Hoven B, Spronk P, et al.; Mycograb Invasive Candidiasis Study Group. A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin Infect Dis. 2006;42(10):1404–13. doi:.https://doi.org/10.1086/503428
  118. Bugli F, Cacaci M, Martini C, Torelli R, Posteraro B, Sanguinetti M, et al. Human monoclonal antibody-based therapy in the treatment of invasive candidiasis. Clin Dev Immunol. 2013;2013(3):403121.
  119. Antunes LCM, Ferreira RBR, Buckner MMC, Finlay BB. Quorum sensing in bacterial virulence. Microbiology. 2010;156(Pt 8):2271–82. doi:.https://doi.org/10.1099/mic.0.038794-0
  120. Malone CL, Boles BR, Horswill AR. Biosynthesis of Staphylococcus aureus autoinducing peptides by using the synechocystis DnaB mini-intein. Appl Environ Microbiol. 2007;73(19):6036–44. doi:.https://doi.org/10.1128/AEM.00912-07
  121. Cirioni O, Ghiselli R, Minardi D, Orlando F, Mocchegiani F, Silvestri C, et al. RNAIII-inhibiting peptide affects biofilm formation in a rat model of staphylococcal ureteral stent infection. Antimicrob Agents Chemother. 2007;51(12):4518–20. doi:.https://doi.org/10.1128/AAC.00808-07
  122. Simonetti O, Cirioni O, Cacciatore I, Baldassarre L, Orlando F, Pierpaoli E, et al. Efficacy of the Quorum Sensing Inhibitor FS10 Alone and in Combination with Tigecycline in an Animal Model of Staphylococcal Infected Wound. PLoS One. 2016;11(6):e0151956–12. doi:.https://doi.org/10.1371/journal.pone.0151956
  123. Silva LN, Da Hora GCA, Soares TA, Bojer MS, Ingmer H, Macedo AJ, et al. Myricetin protects Galleria mellonella against Staphylococcus aureus infection and inhibits multiple virulence factors. Sci Rep. 2017;7(1):2823. doi:.https://doi.org/10.1038/s41598-017-02712-1
  124. Lee J, Zhang L. The hierarchy quorum sensing network in Pseudomonas aeruginosa. Protein Cell. 2015;6(1):26–41. doi:.https://doi.org/10.1007/s13238-014-0100-x
  125. Le Berre R, Nguyen S, Nowak E, Kipnis E, Pierre M, Ader F, et al.; Pyopneumagen Group. Quorum-sensing activity and related virulence factor expression in clinically pathogenic isolates of Pseudomonas aeruginosa. Clin Microbiol Infect. 2008;14(4):337–43. doi:.https://doi.org/10.1111/j.1469-0691.2007.01925.x
  126. Wu H, Song Z, Hentzer M, Andersen JB, Molin S, Givskov M, et al. Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. J Antimicrob Chemother. 2004;53(6):1054–61. doi:.https://doi.org/10.1093/jac/dkh223
  127. Hoffmann N, Lee B, Hentzer M, Rasmussen TB, Song Z, Johansen HK, 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. doi:.https://doi.org/10.1128/AAC.01011-06
  128. Adonizio A, Kong K-F, Mathee K. Inhibition of quorum sensing-controlled virulence factor production in Pseudomonas aeruginosa by South Florida plant extracts. Antimicrob Agents Chemother. 2008;52(1):198–203. doi:.https://doi.org/10.1128/AAC.00612-07
  129. Smyth AR, Cifelli PM, Ortori CA, Righetti K, Lewis S, Erskine P, 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.
  130. O’Loughlin CT, Miller LC, Siryaporn A, Drescher K, Semmelhack MF, Bassler BL. A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation. Proc Natl Acad Sci USA. 2013;110(44):17981–6. doi:.https://doi.org/10.1073/pnas.1316981110
  131. Tsai WC, Rodriguez ML, Young KS, Deng JC, Thannickal VJ, Tateda K, et al. Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection. Am J Respir Crit Care Med. 2004;170(12):1331–9. doi:.https://doi.org/10.1164/rccm.200402-200OC
  132. Tsai WC, Hershenson MB, Zhou Y, Sajjan U. Azithromycin increases survival and reduces lung inflammation in cystic fibrosis mice. Inflamm Res. 2009;58(8):491–501. doi:.https://doi.org/10.1007/s00011-009-0015-9
  133. Giamarellos-Bourboulis EJ, Pechère J-C, Routsi C, Plachouras D, Kollias S, Raftogiannis M, et al. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. Clin Infect Dis. 2008;46(8):1157–64. doi:.https://doi.org/10.1086/529439
  134. van Delden C, Köhler T, Brunner-Ferber F, François B, Carlet J, Pechère J-C. Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing: a randomized controlled trial. Intensive Care Med. 2012;38(7):1118–25. doi:.https://doi.org/10.1007/s00134-012-2559-3
  135. Laserna E, Sibila O, Fernandez JF, Maselli DJ, Mortensen EM, Anzueto A, et al. Impact of macrolide therapy in patients hospitalized with Pseudomonas aeruginosa community-acquired pneumonia. Chest. 2014;145(5):1114–20. doi:.https://doi.org/10.1378/chest.13-1607
  136. Principi N, Blasi F, Esposito S. Azithromycin use in patients with cystic fibrosis. Eur J Clin Microbiol Infect Dis. 2015;34(6):1071–9. doi:.https://doi.org/10.1007/s10096-015-2347-4
  137. Taylor SP, Sellers E, Taylor BT. Azithromycin for the Prevention of COPD Exacerbations: The Good, Bad, and Ugly. Am J Med. 2015;128(12):1362.e1–6. doi:.https://doi.org/10.1016/j.amjmed.2015.07.032
  138. Cotter PD, Ross RP, Hill C. Bacteriocins - a viable alternative to antibiotics? Nat Rev Microbiol. 2013;11(2):95–105. doi:.https://doi.org/10.1038/nrmicro2937
  139. Toke O. Antimicrobial peptides: new candidates in the fight against bacterial infections. Biopolymers. 2005;80(6):717–35. doi:.https://doi.org/10.1002/bip.20286
  140. Mensa B, Howell GL, Scott R, DeGrado WF. Comparative mechanistic studies of brilacidin, daptomycin, and the antimicrobial peptide LL16. Antimicrob Agents Chemother. 2014;58(9):5136–45. doi:.https://doi.org/10.1128/AAC.02955-14
  141. Rea MC, Sit CS, Clayton E, O’Connor PM, Whittal RM, Zheng J, et al. Thuricin CD, a posttranslationally modified bacteriocin with a narrow spectrum of activity against Clostridium difficile. Proc Natl Acad Sci USA. 2010;107(20):9352–7. doi:.https://doi.org/10.1073/pnas.0913554107
  142. Mathur H, Rea MC, Cotter PD, Hill C, Ross RP. The efficacy of thuricin CD, tigecycline, vancomycin, teicoplanin, rifampicin and nitazoxanide, independently and in paired combinations against Clostridium difficile biofilms and planktonic cells. Gut Pathog. 2016;8(1):20. doi:.https://doi.org/10.1186/s13099-016-0102-8
  143. Guidelines for the evaluation of probiotics in food: report of a joint FAO/WHO working group on drafting guidelines for the evaluation of probiotics in food, London, Ontario, Canada, April 30 and May 1,2002. [Internet]. [cited 2017 Jul 10]. Available from: http://www.who.int/foodsafety/fs_management/en/probiotic_guidelines.pdf
  144. Walker WA. Mechanisms of action of probiotics. Clin Infect Dis. 2008;46(s2, Suppl 2):S87–91, discussion S144–51. doi:.https://doi.org/10.1086/523335
  145. Gill HS. Probiotics to enhance anti-infective defences in the gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2003;17(5):755–73. doi:.https://doi.org/10.1016/S1521-6918(03)00074-X
  146. Hopkins MJ, Macfarlane GT. Nondigestible oligosaccharides enhance bacterial colonization resistance against Clostridium difficile in vitro. Appl Environ Microbiol. 2003;69(4):1920–7. doi:.https://doi.org/10.1128/AEM.69.4.1920-1927.2003
  147. Snydman DR. The safety of probiotics. Clin Infect Dis. 2008;46(s2, Suppl 2):S104–11, discussion S144–51. doi:.https://doi.org/10.1086/523331
  148. Enache-Angoulvant A, Hennequin C. Invasive Saccharomyces infection: a comprehensive review. Clin Infect Dis. 2005;41(11):1559–68. doi:.https://doi.org/10.1086/497832
  149. Machairas N, Pistiki A, Droggiti D-I, Georgitsi M, Pelekanos N, Damoraki G, et al. Pre-treatment with probiotics prolongs survival after experimental infection by multidrug-resistant Pseudomonas aeruginosa in rodents: an effect on sepsis-induced immunosuppression. Int J Antimicrob Agents. 2015;45(4):376–84. doi:.https://doi.org/10.1016/j.ijantimicag.2014.11.013
  150. Ruppé E, Armand-Lefèvre L, Estellat C, Consigny P-H, El Mniai A, Boussadia Y, et al. High Rate of Acquisition but Short Duration of Carriage of Multidrug-Resistant Enterobacteriaceae After Travel to the Tropics. Clin Infect Dis. 2015;61(4):593–600. doi:.https://doi.org/10.1093/cid/civ333
  151. Salomão MCC, Heluany-Filho MA, Menegueti MG, Kraker MEAD, Martinez R, Bellissimo-Rodrigues F. A randomized clinical trial on the effectiveness of a symbiotic product to decolonize patients harboring multidrug-resistant Gram-negative bacilli. Rev Soc Bras Med Trop. 2016;49(5):559–66. doi:.https://doi.org/10.1590/0037-8682-0233-2016
  152. Manley KJ, Fraenkel MB, Mayall BC, Power DA. Probiotic treatment of vancomycin-resistant enterococci: a randomised controlled trial. Med J Aust. 2007;186(9):454–7.
  153. Szachta P, Ignyś I, Cichy W. An evaluation of the ability of the probiotic strain Lactobacillus rhamnosus GG to eliminate the gastrointestinal carrier state of vancomycin-resistant enterococci in colonized children. J Clin Gastroenterol. 2011;45(10):872–7. doi:.https://doi.org/10.1097/MCG.0b013e318227439f
  154. Wertheim HFL, Vos MC, Ott A, van Belkum A, Voss A, Kluytmans JAJW, et al. Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet. 2004;364(9435):703–5. doi:.https://doi.org/10.1016/S0140-6736(04)16897-9
  155. Sikorska H, Smoragiewicz W. Role of probiotics in the prevention and treatment of meticillin-resistant Staphylococcus aureus infections. Int J Antimicrob Agents. 2013;42(6):475–81. doi:.https://doi.org/10.1016/j.ijantimicag.2013.08.003
  156. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407–15. doi:.https://doi.org/10.1056/NEJMoa1205037
  157. Cammarota G, Masucci L, Ianiro G, Bibbò S, Dinoi G, Costamagna G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015;41(9):835–43. doi:.https://doi.org/10.1111/apt.13144
  158. Debast SB, Bauer MP, Kuijper EJ ; European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014;20(Suppl 2):1–26. doi:.https://doi.org/10.1111/1469-0691.12418
  159. Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017;389(10075):1218–28. doi:.https://doi.org/10.1016/S0140-6736(17)30182-4
  160. De Palma G, Lynch MDJ, Lu J, Dang VT, Deng Y, Jury J, et al. Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice. Sci Transl Med. 2017;9(379): eaaf6397. doi:.https://doi.org/10.1126/scitranslmed.aaf6397
  161. Laszlo M, Ciobanu L, Andreica V, Pascu O. Fecal transplantation indications in ulcerative colitis. Preliminary study. Clujul Med. 2016;89(2):224–8. doi:.https://doi.org/10.15386/cjmed-613
  162. He C, Shan Y, Song W. Targeting gut microbiota as a possible therapy for diabetes. Nutr Res. 2015;35(5):361–7. doi:.https://doi.org/10.1016/j.nutres.2015.03.002
  163. Jayasinghe TN, Chiavaroli V, Holland DJ, Cutfield WS, O’Sullivan JM. The New Era of Treatment for Obesity and Metabolic Disorders: Evidence and Expectations for Gut Microbiome Transplantation. Front Cell Infect Microbiol. 2016;6:15. doi:.https://doi.org/10.3389/fcimb.2016.00015
  164. Karmarkar D, Rock KL. Microbiota signalling through MyD88 is necessary for a systemic neutrophilic inflammatory response. Immunology. 2013;140(4):483–92. doi:.https://doi.org/10.1111/imm.12159
  165. Balmer ML, Schürch CM, Saito Y, Geuking MB, Li H, Cuenca M, et al. Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling. J Immunol. 2014;193(10):5273–83. doi:.https://doi.org/10.4049/jimmunol.1400762
  166. Deshmukh HS, Liu Y, Menkiti OR, Mei J, Dai N, O’Leary CE, et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med. 2014;20(5):524–30. doi:.https://doi.org/10.1038/nm.3542
  167. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–98. doi:.https://doi.org/10.1016/j.cell.2009.09.033
  168. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci USA. 2011;108(13):5354–9. doi:.https://doi.org/10.1073/pnas.1019378108
  169. Fagundes CT, Amaral FA, Vieira AT, Soares AC, Pinho V, Nicoli JR, et al. Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree mice. J Immunol. 2012;188(3):1411–20. doi:.https://doi.org/10.4049/jimmunol.1101682
  170. Gauguet S, D’Ortona S, Ahnger-Pier K, Duan B, Surana NK, Lu R, et al. Intestinal Microbiota of Mice Influences Resistance to Staphylococcus aureus Pneumonia. Infect Immun. 2015;83(10):4003–14. doi:.https://doi.org/10.1128/IAI.00037-15
  171. Schuijt TJ, Lankelma JM, Scicluna BP, de Sousa e Melo F, Roelofs JJ, de Boer JD, et al. The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. Gut. 2016;65(4):575–83. doi:.https://doi.org/10.1136/gutjnl-2015-309728
  172. Bilinski J, Grzesiowski P, Sorensen N, Madry K, Muszynski J, Robak K, et al. Fecal Microbiota Transplantation in Patients With Blood Disorders Inhibits Gut Colonization With Antibiotic-Resistant Bacteria: Results of a Prospective, Single-Center Study. Clin Infect Dis. 2017;65(3):364–70. doi:.https://doi.org/10.1093/cid/cix252
  173. He Y, Wen Q, Yao F, Xu D, Huang Y, Wang J. Gut-lung axis: The microbial contributions and clinical implications. Crit Rev Microbiol. 2017;43(1):81–95. doi:.https://doi.org/10.1080/1040841X.2016.1176988
  174. Twort FW. An investigation on the nature of ultra-microscopic viruses. Lancet. 1915;186(4814):1241–3. doi:.https://doi.org/10.1016/S0140-6736(01)20383-3
  175. DHerelle F. Sur un microbe invisible antagoniste des bacilles dysentériques. CR Acad Sci Paris. 1917;165:373–4.
  176. Cisek AA, Dąbrowska I, Gregorczyk KP, Wyżewski Z. Phage Therapy in Bacterial Infections Treatment: One Hundred Years After the Discovery of Bacteriophages. Curr Microbiol. 2017;74(2):277–83. doi:.https://doi.org/10.1007/s00284-016-1166-x
  177. Dufour N, Debarbieux L. La phagothérapie - Une arme crédible face à l’antibiorésistance. [Phage therapy: a realistic weapon against multidrug resistant bacteria]. Med Sci (Paris). 2017;33(4):410–6. Article in French. doi:.https://doi.org/10.1051/medsci/20173304011
  178. Knoll BM, Mylonakis E. Antibacterial bioagents based on principles of bacteriophage biology: an overview. Clin Infect Dis. 2014;58(4):528–34. doi:.https://doi.org/10.1093/cid/cit771
  179. Pires DP, Oliveira H, Melo LDR, Sillankorva S, Azeredo J. Bacteriophage-encoded depolymerases: their diversity and biotechnological applications. Appl Microbiol Biotechnol. 2016;100(5):2141–51. doi:.https://doi.org/10.1007/s00253-015-7247-0
  180. Saussereau E, Vachier I, Chiron R, Godbert B, Sermet I, Dufour N, et al. Effectiveness of bacteriophages in the sputum of cystic fibrosis patients. Clin Microbiol Infect. 2014;20(12):O983–90. doi:.https://doi.org/10.1111/1469-0691.12712
  181. Dufour N, Debarbieux L, Fromentin M, Ricard J-D. Treatment of Highly Virulent Extraintestinal Pathogenic Escherichia coli Pneumonia With Bacteriophages. Crit Care Med. 2015;43(6):e190–8. doi:.https://doi.org/10.1097/CCM.0000000000000968
  182. Debarbieux L, Leduc D, Maura D, Morello E, Criscuolo A, Grossi O, et al. Bacteriophages can treat and prevent Pseudomonas aeruginosa lung infections. J Infect Dis. 2010;201(7):1096–104. doi:.https://doi.org/10.1086/651135
  183. Abedon ST. Phage therapy of pulmonary infections. Bacteriophage. 2015;5(1):e1020260. doi:.https://doi.org/10.1080/21597081.2015.1020260
  184. Yilmaz C, Colak M, Yilmaz BC, Ersoz G, Kutateladze M, Gozlugol M. Bacteriophage therapy in implant-related infections: an experimental study. J Bone Joint Surg Am. 2013;95(2):117–25. doi:.https://doi.org/10.2106/JBJS.K.01135
  185. Vouillamoz J, Entenza JM, Giddey M, Fischetti VA, Moreillon P, Resch G. Bactericidal synergism between daptomycin and the phage lysin Cpl-1 in a mouse model of pneumococcal bacteraemia. Int J Antimicrob Agents. 2013;42(5):416–21. doi:.https://doi.org/10.1016/j.ijantimicag.2013.06.020
  186. Oechslin F, Piccardi P, Mancini S, Gabard J, Moreillon P, Entenza JM, et al. Synergistic Interaction Between Phage Therapy and Antibiotics Clears Pseudomonas Aeruginosa Infection in Endocarditis and Reduces Virulence. J Infect Dis. 2017;215(5):703–12.
  187. Rhoads DD, Wolcott RD, Kuskowski MA, Wolcott BM, Ward LS, Sulakvelidze A. Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. J Wound Care. 2009;18(6):237–8, 240–3. doi:.https://doi.org/10.12968/jowc.2009.18.6.42801
  188. Bruttin A, Brüssow H. Human volunteers receiving Escherichia coli phage T4 orally: a safety test of phage therapy. Antimicrob Agents Chemother. 2005;49(7):2874–8. doi:.https://doi.org/10.1128/AAC.49.7.2874-2878.2005
  189. Sarker SA, Sultana S, Reuteler G, Moine D, Descombes P, Charton F, et al. Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations: A Randomized Trial in Children From Bangladesh. EBioMedicine. 2016;4:124–37. doi:.https://doi.org/10.1016/j.ebiom.2015.12.023
  190. Wright A, Hawkins CH, Anggård EE, Harper DR. 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):349–57. doi:.https://doi.org/10.1111/j.1749-4486.2009.01973.x
  191. Jennes S, Merabishvili M, Soentjens P, Pang KW, Rose T, Keersebilck E, et al. Use of bacteriophages in the treatment of colistin-only-sensitive Pseudomonas aeruginosa septicaemia in a patient with acute kidney injury-a case report. Crit Care. 2017;21(1):129. doi:.https://doi.org/10.1186/s13054-017-1709-y
  192. Dy RL, Richter C, Salmond GPC, Fineran PC. Remarkable Mechanisms in Microbes to Resist Phage Infections. Annu Rev Virol. 2014;1(1):307–31. doi:.https://doi.org/10.1146/annurev-virology-031413-085500
  193. Łusiak-Szelachowska M, Żaczek M, Weber-Dąbrowska B, Międzybrodzki R, Kłak M, Fortuna W, et al. Phage neutralization by sera of patients receiving phage therapy. Viral Immunol. 2014;27(6):295–304. doi:.https://doi.org/10.1089/vim.2013.0128
  194. Łusiak-Szelachowska M, Żaczek M, Weber-Dąbrowska B, Międzybrodzki R, Letkiewicz S, Fortuna W, et al. Antiphage activity of sera during phage therapy in relation to its outcome. Future Microbiol. 2017;12(2):109–17. doi:.https://doi.org/10.2217/fmb-2016-0156
  195. Żaczek M, Łusiak-Szelachowska M, Jończyk-Matysiak E, Weber-Dąbrowska B, Międzybrodzki R, Owczarek B, et al. Antibody Production in Response to Staphylococcal MS-1 Phage Cocktail in Patients Undergoing Phage Therapy. Front Microbiol. 2016;7(14802):1681.
  196. Comeau AM, Tétart F, Trojet SN, Prère MF, Krisch HM. Phage-Antibiotic Synergy (PAS): beta-lactam and quinolone antibiotics stimulate virulent phage growth. PLoS One. 2007;2(8):e799. doi:.https://doi.org/10.1371/journal.pone.0000799

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