Bacteriophage to overcome Nosocomial infections associated with multidrug-resistant bacterial pathogens: a systematic review and meta-analysis
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Submitted
August 17, 2020
Published
May 8, 2021
Keywords:
-
Antibiotic resistance, Multidrug resistance, Hospital acquired infections, Phage, Therapy, Clinical practice
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Abstract
Background: Antibiotic-resistant pathogens constitute an important and growing threat to public health. The emergence of multidrug-resistant organisms in nosocomial infections is being highly associated with frequent causes of morbidity and mortality in patients. The antibiotic crisis has rekindled the interest in phage therapy approaches that were developed in Eastern Europe, one of the alternatives recently regaining interest which was first introduced by Felix d’Herelle at the beginning of the 20th century.
Objective: The main objective of this study was to quantify the pooled therapeutic efficacy and safety status of Bacteriophage for bio-control of nosocomial infections associated with but not limited to multidrug-resistant ESKAPE bacteria in humans based on available studies.
Methods: Studies were searched in the PubMed/Medline, Embase and Web of science databases for articles on phage therapy. 14 studies were included in the review with six considered for meta-analysis to quantify the therapeutic efficacy based on available studies on phages that may prevent and eradicate infections associated with but not limited to “Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species pathogens” in humans for control of Nosocomial infections. In addition current gaps in the literature that would prompt further research on bacteriophage in the fight against antibiotic resistance were identified.
Results: Phage safety was sufficiently reported, in that all studies showed no adverse effects related to phage administration. A moderate pooled effect size was obtained with a high evidence of heterogeneity (SMD = 0.52, (C.I. = -1.18, 2.22), P< 0.00001, I2 = 96%). However, there was no significant treatment difference between the two therapeutic arms as observed in the forest plots. Moreover, the therapeutic efficacy of bacteriophage is inconclusive due to the few available randomized phage studies found with even few sample sizes. Hence more streamlined phage clinical trials with large sample sizes are needed to detect sufficient effect sizes.
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References
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10. Sultana S, Reuteler G, Moine D, Descombes P, Charton F, Bourdin G, et al. EBioMedicine Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations : A Randomized Trial in Children From Bangladesh. 2016;4:124–37.
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13. Kutter E, De Vos D, Gvasalia G, Alavidze Z, Gogokhia L, Kuhl S, et al. Phage Therapy in Clinical Practice: Treatment of Human Infections. Curr Pharm Biotechnol [Internet]. 2010;11(1):69–86. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1389-2010&volume=11&issue=1&spage=69
14. Chan BK, Abedon ST, Loc-carrillo C. Coktail Fagos. 2013;769–83.
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17. US CDC. Antibiotic resistance threats in the United States. Centers Dis Control Prev. 2019;1–150.
18. Mauldin PD, Salgado CD, Hansen IS, Durup DT, Bosso JA. Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant gram-negative bacteria. Antimicrob Agents Chemother. 2010;54(1):109–15.
19. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: Elaboration and explanation. BMJ. 2015;349(January):1–25.
20. Chandler J, Higgins J, Deeks J, Davenport C, Clarke M. Cochrane Handbook for Systematic Reviews of Interventions. 2017;1–12.
21. Weber-da B, Ã MIZ, Mulczyk M, Go A. E ¡ ect of phage therapy on the turnover and function of peripheral neutrophils. 2002;34:135–8.
22. Wittig HJ, Raffetto JF, Bason R. Bacteriophage Therapy in Infective Childhood Asthma. JAMA J Am Med Assoc. 1966 May 2;196(5):435.
23. McCallin S, Sarker SA, Sultana S, Oechslin F, Brüssow H. Metagenome analysis of Russian and Georgian Pyophage cocktails and a placebo-controlled safety trial of single phage versus phage cocktail in healthy Staphylococcus aureus carriers. Environ Microbiol [Internet]. 2018 [cited 2020 Jan 24];20(9):3278–93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30051571
24. Jault P, Leclerc T, Jennes S, Pirnay JP, Que Y, Resch G, et al. Articles Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa ( PhagoBurn ): a randomised , controlled , double-blind. 2019;19(January):35–45.
25. 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 Feb 1;4:124–37.
26. 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 [Internet]. 2009 Jun [cited 2019 Jul 24];18(6):237–8, 240–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19661847
27. Wright A, Hawkins CH, Änggård 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 Aug;34(4):349–57.
28. 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 Jun;18(6).
29. Rose T, Verbeken G, Vos D De, Merabishvili M, Vaneechoutte M, Jennes S, et al. Experimental phage therapy of burn wound infection : difficult first steps. 2014;4(2):66–73.
30. Gindin M, Febvre HP, Rao S, Wallace TC, Tiffany L, Gindin M, et al. Bacteriophage for Gastrointestinal Health ( PHAGE ) Study : Evaluating the Safety and Tolerability of Supplemental Bacteriophage Consumption Bacteriophage for Gastrointestinal Health ( PHAGE ) Study : Evaluating the Safety and Tolerability of Supplemental. J Am Coll Nutr [Internet]. 2018;0(0):1–8. Available from: https://doi.org/10.1080/07315724.2018.1483783
31. Febvre HP, Rao S, Gindin M, Goodwin NDM, Finer E, Vivanco JS, et al. PHAGE Study: Effects of Supplemental Bacteriophage Intake on Inflammation and Gut Microbiota in Healthy Adults. Nutrients [Internet]. 2019 Mar 20 [cited 2020 Jan 23];11(3). Available from: http://www.ncbi.nlm.nih.gov/pubmed/30897686
32. Marcuk LM, Nikiforov VN, Scerbak JF, Levitov TA, Kotljarova RI, Naumsina MS, et al. Clinical studies of the use of bacteriophage in the treatment of cholera. Bull World Health Organ. 1971;45(1):77–83.
33. McCallin S, Sarker SA, Sultana S, Oechslin F, Brüssow H. Metagenome analysis of Russian and Georgian Pyophage cocktails and a placebo-controlled safety trial of single phage versus phage cocktail in healthy Staphylococcus aureus carriers. Environ Microbiol. 2018 Sep 1;20(9):3278–93.
34. Procedure N. 27.10.2012. 2012;1–4.
35. Kutateladze M. Experience of the Eliava Institute in bacteriophage therapy. Virol Sin. 2015;30(1):80–1.
36. Furfaro LL, Payne MS, Chang BJ. Bacteriophage Therapy: Clinical Trials and Regulatory Hurdles. Vol. 8, Frontiers in cellular and infection microbiology. NLM (Medline); 2018. p. 376.
37. Gupta P, Singh HS, Shukla VK, Nath G, Bhartiya SK. Bacteriophage Therapy of Chronic Nonhealing Wound: Clinical Study. Int J Low Extrem Wounds [Internet]. 2019;153473461983511. Available from: http://journals.sagepub.com/doi/10.1177/1534734619835115
38. Sulakvelidze A, Alavidze Z, Morris JG. Bacteriophage Therapy - From Lab to Clinical Practice. Antimicrob Agents Chemother [Internet]. 2018;1693(3):649–59. Available from: http://aac.asm.org/cgi/doi/10.1128/AAC.45.3.649-659.2001%0Ahttp://link.springer.com/10.1007/978-1-4939-7395-8
39. Bruttin A, Brüssow H. Human volunteers receiving Escherichia coli phage T4 orally: a safety test of phage therapy. Antimicrob Agents Chemother [Internet]. 2005 Jul [cited 2020 Jan 24];49(7):2874–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15980363
40. Cui Z, Guo X, Feng T, Li L. Exploring the whole standard operating procedure for phage therapy in clinical practice. J Transl Med. 2019;17(1):1–7.
2. Tolera M, Abate D, Dheresa M, Marami D. Bacterial Nosocomial Infections and Antimicrobial Susceptibility Pattern among Patients Admitted at Hiwot Fana Specialized University Hospital, Eastern Ethiopia. Adv Med. 2018 Dec 4;2018:1–7.
3. Sirijan S, Nitaya I. Mechanisms of antimicrobial resistance in bacteria in ESKAPE pahogens. Biomed Res Int. 2006;2016:1–8.
4. de Kraker MEA, Davey PG, Grundmann H. Mortality and hospital stay associated with resistant Staphylococcus aureus and Escherichia coli bacteremia: Estimating the burden of antibiotic resistance in Europe. PLoS Med. 2011;8(10).
5. Biadglegne F, Abera B. Antimicrobial resistance of bacterial isolates from urinary tract infections at Felge Hiwot Referral Hospital, Ethiopia. Ethiop J Heal Dev. 2011;23(3).
6. de Kraker MEA, Stewardson AJ, Harbarth S. Will 10 Million People Die a Year due to Antimicrobial Resistance by 2050? PLoS Med. 2016;13(11):1–6.
7. Tfifha M, Ferjani A, Mallouli M, Mlika N, Abroug S, Boukadida J. Carriage of multidrug-resistant bacteria among pediatric patients before and during their hospitalization in a tertiary pediatric unit in Tunisia. Libyan J Med [Internet]. 2018 Dec [cited 2019 Jul 23];13(1):1419047. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29277142
8. Bereket W, Hemalatha K, Getenet B, Wondwossen T, Solomon A, Zeynudin A, et al. Update on bacterial nosocomial infections. Eur Rev Med Pharmacol Sci. 2012;16(8):1039–44.
9. Hoe S, Semler DD, Goudie AD, Lynch KH, Matinkhoo S, Finlay WH, et al. Respirable Bacteriophages for the Treatment of Bacterial Lung Infections. 2013;26(6):317–35.
10. Sultana S, Reuteler G, Moine D, Descombes P, Charton F, Bourdin G, et al. EBioMedicine Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations : A Randomized Trial in Children From Bangladesh. 2016;4:124–37.
11. Carlton RM. Phage therapy: past history and future prospects. Arch Immunol Ther Exp (Warsz) [Internet]. 1999;47(5):267–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10604231
12. Matsuzaki S, Rashel M, Uchiyama J, Sakurai S, Ujihara T, Kuroda M, et al. Bacteriophage therapy: a revitalized therapy against bacterial infectious diseases. J Infect Chemother [Internet]. 2005 Oct [cited 2019 Jul 24];11(5):211–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16258815
13. Kutter E, De Vos D, Gvasalia G, Alavidze Z, Gogokhia L, Kuhl S, et al. Phage Therapy in Clinical Practice: Treatment of Human Infections. Curr Pharm Biotechnol [Internet]. 2010;11(1):69–86. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1389-2010&volume=11&issue=1&spage=69
14. Chan BK, Abedon ST, Loc-carrillo C. Coktail Fagos. 2013;769–83.
15. Rice LB. Federal Funding for the Study of Antimicrobial Resistance in Nosocomial Pathogens: No ESKAPE. J Infect Dis. 2008;197(8):1079–81.
16. Lomazzi M, Moore M, Johnson A, Balasegaram M, Borisch B. Antimicrobial resistance - Moving forward? BMC Public Health. 2019;19(1):1–6.
17. US CDC. Antibiotic resistance threats in the United States. Centers Dis Control Prev. 2019;1–150.
18. Mauldin PD, Salgado CD, Hansen IS, Durup DT, Bosso JA. Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant gram-negative bacteria. Antimicrob Agents Chemother. 2010;54(1):109–15.
19. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: Elaboration and explanation. BMJ. 2015;349(January):1–25.
20. Chandler J, Higgins J, Deeks J, Davenport C, Clarke M. Cochrane Handbook for Systematic Reviews of Interventions. 2017;1–12.
21. Weber-da B, Ã MIZ, Mulczyk M, Go A. E ¡ ect of phage therapy on the turnover and function of peripheral neutrophils. 2002;34:135–8.
22. Wittig HJ, Raffetto JF, Bason R. Bacteriophage Therapy in Infective Childhood Asthma. JAMA J Am Med Assoc. 1966 May 2;196(5):435.
23. McCallin S, Sarker SA, Sultana S, Oechslin F, Brüssow H. Metagenome analysis of Russian and Georgian Pyophage cocktails and a placebo-controlled safety trial of single phage versus phage cocktail in healthy Staphylococcus aureus carriers. Environ Microbiol [Internet]. 2018 [cited 2020 Jan 24];20(9):3278–93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30051571
24. Jault P, Leclerc T, Jennes S, Pirnay JP, Que Y, Resch G, et al. Articles Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa ( PhagoBurn ): a randomised , controlled , double-blind. 2019;19(January):35–45.
25. 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 Feb 1;4:124–37.
26. 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 [Internet]. 2009 Jun [cited 2019 Jul 24];18(6):237–8, 240–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19661847
27. Wright A, Hawkins CH, Änggård 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 Aug;34(4):349–57.
28. 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 Jun;18(6).
29. Rose T, Verbeken G, Vos D De, Merabishvili M, Vaneechoutte M, Jennes S, et al. Experimental phage therapy of burn wound infection : difficult first steps. 2014;4(2):66–73.
30. Gindin M, Febvre HP, Rao S, Wallace TC, Tiffany L, Gindin M, et al. Bacteriophage for Gastrointestinal Health ( PHAGE ) Study : Evaluating the Safety and Tolerability of Supplemental Bacteriophage Consumption Bacteriophage for Gastrointestinal Health ( PHAGE ) Study : Evaluating the Safety and Tolerability of Supplemental. J Am Coll Nutr [Internet]. 2018;0(0):1–8. Available from: https://doi.org/10.1080/07315724.2018.1483783
31. Febvre HP, Rao S, Gindin M, Goodwin NDM, Finer E, Vivanco JS, et al. PHAGE Study: Effects of Supplemental Bacteriophage Intake on Inflammation and Gut Microbiota in Healthy Adults. Nutrients [Internet]. 2019 Mar 20 [cited 2020 Jan 23];11(3). Available from: http://www.ncbi.nlm.nih.gov/pubmed/30897686
32. Marcuk LM, Nikiforov VN, Scerbak JF, Levitov TA, Kotljarova RI, Naumsina MS, et al. Clinical studies of the use of bacteriophage in the treatment of cholera. Bull World Health Organ. 1971;45(1):77–83.
33. McCallin S, Sarker SA, Sultana S, Oechslin F, Brüssow H. Metagenome analysis of Russian and Georgian Pyophage cocktails and a placebo-controlled safety trial of single phage versus phage cocktail in healthy Staphylococcus aureus carriers. Environ Microbiol. 2018 Sep 1;20(9):3278–93.
34. Procedure N. 27.10.2012. 2012;1–4.
35. Kutateladze M. Experience of the Eliava Institute in bacteriophage therapy. Virol Sin. 2015;30(1):80–1.
36. Furfaro LL, Payne MS, Chang BJ. Bacteriophage Therapy: Clinical Trials and Regulatory Hurdles. Vol. 8, Frontiers in cellular and infection microbiology. NLM (Medline); 2018. p. 376.
37. Gupta P, Singh HS, Shukla VK, Nath G, Bhartiya SK. Bacteriophage Therapy of Chronic Nonhealing Wound: Clinical Study. Int J Low Extrem Wounds [Internet]. 2019;153473461983511. Available from: http://journals.sagepub.com/doi/10.1177/1534734619835115
38. Sulakvelidze A, Alavidze Z, Morris JG. Bacteriophage Therapy - From Lab to Clinical Practice. Antimicrob Agents Chemother [Internet]. 2018;1693(3):649–59. Available from: http://aac.asm.org/cgi/doi/10.1128/AAC.45.3.649-659.2001%0Ahttp://link.springer.com/10.1007/978-1-4939-7395-8
39. Bruttin A, Brüssow H. Human volunteers receiving Escherichia coli phage T4 orally: a safety test of phage therapy. Antimicrob Agents Chemother [Internet]. 2005 Jul [cited 2020 Jan 24];49(7):2874–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15980363
40. Cui Z, Guo X, Feng T, Li L. Exploring the whole standard operating procedure for phage therapy in clinical practice. J Transl Med. 2019;17(1):1–7.
Authors
Benson, N. . (2021). Bacteriophage to overcome Nosocomial infections associated with multidrug-resistant bacterial pathogens: a systematic review and meta-analysis. Journal of Medical Care Research and Review, 4(6). https://doi.org/10.15520/mcrr.v4i6.138
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