Efficiency of phage therapy in humans: systematic review

Successful implementation of lytic virulent bacteriophages in clinical practice requires convincing evidence of its safety and efficacy.

Design: We searched in CENTRAL, MEDLINE, Embase, and Russian-language literature databases in May 2018. Original articles must fulfill the following eligibility criteria: randomized, controlled trials investigating the effects of phage therapy in people with bacterial infections; at least one patient outcome was reported. Three review authors independently selected, studies, extracted, data, and. assessed, risk of bias. We used, random-effects models for meta-analysis.

Participants: adults and. children of both, sexes with bacterial infection, including multi-drug resistant variants, or individuals at risk of infection.

Outcomes: recovery or resolution of infection; clinical improvement; change in number of exacerbations; recurrence of infection; quality of life; elimination or load, reduction of a pathogen in an anatomical compartment.

Results: We included 13 trials (issued in 1965-2018) including 9 treatment studies and. 4 prevention studies. Overall, eight randomized, trials involved, adults. Five studies addressed skin and soft tissues infections, six studies concerned intestinal infections, one study addressed respiratory tract infection and. one study — ear infection. Across bias domains, 35-90% of trials scored, low risk of bias. Meta-analysis for adverse events attributable to phages and. for wound, healing provided us with pooled relative risks of 0.74 (95% CI 0.68;1.2) and 0.91 (95% CI0.68;1.2) respectively.

Conclusions: Beneficial effect of bacteriophages can be demonstrated, and. not refuted. However, our study led. to tentative conclusions. The conduct of well-designed and sufficiently powered, trials would, facilitate registration and. wide accepting of bacteriophage treatment.

1. Bacteriophage therapy: advances in formulation strategies and human clinical trials / Vandenheuvel D., Lavigne R., Brussow H. // Annu. Rev. Virol. — 2015. — №2. — Р. 599-618. doi: 10.1146/annurevvirology-100114-054915.

2. Abedon, S.T. Phage Therapy: Various perspectives on how to improve the art / S.T. Abedon // Methods Mol Biol. — 2018. — 1734. —Р.113-127. doi: 10.1007/978-1-4939-7604-1_11.

3. Phage therapy: combating infections with potential for evolving from merely a treatment for complications to targeting diseases / Gorski A., Miedzybrodzki R., Weber- Weber-Dabrowska B., Fortuna W. [et al.] // Front Microbiol. — 2016. -7. —Р. 1515. doi: 10.3389/fmicb.2016.01515

4. Bacteriophages: a therapy concept against multi-drug resistant bacteria / Rohde C., Wittman J., Kutter E. // Surgical infections. — 2018. -№19(8). — Р. 1-8. doi.org/10.1089/sur.2018.184

5. Optimizacija primenenija bakteriofagov dlja bor>by s in-fekcijami po rezul>tatam regional>nogo mikrobiologicheskogo monitoringa / Chanysheva R.F., Kovalishena O.V., Prisada T.V. // Medicinskij al>manah. — 2017. -№4(49). —S. 33-37.

6. Medina C, Lopez-Baena FJ, editor(s). Host-pathogen interactions: methods and protocols, Methods in molecular biology. 2018; 1734. https://doi.org/10.1007/978-1-4939-7604-1_11

7. Applications of bacteriophages in the treatment of localized infections in humans / Morozova V.V., Vlassov V.V., Tiku-nova N.V. // Front Microbiol. — 2018. — 9. — Р. 1696. https://doi.org/10.3389/fmicb.2018.01696

8. Bacteriophages in therapy and prevention of acute intestinal infections in children // Aleshkin A.V., Zeigarnik M.V., Bochkareva S.S Voprosy // Prakticheskoi Pediatrii. — 2016. — №11(1). — P. 52 — 56. doi: 10.20953/1817-7646-2016-1-52-56

9. Racional'noe primenenie bakteriofagov v lechebnoj i protivojepidemicheskoj praktike : federal'nye klinicheskie (metodicheskie) rekomendacii / [Aslanov B. I. i dr.] ; M-vo zdravoohranenija Rossijskoj Federacii, Nac. assoc. specialistov po kontrolju infekcij, svjazannyh s okazaniem medicinskoj pomoshhi. — Nizhny Novgorod : Remedium Privolzh'e, 2014. — 54 s.

10. Bacteriofagen: huidige kennis, onderzoek en toepassin-gen / David S et al. // RIVM Briefrapport 2018-0044. 38 p. Available from http://hdl.handle.net/10029/621984

11. A wake-up call: we need phage therapy now / Moeling K., Broecker F., Will C. // Viruses. - 2018. - №10. -Р. 688. doi:10.3390/v10120688

12. Higgins, J.P., Green, S., editor(s). Cochrane handbook for systematic reviews of шnterventions version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Режим доступа: handbook.cochrane.org

13. ROBINS-I: a tool for assessing risk of bias in non-ran-domised studies of interventions / Sterne J.A.C., Hernan M.A., Reeves B.C., Savovic J. et al. // BMJ; 2016. - S. 355. DOI: https://doi.org/10.1136/bmj.i4919

14. Prophylactic effectiveness of a dysentery bacteriophage /. Serebrianskii V.S. Sokolovskii A.S. // Voen Med Zh. — 1978. - №6. - Р. 46-48.

15. Anpilov, L.I., Prokudin, A.A. Profilakticheskaja jeffek-tivnost> suhogo polivalentnogo dizenterijnogo bakteriofaga v organizovannyh kollektivah / L.I. Anpilov, A.A.Prokudin // Voenno-medicinskij zhurnal. - 1984. - №5. - S. 39-40.

16. Fagoprofilaktika brjushnogo tifa u detej doshkol>nogo vozrasta / Nevskij M.V., Potatueva O.N., Rakhimov A.R., Bga-sheva V.S. [i dr.] // Zhurnal mikrobiologii, jepidemiologii i im-munobiologii. - 1965. - №42(12). - S 62-63.

17. Profilakticheskoe primenenie suhogo polivalentnogo dizenterijnogo bakteriofaga s pektinom v detskih doshkol>nyh uchrezhdenijah. I. Rezul>taty strogo kontroliruemogo jepide-miologicheskogo opyta (Jaroslavl>, 1968) / Solodovnikov Ju.P., Pavlova L.I., Emel>ianov P.I., Garnova N.A. [i dr.] // Zhurnal mikrobiologii, jepidemiologii i immunobiologii. - 1970. - №5. - S. 131-137.

18. Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial / Rhoads D.D., Wolcott R.D., Kus-kowski M.A., Wolcott B.M. et al. // Journal of Wound Care. -2009. - № 18(6). - Р.237-243.

19. Treatment of recurrent furunculosis with staphylococcal bacteriophage-lysed vaccine / Bryant R.E., Sanford J.P., Alcoze T. // JAMA. - 1965. - №194(1). - Р. 11-14.

20. Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial / Jault P., Leclerc T., Jennes S., Pirnay JP et al. // Lancet Infect Dis. - 2019. - №19(1). - Р. 35-45.

21. Metod profilaktiki infekcionnyh oslozhnenij kesare-va sechenija / Budanov P.V., Novahova Zh.D., Kabisashvili M.K., Shubina, T.I. // Medicinskij sovet. - 2015. - №20. - S. 78-81.

22. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy / Wright A., Hawkins C.H., Anggard E.E., Harper D.R. // Clin Otolaryngol. - 2009. -№34(4). - Р.349-357.

23. Clinical studies of the use of bacteriophage in the treatment of cholera / Marcuk L.M., Nikiforov V.N., Scerbak J.F., Levitov T.A. et al. // Bull World Health Organ. - 1971. - № 45(1). - Р. 77-83.

24. Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: a randomized trial in children from Bangladesh / Sarker S.A., Sultana S., Reuteler G., Moine D. et al. // EBioMedicine. - 2016. - №4. - Р. 124-137.

25. Bondarenko, Elena Arturovna. Kliniko-mikrobiologicheska-ja ocenka jeffektivnosti primenenija topicheskoj fagoterapii v kom-pleksnom lechenii vospalitel'nyh zabolevanij parodonta : dis. ... kan-didata medicinskih nauk : 14.01.14 / Bondarenko Elena Arturovna; [Mesto zashhity: Om. gos. med. akad.]. - Perm', 2011. - 147 s.

26. Bacteriophage therapy in infective childhood asthma / Wittig H.J., Raffetto J.F., Bason R. // JAMA. - 1966. -№196(5). - Р. 435.

27. Application of Bacteriophage-containing Aerosol against Nosocomial Transmission of Carbapenem-Resistant Acinetobacter baumannii in an Intensive Care Unit.2016 / Ho Y.H., Tseng C.C., Wang L.S., Chen Y.T., Ho G.J., Lin T.Y., et al. / PLoS ONE. - №11(12): e0168380. doi:10.1371/journal.pone.0168380

28. Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis / Hurley M.N., Forrester D.L., Smyth A.R. // Cochrane Database of Systematic Reviews 2013; 6: Art. No.: CD008037. DOI: 10.1002/14651858.CD008037.pub3.

29. Bakteriofagi dlja kupirovanija vspyshki, vyzvannoj Staphylococcus aureus, v otdelenii reanimacii novorozhdennyh / Aslanov B.I., Ljubimova A.V., Zueva L.P., Malashenko A.A. [i dr.] // Medicinskij al'manah. - 2015. - № 5 (40). - S. 115118.

30. Decolonisation strategies targeting carriage of multidrug resistant Gram-negative organisms / Tacconelli E., Torre-Cisneros J.R-B., Eggimann Ph., de Smet A.M. et al. // PROS-PERO 2017 CRD42017082729. - (http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017082729

31. Evaluation of bacteriophage therapy against the multidrug resistant ESKAPE organisms in an immunocompromised model: a systematic review / El Haddad L., Harb C., Gebara M., Stibich M. et al. PROSPERO 2018 CRD42018088332. -(http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018088332)