To the content
3 . 2023

Experimental evaluation of clinical and microbiological efficacy of systemic antibiotic therapy and local phage therapy in surgical treatment of burn wound infection

Abstract

Aim – was to evaluate the clinical and microbiological efficacy of systemic antibiotic therapy and local phage therapy of burn wound infection after radical and partial necrectomy.

Material and methods. The experimental study was performed on rats (n=90). Animals of the first group (n=30) were simulated contact skin burn of 5% of the body surface, after which radical necrectomy was performed. In the second group (n=30), after modeling a contact burn of 5% of the body surface and performing radical necrectomy, a ring made of medical steel was sewn into the edges of the post-necrectomy wound. Animals of the third group (n=30) were simulated contact skin burn of 20% of the body surface, partial fascial necrectomy was performed, a ring made of medical steel was sewn into the edges of the post-necrectomy wound. At the stage of necrectomy, the wounds were contaminated with P. aeruginosa. Three days after the moment of contamination, all animals underwent a seven-day course of antimicrobial therapy for the treatment of wound infection. Ten animals from each group received as etiotropic antimicrobial therapy: systemic antibiotic therapy (therapy “A”), local phage therapy (therapy “F”) and their combination (therapy “AF”).

Results. In addition to the lack of clinical efficacy from antimicrobial therapy, we have not achieved the elimination of P. aeruginosa from the wound surface in any animal. When analyzing the results of microbiological examination of wound discharge obtained on the fourth and seventh days of antimicrobial therapy, it was recorded that the formation of mixed infection was statistically significantly more frequent in animals receiving therapy “A” and “AF” (p<0.01).

Conclusion. As a result of the conducted experimental study, data were obtained indicating that the local use of polyvalent pyobacteriophage in a single mode in the treatment of burn wound infection reduces the risk of infection of wounds with nosocomial pathogens and the formation of mixed infection even in the presence of necrotic tissues and foreign bodies in the wound.

Keywords:burn wound; necrectomy; wound infection; antibiotic therapy; phage therapy

Funding. The study was carried out within the framework of the state task of the Ministry of Health of Russia No. 056-00015-21-00 “Study of the mechanisms of complex resistance of microorganisms to antimicrobial drugs and physical antimicrobial factors and the development of ways to overcome it.

Conflict of interest. The authors declare no conflict of interest.

For citation: Tulupov A.A., Beschastnov V.V., Shirokova I.Yu., Kovalishena O.V., Tyumenkov Yu.O. Experimental evaluation of clinical and microbiological efficacy of systemic antibiotic therapy and local phage therapy in surgical treatment of burn wound infection. Clinical and Experimental Surgery. Petrovsky Journal. 2023; 11 (3): 105–15. DOI: https://doi.org/10.33029/2308-1198-2023-11-3-105-115  (in Russian)

References

1.     Murray C.K. Infections in burns. J Trauma. 2007; 62 (6): 73. DOI: https://doi.org/10.1097/ta.0b013e318065af1a  

2.     Boehm D., Menke H. Sepsis in burns-lessons learnt from developments in the management of septic shock. Medicina (Kaunas). 2021; 58 (1): 26. DOI: https://doi.org/10.3390/medicina58010026  

3.     Rex S. Burn injuries. Curr Opin Crit Care. 2012; 18 (6): 671–6. DOI: https://doi.org/10.1097/mcc.0b013e328359fd6e  

4.     Manning J. Sepsis in the burn patient. Crit Care Nurs Clin North Am. 2018; 30 (3): 423–30. DOI: https://doi.org/10.1016/j.cnc.2018.05.010  

5.     Tridente A. Sepsis 3 and the burns patient: do we need Sepsis 3.1? Scars Burn. Heal. 2018; 4: 2059513118790658. DOI: https://doi.org/10.1177/2059513118790658  

6.     Safiri S., Ashrafi-Asgarabad A. Platelet count: a predictor of sepsis and mortality in severe burns; methodological issues. Burns 2018; 44 (3): 728–9. DOI: https://doi.org/10.1016/j.burns.2017.10.027  

7.     Beschastnov V.V., Ryabkov M.G., Leont’ev A.E., Tulupov A.A., et al. In vitro study of the viability of bacteriophages as part of complex hydrogel wound coatings. Sovremennye tekhnologii v meditsine [Modern Technologies in Medicine]. 2021; 13 (2): 32–9. DOI: https://doi.org/10.17691/stm2021.13.2.03  (in Russian)

8.     Bolton L. Burn debridement: are we optimizing outcomes? Wounds. 2019; 31 (12): 298–300.

9.     Moussa A., Lo C.H., Cleland H. Burn wound excision within 24 h: a 9-year review. Burns. 2021; 47 (6): 1300–7. DOI: https://doi.org/10.1016/j.burns.2020.12.014  

10. Martynenko E.E., Usov V.V., Reva G.V., Obydennikova T.N., et al. Results of active surgical treatment of thermal burns. The relationship of clinical results with morphological changes and the state of local immune homeostasis in burn wounds. Sovremennye problemy nauki i obrazovaniya [Modern Problems of Science and Education]. 2017; (5): 81. (in Russian)

11. Glaser J., Ziegler B., Hirche C., Tapking C., et al. The status quo of early burn wound excision: Insights from the German burn registry. Burns. 2021; 47 (6): 1259–64. DOI: https://doi.org/10.1016/j.burns.2021.06.010   

12. Heifets L. Centennial of Metchnikoff's discovery. J Reticuloendothel Soc. 1982; 31 (5): 381–91.

13. Chang K.C., Ma H., Liao W.C., Lee C.K., et al. The optimal time for early burn wound excision to reduce pro-inflammatory cytokine production in a murine burn injury model. Burns. 2010; 36 (7): 1059–66. DOI: https://doi.org/10.1016/j.burns.2010.02.004  

14. Medzhitov R., Horng T. Transcriptional control of the inflammatory response. Nat Rev Immunol. 2009; 9: 692–703.

15. Ivashkiv L.B. Epigenetic regulation of macrophage polarization and function. Trends Immunol. 2013; 34: 216–23.

16. Hajská M., Slobodníková L., Hupková H., Koller J. In vitro efficacy of various topical antimicrobial agents in different time periods from contamination to application against 6 multidrug-resistant bacterial strains isolated from burn patients. Burns. 2014; 40 (4): 713–8. DOI: https://doi.org/10.1016/j.burns.2013.09.003  

17. Žiemytė M., Carda-Diéguez M., Rodríguez-Díaz J.C., Ventero M.P., et al. Real-time monitoring of Pseudomonas aeruginosa biofilm growth dynamics and persister cells’ eradication. Emerg Microbes Infect. 2021; 10 (1): 2062–75. DOI: https://doi.org/10.1080/22221751.2021.1994355  

18. Gutiérrez D., Hidalgo-Cantabrana C., Rodríguez A., García P., et al. Monitoring in real time the formation and removal of biofilms from clinical related pathogens using an impedance-based technology. PLoS One. 2016; 11 (10): e0163966. DOI: https://doi.org/10.1371/journal.pone.0163966   

19. Giorgi F., Curran J.M., Patterson E.A. Real-time monitoring of the dynamics and interactions of bacteria and the early-stage formation of biofilms. Sci Rep. 2022; 12 (1): 18146. DOI: https://doi.org/10.1038/s41598-022-22669-0  

20. Fu J., Zhang Y., Lin S., Zhang W., et al. Strategies for interfering with bacterial early-stage biofilms. Front Microbiol. 2021; 12: 1339. DOI: https://doi.org/10.3389/fmicb.2021.675843  

21. Harrison-Balestra C., Cazzaniga A.L., Davis S.C., Mertz P.M. A wound-isolated Pseudomonas aeruginosa grows a biofilm in vitro within 10 hours and is visualized by light microscopy. Dermatol Surg. 2003; 29 (6): 631–5. DOI: https://doi.org/10.1046/j.1524-4725.2003.29146.x  

22. Nel Van Zyl K., Matukane S.R., Hamman B.L., Whitelaw A.C., et al. Effect of antibiotics on the human microbiome: a systematic review. Int J Antimicrob Agents. 2022; 59 (2): 106502. DOI: https://doi.org/10.1016/j.ijantimicag.2021.106502  

23. Kelly S.A., Nzakizwanayo J., Rodgers A.M., Zhao L., et al. Antibiotic therapy and the gut microbiome: investigating the effect of delivery route on gut pathogens. ACS Infect Dis. 2021; 7 (5): 1283–96. DOI: https://doi.org/10.1021/acsinfecdis.1c00081  

24. Langdon A., Crook N., Dantas G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med. 2016; 78 (1): 39. DOI: https://doi.org/10.1186/s13073-016-0294-z  

25. Giannelli F.R. Antibiotic-associated diarrhea. JAAPA. 2017; 30 (10): 46–7. DOI: https://doi.org/10.1097/01.JAA.0000524721.01579.c9  

26. McDonnell L., Gilkes A., Ashworth M., Rowland V., et al. Association between antibiotics and gut microbiome dysbiosis in children: systematic review and meta-analysis. Gut Microbes. 2021; 13 (1): 1–18. DOI: https://doi.org/10.1080/19490976.2020.1870402  

27. Lange K., Buerger M., Stallmach A., Bruns T. Effects of antibiotics on gut microbiota. Dig Dis. 2016; 34 (3): 260–8. DOI: https://doi.org/10.1159/000443360  

28. Ramirez J., Guarner F., Bustos Fernandez L., Maruy A., et al. Antibiotics as major disruptors of gut microbiota. Front Cell Infect Microbiol. 2020; 10: 572912. DOI: https://doi.org/10.3389/fcimb.2020.572912  

29. Abedon S.T., Katsaounis T.I. Basic phage mathematics. Methods Mol Biol. 2018; 1681: 3–30. DOI: https://doi.org/10.1007/978-1-4939-7343-9_1  

30. Danis-Wlodarczyk K., Dąbrowska K., Abedon S.T. Phage therapy: the pharmacology of antibacterial viruses. Curr Issues Mol Biol. 2021; 40: 81–164. DOI: https://doi.org/10.21775/cimb.040.081  

31. Jault P., Leclerc T., Jennes S., Pirnay J.P., et al. 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. Lancet Infect Dis. 2019; 19 (1): 35–45. DOI: https://doi.org/10.1016/S1473-3099(18)30482-1  

32. Chang RY.K., Okamoto Y., Morales S., Kutter E., et al. Hydrogel formulations containing non-ionic polymers for topical delivery of bacteriophages. Int J Pharm. 2021; 605 (1): 20850. DOI: https://doi.org/10.1016/j.ijpharm.2021.120850  

33. Nepal R., Houtak G., Wormald P.J., Psaltis A.J. et al. Prophage: a crucial catalyst in infectious disease modulation // Lancet Microbe. 2022. Vol. 3, N 3. P. e162–e163. DOI: https://doi.org/10.1016/S2666-5247(21)00354-2  

34. Owen S.V., Wenner N., Dulberger C.L., Rodwell E.V., et al. Prophages encode phage-defense systems with cognate self-immunity. Cell Host Microbe. 2021; 29 (11): 1620–33.e8. DOI: https://doi.org/10.1016/j.chom.2021.09.002  

35. Aslanov B.I., Zueva L.P., Punchenko O.E., et al. Rational use of bacteriophages in therapeutic and antiepidemic practice. Methodological recommendations. Moscow, 2022: 32 p. (in Russian)

36. Voyno-Yasenetsky V.F. Essays on purulent surgery. 4th  ed. Moscow: BINOM, 2006: 704 p. (in Russian)

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)

CHIEF EDITOR
CHIEF EDITOR
Sergey L. Dzemeshkevich
MD, Professor (Moscow, Russia)

Journals of «GEOTAR-Media»