Does antibiotic use accelerate or retard cutaneous repair? A systematic review in animal models

Autoři: Luciana Schulthais Altoé aff001;  Raul Santos Alves aff001;  Mariáurea Matias Sarandy aff002;  Mônica Morais-Santos aff002;  Rômulo Dias Novaes aff003;  Reggiani Vilela Gonçalves aff002
Působiště autorů: Departament of General Biology, Federal University of Viçosa, Viçosa, Minas Gerais, Brazil aff001;  Departament of Animal Biology, Federal University of Viçosa, Viçosa, Minas Gerais, Brazil aff002;  Departament of Structural Biology, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article



The presence of infections is one of the main factors that leads to delays in healing or non-closure of cutaneous wounds. Although the goal of antibiotic use is to treat or prevent infection, there is currently no agreement on the effectiveness of these products.


The aim of this study was to evaluate the efficacy of antibiotic use during the healing process of skin wounds in animal models not intentionally infected, as well as to analyze the advances and limitations of the studies carried out in this field.

Main methods

This systematic review was performed according to the PRISMA guidelines, using a structured search on the MedLine (PubMed) and Scopus platforms to retrieve studies published until August 29, 2018, 13:35p.m. The studies included were limited to those that used excision or incision wound models and that were not intentionally infected. The data for the animal models, antibiotic used, and the main results of the studies were extracted, and compared where possible. Bias analysis and methodological quality assessments were examined through the SYRCLE’s Risk of Bias tool.

Key findings

Twenty-seven studies were selected. Overall, the effects of the antibiotic on the wound decreased inflammatory cell infiltration and promoted an increased number of fibroblasts, extracellular matrix constituents, re-epithelialization and tissue strength. A great deal of important information about the methodology was not presented, such as: the statistical analysis used, the animal model (sex and age), antibiotic dosage, blinding and randomization of the animals chosen.


Based on the results found, we believe that antibiotic therapy can be considered a viable alternative for the treatment of cutaneous wounds. However, current evidence obtained from the methodological quality analysis points towards a high risk of bias. This is due to the incomplete characterization of the experimental design and treatment protocol, which compromises the reproducibility of the studies.

Klíčová slova:

Animal models – Antibiotics – Extracellular matrix – Fibroblasts – Inflammation – Silver – Systematic reviews – Tissue repair


1. Marrot L. Pollution and Sun Exposure: a Deleterious Synergy. Mechanisms and Opportunities for Skin Protection. Curr Med Chem. 2017;25: 5469–5486. doi: 10.2174/0929867324666170918123907 28925870

2. Oryan A, Mohammadalipour A, Moshiri A, Tabandeh MR. Topical application of aloe vera accelerated wound healing, modeling, and remodeling: An Experimental Study. Ann Plast Surg. 2016;77: 37–46. doi: 10.1097/SAP.0000000000000239 25003428

3. Etulain J. Platelets in wound healing and regenerative medicine. Platelets. Taylor & Francis; 2018;29: 556–568. doi: 10.1080/09537104.2018.1430357 29442539

4. Gonzalez AC de O, Andrade Z de A, Costa TF, Medrado ARAP. Wound healing—A literature review [Internet]. Anais Brasileiros de Dermatologia. 2016. pp. 614–620.

5. Selders GS, Fetz AE, Radic MZ, Bowlin GL. An overview of the role of neutrophils in innate immunity, inflammation and host-biomaterial integration. Regen Biomater. 2017;4: 55–68. doi: 10.1093/rb/rbw041 28149530

6. Xue M, Jackson CJ. Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring. Adv wound care. 2015;4: 119–136. doi: 10.1089/wound.2013.0485 25785236

7. Novaes RD, Cupertino MC, Sarandy MM, Souza A, Soares EA, Gonçalves R V. Time-Dependent Resolution of Collagen Deposition During Skin Repair in Rats: A Correlative Morphological and Biochemical Study. Microsc Microanal. 2015;21: 1482–1490. doi: 10.1017/S1431927615015366 26538416

8. Sarandy MM, Miranda LL, Altoé LS, Novaes RD, Zanuncio VV, Leite JPV, et al. Strychnos pseudoquina modulates the morphological reorganization of the scar tissue of second intention cutaneous wounds in rats. PLoS One. 2018;13: 1–15. doi: 10.1371/journal.pone.0195786 29649320

9. Han G, Ceilley R. Chronic Wound Healing: A Review of Current Management and Treatments. Adv Ther. Springer Healthcare; 2017;34: 599–610. doi: 10.1007/s12325-017-0478-y 28108895

10. Lindley LE, Stojadinovic O, Pastar I, Tomic-Canic M. Biology and biomarkers for wound healing. Plast Reconstr Surg. 2016;138: 18–28. doi: 10.1097/PRS.0000000000002682 27556760

11. Pop MA, Almquist BD. Biomaterials: A potential pathway to healing chronic wounds? Exp Dermatol. 2017;26: 760–763. doi: 10.1111/exd.13290 28094868

12. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, et al. Human skin wounds: A major and snowballing threat to public health and the economy. Wound Repair Regen. 2009;17: 763–771. doi: 10.1111/j.1524-475X.2009.00543.x 19903300

13. Frykberg RG, Banks J. Challenges in the Treatment of Chronic Wounds. Adv Wound Care. 2015;4: 560–582. doi: 10.1089/wound.2015.0635 26339534

14. Nussbaum SR, Carter MJ, Fife CE, DaVanzo J, Haught R, Nusgart M, et al. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. Value Heal. Elsevier Inc.; 2018;21: 27–32. doi: 10.1016/j.jval.2017.07.007 29304937

15. Phillips CJ, Humphreys I, Fletcher J, Harding K, Chamberlain G, Macey S. Estimating the costs associated with the management of patients with chronic wounds using linked routine data. Int Wound J. 2016;13: 1193–1197. doi: 10.1111/iwj.12443 25818405

16. Whittam AJ, Maan ZN, Duscher D, Wong VW, Barrera JA, Januszyk M, et al. Challenges and Opportunities in Drug Delivery for Wound Healing. Adv Wound Care. 2016;5: 79–88. doi: 10.1089/wound.2014.0600 26862465

17. Wysocki AB. Evaluating and Managing Open Skin Wounds: Colonization Versus Infection. AACN Clin Issues. 2002;13: 382–397. doi: 10.1097/00044067-200208000-00005 12151992

18. Bowler PG, Duerden BI, Armstrong DG. Wound Microbiology and Associated Approaches to Wound Management. Clin Microbiol Rev. 2001;14: 244–269. doi: 10.1128/CMR.14.2.244-269.2001 11292638

19. Diehr S, Hamp A, Jamieson B. Do topical antibiotics improve wound healing ? J Fam Pract. 2007;56: 140–144. 17270122

20. White RJ, Cutting K, Kingsley A. Topical antimicrobials in the control of wound bioburden. Ostomy Wound Manage. 2006;52: 26–58.

21. Dreifke MB, Jayasuriya AA, Jayasuriya AC. Current wound healing procedures and potential care. Mater Sci Eng C Mater Biol Appl. 2014;48: 651–662. doi: 10.1016/j.msec.2014.12.068 25579968

22. Mariotti AJ, Rumpf DAH. Chlorhexidine-Induced Changes to Human Gingival Fibroblast Collagen and Non-Collagen Protein Production. J Periodontol. 1999;70: 1443–1448. doi: 10.1902/jop.1999.70.12.1443 10632519

23. Hirsch T, Koerber A, Jacobsen F, Dissemond J, Steinau HU, Gatermann S, et al. Evaluation of toxic side effects of clinically used skin antiseptics in vitro. J Surg Res. 2010;164: 344–350. doi: 10.1016/j.jss.2009.04.029 19726054

24. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009;6: e1000097. doi: 10.1371/journal.pmed.1000097 19621072

25. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. Bmc Med Res Methodol. BMC Medical Research Methodology; 2014;14: 1–9.

26. World Health Organization. Critically important antimicrobials for human medicine: Ranking of medically important antimicrobials for risk management of antimicrobial resistance due to non-human use. Fifth revi. 2016.

27. Leitch IOW, Kucukcelebi A, Robson MC. Inhibition of Wound Contraction By Topical Antimicrobials. Aust N Z J Surg. 1993;63: 289–293. doi: 10.1111/j.1445-2197.1993.tb00385.x 8311815

28. Heggers JP, Kucukcelebi A, Stabenau CJ, Ko F, Broemeling LD, Robson MC, et al. Wound healing effects of Aloe gel and other topical antibacterial agents on rat skin. Phyther Res. 1995;9: 455–457.

29. Choi YS, Hong SR, Lee YM, Song KW, Park MH, Nam YS. Study on gelatin-containing artificial skin: I. Preparation and characteristics of novel gelatin-alginate sponge. Biomaterials. 1999;20: 409–417. doi: 10.1016/s0142-9612(98)00180-x 10204983

30. Muller MJ, Hollyoak MA, Moaveni Z, Brown TLH, Herndon DN, Heggers JP. Retardation of wound healing by silver sulfadiazine is reversed by Aloe vera and nystatin. Burns. 2003;29: 834–836. doi: 10.1016/s0305-4179(03)00198-0 14636760

31. Kim JO, Choi JY, Park JK, Kim JH, Jin SG, Chang SW, et al. Development of Clindamycin-Loaded Wound Dressing with Polyvinyl Alcohol and Sodium Alginate. Biol Pharm Bull. 2008;31: 2277–2282. doi: 10.1248/bpb.31.2277 19043213

32. Kim JO, Park JK, Kim JH, Jin SG, Yong CS, Li DX, et al. Development of polyvinyl alcohol-sodium alginate gel-matrix-based wound dressing system containing nitrofurazone. Int J Pharm. 2008;359: 79–86. doi: 10.1016/j.ijpharm.2008.03.021 18440737

33. Simpson JM, Séguin B, Gitelman AI. Effects of topical application of taurolidine on second intention healing of experimentally induced wounds in rats. Am J Vet Res. 2008;69: 1210–1216. doi: 10.2460/ajvr.69.9.1210 18764696

34. Hwang M-R, Kim JO, Lee JH, Kim Y Il, Kim JH, Chang SW, et al. Gentamicin-Loaded Wound Dressing With Polyvinyl Alcohol/Dextran Hydrogel: Gel Characterization and In Vivo Healing Evaluation. AAPS PharmSciTech. 2010;11: 1092–1103. doi: 10.1208/s12249-010-9474-0 20607628

35. Lin Y-H, Lin J-H, Peng S-F, Yeh C-L, Chen W-C, Chang T-L, et al. Multifunctional gentamicin supplementation of poly(γ‐glutamic acid)‐based hydrogels for wound dressing application. J ofAppliedPolymer Sci. 2010;120: 1057–1068. doi: 10.1002/app.33249

36. Huang WY, Yeh CL, Lin JH, Yang JS, Ko TH, Lin YH. Development of fibroblast culture in three-dimensional activated carbon fiber-based scaffold for wound healing. J Mater Sci Mater Med. 2012;23: 1465–1478. doi: 10.1007/s10856-012-4608-4 22415364

37. Gurel MS, Naycı S, Turgut A V, Bozkurt ER. Comparison of the effects of topical fusidic acid and rifamycin on wound healing in rats. Int Wound J. 2013;12: 106–110. doi: 10.1111/iwj.12060 23489386

38. Mittal A, Kumar N. A new, bioactive, antibacterial-eluting, composite graft for infection-free wound healing. Wound Repair Regen. 2014;22: 527–536. doi: 10.1111/wrr.12194 24899130

39. Princely S, Saleem Basha N, Nandhakumar S, Dhanaraju MD. Design and evaluation of controlled release gentamycin incorporated gelatinalginate matrices for wound management. Der Pharm Lett. 2015;7: 145–153.

40. Fu R, Li C, Yu C, Xie H, Shi S, Li Z, et al. A novel electrospun membrane based on moxifloxacin hydrochloride/poly(vinyl alcohol)/sodium alginate for antibacterial wound dressings in practical application. Drug Deliv. 2016;23: 818–829.

41. Li H, Williams GR, Wu J, Lv Y, Sun X, Wu H, et al. Thermosensitive nanofibers loaded with ciprofloxacin as antibacterial wound dressing materials. Int J Pharm. 2017;517: 135–147. doi: 10.1016/j.ijpharm.2016.12.008 27940041

42. Geronemus RG, Mertz PM, Eaglstein WH. Wound healing. The Effects of Topical Antimicrobial Agents. Arch Dermatol Res. 1979;115: 1311–1314.

43. Watcher MA, Wheeland RG. The Role of Topical Agents in the Healing of Full-Thickness Wounds. J Dermatol Surg Oncol. 1989;15: 1188–1195. doi: 10.1111/j.1524-4725.1989.tb03232.x 2509527

44. Singer AJ, Berrutti L, Mcclain SA. Comparative trial of octyl-cyanoacrylate and silver sulfadiazine for the treatment of full-thickness skin wounds. Wound Repair Regen. 1999;7: 356–361. doi: 10.1046/j.1524-475X.1999.00356.x 10564564

45. Faucher LD, Kleinbeck KR, Kao WJ. Multifunctional photopolymerized semiinterpenetrating network (sIPN) system containing bupivacaine and silver sulfadiazine is an effective donor site treatment in a swine model. J Burn Care Res. 2010;31: 137–145. doi: 10.1097/BCR.0b013e3181cb8f27 20061849

46. Theunissen D, Seymour B, Forder M, Cox SG, Rode H. Measurements in wound healing with observations on the effects of topical agents on full thickness dermal incised wounds. Burns. Elsevier Ltd and International Society of Burns Injuries; 2016;42: 556–563. doi: 10.1016/j.burns.2015.09.014 26899619

47. Hebda PA, Whaley D, Kim HG, Wells A. Absence of inhibition of cutaneous wound healing in mice by oral doxycycline. Wound Repair Regen. 2003;11: 373–379. doi: 10.1046/j.1524-475X.2003.11510.x 12950642

48. Zhang M, Jiang Z, Li D, Jiang D, Wu Y, Ren H, et al. Oral Antibiotic Treatment Induces Skin Microbiota Dysbiosis and Influences Wound Healing. Microb Ecol. 2015;69: 415–421. doi: 10.1007/s00248-014-0504-4 25301498

49. Tummalapalli M, Berthet M, Verrier B, Deopura BL, Alam MS, Gupta B. Drug loaded composite oxidized pectin and gelatin networks for accelerated wound healing. Int J Pharm. Elsevier B.V.; 2016;505: 234–245. doi: 10.1016/j.ijpharm.2016.04.007 27063849

50. Kataria K, Gupta A, Rath G, Mathur RB, Dhakate SR. In vivo wound healing performance of drug loaded electrospun composite nanofibers transdermal patch. Int J Pharm. Elsevier B.V.; 2014;469: 102–110. doi: 10.1016/j.ijpharm.2014.04.047 24751731

51. Qian LW, Fourcaudot AB, Leung KP. Silver Sulfadiazine Retards Wound Healing and Increases Hypertrophic Scarring in a Rabbit Ear Excisional Wound Model. J Burn Care Res. 2017;38: 418–422. doi: 10.1097/BCR.0000000000000406 28009700

52. Berry DB, Sullins KE. Effects of topical application of antimicrobials and bandaging on healing and granulation tissue formation in wounds of the distal aspect of the limbs in horses. Am J Vet Res. 2003;64: 88–92. doi: 10.2460/ajvr.2003.64.88 12518884

53. Edwards-Milewski ML, Morello SL, Zhao Q, Mattan-Bell C. The Effect of Intravenous Regional Perfusion of the Distal Limb With Amikacin Sulfate on Wounds Healing by Second Intention in Horses. Vet Surg. 2016;45: 125–132. doi: 10.1111/vsu.12435 26731602

54. Zaman S Bin, Hussain MA, Nye R, Mehta V, Mamun KT, Hossain N. A Review on Antibiotic Resistance: Alarm Bells are Ringing. Cureus. 2017;9: 1–9. doi: 10.7759/cureus.1403 28852600

55. Klein EY, Van Boeckel TP, Martinez EM, Pant S, Gandra S, Levin SA, et al. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc Natl Acad Sci U S A. National Academy of Sciences; 2018;115: E3463–E3470. doi: 10.1073/pnas.1717295115 29581252

56. Sinha M. Advance measures and challenges of wound healing. J Pharmacol Ther Res. 2018;2: 1–3.

57. Rousselle P, Braye F, Dayan G. Re-epithelialization of adult skin wounds: Cellular mechanisms and therapeutic strategies. Adv Drug Deliv Rev. Elsevier B.V.; 2018; doi: 10.1016/j.addr.2018.06.019 29981800

58. Dhivya S, Padma VV, Santhini E. Wound dressings–a review. BioMedicine. 2015;5: 24–28.

59. Edwards R, Harding KG. Bacteria and wound healing. Curr Opin Infect Dis. 2004;17: 91–96. 15021046

60. Kinser PA, Robins JL. Control group design: Enhancing rigor in research of mind-body therapies for depression. Evidence-based Complement Altern Med. 2013;2013: 1–10. doi: 10.1155/2013/140467 23662111

61. Bate ST, Clark RA. The design and statistical analysis of laboratory animal experiments. Cambridge Cambridge Univ Press. 2014; doi: 10.1017/CBO9781139344319

62. Lodhi S, Vadnere GP. Relevance and perspectives of experimental wound models in wound healing research. Asian J Pharm Clin Res. 2017;10: 57–62. doi: 10.22159/ajpcr.2017.v10i7.18276

63. Trøstrup H, Thomsen K, Calum H, Hoiby N, Moser C. Animal models of chronic wound care: the application of biofilms in clinical research. Chronic Wound Care Manag Res. 2016;3: 123–132. doi: 10.2147/CWCMR.S84361

64. Summerfield A, Meurens F, Ricklin ME. The immunology of the porcine skin and its value as a model for human skin. Mol Immunol. 2015;66: 14–21. doi: 10.1016/j.molimm.2014.10.023 25466611

65. Grada A, Mervis J, Falanga V. Research Techniques Made Simple: Animal Models of Wound Healing. J Invest Dermatol. 2018;138: 2095–2105. doi: 10.1016/j.jid.2018.08.005 30244718

66. Bate S, Karp NA. A Common Control Group—Optimising the Experiment Design to Maximise Sensitivity. PLoS One. 2014;9: e114872. doi: 10.1371/journal.pone.0114872 25504147

67. Chen L, Mirza R, Kwon Y, DiPietro LA, Koh TJ. The murine excisional wound model: Contraction revisited. Wound Repair Regen. 2015;23: 874–877. doi: 10.1111/wrr.12338 26136050

68. Koschwanez HE, Broadbent E. The use of wound healing assessment methods in psychological studies: A review and recommendations. British Journal of Health Psychology. 2011. doi: 10.1348/135910710X524633 21226781

69. Heyneman A, Hoeksema H, Vandekerckhove D, Pirayesh A, Monstrey S. The role of silver sulphadiazine in the conservative treatment of partial thickness burn wounds: A systematic review. Burns. Elsevier Ltd and International Society of Burns Injuries; 2016;42: 1377–1386. doi: 10.1016/j.burns.2016.03.029 27126813

70. TUTRONE WD, SPANN CT, ROSS B, WEINBERG JM, SCHEINFELD N. Topical Antibacterial Agents for Wound Care: A Primer. Dermatologic Surg. 2014;29: 620–626. doi: 10.1097/00042728-200306000-00014

71. Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, et al. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018;11: 1645–1658. doi: 10.2147/IDR.S173867 30349322

72. Li B, Webster TJ. Bacteria antibiotic resistance: New challenges and opportunities for implant-associated orthopedic infections. J Orthop Res. 2018;36: 22–32. doi: 10.1002/jor.23656 28722231

73. Cheng G, Hao H, Xie S, Wang X, Dai M, Huang L, et al. Antibiotic alternatives: the substitution of antibiotics in animal husbandry? Front Microbiol. 2014;5: 1–15.

74. Betts JW, Hornsey M, La Ragione RM. Novel Antibacterials: Alternatives to Traditional Antibiotics. Adv Microb Physiol. 2018;73: 123–169. doi: 10.1016/bs.ampbs.2018.06.001 30262108

75. Galvão TF, Pereira MG. Revisões sistemáticas da literatura: passos para sua elaboração. Epidemiol e Serviços Saúde. 2014;23: 183–184.

Článek vyšel v časopise


2019 Číslo 10
Nejčtenější tento týden