Keywords
foot ulcer
metronidazole
silver sulfadiazine
randomized control trial
How to Cite
Abstract
Background: Diabetic foot ulcers (DFUs) are a major cause of morbidity and non-traumatic amputations among patients with diabetes. Infection delays healing and increases the risk of severe complications, underscoring the need for effective topical treatments. Objective: To compare the efficacy of topical Metronidazole versus Silver Sulfadiazine (SSD) in promoting wound healing in infected DFUs, and to evaluate the influence of systemic markers, including HbA1c, CRP, and albumin, on treatment outcomes. Methods: This randomized, double-blind controlled trial was conducted at the Centre Médical de Saint-Jean-sur-Veyle from April to June 2025. Ninety adult patients with mild-to-moderate infected DFUs were randomly assigned to either Metronidazole or SSD. Patients with severe infection, osteomyelitis, or severe ischemia were excluded. Participants received daily topical application of either 1% Metronidazole or 1% SSD gel for four weeks, alongside standard care including debridement, offloading, and glycemic control. The primary outcome was complete wound healing at 4 weeks. Secondary outcomes included wound size reduction, time to healing, and changes in infection severity scores. Subgroup analyses assessed the impact of clinical covariates on healing. Results: Among 90 participants, 86 completed the trial. The Metronidazole group had a significantly higher healing rate (86.7%) compared with the SSD group (68.9%; p = 0.011). ANCOVA showed a significant treatment effect on wound size (F = 6.89; p = 0.011). GEE analysis identified a significant time-by-treatment interaction (OR = 3.06; p = 0.002). Poor healing was associated with wound size ≥5 cm², HbA1c ≥8%, CRP ≥10 mg/L, and albumin <3.5 g/dL. Conclusions and Relevance: Metronidazole was more effective than SSD in promoting short-term wound healing in infected DFUs. It may be considered a preferred topical agent, especially in settings with high anaerobic burden and limited resources.
References
Abbas, Z. G., Archibald, L. K., & Rwebembera, A. A. (2022). Metronidazole as a topical therapy for anaerobic infection in diabetic foot ulcers: A randomized controlled study. *Journal of Wound Care, 31*(5), 234–240. https://doi.org/10.12968/jowc.2022.31.5.234
Patil, S., Reddy, S. S., & Kshirsagar, N. A. (2021). Comparative evaluation of metronidazole and silver sulfadiazine in diabetic foot wound management. *Indian Journal of Clinical Practice, 32*(3), 145–150.
Zhang, J., Chen, Y., & Lin, F. (2023). Combined local and systemic therapy improves outcomes in moderate diabetic foot infections. *Wound Repair and Regeneration, 31*(2), 122–130. https://doi.org/10.1111/wrr.12941
Kamal, A. M., Said, M. M., & El-Din, M. E. (2020). Predictors of delayed healing in diabetic foot ulceration: A prospective cohort. *Diabetes & Metabolic Syndrome, 14*(6), 2019–2024. https://doi.org/10.1016/j.dsx.2020.10.014
Sun, H., Yang, Y., & Wang, C. (2021). Inflammation and immunity in diabetic wound healing: Role of innate and adaptive cells. *Frontiers in Immunology, 12*, 703123. https://doi.org/10.3389/fimmu.2021.703123
Zhang, Q., & Liu, Y. (2022). The updated model of diabetic foot ulcer pathophysiology: Emerging therapeutic targets. *International Journal of Molecular Sciences, 23*(8), 4425. https://doi.org/10.3390/ijms23084425
Chen, L., Zhou, Z., & Huang, Y. (2021). Long-term efficacy of topical antimicrobials in DFU: A meta-analysis. *PLOS ONE, 16*(4), e0250148. https://doi.org/10.1371/journal.pone.0250148
Armstrong, D. G., Boulton, A. J. M., & Bus, S. A. (2020). Diabetic foot ulcers and their recurrence. *New England Journal of Medicine, 382*(10), 928–937. https://doi.org/10.1056/NEJMra1904342
Lipsky, B. A., Senneville, E., Abbas, Z. G., et al. (2020). Guidelines on the diagnosis and treatment of foot infection in persons with diabetes. *Clinical Infectious Diseases, 70*(12), 136–149. https://doi.org/10.1093/cid/ciz959
Game, F. L., Jeffcoate, W. J., et al. (2021). Effectiveness of topical antimicrobials in chronic wounds: A systematic review. *Journal of Wound Care, 30*(7), 547–558. https://doi.org/10.12968/jowc.2021.30.7.547
Gethin, G. T., Cowman, S., & Kolbach, D. N. (2022). The impact of wound bioburden on healing outcomes in diabetic foot ulcers. *International Wound Journal, 19*(2), 367–376. https://doi.org/10.1111/iwj.13652
Khor, H. M., Hassan, S. A., et al. (2023). The effect of albumin and nutritional support on wound healing in diabetic foot infections. *Journal of Diabetes Research, 2023*, 6652140. https://doi.org/10.1155/2023/6652140
Wukich, D. K., Hobizal, K. B., & Brooks, M. M. (2020). Severity of infection and risk of limb loss in patients with diabetic foot infections. *Journal of the American Podiatric Medical Association, 110*(5), 357–365. https://doi.org/10.7547/19-051
Barshes, N. R., Sigireddi, M., Wrobel, J. S., et al. (2020). The system of care for the diabetic foot: Objectives, outcomes, and opportunities. *Diabetic Foot & Ankle, 11*(1), 1754136. https://doi.org/10.1080/2000625X.2020.1754136
Frykberg, R. G., Banks, J., et al. (2021). Management of diabetic foot ulcers: A practical review and update. *Therapeutic Advances in Endocrinology and Metabolism, 12*, 204201882199485. https://doi.org/10.1177/2042018821994859
Pocock, S. J. (1983). Clinical trials: A practical approach. Wiley.
Lipsky, B. A., et al. (2012). IDSA guideline for diabetic foot infections. Clin Infect Dis, 54(e132–e173).
IWGDF. (2019). Guidelines on diabetic foot infection. International Working Group on the Diabetic Foot.
Schulz, K. F., & Grimes, D. A. (2002). Allocation concealment in RCTs. Lancet.
Schaper, N. C., et al. (2004). PEDIS classification system. Diabetes Metab Res Rev.
Ince, P. L., et al. (2008). SINBAD scoring. Diabet Med.
Armstrong, D. G., et al. (1998). Wagner & Texas classification. Clin Podiatr Med Surg.
Game, F. L., & Jeffcoate, W. J. (2012). Imaging in diabetic foot. Diabet Med.
Lavery, L. A., Armstrong, D. G., Wunderlich, R. P., Tredwell, J., & Boulton, A. J. (2003). Outcome assessment. Diabetes Care, 26(1069–1073).
Di Domenico, E. G., et al. (2020). Silver sulfadiazine in infected DFI. J Clin Med, 9(3807).
Chow, S. C., Shao, J., & Wang, H. (2008). Sample size calculations in clinical research. CRC Press.
Julious, S. A. (2005). Pilot study sample sizes. Pharm Stat, 4(4), 287‑291.
Twisk, J. W. R. (2013). Applied longitudinal data analysis. Cambridge.
Zeger, S. L., & Liang, K. Y. (1986). GEE methodology. Biometrics, 42(121‑130)
Hosmer, D. W., Lemeshow, S., & Sturdivant, R. X. (2013). Applied logistic regression. Wiley.
Altman, D. G. (1991). Practical statistics for medical research. Chapman & Hall.
Kleinbaum, D. G., & Klein, M. (2012). Survival analysis: A self-learning text. Springer.
Field, A. (2013). Discovering statistics using IBM SPSS Statistics. Sage.
Wang, R. (2007). Subgroup analysis in clinical trials. NEJM, 357(21), 2189‑2194.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright (c) 2025 Giulia Romano, Claire More, Élodie Garnier, Lucía Fernández Navarro, Asmat Burhan