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Diabetic foot infection is a common diabetic complication that may end in lower limb amputation if not treated properly. We performed this systematic review to assess the clinical efficacy of different antibiotic regimens, whether systemic or topical, in the treatment of moderate to severe diabetic foot infections. We searched Medline, Web of Science, SCOPUS, Cochrane CENTRAL, and ScienceDirect for randomized controlled trials that evaluated the efficacy of antibiotic regimens in moderate to severe diabetic foot infections. The primary outcome of interest was the clinical efficacy (cure/improvement rates) of the regimens. We included 16 trials (4,158 patients) in this review, from which we extracted 10 comparisons: some trials compared systemic antibiotics to each other, others compared systemic to topical agents, while one study compared the combined topical and systemic agents to systemic antibiotics alone. Qualitative analysis of the findings of these studies showed that: (1) pipracillin/tazobactam was superior to ertapenem in severe infections (clinical resolution rate: 91.5% compared with PIP/TAZ 97.2%, p ≤ 0.04), but had similar efficacy in moderate infections, (2) ertapenem was more effective than tigecycline in moderate to severe infections (absolute difference -5.5, [95% CI -11.0, 0.1]), (3) the adjuvant use of topical agents with systemic antibiotics improved the outcomes, compared with systemic antibiotics alone (p = 0.024), (4) the rates of recurrence and re-ulceration were significantly lower in patients using the amino-penicillin regimen, compared with those using oral/intravenous ofloxacin, and (5) lower rates of complications accompanied the imipenem/cilastatin regimen, compared with the pipracillin/tazobactam regimen (p = 0.13). In conclusion, data from the included studies showed better results for ertapenem when compared with tigecycline; however, it was inferior to pipracillin/tazobactam in severe infections. The adjuvant use of topical agents improves the efficacy of systemic antibiotics in diabetic foot infection., (© 2018 by the Wound Healing Society.)