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Skin and soft-tissue infections (SSIs) are among the commonest infections encountered in clinical practice. Spread of methicillin-resistant Staphylococcus aureus SSIs continues to increase in both health care and community settings and presents a challenge for the best treatment choice. Vancomycin has been the mainstay of SSIs treatment, but recently its use has been questioned because of concerns about its efficacy, tolerability, and unfavorable pharmacokinetic/pharmacodynamic profile. The purpose of this review is to establish the current role for vancomycin in light of the literature published from January 2007 to September 2017 on comparison with both old and new alternatives.Meta-analyses show better clinical and microbiological outcomes for drugs approved for the treatment of SSI, including those sustained by methicillin-resistant S. aureus, in the last 10 years than for vancomycin. The newer glycopeptides and linezolid decrease the total treatment costs compared with vancomycin, by reducing the length of stay or avoiding the hospitalization.Vancomycin is noninferior in efficacy and safety to all comparator drugs, including the newest on the market. However, the SSI treatment evidence base presents several shortcomings limiting the clinical applicability of the results. High-level clinical trials should be performed to obtain results that can be generalized and applied effectively in clinical practice.