## 3 Discussion  
In our review of the literature, we evaluated the efficacy of targeting staphylococcal biofilms in skin wounds, considering mainly the effect on wound healing in in vivo studies, where histological assessment was also reported. For this reason, studies without skin histological evaluation were not included, while others with in vitro relevance (e.g., human fibroblast) were cited. Therefore, considering exclusively the selection criteria, this review is not exhaustive for every existing therapy that could have an anti-biofilm effect and represents a selection of all available studies. Regarding antibiotics, beta lactams are indicated in combination with adjuvant therapy for chronic wounds with biofilm-forming staphylococcal infection [33]. To the best of our knowledge, in vivo studies with histological assessment of wound healing in wounds infected with biofilm-producing staphylococci are lacking. However, many adjuvants showed histological benefits in wound healing, and thus, potentially, all the topical therapies described previously may be suitable. (Table 1) Further studies are needed to provide histological evidence of the efficacy of these combinations in wound healing. In addition, teicoplanin, daptomycin and dalbavancin also showed to improve wound healing in vivo in mouse models. For tigecycline better control of infection was achieved in combination with daptomycin or rifampicin, although superiority to teicoplanin in wound healing was demonstrated through modulation of metalloproteinase-9 in a mouse model infected with biofilm-producing _S. aureus_[36]. This may suggest that tigecycline has a greater effect on wound healing than one of the leading antibiotics for MRSA, teicoplanin, but both antibiotics are effective in either controlling infection or promoting better wound healing. In our opinion, tigecycline or teicoplanin may be used in biofilm-forming MRSA skin infections as first line. In the case of non-responsive and non-healing infections, we suggest evaluating the combination with one of the described adjuvant therapies. However, most of these have never been tested in humans and are not readily available. For example, quorum sensing inhibitors are also promising treatment options, but there is a lack of studies in humans to assess their efficacy. RIP has been used topically in two cases of chronic diabetic ulcers in combination with daptomycin, with clinical improvement [115]. Although they have been shown to modulate VEGF expression and wound healing, the best results were obtained in combination with systemic antibiotics, such as FS10 and tiegcycline. These molecules can help increase MRSA sensitivity towards antibiotics to which they are normally resistant. Specifically, F12 and F1 reduced the MIC for cephalothin and nafcillin by about 50-fold [41]. Increased use of these molecules topically, especially in association with a systemic antibiotic, may therefore both promote wound healing and increase the eradicating capacity of the antibiotic used. Similarly, better results are possible for AMPs in combination with systemic antibiotics. In our review of the literature, many studies do not consider the histological evaluation of wound healing, preventing an assessment of their effect on the healing process and their direct correlation with the anti-biofilm action. However, many molecules have been referred with excellent potential against the staphylococcal biofilm and represent an important therapeutic possibility worthy of further studies, including applications on humans [43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162; 163; 164]. For instance, naja atra cathelicidin (NA-CATH):ATRA1-ATRA1, a highly cationic synthetic peptide derived from a natural snake cathelicidin, showed exceptional anti-biofilm properties against _S.