## 3 Wound-Associated Infections  
The skin stays the largest and most exposed human body organ [6; 8; 130; 131], shielding the body against the penetration of pathogenic bacteria [131; 132; 133]. There are two primary components of the skin: the outermost epidermis (epithelial component) and the underlying dermis (connective component) [6; 131; 133; 134]. Skin epidermis includes the interfollicular epidermis, hair follicles, and several stratified layers of differentiated keratinocytes, melanocytes, and Langerhans cells (dendritic immune cells) [131; 134; 135]. These layers of differentiated keratinocytes are mainly responsible for the physical barrier function of the epidermis [133; 134]. Skin dermis includes innate cells (i.e., macrophages, dendritic cells, and mast cells), innate lymphoid cells, and many lymphocytes, which mediate the immunological function of skin, including phagocytosis or killing of invading bacteria that breach the skin [134]. Moreover, preventing pathogenic bacteria from penetrating through and dwelling epithelial surfaces could be a collaboration of two other approaches. First, the non-specific immunity of skin (acidic pH, lipid density, and scarce nutrients) orchestrates a harsh environment against pathogen invasion. Second, the competition between the commensal microbes colonizing cutaneous surfaces and invading bacterial pathogens is achieved via secreting novel natural products [6; 130], highlighting this concept as \"colonization resistance\" [8; 62; 134]. On the other hand, all open wounds lack a protective skin barrier and contain endogenous (skin flora of patient) or exogenous bacteria, which are initially killed by the patient's immune system. However, suppose the bacteria are attached to the wound surface and proliferated to a mature biofilm, resulting in a biofilm-infected wound [62]. In that case, that remains the most common barrier hindering wound healing [8; 68]. Even though inflammatory cells (such as macrophages) at the wound site incur tissue repair and regeneration, dysregulation of the inflammatory response can plausibly occur, converting the wound into chronic [136]. Chronic wounds referred to non-healing wounds from 30 days or more [68; 137]. Notable examples of chronic wounds are diabetic foot ulcers, pressure injuries, venous stasis ulcers, and ischemic ulcers [68; 137; 138; 139]. Chronic wounds also fuel the formation of biofilms because necrotic tissue and debris are niches for bacterial attachment. Compared to acute wounds, chronic wounds are more vulnerable to infection because of compromised immunity of patients [55; 68], reduced susceptibility to antibiotics and greater activation of inflammatory responses [56]. Biofilms in chronic wounds are also a culprit for \"hijacking\" the patient's immune response [138]. This hijacking is facilitated via expressing superantigens (e.g., enterotoxins and toxic shock syndrome toxin-1 of _S. aureus_), enabling a final release of pro-inflammatory cytokines from T lymphocytes [138; 140] and so manipulating the immune response of the patient to be in a perpetual state of hyper-inflammatory. In this hyper-inflammation state, the patient cannot conquer biofilms [138]. A previous study [137] has established a clear-cut more prevalence of biofilms in chronic wounds (60%) than in acute wounds (only 6%). To further perplex biofilms in chronic wounds, multispecies bacterial communities are predominant in biofilms in chronic wounds [68], and limited oxygen in deeper embedded cells of biofilms orchestrates the proliferation of anaerobes [56]. Previous studies have confirmed that _S. aureus_ is the most prevalent universal bacterial insult to chronic wounds [141; 37; 142; 143]. [PERSON] et al. [144] have identified a case of seven patients infected with vancomycin-resistant _S. aureus_ (VRSA) in the USA. All infected patients embraced chronic underlying conditions, such as chronic skin ulcers and diabetes, a history of infection with MRSA and vancomycin-resistant enterococci (VRE), and a previous treatment with vancomycin.