The Problem of Chronic Wounds
and an excess of
is spent annually on their treatment.28
In the US, chronic wounds affect approximately 6.7 million patients, and an excess of $50 billion is spent annually on their treatment, with the presence of a chronic wound extending an inpatient hospital stay by 3.6 days.28 The majority of chronic wounds exist in patients who suffer from other chronic diseases and are often times attributed as a co-morbid outcome of the disease.22 This potentially leads to under-reporting29 of the significance of the chronic wound, in terms of both the financial impact and healthcare resource utilisation.
What is the Role of Inflammation and the EPS in the Pathogenesis of Chronic Wounds?
A chronic wound is generally considered to be one that fails to proceed through an orderly reparative healing process producing an appropriate anatomical and functional result in a timely manner, usually 1-3 months20, whilst causing further deterioration in quality of life and increased financial burden. One of the defining features of wound chronicity is an arrest in the inflammatory stage of wound healing19 characterised by increased neutrophil accumulation and expression of pro-inflammatory cytokines.2 The challenge for the clinician in managing chronic wounds is to determine why the wound has failed to progress through its normal reparative processes to be able to intervene accordingly. In considering the progression from acute to chronic wound, there is an element of pre-disposing and perpetuating factors impairing the reparative process, such as elevated bacterial levels, presence of biofilm, age-impaired stress response, tissue hypoxia and repetitive ischemia/reperfusion injury.31 Compounding these are several patient factors such as smoking, diabetes mellitus, obesity, immunosuppression and peripheral vascular disease. With over 90% of chronic wounds containing bacteria living within a biofilm construct19, and with biofilms becoming established within wounds by 5 hours and mature by 10 hours,32 it is no surprise that the presence of biofilm contributes significantly to the pathogenesis of chronic wounds. Specifically, the EPS matrix of a biofilm forms a complex defensive architecture providing most of the bacterial resistance to the hostile actions of the host immune response, biocides and antimicrobials. The presence of the biofilm facilitates resistance to antibiotics via decreased growth/metabolic rate, altered stress response, and modulation of quorum-sensing pathways19, promoting an environment for the bacteria that optimises their survival and perpetuates the cycle of prolonged inflammation and impaired wound healing. The presence of a biofilm further impairs wound healing by mechanically preventing wound contracture and epithelisation.33
Acute versus Chronic Wound Infection: A Diagnostic and Treatment Dilemma
The clinical diagnosis of an acute wound infection is typically based upon the ‘classic’ signs and symptoms, including pain, erythema, oedema, heat and purulence. However, in the chronic wound alterations to usual wound healing lead to a decreased or altered expression of these clinical signs and symptoms. Diagnosis of chronic wound infection can be indicated by the presence of wound features, such as friability of granulation tissue, increasing pain, wound breakdown and foul odour. The presence of oedema, serous exudate with concurrent inflammation, heat and delayed healing may also suggest infection, however the presence or absence of purulent exudate is not a prerequisite for the diagnosis of an infected chronic wound.34 Accordingly, reliance on the classically described indicators of acute wound infection to diagnose a chronic infection may yield diagnostic errors and delayed treatment.
What is the Current Standard of Care? What are the Limitations?
Current treatment strategies for chronic wound infections generally involve the use of topical antimicrobial dressings and local debridement. However, it is known that the bacteria within a biofilm are inherently resistant to antimicrobials, owing to the shielding action of the EPS matrix, mutual protection of the bacteria within the biofilm, and metabolic quiescence.20 Accordingly, it is not surprising that topical antimicrobials have limited efficacy as they fail to penetrate the EPS matrix to target and eradicate the microbes contained within the biofilm. Whilst local debridement confers some benefit, the presence of persister cells and the ability of the biofilm to reconstitute itself limits the efficacy of this intervention. Therefore, a targeted anti-biofilm approach is necessary that involves disruption and degradation of the EPS matrix of the biofilm, targeting of the bacteria for destruction, and the prevention of biofilm reformation in the wound.16,18
SURGICAL SITE INFECTIONS
What is the Role of Biofilm in the Pathogenesis of Surgical Site Infection?
SSIs CAN ADD UP TO
in additional patient costs35
Surgical site infections (SSI) occur as a result of intraoperative microbial contamination of the surgical site from either endogenous or exogenous sources.40 Post-operative SSI are a significant cause of morbidity, and occasionally mortality, whilst contributing to substantial increases in health expenditure.41 Accordingly, significant effort is expended to prevent microbial contamination in the perioperative environment. As SSI requires microbial contamination, SSI may present as either an acute suppurative infective process or as a chronic indolent infective process. The acute process, consistent with an infection due to planktonic bacteria, is characterised by swelling, erythema, pain and heat. Whilst the chronic process, consistent with a biofilm infection, is characterised by an undulating infection with or without wound dehiscence and delayed healing.41
The Role of Biofilm in SSI in Orthopaedics
Cost of revision hip surgeries37
Orthopaedic surgery often involves significant tissue trauma and the use of implantable prosthesis that are regarded as being almost indispensable components of orthopaedic surgery.42 Tissue trauma in orthopaedics can occur as result of pre-disposing traumatic injury, the trauma of surgery itself, or a combination of both. Irrespective of the aetiology of the tissue trauma a host immune response occurs and a local inflammatory cascade is initiated. The additional use of prosthetic implants and potential microbial contamination can contribute to a chronic low-grade inflammation.43 In terms of the development of a prosthetic infection, the first step is surface adhesion of microbes to the biomaterial surface of an implant initiating subsequent colonisation.44 In the context of complex orthopaedic surgery, such as prosthetic joint surgery, bacteria can attach to multiple surfaces8 and form a biofilm in less than one hour, including the various hardware components and cement, as well as to bone and adjacent soft tissues, with detached aggregates possibly found within the joint fluid.45 In orthopaedic surgery, the biofilms formed may be either mono or polymicrobial, with the common bacteria being S. aureus, coagulase negative Staphylococci, beta-haemolytic Streptococci and P. aeruginosa 42, as well as P. acnes, and the Corynebacterium species.46 Peri-prosthetic infections are devastating complications44 in which the first line of therapy is systemic antibiotics. Following antibiotic therapy, the only viable course of action thereafter is surgical removal of the affected implant.45 Realistically, removal of an infected implant in the face of infection is not immediately feasible, as these implants are giving stability to the bony architecture43 and contribute to a person’s ability to participate in activities of daily living. Ultimately, a peri-prosthetic infection will necessitate prolonged hospital stays resulting in significant economic impact to the both the health system and the patient.
The Role of Biofilm in SSI in Abdominal Surgery
Abdominal Surgeries see an SSI Rate of
The use of minimally invasive surgical techniques is highly regarded for lower rates of SSI, earlier mobilisation, reduced length of stay, and reductions in urinary and pulmonary complications.40 Despite these benefits, the risk of SSI still exists in laparoscopic surgery and there will always remain a role for open surgical techniques. In terms of laparoscopic surgeries, one of the most dreaded complications is mesh infections in hernia repair. Despite the low incidence of this complication, it proves to be a challenging endeavour to rectify it, generally requiring intravenous antibiotics and mesh excision. S. Aureus is a common surgical wound contaminant in hernia surgery and subsequently produces a biofilm on mesh implants, with the resultant host inflammatory response stimulating the development of a fibrous capsule preventing antibiotic penetration into the mesh.40 Given the poor penetration of antibiotics and the inherent resistance characteristics of biofilm, the current standard of care often involves a selection of adjunctive long-term suppressive antibiotics, serial wound debridement and mesh excision.40 Complete mesh excision results in considerable morbidity due to the re-opening of the repaired defect, and in the case of a ventral hernia, this results in a large open abdominal wall defect40 often necessitating delayed closure with or without the use of vacuum assisted wound therapy.
The Role of Biofilm in SSI in Breast Reconstruction
contracture rate is between
Breast reconstructive surgery, including breast lifts, augmentations and reconstructive mammaplasty, comprise a significant volume of cosmetic surgical procedures.47 One of the relatively common complications of these procedures is capsular contracture (CC), which involves an abnormal tightening of the collagen capsule around the breast implant.47 This is a derangement of the normal healing process of fibrous capsule formation, with an increase in capsular thickening and subsequent contracture48 suspected to occur in the context of chronic inflammation and biofilm formation.47 In terms of the microbial environment of breast implant infections, a number of microorganisms have been identified, with two of the most prevalent being S. epidermis and P. acnes.49 The management of breast implant and pocket infections with CC generally involves total capsulectomy with implant removal and replacement.47 This is typically performed in a two-stage process49 involving implant removal and pocket irrigation with antibiotics and/or antibacterial agents47, followed by insertion of a new breast prosthesis. The utilisation of a new implant is essential due to the possible presence of a biofilm on the original implant with its known antibiotic resistance.47 The prevention of CC is a significant focus for clinicians encompassing standard strategies of pre-operative systemic antibiotics, local irrigation with antibiotics and the use of an infra-mammary incision.47 CC is the most common cause of breast surgery revision and may be related to incomplete biofilm removal from previous operations.47 Ajdic et al has advocated for the use antibiotic-coated implants in the aim of preventing biofilm formation, however the utility of this is questionable in the context of growing resistance to antimicrobials, suggesting that an alternate approach is needed.47
What is the Current Standard of Care? What are the Limitations?
As per current Centre for Disease Control and Prevention (CDC) recommendations50, the standard of care for the prevention of SSI is a systems approach to minimise the risk of microbial contamination that includes factors related to staffing, operating theatre design and operation, as well as patient factors. In terms of antimicrobials, the key interventions include the:
- timely administration of antimicrobial prophylaxis
- use of alcohol-containing pre-operative skin preparatory agents (in the absence of contraindications to its use)
- use of appropriate hand and forearm antisepsis strategies and the
- use of povidone-iodine (Betadine) and chlorhexidine solutions as the cornerstone of hand/forearm antisepsis and patient skin preparation.
Chlorhexidine-alcohol is reported to be superior to Betadine in terms of rates of SSI, however sequential skin preparation with betadine and alcohol is superior to chlorhexidine-alcohol. In terms of the prevention of biofilm formation, there is no established consensus position or evidence to suggest an optimal protocol. In the context of wound irrigation, there are multiple options available including:
- Irrigation with added antibiotics: less effective than parenteral antimicrobials
- Irrigation with saline: generally, less efficacious than betadine or chlorhexidine
- Irrigation with dilute betadine or chlorhexidine: no discernible difference in rates of SSI
Over the years, concerns have been raised regarding povidone-iodine and cytotoxicity, however the literature is not completely clear on this issue. In terms of breast reconstructive surgery, the use of povidone-iodine immersion of implants has been banned by the US Food and Drug Administration following concerns of breast implant rupture.47
What is the Role of Inflammation and the EPS in the Pathogenesis of Acne?
Acne is a chronic inflammatory skin disorder of the pilosebaceous unit (a structure consisting of hair, hair follicle, arrector pili muscles and sebaceous gland). Acne has a complex, multifactorial pathogenesis which involves increased sebum production, follicular hyperkeratinisation, inflammation and the presence of Propionibacterium acnes (P. acnes). Whilst genetics and hormones are believed to contribute to the development and progression of acne, it is the role of bacterial colonisation with P. acnes which garners interest due to its pro-inflammatory effects, its ability to produce a biofilm and its antimicrobial resistance.51
P. acnes exists as a skin commensal and is implicated in the pathogenesis of other dermatological infections other than acne, including folliculitis and hydradentitis suppurativia.52 In terms of acne, colonisation of the pilosebaceous unit with P. acnes is associated with biofilm production that occurs in both non-inflamed and inflamed acne lesions.53 The P. acnes biofilm is found over the deeper aspect of the hair follicle structures, with the biofilm spreading over the follicle wall, the hair shaft and the lumen. In terms of inflammation, P. acnes stimulates inflammation by inducing pro-inflammatory mediators, Toll-like receptors and CD 4+ T-cells.52
Ultimately, the impact of antimicrobial resistance poses an additional clinical concern for the treating clinician. Whilst P. acnes stimulates a local inflammatory response, its ability to develop a biofilm contributes to the development of antimicrobial resistance. The key mechanisms by which this occurs is through the restricted penetration of antimicrobials through the EPS matrix, as well metabolic quiescence and the presence of persister cells.54
What is the Impact of Acne on Quality of Life?
Acne can significantly impact a person’s health-related quality of life, with a negative impact noted in areas of physical health and psychosocial well-being. In particular, aspects of health that are commonly negatively impacted include the development of poor body image and decreased self-esteem. Beyond this, patients suffering from acne may experience varying degrees of psychological distress, such as anxiety, frustration, helplessness and suicidal ideation.55
What is the Current Standard of Care? What are the Limitations?
Current treatment strategies for acne incorporate the use of topical and/or systemic antimicrobials in combination with topical anti-acne treatments, such as benzyl peroxide and retinoids56, which are aimed at traditional bacterial reduction as well as downregulating the inflammatory cascade.51 Significant concerns have been raised over the indiscriminate and prolonged use of antimicrobials and the increasing prevalence of antimicrobial resistance.54 Based upon consensus statements, the use of early oral isotretinoin has been advocated in severe acne.57 The use of systemic isotretinoin is problematic due to restrictions on use, including the requirement for prescribing authority and teratogenesis, and the need for ongoing blood monitoring and monitoring of adverse events, which may include dermatological, gastrointestinal and psychiatric effects.58