literature review on the management of diabetic foot ulcer

How Infection Impairs Wound Healing

Biofilms in the context of dfus, evolving microbiology of dfis, debridement: the first step in controlling dfis, managing infected dfus, surgery versus antibiotics in dfo, iv versus oral antibiotics for osteomyelitis: lessons from the oviva trial, topical treatments for dfis, role of modern technology in the prevention and management of biofilms and dfis, article information, diagnosis and management of diabetic foot infections.

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Andrew J.M. Boulton , David G. Armstrong , Matthew J. Hardman , Matthew Malone , John M. Embil , Christopher E. Attinger , Benjamin A. Lipsky , Javier Aragón-Sánchez , Ho Kwong Li , Gregory Schultz , Robert S. Kirsner; Diagnosis and Management of Diabetic Foot Infections. ADA Clinical Compendia 1 January 2020; 2020 (1): No Pagination Specified. https://doi.org/10.2337/db2020-01

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After the success and positive reception of the American Diabetes Association’s 2018 compendium Diagnosis and Management of Diabetic Foot Complications ( 1 ) the association asked us to proceed with a second volume. The first publication offered a broad general overview of diabetic foot issues, encompassing the etiopathogenesis of complications, screening, and wound classification; management of diabetic foot ulcers (DFUs) and diabetic foot infections (DFIs); recognition and treatment of peripheral artery disease (PAD) and Charcot neuroarthropathy; off-loading, wound management, and adjunctive therapies; and maintenance of the foot in remission.

In the past few years, there has been a renaissance in diabetic foot care with respect to evidence-based treatments ( 2 ). Examples include the LeucoPatch system ( 3 ), topical oxygen delivery ( 4 , 5 ), and, for neuroischemic ulcers, sodium octasulfate dressings ( 6 ). There has also been progress in the management of DFUs with infection. For example, a randomized controlled trial (RCT) confirmed that treatment with antibiotics is noninferior to local surgery for localized diabetic foot osteomyelitis (DFO) ( 7 ). (See related discussion on p. 12.) Most recently, the OVIVA (Oral Versus Intravenous Antibiotics) trial confirmed that, for complex bone and joint infections, oral antibiotic therapy had similar outcomes to intravenous (IV) therapy ( 8 ). (See related discussion on p. 13.) Because foot infections are a major contributor to amputation, we decided to make infected DFUs the focus of this second foot care compendium.

The first sections herein cover the impact of infection on healing of experimental wounds (p. 2), the importance of biofilms (p. 4), and a general overview of the microbiology of DFIs (p. 6). Although debridement of DFUs was covered in the first compendium, we deemed it important enough to include here as well, given its pivotal role in the management of DFIs. Whereas molecular markers might inform the extent of wound debridement in the future ( 9 ), at present, clinical assessment is used to ensure that adequate debridement is achieved, as reviewed starting on p. 7. Subsequent sections cover the management of infected DFUs (p. 9) and discussions of antibiotics versus surgery for osteomyelitis (p. 12) and the OVIVA trial (p. 13). There is little doubt that the OVIVA trial will challenge the current management of osteomyelitis, in which IV antibiotics are still commonly used. The remaining sections cover potential topical treatments for DFIs (p. 15) and the role of modern technology in infection control (p. 17).

In addition to this compendium and the previous one ( 1 ), we want to direct readers’ attention to two forthcoming publications that will surely be of interest. First, in the wake of the 8th International Symposium on the Diabetic Foot held in May 2019 in The Netherlands, the International Working Group on the Diabetic Foot (IWGDF) has recently published its revised and updated guidelines on the management of DFIs ( 10 ). In addition, the Infectious Disease Society of America will soon be updating its 2012 guidelines ( 11 ) on the treatment of infected DFUs.

DFUs are a complex, multifactorial clinical problem that, despite decades of research, remain poorly understood at the basic science level. Over millennia, our bodies have evolved a highly orchestrated healing response to skin wounds through which inflammation, cell proliferation, migration, angiogenesis, matrix deposition, and remodeling are sequentially activated to repair injured tissue. We know that, in DFUs, repair becomes dysregulated with widespread tissue necrosis, hyperproliferative wound callus, and excessive inflammation. This drives a matrix metalloproteinase (MMP)–rich proteolytic wound bed, which impedes granulation, delays vascularization, and results in a hypoxic local environment. At the cellular level, DFUs are characterized by accumulation of senescent cells and lack responsiveness to the normal cues that drive timely repair. At the molecular level, there are still major gaps in our knowledge of DFU ontogenesis, underscored by a distinct lack of biological therapies for wound care.

How does this profound state of dysregulation occur, and perhaps more importantly, why do some DFUs resolve quickly, whereas others persist for months or even years? It seems increasingly likely that the answer lies in the concept of wound infection, or more specifically, in every wound’s unique bacterial signature, or microbiome.

Infection is defined clinically by the cardinal signs and symptoms of redness, heat, swelling, and pain, with nearly half of all DFUs classified as infected ( 12 ). Diagnosis of DFU infection strongly correlates with subsequent amputation and increased mortality. The current dogma is that open wounds become contaminated with pathogenic microorganisms, which then colonize the tissue ( Figure 1 ). This transition from contamination to colonization is aided by the unique DFU microenvironment: hyperglycemic, ischemic tissue with dry, cracked neuropathic epidermis. The transition to wound infection is further supported by functional deficiencies in diabetic immune cells, which at this early stage of infection are unable to efficiently phagocytose bacteria or release antimicrobial factors to manage the invading pathogens. There is good evidence that the tipping point to local infection is marked by a shift in wound bacterial composition, specifically toward increased local anaerobic bacteria ( 13 ). Interestingly, wound debridement has been shown to be particularly effective at removing these unwanted anaerobes. If left untreated, local infection can quickly transit to widespread overt infection with involvement of other tissues such as bone.

Gram stain allows visualization of bacteria within a DFU tissue sample. Gram-positive bacteria stain dark blue, gram-negative bacteria stain pink, and DFU tissue stains light blue.

The concept that wound bacteria influence healing (both positively and negatively) in the absence of infection may seem counterintuitive. Yet, recent culture-independent studies have revealed that DFU microbiomes in the absence of infection are dynamic, heterogeneous, and incredibly complex. Wound bacterial signatures strongly link to healing outcome in noninfected DFUs ( 14 ), suggesting a host-microbe relationship that is more subtle than previously thought. Indeed, it is likely that DFU bacteria directly modify the wound milieu, altering the local microclimate (e.g., pH) and producing metabolites that directly affect cellular healing.

So, why do some wounds present with high bioburden but no signs of infection and vice versa? The answer appears to lie in the complexity and diversity of the chronic wound microbial ecosystem. Bacteria, fungi, and other microorganisms do not exist in isolation; they use an array of signaling molecules to interact with each other and with host tissue. Established microbial communities exist as structurally complex biofilms, altering their metabolic state, gene expression, and environment ( 15 ). Biofilm bacteria are surrounded by a protective matrix that confers both protection from the host immune system and recalcitrance to exogenous antimicrobials. In many ways, the number of microorganisms present is irrelevant; it is the environment in which those organisms exist that directs phenotype and virulence, and these factors ultimately trigger the host response that manifests as clinical signs of infection.

Wound microorganisms directly modulate wound cell behavior and modify healing capacity. Compared to the relatively new area of DFU microbial composition profiling, far more is known about how bacteria interact with human skin cells and tissues, an area for which the relevant laboratory techniques have been readily available for years. Wound cells sense the bacterial composition of a wound via an array of pattern recognition receptors (PRRs). These PRRs recognize specific bacterial components known as pathogen-associated molecular pattern molecules, which in turn upregulate host antimicrobial peptides to actively modulate the skin/wound microbial composition.

Defects in a number of PRRs have been linked to diabetes, offering a mechanism for the observed bacterial dysbiosis. Specific bacterial virulence mechanisms have been studied in detail. For example, Pseudomonas aeruginosa is optimized for adherence to the surface of the skin epithelium but is also able to invade into the deeper wound bed tissue ( 16 ). Pseudomonas can even exist inside host cells (keratinocytes), where it effectively evades the immune system. Cells exposed to live P. aeruginosa or Pseudomonas -derived lipopolysaccharide in vitro demonstrate impaired migration, increased proliferation, and increased cell death. These findings are supported by in vivo models demonstrating impaired wound healing after the administration of live bacteria or bacterial components directly on experimental wounds.

Current research, underpinned by the powerful new technologies of shotgun metagenomics and long-read sequencing, is opening our eyes to the bewildering complexity of the skin and wound microbiota. Historically, we have relied on culture-based methods to identify wound bacteria. Indeed, bacterial culture remains the front-line diagnostic technique for wound infection. The problem with these culture-based methods is that they identify only a small fraction of constituent microbes. Bacterial culture has promoted the idea that Staphylococcus aureus , Streptococcus , and P. aeruginosa are the main organisms in DFUs. However, in a game-changing shotgun sequencing study of 100 DFUs, Kalan et al. ( 17 ) reported detailed genus-, species-, and even strain-level characterization of the DFU microbiome. Intriguingly, these authors showed that a strain of S. aureus (SA10757) linked by metagenomics to clinical healing outcome also directly delayed healing in a mouse model. A key theme in emerging microbiome studies is the strong links among reduced diversity, increased temporal stability, and poor healing.

The individual nature of the microbiome poses an ongoing challenge. When the microbiome signature differs substantially among individuals, how does one look for common “healing” or “nonhealing” signatures? The answer is to employ carefully designed (but expensive and time consuming) longitudinal profiling studies looking for common changes in composition or diversity.

So, what does the future hold for the treatment of infected DFUs? It is widely accepted that the number of infected DFUs requiring treatment will continue to increase, driven by the expanding number of diabetic and elderly patients. In the short term, emerging technologies to detect bacteria (e.g., MolecuLight i:X ; Smith & Nephew, Hertfordshire, UK) will be essential to guide treatment. In the next 10 years or so, there will likely be widespread implementation of point-of-care microbiota profiling methodologies in clinics. With these methods, bacterial community–level genetic resistance profiling will revolutionize the ways in which we diagnose, manage, and treat infection. Ultimately, we will reach a level of understanding of the host-microbe continuum that permits a personalized treatment approach, augmenting the endogenous host defense while supporting skin commensals.

WHAT ARE BIOFILMS?

There is no current consensus among researchers regarding the definition of biofilm, but collectively from within the literature, definitions often describe medically related biofilms as “aggregates of microorganisms embedded in a matrix of extracellular polymeric substances.” Biofilms can attach to host tissue or in-dwelling medical devices or exist in fluids adjacent to those surfaces. In contrast to planktonic microorganisms, biofilms demonstrate reduced growth rates and altered gene expression. These changes may help to explain why biofilms show an enhanced tolerance to antimicrobials and the host immune response.

BIOFILMS IN HUMAN HEALTH AND DISEASE

Biofilms can be found in medical, industrial, and natural environments and may affect human health both positively and negatively. When biofilms are implicated in human disease, they are widely acknowledged as a cause of chronic and persistent infections ( 18 ). It is generally believed that biofilms are not the cause of acute infections; these are caused by planktonic microorganisms.

When breaches in the skin envelope occur in the feet of people with diabetes, most open wounds are colonized by microorganisms; however, this does not mean the microorganisms will act pathogenically and incite a host response (i.e., clinical signs of infection). Likewise, not all wounds will form biofilms. Evidence has demonstrated that most acute wounds are not complicated by biofilms. It is also pertinent to note that, whereas biofilms may form in wounds such as DFUs, not all biofilms may act pathogenically or be detrimental to wound healing.

BIOFILMS AND THEIR OCCURRENCE IN DIABETIC FOOT WOUNDS

Biofilms are not the primary mechanism behind the development of foot ulceration; rather, ulceration occurs as a result of precipitating factors that include peripheral neuropathy (loss of protective sensation), altered foot architecture, trauma, and PAD. These factors contribute to breaks in the protective barrier of the skin. However, once pathogenic biofilms become established in DFUs, they may contribute as a cause of chronic and persistent infections, which may delay ulcer healing. In vitro and animal model research has demonstrated that biofilms can delay wound healing. However, the translational evidence from human clinical studies demonstrating biofilms as causal mechanisms for delayed ulcer healing or as drivers of chronic infections in the feet of people with diabetes is scant and requires further exploration ( 17 , 19 , 20 ).

DIAGNOSIS OF BIOFILMS

Contrary to general belief, biofilms are not visible to naked-eye observation. Wound bed material, such as slough or fibrin, or observations of a shiny translucent layer may be mistaken for biofilms. There is no scientific validation to suggest that these clinical features are biofilms or proponents of biofilm. Additionally, biofilms do not form homogenously on the surface of wounds. They are heterogeneously distributed in aggregates and may form on both the wound surface and deeper structures, making diagnosis and treatment more difficult.

In keeping with current expert guidelines ( 10 ), the optimal sampling technique for determining pathogens from infected DFUs is to obtain an appropriate tissue specimen. Obtaining tissue specimens is also the only direct way to visualize the presence of biofilms using microscopy ( 18 ). Biofilm visualization is best performed using microscopy approaches such as scanning electron, confocal, transmission, or light microscopy. The major limitation is that these techniques are typically confined to bench research and are not clinically practical.

Adding to the complexity of diagnosing biofilm infections, there are currently no routine diagnostic tests or biomarkers to confirm their presence. Furthermore, microbiological specimens sent for conventional culture do not necessarily identify microorganisms in biofilms (because of their reduced growth), and most clinical microbiology laboratories will not have the capability to perform biofilm-specific culture approaches.

To circumvent the lack of diagnostics, the clinical characteristics that best define a chronic infection may aid clinicians in identifying potential biofilm infections in DFUs ( Figure 2 ).

Clinical signs and symptoms that may indicate chronic biofilm infection of a DFU.

MICROBIOLOGY OF BIOFILMS IN DFUS

Most studies exploring the presence of biofilms in DFUs have employed molecular (DNA) sequencing technologies and thus report an extended view of the diabetic foot microbiome. Nonetheless, the predominant microorganisms identified from DFUs with biofilm formations are those commonly reported within the preexisting diabetic foot literature. Most DFUs contain polymicrobial biofilms. Aerobic gram-positive cocci (staphylococci and streptococci) are predominant. In addition to aerobic species, other bacteria commonly identified in the same foot ulcers include fastidious anaerobes (namely, those belonging to Clostridiales Family XI), Corynebacterium sp., and gram-negative rods (namely, Klebsiella spp., Acinetobacter spp., Enterobacter spp., P. aeruginosa , and Escherichia coli ).

MANAGEMENT OF BIOFILMS

Across the spectrum of human diseases caused by biofilms (i.e., periodontal, in-dwelling medical device, and human tissue or bone infections), the standard treatment approach is to physically remove the biofilms. Removing biofilms from infected tissue or bone via debridement is one of the most important treatment strategies ( 15 ). However, it may not be possible to completely eradicate biofilms from tissue or bone because treating clinicians are unable to see biofilms and therefore may not debride all infected tissue and because biofilms are tolerant to antimicrobials and the host immune response. Systemic antibiotics may have little effect against chronic biofilm infections in DFUs; therefore, antimicrobial stewardship must be considered with controlled use to help manage planktonic bacteria (acute infection) and to prevent associated systemic infections.

In the context of local wound care for DFUs, there is also a lack of high-quality evidence from human in vivo clinical trials pertaining to the effectiveness of topical antimicrobial agents against biofilms. There are currently no agents with Level 1 evidence (i.e., based on RCTs, systematic reviews, or meta-analyses). In the absence of RCTs or case-control studies, clinicians should consider the cost burden of using topical agents for which there are limited data.

In evaluating and treating DFUs, it is important to distinguish between microbial colonization and infection. Although ulcers may be colonized with microorganisms, infections that require treatment are characterized by bacterial invasion of skin, other soft tissues, or bone. The clinical manifestations of DFIs include local warmth, erythema, induration, pain or tenderness, and purulence. The presence of these clinical signs and symptoms should alert clinicians to consider proceeding with further evaluation and treatment ( 11 , 21 ).

There are several classification systems to define the presence and severity of infection in the feet of people with diabetes. The IWGDF categorizes feet as un- infected if there are no local or systemic manifestations of infection and as infected when there are two or more clinical findings of infection ( Table 1 ) ( 10 ).

IWGDF Classification for Defining the Presence and Severity of DFIs

Adapted from ref. 10 .

Infection refers to involvement of any part of the foot, not just a wound or an ulcer.

In any direction from the rim of the wound. The presence of major foot ischemia makes diagnosis and treatment of infection more difficult.

If osteomyelitis is present in the absence of two or more signs or symptoms of local or systemic inflammation, the foot is classified as having grade 3(O) (if <2 SIRS criteria) or grade 4(O) (if ≥2 SIRS criteria).

Antimicrobial therapy is required for the treatment of DFIs ( 11 , 21 ) but is not required for uninfected wounds ( 10 , 11 , 21 ). Initial treatment of DFIs typically includes empiric antibiotic therapy, because specimen culture results usually are not yet available. For infected wounds, specimen culture results help to identify the causative pathogens, allowing for any necessary modification to optimize antimicrobial therapy. Specimen culture results for clinically uninfected DFUs do not meaningfully benefit decisions on therapy ( 10 , 11 , 21 ).

DFUs typically are colonized initially by gram-positive bacteria such as S. aureus (methicillin-susceptible S. aureus or methicillin-resistant S. aureus [MRSA]) and the β -hemolytic streptococci such as group A Streptococcus ( Streptococcus pyogenes ), group B Streptococcus ( Streptococcus agalactiae ), or group C or G Streptococcus . As an ulcer becomes chronic, it may contain devitalized, necrotic tissue and become colonized with gram-negative bacteria such as P. aeruginosa ; the Enterobacteriaceae , including E. coli , Proteus spp., and Klebsiella spp.; and anaerobic bacteria such as Bacteroides spp. and Clostridium spp. ( 11 , 21 ). With hospitalization and treatment with broad-spectrum antibiotics, ulcer flora may change to include antimicrobial-resistant pathogens such as MRSA, vancomycin-resistant Enterococcus , and gram-negative bacteria that produce extended spectrum β -lactamase or carbapenemase enzymes ( 22 – 24 ).

Most current knowledge about the microbiology of DFIs has been derived from studies conducted in North America and Europe, where the most prevalent pathogens are gram-positive bacteria such as S. aureus ( 10 , 11 , 21 ). In these Western countries, MRSA has become a frequently occurring DFI pathogen ( 25 , 26 ). Infection with MRSA also may occur in patients who do not have any typical risk factors for acquisition of MRSA (e.g., hospitalization or previous antibiotic therapy) because of increased prevalence of MRSA in the community ( 27 ). MRSA infections of DFUs are an increasing problem in India, as are polymicrobial and gram-negative bacilli infections ( 28 ). In Detroit, MI, in the United States, MRSA has been reported as the most common multidrug-resistant pathogen causing DFI, accounting for one-third of infections ( 22 ). In a retrospective case-control study from China, MRSA infections, both hospital-acquired and especially community-associated, were prevalent ( 29 ). Another study from China showed that MRSA accounted for 24.5% of all strains of S. aureus ( 30 ).

In India, DFIs commonly are caused by gram-negative bacilli ( 31 ). Furthermore, pathogens from India ( 32 , 33 ) and other developing nations, such as Egypt ( 24 ) and China ( 34 ), have become highly resistant to antimicrobials. DFIs in regions with warmer climates, including India, the Middle East, and Africa, most commonly are caused by P. aeruginosa ( 35 ), attributed in part to the warm, humid environment causing foot sweating, self-treatment with antimicrobials, and self-contamination from suboptimal perineal and hand hygiene ( 36 , 37 ).

A large multicenter study from Beijing, China, showed that, of the microorganisms recovered from DFIs, gram-negative bacilli accounted for 57.5%, and gram-positive bacilli accounted for 39.6%. The most prevalent microorganisms recovered were Enterobacteriaceae (41%) and Staphylococcus spp. (25.4%), of which S. aureus comprised 17.1%, and MRSA comprised 24.5% of all S. aureus isolates ( 30 ). Many patients in this study from Beijing who had DFUs, especially older adults, were receptive to receiving traditional medicines, and >50% of outpatients were prescribed antibiotics. The high incidence of self-treatment with antibiotics may have caused delays in seeking medical treatment, possibly contributing to the predominance of gram-negative pathogens ( 30 ).

In Africa, some studies of DFIs have shown a predominance of gram-positive pathogens such as S. aureus ( 38 , 39 ), but one study showed that gram-negative bacilli were more common than gram-positive bacteria, with antimicrobial resistance noted in the gram-negative but not the gram-positive bacteria ( 40 ). In Morocco and Brazil, gram-negative pathogens may be more prevalent than gram-positive bacteria ( 41 , 42 ), and the study from Brazil showed MRSA in 22% of wounds, including one-third of MRSA strains that also were resistant to vancomycin ( 41 ).

In summary, DFI are caused primarily by gram-positive bacteria such as S. aureus in North America and Europe. Although S. aureus remains a frequent pathogen in developing countries ( 42 ), gram-negative pathogens may be predominant strains in India, Pakistan, the Middle East, Africa, China, and Brazil ( 28 – 33 , 39 – 42 ).

Establishing a healthy wound bed through adequate debridement of infected, senescent, and devitalized tissue is central to the progression of normal wound healing in diabetic ulcers. In this section, we review the minor and major excisional debridement techniques that represent current medical practice ( 43 ).

Debridement is derived from the French débridement , which means to remove a constraint.

The clinical definition of debridement has subsequently evolved to include the removal of nonviable or contaminated tissue that impedes normal tissue growth. Debridement enables the wound and surrounding tissue to promote normal healing by removing infection, biofilms, and senescent cells.

Ultimately, durable restoration of soft-tissue coverage is dependent on the satisfaction of a number of requisite objectives, including eradication of infection or reduction of bioburden, improvement of local blood flow, revitalization of the wound bed, and correction of biomechanical abnormalities. Debridement, when performed correctly, optimizes diabetic wound healing by meeting these objectives.

DEBRIDEMENT TECHNIQUES

Multiple techniques are used to debride DFUs, and these can be categorized as mechanical, biological, and surgical methods. We have found the surgical approach to be the most effective. However, determining the most appropriate technique mandates the consideration of host-specific factors (e.g., comorbidities, compliance, and social support) and wound-related factors (e.g., infection/contamination status, perfusion, and viability), as well as the resources available at the treatment facility. The European Wound Management Association’s guidelines for debridement provide specific information regarding the indications, contraindications, and potential adverse effects associated with each technique ( 44 ).

Mechanical Debridement

Mechanical debridement includes the use of both wet-to-dry dressings and dry gauze to facilitate removal of infected and nonviable tissue. Wet-to-dry dressing involves applying moist gauze to a wound, then removing it once dry and adherent to underlying tissue. Both wet-to-dry dressings and dry gauze erratically tear necrotic tissue from the underlying wound and are often painful; they are usually insufficient for adequate wound bed preparation due to fluid loss, surfacing cooling, vaso- constriction, impaired immune response, and local tissue hypoxia.

Biological Debridement

Autolytic dressings (i.e., hydrogels, hydrocolloids, and polymeric membrane formulations) are indicated for wounds with necrotic tissue or fibrin coats and act to soften fibrotic wound margins as they stimulate release of endogenous proteolytic enzymes. Using these dressings is relatively painless, which represents a major advantage for patients, particularly those who are sensate. These dressings most often benefit patients who have minimal necrotic loads and cannot tolerate more aggressive forms of debridement.

Enzymatic ointments , which rely on directly hydrolyzing peptide bonds, are recommended for moist or fibrotic wounds, particularly in patients who are poor surgical candidates. Enzymes selectively digest devitalized tissue. This process causes less trauma to healthy tissue than surgical debridement, but it debrides at a very slow rate.

Maggot debridement therapy , using the radiated larvae of the blowfly Phaenicia sericata , is a proven, cost-effective alternative for treating drug-resistant, chronically infected wounds in patients who are poor surgical candidates. Maggots secrete an enzyme that selectively dissolves necrotic tissue and biofilms into a nutrient-rich food source, while sparing healthy tissue. This process reduces the bacterial burden that often plagues gangrenous, recalcitrant wounds.

Surgical Debridement

Excisional debridement can be accomplished as a minor procedure, in the clinic or at patients’ bedside, or as a major procedure under regional block or general anesthesia in the operating room.

When performed as a minor procedure, excisional debridement is limited by pain (mitigable with local block or topical lidocaine) and the risk of having to deal with major bleeding. Clinic or bedside debridement can be an effective means of wound temporization or a definitive treatment in some cases and can be performed easily with local anesthetic in patients with retained sensibility.

Such minor procedures involve the use of a curette to scrape the coagulum, which contains both MMPs and biofilms, off of the wound surface. Although the underlying tissue may look clean, a curette only removes 0.5 logarithm of bacteria. Using a knife or scissors and a pickup, a surgeon can actually cut all necrotic tissue within the wound. By staying at the interface between the necrotic and viable tissue, the surgeon can minimize the risk of bleeding. Again, remember that staying at the wound surface minimally decreases the bacterial count. Any bleeding can usually be handled with direct pressure or topical silver nitrate.

As a major procedure, excisional debridement involves the direct excision of all infected, necrotic, and inflamed tissue of a wound using a combination of knife (steel or hydrosurgical), scissors, curettes, rongeurs, power burrs, and sagittal saws. Surgical debridement is the preferred method used for situations in which urgent or emergent wound decompression is required, deeper structures (e.g., bone, joints, or tendons) are involved, and major bleeding is anticipated.

Major surgical excisional debridement procedures involve tangential excision of all grossly contaminated and devitalized tissue until only normal tissue is present. Removing the indurated and inflamed soft tissue at all borders of the wound ensures the removal of deeply buried biofilms that can easily recolonize the wound. Thin serial slicing minimizes the amount of viable tissue sacrificed, while ensuring that only healthy tissue remains. Gentle tissue handling, sharp dissection, and pinpoint or bipolar cauterization of bleeding vessels serve to minimize trauma and promote tissue viability. The surgeon should avoid harmful maneuvers such as crushing skin edges with forceps or clamps, burning tissues with electro-cautery, or suture-ligating healthy perivascular tissues.

Three technical adjuncts can be used in combination to ensure adequate debridement of the entire wound: 1 ) topical staining of the wound surface with dye (skin marker or methylene blue), 2 ) use of a color-guided approach to debridement (down to healthy red, yellow, and white tissue), and 3 ) tangential excision of indurated or senescent wound margins. Before debridement, methylene blue with a cotton applicator or the pulled-out tip of a skin marker should be liberally applied to the wound base. This provides the surgeon with a color reference to help in removing the entire base of the wound. In addition, the surgeon must be familiar with normal tissue colors (i.e., red [muscle and blood], white [tendon, fascia, nerve, and bone], and yellow [fat]). Using these colors as a guide provides an endpoint to debridement and helps to prevent removal of healthy tissue. Finally, excision of 3–5 mm of marginal tissue during initial debridement removes senescent cells and residual biofilms from chronic wound edges and permits healthy underlying cells to progress through the stages of normal wound healing. Pre- and post-debridement cultures should be obtained to guide future therapy. Surgical wounds may require debridement every 2–3 days until negative post-debridement cultures are obtained.

Debridement is an essential component in the management of both acute and chronic wounds because it removes infected tissue and contaminants, biofilms, and senescent cells that impede the normal progression of wound healing. The mechanical, biological, and surgical techniques described above each have a role, depending on the nature of the specific wound and patient characteristics. The appropriate use of technical adjuncts such as topical tissue staining, tangential excision, and color-guided debridement can enhance the efficiency of wound bed preparation and expedite time to closure. Although debridement methods have improved over time, there is potential for further refinement. Future prospective RCTs will aid in the establishment of evidence-based guidelines to standardize debridement practices for complex wound management.

Among patients with diabetes presenting with a foot wound, about half have clinical evidence of infection ( 10 ). DFIs typically begin in a break in the protective skin envelope, which allows organisms that are either introduced by trauma or colonizing the surrounding skin to gain entrance to subcutaneous tissues. Unless checked by host defenses or medical interventions, infections can spread contiguously to deeper soft tissues, including tendons, ligaments, joints, and bone. The development of a foot infection in a person with diabetes is a sentinel event; it is the most common diabetes-related reason for hospitalizations and in most countries is now the principal cause of lower-extremity amputations. The good news, however, is that recent studies have demonstrated that rapid recognition and appropriate management of DFIs can usually avert these adverse outcomes ( 10 ).

DEFINING INFECTION

Because all open wounds will be colonized by microorganisms, we cannot define a DFI merely by the growth of microorganisms (even potentially virulent pathogens) on culture of the wound. Rather, infection is defined by the response of the host (i.e., the presence of at least two of the classic signs and symptoms of inflammation). However, these findings may be altered in patients with peripheral neuropathy or PAD, which are comorbidities in most patients with a diabetic foot wound. Thus, some clinicians accept the presence of secondary signs such as friable granulation tissue, wound undermining, and foul odor as evidence of infection.

Once a DFI is diagnosed, classifying its severity using standardized criteria helps to define both the approach to treatment and the prognosis. Classification requires careful clinical examination of the wound and review of results of laboratory and imaging tests to determine the depth and extent of infection and whether there is bone involvement or evidence of systemic infection. Clinicians should probe such wounds to delineate their depth and seek palpable bone, which is highly suggestive of osteomyelitis, or foreign bodies. Infection involving an area of <2 cm of skin and only superficial tissues is classified as mild, whereas those with ≥2 cm of cellulitis or involving subcutaneous tissues are deemed moderate. In the forthcoming 2020 update to the IWGDF’s infection classification system, the presence of bone infection (osteomyelitis) is designated separately (as “O”) and is not part of the classification of moderate or severe infection ( 10 ). The presence of findings of systemic inflammatory response syndrome, especially fever or leukocytosis, defines a severe infection.

For all but the mildest DFIs, clinicians should obtain a complete blood count, as well as plain X-rays to look for foreign bodies, tissue gas, or bone abnormalities. Levels of inflammatory markers, especially serum C-reactive protein, erythrocyte sedimentation rate, and perhaps procalcitonin, may help in defining the severity and monitoring the progress of the infection ( 45 ). Advanced imaging techniques, especially magnetic resonance imaging or radiolabeled scintigraphy, may be appropriate for some patients in whom the presence or absence of osteomyelitis is uncertain, or when planning a surgical intervention ( 46 ). Definitively diagnosing bone infection requires aseptically collecting a bone specimen either during surgery or percutaneously. Findings of a positive culture or histological evidence of inflammation and necrosis (preferably both) are the criterion standard for diagnosing osteomyelitis.

A clinically uninfected diabetic foot wound should not be cultured because it does not require antimicrobial therapy. All appropriately diagnosed DFIs should be cultured to define the causative pathogens and their antibiotic susceptibilities. Tissue specimens collected by curettage or biopsy provide more specific and sensitive culture results than wound swabs. For osteomyelitis, cultures of bone more accurately reveal (and generally demonstrate fewer) pathogens than those of even deep soft tissue. Blood cultures are only needed for patients with evidence of sepsis syndrome. More recent studies using molecular microbiological (genotypic) techniques have demonstrated that, compared to standard (phenotypic) microbiology, there are considerably more microorganisms of many more species (especially obligate anaerobes) ( 47 ). What remains unclear, however, is whether it is clinically beneficial to direct antimicrobial therapy against all of these identified organisms, many of which are not classic pathogens.

DFI TREATMENT

DFIs can progress rapidly. Thus, while awaiting the results of cultures (and any additional diagnostic studies), clinicians should initiate empiric antibiotic therapy for most DFIs. Base the choice of a regimen on the clinical characteristics and severity of the infection, any clues to the likely pathogens or recent culture results, any history of recent antibiotic therapy, and knowledge of local antibiotic resistance patterns.

The microbiology of DFIs is discussed in more detail elsewhere in this compendium (p. 6). Briefly, in Western countries, the most common pathogens are aerobic gram-positive cocci, especially S. aureus . For nonsevere infections, in the absence of risk factors for gram-negative pathogens (e.g., previous antibiotic therapy or hospitalization) or obligate anaerobes (e.g., ischemia or gangrene), relatively narrow-spectrum therapy (active against staphylococci and streptococci) often suffices. For severe infections, it is safer to initially prescribe a broader-spectrum regimen ( 48 ). For a clinically stable patient with a chronic infection or at risk for unusual or resistant pathogens (e.g., due to recent antibiotic treatment), discontinuing or withholding antibiotic therapy for a few days may reduce the risk of false-negative cultures.

Topical antimicrobial therapy is discussed elsewhere in this compendium (p. 15). Few data support its effectiveness for mild infections when used alone, and most DFIs require systemic antibiotic therapy ( 48 ). For severe infections, initial parenteral therapy (usually for a few days, followed by a switch to oral therapy) is often safest; otherwise, oral antibiotic agents with good bioavailability are sufficient. Issues related to selecting predominantly oral versus IV antibiotic therapy are discussed on p. 13.

Clinicians should review patients’ clinical responses to empiric therapy and their culture and sensitivity results to determine whether the selected empiric treatment regimen requires adjustment. Several factors help in determining the most appropriate definitive antibiotic regimen, including the safety, cost, and availability of various agents. It is best to follow the principles of antimicrobial stewardship: treat with the narrowest-spectrum regimen appropriate, for the shortest duration necessary ( 49 ). A key point is that antibiotics treat infections, but there is no good evidence that they help heal wounds or prevent DFIs. Thus, although a foot wound may take months to heal, antibiotic treatment of 10–14 days (until the signs and symptoms of infection resolve) is sufficient for most soft-tissue infections. The required therapy duration for bone infections is less clear, but treatment for 4–6 weeks (or shorter if all infected bone is resected) is usually adequate.

There is no evidence to support recommending any proposed adjunctive treatments (e.g., hyperbaric oxygen therapy or negative pressure wound therapy) specifically for treating DFIs. Production of biofilms by causative pathogens appears to contribute to the difficulty in eradicating infections and healing wounds, but it is not clear whether any of the currently available antibiofilm agents are clinically effective, as discussed in the sections starting on p. 4 and p. 17.

In addition to antimicrobial therapy, most patients with a DFI require some type of surgical procedure; these range from bedside sharp debridement to more extensive operative soft-tissue and bone resection. Emergent surgery is required for DFI patients with complications such as compartment syndrome, necrotizing fasciitis, or gas gangrene, but other surgical procedures are mostly considered urgent or elective. Operating surgeons must have a thorough understanding of how to drain infections that may involve several of the compartments in the foot. In general, it is best to perform surgical drainage of deep soft-tissue infection, especially abscesses, as soon as practical, rather than waiting for the infectious process to “cool off” with medical therapy.

Because most cases of DFO are chronic and accompanied by necrotic bone, surgical resection is usually the preferred treatment approach. Recent studies have demonstrated that, in about one-third of cases in which the surgeon biopsies the presumed uninfected bone at the resection margin, cultures are positive. In these cases, patients probably require further anti-infective treatment. Starting on p. 12, we discuss the issues involved in deciding when to consider nonsurgical (antibiotic) treatment for DFO. Because bone infection recurs in about one-third of patients, often months after apparently successful treatment, clinicians should consider osteomyelitis as being only in remission until 1 year after treatment, after which the infection can be considered fully cured.

OUTCOMES OF DFI TREATMENT

In addition to the involvement of bone in a DFI, factors that appear to decrease the likelihood of successful treatment include infection with antibiotic-resistant pathogens (especially MRSA, P. aeruginosa , and gram-negative bacilli with extended-spectrum β-lactamases) and the presence of severe PAD or end-stage renal disease. Patients with these risk factors require especially careful follow-up to ensure that the infection is responding. For patients whose infection fails to respond, consider imaging to detect previously undisclosed deep-tissue involvement that requires drainage or resection, and obtaining optimally collected specimens for repeat culture.

Despite the difficulties in diagnosing and treating DFIs, with proper management, clinicians can expect to achieve resolution of >90% of mild and moderate soft-tissue infections. Appropriate treatment can also resolve infections in >75% of DFO cases (often with minor bone resection) and severe infections (usually with surgical debridement) ( 10 ). Eliminating the clinical manifestations of infection is a key first step in managing DFIs, but patients with these infections also need appropriate wound care, including pressure off-loading, wound cleansing and debridement, revascularization of ischemic limbs, and optimized glycemic control. The best predictor of the development of a foot infection in patients with diabetes is a history of previous DFI, so clinicians should carefully follow patients who have had such infections and also teach them and their caregivers optimal prevention techniques.

The traditional approach to patients with diabetes and foot osteomyelitis has been a surgical one. However, this approach may be associated with biomechanical changes in the foot, significant loss of quality of life, and early mortality. For these reasons, clinicians now favor a more conservative approach to DFO.

The most conservative approach is the use of antibiotics to achieve remission. Treating patients with DFO exclusively with antibiotics offers the potential to avoid hospitalization and the expense and risk involved with surgical procedures. Furthermore, it may help to avoid the biomechanical disturbances associated with surgical resection of all or part of the foot. The available evidence regarding treating DFO exclusively with antibiotics is based on several retrospective series, one prospective noncontrolled series, and one RCT ( 50 ). These series are highly heterogeneous, with variation in several factors, including the use of completely different criteria to define remission or cure of bone infection and the method of obtaining microbiological samples; exclusively empiric treatment was used in one series ( 51 ), whereas “bone debridement” as a part of the medical treatment was used in others ( 52 ).

Bone culture provides the most accurate microbiological information, and surgical or percutaneous bone biopsy is the optimal specimen collection method for obtaining a noncontaminated bone sample ( 50 ). In a series in which 52% of patients without ischemia or gangrene underwent percutaneous bone biopsy, the remission rate was 64%, and bone culture–based antibiotic therapy was the only variable found to be associated with remission in multivariate analyses ( 53 ). Another study reported an 81% remission rate in patients in whom per- ulcer bone samples were obtained after bone debridement. The kind of bone debridement used in this series was quite similar to real surgical debridement, but it was carried out on an outpatient basis ( 52 ). Therefore, it is not possible to know the definitive role of antibiotics in this series. A remission rate of 82.3% was achieved in a series in which the authors exclusively used empiric antibiotic treatment ( 51 ). Although these series demonstrated that remission might be achieved in about two-thirds of cases, their designs precluded them from demonstrating the potential advantages of this approach (i.e., reduced cost and recurrence of ulcers) compared to surgical treatment. Furthermore, there is no information available about the timing of treatment or the clinical and radiological signs indicating that antibiotic treatment should be stopped and surgery carried out.

CONSERVATIVE SURGERY

Surgery for DFO is required in cases involving spreading soft-tissue infection, the presence of severe infection, or where antibiotic therapy alone is likely to be ineffective. Surgical treatment could theoretically have some advantages. It removes necrotic bone, bacteria, and biofilms. Furthermore, for cases in which the ulcer is associated with bone deformities or bony prominences, surgery could correct these problems while also removing the infection from the bone. However, although removing bone deformities seems to play a role in minimizing the risk of recurrence, this has not yet been demonstrated in a prospective study.

Over the past few years, a new surgical concept called “conservative surgery” has been established; this refers to removal of the necrotic (and much of the infected) bone and soft tissue without amputating any part of the foot. This approach has an acceptably low rate of infection recurrence (4.6%) ( 54 ). Conservative surgery aims to preserve the soft-tissue envelope and more distal tissues and is successful in treating almost half of patients admitted for DFO. Aesthetically, this approach could be an appropriate alternative to amputation for patients.

Theoretically, conservative surgery could also be a safe alternative to amputation that minimizes the risk of ulcer recurrences because it removes small pieces of bone. However, this has not yet been demonstrated. Any removal of pieces of bone leads to biomechanical disturbances. Indeed, a prospective series dealing with the outcomes of conservative surgery reported that re-ulcerations at a new site were associated with a plantar location of the ulcer during the first episode and with Charcot deformity ( 54 ). Recurrences after the removal of a metatarsal head could be as high as 41% after 13 months of follow-up ( 55 ). However, nonsurgical treatment of DFO could also be associated with a high rate of re-ulceration. Recurrences may be as high as 40% within 1 year after healing of a DFU, 60% at 3 years, and up to 65% at 5 years ( 56 ). Recurrences after nonoperative treatment frequently occur at the same site as the previous ulceration, even despite the use of an orthosis, whereas recurrences after surgery occur at different sites due to pressure transfer.

To clarify the definitive role of surgery and exclusively antibiotic treatment when treating DFO, a group of authors designed a randomized comparative trial ( 7 ). The authors compared primarily antibiotic treatment based on deep soft-tissue microbiological samples (90 days) with primarily conservative surgical treatment (plus 10 days of antibiotics). The exclusion criteria for this study were strict: patients with severe infections, spreading soft-tissue infections, limb ischemia, necrosis, or Charcot changes. No patients with mid- or rearfoot osteomyelitis were included in the study. No differences were found between the two groups regarding healing rates (considered the remission definition), healing time, and complications requiring a subsequent surgery.

No difference in minor amputations was found between the two groups ( P = 0.336). No recurrences were found in the two groups during the follow-up period. Two re-ulcerations were detected in the antibiotic group (9.5%), and four were found in the surgical group (21%) during the 12 weeks of follow-up after healing ( P = 0.670). This study clarified some previous questions, but its small sample size and short follow-up period were important limitations. It could be concluded that, in mild and moderate cases of neuropathic nonischemic forefoot ulcers complicated by osteomyelitis, antibiotic treatment is as safe as surgery.

Based on the current medical literature and expert opinion, we offer some conclusions. Surgery should be primarily elected in cases of:

► Severe infection, gangrene, spreading soft-tissue infection, or destruction of the soft-tissue envelope;

► Infections associated with substantial bone necrosis or progressive bone destruction despite antibiotic treatment;

► Osteomyelitis associated with deformities or biomechanical disturbances that are surgically correctable; and

► Infecting pathogens that are resistant to available antibiotics.

Antibiotics should be primarily elected in cases involving:

► Noncomplicated forefoot osteomyelitis and when bone biopsy techniques are available;

► Noncomplicated osteomyelitis for which a per-ulcer bone biopsy can be easily collected as an outpatient procedure;

► A high likelihood of poor postoperative biomechanics of the foot;

► Patients who are too medically unstable for surgery; and

► Development of osteomyelitis and critical limb ischemia while waiting for revascularization.

The conventional management of complex bone and joint infections usually comprises surgical debridement, followed by a prolonged course of IV antibiotics lasting at least 4–6 weeks ( 57 ). Alongside the inherent risk associated with IV catheters, the evidence supporting the superiority of IV administration and the belief that antibiotics given this way are somehow “stronger” for a number of infection syndromes is limited and under scrutiny ( 58 ).

The OVIVA trial ( 8 ) was a pragmatic, multicenter, parallel-group, randomized, open-label trial to assess the noninferiority of oral (PO) antibiotics compared to injectable antibiotics in bone and joint infections, including those of the diabetic foot. It was the largest clinical trial to date to assess orthopedic infection outcomes based on different antibiotic administration strategies ( 59 ). A condensed overview of the trial and its key findings has been published ( 8 ).

Researchers recruited adult patients presenting with orthopedic infections from 26 UK centers and randomly assigned them to receive either IV or PO antibiotic therapy for 6 weeks, with or without prior surgical debridement. Adult patients were eligible if they had a bone or joint infection that would normally warrant a prolonged course of antibiotics such as native bone and joint osteomyelitis, including DFO, vertebral osteomyelitis, and prosthetic joint infections. Notable exclusions were patients who did not have oral antibiotic options because of bacterial antibiotic resistance and those who had a concurrent syndrome mandating prolonged IV therapy (e.g., sepsis or endocarditis). Follow-up was for 1 year, with clinical assessments made at 6 weeks, 3 months, and 1 year.

The choice of antibiotics was made by an accredited infection specialist taking into account local epidemiology, antibiotic resistance, drug bioavailability, allergies, drug interactions, and contraindications. Adjunctive oral rifampin as an anti-biofilm agent and antibiotic-impregnated bone cement were each permitted in both groups at the discretion of the infection specialist.

The primary outcome was the rate of definite treatment failure (based on operative findings and microbiological and histopathological criteria) as assessed by an endpoint committee blinded to the randomization strategy. Secondary outcomes included possible and probable treatment failure, serious adverse events, IV catheter complications, Clostridium difficile infections, early termination of randomized therapy, and resource utilization. The full methodological details are available in the published protocol ( 60 ).

Of 1,054 randomized patients, 39 (3.7%) were lost to follow-up with no available endpoint data. Patients in both groups were well matched in baseline characteristics such as demographics (median age 60 years, 64.3% male), surgical procedure performed ( Table 2 ), histology (infected 51.5%, equivocal 2.8%, uninfected 6%, not performed 39.7%), and microbiology results ( Staphylococcus spp. 64.8%, polymicrobial 18%, culture negative 15.5%). Infections of the lower limb comprised the majority of affected sites (81.1%), with the foot accounting for 16.6%. Diabetes was the most common comorbidity (19.5%).

Baseline Surgical Procedures Performed in Patients in the OVIVA Trial (Total N = 1,054)

Adapted from ref. 8 .

The primary outcome of definite treatment failure (imputed lost to follow-up) occurred in 74 of 506 patients (14.6%) in the IV group and 67 of 509 patients (13.2%) in the PO group, giving an absolute risk difference of –1.5% (95% CI –5.7 to 2.8), which satisfied the prespecified noninferiority margin of 7.5%. Further analyses including a worst-case sensitivity analysis in which missing endpoint data were assumed to be treatment failure in the PO group and treatment success in the IV group also supported noninferiority ( Figure 3 ).

Risk difference in failure rates in the OVIVA trial, according to analysis performed. Failure rates are expressed as number of patients with treatment failure/total number of patients. NI, noninferiority. Adapted from ref. 8 .

Secondary outcomes for which the difference between the two groups was statistically significant included: 1 ) early discontinuation of randomized therapy (18.9% in the IV group vs. 12.8% in the PO group, P = 0.006); 2 ) complications from the IV catheter (9.4% in the IV group vs. 1.0% in the PO group, P <0.001); and, 3 ) median hospital length of stay (14 days in the IV group vs. 11 days in the PO group, P <0.001). Secondary outcomes for which the difference between the two groups was not statistically significant included: 1 ) probable or possible treatment failure (1.2% in the IV group vs. 2.0% in the PO group); 2 ) occurrence of at least one serious adverse event (27.7% in the IV group vs. 26.2% in the PO group); and, 3 ) C. difficile infection (1.7% in the IV group vs. 1.0% in the PO group).

Predefined and post-hoc subgroup analyses did not demonstrate an advantage toward: 1 ) the type of surgery performed (i.e., osteomyelitis debrided or not debrided) ( P = 0.26), retention of metalware ( P = 0.13), or antibiotic cement used ( P = 0.98); 2 ) infecting pathogen isolated ( P = 0.30); or, 3 ) presence of peripheral vascular disease ( P = 0.47), which may directly affect the delivery and concentration of antibiotic at distal sites of infection.

The most frequently used IV antibiotics were glycopeptides (41.1%) and cephalosporins (33.2%), reflecting their convenient once-daily dosing and coverage of the predominant staphylococcal infections. The quinolones (36.5%) and combination therapy (16.6%) comprising ciprofloxacin and either clindamycin or doxycycline were the most common oral antibiotics prescribed, reflecting their high oral bioavailability and bone penetration profile. Adjunctive oral rifampin for at least 6 weeks was administered in the PO group more frequently than in the IV group (22.9 vs. 31.4%) but did not significantly affect outcome. Oral follow-on therapy beyond the 6-week study period was observed in the vast majority of patients (76.7%), but the median total duration of antibiotics did not differ significantly (78 days in the IV group vs. 71 days in the PO group).

Notable points in this study are that it is representative of real-world circumstances and pragmatic but necessarily open-label, given the logistics and risks of administering matched placebos. The vast majority of patients in this study had preceding surgery in the form of prosthesis removal or debridement, highlighting the basis of effective osteomyelitis management. The antibiotics selected were specifically tailored to be the most appropriate for each patient, but the resultant heterogeneity hindered subgroup analysis.

The OVIVA trial provided evidence that challenges the widely held belief that the treatment of osteomyelitis requires IV antibiotics. If oral regimens are appropriately selected, they can be as effective, more convenient, and less costly (with a conservative nonsurgical treatment per-patient savings estimated at £2,740 GBP). More importantly, the use of oral antibiotics negates the significantly increased IV catheter-related adverse events observed in this study. Certainly, oral antibiotics are not necessarily suitable for all cases of osteomyelitis; but without a doubt, not all cases of osteomyelitis mandate the use of IV antibiotics.

As elucidated throughout this compendium, multiple comorbidities can contribute to the failure of acute wounds in the legs or feet of people with diabetes to heal, leading to the development of chronic diabetic foot wounds. These conditions include poor arterial perfusion, impaired immune cell functions, and neuropathies. They all result in part from chronically elevated blood glucose levels that lead to non-enzymatic glycation of multiple proteins and activation of advanced glycation end products/receptor for advanced glycation end products pathways that regulate functions of inflammatory cells, neuronal cells, and wound cells (fibroblasts, epithelial cells, and vascular endothelial cells) ( 61 ). Obviously, good clinical management of these comorbidities is essential to reduce the risk of an acute wound converting into a stalled, chronic wound.

High bioburden, which is a rather poorly defined term (i.e., ≥10 5 cfu/g of tissue), is associated with the failure of an acute wound to heal in patients with or without diabetes and is, in most wounds, a combination of both planktonic and biofilm bacteria, as well as fungal species. However, in the past 10 years, animal model studies of wound healing have demonstrated that formation of bacterial biofilms significantly delays healing ( 62 ). This evidence has led to an increased focus on the role of bacterial biofilms in impairing skin wound healing, including in patients with diabetes.

Clinical studies have now established that bacteria in the biofilm phenotype are present in a high percentage (probably >80%) of chronic skin wounds ( 63 , 64 ). The ability of bacteria in biofilm communities to survive under conditions that normally kill planktonic bacteria very effectively is explained by a combination of several factors ( 65 ). These include the difficulty of phagocytic inflammatory cells (neutrophils and macrophages) to engulf and kill large masses of biofilm bacteria that are tightly attached to extra-cellular matrix, bone cortex, or innate surfaces such as metallic orthopedic implants. Also, the dense exopolymeric matrix of many bacterial biofilms has a high negative charge density because of acidic polysaccharides (polyalginic acid in P. aeruginosa biofilms) and free bacterial DNA that can limit diffusion of positively charged antimicrobials such as silver ions. In addition, individual bacteria located deep inside mature biofilms frequently become metabolically dormant, which provides tolerance to antibiotics that typically only kill metabolically active bacteria by interfering with essential bacterial enzyme and protein systems. This combination of factors contributes to bacterial biofilms being a major common cause of persistent infections in skin wounds and multiple other clinical conditions ( 66 , 67 ).

Building on this base of laboratory and clinical data about biofilms and chronic skin wounds, an international panel of wound care clinicians and basic scientists produced consensus guidelines for identification and treatment of biofilms in chronic nonhealing wounds, including DFUs ( 15 ). A key take-home message from the guidelines is that treatment of chronic DFUs should be based on the principles of biofilm-based wound care (BBWC) that emphasize a “step-down-then-step-up” approach. This approach involves starting treatment with a combination of aggressive debridement of biofilms and topical treatments that have been shown in laboratory or clinical studies to be effective at killing residual biofilm bacteria. As the bioburden level of biofilm bacteria is reduced, the level of inflammation (neutrophils and macrophages) and the elevated levels of proteases and reactive oxygen species will also be reduced, which will allow the chronic wound to move out of a chronic inflammatory phase into an active healing (repair) phase. Topical treatments can then “step down” to less frequent and aggressive debridement combined with standard antimicrobial dressings that can effectively kill planktonic bacteria and prevent reformation of biofilm communities in the wound bed. Finally, when the DFU wound bed has been adequately prepared, topical treatments can “step up” to advanced wound treatments such as amnion/chorion dressings, growth factors, and skin grafts that will effectively stimulate healing because the proteins that comprise these advanced wound treatments and their receptors on wound cells will survive and function normally to promote healing.

NEW APPROACHES TO TOPICAL TREATMENT

Building on the principles and concepts of BBWC to control infection and inflammation, it is important to know whether new topical approaches can help control infection and inflammation and what evidence may support their use. A 2019 IWGDF systematic review ( 49 ) and a recent Cochrane systematic review ( 68 ) found no compelling published evidence to support the use of topical antimicrobials to control (either eradicate or prevent) DFIs. However, several new topical treatments do appear to significantly reduce infection by both planktonic and biofilm bacteria based on laboratory and animal wound-healing studies, and a few pilot clinical studies have reported some improved healing. Unfortunately, there are no published, randomized, appropriately controlled, multicenter clinical studies that provide Level 1 evidence that any of these new topical treatments significantly reduce wound bacterial bioburden, including mature, tolerant biofilm bacteria, or improve healing of chronic wounds.

Localizing Bacterial Biofilms and Assessing Successful Debridement

Two of the biggest challenges clinicians face in implementing BBWC are knowing where biofilms are located on a chronic wound bed and assessing whether the biofilms have been removed by debridement. A recent initial clinical study reported that bacterial biofilms were detected and localized on chronic wound beds using a simple and rapid membrane blotting technique followed by brief staining of the membrane with a cationic colored dye that bound to the negatively charged components of the biofilm exopolymeric matrix ( 69 ). Importantly, if no biofilm staining was detected after debridement, there was a significant reduction in generation of wound slough and a reduction in wound area in the following week compared to wounds that had residual biofilm staining on the membrane.

Another new technology (MolecuLight i:X ) that has been reported to localize bacteria in wounds and on surrounding skin uses blue light to stimulate fluorescence of fluorochrome molecules synthesized by some strains of common wound pathogens. This technology does not appear to distinguish between planktonic and biofilm phenotypes of bacteria but may be useful in localizing bacteria in wounds to guide and assess debridement of bacteria ( 70 ).

Negative Pressure Wound Therapy Plus Instillation of Antimicrobial Solutions

Negative pressure wound therapy (NPWT) has become a standard treatment for many types of acute and chronic wounds. This therapy primarily stimulates formation of new granulation tissue by exerting a combination of macro- and microdistortion forces on wound cells that alter patterns of gene expression and by inducing localized regions of ischemia in the wound bed. In general, NPWT alone does not dramatically reduce planktonic or biofilm bacteria in infected wounds ( 71 ). However, laboratory studies have shown dramatic reductions (>4 logarithms) in planktonic and biofilm bacteria levels on pig skin explants with mature biofilms when NPWT was combined with instillation of various antimicrobial solutions ( 72 ), and these findings were confirmed in a pilot clinical study ( 73 ). Well controlled clinical studies are needed to rigorously assess whether NPWT plus instillation reduces levels of planktonic and biofilm bacteria in DFUs and improves progression toward healing.

Concentrated Nonionic Surfactant Wound Gel

Bacterial biofilms tend to be tightly attached (sessile) to extracellular matrix components at the surface of wound beds and in the superficial layers under the surface of the wound bed, which is one reason that simply wiping with a gauze pad does not effectively remove all biofilm bacteria ( 74 ). A recent laboratory study showed that daily application of a concentrated nonionic surfactant gel containing a preservative (Plurogel) with gauze wiping eliminated mature biofilms of P. aeruginosa and S. aureus grown on pig skin explants ( 75 ).

In summary, new topical treatments have shown positive results in significantly reducing levels of planktonic and biofilm bacteria using laboratory models of infected skin wounds. Results from clinical studies are needed to more completely understand the effects of these treatments in actual clinical use.

Although biofilms are more common in chronic wounds than in acute wounds, one of the first associations of biofilms and wounds followed the electron microscopic examination of sutures and staples removed from healed surgical wounds ( 76 ). However, the fact that chronic wounds often harbor biofilms is part of the rationale linking their presence to delayed healing of such wounds ( 63 ). Additionally, acute wounds made experimentally, inoculated with biofilm-forming bacteria, and made to induce biofilms have demonstrated delayed healing. Biofilms develop quickly, and wound-isolated P. aeruginosa in vitro displays characteristics of mature biofilm within 10 hours ( 77 ). As noted previously (p. 4–5), biofilms cannot be detected using routine clinical techniques. Chronic wounds lack overt clinical signs of infection, making lack of clinical suspicion a confounding problem in wound biofilm identification.

TREATMENT MODALITIES

High-quality studies are lacking and thus represent a needed opportunity with regard to elucidating the beneficial role of biofilm eradication and its relationship to healing in patients with chronic wounds. Studies to date have primarily focused on approaches that treat or prevent biofilms using in vitro or in vivo models or have involved patients using purported anti-biofilm approaches (i.e., BBWC) that result in improved healing. However, these latter studies often have not: 1 ) studied a single chronic wound type; 2 ) demonstrated the presence of biofilms before treatment; 3 ) demonstrated the eradication of biofilms originally present; 4 ) confirmed eventual healing status; or, 5 ) included randomized, controlled groups. Despite these significant limitations, reducing, removing, or preventing biofilms remains a logical approach to help clinicians heal chronic wounds. Table 3 lists commercially available products that have demonstrated anti- biofilm activity in vitro or with lower levels of evidence.

Commercially Available Products with Some Level of Evidence Supporting Anti-Biofilm Activity

APPROACHES TO BIOFILM TREATMENT AND PREVENTION

Debridement.

Physical removal of biofilm bacteria is the standard means of managing biofilms, and debridement is considered essential for effective biofilm control, most commonly with sharp debridement to remove and suppress biofilm ( 78 ). However, biofilms are often deep in wound tissue, and removal by more conservative surgical debridement techniques such as by curetting may be incomplete. Other debridement techniques such as plasma-mediated bipolar radiofrequency ablation was found to be better at least in one model ( 79 ). Even with removal, biofilms rapidly recover from mechanical disruption to reform within 24 hours, implying that debridement may best be used in combination with other treatments ( 80 ).

Laser and Ultrasound

Laser treatment, particularly low-level laser therapy (LLLT), is thought to accelerate wound healing by increasing the proliferation of cells involved in wound healing and the synthesis of collagen, while also decreasing the inflammatory response. Laser therapy has also been shown to cause disaggregation of microorganisms ( 81 ). Results from LLLT studies have shown significant bactericidal potential without damaging tissue. LLLT can reduce both cell viability and biofilm growth.

In addition to lasers, ultrasound therapy has been used to investigate oral biofilms, as well as cutaneous wound healing. Noncontact ultrasonic waves can reduce biofilm in vitro and assist in biofilm removal in vivo ( 82 ).

Antibiotics and Antiseptics

Biofilms evade the host’s immune system and may be up to 1,500 times more resistant to antibiotics than planktonic cells. Systemic antibiotics are not part of routine standard care for clinically noninfected DFUs, and biofilm bacteria are more resistant to topical antibiotics than planktonic bacteria. There are multiple mechanisms for biofilm antibiotic resistance: biofilms may contain a subpopulation of specialized survivor cells, the drug target may be modified or unexpressed, biofilms are less susceptible because they contain fewer growing bacteria, or the antimicrobial agent may not adequately penetrate the biofilm.

Anti-Biofilm Agents

With increased knowledge of biofilm formation, anti-biofilm agents that disrupt biofilm community functions and defenses may allow other concomitant therapies and natural host mechanisms to work more effectively to promote healing. As an example, lactoferrin, a component of tears, mucus, and human milk, prevents biofilm formation by altering bacterial motility and decreasing bacterial surface attachment. Lactoferrin use in the disruption of Pseudomonas biofilms has been described and shown to act synergistically with xylitol, which impairs matrix development ( 83 ). Studies regarding BBWC for wound treatment in patients with critical limb ischemia have demonstrated a statistically significant increase in wound healing with BBWC ( 84 , 85 ). In these examples, BBWC included standard care plus lactoferrin and xylitol compounded in a methylcellulose gel as the anti-biofilm agents. Other anti-biofilm agents include ethylenediaminetetraacetic acid, gallium, acetyl salicylic acid, and others.

Novel anti-biofilm agents currently under development include anti-adhesion molecules, quorum-sensing inhibitors, and selectively targeted antimicrobial peptides (STAMPs) ( 86 ). Given that adhesion is the first stage in biofilm formation, anti-adhesion molecules may keep bacteria in the planktonic state, making them more susceptible to the host immune system and antibiotics. Sortase, from gram-positive bacteria, is shared by most of the surface proteins and is an anti-adhesion candidate because it covalently anchors surface proteins to peptidoglycan. Quorum sensing is crucial to the maturation of biofilms; thus, using quorum-sensing inhibitors theoretically can maintain bacteria in a planktonic state by affecting cell-to-cell communication, making bacteria more susceptible to the immune system and antibiotics. Two leading candidates for quorum-sensing inhibitors include the furanones and ribonucleic acid III inhibiting peptide. Species-specific control of biofilms may be achieved with STAMPs, which are an essential part of the innate immune system that contain species-specific binding domains.

Biofilm Extracellular Enzymes

Other novel strategies include matrix-degrading enzymes, which degrade the protective polysaccharide layer and make cells more susceptible to antibiotics ( 78 ). The final stage of the biofilm life cycle, dispersion, allows bacteria to release from the biofilm and colonize other areas. However, dispersion results in an increased number of easier-to-eradicate planktonic bacteria and thus is a therapeutic topic of interest. To facilitate dispersion, bacteria produce extracellular enzymes such as glycosidases, proteases, and deoxyribonucleases that degrade the adhesive components in the biofilm matrix. Two common wound pathogens, P. aeruginosa and S. aureus , produce enzymes that can degrade the biofilm matrix. As an example, P. aeruginosa -produced alginate lyase increases biofilm cell detachment and antibiotic effectiveness ( 86 ). The enzyme dispersin B is able to degrade the polysaccharide matrix of staphylococci and is being developed as a wound care gel. Other matrix-degrading enzymes include deoxyribonuclease, lysostaphin, proteinase K, and trypsin.

Vaccination

New treatment strategies are being explored, including the potential of vaccination against pathogens. In the area of oral biofilms, numerous studies have documented effective vaccination against oral pathogens ( 78 ). Often, biofilms are polymicrobial, and some bacteria, such as Fusobacterium nucleatum in the mouth, bridge other species within the biofilm community.

Finally, there is great interest in developing passive immunotherapy or vaccines for bacterial infections such as staphylococci. Vaccine targeting can disrupt biofilm attachment and growth. Bacteriophages (viruses that affect bacteria) can be used effectively in managing infection, mainly because of their bactericidal activity. Studies involving the interaction of bacteriophages and biofilms have shown that phages can degrade biofilm exopolysaccharide and infect biofilm cells, when experimentally tracing the interaction of bacteriophage with bacterial biofilms using fluorescent and chromogenic probes.

The worldwide burden of diabetic foot complications—particularly DFUs—has been growing ( 1 , 56 ). In this compendium, we have reviewed a number of promising strategies to heal wounds, in addition to some essentials of care such as high-quality surgical wound debridement and off-loading of pressure ( 56 ). We have also included treatments that have received increased support in the literature such as cultured tissue products, topical oxygen therapy, sucrose octasulfate dressings, and autologous platelet-rich fibrin dressings ( 2 – 6 ).

Importantly, major strides have occurred in the management of wound infection during the past decade, and these are also summarized herein. Whereas clinically noninfected wounds do not require antibiotic therapy, we have explained that infected wounds should be cultured, taking tissue from the wound base after debridement, and that antibiotic therapy should be targeted appropriately. Undoubtedly, the results of the OVIVA trial will engender much debate in the near future about the need for IV antibiotics in osteomyelitis.

Although we have made advances in approaches to tissue repair and wound healing, our knowledge of the constantly changing wound milieu remains elusive. Indeed, the development of companion diagnostics and biomarkers to help direct therapy is an important goal. Last year, the U.S. National Institute of Diabetes and Digestive and Kidney Diseases highlighted this need by creating a consortium dedicated to advancing this nascent field ( 87 ). We believe it is highly likely that numerous future therapeutics will come bundled with a companion diagnostic to help target when or whether it is likely to be most effective.

Measuring what we manage is of course crucially important. However, globally accepted definitions of risk are arguably even more central to high-quality care. In the past year, the IWGDF and the Global Vascular Guidelines Writing Group both published important efforts to define risk and better guide care worldwide ( 10 , 88 ). Both groups have made efforts to refine the terminology for PAD. Instead of the previous term “critical limb ischemia,” or CLI, the preferred term is now “chronic limb-threatening ischemia,” or CLTI ( 88 ). This new term better describes the condition and marries well with the concept of chronic DFUs. In addition, a more universally accepted and validated definition of limb threats (“wound, ischemia, and foot infection,” or WIfI) is becoming the new norm in interdisciplinary teams ( 88 , 89 ). WIfI classification allows clinicians to measure and communicate the multifactorial and dynamic nature of diabetic foot disease with an easily understood scoring system. This is similar in nature to the use of “tumor, node, metastasis,” or TNM, terminology in the field of oncology.

Although healing wounds remains a key goal, one could argue that it is a bit too narrow a focus. Indeed, after a wound heals, 40% of people with diabetes will re-ulcerate within 1 year, and nearly two-thirds will do so by 3 years ( 56 ). Thus, recurrence is not only common, it is likely. The foot in diabetes, once healed, is in remission.

Our goals, as mentioned in the first compendium ( 1 ), must focus on innovation in methods to maximize ulcer-free, hospitalization-free, and activity-rich days. As we have shown, much progress has been made toward this end, but there is much work yet to do. We hope this volume will help readers with the early detection, identification, and treatment of infection in diabetic feet, for it is infection in neuroischemic ulcers that often leads to amputation.

The opinions expressed are those of the authors and do not necessarily reflect those of Healogics, Inc., Organogenesis, Inc., or the American Diabetes Association. The content was developed by the authors and does not represent the policy or position of the American Diabetes Association, any of its boards or committees, or any of its journals or their editors or editorial boards.

To request permission to reuse or reproduce any portion of this publication, please contact [email protected] .

ACKNOWLEDGMENTS

The authors thank Dr. Elly Trepman for review and helpful suggestions on the section concerning the microbiology of DFIs.

Editorial and project management services were provided by Debbie Kendall of Kendall Editorial in Richmond, VA.

AUTHOR CONTRIBUTIONS

A.J.M.B. and D.G.A. served as co-editors and, as such, co-wrote the introduction and conclusion and reviewed and edited the entire manuscript. M.J.H. wrote “How Infection Impairs Wound Healing.” M.M. wrote “Biofilms in the Context of DFUs.” J.M.E. wrote “Evolving Microbiology of DFIs.” C.E.A. wrote “Debridement: The First Step in Controlling DFIs.” B.A.L. wrote “Managing Infected DFUs.” J. A.-S. wrote “Surgery Versus Antibiotics in DFO.” H.K.L. wrote “IV Versus Oral Antibiotics for Osteomyelitis: Lessons from the OVIVA Trial.” G.S. wrote “Topical Treatments for DFIs.” R.S.K. wrote “Role of Modern Technology in the Prevention and Management of Biofilms and DFIs.” A.J.M.B. and D.G.A. are the guarantors of this work.

DUALITIES OF INTEREST

A.J.M.B., D.G.A., M.J.H., J.M.E., C.E.A., B.A.L., J.A.-S., G.S., and R.S.K. have no relevant dualities of interest to disclose. M.M. has received research grants and consultant fees for educational activities from Smith & Nephew in the area of wound biofilm. The work of H.K.L. was funded by the National Institute for Health Research—Health Training Assessment.

Suggested citation: Boulton AJM, Armstrong DG, Hardman MJ, et al. Diagnosis and Management of Diabetic Foot Infections . Arlington, Va., American Diabetes Association, 2020 ( https://doi.org/10.2337/db2020-01 )

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Literature review on the management of diabetic foot ulcer.

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Diabetic foot ulcer (DFU) is the most costly and devastating complication of diabetes mellitus, which affect 15% of diabetic patients during their lifetime. Based on National Institute for Health and Clinical Excellence strategies, early effective management of DFU can reduce the severity of complications such as preventable amputations and possible mortality, and also can improve overall quality of life. The management of DFU should be optimized by using a multidisciplinary team, due to a holistic approach to wound management is required. Based on studies, blood sugar control, wound debridement, advanced dressings and offloading modalities should always be a part of DFU management. Furthermore, surgery to heal chronic ulcer and prevent recurrence should be considered as an essential component of management in some cases. Also, hyperbaric oxygen therapy, electrical stimulation, negative pressure wound therapy, bio-engineered skin and growth factors could be used as adjunct therapies for rapid healing of DFU. So, it's suggested that with appropriate patient education encourages them to regular foot care in order to prevent DFU and its complications.

Author and article information

Affiliations, comment on this article.

Vitamin C and the management of diabetic foot ulcers: a literature review

Affiliations.

• 1 Dr William M Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, Illinois, US.
• 2 School of Graduate and Postdoctoral Studies, College of Health Professions, Rosalind Franklin University of Medicine and Science, Illinois, US.
• PMID: 36113854
• DOI: 10.12968/jowc.2022.31.Sup9.S33

Objective: The lifetime risk of developing a diabetic foot ulcer (DFU) in people with diabetes is as high as 25%. A trio of factors constitute the diabetic foot syndrome that characterises DFUs, including neuropathy, vascular disease and infections. Vitamin C has important functions in the nervous, cardiovascular, and immune systems that are implicated in DFU development. Furthermore, vitamin C deficiency has been observed in individuals with DFUs, suggesting an important function of vitamin C in DFU management and treatment. Therefore, this literature review evaluates the role of vitamin C in the nervous, cardiovascular and immune systems in relation to wound healing and DFUs, as well as discussing vitamin C's lesser known role in depression, a condition that affects many individuals with a DFU.

Method: A literature search was done using PubMed, Cochrane Library, Embase, Ovid, Computer Retrieval of Information on Scientific Projects, and NIH Clinical Center. Search terms included 'diabetic foot ulcer,' 'diabetic foot,' 'vitamin C,' and 'ascorbic acid.'

Results: Of the 71 studies initially identified, seven studies met the inclusion criteria, and only three were human clinical trials. Overall, the literature on this subject is limited, with mainly observational and animal studies, and few human clinical trials.

Conclusion: There is a need for additional human clinical trials on vitamin C supplementation in individuals with a DFU to fill the knowledge gap and guide clinical practice.

Keywords: ascorbic acid; diabetic foot; diabetic foot ulcer; infection; neuropathy; vascular disease; vitamin C; wound; wound care; wound healing.

Publication types

• Ascorbic Acid / therapeutic use
• Diabetes Mellitus*
• Diabetic Foot* / drug therapy
• Wound Healing
• Ascorbic Acid

Grants and funding

• T35 DK074390/DK/NIDDK NIH HHS/United States

• Open access
• Published: 10 April 2024

Evidence-based interventions for identifying candidate quality indicators to assess quality of care in diabetic foot clinics: a scoping review

• Flora Mbela Lusendi   ORCID: orcid.org/0000-0002-6207-0800 1 , 2 ,
• An-Sofie Vanherwegen   ORCID: orcid.org/0000-0002-0195-3060 1 ,
• Kris Doggen   ORCID: orcid.org/0000-0003-0374-6863 1 ,
• Frank Nobels   ORCID: orcid.org/0000-0002-8058-8734 3 &
• Giovanni Arnoldo Matricali   ORCID: orcid.org/0000-0001-7370-2175 2 , 4  

BMC Public Health volume  24 , Article number:  996 ( 2024 ) Cite this article

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Metrics details

Foot ulcers in people with diabetes are a serious complication requiring a complex management and have a high societal impact. Quality monitoring systems to optimize diabetic foot care exist, but a formal and more evidence-based approach to develop quality indicators (QIs) is lacking. We aimed to identify a set of candidate indicators for diabetic foot care by adopting an evidence-based methodology.

A systematic search was conducted across four academic databases: PubMed, Embase CINAHL and Cochrane Library. Studies that reported evidence-based interventions related to organization or delivery of diabetic foot care were searched. Data from the eligible studies were summarized and used to formulate process and structure indicators. The evidence for each candidate QI was described in a methodical and transparent manner. The review process was reported according to the “Preferred Reported Items for Systematic reviews and Meta-Analysis” (PRISMA) statements and its extension for scoping reviews.

In total, 981 full-text articles were screened, and 322 clinical studies were used to formulate 42 candidate QIs.

Conclusions

An evidence-based approach could be used to select candidate indicators for diabetic foot ulcer care, relating to the following domains: wound healing interventions, peripheral artery disease, offloading, secondary prevention, and interventions related to organization of care. In a further step, the feasibility of the identified set of indicators will be assessed by a multidisciplinary panel of diabetic foot care stakeholders.

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Introduction

Diabetic foot ulceration (DFU) is a common disability burden, with a 25% lifetime risk in persons with diabetes [ 1 ]; it is estimated that 40 to 60 million people are globally affected by DFU [ 2 ]. The condition has an important impact on quality of life of both persons with diabetes and DFU and their informal caregivers [ 3 , 4 ] and causes substantial healthcare costs [ 2 , 5 , 6 ]. Because of the significant physical, psychosocial and economic impact of diabetic foot disease, there is a global search by the medical community for systems of quality evaluation and monitoring of diabetic foot care [ 7 , 8 , 9 ]. The “International Working Group on the Diabetic Foot” (IWGDF) recommends auditing all aspects of diabetic foot care to ensure that clinical practice meets accepted standards of care [ 10 ].

The management of DFU is complex and demanding. DFU care requires multidisciplinary collaboration across the healthcare landscape, in an often lengthy care process, in which not only the quality of the care provided by each individual healthcare provider is important, but also the quality of the collaboration and of the overall organization of the care.

Quality monitoring of such complex care is equally demanding. It requires several quality of care indicators (QIs) that describe the performance that should occur for a particular type of patient or the related health outcomes, followed by the assessment of whether patients’ care is consistent with the indicators based on evidence-based standards of care [ 11 ]. QIs can be related to structure, process or outcome of healthcare [ 12 ] and/or meet additional quality-of-care frameworks such as the six aims for the “21st Century Health Care System” provided by the Institute of Medicine [ 13 ]. In order to be useful, they must be developed, tested and implemented with scientific rigor. For a care process to be considered as a valid QI, it must have been demonstrated to be associated with a desired outcome. Similarly, a structure of care can be used as QI, if it increases the likelihood of a desired outcome or of a process, which improves an outcome. Further, for outcome indicators to be valid, variations in outcomes must be attributable to variations in care quality [ 14 ]. Two key steps have been emphasized for developing QIs: the synthesis of information from a variety of sources (e.g. literature, clinical data) and a validated method to determine the extent to which experts agree about the proposed set of indicators [ 15 ].

In diabetic foot care, there already exist some national initiatives on quality evaluation and monitoring. Belgium, Germany and the United Kingdom (UK) have issued national quality initiatives for accreditation and auditing of diabetic foot services [ 16 , 17 ]. The German Working group on the Diabetic Foot developed a certification procedure for diabetic foot centers that includes data collection on structure of care and on limited parameters of process of care (e.g. vascular intervention) and outcome (e.g. rate of minor and major amputations) [ 7 , 18 ]. These indicators were defined by an expert board within the working group. In Belgium, indicators were developed by Belgian diabetic foot experts and used in the context of a nationwide quality initiative, named IQED-Foot (Initiative for Quality improvement and Epidemiology in multidisciplinary Diabetic Foot Clinics). A large number of QIs are related to processes of care (e.g. revascularization of ischemic lower limbs) and to outcomes (e.g. ulcer healing rate) [ 19 ]. No indicators of structure of care are used, as only diabetic foot clinics (DFCs) that meet the national requirements for accreditation participate in the quality evaluation. In addition, the UK launched a “National Diabetes Foot Care Audit”, based on a pilot project that assessed methodology for the measurement of processes and outcomes in the management of diabetic foot ulcers using QIs defined by a national working group [ 8 ]. It included indicators related to diabetes management, ulcer outcome but also patient-reported outcome measures.

Although the data collections in the context of these audits are valuable, they have a number of shortcomings that need to be addressed. The QIs used differ from one initiative to another, and do not cover all aspects of care. The current indicators are largely based on expert opinion, without a systematic search of the literature nor any formal consensus among diabetic foot care stakeholders.

Therefore, there is a need for a more systematic and evidence-based approach to develop QIs for diabetic foot care. So far, a detailed methodology describing the identification of QIs in diabetic foot care has not been published. The purpose of this study was to perform a systematic and open-minded (i.e. not limited to guidelines) search of the literature on evidence-based interventions that could be used as process or structure indicators to assess quality in DFCs. The result of this work represented the first key step in developing a set of evidence-based QIs that will be used to achieve consensus among diabetic foot care stakeholders.

This scoping review was conducted to provide an overview of the available scientific evidence. The review process was reported according to the “Preferred Reported Items for Systematic reviews and Meta-Analysis” (PRISMA) statements [ 20 ] and its extension for scoping reviews [ 21 ]. The results of the scoping review aim to be used to formulate a set of candidate quality indicators, which are evaluated by a diabetic foot care stakeholder panel during a modified Delphi consensus.

Search strategy

We searched for systematic reviews and primary clinical studies to identify aspects of the organization of care (structure) or delivery of care (process) that could be defined as quality of care indicators. The topics “foot ulcer” or “amputation” combined with the topic “diabetes mellitus” were used to build the search strategy for four electronic databases: PubMed, Embase, CINAHL and Cochrane Library. Controlled terms from Medical Subject Headings (MeSH) in PubMed and Cochrane Library, from Emtree in Embase.com and from CINAHL Headings in CINAHL were used in the search query. An additional file shows the search query in detail (See Additional file 1 ). We focused on producing a search strategy that was sensitive. To do so, we use more general terms, whilst avoiding specific search terms related to “quality of care” in order to not miss potentially eligible studies. In addition, a lot of research on the effectiveness of interventions do not phrase their results in terms of "quality of care", but simply in terms of improving outcomes. The following publication types were excluded from the search strategy: letter, editorial, comment, case reports, and note. In addition, searches were limited to publications in English, French and Dutch. The search period ran from the inception of the databases to March 03, 2020.

Inclusion and exclusion criteria

To be eligible, a study had to fulfill all the criteria detailed in Table  1 . Because of efficiency concerns, we applied a limitation on publication year. The review team (FML, ASV, KD, FN, GM) decided that the literature review would cover the period from 01/01/2011 to 03/03/2020 based on the assumption that the number of publications on diabetic foot has significantly increased over the last 10 years [ 22 ], and that therefore the relevant and up-to-date interventions will have been reviewed during the past 10 years. We searched for publications reporting clinical research studies that evaluated the effect of an intervention on health-related outcomes.

We included studies reporting interventions which addressed one of the following chapters covered by the guidelines provided by the IWGDF [ 23 ]: interventions to enhance healing of foot ulcers in persons with diabetes (wound healing interventions), peripheral artery disease (PAD), offloading and prevention of foot ulcers in patients with diabetes. Since the success in DFU management also depends on effective organizational features [ 10 ], we also covered interventions related to organization of care. We decided to not cover the domain of infection (e.g. antimicrobial therapy, adjunctive treatment and surgical treatment) since two extensive systematic reviews have been performed recently by the IWGDF, leading to updated Guidelines on the diagnosis and treatment of foot infection in persons with diabetes [ 24 , 25 ]. For the offloading domain, the treatment with “Total Contact Casting” (TCC) was proven to be efficient more than 10 years ago [ 26 , 27 , 28 , 29 , 30 ] and is nowadays commonly used as the gold standard. Therefore, TCC was not included in the evidence-based approach to develop QIs. Moreover, studies exclusively dealing with prevention of foot ulcers in people with diabetes without active or history of foot ulceration (primary prevention) were excluded because it did not inform us about the management of an existing DFU. We also excluded interventions reported by only one single study (not related to organization of care). The main criteria we used were: (i) studies designed with a control group (randomized or non-randomized) or systematic reviews of controlled studies; (ii) inclusion of patients with diabetes and an active or history of foot ulceration (including the different stages of the complication); (iii) description of an intervention related to the organization or delivery of diabetic foot care (diagnostic, treatment, secondary prevention): (iv) measuring change in outcomes related to the foot/limb or to the patient or to the healthcare costs.

Selection process

Following completion of the database searches, the extracted records were entered into the reference management software Zotero ( https://www.zotero.org/ ). Three researchers (FML, KD, SC) independently merged search results and removed duplicates [ 31 , 32 , 33 , 34 ]. Then, one researcher (FML) uploaded the resulting records to the online application “Rayyan” [ 35 ] ( www.rayyan.ai ) to help in the assessment of studies. Two researchers (FML, KD) independently and blindly reviewed studies by titles and abstracts to assess their eligibility based on the criteria mentioned above. At several occasions, they met to discuss any disagreements regarding their selections until consensus was obtained. The level of agreement between the two reviewers was assessed by calculating Cohen’s kappa values [ 36 ]. The full-texts of records that appeared potentially eligible were retrieved by one reviewer (FML), who was helped by an administrative collaborator (VB). The same reviewer (FML) examined the obtained full-text records. If necessary, other members of the reviewer team (ASV, FN, GM) were consulted to make the final decision.

Data extraction

Firstly, we collected comprehensive information about each eligible study using a structured form. The following data were extracted: author, year of publication, study design, sample size, ulcer characteristics, the studies’ exclusion criteria, period of follow-up, intervention type, description of intervention, number of patients randomized to each intervention arm, studied outcomes, and whether differences between study groups were statistically significant. The clinical studies were grouped according to the domains listed above. One reviewer (FML) extracted the data and another reviewer (ASV) checked the entered data. Next, we used a second structured form to group studies within each domain based on the intervention types and outcomes studied. For each study, we recorded if the intervention had a significant or a non-significant effect on the reported outcomes and we defined population parameters based on ulcer characteristics. We used this information to generate evidence-based statements.

An evidence-based statement frames the association between an identified intervention and an eligible outcome using the PICO (population, intervention, control and outcome) criteria. The association of intervention-outcome was established based on the set of eligible publications. Lastly, the generated evidence-based statements were used to phrase candidate quality of care indicators. Each candidate indicator was expressed as a proportion, with a given denominator, i.e. the population evaluated by the indicator, and a numerator, i.e. the portion of the denominator that satisfies the condition of the indicator.

Description of existing supporting evidence

We developed an easy-to-use scoring system to be able to describe the strength of evidence provided by a large amount of identified eligible studies. This allowed us to communicate the certainty of evidence supporting the association between an identified intervention and an outcome.

In this scoring system, we used three factors to determine the quality of a study: the study design, the sample size and the scientific impact of the journal in which the study was published.

For determining the quality of the study design we adapted the levels of evidence provided by the Oxford Centre for Evidence-Based Medicine (OCEBM) [ 37 , 38 , 39 ] (Table  2 ).

We targeted studies that provided high levels of evidence (level 1 or 2). However, because some designs are more difficult to set up for some domains of diabetic foot care, we also allowed level 3 evidence for studies reporting interventions related to organization of care, PAD, surgical procedures to enhance wound healing and secondary prevention, and/or outcomes related to healthcare costs.

Regarding the sample size, a cut-off was applied based on a median of participants for a parallel group trial reported by Chan et al. [ 40 ] and also adopted by the “CONSORT” guidelines [ 41 ]. A sample size of ≥ 32 participants per treatment group was considered as “High”, while a sample size of < 32 participants per treatment group was considered as “Low”.

The scientific impact was reported by using the Journal category ranking and quartiles based on the journal’s impact factor and provided by the Journal Citation Reports (JCR) [ 42 ] (See Additional file 2 ). The publication year of the article was used to select the quartile year.

Our scoring system attributed a weight or “evidence score” to each combination of the three criteria. An additional file shows the evidence score value attributed based on the three criteria (See Additional file 3 ). The reduction in points was non-linear in order to reflect the impact of each factor on publication quality. Finally, an evidence score was assigned to each study, independent of the statistical significance/non-significance of the reported intervention effect.

Following this, a mean score was calculated for the collection of publications reporting the same intervention, subdivided according to outcome. A separate mean score was calculated for publications reporting a significant effect and publications reporting no significant effect. The certainty of the evidence-based statement was categorized based on the mean score of the collection of publications reporting a significant effect. However, the statement was downgraded by one category in cases where the mean evidence score of the publications reporting no significant effect was equal to or higher than the mean evidence score of the publications reporting a significant effect. An additional file shows the categories of certainty of the evidence-based statements (See Additional file 4 ).

Results of the search

The electronic search in online databases yielded a total of 46,826 records. The “PRISMA” flow diagram for the study selection process and reasons for exclusion are shown in Fig.  1 . After removal of duplicates and title/abstract screening, 1,598 records from 2011 up to March 2020 were selected for a full-text search. There were 617 records for which the full-text could not be retrieved either because the full-text was not retrievable from the KU Leuven Libraries collection with institutional access or because they were conference abstracts. We assessed 981 full-text articles for eligibility. A total of 322 clinical studies met our inclusion criteria and were used to develop candidate QIs. We excluded 659 of the assessed full-texts, most often because a detailed inspection showed that the publication did not report a clinical study that evaluates an intervention (non-eligible study type, n  = 177). Numerous studies were also ineligible because the results for outcomes of interest and/or a measure of statistical significance were not reported (non-eligible outcome, n  = 92). A series of publications were excluded because of the reported type of intervention (non-eligible intervention, n  = 122); these were: interventions (not related to organization of care) supported by an only one single study, surgical procedures with another aim than revascularization, offloading, debridement or amputation, investigation of a single revascularization technique without control group, interventions based on natural agents only available in some areas (e.g. Chinese herbals, Papaya pulp dressing, Topical Kiwifruit), interventions outside of conventional clinical settings (e.g. home monitoring tools or telemedicine approach). Studies that regarded mixed or more comprehensive population (e.g. chronic wounds, PAD patients) that did not focus on our target population were also excluded (non-eligible study population, n  = 82). Others reasons for exclusion were the following: study designs which did not provide the expected level of evidence (non-eligible study design, n  = 75), the reported intervention was related to the infection domain (non-eligible domain, n  = 46), records were identified as duplicate after having checked the content of their full-text (duplicate, n  = 48), retrieved full-text was not in an eligible language although an English abstract was previously found (non-eligible language, n  = 17).

Study selection process and reasons for exclusion based on “PRISMA” flow diagram

Included studies and evaluated interventions

The eligible clinical studies evaluated several types of interventions (see the references of included studies in Additional file 5 ). We defined subcategories for most intervention groups to better represent our findings. Among the 28 studies that addressed the organization of care domain , the following intervention groups were listed: introduction of multidisciplinary foot care, integration of a podiatric specialty in the multidisciplinary foot care team, implementation of a care management program for diabetic foot, implementation of a Pay-for-Performance program, implementation of nurse-led care. A large majority of studies ( n  = 241) covered the wound healing intervention domain and evaluated the following interventions: non-biological dressings (2 subcategories: non-biological dressing impregnated with antimicrobial agents, non-biological dressing not impregnated with antimicrobial agents), bioengineered skin substitutes (3 subcategories: acellular dermal matrix, allogeneic skin substitute, autologous skin substitute), isolated cellular therapy, hyperbaric oxygen therapy (HBOT) (3 subcategories according to the patient perfusion status: not specified, adequate or inadequate), isolated growth factor, negative pressure wound therapy (NPWT), physical therapy (4 subcategories: laser/phototherapy, extracorporeal shockwave therapy, ultrasound therapy, physical therapy other than laser, shockwave or ultrasound), gas therapy (2 subcategories: topical oxygen therapy, ozone therapy or combined oxygen-ozone therapy), nutritional supplementation (2 subcategories: single nutrient supplementation, multi-nutrient supplementation), pharmacological agents (2 subcategories: action on vessels, action on immunity), debridement (2 subcategories: biological, enzymatic) and non-revascularization surgical procedures (3 subcategories: amputation, bony surgical offloading, soft tissue surgical offloading). The studies addressing the PAD domain ( n  = 20) compared endovascular surgery and bypass surgery or evaluated the revascularization based on the angiosome concept. Among studies addressing the offloading domain ( n  = 12), some evaluated offloading performed with non-removable knee-high offloading devices in comparison to offloading performed with removable knee-high offloading devices whilst others evaluated offloading performed with knee-high offloading devices in comparison to offloading performed with ankle-high devices. The studies related to the secondary prevention domain included 3 types of interventions ( n  = 21): patient education, footwear and/or insoles (2 subcategories: therapeutic footwear and/or custom-made insoles, or custom-made shoes with and without optimization by plantar pressure measurements) and the application of a prevention management program.

Summary of evidence

In a nutshell, the potential beneficial effect of interventions related to organization of care on DFU outcomes was supported by low evidence. The evidence that indicates that interventions related to the wound healing intervention domain may have a beneficial effect on DFU outcomes was heterogeneous. Overall, a possible beneficial effect on ulcer healing by treatment with non-biological dressings not impregnated with antimicrobial agents, bioengineered skin substitutes, isolated cellular therapy, isolated growth factors and NWPT was supported by moderate to high evidence. Unlike treatment with laser/phototherapy, extracorporeal shockwave therapy, topical oxygen therapy or enzymatic debridement, the possible beneficial effect on ulcer healing by treatment with ozone therapy or combined oxygen-ozone therapy, single nutrient supplementation, pharmacological agents having action on immunity, or biological debridement was supported by low evidence.

In the PAD domain , low evidence indicates that revascularization with endovascular surgery compared to open vascular surgery may have a beneficial effect on limb salvage/amputation-free survival and amputation events. The same certainty of evidence was observed the other way around, when comparing revascularization with open vascular surgery to endovascular surgery. No studies were identified from the literature search with no revascularization as control group. Concerning the offloading domain , very high evidence indicates that non-removable knee-high offloading devices may have a beneficial impact on time to healing, when compared to removable knee-high offloading devices. In the secondary prevention domain , the effect of patient education was the most studied, but the evidence indicating a potential beneficial effect on diverse DFU outcomes was low. A complete overview of the evidence supporting the extracted interventions from the literature is available in Additional file 5 .

Candidate evidence-based indicators

A total of 42 candidate evidence-based QIs for studying quality of care in DFCs were developed from our findings from existing literature. An overview is presented in Table  3 . They were attributed to the level of care (hospital, national) and the aspect of care addressed (structure, process or outcome).

There is a need for a more evidence-based approach in the development of QIs for diabetic foot care. In this study, we adopted a systematic approach to search for evidence-based interventions from the existing literature and to formulate, based on an evaluation of our search findings, evidence-based candidate QIs on the structures and processes of care. It is not our intention to displace existing, deeply rooted QIs, but to propose additional candidate indicators in an evidence-based manner that can reinforce existing indicators. This evidence-based approach does not take into account clinical relevance or feasibility. We therefore consider this a first step in which possible indicators are collected for which good evidence exists, and then in a next step a stakeholder panel will decide which indicators are useful and feasible for implementation in quality monitoring.

Our evidence-based selection approach resulted in the collection of 42 candidate QIs, including 5 structure indicators and 37 process indicators. Although we only based our methodology on clinical studies, not on guidelines, our resulting candidate QIs span the majority of domains defined by the IWGDF guidelines [ 10 ]. Among these are several well-known process indicators, already in use in ongoing quality promotion initiatives (Belgium, Germany, UK), but we also proposed several additional indicators. Our indicators included a larger range of interventions and covered several topics that are not used in many quality evaluation systems and for which clinical interest has been growing. Examples are, nutritional status [ 43 , 44 ], use of lipid-lowering therapy [ 45 ], and of new therapies like cellular therapies [ 46 ] or topical oxygen therapy [ 47 ]. Despite the fact that for some of these candidate indicators no randomized controlled trials are available (or feasible), these processes are already part of clinical practice and could receive attention as QIs during the evaluation by a stakeholder panel.

In the domain of organization of care we selected indicators commonly reported in the literature such as the establishment of a multidisciplinary team approach or the integration of podiatric care but also less frequent indicators such as the implementation of protocolized care or of pay-for-performance, not implemented by most DFCs so far [ 16 ].

In our review, interventions on patient health-related quality of life (QoL) were not included, although the assessment of the patient well-being and function through patient-reported outcome instruments is already proposed as process of care indicator in the UK [ 8 ]. This might be explained by the fact this domain is still in full development. Literature that investigates the relationship between psychological interventions and DFU outcomes is still scarce [ 48 ], and thus too limited to be able to make evidence based recommendations on QIs.

We did not aim to generate outcome of care indicators in this study because they are already considered as an important goal in diabetic foot care. Besides, the methodology to identify and validate such QIs differs from the approach used in this study. It requires adjustment for differences in case mix and other external factors to ensure fair comparisons among institutions or physicians [ 49 , 50 ].

The availability of good quality studies providing high level of evidence was limited for topics such as organization of care or surgical procedures. Recently, proposals have been formulated to produce higher quality studies in the PAD domain [ 51 , 52 ]. Conversely, numerous studies with high evidence were found to support the indicators addressing wound healing interventions and more particularly new therapies like bioengineered skin substitutes or isolated cellular therapy. This can be attributed to the great expansion observed for this body of research over the last decade. Nevertheless, practical concerns could arise in using these wound care procedures as quality indicators in routine care. For instance, issues may rise regarding the storage of such products that requires specific conditions to maintain cell viability. Another challenge may be related to their varied effects and high cost, making it difficult for clinicians to determine which product is appropriate for the patient. This is a clear example of candidate QIs that need the next step of evaluation by a stakeholder panel to decide if they are feasible for implementation in quality monitoring.

Our detailed methodology contributes to the field by using clinical studies as primary sources for possible quality measurements rather than guidelines, predominantly used for the development of QIs so far [ 53 ]. A practical guideline presents a framework for optimal care in the context of complex medical decision-making. However, it may reflect the views of the stakeholders involved in its development and quality measures that can be derived from it may be limited in scope. Our open-minded systematic search in the literature helped to identify domains and indicators of quality of care that are not (yet) considered by expert panels. In addition, we have listed the scientific evidence for each candidate QI in a methodical, precise and transparent manner. We developed an easy-to-use scoring system, based on objective criteria, to be able to describe the strength of evidence provided by a large amount of identified eligible studies in an easy to understand format for a stakeholder panel that need to judge on the feasibility of the candidate indicators. The fact that we did not use the standard systems commonly used for assessing certainty of evidence could be seen as a limitation. Yet, this is mainly due to the purpose of our study. We did not need to apply detailed criteria such as heterogeneity or publication bias because our aim was not to judge about the estimate of an effect [ 54 ].

We conducted a literature review to provide an exhaustive overview of the existing evidence that demonstrates the linkage between an intervention and an outcome, and thus the possible use of that intervention as a structure or process indicator to assess quality in DFCs. In a next step, the described evidence will be used as a supportive element in order to guide a stakeholder panel in their selection of appropriate QIs. Furthermore, if we were to use standard systems, we would have to use several tools to fit to the heterogeneous encountered designs, which will have made our work more complicated, considering the number of studies that we included.

We have limited ourselves to articles from the last 10 years, to keep the number of articles under review feasible, but also to reflect the current practice in DFCs. However, we strongly realize that the evidence for several pre-existing QIs is based on older literature and do not question it. An example is the use of TCC as a gold standard for offloading. A further limitation of our study is that a single review author examined the full-texts of the selected articles, conducted data extraction and rated the evidence. Because these tasks were not conducted dually and independently, we may have introduced some risk of errors. Nonetheless, a large number of records were assessed during the abstract/title phase, which have been performed independently by two reviewers. The calculation of inter-rater reliability (Cohen’s kappa value) indicated an adequate agreement between the 2 reviewers, which increased the reliability of the selected records used for the next selection steps. Full-texts were assessed using straightforward criteria and the reviewer team was frequently consulted to check the plausibility of the decision.

In conclusion, we showed that it is possible to select a set of candidate indicators for diabetic foot care in an evidence-based manner, independently of expert opinion. In this way, various indicators emerged that are not commonly used in quality evaluation of diabetic foot care. In a next step, the identified set of candidate indicators are aimed to be assessed for relevance and practical usefulness by a broad stakeholder panel from all levels of diabetes foot care. A formal methodology needs to be used to stimulate the discussion and measure the collective opinion in an objective way [ 55 ]. In a later stage, it will be recommended to perform an impact analysis to evaluate whether implementation of these QIs changes processes of care and improves patient outcomes and/or reduces costs [ 15 ]. Furthermore, the update of these QIs will be monitored based on the evolving DFU care needs.

Availability of data and materials

Data collated and summarized from this review are available from the corresponding author upon reasonable request.

Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;15(24):2367–75.

Article   Google Scholar  

McDermott K, Fang M, Boulton AJM, Selvin E, Hicks CW. Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers. Diabetes Care. 2023;46(1):209–21.

Article   PubMed   Google Scholar  

Khunkaew S, Fernandez R, Sim J. Health-related quality of life among adults living with diabetic foot ulcers: a meta-analysis. Qual Life Res. 2019;28(6):1413–27.

Nabuurs-Franssen MH, Huijberts MSP, Kruseman ACN, Willems J, Schaper NC. Health-related quality of life of diabetic foot ulcer patients and their caregivers. Diabetologia. 2005;48(9):1906–10.

Article   CAS   PubMed   Google Scholar  

Jodheea-Jutton A, Hindocha S, Bhaw-Luximon A. Health economics of diabetic foot ulcer and recent trends to accelerate treatment. Foot (Edinb). 2022;52:101909.

Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula WV, Bus SA. Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res. 2020;13(1):16.

Article   PubMed   PubMed Central   Google Scholar  

Lobmann R, Müller E, Kersken J, Bergmann K, Brunk-Loch S, Groene C, et al. The diabetic foot in Germany: analysis of quality in specialised diabetic footcare centres. Diabetic Foot J. 2007;10(2):68–72.

Google Scholar  

Holman N, Young B, Stephens H, Jeffcoate W, the members of the National Foot Care Audit Steering Group. Pilot study to assess measures to be used in the prospective audit of the management of foot ulcers in people with diabetes. Diabet Med. 2015;32(1):78–84.

Nuti S, Bini B, Ruggieri TG, Piaggesi A, Ricci L. Bridging the gap between theory and practice in integrated care: the case of the diabetic foot pathway in Tuscany. Int J Integr Care. 2016;16(2). Available from: http://www.ijic.org/articles/10.5334/ijic.1991/ . Cited 2018 Jan 19.

Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA, et al. Practical guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266.

Mainz J. Defining and classifying clinical indicators for quality improvement. Int J Qual Health Care. 2003;15(6):523–30.

Donabedian A. The quality of care. How can it be Assessed? JAMA. 1988;260(12):1743–8.

National Academies of Sciences E. Crossing the global quality Chasm: improving health care worldwide. 2018. Available from: https://www.nap.edu/catalog/25152/crossing-the-global-quality-chasm-improving-health-care-worldwide . Cited 2018 Oct 9.

Mainz J. Developing evidence-based clinical indicators: a state of the art methods primer. Int J Qual Health Care. 2003;15(suppl 1):i5–11.

Stelfox HT, Straus SE. Measuring quality of care: considering conceptual approaches to quality indicator development and evaluation. J Clin Epidemiol. 2013;66(12):1328–37.

Morbach S, Kersken J, Lobmann R, Nobels F, Doggen K, Van Acker K. The German and Belgian accreditation models for diabetic foot services. Diabetes Metab Res Rev. 2016;32:318–25.

Health and Social Care Information Centre. National Diabetes Foot Care Audit (NDFA). 2014. Available from: http://www.hscic.gov.uk/footcare . Cited 2015 Jan 22.

Lobmann R, Achwerdov O, Brunk-Loch S, Engels G, Trocha A, Groene C, et al. The diabetic foot in Germany 2005–2012: analysis of quality in specialized diabetic foot care centers. Wound Med. 2014;4:27–9.

Doggen K, Van Acker K, Beele H, Dumont I, Félix P, Lauwers P, et al. Implementation of a quality improvement initiative in Belgian diabetic foot clinics: feasibility and initial results. Diab/Metab Res Rev. 2014;30:435–43.

Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021;372:n160.

Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for scoping reviews (PRISMA-ScR): Checklist and explanation. Ann Intern Med. 2018;169(7):467–73.

Deng P, Shi H, Pan X, Liang H, Wang S, Wu J, et al. Worldwide Research Trends on Diabetic Foot Ulcers (2004–2020): suggestions for researchers. J Diabetes Res. 2022;2022:e7991031.

Bakker K, Apelqvist J, Lipsky BA, Van Netten JJ, Schaper NC, on behalf of the International Working Group on the Diabetic Foot (IWGDF). The 2015 IWGDF guidance documents on prevention and management of foot problems in diabetes: development of an evidence-based global consensus. Diabetes Metab Res Rev. 2016;32:2–6.

Peters EJG, Lipsky BA, Senneville É, Abbas ZG, Aragón-Sánchez J, Diggle M, et al. Interventions in the management of infection in the foot in diabetes: a systematic review. Diab/Metab Res Rev. 2020;36(S1):e3282.

Senneville É, Lipsky BA, Abbas ZG, Aragón-Sánchez J, Diggle M, Embil JM, et al. Diagnosis of infection in the foot in diabetes: a systematic review. Diab/Metab Res Rev. 2020;36(S1):e3281.

Mueller MJ, Diamond JE, Sinacore DR, Delitto A, Blair VP, Drury DA, et al. Total contact casting in treatment of diabetic plantar ulcers. Controlled clinical trial. Diabetes Care. 1989;12(6):384–8.

Caravaggi C, Faglia E, De Giglio R, Mantero M, Quarantiello A, Sommariva E, et al. Effectiveness and safety of a nonremovable fiberglass off-bearing cast versus a therapeutic shoe in the treatment of neuropathic foot ulcers: a randomized study. Diabetes Care. 2000;23(12):1746–51.

Spencer S. Pressure relieving interventions for preventing and treating diabetic foot ulcers. Cochrane Database Syst Rev. 2000;(3):CD002302. https://doi.org/10.1002/14651858.CD002302 .

Armstrong DG, Nguyen HC, Lavery LA, van Schie CHM, Boulton AJM, Harkless LB. Off-loading the diabetic foot wound: a randomized clinical trial. Dia Care. 2001;24(6):1019–22.

Article   CAS   Google Scholar  

Nabuurs-Franssen MH, Sleegers R, Huijberts MS, Wijnen W, Sanders AP, Walenkamp G, et al. Total contact casting of the Diabetic Foot in Daily Practice: a prospective follow-up study. Dia Care. 2005;28(2):243–7.

Bramer WM, Giustini D, de Jonge GB, Holland L, Bekhuis T. De-duplication of database search results for systematic reviews in EndNote. J Med Libr Assoc. 2016;104(3):240–3.

Rathbone J, Carter M, Hoffmann T, Glasziou P. Better duplicate detection for systematic reviewers: evaluation of systematic Review Assistant-Deduplication Module. Syst Rev. 2015;4(1):6.

Qi X, Yang M, Ren W, Jia J, Wang J, Han G, et al. Find duplicates among the PubMed, EMBASE, and cochrane library databases in systematic review. PLoS One. 2013;8(8):e71838.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Kwon Y, Lemieux M, McTavish J, Wathen N. Identifying and removing duplicate records from systematic review searches. J Med Libr Assoc. 2015;103(4):184–8.

Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan—a web and mobile app for systematic reviews. Syst Rev. 2016;5(1). Available from: https://link.springer.com/epdf/10.1186/s13643-016-0384-4 . Cited 2023 May 19.

McHugh ML. Interrater reliability: the kappa statistic. Biochem Med (Zagreb). 2012;22(3):276–82.

OCEBM Levels of Evidence Working Group. The centre for evidence-based medicine. The Oxford 2011 levels of evidence. Available from: https://www.cebm.net/ . Cited 2022 Dec 16.

Cochrane Childhood cancer. Non-randomised controlled study (NRS) designs. Available from: https://childhoodcancer.cochrane.org/non-randomised-controlled-study-nrs-designs . Cited 2023 Mar 24.

Eric Harding MLS. LibGuides: evidence based practice: study designs & evidence levels. Available from: https://mcw.libguides.com/c.php?g=644314&p=4643389 . Cited 2022 Dec 16.

Chan AW, Altman DG. Epidemiology and reporting of randomised trials published in PubMed journals. Lancet. 2005;365(9465):1159–62.

Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340(mar23 1):c869–869.

Journal Citation Reports: Quartile rankings and other metrics. Available from: https://support-clarivate-com.kuleuven.e-bronnen.be/ScientificandAcademicResearch/s/article/Journal-Citation-Reports-Quartile-rankings-and-other-metrics?language=en_US . Cited 2023 Jun 23.

González-Colaço Harmand M, Tejera Concepción A, Farráis Expósito FJ, Domínguez González J, Ramallo-Fariña Y. Pilot study on the relationship between malnutrition and grip strength with prognosis in diabetic foot. Nutrients. 2023;15(17):3710.

Lauwers P, Dirinck E, Van Bouwel S, Verrijken A, Van Dessel K, Van Gils C, et al. Malnutrition and its relation with diabetic foot ulcer severity and outcome: a review. Acta Clin Belg. 2022;77(1):79–85.

Ulloque-Badaracco JR, Mosquera-Rojas MD, Hernandez-Bustamante EA, Alarcón-Braga EA, Ulloque-Badaracco RR, Al-kassab-Córdova A, et al. Association between lipid profile and apolipoproteins with risk of diabetic foot ulcer: a systematic review and meta-analysis. Int J Clin Pract. 2022;2022:5450173.

Holl J, Kowalewski C, Zimek Z, Fiedor P, Kaminski A, Oldak T, et al. Chronic diabetic wounds and their treatment with skin substitutes. Cells. 2021;10(3):655.

Frykberg RG. Topical wound oxygen therapy in the treatment of chronic diabetic foot ulcers. Med (Kaunas). 2021;57(9):917.

Vileikyte L, Pouwer F, Gonzalez JS. Psychosocial research in the diabetic foot: are we making progress? Diabetes Metab Res Rev. 2020;36(Suppl 1):e3257.

Mant J. Process versus outcome indicators in the assessment of quality of health care. Int J Qual Health Care. 2001;13(6):475–80.

Brook RH, McGLYNN EA, Shekelle PG. Defining and measuring quality of care: a perspective from US researchers. Int J Qual Health Care. 2000;12(4):281–95.

Ali SR, Ozdemir BA, Hinchliffe RJ. Critical appraisal of the quality of evidence addressing the diagnosis, prognosis, and management of peripheral artery disease in patients with diabetic foot ulceration. Eur J Vasc Endovasc Surg. 2018;56(3):401–8.

Jeffcoate WJ, Bus SA, Game FL, Hinchliffe RJ, Price PE, Schaper NC. Reporting standards of studies and papers on the prevention and management of foot ulcers in diabetes: required details and markers of good quality. Lancet Diabetes Endocrinol. 2016;4(9):781–8.

Kötter T, Blozik E, Scherer M. Methods for the guideline-based development of quality indicators–a systematic review. Implementation Science. 2012;7(1). Available from: http://implementationscience.biomedcentral.com/articles/10.1186/1748-5908-7-21 . Cited 2019 Feb 4.

Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–6.

Lusendi FM, Vanherwegen AS, Nobels F, Matricali GA. A multidisciplinary Delphi consensus to define evidence-based quality indicators for diabetic foot ulcer care. Eur J Pub Health. 2024.  https://doi.org/10.1093/eurpub/ckad235 .

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Acknowledgements

The authors wish to thank Krizia Tuand, the biomedical reference librarian of the KU Leuven Libraries – 2Bergen – learning Centre Désiré Collen (Leuven, Belgium), for her help in building the search strategy and providing documentation on methodology.

We would like to express our gratitude to Suchsia Chao for her help in the deduplication process and to Veerle Boonen for her help in retrieving full-texts of records. We are also thankful to Pradhyu Ramesh for performing the language editing.

This study was funded by the Belgian Science Policy Office and the National Institute for Health and Disability Insurance.

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FML, ASV, KD, FN, and GM developed the methodology. FML conducted the review of the literature and extracted data. KD, ASV, FN and GM were involved in the selection of studies, the quality appraisals and development of indicators. FML wrote the first draft manuscript and subsequent versions. KD, ASV, FN and GM reviewed the manuscript. All authors contributed to the article and approved the submitted version.

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Lusendi, F.M., Vanherwegen, AS., Doggen, K. et al. Evidence-based interventions for identifying candidate quality indicators to assess quality of care in diabetic foot clinics: a scoping review. BMC Public Health 24 , 996 (2024). https://doi.org/10.1186/s12889-024-18306-2

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Update on management of diabetic foot ulcers

Diabetic foot ulcers (DFUs) are a serious complication of diabetes that results in significant morbidity and mortality. Mortality rates associated with development of a DFU are estimated to be 5% in the first 12 months, and 5-year morality rates have been estimated at 42%. The standard practices in DFU management include surgical debridement, dressings to facilitate a moist wound environment and exudate control, wound off-loading, vascular assessment, and infection and glycemic control. These practices are best coordinated by a multidisciplinary diabetic foot wound clinic. Even with this comprehensive approach, there is there is still room for improvement in DFU outcomes. Several adjuvant therapies have been studied to reduce DFU healing times and amputation rates. We reviewed the rationale and guidelines for current standard of care practices and reviewed the evidence for the efficacy of adjuvant agents. The adjuvant therapies reviewed include the following categories: non-surgical debridement agents, dressings and topical agents, oxygen therapies, negative pressure wound therapy, acellular bioproducts, human growth factors, energy based therapies, and systemic therapies. Many of these agents have been found to be beneficial in improving wound healing rates, although a large proportion of the data are small randomized controlled trials with high risks of bias.

Introduction

Diabetic foot ulcers (DFUs) are a prevalent complication of diabetes mellitus and account for significant morbidity, mortality, and healthcare expenditures. It is estimated that 19–34% of patients with diabetes are likely to be affected with a diabetic foot ulcer in their lifetimes, and the International Diabetes Federation reports that 9.1–26.1 million people will develop DFUs annually. 1 These numbers are alarming, as the clinical implications for the development of a DFU are not negligible. A population-based cohort study in the United Kingdom demonstrated that the development of a DFU is associated with a 5% mortality in the first 12 months and a 42% mortality within 5 years. Patients with DFUs were also found to have a 2.5-fold increased risk of death compared with their diabetic counterparts without foot wounds. 2 Furthermore, patients living with DFUs suffer great morbidity, lower health-related quality of life, and poorer psychosocial adjustment 3 and have a high burden of healthcare interactions. 4

Treatment of DFUs accounts for approximately one-third the total cost of diabetic care, which was estimated to be U.S $176 billion in direct healthcare expenditures in 2012. 45 Despite these high healthcare costs, about 20% of patients have unhealed DFUs at 1 year. 6 Even after wound resolution, subsequent DFUs are common, with a recurrence rate of roughly 40% of patients within 1 year. 1 Although there are well-established principles to managing DFUs, treatment of DFUs is often challenging. A broad spectrum of novel interventions is being studied to improve wound healing. In this review, we discuss the current standard of care and review current guidelines in DFU management. We also explore the rationale and evidence for several adjuvant agents currently in use or being studied to improve DFU outcomes.

Standard of care

Shortly after DFUs were described in the 19th century, the most prevalent treatment approach was prolonged bedrest. Dr. Frederick Treves (1853–1923) revolutionized the management of DFUs when he established three important principles in DFU treatment, which continue to be the basis of modern day care: sharp debridement, off-loading, and diabetic foot education. 7 Building on these principles, the pillars of treatment today include the following: local wound care with surgical debridement, dressings promoting a moist wound environment, wound off-loading, vascular assessment, treatment of active infection, and glycemic control ( Table 1 ). 8 – 10 In addition to these principles, multidisciplinary diabetic foot care is now becoming a mainstay of therapy.

Standard of care practices

Surgical debridement

Wound debridement involves removal of all necrotic and devitalized tissue that is incompatible with healing, as well as surrounding callus. This process aids in granulation tissue formation and re-epithelialization and reduces plantar pressures at callused areas. 9 Debridement also plays an important role in infection control, as devitalized tissues provide a nidus for bacterial proliferation, act as a physical barrier for antibiotics, and limit immune response to fighting infection. 11 The Infectious Disease Society of America (IDSA) and the Wound Healing Society (WHS) recommend sharp debridement over topical debridement agents (i.e., autolytic dressing or biological debridement). 8 , 9 Sharp debridement has been found to be efficacious in several clinical trials, although overall data are limited. 12 – 14

Choice of dressing

DFUs are heterogeneous, so no single dressing is ideal for all wound types. It is generally agreed that the goal of a dressing should be to create a moist environment that promotes granulation, autolytic processes, angiogenesis, and more rapid migration of epidermal cells across the wound base. 9 , 11 , 15 The selected dressing should also be appropriate to manage excess wound exudates. A wide range of dressing types are available, and several are currently being studied. Currently, there are insufficient data to recommend any particular dressing type. 9 , 12

Wound off-loading

Plantar shear stress, which is the horizontal component of ground reaction forces, and, to a lesser degree vertical plantar pressure are major causative factors in the development and poor healing of DFUs. 16 Relieving plantar pressure and shear stress from a DFU is a vital part of wound care, as it promotes healing and prevents recurrence. 11 Off-loading can be achieved by many mechanisms, including shoe modifications, boots, and orthotic walkers. 11 The modality choice should be based on the location of the wound and history of peripheral arterial disease (PAD). Total contact casting (TCC) is often considered the gold standard device, although TCC, as well as other non-removable devices, should not be used in those with significant PAD or infection. 917 Studies have shown that both TCC and knee-high removable walkers reduce peak pressure in the forefoot up to 87%, as they redistribute plantar pressure to the entire weight-bearing surface of the foot, as well as lower the leg, through the device wall. 18 Devices that extend to the ankle are generally less effective for this reason. 18 Although there was a randomized controlled trial (RCT) that showed similar healing rates between TCC and removable walkers, there are numerous studies demonstrating that non-removable off-loading is more effective than removable off-loading in terms of time to healing and percentage of wounds healed. While TCC has historically been considered the gold standard, it is becoming evident that any non-removable knee-high device can achieve similar results. This is congruent with the International Working Group on the Diabetic Foot (IWGDF) consensus guidelines. Generally considering a non-removable knee-high device as the gold standard also allows for effective off-loading options at facilities where skills in casting are unavailable.

Offloading shoes, cast shoes, and custom-made temporary shoes appear to be effective in healing DFUs, although the evidence comes only from retrospective studies. The IWGDF recommends that these options be used for plantar ulcers in patients for whom knee-high devices are contraindicated or not tolerated or in those with non-plantar ulcers. 17 Felted foam with appropriate footwear can be used if no other biomechanical off-loading is available. Surgical off-loading should only be used if conservative management has failed in a high-risk patient. 17

Vascular assessment

PAD is estimated to occur in 40% of patients with DFUs. 6 Patients who have co-morbid DFUs and PAD have slower healing, higher major amputation rates, and higher mortality rates. 6 It is recommended that those with DFUs be evaluated for PAD by palpating pedal pulses or ankle brachial index (ABI). 11 An ABI below 0.7 correlates with some degree of arterial insufficiency, and those with ABI less than 0.4 have severe PAD. Patients with ABI greater than 1.4 likely have non-compressible vessels at the ankle due to vascular calcifications. This is not uncommon in patients with diabetes and is also observed in renal insufficiency. 19 Those with non-compressible vessels should undergo alternative testing, including toe systolic pressures, pulse volume recordings, transcutaneous oxygen measurement, or duplex ultrasound. Abnormalities in any of these secondary tests reliably confirms the diagnosis of PAD. 19 , 11

Treatment of active infection

Wound infection is a known predictor of poor wound healing and amputation. 20 The appropriate recognition of infection and treatment with antibiotics in diabetic foot infection is imperative to improve outcomes. Conversely, inappropriately treating with antibiotics, often in the setting of fear of missing an infection, to reduce bacterial burden or prophylaxis is associated with several adverse effects, including antibacterial resistance. 21 The IDSA has outlined specific guidelines for the treatment of diabetic foot infections. 9 The IDSA recommends treatment of wounds with at least two signs or symptoms of inflammation (erythema, warmth, tenderness, pain, induration) or purulent secretion. It is recommended that, before antibiotic therapy, a deep tissue culture via biopsy or curettage after debridement be obtained. Swab specimens should be avoided, especially in inadequately debrided wounds. 9 Antibiotic therapy should be targeted to aerobic Gram-positive cocci in mild to moderate infections. Severe infections should be treated with broad-spectrum empiric antibiotics pending cultures. IDSA recommends 1- to 2-week antibiotic course for mild infections and 2–3 weeks for moderate to severe infections, but antibiotics can usually be discontinued once clinical signs and symptoms of infections have resolved. 9 To avoid antibacterial resistance and other adverse outcome of therapy, it is best practice that treatment of clinical diabetic foot infections be completed with narrow=spectrum antibiotics for the shortest duration possible. 922

Glycemic control

It is widely recommended that blood glucose be optimized to improve wound healing and limit adverse effects on cellular immunity and infection. 11 Although a recent Cochrane review was unable to conclude whether intensive glycemic control had a positive or detrimental effect on treatment of DFUs, due to lack of RCTs, several observational studies have found positive correlations with glycemic control and wound healing. 23 – 25 Furthermore, another Cochrane review assessing effects of glycemic targets in type 2 diabetes found that those with intensive glycemic control had a 35% reduction in risk of lower-extremity amputation. 26

Multidisciplinary care

Specialty diabetes foot care is becoming the new standard of care in areas where the resources are available. Most expert guidelines now recommend referral to a multidisciplinary care center for management of DFUs. 9 , 15 , 27 Numerous studies and systematic reviews have showed positive effects on multidisciplinary care in reducing wound healing times, amputation rates, and severity of amputation. 28 – 31 The definition of multidisciplinary diabetic foot care varies broadly in the literature but often includes a surgeon (general, vascular, orthopedic), podiatrist, diabetes specialist, physical therapist, and wound care nurse.

Adjuvant therapies

In addition to standard practices in DFU care, there are a wide range of agents available or currently being studied as adjuvant therapies. In this review, we will characterize these agents in the following categories: non-surgical debridement agents, dressings and topical products, oxygen therapies, negative pressure wound therapy, acellular bioproducts, human growth factors, skin grafts and bioengineered skin, energy-based therapies, and systemic therapies ( Table 2 ). We will review the rationale for use and the data evaluating the efficacy of these interventions.

Efficacy of adjuvant therapies.

Non-surgical debridement agents

Although sharp debridement is the preferred method of debridement, there are other non-surgical options available, including autolytic debridement with hydrogels, enzymatic debridement, biosurgery, and mechanical debridement with hydrotherapy.

Autolytic debridement with hydrogels

Hydrogels are specialized dressings that are made of insoluble polymers that bind a relatively large volume of water. 32 This water can be donated to wounds, but, given that the polymer matrix is not fully saturated, it can absorb wound exudate, resulting in an optimal moisture level in the wound. A moist environment provides optimal conditions for cells and facilitates autolytic debridement, which enhances the breakdown of necrotic tissue through endogenous proteolytic enzymes. 32 A 2013 Cochrane review and meta-analysis of three RCTs found that hydrogel dressings had significantly greater healing when compared with basic wound dressings. 32

Enzymatic debridement

Clostridial collagenase ointment (CCO) is the most common agent used for enzymatic debridement. Although one study found that CCO is used as management for 17% of DFUs, the evidence for its use is lacking. 33 There are only three RCTs specifically exploring the efficacy of CCO in DFU. The first was a 12-week parallel multicenter, open-label RCT of 48 patients in 2012, which showed improved healing in the group treated with CCO compared with saline-moistened gauze with selective sharp debridement. 34 It has been questioned whether the control group received usual best care, as the average wound size increased during the study in this group. 12 Mline et al. compared CCO with hydrogel in a small randomized RCT and found no difference between the groups in days to complete healing. Most recently, in 2017, Jimenez et al . compared CCO to standard care plus hydrogel and also found no difference in the wound size at 6 and 12 weeks. 35

Maggot and larval debridement has been thought to confer several benefits to wounds, including reducing bacterial burden, regulating proteases, degrading the extracellular matrix, promoting fibroblast migration, and potentially improving skin perfusion. 36 Data on the efficacy on this treatment are limited. A case-controlled trial in non-ambulatory patients with DFUs showed that there was no difference in the proportion who healed at 6 months. In those who healed, time to healing was shorter in patients who received maggot debridement. Amputations rates were also lower in the intervention group. 37 Several other studies have shown no difference in healing or amputation rates. 12 There are current ongoing studies exploring a new generation of maggot debridement therapy with transgenic Lucilia sericata larvae that produce and secrete human growth factors. 38

Hydrotherapy

The Verajet ™ hydrosurgery system is a form of mechanical debridement that uses a high-pressure stream of sterile normal saline that is pumped to a hand-held cutting and aspirating tool. There has only been one RCT evaluating the efficacy of Verajet ™ , comparing it to surgical debridement in lower-extremity ulcers. Although debridement times were shorter, there was no difference in time to wound closure. 12

There are several options available for non-surgical wound debridement that may be beneficial, but there is presently insufficient evidence to recommend one approach over other methods.

Dressings and topical products

Alginate and other dressings.

Alginate dressings are derived from seaweed and come in the form of calcium alginate or calcium sodium alginate or alginic acid. These alginate products form a highly absorbent gel that can absorb large volume of wound exudates to avoid skin maceration yet still maintain a moist environment. A Cochrane review and meta-analysis in 2013 showed no significant difference in ulcer healing with alginate products when compared with basic contact dressings or silver hydrocolloid dressings. Another systematic review in 2016 also found no difference in healing time between other synthetic active dressings and traditional dressings, including wet to dry saline moistened gauze, Vaseline gauze, and hydrofiber. As an exception, moderate-quality evidence suggested that hydrogel was more effective in healing DFUs. 39

Topical antiseptics and antimicrobials

Several agents are currently being studied as topical antiseptic and antimicrobial agents for DFUs. A natural substance of popular interest is the use of honey. Honey is thought to have antibacterial activity and other benefits due to its ability to draw fluid from surrounding vessels and provide a moist environment and topical nutrition. Several animal models have shown that honey may accelerate healing. 40 A systematic review in 2016, including five RCTs and 10 observational studies, was conducted to evaluate the efficacy of honey in wound healing. A meta-analysis of three of the five non-blinded RCTs concluded that honey dressings were better than conventional dressings. Given the heterogeneity of studies and lack of high-quality evidence, honey dressings were concluded to be safe, but there was insufficient data to conclude true efficacy. 41 TOone new RCT published since that time compared honey dressing to dressing with normal saline and found that honey dressing were more effective in terms of time to healing and number of wound healed at 120 days. 42

Other topical antimicrobials that have been studied but have not been found to have clear benefits include cadexomer–iodine, carboxymethylcellulose hydrofiber, superoxidized solutions, tobramycin beads, and chloramine treatment. 12 , 43 Nanocrystalline silver was found to cause greater ulcer size reduction rate than both Manuka honey and conventional dressing in one study. 44 Bacteriophage therapy, which uses viruses that target specific bacteria, is being studied in DFUs. There was one compassionate-use study of six patients with culture-proven Staphylococcus aureus infections of soft tissue and bone. All infections reportedly responded to therapy, with an average healing time of 7 weeks.

Other topical products

The 2016 systematic review by the IWGDF showed that topical products, such as phenytoin, angiotensin, and topical insulin, have positive effects on wound healing compared with controls, but these studies had high risk for bias. Since that time, a study exploring phenytoin compared with honey and saline treatment found that phenytoin was comparable to honey, but both show significantly higher reduction in wound area and eradication of infection at 3 weeks of treatment. There has been no additional studies on NorLeu-angiotensin therapy or topical insulin. Studies have also found no difference in wound healing with the use of QRB7 oak extract, polyherbal cream, or bismuth subgallare/borneol. 12

Oxygen therapies

Oxygen is vital to the wound healing process, as it is involved in cell proliferation, collagen synthesis, re-epithelization, and defense against bacteria. 45 Many patients with DFUs have impaired oxygenation to wounded areas, especially in the setting of vascular disease. Therapeutic strategies to correct this include local delivery of oxygen to the wound and systemic oxygen administration.

Topical oxygen

The IWGDF 2016 systematic review did not find that there was enough evidence to support the use of topical oxygen therapy to enhance healing in DFUs on the basis of three available studies with mixed results. These studies included a RCT that showed no difference in healing at 14 days, a prospective cohort study showing benefit at 4 weeks, and a small cohort study that showed apparent improvement in healing at 90 days. 12 , 46 Since that time, Yu et al . performed a small RCT that showed increased wound closure rates in stage 2 and stage 3 DFUs at 8 weeks in those treated with topical oxygen therapy. 47 A larger blinded RCT showed no added benefit when comparing continuous transdermal oxygen with standard of care. A subgroup analysis showed a shorter median healing time to closure in patients greater than 65 years of age. 48 A newer topical agent currently being studied is hemoglobin spray. Topical hemoglobin can transport oxygen from the atmosphere to hypoxic wounds through facilitated diffusion. 49 Hunt et al. showed significant benefit in wound closure at 28 weeks. 50 Larger RCTs are needed to evaluate its true efficacy.

Systemic oxygen

Supplemental inspired oxygen has been explored in wound healing but is limited by the need for intact blood supply to the wound tissue. This mode of treatment has been studied primarily in surgical wounds and is not well studied in DFUs. 45 Hyperbaric oxygen (HBOT) is administered in a compression chamber, which provides 100% oxygen and delivers a greatly increased partial pressure of oxygen to tissues. A 2015 Cochrane review that pooled data from 10 RCTs showed that there was a significant increase rate in healing with HBOT at 6 weeks, although this benefit was not evident at follow-up at 1 year. 51 It was recommended that the results be interpreted with caution owing to various flaws in design in available studies. In 2016, Fedorko et al. published a double-blinded RCT concluding that hyperbaric oxygen therapy does not reduce indication for amputations in patients with Wagner grade 2–4 DFUs as assessed by a vascular surgeon after 12 weeks of HBOT. 52 This study has been criticized because the end points were not amputation events. 53 – 55 Rather, the primary outcome was whether the patient met criteria for amputation, which was a decision made by a vascular surgeon based on a photograph of the wound.

Negative-pressure wound therapy

Negative-pressure wound therapy (NPWT) is often used in wound management, as this vacuum device collects high volumes of wound exudate, the reduces frequency of dressing changes, keeps wounds that are anatomically challenging clean, and reduces odor. It is also theorized that the vacuum forces aid in wound healing by increasing perfusion, extracting infectious material, and approximating wound edges. 56 A recent systematic review analyzing 11 RCTs comparing NPWT with standard dressing changes showed that NPWT had a higher rate of complete healing, shorter healing time, and few amputations. There was no difference in incidence of treatment-related adverse effects. 57

Acellular bioproducts

Acelluar dermal matrix (ADM) has been used for several years for wound healing, tissue repair, and reconstruction. Extracellular matrix plays an important role in wound healing in that it provides structural support and facilitates signals to modulate cellular responses. 58 Donor dermis that is decellularized retains bioactive agents and acts as a scaffold for host cell repopulation. It is thought that it aids in wound healing by promoting vascularization and providing a barrier to bacteria and a moist wound environment, which increases cell regeneration. 58 In 2016, a systematic review of 12 RCTs, six of which were subject to meta-analysis, found that, when compared with standard of care, patients treated with ADM had higher healing rates at 6 and 12 weeks. 58 Since that publication, Zelen et al. published similar findings. 59 , 60 Campitiello et al. published data on an acellular flowable matrix that has a liquid composition that can fill deep cavities and tunneled wounds. They found that healing rates were higher at 6 weeks when compared with usual care with wet dressing. They also noted lower amputation and re-hospitalization rates. 61 Hu et al . compared split grafting with ADM with split grafting alone and found that, in the ADM group, recurrence rates were lower, and wound and scar appearance was better, but wound closure rates were similar in both groups. 62 DermACELL, an ADM that has undergone a unique decellularization process resulting in thorough DNA removal, was evaluated in two studies compared with conventional care and Graftjacket ADM. Both studies showed a higher proportion of ulcers healed with DermACell compared with conventional treatment. 63 , 64 Graftjacket ADM performed variably in these two studies.

Acellular dermal matrix may have benefits in accelerating wound healing when compared with conventional treatment. There is insufficient evidence to recommend a particular type of ADM product.

Human growth factors

Several human growth factors have been studied for adjunct use in the management of DFUs, including fibroblast growth factor, epidermal growth factor, vascular endothelial growth factor, granulocyte colony-stimulating factor, and platelet-derived growth factors.

Fibroblast growth factor

There have been limited studies on adjuvant fibroblast growth factors in DFUs. The first RCTs were performed in the mid-1990s and showed no difference in wound closure rates or percent healed at 12 weeks. 65 Another RCT was conducted in 2009 and found a greater proportion of patients with reduction in wound size by at least 75% at 8 weeks. 66 This was on the per protocol analysis. There have been no other published RCTs, but a completed study in 2014 (documented on ClinicalTrials.gov) showed no differences in wound closure at 12 weeks between those randomized to fibroblast growth factor versus placebo. 67

Epidermal growth factors

Data evaluating the efficacy of epidermal growth factor (EGF) are also limited. There have been a few RCTs with mixed results. Tsang et al . showed no significant improvement in healing in a double-blinded RCT of topical EGF cream at 12 weeks, but two additional RCTs showed no overall benefit. 12 More recent studies have found some benefit in healing, although they are very small studies with high risk of bias. 68 – 70

Vascular endothelial growth factor

There has only been one RCT evaluating the efficacy of vascular endothelial growth factor in DFUs. Kusmanto et al. completed a double-blinded RCT assessing intramuscular vascular endothelial growth factor (VEGF) versus placebo. In this study, a statistically significant number of patients achieved > 60% reduction in ulcer size when compared with controls. 12 There was also a study comparing VEGF to epidermal growth factor, which found that there was a statistically higher proportion of complete wound healing in the EGF group. 71

Granulocyte colony-stimulating factor

The majority of RCTs studying granulocyte colony-stimulating factor (G-CSF) in DFUs were designed to evaluate its impact on infection. Nearly all of these studies show no apparent benefit in wound healing or reduction in amputation rates. 12

Platelet-derived products

Interest in autologous platelet-rich plasma (PRP) to propagate wound healing has increased over the years. PRP is typically derived from a sample of blood from the patient that is centrifuged, and subsequently the platelets are separated into a highly concentrated suspension rich in platelet growth factors. Growth factors can be liberated from platelets by several techniques, including adding thrombin or calcium, freezing, or sonication. A 2016 Cochrane review examined 11 RCTs evaluating the use of PRP in patients with chronic wounds, DFUs, and venous leg ulcers. Although there was an unclear benefit in those with chronic wounds and venous ulcers, there was an apparent benefit in those with DFUs, although the quality of the evidence was poor. Since this review, there have been other RCTs that have found favorable results when PRP was compared with standard of care in patients with clean-base DFUs and chronic refractory DFUs. 72 , 73 There was also a retrospective study that found a positive response even in those with severe peripheral arterial disease. 74 Other platelet products that are currently being studied include combined leukocyte- and platelet-rich fibrin membranes and patches, which are theorized to prolong the release of growth factors and matrix proteins. 75 , 76

There are limited data to conclude the efficacy of growth factors on wound healing in DFUs, but studies evaluating platelet-derived growth factors may show some benefits.

Skin grafts and bioengineered skin

Skin grafting and tissue replacement can be used to reconstruct skin defects in DFUs. There are various types of skin grafts, including autographs, allografts, xenografts, and bioengineered skin. Although the mechanism is unclear, it is thought to promote wound healing by adding extracellular matrices that induce helpful growth factors and cytokines. 77 A 2016 Cochrane review and meta-analysis evaluated RCTs of a variety of skin grafts and tissue replacement products and found that there was increased healing rates of DFUs with these products compared with standard care. 77 This paper notes that the quality of evidence was low and the impact of the intervention varied greatly depending on the product type. It was also noted that nearly all studies had connections to commercial organizations. 77

There is a growing interest in allografts originating from dehydrated human amniotic and chorionic membranes (dHACM). There have been several recent studies comparing dHACM to standard of care that have found improved rates of wound healing and wound closure. 78 , 79 Studies comparing dHACM to bioengineered skin substitutes have had various outcomes. 80 , 81 Another area of interest is the use of cryopreserved umbilical cord as adjunctive therapy. Small retrospective studies show that it may be helpful in wound healing, but RCTs are warranted to evaluate its true efficacy. 82 , 83

Energy-based therapies

Energy-based therapies employ technology to externally stimulate growth in wounds. Modalities currently being studied include electrical stimulation, shockwave therapy, electromagnetic therapy, laser therapy, and phototherapy.

Electrical stimulation

Electrical stimulation has been shown in several basic science studies to aid in wound healing, as it promotes angiogenesis, synthesis of collagen, and migration of keratinocytes, through the release of several factors, including vascular growth factors, hypoxia-inducible factor 1α (HIF-1α), and VEGF in ischemic DFUs. 84 , 85 Unfortunately, the majority of RCTs (limited in number) show no benefit in improving wound healing outcomes. 12

Shockwave therapy

Extracorporeal shockwave therapy (ESWT) is thought to stimulate wound healing by promoting angiogenesis through VEGF and endothelial nitric oxide synthases. It also has been suggested that ESWT propagates immune response and fibroblast proliferation. 86 The few RCTs comparing ESWT with standard care are small and show variable efficacy. 12 , 87 Moretti et al. showed no benefit in healing at 20 weeks. Both Omar et al . and Jeppsen et al. demonstrated a beneficial difference in reduction in wound size and median time for healing when evaluated at 20 weeks and 7 weeks, respectively. 87 , 86 One study show apparent superiority of ESWT when compared with HBOT. 12

Electromagnetic therapy

Therapeutic electromagnetic resonance is thought to locally stimulate and activate physiological healing through factors that reduce oxidative stress and inflammation, as well as increasing proliferation of cells responsible in wound repair. 88 RCTs in patients with DFUs have not demonstrated benefits. 12 , 89 , 88

Laser therapy

Laser therapy promotes reduction of inflammation, angiogenesis, and production of extracellular matrix components. 90 Specifically, CO 2 laser therapy is found to significantly reduce wound bacterial load. 91 The RCTs exploring the efficacy of laser therapy on wound healing are few, have small sample sizes, and show variable results. 92 – 94

Phototherapy

Phototherapy causes photochemical reactions that lead to a rapid increase in cellular metabolic activity and cell growth, vasodilation, and angiogenesis, which can result in faster wound healing. 95 A 2017 Cochrane review and meta-analysis concluded that phototherapy may result in greater reduction in ulcer size when compared with placebo after 2–4 weeks, but the quality of the evidence was low. 95

Although many of these energy-based modalities have been found to be beneficial in some studies, there is currently inadequate quality evidence to recommend any these therapies.

Systemic therapies

Several systemic agents have been studied in wound healing, including low-molecular-weight heparin, iloprost infusion, vildagliptin, oral pentoxyyfilline, and many herbs, but there is insufficient evidence to show efficacy in any of these agents. Systemic insulin use has been associated with a higher chance of complete wound healing when adjusted for multiple co-founders. 96 , 97

There has been growing interest in various vitamins and supplements and their impact on wound healing. In 2017, there several RCTs have evaluated the use of magnesium, omega-3 fatty acids, zinc sulfate, and vitamin D. 98 – 101 All of the aforementioned studies showed significant benefits in reduction in wound size when compared with placebo. More studies will need to be performed to validate these findings.

Conclusions

DFUs are a concern for the growing population of diabetic patients around the world. Although the principles that guide the standard of care are sound, there is still a significant gap between our current and desired wound healing outcomes. The breadth of DFU treatment currently being studied is promising, but there is a need for well-designed blinded randomized controlled trials to determine the true efficacy of these interventions and to develop evidence-based practice guidelines. Until then, good clinical judgment--considering the patient’s clinical context and wound characteristics--is essential to assess the risk and benefits of these adjuvant interventions for current clinical use. One of the challenges of achieving the aforementioned research goals is the staggering disparity in funding for DFU research. Armstrong et al described that between 2002–2011, the National Institute of Health granted over 7 million dollars for diabetes research but only 0.17% of that funding was allocated to DFU studies. 102 This funding gap is alarming considering that DFU care accounts for a third of overall diabetic health care expenditures. Given the large public health burden of DFU, assuring adequate allocation of research dollars must be addressed soon. 102

Competing interests

The authors declare no competing interests.