Management of infected diabetic wound: a scoping review of guidelines

Criteria for considering studies for this review

Types of studies

Types of participants

Types of outcome measures

Search methods for identification of studies

The following databases were searched on 6^th August 2016 using the search terms detailed in Table 1. The databases searched were Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 2000 to July 2016), EMBASE, LILACS, The Database of Abstracts of Reviews of Effects (DARE), American Diabetes Association (ADA), European Diabetes Association, WHO, National Institute for Clinical Excellence (NICE) databases and Google Scholar. Clinical trial registries were not searched as the search was for published articles only.

Data collection and analysis

All the abstracts and titles of the studies identified by the search were scanned by two authors independently (HT and FB) for relevance according to the inclusion criteria. In the first round, publications were screened using the information in the title and abstract. In the second round, full-texts of the articles identified in the first round were studied to confirm the eligibility. Any differences in opinion about the selection of articles were resolved by a third party (LT).

Data extraction

Two authors (HT and FB) independently retrieved relevant patients’ and intervention details using standardized data extraction forms using excel sheets. Data were collected under the following headings: Title, Year of publication, Publisher and the following variables of interest: Pathogenesis of diabetic infected wound, Diagnostic guidelines, Diagnosis of osteomyelitis, Antimicrobial treatment, Debridement, Role of other treatment modalities, Requirement for hospitalization, Role of surgery, Wound care, General considerations for management. Disagreements between reviewers, if any, were resolved through discussion to obtain a consensus.

Reporting guidelines

This report was prepared as per the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) checklist.

Search results

The initial search yielded 1025 abstracts, which were screened for potential inclusion in the review. After screening the abstracts, 982 were excluded due to duplication or irrelevance. A total of 15 reports/reviews were included for the scoping review (see Figure 1 for PRISMA flow diagram)¹¹. The initial plan was to compare the management practices for infected diabetic wounds in different countries around the world. However, most of the research and literature were on infected diabetic foot ulcers/wounds. Since diabetic foot ulcers are the most common presentation of diabetic infected wounds, the search results were confined to infected diabetic ulcers. During the search for management practices being followed in different parts of the world, all of the randomized controlled trials (RCTs) that compared different treatment approaches used in the management of infected diabetic wounds were excluded. Moreover, all case reports, case series, observational studies and cohort studies were excluded. Cochrane Reviews were also excluded because each review has taken into consideration one treatment modality. However, systematic reviews and descriptive reviews on different treatment options were considered.

Figure 1. PRISMA flow diagram.

PRISMA flow diagram summarizing identification, screening and inclusion of studies.

In the next stage, guidelines and recommendations issued by various countries around the world and management review articles were evaluated. Our review included the 2004¹⁰ and 2012 guidelines of the Infectious Diseases Society of America (IDSA)¹², "Management of Diabetes" guidelines by the Scottish Intercollegiate¹³, the International Working Group on the Diabetic Foot (IWGDF) review of systematic reviews¹⁴, a clinical update by Australian Diabetes Foot Network⁸, guidelines for the management of infected ulcers among patients with DM in Portugal¹⁵, the Canadian Diabetes Association Clinical Practice Guidelines¹⁶, and independent guidelines published by Wounds International in 2013^7,9,17–22. A summary of these guidelines is presented in Table 2.

Quality of the reviews included

As our scoping review included guidelines, descriptive reviews and systematic reviews, we didn’t use the Assessment of Multiple Systematic Reviews (AMSTAR) tool, which is generally used for quality assessment of the included systematic reviews²³. The systematic reviews by Braun et al. (2012) and Peters et al. (2016) had included RCTs after searching PubMed and EMBASE^14,17,21. The review by Wukich et al. is a descriptive review without any systematic searches of databases and, of note, the authors had received grants from pharmaceutical companies²². Studies by Joseph and Lipsky, Mansilha and Brandao, and Gemechu et al. were also narrative reviews without any systematic search of the databases^7,15,19.

Outcome measurements

Pathogenesis. The guidelines highlighted that the most common causative organisms of diabetic infections are aerobic gram-positive cocci, especially Staphylococcus aureus, including methicillin-resistant strains (MRSA), and Streptococcus spp. (most often Group B). Chronic infections or those occurring after antibiotic treatment are generally polymicrobial, with aerobic gram-negative bacilli and anaerobes. Obligate anaerobes are isolated more commonly from cases of foot ischemia or necrosis. In southern European countries, gram-negative bacilli are more prevalent^{9,15,16,19,22}.

Diagnosis of the diabetic infected wound. All the guidelines, including IDSA 2004, IDSA 2012, IWGDF 2012, and IWGDF 2016 and those by Wounds International Society, recommend that diagnosis of infections should be made on the basis of clinical signs and symptoms^{9,10,12,14,21}. According to the IDSA 2004 guidelines, the diagnosis of infected wounds should be made clinically on the basis of local (and occasionally systemic) signs and symptoms of inflammation^12,19. Joseph et al. mentioned that patients should have clinical signs and symptoms of inflammation such as erythema, edema, warmth, tenderness, indurations and/or pain¹⁹. The IDSA 2012 guidelines recommend that diagnosis of infections should be based on the presence of at least two classic symptoms or signs of inflammation (erythema, warmth, tenderness, pain or indurations) or purulent secretions. This recommendation was also emphasized by other reviewers^7,10,22.

Suspicion/diagnosis of osteomyelitis. The IDSA 2012 guidelines and NICE recommendations (2015) strongly recommend that clinicians should suspect osteomyelitis as a complication of diabetic foot infections (DFIs)^10,20. In earlier guidelines, microbiological and laboratory investigations were recommended for the diagnosis of osteomyelitis¹². The IDSA 2012, Wounds International guidelines and Australian guidelines suggest that culture and histology findings help with diagnosing osteomyelitis. Due to the unavailability of these tests at many places, clinicians should make a diagnosis in conjunction with clinical, radiographic and laboratory findings^8–10. An increase in skin pigmentation may be considered a sign of inflammation and/or infection among patients with pigmented skin⁸. All guidelines recommend magnetic resonance imaging (MRI) as the best imaging technique to define both soft tissue and bone infections^8–10,20. Plain radiography is considered to be less sensitive for DFIs; however, it may be helpful in assessing bone destruction and the presence of gases or foreign bodies^9,10,22. As the radiological signs of osteomyelitis are delayed, a normal report resulting from a plain X-ray should be cautiously interpreted⁹. The IDSA 2012 guidelines strongly recommend that all patients with a new DFI should have a plain radiograph of the affected foot to check whether bones are affected, and whether gases or foreign bodies are present¹⁰. Probe-to-bone testing, an inexpensive diagnostic tool, may be helpful in confirming the diagnosis⁷. Bone samples for culture and histology should be taken after debridement or by bone biopsy¹⁰. In addition, white blood cell scanning combined with a radionuclide bone scan can be performed to assist diagnosis⁹. After the diagnosis of an infected wound and presence or absence of osteomyelitis, it is equally important to classify the severity of the infection, as the treatment choice depends on the severity.

Antimicrobial treatment. Appropriate culture samples should be taken, preferably from soft tissue or purulent secretions, for appropriate selection of antibiotic to be used^8,9,20. Tissue specimens or deep swabs should be cultured for both aerobic and anaerobic organisms⁹. Superficial sampling can miss the true causative organism, thus deep sampling after cleansing or debridement can be helpful⁹. All guidelines recommend that clinically uninfected ulcers should not be treated with antibiotic therapy. It is strongly recommended that no topical or systemic antibiotic therapy should be given to prevent osteomyelitis, improve wound healing or prevent secondary infection^8–10,18,20. Moreover, NICE guideline (2015) also suggested that antibiotic treatment should be started as soon as possible. Culture samples should be taken before the start of the treatment²⁰. NICE guideline (2015) provides wide criteria to choose the appropriate antibiotic and the regimen, such as the severity of the infection, care setting, person’s preference, clinical situation, medical history, microbiological examination, clinical response and cost²⁰. However, tigecycline should not be offered unless other antibiotics are not suitable²⁰. The IDSA 2012, NICE 2015, Wounds International and Scottish guidelines specified that the duration and route of the antibiotic administration should be based on the severity of the disease, presence or absence of bone infection and clinical response to treatment^9,10,13,20. In the case of neuroischemic foot ulcer, antibiotics should be chosen carefully as it is more serious than an neuropathic foot ulcer⁹.

The IDSA 2012 guidelines stated that the U.S. FDA has approved three antibiotics (ertapenem, linezolid and piperacillin-tazobactum) for the treatment of complicated skin and skin structure infections including DFIs, but not for accompanying osteomyelitis¹⁰. However, there is no evidence for the superiority of any particular antibiotic agent, treatment duration or route of administration^10,13,14. Wukich et al. mentioned that no one agent or regimen has shown superiority over others; however, those that have demonstrated effectiveness include β lactams (penicillins, cephalosporins), glycopeptides, carbapenems, linezolid, clindamycin and fluoroquinolones²². There is weak evidence to suggest that antibiotic therapy against bone culture leads to higher resolution of bone infection compared to that of empiric therapy¹⁰. Also, IDSA 2012 guidelines suggest that antibiotic therapy should be continued only until the resolution of infection¹⁰.

Empiric therapy: IDSA 2004 and 2012 strongly recommend that an empiric antibiotic regimen should be chosen on the basis of the severity of the infection and the likely etiologic agent(s)^10,12,19. The guidelines recommend a broad-spectrum antibiotic for severe cases, whereas a narrow spectrum antibiotic should be used for mild cases. The antibiotic agent can be modified following culture reports and antibiotic susceptibility data^{8–10,16,19,22}. The IDSA 2004 guidelines highlighted the importance of escalation and de-escalation regimes depending upon the culture reports¹². The local prevalence of MRSA strains should determine the choice of empiric therapy¹⁹. Empiric antibiotic therapy against MRSA should be given to patients with a prior history of MRSA infections, or in instances with high local MRSA prevalence colonization, or in cases where the infection is severe⁹. IDSA 2012 highly recommended that empiric therapy directed at Pseudomonas aeruginosa is usually not required except among those patients with risk factors for Pseudomonas aeruginosa infection¹⁰. Recommendations from Wounds International suggest that empiric oral antibiotic therapy against Staphylococcus aureus and β hemolytic Streptococcus are given in the case of mild infections⁹.

Definitive therapy: Definitive therapy depends on the culture and sensitivity results of the wound specimen, and on the patient’s clinical response to the empiric regimen¹⁰.

Mild diabetic foot infections: The guidelines recommend oral antibiotics with a spectrum of activity against gram-positive organisms^8–10,20. The treatment should last no longer than 14 days for mild soft tissue infections^9,14,15. Wounds International suggests that empiric antibiotic treatment should be changed according to the culture reports. Topical antibiotics can be given along with oral agents. However, topical antibiotics should not be used alone for patients with clinical signs of infection⁹.

Moderate diabetic foot infections: Antibiotic agents against gram positive and gram negative organisms, including anaerobic bacteria, should be administered^10,20. The route of administration should depend on the clinical condition and the availability of the antibiotic agents^10,20. Recommendations from Wounds International suggest that treatment lasting one to three weeks should be sufficient; however, no specific time is allocated as each decision must be based on the severity and clinical response of the patient⁹. Other guidelines have also suggested similar periods of 2–3 weeks or 2–4 weeks^10,15,20. The empiric antibiotic agent should be changed according to the culture reports or if the signs of inflammation do not improve^{8,9,13,15,16,19}.

Severe diabetic foot infections: Intravenous administration of antibiotic agents against gram-positive and gram-negative organisms, including anaerobic bacteria, should be elicited. The treatment can be switched to the oral route depending upon the culture results and the condition of the patient^9,10,20.

Osteomyelitis: Surgical resection or debridement may be required in these cases. Generally, antibiotic therapy must be given parenterally and the duration of antibiotic treatment can last up to six weeks. There is no evidence of superiority of any group of antibiotics or their route of administration over others^8–10,16,20.

Topical antibiotic therapy: Although there is no robust evidence to support the use of topical antimicrobials, especially topical antiseptics (such as cadexomeriodine) and silver-based dressings, they are currently being used to decrease the bio-burden of the wound¹⁰. However, they may increase the risk of bacterial resistance in addition to causing local adverse effects. The IDSA 2012 guidelines recommended neither the use of topical antimicrobials for most clinically uninfected wounds nor silver-based dressings for clinically infected wounds¹⁰. Wounds International suggests that topical antimicrobials may be used alone (but not in patients with clinical signs of infection) or as an adjuvant therapy when there are concerns regarding reduced antibiotic tissue penetration, such as patients with poor vascular supply, and in non-healing wounds with no signs and symptoms of infection, but with increased bacterial bio-burden⁹. In these cases, topical antimicrobials may prevent the spread of infection to deeper tissues⁹. Regular monitoring is required to check for improvement and to inform decisions on whether to continue or withdraw treatment⁹.

Debridement. Wounds International states that mild diabetic infections may require debridement and wounds should be cleaned with saline during the application of every dressing⁹. The formation of biofilms can be controlled by repeated debridement and cleansing⁹. IDSA 2012 strongly recommends debridement to remove debris, eschar, or surrounding callus. Sharp debridement methods are considered to be the best; however, other methods such as mechanical, autolytic or larval debridement may be useful in some settings^10,18.

Role of other treatment modalities. So far, there has been insufficient data to support the use of other treatment modalities.

Granulocyte colony stimulating factors: There is a weak recommendation for its use as an adjunctive treatment; adding G-CSF did not affect the resolution of infection or the duration of systemic antibiotic therapy^10,14,16,17.

Hyperbaric oxygen therapy (HBOT): Guidelines and reviews are not in favor of the use of HBOT for ulcer healing, mainly due to the controversial data relating to it^14,16,17.

Negative pressure wound therapy (NPWT): This should be considered in patients with active diabetic foot ulcers or postoperative wounds¹³. Braun et al. stated that there is a moderate level of evidence in favor of using NPWT to heal diabetic foot ulcers¹⁷. IWGDF 2016 also suggested that there is a weak evidence in favor of using NPWT in post-operative wounds, although its effectiveness and cost-effectiveness remains unknown²¹.

Topical antiseptic agents: There is a weak evidence for the use of topical antiseptics such as super oxidized water or iodophor to decrease cellulitis¹⁴. The IWGDF 2016 guidelines state that as a result of poor trial designs, it is difficult to draw conclusions in favor of or against the use of topical treatments with antiseptic agents²¹. The latest IWGDF 2016 recommendations demonstrate little evidence in favor of using honey as an antibiotic agent²¹. The IDSA 2012 guidelines demonstrate a moderate level of evidence and provide weak recommendations for other modalities such as bioengineered skin equivalents, growth factors, and negative pressure wound therapy¹⁰.

Requirement for hospitalization. The IDSA 2012 strongly recommended that patients with a severe infection, some patients with a moderate infection, those who are unable to comply with outpatient treatment, and those with poor response to the therapy should be hospitalized initially^10,22.

Role of surgery. Surgical consultation is required for deep abscesses, gas in deeper tissues, extensive bone or joint involvement, gangrene or necrotizing fasciitis^7,10,19. Evidence from former systematic reviews demonstrated that early surgery decreases the requirement for amputation significantly in two single center studies^14,21.

Wound care. Antibiotic therapy is necessary for virtually all infected wounds, but it is often insufficient without appropriate wound care¹⁹. Dressings should be chosen according to the nature, depth and size of the ulcer¹⁰. Regular monitoring, involving radical and repeated debridement, frequent inspection and bacterial control, are important measures in this regard⁹.

Off-loading: Off-loading is essential for diabetic foot management. According to a consensus guideline at Journal of the American Podiatric Medical Association, there is a strong evidence that adequate off-loading increases the likelihood of diabetic foot ulcer (DFU) healing²⁴. Nonremovable casts or fixed ankle walking braces are currently perceived as optimum off-loading modalities. However, a gap still exists between what the evidence suggests and what is being performed in clinical practice.

General considerations for management.

Role of teams and specialists: All guidelines stressed the importance of having teams of specialists treating diabetic infected wounds^8–10,22. Specialists should be sought if the attending physician is not familiar with the techniques of wound care¹⁰. Diabetic foot care teams can include (or should have ready access to) specialists in various fields¹⁰. It is strongly recommended to consult a vascular surgeon for revascularization for patients with evidence of ischemia of the infected limb¹⁰. Similarly, Wounds International suggested surgical consultation for rapidly deteriorating wounds that do not respond to antibiotic therapy⁹. Glycemic control is also important during the management of diabetic infected wounds as the correction of hyperglycemia may lead to a favorable response^8–10,22. Lipid and blood pressure levels should be within control, and smoking cessation should be advised⁸.

Patient education: Being the primary care-givers for their own feet, patients should be aware of the risk factors that could predispose to or worsen DFIs and the appropriate care and management behaviors. Former studies showed that patient education programs could be of substantial benefit in reducing the incidence of DFUs and improving self-care practices²⁵. Patients should be taught to examine their feet daily and report any abnormality to their physician, trim toenails with a safety clipper and wear offloading casts. Moreover, patients should be aware of the importance of exercise, smoking cessation for smokers and compliance to diabetes control instructions^26,27.

Amputation: Although not a preferred treatment approach, amputation may be required in certain situations, such as life-threatening foot infections that cannot be managed by other measures, non-healing ulcers with a disease burden higher than expected after amputation or where ischemic rest pain cannot be managed by analgesia or revascularization^9,10,22.

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.