Management of infected diabetic wound: a scoping review of guidelines

Background: Various international guidelines and recommendations are available for management of diabetic foot infections. We present a review of the guidelines and recommendations for management of these infections. Methods: A systematic literature search was conducted through MEDLINE, CENTRAL, EMBASE, LILACS, DARE, and national health bodies. Based on the review of fifteen documents, we present details on the importance of suspecting and diagnosing skin, superficial infections, and bone infections in diabetics. Results: The guidelines recommend classifying the infections based on severity to guide the treatment. While antibiotics have shown the best results, other treatments like hyperbaric oxygen therapy and negative wound pressure have been debated. It is suggested that a team of specialists should be in-charge of managing the infected wounds. Infectious Diseases Society of America (IDSA) 2012 guidelines are widely followed world-over. All guidelines and reviews have consistent suggestions on the assessment of the severity of infection, diagnosis, start, selection, and duration of antibiotic therapy. Conclusions: It is reasonable to conclude that the IDSA 2012 guidelines are commonly followed across the world. There is a consensus among the Australian guidelines, Canadian guidelines, IDSA 2012, National Institute for Health and Care Excellence (NICE) 2015, and International Working Group on the Diabetic Foot (IWGDF) 2016 guidelines on the management of infected wounds for patients with diabetes mellitus.


Introduction
Diabetes mellitus (DM) is one of the major public health issues of this century 1 . With an increasing life expectancy, the incidence of complications in diabetics is on the rise 2,3 . Diabetic foot ulcers and infections affect approximately 15% of diabetic patients 4,5 . An infected foot is a serious complication of diabetes 6 and it is a factor in half of all cases of lower extremity amputations 7 .
Various guidelines and recommendations by international health bodies and scientific associations, in addition to several systematic reviews and Cochrane reviews, are currently available to guide the selection of the correct treatment modality for infected diabetic foot ulcers/wounds 1,[8][9][10] .
There is a general lack of understanding on the infected diabetic wound management guidelines. Further, a comparison of these guidelines is necessary to understand the strengths and weaknesses of these guidelines. Hence, we believe that there was a need to conduct a scoping review to analyze the guidelines that are in practice. The purpose of this scoping review was to study the management practices currently being followed for infected diabetic wounds and present a comparative evaluation of the published guidelines and reviews.

Criteria for considering studies for this review
Types of studies • Guidelines, recommendations or reviews from associations related to diabetes (American Diabetes Association, WHO or any regulatory body) published in English since 2000 and before December 2017 were eligible for inclusion. All the associations that have published guidelines were eligible for inclusion.

Types of outcome measures
• Management of infected wounds among patients with DM • Antibiotic therapy

Search methods for identification of studies
The following databases were searched on 6 th August 2016 using the search terms detailed in Table 1

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  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 reviews 23 .   • Management requires debridement, wound dressing, pressure off-loading, good glycemic control and potentially antibiotic therapy and vascular intervention.
• As a minimum, all DRFUs should be managed by a doctor and a podiatrist and/or wound care nurse.
• Health professionals unable to provide appropriate care for people with DRFUs should promptly refer individuals to professionals with the requisite knowledge and skills.
• Indicators for immediate referral to an emergency department or multidisciplinary foot care team (MFCT) include gangrene, limb-threatening ischemia, deep ulcers (bone, joint or tendon in the wound base), ascending cellulitis, systemic symptoms of infection and abscesses.
• Referral to an MFCT should occur if there is lack of wound progress after 4 weeks of appropriate treatment. • Their identifi cation should lead to a prompt and systematic evaluation and treatment, ideally performed by a multidisciplinary team.

Guideline -DOI/URL
• Decisions concerning empirical initial antibiotic agent(s), desirable route of administration, duration and need of hospitalization should be based on the more likely involved pathogen(s), the severity of the infection, the ulcer chronicity and the presence of significant ischemia.
• Wound cultures, ideally from ulcer tissue, are strongly advisable and can help guiding and narrowing the antibiotic spectrum.
• Appropriate wound care and off-loading should not be neglected.
• When revascularization is required, the correct timing can be crucial for limb salvage.
• Since the recurrence of ulcer and infection is high, the implementation of appropriate preventive measures can be critical.
• Ultimately, the definitive goal in the treatment of diabetic foot infections is to prevent the amputation catastrophe. • There is insufficient evidence to recommend any specific dressing type for typical diabetic foot ulcers.
• Debridement of nonviable tissue and general principles of wound care include the provision of a physiologically moist wound environment and off-loading the ulcer.
• There is insufficient evidence to recommend the routine use of adjunctive wound-healing therapies (e.g. topical growth factors, granulocyte colony-stimulating factors or dermal substitutes) for typical diabetic foot ulcers. Provided that all other modifiable factors (e.g. pressure off-loading, infection, foot deformity) have been addressed, adjunctive wound-healing therapies may be considered for nonhealing, nonischemic wounds. 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 skin 8 . 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 interpreted 9 . 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 present 10 . Probe-to-bone testing, an inexpensive diagnostic tool, may be helpful in confirming the diagnosis 7 . Bone samples for culture and histology should be taken after debridement or by bone biopsy 10 . In addition, white blood cell scanning combined with a radionuclide bone scan can be performed to assist diagnosis 9 . 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 organisms 9 . Superficial sampling can miss the true causative organism, thus deep sampling after cleansing or debridement can be helpful 9 . 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 treatment 20 . NICE guideline (2015)  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 regimen 10 .

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 infection 9 .
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 patient 9 . 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 wound 10 . 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 wounds 10 . 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-burden 9 . In these cases, topical antimicrobials may prevent the spread of infection to deeper tissues 9 . Regular monitoring is required to check for improvement and to inform decisions on whether to continue or withdraw treatment 9 .
Debridement. Wounds International states that mild diabetic infections may require debridement and wounds should be cleaned with saline during the application of every dressing 9 . The formation of biofilms can be controlled by repeated debridement and cleansing 9 . 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 wounds 13 . Braun et al. stated that there is a moderate level of evidence in favor of using NPWT to heal diabetic foot ulcers 17 . 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 unknown 21 .
Topical antiseptic agents: There is a weak evidence for the use of topical antiseptics such as super oxidized water or iodophor to decrease cellulitis 14 . 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 agents 21 . The latest IWGDF 2016 recommendations demonstrate little evidence in favor of using honey as an antibiotic agent 21 . 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 therapy 10 .

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 care 19 . Dressings should be chosen according to the nature, depth and size of the ulcer 10 . Regular monitoring, involving radical and repeated debridement, frequent inspection and bacterial control, are important measures in this regard 9 .
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) healing 24 . 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 care 10 . Diabetic foot care teams can include (or should have ready access to) specialists in various fields 10 . It is strongly recommended to consult a vascular surgeon for revascularization for patients with evidence of ischemia of the infected limb 10 . Similarly, Wounds International suggested surgical consultation for rapidly deteriorating wounds that do not respond to antibiotic therapy 9 . 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 advised 8 .

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 practices 25 . 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 lifethreatening 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 .

Discussion
This scoping review aimed to compare the management practices currently being followed in different parts of the world to treat diabetic infected wounds. As described in the results section, research is ongoing to decide appropriate management of diabetic infected wounds. The literature search identified the guidelines/recommendations and systematic reviews published on the management of diabetic infected wounds from 2000 to August 2016. The aim to consider the global practices was achieved, as recommendations from North America 10,16,22 , Europe 13,15,20 , Australia 8 , and International scientific societies 9,18 were included.
Our review highlights that the guidelines across the world provided similar recommendations for the management of infected diabetic wounds. The first stage of suspecting and diagnosing infections was emphasized by all the guidelines. The IDSA 2004 guidelines recommended diagnosis based on the presence of clinical symptoms and signs of local inflammation; however, the IDSA 2012 guidelines recommended diagnosis based on the presence of two clinical symptoms and signs of local inflammation 10,12 . There is a consensus among the guidelines on the requirement to suspect and quickly diagnose osteomyelitis 10,18,21 . MRI was established as the best diagnostic method, while plain X-ray should not be considered for diagnosis 9,10,20 .
All the included reviews and guidelines have concluded that most acute infections are caused by gram-positive cocci, S. aureus and Streptococci, and that gram-negative cocci or anaerobes may be involved, as infections are generally polymicrobial 8-10,15 . The IDSA 2012 clinical practice guideline has suggested the use of any of three antimicrobials (ertapenem, linezolid, and piperacillin-tazobactum) for diabetic infected wounds; however, there is a consensus on the non-superiority of any one antibiotic agent over the other two 9,10,13 . Similarly, there is a consensus on the importance of local protocols, the prevalence of MRSA, and the severity of the wound as important deciding factors while selecting the appropriate antibiotic therapy 9,10 . NICE 2015 further highlighted the importance of cost when choosing the antibiotic agent 20 . The severity classification of IDSA 2012 has been accepted universally 10 . There are similar recommendations for the choice of empiric therapy and the duration of the antibiotic therapy across all included reviews.
The guidelines did not suggest anti-microbial use for clinically uninfected wounds 8-10,20 . Other similar recommendations include the importance of regular monitoring and the crucial role of multidisciplinary teams consisting of microbiologists, infectious disease specialists, surgeons and medical specialists 8,10,15 .
The guidelines and reviews provided strong recommendations on the previously mentioned modalities; however, there is weak evidence to support some routinely followed treatment practices. With respect to hyperbaric oxygen therapy, the latest guidelines provide weak evidence to support the use of alternative modes such as hyperbaric oxygen or NPWT 8-10,20,22 . However, this modality requires further exploration and research. A retrospective study of patients with DM with hand infections demonstrated that the addition of HBOT to standard therapies is safe due to its anti-infective effects 28 .
Regarding wound care, the analysis demonstrates that it is equally as vital as the use of antibiotic agents. However, again, there is a lack of evidence in favor of the many available wound care modalities. At the same time as IDSA and NICE guidelines were released, various systematic reviews have sought to evaluate the options of wound care. Alginate dressings, foam dressings and hydrocolloid dressings were not found to promote the healing of diabetic foot ulcers any better than other alternative dressings. The reviews concluded that the decision-makers may consider other aspects such as cost and wound management properties when selecting the dressing type 2,29 . Another systematic review by Cochrane showed that NPWT may be an effective treatment to heal debrided foot ulcers and postoperative amputation wounds; however, the studies included could be at risk of bias 30 .
While conducting this scoping review, all English guidelines published by the previously mentioned associations from around the world since 2000 were included. Strengths of this scoping review are the inclusion of recommendations from different corners of the world and an extensive search of various databases. However, the inclusion of only English language published reviews limited the search. It was not possible to calculate the quality of all the articles included as some were guidelines that could not be assessed by the scales available.

Conclusion
It is reasonable to conclude that the IDSA 2012 guidelines are commonly followed across the world. There is a consensus among the Australian guidelines, Canadian guidelines, IDSA 2012, NICE 2015 and IWGDF 2016 guidelines on the management of infected wounds for patients with DM. Due to the lack of evidence, the therapeutic status of treatment options like hydrocolloid gels, NPWT, hyperbaric oxygen and aligate dressings could not be ascertained. There is a need to generate stronger evidence regarding the commonly used methods in the treatment of diabetic wound infections.

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

Grant information
The author(s) declared that no grants were involved in supporting this work. , which permits unrestricted use, distribution, and reproduction in any medium, provided the original Attribution License work is properly cited.

Davoud Dastan
School of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, GA, USA This review by Huidi Tchero reports 'Management of infected diabetic wound: a scoping review of et al. guidelines'. The authors claimed that the results are encouraging to develop a plan for diabetic wound and eco-friendly approach. This article signifies the importance of suspecting and diagnosing skin, superficial infections, and bone infections in diabetics. The suggested guidelines seem consistent with the suggestions on the assessment of the severity of infection, diagnosis, start, selection, and duration of antibiotic therapy. The authors further claimed that the IDSA 2012 guidelines are commonly followed across the world and there is a consensus among the Australian guidelines, Canadian guidelines, IDSA 2012, NICE 2015 and IWGDF 2016 guidelines on the management of infected wounds for patients with DM. Due to the lack of evidence, the therapeutic status of treatment options like hydrocolloid gels, NPWT, hyperbaric oxygen and aligate dressings could not be ascertained. There is a need to generate stronger evidence regarding the commonly used methods in the treatment of diabetic wound infections. The authors may refer to this latest literature to enhance their review; Aljerf (2019 ). et al.

Reviewer Expertise:
My area of research is infectious diseases, neurology, and cancer biology. As a bioinformatician, I have expertise in data collection and analysis.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
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