CLINICAL

Overview

This topic focuses on topical antimicrobial agents, systemic antibiotics and surgical interventions for diabetic foot ulcers (DFUs) with soft tissue infection and/or osteomyelitis. It is important to note that management of healable infected DFUs also includes standard diabetic foot ulcer (DFU) care with appropriate debridement, offloading, wound care. For a comprehensive overview on DFU management see "Diabetic Foot Ulcer - Treatment". For assessment and diagnosis of infected DFU, see sections 'Diagnosis: Wound Cultures' and 'Diagnosis: Bone biopsy' in "Diabetic Foot Ulcer - Introduction and Assessment". 

DFU with Soft Tissue Infection

Besides standard DFU care as described in the topic "Diabetic Foot Ulcer - Treatment", management of healable infected DFUs includes debridement, topical antimicrobial agents, systemic antibiotics and surgical interventions, as summarized below:

• Debridement and removal of devitalized tissue reduce bacterial bioburden.[6] 
• Wound culture, obtained right after debridement and before initiation of empiric antibiotic therapy, guides definitive antibiotic therapy. When choosing antibiotics for empiric therapy, clinicians should consider several key factors such as: likely etiologic agents, past antibiotic usage and severity of infection, history of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection, risk factors for Pseudomonas aeruginosa infection, local prevalence of antibiotic-resistant microorganisms, patient history of allergic reactions to antibiotic agents, and presence of renal or hepatic impairment. 
• Surgical procedures are needed for deep abscess, compartment syndrome and virtually all necrotizing soft tissue infections. 

More details on topical antimicrobial agents, systemic antibiotics and surgical interventions can be found below:

Antimicrobial topical agents

• 2CWe suggest use of antimicrobial dressings (e.g., impregnated with medical-grade honey, silver, iodine, polyhexamethylene biguanide or PHMB) for clinically infected DFUs and for DFUs that fail to show progress in healing despite standard care (Grade 2C)
• • Rationale: Clinical guidelines recommend against use of antimicrobial dressings to promote healing in the majority of cases with uninfected DFU.[6][3][7] Instead, topical antimicrobial agents are recommended for DFUs with high level of bacteria (>10^5 CFU/g of tissue) post debridement [6] and for non-healing wounds.[8][9] Despite these recommendations, a recent meta-analysis [10] concluded that there is low-certainty evidence (evidence level C) that more DFUs - infected or not infected - may heal when treated with an antimicrobial dressing than with a non-antimicrobial dressing (relative risk 1.28; 95% confidence interval 1.12 to 1.45). It is not clear if a specific type of antimicrobial dressing is superior to another. However, clinicians should note that evidence is still of low certainty, and use of antimicrobials may result in local adverse effects (e.g., allergy, unknown effect on wound healing) and increased risk of bacterial resistance.[7][11] Furthermore, as it relates to coverage, topical antiseptics and topical antibiotics do not have a special coverage arrangement under the Medicare part B surgical dressing benefit.[12] Also, many antimicrobial impregnated dressings have similar HCPCS codes as their non-antimicrobial impregnated counterparts, even though they are more costly to manufacture. As a result, if an antimicrobial impregnated dressing is ordered for a Medicare part B covered patient, the DME supplier might substitute it for another lower cost product with similar HCPCS.[13] When paid out-of-pocket, antimicrobial impregnated dressings are typically more expensive than their non-antimicrobial impregnated counterparts.
  • For patients with signs of DFU infection, topic and systemic antibiotic therapy should be initiated promptly

Systemic antibiotics

• 1CIn the absence of infection, the IDSA/IWGDF recommend against treating wounds with antibiotics (Grade 1C)
• • Rationale: In the absence of infection, no evidence has been found in the literature supporting use of antibiotics to promote DFU healing or prevent infection. Furthermore, the IWGDF considers bacterial ‘bioburden’ a poorly defined concept that does not justify use of antibiotics in clinically uninfected wounds. [6][7][14][15][16]
• The IDSA/IWGDF state that patients with infected DFUs should have their ulcers cultured before initiation of antibiotics if possible (See 'Diagnosis: Wound Cultures' and 'Diagnosis: Bone biopsy' in "Diabetic Foot Ulcer - Introduction and Assessment").

• 1CFor infected DFUs, we recommend clinicians start empiric antibiotic regimen on the basis of the severity of the infection and the likely etiologic agents, and then implement definitive therapy based on culture/ sensitivity results and the patient’s clinical response to the empiric regimen (Grade 1C)
• • Rationale: Infected DFUs can turn into a limb and life-threatening condition, and must be treated promptly. The IDSA/IWGDF [14][7] and other clinical guidelines [6][3] recommend starting empiric antibiotic regimen after a specimen for culture is properly collected, and adjusting the regimen based on culture and sensitivity results and response to the initial course of antibiotics. Antibiotic therapy alone is insufficient, unless combined with standard wound care (debridement, offloading, moisture balance).[7]

Deciding on an empiric antibiotic regimen

• 1CWhen deciding on an empiric antibiotic regimen to treat DFU infections, consider several key factors such as: severity of infection, likely etiologic agents, past antibiotic usage, history of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection, risk factors for Pseudomonas aeruginosa infection, local prevalence of antibiotic-resistant microorganisms, patient history of allergic reactions to antibiotic agents, and presence of renal or hepatic impairment (Grade 1C). 
• • Rationale: As for choice of specific antibiotic agents for empiric therapy, low certainty evidence shows that no one antibiotic treatment is superior to others in promoting infection resolution or in having fewer side effects (evidence level C).[7][15][16][17] One RCT suggested that ertapenem with or without vancomycin is more effective in achieving clinical resolution of infection than tigecycline.[15][18] When selecting an antibiotic regimen, clinicians need to decide on antibiotic agents, route of administration and duration of treatment. An empiric regimen should virtually always include an antibiotic active against standard strains of staphylococci and streptococci. Other agents can be combined as needed, depending on the key factors above.[7][14] In the absence of a compelling reason to choose a specific antibiotic, the one with the lowest acquisition cost is preferred.[14] 
  • Algorithm 1 offers a framework to help clinicians consider these factors in this decision process. Table 1 lists the IDSA classification of infection severity. Table 2 details type of antibiotic, route and duration based on infection severity. 

Algorithm 1. Considerations when selecting an empiric antibiotic regimen for infected DFUs (click this link to enlarge)

• Consider any available microbiological data that can help uncover the probable etiologic agent:
• • Methicillin-resistant Staphylococcus aureus (MRSA): MRSA should be covered in any of the circumstances below:
  • • The patient has a history of previous MRSA infection or colonization within the past year.
    • The local prevalence of MRSA (ie, percentage of all S. aureus clinical isolates in that locale that are methicillin resistant) is high enough (perhaps 50% for a mild and 30% for a moderate soft tissue infection) that there is a reasonable probability of MRSA infection.
    • The infection is sufficiently severe that failing to empirically cover MRSA while awaiting definitive cultures would pose an unacceptable risk of treatment failure.
  • Pseudomonas: P. aeruginosa should be covered in any of the circumstances below
  • • P. aeruginosa is a frequent isolate in the country where the patient lives
    • The patient has been soaking his/her feet
    • Failure of non-pseudomonal therapy
    • Severe infection
• Consider past antibiotic usage: antibiotic usage in the month previous to the episode of infection affects etiologic agents
• • Acute infections in patients not treated with antibiotics in the past month are most likely caused by aerobic Gram-positive cocci, especially staphylococci.
  • Chronic infections or infections occurring after antibiotic treatment are often polymicrobial (aerobic Gram-negative bacilli, aerobic Gram-positive cocci, anaerobes)
• Consider infection severity:
• • See Table 1 for classification of severity of diabetic foot infections, by the Infectious Diseases Society of America (IDSA).[7]
  • See Table 2 for general guidance on type of antibiotic, route and duration of therapy according to site of infection and severity. Agents that are not listed in the table still can be used, depending on safety, clinical, availability and financial considerations.[7][16]
• Antibiotic administration route: Mild and most moderate DFU infection can be treated with oral antibiotics. Some patients with moderate DFU infection who cannot tolerate oral antibiotics or who are infected with pathogens insensitive to available oral agents require parenteral antibiotics. Severe infection should be treated initially with parenteral antibiotics, and then with oral once the patient no longer shows systemic inflammatory response syndrome as described by the IDSA classification.[14] When available and patient’s conditions allow, clinicians might consider parenteral therapy in an outpatient setting to reduce costs.[14]

Table 1. Classification of severity of diabetic foot infections, by the Infectious Diseases Society of America (IDSA) [7]

Table 2. General guidance on type of antibiotic, route and duration of therapy according to infection severity [14][7]

Switching to definitive antibiotic therapy

• Once culture and sensitivity results are available, the IDSA/IWGDF recommend a switch to narrower spectrum agents to reduce the likelihood of antibiotic resistance. However it is important to evaluate patient’s response to initial therapy and follow steps below [14][7]:
• • If the infection responded well to the initial empiric regimen, clinicians might opt to keep the same antibiotics, even if some or all bacteria are resistant to the prescribed antibiotics.
  • If infection is not responding or worsening and initial therapy does not cover isolated pathogens, therapy should be broadened to cover all isolated pathogens
  • If infection is not responding or worsening despite the fact that initial therapy covers isolated pathogen:
  • • Reassess need for surgical intervention (e.g, abscess drainage)
    • Reassess indication for coverage of MRSA, pseudomonas, or fastidious infecting organisms (e.g., Mycobacterium tuberculosis)
    • Check patient adherence to treatment and if there is any drug interaction causing rapid metabolism or low absorption of the antibiotic.
• Duration: Duration of antibiotic therapy for a DFI should be based on the severity of the infection, the presence or absence of bone infection, and clinical response to therapy (Table 2). Antibiotics can usually be discontinued once the clinical signs and symptoms of infection have resolved. There is no good evidence to support continuing antibiotic therapy until the wound is healed in order to either accelerate closure or prevent subsequent infection.[14][7]

Surgical procedures for soft tissue infections

• 1C In most cases of deep abscesses, compartment syndrome and virtually all necrotizing soft tissue infections, the IWGDF recommends urgent surgical intervention. (Grade 1C)
• Interventions can range from minor debridement or drainage to extensive resections, revascularization or major amputation, and should be performed by a surgeon with thorough knowledge of anatomy of the foot and its compartments [14] :
• • For DFU with dry eschars: avoid debridement and allow for autoamputation
  • Non-viable limb, affected by a potentially life-threatening infection (e.g. gas gangrene or necrotizing fasciitis), extensive soft tissue necrosis: may need amputation, but best to avoid major amputations
  • Severely ischemic limb: may need revascularization
  • For non-urgent infections with abscess: limit to incision and drainage. The aim of surgical treatment is to drain any deep pus and to minimize tissue necrosis by decompressing foot compartments and removing devitalized and infected tissue.

DFU with Osteomyelitis

Surgical and Medical Approaches

• 2B For patients with DFU and forefront osteomyelitis but no ischemia or necrotizing soft tissue infections, clinicians may opt to use either primarily surgical or primarily medical strategies to treat osteomyelitis (Grade 2B).
• 2CFor patients with DFUs and osteomyelitis in any foot location, with or without comorbidities, clinicians may also opt to use either primarily surgical or primarily medical strategies (Grade 2C). 
• Selection of approach should be based on several factors such as patient condition and preference, mobility, comorbidities and others (Table 3)
• • Rationale: While many cases of diabetic foot osteomyelitis require, or benefit from, surgical debridement or resection of bone, some can be treated successfully by medical therapy alone. Retrospective series have shown success rates with prolonged antibiotic therapy of 65-80%.[7][14][19][20] However, both interventions have pros and cons that need to be carefully weighed. Prolonged use of antibiotics leads to increased likelihood of drug-resistance, which is a risk factor for development of diabetic foot osteomyelitis.[21] Definitive surgical interventions such as as ray and transmetatarsal amputations, may risk architectural reorganization of the foot, resulting in altered biomechanics and additional cycles skin breakdown at a new high-pressure locations.[7] Moderate quality evidence (evidence level B) [22] and low quality evidence (evidence level C) [23] indicate that either intervention may be equally effective in patients with forefoot osteomyelitis, without ischemia or necrotizing soft tissue infections and in the general population of patients with diabetic foot osteomyelitis without exclusion criteria, respectively. Table 3 illustrates factors that can guide clinicians in choosing between primarily surgical or primarily medical strategies in the treatment of diabetic foot osteomyelitis. If based on these factors a primarily surgical strategy is elected and there is indication for conservative surgery (e.g. ostectomy, metatarsal head resection, distal phalangectomy, interphalangeal joint resection, metatarsal resection, metatarsal-phalangeal, joint resection, sesamoidectomy, partial calcanectomy, and exostectomy), this approach in combination with antibiotics may reduce the changes in the biomechanics of the foot and minimize the duration of antibiotic therapy.[21]

Table 3. Considerations when opting between medical or surgical approaches in the treatment of diabetic foot osteomyelitis[14]

• Choice of antibiotic agent: should be based on the results of a bone culture, especially because of the need for long-duration therapy [14], and evidence that culture-directed antibiotic treatment results in enhanced outcomes in osteomyelitis. [6] If empiric therapy is needed, S. aureus - the most common pathogen, should be covered. However, there might be a need to broaden coverage depending on patient’s history or previous culture results.[6] See Algorithm 1, Tables 1 and 2.
• Route of administration: If there is no residual infected tissue or the residual infected tissue is soft tissue only, antibiotics can be given orally or parenterally. Any selected oral antibiotics should have good bioavailability. If there is residual infected bone or if the patient has not undergone surgical resection or debridement, antibiotics should be initially parenteral, then switched to oral when the patient stops showing signs of systemic inflammatory response syndrome. See Table 2.
• Duration of antibiotic therapy: Table 2 also illustrates duration of therapy as suggested by the IDSA/IWGDF. Basically, in cases treated primarily with surgical resection of the infected tissue, antibiotic therapy should last no longer than 1 week. For cases treated primarily with antibiotics and no bone surgical resection, patients should receive antibiotics for 6 weeks. This IWGDF recommendation is based on a recent randomized controlled trial that compared 6 versus 12 weeks of antibiotic therapy for nonsurgically treated diabetic foot osteomyelitis (DFO) in 40 patients found no significant difference in the remission rate (60% versus 70%). There were significantly fewer adverse effects with the shorter treatment (evidence level B).[24][14]

Adjunctive therapy for DFU with soft tissue infection or osteomyelitis

• 2CThe IDS A/IWGDF suggest against using any adjunctive treatments for DFI (Grade 2C).
• • Rationale: More evidence is needed before these guidelines can recommend use of adjunctive therapies such as negative pressure wound therapy (NPWT), systemic hyperbaric oxygen therapy (HBOT), granulocyte colony-stimulating factors (G-CSF), larval (maggot) therapy, and platelet-derived growth factors to treat infection of DFU. While there is evidence that some of these adjunctive therapies are effective in promoting healing of DFUs, there is currently no strong evidence that can justify use of adjunctive therapies to resolve infection or osteomyelitis of DFU.[7][14][16] 

APPENDIX

Summary of Evidence