Diabetes

Diabetic Foot Infections: Diagnosis and Treatment

SUMMARY:

Over half a billion adults worldwide are living with diabetes, with many of them coping with its attendant complications such as diabetic retinopathy, diabetic nephropathy, and diabetic foot infections. Diabetic foot infections (DFI) are a major cause of morbidity and mortality, including recurrent hospital stays, prolonged antibiotic courses, limb amputation and death. Even with adequate treatment many DFI and diabetic foot ulcers recur or fail to heal. The International Working Group on the Diabetic Foot (IWGDF) and the Infectious Diseases Society of America (IDSA) have joined forces to update prior independently published guidelines into one comprehensive document to assist with the challenging multidisciplinary endeavor to diagnose and treat DFI.

Clinical Presentation
Diagnosis and Staging
Treatment

Clinical Presentation

Skin and soft tissue infections occur in patients with diabetes when there is a break in the skin’s protective layer
Most commonly these breaks occur in the feet, causing diabetic foot ulcers (DFU)
- DFU involve at least the epidermis and part of the dermis
- They generally occur in patients with pre-existing diabetic neuropathy +/- peripheral arterial disease (PAD)
DFU can transform into DFI when bacterial colonization of the wound becomes pathologic due to invasion of the host tissues and a subsequent inflammatory response
Roughly half of all DFU are uninfected at time of presentation
Wound cultures cannot diagnose DFI; all diabetic foot ulcers will be colonized and grow bacteria when cultured
Risk factors that predispose to DFI include
- Deep long-standing wounds | Recurrent wounds | Traumatic etiology | Neutrophil dysfunction | Renal failure | Peripheral arterial disease | Peripheral neuropathy | Chronic hyperglycemia
DFI is diagnosed clinically by careful examination of the feet in patients with diabetes, looking for DFU that demonstrate signs and symptoms of infection such as wounds that:
- Probe to bone (e.g., have evidence of osteomyelitis)
- Express purulence
- Have evidence of surrounding cellulitis
- Are associated with systemic inflammatory symptoms (e.g., Fever | Malaise | Hypotension | Tachycardia)

Diagnosis and Staging

In the IWGDF/IDSA guidelines, DFI is clinically defined as a DFU with:
- Inflammation of any part of the foot (i.e., not just of the ulcer) and the presence of SIRS (Systemic inflammatory response syndrome)
If DFI is diagnosed, the clinician should classify the infection’s severity using the IWGDF/IDSA classification scheme
The IWGDF/IDSA classification system ranks DFI from uninfected to severe infection
Grade I – Uninfected
- No systemic or local symptoms or signs of infection
Grade 2 – Mild infection
- At least 2 of the following are present: Local Swelling or induration | Erythema >0.5 but <2 cm around the wound | Local tenderness or pain | Local increased warmth | Purulent discharge
- Must have no other cause of inflammation of the foot (e.g., DVT | Trauma | Gout | Fracture | Venous stasis)
Grade 3 – Moderate Infection
- No systemic manifestations
- Erythema extending > 2cm from the wound margin and/or infection involves tissue deeper than skin and subcutaneous tissue (e.g., Bone | Tendon | Muscle | Joint)
Grade 4 – Severe Infection
- Foot infection with systemic response defined as at least 2 SIRS criteria
- SIRS criteria include: Temperature > 38°C or <36°C | Heart rate > 90 bpm | Respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg | WBC >12,000 or < 4K or >10% immature (band) forms
Signs and symptoms that also suggest severe infection include
- Crepitus | Bullae | Necrosis or gangrene | Ecchymoses or petechiae
- Altered mental status or confusion
- High CRP/ESR
- Azotemia | Acidosis | Electrolyte abnormalities
- Failure to improve on appropriate antibiotic therapy

Osteomyelitis

Diagnosing osteomyelitis (OM) is especially important as most DFI complicated by OM progress to amputation
Probe-to-bone (PTB) test is the most useful diagnostic study for OM, but efficacy depends on the physician preforming the exam
- Done using a sterile blunt metal probe
- Should not be done by physicians not skilled in this test as it increases chance of false negatives
Additional diagnostic studies for diagnosis of OM include: Plain foot x ray | ESR | CRP | Procalcitonin (PCT)

Labs and Cultures

Bloodwork includes: CBC | BMP | ESR | CRP | PCT
- WBC in studies does not correlate well with infection severity
- CRP rises faster infection and resolves quicker with resolution when compared to ESR
- PCT values are higher in DFI compared to DFU, but there the value does not correlate to the infection severity (I.e., a higher value does not necessarily mean a more severe infection)
Do NOT use quantitative microbial analysis to diagnosis DFI OR wound cultures to guide antibiotic therapy in the absence of clinical DFI
Aseptically collected tissue specimen from the wound (e.g., via curettage or biopsy) is the best sample to culture for antibiotic guidance
- Cultures should be done with conventional (and not molecular) culture techniques
If OM is suspected or diagnosed, bone culture should be considered to guide antimicrobial therapy in lieu of tissue culture
- Studies consistently demonstrate a low correlation between bone and non-bone culture results with most studies showing < 50% correlation
- Bone biopsy for culture should be obtained intraoperatively or via aseptic percutaneous methods

Imaging

Do NOT use foot temperature imaging to diagnose DFI (e.g., Infrared thermography)
Imaging is generally done to rule out or diagnosis OM associated with DFI
First line recommended imaging for concern for OM: Foot X-ray
- Inexpensive and accessible
- Insensitive to acute OM, so should be repeated in 2 – 3 weeks if suspicion is high
If following clinical exam, inflammatory markers and x-ray the diagnosis of OM remains unclear
- MRI should be obtained
- Can also consider MRI alternative such as PET | Leukocyte scintigraphy | SPECT

Treatment

Treatment should consist of a multidisciplinary approach including: ID specialists | Wound care | Vascular Surgery | Podiatry
Patients with IWGDF/IDSA classification system Grade 4 – Severe infection OR with Grade 3 – Moderate infection and high risk co-morbid conditions should be hospitalized for treatment
Hospitalization should also be considered in cases where
- IV therapy is needed and not available as outpatient
- Necessary diagnostic tests not available as outpatient
- Severe foot ischemia is present
- Surgical procedures needed urgently
- Outpatient management has failed
- More complex dressing changes required
- Careful, continuous monitoring is needed
Most patients with mild to moderate infections can be treated as an outpatient with oral antibiotic therapy
- This includes cases of osteomyelitis where the patient is clinically stable

Antibiotic Selection

Uninfected diabetic foot ulcers should NOT be treated with antibiotics
- That includes local topical antibiotics and systemic antibiotics
- Antibiotic use does not reduce risk of infection or improve ulcer healing in uninfected ulcers
Antibiotic selection should be tailored to cultures, if available
In the absence of cultures, choose an antibiotic taking in account:
- Patient’s co-morbid conditions
- Drug interactions
- Likely pathologic organism
- Culture history
- Risk of drug resistant microbes
- Clinical severity of infection
- Antibiotic side effects and cost
For North American patients with mild DFI and no recent antibiotic use, target aerobic gram-positive pathogens (e.g., beta-hemolytic streptococci | Staphylococcus aureus)
PO antibiotic agents should generally not be used for severe infections
- Except for improving patients after initial IV therapy

For mild infections

With no complicating features
- Target GPCs
- Semisynthetic penicillinase-resistant penicillin (cloxacillin) | 1st generation cephalosporin
Beta lactam allergy or intolerance
- Target GPCs
- Clindamycin (Cleocin) | Fluoroquinolone* | Trimethoprim-sulfamethoxazole (Bactrim) | Doxycycline
Recent antibiotic exposure
- Target GPCs + GNR
- ß-lactam- ß lactamase inhibitor1 (e.g., amoxicillin/clavulanate (Augmentin) | ampicillin/sulbactam (Unasyn)| Fluoroquinolone | Trimethoprim-sulfamethoxazole (Bactrim)
MRSA risk
- Target MRSA
- Linezolid | Trimethoprim-sulfamethoxazole (Bactrim) | Clindamycin (Cleocin) | Doxycycline | Fluoroquinolone

*Suitable Fluoroquinolones for mild DFI include Moxi- and Levo- floxacin

For moderate to severe infections

With no complicating features
- Target GPC +/- GNR
- ß-lactam- ß lactamase inhibitor1 (e.g., amoxicillin/clavulanate (Augmentin) | ampicillin/sulbactam (Unasyn)) | 2^nd and 3rd generation cephalosporine (e.g., Cefuroxime (Zinacef) | Cefotaxime (Claforin) | Ceftriaxone (Rocephin))
Recent antibiotic use
- Target GPC +/- GNR
- ß-lactam- ß lactamase inhibitor2 (Ticarcillin/Clavulanate (Timentin) | Piperacillin/Tazobactam (Zosyn)) | 2^nd and 3^rd generation cephalosporine (e.g., Cefuroxime (Zinacef) | Cefotaxime (Claforin) | Ceftriaxone (Rocephin)) | group 1 carbapenem (Ertapenem (Ivanz))
- Antibiotic selection depends on prior therapy and may require ID consultation
Macerated ulcer or warm climate
- Target GNR, including Pseudomonas species
- ß-lactam- ß lactamase inhibitor2 (Ticarcillin/Clavulanate (Timentin) | Piperacillin/Tazobactam (Zosyn)) | Semisynthetic penicillinase-resistant penicillin (cloxacillin) AND Ceftazidime | Ciprofloxacin
- Group 2 carbapenem (e.g, Meropenem (Merrem) | Imipenem (Primaxin))
Ischemic/limb necrosis/gas forming
- Target GPC +/- GNR +/- strict anaerobes
- ß-lactam- ß lactamase inhibitor1 (e.g., amoxicillin/clavulanate (Augmentin) | ampicillin/sulbactam (Unasyn)) | ß-lactam- ß lactamase inhibitor2 (Ticarcillin/Clavulanate (Timentin) | Piperacillin/Tazobactam (Zosyn))
- Group 1 (Ertapenem (Ivanz)) | Group 2 Carbapenem (Meropenem (Merrem) | Imipenem (Primaxin))
- 2^nd and 3^rd generation cephalosporine (e.g., Cefuroxime (Zinacef) | Cefotaxime (Claforin) | Ceftriaxone (Rocephin)) AND Clindamycin or Metronidazole
MRSA risk factors
- Target MRSA
- Consider adding or substituting with MRSA covering antimicrobials
- Glycopeptides (e.g., Vancomycin | Teicoplanin) | Linezolid (Zyvox) | Daptomycin (Cubicin) | Trimethoprim-sulfamethoxazole (Bactrim) | Doxycycline
Resistant GNR risk
- Target ESBL
- Carbapenem (e.g., Ertapenem (Ivanz) | Meropenem (Merrem) | Imipenem (Primaxin) | Fluoroquinolone (Ciprofloxacin) | Aminoglycoside (Amikacin) | Colistin

Antibiotic Duration

DFI antibiotics should generally be given for 1 – 2 week durations
- Treatment can be extended up to 3 – 4 weeks, if the infection is improving at a slower rate than expected, or if patient has significant PAD
- If infection has not resolved in 4 weeks patient should be re-evaluated and further diagnostic work up considered
A 10-day duration of antibiotics is recommended for moderate-severe DFI post-surgical debridement
OM antibiotics should be considered for 3 – 6 week courses
- Consider a duration up to 3 weeks following a minor amputation with positive bone margin culture
- Consider a duration of 6 weeks for OM without bone resection or amputation
- Antibiotic dosing for OM may require higher than standard dosing

Surgery

Urgent surgical evaluation should be obtained when there is severe or moderate DFI complicated by
- Extensive gangrene
- Necrotizing infection
- Signs suggesting deep abscess
- Compartment syndrome
- Severe lower limb ischemia
Early surgery (within 24 to 48 hours) is preferred in these instances in conjunction with antibiotics
Vascular surgery consultation should be obtained for DFI patients with PAD to determine timing of surgical intervention and revascularization options
- All patients with DFI should be assessed for presence and severity of PAD with objective diagnostic tools (e.g., ABI (ankle brachial index) | TBI (toe brachial index))
Patients with OM should generally undergo surgical resection of infected bone in addition to systemic antibiotic therapy
Clinicians may consider deferring surgery in select cases of forefoot osteomyelitis that meet the following criteria:
- No immediate need for incision and drainage to control infection (e.g., deep seated abscess) AND
- No peripheral arterial disease AND
- No exposed bone

Ineffective Therapies

It is recommended NOT to use the following therapies for infected diabetic foot ulcers
- Adjunctive G-CSF treatment
- Topical antiseptics
- Topical silver preparations (e.g., Creams | Dressings)
- Topical honey
- Bacteriophage therapy
- Negative-pressure wound therapy
- Topical antibiotics in patients already on systemic antibiotics
- Hyperbaric oxygen therapy or topical oxygen therapy

Follow Up

Given the high likelihood of recurrence and relapse of DFI, it is recommended to use the clinical presentation at a minimum of 6 months after completing antibiotics to determine if a patient is in remission or cured
Remission and cure are suggested by
- Resolution of overlying soft tissue infection
- Normalization of previously elevated inflammatory markers
- Improvement on imaging or imaging showing bone healing
Patients with prior DFI should receive lifelong serial foot examinations

KEY POINTS:

Patients with diabetes are at risk of developing diabetic foot ulcers, and this breakdown in the skin’s protective barrier can lead to diabetic foot infections
Diabetic foot infections are difficult to treat, and require a multidisciplinary approach including ID, foot, wound and vascular specialists
DFI are a clinical diagnosis, but bloodwork and imaging can be of assistance, especially when osteomyelitis is suspected
Antibiotics should be tailored to the individual patient’s risk profile and medical history
Concomitant PAD should be treated to improve wound healing and blood flow (e.g., antibiotic delivery)
Many patients with DFI ultimately progress to amputation, and diabetic foot ulcers are a leading cause of limb amputations