Diabetic foot medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2] Anahita Deylamsalehi, M.D.[3]

Overview

Appropriate wound care is essential for the management of all diabetic foot ulcers. Uninfected diabetic ulcers do not require antibiotic therapy. For acutely infected wounds, empiric antibiotic with efficacy against Gram-positive cocci should be initiated after obtaining a post-debridement specimen for aerobic and anaerobic culture. Infections with antibiotic-resistant organisms and those that are chronic, previously treated, or severe usually require broader spectrum regimens.

Diabetic Foot Infection

Principles of Therapy Adapted from Diabetes Care. 2013;36(9):2862-71. and Clin Infect Dis. 2012;54(12):e132-73.

• Treatment strategies are dependent on ulcer's grade, presence of infection and perfusion.
• Treatment of diabetic foot should consist of intensive wound therapy, infection treatment, control of blood sugar, pressure off-loading and treatment of comorbidities.
• Aim of treatment should be focused on improving prognosis and decreasing complications such as amputation.
• Saline wet-to-dry dressings are recommended for diabetic foot ulcers.
• Dressings such as foams, semipermeable films, hydrocolloids, and calcium alginate swabs are recommended since they provide a warm and moist environment that augment wound healing and prevent ulcer contamination.
• Using topical antiseptics such as povidone-iodine must be avoided due to toxic effects of these agents on wound healing.

Diagnosis of Diabetic Foot Infection

• Diabetic foot infection (DFI) is diagnosed clinically by the presence of at least two signs or symptoms of inflammation:

• Local swelling or induration
• Erythema
• Local tenderness or pain
• Local warmth
• Purulent discharge (thick, opaque to white or sanguineous secretion)

Indications for Hospitalization

• Hospitalization is appropriate for the following conditions:

• Severe (grade 4) infections
• Moderate (grade 3) infections with complicating features

• Severe peripheral arterial disease or limb ischemia
• Lack of home support

• Patients unable to comply with the required outpatient treatment regimen for psychological or social reasons
• Patients not responding to outpatient treatment

Obtaining Specimens

• Properly obtained specimens for culture prior to initiating empiric therapy provide useful information for guiding antibiotic selection, particularly in those with chronic or previously treated infections which are commonly caused by Gram-negative bacilli or obligate anaerobic organisms.

• Infected wounds should be cultured by obtaining tissue samples during any surgical procedure or by tissue biopsy or wound base curettage.
• Bone cultures are optimal for detecting the pathogen in osteomyelitis, but blood cultures are only necessary for those with a severe (grade 4) infection.
• Cultures may be unnecessary for mild infections in patients who have not recently received antibiotic therapy and who are at low risk for methicillin-resistant Staphylococcus aureus (MRSA) infection; these infections are predictably caused solely by staphylococci and streptococci.
• Cultures may yield organisms that are commonly considered to be contaminants (eg, coagulase-negative staphylococci, corynebacteria), but these may be true pathogens in DFIs and are often resistant to the empiric antibiotics.

Consultation

• Conditions to request consultation from specialists:

• Urgent surgical intervention should be sought for DFIs accompanied by gas in the deeper tissues, an abscess, or necrotizing fasciitis, and less urgent surgery for DFIs with substantial nonviable tissue or extensive bone or joint involvement.
• Consult a vascular surgeon to consider revascularization if ischemia complicates a DFI.
• Infectious diseases specialists should be consulted when cultures yield multiple or antibiotic-resistant organisms, the patient has substantial renal impairment, or the infection does not respond to appropriate medical or surgical therapy in a timely manner.

Adjunctive Therapy

• No adjunctive therapy has been proven to improve infection resolution, but for selected diabetic foot wounds that are slow to heal, physicians might consider using bioengineered skin equivalents, growth factors, granulocyte colony-stimulating factors, hyperbaric oxygen therapy, or negative pressure wound therapy.
• Becaplermin is a human platelet-derived growth factor (also known as Regranex gel) can be used for neuropathic diabetic foot ulcers. It can augment wound healing by causing chemotaxis and mitogenesis of cells such as neutrophils, fibroblasts, and monocytes.
• Some new types of biologically active implants such as bioengineered skin (Apligraf) and human dermis (Dermagraft) (which are derived from neonatal foreskin) are recommended for faster wound healing. These implants function as a source of growth factors and extracellular matrix which are critical for wound healing.

Selection of Antibiotic Regimen

• Clinically uninfected wounds should not be treated with antibiotic therapy. For all infected wounds, antibiotic therapy combined with appropriate wound care is recommended.
• For clinically infected wounds, consider the questions below:

1. Is there high risk of MRSA?

• Methicillin-resistant Staphylococcus auerus (MRSA) coverage should be considered in the following conditions:

• Prior history of MRSA infection or colonization within the past year
• High local prevalence of MRSA infection or colonization (50% for a mild and 30% for a moderate soft tissue infection)
• Clinically severe diabetic foot infection

2. Is the infected wound chronic or treated with antibiotics in the past month?

• If so, include agents active against aerobic gram-negative bacilli in regimen.
• If not, agents targeted against just aerobic Gram-positive cocci may be sufficient.

• Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment
• Obligate anaerobes may be copathogens in ischemic or necrotic wounds.

3. Are there risk factors for infection with Pseudomonas aeruginosa or extended-spectrum β-lactamase (ESBL)–producing organisms?

• Anti-pseudomonal agent is usually unnecessary except for patients with risk factors:

• High local prevalence of Pseudomonas aeruginosa infection
• Frequent exposure of the foot to water
• Warm climate

• Coverage of ESBL-producing gram-negative organisms should be considered in countries in which they are relatively common.

4. What is the severity status?

• DFI is classified based on its severity according to the Infectious Diseases Society of America (IDSA) guideline or the PEDIS grade developed by International Working Group on the Diabetic Foot (IWGDF). (see Table below)
• Selection of empiric antimicrobial regimen should be determined by the severity of DFI and the likely etiologic agents.

• Mild (grade 2) to moderate (grade 3) DFI without recent antibiotic treatment:

• Highly bioavailable oral antibiotics against aerobic Gram-positive cocci may be sufficient.

• Severe (grade 4) DFI:

• Broad-spectrum antibiotics are recommended while culture results and susceptibility data are pending.

Clinical Manifestation PEDIS Grade IDSA Severity Wound lacking purulence or any manifestations of inflammation 1 Uninfected Presence of ≥2 manifestations of inflammation (purulence, or erythema, pain, tenderness, warmth, or induration) Any cellulitis or erythema extends ≤2 cm around the ulcer Limited to the skin or superficial subcutaneous tissues No other local complications (eg, trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis, venous stasis) or systemic illness 2 Mild Infection in a patient who is metabolically stable and systemically well, but with ≥1 of the following characterisitics: Cellulitis extending >2 cm Lymphangitic streaking Spread beneath the superficial fascia Deep-tissue abscess Gangrene Involvement of muscle, tendon, joint, or bone 3 Moderate Infection in a patient with metabolic instability (eg, acidosis, severe hyperglycemia, or azotemia) or systemic toxicity as manifested by ≥2 of the following: Temperature >38 °C or <36 °C Heart rate >90 beats/min Respiratory rate >20 breaths/min or PaCO2 <32 mm Hg White blood cell count >12,000 or <4,000 cells/μL or ≥10% immature (band) forms 4 Severe

5. What is the appropriate route, setting, and duration of antibiotic therapy?

• The table below describes the recommended route, setting, and duration of antibiotic therapy based on the extent and severity of DFI.

Site of Infection, by Severity or Extent Route of Administration Setting Duration of Therapy Soft-tissue only Mild (Grade 2) Oral (or topical for superficial infections) Outpatient 1–2 wk Moderate (Grade 3) Oral (or initial parenteral) Outpatient (or inpatient) 1–3 wk Severe (Grade 4) Initial parenteral, switch to oral when possible Inpatient, then outpatient 2–4 wk Bone or joint No residual infected tissue Parenteral or oral Inpatient, then outpatient 2–5 d Residual infected soft tissue Parenteral or oral Inpatient, then outpatient 1–3 wk Residual infected, viable bone Initial parenteral, switch to oral when possible Inpatient, then outpatient 4–6 wk Residual dead bone or no surgery Initial parenteral, switch to oral when possible Inpatient, then outpatient ≥3 mo

Empiric Therapy

▸ Click on the following categories to expand treatment regimens.

Uninfected (Grade 1)   ▸  No Evidence of Infection     Mild (Grade 2)   ▸  Acute Infection Without Recent Antibiotic Use   ▸  High Risk for MRSA     Moderate to Severe (Grade 3–4)   ▸  Chronic Infection or Recent Antibiotic Use   ▸  High Risk for MRSA   ▸  High Risk for Pseudomonas aureuginosa   ▸  Polymicrobial Infection

Uninfected Wound, No Evidence of Infection ▸ Uninfected wounds should be managed with appropriate wound care. ▸ Antibiotic therapy is not recommended. Mild DFI, Acute Infection Without Recent Antibiotic Use Preferred Regimen ▸ Dicloxacillin 125–250 mg PO qid OR ▸ Clindamycin 150–300 mg PO qid † OR ▸ Cephalexin 500 mg PO qid OR ▸ Levofloxacin 750 mg PO qd OR ▸ Amoxicillin-Clavulanate 500 mg PO bid (or 250 mg PO tid) ‡ † Usually active against community-associated MRSA, but check macrolide sensitivity and consider ordering a D-test before using for MRSA. ‡ Relatively broad-spectrum oral agent that includes anaerobic coverage. Mild DFI, High Risk for MRSA Preferred Regimen ▸ Doxycycline 100 mg PO q12h † OR ▸ TMP–SMX 80-160 mg/400-800 mg PO q12h † † Active against many MRSA & some gram-negatives; uncertain against streptococci. Moderate to Severe DFI, Chronic Infection or Recent Antibiotic Use Preferred Regimen ▸ Levofloxacin 750 mg IV/PO q24h OR ▸ Cefoxitin 1 g IV q4h (or 2 g IV q6–8h) OR ▸ Ceftriaxone 1–2 g/day IV/IM q12–24h OR ▸ Ampicillin–Sulbactam 1.5–3 g IV/IM q6h OR ▸ Moxifloxacin 400 mg IV/PO q24h OR ▸ Ertapenem 1 g IV/IM q24h OR ▸ Tigecycline 100 mg IV, then 50 mg IV q12h † OR ▸ Imipenem–Cilastatin 0.5–1 g IV q6–8h ‡ Alternative Regimen ▸ Levofloxacin 750 mg IV/PO q24h OR ▸ Ciprofloxacin 600–1200 mg/day IV q6–12h OR ▸ Ciprofloxacin 1200–2700 mg IV q6–12h (for more severe cases) PLUS ▸ Clindamycin 150–300 mg PO qid † Active against MRSA. ‡ Not active against MRSA; consider when ESBL-producing pathogens suspected. Moderate to Severe DFI, High Risk for MRSA Preferred Regimen ▸ Linezolid 600 mg IV/PO q12h OR ▸ Daptomycin 4 mg/kg IV q24h OR ▸ Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L) Moderate to Severe DFI, High Risk for Pseudomonas aeruginosa Preferred Regimen ▸ Piperacillin–Tazobactam 3.375 g IV q6–8h Moderate to Severe DFI, Polymicrobial Infection Preferred Regimen ▸ Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L) OR ▸ Linezolid 600 mg IV/PO q12h OR ▸ Daptomycin 4 mg/kg IV q24h PLUS ▸ Piperacillin–Tazobactam 3.375 g IV q6–8h OR ▸ Imipenem–Cilastatin 0.5–1 g IV q6–8h OR ▸ Ertapenem 1 g IV/IM q24h OR ▸ Meropenem 1 g IV q8h Alternative Regimen ▸ Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L) OR ▸ Linezolid 600 mg IV/PO q12h OR ▸ Daptomycin 4 mg/kg IV q24h PLUS ▸ Ceftazidime 2 g IV q8h OR ▸ Cefepime 2 g IV q8h OR ▸ Aztreonam 2 g IV q6–8h PLUS ▸ Metronidazole 15 mg/kg IV, then 7.5 mg/kg IV q6h

References

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