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ISSN: 2329-910X
Clinical Research on Foot & Ankle
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Management of Diabetic Foot Infections with Appropriate Use of Antimicrobial Therapy

Afsaneh Alavi1*, Mazen S Bader2 and R Gary Sibbald3
1 Department of Medicine (Dermatology), Women’s College Hospital, University of Toronto, Toronto, Ontario, Canada
2 Department of Medicine, Division of infectious diseases, Hamilton Health sciences, Juravinski hospital and Cancer Centre, Hamilton, Ontario, Canada
3 Department of Medicine (Dermatology), University of Toronto, Toronto, Ontario, Canada
Corresponding Author : Afsaneh Alavi
Women’s College Hospital (main building) 76 Grenville Street (5th floor) Toronto
ON M5S 1B2, Canada
Tel: 416-323-6407
Fax: 416-323-6215
E-mail: [email protected]
Received December 11, 2013; Accepted January 26, 2013; Published February 05, 2014
Citation:Alavi A, Bader MS, Sibbald RG (2014) Management of Diabetic Foot Infections with Appropriate Use of Antimicrobial Therapy. Clin Res Foot Ankle S3: 010. doi:10.4172/2329-910X.S3-010
Copyright: © 2014 Alavi A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Up to 25% of patients with diabetes will develop a foot ulcer during their lifetime with a 50-70% recurrence rate over the ensuing 5 year. Additionally more than 50% of patients with a diabetic foot ulcer (DFU) develop a diabetic foot infection (DFI). DFI remains a challenge to manage because of coexisting immunopathy. Antibiotic therapy is the main stay of treatment for patients with deep and surrounding tissue infection. A multidisciplinary approach is required with the focus on the comprehensive patient assessment, vascular assessment with revascularization, proper offloading devices and use of appropriate antimicrobials. Wound care professionals have a unique position to lessen the inappropriate use of antimicrobials.

Keywords
Diabetic foot infections; Antimicrobial therapy; Diabetes
Introduction
Diabetes mellitus is a prevalent disease worldwide where its prevalence in developed countries is 6 to 11% while in developing countries it may reach up to 30%. Although its prevalence increases with age, it is becoming more prevalent in working age group [1-3]. Diabetic foot ulcers (DFUs) are commonly encountered as a complication of diabetes where its lifetime risk can reach up to 25% [4].
Diabetic foot infections (DFIs) commonly start from infected DFUs where more than half of DFUs get infected. However, DFIs can occur without pre-existing DFUs. All wounds are contaminated from surface bacteria. When the bacteria attach to tissue and multiply, a state of colonization exists where host resistance is still predominant. As soon as colonized bacteria cause local damage to the tissue, a state of localized infection is created often termed critical colonization. The high bacterial count in the critical colonization stage may delay healing and lead to overt deeper and surrounding tissue infection when host resistance is compromised [5].
DFIs are associated with increased morbidity, mortality, rate of hospitalization, amputation, and cost. They are also associated with a significant decline of individuals’ functional status and their psychological well being [6,7]. There is a tenfold increase in rate of hospitalization with bone and soft tissue infections in individuals with diabetes than without diabetes [8-10]. Worldwide, lower extremity amputation is mainly due to diabetes where the risk of a lower extremity amputation is twenty fold increased in patients with diabetes and 25- 90% of amputations worldwide is associated with diabetes [11,12].
It is easy to imagine the current healthcare cost burden from DFIs and the need for improved patient quality of life and decreased healthcare costs with early diagnosis and management of DFIs. The thoughtful use of systemic antimicrobial s is important for all health care professionals since their use is one of the main treatment elements of DFIs. Wound care professionals need to balance the concern regarding overuse of systemic antimicrobials with improved chronic wound outcomes with longer-term antimicrobial therapy. This article reviews antimicrobial therapy as a key part in the management of DFIs.
Management of the Diabetic Foot Infections
DFUs are divided to diabetic neurotrophic foot ulcers and diabetic neuroischemic foot ulcers with the occasional patient having distal ischemia without neuropathy. The approach to DFIs is different in the ischemic foot. Although all diabetic neurotrophic ulcers have some degree of ischemia, neuroischemic ulcers often are less likely to respond to appropriate systemic therapy. Large vessel ischemia (macrovascular disease) often requires vascular procedures for successful control of infection and ulcer healing [13-17].
The management of DFIs is challenging with high cost for both the patient and the health care system. A multi-professional approach with attention to local and systemic factors is required for the management of DFI [18,19]. A holistic approach to the whole patient is critical in the management of DFUs and DFIs along with optimizing local wound care. Control of blood sugar is important. As each 1% drop in HbA1-c is associated with 37% risk reduction in micro vascular disease such as neuropathy [20]. There is also the need to control of hypertension and the associated risk of cardiovascular and kidney disease [20]. A comprehensive assessment including history and physical exam is required for all patients with concerns regarding activities of daily living, the presence of depression, as well as alcohol consumption and smoking.
The evidence of appropriate management of DFIs depends on early detection and prescription of pathogen-appropriate antimicrobial therapy. The clinical signs and symptoms of the infections are key to the diagnosis but the diabetes-associated challenge of immunopathy and neuropathy especially with uncontrolled diabetes may mask the symptoms of infection. The manifestations of infections such as erythema or swelling are not specific to DFIs and can occur in other conditions. For example, acute degenerative neuroarthropathy which is characterized by a progressive deterioration of weight-bearing joints, usually in the foot or ankle, can clinically mimic cellulitis and presents as erythema, edema and elevated temperature of the foot [7].
Although the diagnosis of the infection is clinical, the decision for antimicrobial therapy is often erroneously based on laboratory culture reports that may have identified resistant organisms or recent consensus guidelines. The culture techniques including superficial bacterial swab may detect resistant organisms but may identify surface contamination or colonizers but not necessarily pathogens. A culture from curetted tissue or punch biopsy would provide more accurate information of the deep and surrounding ulcer compartment. The Levine bacterial swab technique includes:
• Cleaning the wound with saline or water compress.
• Identifying a normal appearing area in the wound base to apply the swab.
• Press firmly to extract fluid and rotate 360 degrees.
• If the surface is too dry for an adequate swab, the cotton tip can be placed in the transport media first to moisten the surface prior to swabbing the wound.
The microbiology of DFIs is not the same for all infections. It depends on several factors that include the duration of the infection, setting of acquiring the infection, prior history of infection, prior use of antimicrobial agents, presence of ischemia, and geographic area. Aerobic Gram-positive cocci, especially Staphylococcus aureus, are the most common cause of DFIs. Individuals with chronic foot ulcers and previous antimicrobial therapy often have infections with both gram positive and gram-negative organisms and often become co-infected over time with anaerobic pathogens [19].
Antimicrobial Therapy for the Diabetic Foot Infections
Antimicrobial therapy is one of the main treatment arms of DFIs. There are two types of antimicrobial therapy for DFIs: empiric and directed therapy. Empiric antimicrobial therapy should be started after taking all appropriate cultures. However, in patients with severe DFIs and hemodynamic instability, empiric antimicrobial therapy should be started as early as possible, even before taking appropriate cultures if it will be delayed. The choice of empiric antimicrobial therapy is based mainly on the expected pathogens, risk of antimicrobial resistance, and the severity of the infection (Table 1). The choice of directed antimicrobial therapy is mainly based on the isolated organisms and their susceptibility testing results and response to the antimicrobial [7]. Directed antimicrobial therapy should be as narrow-spectrum as possible and cost-effective as well. Antimicrobial’s that are associated with high risk of Clostridium difficile infection (CDI) should be avoided if possible (ceftriaxone, fluoroquinolones, clindamycin). CDI should be suspected if the patient has had more than 3 unformed bowel movements in the previous 24 hours, fever, abdominal pain, and leukocytosis [21].
There is no evidence for the superiority of one type of antimicrobial therapy over another due to lack of high-quality DFIs clinical studies. However, knowing the antimicrobials and their main characteristics is important to guide the choice of treatment for patients with DFIs (Table 2). Antimicrobials should be initiated parenterally for moderate and severe infections and then continued for the whole course of treatment if there is no alternative oral antimicrobial (due to resistant organisms or poor tissue penetration). Oral antimicrobial therapy can administer initially for mild to moderate infections and as a step down for moderate and severe infections if the infection is responding to initial parenteral antimicrobial therapy. The best antimicrobial therapy results occur if the isolated organisms are susceptible to prescribed antimicrobial with good bioavailability and tissue penetration. Clinicians should always remember that cultures may not always identify all the pathogens and unless special precautions are taken, anaerobes present in the wound may not be represented in the bacterial culture result. Other consideration that should be taken when selecting antimicrobial for treatment of DFIs include frequency of administration, gastrointestinal tract absorption function, potential adverse effects, drug interactions, cost, and patient’s history of allergy and comorbid conditions such as renal and hepatic disease [14,22].
Antimicrobial therapy should not be used prophylactically to treat uninfected diabetic foot ulcers since it does not improve healing or prevent infections but may further drive resistance and adverse effects [23]. There are two types of antimicrobial agents than can be used in the treatment of DFIs: topical and systemic antimicrobials. The presence of bacteria in the wounds may be detrimental with critical colonization often amenable to topical antimicrobials and the deep and surrounding infection requiring systemic antimicrobial agents.
Antimicrobial resistance is a growing problem worldwide. The main resistant organisms that involved in DFIs are so called the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and enterobacteriaceae). The prevalence of MRSA in DFIs is approximately 5-30% and its incidence is increasing. MRSA is associated with poor wound healing and a higher risk of lower extremity amputation in patients with DFIs. Risk factors for MRSA infection include previously colonization or infection with MRSA, household contact of patient with MRSA, exposure to a unit/area with an MRSA outbreak, hemodialysis, comorbid conditions, hospitalization, surgery, admission to ICU, antimicrobial exposure (fluoroquinolones), and in communities where the prevalence of MRSA infection exceeds 10-15% [24-26]. More recently, there is an increasing presence of antimicrobial resistant Gram-negative organisms from DFIs. Risk factors for infections with antimicrobial-resistant organisms include previous colonization or infection with the same organism, contact of a known case of same organism, elderly, patients who have been soaking their feet, hospitalization, ICU admission, surgery, immunocompromised status, prior antimicrobial therapy (fluoroquinolones, cephalosporins, carbapenems), recurrent urinary tract infection, hemodialysis, receipt of care in a hospital on the U.S. eastern seaboard region (e.g., New York City) or in Greece, middle east or the Indian subcontinent in the past 12 months [27,28]. Finally, antimicrobial resistance is an evolving problem. Therefore, ongoing surveillance for antimicrobial -resistant organisms is vital for the treatment of DFIs and optimization of infection-control measures to prevent their spread.
The treatment duration of DFIs with antimicrobial is based primarily on response to treatment (good response is indicated by resolution of systemic symptoms and signs (such as fever) associated with the infection, improvement/resolution of local symptoms and signs of infection (redness, drainage), healing of the wound, and decreasing inflammatory markers including ESR and CRP, type and extent of the infection, the vascular status of the infected foot and its treatment, and type of surgical treatment. Treatment for 1 to 2 weeks is usually adequate for mild DFI while moderate and severe soft tissue infections may require treatment for 2 to 4 weeks or longer. The recommended duration of antimicrobial therapy for diabetic foot osteomyelitis (DFO) has traditionally been 4 to 6 weeks but can be extended based beyond this duration based on the response, presence of ischemia, and type and extents of surgical treatment [19].
Superficial soft-tissue infection can be managed with topical antimicrobials, oral or parenteral antimicrobial agent and with or without debridement. Deeper soft-tissue or bone infections may require hospital admission with parenteral antimicrobial agents and serial surgical debridement/decompression. Deep soft-tissue infections of are often polymicrobial with gram-positive species as well as gram-negative bacteria, whereas superficial soft-tissue infection bone infections are usually monomicrobial [29].
Outpatient parenteral antimicrobial therapy (OPAT) facilitates treatment of DFIs and DFO as outpatient. However, OPAT requires patient selection and evaluation; antimicrobial selection including efficacy, route, frequency, dosage, duration, and clinical and laboratory monitoring for adverse effects (vancomycin trough) and type of venous access. The need for OPAT should be determined by a physician who is experienced in treating DFIs. The infection should be controlled and stabilized and all necessary surgical procedures should have been performed before starting OPAT. Ongoing maintenance debridement may be required to accelerate healing. Patients or caregiver’s require adequate counselling on the care of wounds, venous access, and adverse effects of antimicrobial therapy and the need to report adverse events to their provider. It is preferable to choose an antimicrobial agent that is administered once or twice daily without compromising the clinical efficacy [30]. However, it is recommended to use cefazolin given 3 or 4 times daily over vancomycin given once or twice daily for DFIs, particularly for osteomyelitis, due to methicillin-sensitive S. aureus [25]. The first dose of antimicrobial should be administered in a supervised setting equipped for emergencies to deal with any serious reactions such as anaphylaxis (e.g. Outpatient medical clinic or emergency department). Treating physician should be familiar with complications of venous access such phlebitis, bloodstream infections, thrombosis of the veins, clotting of the catheter, pulmonary emboli, migration of the catheter tip, erosion of the catheter through the vein [31].
Biofilms [32] are produced by bacteria often between two surfaces of different viscosity such as slough on the surface of a wound. A biofilm is a colony of bacteria that excrete a glycocalyx for protection from antimicrobial agents, and allows a symbiotic relationship with the community of bacteria so that some organisms may be in a relatively protected resting state [32]. The use of antimicrobial therapy alone (without proper debridement) may reverse the signs of infection but often does not penetrate the outer protective covering of the biofilm and fails to kill the biofilm-associated bacteria. The treatment strategy of biofilm includes sharp excision of the wound to disrupt the biofilm, with immediate antimicrobial therapy to prevent its rapid reformation [33].
Conclusion
Proper utilization of antimicrobials is important for all wound care professionals. Wound care professionals have a unique position to lessen the inappropriate use of antimicrobials.
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