Foot infections in persons with diabetes are

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1 DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT INFECTION * James S. Tan, MD, MACP, FCCP ABSTRACT According to the American Diabetes Association, approximately nontraumatic lower-limb amputations were performed among people with diabetes in the United States in Guidelines on managing the patient with diabetes with suspected or evident foot infection, prepared by members of the Infectious Diseases Society of America, were published recently. This article reviews the information from those guidelines focusing on the workup and treatment of a patient with diabetic foot infection. Optimal management of diabetic foot infections requires appropriate culture (ie, after the wound has been cleaned, and from the deepest site possible) and appropriate antibiotic (ie, empirically covering for Staphylococcus and Streptococcus for mild infections and covering aerobic and anaerobic organisms in patients with moderate to severe infections). If hospitalization is required, timely surgical consultation and intervention is critical. Surgical consultation should involve surgeons experienced with diabetic foot complications. (Adv Stud Med. 2006;6(6C):S549-S554) *This article is based on a satellite symposium held in conjunction with the Interscience Conference on Antimicrobial Agents and Chemotherapy Annual Meeting in Washington, DC, on December 17, Professor and Vice Chairman of Internal Medicine, Head, Infectious Disease Section, Northeastern Ohio Universities College of Medicine, Chairman, Department of Medicine, Summa Health System, Akron, Ohio. Address correspondence to: James S. Tan, MD, MACP, FCCP, Chairman, Department of Medicine, Summa Health System, 55 Arch Street, Suite 1A, Akron, OH tanj@summa-health.org. Foot infections in persons with diabetes are common and costly. 1 They account for the largest number of diabetes-related hospital bed days. 2 They are also the most common cause of nontraumatic leg amputations. 3,4 According to the American Diabetes Association, approximately nontraumatic lower-limb amputations were performed among people with diabetes in the United States in The risk of a leg amputation the most severe and permanent local morbidity of diabetic foot infection is 15 to 40 times greater for a person with diabetes than the general population. 5 THE GUIDELINES Lipsky et al published guidelines on managing the patient with diabetes with suspected or evident foot infection, prepared by members of the Infectious Diseases Society of America. 2-4 The information focusing on the management of a patient with diabetic foot infection is summarized in Figure 1. 6 For patients with clinically infected wounds, the most important initial task is to recognize those patients who require immediate hospitalization, parenteral and broad-spectrum empirical antibiotic therapy, and urgent consideration of diagnostic testing and surgical consultation. 6 Hospitalization should be considered in patients who present with any of the following: systemic toxicity (eg, fever and leukocytosis), metabolic instability (eg, severe hypoglycemia or acidosis), rapidly progressive deep-tissue infection, substantial necrosis or gangrene, the presence of critical ischemia, requirement of urgent diagnostic or therapeutic intervention, and inability to care for self or inadequate home support. 6 The guidelines classify diabetic foot infections using 4 categories: uninfected, mild, moderate, and severe (Table 1). 6 For patients with an infected foot wound, it is important to assess the severity of infec- Johns Hopkins Advanced Studies in Medicine S549

2 tion: the depth and the tissue involved, evidence of systemic infection, presence of metabolic instability, and critical limb ischemia. Although it is not usually necessary to perform an magnetic resonance imaging (MRI), a plain X ray should be obtained. The patient s comorbid conditions and psychosocial status should also be reviewed. If hospitalization is not required, the wound should be debrided and probed. If bone is felt with a metal probe, there is a high probability of osteomyelitis. Obtaining the appropriate wound culture is also important. We recommend cleaning the wound first, and taking a deep-tissue specimen for culturing. Swabs taken directly from the ulcer can be misleading. After a wound care regimen is prescribed, empiric therapy can be initiated. Mild infections can be treated on an outpatient basis with oral therapy with antistaphylococcal and antistreptococcal activities. However, if the patient has gastroparesis, oral agents may not be well absorbed. In any case, the patient should be re-evaluated in 3 to 5 days (prefer- CASE STUDY A 56-YEAR-OLD MAN WITH DIABETIC FOOT INFECTION DS is a 56-year-old man who presents with a 5-day history of a rapidly swelling and foul-smelling left forefoot (Figure 1). DS has insulin-dependent diabetes, with a known history of a chronic foot ulcer. As shown in Figure 1, the surrounding tissue had color indicating generally good vascularity. Figure 1. Presentation Figure 1. Approach to Treating a Patient with Diabetes with Foot Infection EVALUATION His temperature was 38.2ºC, with mild hypertension (130/85 mm Hg) and normal heart rate (90 beats per minute). His blood glucose was 350 mg/dl with an elevated white blood cell count ( cells/mm 3 ). Plain radiograph of the foot showed no osteomyelitis. The ulcer dimensions are 2.5 cm 0.8 cm with a depth of 1 cm. A probe to the bone is negative. DS was hospitalized and antibiotic therapy covering both aerobes and anaerobes was initiated. The wound was debrided on admission, on day 3 of his hospitalization, and again during surgery. The culture grew mixed aerobic/anaerobic bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), thus an anti-mrsa agent was added. DS was clinically stable, and on day 7 of the hospitalization, DS showed continued improvement. Parenteral therapy was continued for 2 weeks, and DS was sent home on 2 weeks of oral therapy. DISCUSSION Hospitalization was the appropriate choice for DS. He had 2 criteria for hospital admission: presence of CT = computed tomography; MRI = magnetic resonance imaging. Reprinted with permission from Lipsky et al. Clin Infect Dis. 2004;39: (Continued on page S551) S550 Vol. 6 (6C) June 2006

3 Table 1. Clinical Classification of Diabetic Foot Infections Based on Severity Uninfected Mild Moderate Severe Wound lacking purulence or any manifestation of infection Presence of 2 manifestations of inflammation (purulence, erythema, pain, tenderness, warmth, or induration), but any cellulitis/erythema extends <2 cm around the ulcer, and infection is limited to the skin or superficial subcutaneous tissues; no other local complications or systemic illness Infection (as above) in a patient who is well and metabolically stable but has 1 of the following characteristics: Cellulitis extending >2 cm Lymphangitis streaking Spread beneath the superficial fascia, deeptissue abscess, gangrene, and involvement of muscle, tendon, joint, or bone Infection in a patient with systemic toxicity or metabolic instability Fever, chills, tachycardia, hypotension, confusion, and vomiting Leukocytosis, acidosis, azotemia, and severe hyperglycemia (Continued from page S550) fever and leukocytosis and a rapidly progressive or deep-tissue infection. Although his blood sugar was high, it is not a criterion for hospitalization and could be managed as an outpatient; however, high blood sugar can be an indication of the severity of his illness. Figure 2 is an algorithm of DS s case. 1 It follows the guidelines for managing patients with evidence of a diabetic foot infection. Figure 2. Management Data from Lipsky et al. 3 ably 3 days) and the necessary consultations should be set up, especially surgical consultation. If hospitalization is required, the patient should be medically stabilized (ie, fluid and electrolyte replacement and maintenance, control of blood sugar and acidosis, determination of the extent of local infection, and identification of other infection sites; Figure 1). Surgical consultation should involve surgeons experienced with diabetic foot complications (ie, orthopedic, vascular, or podiatric surgeons). Appropriate cultures should be obtained (ie, wound, blood, and other sites as necessary) and additional imaging may be considered. Bone scans are nonspecific and generally do not yield more clinically relevant information. Plain radiograph of the foot is more cost effective. The most useful imaging is MRI of the foot. Empiric antimicrobial therapy should be initiated (usually parenterally) and the patient should be re-evaluated at least daily. 6 The importance of timely surgical consultation and intervention cannot be overstated. The key to reducing above-ankle amputation rates and hospital length of stay is to obtain early surgical debridement and removal of dead bone. The rate of above-ankle ampu- MRSA = methicillin-resistant Staphylococcus aureus. Reprinted with permission from Lipsky et al. Clin Infect Dis. 2004;39: REFERENCE 1. Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2004;39: Johns Hopkins Advanced Studies in Medicine S551

4 tation was compared in 164 patients with diabetic infection, who were divided into 2 groups: those patients who did not undergo surgical intervention during the first 3 days of hospitalization but received intravenous empiric antimicrobial therapy (87 patients) and those who underwent surgical intervention promptly and received intravenous antimicrobial therapy (77 patients). As shown in Figure 2, those patients Figure 2. Effect of Early Surgical Intervention on Subsequent Above-Ankle Amputation Table 2. Diabetic Foot Infection: Concordance of Wound Cultures in Patients Undergoing Amputations for Diabetic Foot Infections No. positive/no. done Sampling modality Mixed Aerobes Anaerobes Preamputation ulcer swab 1/8 2/8 3/8 Postamputation ulcer swab 2/11 6/11 5/11 Curettage 5/11 7/11 7/11 Needle aspiration 5/13 9/13 8/13 Concordance is defined as complete qualitative agreement in the bacteriologic results with cultures of amputated extremity. Adapted with permission from Sapico et al. J Clin Microbiol. 1980;12: Subsequent amputation * Antibiotics alone No amputation Antibiotics plus initial surgical intervention Early surgical intervention is defined as within the first 72 hours. Patients were followed for 1 year. *P <.01 Data from Tan et al. Clin Infect Dis. 1996;23: Figure 3. Relative Distribution of Bacterial Pathogens Superficial infection Deep infection Anaerobes Staphylococcus Streptococcus Gramnegative bacilli This diagram illustrates why it is important to obtain a specimen from as deep in the wound as possible. Wound depth affects the type of organisms that are likely to be cultured, and thus affects treatment choices. For example, Staphylococcus and Streptococcus are common in all infections, but anaerobes and gram-negative organisms become more common as the wound becomes deeper. who received surgical intervention had significantly fewer above-ankle amputations during the same hospitalization or subsequent admission after a 12-month follow-up. The early surgical intervention group was also associated with a reduced length of stay by at least 6 days. 7 As discussed earlier in this article, specimens should be obtained from as deep in the wound as possible. As shown in Figure 3, wound depth affects the type of organisms that are likely to be cultured, thus it affects treatment choices. The guidelines also note that needle aspiration may be useful for obtaining purulent collections or, perhaps, a specimen from an area of cellulitis. 6 Sapico et al obtained quantitative deep-tissue aerobic and anaerobic cultures from amputated infected lower limbs of 13 patients with diabetes immediately after surgery. 8 The results were compared to those obtained from ulcer swabs, (before and after amputation), curettage of the ulcer base, and needle aspiration. They found poor concordance between deeptissue culture results and the other types of specimen collection methods, such as ulcer swabs (Table 2). 8 In another study, Sapico et al demonstrated that Bacteroides species bacteremia can be present even when the anaerobic wound culture yields no growth (Table 3). 9 Therefore, it is advisable to cover anaerobes in all patients with deep diabetic foot infections. 9 TREATMENT Table 4 summarizes the recommended treatments for diabetic foot infection based on severity. 6,7 Mild infection can be treated on an outpatient basis with oral therapy for 1 to 2 weeks (4 weeks maximum). For S552 Vol. 6 (6C) June 2006

5 Table 3. Blood and Foot Culture Isolates in 11 Patients with Bacteremia Secondary to Diabetic Foot Infections Foot Blood Anaerobes Bacteroides fragilis 2 4 Bacteroides species 0 1 Total 2 5 Aerobes Staphylococcus aureus 3 3 Streptococcus agalactiae 1 1 Viridans Streptococcus 1 1 Enterococcus 2 0 Coagulase-negative Staphylococci, diphtheroids 3 0 Escherichia coli and other gram-negative bacilli 8 1 n = 11. Adapted with permission from Sapico et al. Diabetes Care. 1982;5: moderate infections, begin intravenous antibiotics and switch to oral agents; some patients can receive oral therapy if their adherence is expected to be good. Severe infections require parenteral therapy for 2 to 4 weeks. Rarely, some patients may need longer treatment, but that should be a clinical judgment. The suggested empiric antibiotic regimens are also outlined in Table 4. Note that trimethoprim/sulfamethoxazole may not be effective against some Streptococci spp. Lipsky et al performed a head-to-head comparison of ertapenem (1 g daily; n = 295) to piperacillin/ tazobactam (3.375 g every 6 hours; n = 291) for moderate to severe diabetic foot infections. 2 Of the 445 patients who were treated and assessed, favorable clinical response rates occurred in 94% of the ertapenem- Table 4. Suggested Route, Setting, Duration, and Choice of Antibiotic Therapy by Clinical Syndrome Site and Severity Route of Setting for Duration of Antibiotic Administration Therapy Therapy Mild Topical or oral Outpatient 1 2 weeks; extend up to Dicloxacillin 4 weeks if slow response Clindamycin Cephalexin Trimethoprim/sulfamethoxazole Amoxicillin/clavulanate Levofloxacin Moderate Oral or initial Outpatient or 2 4 weeks Trimethoprim/sulfamethoxazole parenteral inpatient Levofloxacin or ciprofloxacin with clindamycin Amoxicillin/clavulanate; ampicillin/sulbactam Ticarcillin/clavulanate Piperacillin/tazobactam Cefoxitin; cefuroxime (with or without metronidazole) Ceftriaxone Ertapenem Linezolid (with or without aztreonam) Daptomycin (with or without aztreonam) Severe Parenteral to oral Inpatient, then 2 4 weeks Levofloxacin or ciprofloxacin with clindamycin when possible outpatient Piperacillin/tazobactam Imipenem/cilastatin Ertapenem* Vancomycin and ceftazidime (with or without metronidazole) With increasing MRSA isolates found, adding an anti-mrsa antimicrobial agent should be considered, depending on local epidemiology and clinical judgment Linezolid (with or without aztreonam) Daptomycin (with or without aztreonam) *Ertapenem has just been approved for severe diabetic foot infections. MRSA = methicillin-resistant Staphylococcus aureus. Data from Lipsky et al. 2,3 Johns Hopkins Advanced Studies in Medicine S553

6 treated group and 92% of the piperacillin/tazobactamtreated group. 2 Also, as noted in the guidelines, aerobic gram-positive cocci (especially Staphylococcus aureus) are the predominant pathogens in diabetic foot infections, and methicillin-resistant Staphylococcus aureus (MRSA) incidence is an ever-increasing concern, especially with associated worse outcomes. Therefore, adding an anti- S aureus (and anti-mrsa, depending on local epidemiology and clinical judgment) antimicrobial agent should be considered. 6 CONTINUING TREATMENT If the patient improves, the antimicrobial regimen should reassessed, thus a therapy with narrower spectrum, lower cost, or greater convenience can be considered (Figure 1). 6 The wound care regimen should also be reviewed, and the patient can be prepared for discharge if hospitalized. Follow-up should occur within 1 to 2 weeks, preferably by 1 week. 6 If the patient is not improving after empiric therapy, the physician needs to consider whether the surgical intervention was adequate; the infection was adequately treated regarding the cultured organism(s), susceptibility, and antimicrobial agent; the patient s vascular status needs augmentation; or if the wound care regimen needs to be adjusted (Figure 4). 6 CONCLUSIONS Optimal management of diabetic foot infections requires appropriate culture (ie, after the wound has been cleaned, and from the deepest site possible) and appropriate antibiotic (ie, empiric coverage for aerobic and anaerobic organisms). If hospitalization is required, timely surgical consultation and intervention is critical. Surgical consultation should involve surgeons experienced with diabetic foot complications. Figure 4. Approach to Assessing a Patient with Diabetes with a Foot Infection Who Is Not Responding Well to Treatment revascularization REFERENCES 1. American Diabetes Association Web site press release. World Diabetes Day focuses on preventing lower limb amputations. November 14, Available at: Day2005FINAL.pdf. Accessed February 15, Lipsky BA, Armstrong DG, Citron DM, et al. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, doubleblinded, multicentre trial. Lancet. 2005;366: Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2004;39: Lipsky BA. A report from the international consensus on diagnosing and treating the infected diabetic foot. Diabetes Metab Res Rev. 2004;20(suppl 1):S68-S Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation: basis for prevention. Diabetes Care. 1990;13: Reiber GE, Vileikyte L, Boyko EJ, et al. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care. 1999;22: Tan JS, Friedman NM, Hazelton-Miller C, et al. Can aggressive treatment of diabetic foot infections reduce the need for above-ankle amputation? Clin Infect Dis. 1996;23: Sapico FL, Canawati HN, Witte JL, et al. Quantitative aerobic and anaerobic bacteriology of infected diabetic feet. J Clin Microbiol. 1980;12: Sapico FL, Bessman AN, Canawati HN. Bacteremia in diabetic patients with infected lower extremities. Diabetes Care. 1982;5: TcPO 2 = transcutaneous partial pressure of oxygen. Reprinted with permission from Lipsky et al. Clin Infect Dis. 2004;39: S554 Vol. 6 (6C) June 2006