SUPPLEMENT ARTICLE

Medical Treatment of Diabetic Foot Infections Benjamin A. Lipsky Department of Medicine, University of Washington School of Medicine, and General Internal Medicine Clinic, VA Puget Sound Health Care System, Seattle, Washington

Diabetic foot infections frequently cause morbidity, hospitalization, and amputations. Gram-positive cocci, especially staphylococci and also streptococci, are the predominant pathogens. Chronic or previously treated wounds often yield several microbes on culture, including gram-negative bacilli and anaerobes. Optimal culture specimens are wound tissue taken after debridement. Infection of a wound is defined clinically by the presence of purulent discharge or inflammation; systemic signs and symptoms are often lacking. Only infected wounds require antibiotic therapy, and the agents, route, and duration are predicated on the severity of infection. Mild to moderate infections can usually be treated in the outpatient setting with oral agents; severe infections require hospitalization and parenteral therapy. Empirical therapy must cover gram-positive cocci and should be broad spectrum for severe infections. Definitive therapy depends on culture results and the clinical response. Bone infection is particularly difficult to treat and often requires surgery. Several adjuvant agents may be beneficial in some cases. Foot infections in diabetic patients usually begin in a skin ulceration [1]. Although most infections remain superficial, ∼25% will spread contiguously from the skin to deeper subcutaneous tissues and/or bone. Up to half of those who have a foot infection will have another within a few years. About 10%–30% of diabetic patients with a foot ulcer will eventually progress to an amputation, which may be minor (i.e., foot sparing) or major. Conversely, an infected foot ulcer precedes ∼60% of amputations [2–4], making infection perhaps the most important proximate cause of this tragic outcome. PATHOPHYSIOLOGY Among the factors predisposing diabetic patients to foot infections are poorly understood immunologic disturbances, such as impaired polymorphonuclear leukocyte migration, phagocytosis, intracellular killing, and chemotaxis [5]. The prevalence of these defects appears to be correlated, at least in part, with the ad-

Reprints or correspondence: Dr. Benjamin A. Lipsky, VA Puget Sound Health Care System, S-111-GIMC, 1660 South Columbian Way, Seattle, WA 98108-1597 ([email protected]). Clinical Infectious Diseases 2004; 39:S104–14  2004 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2004/3903S2-0007$15.00

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equacy of glycemic control [6]. Ketosis, in particular, impairs leukocyte function [7]. Some evidence suggests that in diabetic patients, cellular immune responses, monocyte function, and complement function are reduced as well. Their higher rates of carriage of Staphylococcus aureus in the anterior nares and skin [8], and several types of skin and nail disorders, may increase the risk of skin and soft-tissue infections in diabetic patients. Accelerated atherosclerosis, especially of the arteries between the knee and ankle, increases the likelihood of ischemia at the infection site. The anatomy of the foot, with its various compartments, tendon sheaths, and neurovascular bundles, may lead to proximal spread of infection and favors ischemic necrosis of the confined tissues [7, 9]. MICROBIOLOGICAL CONSIDERATIONS Selecting appropriate antimicrobial therapy for diabetic foot infections requires knowledge of the likely etiologic agents. Various skin disorders and environmental exposures, as well as recent antibiotic therapy, can alter the colonizing flora of skin wounds [10, 11]. Although acute infections in previously untreated patients are usually caused by aerobic gram-positive cocci (often as monomicrobial infections), chronic wounds develop complex flora.

Determining the microbial etiology of an infected wound will usually assist in subsequent management. The etiologic agent(s) can be identified by culture only if specimens are collected and processed properly. Antibiotic-susceptibility results generally help tailor (and in many cases constrain) antibiotic regimens. Deep tissue specimens, obtained aseptically at surgery, contain the true pathogens more often than do samples obtained from superficial lesions. A curettage, or tissue scraping with a scalpel, from the base of a debrided ulcer provides more accurate results than does a wound swab [10–13]. Therapy directed against organisms isolated from culture of a swab sample is likely to be unnecessarily broad and may occasionally miss key pathogens. If multiple organisms are isolated, the clinician must decide which require specifically targeted therapy. Less virulent bacteria, such as enterococci, coagulase-negative staphylococci, or corynebacteria, may represent pathogens but can sometimes be ignored. Organisms isolated from reliable specimens that are the sole or predominant pathogens both on the Gram-stained smear and in the culture are likely to be true pathogens. S. aureus is the most important pathogen in diabetic foot infections; even when it is not the only isolate, it is usually a component of a mixed infection [8]. Serious infections in hospitalized patients are often caused by 3–5 bacterial species, including both aerobes and anaerobes [11, 13]. Gram-negative bacilli, mainly of the family Enterobacteriaceae, are found in many patients with chronic or previously treated infections. Pseudomonas species are often isolated from wounds that have been soaked or treated with wet dressings or hydrotherapy. Enterococci are commonly obtained by culture from patients who have previously received a cephalosporin. Obligate anaerobic species are most frequent in wounds with ischemic necrosis or that involve deep tissues. Anaerobes are rarely the sole pathogen; most often they constitute a mixed infection with aerobes [14]. Antibiotic-resistant organisms, especially methicillin-resistant S. aureus, are frequently isolated from patients who have previously received antibiotic therapy; they are often (but not always) acquired during previous hospitalizations or at longterm care facilities [15]. Definitive antibiotic therapy should take into consideration the results of Gram-staining a smear from a wound [16] and the culture and susceptibility tests. Because some patients with diabetic foot infections are not cured by antibiotics that cover the isolated bacteria, more sensitive methods, such as rDNA sequencing, may detect missed organisms [17]. DIAGNOSIS AND CLINICAL PRESENTATION Diagnosing infection. Because all skin wounds contain microorganisms, infection must be diagnosed clinically, that is, by the presence of systemic signs (e.g., fever, chills, and leukocytosis), purulent secretions (pus), or ⭓2 local classical signs

or symptoms of inflammation (warmth, redness, pain or tenderness, and induration). In chronic wounds, additional signs suggesting infection may include delayed healing, abnormal coloration, friability, or foul odor. Infection should be suspected at the first appearance of a foot problem and at evidence of a systemic infection or of a metabolic disorder. Peripheral neuropathy or ischemia can either mask or mimic inflammation. Occasionally, inflammatory signs may be caused by other noninfectious disorders; on the other hand, some uninflamed ulcers may be associated with underlying osteomyelitis [18]. Signs of systemic toxicity are surprisingly uncommon in diabetic foot infections [19], even those that are limb threatening. Proper evaluation of a diabetic foot infection requires a methodical approach [20]. Whenever infection is considered, this diagnosis should be pursued aggressively; these infections can worsen quickly, sometimes in a few hours. Clinical presentation. Almost two-thirds of patients with a diabetic foot infection have evidence of peripheral vascular disease, and ∼80% have lost protective sensation [1]. Infections most often involve the forefoot, especially the toes and metatarsal heads, particularly on the plantar surface. About half of the patients in reported series have received antibiotic therapy for the foot lesion by the time they present, and up to onethird have had a foot lesion for 11 month. Many patients do not report pain, and more than half, including those with serious infections, do not have a fever, elevated WBC count, or elevated erythrocyte-sedimentation rate [19–21]. Assessing severity. Several classification systems have been proposed for diabetic foot lesions, none of which is universally accepted. Keys to classifying a foot wound are assessing the depth of the lesion (by visually inspecting the tissues involved and by estimating the depth in millimeters) and checking for ischemia (absent pulses or diminished blood pressure in the foot) and for infection [22]. Whereas mild infections are relatively easily treated, moderately severe infections may be limb threatening, and severe infections may be life threatening. Assessing the severity of infection is essential to selecting an antibiotic regimen, influences the route of drug administration, and helps determine the need for hospitalization. Severity of infection also helps assess the potential necessity and timing of surgery and the likelihood of amputation [22]. The wound should be carefully explored to seek foreign or necrotic material, and it should be probed with a sterile metal instrument. Deep space infections often have deceptively few superficial signs. The clinician should suspect spread of infection when there is inflammation distant from the skin wound, or when suppurative lesions persist despite apparently appropriate therapy [23]. A knowledgeable surgeon should evaluate any patient with systemic toxicity for an occult deep space infection [9]. Clinical features that help define the severity of infection are shown in table 1. Diabetic Foot Treatment • CID 2004:39 (Suppl 2) • S105

Table 1.

Clinical characteristics that help define the severity of an infection.

Feature

Mild infection

Severe infection

Presentation Ulceration

Slowly progressive Involves only skin

Acute or rapidly progressive Penetrates to subcutaneous tissues

Tissues involved Cellulitis

Fascia, muscle, joint, bone

Local signs

Epidermis, dermis Minimal (!2 cm around ulcer rim) Limited inflammation

Systemic signs

None or minimal

Metabolic control

Mildly abnormal (hyperglycemia)

Foot vasculature Complicating features

Minimally impaired (normal/reduced pulses) None or minimal (callus, ulcer)

Fever, chills, hypotension, confusion, volume depletion, leukocytosis Severe hyperglycemia, acidosis, azotemia, electrolyte abnormalities Absent pulses, reduced ankle or toe blood pressure Eschar, foreign body, puncture wound, abscess, marked edema, implanted metalwork or other prostheses

One of the first, and the most financially dominant, decisions when faced with a diabetic foot infection is to determine whether a patient should be hospitalized [10]. Patients with a serious infection should be admitted for possible surgical interventions, fluid resuscitation, and control of metabolic derangements. Hospitalization should also be considered if the patient is unable or unwilling to perform proper wound care, cannot or will not be able to off-load the affected area, is unlikely to comply with antibiotic therapy, requires parenteral antibiotic therapy, or needs close monitoring of response to treatment. In the absence of these factors, most patients can be treated cautiously on an outpatient basis, with frequent (i.e., every few days, initially) [10] reevaluation. Wound care (debridement, dressing changes, and pressure off-loading) and glycemic control should be optimized; antibiotics will not overcome inattention to these fundamentals. BONE INFECTION Diabetic patients can have destructive bone changes caused by peripheral neuropathy (i.e., neuroarthropathy, osteoarthropathy, or Charcot disease) [24] that may be difficult to distinguish from those caused by bone infection [25]. The latter generally results from contiguous spread of a deep soft-tissue infection through the bone cortex (osteitis) to the marrow (osteomyelitis). About 50%–60% of serious foot infections are complicated by osteomyelitis. The proportion of apparently mild to moderate infections that have bone involvement is probably in the range of 10%–20%. There are no validated or well-accepted guidelines for diagnosing or treating diabetic foot osteomyelitis. Among the important considerations are the anatomic site of infection (i.e., forefoot, midfoot, or hindfoot), the vascular supply to the area, the extent of soft-tissue and bone destruction, the degree of systemic illness, and the patient’s preferences. Foot ulcers that are long standing (14 weeks), large (12 cm), and deep (13 mm) or are associated with a substantially elevated erythrocyte-sedimentation rate (170 mm/h) should be S106 • CID 2004:39 (Suppl 2) • Lipsky

Extensive, or distant from ulceration Severe inflammation, crepitus, bullae, necrosis or gangrene

evaluated for possible osteomyelitis [18, 25]. Clinical evaluation should include gently “probing to bone” [26]; in one study of patients with limb-threatening infections, the positive predictive value of this test was almost 90%. Plain radiographs should be obtained for most patients with a diabetic foot infection. Radiographic changes in infected bone generally take at least 2 weeks to be evident; when the presence of bone infection is in doubt but the patient is stable, repeating a plain radiograph in a couple of weeks may be more cost effective than undertaking more sophisticated imaging procedures. If clinical and radiographic findings are not diagnostically adequate, various types of scans may be useful [25, 27]. Bone (e.g., Tc-99) scans are sensitive (∼85%) but too nonspecific (∼45%). Leukocyte (e.g., In-111 or 99mTc-HMPAO) scans are similarly sensitive but more specific (∼75%) and may also be useful for demonstrating that the infection has been arrested. Radiolabeled antigranulocyte fragments (e.g., sulesomab) also may increase the accuracy of scanning [28]. Among the diagnostic techniques for osteomyelitis that show promise are high-resolution ultrasound [29] and positron-emission tomography. However, MRI is usually the diagnostic procedure of choice, with a sensitivity of 190% and a specificity of 180% [30, 31]. The diagnostic test characteristics of all these procedures exhibit great variability across studies. Their interpretation is highly influenced by the pretest probability of disease [27], and they are most helpful when the pretest probability is intermediate. Definitive diagnosis of osteomyelitis and identification of the etiologic agent(s) generally require obtaining a specimen of bone. This should be processed for both culture and histology. Specimens may be obtained by open (e.g., at the time of debridement [32] or surgery) or percutaneous (usually image guided) biopsy. To avoid contamination, specimens must be obtained without traversal of an open wound. Patients who are receiving antibiotic therapy may have a negative culture result, but histopathologic findings (leukocytes and necrosis) can help

diagnose infection. These procedures are easy to perform and are safe in experienced hands [33], although somewhat expensive. Bone biopsy is appropriate if the diagnosis of osteomyelitis remains in doubt after other diagnostic tests are performed, or if the etiologic agent(s) cannot be predicted because of previous antibiotic therapy or confusing culture results. Microbiological studies of diabetic foot osteomyelitis have revealed that the majority of cases are polymicrobial; S. aureus is the most common etiologic agent (isolated in ∼40% of infections), but Staphylococcus epidermidis (∼ 25%), streptococci (∼30%), and Enterobacteriaceae (∼40%) are also common isolates [25]. TREATMENT Almost all infected foot lesions (other than primary cellulitis) require some surgical intervention, which is covered elsewhere in this supplement issue of Clinical Infectious Diseases. Basic factors that should be considered in choosing an antibiotic regimen are outlined in table 2. Antibiotic Therapy

Indications for therapy. Available data suggest that ∼40%– 60% of diabetic patients who are treated for a foot ulcer receive antibiotic therapy [34]. The role of antibiotics for clinically uninfected wounds is a controversial issue. The concept that reducing the “bioburden” of chronic skin wounds with antimicrobial therapy may improve healing is plausible, and some experimental animal data and studies with burn wounds and skin grafts support this theory [35]. Although some practitioners believe that any foot ulcer requires administration of antibiotics, either for therapy or for prophylaxis, available studies do not generally support this view [36]. In most of the published clinical trials, antibiotic therapy did not improve the outcome of uninfected lesions [37, 38]. One abstract [39] reported a randomized trial in which 64 diabetic patients who received antibiotic therapy for clinically uninfected foot ulcers had a significantly increased likelihood of healing and had a reduced incidence of clinical infection, hospitalization, and amputation. This provocative work will need to be published and replicated before this strategy is considered. Antibiotic therapy is associated with frequent adverse effects, substantial financial costs, and the development of resistance and, thus, should currently be used only to treat established infection. Route of therapy. The key to successful antibiotic therapy is achieving a therapeutic drug concentration at the site of infection. This typically requires first achieving adequate serum levels. Intravenous antibiotics are indicated for patients who are systemically ill, have a severe infection, are unable to tolerate oral agents, or are known or suspected to have pathogens that are not susceptible to available oral agents. After the patient’s condition is stabilized and the infection is clearly responding, most patients can have their treatment switched to oral therapy.

Table 2. Factors that may influence antibiotic treatment of diabetic foot infections (specific agents, route of administration, and duration of therapy). Factor Clinical severity of the infection Etiologic agent(s) (known or presumed) Recent antibiotic therapy Bone infection Vascular status at infected site Allergies to antibiotics Renal or hepatic insufficiency Gastrointestinal absorption impairment Drug toxicity (interactions) potential Local antibiotic susceptibility data Formulary and cost considerations Patient preferences Published efficacy data

Patients who require prolonged intravenous therapy, such as for osteomyelitis or infections resistant to oral agents, can often be treated on an outpatient basis when a program to provide this service is available. Oral antibiotic therapy is less expensive, more convenient, and probably associated with fewer complications than is parenteral therapy. Delivery of the first dose of antibiotic to the infected site is slower with oral therapy, but this is an issue only for critically ill patients. The main concern is the bioavailability of orally administered agents. Gastrointestinal absorption of oral antibiotics is variable, but some agents, such as clindamycin and the fluoroquinolones, have been shown to be well absorbed with oral dosing [40]. Fluoroquinolones, in particular, achieve high tissue concentrations at the site of diabetic foot infections (including in inflamed tissues [41]) when administered orally, even for patients with gastroparesis [42]. Several newly licensed agents cover an expanded spectrum of organisms; drugs with greater activity against antibiotic-resistant gram-positive cocci, such as linezolid, daptomycin, and newer fluoroquinolones, are especially appealing. When peripheral vascular disease is present, therapeutic antibiotic concentrations are often not achieved in the infected tissues, even when serum levels are adequate. Recently, a study of patients with leg ischemia (many of whom were diabetic) who received intravenous ceftazidime before limb surgery showed that delivery of the antibiotic to the skin was better than to the muscles or bone, but the key hindrance to penetration was the presence of ischemia, not diabetes [43]. Problems with arterial insufficiency have led to experimentation with novel methods of antibiotic delivery. Retrograde venous perfusion consists of injecting antibiotic solutions under pressure into a foot vein while a sphygmomanometer is inflated on the thigh. High local antibiotic concentrations have been Diabetic Foot Treatment • CID 2004:39 (Suppl 2) • S107

observed in anecdotal and uncontrolled reports [44]. Some clinicans have also tried lower-extremity intra-arterial (e.g., femoral) antibiotic injections [45]. Still others have advocated primary closure of carefully debrided wounds, with closedcatheter instillation of antibiotics [46]. New vascular catheters are being developed that may allow threading through leg veins to the site of a foot infection; this might allow high local concentrations of antibiotics with minimal systemic exposure. Several other novel routes of therapy have been explored. Superficial wounds allow consideration of direct applications of antimicrobial agents. For infections that have undergone surgical tissue resection, antibiotic-loaded beads (usually containing an aminoglycoside) or cement have been used to supply high local antibiotic concentrations and, in some instances, to fill the dead space [47, 48]. Another approach is to implant an antibioticimpregnated bovine-collagen sponge into an infected lesion [49]. Collagen is well tolerated, biodegradable, and an excellent drug carrier. Limited anecdotal data have shown efficacy of antibioticimpregnated collagen (combined, at least initially, with oral antibiotics) in treating diabetic foot infections (including osteomyelitis) [49]. For mildly infected foot ulcers, an additional option is topical antimicrobial therapy. This has several theoretical advantages, including high local drug levels, avoidance of systemic antibiotic adverse effects, the possibility of using novel agents not available for systemic use, and the focusing of the attention of both the patient and the physician to the foot and to the need for good wound care. Antiseptics are generally too harsh on the host tissues, but topical antibiotics may have a role. Silver sulfadiazine, neomycin, polymixin B, gentamicin, metronidazole, and mupirocin have each been used for soft-tissue infections in other sites, but there are no published data on their efficacy in treating diabetic foot infections. An investigational peptide antibiotic, pexiganin acetate 1% cream (MSI-78), has been shown, in 2 large multicenter phase III randomized trials, to be safe and nearly as effective (∼85%–90% clinical response rate) as oral ofloxacin for mildly infected diabetic foot ulcers [50]. These results are encouraging and suggest that other topical antimicrobial agents should be explored. None of these therapies has been adequately evaluated, and they cannot currently be routinely recommended. Choice of antibiotic agents. Most patients will begin antibiotic therapy with an empirical regimen. This should aim to cover the most common pathogens, with some modification according to severity of infection. Relatively narrow-spectrum agents may be used for minor infections, because there is likely to be time to alter treatment if there is no clinical response. Regimens for severe infection should be broader spectrum and most often administered intravenously, because the stakes are higher. Empirical regimens must also take into consideration such factors as patient allergies, renal dysfunction, recent antibiotic therapy, and known local antibiotic susceptibility patS108 • CID 2004:39 (Suppl 2) • Lipsky

terns. Obtaining a Gram-stained smear of a wound specimen may help direct empirical antibiotic therapy. Culture results show organisms consistent with the Gram staining in ∼95% of cases [16]. The overall sensitivity of the smear in identifying organisms that grow on culture is ∼70%, but the sensitivity is about twice as good for gram-positive cocci as for gramnegative bacilli. This is unfortunate, because empirical antibiotic therapy for gram-positive organisms is usually required, and the important question is whether to broaden the spectrum to cover gram-negative species. An antibiotic regimen should almost always include an agent active against staphylococci and streptococci. Previously treated or severe cases may need extended coverage that also includes commonly isolated gram-negative bacilli and Enterococcus species. Necrotic, gangrenous, or foul-smelling wounds usually require anti-anaerobic therapy. When culture and susceptibility results are available, more specific therapy should be chosen. Narrower-spectrum agents are preferred, but it is important to assess how the infection has been responding to the empirical regimen. If the lesion is healing and the patient is tolerating therapy, there may be no reason to change, even if some or all of the isolated organisms are resistant to the agents prescribed. On the other hand, if the infection is not responding, treatment should cover all the isolated organisms. If the infection is worsening despite susceptibility of the isolated bacteria to the chosen regimen, the need for surgical intervention or the possibility that fastidious organisms were missed on culture should be reconsidered. Although theoretical and pharmacokinetic considerations are important, the proof of an antibiotic’s efficacy is the clinical trial. Agents that have demonstrated clinical effectiveness, alone or in combination, in prospective studies including entirely or mostly patients with diabetic foot infections, include the following [51]: cephalosporins (cephalexin orally; cefoxitin and ceftizoxime parenterally) [10, 52–56]; penicillin/b-lactamase inhibitor congeners (amoxicillin/clavulanate orally; ampicillin/ sulbactam, piperacillin/tazobactam, and ticarcillin/clavulanate parenterally) [57–61]; fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin, and trovafloxacin orally and parenterally) [57, 61–65]; and the miscellaneous agents clindamycin (orally and parenterally) [10, 63, 65], imipenem/cilastatin (parenterally) [58, 66], amdinocillin (parenterally) [55], linezolid (orally and parenterally) [67], and pexiganan acetate (topically) [50]. A few randomized controlled studies have compared different oral and parenteral regimens; all had power only to demonstrate equivalence, and they did. Overall, the clinical and microbiological response rates have been similar in trials with the various antibiotics, and no agent or combination has emerged as most effective [68]. Currently, several trials testing different dosing regimens of established agents (e.g., piperacillin/tazobactam) or newly approved agents (e.g., ertapenem

Adequate debridement, resection, or amputation of infected tissue can shorten the necessary duration of therapy. For those few patients with diabetic foot infection who develop bacteremia, therapy for at least 2 weeks seems prudent. Antibiotic therapy can generally be discontinued when all signs and symptoms of infection have resolved, even if the wound has not completely healed. Healing any skin ulcer is a separate, albeit important, issue in treating diabetic foot infections. In some instances of extensive infection, large areas of gangrene or necrotic tissue, or poor vascular supply, more prolonged therapy may be needed. Some patients who cannot, or will not, undergo surgical resection or who have surgical hardware at the site of infection may require prolonged or intermittent suppressive antibiotic therapy.

and daptomycin) are under way. New antibiotics are introduced, and some older ones are made obsolete by the emergence of resistance or newly appreciated toxicities. Understanding the principles of antibiotic therapy is therefore more important than knowing the specific agents that are currently in vogue [51, 68]. Whereas the US Food and Drug Administration has approved all the above agents (and others) for treating complicated skin and soft-tissue infections, the only drugs specifically approved for diabetic foot infections are trovafloxacin (which is now rarely used) and linezolid. Cost of therapy is also an important factor in selecting a regimen. A large prospective study of deep foot infections in Sweden found that antibiotics accounted for only 4% of the total costs of treatment; costs of topical wound treatments were considerably higher [69]. Variables that explained 95% of the total treatment costs were the time intervals between diagnosis, the final required procedure, and wound healing and the number of surgical procedures performed [69]. One American study demonstrated that therapy with ampicillin/sulbactam was significantly less expensive than therapy with imipenem/cilastatin, for limb-threatening diabetic foot infections, primarily because of the lower drug and hospitalization costs and the less severe side effects associated with the former treatment [70]. More comparative trials and economic analyses are needed. Published suggestions on specific antibiotic regimens for diabetic foot infections vary but are more alike than different. My empirical antibiotic recommendations, by type of infection, are given in table 3. Duration of therapy. The optimal duration of antibiotic therapy for diabetic foot infections has not been studied. For mild to moderate infections, a 1–2-week course has been found to be effective [10], whereas for more serious infections, treatment has usually been given for ∼2 weeks, sometimes longer. Table 3.

Treatment of Osteomyelitis

Antibiotic choices should optimally be based on results of bone culture, when possible, especially because of the need for longduration therapy [25]. Soft-tissue or sinus-tract cultures do not accurately predict bone pathogens. If empirical therapy is necessary, it should always cover S. aureus; broader coverage should be considered if the history or results of soft-tissue culture suggest the necessity. Antibiotics may not penetrate well to infected bone, and the number and function of leukocytes in this environment are suboptimal. Thus, treatment of osteomyelitis should usually be parenteral (at least initially) and prolonged (at least 6 weeks). Cure of chronic osteomyelitis has generally been thought to require removing the infected bone by debridement or resection. Several recent retrospective series have shown, as discussed elsewhere in this supplement issue of Clinical Infectious Diseases, that diabetic foot osteomyelitis can be arrested with antibiotic therapy alone in about two-thirds

Suggested antibiotic regimens for treatment of diabetic foot infections.

Severity of infection (administration) Mild/moderate (oral for entire course)

Recommended

a

b

Alternative

c

Cephalexin (500 mg. q.i.d.)

Levofloxacin (750 mg q.d.)  clindamycin (300 mg t.i.d.)

Amoxicillin/clavulanate (875/125 mg b.i.d.)

Trimethoprim-sulfamethoxazole (2 double-strength b.i.d.)

Clindamycin (300 mg t.i.d.) Moderate/severe (iv until stable, then switch to oral equivalent)

d,e

Ampicillin/sulbactam

d

(3.0 g q.i.d.)

Piperacillin/tazobactam (3.3 g q.i.d.)

Clindamycin (450 mg q.i.d.) + ciprofloxacin (750 mg b.i.d.) Life-threatening (prolonged iv)

Imipenem/cilastin (500 mg q.i.d.)

d,e

Clindamycin (600 t.i.d.) + ceftazidime (2 g t.i.d.)

b

Vancomycin (15 mg/kg b.i.d.) + aztreonam (2.0 g t.i.d.) + metronidazole (7.5 mg/kg q.i.d.) d

Clindamycin (900 mg t.i.d.) + tobramycin (5.1 mg/kg./d) + ampicillin (50 mg/kg. q.i.d.) NOTE.

Regimen should be given at usual recommended doses for serious infections; modify for conditions such as azotemia.

a

On the basis of theoretical considerations and available clinical trials. b Prescribed in special circumstances, for example, patient allergies, recent treatment with recommended agent, and cost considerations. c , with or without. d A similar agent of the same class or generation may be substituted. e A high local prevalence of methicillin resistance among staphylococci may require use of vancomycin, linezolid, or other appropriate agents active against these organisms.

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Figure 1.

Approach to treating a foot infection in a patient with diabetes

of cases [71, 72]. Furthermore, oral antibiotics with good bioavailability (e.g., fluoroquinolones and clindamycin) may be adequate for most, or perhaps all, of the therapy. If all the infected bone is removed, a shorter course of antibiotic therapy (e.g., 2 weeks) may be sufficient. For some patients, long-term suppressive therapy, or intermittent short courses of treatment for recrudescent symptoms, may be the most appropriate approach. Some data suggest that antibiotic-impregnated beads (made of methylmethacrylate or other materials) may be useful for delivering high antibiotic concentrations to infected bones while also filling dead space [47]. Antibiotic-impregnated orthopedic implants have shown success in treating osteomyelitis in a few small series [48]. Evidence of resolution of osteomyelitis includes a drop in the erythrocyte sedimentation rate to normal or a loss of increased uptake on leukocyte scan [25].

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Adjuvant Therapies

Several additional measures have been used to improve infection resolution, wound healing, and host response. Those for which there are published data are briefly reviewed here. Recombinant granulocyte-colony stimulating factor (GCSF). A randomized controlled study from England of 40 diabetic patients with serious foot infections showed that adding (to the usual care, including antibiotic therapy) subcutaneous injections of G-CSF (filgrastim) led to significantly more rapid resolution of infection and to better outcomes [73]. To the contrary, another randomized controlled trial conducted in Italy found that there was no significant improvement in cure rates or microbiological results with adjuvant G-CSF (lenograstim) among 40 patients with limb-threatening diabetic foot infections at 3 or 9 weeks after enrollment [74]. The amputation rate was,

Figure 2. Approach to selecting antibiotic therapy for a foot infection in a patient with diabetes. GNR, gram-negative rods; GPC, gram-positive cocci; MRSA, methicillin-resistant Staphylococcus aureus.

however, significantly lower at 9 weeks among the G-CSF–treated patients. A Korean study found that neutrophil superoxide production in 12 diabetic patients with foot infections was significantly lower than in 12 healthy nondiabetic controls [75]. GCSF (lenograstim) dramatically enhanced in vitro neutrophil function in the diabetic patients, compared with the controls. Larger trials are needed to define whether, and for whom, these promising compounds can be recommended. Hyperbaric oxygen. This treatment is designed to increase oxygen delivery to ischemic tissue, which may help fight infection and improve wound healing in the high-risk foot. For years, anecdotal and uncontrolled reports have suggested benefit in diabetic foot infections. Recently, prospective studies, including a double-blind randomized trial, have shown improved wound healing and a reduced rate of amputation with hyperbaric oxygen therapy [76, 77]. Of 8 published studies of hyperbaric oxygen therapy for diabetic foot disorders, 5 in-

cluded a control group. Inadequate evaluation of comorbid conditions, small sample size, and poor documentation of wound size and severity hamper interpretation of these reports [77, 78]. Potential candidates for hyperbaric oxygen include those with deeply infected lesions who have not responded to standard therapy and for whom amputation is a realistic possibility [79]. If hyperbaric oxygen is used, it should usually be continually assessed for whether it is of value. Typically, the treatment can be expected to be beneficial if the transcutaneous oxygen pressure near the ulcer is !40 mm Hg before therapy and rises to 1200 mm Hg after therapy [79]. Hyperbaric oxygen is an expensive and limited resource that should remain reserved for severe cases, even if it is further confirmed as effective. Revascularization. Improving blood flow may also be crucial to controlling infection in an ischemic foot. Although initial debridement must be done even in the face of poor arterial

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circulation, revascularization is generally postponed until sepsis is controlled [80]. However, waiting for more than a few days in hopes of sterilizing the wound is inappropriate and may result in further tissue loss [81, 82]. An aggressive approach to revascularization in an ischemic infected foot can result in 3year limb-salvage rates of up to 98% [83]. Larval (maggot) therapy. “Biosurgery” with fly larvae (maggots) has been used for many years, but it is enjoying a recent revival [32, 84]. Uncontrolled trials with sterilized larvae suggest they are useful for treating infection (of soft tissue and bone), debriding wounds, and controlling wound odor. Larvae are relatively inexpensive and are available from commercial laboratories. This treatment is currently used with apparent benefit at several centers, but it requires proper staff training and acceptance by the patient. Controlled trials are needed to define which types of infections may benefit from this therapy. Edema control. Edema caused by increased hydrostatic pressure frequently complicates diabetic foot infections. By impairing antegrade nutrient (and perhaps leukocyte) delivery, as well as restricting removal of metabolites and cell debris, edema can hinder wound healing. A recent randomized trial found that aggressively controlling edema with a pneumatic pedal compression device increased wound healing in diabetic patients with a foot infection. Simpler interventions, such as leg elevation and compression stockings, are likely to be beneficial as well [85]. An algorithmic overview of the approach to treating a diabetic patient with a foot lesion is shown in figure 1. The approach to selecting an antibiotic regimen for a diabetic foot infection is outlined in figure 2. OUTCOME OF TREATMENT A good clinical response for mild to moderate infections can be expected in 80%–90% of appropriately treated patients [10, 50] and, for deeper or more extensive infections, in 50%–60% [64, 86]. When infection involves deep soft-tissue structures or bone, more thorough debridement is usually needed. Bone resections or partial amputations are required in about two-thirds of this patient group. Most of these amputations can be foot sparing, and long-term control of infection is achieved in 180% of cases. Infection recurs in 20%–30% of patients, many of whom have underlying osteomyelitis. Factors that predict healing include the absence of exposed bone, a palpable popliteal pulse, toe pressure of 145 mm Hg or an ankle pressure of 180 mm Hg, and a peripheral WBC count of !12,000/mm3 [19]. The presence of edema or atherosclerotic cardiovascular disease increases the likelihood of amputation. Amputation may be more often required for patients with combined soft-tissue and bone infection than for patients with either type of infection alone [86]. Patients who have had one infection are at substantial risk of having another within a few years; thus, eduS112 • CID 2004:39 (Suppl 2) • Lipsky

cating them about prevention techniques and about prompt consultation when foot problems occur is critical.

Acknowledgments Financial support. The author has received research support from Pfizer (formerly Pharmacia) and Merck. Conflict of interest. The author is a member of the speakers’ bureaus and advisory boards for Pfizer (formerly Pharmacia) and Merck.

References 1. Lipsky BA. Infectious problems of the foot in diabetic patients. In: Bowker JH, Pfeifer MA, eds. The diabetic foot. 6th ed. St. Louis: Mosby, 2001: 467–80. 2. International Working Group on the Diabetic Foot. International consensus on the diabetic foot. Amsterdam, 1999: 1–96. 3. Pecoraro RE, Ahroni JH, Boyko EJ, Stencil VL. Chronology and determinants of tissue repair in diabetic lower-extremity ulcers. Diabetes 1991; 40:1305–13. 4. Reiber GE, Pecoraro RE, Koepsell TD. Risk factors for amputation in patients with diabetes mellitus: a case control study. Ann Intern Med 1992; 117:97–105. 5. Wilson RM. Neutrophil function in diabetes. Diabet Med 1986; 3: 509–12. 6. McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am 1995; 9:1–10. 7. Sentochnik DE, Eliopoulos GM. Infection and diabetes. In: Kahn CR, Weir GC, eds. Joslin’s diabetes mellitus. 13th ed. Philadelphia: Lea & Febiger, 1994: 867–88. 8. Breen JD, Karchmer AW. Staphylococcus aureus infections in diabetic patients. Infect Dis Clin North Am 1995; 9:11–24. 9. Bridges RM, Deitch EA. Diabetic foot infections. Pathophysiology and treatment. Surg Clin North Am 1994; 74:537–55. 10. Lipsky BA, Pecoraro RE, Larson SA, Ahroni JH. Outpatient management of uncomplicated lower-extremity infections in diabetic patients. Arch Intern Med 1990; 150:790–7. 11. Lipsky BA, Pecoraro RE, Wheat JL. The diabetic foot: soft tissue and bone infection. Infect Dis Clin North Am 1990; 4:409–32. 12. Wheat LJ, Allen SD, Henry M, et al. Diabetic foot infections: bacteriologic analysis. Arch Intern Med 1986; 146:1935–40. 13. Sapico FL, Witte JL, Canawati HN, Montgomerie JZ, Bessman AW. The infected foot of the diabetic patient: quantitative microbiology and analysis of clinical features. Rev Infect Dis 1984; 6(Suppl 1):171–6. 14. Gerding DN. Foot infections in diabetic patients: the role of anaerobes. Clin Infect Dis 1995; 20(Suppl 2):S283–8. 15. Tentolouris N, Jude EB, Smirnof I, Knowles EA, Boulton AJM. Methicillin-resistant Staphylococcus aureus: an increasing problem in a diabetic foot clinic. Diabet Med 1999; 16:767–71. 16. Lipsky BA, Hiatt HI, Holroyd KJ. Results and prognostic value of Gram stain of tissue curettage specimens of infected diabetic foot ulcers [abstract 145]. In: Proceedings of the 37th annual meeting of the Infectious Diseases Society of America (Philadelphia). Alexandria, VA: Infectious Diseases Society of America, 1999. 17. Redkar R, Kalns J, Butler W, et al. Identification of bacteria from a non-healing diabetic foot wound by 16 S rDNA sequencing. Mol Cell Probes 2000; 14:163–9. 18. Newman LG, Waller J, Palestro CJ, et al. Unsuspected osteomyelitis in diabetic foot ulcers: diagnosis and monitoring by leukocyte scanning with indium 111 oxyquinoline. JAMA 1991; 266:1246–51. 19. Eneroth M, Apelqvist J, Stenstrom A. Clinical characteristics and outcome in 223 diabetic patients with deep foot infections. Foot Ankle Int 1997; 18:716–22.

20. Edelson GW, Armstrong DG, Lavery LA, Caicco G. The acutely infected diabetic foot is not adequately evaluated in an inpatient setting. Arch Intern Med 1996; 156:2373–8. 21. Armstrong DG, Perales TA, Murff RT, Edelson GW, Welchon JG. Value of white blood cell count with differential in the acute diabetic foot infection. J Am Podiatr Med Assoc 1996; 86:224–7. 22. Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system: the contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care 1998; 21:855–9. 23. Ger R. Newer concepts in the surgical management of lesions of the foot in the patient with diabetes. Surg Gynecol Obstet 1984; 158:213–5. 24. Frykberg RG, Mendeszoon ER. Charcot arthropathy: pathogenesis and management. Wounds 2000; 12(Suppl B):35B–42B. 25. Lipsky BA. Osteomyelitis of the foot in diabetic patients. Clin Infect Dis 1997; 25:1318–26. 26. Grayson ML, Gibbons GW, Balogh K, Levin E, Karchmer AW. Probing to bone in infected pedal ulcers: a clinical sign of underlying osteomyelitis in diabetic patients. JAMA 1995; 273:721–3. 27. Wrobel JS, Connolly JE. Making the diagnosis of osteomyelitis: the role of prevalence. J Am Podiatr Med Assoc 1998; 88:337–43. 28. Harwood SJ, Valdivia S, Hung GL, Quenzer RW. Use of sulesomab, a radiolabeled antibody fragment, to detect osteomyelitis in diabetic patients with foot ulcers by leukoscintigraphy. Clin Infect Dis 1999; 28: 1200–5. 29. Enderle MD, Coerpre S, Schweizer HP, et al. Correlation of imaging techniques to histopathology in patients with diabetic foot syndrome and clinical suspicion of chronic osteomyelitis. The role of highresolution ultrasound. Diabetes Care 1999; 22:294–9. 30. Craig JG, Amin MB, Wu K, et al. Osteomyelitis of the diabetic foot: MR imaging-pathological correlation. Radiology 1997; 203:849–55. 31. Rosenberg ZA, Beltran J, Bencardino JT. MR imaging of the ankle and foot. Radio Graphics 2000; 20(Special issue):S153–79. 32. Jones V. Debridement of diabetic foot lesions. Diabetic Foot 1998; 1: 88–94. 33. Sutton P, Harley J, Jacobson A, Lipsky BA. Diagnosing osteomyelitis with percutaneous bone biopsy in patients with diabetes and foot infection [abstract 30]. In: Proceedings of the 38th annual meeting of the Infectious Diseases Society of America (New Orleans). Alexandria, VA: Infectious Diseases Society of America, 2000. 34. Jaegeblad G, Apelqvist J, Nyberg P, Berger B. The diabetic foot: from ulcer to multidisciplinary team approach; a process analysis [abstract P87]. In: Abstracts of the 3rd International Symposium of the Diabetic Foot (Noordwijkerhout, The Netherlands), 1998: 149. 35. Robson MC, Mannari RJ, Smith PD, Payne WG. Maintenance of wound bacterial balance. Am J Surg 1999; 178:399–402. 36. O’Meara SM, Cullum NA, Majid M, Sheldon TA. Systemic review of antimicrobial agents used for chronic wounds. Br J Surg 2001; 88:4–21. 37. Chantelau E, Tanudjaja T, Altenho¨fer F, Ersanli Z, Lacigova S, Metzger C. Antibiotic treatment for uncomplicated neuropathic forefoot ulcers in diabetes: a controlled trial. Diabet Med 1996; 13:156–9. 38. Hirschl M, Hirschl AM. Bacterial flora in mal perforant and antimicrobial treatment with ceftriaxone. Chemotherapy 1992; 38:275–80. 39. Foster AVM, Bates M, Doxford M, Edmonds ME. Should oral antibiotics be given to “clean” foot ulcers with no cellulitis? [abstract O13]. In: Abstracts of the 3rd International Symposium of the Diabetic Foot (Noordwijkerhout, The Netherlands), 1998. 40. Kuck EM, Bouter KP, Hoekstra JBL, Conemans JMH, Diepersloot RJA. Tissue concentrations after a single-dose, orally administered ofloxacin in patients with diabetic foot infections. Foot Ankle Int 1998; 19:38–40. 41. Muller M, Brunner M, Hollenstein U, et al. Penetration of ciprofloxacin into the interstitial space of inflamed foot lesions in non–insulindependent diabetes mellitus patients. Antimicrob Agents Chemother 1999; 43:2056–8. 42. Marangos MN, Skoutelis AT, Nightengale CH, et al. Absorption of ciprofloxacin in patients with diabetic gastroparesis. Antimicrob Agents Chemother 1995; 39:2161–3. 43. Raymakers JT, Houben AJ, van de Heyden JJ, Tordoir JH, Kitslaar PJ,

44. 45.

46.

47. 48.

49.

50.

51. 52.

53.

54. 55.

56. 57.

58.

59.

60.

61.

62.

63. 64.

65.

Schaper NC. The effect of diabetes and severe ischaemia on the penetration of ceftazidime into tissues of the limb. Diabet Med 2001; 18: 229–34. El-Sherif El-Sarkey M. Local intravenous therapy in chronic inflammatory and vascular disorders of the foot. Int Surg 1997; 82:175–81. Dorigo B, Cameli AM, Trapani M, Raspanti D, Torri M, Mosconi G. Efficacy of femoral intra-arterial administration of teicoplanin in grampositive diabetic foot infections. Angiology 1995; 46:1115–22. Connolly JE, Wrobel JS, Anderson RF. Primary closure of infected diabetic foot wounds: a report of closed instillation in 30 cases. J Am Podiatr Med Assoc 2000; 90:175–82. Roeder B, Van Gils CC, Maling S. Antibiotic beads in the treatment of diabetic pedal osteomyelitis. J Foot Ankle Surg 2000; 39:124–30. Yamashita Y, Uchida A, Yamakawa T, Shinto Y, Araki N, Kato K. Treatment of chronic osteomyelitis using calcium hydroxyapatite ceramic implants impregnated with antibiotics. Int Orthop 1998; 22:247–51. Kollenberg LO. A new topical antibiotic delivery system. World Wide Wounds 1998; 1:1–19. Available at: http://www.worldwidewounds .com/1998/july/Topical-Antibiotic-Delivery-System/topical-antibiotic -delivery-system.html. Accessed on 8 July 2004. Lipsky BA, McDonald D, Litka PA. Treatment of infected diabetic foot ulcers: topical MSI-78 vs. oral ofloxacin [abstract]. Diabetologia 1997; 40(Suppl 1):482. Lipsky BA. Evidence-based antibiotic therapy of diabetic foot infections. FEMS Immunol Med Microbiol 1999; 26:267–76. Fierer J, Daniel D, Davis C. The fetid foot: lower extremity infections in patients with diabetes with diabetic mellitus. Rev Infect Dis 1979; 1:210–7. Hughes CA, Johnson CC, Bamberger DM, et al. Treatment and longterm follow-up of foot infections in patients with diabetes or ischemia: a randomized, prospective, double-blind comparison of cefoxitin and ceftizoxime. Clin Ther 1987; 10(Suppl A):36–49. LeFrock JL, Blais F, Schell RF, et al. Cefoxitin in the treatment of diabetic patients with lower extremity infections. Infect Surg 1983 May: 361–74. File TM, Tan JS. Amdinocillin plus cefoxitin versus cefoxitin alone in therapy of mixed soft tissue infections (including diabetic foot infections). Am J Med 1983; 80(Suppl):100–5. Anania WC, Chinkes SL, Rosen RC, Turner PR, Helfand AE. A selective clinical trial of ceftizoxime. J Am Podiatr Med Assoc 1987; 77:648–652. Lipsky BA, Baker PD, Landon GC, Fernau R. Antibiotic therapy for diabetic foot infections: comparison of two parental-to-oral regimens. Clin Infect Dis 1997; 24:643–8. Grayson ML, Gibbons GW, Habershaw GM, et al. Use of ampicillin/ sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis 1994; 18: 683–93. ¨ zcebe O, Gu¨llu¨ U ¨ nal S, et al. Efficacy of sulbactam-amAkova M, O picillin for the treatment of severe diabetic foot infections. J Chemother 1996; 8:284–9. Zeillemaker AM, Veldkamp KE, van Kraaij MG, Hoekstra JBL, van Papendrecht AA, Dipersloot RJ. Piperacillin/tazobactam therapy for diabetic foot infection. Foot Ankle Int 1998; 19:169–72. Graham DR, Talan DA, Nichols RL, et al. Once-daily, high-dose levofloxacin versus ticarcillin-clavulanate alone or followed by amoxicillin-clavulanate for complicated skin and skin-structure infections: a randomized, open-label trial. Clin Infect Dis 2002; 35:381–9. Peterson LR, Lissack LM, Canter K, Fasching CE, Clabots C, Gerding DN. Therapy of lower extremity infections with ciprofloxacin in patients with diabetes mellitus, peripheral vascular disease, or both. Am J Med 1989; 86:801–8. Sesin GP, Paszko A, O’Keefe EO. Oral clindamycin and ciprofloxacin therapy for diabetic foot infections. Pharmacotherapy 1990; 10:154–6. Beam TR, Gutierrez I, Powell S, et al. Prospective study of the efficacy and safety of oral and intravenous ciprofloxacin in the treatment of diabetic foot infections. Rev Infect Dis 1989; 11(Suppl 5):S1163. Diamantopoulos EJ, Haritos D, Yfandi G, et al. Management of severe

Diabetic Foot Treatment • CID 2004:39 (Suppl 2) • S113

66.

67.

68. 69.

70.

71.

72.

73.

74.

75.

diabetic foot infections. Exp Clin Endocrinol Diabetes 1998; 106: 346–52. Calandra GB, Raupp W, Brown KR. Imipenem/cilastatin treatment of lower extremity skin and soft tissue infections in diabetics. Scand J Infect Dis Suppl 1987; 52:15–9. Lipsky BA, Itani K, Norden C, and the Linezolid Diabetic Foot Infections Study Group. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillinsulbactam/amoxicillin-clavulanate. Clin Infect Dis 2004; 38:17–24. Cunha BA. Antibiotic selection for diabetic foot infections: a review. J Foot Ankle Surg 2000; 39:253–7. Tennvall GR, Apelqvist J, Eneroth M. Costs of deep foot infections. An analysis of factors determining treatment costs. Pharmacoeconomics 2000; 18:225–38. McKinnon PS, Paladino JA, Grayson ML, Gibbons GW, Karchmer AW. Cost effectiveness of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis 1997; 24:57–63. Venkatesan P, Lawn S, Macfarlane RM, Fletcher EM, Finch RG, Jeffcoate WJ. Conservative management of osteomyelitis in the feet of diabetic patients. Diabet Med 1997; 14:487–90. Pittet D, Wyssa B, Herter-Clavel C, Kursteiner K, Vaucher J, Lew DP. Outcome of diabetic foot infections treated conservatively: a retrospective cohort study with long-term follow-up. Arch Intern Med 1999; 159:851–6. Gough A, Clapperton M, Rolando N, Foster AVM, Philpott-Howard J, Edmonds ME. Randomized placebo-controlled trial of granulocytecolony stimulating factor in diabetic foot infections. Lancet 1997; 350: 855–9. De Lalla F, Pellizzer G, Strazzabosco M, et al. Randomized prospective controlled trial of recombinant granulocyte-colony stimulating factor as adjunctive therapy for limb-threatening diabetic foot infection. Antimicrob Agents Chemother 2001; 45:1094–8. Peck KR, Son DW, Song JH, Kim S, Oh MD, Choe KW. Enhanced neutrophil functions by recombinant human granulocyte colony-stim-

S114 • CID 2004:39 (Suppl 2) • Lipsky

76.

77.

78.

79. 80.

81. 82.

83.

84.

85.

86.

ulating factor in diabetic patients with foot infections in vitro. J Korean Med Sci 2001; 16:39–44. Stone JA, Cianci P. The adjunctive role of hyperbaric oxygen in the treatment of lower extremity wounds in patients with diabetes. Diabetes Spectrum 1997; 10:118–23. Wunderlich RP, Peters EJG, Lavery L. Systemic hyperbaric oxygen therapy: lower-extremity wound healing and the diabetic foot. Diabetes Care 2000; 23:1551–5. Lee SS, Chen CY, Chan YS, Yen CY, Chao EK, Ueng SWN. Hyperbaric oxygen in the treatment of diabetic foot infection. Chang Gung Medical Journal 1997; 20:17–22. Bakker DJ. Hyperbaric oxygen therapy and the diabetic foot. Diabetes Metab Res Rev 2000; 16(Suppl 1):S55–8. Caputo GM, Cavanaugh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with diabetes. N Engl J Med 1994; 331:854–60. Estes JM, Pomposelli FB Jr. Lower extremity arterial reconstruction in patients with diabetes mellitus. Diabet Med 1996; 13:S43–7. Chang BB, Darling RC III, Paty PSK, Lloyd WE, Shah DM, Leather RP. Expeditious management of ischemic invasive foot infections. Cardiovasc Surg 1996; 4:792–5. Tannenbaum GA, Pomposelli FB Jr, Marcaccio EJ, et al. Safety of vein bypass grafting to the dorsal pedal artery in diabetic patients with foot infections. J Vasc Surg 1992; 15:982–90. Rayman A, Stansfield G, Woollard T, Mackie A, Rayman G. Use of larvae in the treatment of the diabetic necrotic foot. Diabetic Foot 1998; 1:7–13. Armstrong DG, Nguyen HC. Improvement in healing with aggressive edema reduction after debridement of foot infection in persons with diabetes. Arch Surg 2000; 135:1405–9. Eneroth M, Larsson J, Apelqvist J. Deep foot infection in diabetes mellitus: an entity with different characteristics, treatment, and prognosis [abstract P01]. In: Abstracts of the 3rd International Symposium of the Diabetic Foot (Noordwijkerhout, The Netherlands), 1998:21.