Diabetic Foot Infections

Practice Essentials

Compromise of the blood supply from microvascular disease, often in association with lack of sensation because of neuropathy, predisposes persons with diabetes mellitus to foot infections. These infections span the spectrum from simple, superficial cellulitis to chronic osteomyelitis.

The radiograph below demonstrates a foot lesion in a patient with diabetes.

View Image

Chronic diabetic ulceration with underlying osteomyelitis. Plain film radiograph exhibiting cortical disruption at the medial aspect of the first MTP ....

Signs and symptoms

Diabetic foot infections typically take one of the following forms:

• Cellulitis
• Deep-skin and soft-tissue infections
• Acute osteomyelitis
• Chronic osteomyelitis

Cellulitis

• Tender, erythematous, nonraised skin lesions are present, sometimes with lymphangitis
• Lymphangitis suggests group A streptococcal infection
• Bullae are typical of Staphylococcus aureus infection, but occasionally occur with group A streptococci

· No ulcer or wound exudate is present

Deep-skin and soft-tissue infections

• The patient may be acutely ill, with painful induration of the soft tissues in the extremity
• Wound discharge is usually not present
• In mixed infections that may involve anaerobes, crepitation may be noted over the afflicted area
• Extreme pain and tenderness may indicate compartment syndrome or clostridial infection (ie, gas gangrene)
• The tissues are not tense, and bullae may be present
• Discharge, if present, is often foul

Acute osteomyelitis

• Unless peripheral neuropathy is present, the patient has pain at the site of the involved bone
• Usually, fever and regional adenopathy are absent

Chronic osteomyelitis

• The patient's temperature is usually less than 102°F
• Discharge is commonly foul
• No lymphangitis is observed
• Pain may or may not be present, depending on the degree of peripheral neuropathy
• Deep, penetrating ulcers and deep sinus tracts (diagnostic of chronic osteomyelitis) are usually located between the toes or on the plantar surface of the foot
• The medial malleoli, shins, or heels are not usually sites of involvement

See Clinical Presentation for more detail.

Diagnosis

Cellulitis

• The WBC and ESR are slightly or moderately elevated, but these elevations are not diagnostic
• Blood culture results are usually negative; if positive, they usually indicate the presence of group A or group B streptococci

Cultures of skin via aspiration or biopsy are generally unrewarding; aspiration of a sample from the leading edge of the erythematous border has a low yield (likely < 5%) but may be used if the likely organism must be identified on initial presentation

Skin and soft-tissue infections

• The WBC and ESR are mildly or moderately elevated
• If bullae are present, Gram stain and culture results from aspirated exudate from a bullous lesion may help identify the pathogen
• Blood culture results may be positive
• In suspected deep soft-tissue infection, plain radiography, CT, or MRI may be performed to evaluate for compartment syndrome or for gas or a foreign body in the deep tissues^[1] ; excessive gas signifies a mixed aerobic-anaerobic infection, in contrast to gas gangrene (clostridial myonecrosis)
• Gram stains and/or cultures of samples aspirated from deep-skin and soft-tissue infections may be used to identify the organism

Acute osteomyelitis

• The WBC usually reveals leukocytosis, and the ESR is moderately or highly elevated^[2]
• Blood culture results are usually negative; when positive, the findings most frequently indicate the presence of S aureus
• For affected long bones, plain radiographic findings generally become abnormal after 10-14 days; soft-tissue swelling and periosteal elevation are the earliest signs
• Bone scans are preferred to gallium or indium scans; bone-scan findings are positive within 24 hours
• Bone biopsy is not necessary

Chronic osteomyelitis

• The WBC is often within the reference range; the ESR is usually very highly elevated and may exceed 100 mm/hr^[2] ; the platelet count is also often elevated
• Blood culture results are usually negative
• Plain radiographic findings are invariably abnormal
• Bone scans are usually unnecessary unless diagnostic confusion exists with another disorder (eg, bone tumor); an MRI scan would also be helpful in such a situation
• Bone biopsy performed under aseptic conditions in the operating room is the preferred way to identify the causative pathogen
• Important pathogens include Bacteroides fragilis, E coli, Proteus mirabilis, and Klebsiella pneumoniae; Pseudomonas aeruginosa is usually not the causative organism

See Workup for more detail.

Management

Treatment of diabetic foot infections varies by type, as follows:

• Cellulitis – Most responsive to antibiotics
• Deep skin and soft-tissue infections – Usually curable, but additional debridement is usually indicated
• Acute osteomyelitis – Infecting microorganisms and the likelihood of successful treatment with antimicrobial therapy are essentially the same as in patients without diabetes
• Chronic osteomyelitis – Surgical debridement is essential, in addition to antibiotics; amputation may be necessary

See Treatment and Medication for more detail.

• References

Background

Foot infections are the most common problems in persons with diabetes. These individuals are predisposed to foot infections because of a compromised vascular supply secondary to diabetes. Local trauma and/or pressure (often in association with lack of sensation because of neuropathy), in addition to microvascular disease, may result in various diabetic foot infections that run the spectrum from simple, superficial cellulitis to chronic osteomyelitis.

The radiograph below demonstrates a foot lesion in a patient with diabetes.

View Image

Chronic diabetic ulceration with underlying osteomyelitis. Plain film radiograph exhibiting cortical disruption at the medial aspect of the first MTP ....

Infections in patients with diabetes are difficult to treat because these individuals have impaired microvascular circulation, which limits the access of phagocytic cells to the infected area and results in a poor concentration of antibiotics in the infected tissues. In addition, diabetic individuals can not only have a combined infection involving bone and soft tissue called fetid foot, a severe and extensive, chronic soft-tissue and bone infection that causes a foul exudate, but they may also have peripheral vascular disease that involves the large vessels, as well as microvascular and capillary disease that results in peripheral vascular disease with gangrene.^{[3, 4, 5, 6, 7]}

Except for chronic osteomyelitis, infections in patients with diabetes are caused by the same microorganisms that can infect the extremities of persons without diabetes. Gas gangrene is conspicuous because of its low incidence in patients with diabetes, but deep-skin and soft-tissue infections, which are due to gas-producing organisms, frequently occur in patients with these infections.

In general, foot infections in persons with diabetes become more severe and take longer to cure than do equivalent infections in persons without diabetes.

Staging in diabetic foot infections is applicable only in cases of chronic osteomyelitis that require surgery.

Go to Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, and Diabetic Ulcers to see more complete information on these topics.

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Pathophysiology

In chronic osteomyelitis, a sequestrum and involucrum form; these represent islands of infected bone. Bone fragments that are isolated have no blood supply.

Bacteremia may accompany cellulitis, skin or soft-tissue infections, and/or acute osteomyelitis, but this is not a complication per se. If chronic osteomyelitis is left untreated for years, it may lead to complications such as amyloidosis or squamous cell carcinoma at the site of drainage through the skin. Bacteremia and septic shock rarely, if ever, occur as a result of chronic osteomyelitis.

Research indicates that when present in Staphylococcus aureus, the prophage ROSA-like inhibits the bacterium from infecting diabetic foot ulcers and also prevents S aureus from replicating inside osteoblasts, diminishing cell damage to these lesions.^[8]

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Etiology

Diabetes mellitus is a disorder that primarily affects the microvascular circulation. In the extremities, microvascular disease due to "sugar-coated capillaries" limits the blood supply to the superficial and deep structures. Pressure due to ill-fitting shoes or trauma further compromises the local blood supply at the microvascular level, predisposing the patient to infection, which may involve the skin, soft tissues, bone, or all of these combined.

Diabetes also accelerates macrovascular disease, which is evident clinically as accelerating atherosclerosis and/or peripheral vascular disease. Most diabetic foot infections occur in the setting of good dorsalis pedis pulses; this finding indicates that the primary problem in diabetic foot infections is microvascular compromise.

Impaired microvascular circulation hinders white blood cell migration into the area of infection and limits the ability of antibiotics to reach the site of infection in an effective concentration. Diabetic neuropathy may be encountered in conjunction with vasculopathy. This may allow for incidental trauma that goes unrecognized (eg, blistering, penetrating foreign body). Go to Diabetic Neuropathy for more complete information on this topic.

Microbial characteristics

The microbiologic features of diabetic foot infections vary according to the tissue infected. In patients with diabetes, superficial skin infections, such as cellulitis, are caused by the same organisms as those in healthy hosts, namely group A streptococci and S aureus. In unusual epidemiologic circumstances, however, organisms such as Pasteurella multocida (eg, from dog or cat bites or scratches) may be noted and should always be considered. Group B streptococcal cellulitis is uncommon in healthy hosts but not uncommon in patients with diabetes. In diabetic individuals, group B streptococci may cause urinary tract infections and catheter-associated bacteriuria in addition to cellulitis, skin and/or soft-tissue infections, and chronic osteomyelitis. Such infections may be complicated by bacteremia.

Furthermore, as previously mentioned, deep soft-tissue infections in diabetic persons can be associated with gas-producing, gram-negative bacilli. Clinically, these infections appear as necrotizing fasciitis, compartment syndrome, or myositis. Gas gangrene is uncommon in persons with diabetes.

Acute osteomyelitis usually occurs as a result of foot trauma in an individual with diabetes. The distribution of organisms is the same as that in an individual without diabetes who has acute osteomyelitis. In chronic osteomyelitis, however, the pathogens include group A and group B streptococci, aerobic gram-negative bacilli, and Bacteroides fragilis.

Other pathogens implicated in chronic osteomyelitis in patients with diabetes include B fragilis, Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae.

Pseudomonas aeruginosa is generally not a pathogen in chronic osteomyelitis in these individuals. Although P aeruginosa is frequently cultured from samples obtained from a draining sinus tract or deep penetrating ulcers in patients with diabetes, these organisms are superficial colonizers and are generally not the cause of the bone infection.

Because Pseudomonas organisms are water-borne, superficial ulcers may be contaminated by bacteria in wet socks or dressings. To the authors' knowledge, however, no well-documented cases of biopsy-proven P aeruginosa infection have been reported in patients with chronic osteomyelitis.

Fetid foot represents a combined deep-skin and soft-tissue infection caused by pathogens involved in chronic osteomyelitis.

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Epidemiology

Globally, diabetic foot infections are the most common skeletal and soft-tissue infections in patients with diabetes. The incidence of diabetic foot infections is similar to that of diabetes in various ethnic groups and most frequently affect elderly patients. There are no significant differences between the sexes.

Mortality is not common, except in unusual circumstances. The mortality risk is highest in patients with chronic osteomyelitis and in those with acute necrotizing soft-tissue infections.

A prospective cohort study by Lynar et al indicated that in patients with diabetic foot infections, the mortality risk is increased in those who are undergoing hemodialysis or of older age. The 1-year, cumulative mortality risk in patients receiving hemodialysis was determined to be 24.5%.^[9]

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Prognosis

The prognosis for cases of cellulitis, skin and/or soft-tissue infections, and acute osteomyelitis depends on the adequacy of antimicrobial therapy and surgical debridement. For cases of chronic osteomyelitis, the prognosis is directly related to the vascular supply in the affected limb and the adequacy of surgical debridement.

In a German study, nearly 250 patients with diabetic foot ulcers were evaluated and followed over time. Major adverse risk factors for long-term limb salvage included the presence of significant peripheral artery disease and renal insufficiency.^[10]

A study by Chammas et al indicated that ischemic heart disease is the primary cause of premature death in patients with diabetic foot ulcer, finding it to be the major source of mortality on postmortem examination in 62.5% of 243 diabetic foot ulcer patients. The study also found that in patients with diabetic foot ulcer, the mean age of death from ischemic heart disease, as derived from postmortem examination, was 5 years below that of controls. Patients with neuropathic foot ulcers were determined to have the highest risk of premature death from ischemic heart disease.^[11]

A study by Chen et al indicated that following hospital treatment for diabetic foot ulcer, invasive systemic infection associated with the ulcer (DFU-ISI) is an important late complication that increases mortality risk. In the study’s patients, methicillin-resistant Staphylococcus aureus (MRSA) gave rise to 57% of the ISIs. Using Cox regression modeling, the investigators found that complicated ulcer healing and the presence of MRSA in the initial ulcer culture predicted the development of DFU-ISIs (hazard ratios of 3.812 and 2.030, respectively), with the hazard ratio for mortality risk in association with DFU-ISIs being 1.987.^[12]

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Patient Education

Patients with diabetes must be careful to avoid foot trauma and to properly care for their feet to minimize the possibility of infection. In addition, they must understand that chronic osteomyelitis cannot be cured with antibiotics alone and that adequate surgical debridement is necessary.

Patients who are unwilling to undergo the surgical procedure must understand the long-term complications of chronic osteomyelitis. They should be advised that if the infection is not adequately treated with sufficient surgical debridement and/or amputation, systemic complications, including bacteremia and/or systemic infection, amyloidosis, and squamous cell carcinoma at the affected site, may occur over time.

Long-term suppressive therapy may decrease the incidence of septic complications, but it does not affect the long-term complications, which may include amyloidosis or squamous cell carcinoma at the drainage site.

For patient education information, see the Diabetes Center, as well as Diabetic Foot Care.

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History

As previously mentioned, local trauma and/or pressure (often in association with lack of sensation because of neuropathy), in addition to microvascular disease, may lead to a diabetic foot infection. However, patients may not necessarily have a history of trauma or have suffered a previous infection.

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Physical Examination

Cellulitis

Cellulitis may involve tender, erythematous, nonraised skin lesions on the lower extremity that may or may not be accompanied by lymphangitis. Lymphangitis suggests a group A streptococcal etiology. If bullae are present, S aureus is the most likely pathogen, but group A streptococci occasionally cause bullous lesions. No ulcer or wound exudate is present in patients with cellulitis.

Deep-skin and soft-tissue infections

Patients with deep-skin and soft-tissue infections may be acutely ill, with painful induration of the soft tissues in the extremity. These infections are particularly common in the thigh area, but they may be seen anywhere on the leg or foot. Wound discharge is usually not present.

In mixed infections that may involve anaerobes, crepitation may be noted over the afflicted area. Extreme pain and tenderness indicate the possibility of a compartment syndrome. Similarly, extreme pain may be an indication of infection with clostridial species (ie, gas gangrene). The tissues are not tense, and bullae may be present. If a discharge is present, it is often foul.

Acute osteomyelitis

Unless peripheral neuropathy is present, the patient has pain at the site of the involved bone. Usually, fever and regional adenopathy are absent.

Chronic osteomyelitis

In chronic osteomyelitis, the patient's temperature is usually less than 102°F. Discharge is commonly foul. No lymphangitis is observed, and pain may or may not be present, depending on the degree of peripheral neuropathy.

The deep, penetrating ulcers and deep sinus tracts (which are diagnostic of chronic osteomyelitis) are usually located between the toes or on the plantar surface of the foot. In patients with diabetes, chronic osteomyelitis usually does not occur on the medial malleoli, shins, or heels. (See the image below.)

View Image

Chronic diabetic ulceration with underlying osteomyelitis. Plain film radiograph exhibiting cortical disruption at the medial aspect of the first MTP ....

• References

Approach Considerations

The patient’s white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) vary according to the type of diabetic foot infection.^[2] Gram stain and cultures can aid in determining the etiology of infection in skin and soft-tissue infections, while in acute osteomyelitis and cellulitis, blood cultures can help to identify causative organisms. In chronic osteomyelitis, bone biopsy can be used to find the infecting microbe.

A multicenter, prospective, cross-sectional study by Nelson et al indicated that the use of tissue samples is superior to that of wound swabs in identifying pathogens in infected diabetic foot ulcers. The investigators found that pathogens were more often identified, and nonpathogens less often identified, using tissue samples than wound swabs, with antibiotic regimen changes more frequently recommended by blinded clinicians in response to the results of tissue samples than to those of swabs.^[13]

Imaging studies do not play a role in the diagnosis of cellulitis, but they are a valuable tool in the assessment of the other infection types.

• References

Cellulitis

The WBC and ESR are slightly or moderately elevated in cellulitis. However, the elevations are not diagnostic and, therefore, are unhelpful.

Blood culture results are usually negative. If positive, they usually indicate the presence of group A or group B streptococci.

Cultures of skin via aspiration or biopsy are generally unrewarding. Aspiration of a sample from the leading edge of the erythematous border may be performed if the likely organism must be identified on initial presentation. However, the yield is low, likely to be less than 5%.

Imaging studies are not applicable in cellulitis.

• References

Skin and Soft-Tissue Infections

The WBC and ESR are mildly or moderately elevated in these tissue infections. If bullae are present, Gram stain and culture results from aspirated exudate from a bullous lesion may provide clues to the etiology of the infection. Blood culture results may be positive.

In a patient with diabetes who are considered to have a deep soft-tissue infection, plain radiography, computed tomography (CT), or magnetic resonance imaging (MRI) may be performed to rule out a compartment syndrome, which may present as extreme pain and tenderness of the affected limb, or to demonstrate the presence of gas or a foreign body in the deep tissues.^[1] A finding of excessive gas signifies a mixed aerobic-anaerobic infection, in contrast to gas gangrene (clostridial myonecrosis).

Samples from deep-skin and soft-tissue infections may be aspirated. Gram stains, cultures, or both may be used to identify the organism.

• References

Acute Osteomyelitis

In acute osteomyelitis, the WBC is usually elevated and the ESR is moderately or highly elevated.^[2] Blood culture results are usually negative; when positive, blood cultures most frequently indicate the presence of Staphylococcus aureus.

For affected long bones, plain radiographic findings generally become abnormal after 10-14 days. Soft-tissue swelling and periosteal elevation are the earliest signs of acute osteomyelitis on a plain radiograph.

Bone scans are preferred to gallium or indium scans in the assessment of acute osteomyelitis, as the latter imaging studies offer no additional information, and the findings are not more specific than those of bone scans. In addition, indium scans often show false-negative results in acute or chronic osteomyelitis. Bone-scan findings are positive within 24 hours.

Bone biopsy is not necessary in acute osteomyelitis, because the pathogens are predictable.

• References

Chronic Osteomyelitis

In chronic osteomyelitis, the WBC is often within the reference range. Usually, the ESR is very highly elevated and may exceed 100 mm/h.^[2] The platelet count is also often elevated in chronic osteomyelitis. Blood culture results are usually negative.

When osteomyelitis becomes chronic, plain radiographic findings are invariably abnormal, as shown in the image below.

View Image

Chronic diabetic ulceration with underlying osteomyelitis. Plain film radiograph exhibiting cortical disruption at the medial aspect of the first MTP ....

Bone scans are usually unnecessary unless diagnostic confusion exists with another disorder, as when a bone tumor must be differentiated from chronic osteomyelitis before definitive bone biopsy. An MRI would also be helpful in such a situation.

Bone biopsy performed under aseptic conditions in the operating room is the preferred way to identify the pathogen in chronic osteomyelitis. Bacteroides fragilis is an important cause of chronic osteomyelitis in patients with diabetes, as are Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. Pseudomonas aeruginosa is usually not the causative organism.

Because surgical debridement is critical in treating chronic osteomyelitis, bone biopsy specimens are usually not obtained during the surgical debridement procedure.

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Histologic Findings

Subperiosteal elevation and/or infection may involve the cortex in acute osteomyelitis. Involucrum and/or sequestrum may be present in the cortical bone in cases of chronic osteomyelitis.

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Approach Considerations

Cellulitis is the easiest diabetic foot infection to cure, because it does not pose the same circulatory limitations that the more serious infections do, making it easier for medications to reach the infection site. In contrast, chronic osteomyelitis, which is the most difficult diabetic foot infection to cure, requires surgical debridement before antibiotic therapy can be effective. The patient may participate in activities as tolerated. However, weight bearing may be contraindicated. Glycemic control must be achieved to favorably affect outcome; it is important for microbial eradication and tissue healing. 

Collaborative clinical practice guidelines for treating diabetic foot have been published by the Society for Vascular Surgery, the American Podiatric Medical Association, and the Society for Vascular Medicine.^[14] Guideline developers highlighted the strong evidence for total contact casting in the treatment of plantar diabetic foot ulcers, which they indicated was not a new treatment, but one that is underutilized. Other important aspects in the guidelines are as follows:

• Help identify high-risk patients
• Periodic updates required based on the emergence of new evidence
• Identification of, grading of, and protocols for various wound care treatments in diabetic foot
• Implementation of guidelines into training programs

A literature review by Matos et al suggested that exercise and physical activity are effective against the complications of diabetic foot. The investigators found that patients involved in physical activity and exercise had a lower annual incidence of ulcers than other patients in the study (0.02 vs 0.12, respectively). Moreover, nerve velocity conduction, peripheral sensory function, and foot peak pressure distribution significantly improved in the physical activity/exercise group.^[15]

A prospective observational study by Hwang et al indicated that treatment with allogeneic keratinocyte dressings is effective in patients with chronic, intractable diabetic foot ulcers. Of the 71 patients in the study, all of whom underwent weekly keratinocyte therapy, 56 (78.9%) experienced complete wound healing, including 46 (64.8%) in whom complete healing occurred within an average of 6.1 weeks.^[16]

Go to Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Foot; and Diabetic Ulcers to see more complete information on these topics.

• References

Offloading

A 9-member panel of podiatrists, surgeons, and other experts in diabetic foot care provided the following new guidelines based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system:^{[17, 18]}

• Vascular management, infection management and prevention, and pressure relief are essential to diabetic foot ulcer healing. Often denoted in the wound-care literature as VIP, this is the overall aggressive approach the panel deems necessary for foot ulcer healing.
• Vascular assessment requires a combination of physical examination and laboratory tests. Blood pressure indices such as the ankle-brachial index have poor reliability in patients with diabetes, so they should not be used as the only assessment.
• For infection diagnosis and treatment, the panel endorses the clinical practice guidelines of the Infectious Diseases Society of America.
• Adequate offloading increases the likelihood of diabetic foot ulcer healing. Several studies suggest that offloading facilitates healing by reducing both pressure on the foot and strain rate.
• For guidance on offloading the Charcot foot, the panel endorses the Charcot Foot in Diabetes Consensus Report.^[19]
• Total contact casting is the preferred method for offloading plantar diabetic foot ulcers because it has most consistently demonstrated the best healing outcomes and is a cost-effective treatment.
• Advanced therapeutics are unlikely to succeed in improving wound-healing outcomes unless effective offloading is achieved.
• Several studies support the use of advanced therapies, such as cellular or tissue-based wound-healing products, as adjunctive wound care treatments, but only if offloading is also achieved.

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Antimicrobial Therapy

Infections in patients with diabetes are difficult to treat because these patients have impaired microvascular circulation, which limits the access of phagocytic cells to the infected area and results in a poor concentration of antibiotics in the infected tissues. For this reason, cellulitis is the most easily treatable and reversible form of foot infections in patients with diabetes. Deep-skin and soft-tissue infections are also usually curable, but they can be life threatening and result in substantial long-term morbidity.^{[3, 4, 5, 6, 7]}

For specific information concerning the evaluation and management of diabetic foot infections, including choices of antimicrobial agents, the reader is referred to authoritative guidelines published by the Infectious Diseases Society of America.^[20]

If infection is suspected, the choice of antibiotics should be based on type/severity of the infection and the likelihood that resistant organisms are involved. Ideally, antibiotics should be chosen based on culture and sensitivity data, but these are not always available. Because data are limited, it is often difficult to compare treatment regimens for efficacy.

Patients with mild infections can be treated in outpatient settings with oral antibiotics that cover skin flora including streptococci and Staphylococcus aureus. Agents such as cephalexin, dicloxacillin, amoxicillin-clavulanate, or clindamycin are effective choices. If methicillin-resistant S aureus (MRSA) infection is suspected, then clindamycin, trimethoprim-sulfamethoxazole, minocycline, or linezolid may be used. If gram-negative aerobes and/or anaerobes are suspected, dual drug treatment with trimethoprim-sulfamethoxazole plus amoxicillin-clavulanate or clindamycin plus a fluoroquinolone such as levofloxacin or moxifloxacin may be used.

For moderate-to-severe infections, patients should be hospitalized for parenteral antibiotic therapy. Empiric choices should cover streptococci, MRSA, aerobic gram-negative bacilli, and anaerobes. MRSA is covered by vancomycin, linezolid, or daptomycin. Acceptable choices for gram-negative aerobic organisms and anaerobes include ampicillin-sulbactam, piperacillin-tazobactam, meropenem, or ertapenem. Alternatively, ceftriaxone, cefepime, levofloxacin, moxifloxacin, or aztreonam plus metronidazole would be sufficient to cover aerobic gram-negative and anaerobic organisms. Tigecycline has been studied, but published experience is limited.

Duration of therapy should be individualized. For those treated in outpatient settings with oral antibiotics, duration of treatment is usually 7-14 days. In those treated parenterally but without osteomyelitis, 2-4 weeks is sufficient.

In patients with diabetic foot osteomyelitis, a 6-week course of antibiotics may be sufficient even in the absence of surgery, according to a randomized prospective study of 40 French patients. Current guidelines recommend at least 3 months or more of antibiotic therapy when diabetic foot osteomyelitis is not treated surgically or when residual dead bone remains after surgery. In the study, however, remission occurred in 12 patients (60%) treated for 6 weeks and in 14 patients (70%) treated for 12 weeks (P = 0.50).^{[21, 22]}

Antibiotics were administered orally for the entire treatment period or intravenously for 5 to 7 days and then orally. Remission was defined as complete and sustained healing of the wound, if present; absence of recurrent infection; and no need for surgical intervention by at least 1 year months after completion of antibiotic treatment. Antibiotic-related adverse events were observed in six (30%) of the patients in the 6-week-treatment group and 10 (50%) of the patients in the 12-week treatment group.^{[21, 22]}

Duration of treatment may be shortened in those patients who undergo amputation as part of the treatment regimen. Consultation with an infectious diseases expert is recommended.

In terms of the infecting microorganisms and the likelihood of successful treatment with antimicrobial therapy, acute osteomyelitis in patients with diabetes is essentially the same as in those without diabetes.

As previously mentioned, in chronic osteomyelitis, a sequestrum and involucrum form; these represent islands of infected bone. Bone fragments that are isolated have no blood supply; systemic antibiotics do not penetrate these devascularized, infected bone fragments. Therefore, antibiotic therapy alone cannot cure patients with chronic osteomyelitis.

Adequate surgical debridement, in addition to antimicrobial therapy, is necessary to cure chronic osteomyelitis. Immobilization is important in acute or chronic osteomyelitis.

Dry gangrene is usually managed with expectant care, and gross infection is usually not present. Wet gangrene usually has an infectious component and requires surgical debridement and/or antimicrobial therapy to control the infection.

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Surgical Debridement

Surgical debridement in diabetic patients with chronic osteomyelitis is the most important therapeutic intervention, as this condition cannot be cured without it. This is because debridement removes the infected, bony fragments that antibiotics cannot reach so that affected areas can be treated with antimicrobial therapy; in some cases, amputation is required. Patients who have fetid foot require extensive surgical debridement and/or amputation. If amputation is performed, physical therapy and rehabilitation may be started on an inpatient basis and completed on an outpatient basis.

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Consultations

Appropriate consultation with a surgeon should be obtained for debridement and/or amputation in chronic osteomyelitis, as well as for debridement or decompression of compartment syndromes in patients with deep-skin and soft-tissue infections. In addition, a vascular surgical evaluation to bypass large-vessel occlusive disease should be considered in patients with diabetic foot infections and peripheral vascular disease. Note, however, that large-vessel bypass does not cure the microvascular component of diabetic foot infections.

An infectious disease specialist should be consulted in the treatment of all patients with diabetic foot infections to optimize the antimicrobial therapy.

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Long-Term Monitoring

Cellulitis

No further care is necessary.

Skin and soft-tissue infection

Additional debridement is generally indicated. The best care plan is aggressive therapy to avoid surgery beyond transmetatarsal amputation (ie, limit surgical extirpation to the forefoot).

Acute osteomyelitis

Monitor the patient's condition to ensure that the infection has resolved.

Chronic osteomyelitis

Ensure that debridement is complete and that no further remnants of infected bone remain.

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Guidelines Summary

A 2016 study by Allahabadi et al developed consensus statements on the surgical management of diabetic foot osteomyelitis. These included the following with regard to the operative management of diabetic forefoot osteomyelitis^[23] :

• Before bone is definitively resected and soft-tissue closure/reapproximation is performed over remaining bone, concomitant deep soft-tissue infection (ie, abscess, joint-space infection) or soft-tissue necrosis should be drained/debrided and controlled
• When serial operations are performed for soft-tissue infection in patients with diabetic foot osteomyelitis, the use of negative-pressure wound therapy dressings with instillation may be considered during intervals between surgeries
• Whenever possible, bone should be resected until grossly healthy bone is revealed (that is, bone with normal caliber, smooth cortical contour, firm density, and punctate bleeding)
• All areas of significant cortical destruction demonstrated on plain radiography, as well as any grossly infected, necrotic, or fragmented bone, should be included in the bone resection.
• Grossly abnormal or infected bone should be sent for microbiology
• Analysis of operative bone specimens sent for microbiology should include microscopic examination of a Gram-stained smear, along with the assessment of aerobic and anaerobic cultures
• Grossly abnormal or infected bone should be sent for histopathology
• A sample of the proximal-most bone resected (ie, a bone-margin specimen) should be labeled separately and sent for histopathology
• A sample of the proximal-most bone resected (ie, a bone-margin specimen) should be labeled separately and sent for microbiology
• A power saw is the preferred instrument for bone transection
• Final bone resection and attempted delayed primary skin and soft-tissue closure should be performed 3-7 days after soft-tissue infection or necrosis has been attended to and appropriate antibiotic therapy has commenced
• Preferably, grossly normal-appearing bone margins should be obtained at the time of the final planned operative debridement
• For selected patients with osteomyelitis, partial ostectomy of the distal metatarsal and/or proximal phalanx is an acceptable alternative to ray amputation if there is no radiographic involvement of the remaining bone, if the bone looks normal at surgery, and if abnormal biomechanics of the residual forefoot are not anticipated
• In patients with significant ankle equinus deformity (inability to dorsiflex the ankle past neutral), adjunctive tendo-Achilles lengthening should always be considered
• When significant forefoot biomechanical issues (eg, hallux valgus and hammertoe deformities) pose the risk of reulceration or new (transfer) ulcers, podiatric/orthopedic procedures should always be considered

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Medication Summary

For specific information concerning the evaluation and management of diabetic foot infections, including choices of antimicrobial agents, the reader is referred to authoritative guidelines published by the Infectious Diseases Society of America.^[20]

Patients with mild infections can be treated in outpatient settings with oral antibiotics that cover skin flora including streptococci and Staphylococcus aureus. Agents such as cephalexin, dicloxacillin, amoxicillin-clavulanate, or clindamycin are effective choices. If methicillin-resistant S aureus (MRSA) infection is suspected, then clindamycin, trimethoprim-sulfamethoxazole, minocycline, or linezolid may be used. If gram-negative aerobes and/or anaerobes are suspected, dual drug treatment with trimethoprim-sulfamethoxazole plus amoxicillin-clavulanate or clindamycin plus a fluoroquinolone such as levofloxacin or moxifloxacin may be used.

For moderate-to-severe infections, patients should be hospitalized for parenteral antibiotic therapy. Empiric choices should cover streptococci, MRSA, aerobic gram-negative bacilli, and anaerobes. MRSA is covered by vancomycin, linezolid, or daptomycin. Acceptable choices for gram-negative aerobic organisms and anaerobes include ampicillin-sulbactam, piperacillin-tazobactam, meropenem, or ertapenem. Alternatively, ceftriaxone, cefepime, levofloxacin, moxifloxacin, or aztreonam plus metronidazole would be sufficient to cover aerobic gram-negative and anaerobic organisms. Tigecycline has been studied, but published experience is limited.

Duration of therapy should be individualized. For those treated in outpatient settings with oral antibiotics, duration of treatment is usually 7-14 days. In those treated parenterally but without osteomyelitis, 2-4 weeks is sufficient. Longer duration of therapy is required for those with osteomyelitis—4-6 weeks at a minimum is suggested. Duration of treatment may be shortened in those patients who undergo amputation as part of the treatment regimen.

Consultation with an infectious diseases expert is recommended.

• References

Dicloxacillin

• Dosing, Interactions, etc.

Clinical Context:  Dicloxacillin binds to one or more penicillin binding proteins, which, in turn, inhibits synthesis of bacterial cell walls. It is used for the treatment of infections caused by penicillinase-producing staphylococci. It may be used as initial therapy when staphylococcal infections are suspected.

• References

Ampicillin/sulbactam (Unasyn)

• Dosing, Interactions, etc.

Clinical Context:  Ampicillin/sulbactam is a drug combination of beta-lactamase inhibitor with ampicillin. It interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. It is an alternative to amoxicillin when patients are unable to take medication orally. It covers skin, enteric flora, and anaerobes but is not ideal for nosocomial pathogens.

• References

Amoxicillin/clavulanate (Augmentin, Augmentin XR)

• Dosing, Interactions, etc.

Clinical Context:  Amoxicillin inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. The addition of clavulanate inhibits beta-lactamase–producing bacteria. It is a good alternative antibiotic for patients allergic to or intolerant of the macrolide class. Usually, it is well tolerated and provides good coverage of most infectious agents. It is not effective against Mycoplasma and Legionella species.

• References

Piperacillin/tazobactam (Zosyn)

• Dosing, Interactions, etc.

Clinical Context:  The piperacillin/tazobactam drug combination is composed of an antipseudomonal penicillin plus a beta-lactamase inhibitor. It inhibits biosynthesis of cell wall mucopeptide and is effective during the active multiplication stage.

• References

Ticarcillin/clavulanate (Timentin)

• Dosing, Interactions, etc.

Clinical Context:  Ticarcillin/clavulanate inhibits the biosynthesis of cell wall mucopeptide and is effective during the stage of active growth. It is an antipseudomonal penicillin plus beta-lactamase inhibitor that provides coverage against most gram-positives, most gram negatives, and most anaerobes.

• References

Class Summary

The penicillins are bactericidal antibiotics that work against sensitive organisms at adequate concentrations and inhibit the biosynthesis of cell wall mucopeptide.

• References

Cephalexin (Keflex)

• Dosing, Interactions, etc.

Clinical Context:  Cephalexin is a first-generation cephalosporin that inhibits bacterial replication by inhibiting bacterial cell wall synthesis. It is bactericidal and effective against rapidly growing organisms forming cell walls. Resistance occurs by alteration of penicillin-binding proteins. It is effective for the treatment of infections caused by streptococcal or staphylococcal organisms, including penicillinase-producing staphylococci. It may be used as initial therapy when streptococcal or staphylococcal infection is suspected.

• References

Ceftriaxone (Rocephin)

• Dosing, Interactions, etc.

Clinical Context:  Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Bactericidal activity results from inhibiting cell wall synthesis by binding to one or more penicillin-binding proteins. It exerts its antimicrobial effect by interfering with the synthesis of peptidoglycan, a major structural component of the bacterial cell wall. Bacteria eventually lyse from the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested.

• References

Cefoxitin

• Dosing, Interactions, etc.

Clinical Context:  Cefoxitin is a second-generation cephalosporin with activity against some gram-positive cocci, gram-negative rod infections, and anaerobic bacteria. It inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins. It inhibits the final transpeptidation step of peptidoglycan synthesis, resulting in cell wall death. Infections caused by cephalosporin- or penicillin-resistant gram-negative bacteria may respond to cefoxitin.

• References

Cefuroxime (Ceftin)

• Dosing, Interactions, etc.

Clinical Context:  Cefuroxime is a second-generation cephalosporin that maintains the gram-positive activity of first-generation cephalosporins. It adds activity against P mirabilis, H influenzae, E coli, K pneumoniae, and Moraxella catarrhalis. It binds to penicillin-binding proteins and inhibits the final transpeptidation step of peptidoglycan synthesis, resulting in cell wall death. The condition of the patient, the severity of the infection, and the susceptibility of the microorganism determine the proper dose and route of administration.

• References

Class Summary

Cephalosporins are structurally and pharmacologically related to penicillins. They inhibit bacterial cell wall synthesis, resulting in bactericidal activity. Cephalosporins are divided into first, second, third and fourth generation. First-generation cephalosporins have greater activity against gram-positive bacteria, and succeeding generations have increased activity against gram-negative bacteria and decreased activity against gram-positive bacteria.

• References

Meropenem (Merrem)

• Dosing, Interactions, etc.

Clinical Context:  Meropenem is a bactericidal broad-spectrum carbapenem antibiotic that inhibits cell-wall synthesis. It is effective against most gram-positive and gram-negative bacteria. It has slightly increased activity against gram-negatives and slightly decreased activity against staphylococci and streptococci compared with imipenem.

• References

Ertapenem (Invanz)

• Dosing, Interactions, etc.

Clinical Context:  The bactericidal activity of ertapenem results from the inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin-binding proteins. It is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, cephalosporinases, and extended-spectrum beta-lactamases.

• References

Class Summary

Carbapenems are structurally related to penicillins and have broad-spectrum bactericidal activity. The carbapenems exert their effect by inhibiting cell wall synthesis, which leads to cell death. They are active against gram-negative, gram-positive, and anaerobic organisms.

• References

Levofloxacin (Levaquin)

• Dosing, Interactions, etc.

Clinical Context:  Levofloxacin is used for infections caused by various gram-negative organisms and antipseudomonal infections due to multidrug resistant gram-negative organisms.

• References

Moxifloxacin (Avelox)

• Dosing, Interactions, etc.

Clinical Context:  Moxifloxacin is a fluoroquinolone that inhibits A subunits of DNA gyrase, inhibiting bacterial DNA replication and transcription.

• References

Class Summary

Fluoroquinolones have broad-spectrum activity against gram-positive and gram-negative aerobic organisms. They inhibit DNA synthesis and growth by inhibiting DNA gyrase and topoisomerase, which is required for replication, transcription, and translation of genetic material.

• References

Clindamycin (Cleocin)

• Dosing, Interactions, etc.

Clinical Context:  Clindamycin is a semisynthetic antibiotic produced by 7(S)-chloro-substitution of 7(R)-hydroxyl group of the parent compound lincomycin. It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is used for the treatment of serious skin and soft-tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci, except enterococci.

• References

Metronidazole (Flagyl, Flagyl ER)

• Dosing, Interactions, etc.

Clinical Context:  Metronidazole is an imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. It is used in combination with other antimicrobial agents.

• References

Vancomycin (Vancocin)

• Dosing, Interactions, etc.

Clinical Context:  Vancomycin is used in prophylaxis. It is a potent antibiotic directed against gram-positive organisms and is active against Enterococcus species. It is useful in the treatment of septicemia and skin structure infections. It is indicated for patients who cannot receive or have not responded to penicillins and cephalosporins or have infections with resistant staphylococci.

• References

Linezolid (Zyvox)

• Dosing, Interactions, etc.

Clinical Context:  Linezolid is indicated to treat diabetic foot infections without osteomyelitis that are caused by gram-positive bacteria, including resistant strains (eg, methicillin-resistant S aureus [MRSA]). It prevents the formation of functional 70S initiation complex, which is essential for the bacterial translation process. It is bacteriostatic against enterococci and staphylococci and is bactericidal against most streptococci strains.

The FDA warns against the concurrent use of linezolid with serotonergic psychiatric drugs, unless indicated for life-threatening or urgent conditions. Linezolid may increase serotonin CNS levels as a result of MAO-A inhibition, increasing the risk of serotonin syndrome.^[15]

• References

Tigecycline (Tygacil)

• Dosing, Interactions, etc.

Clinical Context:  Tigecycline is a glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. It inhibits bacterial protein translation by binding to the 30S ribosomal subunit, and it blocks the entry of amino-acyl tRNA molecules in the ribosome A site. It is indicated for complicated skin and skin structure infections caused by E coli, Enterococcus faecalis (vancomycin-susceptible isolates only), S aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus agalactiae, Streptococcus anginosus group (includes S anginosus, Streptococcus intermedius, and Streptococcus constellatus), S pyogenes, and B fragilis.

• References

Class Summary

Anti-infectives such as metronidazole, clindamycin, tigecycline, linezolid, and vancomycin are effective against many types of bacteria that have become resistant to other antibiotics.

• References

Daptomycin

• Dosing, Interactions, etc.

Clinical Context:  Daptomycin binds to bacterial membranes and causes rapid membrane potential depolarization, thereby inhibiting protein, DNA, and RNA synthesis, and ultimately causing cell death. It is indicated for complicated skin and skin structure infections caused by S aureus (including methicillin-resistant strains), S pyogenes, S agalactiae, S dysgalactiae, and E faecalis (vancomycin-susceptible strains only).

• References

Class Summary

Daptomycin is the first in the new antibiotic class called cyclic lipopeptides.

• References