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    S104 CID 2004:39 (Suppl 2) Lipsky

    S U P P L E M E N T A R T I C L E

    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 infectionsrequire 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 anamputation, which may be minor (i.e., foot sparing)

    or major. Conversely, an infected foot ulcer precedes

    60% of amputations [24], 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 dis-

    turbances, such as impaired polymorphonuclear leu-

    kocyte 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:S10414

    2004 by the Infectious Diseases Society of America. All rights reserved.

    1058-4838/2004/3903S2-0007$15.00

    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 re-

    duced as well. Their higher rates of carriage ofStaph-

    ylococcus aureusin the anterior nares and skin [8], and

    several types of skin and nail disorders, may increasethe risk of skin and soft-tissue infections in diabetic

    patients. Accelerated atherosclerosis, especially of the

    arteries between the knee and ankle, increases the like-

    lihood of ischemia at the infection site. The anatomy

    of the foot, with its various compartments, tendon

    sheaths, and neurovascular bundles, may lead to prox-

    imal spread of infection and favors ischemic necrosis

    of the confined tissues [7, 9].

    MICROBIOLOGICAL CONSIDERATIONS

    Selecting appropriate antimicrobial therapy for diabeticfoot infections requires knowledge of the likely etiologic

    agents. Various skin disorders and environmental ex-

    posures, 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.

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    Diabetic Foot Treatment CID 2004:39 (Suppl 2) S105

    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 col-

    lected and processed properly. Antibiotic-susceptibility results

    generally help tailor (and in many cases constrain) antibiotic

    regimens. Deep tissue specimens, obtained aseptically at sur-

    gery, contain the true pathogens more often than do samples

    obtained from superficial lesions. A curettage, or tissue scrapingwith a scalpel, from the base of a debrided ulcer provides more

    accurate results than does a wound swab [1013]. Therapy

    directed against organisms isolated from culture of a swab sam-

    ple 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 ther-

    apy. Less virulent bacteria, such as enterococci, coagulase-neg-

    ative 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 hos-

    pitalized patients are often caused by 35 bacterial species, in-

    cluding 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.

    Pseudomonasspecies 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 anaer-

    obic species are most frequent in wounds with ischemic necrosis

    or that involve deep tissues. Anaerobes are rarely the sole path-

    ogen; most often they constitute a mixed infection with aerobes

    [14]. Antibiotic-resistant organisms, especially methicillin-re-

    sistantS. aureus,are frequently isolated from patients who have

    previously received antibiotic therapy; they are often (but not

    always) acquired during previous hospitalizations or at long-

    term 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 sen-

    sitive methods, such as rDNA sequencing, may detect missed

    organisms [17].

    DIAGNOSIS AND CLINICAL PRESENTATION

    Diagnosing infection. Because all skin wounds contain mi-

    croorganisms, infection must be diagnosed clinically, that is,

    by the presence of systemic signs (e.g., fever, chills, and leu-

    kocytosis), purulent secretions (pus), or 2 local classical signs

    or symptoms of inflammation (warmth, redness, pain or ten-

    derness, 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 neu-

    ropathy or ischemia can either mask or mimic inflammation.

    Occasionally, inflammatory signs may be caused by other non-infectious 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 meta-

    tarsal 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 one-

    third have had a foot lesion for 11 month. Many patients do

    not report pain, and more than half, including those with se-

    rious infections, do not have a fever, elevated WBC count, or

    elevated erythrocyte-sedimentation rate [1921].

    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 involvedand 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 rel-

    atively easily treated, moderately severe infections may be limb

    threatening, and severe infections may be life threatening. As-

    sessing the severity of infection is essential to selecting an an-

    tibiotic 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. Deepspace 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 suppu-

    rative 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.

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    S106 CID 2004:39 (Suppl 2) Lipsky

    Table 1. Clinical characteristics that help define the severity of an infection.

    Feature Mild infection Severe infection

    Presentation Slowly progressive Acute or rapidly progressive

    Ulceration Involves only skin Penetrates to subcutaneous tissues

    Tissues involved Epidermis, dermis Fascia, muscle, joint, bone

    Cellulitis Minimal (!2 cm around ulcer rim) Extensive, or distant from ulceration

    Local signs Limited inflammation Severe inflammation, crepitus, bullae, necrosis or gangrene

    Systemic signs None or minimal Fever, chills, hypotension, confusion, volume depletion,

    leukocytosis

    Metabolic control Mildly abnormal (hyperglycemia) Severe hyperglycemia, acidosis, azotemia, electrolyte

    abnormalities

    Foot vasculature Minimally impaired (normal/reduced pulses) Absent pulses, reduced ankle or toe blood pressure

    Complicating features None or minimal (callus, ulcer) 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 in-

    terventions, fluid resuscitation, and control of metabolic de-

    rangements. 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 (de-

    bridement, dressing changes, and pressure off-loading) and gly-

    cemic control should be optimized; antibiotics will not over-

    come inattention to these fundamentals.

    BONE INFECTION

    Diabetic patients can have destructive bone changes caused by

    peripheral neuropathy (i.e., neuroarthropathy, osteoarthropa-

    thy, 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 (osteomye-

    litis). About 50%60% of serious foot infections are compli-

    cated 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 sup-

    ply to the area, the extent of soft-tissue and bone destruction,

    the degree of systemic illness, and the patients preferences.

    Foot ulcers that are long standing (14 weeks), large (12 cm),

    and deep (13 mm) or are associated with a substantially ele-

    vated erythrocyte-sedimentation rate (170 mm/h) should be

    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 predic-

    tive 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 under-

    taking 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 di-

    agnostic techniques for osteomyelitis that show promise are

    high-resolution ultrasound [29] and positron-emission to-

    mography. However, MRI is usually the diagnostic procedure

    of choice, with a sensitivity of190% and a specificity of180%

    [30, 31]. The diagnostic test characteristics of all these proce-

    dures exhibit great variability across studies. Their interpreta-

    tion 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 theetiologic 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 de-

    bridement [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

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    Table 2. Factors that may influence anti-biotic treatment of diabetic foot infections(specific agents, route of administration, andduration 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

    diagnose infection. These procedures are easy to perform and

    are safe in experienced hands [33], although somewhat expen-

    sive. 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. aureusis the most com-mon etiologic agent (isolated in 40% of infections), but Staph-

    ylococcus epidermidis ( 25%), streptococci (30%), and En-

    terobacteriaceae (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 anti-

    microbial 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 practi-

    tioners believe that any foot ulcer requires administration of

    antibiotics, either for therapy or for prophylaxis, available stud-

    ies do not generally support this view [36]. In most of thepublished clinical trials, antibiotic therapy did not improve the

    outcome of uninfected lesions [37, 38]. One abstract [39] re-

    ported 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 am-

    putation. 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 cur-

    rently 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 patients

    condition is stabilized and the infection is clearly responding,

    most patients can have their treatment switched to oral therapy.

    Patients who require prolonged intravenous therapy, such asfor 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 par-

    enteral 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 bioa-

    vailability of orally administered agents. Gastrointestinal ab-

    sorption 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, inparticular, achieve high tissue concentrations at the site of di-

    abetic 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-resis-

    tant gram-positive cocci, such as linezolid, daptomycin, and

    newer fluoroquinolones, are especially appealing.

    When peripheral vascular disease is present, therapeutic an-

    tibiotic 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 pene-

    tration was the presence of ischemia, not diabetes [43]. Prob-

    lems with arterial insufficiency have led to experimentation

    with novel methods of antibiotic delivery. Retrograde venous

    perfusion consists of injecting antibiotic solutions under pres-

    sure into a foot vein while a sphygmomanometer is inflated

    on the thigh. High local antibiotic concentrations have been

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    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 closed-

    catheter 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 con-

    centrations of antibiotics with minimal systemic exposure.Several other novel routes of therapy have been explored. Su-

    perficial 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 antibiotic-

    impregnated 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 antibiotic-

    impregnated collagen (combined, at least initially, with oral an-

    tibiotics) in treating diabetic foot infections (including osteo-

    myelitis) [49]. For mildly infected foot ulcers, an additional

    option is topical antimicrobial therapy. This has several theo-

    retical 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, metron-

    idazole, and mupirocin have each been used for soft-tissue in-

    fections in other sites, but there are no published data on theirefficacy 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 an-

    tibiotic therapy with an empirical regimen. This should aim to

    cover the most common pathogens, with some modificationaccording 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 an-

    tibiotic therapy, and known local antibiotic susceptibility pat-

    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 gram-

    negative bacilli. This is unfortunate, because empirical antibi-

    otic 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 Enterococcusspe-

    cies. 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 wors-

    ening 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 antibiotics efficacy is the clinical

    trial. Agents that have demonstrated clinical effectiveness,aloneor in combination, in prospective studies including entirely or

    mostly patients with diabetic foot infections, include the fol-

    lowing [51]: cephalosporins (cephalexin orally; cefoxitin and

    ceftizoxime parenterally) [10, 5256]; penicillin/b-lactamasein-

    hibitor congeners (amoxicillin/clavulanate orally; ampicillin/

    sulbactam, piperacillin/tazobactam, and ticarcillin/clavulanate

    parenterally) [5761]; fluoroquinolones (ciprofloxacin, oflox-

    acin, levofloxacin, and trovafloxacin orally and parenterally)

    [57, 6165]; and the miscellaneous agents clindamycin (orally

    and parenterally) [10, 63, 65], imipenem/cilastatin (parenter-

    ally) [58, 66], amdinocillin (parenterally) [55], linezolid (orally

    and parenterally) [67], and pexiganan acetate (topically) [50].A few randomized controlled studies have compared differ-

    ent oral and parenteral regimens; all had power only to dem-

    onstrate 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., pipera-

    cillin/tazobactam) or newly approved agents (e.g., ertapenem

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    Table 3. Suggested antibiotic regimens for treatment of diabetic foot infections.

    Severity of infection (administration) Recommendeda

    Alternativeb

    Mi ld/moderate ( oral for entir e cour se) C ephalexin (500 mg. q.i .d.) Levofloxacin (750 mg q.d.) clindamycin (300 mg t.i.d.)c

    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)

    Ampicillin/sulbactamd,e

    (3.0 g q. i.d.) Pip er ac il lin/ta zob act am (3.3 g q. i.d.)d

    Clindamycin (450 mg q.i.d.) + ciprofloxacin

    (750 mg b.i.d.)

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

    Life-threatening (prolonged iv) Imipenem/cilastin (500 mg q.i.d.)d,e

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

    metronidazole (7.5 mg/kg q.i.d.)

    Clindamycin (900 mg t.i.d.) + tobramycind

    (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.

    dA similar agent of the same class or generation may be substituted.

    eA high local prevalence of methicillin resistance among staphylococci may require use of vancomycin, linezolid, or other appropriate agents active against

    these organisms.

    and daptomycin) are under way. New antibiotics are intro-

    duced, and some older ones are made obsolete by the emer-

    gence of resistance or newly appreciated toxicities. Understand-

    ing 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 Adminis-

    tration has approved all the above agents (and others) for treat-

    ing complicated skin and soft-tissue infections, the only drugsspecifically approved for diabetic foot infections are trovaflox-

    acin (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 num-

    ber of surgical procedures performed [69]. One American study

    demonstrated that therapy with ampicillin/sulbactam was sig-

    nificantly 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 12-week course has been found

    to be effective [10], whereas for more serious infections, treat-

    ment has usually been given for 2 weeks, sometimes longer.

    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 bacter-

    emia, therapy for at least 2 weeks seems prudent. Antibiotic

    therapy can generally be discontinued when all signs and symp-

    toms 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 someinstances of extensive infection, large areas of gangrene or ne-

    crotic 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.

    Treatment of Osteomyelitis

    Antibiotic choices should optimally be based on results of bone

    culture, when possible, especially because of the need for long-

    duration therapy [25]. Soft-tissue or sinus-tract cultures do notaccurately predict bone pathogens. If empirical therapy is nec-

    essary, it should always coverS. 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 osteo-

    myelitis 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

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    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-CSFtreated

    patients. A Korean study found that neutrophil superoxide pro-

    duction in 12 diabetic patients with foot infections was signifi-

    cantly lower than in 12 healthy nondiabetic controls [75]. G-

    CSF (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 in-

    fection and improve wound healing in the high-risk foot. For

    years, anecdotal and uncontrolled reports have suggested ben-

    efit in diabetic foot infections. Recently, prospective studies,

    including a double-blind randomized trial, have shown im-

    proved 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 pos-

    sibility [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 re-

    served for severe cases, even if it is further confirmed as

    effective.

    Revascularization. Improving blood flow may also be cru-

    cial to controlling infection in an ischemic foot. Although initial

    debridement must be done even in the face of poor arterial

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    S112 CID 2004:39 (Suppl 2) Lipsky

    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 3-

    year 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 arecent 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 im-

    pairing antegrade nutrient (and perhaps leukocyte) delivery, as

    well as restricting removal of metabolites and cell debris, edemacan hinder wound healing. A recent randomized trial found

    that aggressively controlling edema with a pneumatic pedal

    compression device increased wound healing in diabetic pa-

    tients 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 dia-

    betic patient with a foot lesion is shown in figure 1. The ap-

    proach 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 re-

    sections 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 heal-

    ing include the absence of exposed bone, a palpable poplitealpulse, toe pressure of145 mm Hg or an ankle pressure of180

    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 sub-

    stantial risk of having another within a few years; thus, edu-

    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.

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