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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. LipskyDepartment of Medicine, University of Washington School of Medicine, and General Internal Medicine Clinic, VA Puget Sound Health CareSystem, Seattle, Washington

Diabetic foot infections frequently cause morbidity, hospitalization, and amputations. Gram-positive cocci,

especially staphylococci and also streptococci, are the predominant pathogens. Chronic or previously treated

wounds often yield several microbes on culture, including gram-negative bacilli and anaerobes. Optimal culture

specimens are wound tissue taken after debridement. Infection of a wound is defined clinically by the presence

of purulent discharge or inflammation; systemic signs and symptoms are often lacking. Only infected wounds

require antibiotic therapy, and the agents, route, and duration are predicated on the severity of infection.

Mild to moderate infections can usually be treated in the outpatient setting with oral agents; severe infections

require hospitalization and parenteral therapy. Empirical therapy must cover gram-positive cocci and should

be broad spectrum for severe infections. Definitive therapy depends on culture results and the clinical response.

Bone infection is particularly difficult to treat and often requires surgery. Several adjuvant agents may be

beneficial in some cases.

Foot infections in diabetic patients usually begin in a

skin ulceration [1]. Although most infections remain

superficial, ∼25% will spread contiguously from the

skin to deeper subcutaneous tissues and/or bone. Up

to half of those who have a foot infection will have

another within a few years. About 10%–30% of diabetic

patients with a foot ulcer will eventually progress to an

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

or major. Conversely, an infected foot ulcer precedes

∼60% of amputations [2–4], making infection perhaps

the most important proximate cause of this tragic

outcome.

PATHOPHYSIOLOGY

Among the factors predisposing diabetic patients to

foot infections are poorly understood immunologic 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 HealthCare System, S-111-GIMC, 1660 South Columbian Way, Seattle, WA 98108-1597([email protected]).

Clinical Infectious Diseases 2004; 39:S104–14� 2004 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2004/3903S2-0007$15.00

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 of Staph-

ylococcus aureus in the anterior nares and skin [8], and

several types of skin and nail disorders, may increase

the risk of skin and soft-tissue infections in diabetic

patients. Accelerated atherosclerosis, especially of the

arteries between the knee and ankle, increases the 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 diabetic

foot 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 scraping

with a scalpel, from the base of a debrided ulcer provides more

accurate results than does a wound swab [10–13]. Therapy

directed against organisms isolated from culture of a swab 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 3–5 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.

Pseudomonas species are often isolated from wounds that have

been soaked or treated with wet dressings or hydrotherapy.

Enterococci are commonly obtained by culture from patients

who have previously received a cephalosporin. Obligate 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-

sistant S. aureus, are frequently isolated from patients who have

previously received antibiotic therapy; they are often (but not

always) acquired during previous hospitalizations or at 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 [19–21].

Assessing severity. Several classification systems have been

proposed for diabetic foot lesions, none of which is universally

accepted. Keys to classifying a foot wound are assessing the

depth of the lesion (by visually inspecting the tissues involved

and by estimating the depth in millimeters) and checking for

ischemia (absent pulses or diminished blood pressure in the

foot) and for infection [22]. Whereas mild infections are 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. Deep

space infections often have deceptively few superficial signs.

The clinician should suspect spread of infection when there is

inflammation distant from the skin wound, or when 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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Table 1. Clinical characteristics that help define the severity of an infection.

Feature Mild infection Severe infection

Presentation Slowly progressive Acute or rapidly progressiveUlceration Involves only skin Penetrates to subcutaneous tissuesTissues involved Epidermis, dermis Fascia, muscle, joint, boneCellulitis Minimal (!2 cm around ulcer rim) Extensive, or distant from ulcerationLocal signs Limited inflammation Severe inflammation, crepitus, bullae, necrosis or gangreneSystemic signs None or minimal Fever, chills, hypotension, confusion, volume depletion,

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

abnormalitiesFoot vasculature Minimally impaired (normal/reduced pulses) Absent pulses, reduced ankle or toe blood pressureComplicating 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 patient’s 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 of 190% and a specificity of 180%

[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 the

etiologic agent(s) generally require obtaining a specimen of

bone. This should be processed for both culture and histology.

Specimens may be obtained by open (e.g., at the time of 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 infectionEtiologic agent(s) (known or presumed)Recent antibiotic therapyBone infectionVascular status at infected siteAllergies to antibioticsRenal or hepatic insufficiencyGastrointestinal absorption impairmentDrug toxicity (interactions) potentialLocal antibiotic susceptibility dataFormulary and cost considerationsPatient preferencesPublished 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. aureus is 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 the

published 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 patient’s

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 as

for osteomyelitis or infections resistant to oral agents, can often

be treated on an outpatient basis when a program to provide

this service is available.

Oral antibiotic therapy is less expensive, more convenient,

and probably associated with fewer complications than is 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, in

particular, 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 their

efficacy in treating diabetic foot infections. An investigational

peptide antibiotic, pexiganin acetate 1% cream (MSI-78), has

been shown, in 2 large multicenter phase III randomized trials,

to be safe and nearly as effective (∼85%–90% clinical response

rate) as oral ofloxacin for mildly infected diabetic foot ulcers

[50]. These results are encouraging and suggest that other topical

antimicrobial agents should be explored. None of these therapies

has been adequately evaluated, and they cannot currently be

routinely recommended.

Choice of antibiotic agents. Most patients will begin an-

tibiotic therapy with an empirical regimen. This should aim to

cover the most common pathogens, with some modification

according to severity of infection. Relatively narrow-spectrum

agents may be used for minor infections, because there is likely

to be time to alter treatment if there is no clinical response.

Regimens for severe infection should be broader spectrum and

most often administered intravenously, because the stakes are

higher. Empirical regimens must also take into consideration

such factors as patient allergies, renal dysfunction, recent 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 Enterococcus spe-

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 antibiotic’s efficacy is the clinical

trial. Agents that have demonstrated clinical effectiveness, alone

or in combination, in prospective studies including entirely or

mostly patients with diabetic foot infections, include the fol-

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

ceftizoxime parenterally) [10, 52–56]; penicillin/b-lactamase in-

hibitor congeners (amoxicillin/clavulanate orally; ampicillin/

sulbactam, piperacillin/tazobactam, and ticarcillin/clavulanate

parenterally) [57–61]; fluoroquinolones (ciprofloxacin, oflox-

acin, levofloxacin, and trovafloxacin orally and parenterally)

[57, 61–65]; 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

Mild/moderate (oral for entire course) Cephalexin (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, thenswitch to oral equivalent)

Ampicillin/sulbactamd,e (3.0 g q.i.d.) Piperacillin/tazobactam (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 (5.1mg/kg./d) + ampicillin (50 mg/kg. q.i.d.)

NOTE. Regimen should be given at usual recommended doses for serious infections; modify for conditions such as azotemia.a On the basis of theoretical considerations and available clinical trials.b Prescribed in special circumstances, for example, patient allergies, recent treatment with recommended agent, and cost considerations.c

�, with or without.d A similar agent of the same class or generation may be substituted.e A high local prevalence of methicillin resistance among staphylococci may require use of vancomycin, linezolid, or other appropriate agents active against

these organisms.

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 drugs

specifically 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 1–2-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 some

instances 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 not

accurately predict bone pathogens. If empirical therapy is nec-

essary, it should always cover S. aureus; broader coverage should

be considered if the history or results of soft-tissue culture

suggest the necessity. Antibiotics may not penetrate well to

infected bone, and the number and function of leukocytes in

this environment are suboptimal. Thus, treatment of 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 1. Approach to treating a foot infection in a patient with diabetes

of cases [71, 72]. Furthermore, oral antibiotics with good bio-

availability (e.g., fluoroquinolones and clindamycin) may be

adequate for most, or perhaps all, of the therapy. If all the

infected bone is removed, a shorter course of antibiotic therapy

(e.g., 2 weeks) may be sufficient. For some patients, long-term

suppressive therapy, or intermittent short courses of treatment

for recrudescent symptoms, may be the most appropriate ap-

proach. Some data suggest that antibiotic-impregnated beads

(made of methylmethacrylate or other materials) may be useful

for delivering high antibiotic concentrations to infected bones

while also filling dead space [47]. Antibiotic-impregnated or-

thopedic implants have shown success in treating osteomyelitis

in a few small series [48]. Evidence of resolution of osteo-

myelitis includes a drop in the erythrocyte sedimentation rate

to normal or a loss of increased uptake on leukocyte scan [25].

Adjuvant Therapies

Several additional measures have been used to improve infec-

tion resolution, wound healing, and host response. Those for

which there are published data are briefly reviewed here.

Recombinant granulocyte-colony stimulating factor (G-

CSF). A randomized controlled study from England of 40

diabetic patients with serious foot infections showed that adding

(to the usual care, including antibiotic therapy) subcutaneous

injections of G-CSF (filgrastim) led to significantly more rapid

resolution of infection and to better outcomes [73]. To the con-

trary, another randomized controlled trial conducted in Italy

found that there was no significant improvement in cure rates

or microbiological results with adjuvant G-CSF (lenograstim)

among 40 patients with limb-threatening diabetic foot infections

at 3 or 9 weeks after enrollment [74]. The amputation rate was,



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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-positivecocci; MRSA, methicillin-resistant Staphylococcus aureus.

however, significantly lower at 9 weeks among the G-CSF–treated

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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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 a

recent revival [32, 84]. Uncontrolled trials with sterilized larvae

suggest they are useful for treating infection (of soft tissue and

bone), debriding wounds, and controlling wound odor. Larvae

are relatively inexpensive and are available from commercial

laboratories. This treatment is currently used with apparent

benefit at several centers, but it requires proper staff training

and acceptance by the patient. Controlled trials are needed to

define which types of infections may benefit from this therapy.

Edema control. Edema caused by increased hydrostatic

pressure frequently complicates diabetic foot infections. By im-

pairing antegrade nutrient (and perhaps leukocyte) delivery, as

well as restricting removal of metabolites and cell debris, edema

can hinder wound healing. A recent randomized trial found

that aggressively controlling edema with a pneumatic pedal

compression device increased wound healing in diabetic 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 popliteal

pulse, toe pressure of 145 mm Hg or an ankle pressure of 180

mm Hg, and a peripheral WBC count of !12,000/mm3 [19].

The presence of edema or atherosclerotic cardiovascular disease

increases the likelihood of amputation. Amputation may be

more often required for patients with combined soft-tissue and

bone infection than for patients with either type of infection

alone [86]. Patients who have had one infection are at 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 fromPfizer (formerly Pharmacia) and Merck.

Conflict of interest. The author is a member of the speakers’ bureausand advisory boards for Pfizer (formerly Pharmacia) and Merck.

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