SUPPLEMENT ARTICLE

Medical Treatment of Diabetic Foot Infections

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

Diabetic foot infections frequently cause morbidity, hospitalization, and amputations. Gram-positive cocci,
especially staphylococci and also streptococci, are the predominant pathogens. Chronic or previously treated
wounds often yield several microbes on culture, including gram-negative bacilli and anaerobes. Optimal culture
specimens are wound tissue taken after debridement. Infection of a wound is defined clinically by the presence
of purulent discharge or inflammation; systemic signs and symptoms are often lacking. Only infected wounds

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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 equacy of glycemic control [6]. Ketosis, in particular,
skin ulceration [1]. Although most infections remain impairs leukocyte function [7]. Some evidence suggests
superficial, ∼25% will spread contiguously from the that in diabetic patients, cellular immune responses,
skin to deeper subcutaneous tissues and/or bone. Up monocyte function, and complement function are re-
to half of those who have a foot infection will have duced as well. Their higher rates of carriage of Staph-
another within a few years. About 10%–30% of diabetic ylococcus aureus in the anterior nares and skin [8], and
patients with a foot ulcer will eventually progress to an several types of skin and nail disorders, may increase
amputation, which may be minor (i.e., foot sparing) the risk of skin and soft-tissue infections in diabetic
or major. Conversely, an infected foot ulcer precedes patients. Accelerated atherosclerosis, especially of the
∼60% of amputations [2–4], making infection perhaps arteries between the knee and ankle, increases the like-
the most important proximate cause of this tragic lihood of ischemia at the infection site. The anatomy
outcome. of the foot, with its various compartments, tendon
sheaths, and neurovascular bundles, may lead to prox-
PATHOPHYSIOLOGY
imal spread of infection and favors ischemic necrosis
Among the factors predisposing diabetic patients to of the confined tissues [7, 9].
foot infections are poorly understood immunologic dis-
turbances, such as impaired polymorphonuclear leu- MICROBIOLOGICAL CONSIDERATIONS
kocyte migration, phagocytosis, intracellular killing,
and chemotaxis [5]. The prevalence of these defects Selecting appropriate antimicrobial therapy for diabetic
appears to be correlated, at least in part, with the ad- 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
Reprints or correspondence: Dr. Benjamin A. Lipsky, VA Puget Sound Health
Care System, S-111-GIMC, 1660 South Columbian Way, Seattle, WA 98108-1597 acute infections in previously untreated patients are
([email protected]). usually caused by aerobic gram-positive cocci (often as
Clinical Infectious Diseases 2004; 39:S104–14
 2004 by the Infectious Diseases Society of America. All rights reserved.
monomicrobial infections), chronic wounds develop
1058-4838/2004/3903S2-0007$15.00 complex flora.

S104 • CID 2004:39 (Suppl 2) • Lipsky

 Determining the microbial etiology of an infected wound or symptoms of inflammation (warmth, redness, pain or ten-
will usually assist in subsequent management. The etiologic derness, and induration). In chronic wounds, additional signs
agent(s) can be identified by culture only if specimens are col- suggesting infection may include delayed healing, abnormal
lected and processed properly. Antibiotic-susceptibility results coloration, friability, or foul odor. Infection should be suspected
generally help tailor (and in many cases constrain) antibiotic at the first appearance of a foot problem and at evidence of a
regimens. Deep tissue specimens, obtained aseptically at sur- systemic infection or of a metabolic disorder. Peripheral neu-
gery, contain the true pathogens more often than do samples ropathy or ischemia can either mask or mimic inflammation.
obtained from superficial lesions. A curettage, or tissue scraping Occasionally, inflammatory signs may be caused by other non-
with a scalpel, from the base of a debrided ulcer provides more infectious disorders; on the other hand, some uninflamed ulcers
accurate results than does a wound swab [10–13]. Therapy may be associated with underlying osteomyelitis [18]. Signs of
directed against organisms isolated from culture of a swab sam- systemic toxicity are surprisingly uncommon in diabetic foot
ple is likely to be unnecessarily broad and may occasionally infections [19], even those that are limb threatening. Proper
miss key pathogens. If multiple organisms are isolated, the evaluation of a diabetic foot infection requires a methodical
clinician must decide which require specifically targeted ther- approach [20]. Whenever infection is considered, this diagnosis
apy. Less virulent bacteria, such as enterococci, coagulase-neg- should be pursued aggressively; these infections can worsen
ative staphylococci, or corynebacteria, may represent pathogens quickly, sometimes in a few hours.
but can sometimes be ignored. Organisms isolated from reliable Clinical presentation. Almost two-thirds of patients with
specimens that are the sole or predominant pathogens both on

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a diabetic foot infection have evidence of peripheral vascular
the Gram-stained smear and in the culture are likely to be true disease, and ∼80% have lost protective sensation [1]. Infections
pathogens. most often involve the forefoot, especially the toes and meta-
S. aureus is the most important pathogen in diabetic foot tarsal heads, particularly on the plantar surface. About half of
infections; even when it is not the only isolate, it is usually a the patients in reported series have received antibiotic therapy
component of a mixed infection [8]. Serious infections in hos- for the foot lesion by the time they present, and up to one-
pitalized patients are often caused by 3–5 bacterial species, in- third have had a foot lesion for 11 month. Many patients do
cluding both aerobes and anaerobes [11, 13]. Gram-negative not report pain, and more than half, including those with se-
bacilli, mainly of the family Enterobacteriaceae, are found in rious infections, do not have a fever, elevated WBC count, or
many patients with chronic or previously treated infections. elevated erythrocyte-sedimentation rate [19–21].
Pseudomonas species are often isolated from wounds that have Assessing severity. Several classification systems have been
been soaked or treated with wet dressings or hydrotherapy. proposed for diabetic foot lesions, none of which is universally
Enterococci are commonly obtained by culture from patients
accepted. Keys to classifying a foot wound are assessing the
who have previously received a cephalosporin. Obligate anaer-
depth of the lesion (by visually inspecting the tissues involved
obic species are most frequent in wounds with ischemic necrosis
and by estimating the depth in millimeters) and checking for
or that involve deep tissues. Anaerobes are rarely the sole path-
ischemia (absent pulses or diminished blood pressure in the
ogen; most often they constitute a mixed infection with aerobes
foot) and for infection [22]. Whereas mild infections are rel-
[14]. Antibiotic-resistant organisms, especially methicillin-re-
atively easily treated, moderately severe infections may be limb
sistant S. aureus, are frequently isolated from patients who have
threatening, and severe infections may be life threatening. As-
previously received antibiotic therapy; they are often (but not
sessing the severity of infection is essential to selecting an an-
always) acquired during previous hospitalizations or at long-
tibiotic regimen, influences the route of drug administration,
term care facilities [15]. Definitive antibiotic therapy should
and helps determine the need for hospitalization. Severity of
take into consideration the results of Gram-staining a smear
infection also helps assess the potential necessity and timing of
from a wound [16] and the culture and susceptibility tests.
surgery and the likelihood of amputation [22]. The wound
Because some patients with diabetic foot infections are not
should be carefully explored to seek foreign or necrotic material,
cured by antibiotics that cover the isolated bacteria, more sen-
and it should be probed with a sterile metal instrument. Deep
sitive methods, such as rDNA sequencing, may detect missed
space infections often have deceptively few superficial signs.
organisms [17].
The clinician should suspect spread of infection when there is
inflammation distant from the skin wound, or when suppu-
DIAGNOSIS AND CLINICAL PRESENTATION
rative lesions persist despite apparently appropriate therapy
Diagnosing infection. Because all skin wounds contain mi- [23]. A knowledgeable surgeon should evaluate any patient with
croorganisms, infection must be diagnosed clinically, that is, systemic toxicity for an occult deep space infection [9]. Clinical
by the presence of systemic signs (e.g., fever, chills, and leu- features that help define the severity of infection are shown in
kocytosis), purulent secretions (pus), or ⭓2 local classical signs table 1.

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

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

Feature Mild infection Severe infection

Presentation 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 evaluated for possible osteomyelitis [18, 25]. Clinical evaluation
when faced with a diabetic foot infection is to determine should include gently “probing to bone” [26]; in one study of

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whether a patient should be hospitalized [10]. Patients with a patients with limb-threatening infections, the positive predic-
serious infection should be admitted for possible surgical in- tive value of this test was almost 90%. Plain radiographs should
terventions, fluid resuscitation, and control of metabolic de- be obtained for most patients with a diabetic foot infection.
rangements. Hospitalization should also be considered if the Radiographic changes in infected bone generally take at least
patient is unable or unwilling to perform proper wound care, 2 weeks to be evident; when the presence of bone infection is
cannot or will not be able to off-load the affected area, is in doubt but the patient is stable, repeating a plain radiograph
unlikely to comply with antibiotic therapy, requires parenteral in a couple of weeks may be more cost effective than under-
antibiotic therapy, or needs close monitoring of response to taking more sophisticated imaging procedures.
treatment. In the absence of these factors, most patients can If clinical and radiographic findings are not diagnostically
be treated cautiously on an outpatient basis, with frequent (i.e., adequate, various types of scans may be useful [25, 27]. Bone
every few days, initially) [10] reevaluation. Wound care (de- (e.g., Tc-99) scans are sensitive (∼85%) but too nonspecific
bridement, dressing changes, and pressure off-loading) and gly- (∼45%). Leukocyte (e.g., In-111 or 99mTc-HMPAO) scans are
cemic control should be optimized; antibiotics will not over- similarly sensitive but more specific (∼75%) and may also be
come inattention to these fundamentals. useful for demonstrating that the infection has been arrested.
Radiolabeled antigranulocyte fragments (e.g., sulesomab) also
BONE INFECTION may increase the accuracy of scanning [28]. Among the di-
Diabetic patients can have destructive bone changes caused by agnostic techniques for osteomyelitis that show promise are
peripheral neuropathy (i.e., neuroarthropathy, osteoarthropa- high-resolution ultrasound [29] and positron-emission to-
thy, or Charcot disease) [24] that may be difficult to distinguish mography. However, MRI is usually the diagnostic procedure
from those caused by bone infection [25]. The latter generally of choice, with a sensitivity of 190% and a specificity of 180%
results from contiguous spread of a deep soft-tissue infection [30, 31]. The diagnostic test characteristics of all these proce-
through the bone cortex (osteitis) to the marrow (osteomye- dures exhibit great variability across studies. Their interpreta-
litis). About 50%–60% of serious foot infections are compli- tion is highly influenced by the pretest probability of disease
cated by osteomyelitis. The proportion of apparently mild to [27], and they are most helpful when the pretest probability is
moderate infections that have bone involvement is probably in intermediate.
the range of 10%–20%. There are no validated or well-accepted Definitive diagnosis of osteomyelitis and identification of the
guidelines for diagnosing or treating diabetic foot osteomyelitis. etiologic agent(s) generally require obtaining a specimen of
Among the important considerations are the anatomic site of bone. This should be processed for both culture and histology.
infection (i.e., forefoot, midfoot, or hindfoot), the vascular sup- Specimens may be obtained by open (e.g., at the time of de-
ply to the area, the extent of soft-tissue and bone destruction, bridement [32] or surgery) or percutaneous (usually image
the degree of systemic illness, and the patient’s preferences. guided) biopsy. To avoid contamination, specimens must be
Foot ulcers that are long standing (14 weeks), large (12 cm), obtained without traversal of an open wound. Patients who are
and deep (13 mm) or are associated with a substantially ele- receiving antibiotic therapy may have a negative culture result,
vated erythrocyte-sedimentation rate (170 mm/h) should be but histopathologic findings (leukocytes and necrosis) can help

S106 • CID 2004:39 (Suppl 2) • Lipsky

diagnose infection. These procedures are easy to perform and Table 2. Factors that may influence anti-
are safe in experienced hands [33], although somewhat expen- biotic treatment of diabetic foot infections
(specific agents, route of administration, and
sive. Bone biopsy is appropriate if the diagnosis of osteomyelitis
duration of therapy).
remains in doubt after other diagnostic tests are performed, or
if the etiologic agent(s) cannot be predicted because of previous Factor
antibiotic therapy or confusing culture results. Microbiological Clinical severity of the infection
studies of diabetic foot osteomyelitis have revealed that the Etiologic agent(s) (known or presumed)
majority of cases are polymicrobial; S. aureus is the most com- Recent antibiotic therapy
mon etiologic agent (isolated in ∼40% of infections), but Staph- Bone infection
ylococcus epidermidis (∼ 25%), streptococci (∼30%), and En- Vascular status at infected site
terobacteriaceae (∼40%) are also common isolates [25]. Allergies to antibiotics
Renal or hepatic insufficiency
TREATMENT Gastrointestinal absorption impairment
Drug toxicity (interactions) potential
Almost all infected foot lesions (other than primary cellulitis) Local antibiotic susceptibility data
require some surgical intervention, which is covered elsewhere Formulary and cost considerations
in this supplement issue of Clinical Infectious Diseases. Basic Patient preferences
factors that should be considered in choosing an antibiotic Published efficacy data

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regimen are outlined in table 2.
Patients who require prolonged intravenous therapy, such as
Antibiotic Therapy for osteomyelitis or infections resistant to oral agents, can often
Indications for therapy. Available data suggest that ∼40%– be treated on an outpatient basis when a program to provide
60% of diabetic patients who are treated for a foot ulcer receive this service is available.
antibiotic therapy [34]. The role of antibiotics for clinically Oral antibiotic therapy is less expensive, more convenient,
uninfected wounds is a controversial issue. The concept that and probably associated with fewer complications than is par-
reducing the “bioburden” of chronic skin wounds with anti- enteral therapy. Delivery of the first dose of antibiotic to the
microbial therapy may improve healing is plausible, and some infected site is slower with oral therapy, but this is an issue
experimental animal data and studies with burn wounds and only for critically ill patients. The main concern is the bioa-
skin grafts support this theory [35]. Although some practi- vailability of orally administered agents. Gastrointestinal ab-
tioners believe that any foot ulcer requires administration of sorption of oral antibiotics is variable, but some agents, such
antibiotics, either for therapy or for prophylaxis, available stud- as clindamycin and the fluoroquinolones, have been shown to
ies do not generally support this view [36]. In most of the be well absorbed with oral dosing [40]. Fluoroquinolones, in
published clinical trials, antibiotic therapy did not improve the particular, achieve high tissue concentrations at the site of di-
outcome of uninfected lesions [37, 38]. One abstract [39] re- abetic foot infections (including in inflamed tissues [41]) when
ported a randomized trial in which 64 diabetic patients who administered orally, even for patients with gastroparesis [42].
received antibiotic therapy for clinically uninfected foot ulcers Several newly licensed agents cover an expanded spectrum of
had a significantly increased likelihood of healing and had a organisms; drugs with greater activity against antibiotic-resis-
reduced incidence of clinical infection, hospitalization, and am- tant gram-positive cocci, such as linezolid, daptomycin, and
putation. This provocative work will need to be published and newer fluoroquinolones, are especially appealing.
replicated before this strategy is considered. Antibiotic therapy When peripheral vascular disease is present, therapeutic an-
is associated with frequent adverse effects, substantial financial tibiotic concentrations are often not achieved in the infected
costs, and the development of resistance and, thus, should cur- tissues, even when serum levels are adequate. Recently, a study
rently be used only to treat established infection. of patients with leg ischemia (many of whom were diabetic)
Route of therapy. The key to successful antibiotic therapy who received intravenous ceftazidime before limb surgery
is achieving a therapeutic drug concentration at the site of showed that delivery of the antibiotic to the skin was better
infection. This typically requires first achieving adequate serum than to the muscles or bone, but the key hindrance to pene-
levels. Intravenous antibiotics are indicated for patients who tration was the presence of ischemia, not diabetes [43]. Prob-
are systemically ill, have a severe infection, are unable to tolerate lems with arterial insufficiency have led to experimentation
oral agents, or are known or suspected to have pathogens that with novel methods of antibiotic delivery. Retrograde venous
are not susceptible to available oral agents. After the patient’s perfusion consists of injecting antibiotic solutions under pres-
condition is stabilized and the infection is clearly responding, sure into a foot vein while a sphygmomanometer is inflated
most patients can have their treatment switched to oral therapy. on the thigh. High local antibiotic concentrations have been

Diabetic Foot Treatment • CID 2004:39 (Suppl 2) • S107

observed in anecdotal and uncontrolled reports [44]. Some terns. Obtaining a Gram-stained smear of a wound specimen
clinicans have also tried lower-extremity intra-arterial (e.g., may help direct empirical antibiotic therapy. Culture results
femoral) antibiotic injections [45]. Still others have advocated show organisms consistent with the Gram staining in ∼95% of
primary closure of carefully debrided wounds, with closed- cases [16]. The overall sensitivity of the smear in identifying
catheter instillation of antibiotics [46]. New vascular catheters organisms that grow on culture is ∼70%, but the sensitivity is
are being developed that may allow threading through leg veins about twice as good for gram-positive cocci as for gram-
to the site of a foot infection; this might allow high local con- negative bacilli. This is unfortunate, because empirical antibi-
centrations of antibiotics with minimal systemic exposure. otic therapy for gram-positive organisms is usually required,
Several other novel routes of therapy have been explored. Su- and the important question is whether to broaden the spectrum
perficial wounds allow consideration of direct applications of to cover gram-negative species.
antimicrobial agents. For infections that have undergone surgical An antibiotic regimen should almost always include an agent
tissue resection, antibiotic-loaded beads (usually containing an active against staphylococci and streptococci. Previously treated
aminoglycoside) or cement have been used to supply high local or severe cases may need extended coverage that also includes
antibiotic concentrations and, in some instances, to fill the dead commonly isolated gram-negative bacilli and Enterococcus spe-
space [47, 48]. Another approach is to implant an antibiotic- cies. Necrotic, gangrenous, or foul-smelling wounds usually
impregnated bovine-collagen sponge into an infected lesion [49]. require anti-anaerobic therapy. When culture and susceptibility
Collagen is well tolerated, biodegradable, and an excellent drug results are available, more specific therapy should be chosen.

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carrier. Limited anecdotal data have shown efficacy of antibiotic- Narrower-spectrum agents are preferred, but it is important to
impregnated collagen (combined, at least initially, with oral an- assess how the infection has been responding to the empirical
tibiotics) in treating diabetic foot infections (including osteo- regimen. If the lesion is healing and the patient is tolerating
myelitis) [49]. For mildly infected foot ulcers, an additional therapy, there may be no reason to change, even if some or all
option is topical antimicrobial therapy. This has several theo- of the isolated organisms are resistant to the agents prescribed.
retical advantages, including high local drug levels, avoidance of On the other hand, if the infection is not responding, treatment
systemic antibiotic adverse effects, the possibility of using novel should cover all the isolated organisms. If the infection is wors-
agents not available for systemic use, and the focusing of the ening despite susceptibility of the isolated bacteria to the chosen
attention of both the patient and the physician to the foot and regimen, the need for surgical intervention or the possibility
to the need for good wound care. Antiseptics are generally too that fastidious organisms were missed on culture should be
harsh on the host tissues, but topical antibiotics may have a role. reconsidered.
Silver sulfadiazine, neomycin, polymixin B, gentamicin, metron- Although theoretical and pharmacokinetic considerations are
idazole, and mupirocin have each been used for soft-tissue in- important, the proof of an antibiotic’s efficacy is the clinical
fections in other sites, but there are no published data on their trial. Agents that have demonstrated clinical effectiveness, alone
efficacy in treating diabetic foot infections. An investigational or in combination, in prospective studies including entirely or
peptide antibiotic, pexiganin acetate 1% cream (MSI-78), has mostly patients with diabetic foot infections, include the fol-
been shown, in 2 large multicenter phase III randomized trials, lowing [51]: cephalosporins (cephalexin orally; cefoxitin and
to be safe and nearly as effective (∼85%–90% clinical response ceftizoxime parenterally) [10, 52–56]; penicillin/b-lactamase in-
rate) as oral ofloxacin for mildly infected diabetic foot ulcers hibitor congeners (amoxicillin/clavulanate orally; ampicillin/
[50]. These results are encouraging and suggest that other topical sulbactam, piperacillin/tazobactam, and ticarcillin/clavulanate
antimicrobial agents should be explored. None of these therapies parenterally) [57–61]; fluoroquinolones (ciprofloxacin, oflox-
has been adequately evaluated, and they cannot currently be acin, levofloxacin, and trovafloxacin orally and parenterally)
routinely recommended. [57, 61–65]; and the miscellaneous agents clindamycin (orally
Choice of antibiotic agents. Most patients will begin an- and parenterally) [10, 63, 65], imipenem/cilastatin (parenter-
tibiotic therapy with an empirical regimen. This should aim to ally) [58, 66], amdinocillin (parenterally) [55], linezolid (orally
cover the most common pathogens, with some modification and parenterally) [67], and pexiganan acetate (topically) [50].
according to severity of infection. Relatively narrow-spectrum A few randomized controlled studies have compared differ-
agents may be used for minor infections, because there is likely ent oral and parenteral regimens; all had power only to dem-
to be time to alter treatment if there is no clinical response. onstrate equivalence, and they did. Overall, the clinical and
Regimens for severe infection should be broader spectrum and microbiological response rates have been similar in trials with
most often administered intravenously, because the stakes are the various antibiotics, and no agent or combination has
higher. Empirical regimens must also take into consideration emerged as most effective [68]. Currently, several trials testing
such factors as patient allergies, renal dysfunction, recent an- different dosing regimens of established agents (e.g., pipera-
tibiotic therapy, and known local antibiotic susceptibility pat- cillin/tazobactam) or newly approved agents (e.g., ertapenem

S108 • CID 2004:39 (Suppl 2) • Lipsky

and daptomycin) are under way. New antibiotics are intro- Adequate debridement, resection, or amputation of infected
duced, and some older ones are made obsolete by the emer- tissue can shorten the necessary duration of therapy. For those
gence of resistance or newly appreciated toxicities. Understand- few patients with diabetic foot infection who develop bacter-
ing the principles of antibiotic therapy is therefore more emia, therapy for at least 2 weeks seems prudent. Antibiotic
important than knowing the specific agents that are currently therapy can generally be discontinued when all signs and symp-
in vogue [51, 68]. Whereas the US Food and Drug Adminis- toms of infection have resolved, even if the wound has not
tration has approved all the above agents (and others) for treat- completely healed. Healing any skin ulcer is a separate, albeit
ing complicated skin and soft-tissue infections, the only drugs important, issue in treating diabetic foot infections. In some
specifically approved for diabetic foot infections are trovaflox- instances of extensive infection, large areas of gangrene or ne-
acin (which is now rarely used) and linezolid. crotic tissue, or poor vascular supply, more prolonged therapy
Cost of therapy is also an important factor in selecting a may be needed. Some patients who cannot, or will not, undergo
regimen. A large prospective study of deep foot infections in surgical resection or who have surgical hardware at the site of
Sweden found that antibiotics accounted for only 4% of the infection may require prolonged or intermittent suppressive
total costs of treatment; costs of topical wound treatments were antibiotic therapy.
considerably higher [69]. Variables that explained 95% of the
total treatment costs were the time intervals between diagnosis,
Treatment of Osteomyelitis
the final required procedure, and wound healing and the num-
Antibiotic choices should optimally be based on results of bone
ber of surgical procedures performed [69]. One American study

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culture, when possible, especially because of the need for long-
demonstrated that therapy with ampicillin/sulbactam was sig-
duration therapy [25]. Soft-tissue or sinus-tract cultures do not
nificantly less expensive than therapy with imipenem/cilastatin,
for limb-threatening diabetic foot infections, primarily because accurately predict bone pathogens. If empirical therapy is nec-
of the lower drug and hospitalization costs and the less severe essary, it should always cover S. aureus; broader coverage should
side effects associated with the former treatment [70]. More be considered if the history or results of soft-tissue culture
comparative trials and economic analyses are needed. Published suggest the necessity. Antibiotics may not penetrate well to
suggestions on specific antibiotic regimens for diabetic foot infected bone, and the number and function of leukocytes in
infections vary but are more alike than different. My empirical this environment are suboptimal. Thus, treatment of osteo-
antibiotic recommendations, by type of infection, are given in myelitis should usually be parenteral (at least initially) and
table 3. prolonged (at least 6 weeks). Cure of chronic osteomyelitis has
Duration of therapy. The optimal duration of antibiotic generally been thought to require removing the infected bone
therapy for diabetic foot infections has not been studied. For by debridement or resection. Several recent retrospective series
mild to moderate infections, a 1–2-week course has been found have shown, as discussed elsewhere in this supplement issue of
to be effective [10], whereas for more serious infections, treat- Clinical Infectious Diseases, that diabetic foot osteomyelitis can
ment has usually been given for ∼2 weeks, sometimes longer. be arrested with antibiotic therapy alone in about two-thirds

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

a b
Severity of infection (administration) Recommended Alternative
c
Mild/moderate (oral for entire course) Cephalexin (500 mg. q.i.d.) Levofloxacin (750 mg q.d.)  clindamycin (300 mg t.i.d.)
Amoxicillin/clavulanate (875/125 mg b.i.d.) Trimethoprim-sulfamethoxazole (2 double-strength b.i.d.)
Clindamycin (300 mg t.i.d.)
d,e d
Moderate/severe (iv until stable, then Ampicillin/sulbactam (3.0 g q.i.d.) Piperacillin/tazobactam (3.3 g q.i.d.)
switch to oral equivalent)
b
Clindamycin (450 mg q.i.d.) + ciprofloxacin Clindamycin (600 t.i.d.) + ceftazidime (2 g t.i.d.)
(750 mg b.i.d.)
d,e
Life-threatening (prolonged iv) Imipenem/cilastin (500 mg q.i.d.) Vancomycin (15 mg/kg b.i.d.) + aztreonam (2.0 g t.i.d.) +
metronidazole (7.5 mg/kg q.i.d.)
d
Clindamycin (900 mg t.i.d.) + tobramycin (5.1
mg/kg./d) + ampicillin (50 mg/kg. q.i.d.)

NOTE. Regimen should be given at usual recommended doses for serious infections; modify for conditions such as azotemia.
a
On the basis of theoretical considerations and available clinical trials.
b
Prescribed in special circumstances, for example, patient allergies, recent treatment with recommended agent, and cost considerations.
c
, with or without.
d
A similar agent of the same class or generation may be substituted.
e
A high local prevalence of methicillin resistance among staphylococci may require use of vancomycin, linezolid, or other appropriate agents active against
these organisms.

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Figure 1. Approach to treating a foot infection in a patient with diabetes

of cases [71, 72]. Furthermore, oral antibiotics with good bio- Adjuvant Therapies
availability (e.g., fluoroquinolones and clindamycin) may be Several additional measures have been used to improve infec-
adequate for most, or perhaps all, of the therapy. If all the tion resolution, wound healing, and host response. Those for
infected bone is removed, a shorter course of antibiotic therapy which there are published data are briefly reviewed here.
(e.g., 2 weeks) may be sufficient. For some patients, long-term Recombinant granulocyte-colony stimulating factor (G-
suppressive therapy, or intermittent short courses of treatment CSF). A randomized controlled study from England of 40
for recrudescent symptoms, may be the most appropriate ap- diabetic patients with serious foot infections showed that adding
proach. Some data suggest that antibiotic-impregnated beads (to the usual care, including antibiotic therapy) subcutaneous
(made of methylmethacrylate or other materials) may be useful injections of G-CSF (filgrastim) led to significantly more rapid
for delivering high antibiotic concentrations to infected bones resolution of infection and to better outcomes [73]. To the con-
while also filling dead space [47]. Antibiotic-impregnated or- trary, another randomized controlled trial conducted in Italy
thopedic implants have shown success in treating osteomyelitis found that there was no significant improvement in cure rates
in a few small series [48]. Evidence of resolution of osteo- or microbiological results with adjuvant G-CSF (lenograstim)
myelitis includes a drop in the erythrocyte sedimentation rate among 40 patients with limb-threatening diabetic foot infections
to normal or a loss of increased uptake on leukocyte scan [25]. at 3 or 9 weeks after enrollment [74]. The amputation rate was,

S110 • CID 2004:39 (Suppl 2) • Lipsky

 Downloaded from http://cid.oxfordjournals.org/ by guest on July 22, 2012
Figure 2. Approach to selecting antibiotic therapy for a foot infection in a patient with diabetes. GNR, gram-negative rods; GPC, gram-positive
cocci; MRSA, methicillin-resistant Staphylococcus aureus.

however, significantly lower at 9 weeks among the G-CSF–treated cluded a control group. Inadequate evaluation of comorbid
patients. A Korean study found that neutrophil superoxide pro- conditions, small sample size, and poor documentation of
duction in 12 diabetic patients with foot infections was signifi- wound size and severity hamper interpretation of these reports
cantly lower than in 12 healthy nondiabetic controls [75]. G- [77, 78]. Potential candidates for hyperbaric oxygen include
CSF (lenograstim) dramatically enhanced in vitro neutrophil those with deeply infected lesions who have not responded to
function in the diabetic patients, compared with the controls. standard therapy and for whom amputation is a realistic pos-
Larger trials are needed to define whether, and for whom, these sibility [79]. If hyperbaric oxygen is used, it should usually be
promising compounds can be recommended. continually assessed for whether it is of value. Typically, the
Hyperbaric oxygen. This treatment is designed to increase treatment can be expected to be beneficial if the transcutaneous
oxygen delivery to ischemic tissue, which may help fight in- oxygen pressure near the ulcer is !40 mm Hg before therapy
fection and improve wound healing in the high-risk foot. For and rises to 1200 mm Hg after therapy [79]. Hyperbaric oxygen
years, anecdotal and uncontrolled reports have suggested ben- is an expensive and limited resource that should remain re-
efit in diabetic foot infections. Recently, prospective studies, served for severe cases, even if it is further confirmed as
including a double-blind randomized trial, have shown im- effective.
proved wound healing and a reduced rate of amputation with Revascularization. Improving blood flow may also be cru-
hyperbaric oxygen therapy [76, 77]. Of 8 published studies of cial to controlling infection in an ischemic foot. Although initial
hyperbaric oxygen therapy for diabetic foot disorders, 5 in- debridement must be done even in the face of poor arterial

Diabetic Foot Treatment • CID 2004:39 (Suppl 2) • S111

circulation, revascularization is generally postponed until sepsis cating them about prevention techniques and about prompt
is controlled [80]. However, waiting for more than a few days consultation when foot problems occur is critical.
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- Acknowledgments
year limb-salvage rates of up to 98% [83]. Financial support. The author has received research support from
Larval (maggot) therapy. “Biosurgery” with fly larvae Pfizer (formerly Pharmacia) and Merck.
Conflict of interest. The author is a member of the speakers’ bureaus
(maggots) has been used for many years, but it is enjoying a
and advisory boards for Pfizer (formerly Pharmacia) and Merck.
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 References
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