13920850-ref for diabetic foot
TRANSCRIPT
-
8/10/2019 13920850-Ref for Diabetic Foot
1/14
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
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.
-
8/10/2019 13920850-Ref for Diabetic Foot
2/14
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.
-
8/10/2019 13920850-Ref for Diabetic Foot
3/14
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
-
8/10/2019 13920850-Ref for Diabetic Foot
4/14
Diabetic Foot Treatment CID 2004:39 (Suppl 2) S107
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
-
8/10/2019 13920850-Ref for Diabetic Foot
5/14
S108 CID 2004:39 (Suppl 2) Lipsky
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
-
8/10/2019 13920850-Ref for Diabetic Foot
6/14
Diabetic Foot Treatment CID 2004:39 (Suppl 2) S109
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
-
8/10/2019 13920850-Ref for Diabetic Foot
7/14
-
8/10/2019 13920850-Ref for Diabetic Foot
8/14
Diabetic Foot Treatment CID 2004:39 (Suppl 2) S111
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
-
8/10/2019 13920850-Ref for Diabetic Foot
9/14
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.
References
1. Lipsky BA. Infectious problems of the foot in diabetic patients. In:
Bowker JH, Pfeifer MA, eds. The diabetic foot. 6th ed. St. Louis: Mosby,
2001: 46780.
2. International Working Group on the Diabetic Foot. International con-
sensus on the diabetic foot. Amsterdam, 1999: 196.
3. Pecoraro RE, Ahroni JH, Boyko EJ, Stencil VL. Chronology and de-
terminants of tissue repair in diabetic lower-extremity ulcers. Diabetes
1991; 40:130513.
4. Reiber GE, Pecoraro RE, Koepsell TD. Risk factors for amputation in
patients with diabetes mellitus: a case control study. Ann Intern Med
1992; 117:97105.
5. Wilson RM. Neutrophil function in diabetes. Diabet Med 1986; 3:
50912.
6. McMahon MM, Bistrian BR. Host defenses and susceptibility to in-
fection in patients with diabetes mellitus. Infect Dis Clin North Am
1995; 9:110.
7. Sentochnik DE, Eliopoulos GM. Infection and diabetes. In: Kahn CR,
Weir GC, eds. Joslins diabetes mellitus. 13th ed. Philadelphia: Lea &
Febiger, 1994:86788.
8. Breen JD, Karchmer AW. Staphylococcus aureus infections in diabetic
patients. Infect Dis Clin North Am 1995; 9:1124.
9. Bridges RM, Deitch EA. Diabetic foot infections. Pathophysiology and
treatment. Surg Clin North Am 1994; 74:53755.
10. Lipsky BA, Pecoraro RE, Larson SA, Ahroni JH. Outpatient manage-
ment of uncomplicated lower-extremity infections in diabetic patients.
Arch Intern Med 1990; 150:7907.11. Lipsky BA, Pecoraro RE, Wheat JL. The diabetic foot: soft tissue and
bone infection. Infect Dis Clin North Am 1990; 4:40932.
12. Wheat LJ, Allen SD, Henry M, et al. Diabetic foot infections: bacte-
riologic analysis. Arch Intern Med 1986; 146:193540.
13. Sapico FL, Witte JL, Canawati HN, Montgomerie JZ, Bessman AW.
The infected foot of the diabetic patient: quantitative microbiologyand
analysis of clinical features. Rev Infect Dis 1984; 6(Suppl 1):1716.
14. Gerding DN. Foot infections in diabetic patients: the role of anaerobes.
Clin Infect Dis 1995; 20(Suppl 2):S2838.
15. Tentolouris N, Jude EB, Smirnof I, Knowles EA, Boulton AJM. Meth-
icillin-resistant Staphylococcus aureus: an increasing problem in a di-
abetic foot clinic. Diabet Med 1999; 16:76771.
16. Lipsky BA, Hiatt HI, Holroyd KJ. Results and prognostic value of Gram
stain of tissue curettage specimens of infected diabetic foot ulcers [ab-
stract 145]. In: Proceedings of the 37th annual meeting of the InfectiousDiseases Society of America (Philadelphia). Alexandria, VA: Infectious
Diseases Society of America, 1999.
17. Redkar R, Kalns J, Butler W, et al. Identification of bacteria from a
non-healing diabetic foot wound by 16 S rDNA sequencing. Mol Cell
Probes 2000; 14:1639.
18. Newman LG, Waller J, Palestro CJ, et al. Unsuspected osteomyelitis in
diabetic foot ulcers: diagnosis and monitoring by leukocyte scanning
with indium 111 oxyquinoline. JAMA 1991; 266:124651.
19. Eneroth M, Apelqvist J, Stenstrom A. Clinical characteristics and out-
come in 223 diabetic patients with deep foot infections. Foot Ankle
Int 1997; 18:71622.
-
8/10/2019 13920850-Ref for Diabetic Foot
10/14
Diabetic Foot Treatment CID 2004:39 (Suppl 2) S113
20. Edelson GW, Armstrong DG, Lavery LA, Caicco G. The acutely infected
diabetic foot is not adequately evaluated in an inpatient setting. Arch
Intern Med 1996; 156:23738.
21. Armstrong DG, Perales TA, Murff RT, Edelson GW, Welchon JG. Value
of white blood cell count with differential in the acute diabetic foot
infection. J Am Podiatr Med Assoc 1996; 86:2247.
22. Armstrong DG, Lavery LA, Harkless LB. Validation of adiabetic wound
classification system: the contribution of depth, infection, and ischemia
to risk of amputation. Diabetes Care 1998; 21:8559.
23. Ger R. Newer concepts in the surgical management of lesions of the
foot in the patient with diabetes. Surg Gynecol Obstet 1984; 158:2135.
24. Frykberg RG, Mendeszoon ER. Charcot arthropathy: pathogenesis and
management. Wounds 2000; 12(Suppl B):35B42B.
25. Lipsky BA. Osteomyelitis of the foot in diabetic patients. Clin Infect
Dis 1997; 25:131826.
26. Grayson ML, Gibbons GW, Balogh K, Levin E, Karchmer AW. Probing
to bone in infected pedal ulcers: a clinical sign of underlying osteo-
myelitis in diabetic patients. JAMA 1995; 273:7213.
27. Wrobel JS, Connolly JE. Making the diagnosis of osteomyelitis: the
role of prevalence. J Am Podiatr Med Assoc 1998; 88:33743.
28. Harwood SJ, Valdivia S, Hung GL, Quenzer RW. Use of sulesomab, a
radiolabeled antibody fragment, to detect osteomyelitis in diabetic pa-
tients with foot ulcers by leukoscintigraphy. Clin Infect Dis 1999;28:
12005.
29. Enderle MD, Coerpre S, Schweizer HP, et al. Correlation of imaging
techniques to histopathology in patients with diabetic foot syndromeand clinical suspicion of chronic osteomyelitis. The role of high-
resolution ultrasound. Diabetes Care 1999; 22:2949.
30. Craig JG, Amin MB, Wu K, et al. Osteomyelitis of the diabetic foot:
MR imaging-pathological correlation. Radiology1997; 203:84955.
31. Rosenberg ZA, Beltran J, Bencardino JT. MR imaging of the ankle and
foot. Radio Graphics2000; 20(Special issue):S15379.
32. Jones V. Debridement of diabetic foot lesions. Diabetic Foot 1998; 1:
8894.
33. Sutton P, Harley J, Jacobson A, Lipsky BA. Diagnosing osteomyelitis
with percutaneous bone biopsy in patients with diabetes and foot in-
fection [abstract 30]. In: Proceedings of the 38th annual meeting of
the Infectious Diseases Society of America (New Orleans). Alexandria,
VA: Infectious Diseases Society of America, 2000.
34. Jaegeblad G, Apelqvist J, Nyberg P, Berger B. The diabetic foot: from
ulcer to multidisciplinary team approach; a process analysis [abstractP87]. In: Abstracts of the 3rd International Symposium of the Diabetic
Foot (Noordwijkerhout, The Netherlands), 1998:149.
35. Robson MC, Mannari RJ, Smith PD, Payne WG. Maintenance of
wound bacterial balance. Am J Surg 1999; 178:399402.
36. OMeara SM, Cullum NA, Majid M, Sheldon TA. Systemic review of
antimicrobial agents used for chronic wounds. Br J Surg2001; 88:421.
37. Chantelau E, Tanudjaja T, Altenhofer F, Ersanli Z, Lacigova S, Metzger
C. Antibiotic treatment for uncomplicated neuropathic forefoot ulcers
in diabetes: a controlled trial. Diabet Med 1996; 13:1569.
38. Hirschl M, Hirschl AM. Bacterial flora in mal perforant and antimi-
crobial treatment with ceftriaxone. Chemotherapy1992; 38:27580.
39. Foster AVM, Bates M, Doxford M, Edmonds ME. Should oral anti-
biotics be given to clean foot ulcers with no cellulitis? [abstract O13].
In: Abstracts of the 3rd International Symposium of the Diabetic Foot
(Noordwijkerhout, The Netherlands), 1998.
40. Kuck EM, Bouter KP, Hoekstra JBL, Conemans JMH, Diepersloot RJA.
Tissue concentrations after a single-dose, orally administered ofloxacin
in patients with diabetic foot infections. Foot Ankle Int1998; 19:3840.
41. Muller M, Brunner M, Hollenstein U, et al. Penetration of ciprofloxacin
into the interstitial space of inflamed foot lesions in noninsulin-
dependent diabetes mellitus patients. Antimicrob Agents Chemother
1999; 43:20568.
42. Marangos MN, Skoutelis AT, Nightengale CH, et al. Absorption of
ciprofloxacin in patients with diabetic gastroparesis. AntimicrobAgents
Chemother1995; 39:21613.
43. Raymakers JT, Houben AJ, van de Heyden JJ, Tordoir JH, Kitslaar PJ,
Schaper NC. The effect of diabetes and severe ischaemia on the pen-
etration of ceftazidime into tissues of the limb. Diabet Med 2001;18:
22934.
44. El-Sherif El-Sarkey M. Local intravenous therapy in chronic inflam-
matory and vascular disorders of the foot. Int Surg 1997; 82:17581.
45. Dorigo B, Cameli AM, Trapani M, Raspanti D, Torri M, Mosconi G.
Efficacy of femoral intra-arterial administration of teicoplanin in gram-
positive diabetic foot infections. Angiology1995; 46:111522.
46. Connolly JE, Wrobel JS, Anderson RF. Primary closure of infected
diabetic foot wounds: a report of closed instillation in 30 cases. J AmPodiatr Med Assoc2000; 90:17582.
47. Roeder B, Van Gils CC, Maling S. Antibiotic beads in the treatment
of diabetic pedal osteomyelitis. J Foot Ankle Surg 2000; 39:12430.
48. Yamashita Y, Uchida A, Yamakawa T, Shinto Y, Araki N, Kato K. Treat-
ment of chronic osteomyelitis using calcium hydroxyapatite ceramic
implants impregnated with antibiotics. Int Orthop 1998; 22:24751.
49. Kollenberg LO. A new topical antibiotic delivery system. World Wide
Wounds 1998; 1:119. Available at: http://www.worldwidewounds
.com/1998/july/Topical-Antibiotic-Delivery-System/topical-antibiotic
-delivery-system.html. Accessed on 8 July 2004.
50. Lipsky BA, McDonald D, Litka PA. Treatment of infected diabetic foot
ulcers: topical MSI-78 vs. oral ofloxacin [abstract]. Diabetologia
1997; 40(Suppl 1):482.
51. Lipsky BA. Evidence-based antibiotic therapy of diabetic foot infec-
tions. FEMS Immunol Med Microbiol 1999; 26:26776.
52. Fierer J, Daniel D, Davis C. The fetid foot: lower extremity infections
in patients with diabetes with diabetic mellitus. Rev Infect Dis1979;
1:2107.
53. Hughes CA, Johnson CC, Bamberger DM, et al. Treatment and long-
term follow-up of foot infections in patients with diabetes or ischemia:
a randomized, prospective, double-blind comparison of cefoxitin and
ceftizoxime. Clin Ther1987; 10(Suppl A):3649.
54. LeFrock JL, Blais F, Schell RF, et al. Cefoxitin in the treatmentof diabetic
patients with lower extremity infections. Infect Surg1983May:36174.
55. File TM, Tan JS. Amdinocillin plus cefoxitin versus cefoxitin alone in
therapy of mixed soft tissue infections (including diabetic foot infec-
tions). Am J Med 1983; 80(Suppl):1005.
56. Anania WC, Chinkes SL, Rosen RC, Turner PR, Helfand AE. A selective
clinical trial of ceftizoxime. J Am Podiatr Med Assoc 1987; 77:648652.
57. Lipsky BA, Baker PD, Landon GC, Fernau R. Antibiotic therapy for
diabetic foot infections: comparison of two parental-to-oral regimens.
Clin Infect Dis 1997; 24:6438.
58. Grayson ML, Gibbons GW, Habershaw GM, et al. Use of ampicillin/
sulbactam versus imipenem/cilastatin in the treatment of limb-threat-
ening foot infections in diabetic patients. Clin Infect Dis 1994;18:
68393.
59. Akova M, Ozcebe O, Gullu Unal S, et al. Efficacy of sulbactam-am-
picillin for the treatment of severe diabetic foot infections. J Chemother
1996; 8:2849.
60. Zeillemaker AM, Veldkamp KE, van Kraaij MG, Hoekstra JBL, van
Papendrecht AA, Dipersloot RJ. Piperacillin/tazobactam therapy for
diabetic foot infection. Foot Ankle Int 1998; 19:16972.
61. Graham DR, Talan DA, Nichols RL, et al. Once-daily, high-dose lev-
ofloxacin versus ticarcillin-clavulanate alone or followed by amoxicil-
lin-clavulanate for complicated skin and skin-structure infections: a
randomized, open-label trial. Clin Infect Dis 2002; 35:3819.
62. Peterson LR, Lissack LM, Canter K, Fasching CE, Clabots C, Gerding
DN. Therapy of lower extremity infections with ciprofloxacin in pa-
tients with diabetes mellitus, peripheral vascular disease, or both. Am
J Med 1989; 86:8018.
63. Sesin GP, Paszko A, OKeefe EO. Oral clindamycin and ciprofloxacin
therapy for diabetic foot infections. Pharmacotherapy1990; 10:1546.
64. Beam TR, Gutierrez I, Powell S, et al. Prospective study of the efficacy
and safety of oral and intravenous ciprofloxacin in the treatment of
diabetic foot infections. Rev Infect Dis 1989; 11(Suppl 5):S1163.
65. Diamantopoulos EJ, Haritos D, Yfandi G, et al. Management of severe
-
8/10/2019 13920850-Ref for Diabetic Foot
11/14
S114 CID 2004:39 (Suppl 2) Lipsky
diabetic foot infections. Exp Clin Endocrinol Diabetes 1998;106:
34652.
66. Calandra GB, Raupp W, Brown KR. Imipenem/cilastatin treatment of
lower extremity skin and soft tissue infections in diabetics. Scand J
Infect Dis Suppl 1987; 52:159.
67. Lipsky BA, Itani K, Norden C, and the Linezolid Diabetic Foot Infec-
tions Study Group. Treating foot infections in diabetic patients: a ran-
domized, multicenter, open-label trial of linezolid versus ampicillin-
sulbactam/amoxicillin-clavulanate. Clin Infect Dis 2004; 38:1724.
68. Cunha BA. Antibiotic selection for diabetic foot infections: a review.
J Foot Ankle Surg 2000; 39:2537.
69. Tennvall GR, Apelqvist J, Eneroth M. Costs of deep foot infections.
An analysis of factors determining treatment costs. Pharmacoecon-
omics2000; 18:22538.
70. McKinnon PS, Paladino JA, Grayson ML, Gibbons GW, Karchmer AW.
Cost effectiveness of ampicillin/sulbactam versus imipenem/cilastatin
in the treatment of limb-threatening foot infections in diabetic patients.
Clin Infect Dis 1997; 24:5763.
71. Venkatesan P, Lawn S, Macfarlane RM, Fletcher EM, Finch RG, Jeff-
coate WJ. Conservative management of osteomyelitis in the feet of
diabetic patients. Diabet Med 1997; 14:48790.
72. Pittet D, Wyssa B, Herter-Clavel C, Kursteiner K, Vaucher J, Lew DP.
Outcome of diabetic foot infections treated conservatively: a retro-
spective cohort study with long-term follow-up. Arch Intern Med
1999; 159:8516.
73. Gough A, Clapperton M, Rolando N, Foster AVM, Philpott-HowardJ, Edmonds ME. Randomized placebo-controlled trial of granulocyte-
colony stimulating factor in diabetic foot infections. Lancet1997; 350:
8559.
74. De Lalla F, Pellizzer G, Strazzabosco M, et al. Randomized prospective
controlled trial of recombinant granulocyte-colony stimulating factor
as adjunctive therapy for limb-threatening diabetic foot infection. An-
timicrob Agents Chemother 2001; 45:10948.
75. Peck KR, Son DW, Song JH, Kim S, Oh MD, Choe KW. Enhanced
neutrophil functions by recombinant human granulocyte colony-stim-
ulating factor in diabetic patients with foot infections in vitro. J Korean
Med Sci 2001; 16:3944.
76. Stone JA, Cianci P. The adjunctive role of hyperbaric oxygen in the
treatment of lower extremity wounds in patients with diabetes. Diabetes
Spectrum1997; 10:11823.
77. Wunderlich RP, Peters EJG, Lavery L. Systemic hyperbaric oxygen ther-
apy: lower-extremity wound healing and the diabetic foot. Diabetes
Care2000; 23:15515.
78. Lee SS, Chen CY, Chan YS, Yen CY, Chao EK, Ueng SWN. Hyperbaric
oxygen in the treatment of diabetic foot infection. Chang Gung MedicalJournal1997; 20:1722.
79. Bakker DJ. Hyperbaric oxygen therapy and the diabetic foot. Diabetes
Metab Res Rev2000; 16(Suppl 1):S558.
80. Caputo GM, Cavanaugh PR, Ulbrecht JS, Gibbons GW, Karchmer AW.
Assessment and management of foot disease in patients with diabetes.
N Engl J Med 1994; 331:85460.
81. Estes JM, Pomposelli FB Jr. Lower extremity arterial reconstruction in
patients with diabetes mellitus. Diabet Med 1996; 13:S437.
82. Chang BB, Darling RC III, Paty PSK, Lloyd WE, Shah DM, Leather
RP. Expeditious management of ischemic invasive foot infections. Car-
diovasc Surg 1996; 4:7925.
83. Tannenbaum GA, Pomposelli FB Jr, Marcaccio EJ, et al. Safety of vein
bypass grafting to the dorsal pedal artery in diabetic patients with foot
infections. J Vasc Surg 1992; 15:98290.
84. Rayman A, Stansfield G, Woollard T, Mackie A, Rayman G. Use oflarvae in the treatment of the diabetic necrotic foot. Diabetic Foot
1998; 1:713.
85. Armstrong DG, Nguyen HC. Improvement in healing with aggressive
edema reduction after debridement of foot infection in persons with
diabetes. Arch Surg 2000; 135:14059.
86. Eneroth M, Larsson J, Apelqvist J. Deep foot infection in diabetes
mellitus: an entity with different characteristics, treatment, and prog-
nosis [abstract P01]. In: Abstracts of the 3rd International Symposium
of the Diabetic Foot (Noordwijkerhout, The Netherlands), 1998:21.
-
8/10/2019 13920850-Ref for Diabetic Foot
12/14
-
8/10/2019 13920850-Ref for Diabetic Foot
13/14
-
8/10/2019 13920850-Ref for Diabetic Foot
14/14