Diabetic Foot Infection MAZEN S. BADER, MD, MPH, Memorial University of Newfoundland School of Medicine, St. John’s, Newfoundland, Canada Foot infections are common in patients with diabetes and are associated with high morbidity and risk of lower extrem- ity amputation. Diabetic foot infections are classified as mild, moderate, or severe. Gram-positive bacteria, such as Staphylococcus aureus and beta-hemolytic streptococci, are the most common pathogens in previously untreated mild and moderate infection. Severe, chronic, or previously treated infections are often polymicrobial. The diag- nosis of diabetic foot infection is based on the clinical signs and symptoms of local inflammation. Infected wounds should be cultured after debridement. Tissue specimens obtained by scraping the base of the ulcer with a scalpel or by wound or bone biopsy are strongly preferred to wound swabs. Imaging studies are indicated for suspected deep soft tissue purulent collections or osteomyelitis. Optimal management requires aggressive surgical debridement and wound management, effective antibiotic therapy, and correction of metabolic abnormalities (mainly hyperglycemia and arterial insufficiency). Treatment with antibiotics is not required for noninfected ulcers. Mild soft tissue infection can be treated effectively with oral antibiotics, including dicloxacillin, cephalexin, and clindamycin. Severe soft tissue infection can be initially treated intravenously with ciprofloxacin plus clindamycin; piperacillin/tazobactam; or imi- penem/cilastatin. The risk of methicillin-resistant S. aureus infection should be considered when choosing a regimen. Antibiotic treatment should last from one to four weeks for soft tissue infection and six to 12 weeks for osteomyelitis and should be followed by culture-guided definitive therapy. (Am Fam Physician. 2008;78(1):71-79, 81-82. Copyright 2008 American Academy of Family Physicians.)
T Patient informa- tion: A handout on diabetic foot infection, written by the author of this article, is provided on page 81.
Inpatientswithdiabetes,anyfootinfec- blistering,orpenetratingforeignbody.Motor
neuropathy can result in foot deformities
(e.g., claw toe) that contribute to local pres-
superficial paronychia to deep infection
sure from footwear, making skin ulceration
involving bone. Types of infection include
even more likely. Once the skin is broken
cellulitis, myositis, abscesses, necrotizing
(typically on the plantar surface), the under-
fasciitis, septic arthritis, tendinitis, and
lying tissues are exposed to colonization by
osteomyelitis. Foot infections are among the
pathogenic organisms. The resulting wound
infection may begin superficially, but with
diabetes mellitus. They are associated with
delay in treatment and impaired body defense
increased frequency and length of hospital-
ization and risk of lower extremity amputa-
tion and vascular insufficiency, it can spread
tion.1 Foot ulceration and infection are the
to the contiguous subcutaneous tissues and to
leading risk factors for amputation.2 Preven-
tion and prompt diagnosis and treatment are
necessary to prevent morbidity, especially
begin with an ulcer, localized cellulitis
and necrotizing fasciitis can develop in theabsence of an ulcer or traumatic injury. Pathophysiology
Patients with diabetes are particularly sus-
Microbiology
ceptible to foot infection primarily because
of neuropathy, vascular insufficiency, and
viously untreated, superficial infected foot
diminished neutrophil function.3 Peripheral
wounds in patients with diabetes are aerobic
neuropathy has a central role in the devel-
gram-positive bacteria, particularly Staphy-
opment of a foot infection and it occurs in
lococcus aureus and beta-hemolytic strepto-
about 30 to 50 percent of patients with diabe-
cocci (group A, B, and others).5 Infection
tes. Patients with diabetes lose the protective
in patients who have recently received anti-
sensations for temperature and pain, impair-
biotics or who have deep limb-threatening
ing awareness of trauma such as abrasions,
Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2008 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact copyrights@aafp.org for copyright questions and/or permission requests. Diabetic Foot Infection SORT: KEY RECOMMENDATIONS FOR PRACTICE
The existence, severity, and extent of infection, as well as vascular status, neuropathy, and glycemic
control should be assessed in patients with a diabetic foot infection.
Visible bone and palpable bone on probing are suggestive of underlying osteomyelitis in patients with
Before an infected wound of a diabetic foot infection is cultured, any overlying necrotic debris should
be removed to eliminate surface contamination and to provide more accurate results.
Routine wound swabs and cultures of material from sinus tracts are unreliable and strongly discouraged
in the management of diabetic foot infection.
The empiric antibiotic regimen for diabetic foot infection should always include an agent active against
Staphylococcus aureus, including methicillin-resistant S. aureus if necessary, and streptococci. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see http://www.aafp. org/afpsort.xml.
caused by a mixture of aerobic gram-positive, aerobic
It can clinically mimic cellulitis and presents as erythema,
gram-negative (e.g., Escherichia coli, Proteus species,
edema, and elevated temperature of the foot. Most patients
Klebsiella species), and anaerobic organisms (e.g., Bacte-
with diabetic foot infection do not have systemic features
roides species, Clostridium species, Peptococcus and Pep-
such as fever or chills. The presence of systemic signs or
tostreptococcus species).5 Anaerobic bacteria are usually
symptoms indicates a severe deep infection.12
part of mixed infections in patients with foot ischemiaor gangrene.6 Methicillin-resistant S. aureus (MRSA) is
ESTABLISHING EXTENT OF INFECTION
a more common pathogen in patients who have been
Early recognition of the area of involved tissue can facili-
previously hospitalized or who have recently received
tate appropriate management and prevent progression of
antibiotic therapy. MRSA infection can also occur in the
the infection (Figure 3). The wound should be cleansed
absence of risk factors because of the increasing preva-
and debrided carefully to remove foreign bodies or
necrotic material and should be probed with a sterilemetal instrument to identify any sinus tracts, abscesses,
Clinical Evaluation
Key elements for evaluating and treating diabetic foot
Osteomyelitis is a common and serious complication of
infection are summarized in Figure 1.9
diabetic foot infection that poses a diagnostic challenge. A delay in diagnosis increases the risk of amputation.13
CONFIRMING THE DIAGNOSIS
Risk factors associated with osteomyelitis are summa-
Diabetic foot infection must be diagnosed clinically rather
rized in Table 1.3,13-16 Visible bone and palpable bone by
than bacteriologically because all skin ulcers harbor micro-
probing are suggestive of underlying osteomyelitis in
organisms (Figure 2). The clinical diagnosis of foot infec-
patients with a diabetic foot infection.13-14 Laboratory
tion is based on the presence of purulent discharge from an
studies, such as white blood cell count and the erythrocyte
ulcer or the classic signs of inflammation (i.e., erythema,
sedimentation rate (ESR), have limited sensitivity for the
pain, tenderness, warmth, or induration). Other sugges-
diagnosis of osteomyelitis. Osteomyelitis is unlikely with
tive features of infection include foul odor, the presence
normal ESR values; however, an ESR of more than 70 mm
of necrosis, and failure of wound healing despite optimal
per hour supports a clinical suspicion of osteomyelitis.13
management.10 Local inflammatory findings may be less
Definitive diagnosis requires percutaneous or open bone
prominent or absent in some diabetic foot infections. For
biopsy. Bone biopsy is recommended if the diagnosis of
example, pain and tenderness may be reduced or absent
osteomyelitis remains in doubt after imaging.3
in patients who have neuropathy, whereas erythema maybe absent in those with vascular disease.11 Acute Char-
ESTABLISHING SEVERITY OF INFECTION
cot’s foot is characterized by a progressive deterioration
The severity of the infection determines the appropriate
of weight-bearing joints, usually in the foot or ankle.
antibiotic regimen and route of administration. It also is
72 American Family Physician Volume 78, Number 1 V July 1, 2008Evaluation and Treatment of Diabetic Foot Infection
Assess neurologic and vascular status of foot
Reassess in two to four days (earlier, if dramatically worsens)
therapy, granulocyte colony-stimulating factor, etc. Figure 1. Algorithm for the evaluation and treatment of diabetic foot infection. Adapted with permission from Lipsky BA. Medical treatment of diabetic foot infections. Clin Infect Dis. 2004;(39 suppl 2):S110. July 1, 2008 V Volume 78, Number 1American Family Physician 73 Diabetic Foot Infection Figure 2. A noninfected ulcer of the dorsum of the foot in Figure 3. Plantar foot ulcers with a deep space infection.
a patient with previous amputation of the toes.
Venous insufficiency can be diagnosed clinically by
the primary consideration in determining the need for
the presence of edema and skin changes and confirmed
hospitalization and the indications and timing for any
surgical intervention. A practical and simple approach toclassifying diabetic foot infection is provided in Table 2.3
ASSESSING NEUROPATHY
Touch, vibration, and pressure sensations should be
OBTAINING CULTURES
checked routinely using cotton wool, tuning fork, and
Before an infected wound is cultured, any overlying
10-g nylon monofilament, respectively.
necrotic debris should be removed by scrubbing thewound with saline-moistened sterile gauze to eliminate
Diagnostic Imaging
surface contamination.3,17 For wound culture, tissue
Diagnostic imaging is not necessary for every patient
specimens should be obtained by scraping the base of
with diabetes who has a foot infection. Plain radiography
the ulcer with a scalpel or curette, or by a biopsy of the
of the foot is indicated for detection of osteomyelitis, for-
wound or bone. Needle aspiration of the pus or tissue
eign bodies, or soft tissue gas. Bony abnormalities asso-
fluid performed aseptically is an acceptable alternative
ciated with osteomyelitis may be indistinguishable from
method. Cultures of wound swabs or material from sinus
the destructive effects of Charcot’s foot and are usu-
tracts are unreliable and are strongly discouraged.17-19
ally not evident on plain radiography until two to four
The specimen should be processed for a Gram-stained
weeks after initial infection.21 When plain radiography is
smear and aerobic and anaerobic cultures.
negative but osteomyelitis is clinically suspected, radio-nuclide scan or magnetic resonance imaging should be
ASSESSING VASCULAR STATUS
performed (Table 321-23). Combining technetium bone
Peripheral artery disease (PAD) can be diagnosed byabsence of foot pulses and reduced ankle-brachial index(ABI). Calculation of ABI is done by measuring the rest-
Table 1. Risk Factors for Osteomyelitis
ing systolic blood pressure in the ankle and arm using
in Patients with Diabetic Foot Infection
a Doppler probe. An ABI of 0.91 to 1.30 is borderline ornormal. An ABI of 0.41 to 0.90 indicates mild to moder-
Appearance of a swollen, deformed red toe (also called
ate PAD and an ABI of 0.40 or less indicates advanced
ischemia. An ABI greater than 1.30 suggests the presence
of calcified vessels and the need for additional vascular
Infected ulcer with an erythrocyte sedimentation rate
studies, such as pulse volume recording or measure-
ment of the toe-brachial index. Patients with atypical
Nonhealing ulcer after a few weeks of appropriate care and
symptoms, or whose diagnosis is in doubt, should have
Radiologically evident bone destruction beneath ulcer
ABI measured after exercise on a treadmill. An ABI that
Ulcer area greater than 2 cm2 or more than 3 mm deep
decreases by 20 percent following exercise is diagnostic
Ulceration presents over bony prominences for more than
of PAD, whereas a normal ABI following exercise rules
out PAD. If a PAD diagnosis is confirmed and revascu-
Ulceration with unexplained leukocytosis
larization is planned, magnetic resonance angiography,computed tomography angiography, or contrast angiog-
Information from references 3 and 13 through 16.
raphy can be performed for anatomic evaluation.20
74 American Family Physician Volume 78, Number 1 V July 1, 2008Diabetic Foot Infection Table 2. Clinical Classification of Diabetic Foot Infection Clinical manifestations of infection
Wound lacking purulence or any manifestations of inflammation (i.e., erythema, pain, tenderness, warmth,
Presence of purulence and/or two or more manifestations of inflammation, but any cellulitis or erythema extends
2 cm or less around the ulcer; infection is limited to the skin or superficial subcutaneous tissues; no other local complications or systemic illness
Infection (purulence and/or two or more manifestations of inflammation) in a patient who is systemically well
and metabolically stable, but who has at least one of the following characteristics: cellulitis extending more than 2 cm around the ulcer; lymphangitic streaking; spread beneath the superficial fascia; deep tissue abscess; gangrene; involvement of muscle, tendon, joint, or bone
Infection (purulence and/or two or more manifestations of inflammation) in a patient with systemic toxicity or
metabolic instability (e.g., fever, chills, tachycardia, hypotension, confusion, vomiting, leukocytosis, acidosis, severe hyperglycemia, azotemia)
Adapted from Lipsky BA, Berendt A, Deery G, et al., for the Infectious Diseases Society of America. Diagnosis and treatment of diabetic foot infec-tions. Clin Infect Dis. 2004;39(7):894. Table 3. Diagnostic Imaging Studies for Osteomyelitis of the Foot in Patients with Diabetes
Lateral, anteroposterior, and oblique views should be done initially in all
patients with diabetes who are suspected to have a deep infection
Because 30 to 50 percent of the bone must be destroyed before lytic
lesions appear, plain radiography should be repeated at two-week intervals if initial findings are not normal, but the infection fails to resolve
Soft tissue swelling and subperiosteal elevation are the earliest findings of
Useful in between soft tissue and bone infection and for determining the
Should be considered for patients with diabetes who have an infection
with no bone exposed, who have been treated for two to three weeks with modest clinical improvement, and who have negative or inconclusive results on plain radiography
High sensitivity for osteomyelitis and can differentiate it from cellulitis
Abnormal findings for osteomyelitis (which typically become evident
within 24 to 48 hours after onset of symptoms) include increased flow activity, blood pool activity, and positive uptake on three-hour images
Specificity for osteomyelitis is decreased in patients with diabetes who
have Charcot’s foot or recent trauma or surgery; further imaging is usually required
Sensitivity and specificity are increased when combined with technetium
The main advantage is the marked improvement in specificity when
Should not be used as part of regular osteomyelitis imaging
Superior to magnetic resonance imaging for detecting sequestra
Information from references 21 through 23.July 1, 2008 V Volume 78, Number 1American Family Physician 75 Diabetic Foot Infection
scan with gallium scan or white blood cell scan may
for more extensive amputation.32 Emergent surgery is
improve the diagnostic yield for osteomyelitis.21,22 Mag-
required for severe infection in an ischemic limb, necro-
netic resonance imaging provides more accurate infor-
tizing fasciitis, gas gangrene, and an infection associated
mation regarding the extent of the infectious process.23
with compartment syndrome. Surgical excision of affected
Ultrasonography and computed tomography are also
bone has historically been the standard of care in patients
helpful in evaluating abnormalities in the soft tissue
with osteomyelitis. Nevertheless, successful therapy with
(e.g., abscess, sinus tract, cortical bone involvement) and
a long course of antibiotics alone has been achieved in two
may provide guidance for diagnostic and therapeutic
thirds of patients with osteomyelitis.12 As infection is con-
aspiration, drainage, or tissue biopsy.21
trolled and the wound starts to granulate, primary closuremay be successful. The wound may also be treated surgi-
Treatment
cally with a flap or graft, left to heal by secondary inten-
Effective management of diabetic foot infection requires
tion, or managed with negative pressure dressings.33
If the infected limb appears to be ischemic, the patient
debridement and resection of dead tissue, appropriate
should be referred to a vascular surgeon. Although non-
wound care, and correction of metabolic abnormalities.
critical ischemia can usually be treated without a vascu-lar procedure, early revascularization within a few days
ANTIBIOTIC THERAPY
of the infection is required for successful treatment of an
The selection of antibiotic therapy for diabetic foot
infection involves decisions about choice of empiricand definitive antibiotic agent, route of administration,and duration of treatment (Tables 43,9 and 53,24-30). Initial
Table 4. Principles of Antibiotic Therapy
empiric antibiotic therapy should be based on the sever-
for Diabetic Foot Infection
ity of the infection, history of recent antibiotic treatment,previous infection with resistant organisms, recent cul-
Empiric antibiotic regimen should include an agent active
ture results, current Gram stain findings, and patient
against Staphylococcus aureus, including methicillin-resistant
factors (e.g., drug allergy). A Gram-stained smear of an
S. aureus if necessary, and streptococci
appropriate wound specimen may help guide therapy.
Coverage for aerobic gram-negative pathogens is required for
The overall sensitivity of a Gram-stained smear for iden-
severe infection, chronic infection, or infection that fails to
tifying organisms that grow on culture is 70 percent.9 The
empiric antibiotic regimen for diabetic foot infection
Necrotic, gangrenous, or foul-smelling wounds usually require
should always include an agent active against S. aureus,
Initial empiric antibiotic therapy should be modified on the basis
including MRSA if necessary, and streptococci.3,5,7,8
of the clinical response and culture or susceptibility testing
The patient should be reassessed 24 to 72 hours after
Virulent organisms, such as S. aureus and streptococci, should
initiating empiric antibiotic therapy to evaluate the
always be covered in polymicrobial infection
response and to modify the antibiotic regimen, if indi-
Coverage for less virulent organisms, such as coagulase-negative
cated by early culture results. Several antibiotics have
been shown to be effective, but no single regimen has
Parenteral antibiotics are indicated for patients who are
shown superiority.3,24-30 Antibiotic therapy should not be
systemically ill, have severe infection, are unable to tolerate oral agents, or have infection caused by pathogens that are
used for foot ulcers without signs of infection because
it does not enhance wound healing or prevent infec-
Using oral antibiotics for mild to moderate infection and
tion.31 Clinical failure of appropriate antibiotic therapy
switching early from parenteral to oral antibiotics with
might be because of patient nonadherence, antibiotic
appropriate spectrum coverage and good bioavailability and
resistance, superinfection, undiagnosed deep abscess or
osteomyelitis, or severe tissue ischemia.
Although topical antibiotics can be effective for the treatment
of mildly infected ulcers, they should not be routinely used
SURGICAL TREATMENT
Discontinuation of antibiotics should be considered when all
signs and symptoms of infection have resolved, even if the
Surgery is the cornerstone of treatment for deep diabetic
foot infection. Procedures range from simple incision and
Cost should be considered when selecting antibiotic therapy
drainage to extensive multiple surgical debridements andamputation. Timely and aggressive surgical debridement
Information from references 3 and 9.
or limited resection or amputation may reduce the need
76 American Family Physician Volume 78, Number 1 V July 1, 2008Diabetic Foot Infection Table 5. Empiric Antibiotic Regimens for Treatment of Diabetic Foot Infection Soft tissue infection
Dicloxacillin 500 mg orally four times per day
Cephalexin (Keflex) 500 mg orally four times per day
For penicillin-allergic patients, except those
with immediate hypersensitivity reactions
Amoxicillin/clavulanate (Augmentin) 875/125 mg orally
Clindamycin (Cleocin) 300 to 450 mg orally three times
Potential cross-resistance and emergence
of resistance in erythromycin-resistant Staphylococcus aureus; inducible resistance in MRSA
Doxycycline (Vibramycin) 100 mg orally twice per day
Sulfamethoxazole/trimethoprim (Bactrim) 160/800 mg
is two to four weeks, depending on response; administer orally or parenterally followed by orally)
Ampicillin/sulbactam (Unasyn) 3 g IV four times per day
Ceftriaxone (Rocephin) 1 to 2 g IV once per day plus
clindamycin 600 to 900 mg IV or orally three times per day or metronidazole (Flagyl) 500 mg IV or orally three times per day
Levofloxacin (Levaquin) 500 mg IV or orally once per
day plus clindamycin 600 to 900 mg IV or orally three times per day
Moxifloxacin (Avelox) 400 mg IV or orally once per day
Ciprofloxacin (Cipro) 400 mg IV twice per day plus
clindamycin 600 to 900 mg IV three times per day
Piperacillin/tazobactam (Zosyn) 3.375 to 4.500 g IV
Imipenem/cilastatin (Primaxin) 500 mg IV four times
Vancomycin 30 mg per kg IV twice per day plus
Vancomycin is the parenteral drug of choice
ciprofloxacin 400 mg IV twice per day plus
metronidazole 500 mg IV or orally three times per day
or orally twice per day or daptomycin (Cubicin) 4 mg per kg IV once per day can also be used for MRSA
Use vancomycin for penicillin-allergic patients
Tigecycline (Tygacil) 100 mg IV loading dose then
Bone or joint infection
Use the above parenteral or oral antibiotic regimens
Use the above parenteral or oral antibiotic regimens
Initially use the above parenteral antibiotics followed
by oral antibiotics for four to six weeks
Initially use the above parenteral antibiotics followed
by oral antibiotics for eight to 12 weeks
IV = intravenously; MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-susceptible S. aureus.*—Risk factors for polymicrobial infection include chronic ulcers, recent antibiotic use, and foot ischemia or gangrene.Information from references 3 and 24 through 30.Diabetic Foot Infection WOUND MANAGEMENT
Figures 2 and 3 courtesy of David G. Armstrong, MD.
The wound should be dressed to allow for careful inspec-tion for evidence of healing and early identification of
The Author
new necrotic tissue. Necrotic or unhealthy tissue should
MAZEN S. BADER, MD, MPH, is an assistant professor of medicine at the
be debrided, preferably surgically or with topical debrid-
Memorial University of Newfoundland School of Medicine in St. John’s,
ing agents. Removing pressure from the foot wound is
Canada. He received his medical degree from Istanbul (Turkey) University School of Medicine and his master of public health degree from the Uni-
crucial for healing35 and can be achieved through total
versity of Kansas in Lawrence. Dr. Bader completed an internal medicine
contact casting, removable cast walkers, and various
residency at the University of Chicago (Ill.) Pritzker School of Medicine
ambulatory braces, splints, modified half-shoes, and
and an infectious diseases fellowship at the University of Kansas Medical Center in Kansas City.
sandals.36 Edema of the legs can delay wound healing;controlling edema with leg elevation, compression stock-
Address correspondence to Mazen S. Bader, MD, MPH, 300 Prince Phil-lip Dr., Division of Infectious Diseases, St. John’s, NL, Canada A1B3V6
ings, or a pneumatic pedal compression device enhances
(e-mail: msbader1@hotmail.com). Reprints are not available from the
the healing process.37 Evidence of resolution of infec-
tion includes formation of granulation tissue, absence of
Author disclosure: Nothing to disclose.
necrotic tissue, and closing of the wound. If osteomyeli-tis is present, signs of healing include a drop in ESR and
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Synthesis of Molecularly Imprinted Polymer for Selective Solid-Phase Extraction of Salbutamol from Urine Samples ALI MOHAMMADI*†, TAHER ALIZADEH‡, RASSOUL DINARVAND†,MOHAMMAD REZA GANJALI‡ and RODERICK B. WALKER§ Department of Drug and Food Control, School of Pharmacy Tehran University of Medical Sciences, P.O. Box: 14155-6451, Tehran 14174, Iran Fax: (98)(21)6461178; Tel: (98
Neurodermitis im Kindesalter Die frühzeitige Therapie ist matchentscheidendMARC PLEIMES, PETER SCHMID-GRENDELMEIER, LISA WEIBEL, ZÜRICH Eine grundsätzliche Heilung der Veranlagung zur atopischen Derma- titis ist nicht möglich. Die genetische Disposition besteht lebenslang. Entgegen gängigen Vorstellungen bestehen weiterhin nur bei einem ekzematösen Entzündungsreaktionen.