CLINICAL ORTHOPAEDICS AND RELATED RESEARCH
Number 439, pp. 87–90
Anti-Infective Therapy for Foot Ulcers in Patients
with Diabetes
Nalini Rao, MD
Foot infection is a huge economic and social burden for pa-
Downloaded from http://journals.lww.com/clinorthop by BhDMf5ePHKbH4TTImqenVJua3JJgqHHlf/G3FfXihNmjHb1jP99wmP2dOZ3XyB8xEEHWezw6a9Q= on 10/30/2020
tients with diabetes. The etiology is multifactorial, necessi-
tating a multidisciplinary team for successful treatment and
prevention. Infection usually is a consequence rather than
the cause of foot ulcers in patients with diabetes. Infection is
a clinical diagnosis and can be categorized as mild cellulitis,
moderate to severe cellulitis, and osteomyelitis. No single im-
aging technique is 100% sensitive or specific for the diagno-
sis of osteomyelitis. Infected foot ulcers require appropriate
tissue and bone cultures to guide antibiotic therapy whereas
uninfected ulcers, which may be colonized with bacteria, do
not require antibiotics. Gram-positive organisms account for
a substantial proportion of infections with increasing preva-
lence of methicillin-resistant Staphylococcus aureus in recent
years. Osteomyelitis in patients with diabetes requires ag-
gressive surgical intervention in addition to antibiotics. Du-
ration of treatment varies from 2 to 6 weeks based on the
severity of infection, along with surgical debridement. Pre-
vention of foot ulcer and infection requires patient education,
detection of neuropathy, glycemic control, and proper foot
care with foot hygiene and appropriate footwear. The patient
is an important member of the team and should be taught the
importance of self examination and early reporting of foot
problems.
Level of Evidence: Therapeutic study, Level V-1 (expert
opinion). See the Guidelines for Authors for a complete de-
scription of levels of evidence.
Foot infections in patients with diabetes are a huge eco-
nomic and social burden. A major cause of diabetes-
related hospitalization is infected or ischemic foot ulcers,
which account for 25% of hospital admissions of patients
From the Division of Infectious Diseases, Department of Medicine, Univer-
sity of Pittsburgh School of Medicine, Pittsburgh, PA.
The author certifies that he or she has or may receive payments or benefits
from a commercial entity related to this work.
Correspondence to: Nalini Rao, MD, UPMC Shadyside, Division of Infec-
tious Diseases, School of Nursing 2nd Floor, 5230 Centre Avenue, Pitts-
burgh, PA 15232. Phone: 412-623-1649; Fax: 412-623-1782; E-mail:
raon@upmc.edu.
DOI: 10.1097/01.blo.0000181497.42117.fa
87
© 2005 Lippincott Williams & Wilkins
with diabetes.5 Eighty-five percent of lower limb amputa-
tions in patients with diabetes are preceded by foot ul-
cers.2,15 The estimated cost of treating one foot ulcer dur-
ing a 2-year period is $28,000.16
I will provide a brief summary of the approach to the
patient with diabetes with a foot infection, focusing on
anti-infective therapy and the factors that affect therapy.
For more information, readers are referred to the re-
cently published guidelines developed and issued on
behalf of the Infectious Disease Society of America,12
which provide an excellent comprehensive review of the
diagnosis and treatment of foot infections in patients with
diabetes.
Who Is at Risk for Progression to Ulceration?
Assessment should begin with consideration of risk factors
often found in patients with diabetes that interact to cause
ulceration. Based on the sum of the weighted value for
each risk value (Table 1), patients can be categorized as
being at low, medium, or high risk for progression to foot
ulceration.6 The major predisposing factor is neuropathy;
peripheral vascular disease, metabolic disturbances, and
immunologic abnormalities also contribute to the devel-
opment of ulcers. The triad of neuropathy, deformity, and
trauma is present in 2⁄3 of patients.17 Inappropriate foot-
wear is the most common cause of trauma, which leads to
ulceration.13
What Is Infection?
Infection usually is the consequence rather than the cause
of foot ulcers in patients with diabetes. Infection is a
clinical diagnosis based on the presence of either purulent
secretions or two or more signs or symptoms of inflam-
mation. It can be classified into mild soft tissue infec-
tion, moderate to severe soft tissue infection, and osteo-
myelitis. Mild infection is characterized by local cellulitis
of < 2 cm, presence of drainage, absence of proximal
spread, absence of systemic signs and symptoms, and nor-
mal laboratory values. Moderate to severe infection is

88 Rao
TABLE 1. Risk Factors for Progression to Foot
Ulceration in Patients with Diabetes
Risk Factor Weighted Value*
Vasculopathy
Structural deformity
Loss of protective sensation
Heart disease or smoking history
Number of years with diabetes (> 10)
Nephropathy or retinopathy
Previous ulceration or amputation
*The risk for progression is low if the sum of the weighted values is 1 to 3,
medium if the sum is 4 to 6, and high if the sum is 9 to 13.6
characterized by cellulitis of > 2 cm, proximal spread,
constitutional signs and symptoms, and abnormal labora-
tory values (eg, elevated white blood cell count and
glucose).
Two-thirds of the patients with diabetes and foot ulcers
have underlying osteomyelitis,14 which is diagnosed by
clinical, radiographic, and histopathologic findings. Plain
radiographs show evidence of osteomyelitis by periosteal
reaction and bony destruction. These findings are specific
but often are not seen for several weeks into the course of
the disease. Histology and bone cultures are considered the
gold standard for diagnosis. The ability to probe bone with
a blunt stainless steel probe has a positive predictive value
of 89% but needs to be validated by independent studies.8
Bone scans tend to be too nonspecific; white blood cell
scans, although more specific, are difficult and expensive.
Magnetic resonance imaging (MRI) generally is the pro-
cedure of choice for diagnosis. No imaging modality, how-
ever, is 100% sensitive or specific for diagnosing (or rul-
ing out) the presence of bone infection.5
The clinical diagnosis of soft tissue infection and os-
teomyelitis should be supplemented by cultures to aid in
the selection of appropriate antibiotic therapy. Cultures
should be obtained by rigorous curettage, aspiration of
purulent secretions, and/or biopsy of deeper tissue/bone.5
Swabbing should be avoided. The material should be cul-
tured promptly for aerobic and anaerobic organisms.
Conditions that do not warrant anti-infective therapy
should be ruled out. Colonization must be distinguished
from infection because bacteria are present in both situa-
tions. Bacterial growth of more than 105 organisms per
gram of wound tissue is necessary for infection to occur.20
Other criteria suggestive of infection include isolating an
organism in pure culture, repeatedly isolating the organ-
ism, isolating the organism from deep tissue, and observ-
ing inflammatory response and purulent drainage.1 An-
other condition that does not require anti-infective therapy
is acute Charcot’s arthropathy, which frequently is misdi-
agnosed as infection.
Clinical Orthopaedics
and Related Research
What Are the Causative Bacteria and Their
Resistance Patterns?
Typically more than one type of organism is involved
1
including gram-positive, gram-negative, aerobic, and an-
2 aerobic species, although gram-positive organisms pre-
3 dominate the majority of cases.9 The microbiologic profile
1 was characterized in a study of 812 patients with diabetes
2 who had foot infections. Gram-positive aerobic bacteria
1
3
comprised 68% of the 1817 isolates. The most frequently
recovered genus was staphylococcus, accounting for ap-
proximately 1⁄3 of all isolates. Staphylococcus aureus ac-
counted for 17% of all isolates and was present in 42% of
culture-positive wounds.7 Three-fourths of infected foot
ulcers had more than one microorganism, especially the
limb-threatening infections. Polymicrobial infections typi-
cally comprised of S. aureus, Group B streptococci, en-
terococci, and facultative gram-negative bacilli. Anaerobic
organisms such as peptostreptococcus and bacteroides also
may be present.3
Methicillin resistance is problematic in patients with
diabetes who have foot ulcers. In the previous study,7 12%
of S. aureus [methicillin-resistant S. Aureus (MRSA)],
46% of S. epidermidis, and 45% of S. haemolyticus iso-
lates were resistant to methicillin. Authors of two stud-
ies4,19 conducted at the same institution in the United
Kingdom confirm the increase with time. The predominant
organism isolated from foot ulcers of patients with diabe-
tes was S. aureus with a prevalence of 48.3% in a 2001
study,4 which is considerably higher than the 28.8% preva-
lence observed in a 1998 study.19 Methicillin-resistant S.
aureus was isolated from 30.2% of patients,4 almost
double the 15.2% reported 3 years earlier.19
How Should Foot Infection in Patients with Diabetes
Be Treated?
Standard treatment of patients with diabetes and infected
foot ulcers includes (1) comprehensive medical care, (2)
eradication of infection, (3) vascular reconstruction, (4)
off-loading, and (5) ulcer treatment. Therefore, treatment
is best rendered through a multidisciplinary team consist-
ing of a team leader, infectious disease specialist, endo-
crinologist, educators, wound care specialists, orthotic
specialists, vascular surgeons, and orthopedic surgeons.
The team leader coordinates activities done by specialists
and ensures that appropriate monitoring occurs at each
visit.
Comprehensive medical treatment is addressed by the
patient’s primary care physician and medical specialists
and includes glycemic control, treatment of nephropathy,
and smoking cessation. Smoking adversely affects the vas-
cular factors and in addition, smokers also have a higher
rate of incisional wound infections than nonsmokers or
former smokers.18
Number 439
October 2005 Foot Ulcers and Infection in Patients with Diabetes 89

TABLE 2. Antimicrobial Therapy for Infected Foot Ulcers in

Patients with Diabetes
Clean, uninfected ulcers—no antimicrobial therapy needed
Mild infection (staphylococci and streptococci)
Oral therapy
Dicloxacillin 250–500 mg every 6 hours
Amoxicillin/clavulanate 500 mg every 8 hours or 875 mg every 12 hours
Cefadroxil 1 g every 12 hours
If allergic to penicillin:
Clindamycin 150 to 300 mg every 6 hours plus
Levofloxacin 750 mg once daily or Ciprofloxacin 750 mg every 12 hours
Moderate to severe infection (mixed aerobic and anaerobic bacteria)
Intravenous therapy
Ampicillin/Sulbactam 3 g every 6 hours
Piperacillin/Tazobactam 4.5 mg every 8 hours
Ertapenum 1 g every day
Moxifloxacin 400 mg every day
Clindamycin 900 mg every 8 hours plus
Ciprofloxacin 400 mg every 12 hours or Levofloxacin 500 mg every 24 hours
If resistant gram-positive infection:
Linezolid 600 mg every 12 hours or Daptomycin 4 mg/kg

TABLE 3. Prevention of Foot Ulcers in Patients with Diabetes

Risk Factors Relevant Problems Investigations
Patient Lack of education Education
Non-compliance Foot hygiene
Lack of foot hygiene Interviews with family and friends
Lack of home support Complete foot examination with and without shoes each office visit (1–3 months)
Reduced vision Early reporting of foot problems
Metabolic State Hyperglycemia Blood glucose
Metabolic acidosis Hemoglobin AIC
Volume depletion Serum chemistries at each office visit within 1 to 3 months
Psychological and Dementia Assessment of mental and psychological state each office visit
Cognitive States Impaired cognition
Depression
Foot
Biomechanics Deformities including Clinical exam
Charcot’s arthropathy Proper imaging
Proper footwear
Consultation with foot and ankle surgeon
Sensory neuropathy Lack of protective sensation Light touch and vibration perception
Autonomic neuropathy Dry cracked skin Skin care, use of emollients
Vascular
Arterial Ischemia Pedal pulses
Necrosis Arterial doppler
Gangrene Vascular surgery consultation
Venous Edema Skin and soft tissue exam
Stasis Venous dopplers
Thombosis Compressive stockings
Vascular surgery consultation
Wound Depth Inspection
Foreign body Debridement
Infection Wound probing
Gangrene Radiography
Appropriate cultures
Consultation with infectious disease specialist, foot and ankle surgeon, and
plastic surgeon

90 Rao
Vascular reconstruction, off-loading, and ulcer treat-
ment, including surgical intervention, are addressed by
surgical specialists. Aggressive surgical intervention is in-
dicated for osteomyelitis. Surgical attention should also be
sought for infections associated with deep abscess, necro-
sis, or gangrene.
Eradication of infection requires treatment with anti-
infectives that are guided by appropriate cultures. Recom-
mended strategies for anti-infective therapy are based on
clinical experience with very few randomized controlled
trials.10,11 No evidence exists that anti-infective therapy
changes outcome for clean, uninfected ulcers. It may ac-
tually lead to resistance and adverse affects. The best ap-
proach to treating infected ulcers is by categorizing them.
Mild soft tissue infections can be treated with oral anti-
infectives, whereas moderate to severe infections should
initially be treated with parenteral anti-infectives. Topical
anti-infective agents should be avoided.
The optimal duration of anti-infective therapy is un-
known, although soft tissue infections usually require 2
weeks of therapy whereas osteomyelitis requires 4 to 6
weeks of therapy. The antibiotic treatment regimens in
Table 2 seem to have equal efficacy; their selection should
be guided by appropriate cultures, consideration of drug
allergies, and patient tolerance.
All patients require careful and long-term followup.
Further research is required to assess the role of adjunct
therapy such as granulocyte-stimulating factor and hyper-
baric oxygen.
How Can Infection Be Prevented?
Prevention is the most important factor in reducing the risk
of foot infection (Table 3). This is best achieved by edu-
cation of patients regarding the importance of glucose con-
trol, proper foot care, and early reporting of foot problems.
Patients should be counseled to monitor blood glucose
because fluctuations from an individual’s pattern are often
the first sign of infection. Foot hygiene and use of proper
footwear should be emphasized. Early detection of neu-
ropathy helps prevent ulcers caused by unrecognized foot
injuries. Office visits should be performed routinely, ap-
proximately every 1 to 3 months. Every office visit should
include a thorough foot examination, with shoes off and
on, for evidence of deformity, neuropathy, vascular dis-
ease, skin cracks, blisters, and ulcers. When abnormalities
are found, patients should be referred to appropriate spe-
cialists. A multidisciplinary team approach is essential for
a favorable outcome.
The etiology of diabetic foot ulcers is multifactorial and
includes local and systemic (metabolic) issues. Therefore,
Clinical Orthopaedics
and Related Research
optimal treatment requires a multidisciplinary approach.
Empiric anti-infective therapy should be guided by the
clinical category of infection and likely etiologic agent
with consideration of the increasing prevalence of MRSA.
The patient is an important member of the team and should
be instructed in techniques to reduce the risk of future foot
infection.
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