US Pharm. 2013;38(4):23-26.
ABSTRACT: Foot infections are a common and serious complication of
diabetes. While gram-positive cocci—particularly staphylococci and
streptococci—are the most common causes of mild-to-moderate infections,
mixed gram-positive cocci and gram-negative bacilli with or without
anaerobic organisms tend to cause chronic infections. Mild infections
should be treated on an outpatient basis with oral antibiotics directed
against staphylococci and streptococci, and severe infections should be
treated initially with broad-spectrum parenteral antibiotics on an
inpatient basis, followed by oral antibiotics when possible. Pharmacists
play an important role in educating health care professionals and
patients about the proper treatment and prevention of diabetic foot
Foot infection, a common and serious complication of diabetes,
increases the risk of hospitalization, amputation, and death. According
to the CDC, 25.8 million Americans have diabetes, and these patients
have up to a 3% annual risk and a 25% lifetime risk of developing a foot
ulcer.1,2 In 2007, hospitalization for ulcer, inflammation, and/or infection as a primary diagnosis was 5.7 per 1,000 diabetic patients.1 Diabetic ulceration is the primary cause of 85% of all lower-extremity amputations.2,3 Mortality following amputation ranges from 13% to 67% after 1 year, 35% to 65% after 3 years, and 31% to 39% after 5 years.4,5
Given this increase in morbidity and mortality, the treatment and
prevention of diabetic foot infections (DFI) are key. It is estimated
that 40% of amputations could be prevented with appropriate wound care.2 The Infectious Diseases Society of America (IDSA) updated its guidelines for the treatment of DFIs in 2012.6 This review is intended to educate pharmacists about the proper management of DFIs according to current guidelines.
Etiology and Risk Factors
DFIs may be caused by a number of infecting bacteria, including
gram-positive cocci (GPC), gram-negative bacilli (GNB), and anaerobic
organisms.7 GPC, particularly Staphylococcus aureus and
beta-hemolytic streptococci, are the most common infecting organisms in
patients with mild-to-moderate DFIs and patients who did not receive
antibiotics in the previous month.6-8 Patients who experience
chronic infections and those who have undergone recent antibiotic
therapy tend to develop mixed infections of GPC and GNB with or without
anaerobic organisms.6-8 The presence of obligate anaerobes is
associated with necrotic, gangrenous, or ischemic tissue, and this is
usually the case in chronic and severe infections.6-8 Infection with drug-resistant organisms like methicillin-resistant S aureus usually occurs in patients exposed to the health care system and in communities with a high prevalence of drug resistance.6-8 Pseudomonas aeruginosa infections typically are associated with warm climate and exposure to water.6-8 Types of infecting organisms are listed in TABLE 1.6-8
Although any wound, ulcer, or traumatic injury involving the foot may
lead to infection, certain factors increase the risk at least twofold.9
In a 2-year prospective study of 1,666 diabetic patients at an
outpatient clinic, the following risk factors were associated with DFI
development: wound depth to bone, wound duration exceeding 30 days,
recurrent foot wound, traumatic wound etiology, and peripheral vascular
disease (PVD).9 In addition to these risk factors, the IDSA
guidelines include previous lower-extremity amputation, loss of
protective sensation, renal insufficiency, and a history of walking
barefoot.6 A DFI that extends to the leg can prolong healing time and increase the risk of amputation.10 In
a retrospective case-control study of 48 diabetic patients with DFI,
risk factors associated with extension of the infection into the leg
were previous toe amputation, presence of systemic signs of infection,
necrosis, large size of primary wound, ulcer on the heel, and advanced
Wagner and infection grades.10
Although DFIs can develop in the absence of an ulcer or traumatic injury, most cases begin with a wound.8,11
Typically, these wounds begin superficially but spread to deeper
structures, potentially leading to deep abscesses, cellulitis, chronic
ulcers, and osteomyelitis (OM).8,11 Neuropathy, ischemia from
peripheral arterial disease (PAD), and diminished immunity put diabetic
patients at greater risk for developing DFIs.2,8 Neuropathy
affects sensory, motor, and autonomic innervation. Often, loss of
sensation causes wounds to go unnoticed. The injury becomes
progressively worse from weight-bearing pressure. Damage to the motor
nerves and the foot muscles causes an imbalance in flexion and
extension, leading to foot deformities and abnormal pressure points,
which contribute to skin breakdown and ulceration. Autonomic neuropathy
results in decreased functioning of sweat and oil glands, which makes
the skin dry and more susceptible to tearing and infection.2,11
PAD is another contributor to the development of foot ulcers.
Long-term hyperglycemia causes endothelial and smooth-muscle cell
dysfunction in the peripheral arteries. The breakdown of glucose also
depletes nicotinamide adenine dinucleotide phosphate, which normally
detoxifies reactive oxygen species and aids in the production of the
vasodilator nitric oxide. Smoking, hypertension, and hyperlipidemia are
other factors that contribute to the development and worsening of
existing PAD. This increase in oxidative stress and vasoconstriction
promotes poor healing, ischemia, and cell death and further contributes
to the development of DFI.2 The resulting angiopathy, low
oxygen environment, and chronic hyperglycemia decrease cell-mediated
immunity, rendering diabetic patients more susceptible to infection.11
Clinical Presentation and Diagnostic Considerations
Patients may present with classic signs and symptoms of inflammation
(erythema, warmth, tenderness, pain, or induration) and with purulent,
possibly foul-smelling, discharge from an ulcer.8,11 It is
important to note that pain and tenderness may be reduced in patients
with neuropathy and that erythema may be decreased in patients with
vascular disease.8,11 Most patients with DFIs do not have
systemic signs of infection (e.g., fever, chills); however, the presence
of these signs indicates a severe and deep infection.8,11
In DFI diagnosis, it is important to establish the extent of the infection. TABLE 2 illustrates the two commonly used and validated systems for wound classification: PEDIS (Perfusion, Extent/size, Depth/tissue loss, Infection, Sensation)—established by the International Working Group on the Diabetic Foot—and IDSA.6,12,13 For clinically uninfected wounds, the IDSA guidelines do not recommend that a specimen be collected for culture.6
For infected wounds, however, the guidelines generally recommend that
appropriate specimens be obtained before empiric therapy is initiated.
Wounds should be properly cleaned and debrided before specimens are
obtained, and specimens should preferably be collected from deep tissue
or by bone biopsy.6
Plain radiographs to assess bone abnormalities and soft-tissue gas are recommended for all patients presenting with a new DFI.6
MRI is indicated if radiography is inconclusive and OM is suspected. OM
is a serious complication, and diagnosis may be difficult. Laboratory
studies, such as WBC count and erythrocyte sedimentation rate, have
little predictive value. Visible bone and palpable bone detected by
probe-to-bone testing are suggestive of underlying OM in patients with
DFI.6,8,14 The probe-to-bone test has low positive predictive value, but a negative test may exclude a diagnosis of OM.14 Imaging studies and radionuclide scans are more accurate, but confirmation requires a bone culture if imaging is inconclusive.6
To manage DFIs, the IDSA guidelines recommend a multidisciplinary
diabetic foot-care team consisting of infectious disease specialists,
clinical microbiology specialists, foot surgeons, and wound-care
specialists.6 Empiric antibiotic treatment depends upon the severity of the infection (TABLE 3).6,15
Uninfected wounds should not be treated with topical or systemic
antibiotics, and mild infections should be treated with oral antibiotics
on an outpatient basis for 1 to 2 weeks.6 Moderate
infections should be treated initially with oral antibiotics or with IV
antibiotics, followed by oral therapy for 1 to 3 weeks.6
Severe infections require treatment with IV antibiotics in an inpatient
setting followed by oral therapy, when possible, for a total of 2 to 4
Patients with complicating features, such as severe PAD, lack of home
support, or nonadherence, should be hospitalized for the entire course
of therapy.6 Patients with OM require a longer therapy
duration: 4 to 6 weeks in the case of residual infected viable bones,
and more than 3 months in the case of residual dead bones
postoperatively.6 Clinicians should streamline antibiotic therapy based upon appropriately obtained culture and sensitivity reports.6
All DFI patients should receive wound care, which may consist of
incision and drainage to decrease bacterial load, debridement to remove
necrotic tissues, offloading to redistribute pressure off the wound, and
appropriate dressings (TABLE 4) to allow for optimal wound healing.6
Finally, hyperbaric oxygen therapy, platelet-derived growth factors,
granulocyte colony-stimulating factors, bioengineered skin equivalents,
and topical negative pressure may be considered as adjunctive treatment
in certain settings to further promote wound healing.6
Comprehensive foot-care programs that include risk assessment,
education, treatment of foot problems, and appropriate referrals can
reduce amputation rates by 45% to 85%.1 In order to reduce
contributing factors to DFI, it is recommended to use monofilament
testing to screen for neuropathy and to use the ankle-brachial index to
screen for PAD.4 Studies have shown that improved glycemic
and blood pressure (BP) control prevent microvascular complications and
lessen the risk of infection. In fact, for every percentage-point drop
in hemoglobin A1C, microvascular complications are reduced by 40%, and
for every 10-mmHg reduction in systolic BP, any complication related to
diabetes is reduced by 12%.1
The Pharmacist’s Role
As the most accessible health care professional, the pharmacist
occupies a prime position in helping prevent DFI. Pharmacists should
frequently remind their diabetic patients to wear socks and properly
fitting closed-toe footwear, to moisturize and visually inspect their
feet nightly, and to see a physician for evaluation of cracks, sores,
and other injuries. Pharmacists should empower patients with diabetes to
achieve optimal glucose and BP control through individualized diet and
exercise and medication adherence, since worsening control contributes
to the development of neuropathy, PVD, and infections. Once a foot
infection develops, the pharmacist should engage with other health care
professionals to select the most appropriate antimicrobial regimen for
the patient, including dosage, route of administration, frequency, and
duration of therapy. The pharmacist is also well positioned to assist in
monitoring the efficacy and safety of the patient’s prescribed
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3. CDC. Diabetes data & trends. Age-adjusted hospital discharge
rates for peripheral arterial disease (PAD),
ulcer/inflammation/infection (ULCER), or neuropathy as first-listed
diagnosis per 1,000 diabetic population, United States, 1988–2007.
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Society of America clinical practice guideline for the diagnosis and
treatment of diabetic foot infections. Clin Infect Dis. 2012;54:e132-e173.
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11. Fish DN, Pendland SL, Danziger LH. Skin and soft-tissue infections. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill Medical; 2011:1893-1912.
12. International Working Group on the Diabetic Foot. Ulcer
Accessed November 27, 2012.
13. Bakker K, Apelqvist J, Schaper NC; International Working Group on
Diabetic Foot Editorial Board. Practical guidelines on the management
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14. Lavery LA, Armstrong DG, Peters EJ, Lipsky BA. Probe-to-bone test
for diagnosing diabetic foot osteomyelitis: reliable or relic? Diabetes Care. 2007;30:270-274.
15. Lexi-Comp Online [Internet database]. Hudson, OH: Lexi-Comp, Inc; 2012. www.lexi.com. Accessed November 27, 2012.
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