A Clinical Review of Diabetic

Foot Infections
a a,b a,b
Cody A. Chastain, MD , Nathan Klopfenstein, BSc , Carlos H. Serezani, PhD ,
a,b,
David M. Aronoff, MD *

KEYWORDS
 Diabetic foot infection  Diabetic foot ulcer  Diagnosis  Assessment  Treatment

KEY POINTS
 Diabetic foot infections are common and are usually a consequence of neuropathic
ulceration.
 Osteomyelitis is a complication of diabetic foot infections, particularly those associated
with longstanding and large foot ulcers.
 Clinical assessment of diabetic foot infections should include the wound, the foot, and the
patient as a whole.
 Antimicrobial therapy for diabetic foot infections should be tailored to disease severity, mi-
crobial pathogen, and host factors.

INTRODUCTION

Foot infections in persons with diabetes are an important threat to life and limb. This
threat is growing, as the number of persons with diabetes has nearly quadrupled in
the past 4 decades.1 It is estimated that diabetic foot infections (DFIs) increase the
risk of hospitalization more than 50 times compared with persons without diabetes.2
DFIs are among the most common diabetes-related cause of hospitalization in the
United States, accounting for perhaps 1 in 5 of such hospital admissions.3 Further-
more, DFIs dramatically increase the likelihood of amputation, to nearly 155 times
higher than that for patients without diabetes.2 Patient anxiety about amputation is
extremely high. A recent study found that persons with diabetes and foot disease

Disclosure Statement: The authors have nothing to disclose.

a
Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical
Center, 1161 21st Avenue South, A-2200 Medical Center North, Nashville, TN 37232-2582, USA;
b
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical
Center, 1161 21st Avenue South, A-2200 Medical Center North, Nashville, TN 37232-2582, USA
* Corresponding author. Division of Infectious Diseases, Department of Medicine, Vanderbilt
University Medical Center, 1161 21st Avenue South, A-2200 Medical Center North, Nashville,
TN 37232-2582.
E-mail address: d.aronoff@vumc.org
; @HSerezani (C.H.S.); ; @DMAronoff (D.M.A.)

Clin Podiatr Med Surg - (2019) -–-

https://doi.org/10.1016/j.cpm.2019.02.004 podiatric.theclinics.com
0891-8422/19/ª 2019 Elsevier Inc. All rights reserved.
2 Chastain et al

feared amputation more than death, when compared with persons with diabetes but
without foot disease.4
The risk of death is significant once infection sets in.5 Depending on the type of
pedal infection, it is estimated that between 1 in 4 to 1 in 8 hospitalized patients will
be dead at 1 year.5 The estimated 5-year mortality of patients with diabetic foot dis-
ease (such as ulcers and infections) approaches 50%, a mortality rate that is higher
than that for prostate cancer, breast cancer, and Hodgkin lymphoma.6,7
Compounding the problem of the rising incidence of DFIs is the increase in antimi-
crobial resistance (AMR) among common bacterial pathogens found in infected feet.8
New molecular techniques for the identification of uncultivatable microbes are also
broadening our understanding of DFI,9 while challenging clinicians to think anew about
which microbes need to be targeted and which can be ignored.
The purpose of this review was to provide a fresh introduction to the epidemiology
of DFIs, summarize key points in their pathogenesis, describe challenges with antimi-
crobial resistance, review common practices for the diagnosis and management of
DFIs (including involvement of bone) and identify important complications of therapy
relevant to clinicians.

EPIDEMIOLOGY AND PATHOGENESIS OF DIABETIC FOOT INFECTIONS

Nearly 435 million people are living with diabetes worldwide,10 and it is estimated that
as many as 148 million of those people will a develop foot ulcer (DFU) in their life-
time.11,12 Because more than 50% of DFUs become infected,11,13 this translates
into nearly 75 million people currently living with diabetes who are likely to develop
a foot infection in their lifetime. Broadly defined, DFIs are “any infra-malleolar infection
in a person with diabetes mellitus.”14 Common types of DFI are listed in Table 1.
There are a number of well-characterized risk factors for foot infection in persons
living with diabetes. The primary risk factor for pedal infection in people living with dia-
betes is an open wound,2 which is generally a neuropathic DFU.15,16 Ulcerations pre-
cede most foot infections in persons with diabetes2 and significantly increase the risk
of death in this population.17 In fact, it has been estimated by a prospective study that
the risk of developing an infection is >2000 times greater in persons with a foot wound
compared with those with intact skin.2 Apart from a wound itself, other significant risk
factors for infection include chronic ulceration (duration more than 30 days), prior
lower extremity amputation, the presence of peripheral arterial disease, peripheral
neuropathy (described later in this article), renal impairment or transplantation, and
walking barefoot.2,18

Table 1
Types of diabetic foot infections

Type of Infection Involved Structure(s) or Tissue Layer(s)

Paronychia Soft tissue around a toenail
Cellulitis Dermis and subcutaneous fat
Myositis Muscle
Abscess Inflammatory fluid collection
Necrotizing soft tissue infection Subcutaneous fat, muscle, and/or fascia
Septic arthritis Joint space
Tendonitis Tendon
Osteomyelitis Bone
 A Clinical Review of Diabetic Foot Infections 3

The pathogenesis of DFIs is complex and multifactorial. The major processes at play
that can result in a DFI are summarized in Fig. 1.14,19 Most DFIs develop because of
contiguous spread of bacteria (or, less commonly, fungi) breaching normal skin bar-
riers to establish infection. Less commonly, the soft tissues of the lower extremity
can be seeded hematogenously. Contrary to popular belief, most DFIs do not begin
as a result of a sudden traumatic event, such as cutting one’s foot on a sharp object
or stubbing a toe on a foreign object, though such events do occur.
Neuropathic DFUs are the root cause of most DFIs. Thus, the earliest steps in the
pathogenesis of DFI is commonly the establishment of a DFU. Neuropathy (auto-
nomic, sensory, and/or motor) is the most critical risk factor driving DFU formation,
and this results from chronic, poorly controlled hyperglycemia.20 Diabetic peripheral
neuropathy initially presents as a loss of protective sensation (commonly abbreviated
as LOPS), which may not be consciously recognized by the patient. Sensory neurop-
athy and LOPS allows for improper biomechanics of ambulation (and abnormal load-
bearing),21 which begets osteoarticular damage and deformity (osteoarthropathy), the
establishment of callous, and soft tissue necrosis and ulceration.14,21 Autonomic dia-
betic neuropathy contributes to skin dryness, increasing the risk for a small crack or
wound to occur.14,21 Peripheral edema of any cause and tinea pedis can also exacer-
bate skin breakdown and foster cellulitis.
Peripheral vascular disease is a compounding problem in disease pathogenesis.
Arterial vascular occlusive disease deprives tissue of needed oxygen, rendering it
vulnerable to injury and less capable of healing wounds. It also restricts the arrival
of circulating leukocytes to the site of infection.11 As discussed later in this article,
assessing vascular flow, and correcting deficient flow when possible, are important
aspects of DFI management and prevention.
Once a wound occurs in a patient with neuropathy, it can become contaminated
and colonized with microbes, setting the stage for infection. The risk of skin infection
is heightened in persons with diabetes.22 Although well documented, the cause of this
increased susceptibility to infection in the setting of diabetes is not fully understood.
Diabetes has been associated with multiple defects in immune defenses.23

Fig. 1. The pathogenesis of diabetic foot infection (DFI). In this model, DFIs are the result of
complex interactions among many preventable factors, including neuropathy, osteoarthro-
pathic bone changes, arterial disease, dysglycemia, maladaptive behaviors, and health care
system deficiencies. The primary drivers are noted within the pyramid, whereas pathoge-
netic features associated with each driver are listed to the side. (Data from Lipsky BA, Be-
rendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect
Dis 2004;39(7):885–910; and Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment
of diabetic foot infections. Plast Reconstr Surg 2006;117(7 Suppl):212S–38S.)
4 Chastain et al

Hyperglycemia per se has been suggested as a main culprit of this impaired host de-
fense.24 Certainly, polymorphonuclear leukocytes (neutrophils) from patients with dia-
betes have been found to exhibit multiple defects,25 including impaired chemotactic,
phagocytic, and microbicidal activities.26 Monocytes and macrophages isolated from
patients with diabetes have also revealed impaired phagocytic capacity and dimin-
ished reactive oxygen species release compared with those from control patients in
response to bacterial challenge, resulting in decreased microbial killing.27 In addition,
dendritic cells from persons with diabetes exhibited a diminished ability to migrate to
regional lymph nodes, demonstrating impairments in host defense in diabetic patients
extend to both innate and adaptive immune responses.28 Although it is known that hy-
perglycemia as a result of diabetes is strongly correlated with these impaired immune
cell phenotypes, the exact mechanisms by which this occurs remain elusive and are
an active area of study.29,30

THE IMPORTANCE OF ANTIMICROBIAL RESISTANCE

It has now become apparent that all antibiotics are destined to become ineffective
over time.
—Benjamin Lipsky.31

Patients with diabetes and foot wounds frequently are treated with antimicrobials,
fostering the development of AMR. Globally, AMR is a crisis. It is estimated that by
2050 (unless current trends are reversed), infections due to antibiotic-resistant
pathogens will kill more than 10 million people per year worldwide, equating to 1
person dying every 3 seconds.32,33 Recent studies document the rise in
multidrug-resistant pathogens associated with DFIs and their potentially dreadful
effects on outcome.8
The gram-positive bacterium Staphylococcus aureus is a major (if not the major)
causative agent in nearly all clinical phenotypes of DFI, ranging from mild paronychia
to chronic bone infection to life-threatening necrotizing soft tissue infection.8,34
Methicillin-resistant S aureus (MRSA) is now a mainstay of skin and soft tissue infec-
tions, particularly those in the feet of persons with diabetes. Compared with hospital-
ized patients without diabetes, MRSA skin and soft tissue infections in patients with
diabetes do not appear to respond as well to antibiotic therapy.35 There is debate
regarding consequences that MRSA infection has on other clinical outcomes in DFI.
For example, studies conflict on whether MRSA increases predicted mortality, length
of hospital stay, duration of antibiotic therapy, risk for recurrence, or clinical resolution
of infection.36
The growing threat of AMR in gram-negative bacteria now involves nearly all classes
of available agents. Resistance to advanced-generation cephalosporins has emerged
in the shape of extended-spectrum beta lactamases and AmpC beta lactamases.37,38
In addition, a loss of susceptibility to carbapenems has been rapid of late, which oc-
curs as a result of many different mechanisms, including carbapenemase expression.
Carbapenem-resistant Enterobacteriaceae are a leading threat to human health.
“Pan-resistant” gram-negative bacteria, such as particular isolates of Pseudomonas
and Acinetobacter, are particularly troubling and are being reported in DFIs.39 There
are several risk factors that have been identified predicting the presence of
antibiotic-resistant microbes in DFIs and are listed in Box 1.
An important driver of AMR in the setting of diabetic foot wounds is biofilm forma-
tion, which can provide shielding for microbes against antibiotics, contributing greatly
to treatment resistance and persistence.40,41 Surgical debridement of wounds can be
an important traditional therapy for removing or disrupting biofilms. Novel approaches
 A Clinical Review of Diabetic Foot Infections 5

Box 1
Common and important risk factors for antimicrobial-resistant pathogens

Risk factor
Previous use of antibiotics in the past 6 months (especially for the same infection/wound)
Frequent contact with the health care system, including hospitalizations and long-term care
facilities
Presence of multiple comorbidities
Prolonged foot wound duration (>30 days)
Chronic infection (eg, osteomyelitis)
Known nasal or rectal carriage (MRSA and gram-negative organisms)
Previous infection with an antibiotic-resistant pathogen
Abbreviation: MRSA, methicillin-resistant S. aureus.

Data from Refs.18,37,92

to combatting biofilms in DFI will gain importance, but their development and applica-
tion extends beyond the scope of this review.

INITIAL APPROACH TO THE PATIENT WITH DIABETIC FOOT INFECTION

A clinically appropriate and consistent approach to possible DFI is to assess the

wound, the foot, and then the patient as a whole. This method is consistent with
that outlined by the Infectious Diseases Society of America (IDSA) and the Interna-
tional Working Group on the Diabetic Foot (IWGDF).42,43 Wound assessment should
include evaluation for signs and symptoms of active infection, which may include
swelling, induration, erythema, pain, warmth, and/or purulent discharge. The absence
of these factors should exclude clinical infection, whereas their presence increases
the likelihood of active disease. The involved foot should then be assessed for evi-
dence of distal spread of infection beyond 2 cm from a wound, as well as for other
causes of foot inflammation (eg, trauma, fracture, thrombosis, or gout). Furthermore,
the involved foot should be assessed for biomechanical, vascular, and neurologic ab-
normalities that may indicate the underlying risk or cause of a diabetic foot ulcer and/
or infection (eg, LOPS). Finally, clinicians should evaluate the whole patient for sys-
temic inflammation, and specifically for 2 systemic inflammatory response syndrome
criteria, such as temperature greater than 38 C or less than 36 C; heart rate greater
than 90 beats per minute; respiratory rate greater than 20 breaths per minute or
PaCO2 less than 32 mm Hg; and white blood cell count greater than 12,000 or less
than 4000 cells/mL or 10% immature (band) forms. Although the definition of sepsis
has evolved since the prior publication of IDSA and IWGDF guidelines, the application
of updated sepsis definitions or utilization of the Sequential (Sepsis-Related) Organ
Failure Assessment Score may not be consistently used in practice.44 As such, clini-
cians should recognize that the historical criteria for “severe” DFIs correlated with a
definition of sepsis, which has now been defined as life-threatening organ dysfunction
caused by a dysregulated host response to infection.
Prior classifications devised by the IDSA and IWGDF organize DFI assessments in a
similar fashion.42,43 The IDSA Infection Severity classification system and PEDIS
Grade, respectively, are both easy to apply clinically and provide consistent definitions
for research use. Clinical presentations may be classified as follows: uninfected (PE-
DIS Grade 1); mild local infection (PEDIS Grade 2); progressive local, deeper, or
complicated infections without systemic inflammation (PEDIS Grade 3); or severe
infection with evidence of systemic inflammation (PEDIS Grade 4). A consistent
6 Chastain et al

approach to DFI assessment may allow clinical programs to engage multidisciplinary

and systematic interventions at multiple levels. Other classification systems are avail-
able and may assist with other specific institutional needs.45
Once the presence, acuity, and severity of a DFI has been established, medical and
surgical resources may be appropriately triaged. For patients with acute, mild infection
without complication, empiric antibiotic therapy may be prescribed based on likely mi-
crobial pathogens without further evaluation or intervention. For patients with sub-
acute, chronic, or more complicated moderate infections, microbial assessment
and aggressive wound management before empiric antibiotic therapy may assist in
selecting the appropriate antibiotic as well as duration of treatment. For patients
with evidence of severe infection, empiric antimicrobial therapy while urgently coordi-
nating diagnostic and surgical evaluation may be the most prudent course, although
this may diminish subsequent microbiologic culture yield.42,43

DIAGNOSING OSTEOMYELITIS

Diabetic foot osteomyelitis (DFO) is important to diagnose because it impacts treat-

ment and increases the risk for amputation.46 DFO almost always results from direct,
contiguous extension through an overlying infected chronic ulcer. Hematogenous
seeding of bone in the foot is much less common. The diagnosis should be suspected
when the overlying ulcer is larger than 2 cm2, the ulcer extends down to bone, and/or
the patient has an erythrocyte sedimentation rate greater than 70 mm/h.37 A high
serum C-reactive protein may also be suggestive of DFO (and useful in monitoring
the response to therapy).47,48 The diagnosis of bone infection should be based on clin-
ical signs of infection and supported by a combination of laboratory, microbiological,
and radiological evidence.46
The ability of a clinician to probe to bone (PTB) through an ulcer with a blunt metal
instrument can be helpful in the initial evaluation of DFO, but this is a controversial sub-
ject. In the setting of a high clinical suspicion for infection, a positive PTB test is further
suggestive of infection, whereas a negative PTB test is not particularly helpful because
of a poor negative predictive value.37,46 On the other hand, in the setting of a low sus-
picion for contiguous DFO, a positive PTB test should trigger further evaluation (to in-
crease specificity of the diagnosis), whereas a negative PTB test essentially rules out
the diagnosis.37,46
Radiographic evaluation for DFO continues to evolve, and excellent reviews of this
topic are available.49,50 The standard plain radiograph of the foot is a good first imag-
ing study, which can assess for the presence of radiopaque foreign bodies, soft tissue
gas, osteolytic bone changes, and periosteal elevation.49 However, it can take weeks
for such bone changes to occur following the onset of infection, and these studies lack
specificity.49 At present, reflecting its widespread availability and accuracy, MRI re-
mains the primary imaging modality for investigating DFO.49 In patients with renal
insufficiency, it is acceptable to obtain an MRI without gadolinium contrast, because
changes consistent with bone infection (edema) can be observed without contrast.
Nuclear medicine studies, including radiolabeled white blood cell scintigraphy (either
with 99mTc-hexamethylpropyleneamineoxime or 111In-oxine), and [18F]fluorodeoxyglu-
cose positron emission tomography/computed tomography are emerging as excellent
modalities for diagnosing DFO but are not readily available to many clinicians.50
Common radiographic modalities struggle to differentiate midfoot Charcot
neuro-osteoarthropathic changes from bone infection.51 DFO should be highly sus-
pected when radiographic evidence of infection is adjacent to a clinically infected
ulcer.51 DFO in the midfoot without contiguous spread from an adjacent wound is
 A Clinical Review of Diabetic Foot Infections 7

uncommon. When Charcot changes are present, the clinician should consider
acute fracture as a likely cause of midfoot erythema, edema, pain, and warmth.
Seeking a specific microbial etiology of bone infection can improve treatment out-
comes.52 Culturing bone is important because bone cultures are often discordant with
cultures obtained from overlying soft tissue or sinus tracts.53–55 An important, albeit
small, study reported that medical therapy for DFO was significantly more successful
when therapy was guided by bone biopsy as opposed to soft tissue swab culture.52
Bone biopsy is best performed following an antibiotic-free period of at least 2 weeks,
provided the infection is not severe and that the patient does not need urgent antibiotic
therapy.53 Results of a larger study comparing bone culture–directed therapy to soft
tissue culture–directed therapy, the Concordance in Diabetic Foot Ulcer Infection
study, are eagerly awaited.55

EMPIRIC AND DIRECTED ANTIBIOTIC TREATMENT FOR DIABETIC FOOT INFECTION

Once a DFI has been clinically assessed, microbial etiologies and antibiotic treatment
options may be considered. Microbiologic assessment should be obtained before
initiation of empiric antibiotic therapy if the patient is clinically stable and therapy
can be deferred safely.42,43 The need for antibiotic therapy before surgical debride-
ment may vary depending on the acuity of presentation, the impact of preoperative
antibiotic therapy on subsequent interventions, as well as the diagnostic and thera-
peutic goals of surgical intervention.
Despite the prevalence and impact of DFI, there is a lack of data to support specific
antimicrobial approaches. This is in part due to the broad definition of DFI, the variation
of anatomic and host settings for infection, as well as the wide spectrum of microbes
that may cause infection. Clinical trials that have been performed addressing the treat-
ment of DFI have provided a handful of core observations that support general recom-
mendations; however, additional data are necessary to shape future guidance.56,57
The ideal route of antibiotic therapy (ie, oral vs intravenous) for DFI remains contro-
versial. Although topical therapy has theoretic advantages, including direct antibiotic
delivery while mitigating systemic toxicity, there are few robust clinical data that sup-
port the efficacy of topical antimicrobial treatment; further study in this area may reveal
a future, consistent role for topical therapy as a preferred or adjunctive treatment op-
tion.58 As such, oral and intravenous formulations remain the most common adminis-
tration routes. Although most experts recommend intravenous antibiotic therapy at
least initially for severe infections, the duration of intravenous therapy required for
optimal outcomes remains uncertain.42,43 Limited but important literature has demon-
strated effective oral antibiotic bioavailability as well as outcomes in skin and soft tis-
sue infections, including osteomyelitis. Although critics have suggested that oral
therapy has limited empirical support, there is also a paucity of data to suggest that
intravenous antibiotics are superior.59 Emerging data are promising in that at least
some cases of bone and joint infection may be treated equally well by either oral or
intravenous therapy.60,61 Other clinical trial data suggest that oral therapy has at least
a partial role after initial intravenous therapy.62 For mild infections, oral therapy is likely
sufficient. For moderate infections, oral therapy alone or a short course of intravenous
therapy followed by oral therapy may be appropriate. The optimal approach for severe
DFI remains uncertain, and definitive future recommendations will require additional
clinical data; in the interim, clinical judgment based on individual patient factors will
continue to drive clinical decision making.42,43
Acute, mild infections are most commonly attributed to gram-positive organisms
including Staphylococcus and Streptococcus. Empiric antibiotic regimens often
8 Chastain et al

include cephalexin, amoxicillin-clavulanate, and clindamycin. Expanding antibiotic

spectra of activity to include MRSA as well as gram-negative bacteria may be neces-
sary for DFIs that have failed to respond to prior antibiotic regimens. Patients with
unique risk factors predisposing to Pseudomonas aeruginosa (ie, exposure to water,
puncture wounds, warm climate such as in Africa and Asia) may benefit from empiric
therapy addressing this pathogen. Infections that are associated with chronic wounds
and/or have failed prior antibiotic treatment courses are more likely to be polymicro-
bial and may warrant appropriately broadened antimicrobial spectra of activity.
Wounds that are necrotic or with fetid odor may include anaerobic pathogens; as
such, anaerobic antimicrobial coverage should be included when treating these
cases. Patients with severe infections with systemic inflammation may benefit from
initial treatment with intravenous therapy including broad antimicrobial spectra of ac-
tivity, such as vancomycin in combination with a beta-lactam and beta-lactamase in-
hibitor (eg, ampicillin-sulbactam, piperacillin-tazobactam) or a carbapenem (eg,
ertapenem, meropenem). Once a specific microbial pathogen(s) has been identified,
antimicrobial therapy should be directed toward that pathogen to reduce unnecessar-
ily broad antimicrobial treatment.42,43
DFO is usually a polymicrobial process.46,53,63,64 Staphylococci (such as S aureus
and coagulase-negative Staphylococcus) and streptococci are commonly involved,55
whereas in warm climates gram-negative bacteria such as Escherichia coli and Pseu-
domonas should be considered.53 Increasingly, studies suggest that anaerobic bacte-
ria are involved.64 Thus, anaerobic cultures of bone samples should be performed if at
all possible. Empiric and directed treatment for DFO may be selected accordingly.
Once the need for therapy is established, a route is selected, and empiric or directed
antimicrobials are prescribed, the duration of antibiotic therapy must be determined.
The severity of infection as well as the presence of bone or joint infection are the most
important factors to guide providers. Based on guideline recommendations, patients
with mild soft tissue infection may be treated with 1 to 2 weeks of therapy. Those with
moderate soft tissue infection are suggested to receive 1 to 3 weeks of therapy,
whereas those with severe soft tissue infections are suggested to receive 2 to 4 weeks
of therapy. The recommended duration of antibiotic therapy in the setting of bone or
joint infection is highly dependent on the nature of surgical intervention, ranging from
as little as 2 to 5 days when no resident infected tissue is presented after surgery to
3 months for patients with residual dead bone present with or without surgery.43
Additional data are necessary to amend these expert recommendations. In patients
without necrotic bone or other persistent sources of infection, 6 weeks of therapy is
likely appropriate for most cases.65 The duration of therapy may be adjusted based
on clinical response to therapy in some cases; in 1 randomized prospective trial, pa-
tients without peripheral arterial disease (PAD) who discontinued antibiotic therapy af-
ter signs and symptoms of DFI had resolved did equally well as those who continued
antibiotics for the full prescribed duration.66

MEDICAL, SURGICAL, AND EMERGING MANAGEMENT OF DIABETIC FOOT

INFECTION

Although antibiotic therapy is a cornerstone of DFI treatment, other medical treatments

are essential for infection cure, wound healing, and overall patient health. Medical treat-
ment of diabetes mellitus should promote optimal blood glucose management as well
as reduce microvascular and macrovascular complications; whereas there are few
data to support diabetic control as an essential component of DFI management, it is
plausible and remains appropriate for general medical care.67–69 As noted, PAD is a
 A Clinical Review of Diabetic Foot Infections 9

common comorbid condition of patients with diabetes. Medical treatment of this condi-
tion as well as revascularization with endovascular or open surgical techniques may be
necessary to provide adequate perfusion for antibiotic delivery and wound healing.70
Wound off-loading, in the form of diabetic insoles, total contact casts, or other mechan-
ical devices, is an important and often underutilized element of ulcer management.71
Conservative care can be effective in treating DFI; it is important to note that small, ran-
domized, controlled trials have demonstrated similar outcomes between antibiotic-only
and conservative surgery groups in select patients.72
Direct wound care and associated surgical intervention remain important for many
DFI and DFU treatment plans. Debridement is a key intervention for wound care and
healing. Although this may be obtained via sharp debridement or other intensive sur-
gical interventions, topical and other wound care therapies may also assist in wound
debridement. In addition, innovative wound care strategies including vacuum-
assisted wound closure, hyperbaric oxygen therapy, granulocyte colony-stimulating
factor, and novel wound dressings may have increasing roles in DFU as well as DFI
management as more robust data become available.73–77 Despite maximal efforts
to manage infection, debride wounds, and revascularize limbs, partial limb amputation
may be necessary in cases of severe necrosis, gangrene, or resistant infection.78–80
Further medical optimization postamputation is critical, as prior DFU and DFI are high-
ly associated with recurrent pathology.81,82

COMPLICATIONS OF MEDICAL MANAGEMENT OF DIABETIC FOOT INFECTION

Although antibiotic therapy remains a cornerstone of DFI management, adverse ef-

fects and unintended consequences do occur. Direct adverse effects of antibiotic
therapy may include drug allergy, gastrointestinal side effects, hematologic side ef-
fects, and renal and hepatic toxicity.83,84 Certain medication, including intravenous
vancomycin, require appropriate laboratory monitoring for appropriate dosing as
well as for end organ dysfunction (ie, acute kidney injury).85 Unique drug adverse in-
teractions and adverse effects, such as serotonin syndrome with linezolid or rhabdo-
myolysis with daptomycin, should be considered and monitored by prescribing
providers.86,87 As previously noted, AMR due to antibiotic exposure has and continues
to occur.88 The emergence of multidrug pathogens as a part of the microbial
ecosystem for DFI is both a caution to unnecessary antibiotic prescribing but also
an invitation to use advanced agents when necessary. In addition to multidrug resis-
tant pathogens, Clostridium difficile infection has emerged as a community and hos-
pital complication in part due to antibiotic exposure.89 In light of these concerns, it is
important for providers to differentiate between uninfected and infected wounds and
to select appropriate spectrum and duration of treatment to reduce individual patient
as well as public health harm.

THE ROLE OF INFECTIOUS DISEASES SPECIALISTS

It should be noted that health care providers (including pharmacists) with expertise in
infectious disease medicine can be an important asset to a team-based approach to
diagnosis and management of skin and skin structure infections, including DFI and
DFO. In fact, multiple studies have shown, particularly for MRSA infections, that infec-
tious diseases consultation is associated with improved clinical and cost out-
comes.90,91 The appropriate use of antimicrobials, referred to as antimicrobial
stewardship, is increasingly important in the era of AMR. Both infectious disease phy-
sicians and pharmacists can help reduce inappropriate antibiotic use, avoid complica-
tions, and improve outcomes for patients with DFI and DFO.
10 Chastain et al

SUMMARY

The aging of the population and the rise in the prevalence of diabetes are factors
driving an increase in the global burden of DFIs. The appropriate clinical approach
to the patient with a suspected DFI includes assessment of the infected wound, the
associated limb, and the patient as a whole. Bone infection is important to consider
in select patients because of its impact on therapy and prognosis. The increasing chal-
lenge of AMR compels the need for good cultures of infected sites, appropriate selec-
tion of empiric and directed antibiotic therapy, use of all appropriate treatment
modalities, as well and coordination among multiple disciplines.

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