Diabetic Foot Infections

Laila M. Castellino, MDa,*, Peter A. Crisologo, DPMa,b,

Avneesh Chhabra, MDc,d,e, Orhan K. Öz, MD, PhDc

KEYWORDS
 Diabetic foot infection  Osteomyelitis  Peripheral vascular disease  Offloading

KEY POINTS
 Diabetes is a growing public health concern, with diabetic foot infections (DFI) being one
of the leading causes of lower extremity limb amputation in the United States.
 Accurate diagnosis of DFI requires a combination of clinical, laboratory, and radiologic
tests to determine the extent and depth of infection, including the presence of
osteomyelitis.
 Increased recognition of the value of multidisciplinary collaborative care can lead to
personalized treatment plans, and ultimately improved outcomes and functionality for pa-
tients with diabetic foot infection.

INTRODUCTION AND EPIDEMIOLOGY

Diabetes is increasingly recognized as a public health concern worldwide, causing 1.6

million deaths and an increased prevalence of 14% among adults worldwide in 2022,
compared to 7% in 1990.1 In the United States, in 2021, an estimated 29.7 million peo-
ple—or 8.9% of the population—were diagnosed with diabetes, with variations across
race and ethnic groups; prevalence is highest among American Indian and Alaska
Native Americans (13.6%), followed by non-Hispanic Blacks (12.1%), Hispanics
(11.7%), Non-Hispanic Asians (9.1%), and non-Hispanic Whites (6.9%). Additionally,
in 2021, an estimated 97.6 million adults, or more than a third of the US adult popula-
tion had prediabetes, though only 19% of adults with prediabetes were aware of the
diagnosis. The US Centers for Disease Control and Prevention estimates the total
direct and indirect costs of diagnosed diabetes in 2022 was $413 billion.2 Diabetic
foot infections (DFI) are the most frequent cause of diabetes-related hospitalization
and the most common cause of lower extremity amputation in the general US popu-
lation.3,4 The lifetime incidence of foot ulcers among persons with diabetes is between

a
Division of Infectious Diseases and Geographic Medicine, University of Texas Southwestern
Medical Center, Dallas, TX, USA; b Department of Plastic Surgery, University of Texas South-
western Medical Center, Dallas, TX, USA; c Department of Radiology, University of Texas
Southwestern Medical Center, Dallas, TX, USA; d Adjunct faculty, Johns Hopkins University,
Baltimore, MD, USA; e Walton Center of Neurosciences, Liverpool, UK
* Corresponding author. Division of Infectious Diseases and Geographic Medicine, UT South-
western Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9113.
E-mail address: [email protected]

Infect Dis Clin N Am - (2025) -–-

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2 Castellino et al

Abbreviations
ABI ankle-brachial index
CNA Charcot neuroarthropathy
CRP C-reactive protein
CT computed tomography
DECT dual energy CT
DFI diabetic foot infections
DFO diabetic foot osteomyelitis
DFU diabetic foot ulcer
ESR erythrocyte sedimentation rate
IDSA Infectious Diseases Society of America
IWGDF International Working Group on the Diabetic Foot
MRSA methicillin-resistant S. aureus
OM osteomyelitis
PAD peripheral arterial disease
PVD peripheral vascular disease
RCTs randomized controlled trials
T1W T1-weighted
WBC white blood cell

19% and 34%, with widely varying statistics around healing and ulcer recurrence, with
some reports of up to 40% recurrence within 1 year.5 In a prospective series of pa-
tients with an infected diabetic foot ulcer (DFU) followed for 12-months, the ulcer
healed in only 46% of patients; 17% required a lower extremity amputation, and
15% had died in 1 year.6 The 5-year mortality rate of patients with a DFI requiring a
minor amputation is reported to be as high as 46.2%, in stark contrast to the 5-year
pooled mortality of 31% for all reported cancer.5

CLINICAL PRESENTATION

Patients with diabetes are prone to develop ulceration due to a combination of factors,
including repetitive stress, particularly over bony prominences, foot deformity, periph-
eral neuropathy, and peripheral artery disease.7 Most patients develop a superficial
wound or ulceration that progresses to cellulitis, abscess, fasciitis, joint infection,
and/or osteomyelitis (OM) with or without systemic infection. Patients may not recog-
nize the symptoms of infection, as neuropathy leads to lack of the gift of pain, as
described in patients with leprosy.8
Not all DFU are infected, and diagnosis of DFI is usually made clinically, based on the
presence of signs of inflammation such as swelling, erythema, tenderness, warmth,
and purulence, as well as presence of systemic symptoms such as fever, tachycardia,
and leukocytosis. Several classification systems exist to define the severity of DFI,
including systems developed by the International Working Group on the Diabetic
Foot (IWGDF) and the Infectious Diseases Society of America (IDSA),3 the Perfusions,
Extent/size, Depth/tissue loss, Infection and Sensation (PEDIS) system;9 Wagner,10
University of Texas,11 and the Society for Vascular Surgery’s WIfI ( Wound, Ischemia,
foot Infection) systems.12 Classification systems have been used to standardize
research methodologies, develop treatment guidance, and prognosticate the risk of
amputation and benefit of revascularization. Patients with clinically diagnosed DFI
should also be evaluated for predisposing risk factors that led to the development of
DFI, such as peripheral vascular disease (PVD), poorly controlled diabetes, pressure
ulcer, tinea pedis, maceration, and lymphedema, as these factors contribute to poor
healing and risk of recurrence. Additionally, the presence of underlying bone infection

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 Diabetic Foot Infections 3

(diabetic foot osteomyelitis, DFO) is important to define, as this has implications for
both medical and surgical treatment options.3

EVALUATION
Microbiology
DFIs are often polymicrobial with a vast majority having gram-positive organisms
particularly Staphylococcus aureus and Streptococci. Modern studies report an in-
crease in gram-negative organisms ranging from 30% to 62%.13–15 The prevalence
of pseudomonas varies around the world with tropical and sub-tropical climates
reporting higher prevalence compared to northern climates.16 Even within North
America, the prevalence of pseudomonas varies based on climate zones, ranging
from 11.6% in hot humid climates to 6.2% in very cold climates.17 The presence of
anaerobes in DFI ranges from 7.7% to as high as 83.8% using newer molecular
methods for microbiologic diagnosis, and are usually associated with ischemia, necro-
sis, deeper lesions, fever, malodor and long duration of ulceration.18,19 However, the
pathogenic role of anaerobes remains poorly understood, as they are present in poly-
microbial infections, often in the presence of ischemia and tissue necrosis, which pro-
vide a favorable environment. In patients with DFO, bone sample cultures should be
obtained to diagnose a pathogen, as soft tissue swab cultures do not reliably corelate
to bone culture.20
Osteomyelitis
DFO is a much-feared complication and develops in 20% to 50% of patients with
DFU.21,22 Osteomyelitis should be suspected in a patient with ulceration present for
many weeks despite proper wound care and offloading, ulcers that are wide, deep,
located over bony prominences, with visible bone or presence of a swollen sausage
toe.3 Patients with clinically diagnosed DFI, or a long standing DFU that is clinically un-
infected, must be evaluated for underlying OM, in order to best determine duration of
antimicrobial therapy as well as surgical planning. DFO is usually diagnosed based on
a combination of clinical, laboratory, and imaging findings, with multiple tests having
varying sensitivity and specificity. The IWGDF/IDSA guidelines suggest starting with a
combination of probe-to-bone, plain X-rays, and erythrocyte sedimentation rate
(ESR), or C-reactive protein (CRP), all of which are widely available and inexpensive.
While the medical community has generally shifted away from the use of ESR for
the patient with infection, the body of literature in the diabetic foot space has shown
value and use for this peripheral serum biomarker in the diagnosis of foot infection
and the stratification of soft tissue infection versus OM.23–25 Lack of a standard defi-
nition of OM, combined with differences in inter-test agreement between various tests
and discrepancies in values of ESR and CRP between laboratories can lead to chal-
lenges in the diagnostic certainty of DFO. Additionally, imaging alone often cannot
distinguish between changes from OM versus Charcot arthropathy. Berendt and col-
leagues have proposed consensus criteria that assess the probability of DFO, using a
combination of tests that are commonly used in the clinical setting (Table 1).26
Imaging
Anatomic imaging methods
Plain film radiography is the first choice in persons with diabetes and suspected foot
infections, as it facilitates identification of bone changes associated with infection as
well as changes in soft tissue (Fig. 1A). Although conventional radiography is inexpen-
sive, convenient, and fast, there is a delay in reaching the threshold of detection for
visualizing OM. Clear evidence of bone erosion in DFO may not occur until 10 to

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Castellino et al
Table 1
Proposed consensus criteria for diagnosing osteomyelitis in the diabetic foot

Post-Test Probability
Category of Osteomyelitis Management Advice Criteria
Definite (‘beyond >90% Treat for osteomyelitis Bone sample with positive culture AND positive
reasonable doubt’) histology OR
Purulence in bone found at surgery OR
Atraumatically detached bone fragment removed from
ulcer by podiatrist/surgeon OR
Introsseous abscess found on MRI OR
Any 2 probably criteria OR one probable and 2 possible
criteria OR, any 4 possible criteria below
Probably (‘more likely 51%–90% Consider treating, but further Visible cancellous bone in ulcer OR
than not’) investigation may be needed MRI showing bone edema with other signs of
osteomyelitis OR
Bone sample with positive culture but negative or
absent histology OR
Bone sample with positive histology but negative or
absent culture OR
Any two possible criteria below
Possible (but on balance, 10%–50% Treatment may be justifiable, Plain X-rays show cortical destruction OR
less rather than more likely) but further investigation MRI shows bone edema OR cloaca, OR
usually advised Probe to bone positive OR, Visible cortical bone OR
ESR >70 mm/h with no other plausible explanation OR
Nonhealing wound despite adequate offloading and
perfusion for >6 wk OR ulcer of >2 wk duration with
clinical evidence of infection.
Unlikely <10% Usually no need for further No signs or symptoms of inflammation AND normal
investigation or treatment X-rays AND ulcer present for <2 wk or absent AND
any ulcer present is superficial OR
Normal MRI OR
Normal bone scan
 Diabetic Foot Infections 5

Fig. 1. Anatomic imaging methods. (A) Radiograph of osteomyelitis involving the great toe
with an osteolytic lesion in the distal phalanx. (B) CT images showing soft tissue edema and
cortical destruction on the inferior surface of the calcaneus. (C) Bone marrow edema in the
calcaneus on DECT. (D) T1W image showing hypointensity (arrow) of bone marrow edema in
a metatarsal bone consistent with osteomyelitis.

14 days after infection onset.27 Visualization of subtle soft tissue changes and non-
radiopaque foreign bodies can be challenging.28
Computed tomography (CT) imaging offers advantages of 3D and multiplanar re-
constructions, can be done relatively quickly, and when properly obtained with intra-
venous iodinated contrast, can delineate bone changes as well as soft tissue findings,
extent of infection, multicompartment involvement, abscess, and air associated with
necrotizing fasciitis. Dual energy CT (DECT) and photon-counting CT are new ad-
vancements that can create bone marrow 3D maps without bony cortices, showing
marrow edema as seen in DFO and inflammatory arthropathies, in addition to conven-
tional CT findings as above.29–31 DECT also depicts alternative causes of extremity
inflammation, for example, gouty tophi deposition in the adjacent soft tissue structures
(Fig. 1B, C). Additionally, the ability to reduce metal artifact makes this an attractive
alternative in patients with contraindications to MRI to assess OM.29
Besides X-ray, MRI is the most recommended imaging modality for suspected infec-
tion in the diabetic foot.3,32 The MRI signature of confluent low T1-weighted (T1W)
marrow signal intensity alteration in a medullary distribution (Fig. 1D) has reported char-
acteristics as high as 95% sensitivity for the prediction of OM, 91% specificity, and 98%
negative predictive value for excluding OM,33 though performance can vary with the
experience of the reader.34 MRI has added advantages of being a radiation-free modal-
ity that allows assessment of both cortical and marrow involvement, deep tissue extent
of infection, anatomic and functional evaluations (diffusion-weighted imaging and
perfusion imaging),35 and differentiation of alternative diagnoses; for example, gout

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6 Castellino et al

and Charcot neuroarthropathy (CNA). However, MRI quality can be degraded in the
presence of local metal or may not be possible due to MRI-unsafe devices in-situ.
Bone marrow edema is also nonspecific if taken in isolation for characterization of
OM, with MRI-scoring systems being developed to standardize the reporting of extrem-
ity infections including OM and septic arthritis.36
Molecular and cellular imaging methods
Nuclear medicine imaging for suspected foot infection in persons with diabetes in-
cludes bone scans, radiolabeled white blood cell (WBC) scans, dual isotope (99mTc)
WBC scan and (111In sulfur colloid) marrow imaging, and 18F-fluorodeoxyglucose
PET (FDG PET) imaging.37
Routine bone scintigraphy for suspected infection utilizes radiolabeled diphospho-
nates, which localize to and are retained in bone. The 3-phase bone scan is sensitive
for identifying infection but with low specificity. A meta-analysis by Llewellyn reported
an average sensitivity of 84.2% and a specificity of 67.7%.38 In the first or perfusion
phase, and in the second phase aka blood pool or tissue phase, both soft tissue
and bone infections show greater uptake in the affected foot, while in the third or delay
phase, infected bone shows greater uptake than normal bone and surrounding soft
tissue (Fig. 2A–C).
WBCs can be labeled with either 99mTc for same day scanning or 111In for delayed
scanning or dual radiotracer scanning in the setting of suspected infections in compli-
cated foot problems such as recent trauma, CNA, or orthopedic hardware. WBC scan-
ning is based on the host response of migration of labeled leukocytes to the site of
infection. Previous analyses have found that 99mTc-HMPAO WBC (99mTc-WBC) scans
are highly sensitive (91%) and specific (92%) for the detection of OM.39 When com-
bined with SPECT/CT 99mTc-WBC scans show localization of cells to bone in OM
versus soft tissue in cases of abscess or cellulitis (Fig. 2D–F).
Dual tracer radiolabeled 99mTc-WBC and 111In-sulfur colloid scanning is used to
identify superimposed infection in the setting of CNA or presence of orthopedic hard-
ware that might activate marrow/marrow expansion and cause some low level of leuko-
cyte migration into the site. Diagnoses in the dual isotope dual tracer scan is based
on spatial or intensity discordance to identify infection. In the case of active infection,
radiolabeled cells will show either uptake in a location different than marrow expansion/
activation or much greater intensity than the marrow background (Fig. 2G–J).
FDG PET relies on the increased utilization of glucose by inflammatory cells in the site
of infection. The higher resolution of PET compared with SPECT combined with CT yields
high quality images (Fig. 2K–M). In a recently published retrospective study comparing
WBC scanning, FDG PET, and MRI in suspected DFI, FDG PET had a specificity of 97.9%
for soft tissue infection, and for pedal OM had 69%, 72.4%, and 70.7% for sensitivity,
specificity, and accuracy, respectively.40 However, FDG PET application in complica-
tions in the diabetic foot suffers from the accumulation of FDG in sterile inflammation
and lack of uniform interpretation criteria for distinguishing OM from CNA.41
While many of these imaging techniques offer advantages when the diagnosis of
soft tissue versus bone infection is in doubt, the cost and availability of these tech-
niques limits their use to situations where other diagnostic tests such bone biopsy
are limited or inconclusive.

TREATMENT
Antimicrobial Therapy
For mild infections, without underlying OM, empiric antibiotic therapy is a reasonable
approach, targeting gram-positive organisms, particularly beta-hemolytic streptococci

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 Diabetic Foot Infections 7

Fig. 2. (A–C) Three phase bone scan shows increased flow (A) and blood pool (B) activity in
the left foot and increased uptake in the head of the first metatarsal (arrow) on the delay
phase (C). (D) Soft tissue infection of 111In-WBC SPECT/CT (E, F) Soft tissue infection and OM
on 99mTc-WBC SPECT/CT. (G–J) Dual isotope dual radiotracer 111In-WBC (G, H) and 99mTc-sul-
fur colloid scan (I, J) in a patient with CNA in the hindfoot and ankle, and osteomyelitis in
the great toe and posterior aspect (discordant spatial activity, arrow) in the ankle. (K–M)
FDG PET/CT images of osteomyelitis involving the head of the first metatarsal in the left
foot incidentally found on a scan obtained for oncology purposes. (K) CT showing cortical
erosion (arrow). (L) FDG PET showing FDG accumulation at the erosion site (arrow) and in
the soft tissue around the joint (arrowhead). (M) Fused PET/CT image (arrow points to focal
uptake at the erosion site, arrowhead FDG accumulation in soft tissue around the joint).

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8 Castellino et al

and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) based

on risk factors.3 For moderate to severe infections based on the IWGDF/IDSA classifi-
cation, expanding coverage to include gram-negative and anaerobic bacteria is rec-
ommended, and should be guided by local antibiogram data. Several studies have
compared different antibiotics in the treatment of DFI, with no specific antibiotic class
noted to be superior to another, one exception being a trial comparing ertapenem
with or without vancomycin versus tigecycline, in which the tigecycline arm had poorer
outcomes.42 Typical recommendations include beta-lactam antibiotics with or without
beta-lactamase inhibitors, cephalosporins, carbapenems, and metronidazole for
anaerobic coverage in combination with other antibiotics, clindamycin, linezolid, tetra-
cycline, trimethoprim-sulfamethoxazole, daptomycin, fluoroquinolones, or vancomy-
cin3 (Table 2), though knowledge of local antibiogram data should guide empiric
regimens. Limited retrospective data exists for the use of long acting lipoglycopepti-
des.43 Pseudomonas is not common among North American studies of DFI, and
empiric coverage should be considered only in cases with maceration, water exposure,
prior antibiotic exposure or P. aeruginosa isolated in recent cultures.3 The prevalence
of common drug-resistant organisms, such as MRSA and resistant gram-negative
organisms can vary widely and initial empiric antibiotic regimens should take into
consideration local rates of these organisms.44 Many empiric antibiotic regimens
cover most anaerobes, though the severity of infection often warrants surgical debride-
ment, which might be sufficient to disrupt the anaerobic environment, thus decreasing
the need for antibiotics that specifically target anaerobes.18 Use of appropriately
selected oral antibiotics to treat DFI is supported by the literature,14,45–47 though it is
imperative that patients have close follow-up similar to those on IV antibiotics, as up
to one-third of patients being treated with oral antibiotics for orthopedic infections
have been reported to develop side effects that warrant additional medical
intervention.48
Duration of therapy is usually based on the extent of infection with few randomized
controlled trials (RCTs) having compared the duration of antibiotic therapy in DFI. In a
prospective RCT of 10 days versus 20 days of treatment post-debridement for soft tis-
sue infection, rates of remission and adverse events were similar.13 OM is typically
treated for 6 weeks, and at least 1 RCT has shown no significant differences in out-
comes for appropriately selected patients treated nonsurgically, with 6 weeks versus
12 weeks of antibiotics for DFO. An important caveat to note is that patients were
excluded from this trial if they had PVD or had other indications for surgical debride-
ment.49 A recent RCT comparing 3 versus 6 weeks of antibiotics for DFO in patients
that had surgical debridement showed no significant differences in treatment out-
comes between the groups,14 leading to a recommendation to treat residual OM for
3 weeks post-debridement.3 However, this was a pilot study with 90 patients and
wide noninferiority margins in which approximately half of all patients had a minor
amputation for OM of the toes, with a larger follow-up study underway.50 Clinicians
often use microbiological and/or histopathological data from the proximal margin of
amputation to determine if there is residual OM and thus determine the duration of
treatment, though data around this approach is conflicting. While some studies
have shown that residual OM at the pathologic margin was associated with a higher
rate of treatment failure,51,52 treating with a longer course of antibiotics has not
been shown to clearly affect the outcome.53,54 A more recent study showed no differ-
ences in reinfection, amputation, or hospitalization among patients with negative sur-
gical resection margins (negative microbiology and negative pathology).55 In practice,
most clinicians default to a 6-week course of antibiotics if there is concern for residual
OM, but this extended course of antibiotics may not lead to improved outcomes.

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Table 2
Suggested empiric antibiotics for diabetic foot infections

Infection Severitya Pathogens Antibiotics Additional Considerations

Mild Gram positive cocci Cephalexin/cefazolin Add doxycycline or tmp/sx if purulence or MRSA risk factors
S. aureus, Streptococcus Amoxicillin-clavulanate Add doxycycline or tmp/sx if purulence or MRSA risk factors
species Clindamycin —
Trimethoprim-sulfamethoxazole
Doxycycline
Moderate/Severe Gram-positive cocci Ampicillin/Sulbactam —
Enterobacteriaceae Piperacillin/tazobactam
Ceftriaxone 1 metronidazole
Obligate anaerobes Cefepime1metronidazone If risk factors for Pseudomonas
Carbapenems If risk factors for ESBL producing or ganisms
Vacomycin/Daptomycin/Linezolid Added if purulence/MRSA risk factors/hypotension

Abbreviations: ESBL, extended spectrumbeta-lactamase; Tmp/sx, trimethoprim/sulfamethoxazole.

Diabetic Foot Infections

a
Infection severity based on IDSA/IWGDF classification.

9
10 Castellino et al

Surgical Approach and Considerations

Surgical management of DFIs can be an unfortunate necessity to preserve a functional
limb. Urgent operative intervention within the first 24 to 48 hours after hospital admis-
sion is often required to obtain infectious source control in severe foot infections, such
as patients with deep abscess, necrotizing soft tissue infection, and/or soft tissue
emphysema. To stratify and triage patients, a methodical and repeatable assessment
is paramount. Aside from a thorough history and physical, an assessment of this pa-
tient population should include proper laboratory and imaging resources. Imaging the
diabetic foot is discussed elsewhere in this work, but plays a large role in the surgical
decision making.56 Specifically, the finding of soft tissue emphysema on radiographs,
CT, or MRI should increase the clinical suspicion of a gas forming infection, necessi-
tating a more urgent operative intervention. Other clinical assessment tools such as
the laboratory risk indicator for necrotizing fasciitis (LRINEC) score may be useful
but have shown limited utility in this patient population.57
A variety of surgical procedures may be used depending on the severity of the infec-
tion, the extent of tissue loss, and associated comorbidities. When approaching the
surgical management of the diabetic foot, staged operative management is required,
and proper expectations should be conveyed to the patient that multiple procedures
will likely be required to preserve a functional limb. The acute operative intervention of
the infected foot should first address infectious source control to remove infected,
necrotic, and nonviable soft tissue and bone to arrest further progression of the infec-
tion. During the index procedure, proper microbiological and pathologic specimens
should be obtained to evaluate for the causative pathogen of the soft tissue infection
and, if relevant, OM. Obtaining appropriate osseous specimens for microbiology and
pathology can improve the success of medical treatment of residual OM by approx-
imately 30%.58 It is often not known if the entirety of the infected tissues were excised,
further necessitating both the intraoperative specimens and staged operative man-
agement of the foot infection. This is especially true in cases with OM. In many situ-
ations, the patient is brought back to the operating room for the subsequent stage
in 48 to 72 hours for resection of any remaining infected or nonviable tissue. The final
operative procedure often includes any combination of wound bed preparation,
wound closure, coverage of the wound with a bioengineered skin substitute, cellular
or tissue-based product, or continuing with wound care.
When specifically addressing the operative management of the patient with OM,
additional considerations should be taken. If OM is isolated to a small bone such
as a phalanx or a structure like a toe, infection can be completely excised by way
of an amputation. This becomes a complex issue when a more structurally important
bone becomes infected, such as a metatarsal or any bone proximal to a metatarsal.
While OM may be within a defined bone, such as the 5th metatarsal, complete exci-
sion is often not preferable when considering the functional status of the patient. In
this specific example, the complete excision of an infected 5th metatarsal would
cause the loss of the peroneus brevis muscle insertion and a subsequent varus defor-
mity of the foot. This deformity could then cause further ulcerations and infections
secondary to this deformity. While the full purview of postamputation pathome-
chanics is outside the scope of this work, there are many other works on this sub-
ject.59–61 Nonetheless, in clinical situations such as this, the surgeon may decide
not to fully excise the OM to preserve a functional limb, opting to treat the residual
OM medically. This is especially challenging in the patient with calcaneal OM as com-
plete resection is often not a viable option. A subtotal calcanectomy may be a viable
option for resection of much of the infected bone while allowing for additional wound

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 Diabetic Foot Infections 11

coverage options.62,63 The subtotal calcanectomy, in the setting of DFO specifically,

has been shown to preserve the functional status of the patient although approxi-
mately 25% of patient with DFO of the calcaneus may already be nonambulatory.64
In the non-ambulatory patient with no reasonable expectation to rehabilitate to an
ambulatory status, further consideration should be given to a higher level amputation,
the exact extent of which needs to take into consideration the level of infection and
the vascular status of the patient.

COMORBIDITIES
Peripheral Vascular Disease
The prevalence of peripheral vascular disease among patients with DFU is as high as
49%.65 Peripheral arterial disease (PAD) is consistently associated with treatment
failure and risk of amputation.15,66,67 The IWGDF intersocietal PAD guideline recom-
mends all patients with DFU/DFI should be assessed for PVD with palpation of pedal
pulses, evaluation of pedal doppler waveforms, ankle-brachial index (ABI) and toe
brachial index.68 Absent pulses, ankle pressure <100 mm Hg, toe pressure <60 mm
Hg or monophasic/absent pedal Doppler waveforms warrant further evaluation by
vascular surgery. While no single cut-off value can be used to diagnose PVD, a low
ankle pressure (<50mmg Hg) or ABI <0.5 is associated with greater risk of major
amputation, while toe pressure <30 mm Hg increases probability of major amputation
by 20%.68 Revascularization should ideally be completed prior to surgical debride-
ment to maximize the chance of wound healing, though the severity of infection and
practical logistics within a hospital often dictate the timing of revascularization. Alt-
mann and colleagues reviewed 608 patients with ischemia and DFI, comparing pa-
tients who had revascularization 2 weeks before or after debridement surgery, and
did not show any significant difference in outcome as regards to the sequence or
timing of revascularization as related to debridement.69

Glycemic Control
Patients with DFU fear major amputation more than death, compared to diabetic pa-
tients without ulcers,70 and oftentimes an episode of DFI serves as a wakeup call for a
patient to improve glycemic control. Poor glycemic control is a major risk factor for the
development of DFI and is associated with poorer outcomes after surgical manage-
ment.71,72 Intensive glycemic control, in which the glycemic levels are maintained as
close to the nondiabetic range of Hemoglobin A1c (HbA1c) <6.05% compared to con-
ventional glycemic control without specific glycemic targets, has been shown to
reduce the risk of all DFUs. In a retrospective review of 183 patients with diabetes
seen at a wound center, HbA1c at baseline was inversely related to change in wound
area, such that for each 1% increase in HbA1c, the wound-area healing rate decreased
by 0.0028 cm2 per day.73 With many newer drugs for diabetes, technologies such as
continuous glucose monitors, multimodal diabetes care models, and use of electronic
consultation to access specialty care, every effort must be made to ensure patients
have access to a holistic plan for diabetes management.74,75 In addition to an annual
comprehensive foot examination, patients should be taught to examine their feet daily
for early detection of new foot problems.

Offloading
Offloading is critical to promote wound healing7 and can be achieved via a combina-
tion of offloading devices, surgery, and orthotics. For patients with plantar forefoot or
midfoot ulceration a nonremovable knee-high offloading device such as a total contact

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12 Castellino et al

cast or nonremovable knee-high device such as a walking boot is recommended.

However, in patients with ischemia or ongoing infection, removable knee-high or
ankle-high offloading devices should be used, to facilitate frequent inspection and
wound care. In general, patient-selected footwear is discouraged due to increased
risk of new lesions.76–78 Surgical strategies such as Achilles tendon lengthening, dig-
ital flexor tenotomies etc., are recommended in selected cases that have failed
nonsurgical offloading. Patient balance and comfort can be improved by addressing
leg-length discrepancy with a shoe lift for the contralateral limb, and/or a walking aid.79

Wound Care
In addition to treating infection, addressing comorbidities, and ensuring appropriate
offloading, regular wound care is essential to ensure healing of a DFU. Debridement
of the ulcer and any surrounding callus results in removal of necrotic or devitalized tis-
sues, in order to promote wound healing and decrease the risk of infection. Debride-
ment can be achieved by surgery, or other mechanical means (wet-to-dry dressing,
hydro-debridement, or gaseous debridement), biochemical methods (use of enzymes
to liquefy necrotic tissue), or biological methods (use of medical grade larvae). IWGDF
guidelines recommend sharp debridement of the ulcer as a standard of care, though
sharp debridement should be avoided in case of ischemic or painful ulcers. Enzymatic
debridement is suggested as an alternative when sharp debridement is not available
or contraindicated.80 While no recommendation is made on the frequency of debride-
ment, retrospective data suggests that wounds that are debrided with intervals of
one week or less heal significantly faster.81 No specific type of wound dressing has
been shown to be superior for DFU, and in general, choice of dressing is often deter-
mined by cost and availability. Negative pressure therapy has been shown to decrease
the time to healing for postsurgical wounds compared to standard of care dress-
ings,82,83 though this can be costly and time consuming.

Monitoring treatment
Patients that have been treated for DFI/DFO should be monitored clinically for resolu-
tion of infection, recognizing that ulcers might not be completely healed at the end of
antibiotic treatment.6 Routine monitoring of inflammatory markers at the end of treat-
ment has not been shown to predict treatment failure, and similarly radiographs are
not recommended as there is often a radiographic lag in improvement.84,85 Wounds
that do not heal appropriately should be evaluated for risk factors that contribute to
wound healing—particularly PVD and offloading. All patients should have close clinical
follow-up and education to ensure modifiable risk factors for ulcer recurrence, such as
off-loading with appropriate foot wear, glucose control, smoking cessation, and PVD
are consistently addressed. Foot care should be reevaluated every three to six months
for patients who are risk for foot ulceration.76
DFI is a complex disease with patients having to cope with multiple recommended
interventions simultaneously, with hospitalized patients reporting worse quality of life
outcomes as regards to physical function, pain, anxiety, depression,86 lack of moti-
vation, high costs of care, challenges in limiting activity to achieve appropriate off
loading, and difficulty in obtaining timely appointments, described as barriers to
care.87 Potential solutions have been suggested to address barriers to care, partic-
ularly as related to social determinants of health.88 Finally, given the complexity of
patients with DFU, multidisciplinary teams and access to specialty care including
endocrinology, infectious diseases, podiatry, plastics, vascular surgery, have been
shown to improve survival of patients with a longer time to ulcer progression, major
amputation, or death.89,90

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 Diabetic Foot Infections 13

The care of patients with DFI continues to evolve with improved diagnostic studies
and increasing literature demonstrating that many patients can be treated without
amputation, with improved surgical techniques that support conservative surgery,
increasing the use of oral antibiotics, given for a shorter duration, and use of technol-
ogy to better support patients living with diabetes. Increased recognition of the value
of multidisciplinary collaborative care can lead to personalized treatment plans, and
ultimately improved outcomes and functionality for patients with DFI.

CLINICS CARE POINTS

 Patients with diabetic foot infection must be evaluated for underlying osteomyelitis, using a
combination of clinical, laboratory, and radiographic tests.
 Soft tissue infections can be treated with antibiotics for 10-days, whereas for diabetic foot
osteomyelitis, antibiotics for three to six weeks is recommended.
 Knowledge of local microbiology/antibiogram is important to determine empiric antibiotic
regimens. Appropriately selected oral antibiotics can be just as effective as intravenous
antibiotics.
 Evaluate and address comorbidities that can affect outcomes, especially peripheral vascular
disease, offloading, and glucose control. This is ideally done with an interdisciplinary team.

DISCLOSURE

All authors report no conflicts of interest related to this work.

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