Accepted Manuscript

The Diabetic Foot

Dennis F. Bandyk, M.D.

PII: S0895-7967(19)30011-0
DOI: https://doi.org/10.1053/j.semvascsurg.2019.02.001
Reference: YSVAS 50567

To appear in: Seminars in Vascular Surgery

Please cite this article as: Bandyk DF, The Diabetic Foot, Seminars in Vascular Surgery (2019), doi:
https://doi.org/10.1053/j.semvascsurg.2019.02.001.

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Seminars in Vascular Surgery

Fighting Foot Ulcers and Preventing Amputation in the Diabetic Population
Guest Editor: Carlo Setacci

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The Diabetic Foot

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Pathophysiology, Evaluation, and Treatment

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Dennis F. Bandyk, M.D.
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Professor of Surgery, Division of Vascular & Endovascular Surgery
University of California – San Diego, La Jolla, CA
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Address correspondence to:

Dennis Bandyk MD
Division of Vascular & Endovascular Surgery
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9434 Medical Center Drive – Mail Code 7403

La Jolla, CA 92037
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email: dbandyk@ucsd.edu
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ABSTRACT

The pathophysiology of the diabetic foot ulcer and soft tissue infection is due to

neuropathy, trauma, and in many patient, concomitant peripheral artery occlusive disease (PAD).

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Diabetes neuropathy results in foot deformity leading to increased skin pressure with walking.

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Once a foot ulcer develops, the limb is at high risk for invasive infection and when combined

with PAD, the patient should be considered to have critical limb ischemia. A multi-disciplinary

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approach to care for the “diabetic foot” is recommended which includes annual (3-month

intervals in “high-risk” patients) assessments by a primary care physician, and referral to a

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podiatrist and vascular surgeon in diabetics with a foot ulcer for the evaluation of foot arterial
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perfusion and off-loading therapy to reduce plantar skin pressure with walking. When invasive

foot infection develops and tissue beneath fascia are involved , in-patient care is recommend
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for systemic antibiotic therapy, vascular lab testing of artery limb perfusion, and surgical
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debridement of infected tissue. The goals of treatment are to achieve a healed foot and keep the
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patient ambulatory.
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Introduction

Foot related disorders, including infection, ulceration, and gangrene, are a frequent

indication for hospitalization of diabetic patients. The diabetic population in the United States

continues to increase; more than 100 million U.S. adults are nor living with diabetes or pre-

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diabetes. As of 2015, the Centers for Disease Control and Prevention (CDC) report found 30

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million Americans (9% of the population) have diabetes.1 It is estimated that up to 20% of these

patients will require hospitalization with a diabetic foot condition. Epidemiologic studies

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indicate the risk of developing a foot ulcer is 2.5% per year.2 The development of skin ulceration

in the foot of a diabetic is a serious medical condition which if not healed promptly can lead to

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amputation. Annually, non-healing diabetic foot wounds account for >100,000 amputations, and
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in 60% of patients, the inciting event was a foot ulcer. The societal impact of the diabetic foot is

significant in terms of individual disability, ensuing hospitalizations, and health care costs –
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estimated to be in excess of $1 billion annually.2 The development of multidisciplinary care

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programs that include surgeons can reduce both the number and extent of lower extremity
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amputations.3-5 Theprevalence of diabetic foot problems is expected to increase due to the aging

United States population and the problem of obesity in the population with its concomitant
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development of Type II diabetes.

Significant peripheral artery disease is present in over one-half of diabetic patients

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presenting with a foot ulcer.4 Thus, the vascular surgeon needs to be involved in the care of
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these patients and remain informed with updated data on the pathophysiology, diagnostics,

management, and prevention of the diabetic foot problems.

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Pathophysiology of the Diabetic Foot.

A triad of neuropathy, trauma with secondary infection, and arterial occlusive disease

account for the pathophysiology of the diabetic foot ulcer (Table 1). Peripheral neuropathy

produces intrinsic muscle atrophy leading to functional anatomical changes of hammer toe

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formation, and the development of “high-pressure” zones on the plantar surface of the foot at the

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metatarsal heads (Figure 1). Repetitive trauma with walking in concert with decreased sensation

and proprioception predisposes to skin injury by producing atrophy and dislocation of protective

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plantar fat pads leading to ulceration and infection with inadequate skin protection or improper

footwear (Figure 2).6 Inattention to skin care, such as failure to use moisturizing creams or

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prompt recognition of dermal trauma (redness, blister formation) can lead to ulceration and the
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development of an invasive soft tissue infection. If not promptly treated, tissue breakdown will

continue especially if the individual continues to walk. Risk for ulceration increases
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dramatically (by 32 times) in the presence neuropathy, foot deformity, or prior digit amputation.
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Eventually, the destructive processes of trauma and infection penetrate the deep fascia enabling
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infection to extend into the mid-foot muscles, joints, and along tendon sheaths. Infection

accounts for one-half of major (above- or below-knee) lower extremity amputations in diabetics.
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Neuropathy: The neuropathy produced by diabetes mellitus is a symmetric

polyneuropathy, in which motor, sensory, and autonomic functions are affected to varying
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degrees. In some patients, the peripheral myelin motor fibers are affected in a length-dependent
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pattern with the longest nerves affected first, resulting in a stocking distribution of sensory/motor

loss. Loss of the Achilles reflex is the earliest sign of these changes. With atrophy of the

lumbricals and interosseous muscles, the anatomy of foot arch changes with a relative increase in

extensor tendon forces producing a “claw” deformity of the toes. A shift to extrinsic
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muscle/tendon function contributes to depression of the metatarsal heads, hammertoe contracture

of the digits, and equine ankle deformity.

In addition to the motor fiber dysfunction, sensory loss involving Type A myelin fibers

causes a loss of proprioception, pressure sensation, vibratory perception, and impaired gait.

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Destruction of the type C sensory fibers leads to an inability to appreciate painful stimuli. As a

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result of these impaired sensations, the diabetic patient can experience repetitive foot trauma,

including blister formation or even metatarsal bone fracture, without an appreciation of foot

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discomfort. Neuroarthropathy or Charcot’s foot involves extensive destruction of the midfoot

with collapse of the arch and loss of foot stability. The warmth and swelling of the inflammatory

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stage of neuroarthropathy can mimic infection. Subluxation or dislocation of tarsal bones
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produces a bowed, “rocker-bottom” appearance of the foot, which is susceptible to “high-

pressure” ulceration. Autonomic system dysfunction, with impaired microvascular

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thermoregulation and anhidrosis, further adds to the motor and sensory disturbances. The skin
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becomes dry and prone to fissuring which diminishes its effectiveness as a barrier to
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microorganism invasion, and becoming susceptible to dermal infection, i.e. cellulitis.

Arterial Insufficiency. Hyperglycemia and associated changes in glucose metabolism

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produces endothelial injury, hyperlipidemia, increased platelet viscosity and activity; and with

time the development of atherosclerosis. The distribution of lower extremity atherosclerotic

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disease in diabetics differs from non-diabetics, and preferentially involves the infra-geniculate
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leg arteries (posterior and anterior tibial arteries) with less common involvement of the

femoropopliteal arterial segment (superficial femoral, popliteal), and often sparing of the

aortoiliac artery segment. With the development of diffuse tibial artery occlusive disease or more

proximal arterial occlusion, perfusion of the foot below a level adequate to maintain skin
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integrity can result and an ischemic ulcer or gangrene can develop. Typically, the peroneal and

dorsalis pedis artery are less involve with atherosclerosis which allows limb revascularization via

vein bypass grafting from the popliteal or a more proximal artery to restore foot perfusion and

achieve ulcer or foot (digit, transmetatarsal) amputation healing.

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Infection. The nature of diabetic foot infection can range from uncomplicated cellulitis

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to limb- and life-threatening necrotizing fasciitis. Intervals of poor glycemic control produce

immunologic dysfunction with impaired leukocyte activity and complement function that

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facilitate development of invasive tissue infection. In the presence of damaged, or poorly

perfused skin and soft tissues, rapid bacteria penetration deep to fascia can occur producing a

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foot-threatening infection and sepsis. Polymicrobial (staphlycocci, streptococci, enterococci,
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E.coli and other gram-negative bacteria) infections are common, as are the presence of antibiotic

resistant bacterial strains , especially methicillin-resistant Staphlycoccus aureus (MRSA) –

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present in 30-40% of cases. Amputation risk increases when the diabetic foot infection involves
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resistant bacterial strains; which often are the result of repeated or prolonged antibiotic usage.
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Gas-forming infections, present in approximately one-third of patients, as caused by clostridial

species, or a mixed infection of anaerobic streptococcus and E. coli.

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Evaluation of the Diabetic Foot

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A thorough patient history and physical examination with special consideration for co-
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existing renal and cardiac conditions initiate a comprehensive assessment of foot anatomy,

neurosensory dysfunction, and vascular perfusion. Recent foot trauma, including the possibility

of a foreign body being present, should be queried as well as the duration of and prior treatment

of a ulcer or foot wound. Both lower extremities should be inspected for skin trauma (redness,
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induration, edema), ulceration, foot/toe deformity, and popliteal and ankle (posterior tibial,

dorsalis pedis) pulses palpated. When pulses are not palpable, arterial flow assessment using a

hand-held, continuous-wave (5-7 MHz) Doppler should be performed to verify pulsatile flow in

the pedal and digital arteries. Site(s) of inflammation should be evaluated for crepitus or

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tenderness along tendon sheaths which indicate involvement of deep structures. Probing a

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plantar wound to verify penetration of deep fascia to bone is highly predictive (>90%) of

osteomyelitis.

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Neurologic examination includes testing of vibratory (128 Hz tuning fork) sense,

sensation to light touch (Semmes-Weinstein 5.07 microfilment), pin prick and temperature

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(tuning fork placed in warm or ice water applied to dorsum of foot and positional sense in the
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toes, and assessment of deep tendon (Achilles) and patellar reflexes. Loss of these neurologic

functions is predictive of foot ulceration with the annual risk increasing to > 6% if all are
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abnormal. Laboratory examinations should include: complete blood count with differential,
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hemoglobin A1C, urinalysis, and metabolic panel of serum electrolytes, creatinine, blood urea
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nitrogen, and glucose level.

Noninvasive arterial testing of limb/foot perfusion should be performed in all patients

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without palpable pulses, and include measurements of ankle and toe pressure in combination

Doppler or plethysmographic waveforms. The normal ankle-brachial systolic pressure index

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(ABI) is 0.9 to 1.3 and toe systolic pressure should be 80% of the ankle pressure. Artery wall
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calcification producing incompressibility to external cuff pressure can falsely elevate ankle

pressure measurements and should be suspected when the ABI is > 1.3 but abnormal arterial

waveforms or toe pressure (<80% of brachial pressure) measurements are recorded. An ankle

systolic pressure > 65 mm Hg and/or toe pressure of 40 mm Hg or greater is required for healing
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a superficial ulcer or digit amputation. Transcutaneous oximetry testing also is predictive of

healing when TcpO2 level > 30 mmHg.

Anatomic imaging studies. Plain radiographs of the foot (anterior-posterior and lateral

views) is the initial imaging study to evaluate for fracture, osteomyelitis, artery wall and soft

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tissue calcifications, foreign bodies, edema, or tissue air produced by a gas-forming infection.

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Presence of cortical bone erosion or periosteal elevation is indicative chronic infection of > 14

days. Three phase bone scans are highly sensitive for osteomyelitis but are prone to error in the

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presence of severe arterial occlusive disease, and following amputation. Magnetic resonance

(MR) imaging is highly diagnostic (sensitivity and specificity >80%) in determining the presence

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and extent of soft tissue infection, plantar abscess, and osteomyelitis (characterized by altered
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bone marrow signal). Simultaneous MR angiography of the lower limb can also be performed to

image the femoropopliteal and tibial arteries for patency, presence of occlusive disease, and
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communication with the pedal arch. Duplex ultrasonography can also be used to assess artery
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patency, determine extent and severity of occlusive disease, and identify lesions amenable to
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endovascular intervention. Digital subtraction angiography has a risk of producing contrast

media induced nephropathy, and thus its use in diabetics with renal insufficiency (serum
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creatinine > 2 mg/L) should be limited or avoided if possible. When necessary to evaluate

patients with multilevel occlusive disease or to monitor an endovascular intervention, using

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carbon dioxide gas as a contrast agent supplemented by small volumes (10-15 ml) of contrast
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media when necessary minimizes renal toxicity, especially if the patient has received oral

mucomyst 600 mg and intravenous fluids prior to the angiogram procedure. The risk of

radiocontrast nephropathy may also be reduced by an intravenous infusion of fenoldopam

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(Corlopam), a potent vasodilator of the renal circulation, which produces an increase in renal

blood flow and prevents a rise in serum creatinine in patients with pre-existing renal dysfunction.

Management of the Diabetic Foot.

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The goals of diabetic foot treatment are to achieve tissue healing while maintaining

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adequate function and weight-bearing for ambulation. Antibiotic treatment of invasive infection

in conjunction with tissue debridement or amputation, and off-loading foot pressure until healing

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is achieved are the essential management principles. In patients presenting with advanced

ischemia, control of infection takes precedent over limb revascularization. The risk of limb

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amputation can be estimated using the Society for Vascular Surgery WIfI classification of tissue
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loss, ischemia severity, and presence of invasive foot infection.8 Patients presenting with

advanced tissue injury, absent pedal pulses, and invasive infection require inpatient care. A
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vascular surgery consultation is imperative and when foot sepsis is present; emergent foot
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debridement may be necessary. Procastination can result in major limb amputation due to
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rapidly progressing soft tissue infection. Once the foot condition is treated, a multidisciplinary

team that includes the primary physician, diabetologist, nurse educator, prosthetist, and home
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care nurse is indispensable to assist the surgeon in treating patients presenting with invasive foot

infections, neuropathic ulcers, or tissue ischemia with and without gangrene.

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Specific adjunctive therapies have been shown to aid in ulcer/wound healing such as
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topical antimicrobial ointments (silver sulfadiazine, murpicin), wound growth factors, biologic

dressings, negative pressure wound therapy, and hyperbaric oxygen treatments. Wound healings

rates have be optimized in clinics that provided specialized treatments in conjunction with

pressure off-loading techniques.

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Invasive foot infection. Acute foot sepsis can develop from a site chronic infection or

following acute trauma. Antibotic therapy is based on the extent of foot infection, expected

pathogens, and presence of arterial occlusive disease (Table 2). Hospitalization with parenteral

antibiotic therapy is recommended when the infection penetrates to the deep fascia with or

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without the presence of pedal pulses. Patients with chronic ulcers, prior antibiotic treatment, and

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recurring infection should be assumed to have MRSA infection and empiric treatment instituted.

Soft tissue erythema, swelling with overlying skin gangrene indicates a deep space infection and

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the need for surgical exploration in the operating room for abscess drainage, debridement of

necrotic tissue, and if necessary resection of bone or digit amputation to establish open drainage

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of infected tissue planes. Wounds should be left open and may require serial wound debridement
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to achieve control of an invasive foot infection. Culture of deep tissues should be performed to

guide antibiotic therapy.

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In patients presenting with erythema and swelling but clinical response to antibiotic
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therapy is not evident within 24-36 hours, additional diagnostic imaging such as MRI should be
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performed to exclude presence of deep space infection or osteomyelitis. For advanced foot

infections with exposed joint spaces or gangrenous digits, prompt surgical debridement is
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necessary including toe and corresponding metatarsal amputation to adequate drain the infection

and facilitate tissue debridement. On occasion, an ankle disarticulation may be necessary to

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remove the septic foot when surgical exploration confirms invasive infection involving the mid-
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and hind-foot. These patients commonly present with septic shock requiring intensive care unit

monitoring, fluid resuscitation, insulin infusion to control hyperglycemia, and broad-spectrum

antibiotic therapy to include anaerobe coverage.

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Neuropathic ulceration. Diabetic foot ulceration may be caused by neuropathy,

ischemia, or both etiologies. When arterial circulation is confirmed to be normal by pedal pulse

palpation and pressure measurement, management of the neuropathic ulcer includes debridement

of non-viable tissue and callus, antibiotics if inflammation is present, and off-loading of skin

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pressure . Treatment is site specific with off-loading techniques tailored to prevent focal high-

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pressure zones with walking using specially formed orthotic insoles, an aircast walker, Bledsole

boot, or total contact casting (Figure 4). For neuropathic ulcers on the plantar foot surface, the

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metatarsal head is typically the culprit and healing at this site may require metatarsophalangeal

joint resection via a ventral incision to remove protruding bone and achieve skin healing. It may

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require 3-months of off-loading therapy to achieve healing, and longer in the non-compliant
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patient. When healing is not progressing based on serial assessment of ulcer size and depth,

patients should be re-evaluated for surgical intervention to achieve a more functional weight-
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bearing plantar surface.

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Amputation. Dorsal skin ulceration on a hammer toe or osteomyelitis involving a digit

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may require digit amputation if healing does not promptly occur. Digit-metatarsal amputation

for neuropathic ulcer is performed to redistribute plantar surface pressure to larger area and is
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used in conjunction with prescription orthotic shoes to prevent recurrence (Figure 3). More

proximal foot amputations (transmetatarsal, transtarsal) may be required to treat advanced

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plantar space infection or following revascularization in patients presenting with ischemia

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forefoot gangrene. Ankle systole pressure > 100 mm Hg and/or toe pressure >50 mm Hg have a

positive predictive value of 80% for healing of midfoot amputations, but decreased healing rates

occur in the diabetic with end-stage renal disease (ESRD). Aggressive measure for foot salvage

is justified in diabetic patients since ambulation rate of 90% and limb salvage rate of 60-70% at
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5-years is possible after a transmetatarsal or midfoot (LeFranc, Chopart) amputation. It is

essential to perform an adjunctive Achilles tendolysis to prevent development of an equines

deformity and patients ambulate using a orthotic, padded shoe and ankle brace, or clamshell

prosthesis.

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In diabetics with total bony collapse of the ankle and arch, or advanced Charcot foot

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deformity involving the tarsal bones with non-healing ulceration, a below-knee amputation

should be recommended. In selected diabetics, arch reconstruction or midfoot/ankle may be

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possible. When providing consul to the diabetic prior to amputation, it should be emphasized

that patients who are ambulatory at the time of amputation are likely to be ambulatory following

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major limb amputation because of advances in prosthetic limb technology.
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Ischemic ulceration or gangrene: Tissue ischemia manifest as dependent rubor with rest

pain, ulceration, or gangrene requires prompt evaluation for correctable arterial occlusive disease
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to improve perfusion and achieve limb salvage. Invasive infection should be controlled prior to
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open arterial bypass. In general, all patients with foot lesions and vascular testing demonstrating
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an ankle pressure < 100 mm Hg or toe pressure < 55 mm Hg should undergo arterial imaging

studies to identify occlusive lesion amenable to endovascular or surgical intervention. Nearly all
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patients are candidates for arterial intervention using advanced endovascular techniques,

including recannalization of chronic arterial occlusion, angioplasty of infragenculate tibial

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arteries, or bypass grafting to tibial or pedal arteries. Often these services are available only at
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tertiary referral vascular centers. When bypass grafting is required, an autogenous venous

conduit should be used. Foot salvage can be expected in >90% of diabetics requiring

concomitant arterial intervention and minor foot amputation with failure related to graft or

angioplasty-site thrombosis, recurrent foot infection, or persistent forefoot ischemia. In the

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absence of ESRD, outcomes after arterial intervention are similar in diabetic and non-diabetic

patients.

Prevention of Diabetic Foot Problems and Patient Education

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Patient education in techniques of meticulous foot care and appropriate foot-ware cannot

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be overstated. A multi-disciplinary approach that includes annual (3-month intervals in “high-

risk” patients) assessments to primary care physicians, a podiatrist, or vascular specialist to

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evaluate arterial perfusion is imperative. The diabetic with peripheral neuropathy should be

instructed to perform routine self examination of the skin and foot, and be educated in skin

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hygiene and footwear use. Self-examination and education is the cornerstone of a prevention,
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surveillance program. Education of the diabetic, their families, or caregivers should include:

instructions for foot hygiene, proper footwear use, and the importance of prompt evaluation of
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any new skin lesion or foot pain. Diabetics with peripheral neuropathy, foot deformity, absent
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pedal pulses or toe pressure < 40 mm Hg, and prior ulceration are at high-risk for development of
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a diabetic foot condition would benefit from a multidisciplinary diabetic foot care program.

Prospective studies had demonstrated the risk for diabetic ulcer formation to be 5/100 person-
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years. The goals of treatment are to heal diabetic foot ulcers and keep the patient ambulatory.
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References

1. www.cdc.gov/media/releases/2017/p0718-diabetes-report.htmlAmerican Diabetes

Association.

2. Consensus development conference on diabetic foot wound care. Diabetes Care.

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1999;22:1354-1360.

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3. Akbari CM, LoGerfo FW. Diabetes and peripheral vascular disease. J Vasc Surg 1999;30:373-

384.

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4. Boyko EJ, Ahron JH, Cohen V, et al. Prediction of diabetic foot ulcer occurrence using

commonly available clinical information. Diabetes Care 2006;29:1202-1207.

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5. Sumpio BE. Foot Ulcers. N Engl J Med 2000;343:787-793.
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6. Boulton AJM, Kirsner RS, Vileikyte L. Neuropathic diabetic foot ulcers. N Engl J Med

2004;351 :48-55.
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7. Miller J, Armstrong DG. Off-loading the diabetic and ischemic foot: Solutions for the vascular
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specialist. Semin Vasc Surg 2014:

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8. Mills JL, Conte MS, Armstrong DG, et al. The Society for Vascular Surgery lower extremity

threatened limb classification system: Risk stratification based on wound, ischemia, and
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foot infection (WIfI). J Vasc Surg 2014;59:220-34.

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Table 1. Pathways for the development of a diabetic foot ulcer.

- Combination of diabetic neuropathy, foot deformity, callus formation,and elevated skin

pressure

- Reduced skin perfusion due to peripheral artery occlusive disease

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- Repetitive trauma

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- Ill-fitting shoes producing friction induced skin trauma

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Table 2. Empiric antibiotic therapy for diabetic foot infection.
Extent of Infection
Superficial ulcer without
infection
Superficial ulcer with < 2 cm
of inflammation; pedal pulses
present
Ulcer with > 2 cm of
inflammation with extension
to fascia; pedal pulses present
Extensive local inflammation
plus systemic toxicity
or
ulcer/gangrene with
penetration of fascia and
absent pedal pulses
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Adapted from the Sanford Guide to Antimicrobial Therapy 2017.
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Pathogens Antibiotic Regimen
Colonizing skin flora No antibiotic therapy
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S. aureus (assume MRSA) Oral Therapy:
Streptococcus sp. (S. Trimethoprim/Sulfamethaxole-DS or
pyogenes predominate) minocycline, or amoxicillin/clavulonic
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acid; plus linezolid
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As above plus coliforms Oral Therapy:
Trimethoprim/Sulfamethaxole-DS plus
amoxicillin/clavulonic acid; plus linezolid
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or clindamycin
Or
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Ciprofloxacin or levoquin; plus linezolid
As above plus anaerobic Parenteral Therapy:
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bacteria
Vancomycin or Daptomycin plus
pipericillin/tazobactam or imipenum
cilastatin or meropenum
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MSSA only: ampicillin-sulbactam; or
cefepime
Or
Linezolid or vancomycin plus
ciprofloxacin or levoquin or aztreonam
If clostridia sp. suspected or gas gangrene
add penicillin G and/or clindamycin
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Figure 1. Mechanisms involved in diabetic foot disorders.

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Figure 2. Photo of diabetic foot with multiple skin ulcers caused by toe deformity and skin-

friction trauma due to ill-footing shoes.

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Figure 3. Photo of a malperforans diabetic foot ulcer due to peripheral neuropathy and

metatarsal head skin pressure with walking. Resection of metatarsal head via a dorsal incision

can result in plantar ulcer healing in conjunction with offloading walking boot.

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Figure 4. Photos of foot off-loading orthotics

(A) Removable leg-length walking cast boot

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(B) Patient with total contact cast and foot orthotic boot
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