Immun., Endoc. & Metab. Agents in Med. Chem., 2007, 7, 95-104 95

1871-5222/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.

Treatment of Diabetic Foot Ulcers

N.C. Schaper*, L.M. Prompers and M.S.P. Huijberts

Division of Endocrinology, Department of Internal Medicine, University Hospital Maastricht, Maastricht, TheNetherlands

Abstract: The development of diabetic foot ulcers is a well-known complication of diabetes. The pathophysiologicalmechanism is complex, and different clinical presentations are possible, depending on the specific underlying pathology.Diabetic foot ulcers are usually caused by several factors acting in concert, with polyneuropathy, altered biomechanics,inadequate shoes and peripheral arterial disease (PAD) as major factors. Neuropathy is present in most patients with dia-betic foot ulcers, while PAD is present in 30 – 50 %; infection can be diagnosed in up to 50% of patients presenting with afoot ulcer. Therefore careful examination of the patient and identification of these specific pathologies is needed beforethe start of any treatment. Because most patients have lost the natural protective mechanism to relieve pressure from thewound, off-loading of these ulcers is extremely important. For plantar foot ulcers total contact casting is the current stan-dard: with this technique up to 90% of neuropathic ulcers can be healed within two months. The recognition and treatmentof infection is equally important. Diagnosing infection is a challenge in these patients because signs and symptoms can beabsent. The choice of the initial antimicrobial therapy is usually empiric and based on the severity of the infection, priorantibiotic use and local resistance to most common pathogens. Evaluation of the severity of PAD is indicated in many pa-tients. Patients with critical limb ischemia should undergo revascularisation as soon as possible, and both endovasculartreatment and bypass surgery are suitable interventions to improve tissue perfusion. Most other strategies to improvewound healing, such as local application of growth factors, have failed to show significant clinical benefits. Recently,negative pressure wound therapy was shown to improve wound healing in patients with a partial foot amputation in alarge randomised trial. Many patients not only have foot problems but also other health problems such as cardiovascularand renal disease and self care problems. Therefore an integrated management programme is needed, in which optimalregulation of diabetes and associated co-morbidity, and regular communication and instruction of the patient and his orher caregivers are taken care of.

INTRODUCTION

Diabetic foot ulcers have a major impact on the patient aswell as on the health care system. These ulcers tend to healslowly, need intensive care and healing can be complicatedby infection and gangrene, leading to long-term in-hospitaltreatment and/or amputation [1, 2]. On first glance manydiabetic foot ulcers seem relatively benign: a skin defect of afew square centimetres, which is partly covered by callus oran eschar, in a patient who has few specific complaints. Thislack of overt symptoms may falsely reassure both the patientand the clinician; however, the absence of symptoms, as wewill discuss in this article, should actually be seen a sign of aseverely diseased foot. Moreover, foot ulcers have majornegative effects on quality of life, due to loss of mobility,loss of work and reduction of social activities; in one study itwas comparable with the quality of life of patients with re-current breast cancer [3, 4]. After an amputation prognosis iseven worse and quality of life is further reduced [5]; in a 5years of follow-up study, 49% had undergone a second am-putation, 68% had died and only 19% of the patients with alower leg amputation were able to walk 1 km [6]. Despitethese poor outcomes, the feet of diabetic patients have tradi-tionally received relatively little attention from health careworkers and scientists. However, in recent decades our

*Address correspondence to this author at the Department of Internal Medi-cine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht,The Netherlands; Tel: + 31-43-3877019; Fax: + 31-43-3875006;E-mail: nsc@sint.azm.nl

knowledge on diabetic foot ulcers has clearly increased, witha rise in the number of scientific publications and the pro-duction of guidelines on prevention and management [1, 7,8]. In this review we describe the epidemiology, costs,pathogenesis, and in particular current treatment modalitiesfor diabetic foot ulcers.

EPIDEMIOLOGY AND COSTS

On a population basis diabetic foot ulcers are a relativerare disease: the prevalence in cross-sectional studies in theUK, was 1-2% of the diabetic patients screened [9, 10], andthe annual incidence of new ulcers in the Western world wasapproximately 2% in community based studies [10, 11]. Thisincidence rises to 5-7% in patients with risk-factors, such asloss of sensation or foot deformities [10, 12]. Foot ulcers andtheir consequences are associated with major health careconsumption and high costs. The costs of amputation and itsconsequences are even higher, because of the rehabilitation,care in nursing homes, etc. In a prospective Swedish studyfrom 1994, the direct costs to treat 274 individuals with afoot ulcer were approximately 4 million Euros annually, withinpatient care and topical wound treatment incurring morethan 80% of the costs in subjects who healed without ampu-tation [13]. On the longer term costs are probably muchhigher as diabetic foot ulcers are a recurrent disease, withrecurrence rates up to 70% in centres of excellence, resultingin repeated interventions and progressive disability [14], (seeTable 1).

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Table 1. Foot Facts

One in every six people with diabetes will have a foot ulcer duringtheir lifetime

Every year 4 million people with diabetes will develop a foot ulcer

Every 30 seconds a leg is lost due to diabetes somewhere in the world

Foot problems are the most common cause of admission to hospitalfor people with diabetes

In developing countries foot problems may account up to 40% ofhealth care resources

The direct cost of an amputation is estimated to be between US$30,000 and US$ 60,000

Ulcers can be prevented and up to 85% of amputations can be avoided

PATHWAYS TO ULCERATION AND AMPUTATION

Diabetic foot ulcers are usually caused by several factorsacting in concert, with polyneuropathy, altered biomechan-ics, inadequate shoes and peripheral vascular disease (PAD)as major factors. Each of these components is usually notsufficient to cause ulceration, but it is the combination of twoor more factors that typically results in a poorly healing footulcer [15]. Approximately 50-60% of all foot ulcers can beclassified as neuropathic, in the absence of limb threateninginfection nearly all of these ulcers should heal with optimaltreatment [1]. Signs or symptoms of PAD are usually ob-served in 40-50% of all patients and the vast majority ofthese patients have neuro-ischemic ulcers, only a minority ofpatients have purely ischemic ulcers. As discussed below,the severity of the perfusion deficit can vary substantiallybetween patients from minimal reduction in perfusion pres-sure to chronic critical limb ischemia. Short term outcome ofthese patients will depend on the ability of the foot to sustainadequate perfusion for healing and if this is not likely, a re-vascularisation procedure will be necessary to save the foot.Healing rates of neuro-ischemic ulcers can, therefore not begiven, as they depend on factors such the severity of thePAD and the possibility to perform a revascularisation pro-cedure. In our experience at least 50% of all diabetic footulcers will become infected and adequate skin perfusion is amajor determinant of outcome of this infection. In one studya midfoot or leg amputation was performed in 76% of thepatients with a foot infection and PAD [16].

DISTAL SENSORI-MOTOR POLYNEUROPATHYAND ALTERED BIOMECHANICS

In daily life our feet are continuously threatened by mul-tiple minor and major insults, and loss of protective sensa-tion is a cardinal event in the pathway to foot ulceration inmany patients [17]. The sensory deficits include diminishedperception of pain, temperature, light touch, and pressure[18]. Although some patients have symptoms such as pares-thesia or pain, many patients do not have major symptomsand are not aware of the diminished protective sensation.The majority of neuropathic or neuro-ischemic ulcers arecaused by chronic repetitive biomechanical stress with ab-

normal loading of the foot during standing and walkingand/or ill-fitting shoes [1]. This abnormal loading of the footcan be the consequence of loss of muscle function due toneuropathy, foot deformities (such as claw toes or bonyprominences), changes in shock absorbing capacity and lim-ited joint mobility of the joints of the foot [19, 20]. The re-petitive biomechanical stress induces the formation of callusat the sites of abnormal load. This callus further elevatespressures and is associated with a high risk of future ulcera-tion in neuropathic patients [21]. Finally the skin breaksdown, sometimes preceded by a subcutaneous haemorrhage,with the formation of a painless neuropathic ulcer [1]. Thesame pathways are probably followed in neuro-ischemiculcers, except that ischemia would render the foot more sus-ceptible to damage and after a minor trauma perfusion maybe insufficient to support healing.

Several lines of evidence suggest that abnormalities intissue perfusion can also be the consequence of neuropathy.Autonomic neuropathy of the foot leads to diminished sweatsecretion and increased thermoregulatory shunt blood flow,resulting in a warm foot with a dehydrated skin [22]. Due tothis increased shunt blood flow venous pressure in the footrises resulting in an enhanced susceptibility to edema forma-tion, which may impair diffusion of oxygen and nutrients[23]. In type 2 diabetic patients the increased shunt bloodflow seems to be associated with a “capillary steal” phe-nomenon of the nutritive skin microcirculation [24] and, inline with this hypothesis, a recent study showed that tissueoxygenation was reduced in the neuropathic foot [25]. Neu-ropathy is also associated with impaired vasodilatory re-sponses of the skin microcirculation to various (noxious)stimuli [25]. These microvascular abnormalities could renderthe skin more susceptible to the deleterious effects of theincreased biomechanical stress and could negatively affecttissue healing.

In Fig. 1 the classical development of a neuropathic footulcer is summarised: bony deformities with abnormal load-ing in an insensate foot lead to repetitive tissue damage, theformation of callus, a subcutaneous haemorrhage, the devel-opment of a poorly healing ulcer, which subsequently

Fig. (1). Pathogenesis of a neuropathic foot ulcer.

Treatment of Diabetic Foot Ulcers Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 1 97

becomes infected. In each of these stages a specific inter-vention could help to prevent further progression. Examplesare shoe wear to reduce the elevated plantar pressures, chi-ropody in case of callus, immobilisation and/or local meas-ures to reduce biomechanical stress in case of an impedingulcer, specific off-loading devices such as the total contactcast in case of an ulcer and finally bed rest, antibiotics and, ifnecessary surgery in case of an infected ulcer. Although at-tractive, this scheme does not seem to fit all patients. Pro-spective studies have indeed shown that elevated peak plan-tar pressures during walking can predict future ulceration inpatients with diabetic neuropathy [7, 27], but the predictivevalue of elevated foot pressures is relative low (sensitivity64% and specificity 46%) [28]. In an intriguing study ofArmstrong et al. using continuous activity monitoring inpatients with neuropathy, the subjects who developed aplantar ulcer had unexpectedly a lower overall daily activitythan the their non-ulcerated counterparts. [29]. Althoughseveral biomechanical explanations are possible [30] thesestudies suggest perhaps in addition to elevated foot pres-sures, other factors could play a central role in plantar footulceration. Finally, preliminary data of a large Europeanstudy of the Eurodiale consortium suggest that only a relativesmall number of patients do have such a classical ulcer onthe plantar forefoot. The majority (> 70%) of ulcers werelocated on other areas such as toes or the dorsum of the foot(L. Prompers, personal communication). In these patientsother factors must be responsible for ulceration, such as ele-vated shear forces due to ill-fitting shoes or impaired of mi-crocirculatory blood flow responses to relative low externalpressure [31]. However, the impressive healing rates that canbe observed with off-loading techniques in (neuro-)ischemiculcers, as described below, are a strong argument that oncean ulcer has developed, increased biomechanical stress im-pedes healing.

PERIPHERAL VASCULAR DISEASE

Atherosclerotic, obstructive, peripheral arterial disease(PAD) is a major determinant of the outcome of a diabeticfoot ulcer [15]. PAD is a common finding in patients withtype 2 diabetes mellitus, with a prevalence of approximately20 to 40% [32, 33]. In many patients the disease has no orfew symptoms and runs a relatively benign course, but inothers it leads to gangrene or impaired healing of foot ulcers.PAD in diabetes frequently has a specific anatomical pattern,which can be interpreted as a sign of premature ageing of thevascular tree. The proximal vessels are relatively spared,with less involvement of the aortic iliac arteries and moreextensive disease in the arteries of the lower leg [34-36]. Indiabetic patients, the atherosclerotic changes seem to bemore extensive and also more aggressive, with a faster pro-gression of disease. McDaniel showed that patients withclaudication and diabetes had a 35% risk of sudden ischemiaand a 21% risk of major amputation, compared to 19 and3%, respectively, in non-diabetic patients [37]. Major riskfactors for the development of PAD (other than diabetes) areolder age, smoking, and possibly hypertension [3]. Recently,several novel risk factors have been identified in the generalpopulation for the development of PAD, such as hyperhomo-cysteinemia, elevated markers of inflammation, and insulinresistance [38-42].

Diagnosis

Evaluation of the adequacy of tissue perfusion in the feetof diabetic patients can be a difficult clinical challenge, asalmost all tests have a moderate accuracy in predicting out-come. Many patients do not have claudication or severeischemic rest pain, probably due to sensory neuropathy.However, if claudication or rest pain are present, the prob-ability of amputation is greatly enhanced [2]. The pulses ofthe femoral, popliteal, dorsalis pedis, and posterior tibialartery should be palpated. The proximal vessels should beauscultated for bruits, particularly the iliofemoral segment. Ifboth foot arteries are palpated, severe ischemia is unlikely.Additional signs of severe ischemia are skin necrosis, gan-grene, and blanching of the feet on elevation with a red-purple discoloration on dependency (in the absence of infec-tion). Other signs are probably of little value in diabetic pa-tients [43]. The colour and temperature of the skin is usuallynot helpful as the feet of diabetic patients can be red andwarm, despite (severe) ischemia, which is probably causedby the relative high (thermoregulatory) shunt blood in dia-betic patients with peripheral ischemia [44].

Non-invasive vascular evaluation is indicated in case ofnonpalpable pulses, or other signs of ischemia and in non-healing ulcers. In nondiabetic patients measurement of thesystolic arterial pressure at the ankle with a hand held Dop-pler is a reliable screening test for severe ischemia [45].Also, in diabetic patients an absolute ankle pressure less than50 mmHg indicates critical limb ischemia. However, due tomedia calcification, these arteries can become less com-pressible in diabetic patients, resulting in falsely elevatedankle pressures. Ankle pressures above 50 mmHg, therefore,are of very limited predictive value. In contrast, measure-ment of systolic toe pressures is probably more reliable andcan predict wound healing in diabetic patients [45]. In par-ticular, values below 30 mmHg are associated with a pooroutcome, and values between 30 and 50 mmHg should alertthe clinician of the possibility of severe PAD. Unfortunately,toe pressure measurements can also be affected by mediacalcification in a minority of patients. Measurement of thetranscutaneous pressure of oxygen (TcPO2) can give addi-tional information on the probability of wound healing [46].Wound healing is very unlikely if TcPO2 values are below20-30 mmHg and healing is likely with a TcPO2 value above40 mmHg [45].

If clinical and noninvasive assessments suggest signifi-cant PAD with a low probability of wound healing, or if thepatient has persistent rest pain, revascularisation should beconsidered in all patients [1]. In these patients further inves-tigations are necessary to localise arterial lesions, to gradetheir severity, and to assess the possibility of a revasculari-sation procedure [45]. As stated in the International Consen-sus, in all cases the arterial tree of the lower extremity shouldbe visualised. It is crucial to visualise the entire tibial andfoot circulation, as the former is a common location of themost significant occlusive lesion and the latter is an impor-tant potential site for the anastomosis of a distal bypass. Inmost centers angiography will be performed, but this tech-nique might be replaced progressively by magnetic reso-nance angiography (MRA) [47].

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Endovascular Treatment

Endovascular treatment of peripheral arterial disease hasa number of advantages over bypass surgery, including thelow morbidity and mortality of the procedure, the shortpreparation time and the limited hospital stay. The maincontra-indications are problems with haemostasis, severeheart failure or renal disease and specific anatomical char-acteristics such as long occlusions of iliac or femoral arter-ies. The restenosis rate might be relatively high, especially inprocedures below the knee in which restenosis over a 5 year-period in 50% of cases has been reported [48]. However, inpatients with a foot ulcer the main aim is to heal the ulcerand to save the limb. The temporary improvement of skinperfusion can be sufficient to promote healing of a chroniculcer and to avoid amputation in a patient with a relativelyshort life expectancy. Moreover, once the ulcer is healedlower perfusion pressures are necessary to maintain skinintegrity. Faglia et. reported on the results of peripheral per-cutaneous angioplasty (PTA) as first line revascularisationtherapy in 993 patients with diabetic foot ulcers [49]. Allpatients with absent foot pulses and a TcPO2 below 50mmHg and stenoses > 50% of vessel diameter underwentangiography and if possible PTA. In 62 % of patients ob-structions both in the femoro-popliteal and infrapopliteal axiswere present. With a mean follow-up of more than two yearsrelatively good outcomes were reported: All but 6 ulcershealed, and major amputation was performed in only 17 pa-tients (1.7%). The number of minor amputations was how-ever high with almost 50 % (478 patients). The estimate ofclinical restenosis was 2.2 % per year, but in most of thesepatients PTA could be repeated successfully. 12% of thepatients died during follow-up. The complication rate was3.4 %, including 10 cases of distal thrombosis, 7 cases ofcardiac events (chest pain, myocardial infarction) and onedeath. Recently also the results of the BASIL trial have beenreported. In this multicentre randomised controlled trial, re-sults of bypass surgery versus angioplasty in patients withsevere limb ischaemia with or without tissue loss have beenevaluated. 42% of this cohort consisted of patients withknown diabetes. The median results for the outcomes ampu-tation-free survival, all cause mortality and Health RelatedQuality of Life (HR-QOL) were quite similar. In the firstyear bypass surgery resulted in increased morbidity, mortal-ity and higher costs, but in the long term patients who un-derwent surgery seemed to have a reduced risk of future am-putation and death [50]. The results of these studies mightindicate that endovascular therapy should take a prominentplace in the treatment of PAD, especially in patients withsignificant co-morbidity and a shorter life expectancy.

Peripheral Bypass Surgery

Peripheral bypass surgery remains an effective treatmentin many diabetic patients with PAD and critical limb ische-mia. The basic principles of this type of surgery are that anyartery can be used for the proximal anastomosis providedinflow is uncompromised. The graft should bypass the majorobstructive lesions and for the distal anastomoses an arteryrelatively free of occlusive disease, providing the best out-flow into the arteries of the foot, should be selected. Thebypass graft should preferably be constructed with autoge-

nous vein(s), although acceptable results have been obtainedwith prosthetic grafts that do not cross the knee [51]. Anadequate ipsilateral saphenous vein is preferred in a below-knee bypass, but other good quality veins can be used. Ifpossible the contralateral saphenous vein should be spared,as a substantial number of patients will require a bypass onthe contralateral leg in the future [52]. The crural and pedalarteries are common outflow sites of the graft in diabeticpatients, given the characteristic anatomic pattern of PAD.Long-term results of these distal procedures in diabetic pa-tients are good, with 5-year secondary patency rates of ≥70%and limb salvage rates of 75-85% [53, 54]. In addition, suchdistal procedures in diabetic patients are more cost-effectivethan primary amputation [55]. Antiplatelet therapy should bestarted preoperatively and continued after an endovascular orsurgical procedure [45]. In general diabetes does not seem tohave an important negative effect on the long-term patency-and limb salvage rates of bypass surgery [53, 54].

Stimulation of Neovascularisation

Successful revascularisation through endovascular inter-vention or peripheral bypass surgery is not always possiblein patients with foot ulcers and ischemia. Failure to restoretissue perfusion is currently probably the most importantdeterminant of lower extremity amputation in patients withdiabetes. Stimulation of the formation of collateral arteriescould form an attractive medical therapy to improve bloodflow to the leg. Outward remodelling is an important processduring the development of a collateral network. Animalstudies suggest that in the legs these collaterals are pre-formed and in case of a severe reduction in blood flow, growin diameter to restore peripheral blood flow in a processcalled arteriogenesis [56]. However, as recently shown in thecoronary circulation, the formation of these collateral vesselsseems to be impaired in diabetic patients with ischemic heartdisease [57]. The same observation was made in diabeticanimals with peripheral ischemia [58]. It is likely that in dia-betic patients several mechanisms contribute to the impairedarteriogenesis during ischemia, such as endothelial dysfunc-tion, diminished cellular responses to several growth factorsor cytokines, and impaired degradation of the extracellularmatrix [59-61]. Also dysfunction of endothelial progenitorcells, that play a role in neovascularisation in responseto tissue ischemia, has been demonstrated in patients withtype 1 diabetes [62]. Gene transfer using growth factorshas been evaluated in a number of studies as a tool to en-hance vascular growth. In the RAVE trial patients with in-termittent claudication were treated with VEGF gene transfer(AdVEGF121), which did not result in improved exerciseperformance or quality of life. [63, 64]. However, in theTRAFFIC study repeated intra-arterial administration ofFGF-2 slightly but significantly improved walking time inpatients with intermittent claudication [65]. Currently thereare however no studies that have demonstrated effects inpatients with diabetes, critical limb ischemia and foot ulcers.

Moreover, one recent study has demonstrated that sig-nalling of growth factors such as VEGF is impaired in dia-betic patients [66], which might limit the effectiveness ofstrategies aimed at increasing tissue levels of growth factorssuch as VEGF.

Treatment of Diabetic Foot Ulcers Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 1 99

Hyperbaric Oxygen Therapy

For those patients with foot ulcers and severe ischemia inwhom revascularisation is not possible, improving oxygendelivery by hyperbaric oxygen (HBO) therapy might be auseful adjunctive therapy. Five RCTs in diabetic patientswith chronic foot ulcers were recently analysed in a system-atic review. HBO was associated with a reduction in majoramputations, but not in minor amputations nor was an effecton wound healing observed [67]. The authors concluded thatHBO may be regarded as a promising treatment option whenother strategies have failed, but the small numbers of patientsand methodological problems necessitate a cautious inter-pretation of the results and a large RCT is needed.

INFECTION

Infection in a diabetic foot ulcer is potentially a limb-threatening condition and in particular the combination in-fection and PAD has a poor prognosis. It generally assumedthat poor metabolic control is associated with impaired im-munity, but it still a matter of debate whether patients withonly moderately elevated blood glucose levels diabetes aremore susceptible to infection. Neutrophil function is im-paired in diabetic patients with poor metabolic control, re-sulting in defective chemotaxis, phagocytosis, and intracel-lular killing [61, 68-70]. Increased shunting of glucose dur-ing hyperglycemia through the polyol pathway might be re-sponsible for the defect in intracellular killing [71]. In addi-tion, hyperglycemia could also have long-term effects onleukocyte function. As discussed elsewhere in this journalchronic hyperglycemia can result in the accumulation of ad-vanced glycation end products (AGEs), which can bind tospecific AGE receptors (RAGE) on the cell membrane. Thisreceptor is also present on human leukocytes and AGEs caninhibit the bactericidal activity of neutrophils [72].

Infection is characterised by tissue damage due to multi-plying micro-organisms and the host response. As openwounds tend to become colonised with micro-organisms andeven virulent pathogens (e.g. Staphylococcus aureus) cansometimes be colonisers, isolating a micro-organism in a

culture does not help to identify the patient with an infectionand the diagnosis should be made on clinical grounds (8).Unfortunately, local signs of inflammation, such as erythemaor pain, can be less apparent in diabetic patients with a footinfection, probably due to factors as ischemia and neuropa-thy [1]. Also systemic signs of infection can be markedlyabsent. In one study of patients with a deep foot infectionapproximately 50% of the patients did not have systemicsigns of inflammation, such as elevated body temperature orCRP [73]. On the other hand when increased body tempera-ture or laboratory parameters of inflammation are present, asevere infection is more likely (see Table 2) [74]. The spe-cific anatomy of the foot can also affect the presentation andcourse of an infection. In case of a penetrating ulcer, infec-tion of one of the muscle compartments of the foot can resultin tissue edema with a rise in compartmental pressure andsubsequent microvascular occlusion. This foot compartmentsyndrome, with its vicious cycle of infection, edema andmicrovascular failure, can result in extensive tissue necrosis[75].

Superficial infections in patients not treated previouslywith antibiotics are usually caused by gram-positive micro-organisms, in particular Staphylococcus Aureus and bacteriasuch as β haemolytic Streptococci. Deep foot infections,chronic infections and wounds that have previously beentreated with antibiotics often have a mixed flora of gram-positive and gram-negative aerobes and anaerobes [76].Multiresistant micro-organisms and methicillin-resistant S.aureus (MRSA) are a growing problem and in one recentlarge American trial in which 2 intravenous broad spectrumantibiotics were compared, MRSA was isolated in 20% ofthe cultures [77]. MRSA was isolated in 30% in outpatientswith an infected foot ulcer in a retrospective study from theUK, which was almost twice as high compared to figuresobserved 3 years earlier [78].

Diagnosis of Infection

In patients in whom infection is considered the woundshould be debrided aggressively to determine the extent ofthe infection. The depth of the wound should be determined,

Table 2.

Clinical manifestations of infection IDSA severity* Pedis Grade**

No signs of infection Uninfected 1

Presence of >2 manifestations of inflammation (purulence, or erythema, pain, tenderness, warmth, or induration),but any cellulitis/erythema extends <2 cm around the ulcer, and infection is limited to the skin or superficial sub-

cutaneous tissues; no other local complications or systemic illness.Mild 2

Infection (as above) in a patient who is systemically well and metabolically stable but which has >1 of the fol-lowing characteristics: cellulitis extending >2 cm, lymphangitic streaking, spread beneath the superficial fascia,

deep-tissue abscess, gangrene, and involvement of muscle, tendon, joint or boneModerate 3

Infection in a patient with systemic toxicity or metabolic instability (e.g., fever, chills, tachycardia, hypotension,confusion, vomiting, leukocytosis, acidosis, severe hyperglycemia, or azotemia)

Severe 4

*IDSA= Infectious Diseases Society of America (Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, LeFrock JL, Lew DP, Mader JT, Norden Cl, Tan JS.Diagnosis and treatment of diabetic foot infections, Clin Infect Dis 2004; 39: 885–910)**PEDIS= Classification system for research purposes of the International Consensus on the Diabetic Foot (Schaper NC. Diabetic foot ulcer classification system for research pur-poses: a progress report on criteria for including patients in research studies. Diabetes Metab Res Rev. 2004; 20 Suppl 1: S90-5.).

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if necessary by probing the wound with a blunt instrument. Ifa deep foot infection is suspected, an X-ray of the footshould be obtained and in some cases a MRI will be helpfulto determine the extent of tissue involvement. Material forculture should be obtained, preferably pus or tissue of thebase of the wound by scraping with a scalpel or a curette. Ifthis is not possible, aseptically obtained aspirates of pus ortissue fluid can also provide good specimens for culture [76].Wound swabs are less preferable as they provide, in com-parison to tissue specimens, less sensitive and specific results[74]. The material obtained should be immediately processedfor gram stain and culture, both aerobic and anaerobic.

Treatment of Infected Foot Ulcers

Treatment of an infected diabetic foot ulcer should bebased on the severity of the infection and the presence ofischemia. Superficial ulcers without severe ischemia, canusually be treated on an outpatient basis with repeated de-bridement, meticulous wound care, off-loading and oral anti-biotics [74]. Patients with deep foot infections, signs of sys-temic toxicity or severe ischemia should be admitted to thehospital; especially the combination of infection and ische-mia should be considered as a medical emergency [1]. Sur-gery should be considered in all patients, which may rangefrom minor debridement or drainage to extensive resectionsor amputation. In one prospective study surgery was requiredto achieve healing in almost all patients with a deep soft tis-sue infection [79]. A surgical debridement in the operatingtheatre should therefore be considered in case of a deep softtissue infection, with decompression of the infected com-partment, removal of all necrotic tissue and the creation ofadequate drainage [75]. The choice of the initial antimicro-bial therapy is usually empiric and based on the severity ofthe infection, prior antibiotic use and local resistance to mostcommon pathogens. Unfortunately, there is currently littleevidence in the literature to guide the clinician in the choice,the route (oral or parenteral) and the duration the antibiotictreatment [74]. The number of randomised clinical trials inwhich antibiotic regimens were compared are limited (forreferences see [74]) and interpretation is difficult as in thesetrials different classification systems and different end-pointswere used. Hopefully, the introduction of the PEDIS classifi-cation system by the International Consensus on the DiabeticFoot can help to standardise future clinical trials (see Table2) [80]. As summarised in the guidelines of the InfectiousDiseases Society of America guidelines, no single drug orcombination of drugs seems superior to another [74]. Super-ficial infections can usually be treated initially with oral an-tibiotics aimed at gram positive cocci, such as flucloxacillinor, in case of penicillin allergy, clindamycin. Deep soft tissueinfections are initially treated with an i.v. broad spectrumregimen aimed at gram positive, gram negative aerobic andanaerobes, e.g. amoxicillin/clavulanate, piperacillin/tazobac-tam, or a combination of a third generation cephalosporinand clindamycin [76]. After 2-3 days of empirical treatment,therapy should be modified on the basis of the clinical re-sponse of the patient and the results of the wound culture.The optimal duration of treatment for soft tissue infections isunknown, but mild infections can usually be treated for 7-10days and more severe infections for 2-3 weeks [76]. In ourexperience duration of treatment is especially difficult to

determine in patients with infected ischemic wounds, inwhom signs and symptoms of infection can be mitigated.Antibiotics may penetrate less effectively in bone and some(retrospective) studies suggest that the combination of afluoroquinolon and clindamycin can be effective treatment inpatients with (suspected) osteomyelitis. [81-83]. As thesedrugs have a high bioavailability they can be prescribed asoral agents and, in case of a (chronic) osteomyelitis, therapycan be continued until eradication of the infection is likely,which usually takes 2-3 months. However, some authorshave argued that compared to antibiotic therapy conservativesurgery could result in faster healing and shorter duration ofantibiotic treatment [84]. Future clinical trials, in which thecost-effectiveness of long term antibiotic treatment is com-pared with conservative surgery, are needed in order to guidethe clinician in this difficult choice.

Tissue perfusion is a major determinant of the penetrationof antibiotics and in one amputation study already moderatelevels of ischemia resulted in poorer penetration of a thirdgeneration cephalosporin into skin, muscle and bone [85].Unfortunately, limb ischemia was an exclusion criterion inmost RCT’s on antibiotics and more insight is needed on thepharmacodynamics and efficacy of antibiotics in patientswith infected ischemic wounds. Relatively high doses ofantibiotics seem preferable in patients with ischemia to reachsufficient tissue concentrations. In patients with severeischemia it is advisable to first treat the infection with broad-spectrum antibiotics and, if necessary, a drainage procedureor minor amputation. Once the infection is controlled a re-vascularisation procedure can be performed after 4-5 days;with this approach excellent long-term results have beenobtained [86].

Although theoretically attractive there is currently littleevidence to support the use of topical antimicrobials [87, 88].In our opinion, antiseptics such as acetic acid or Iodosorb,probably do have a place in the treatment of mildly infectedwounds. With the advent of newer wound products, such assilver medicated dressings, topical antimicrobials havegained renewed attention [88]. However, there is currentlylittle evidence to support the use of medicated dressings, inorder to treat infection. These dressings might have a placein mild/early infections but given their relative high cost,clinical trials are necessary. Local antibiotic therapy couldalso have advantages as higher drug concentrations could bereached and agents can used that cannot be prescribed sys-temically. Especially in patients with superficial infectionscaused by MRSA, topical antibiotic treatment might be bene-ficial, but again clinical trials are needed. As discussedabove, there is some evidence suggesting that leukocytefunction is impaired in diabetes. Granulocyte colony-stimulating factor (G-CSF) increases the release of neutro-phils from the bone marrow and improves neutrophil func-tion in patients with infected diabetic foot ulcers. G-CSFmight therefore be an attractive adjunctive therapy and wasevaluated in five RCT’s in diabetic patients with an infectedfoot, with variable results [89-93]. A recent meta-analysisconcluded that G-CSF therapy is associated with a reductionin the number of amputations and other surgical procedure[94]. However, given the high costs of this treatment itshould probably only be reserved for patients with a limb-threatening infection.

Treatment of Diabetic Foot Ulcers Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 1 101

OFF-LOADING

No vascular intervention, infection treatment or advancedwound care product is likely to be successful if a diabeticfoot ulcer is not protected against external trauma. An indi-vidual without neuropathy will respond to a foot lesion byavoiding any further damage. Unfortunately, a patient withloss of protective sensation will not spare his feet, but willcontinue to walk or to wear an ill-fitting shoe, with a poorlyhealing foot ulcer as the consequence. Moreover, many dia-betic patients do not seem to be aware of the presence of anulcer [10], probably because of factors like poor vision orinability to inspect the feet. Even after being told, patientshave difficulties in realizing the consequences of the loss ofsensation. Clinicians have probably the same problem, whichcould be one of the reasons why off-loading to protect theulcer has received so little attention until recently [95]. Al-ready in 1989 Mueller showed that with the total contactcasting technique (TCC) significantly higher healing ratescould be achieved compared to accommodative shoe wear.[96]. With this technique a minimally padded cast is usedwhich is molded to the contours of the foot and the lowerleg, thereby redistributing elevated pressures under the foot[97, 98]. In addition, the cast protects the wound, limits am-bulation and reduces edema. To our knowledge 4 prospectiveRCT’s have been performed on various off-loading tech-niques, which had a sufficient study-duration (see Table 3).Healing rates were 32-58% in patients treated with insoles orhalf-shoe and 52-65% in the patients treated with a Remov-able Cast Walker, which is a commercial device up to theknee of standard dimensions. Healing rates were markedlyhigher, 74-90%, in the patients treated with a TCC, with ashorter duration of treatment [96, 99, 100]. Although a TCCseems a highly attractive off-loading modality, several disad-vantages have been reported such as skin maceration, newulcers, joint rigidity and muscle atrophy [101]. Moreover,daily wound care is not possible, the cast usually needs to bechanged every week, costs may be relatively high, and spe-cialised staff seems necessary. The Irremovable Cast Walker

Table 3. RCT’s on Off-Loading in Plantar Neuropathic Ul-cers with Follow-Up ≥ 12 Weeks

Off-loading n % HealedTime to heal

(days)

TCC 21 90 42Mueller,1989 Insole 19 32 65

TCC 19 90 34

RCW 20 65 50Armstrong,

2001

Half-shoe 24 58 61

ICW 23 83 42Armstrong,2005 RCW 27 52 58

TCC 20 74 35Katz,2005 ICW 21 80 28

TCC= Total Contact Cast; RCW = Removable Cast Walker, ICW= irremovable CastWalker

(ICW) might be an easier and cheaper alternative to theTCC, possibly without loss of efficacy [102]. With this tech-nique a band of casting is wrapped around a Removable CastWalker, which is thereby rendered irremovable. This simpleprocedure resulted in an increase of healing rates from 52 to83%, stressing that the fact that patients with loss of protec-tive sensation are difficult to motivate to wear their off-loading devices. It is probably the “forced compliance” ofboth the TCC and ICW, that are the major determinants oftheir success. Clearly more research is needed to confirm thecost-effectiveness of the ICW and to determine if the princi-ple of “forced compliance” could also improve the efficacyof other frequently used (removable) devices.

Most studies, and all RCTs, on casting had been per-formed in superficial, non-ischemic and non-infected ulcers.Unfortunately, only a limited number of ulcers actually fulfilthese criteria in daily practice. In a recent prospective studywe showed that compared to non-infected neuropathic ulcers(healing rate 90% in median 18 days) TCC can also be ef-fectively and safely used in patients with superficially in-fected neuropathic ulcers treated with oral antibiotics (heal-ing rate 90%) and with moderate neuro-ischemic ulcers(healing rate 69%). However, poor results were obtained inpatents with infected neuro-ischemic ulcers (36%), this cate-gory of patients should not be treated with a TCC until theinfection is adequately treated [103]. Non-plantar ulcers canbe off-loaded with various techniques individualised to thespecific causes of the ulcers. Examples are felted foam that isfixed around an ulcer [104], orthoses to separate overlappingtoes in case of interdigital ulcers but sometimes simply theremoval of a small part of the lateral or dorsal aspect of ashoe can be sufficient to temporarily off-load a bony promi-nence and to enable healing.

PROMOTION OF WOUND HEALING

Several lines of evidence suggest that, apart from repeti-tive biomechanical stress and impaired tissue perfusion, dia-betic foot ulcers have an intrinsic defect in wound healing.Recruitment of leukocytes is an important early event inwound healing and is impaired in experimental models ofdiabetes [105] and several lines of evidence suggest thatAGE formation can lead to impaired wound healing. AGEsmight be involved in a defective inflammatory response totissue damage as blockade of the AGE receptor in diabeticmice accelerated the development of an inflammatory infil-trate, with restoration of the impaired wound healing [106].Glycation of skin collagen and possibly of other matrix com-ponents probably impairs matrix degradation [107]; blockadeof AGE formation restored matrix degradation and normal-ized impaired ischemia-induced angiogenesis in diabeticmice [108]. Currently, AGE-breakers are being developed astherapeutic intervention in the treatment of diabetes [109]and their efficacy in promoting wound healing in diabetes,either by topical or systemic treatment, needs to be evaluatedin the future. In addition, glycation can reduce the bioavail-ability of growth factors [110] and the increased activity ofmetalloproteinases, as observed in diabetic foot ulcers, ulcercould result in enhanced degradation of growth factors [111].However, a dressing that was developed to inhibit matrixmetalloproteinases did not promote wound healing in onetrial in diabetic foot ulcers [112]. Abnormalities have also

102 Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 1 Schaper et al.

been observed in the proliferative capacity of fibroblasts ofdiabetic patients, derived from normal skin and from footulcers [60, 113]. The mechanism of this decreased fibroblastproliferation is unclear, but could be caused by impairedcellular responsiveness to one or more growth factors, suchas PDGF and TGF-beta [114, 115]. Topical treatment withrecombinant human PDGF has been evaluated in large scaleclinical trials in patients with neuropathic ulcers and resultedin an absolute increase in wound healing rates of approxi-mately 15% after 20 weeks of treatment [116-118]. Given itsmodest efficacy in the aforementioned trials and its highcosts, PDGF is in our experience seldom used. It shouldprobably be reserved for non-healing neuropathic ulcers,without any sign of infection and which do not heal despiteoptimal off-loading. Tissue engineering is a theoreticallyattractive modality for non-healing ulcers and in last decadeseveral clinical trials have been performed with varioustechniques. Dermagraft, a skin substitute derived from cul-tured human fibroblasts, was effective in patients with achronic neuropathic ulcer (> 6 weeks) and in this RCT wastreatment was associated with an absolute increase in healingrates of 12% [119]. In another RCT Apligraf, a living skinequivalent, was evaluated and resulted in an absolute in-crease in healing rate of 18% in chronic neuropathic ulcers[120].

A disadvantage of the aforementioned studies on tech-niques to stimulate wound healing, was that according tocurrent insights the wounds were not properly off-loaded,rendering these studies difficult to interpret. In contrast, inone Italian study standardised off-loading was combinedwith treatment with autologous cultured fibroblasts, obtainedby skin biopsy. Plantar ulcers were treated with a total con-tact cast, dorsal ulcers with (removable) therapeutic shoes.Cultured fibroblasts did not have a significant effect onwound healing in this RCT. However, when the ulcers on theplantar and dorsal side of the foot were analysed separately,healing rate of the dorsal ulcers in fibroblast group was 67%compared to 32% in the control group of dorsal ulcers, whileno effect was seen in the plantar ulcers [121]. These datasuggest that stimulation of wound healing might be indicatedfor patients in whom off-loading with “forced compliance” isnot possible. An alternative explanation could be that inpoorly healing dorsal ulcers other factors are involved thanin plantar ulcers.

An interesting development is negative pressure woundtherapy, with this treatment intermittent or continuoussubatmospheric pressure is applied to the wound in order toremove exsudate, to reduce tissue edema and to stimulategranulation tissue formation. In diabetic patients with a par-tial foot amputation, negative pressure wound therapy wasassociated with higher healing rates compared to the controlgroup, 56% vs 39%, respectively [122]. Further studies areneeded to define the cost-effectiveness and to evaluate if thistherapy is also efficacious in the treatment of chronic footulcers.

In summary, various strategies can be used to stimulatewound healing in a chronic ulcer but in the RCTs on theseadjunctive strategies success was limited. Due to the highcosts and the limited evidence few of these modalities havereached daily clinical practice, possibly with exception of

negative pressure wound therapy, which is already used innon-diabetic patients with surgical or chronic wounds [123].Meticulous wound care remains one of the cornerstones inthe treatment of diabetic foot ulcers, with removal of all ne-crotic tissue and callus with a scalpel [124]. This procedureshould be repeated as frequently as necessary, e.g. once aweek in an outpatient. Inadequate relief of elevated biome-chanical stress might be one of the main reasons of the rela-tive poor results the new treatment strategies. Wounds ofpatients with a chronic ulcer showed in one study histologi-cally signs of inflammation and little granulation or angio-genesis. In contrast, in patients treated with adequate off-loading, signs of repair were noted with an increase in thenumber of fibroblasts, an increase in granulation tissue andneo-angiogenesis [125]. Adequate off-loading, as describedin the previous paragraph, together with stratification ofplantar and non-plantar ulcers, should be included in theprotocol of future studies evaluating new adjunctive thera-pies to promote wound healing.

TAKING CARE OF THE PATIENT

In the process of treating patients with diabetic foot ul-cers, it is not always taken into account that diabetic footdisease often reflects a poor health status. Especially in pa-tients with neuro-ischemic ulcers there is a clustering of co-morbid conditions such as heart failure, renal disease andimpaired mobility. Also, many patients have self-care prob-lems and are dependent on others for daily care. It is notmore than logical that health care professionals that are in-volved in treatment of diabetic foot ulcers are primarily fo-cussed on treatment of the foot. However effective treatmentof patients with diabetic foot ulcers requires an integratedprogramme in which optimal regulation of diabetes and as-sociated co-morbidity, and regular communication and in-struction of the patient and his or her caregivers are takencare of. It will be evident that such a programme requires thecontribution of different health care professionals. Multidis-ciplinary treatment of patients with foot ulcers has beenshown to improve outcome [126]. The participation of a dia-betologist, vascular surgeon, and rehabilitation specialist ismandatory for a successful team. Techniques that should beavailable are casting, manufacturing of off-loadingshoewear, facilities for vascular assessment, endovasculartherapy and bypass surgery. Moreover, the complex processof diagnosis and multidisciplinary treatment requires optimalcoordination and definition of responsibilities within theteam.

CONCLUSION

The treatment of diabetic foot ulcers remains a challenge,in view of the complexity of the underlying problems and theinvolvement of many different health care professionals.However, if the basic principles such as off-loading of thewound, treatment of infection, and revascularisation if neces-sary are followed, and patients receive this care without de-lay, a favourable outcome can be obtained in most patients.

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Received: November 24, 2005 Accepted: April 27, 2006