J Antimicrob Chemother 2010; 65 Suppl 3: iii3 9

doi:10.1093/jac/dkq299

The treatment of diabetic foot infections

Andrew S. Powlson and Anthony P. Coll *
Wolfson Diabetes and Endocrine Clinic, Institute of Metabolic Science, Box 281, Addenbrookes Hospital, Hills Road,
Cambridge CB2 0QQ, UK
*Corresponding author. Tel: +44-1223-769041; Fax: +44-1223-330598; E-mail: apc36@cam.ac.uk

Keywords: diabetes, microbiology, osteomyelitis

Diabetic foot disease: a costly problem

Diabetes mellitus (DM) is a complex metabolic disorder with an
ever-increasing prevalence.1 An estimated 2.6 million people
are thought to have DM in the UK at present, with this likely to
reach close to 4 million by 2025.2 Among the many complications associated with diabetes, issues related to foot disease
represent a significant and often challenging clinical problem.
The proportion of patients with DM who develop foot infections is 2% per year in the UK, with the annual prevalence of
such infections in this population reaching 5%.3 Patients with
diabetic foot disease are over-represented in hospital inpatient
populations and, despite often prolonged4 and repeated admission, many come to amputation.5 Indeed, diabetes is the most
common cause of non-traumatic limb amputation, with a foot
ulcer being an antecedent event in the majority of cases.6

Pathogenesis of diabetic foot disease

The development of a foot ulcer invariably involves the convergence of several pathological mechanisms.7 Diabetic peripheral
sensorimotor neuropathy is a key factor in the majority of
cases. As a result of damage to sensory nerves, minor trauma
(from something as seemingly trivial as an ill-fitting pair
of shoes or walking barefoot on unfamiliar terrain) can go unnoticed. Neuropathy can also deform the architecture of the
foot to such a degree that joints and digits are placed in
mechanically unfavourable positions, making them highly vulnerable to injury.
Once the skin has been breached, continued mobilization on a
broken area impairs the healing process. Inevitably, direct

contiguous spread of microbes on the skin follows on, with colonization and infection of superficial and then deeper tissues likely
if the process is allowed to proceed unchecked. Both the healing
process and the response to infection are further compromised
by vascular insufficiency, which is commonly present in patients
burdened with complications of diabetes. Each pathological
driverinappropriate weight-bearing due to neuropathy, ischaemia and infectionneeds tackling for resolution of the ulcer but
the major focus of this review will be the infection burden.

Presentation and diagnosis of infection

in the diabetic foot
Clinical diagnosis
One major problem facing the management and study of diabetic foot disease is that there is no unifying standard that
defines infection. Classic features such as purulence, erythema,
pain, swelling and systemic upset can all be present but none
is pathognomonic of infection. Indeed, as a result of peripheral
neuropathy, limb-threatening lesions can present entirely
without pain and the concomitant ischaemia present in many
limbs also means that the florid inflammatory response typically
seen in a severe soft tissue infection may be greatly muted.
Despite these challenges, a variety of scoring systems for foot
lesions have been used in the literature. For example, the
Wagner8 score classifies a wound from grade 0 (pre- or
post-ulcerative lesion) through a range of increasing depth and
severity to grade 5 (whole-foot gangrene). It does not,
however, distinguish aetiology. The University of Texas system9
also uses a stepwise progression in grading (0 3) depending

# The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

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Successful treatment of infection in the feet of patients with diabetes mellitus remains a challenge. Although
the diagnosis of infection remains a clinical decision, presentation in feet rendered insensate from diabetic
neuropathy plus co-existing vascular insufficiency means presentation is often atypical. Wounds frequently
yield polymicrobial growth and differentiating commensal from pathogenic organisms can be difficult;
isolates from diabetic foot wounds are often multidrug resistant. Affected patients often have many other
co-morbidities, which not only affect the choice of appropriate antimicrobial regimen but also impede
healing. Further, much contention surrounds the management of osteomyelitis, with the merits and role of
surgery still undecided. In this review we briefly consider the epidemiology and pathogenesis of diabetic foot
disease, before discussing emerging best microbiological practice and how this fits with the multidisciplinary
approach required to tackle this difficult clinical problem.

Powlson and Coll

upon depth of wound and, additionally, takes account of the

presence of infection and/or ischaemia. In neither classification,
however, is there the ability to record infective burden. The classification developed by the Infectious Diseases Society of America
(IDSA)10 is a simple, validated system that ranks infected
wounds as mild, moderate or severe (Table 1) and appears to
be a reliable and useful tool for predicting relevant clinical outcomes, such as the need to be admitted to hospital and amputation.11 It is noteworthy that the severe categorythat
associated with the highest percentage rate of amputationis
reliant upon assessing systemic clinical (blood pressure, pulse,
temperature) and laboratory (acidosis, glucose levels, white cell
count) parameters, indicating that an assessment of the
patient as a whole is as critical as examination of the wound.

molecular biology are beginning to emerge that suggest it may

become possible not only to differentiate more objectively infection from non-infection but also to determine the virulence of
infecting pathogens and hence predict clinical outcome. For
example, Sotto et al. 13 used a PCR-based approach to detect
the presence of 31 of the most prevalent virulence-associated
genes in Staphylococcus aureus isolated from diabetic foot
ulcers. Logistic regression showed that five markers (cap8, sea,
sei, lukE and hlgv) had utility in distinguishing non-infected
from infected ulcers and were able to predict wound status at
follow-up. Although this approach has some way to go before
finding its way into routine clinical practice, it does open up
the possibility that a relatively easy multiplex PCR might be
able to identify at an early stage ulcers that have the potential
to become clinically difficult and highlight the need for a more
aggressive approach to be taken early on.

Microbiological diagnosis
Responding to the laboratory result
There are no data to validate the treatment of culture-positive
wounds when the clinical appearance is not one of infection.
Indeed, responding solely to laboratory findings without reference to the clinical scenario puts patients at unnecessary risk
of antibiotic-associated side effects and is likely to increase the
prevalence of drug-resistant organisms. Current best practice14
advocates immediate treatment in the face of clinical infection, with initial therapy directed against the most likely
pathogens, aiming for revision of this empirical choice on the
basis of culture results and clinical progress. Thus Grampositive cocci are invariably involved in mild and moderate
infection and should respond to antistaphylococcal therapies
such as semi-synthetic penicillins (e.g. flucloxacillin), while
recent antecedent therapy increases the likelihood of Gramnegative bacilli (GNB) also being involved, necessitating the
addition of b-lactam/b-lactamase inhibitor combinations or
fluoroquinolones.
Oral agents are adequate for mild and moderate infections.
However, severe infections invariably require intravenous
therapy covering Gram-positive cocci [with a low threshold to
use a glycopeptide to cover the possibility of infection with
methicillin-resistant S. aureus (MRSA)], GNB and anaerobes.
Moreover, it is our view that a severe infection with clinical evidence of systemic involvement, such as spiking temperature or

Table 1. IDSA classification of wound infection (modified from reference 11)

Mild
More than two of:

Purulence, erythema, pain, tenderness, warmth or

induration
Any cellulitis/erythema extending 2 cm around ulcer
Infection is limited to skin/superficial subcutaneous tissues
No local complications or systemic illness

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Moderate
Patient is systemically well and
metabolically stable but has any of:

Cellulitis extending .2 cm
Lymphangitis
Spread beneath fascia
Deep tissue abscess
Gangrene
Muscle, tendon, joint or bone
involved

Severe
Infection in a patient with systemic
toxicity or metabolic instability

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Once a clinical diagnosis of infection has been made, the next

challenge is to determine the aetiology so that rational and
appropriate therapy can be instigated. Important clues as to
potential pathogens can be garnered from the clinical history.
Infection in a very recently acquired superficial ulcer is likely to
be due to aerobic Gram-positive cocci (for example staphylococci) while a long duration of ulceration, increased depth/severity and antecedent therapy are likely to increase the chances of
the wound yielding both polymicrobial growth (often comprising
aerobic and anaerobic Gram-positive and Gram-negative bacteria) and resistant organisms (Figure 1).12
Because the skin has an indigenous microbial flora, great care
must be taken not only in obtaining a sample for microbiological
analysis but also in interpreting the result. Invariably, a positive
laboratory culture can only suggest the presence of infection
and must be correlated with clinical findings. A simple superficial
swab across the ulcer runs the great risk of isolating commensal
organisms unrelated to the infection, leading to misdirected
treatment against an innocent bystander rather than focusing
on the pathogenic culprit. When used, swabs should always be
taken from the base of a lesion after debridement of superficial
slough and necrosis. Ideally, biopsy of tissue from a debrided
ulcer base or, if applicable, extruded bony fragments, offers
more useful material for microbiological analysis.
Even when such best practice is observed, there remains a
degree of subjectivity in analysis. Preliminary data employing

JAC

Diabetic foot infections

(a)

(b)

rigors, should trigger evaluation by an experienced surgeon. A

collection within the foot may be best served by surgical intervention to limit further spread and tissue loss, reduce the
septic burden on the patient and allow collection of appropriate
material for microbiological investigation, which should optimize
the likelihood of pathogen detection and initiation of correctly
targeted treatment at the earliest possible juncture.

Drug-resistant organisms and diabetic

foot infections
Drug-resistant organisms are over-represented in samples
obtained from diabetic foot ulcers. A study from a secondary
care multidisciplinary diabetic foot clinic in Melbourne, Australia
is typical of many such units,15 in that patients attending had
a high prevalence of MRSA. Of 653 specimens from 379 patients,
MRSA was isolated from 23%. Chronicity of ulcer, previous
in-patient care and chronic kidney disease (CKD) each independently predisposed patients to MRSA infection.
But does isolation of a drug-resistant organism matter?
A French study in 200816 looked to determine the impact of
multidrug-resistant (MDR) organisms on healing rates 1 year
after discharge in 188 patients admitted for an infected foot
ulcer. Organisms identified included MRSA, Enterobacteriaceae
resistant to third-generation cephalosporins, Pseudomonas
aeruginosa resistant to two antibiotics from among ticarcillin,
ciprofloxacin, ceftazidime and imipenem, and Enterococcus spp.
resistant to glycopeptides. The complexity of the ulcers in the
study can be judged by the fact that two-thirds were graded as
moderate or severe, .70% were judged to be neuroischaemic
ulcers and around a quarter of the lesions yielded resistant organisms. The presence of MDR organisms was associated with a
higher incidence of lower-limb amputation (35.6% versus 11.2%
in non-MDR infection), with the majority (87.5%) of these amputations being minor. After adjustment for other factors, however,
multivariate analysis indicated that the presence of MDR bacteria

did not affect healing time. This is in keeping with a similar study
directed by investigators in Nottingham UK, where Game et al.17
found no evidence that the presence of MRSA was associated
with a significant difference in healing time or percentage of
healed wounds. In the case of the French study,16 this may be a
direct consequence of prescribing practice in the unit in question
being vigilant to the high prevalence of MDR organisms seen
locally, with the first-line antibiotic regimen frequently including
an agent active against MRSA given immediately after obtaining
specimens for culture, to be reassessed thereafter according to
the microbiological results.

Guidelines for therapy

One of the major difficulties in developing guidelines for therapy
is the lack of randomized controlled trial evidence to support
them.18 The lack of a standardized objective definition of infection and its subsequent eradication, the heterogeneous influences from variation in vascular supply, position and duration
of ulceration, the variability in strategies to prevent weight
bearing through the affected tissue and the diverse multiple
co-morbidities invariably found in patients with diabetic foot
disease are just some of the many factors that conspire to
make study design challenging. Industry is also unlikely to offer
financial support to evaluate the comparative efficacy of
generic antibiotic agents long-since off patent. In addition, any
guidelines relating to the use of antimicrobial therapy must
factor-in local susceptibility and resistance data. Thus, in the
face of an increasing clinical problem, there remains unsatisfactory uncertainty about the optimal route and effective duration
of antimicrobial treatment. At present, the situation is one of
consensus agreement from multidisciplinary panels of experts
assimilating other published guidelines and the limited available
support from published studies, rather than guidance backed by
rigorous trial data. One such example is that of the Scottish
working group19 who contend that local differences across the

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Figure 1. Case History. A 38-year-old man with long-standing poorly controlled diabetes presented with a 4 month history of a painless red swollen
foot. The problem first appeared 3 months after the appearance of a small neuropathic ulcer under the second metatarsal head. Repeated courses of
antibiotics in the community reduced the severity of the swelling but this always recurred on cessation of therapy. (a) Initial plain X-ray showed loss of
the head of the second metatarsal and periosteal reaction around the proximal phalanx of the second toe (arrows). (b) An MRI showed a 2617 mm
collection on the dorsum of the foot (arrows) with some destruction of the second proximal phalanx. At operation the head of the second metatarsal
was found to be purulent and was removed along with the phalanges of the second toe. Analysis of biopsied tissue showed Citrobacter spp. and
coagulase-negative staphylococci, resistant to flucloxacillin. The patient received 4 weeks of intravenous vancomycin and oral ciprofloxacin post
operatively with full resolution of clinical signs.

Powlson and Coll

country in causative organisms and their susceptibility to specific

agents are insignificant enough to make such a document valid
in most instances. This approach has much merit, emphasizing
as it does the importance of a multidisciplinary approach to
management, the categorization of infection on clinical
grounds and the acknowledgement that, although culturesupported specific targeted therapy is the gold standard, there
must be a role for initial empirical treatment.

Osteomyelitis

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An established consensus view on the diagnosis of osteomyelitis is

yet to emerge but is an important aim both for informing treatment and to enable meaningful comparison of management
strategies in determining best practice. Recent work under the
auspices of the International Working Group on the Diabetic
Foot (IWGDF) has attempted to formulate a criteria-based
approach to diagnosis in the manner already accepted for similarly diagnostically challenging conditions such as infective endocarditis or various rheumatological conditions.24 This aims to
classify osteomyelitis as definite, probable, possible or unlikely,
based on a combination of clinical, microbiological and radiological features as well as response to antimicrobial therapy
(Figure 2). Each criterion is in turn weighted as indicating either
possible or probable infection. The decision to treat for osteomyelitis is then based on this probability. This approach has not been
validated in practice but represents a quantum leap forward
towards standardizing diagnosis and the decision to treat.

Management of osteomyelitis
Once the diagnosis has been made and the decision to treat
taken, there is currently no evidence-based consensus view on
the best way to manage osteomyelitis in the diabetic foot.
Broadly, the approach is either conservative or surgical. The
choice of treatment is all too often based on local prejudices
and facilities with surprisingly little evidence to drive the development of robust guidelines. For many years, harking back to the
days of limited antibiotic availability and effectiveness, the surgical removal of infected bone was held to be paramount. More
recently, a primarily medical approach has been advocated,
with the view that appropriate antibiotic and adjunctive treatments can obviate the need for surgery. So who is correct? No
randomized controlled trials addressing this question exist. The
group responsible for postulating the consensus criteria
approach to diagnosis described above went on to undertake a
systematic literature review of the effectiveness of osteomyelitis
treatment in the diabetic foot and Fran Game of the Nottingham
Foot Ulcer Trials Unit also recently evaluated this question. Both
drew similar conclusions: there is little evidence to support the
case for early surgical intervention but, equally, there are no
robust comparative data to conclude that there is a significant
difference in outcome after either primarily surgical or conservative management.24,25

Role of surgery
A handful of limited observational studies do support the case
for surgery. Successful treatment after surgery is reported in
60% 90% of cases though how this is defined is somewhat
nebulous.24 One retrospective series analysis suggested that
surgical intervention within the first 3 days reduced the subsequent need for lower-limb amputation (10/77 patients)
when compared with initial therapy with antibiotics alone (24/
87).26 Henke et al. 27 also report that delaying surgery leads
to an increased risk of major amputation. Others indicate that
limited surgical intervention improves the degree of healing

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The significance of diagnosing osteomyelitis in diabetic foot infections is clear; it increases refractoriness to antibiotic treatment
and is associated with an elevated risk that lower-limb amputation, either minor or major, will subsequently be required.20,21
The correct determination of the presence or absence of osteomyelitis therefore carries high clinical importance. In theory, the
diagnosis should be an easy one to make since, put simply, osteomyelitis is infection of bone. In practice, however, it remains a
challenging condition. The gold standard for diagnosis is the
culture of pathogenic organisms from an isolated bone culture
in the presence of characteristic histological changes suggesting
necrosis, inflammation and reparative processes. However, such
biopsies are infrequently taken and are not infallible: false
negatives can result from poor sampling or samples being taken
after antibiotic therapy; false-positive microbiology can be introduced by contamination and other inflammatory conditions can
mimic the histological findings. A diagnosis is more usually
made on clinical suspicion (refractory infections, bone visible or
palpable on probing the ulcer, failure to respond to antibiotics)
in conjunction with one or more imaging modalities.
Plain radiographs are readily available in most centres and
represent the first imaging step if osteomyelitis is suspected.
The films, ideally weight-bearing and in two projections, may
demonstrate the discrete areas of radiolucency, cortical destruction and loss of trabecular patterning found in early osteomyelitis. Periosteal reaction, sclerosis and osteogenesis may follow
(Figure 1). However, radiographic features only typically start to
appear after at least 2 weeks and can be mimicked by other processes such as Charcot neuroarthropathy or trauma.10 If the
plain radiograph findings are equivocal, magnetic resonance
imaging (MRI) should be considered as it is the most sensitive
and specific imaging modality in diabetic foot infections for diagnosing and assessing the extent of both bone and soft tissue
involvement. Osteomyelitis is seen as areas of decreased signal
on T1 imaging/high signal on T2 imaging and MRI can also
demonstrate intraosseous abscess formation and breaching of
the cortex. Soft tissue involvement can be further evaluated
with the use of gadolinium enhancement. Diagnostic yield is
reliant on experienced radiological reporting but provides a sensitivity and specificity of 90% and 80%, respectively.22 As
such, MRI can prove extremely valuable in informing diagnosis,
extent and thus management of osteomyelitis in diabetic foot
infections. CT can also prove superior to plain radiography in
demonstrating the described bony radiological features of osteomyelitis. However, MRI gives superior imaging of the soft tissues
and is the preferred modality. Radionuclide bone scanning and
white cell scanning also have their place when the diagnosis is
unclear but a full review of their role lies outside the remit of
this review.23

Consensus criteria for diagnosis

of osteomyelitis

JAC

Diabetic foot infections

DEFINITE
positive bone culture and positive histology
pus in bone at surgery
atraumatically detached bone fragment removed from ulcer
intraosseous abscess on MRI
PROBABLE
Visible cancellous bone in ulcer
MRI showing bone oedema with other signs of osteomyelitis
Bone sample with positive culture but negative/absent histology
Bone sample with positive histology but negative/absent culture

SCORE

PROBABILITY

MANAGEMENT

1 definite

>90%

Treat

2 probable OR
1 probable + 2 possible OR
4 possible

50%90%

Consider treating but may need

further investigation

2 possible

10%50%

Further investigation advised

before treatment

Figure 2. Diagnostic criteria to guide the management of osteomyelitis in patients with diabetic foot disease (modified from Berendt et al.24).

and limits the required degree of antibiotic therapy usage when

compared with conservative management only.28 AragonSanchez et al.29 advocate the use of early minimal debridement
in conjunction with antibiotics and subsequent minor or major
amputation as required. All of these studies are limited observational series and the inclusion criteria, indications for
surgery and endpoint measures are ill defined and vary considerably. A pragmatic view would consider that there will be
cases where surgery is absolutely required (e.g. a large collection of pus in a patient with systemic signs of sepsis) but
there is not convincing evidence to mandate early surgery in
all cases or sufficient clarity in the literature to adequately
define when surgery becomes a necessity. As a minimum,
consideration is needed to determine whether an intervention
has an acceptable chance of resulting in a sound, weightbearing unit with a low chance of ulceration in the future. We
also believe antibiotic therapy alongside surgical treatment
remains obligatory.

Medical treatment
Conservative management, based primarily on antibiotic
therapy alone, was found to eradicate diabetic foot osteomyelitis in .60% of cases when 500 case reports were reviewed.30
A series of patients treated this way in a single centre31 showed
arrest of the infection in 80% of cases, though 37% of their

total of 147 cases of osteomyelitis did in fact undergo early

surgery, suggesting that there remains a clinical judgement
call to be made in all presentations. Major amputation rates
and relapse rates have been shown to be equivalent between
primarily conservative management and where initial minor
surgery is used.29,31 Medical management is not without its
problems. The mean duration of antibiotic therapy in the
Game series was 61 days while others have suggested that
treatment for .6 months is required in up to 50% of cases.32
Such prolonged courses of antibiotics potentiate the side
effects, discourage compliance and encourage the development of drug-resistant organisms. It is, therefore, a priority to
optimize antibiotic therapy. Surgery may be one route to reducing the need for antibiotics as suggested above. There is little
evidence, however, to inform choice of antibiotic or route of
administration. Antistaphylococcal agents and broad-spectrum
antibiotics have been shown to be equally efficacious and,
despite the frequent preference for parenteral administration
in osteomyelitis, there is little evidence to support its superiority
over oral therapy.
In the absence of high-quality comparative data, we suggest
that each presentation must be evaluated on its own clinical
merits and that the need for surgery should be judged throughout the course of treatment by an experienced clinical team, in
the knowledge that antibiotic therapy alone may prove effective
in some cases.

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POSSIBLE
Plain X-rays show cortical destruction
MRI shows bone oedema OR cloaca
Probe to bone positive
Visible cortical bone
ESR >70 mm/h with no other plausible explanation
Non-healing wound despite adequate off-loading, and perfusion for >6 weeks OR ulcer of >2 weeks
duration with clinical evidence of infection

Powlson and Coll

Beyond antimicrobial therapy in diabetic

foot infections

Transparency declarations
This article is part of a Supplement sponsored by the BSAC.

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diabetic foot infections. Clin Infect Dis 2004; 39: 885910.
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diabetic foot infections in predicting treatment outcome: a prospective
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Successful treatment of infection in a diabetic foot often requires

interventions beyond the prescription of even correctly targeted
antimicrobial therapy. Appropriate and aggressive attention
needs to be given to the wound bed and the surrounding
tissue. This includes removal of necrotic or poorly vascularized
tissue from the surface and edges of the wound, which may
be done in a clinic environment by sharp debridement, but if
the nature of the wound dictates, may require a more invasive
procedure in the controlled environment of the operating
theatre. A major factor in the failure of chronic wounds to heal
is the continued, unchallenged trauma to the wound bed as a
result of continued weight bearing in an insensate neuropathic
foot. Effective redistribution of this pathological pressure is a critical adjunct to successful healing This may be as intensive as a
total contact plaster cast to redistribute the force but can be
as simple as instigating a non-weight bearing policy on the
affected foot. A lesion occurring on a limb with clinical evidence
of impaired blood flow mandates consideration of revascularization, via either bypass or endovascular intervention. This is particularly important with infection in the presence of arterial disease, as
penetration of antibiotic into infected tissue may be poorer.33 It is
worthwhile highlighting the sinister combination of ischaemia and
infection. In an Italian study looking at 564 patients presenting
with critical limb ischaemia, two-thirds of them also had clinical
evidence of infection. Despite 95% of the patients undergoing a
revascularization procedure, at follow-up 6 years later, 50% of
the patients were dead.34 The fact that coronary artery disease
was the leading cause of death is also testament to the fact that
diabetic foot disease has a predilection to occur in patients
already overburdened with disabling co-morbidities, in particular
cardiovascular pathologies.35
Successful delivery of these key interventions can only be
done with the involvement of a multidisciplinary team, which
requires the expertise of a whole range of professionals ranging
from diabetologist, orthopaedic surgeon and specialist podiatrist
right through to orthotist, diabetes specialist nurse and plaster
technician. The concept of a team approach is core to recent
documentation produced by a Diabetes UK specialist foot care
services working group,36 in which effective integration of the
input of different healthcare professionals is highlighted as
being essential for effective management of disease of the
foot in diabetes.
The lack of robust validated protocols to guide treatment of
infection in the diabetic foot can engender a feeling of therapeutic nihilism, but to take such a stance risks unjustly dismissing
beneficial interventions and condemning a fragile patient group
to undeserved suffering and debility. We welcome the recent
initiative supported by the UK National Institute for Health and
Clinical Excellence (NICE) to develop clinical practice guidelines
on the inpatient management of diabetic foot problems37 and
look forward to the results of properly constructed trials to
inform treatment of this difficult clinical problem.

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