review article

Diabetes, Obesity and Metabolism 16: 305–316, 2014.

© 2013 John Wiley & Sons Ltd

article
review
Diabetic foot infections: state-of-the-art
I. Uçkay1,2 , K. Gariani3 , Z. Pataky4 & B. A. Lipsky1,5
1 Service of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
2 Orthopaedic Surgery Service, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
3 Service of Internal Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
4 Division of Therapeutic Education for Chronic Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
5 Department of Medicine, University of Oxford, Oxford, UK

Foot infections are frequent and potentially devastating complications of diabetes. Unchecked, infection can progress contiguously to involve the
deeper soft tissues and ultimately the bone. Foot ulcers in people with diabetes are most often the consequence of one or more of the following:
peripheral sensory neuropathy, motor neuropathy and gait disorders, peripheral arterial insufficiency or immunological impairments. Infection
develops in over half of foot ulcers and is the factor that most often leads to lower extremity amputation. These amputations are associated
with substantial morbidity, reduced quality of life and major financial costs. Most infections can be successfully treated with optimal wound
care, antibiotic therapy and surgical procedures. Employing evidence-based guidelines, multidisciplinary teams and institution-specific clinical
pathways provides the best approach to guide clinicians through this multifaceted problem. All clinicians regularly seeing people with diabetes
should have an understanding of how to prevent, diagnose and treat foot infections, which requires familiarity with the pathophysiology of the
problem and the literature supporting currently recommended care.
Keywords: diabetes complications, diabetes mellitus, foot complications, infections

Date submitted 11 June 2013; date of first decision 5 July 2013; date of final acceptance 11 July 2013

Introduction Developing a DFI is often the pivotal event leading to lower

extremity amputation. Diabetes is the leading cause of non-
Diabetic foot infections (DFIs) are defined as a clinical traumatic lower extremity amputation worldwide. Diabetes-
syndrome characterized by local findings of inflammation or related amputations at various levels (from toe to above-knee)
purulence (sometimes accompanied by systemic manifesta- are responsible for about 60% of all amputations in developed
tions of sepsis) occurring in a site below the malleoli in a person countries [8] and confer a high burden of financial cost,
with diabetes. Estimates of the incidence DFIs range from a morbidity and mortality. In high-income countries, treatment
lifetime risk of 4% in all persons with diabetes to 7% yearly in costs (published in 2000) for a DFI range between US $30 000
patients treated in a diabetic foot centre [1]. Most DFIs occur without amputation and US $58 000 with amputation [9].
in a neuropathic or neuroischaemic ulcer, which serves as a Diabetes is also associated with a significantly higher rate of
point of entry for pathogens. With the exception of erysipelas postoperative stump dehiscence compared to amputations for
and posttraumatic (including postsurgical) infection [2], DFIs purely ischaemic reasons [10]. The presence of osteomyelitis
are almost always epiphenomena, i.e. the consequence of further raises the costs for hospitalization because of the need
for additional diagnostic studies, prolonged medical treatment
progressive peripheral polyneuropathy, with associated loss
and surgeries; specifically, the use of antibiotics is at least
of protective sensation coupled with gait disorders, anterior
doubled [11]. When amputation is needed, a high level (i.e.
displacement of weight-bearing during walking [3] with transtibial) procedure is more often indicated because of
reduced mobility, and arterial insufficiency in a mostly elderly irreversible ischaemia than because of uncontrolled infection
patient population [4]. Vascular disease, mostly in the form of [12]. Most amputations, however, reflect the multimodal
occlusive atherosclerotic disease of the arteries below the knee, foot problems related to diabetes, emphasizing the need
sometimes accompanied by small vessel dysfunction [5], can for a multidisciplinary approach (figure 1) [7]. All clinicians
cause ischaemic ulcers and may contribute to elevated plantar regularly seeing persons with diabetes should have an
pressures and to prolonged duration of foot-to-floor contact understanding of how to prevent, diagnose and treat DFIs.
[6]. Figure 1 shows the major steps in the pathophysiological Because of the burgeoning research in this area, this review
‘chain’ ultimately leading to DFI [7], and the role of different aims to help these clinicians be aware of the developments in
healthcare workers who may help reverse or postpone the this field of science.
progression of infection and lower extremity amputation.
Literature Search Methodology
Correspondence to: Prof. Benjamin A. Lipsky, MD, FACP, FIDSA, FRCP, Department of
Medicine, University of Oxford, 79 Stone Meadow, Oxford, Oxfordshire OX2 6TD, UK. Several systematic reviews of the literature have been
E-mail: [email protected] conducted in recent years [13]. To update and expand
review article DIABETES, OBESITY AND METABOLISM

Figure 1. Overview of causes and management of diabetic foot complications.

on these, we conducted a non-systematic literature search compared 150 diabetic patients with DFI with 97 who did not
through June 2013 using the PubMed database with the MeSH develop infection [14]. Factors significantly associated with DFI
terms ‘diabetic’, ‘foot’ and ‘infection’ in English and French were bone contact on probing; foot ulcer duration of longer
languages. We concentrated on in vivo human data published than 30 days; a history of recurrent foot ulcers; traumatic
within the last 10 years, and excluded basic experimental aetiology of the ulcer; and, peripheral vascular disease. Another
publications, studies performed in animals, papers lacking retrospective review of 112 patients with a severe DFI found that
original human clinical data (other than guidelines), those risk factors for infection were previous amputation, peripheral
highlighting only surgical techniques or radiological diagnoses vascular disease and neuropathy [15]. Other studies have
and those with non-clinical data. We selected papers initially identified walking barefoot as a risk for infection. Of note,
by reading their abstracts, then obtaining the full contents of these risk variables are similarly associated with recurrence of
relevant sources. We also reviewed the references of retrieved ulcers [16] or reinfection after successful treatment.
articles seeking any additional references. In this review, we
will concentrate on the epidemiology and medical treatment
of DFIs, rather than their pathophysiology. Definition and Classification of Infection
Multiple classification schemes have been promulgated for
diabetic foot complications, for most of which the infection
Risk Factors for Infection information is a subsection of broader ulcer classifications. In
Few studies have specifically assessed factors associated with contrast, the Infectious Diseases Society of America (IDSA)
the occurrence of a DFI. One prospective, multicenter study and the International Working Group on the Diabetic Foot

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DIABETES, OBESITY AND METABOLISM review article
(IWGDF) developed guidelines specifically aimed to define if it is chronic and overlying bone, or if a toe is red and swollen.
and classify DFI, and thereby guide the therapy. The IWGDF- Most blood tests are of limited value in diagnosing osteomyeli-
PEDIS-classification (an acronym standing for perfusion, tis, but an erythrocyte sedimentation rate of over 70 is highly
extent [size], depth, infection and sensation/neuropathy) suggestive. Of note is that one study found that a physician’s
suggests a semi-quantitative 4-point scale to describe infection clinical judgment about the presence of osteomyelitis had a
that can be used for including patients in research studies, but positive likelihood ratio of 5.5 and a negative likelihood ratio of
also appears to help predict the outcome of a DFI [17]. 0.54 [22]. The probe-to-bone test, in which a hard gritty struc-
Because all open wounds will be colonized with microorgan- ture is palpated with a sterile, blunt metal probe, is both easy to
isms, occasionally even virulent bacteria, culture results alone perform and useful. A negative probe-to-bone test in a patient
cannot define infection. Some favour using quantitative micro- in whom the pretest probability of osteomyelitis is low is reas-
biology (e.g. the presence of ≥105 colony forming units/gram suring [23], but does not rule out osteomyelis [24]. On the other
of tissue) to differentiate colonization from infection, but no hand, a positive test in a patient in whom clinical suspicion is
data support this criterion in the diabetic foot and very few high (especially if the plain X-ray is suggestive of osteomyelitis)
clinical microbiology laboratories offer this procedure. Thus, has a high predictive value for bone infection [25].
most authorities suggest that DFI be diagnosed based on clinical The gold standard for diagnosing osteomyelitis remains the
findings, i.e. the classical signs and symptoms of inflammation: combination of microbiological culture and histopathological
redness, warmth, induration, pain or tenderness and purulence. examination of bone [26]. Bone specimens may be obtained at
Unfortunately, these findings are somewhat subjective. For surgery or by transcutaneous biopsy. Although needle puncture
example, foot ischaemia, gout, pyoderma gangrenosum [18] of deep soft tissue near bone does not reliably predict the
or Charcot neuro-osteoarthropathy may mimic the inflamma- results of bone cultures [27], puncture of the bone itself may
tion of infection. Furthermore, pain may be mitigated by (or be an easy way to obtain bone culture at the bedside [28].
attributed to) peripheral neuropathy, and ischaemia may limit The first test to consider when osteomyelitis is suspected is
erythema, warmth and induration. Therefore, some wound- plain radiography, but early infection maybe missed because
healing authorities suggest using ‘secondary’ findings to diag- it takes several weeks for the findings of bone infection to
nose infection, such as wound friability, undermining or poor be detected. Characteristic features of osteomyelitis on plain
granulation tissue, foul odour or unexpectedly slow healing. X-rays include periosteal elevation and erosions of the osseous
Systemic inflammatory signs (such as fever, chills, hypotension, borders, but interobserver reproducibility of detecting these
delirium), elevated serological inflammatory markers (such as signs is poor, especially among inexperienced observers [29].
leukocytosis, elevated sedimentation rate, C-reactive protein The reported sensitivity of plain radiography in diagnosing
or procalcitonin levels) [19] or positive blood cultures define osteomyelitis ranges from 28 to 75%, with one review citing
serious infections, but are infrequent in DFI. a pooled sensitivity among four studies of 0.54 and specificity
The results of microbiological tests, such as a Gram-stained 0.68 [22]. Repeating and comparing foot X-rays over time is
smear or culture from diabetic foot wound specimens, must more likely to detect osteomyelitis than a single series.
be interpreted with reference the clinical situation. There is In some patients, advanced imaging is needed to detect
no evidence that treating a clinically uninfected wound with osteomyelitis. In these situations, magnetic resonance imaging
antimicrobials has any value in either preventing infection (MRI) is considered the best available technique, not only for
or improving ulcer healing. When there are clinical signs of diagnosing osteomyelitis but also for better visualizing deep soft
infection, however, obtaining an appropriate sample for culture tissue infection or sinus tracts. One meta-analysis, reported a
and sensitivity testing helps guide antibiotic therapy. Specimens pooled sensitivity of 0.90, and the diagnostic odds ratio was
should be taken after cleansing and debriding the wound from 24.4 [30]. In another meta-analysis the pooled sensitivity was
deep, non-necrotic tissue or pus, to lessen the chance of 77–100%, but the specificity was only 40% [31]. Undoubtedly,
isolating colonizing species. Superficial cultures obtained with the value of this (like most tests) varies with the skill and
cotton swabs are easily collected, but are less reliable than experience of the interpreting radiologist, and MRI does not
tissue biopsies and should be avoided. Most studies have found need to be routinely obtained [32]. Computed tomography
that swab specimens have more isolates (likely contaminating (CT) scans, more readily available in some centres, are usually
or colonizing flora) than aseptically obtained deep tissue less expensive and may be useful when MRI is contraindicated.
specimens and also may miss true pathogens, especially
Nuclear medicine scintigraphic examinations are certainly
anaerobic or fastidious species. In particular, most studies with
more sensitive than plain X-rays for detecting osteomyelitis,
diabetic foot osteomyelitis have found that neither superficial
but bone scans have a low specificity. If scintigraphy is needed,
nor deep soft tissue cultures correlate well with those of bone
leukocyte scans are superior to bone scans, but we think these
specimens [20]. One study suggested, however, that repeated
tests should usually be reserved for long-bone osteomyelitis or
bone surface swabbing yields similar results compared with
prosthetic joint infections. Newer procedures, such as SPECT-
bone culture in patients with a wound with underlying clinical
CT, PET/CT or PET/MRI, show promise and may be even more
osteomyelitis [21], but this needs to be confirmed in larger trials.
accurate than MRI, but to date there have been only a limited
number of studies in DFI. Of note, in patients undergoing
Diagnosis of Osteomyelitis percutaneous bone biopsy for suspicion of osteomyelitis who
Infection of bone underlying a diabetic foot ulcer should be have a negative culture, one of four will develop osteomyelitis
suspected in the presence of a large or deep wound, especially in the next 2 years [33].

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Microbiology of DFIs Around the World Treatment

In Western developed countries, mild community-acquired Orthopaedic Surgery, Podiatry and Revascularization
infections in patients who have not recently been treated Most DFIs require both medical and surgical interventions.
with antibiotics are mainly caused by aerobic Gram-positive Surgery is particularly important for dealing with abscesses,
cocci, especially Staphylococcus aureus and, to a lesser degree, necrotizing fasciitis and a substantial proportion of osteomyeli-
by β-streptococci (usually group B) or coagulase-negative tis cases (e.g. when there is necrotic bone [47]). Many DFIs
staphylococci. One study using molecular microbiological will require debridement or incision and drainage, and some
methods found that ulcer depth is directly correlated with patients will benefit from revascularization or procedures to
the presence of S. aureus [34]. In chronic wounds, especially correct anatomic problems or gait disorders. Details regarding
those in a patient who has been treated with antibiotics, the surgical approach to DFIs are important, but beyond the
infections are more often polymicrobial, including aerobic scope of this review.
Gram-negative and obligate anaerobic bacteria. Recently, Podiatric care is especially aimed at debridement of callus
epidemiological surveys from subtropical, less-developed and necrotic tissue, treatment of blisters, caring for nails and
countries have reported that S. aureus is less prevalent than selecting proper footwear. Repeated removal of calluses is
noted in developed countries (30% vs. 75%) while there especially important, as emphasized by the fact that their
is a considerably higher prevalence of Gram-negative rods, presence may cause 18 tons of excess plantar pressure each
especially Pseudomonas aeruginosa (Table 1). The reasons for day [48]. Surgical treatment for DFI without concomitant
this geographical difference has not been elucidated, but may be antimicrobial therapy is possible [49], but the available reports
related to differences in specimen types, laboratory techniques, from the pre-antibiotic era demonstrate high mortality rates,
prior antibiotic use, availability of non-prescription (over- despite the fact that most patients underwent major (often
the-counter) antibiotic agents, foot sweating and washing above the knee) amputations. While urgent surgery is needed
or reporting bias. Of note, most of these reports emanate for most deep severe infections, some orthopaedic or vascular
from countries in arid and hot areas, especially India [35]. procedures may best be delayed until infection is better
It might also be that the microbiology of DFIs is evolving controlled. Some procedures, such as the correction of foot
slowly towards more Gram-negative microorganisms [35] deformities, arthrodesis [50] or combination of correction and
in some regions, whereas in other regions of the same debridement for infection [51], may also serve to prevent DFIs.
country infections with S. aureus may still be dominant For example, flexor tenotomy, a surgical intervention with a
[36]. Areas of the southwest of the USA have also reported low surgical site infection rate [52], may be highly efficacious
a relatively low proportion of DFIs caused by S. aureus [37] (>90% success within 5–8 weeks) for prevention and healing
and isolation of P. aeruginosa is more frequent in nosocomial of distal toe ulcers [52,53].
DFIs [38]. All patients with a diabetic foot wound require a vascular
Traumatic wound infections [39,40] and cultures of deep assessment. Those with clinically compromising arterial
wounds with moderate to severe infections, especially in pre- insufficiency of the foot require revascularization, if feasible.
viously antibiotic-treated patients, are usually polymicrobial This may be done by either endovascular or open methods [54].
with mixed Gram-positive cocci (vide supra), Gram-negative Contrary to what some profess, infrapopliteal endovascular
rods (e.g. Escherichia coli, Proteus, Klebsiella), sometimes revascularization, even in patients with long-standing diabetes,
including non-fermentative Gram-negatives (P. aeruginosa), is possible with modern techniques, at least in resource-rich
and anaerobes (e.g. Finegoldia, Bacteroides) (Table 1). Severe settings [55,56].
infections may harbour P. aeruginosa, especially in cases of deep
puncture wounds and in patients whose feet are frequently Antimicrobial Therapy
exposed to water. Fungi are rarely principal pathogens and are Antibiotic therapy is almost always necessary, but often not
thus mostly highlighted in case reports [41]. When looked for sufficient, to cure DFIs. It must usually be combined with one
carefully by clinical laboratories, fungi have be regularly culti- or more surgical procedures, pressure off-loading and proper
vated, as have anaerobes [41–44], but the clinical importance wound care. Initial antibiotic therapy for most patients must
of these findings is unclear. Parasitic or mycobacterial DFIs be selected empirically, and should be based on the presenting
have rarely been noted in published reports. clinical features, knowledge of the local antibiotic resistance
A recent problem has been the isolation of multidrug patterns and an assessment of infection severity. Several
resistant organisms (MDROs) from DFIs. The predominant principles may help to avoid selecting either an unnecessarily
resistant pathogen has been methicillin-resistant S. aureus broad or an inappropriately narrow regimen [57]. Antibiotic
(MRSA). After many reports of this pathogen in DFIs from coverage should always include S. aureus, the commonest
the mid-1990s to the early 2000s, more recent studies suggest pathogen in most situations. If the prevalence of methicillin-
the prevalence may be decreasing in most countries. Lately, resistance among S. aureus isolates is known to be high, or if the
the antibiotic resistance problem of greatest concern has been infection is more than mild, anti-MRSA therapy is advisable.
Gram-negative organisms that produce extended-spectrum Therapy should be broadened to target Gram-negative
β-lactamases-(ESBLs) or carbapenemases. Overall, the pathogens in all severe and many moderate infections, or
likelihood of isolating MDROs from a DFI has increased over if the patient has failed to respond to prior narrower-spectrum
the past decade [42,45,46]. antibiotic therapy. In these latter cases, it is especially important

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Table 1. Results of selected reports from around the world over the past decade of the microbiology of diabetic foot wounds.

Percentage of isolates from wound culture

First author Types of No. of Gram- Gram-
[Reference] Country Year wounds patients Staphylococci Streptococci positive negative Ps. aeruginosa Anaerobes
Carvalho [109] Brazil 2003 Infections 141 20 4 29 59 7 12
Candel [110] Spain 2003 Infections 27 49 15 78 22 1 2
Anandi [111] India 2004 Infections 107 14 — — — — 4
Unachukwu [112] Nigeria 2005 Gangrene 60 56 — — — — —
Senneville [113] France 2005 Bone 76 52 12 — 18 2 5
Abdulrazak [114] Kuwait 2005 Infections 86 38 17 74 26 18 11
Shankar [115] India 2005 Infections 77 — 3 42 58 30 6
Yoga [116] Malaysia 2006 Infections 44 20 — — — 14 —
Gadepalli [72] India 2006 Ulcers 80 20 0 33 51 10 15
Sharma [117] Nepal 2006 Ulcers — 38 — — — 18 —
Őrmen [118] Turkey 2007 Bone 50 — — 40 60 — —
Raja [119] Malaysia 2007 Infections 194 44 25 45 52 25 —
Çetin [120] Turkey 2007 Infections 65 18 6 59 41 8 3
Dowd [121] USA 2008 Ulcers 40 8 37 — — 15 18
Umadevi [122] India 2008 Infections 105 17 0 29 71 17 0
Khoharo [123] Pakistan 2009 Infections 60 20 3 27 73 48 2
Ramakant [35] India 2010 Ulcers 447 19 3 31 57 17 1
Zubair [124] India 2010 Infections 60 31 0 38 62 11 0
Őzer [43] Turkey 2010 Infections 78 17 7 38 56 19 —
Mendes [125] Portugal 2011 Infections 49 84 4 85 19 1 14
Hayat [126] Pakistan 2011 Infections 85 18 5 27 68 27 2
Pappu [127] India 2011 Infections 104 21 4 — >67 23 0
Malone [128] Saudi-Arabia 2011 Toe bone 34 33 9 57 29 9 0
Aziz [129] Singapore 2011 Infections 100 40 21 — — 26 30
Dezfulian [138] Iran 2011 Infections 69 43 5 55 45 6 5
Aamir [36] Pakistan 2011 Wounds 114 55 5 — — 4 —
Tiwari [130] India 2012 Infections 62 — — 32 68 — —
Swarna [131] India 2012 Infections 62 30 0 44 56 20 0
Pai [38] India 2012 Infections 55 7 — 24 65 2 —
Widatella [47] Sudan 2012 Bone 330 33 — — — 32 —
Parvez [132] India 2012 Bone 60 9 0 14 70 7 16
Banashankari [133] India 2012 Infections 202 19 — 32 66 13 —
Al Benwan [134] Kuwait 2012 Infections 440 20 — 32 51 17 15
Shanmugam [135] India 2013 Infections 50 13 — 35 65 16 —
Anjali [136] India 2013 Infections 100 — — 42 58 19 —
Osariemen [137] Nigeria 2013 Infections 150 38 0 38 62 8 0
Djahmi [45] Algeria 2013 Infections 128 43 1 45 55 8 0

Percentage values do not sum up to 100% because of mixed infections and reporting of only selected isolates.

to obtain optimal specimens for culture and to initiate an may be sufficient to treat just the likeliest pathogens, such as
empiric regimen different from the failing one. Adding agents S. aureus, streptococci and any Enterobacteriaceae present in
that are specifically active against obligate anaerobes is usually large numbers. Skin commensals, such as coagulase-negative
needed only if the wound is gangrenous or if there is a staphylococci, corynebacteria or Bacillus spp., in the absence
foetid odour. Finally, most severe infections require initial of an infection involving osteosynthetic material or hardware
parenteral, broad-spectrum therapy [57]. Table 2 displays [59,60] can usually be dismissed. Similarly, the mere presence
suggested antibiotic regimens (most often used at Geneva of skin colonization with healthcare-associated MRSA does
University Hospitals), based on the recent IDSA guidelines [13]. not oblige the clinician to empirically cover this organism [58],
Using the results of appropriately obtained specimens for even in the presence of underlying osteosynthetic material [61].
culture allows more targeted therapy, which usually can be Because most DFIs occur in the setting of some degree of
narrower in scope than the empiric regimen. When cultures peripheral arterial disease, some have raised concerns about
yield multiple organisms deciding which isolates need to be how well various antibiotic agents penetrate, especially in the
covered depends on the quality of the specimen sent for presence of bone infection. Several studies have shown that
culture and the specific organisms isolated. If the specimen at standard doses most β-lactam antibiotics achieve relatively
was aseptically obtained deep soft tissue or bone, covering low (albeit likely therapeutic) tissue levels, but clindamycin,
all isolates may be prudent. In most situations, however, it fluoroquinolones, linezolid, rifampin, and to some degree,

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Table 2. Antibiotic recommendations for empirical treatment of diabetic foot infections (adapted from Ref [13])

Severity of infection Expected pathogens Potential antibiotic agents Administration route Duration of treatment
Mild Staphylococcus aureus* Cephalosporins, clindamycin, Oral 1–2 weeks
Streptococci co-amoxiclav
Moderate Similar to those for mild Co-amoxiclav, combination of Oral or parenteral (to 2–3 weeks
infections, plus quinolone + clindamycin start)
Enterobacteriaceae
Severe All pathogens, maybe anaerobes Piperacillin-tazobactam, Parenteral, with oral 2–3 weeks
and Pseudomonas aeruginosa cefepime, carbapenem switch when stable
Recent Rx with Consider covering Ps. aeruginosa, Piperacillin-tazobactam, Parenteral 2–3 weeks
antibiotics MRSA cefepime, carbapenem
Bacteremic† Most often S. aureus but others Based on culture and sensitivity Parenteral 2–3 weeks
possible results
Osteomyelitis‡ S. aureus, streptococci, Based on bone culture, if possible Oral (perhaps after 4–6 weeks (if not
Enterobacteriacae initial parenteral) surgically resected)

No evidence supports superiority of parenteral route over oral administration except for patients who are bacteremic or for whom antimicrobials only
appropriate antibiotics are in parenteral form. Exclusion of abscesses, either clinically or radiologically (ultrasound).
*Skin colonization due to healthcare-associated methicillin-resistant S. aureus (MRSA) does not always require anti-MRSA coverage [58].
†Perform blood cultures if signs or symptoms of sepsis (systemic inflammatory response syndrome).
‡Avoid empirically selected therapy, if possible. Ideal antibiotic-free time before bone sampling for culture is probably 10–14 days.

tetracyclines and co-trimoxazole, have shown good oral Only a few studies on newer antimicrobial agents for DFIs
bioavailability coupled with good penetration in bone, synovia, have been reported since the comprehensive systematic review
biofilm and necrotic tissue [59,62]. Practically speaking, how- of literature through August 2010 that was published in 2012
ever, oral absorption of almost all currently used antibiotics [68]. Among systemic antibiotics, a retrospectively evaluated
is usually sufficient for effective oral therapy, even in patients subset of patients in a randomized controlled trial published
with vascular insufficiency. Several randomized trials in DFI in 2013 found that intravenous and/or oral moxifloxacin,
have shown no superiority for any particular antibiotic agent or compared with intravenous piperacillin/tazobactam followed
route of administration [63–65]. A systematic review of antimi- by oral amoxicillin/clavulanate, gave similar rates of clinical
crobial treatments for DFI concluded that the evidence was too cure, bacteriological eradication and adverse events [76]. In one
weak to recommend any particular antimicrobial agent [66]. A new study of topical antimicrobial therapy recently published,
critical review of randomized controlled trials on the antibiotic a superoxidized solution applied to wounds of 14 patients who
treatment of DFI [67] noted that discrepancies in study design, had undergone limited surgery for diabetic foot osteomyelitis
inclusion criteria, statistical methodology and definitions of was associated with healing in all [77]. Several new systemic
both clinical and microbiological endpoints made it difficult antibiotics, including some with novel mechanisms of action,
to compare the studies or to determine which regimen may are currently under investigation for treating DFIs.
be the most appropriate. The IWGDF systematically reviewed
publications through 2010 on the management of DFI [68]. Osteomyelitis
Among 7517 articles reviewed, only 12 studies met the criteria Osteomyelitis in the diabetic foot is almost always established by
for comparing different antibiotic regimens for soft-tissue contiguous spread of infection from a chronic ulcer. It occurs in
infection, none of which demonstrated superiority. Similarly, up to 15% of patients with a diabetic foot ulcer [78] and about
there are no published data demonstrating the superiority 20% of all DFIs (and over half of severe infections) involve bone
of any particular route of delivery or duration of antibiotic at presentation [22]. The most common causative pathogen is
therapy, either in soft-tissue infection or osteomyelitis [69,70]. S. aureus, either alone, or in a polymicrobial infection. Because
Studies examining whether outcomes of DFIs caused by the pathogenesis of bone infection is by extension from an
multiresistant pathogens are worse than for other organisms ulcer that often has polymicrobial infection or colonization,
have produced conflicting data. Some have reported that predicting the causative pathogen(s) can be difficult. Since
patients with MDROs did not have worse outcomes [46,71], osteomyelitis usually requires a long duration of antibiotic
while others found that infections with MRSA were associated treatment, often with initial parenteral therapy followed by
with poorer outcomes [72]. A potential confounder in these oral agents, it is important to try to accurately identify
studies is that patients colonized with MRSA may have more the underlying microorganism(s). The optimal duration of
often had previous unsuccessful antibiotic treatment. In light antibiotic therapy for diabetic foot osteomyelitis is uncertain. A
of the growing problem of antibiotic resistance, there is active systematic review of treatment of osteomyelitis in patients with
research addressing various types of non-antibiotic treatment and without diabetes [79] found that there was no evidence
for DFIs. Among these, photodynamic inactivation [73], topical that antibiotic therapy for more than 4–6 weeks improves
antimicrobial peptides [74] and bacteriophages [75] appear to outcomes compared with shorter regimens, including for the
show promise. diabetic foot (Table 2). We share this view [62,70,80].

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Established wisdom has held that diabetic foot osteomyelitis, those of an oral antibiotic (ofloxacin) [74]. In an open-label
like most chronic bone infections, requires surgical debride- study, daily application of a gentamicin-collagen sponge for up
ment or resection of necrotic and infected bone. For example, in to 28 days in combination with systemic antibiotic therapy was
a study of 50 patients with chronic toe osteomyelitis, patients compared to systemic antibiotic therapy alone in the treatment
who underwent surgical resection had a significantly lower of moderate DFIs [97]. Although this study failed to meet its
relapse rate [81]. There are, however, hundreds of reports of primary endpoint (percent of patients with an outcome of
apparently successful treatment without surgery, with most clinical cure at day 7 of treatment), the gentamicin-collagen
series reporting remission rates of 60% to 70% [82,83]. Thus, sponge showed superior efficacy in eradicating baseline
when the patient or the medical team prefer to avoid surgery, pathogens and achieving clinical cure at the final visit [97].
a trial of exclusively antibiotic therapy may be reasonable. But,
the advantages of surgical therapy (especially in case of toe Vacuum-Assisted Negative-Pressure Therapy
amputations), including the relatively short lengths of hos-
While widely used for accelerating wound healing, there are
pital stay, reduced antibiotic consumption and likely higher
limited published data on the effectiveness of vacuum-assisted
remission rates, should be weighed against the potential risks.
negative-pressure therapy on DFI, including osteomyelitis [98].
Concerning diabetic foot ulcers, a systematic review identified
Hyperbaric Oxygen Therapy and Stimulating Factors four randomized trials [99]. While all, including a multicentre
The value of hyperbaric oxygen therapy for non-infected dia- study that enrolled 342 patients [100], found that vacuum-
betic ulcers is a question of ongoing debate [80,84–86]. A 2012 assisted therapy was more effective than conventional dressings,
Cochrane systematic review concluded that hyperbaric oxygen the quality of each of the studies was weak and the outcomes
therapy significantly increased ulcer healing in the short term studied and patient selection were divergent [99,101].
but not the long term, but because of the flawed trials they were
not confident in the results [87]. Some suggest that hyperbaric Off-Loading
oxygen decreases rates of lower extremity amputation in
Off-loading pressure is a critical part of the treatment of almost
patients with diabetic foot ulcers or postsurgical amputation
all diabetic foot ulcers, including those that are infected [102].
wounds in persons with diabetes, and facilitates ulcer healing
While the principle of off-loading is easy to understand, in
[88]. There are, however, no published data directly related to
practice it greatly depends on near total compliance on the part
the effect of hyperbaric oxygen therapy for infectious aspects
of the patient. The criterion standard for off-loading is the total
(either soft tissue or bone) of the diabetic foot [84].
contact cast, which is associated with ulcer healing rates of over
Several studies have examined the usefulness of adjunctive
90% [102]. The main advantage of this device may be that the
treatment of DFIs with granulocyte-colony stimulating factors.
patient cannot easily remove it. Given the high recurrence rates
A Cochrane systematic review of the five eligible trials
of neuropathic foot ulcers, new approaches include helping
concluded that these treatments did not increase the likelihood
patients to modify their walking pattern over the long term,
of resolution of infection but did appear to reduce the need for
perhaps with feedback-based approaches [103].
surgical interventions, especially amputations, and the duration
of hospitalization. Studies of platelet-derived [89] and other
growth factors and skin substitutes have not shown any specific Clinical Pathways, Guidelines and Bundle
benefit regarding resolution or prevention of infection [90,91]. Interventions
DFIs exemplify a multifaceted problem that particularly bene-
Antiseptic Dressings and Other Topical Treatments fits from a multidisciplinary approach [7]. In the past decade,
Several studies have assessed topical treatments in patients with several evidence-based DFI guidelines have been published
diabetic foot ulcers and, to a lesser extent, for DFI. For the that provide an approach to optimize outcomes [7,104] and to
majority, ulcer healing rather than resolution or prevention avoid amputations [105]. All consistently address the critical
of infection was the primary outcome of interest. Most of the role of multidisciplinary teams involving specialists such as dia-
studies evaluated topical antiseptic agents (e.g. silver, povidone betologists, orthopaedic/podiatric surgeons, infectious diseases
iodine, hypochlorite, peroxide, zinc oxide) as adjuncts to other specialists, vascular surgeons, angiologists, interventional radi-
standard treatments. None of these agents has been proven to ologists, specialized nurses and physiotherapists; such teams
provide superior outcomes compared to other non-antiseptic have been established in many large hospitals in resource-rich
dressings [92]. Similarly, recent systematic reviews have failed countries all over the world [7,13]. These teams have been
to detect a superiority of various other dressings, such as foam shown to be beneficial in avoiding adverse outcomes in both
[93,94], hydrocolloid [95] and alginate [96], for ulcer healing or inpatients and outpatients in many studies. They are, however,
resolution of infection. A review of topical antimicrobial ther- hampered by several logistic problems: (a) it is often difficult
apy for treating chronic wounds concluded that there are few to bring the members of the multidisciplinary team together
proven indications for any of the currently available agents [91]. outside of a fixed meeting time; (b) the number of patients
Two topical antimicrobial agents have been investigated for requiring evaluation often exceeds the capacity of fixed mul-
DFIs. A large randomized controlled trial in patients with a tidisciplinary meetings; and (c) members of the team often
mild DF showed that treatment with a topical antimicrobial turnover. For example, at Geneva University Hospitals, there
peptide (pexiganan) produced clinical outcomes similar to is a 45-min diabetic foot team meeting weekly, but we have

Volume 16 No. 4 April 2014 doi:10.1111/dom.12190 311

review article DIABETES, OBESITY AND METABOLISM

Figure 2. Schema of the clinical pathway for the infected diabetic foot, Geneva University Hospitals.

observed that team meetings are time-consuming, key members and approach to treatment, including avoiding unnecessary
are frequently absent and the teams are often not able to rapidly examinations and therapies. This schema is based on the
assess all of the DFI patients in need of evaluation and care. guidelines developed by the Infectious Diseases Society of
To provide the advantages of a multidisciplinary DFI team America for diabetic foot infections [13].
while attempting to overcome some of its logistic problems, we In summary, DFIs are a common, complex and costly
are developing, and plan to evaluate, a clinical pathway (with problem. Clinical research over the past decade has markedly
electronic ordersets) to aid all healthcare providers in both our increased our understanding of the epidemiology, pathophys-
outpatient and inpatient settings. Ordersets are a modern and iology diagnosis and treatment of both soft tissue and bone
powerful tool to implement ‘bundles’ (a package of procedures) infections. These have allowed the development of evidence-
and to change processes to encourage and facilitate optimal based and validated guidelines. The task now is to implement
and evidence-based care. They have proven efficacy in several these guidelines, to audit the process and outcomes in individ-
fields of medicine [106], are practical, easy to implement and, ual settings and to continue to look for ways to improve care.
unlike classical campaigning, may show a sustained effect over
time [104–108]. Clinical pathways provide an easy and cost-
effective way to instruct physicians, surgeons, nurses and other
Acknowledgements
healthcare workers on what diagnostic and therapeutic inter- We are indebted to our colleagues in the services of Orthopaedic
ventions are available and most appropriate and, combined Surgery, Diabetology, and the Laboratory of Microbiology of
with ordersets, make it easy and quick to do the right thing. If Geneva University Hospitals.
they are coupled with the electronic computerized prescription
programs and the hospitals’ antibiotic stewardship program, Conflict of Interest
ordersets may increase our understanding of the number, K. G. and Z. P. declare no conflict of interest. B. A. L. has served
types and outcomes of treatment of DFI in a given hospital. as a consultant to KCI, Innocoll, Dipexium. I. U. has received
This may uncover problems related to improper diagnostic or research funding from Innocoll.
therapeutic approaches, or bottlenecks in providing optimal
care. Moreover, they might help to optimize (and minimize)
use of antibiotic agents in patients with a DFI. References
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