Infection in the diabetic foot

General introduction

The development of a foot infection in people with diabetes is associated with substantial
morbidity, including discomfort, the need for visits to health care providers, antibiotic therapy,
wound care and often surgical procedures. Furthermore, foot infection is now the most frequent
diabetic complication requiring hospitalization and the most common precipitating event leading
to lower extremity amputation Managing infection requires careful attention to properly
diagnosing the condition, obtaining specimens for culture, selecting empirical and definitive
antimicrobial therapy, determining when surgical interventions are needed and caring for the
wound. In 2007 the International Working Group on the Diabetic Foot (IWGDF) conducted a
systematic review of treatment of diabetic foot osteomyelitis. In 2009 the IWGDF has invited
again a group of experts to form the IWGDF working group on "Infection" . This working group
has developed a "Systematic review of the effectiveness of interventions in the management of
infection in the diabetic foot" and a document on "Expert opinion on the management of
infections in the diabetic foot". Based on these documents "Specific Guidelines" were
formulated. These three documents were launched at the ISDF in May 2011. The present
systematic review includes an update of the 2007 osteomyelitis guideline, but is extended to
include bacterial diabetic foot infections (DFI's) in general. This review focuses on therapy, and
does not cover definitions for infection, methods for diagnosis (clinical, imaging and
microbiological sampling), and the interface between critical colonisation and infection. These
items are covered in the expert opinion document. In this chapter the following texts on the
infected diabetic foot could be found:

A systematic review of the effectiveness of interventions in the management of infection

in the diabetic foot Expert opinion on the management of infections in the diabetic foot
Specific guidelines for the treatment of diabetic foot infections

A systematic review of the effectiveness of interventions in the management of infection in

the diabetic foot.

Contents

Chapters

Abstract Introduction Methods Results

Types of study Individual topics
Early surgical intervention Health economics Topical treatment with
antiseptic agents Granulocyte-colony stimulating factor Procaine plus
polyvinylpyrrolidone Hyperbaric oxygen therapy Antibiotic choice based
on bone biopsy Comparison of antibiotic regimens - skin and soft tissue
infection alone Comparison of antibiotic regimens - studies including
patients with osteomyelitis
Discussion Acknowledgements References
Appendices

Literature search strings for Pubmed Literature search strings for Embase Evidence tables

1. Early surgical intervention

2. Health economics
3. Topical treatment with antiseptic agents
4. Granulocyte-colony stimulating factor
5. Procaine plus polyvinylpyrrolidone
6. Hyperbaric oxygen therapy
7. Comparison of antibiotic regimens - skin and soft tissue infection alone
8. Comparison of antibiotic regimens - studies including patients with osteomyelitis

I. Abstract

The International Working Group on the Diabetic Foot working group on Infection in the
diabetic foot was installed at the end of 2009. This expert panel on infection conducted a
systematic review of the published evidence relating to treatment of foot infection in diabetes.
Our search for of the literature published prior to August 2010 identified 7517 articles, 29 of
which fulfilled criteria for detailed data extraction; of these 25 were randomised controlled trials,
and four were cohort studies. Four additional papers were identified from other sources. Of the
total of 33 studies, 29 were randomised controlled trials, and four were cohort studies.

Among 12 studies comparing different antibiotic regimens in the management of skin and soft
tissue infection, none reported a better response with any particular regimen. Of seven studies
that compared antibiotic regimens in patients with infection that involved both soft tissue and
bone, one reported a better clinical outcome with use of cefoxitin rather than
ampicillin/sulbactam, but the others reported no differences between treatment strategies. In two
health economic analyses there was a small saving using one regimen versus another. No other
published data support the superiority of any particular route of delivery of systemic antibiotics
or clarify the optimal duration of antibiotic therapy in either soft tissue infection or
osteomyelitis. In one non-randomised cohort study, the outcome of treatment of osteomyelitis
was better when the antibiotic choice was based on culture of bone biopsy specimens as opposed
to wound swabs in patients with osteomyelitis, but this study was not randomised and the results
may have been affected by confounding factors.

Results from two studies suggested that early surgical intervention was associated with a
significant reduction in major amputation, but the methodological quality of both was low. In
two studies the use of superoxidised water was associated with a better outcome than soap or
povidone iodine, but in both there was a risk of bias. Studies using granulocyte colony
stimulating factor G-CSF reported mixed results. There was no improvement in infection
outcomes following the use of hyperbaric oxygen. No benefit has been reported with any other
intervention and, overall, there are currently no trial data to justify the adoption of any particular
therapeutic approach in diabetic patients with infection of either soft tissue or bone of the foot.

II. Introduction

Infection is a common complication of the foot in patients with diabetes mellitus, and although it
can lead to significant morbidity (including lower extremity amputation) and mortality. Several
groups have developed guidelines for treating diabetic foot complications, but they are based on
limited published data. The Infectious Diseases Society of America (IDSA) has developed
evidence-based guidelines specifically on managing diabetic foot infections (DFI), but the
authors did not conduct a systematic review of the literature. Two systematic reviews of some
types of diabetic foot infections have been published.

In 2008 the International Working Group on the Diabetic Foot (IWGDF) conducted a systematic
review of treatment of diabetic foot osteomyelitis [1] and more recently The National Institute
for Health and Clinical Excellence (NICE, United Kingdom) published the results of a
systematic review of the management of all aspects of care for inpatients with a diabetic foot
complication [2]. The present systematic review includes an update of the 2008 osteomyelitis
guideline, but is extended to include bacterial diabetic foot infections (DFI's) in general. This
review focuses on therapy, and does not cover definitions for infection, methods for diagnosis
(clinical, imaging and microbiological sampling), and the interface between critical colonisation
and infection.

III. Methods

A literature search was conducted using PubMed and Embase for all prospective and
retrospective studies in any language that evaluated interventions for the treatment of diabetic
foot infections in people aged 18 years or older with diabetes mellitus. The search strategy
employed is described in Appendix A. Eligible studies included randomised controlled trials
(RCTs), case-control studies, prospective and retrospective cohort studies, and those of
interrupted time series (ITS) or controlled before-and-after design (CBA). Uncontrolled case
series, studies in which controls were historical and case reports were excluded. Studies where
patients with diabetic foot infections formed part of the total population were excluded if the
data for the subgroup with diabetes were not separately described.

One author assessed each identified reference by title and abstract for potential eligibility. Full
copies of potentially eligible publications were independently reviewed by two authors to
determine whether they should be included. When the two reviewers disagreed, consensus was
reached. The reviewers noted the study design, patient populations, interventions, outcomes and
duration of, and follow-up of included patients. Studies were scored for methodological quality
using scoring lists developed by the Dutch Cochrane Centre [3]. Quality items were rated as
'done', 'not done', or 'not reported' and only those rated as 'done' contributed to methodological
quality score. Equal weighting was applied to each validity criterion for every study design.

The methodological quality score was translated into a level of evidence according to the
Scottish Intercollegiate Guidelines Network (SIGN) instrument as follows: (1) randomised
controlled trials and (2) studies with case-control, cohort, CBA or ITS design. Studies were also
rated as: ++ (high quality with low risk of bias), + (well conducted with low risk of bias) and -
(low quality with higher risk of bias). Co-reviewers agreed the findings from the data extraction
and the evaluation of methodological quality of each paper. Extracted data were summarised in
evidence tables (see Appendix B) and described on a study-by-study narrative basis. Because of
the heterogeneity of study designs, interventions, follow-up and outcomes, no attempt was made
to pool the results. These evidence tables were compiled following collective discussions (by
electronic and in-person conferences) by all members of the working party.

IV. Results

A total of 7517 papers were identified in the initial search: 4549 in Pubmed and 2968 in Embase.
After first selection based on title and abstract and after excluding duplicate citations, a total of
509 papers (460 papers in English, 26 in Russian, six in Ukranian, six in Spanish, four in
German, four in French, two in Chinese and one in Bulgarian) were selected for full paper
review. Of these, 29 papers met the criteria for inclusion. All of these papers were in English,
except one paper which was written in Chinese. Four additional papers were initially not
identified with the search strategy, but were added manually [4-7]. The data of all papers are
summarised in the evidence table (See appendix C).

Types of study

Of the 33 studies, 29 were randomised controlled trials, and four were cohort studies. Of the 29
reported RCTs, one was actually a description of two studies in one article [8]. In some reports,
patients with diabetes and a foot infection formed a subgroup of a larger group of, for instance,
patients with a skin and soft tissue infection Such studies were excluded if insufficient detail was
provided on the subpopulation and the results not separately described. Twelve studies were on
the use of antibiotics in skin and soft tissue infection. Eight studies were on patients with
diabetic foot infections including osteomyelitis, of which one study was on the use of bone
biopsy [9]. The topic in three studies was topical antiseptic agents. There were two studies of the
use of surgery, and two which reported the costs of antibiotic use. There were four studies of
granulocyte colony stimulating factor (G-CSF), and one each on the intramuscular
administration of procaine plus polyvinylpyrrolidine and the use of hyperbaric oxygen therapy.
One additional paper on the use of G-CSF had not been identified in the literature search because
it was filed as a letter to the editor rather than as an original study. The data of this study were
extracted and added to the evidence table [6].

Individual topics

a. Early surgical intervention

The two selected studies were both single centre cohort studies of the effect of early surgery and
antibiotics versus antibiotics alone in deep foot infections with and without osteomyelitis
[10,11]. Both studies suggested a significant reduction of risk of major amputation when minor
surgery was deployed early. The risk reduction was 27% to 13% in one study [10], and 8% to
0% in the other [11]. Both studies examined outcomes of earlier surgery, and not the particular
indication for operative intervention. Because of the high risk of selection bias on which patients
underwent early surgery in both studies, it is hard to draw any conclusions from these data.

b. Health economics

Two studies explored the cost-effectiveness of different antibiotic regimens. The first was a cost-
minimisation assessment comparing treatment with ertapenem and with piperacillin/tazobactam
[12], and was a subgroup analysis of a larger RCT [13]. Because piperacillin/tazobactam
requires a more frequent dosing schedule than ertapenem, the total costs of its use, including
drug preparation and administration costs, were higher. The difference in cost per patient per day
was, however, only of the order of $6. The second study explored cost-effectiveness in subjects
admitted to hospital with skin and soft tissue infection and reported a total potential cost saving
of $61 per subject treated with ceftriaxone and metronidazole as opposed to
ticarcillin/clavulanate [14].

c. Topical treatment with antiseptic agents

Two single-centre RCTs have been published comparing topical treatment with superoxidised
water with either soap or povidone iodine in a limited number of patients. One of these studies
was in patients with infected diabetic foot ulcers and outcomes of interest, ie odour reduction,
cellulitis and extent of granulation tissue were significantly better in the group of patients treated
with superoxidised water than in the control group treated with another topical disinfectant [15].

There was 81% reduction in periwound cellulitis in the intervention group versus 44% reduction
in controls. The other study was non-blinded and was conducted in patients with post-surgical
wounds [16]. The duration of antibiotic treatment was significantly longer in the group of
patients treated with povidone iodine, compared to the group of patients treated with
superoxidised water (15.8 days versus 10.1 days; p=0.016). Both studies included long term
outcomes of wound healing, but neither study specifically addressed the potentially negative
effect of other topical disinfectants in the comparator groups. One additional small study in thirty
subjects compared the results of one single application of topical antiseptics, iodophor and
rivanol, compared with a control group [17]. Reported results included bacterial growth at
baseline, after 5 minutes and after 24 hours. There was significantly less growth of bacteria after
24 hours in the iodophor group compared with the rivanol and control group. With its short
follow up and strictly microbiological (rather than clinical) outcome criteria, it is impossible to
draw conclusions regarding clinical practice.

d. Granulocyte-colony stimulating factor

Four studies of the adjunctive use of granulocyte-colony stimulating factor (G-CSF) in diabetic
foot infections were identified [18-20]. A fifth study was published as a letter to the editor [6].
Patients had soft tissue infection in four studies, but associated osteomyelitis in one [19]. All of
the studies were single centre RCTs. In two cases, the design was double blind, in one case the
assessor was blinded, and in one case the patient was blinded. Blinding was not mentioned in the
fifth. In the study by Viswanathan et al. [6], a total of 85 patients were treated with 5 µg/kg or a
fixed dose 263 µg of G-CSF and compared with 82 controls that were not treated with G-CSF,
but who also received antibiotics and appropriate surgical wound care. Time to infection
resolution was significantly lower for subjects who received G-CSF in the one study [21], but
not in the others. This study also reported a shorter duration of intravenous antibiotic use with G-
CSF, but this was not observed in another [18]. Hospital length of stay was shorter for the G-
CSF group in two studies [6,21], but not in a third [18]. The need for surgical intervention was
not statistically different between the two groups in the three studies that examined it [6,19,21],
and neither was the time to eliminate pathogens from the wound [19,21]. The results of these
studies are inconsistent and provide no clear evidence to support the use of G-CSF in diabetic
foot infections.

A meta-analysis of these five studies also concluded that adding G-CSF did not significantly
affect the likelihood of resolution of infection or wound healing, although it was associated with
a reduced likelihood of lower extremity surgical interventions, including amputation [22]. The
use of G-CSF also reduced the duration of hospital stay, although it did not significantly affect
the duration of systemic antibiotic therapy.

e. Procaine plus polyvinylpyrrolidone

One study was identified in which the use of intramuscular injection of 0.15 ml/day of procaine
and polyvinylpyrrolidone for ten days was assessed in 118 patients with a diabetic foot infection
affecting an ischaemic limb [23]. The study was an observer blinded, single centre, RCT. No
significant difference was observed between groups.

f. Hyperbaric oxygen therapy

Although there have been a number of trials that have examined the effect of hyperbaric oxygen
therapy (HBOT) in patients with diabetic foot complications, including two double-blind
randomised controlled trials [24,25], we could identify only one study that investigated diabetic
foot infection as an outcome [26]. This was a single-centre, open label, study comparing the use
of HBOT in 15 patients with 15 control subjects, with both groups receiving standard antibiotic
treatment and wound debridement. Although it was not explicitly stated that the subjects had a
foot infection, this was implied by the use of antibiotics. There were no significant differences in
the numbers of positive wound cultures, major and minor amputations, and hospital stay between
the intervention and control groups.

g. Antibiotic choice based on bone biopsy

A single cohort study attempted to explore the effect of basing antibiotic selection on the results
of culture of a bone biopsy specimen in patients with osteomyelitis [9]. Among 50 subjects, 32
had had previous unsuccessful treatment for osteomyelitis. The rate of remission of infection
was significantly higher in the group for whom antibiotic choice was based on bone culture than
in those in whom therapy based on wound swab culture (82% versus 50%, respectively
[p=0.02]). Nevertheless, it is possible that this difference was the result of confounding
variables: especially the fact that patients in one of the highest enrolling centres only received a
rifampicin-containing regimen if they had a bone culture.
h. Comparison of antibiotic regimens - skin and soft tissue infection alone

Eleven of the available studies on antibiotic treatment of skin and soft tissue infections were
RCTs, and one was a prospective cohort study [27]. Of the randomised trials, nine were
multicentre trials [4,7,8,28-33], and two were single centre trials [14,34].Furthermore, three were
double blind [4,8,32], two were investigator blinded [29,31], and six were non-blinded
[7,14,28,30,33,34]. Three studies were subset analysis of larger trials [4,7,32]. One report
consisted of two consecutive studies of the topical antibiotic peptide, pexiganan [8]. The other
studies compared systemic antimicrobial regimens: one compared two oral antibiotic regimens
[34], while the majority involved a switch from parenteral to oral antibiotic therapy.

Classes of antibiotics that were compared were: 1st and 3rd and 5th generation cephalosporins
(cephalexin, ceftriaxone and ceftobiprole, respectively), fluoroquinolones (ofloxacin,
levofloxacin, ciprofloxacin and moxifloxacin), lincosamides (clindamycin), extended-spectrum
penicillins and beta lactamase inhibitors (piperacillin/tazobactam, ticarcillin/clavulanate,
amoxicillin/clavulanate), carbapenems (ertapenem), nitroimidazoles (metronidazole),
lipopeptides (daptomycin), and glycopeptides (vancomycin). Each of these agents is in
widespread use, except ceftobiprole, which is not currently available in North America or
Europe.

The mean duration of antibiotic administration in patients with skin and soft tissue infection
ranged from 6 days to 27 days [8,14], but the duration of antibiotic treatment was not mentioned
in two studies [28,31]. In the study of oral regimens, the duration of administration was only two
weeks, although three patients were actually treated for longer [34]. No differences were
observed in the ten studies with regard to infection outcome, length of hospital admission or
amputation. Clinical cure rates in all studies without osteomyelitis ranged from 48% [29] to 90%
[8]. One RCT of mildly infected diabetic foot ulcers reported that a topical antibiotic, pexiganan,
was similar in clinical and microbiological effectiveness to the oral fluoroquinolone, ofloxacin,
with fewer adverse effects [8]. We identified no studies that demonstrated a benefit of any
specific antibiotic agent, route of administration, or duration of treatment.

i. Comparison of antibiotic regimens - studies including patients with osteomyelitis

In addition to the previously mentioned cohort study of the use of bone biopsy in selecting an
antibiotic in patients with osteomyelitis [9], we identified seven studies of antibiotic treatment of
diabetic foot infection in which a proportion the study population had infection of underlying
bone [5,13,35-39]. All other seven studies were RCTs: three were double blind, one was single
blind, three were open label; four were multicentre and three were single centre trials. The
prevalence of osteomyelitis varied from 6 % [8,13,29,36] to 81% [5]. The groups of antibiotics
that were compared were: penicillins with beta lactamase inhibitors (parenteral ampicillin/
sulbactam and oral amoxicillin/clavulanate), extended-spectrum penicillins and beta lactamase
inhibitors (piperacillin/tazobactam), carbapenems (imipenem/ cilastatin, ertapenem), 2nd
generation cephalosporins (cefoxitin), fluoroquinolones (ofloxacin, moxifloxacin) and
oxazolidinones (linezolid).

Outcomes included clinical cure [5,13,36-39], adverse drug reactions [5,13,37- 39], and duration
of therapy [5,36]. Only one study reported a difference in clinical and microbiological outcomes,
and this was a comparison of ampicillin/sulbactam with cefoxitin [35]. The clinical cure rates in
this study were significantly different (p=0.03) but were exceptionally low, and there were no
significant differences between groups in bacteriological response (100% versus 73%),
amputations (8 versus 8), and duration of hospitalisation (21 versus 12 days). In the other studies
in which patients with osteomyelitis were included, clinical cure rates ranged from 61% [38] to
94% [13,39]. The mean duration of antibiotic treatment in the six studies was short, ranging
from 6 days [35] to 28 days [5]. We found no studies that demonstrated a significant advantage
of a particular antibiotic agent or route of administration in diabetic foot osteomyelitis.

V. Discussion

In planning this review, a search was made only for studies in which a treatment of diabetic foot
infection was compared with a contemporaneous control group, but this led to the identification
of only a very small number of suitable publications. Studies were only included if at least the
outcome data of the (sub)population of subjects with diabetes were reported. It has to be
accepted that trial design can pose problems in attempts to determine the effectiveness of
different treatments in this field, and this is especially true for studies intended to evaluate the
role of surgical interventions. Early surgery is accepted as essential in some cases of foot
infection and yet the trial evidence to substantiate the benefit is weak, and based on just two
studies - each of which had a very a high chance of bias. Another caution attaches to the use of
the SIGN criteria for documenting study quality. This system ranks work mainly on the quality
of study design, rather than study conduct, and this can result in apparent anomalies - with
weaker studies occasionally achieving higher scores.

For most clinical trials evaluating the efficacy of antimicrobial agents, patients with diabetic foot
infections are either excluded or comprise a small proportion of the study population. Some
clinical trials have allowed a post hoc analysis focusing on the subset of patients with a diabetic
foot infection, but the small number of subjects limits their usefulness. Not only is the number of
reasonably designed studies in this field remarkably small, but most had a low score for study
design, were marred by the use of small and heterogeneous populations, were poorly described,
or had a high risk of bias. Thus, readers should be cautious in interpreting the results of the
available published work. Furthermore, circumstances dictating the choice of treatment in
different countries and settings will vary according to the behaviours of affected population,
nature of the presentation of infection, prevalence of different microorganisms and their
antibiotic sensitivities. Selection of treatment is also severely restrained by limitation of
resources in many parts of the world, and poses particular problems in the management of those
who live far from urban centres.

The available data suggest that it is possible to treat selected patients with a diabetic foot
infection in an outpatient setting with an oral antibiotic regimen, either initially or after switch
from parenteral therapy. The study of a topical antibiotic, pexiganan, is promising, but this agent
will need to undergo further testing before it can be evaluated for approval. We identified few
new data on the management of diabetic foot osteomyelitis since our relatively recent systematic
review [1].
The reported data on skin and soft tissue infection confirmed earlier observations suggesting that
Gram-positive microorganisms play a large role in infection of the foot in diabetes. Despite this,
there is emerging observational evidence that Gram-negative species might be of greater
significance in some populations, and in South Asia, in particular [40-42]. If confirmed, this
would have an important impact on the selection of antibiotic regimens and the rates of clinical
success.

In the studies reported here it was also of note that no great difference was observed in
comparisons between regimens with a relatively broader or a narrower spectrum of activity. It
was also noteworthy that the randomised comparisons of antibiotic regimens were generally
based on a shorter duration of treatment - even when bone infection was present - and reported
good outcomes. These observations conflict with current understanding regarding the use of
antibiotics in osteomyelitis and need to be formally tested.

This systematic review makes clear the need for more robust, well-designed comparative studies
to help clinicians make an optimal choice of antibiotic regimen in various situations, as well as
of route of therapy and duration of administration. Such studies should use a validated system
for defining and classifying infections [43,44], and look at all relevant clinical and
microbiological, as well as other, outcomes. Furthermore, future studies should make a clear
distinction between patients whose infection is limited to soft tissue and those with
accompanying osteomyelitis.

VI. Acknowledgements

We thank Dr. Oleg Udovichenko, Russia, and Prof. Zhangrong Xu, China, for their help in the
assessment of papers published in languages other than English.

Furthermore, we would like to thank the following corresponding members of the expert panel:
Dr ZG Abbas, Tanzania
Dr. F. Javier Aragón Sánchez, Spain
Dr BM Ertugrul Turkey
Prof Hanan Gawish, Egypt
Dr Irina Gurieva, Russia
Dr Shigeo Kono, Japan
Dr A Nather, Singapore
Dr. J.-L. Richard, France
Dr Nina Rojas, Chile
Dr Lynn Tudhope, South Africa
Dr Steven Twigg , Australia
Dr Vijay Viswanathan, India

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24. Abidia A, Laden G, Kuhan G, Johnson BF, Wilkinson AR, Renwick PM, Masson EA,
McCollum PT. The role of hyperbaric oxygen therapy in ischaemic diabetic lower
extremity ulcers: a double-blind randomised-controlled trial. Eur J Vasc Endovasc Surg
2003; 25(6): 513-518.

25. Löndahl M, Katzman P, Nilsson A, Hammarlund C. Hyperbaric oxygen therapy

facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care 2010;
33(5): 998-1003.

26. Doctor N, Pandya S, Supe A. Hyperbaric oxygen therapy in diabetic foot. J Postgrad
Med 1992; 38(3): 112-4, 111.

27. Lobmann R, Ambrosch A, Seewald M, Dietlein M, Zink K, Kullmann KH, Lehnert H.

Antibiotic therapy for diabetic foot infections: comparison of cephalosporines with
chinolones. Diabetes Nutr Metab 2004; 17(3): 156-162.

28. Bradsher RW,Jr., Snow RM. Ceftriaxone treatment of skin and soft tissue infections in a
once daily regimen. Am J Med 1984; 77(4): 63-67.

29. Siami G, Christou N, Eiseman I, Tack KJ. Clinafloxacin versus piperacillintazobactam in

treatment of patients with severe skin and soft tissue infections. Antimicrob Agents
Chemother 2001; 45(2): 525-531.

30. Harkless L, Boghossian J, Pollak R, Caputo W, Dana A, Gray S, Wu D. An open-label,

randomized study comparing efficacy and safety of intravenous piperacillin/tazobactam
and ampicillin/sulbactam for infected diabetic foot ulcers. Surg Infect (Larchmt ) 2005;
6(1): 27-40.

31. Lipsky BA, Stoutenburgh U. Daptomycin for treating infected diabetic foot ulcers:
evidence from a randomized, controlled trial comparing daptomycin with vancomycin or
semi-synthetic penicillins for complicated skin and skin-structure infections. J
Antimicrob Chemother 2005; 55(2): 240-245.

32. Noel GJ, Bush K, Bagchi P, Ianus J, Strauss RS. A randomized, double-blind trial
comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of
patients with complicated skin and skin-structure infections. Clin Infect Dis 2008; 46(5):
647-655.

33. Vick-Fragoso R, Hernández-Oliva G, Cruz-Alcázar J, Amábile-Cuevas CF, Arvis P,

Reimnitz P, Bogner JR, STIC Study Group. Efficacy and safety of sequential
intravenous/oral moxifloxacin vs intravenous/oral amoxicillin/clavulanate for
complicated skin and skin structure infections. Infection 2009; 37(5): 407-417.
 34. Lipsky BA, Pecoraro RE, Larson SA, Hanley ME, Ahroni JH. Outpatient management of
uncomplicated lower-extremity infections in diabetic patients. Arch Intern Med 1990;
150(4): 790-797.

35. Erstad BL, McIntyre J. Prospective, randomized comparison of ampicillin/ sulbactam and
cefoxitin for diabetic foot infections. Vasc Surg 1997; 31(4): 419-426.

36. Lipsky BA, Baker PD, Landon GC, Fernau R. Antibiotic therapy for diabetic foot
infections: comparison of two parenteral-to-oral regimens. Clin Infect Dis 1997; 24(4):
643-648.

37. Lipsky BA, Itani K, Norden C. Treating foot infections in diabetic patients: a
randomized, multicenter, open-label trial of linezolid versus ampicillinsulbactam/
amoxicillin-clavulanate. Clin Infect Dis 2004; 38(1): 17-24.

38. Lipsky BA, Giordano P, Choudhri S, Song J. Treating diabetic foot infections with
sequential intravenous to oral moxifloxacin compared with piperacillintazobactam/
amoxicillin-clavulanate. J Antimicrob Chemother 2007; 60(2): 370-376.

39. Grayson ML, Gibbons GW, Habershaw GM, Freeman DV, Pomposelli FB, Rosenblum
BI, Levin E, Karchmer AW. Use of ampicillin/sulbactam versus imipenem/cilastatin in
the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis
1994; 18(5): 683-693.

40. Bansal E, Garg A, Bhatia S, Attri AK, Chander J. Spectrum of microbial flora in diabetic
foot ulcers. Indian J Pathol Microbiol 2008; 51(2): 204-208.

41. El-Tahawy AT. Bacteriology of diabetic foot. Saudi Med J 2000; 21(4): 344-347.

42. Viswanathan V, Jasmine JJ, Snehalatha C, Ramachandran A. Prevalence of pathogens in

diabetic foot infection in South Indian type 2 diabetic patients. J Assoc Physicians India
2002; 50: 1013-1016.

43. Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, LeFrock JL,
Lew DP, Mader JT, Norden C, Tan JS. Diagnosis and treatment of diabetic foot
infections. Clin Infect Dis 2004; 39(7): 885-910.

44. International Working Group on the Diabetic Foot. International Consensus on the
Diabetic Foot and Supplements. 2007; : DVD.

APPENDIX

A. Literature search string for Pubmed

((Diabetes Mellitus OR diabetic))

AND
(((Clinical Trials) OR (comparative study) OR (epidemiologic study characteristics) OR
(Clinical Trial*) OR (case-control stud*) OR (case control stud*) OR (cohort stud*) OR
(Comparative stud*)))

AND

((Infection OR infected OR cellulitis OR abscess OR necrotizing fasciitis OR osteomyelitis OR

gangrene OR erysipelas OR osteitis OR (Bone Diseases, Infectious) OR (Diabetic Foot)) AND
(Surgery OR Amputation OR (Surgery, Plastic) OR (Preoperative Care) OR (dead space) OR
drain OR hardware OR (bone samples) OR biopsy OR (Vascular Surgical Procedures) OR
(Thrombolytic Therapy) OR (Costs and Cost Analysis) OR (Wound Healing) OR (Anti-Bacterial
Agents) OR (Anti-Infective Agents) OR (administration and dosage) OR (Drug Administration
Routes) OR parenteral OR oral OR topical OR duration OR cement OR (Methylmethacrylate)
OR (Calcium Sulfate) OR implant OR collagen OR ceramic OR (Aminoglycosides OR
gentamicin OR amikacin OR tobramycin) OR (Glycopeptides OR vancomycin OR Oritavancin
OR dalbavancin) OR teicoplanin OR Metronidazole OR Linezolid OR (Fusidic Acid) OR
Daptomycin OR Monobactam OR (Carbapenem OR imipenem OR meropenem) OR (beta-
Lactams) OR (Cephalosporins) OR cefuroxime OR ceftazidime OR cephalexin OR ceftriaxone
OR cefpirome OR (Clavulanic Acids) OR (Clavulanic Acid*) OR (Moxalactam) OR
(Penicillins) OR penicillin OR flucloxacillin OR oxacillin OR Methicillin OR nafcillin OR
ampicillin OR penicillin OR piperacillin OR (Tetracyclines) OR tetracycline OR minocycline
OR doxycycline OR (Macrolides) OR erythromycin OR azithromycin OR clarithromycin OR
(Lincomycin) OR clindamycin OR (Trimethoprim-Sulfamethoxazole Combination) OR
cotrimoxazole OR co-trimoxazole OR (Quinolones) OR ciprofloxacin OR ofloxacin OR
moxifloxacin OR levofloxacin OR (Anti-Infective Agents, Local) OR (Silver OR Silver
Sulfadiazine OR iodine) OR honey OR larvae OR maggots OR larval OR (hyperbaric oxygen
therapy OR hyperbaric OR (vacuum assisted wound therapy) OR (VAC therapy) OR (negative
pressure therapy) OR (growth factors) OR (G-CSF) OR (granulocyte colony stimulating growth
factor)))

B. Literature search strings for Embase

Map to preferred terminology (with spell check)

Also search as free text
Include sub-terms/derivatives (explosion search)

(Diabetes Mellitus) OR diabetic

AND

(Clinical Trials) OR (comparative study) OR (epidemiologic study characteristics) OR (Clinical

Trial*) OR (case-control stud*) OR (case control stud*) OR (cohort stud*) OR (Comparative
stud*) OR (case control study) OR (Comparative study) OR (RCT) OR (Randomised controlled
trial) OR (Costs and Cost Analysis)

AND
Infection OR infected OR cellulitis OR abscess OR (necrotizing fasciitis) OR osteomyelitis OR
gangrene OR erysipelas OR osteitis OR (Bone Diseases, Infectious) OR (Diabetic Foot)

AND

(Wound Healing) OR (Anti-Bacterial Agents) OR (Anti-Infective Agents) OR (administration

and dosage) OR (Drug Administration Routes) OR parenteral OR oral OR topical OR duration
OR cement OR Methylmethacrylate OR (Calcium Sulfate) OR implant OR collagen OR ceramic
OR Aminoglycosides OR gentamicin OR amikacin OR tobramycin OR Glycopeptides OR
vancomycin OR Oritavancin OR dalbavancin OR teicoplanin OR Metronidazole OR Linezolid
OR (Fusidic Acid) OR Daptomycin OR Monobactam OR Carbapenem OR imipenem OR
meropenem OR (beta-Lactams) OR Cephalosporins OR cefuroxime OR ceftazidime OR
cephalexin OR ceftriaxone OR cefpirome OR (Clavulanic Acids) OR (Clavulanic Acid*) OR
Moxalactam OR Penicillins OR penicillin OR flucloxacillin OR oxacillin OR Methicillin OR
nafcillin OR ampicillin OR penicillin OR piperacillin OR Tetracyclines OR tetracycline OR
minocycline OR doxycycline OR Macrolides OR erythromycin OR azithromycin OR
clarithromycin OR Lincomycin OR clindamycin OR (Trimethoprim-Sulfamethoxazole
Combination) OR cotrimoxazole OR (co-trimoxazole) OR Quinolones OR ciprofloxacin OR
ofloxacin OR moxifloxacin OR levofloxacin OR (Anti-Infective Agents, Local) OR Silver OR
(Silver Sulfadiazine) OR iodine OR honey OR larvae OR maggots OR larval OR (hyperbaric
oxygen therapy) OR hyperbaric OR (vacuum assisted wound therapy) OR (VAC therapy) OR
(negative pressure therapy) OR (growth factors) OR (G-CSF) OR (granulocyte colony
stimulating growth factor)

C. Evidence tables

Open in new window

Early surgery

Interventio
Study Difference Level
n and
Referenc desig s and of
Population control Outcomes Comments
e n and statistical evidenc
manageme
score results e (sign)
nt
Tan 1996 Cohor Cohort 87 Infection Amputatio 2- No
[10] t study of 112 infections outcome: n rate information
Single patients with treated Above ankle 27.6% vs regarding
centre 164 diabetic without amputation 13.0% (appropriatene
. foot surgery in antibiotic ss of)
infections, the first 3 group and antibiotic
Study hospitalized days vs 77 antibiotic treatment.
qualit for treated with and High risk of
y 3/8 treatment of antibiotics + surgical bias as there is
the foot surgery (of interventio no assessment
 infection. Of which 46 n groups, of severity and
these, 76 antibiotics respectivel there is a high
had a deep and y (p<0.01) chance of
infection, 65 debridement indication bias
had and 31
osteomyeliti antibiotic Provides no
s. No early and early evidence to
surgery and local confirm the
antibiotics amputation) role of
in 87 . Duration surgery, as
subjects vs of treatment opposed to
early with timing of
surgery and antibiotics intervention
antibiotics unknown
in 77 No sponsor
subjects identified.
Faglia Cohor Diabetes Group 1: Drainage Group 1: 9 2- Poor quality
2006 [11] t and deep Immediate without vs Group study despite
Single foot space surgical amputation: 2: 4 the 5/8 score
centre abscess debridement
N=106, , group 2: One or more Group 1: Concluded that
Study group 1: 43 Referred ray 21 vs delay in
qualit subjects, from amputations: Group 2: drainage
y 5/8 group 2: 63 another 21 increases the
subjects hospital Transmetatars incidence of
after a mean al amputation: Group 1: amputation,
delay of 6.2 12 vs but this is not
±7.5 days Chopart: Group 2: justified by
without 10 these data
debridement Major because of the
. Duration amputation: Group 1: 1 possibility of
of treatment vs Group bias
with 2: 23
antibiotics No sponsor
unknown Group 1: 0 identified
vs Group
2: 5

p<0.001

X2 24.4
Open in new window

Health economics
 Interventio
Difference
Study n and Level of
Referenc s and Comment
design Population control Outcomes evidenc
e statistical s
and score managemen e (sign)
results
t
Tice 2007 RCT, 99 patients Substudy of Infection 1+ High
[12] Subset with DFI, SIDESTEP outcomes: drop-out
analysis including [13], cost- rate.
based on osteomyeliti minimisatio Mean days of I7.6 vs 7.4 Length of
multicentr s provided n treatment: (p=0.8) stay was a
e, double all infected assessment days of proxy
blinded bone was of treatment, measure.
study. surgically ertapenem 7.5 vs 25.5 The length
removed. 56 vs (p<0.0001) of stay
Study subjects in piperacillin/ Total i.v. might
quality 6/9 ertapenem tazobactam. drug doses: total i.v. have been
group vs 43 No duration doses 8.6 prolonged
in of treatment vs 26.8 due to the
piperacillin/ given Total (p<0.0001) trial
tazobactam antibiotic design
group dosages: total i.v
and oral Sponsored
doses, by Merck
$356 vs
Mean drug $503
preparation (p<0.001)
and
administratio total cost
n cost: of
treatment
for
ertapenem
and
pip/tazo,
respectivel
y
Open in new window

Topical treatment with antiseptic agents

Study Differences
Intervention Level of
design and
Reference Population and control Outcomes evidence Comments
and statistical
management (sign)
score results
Martinez- RCT Type 2 n=21 Odour, Odour 1- Alternate
De Jesus Single diabetes intervention periwound reduction patient
2007 [15] centre and group: cellulitis was group
Patient infected, neutral pH and achieved in allocation,
blinded. deep superoxidised granulation all yet different
diabetic aqueous tissue superoxide numbers in
Study foot ulcers, solution. patients each group.
quality 21 subjects (100% Non-
4/9 in n=16 control versus 25%; standardized
intervention group: p< 0.01) and wound
group vs 16 disinfectant surrounding classification
in control such as soap cellulitis criteria
group or povidone diminished
iodine. (p<0.001) in No sponsor
17 patients identified
Duration of (80.9%
antibiotic versus
treatment 43.7%)
more than 10
days
Chen RCT 30 patients 10 diabetic Infection Number of 1+ Use of
2008 [17] Single with foot ulcers outcomes: colonies systemic
centre diabetic treated with Bacteria after 24 antibiotics
Patient foot ulcers, iodophor, 10 number in hours / not
blinded. 10 patients with rivanol, wound number of mentioned.
in each 10 controls. colonies at Study only
Study subgroup One single t=0 was looked at
quality application of 0.961, 0.918 bacterial
6/9 topical and 0.986for growth after
treatment the control 5 minutes
after ulcer group, and 24 hours
debridement iodophor
group and No sponsor
rivanolol, identified
respectively.
Significantly
less growth
of bacteria
after 24
hours in the
iodophor
group
compared
with the
rivanol and
control
group
Piaggesi RCT 40 patients Dermacyn vs Infection Duration of 1+ 2 patients
2010 [16] Single with povidone outcomes: antibiotic lost to
centre diabetes iodine. All use of use: 10.1 ± follow up.
Open with post- patients had antibiotics. 6.1 weeks Details of
label. surgical systemic the
wounds, antibiotic Non- Dermacyn interventions
Study who had therapy and infection group vs and
quality surgery for surgical outcomes: 15.8 ± 7.8 outcomes
6/9 a diabetic debridement Healing weeks in were
foot if needed. rate at 6 povidone suboptimal.
infection, Ischemia was months iodine group Possible
20 subjects an exclusion and (p=0.016). adverse
in each criterion. healing effect of
treatment Duration of time Healing rate iodine on
group treatment at 6 months wound
with 90% in healing not
piperacillin/ Dermacyn taken into
tazobactam vs 55% in account.
and iodine group Very long
metronidazol (X2 9.9, p= antibiotic
with or 0.002). treatment
without period
teicoplanin Healing
10. 1± 6.1 time 10.5 ± Sponsored
weeks for 5.9 vs 16.5 by Oculus
Dermacyn ±7.1 Innovative
and 15.8 ± respectively Sciences
7.8 for (p=0.007)
control group
(p=0.016).
Duration of
antibiotic use
was an
outcome
measure
Open in new window

Granulocyte-colony stimulating factor

Interventio Level
Difference
Study n and of
Referenc s and Comment
design and Population control Outcomes eviden
e statistical s
score manageme ce
results
nt (sign)
Gough RCT Single 40 patients Intervention Infection 1++ Well
1997 [21] centre with : G-CSF outcome designed
Double blind diabetes 5µg/kg measures: RCT
with adjusted on showing
Study moderate basis of 1 Time to Interventio significant
quality 9/9 (Internation WCC, for 7 resolution n: 7 (5-20) benefit in
al days versus of days versus moderate
Consensus saline infection: Control 12 infection.
Guidelines control. (5-93)
Grade 3) Both groups p=0.03 See
infection of received 4 metaanaly
DFU, n=20 antibiotics, 2 Total Interventio sis [22]
subjects in mean time of n: 8.5 (5- which
both duration of intravenous 30) versus concluded
treatment iv antibiotics: Control that GCSF
arms antibiotics 14.5 (8-63) did not
8.5 for days have a
GCSF and p=0.02 significant
14.5 for 3 Hospital benefit
controls (p= length of Interventio with
0.02) stay: n: 10.0 (7- regard to
31) days either
15 patients versus 17.5 resolution
treated with (9-100) of
standard p=0.02 infection
treatment 4 Need for or healing
(antibiotics surgery: Interventio of
and wound n: 0 versus wounds,
care), 15 4/20 (20%) although
patients p=0.114 there was
treated with 5 Time a
standard taken to Interventio significant
treatment + eliminate n: 4 (2-10) reduction
G-CSF 5 pathogens days versus in the
µg/kg, from control:8 need for
duration of wound (2-75) days lower
antibiotic Non- p=0.02 extremity
treatment infection surgery
22.9 ± 2.0 outcome:
days in Interventio Sponsored
GCSF 23.3 6 Effect of n: 16.1 by Amgen
± 1.9 days GCSF on (4,2-24.2)
in control generation nmol per
group, of 106
standard neutrophil neutrophils/
treatment superoxide: 30 mins
with GCSF versus 7.3
 3 days. (2.1-11.5)
Duration of p<0.0001
antibiotic
treatment
22.9 ± 2.0
days in
GCSF 22.3
± 1.9 days
in control
group
Yönem, RCT, Single 15 subjects 15 patients Infection No 1- Also
2001 [18] centre, with treated with outcomes: significant includes
Blinding cellulitis or standard Time to differences results of
unknown Wagner 2 or treatment resolution in time to respirator
less in each (antibiotics of resolution y burst,
Study of the two and wound infection, of granulocy
quality 2/9 treatment care), 15 duration of infection, te count
arms patients hospitalisati duration of etc.
treated with on, duration hospitalisat Typing
standard t of ion error in
reatment + parenteral duration of abstract
G-CSF 5 antibiotic parenteral (p< 0.05
µg/kg, administrati antibiotic should be
duration of on, need for administrati p>0.05)
antibiotic surgical on,
treatment intervention amputation No
22.9 ± 2.0 in the G- sponsor
days in CSF treated identified
GCSF 23.3 group
± 1.9 days compared
in control to the
group, standard
standard group
treatment
with GCSF
3 days.
Duration of
antibiotic
treatment
22.9 ± 2.0
days in
GCSF 22.3
± 1.9 days
in control
group
De Lalla RCT Single Severe limb Intervention 1 Cure At 3 weeks 1+ No effect
2001 [19] centre threatening : (complete - of GCSF
Observerblin foot conventiona closure of Interventio on
ded infection, l treatment the ulcer n 0 vs eradicatio
all with plus G-CSF without Controls 0 n of
Study osteomyeliti 263µg sc signs of infection,
quality 6/9 s in diabetes daily for 21 bone At 9 weeks in contrast
N=40 days versus infection) - to [21].
conventiona Interventio Difference
Patients l treatment n 7 vs s with
with ABPI (no 2 Controls 7, [21] study
<0.5 or placebo). improveme p=1.0 relating to
ankle Mean nt prevalenc
systolic duration of (eradication At 3 weeks e of
pressure antibiotics of - osteomyel
<50mmHg, 68.9 ±29.2 pathogens Interventio itis and
and patients days for G- in addition n 12 vs choice of
with serum CSF patients to marked Controls 9, outcome
creatinine and 58.7± or complete p=0.34 measures
>1.6mg/100 23.7 for reduction of
mL were controls (not cellulitis At 9 weeks No
excluded. significant) but - sponsor
20 subjects incomplete Interventio identified
in each ulcer n 8 vs
treatment healing, or Controls 4,
group ulcer p=0.17
healing but
persistent
osteomyelit
is

3 failure At 3 weeks
(absence of -
any clinical Interventio
improveme n 8 vs
nt) or Controls
amputation 11, p=0.34
for
persistent At 9 weeks
infection -
Interventio
n 5 vs
Controls 9,
p=0.19
Kästenba RCT Single Soft tissue The patients Infection Patients 1+ Infection
uer 2003 centre infection of in the outcomes: who score non-
[20] Patient DFU, 20 intervention Infection received G- validated
 blinded subjects in
group scores pre CSF did
intervention
received vs post not have an No
Study group, 17 in
daily an treatment, earlier difference
quality 7/9 placebo initial dose putrid, resolution s, like
group. of either 5 erythema, of clinically [18],
µg/kg G- oedema defined whereas
CSF or infection significant
placebo than difference
(0.9% sterile placebo s in
saline patients resolution
solution), of signs of
s.c.. infection
Subjects contrast
were treated with [21]
with i.v.
antibiotics Sponsored
(clindamyci by Amgen
n and
ciprofloxaci
n) until the
inflammatio
n had
visibly
improved.
Oral
antibiotics
were
administere
d thereafter
if necessary.
Duration of
treatment
with GCSF
10 days.
Mean
antibiotic
treatment
duration 5.6
± 2.5 days
in G-CSF
group, 5.8 ±
2.3 days in
placebo
group
Viswanat RCT Single N=20, with The patients Eradication Interventio 'Foot
han 2003 centre extensive received of n: 9 ulcers
[6] Double blind cellulitis, daily initial infection: Control 3 excluded'
Wagner II- dose of (N.S.)
Study III ulcers, either 5 Surgery: Sponsored
quality Not 10 subjects µg/kg body Interventio by Amgen
scored in each weight G- Hospital n:0 Control
treatment CSF or length of 3 (N.S.)
arm placebo stay:
(0.9% sterile Interventio
saline n 7.4
solution), Control 8.8
injected (p=0.02)
subcutaneou
sly.
Duration of
treatment
with GCSF
10 days
Open in new window

Procaine plus polyvinylpyrrolidone

Study Differences Level

Intervention and
Referen design Populatio and of Comment
control Outcomes
ce and n statistical evidenc s
management
score results e (sign)
Duarte RCT, 118 59 patients treated Infection Amputation 1+ Unknown
2009 Single patients with De Marco outcomes: rate 45.8% risk of
[23] centre with Formula 0.15 ml/ Amputatio vs 25.4% bias,
Assess ischemic day intramuscular n (toes 30.4% unclear
or diabetic injection (DMF = vs 28.8%, criteria for
blinded foot combination of transmetatars reason of
, infection, procaine HCl and al amputatio
of which polyvinylpyrrolidon amputation n or level
Study Ischemic e), for ten days, 18. 6% vs of
quality gangrene then twice weekly 8.5%) in the amputatio
7/9 n=63, until wound healing control group n. Little
ischemic or completion of a and DMF obvious
ulcer 6-week period. 59 group, evidence
n=55. 59 patients treated with respectively of benefit
subjects standard care (N.S.)
in each Sponsored
treatment by Gen
arm Cell
Open in new window
Hyperbaric oxygen therapy

Study Differences
Intervention Level of
Referenc desig Populatio and
and control Outcomes evidenc Comments
e n and n statistical
management e (sign)
score results
Doctor RCT, 30 patients All patients Infection Hospital 1- It was not
1992 [26] Single with treated with outcome: stay 41 vs described how
centre chronic systemic positive 47 days, many diabetic
Open diabetic antibiotic wou nd major foot ulcers were
label. foot ulcers, therapy and cultures. amputation infected, but
15 subjects wound Non- 2 vs 7, most received
Study in both debridement, infection minor antibiotics.
qualit interventio 15 patients outcomes: amputations Method of
y 3/9 n and treated with hospital 4 vs 2, pre randomisation
control hyperbaric days, procedure was not
oxygen amputatio positive described.
treatment n and wound Antibiotics
(HBOT), 15 level culture 19 used were
treated vs 16, post based on
conservatively procedure sensitivity
. 4 HBOT positive spectrum and
sessions of 45 wound included
minutes over culture 3 vs cephalosporins,
2 weeks. 12, in the aminoglycoside
Antibiotic HBOT s and
duration 3 group vs metronidazole
days the control
group, No evidence of
respectively benefit
. All
differences No sponsor
were not identified.
significant
Open in new window

Comparison of antibiotic regimens - skin and soft tissue infection alone

Interventi Level
Study
on and Differences of
Referen design
Population control Outcomes and statistical evide Comments
ce and
manageme results nce
score
nt (sign)
Bradsher RCT, Subset of 10 patients Infection Elimination of 1- Insufficient
1984 Multicen RCT in 84 with DFI outcomes: infection: 6 vs data
[28] tre Open patients with treated only 4, reduction: 3 available for
label, soft tissue with microbiolo vs 2, the diabetic
infection. Of ceftriaxone gical persistence: 1 vs foot
Study these 84, 20 , 10 with evaluation: 4 In ceftriaxone infection
quality patients had cefazolin. eliminatio and cefazolin, subgroup.
4/9 diabetic foot Duration of n, respectively. No clinical
infection, 10 antibiotic reduction, assessment
subjects in treatment persistence in diabetic
each unknown , relapse, foot
treatment reinfection infection
arm. subgroup

No sponsor
identified
Lipsky RCT, Outpatient Oral Infection No difference in 1- No ITT
1990 Single infected clindamyci outcomes: eradication, analysis. No
[34] centre diabetic foot n Eradicatio clinical data on
Open ulcers N=56, hydrochlori n of response or blinding of
label 27 vs 29 de (n=27) bacteria by wound healing patient/clini
subjects in or wound response cian/
Study each cephalexin culture, between the two assessor
quality treatment (n=29). clinical antibiotic. Fifty-
4/9 arm. Duration of cure one infections Only study
therapy 2 (91%) were on
weeks. eradicated, 42 clindamycin
Additionall (75%) after 2 monotherap
y, 3 weeks of y.
patients treatment; only
received an 5 (9%) were First
additional initially treatment
2 weeks of treatment trial of out-
antiobiotic failures, and 3 patients
treatment (5%) were
after their subsequently Sponsored
initial cured with by the Dept
course further of Veterans
outpatient oral Affairs and
antibiotic Upjohn
treatment. After Company
a mean follow-
up of 15
months, no
further
treatment was
required in 43
 (84%) of the
cured patients
Siami RCT, 409 patients 29 patients Infection 15/29 clinically 1+ Approximat
2001 multicent with skin and treated outcomes: cured in ely one
[29] re soft tissue with Clinical clinafloxacin third of
Investiga infection, of clinafloxac cure group vs 12/25 patients not
tor which 279 in IV, 25 in pip/tazo clinically or
blinded, patients with Microbiolo group. microbiolog
clinically piperacillin gical ically
Study evaluable, 54 / eradication Microbiological evaluable
quality patients with tazobactam eradication:
5/9 diabetic foot IV with or 32/73 and 15/47 Short
infection, 25 without isolates duration of
subjects in vancomyci eradicated for treatment,
each of the n (in case clinafloxacin also
two of MRSA). and piperacillin/ relatively
treatment Duration of tazobactam low rate of
arms. treatment groups, clinical cure
Patients with for whole respectively
osteomyelitis group Sponsored
were (including by Parke-
excluded. group with Davis.
DFIs): at
least 3 days
of iv
therapy
followed
by oral
therapy for
a
maximum
total
duration of
14 days.
Median
duration of
treatment
of patients
that
completed
treatment
was 13
days (total
patients)
Clay RCT DFU N=70, Group 1 Temperatu No statistically 1- Men only
2004 Single only men n=36 re: significant 27 patients
[14] centre with diabetes Metronidaz differences (NS) had
Open and lower ole 1g and antibiotics
label. extremity 1g NS changed
(Veteran infection ceftriaxone WCC: and no
s were IV each indication
Admin.) included, 36 day for a Finger NS of whether
vs 34 mean of stick blood the analysis
Study subjects in 6.7 ± 3.3 glucose: Stage changed was strictly
quality each days in "minimally" - per
3/9 treatment patients Improvem details not protocol.
arm with ent of shown No stated
successful wound time of day
outcome. stage: for blood
15 protocol NS glucose
violations Creatinine measureme
clearance: Cost saving of nt, and only
Group 2 $61 per hospital undertaken
n=34 Costs: admission in in 39/70.
Ticarcillin/ metronidazole/ Creatinine
clavulanate ceftriaxone clearance
3.1g IV group assessed in
each 6 only 31/70
hours for a "Treatment
mean of success"
6.1 ± 4.3 achieved in
days in 29 patients
patients in Cef/Met
with and in 29 in
successful the Tic/clav
outcome. group
p=NS.
12 protocol Inappropriat
violations e measures
of treatment
success
besides
clinical
staging
(which is
not
standardize
d).
Treatment
duration is
only
assessed in
 those who
achieved
treatment
success.
This causes
some doubt
on the cost
analysis No
conclusions
can be
drawn from
the study

Pharmacist-
led study

Sponsored
by Roche
Lobman Cohort. 180 diabetic 90 Non- Treatment with 2- Clindamyci
n 2004 Prospecti patients with ceftriaxone infection a third n could be
[27] ve severe, limb- vs 90 outcomes generation added in
threatening quinolones Wound cephalosporin is both groups
Study foot infection in addition healing, as effective as a (added in
quality were to standard amputation treatment with 27%). Not
4/8 consecutivel treatment rate, length quinolones. clear how
y enrolled. of foot of stay Clinical many
300 patients infection. Infectious: response was patients in
were Mean clinical achieved in each group
screened, 90 duration of (reaching 58.0% in the received
vs 90 treatment Wagner I ceftriaxone clindamycin
subjects in in or 0) and group and in . Definition
each ceftriaxone microbiolo 51.1% in the of clinical
treatment group 18.7 gical cure quinolone group response is
arm days, in rate of (NS.). Fourteen unusual
quinolone infection, days after (change in
group 23.8 duration of initiation of Wagner
days. antibiotic treatment, the grades)
Median therapy, number of
duration of need to patients with Sponsored
treatment change microbiological by
in antibiotic isolates Hoffmann
ceftriaxone therapy decreased in La Roche
group 11.5 both groups (52
days, and to 5 in the
16.5 days ceftriaxone
in the group and 60 to
 quinolone 12 in the
group quinolone
group). At
hospital disch
arge, 66.0% of
ceftriaxone and
64.4 of
quinolonetreate
d diabetic ulcers
were cured or
improved.
Median duration
of antibiotic
therapy 11.5
days for
ceftriaxone vs
16.5 days for
quinolone
(p<0.01). Need
to change
antibiotic
therapy 7.8%
ceftriaxone vs
16.7% for
quinolones
Harkless RCT 314 Patients 155 adult Clinical Clinical efficacy 1- Very large
2005 Multicen with patients success rates (cure or number of
[30] tre Open polymicrobia with (resolution improvement) dropouts
label l infections moderateto of ulcer were (38 and
involving - severe and of statistically 44% non
Study methicillinre infected symptoms equivalent evaluable)
quality sistant diabetic of overall (81% for
2/9 Staphylococc foot ulcers infection, P/T vs. 83% for Sponsored
us aureus received no A/S), and by Wyeth
also received piperacillin additional median duration
vancomycin / antibiotics of treatment was
1 g q12h, tazobactam needed) similar in the
n=155 vs (P/T) (4 Bacteriolo clinically
n=159 g/0.5 g gical evaluable
subjects in q8h) and success populations
each of two 159 (end of (nine days for
treatment received cure or end P/T, 10 days for
arms ampicillin/ of A/S).
sulbactam treatment Drugrelated
(A/S) (2 eradication adverse events
g/1 g q6h) or for both study
 as a presumed drugs were
parenteral eradication comparable in
treatment. ) frequency and
Median type
duration of
treatment
8.0 days
P/T vs 8.5
days A/S
Lipsky RCT N=133, all Patients Infection Of 133 subjects, 1- Infection
2005 Subset subjects had with a outcomes: 103 were presumptive
[31] analysis a DFU with diabetic Success clinically ly caused by
of infection, 47 ulcer rates evaluable. Most Gram-
multicent vs 56 nfection microbiolo infections were positive
re trial subjects in were gical monomicrobial, organisms.
Investiga each of two prospective adverse and 30 of 133
tor treatment ly stratified events Staphylococcus subjects
blinded, arms to ensure aureus was the were not
they were predominant clinically
Study equally pathogen. evaluable. 8
quality represented Success rates patients had
4/9 in the for patients MRSA
treatment treated with infections: 1
groups, daptomycin or in
then the comparators daptomycin
randomize were not group, 7 in
d to either statistically vancomycin
daptomyci different for group.
n (n=47) [4 clinical (66%
mg/kg versus 70%, Note: No
every 24 h respectively; ITT
intravenous 95% CI, -14.4, analysis
ly (iv)] or a 21.8) or
pre- microbiological Sponsored
selected (overall or by by Cubist
comparator pathogen)
(n=56) outcomes. Both
(vancomyc treatments were
in or a generally well
semi- tolerated, with
synthetic most adverse
penicillin) events of mild
for 7-14 to moderate
days. Exact severity
duration of
treatment
 not given
Lipsky 2 RCTs Mildly 2 studies: Infection Although study 1++ Mild
2008 [8] consecuti infected 303 and outcomes: 303 failed to infection
ve, diabetic foot 304: 418 clinical demonstrate not
multicent ulcers. subjects cure or equivalence, adequately
re N=835 received improvem study 304 and defined.
doublebli subjects, of the active ent of the the combined Developme
nd whom 418 in topical infection, data for the 2 nt of
the agent eradication trials resistance in
Study intervention pexiganan of wound demonstrated the oral
quality group, and plus an oral pathogens, equivalent antibiotic
8/9 417 in the placebo vs bacterial results (within group.
control group 417 resistance, the 95%
subjects adverse confidence Only study
that events. interval) for of oral vs
received Non- topical topical
oral infection pexiganan and treatment
ofloxacin outcomes: oral ofloxacin in
plus a wound clinical i Low
topical healing mprovement incidence of
placebo. rates (85%- pexiganin
Mean 90%), overall resistance
duration 23 microbiological
days in eradication rates Sponsored
study 303 (42%- 47%), by
and 25 and wound Magainin
days in healing rates. and SKB
study 304. The incidence
Median of worsening
duration 27 cellulitis (2%-
days in 4%) and
study 303 amputation
and 22 (2%-3%) did
days in not differ
study 304 significantly
between
treatment arms.
Bacterial
resistance to
ofloxacin
emerged in
some patients
who received
ofloxacin, but
no significant
resistance to
 pexiganan
emerged among
patients who
received
pexiganan.
More adverse
effects in the
ofloxacin group
Noel RCT Subgroup Group 1: Clinical Clinically 1+ No baseline
2008 Multicen analysis of 169 outcomes cured: Group 1 details of
[32] tre 257 people subjects: assessed at 86.2% Group 2 the DFI
Double with DFI in a Ceftobiprol TOC visit 81.8% (CI of patients.
blind larger study e 500mg (7-14 days comparison -5.4 Only
of skin and IV 8 hourly after EOT) - 15.7) outcome
Study skin structure and measure
quality infections: Group 2: defined as: available for
6/9 total N=828 89 cure, the DFI
(31% subjects: failure and patients is
patients with Vancomyci not the
DFI) 169 vs n 1g each evaluable proportion
89 subjects 12 hours of clinically
in each of the and Microbiolo No further cured in the
two ceftazidime gical details given for clinically
treatment 1g each 8 outcomes the DFI group evaluable
arms. Group hours assessed at patients at
allocation test-of- TOC visit.
2:1, only Both for 7- cure visit Efficacy of
222/257 14 days. (7-14 days the two
were Mean after end groups
clinically duration of of seemingly
evaluable total treatment): equivalent.
population Eradicatio Drug is
9.0 days n, currently
for presumed not FDA or
ceftobiprol eradication EMA
e and 9.1 , approved.
days for persistence Centres
control , resumed targeted had
group (per persistence high
protocol , prevalence
analysis of colonisatio of MRSA
N=828) n,
superinfect Sponsored
ion, not by Johnson
evaluable & Johnson
Vick- RCT Large Group 1 Clinical Group 1 : 25/49 1- No apparent
Fragoso Multinati multinational Sequential success (51.0%) difference
2009 onal study of skin IV/ oral rate in the subset
[33] Randomi and soft moxifloxac (success= Group 2 : 42/63 with
sed Open tissue in otal (66.7%) diabetic
label infections, 400mg/day resolution foot
N=804. Group 2 : or marked (5%CI for infection.
Study Subset with Sequential improvem difference -34 to No
quality diabetic foot IV/oral ent of all 2.7, formal difference
4/9 infection amoxicillin symptoms statistical observed in
n=134. / clavulanic and signs; significance not the total
Group 1 63 acid no calculated) population.
subjects vs 1000/200m additional
group 2 71 g three or Sponsored
subjects. times daily. alternative by Bayer
Total Mean antimicrob
withdrawal duration of ial
22/134 antibiotic treatment)
treatment
14.1 ± 5.5
days for
moxifloxac
in and
15.2±5.4
days for
amoxicillin
/ clav (i.v.
and oral
combined)
Graham RCT 540 adults 53 subjects Clinical Clinical cure in 1- Very
2002 Multicen with received 1 cure evaluable limited
Ertapene tre complicated g daily patients demographi
m vs Double skin and ertapenem (modified cal and
piperacil blind skin- with TID intention to reat baseline
lin/ Study structure placebo analysis): data on the
tazobact quality infections. infusions, Ertapenem subjects of
am [4] 5/9 Of these, 98 compared group: 23/35 the
had a lower with 45 (66%) cure, subgroup
extremity subjects Piperacillin/tazo with
infection who bactam group: diabetes.
with received 22/31 (71%) Only data of
diabetes, of 3.375 g cure (no 66 of 98
which the QID significant subjects
data of 66 piperacillin difference) were
patients were / available for
evaluable. tazobactam review and
Subjects with analysis.
 osteomyelitis Mean More
were duration of outcome
excluded therapy measures
was are
9.1±3.1 available for
days for the total
ertapenem studied
and group, but
9.8±3.3 not for the
days for subgroup of
piperacillin patients
/ with
tazobactam diabetes
related
lower
extremity
infection

Sponsored
by Merck
Graham RCT 399 adults Patients Clinical Clinical cure in 1- Very
2002 Multicen with were cure evaluable limited
Levoflox tre Open complicated randomised patients in demographi
acin vs label skin and skin to 1 of the ticarcillin/ cal and
ticarcilli structure 2 study clavulanate baseline
n [7] Study infections. arms:Ticar group 18/26 data on the
quality Of these, 66 cillin/ (69%) versus subjects of
1/9 had an clavulanate 16/28 (57%) in the
infected (3.1 g the levofloxacin subgroup
diabetic foot given iv group (no with
ulcer. every 4-6 significant diabetes
Subjects with h) with a difference) Only data of
osteomyelitis switch to Seven patients 54 of 66
or who oral taking subjects
needed amoxicillin levofloxacin were
emergency / and 2 taking available for
surgery were clavulanate TC/AC had review and
excluded (875 mg osteomyelitis analysis.
BID) at the diagnosed after More
investigato admission to the outcome
r's study, resulting measures
discretion, in 4 are
or amputations. available for
levofloxaci Five of 9 of the the total
n (750 mg osteomyelitis studied
given by cases were due group, but
 mouth to diabetic not for the
and/or iv ulcers subgroup of
QD). patients
Subjects in with
both diabetes
groups related
received 7- lower
14 days of extremity
therapy. infection.
The Not
randomizat reported to
ion which
schedule group the
was subjects
stratified with
by study osteomyeliti
centre and s were
by randomised
diagnosis
of diabetic Sponsored
ulcer. by Johnson
& Johnson
Mean Research
duration of and
therapy Developme
was nt
12.1±4.9
days in the
levofloxaci
n group
and
12.1±4.9
days in the
ticarcillin/
clavulanate
group
Open in new window

Comparison of antibiotic regimens - studies including patients with osteomyelitis

Level
Study
Intervention Differences of
Refere design Comment
Population and control Outcomes and statistical evide
nce and s
management results nce
score
(sign)
Grayso RCT Limbthreaten Group 1: Eradicatio Group 1 28/48 1++ High
n 1994 Single ing infection Ampicillin/ n of vs Group 2 quality
[39] centre of the foot in sulbactam infection at 29/48 RCT
Double 93 2g/1g (AS) IV 5 days:
blind hospitalised 6-hourly No
Study subjects with Eradicatio Group 1 39/48 difference
quality 96 episodes Group 2: n of vs Group 2 between
9/9 of DFI, some Imipenem/ infection at 41/48 (p=0.78) two
despite cilastatin (I/c) End of intravenou
previous 500mg IV Therapy s regimens
antibiotic every 6 hours (EOT): in terms of
therapy. Doses adjusted Group 1 32/48 resolution
Prevalence of to renal Microbiolo vs group 2 of signs of
osteomyelitis function. Mean gical 36/48 (p=0.5) STI and of
68% vs 56% duration of eradication systemic
episodes in treatment in : Group 1 8/48 vs signs.
the A/S group 13 ± Group 2 6/48 There was
ampicillin/ 6.5 days, vs 15 Failure at a very high
sulbactam ±8.6 days in the EOT: Group 1 16 vs incidence
and I/c group, Group 2 17 of
imipenem/cil folllow up Adverse amputation
astatin group, period 1 year reactions: 69 vs 58%
respectively. for amp/
Group 1: 48 sul and
episodes in imi/cil,
47 respectivel
participants, y
group 2: 48
episodes in Osteomyel
46 itis -
participants. cannot be
One person assessed in
was this way
randomised although
in error did have
follow-up
for one
year in this
study, but
they have
also treated
surgically

High
prevalence
of
 osteomyeli
tis. Osteo
also treated
with
resection
of bone. 1
year follow
up.

No diff
narrow
(G+ve
targeted)
versus
broad
spectrum
antibiotics

Research
question
must be to
isolate
osteo. But
if included,
need one
year
follow-up

Sponsored
by Pfizer
Erstad RCT, 36 patients 18 patients Infection Cure 6% vs 1+ Unclear
1997 Single with DFI, treated with outcomes: 39% (p=0.03), what day
[35] centre majority ampicillin/ Cure (= improvement in of
Double superficial sulbactam 3 g complete 78% vs 50%, treatment
blind infection QID (AS), 18 alleviation cure + the
(56%). 18 treated with of signs or improvement assessment
Study patients in cefoxitin, 2 g symptoms 15/17 vs 16/17, of clinical
quality each of 2 QID (Cef) for of bacteriological outcome
6/9 treatment at least 5 days, infection), response in was made
arms. 44% vs in both groups improvem 100% vs 73%,
28% combined with ent, toe/ray Note:
suspected or surgical bacteriolog amputation n=7 higher cure
proven intervention. ical vs n=7, below rate.
osteomyelitis Mean duration response, knee Difficult to
in the of amputation amputation n=1 see why
ampicillin/ hospitalization , duration vs =1 and days there is a
 sulbactam 21.1 (range 6- of of difference
group vs the 58) days in A/S hospitaliza hospitalization in cure as
cefotixin group, 12.1 tion 21.1 vs 12.1 in opposed to
group, (range 4-39) the ampicllin/ cure plus
respectively days in Cef sulbactam and improveme
group (p=0.06) cefotixin group, nt
respectively
Sponsored
by Pfizer
Lipsky RCT N=108, 55 vs 55 subjects IV Infection No differences 1+ 20
1997 Multice 53 subjects in then oral outcomes: in outcomes Subjects
[36] ntre the treatment ofloxacin vs 53 Treatment between groups. non
Open arms. subjects of Cured or evaluable.
label Prevalence of ampicillin/ infection: improved 85% Persistence
osteomyelitis sulbactam Cured or Ofloxacin vs of
Study 4/55 vs 1/53 (A/S), then oral improved, 83% A/S. The streptococc
quality in the amoxicillin/ mean mean duration i in
5/9 ofloxacin and clavulanate duration of of therapy with ofloxacin
Amoxicillin/ (A/C). Mean therapy the ofloxacin treatment
sulbactam duration of regimen was 7.8 group.
group, treatment iv days (range, 1- Infected
respectively. ofloxacin 7.8 25 days) bone was
Subjects with days, oral 13.2 intravenously supposed
osteomyelitis days, A/S iv and 13.2 days to be
included if 7.1, oral 12.0 (range, 3-25 removed,
the infected days, duration days) orally. but in the
bone was of treatment in The mean results it
removed osteomyelitis: duration of turned out
ofloxacin iv 9.2 therapy with the that it was
days oral 11.5 aminopenicillin only
days, A/S i.v. regimen was 7.1 removed in
7.0, days, 12.9 days (range, 1- 71%.
days oral A/C 20 days) Numbers
intravenously of
and 12.0 days osteomyeli
(range, 1-24 tis do not
days) orally. seem to
Patients with match in
osteomyelitis the tables
received a
somewhat Sponsored
longer course of by Johnson
intra- venous Pharmaceu
therapy (mean ticals
duration, 9.2 vs.
7.0 days,
 respectively)
but a slightly
shorter course
of oral therapy
(mean duration,
11.5 vs. 12.9
days,
respectively)
than did
patients with
only soft-tissue
infections
Lipsky RTC 371 enrolled, 241 linezolid, Infection Overall, the 1- Investigato
2004 Multice of whom 10 120 ampicillin/ outcomes: clinical cure ra rs
[37] ntre were not sulbactam, and clinical tes were diagnosed
Open treated, 241 amoxicillin/ cure and statistically osteomyeli
label vs 120 in clavulanate. safety equivalent tis in 77
each Mean duration data. (linezolid 81% patients.
Study treatment linezolid 17.2 vs. ampicillin/ The
quality arm. ±7.9 days, sulbactam analysis of
4/9 Prevalence of ampicillin/ 71%,). Subjects clinical
osteomyelitis sulbactam 16.5 with linezolid outcome
24% vs 17% ± 7.9 days. had a higher by
in the Duration of i.v cure rate for pathogen is
linezolid and linezolid infected DFU a modified
ampicillin/ therapy 7.8 (81% vs. 68%; intent-
sulbactam ±5.5 days, oral p=0.018) and in totreat
group, linezolid cases without population
respectively therapy osteomyelitis which
15.9±7.4 days, (87% vs. 72%; consisted
duration of p=0.003). of patients
ampicillin/ Significantly in the
sulbactam more anaemia, intent-
therapy 10.4 thrombocytopen totreat
±5.7 days, oral ia and population
amoxicillin/ discontinuation with a
clavulanate of therapy in the baseline
therapy 15.0 linezolid group. pathogen
±7.8 days Any event and
26.6% vs 10.0% evaluable
in the linezolid clinical
group vs the response of
ampicillin/ success or
sulbactam failure).
group, The
respectively clinical
 (p<0.01) cure rate is
actually a
per
protocol
analysis
instead of
an ITT
analysis

Only study
to show
higher
incidence
of AEs in
one group

Sponsored
by Pfizer.
Lipsky RCT 586 subjects Intravenous Infection Of the 576 1+ Drop out
2005 Multice with a ertapenem (1 g outcomes: treated subjects, rate 23%
[13] ntre diabetic foot daily; n=295) Clinical 445 were analyzed
Double infection or piperacillin/ cure, available for by
blind classified as tazobactam bacteria assessment at modified
moderateto- (P/T) (3.375 g eradication the end of ITT. 12%
Study severe and every 6 h; , safety intravenous were leg
quality requiring n=291) given data therapy. Both ulcers.
7/9 intravenous for a minimum baseline Data on
antibiotics, of 5 days, after characteristics site
295 vs 291 which oral and favourable missing in
subjects in amoxicillin/ clinical n=174.
each clavulanic acid response rates Proportion
treatment (875/125 mg were similar for of cure for
arm. 12% of every 12 h) the 226 who organisms
subjects had could be given received resistant to
leg ulcers. for up to 23 ertapenem and ertapenem
Prevalence of days. Mean the 219 who (pseudomo
osteomyelitis duration of received nas and
8% vs 6% in treatment 11.1 piperacillin/ enterococc
the days for tazobactam i) was
ertapenem ertapenem and (94%vs 92%, similar to
and 11.3 days for respectively. success
piperacillin/ P/T. Mean Rates of rates of
tazobactam duration of oral favourable P/T.
group, follow up microbiological Number of
respectively. therapy 9.7 responses patients
Osteomyeliti days (eradication that
 s was rates and received
surgically clinical additional
removed <48 outcomes, by antibiotics
hours pathogen) and is not
adverse events mentioned
did not differ
between groups. Only 11
No differences days
in number of treatment
adverse events duration

Sponsored
by Merck
Lipsky RCT, 617 Subjects, Moxifloxacin Infection Among 617 1++ Patients
2007 Subanal hospitalized (400 mg/day) outcomes: patients with
[38] ysis of for DFI, 78 or clinical enrolled in the osteomyeli
multice patients with piperacillintazo response original study, tis were
ntre DFIs bactam of the 78 with DFIs excluded if
double available for (3.0/0.375 g infection at were evaluable the bone
blind, treatment every 6 h) for test-ofcure for treatment could not
double efficacy. at least 3 days, (TOC), 10- efficacy. be fully or
dummy Prevalence of followed by 42 days Clinical cure partially
study. osteitis 11% moxifloxacin post- rates at TOC resected
Study vs 20% in (400 mg/day therapy, were similar for
quality moxifloxacin orally) or pathogen moxifloxacin Short
8/9 vs amoxicillinclav eradication and duration of
piperacillin/ ulanate (800 , safety piperacillintazo total
tazobactam mg every 12 h data bactam/ treatment
group, orally). amoxicillinclav
respectively. Duration of ulanate (68% Sponsored
Bone treatment: versus 61%) for by Bayer
infection was moxifloxacin iv patients with
surgically 6.7 days, oral infection
"fully or 7.4 days, (p=0.54).
partially amoxicillinclav Overall
resected" ulanate 6.3 pathogen
days iv, 7.9 eradication rates
days oral in the
microbiological
lyvalid
population were
69% versus
66% for
moxifloxacin
and comparator,
respectively
 (p=1.0). No
differences in
safety outcomes
Sennev Cohort 50 patients Bone culture Infection Positive 2+ 9 patients
ille Multice with diabeticbased antibiotic outcomes: association: lost to
2008 ntre foot therapy. Failure 18Bone culture follow up.
[9] InvestigosteomyelitisDuration of (36%), 32 based antibiotic There was
ator treated in treatment 11.0 remission therapy 4 variability
blinded.different ± 4.1 weeks for (64%). 20 (22.2%) in in practice
centres, of success group predictive failure group, and
Study whom 16 and 12.4 ± 4.2 criteria 18 (56.3%) in antibiotic
quality (32%) had week for failure were remission group therapy
4/7 already been group (p=0.19). evaluated (p=0.02). among
treated for In the two Multivariate centres
osteomyelitisgroups analysis OR
of the foot combined : 4.78, CI 1.02- No sponsor
11.5 ± 4.2 22.7, p=0.04) identified
weeks
Saltogl RCT In-patients Group 1 IV Clinical Group 1: 14 1- Total
u 2010 Single with diabetes piperacillin/ success (46.7%) Group number
[5] Centre and severe tazobactam rate 2 9 (28.1%) recruited
Open DFI, and who 4.5g 8 hourly, (success= p=0.13 was 64 and
label were known group 2: IV total yet
Study to have imipenem/ resolution analysis
quality organisms cilastatin 0.5g 6 of all conducted
5/9 sensitive to hourly, with symptoms on only 62:
study drugs. glycopeptide and signs , technically
Total number added if MRSA without per
randomised positive (n=3), amputation 0/14 versus 2/9 protocol
N=64, but with excision ) analysis.
two of infected Despite
withdrawn bone and with Relapse inclusion
early and not negative within two criteria,
included in pressure months of 21days versus microbiolo
analysis. therapy if hospital 24 days gical data
Group 1 necessary. discharge available
n=30 Intended in only
(Osteomyeliti duration of Treatment Complete in "approxim
s 73%), treatment: 14 duration 96% in both ately
group 2 n=32 days for soft groups 80%". 57%
(Osteomyeliti tissue infection; Microbiolo isolated
s 81%) 28 days for soft gical 18 total organisms
p=0.05 tissue plus response amputations were Gram
bone, but only versus 22 total negative,
5 days if all Total p=0.739 reflecting
infected bone amputation disease
 removed s 22.5% of the duration
surgically whole group and
had a BKA previous
Major treatment.
amputation No difference Mean
s between groups duration of
(p=0.55) infection
Adverse was 30
events days and
40.5 days
in the two
groups -
and yet all
had had no
antibiotics
for 48h
prior to
inclusion -
which is
surprising
in people
with severe
infection

Not
sponsored

Expert Opinion on the Management of Infections in the Diabetic Foot

Contents

Chapters

Introduction Pathophysiology Classification Diagnosis

Soft tissue infection Osteomyelitis
Clinical evaluation Probe-to-bone test Blood tests Imaging studies
Plain radiography Magnetic resonance imaging Nuclear medicine
Radiological studies - other techniques
Bone biopsy
Assessing severity Microbiological considerations
When to send specimens for culture Obtaining specimens for wound cultures
Interpreting wound culture results Bone infection
Treatment
Antimicrobial therapy
Indications for therapy Route of therapy Choice of antibiotics Duration of
therapy
 Wound care Treating osteomyelitis Adjunctive therapies Outcome of treatment
Issues of particular importance in developing countries References

I. Introduction

This report from the expert panel on infectious diseases of the International Working Group on
the Diabetic Foot (IWGFD) is an update of the one published in 2004 [1], incorporating some
information from a related IWGDF 2008 publication on osteomyelitis [2] and from the
concurrently published "Systematic Review of the Effectiveness of Interventions in the
Management of Infection in the Diabetic Foot"[3]. Our intention is to present a brief overview to
assist clinicians worldwide in diagnosing and treating foot infections in persons with diabetes.
Separately, we have proposed "Specific Guidelines on the Management of Diabetic Foot
infections," also published concurrently in this journal.

The development of a foot infection is associated with substantial morbidity, including

discomfort, the need for visits to health care providers, antibiotic therapy, wound care and often
surgical procedures. Furthermore, foot infection is now the most frequent diabetic complication
requiring hospitalization and the most common precipitating event leading to lower extremity
amputation [4-6]. Managing infection requires careful attention to properly diagnosing the
condition, obtaining specimens for culture, selecting empirical and definitive antimicrobial
therapy, determining when surgical interventions are needed and caring for the wound. A
systematic and, to the extent possible, evidence-based approach to diabetic foot infections (DFIs)
should result in better outcomes.

II. Pathophysiology

In diabetic persons, foot infection is a common problem. Infection is best defined as invasion
and multiplication of microorganisms in host tissues that induces a host inflammatory response,
usually followed by tissue destruction. DFI is defined clinically as a soft tissue or bone infection
anywhere below the malleoli. These infections usually occur in a site of skin trauma or
ulceration [7]. Peripheral neuropathy is the main factor leading to skin breaks and ulcerations,
which then become colonized with skin flora, and ultimately infected. Foot ischemia, related to
peripheral arterial disease, is also common in patients with a DFI; while rarely the primary cause
of foot wounds, the presence of limb ischemia increases the risk of a wound becoming infected
[8], and adversely affects the outcome of infection [9]. Factors that predispose to foot infection
include having a wound that is deep, long-standing or recurrent, as well as ill-defined diabetes-
related immunological perturbations and chronic renal failure [8,10,11]. While most DFI are
relatively superficial at presentation, microorganisms can spread contiguously to subcutaneous
tissues, including fascia, tendons, muscle, joints, and bone. The anatomy of the foot, which is
divided into several rigid but intercommunicating compartments, fosters proximal spread of
infection. When infection-induced pressure in a compartment exceeds capillary pressure
ischemic necrosis may ensue [12,13]. Systemic symptoms (e.g., feverishness, chills), marked
leukocytosis or major metabolic disturbances are uncommon in patients with a DFI, but their
presence denotes a more severe, potentially limb (or even life) threatening infection [14,15]. If
not diagnosed and properly treated, DFI they tend to progress, sometimes rapidly.
III. Classification

The clinician must first diagnose the presence of a DFI, then should classify the infection's
severity. Over the past 3 decades investigators have proposed many classification schemes for
diabetic foot wounds. Most of these take into account the size and depth of the ulcer, and the
presence or absence of gangrene, neuropathy, or arterial insufficiency. While several include the
presence or absence of "infection" (rarely defined), only two (nearly identical schemes proposed
by the Infectious Diseases Society of America and the IWGDF, see Table 1) describe how to
define both the presence and severity of infection [16].

Table 1

<PThe classification systems for defining the presence and severity of an infection of the foot in
a person with diabetes developed by the Infectious Diseases Soceity of America (IDSA) and the
International Working Group on the Diabetic Foot (IWGDF)
IWGDF grade
Clinical classification of infection (IDSA), with definitions [4,81] (IDSA
classification) [16]
Uninfected: No systemic or local symptoms or signs of infection 1 (Uninfected)
Infected 2 (Mild infection)

 At least 2 of the following items are present:

o Local swelling or induration

o Erythema > 0.5 cm* around the ulcer

o Local tenderness or pain

o Local warmth

o Purulent discharge

 Other causes of an inflammatory response of the skin should be

excluded (e.g. trauma, gout, acute Charcot neuro-
osteoarthropathy, fracture, thrombosis, venous stasis)

 Infection involving the skin /or subcutaneous tissue only

(without involvement of deeper tissues and without systemic
signs as described below). Any erythema present extends < 2
cm* around the wound

 No systemic signs or symptoms of infection (see below)

 Infection involving structures deeper than skin and 3 (Moderate

 subcutaneous tissues (e.g., bone, joint, tendon) or erythema infection)
extending >2 cm* from the wound margin.

 No systemic signs or symptoms of infection (see below)

 Any foot infection with the following signs of a systemic 4 (Severe infection)
inflammatory response syndrome (SIRS). This response is
manifested by two or more of the following conditions:

o Temperature > 38° or < 36° Celsius

o Heart rate > 90 beats/minute

o Respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg

o White blood cell count > 12,000 or < 4,000 cu/ mm or

10% immature (band) forms

* In any direction

The presence of clinically significant foot ischemia makes both diagnosis and treatment
considerably more difficult.

IV. Diagnosis

A. Soft tissue infection

Because all skin wounds harbor microorganisms, their mere presence, even if they are virulent
species, cannot be taken as evidence of infection. Some maintain that the presence of high
numbers of bacteria (usually defined as ≥105 colony forming units) should be the basis for
diagnosing infection [17], but no convincing data sup- port this concept in the diabetic foot and
quantitative microbiology is rarely available outside of research laboratories. Thus, DFI must be
diagnosed clinically (see Table1), with wound cultures reserved for determining the causative
organism(s) and their antibiotic sensitivities. Clinical diagnosis rests on the presence of at least
two local findings of inflammation, i.e., redness (erythema or rubor), warmth (calor), pain or
tenderness (dolor), induration (swelling or tumor) or purulent secretions [16]. Other (sometimes
called secondary) features suggestive of infection include the presence of necrosis, friable or
discolored granulation tissue, non-purulent secretions, fetid odor, or failure of a properly treated
wound to heal [18]. These may be helpful when local and systemic inflammatory signs are
diminished because of peripheral neuropathy or ischemia [19-21]. Because infection can worsen
quickly, it should be pursued methodically [19] and aggressively [22]. All wounds must be
carefully inspected, palpated, and probed, both at initial presentation and on follow-up. Various
imaging and laboratory studies may be useful in some cases.

B. Osteomyelitis
Accurately diagnosing bone infection can be difficult, but is essential to ensure appropriate
treatment. A definite diagnosis of osteomyelitis requires both the presence of histological
findings consistent with bone infection (inflammatory cells, necrosis) and isolation of bacteria
from an aseptically obtained bone sample [2]. Because these procedures are not routinely
available in many settings, clinicians must use surrogate diagnostic markers, including clinical,
laboratory and imaging findings.

The clinical presentation of osteomyelitis in the diabetic foot can vary with the site involved, the
extent of infected and dead bone, the presence of associated abscess and soft tissue involvement,
the causative organism(s) and the adequacy of limb perfusion. The main problems in diagnosing
osteomyelitis are the delay in detecting bony changes early in infection on plain radiographs and
the difficulty in distinguishing bony changes caused by infection from those related to neuro-
osteo (Charcot) arthropathy on most imaging studies. As discussed below, analyses from recent
expert publications [2,23] and systematic reviews [2,24,25] provide guidance on the best
diagnostic studies.

1. Clinical evaluation:

Clinicians should suspect osteomyelitis when an ulcer overlying a bony prominence fails to heal
despite adequate off-loading, or when a toe is erythematous and indurated. The likelihood ratio
(LR) of a clinician's suspicion of osteomyelitis is surprisingly good: positive LR 5.5 and
negative LR 0.54 [24,25]. The presence of exposed bone has a positive LR for osteomyelitis of
9.2; large ulcers (area > 2 cm2) are much more likely to have underlying bone infection than
smaller ones [24-27]. Certainly, osteomyelitis can also occur in the absence of overlying local
signs of inflammation [26].

2. Probe-to-Bone Test:

This is another useful clinical diagnostic tool. Striking bone with a sterile metal probe gently
inserted through a wound increases the likelihood that the patient has osteomyelitis if the
prevalence of bone infection is high (i.e., >60%) in the population under scrutiny [28,29].
Conversely, a negative probe to bone test in a patient at low risk (i.e., ≤20%) essentially rules out
osteomyelitis [30-32].

3. Blood tests:

An erythrocyte sedimentation rate (ESR) is diagnostically useful; when elevated (usually defined
as > 70 mm/hour) it increases the likelihood of osteomyelitis un- derlying a diabetic foot wound
(positive LR 11) while lower levels reduce the likelihood (negative LR of 0.34) [24,26,33,34].
Based on fewer data, an elevated C-reactive protein, procalcitonin, or blood leukocyte count (or
a positive swab culture of an ulcer) may also be predictive of osteomyelitis [34,35].

4. Imaging studies:

A. Plain radiography
Characteristic features of osteomyelitis on plain X-rays of the foot (usually 2 or 3 views) are
summarized in Table 2 [26,36-38]. Among the many studies that have assessed the accuracy of
plain radiography in diagnosing osteomyelitis [26,36,38-53]7, nine were prospective in design
[26,36,38- 41,44,45,52]. Overall, the sensitivity varied from 28% to 75%. The timing of the
imaging greatly influences its usefulness, as longer-standing cases are more likely to show bony
abnormalities on plain radiographs than those present for less than a couple of weeks. In the
systematic review by Dinh et al [25], the pooled sensitivity of the four eligible studies was 0.54
and the pooled specificity was 0.68, with a diagnostic odds ratio of 2.84 and a Q statistic of 0.60
[26,36,38,52]. In the systematic review by Butalia [24], analyzing 7 studies of plain radiographs
the summary positive likelihood ratio was 2.3 (95% confidence intervals 1.6-3.3) while the
negative likelihood ratio was 0.63 (95% CI 0.5-0.8) [26,36,38,43,47,48,50]. These results
suggest that radiographic findings are only marginally predictive of osteomyelitis if positive and
even less predictive of the absence of osteomyelitis if negative. Of note is that neither review
identified a study that obtained sequential plain radiographs of the foot over time. Changes in
radiological appearance over an interval of at least 2 weeks are far more likely to predict the
presence of osteomyelitis than a single study, although correctly targeted antibiotic therapy may
prevent these changes.

B. Magnetic resonance imaging

MRI is a valuable tool for diagnosing osteomyelitis, as well as helping define the presence and
anatomy of deep soft tissue infections [16]. The key features suggestive of osteomyelitis on MRI
are listed in Table 2. In their meta-analysis, Dinh and coworkers [25] identified four trials using
MRI, all of which were prospective [27,36,38,54] and two of which used a consecutive
recruitment method [36,38] Only one study, however, was conducted within the past 10 years
[27]. The prevalence of osteomyelitis in the four studies ranged from 44% to 86%. The pooled
sensitivity of MRI for diabetic foot osteomyelitis was 0.90 (CI 0.82-0.95) and the diagnostic
odds ratio was 24.4. In 16 trials identified in the meta-analysis by Kapoor et al. [55], 9 were
prospective studies and 11 included only subjects with diabetes, although enrollment criteria
were quite varied. The prevalence of standard defined osteomyelitis was 50% (range 32% to
89%), the pooled sensitivity was 77%- 100%, and the specificity was 40%-100%. In subjects
with diabetes the diagnostic odds ratio was 42 (CI 15-120), the summary positive likelihood ratio
was 3.8 (CI 0.2.5-5.8), and the summary negative likelihood ratio was 0.14 (CI 0.08-0.26)
[27,36,38,41,45,49,51,56-64]. More recently performed studies reported lower diagnostic odds
ratios (25, CI 6-117) compared to older ones, perhaps because their study designs were better.
The subgroups of patients with other diagnoses (e.g., Charcot arthropathy) were too small to
analyze any differences among the studies.

C. Nuclear medicine

Three recent meta-analyses reviewed nuclear medicine techniques for evaluating the diabetic
foot [25,55,65]. Capriotti and coworkers reviewed 57 papers, including 7 reviews on the clinical
value of several nuclear medicine methods [65]. Among the several types of nuclear imaging
scans, a bone scan, usually performed with 99mTc-methylene diphosphate and done in
timesequence phases, is considered suggestive of osteomyelitis when it discloses increased
blood-pool activity and radionuclide intensity localized to the bone[25]. Three-phase bone scans
are sensitive (90%), but not specific (46%) [65], with a calculated summary negative predictive
value of 71% and positive predictive value of 65%. Among six studies with 185 subjects that
qualified for the meta-analysis by Dinh and coworkers [25], the pooled sensitivity was 80% but
the specificity was only 28% [26,36,38,52,66,67]. The pooled diagnostic odds ratio was 2.1,
indicating poor discriminating ability, while the Q-statistic was 0.6, indicating moderate
accuracy for the diagnosis of osteomyelitis [25]. Based on seven studies, Kapoor et al. [55]
found the performance characteristics of to a triple-phase bone scan were markedly inferior to
MRI [38,41,45,49,58,63,64], with a diagnostic odds ratio 3.5 of (CI 1.0-13) compared to 150 (CI
55-411) [55]. Healthy bone may also have an increased uptake of the radiopharmaceutical,
especially in the forefoot [65] While a positive bone scan is certainly not specific for
osteomyelitis (or Charcot neuro-osteoarthropathy), a negative one largely rules it out.

Radiolabelled white blood cells (usually using either 99mTechnetium or 111Indium) are
generally not taken up by healthy bone, making positive leukocyte scans more specific than bone
scans for diagnosing osteomyelitis (and excluding Charcot osteoarthropathy) [65]. In a review of
these scans by Capriotti et al, the summary positive predictive values for osteomyelitis were 90%
and 72%, respectively, the negative predictive values were 81% and 83%, respectively[65].
99mTc labeling appears to provide superior physical characteristics, leading to better spatial
resolution than 111In [65]. In another recent review, Palestro and Love concluded that among
radionuclide procedures, labeled leukocyte imaging is the best choice for evaluating diabetic
pedal osteomyelitis, with a sensitivity of 72% to 100% and specificity of 67% to 98% [68]. Dinh
and coworkers [25] identified 6 studies using 111Indium radiolabel leukocytes, with a pooled
sensitivity of 74% and a specificity of 68% [26,36,38,52,66,67].The pooled diagnostic odds ratio
was 10, indicating moderately good discriminating characteristics, while the Q-statistic of 0.59
suggests a low to moderate accuracy for the diagnosis of osteomyelitis [25]. Kapoor et al. [55]
found that in three studies MRI outperformed leukocyte scanning (with 99mTc [64] or 111In
[45,49]) with diagnostic odds ratios of 120 (CI 62-234) and 3.4 (CI 0.2-62), respectively. The
combination of labeled leukocytes with a bone scan (dual tracer technique) does not substantially
improve diagnostic accuracy [46].

Other available nuclear medicine techniques include in vivo methods of labeling leukocytes,
radiolabeled polyclonal IgG, and radiolabeled antibiotics. Results of studies using these
techniques have varied and most of the methods are unavailable in many countries. 99mTc-
/111In labeled human immunoglobin G uptake is related to vascular permeability, not inflamed
tissue, and thus not as specific as radiolabeled leukocytes [50,69]. The pooled positive and
negative predictive values for this technique, calculated from 97 lesions were 72 and 88%,
respectively [65].

D. Other imaging techniques

Two published studies of computer tomography (CT) and CT combined with positron emission
tomography (PET) scans for the diagnosis of osteomyelitis [25] did not include histopathological
examination of bone [70,71]. A recent prospective study that enrolled 110 patients reported that
PET/CT scan had a sensitivity of 81%, specificity of 93%, positive predictive value of 78%,
negative predictive value 94%, and accuracy of 90%, somewhat better than a simultaneous MRI
[72]. While the data on this new procedure are limited, there seems to be place for CT
(especially if combined with PET) scans when MRI is unavailable or contraindicated.

5. Bone biopsy:

The weight of current evidence supports bone biopsy as the best available diagnostic technique
for both diagnosing bone infection and providing reliable data on the responsible organisms and
their antibiotic susceptibility profile [3]. Soft tissue or sinus tract cultures are not sufficiently
accurately in predicting bone pathogens [73,74]. Ideally, it would be best to process a bone
specimen for both culture and histopathology. While infected bone usually has inflammatory
cells (granulocytes early and mononuclear cells later), the histomorphology of uninfected bone is
normal in diabetic patients, including in those with neuropathy or vasculopathy [75].
Unfortunately, both histology and culture may lead to misleading results. Culture of a bone
specimen may be falsely negative because of sampling errors, prior antibiotic therapy or a failure
to isolate fastidious organisms. It may also be falsely positive because of contamination by
wound-colonizing flora not involved in bone infection. Similarly, bone histopathology may be
falsely negative due to sampling error or potentially falsely positive due to some non-infectious
inflammatory disorder. In a recent analysis of 44 patients, a comparison of microbiological and
histopathological testing demonstrated that they performed similarly in identifying the presence
of pedal osteomyelitis in the diabetic foot [76].

In one retrospective multicenter study, using bone culture-guided antibiotic treatment was
associated with a significantly better clinical outcome than using soft tissue culture results [77].
While success rates of 75% or higher have been reported with empiric treatment of DFO, it is
difficult to compare the results of available published studies because of their differences in the
populations, in the criteria for both diagnosis and remission of infection they used, and in their
durations of followup [78]. Bone culture is not always needed when DFO is suspected, but
clinicians should consider this procedure when the diagnosis of osteomyelitis remains uncertain
despite clinical and imaging evaluations, in cases of non-informative data from soft tissue
cultures, when the infection has failed to respond to an initial empiric antibiotic therapy, or when
considering an antibiotic regimen with a high potential for selecting resistant organisms (e.g.,
rifampin, fluoroquinolones, fusidic acid or clindamycin) [2].

To reduce the likelihood of false-negative culture results, it is presumably best to perform bone
biopsy after an antibiotic-free period in clinically stable patients. As certain antibiotic agents
have a prolonged release from bone tissue, holding antibiotics for two-weeks is ideal, but even a
couple of days may be helpful [79]. Because DFO (in the absence of substantial soft tissue
infection) is typically a slowly progressive disease, such a delay is usually safe. Percutaneous
biopsy of bone through clinically uninvolved skin reduces the likelihood of false positive
culture, although one study found good results (based on favourable clinical outcome) using a
simpler per-wound bone biopsy after careful debridement [79]. Similarly, while there are
potential risks of bone biopsy, e.g., tracking contaminating organisms into the bone or causing a
bone fracture, several large series have shown that complications from percutaneous (and
surgical) procedures are very rare [26,80]. Any properly trained physician (e.g., an orthopedic
surgeon, podiatrist or interventional radiologist) can perform the biopsy. Percutaneous biopsy
should preferably be done under fluoroscopic or CT guidance, traversing intact and uninfected
skin. Patients with sensory neuropathy often do not need anaesthesia. If possible, the operator
should attempt to obtain at least 2 specimens-- one for culture and the other for histological
analysis. With small toe bones, it may only be possible to aspirate a few bony spicules.

Table 2

Common imaging features of diabetic foot osteomyelitis

Plain Radiographs

 Periosteal reaction or elevation

 Loss of cortex with bony erosion

 Focal loss of trabecular pattern or marrow radiolucency,

 New bone formation

 Bone sclerosis with or without erosion

 Sequestration: devitalized bone with radiodense appearance that has become separated
from normal bone

 Involucrum: a layer of new bone growth outside existing bone resulting from the
stripping off of the periosteum and new bone growing from the periosteum

 Cloacae: opening in involucrum or cortex through which sequestra or granulation

tissue may be discharged

Magnetic resonance imaging (MRI)

 Low focal signal intensity on T-1 weighted images

 High focal signal on T2-weighted images

 High bone marrow signal in Short tau inversion recovery (STIR) sequences

 Less specific or secondary changes:

o Cortical disruption

o Adjacent cutaneous ulcer

o Soft tissue mass

o Sinus tract

o Adjacent soft tissue inflammation or edema

 For both modalities, bony changes are often accompanied by contiguous soft tissue swelling

V. Assessing severity

Accurately assessing a diabetic foot wound usually requires debridement of callus and necrotic
tissue. Keys to classifying a foot infection are defining the extent of the tissues involved,
determining the adequacy of arterial perfusion, and assessing for systemic toxicity [16,82,83].
While mild infections are relatively easily treated, moderate infections may be limb threatening
and severe infections may be life threatening (Table 3A). Infection severity largely guides the
choice of antibiotic and its route of administration, and helps to determine the need for
hospitalization (Table 3B), the potential necessity and timing of foot surgery, and the likelihood
of amputation [15,83-85].

Deep space infections may have deceptively few superficial signs, but clinicians should consider
these in a patient with systemic toxicity (e.g. fever, chills, leukocytosis), inflammation distant
from the skin wound, persistent infection or elevated inflammatory markers despite appropriate
therapy, or pain in a previously insensate foot [13,22,86].

Table 3

Characteristic suggesting a more serious diabetic foot infection and potential indications for
hospitalization

(A) Findings suggesting a more serious diabetic foot infection

Wound specific

Wound Penetrates into subcutaneous tissues, e.g. fascia, tendon, muscle, joint, bone

Cellulitis Extensive (>2 cm), distant from ulceration, or rapidly progressive

Local Severe inflammation, crepitus, bullae, marked induration, discoloration,

signs necrosis/gangrene, ecchymoses, or petechiae

General

Presentation Acute or rapidly progressive

Systemic signs Fever, chills, hypotension, confusion, volume depletion

Laboratory tests Leukocytosis, severe or worsening hyperglycemia, acidosis, azotemia,

electrolyte abnormalities

Complicating Presence of a foreign body (accidental or surgically implanted),

features puncture wound, abscess, arterial or venous insufficiency, lymphedema
 Current Progression while on apparently appropriate antibiotic therapy
treatment

(B) Factors suggesting hospitalization may be necessary

 Severe infection (see Table 3A)

 Metabolic instability

 Intravenous therapy needed (and not available/appropriate as outpatient)

 Diagnostic tests needed (and not available as outpatient)

 Critical foot ischemia present

 Surgical procedures (more than minor) required

 Failure of outpatient management

 Inability or unwillingness to comply with outpatient-based treatment

 Need for more complex dressing changes than patient/carers can provide

VI. Microbiological considerations

A. When to send specimens for culture:

Knowing the likely etiologic agent(s) helps the clinician select appropriate antimicrobial therapy.
Acute infections in previously untreated patients are usually caused by aerobic gram-positive
cocci (often as a monomicrobial infection)[87], but deep or chronic wounds may harbor
polymicrobial flora, including gram-negative and anaerobic bacteria [82]. Skin disorders,
environmental exposures, or recent antibiotic therapy can predispose to unusual or antibiotic-
resistant pathogens. Wound cultures are helpful for most infections, but are difficult to obtain in
cases with just cellulitis (where skin aspiration has limited sensitivity) and generally unnecessary
for clinically uninfected lesions. Blood cultures are only needed for severe infections, and bone
cultures help diagnose and direct therapy of osteomyelitis (see above). In the past decade
molecular microbiological techniques have demonstrated a far more complex mix of organisms
in diabetic foot infections [88,89], but the clinical significance of these isolates is not yet clear.

B. Obtaining specimens for wound cultures:

A wound culture is useful only if the specimen is appropriately collected and processed.
Antibiotic susceptibility results generally help in focusing (and often constraining) antibiotic
regimens. Deep tissue specimens, obtained aseptically at surgery, usually contain only the true
pathogens, while cultures of superficial lesions often yield contaminants [87,90]. Curettage
(tissue scraping) with a scalpel from the base of a debrided ulcer or needle aspirates of purulent
secretions generally provide more accurate results than wound swabbing [87,91]. Where swabs
are the only available method, they should be taken only after debriding and cleaning the wound.
Specimens should be sent to the laboratory promptly, in suitable sterile transport containers.

C. Interpreting wound culture results:

Sole or predominant bacteria identified on culture (and, where available, Gram stained smear)
and isolated from reliable specimens are likely true pathogens. If multiple organisms are
isolated, especially from superficial ulcers, it can be difficult to determine which are pathogens.
Targeting less virulent isolates (e.g., coagulasenegative staphylococci, corynebacteria) may be
unnecessary. These species can, however, represent true pathogens, especially if they grow
repeatedly or from reliable specimens. Staphylococcus aureus is the most frequently isolated and
virulent pathogen in diabetic foot infections; even when it is not the sole isolate, it is usually a
component of a mixed infection. Streptococci (various groups of β-hemolytic, and others) are
also important pathogens. Enterococci are relatively frequent isolates, but usually of secondary
clinical importance.

Infections requiring hospitalization are often polymicrobial, including aerobes and anaerobes
[16,92]. gram-negative bacilli (mainly Enterobacteriaceae, sometimes Pseudomonas aeruginosa
or other non-fermentative species) are usually isolated in conjunction with gram-positive cocci
from patients with chronic or previously treated infections; they are often, but not always, true
pathogens. Many recent studies have reported that gram-negative organisms are the most
frequent isolates in DFIs occurring in patients in warm climates, especially in developing
countries [93-96]. It is unclear if this is related to environmental factors, footwear practices,
personal hygiene habits, antimicrobial pretreatment, or other factors. Obligate anaerobic species
are most frequent in wounds with ischemic necrosis or those that involve deep tissues; they are
rarely the sole pathogen and most often are part of a mixed infection with aerobes [97].

Multi-drug resistant organisms (MDROs), especially methicillin-resistant S. aureus (MRSA), are

more frequently isolated from patients who have recently received antibiotic therapy, have been
previously hospitalized, or reside in a chronic care facility[98]. After the rates of MRSA
dramatically increased in many countries starting in the late 1990s, they have begun to decline in
most recent reports, concomitant with improved hospital (and outpatient) infection control
measures [99-101]. The previously useful distinction of community-acquired (more-resistant)
versus healthcare-associated strains has become blurred in recent years. In some, but not all,
reports on DFIs, those caused by MRSA have been associated with worse outcomes, e.g., higher
clinical failure and amputation rates [102-104]. In the past decade other multidrug-resistant
organisms, especially gram-negatives with extended-spectrum beta-lactamases (ESBL) and
occasionally vancomycinresistant enterococci, have been more commonly isolated from DFIs
[96,105,106]. ESBL-producing organisms usually require treatment with very broad-spectrum
antibiotics, e.g., carbapenems. Fungi may be isolated from both infected and uninfec- ted foot
wounds, but rarely require systemic antifungal therapy [107]. They are, however, a frequent
cause of onychomycosis.

D. Bone infection
DFO can present the clinician with formidable diagnostic and therapeutic challenges [78]. It
complicates about 50% to 60% of serious, and 10% to 20% of apparently less severe, foot
infections in patients presenting to diabetic foot clinics. Bone infection typically occurs by
contiguous spread from overlying soft tissue, which may penetrate through the cortex into the
marrow. Bone destruction caused by neuroarthropathy (Charcot foot) may be difficult to
distinguish from that caused by infection, although the former is less common, tends to occur in
patients with profound peripheral neuropathy but adequate arterial perfusion, more frequently
involves the midfoot and often occurs in the absence of a skin break [108,109]. Many cases of
osteomyelitis are monomicrobial, but most are polymicrobial; S. aureus is the most commonly
isolated agent (~50% of cases), while S. epidermidis (~25%), streptococci (~30%), and
Enterobacteriaceae (~40%) are also frequent isolates [108].

VII. Treatment

Patients with a severe infection (Table 3A) should usually be hospitalized, as they often require
surgical interventions, fluid resuscitation, and control of metabolic derangements. Also consider
admitting patients with moderate infections if they are unable or unwilling to be adequately
involved in wound care, can or will not be able to off-load the affected area, are unlikely to
comply with antibiotic therapy, require parenteral antibiotic therapy (that is not available as an
outpatient), or need close monitoring of treatment response (see Table 3B). Most other patients
with a moderate infection, and almost all with a mild infection, can cautiously be treated as
outpatients, with instructions to return if the infection worsens or in-office reevaluation every
few days initially [91].

Surgery is the cornerstone of treating many deep soft tissue infections [86], and early
intervention might be associated with better outcomes [22,110-112]. Intervening emergently,
however, is only needed in specific circumstances, such as: severe infection in an ischemic limb;
an abscess accompanied by compartment syndrome or necrosis; systemic sepsis syndrome; or,
local infection with bullae, ecchymoses, extreme pain, or unexpected anesthesia. The treating
clinician should consider the need for surgery in every infection, which may range from minor
debridement or drainage to extensive resections or major amputation. When the wound has a dry
eschar, especially in an ischemic foot, it is often best to avoid debriding the necrotic tissue.
Major amputation should, and usually can, be avoided except when the limb is non-viable, is
affected by life-threatening infection (e.g., gas gangrene or necrotizing fasciitis), or is
functionally useless. Revascularization may be needed for an infected ischemic limb. Surgeons
operating on a patient with a DFI should have adequate knowledge of the complex anatomy of
the foot [22,113]. Figure 1 shows an algorithmic overview of the approach to treating a diabetic
patient with a foot lesion.

Figure 1

Open in new window Approach to a diabetic patient with a potentially infected foot wound
MDRO= multi-drug resistant organism

A. Antimicrobial therapy