infection in the diabetic foot

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, TanzaniaDr. F. Javier Aragón Sánchez, SpainDr BM Ertugrul TurkeyProf Hanan Gawish, EgyptDr Irina Gurieva, RussiaDr Shigeo Kono, JapanDr A Nather, SingaporeDr. J.-L. Richard, FranceDr Nina Rojas, ChileDr Lynn Tudhope, South AfricaDr Steven Twigg , AustraliaDr Vijay Viswanathan, India

VII. References

1. Berendt AR, Peters EJ, Bakker K, Embil JM, Eneroth M, Hinchliffe RJ, Jeffcoate WJ, Lipsky BA, Senneville E, Teh J, Valk GD. Diabetic foot osteomyelitis: a progress report on diagnosis and a systematic review of treatment. Diabetes Metab Res Rev2008;

24(Suppl 1): S145-S161.

2. National Institute for Health and Clinical Excellence. Diabetic foot - inpatient management of people with diabetic foot ulcers and infection. http://guidance.nice.org.uk/CG119. 2011; 2011(6/4/2011).

3. Dutch Cochrane Centre. http://www.cochrane.nl/. 2011; 2011(8/4/2011).

4. Graham DR, Lucasti C, Malafaia O, Nichols RL, Holtom P, Perez NQ, McAdams A, Woods GL, Ceesay TP, Gesser R. Ertapenem once daily versus piperacillin-tazobactam 4 times per day for treatment of complicated skin and skin-structure infections in adults: results of a prospective, randomized, double-blind multicenter study. Clin Infect Dis 2002; 34(11): 1460-1468.

5. Saltoglu N, Dalkiran A, Tetiker T, Bayram H, Tasova Y, Dalay C, Sert M. Piperacillin/tazobactam versus imipenem/cilastatin for severe diabetic foot infections: a prospective, randomized clinical trial in a university hospital. Clin Microbiol Infect 2010; 16(8): 1252-1257.

6. Viswanathan V, Mahesh U, Jayaraman M, Shina K, Ramachandram A. Beneficial role of granulocyte colony stimulating factor in foot infection in diabetic patients. J Assoc Physicians India 2003; 51: 90-91.

7. Graham DR, Talan DA, Nichols RL, Lucasti C, Corrado M, Morgan N, Fowler CL. Once-daily, high-dose levofloxacin versus ticarcillin-clavulanate alone or followed by amoxicillin-clavulanate for complicated skin and skin-structure infections: a randomized, open-label trial. Clin Infect Dis 2002; 35(4): 381-389.

8. Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin Infect Dis 2008; 47(12): 1537-1545.

9. Senneville E, Lombart A, Beltrand E, Valette M, Legout L, Cazaubiel M, Yazdanpanah Y, Fontaine P. Outcome of diabetic foot osteomyelitis treated nonsurgically: a retrospective cohort study. Diabetes Care 2008; 31(4): 637-642.

10. Tan JS, Friedman NM, Hazelton-Miller C, Flanagan JP, File TM,Jr. Can aggressive treatment of diabetic foot infections reduce the need for above-ankle amputation? Clin Infect Dis 1996; 23(2): 286-291.

11. Faglia E, Clerici G, Caminiti M, Quarantiello A, Gino M, Morabito A. The role of early surgical debridement and revascularization in patients with diabetes and deep foot space abscess: retrospective review of 106 patients with diabetes. J Foot Ankle Surg 2006; 45(4): 220-226.

12. Tice AD, Turpin RS, Hoey CT, Lipsky BA, Wu J, Abramson MA. Comparative costs of ertapenem and piperacillin-tazobactam in the treatment of diabetic foot infections. Am J

Health Syst Pharm 2007; 64(10): 1080-1086.

13. Lipsky BA, Armstrong DG, Citron DM, Tice AD, Morgenstern DE, Abramson MA. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial. Lancet 2005; 366(9498): 1695-1703.

14. Clay PG, Graham MR, Lindsey CC, Lamp KC, Freeman C, Glaros A. Clinical efficacy, tolerability, and cost savings associated with the use of open-label metronidazole plus ceftriaxone once daily compared with ticarcillin/clavulanate every 6 hours as empiric treatment for diabetic lower-extremity infections in older males. Am J Geriatr Pharmacother 2004; 2(3): 181-189.

15. Martínez-De Jesús FR, Ramos-De la Medina A., Remes-Troche JM, Armstrong DG, Wu SC, Lázaro-Martínez JL, Beneit-Montesinos JV. Efficacy and safety of neutral pH superoxidised solution in severe diabetic foot infections. Int Wound J 2007; 4(4): 353-362.

16. Piaggesi A, Goretti C, Mazzurco S, Tascini C, Leonildi A, Rizzo L, Tedeschi A, Gemignani G, Menichetti F, Del PS. A randomized controlled trial to examine the efficacy and safety of a new super-oxidized solution for the management of wide postsurgical lesions of the diabetic foot. Int J Low Extrem Wounds 2010; 9(1): 10-15.

17. Chen W, Xu K, Zhang H, Shang Y, Hao P. [A comparative study on effect of bacterial load in diabetic foot ulcers dealing with iodophor and rivanol respectively]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2008; 22(5): 567-570.

18. Yönem A, Cakir B, Guler S, Azal OO, Corakci A. Effects of granulocyte-colony stimulating factor in the treatment of diabetic foot infection. Diabetes Obes Metab 2001; 3(5): 332-337.

19. de Lalla F, Pellizzer G, Strazzabosco M, Martini Z, Du JG, Lora L, Fabris P, Benedetti P, Erle G. Randomized prospective controlled trial of recombinant granulocyte colony-stimulating factor as adjunctive therapy for limbthreatening diabetic foot infection. Antimicrob Agents Chemother 2001; 45(4): 1094-1098.

20. Kästenbauer T, Hornlein B, Sokol G, Irsigler K. Evaluation of granulocytecolony stimulating factor (Filgrastim) in infected diabetic foot ulcers. Diabetologia 2003; 46(1): 27-30.

21. Gough A, Clapperton M, Rolando N, Foster AV, Philpott-Howard J, Edmonds ME. Randomised placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection. Lancet 1997; 350(9081): 855-859.

22. Cruciani M, Lipsky BA, Mengoli C, de Lalla F. Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections. Cochrane Database Syst Rev 2009; Jul 8(3): CD006810.

23. Duarte HA, Fernández Montequin JI, Fors López MM, Carretero JH, Vilas MM, Mesa MG. Clinical evaluation of De Marco formula as an adjunctive therapy for infected ischemic diabetic foot: a prospective randomized controlled trial. Can J Clin Pharmacol 2009; 16(2): e381-e391.

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 textInclude 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

Reference

Study design and score

Population

Intervention and

control managemen

t

Outcomes

Differences and

statistical results

Level of evidence (sign)

Comments

Tan 1996 [10]

Cohort Single centre.

Study quality 3/8

Cohort study of 112 patients with 164 diabetic foot infections, hospitalized for treatment of the foot infection. Of

87 infections treated without surgery in the first 3 days vs 77 treated with antibiotics + surgery (of which 46

Infection outcome: Above ankle amputation

Amputation rate 27.6% vs 13.0% antibiotic group and antibiotic and surgical interventio

2- No information regarding (appropriateness of) antibiotic treatment. High risk of bias as there is no assessment of severity and there is a high

these, 76 had a deep infection, 65 had osteomyelitis. No early surgery and antibiotics in 87 subjects vs early surgery and antibiotics in 77 subjects

antibiotics and debridement and 31 antibiotic and early local amputation). Duration of treatment with antibiotics unknown

n groups, respectively (p<0.01)

chance of indication bias

Provides no evidence to confirm the role of surgery, as opposed to timing of intervention

No sponsor identified.

Faglia 2006 [11]

Cohort Single centre

Study quality 5/8

Diabetes and deep foot space abscess N=106, group 1: 43 subjects, group 2: 63 subjects

Group 1: Immediate surgical debridement, group 2: Referred from another hospital after a mean delay of 6.2 ±7.5 days without debridement. Duration of treatment with antibiotics unknown

Drainage without amputation:

One or more ray amputations:

Transmetatarsal amputation:

Chopart:

Major amputation:

Group 1: 9 vs Group 2: 4





p<0.001

X2 24.4

2- Poor quality study despite the 5/8 score

Concluded that delay in drainage increases the incidence of amputation, but this is not justified by these data because of the possibility of bias

No sponsor identified

Open in new window

Health economics

Reference Study design and

score

Population Intervention and

control managemen

Outcomes Differences and

statistical results


Comments

t Tice 2007 [12]

RCT, Subset analysis based on multicentre, double blinded study.

Study quality 6/9

99 patients with DFI, including osteomyelitis provided all infected bone was surgically removed. 56 subjects in ertapenem group vs 43 in piperacillin/ tazobactam group

Substudy of SIDESTEP [13], cost-minimisation assessment of ertapenem vs piperacillin/ tazobactam. No duration of treatment given

Infection outcomes:

Mean days of treatment:

Total i.v. drug doses:

Total antibiotic dosages:

Mean drug preparation and administration cost:

I7.6 vs 7.4 (p=0.8) days of treatment, 7.5 vs 25.5 (p<0.0001)

total i.v. doses 8.6 vs 26.8 (p<0.0001)

total i.v and oral doses, $356 vs $503 (p<0.001)

total cost of treatment for ertapenem and pip/tazo, respectively

1+ High drop-out rate. Length of stay was a proxy measure. The length of stay might have been prolonged due to the trial design

Sponsored by Merck

Open in new window

Topical treatment with antiseptic agents

Reference

Study design

and score

Population Intervention and control

management Outcomes

Differences and

statistical results

Level of evidence

(sign) Comments

Martinez-De Jesus 2007 [15]

RCT Single centre Patient blinded.

Type 2 diabetes and infected, deep diabetic

n=21 intervention group: neutral pH superoxidised aqueous

Odour, periwound cellulitis and granulation tissue

Odour reduction was achieved in all superoxide

1- Alternate patient group allocation, yet different numbers in each group.

Study quality 4/9

foot ulcers, 21 subjects in intervention group vs 16 in control group

solution.

n=16 control group: disinfectant such as soap or povidone iodine.

Duration of antibiotic treatment more than 10 days

patients (100% versus 25%; p< 0.01) and surrounding cellulitis diminished (p<0.001) in 17 patients (80.9% versus 43.7%)

Non-standardized wound classification criteria


Chen 2008 [17]

RCT Single centre Patient blinded.

Study quality 6/9

30 patients with diabetic foot ulcers, 10 patients in each subgroup

10 diabetic foot ulcers treated with iodophor, 10 with rivanol, 10 controls. One single application of topical treatment after ulcer debridement

Infection outcomes: Bacteria number in wound

Number of colonies after 24 hours / number of colonies at t=0 was 0.961, 0.918 and 0.986for the control group, iodophor group and rivanolol, respectively. Significantly less growth of bacteria after 24 hours in the iodophor group compared with the rivanol and control group

1+ Use of systemic antibiotics not mentioned. Study only looked at bacterial growth after 5 minutes and 24 hours


Piaggesi 2010 [16]

RCT Single centre Open label.

40 patients with diabetes with post-surgical

Dermacyn vs povidone iodine. All patients had systemic

Infection outcomes: use of antibiotics.

Duration of antibiotic use: 10.1 ± 6.1 weeks

1+ 2 patients lost to follow up. Details of the interventions

Study quality 6/9

wounds, who had surgery for a diabetic foot infection, 20 subjects in each treatment group

antibiotic therapy and surgical debridement if needed. Ischemia was an exclusion criterion. Duration of treatment with piperacillin/ tazobactam and metronidazol with or without teicoplanin 10. 1± 6.1 weeks for Dermacyn and 15.8 ± 7.8 for control group (p=0.016). Duration of antibiotic use was an outcome measure

Non-infection outcomes: Healing rate at 6 months and healing time

Dermacyn group vs 15.8 ± 7.8 weeks in povidone iodine group (p=0.016).

Healing rate at 6 months 90% in Dermacyn vs 55% in iodine group (X2 9.9, p= 0.002).

Healing time 10.5 ± 5.9 vs 16.5 ±7.1 respectively (p=0.007)

and outcomes were suboptimal. Possible adverse effect of iodine on wound healing not taken into account. Very long antibiotic treatment period

Sponsored by Oculus Innovative Sciences

Open in new window

Granulocyte-colony stimulating factor

Reference Study

design and score

Population

Intervention and

control managemen

t

Outcomes

Differences and

statistical results

Level of

evidence

(sign)

Comments

Gough 1997 [21]

RCT Single centre Double blind

Study quality 9/9

40 patients with diabetes with moderate (International

Intervention: G-CSF 5µg/kg adjusted on basis of WCC, for 7 days versus

Infection outcome measures:

1 Time to resolution of infection:

Intervention: 7 (5-20) days versus

1++ Well designed RCT showing significant benefit in moderate

Consensus Guidelines Grade 3) infection of DFU, n=20 subjects in both treatment arms

saline control. Both groups received 4 antibiotics, mean duration of iv antibiotics 8.5 for GCSF and 14.5 for controls (p= 0.02)

15 patients treated with standard treatment (antibiotics and wound care), 15 patients treated with standard treatment + G-CSF 5 µg/kg, duration of antibiotic treatment 22.9 ± 2.0 days in GCSF 23.3 ± 1.9 days in control group, standard treatment with GCSF 3 days. Duration of antibiotic treatment 22.9 ± 2.0 days in GCSF 22.3

2 Total time of intravenous antibiotics:

3 Hospital length of stay:

4 Need for surgery:

5 Time taken to eliminate pathogens from woundNon-infection outcome:

6 Effect of GCSF on generation of neutrophil superoxide:

Control 12 (5-93)p=0.03

Intervention: 8.5 (5-30) versus Control 14.5 (8-63) daysp=0.02

Intervention: 10.0 (7-31) days versus 17.5 (9-100)p=0.02

Intervention: 0 versus 4/20 (20%)p=0.114

Intervention: 4 (2-10) days versus control:8 (2-75) daysp=0.02

Intervention: 16.1 (4,2-24.2) nmol per 106 neutrophils/30 mins versus 7.3 (2.1-11.5)p<0.0001

infection.

See metaanalysis [22] which concluded that GCSF did not have a significant benefit with regard to either resolution of infection or healing of wounds, although there was a significant reduction in the need for lower extremity surgery

Sponsored by Amgen

± 1.9 days in control group

Yönem, 2001 [18]

RCT, Single centre, Blinding unknown

Study quality 2/9

15 subjects with cellulitis or Wagner 2 or less in each of the two treatment arms

15 patients treated with standard treatment (antibiotics and wound care), 15 patients treated with standard t reatment + G-CSF 5 µg/kg, duration of antibiotic treatment 22.9 ± 2.0 days in GCSF 23.3 ± 1.9 days in control group, standard treatment with GCSF 3 days. Duration of antibiotic treatment 22.9 ± 2.0 days in GCSF 22.3 ± 1.9 days in control group

Infection outcomes: Time to resolution of infection, duration of hospitalisation, duration of parenteral antibiotic administration, need for surgical intervention

No significant differences in time to resolution of infection, duration of hospitalisation duration of parenteral antibiotic administration, amputation in the G-CSF treated group compared to the standard group

1- Also includes results of respiratory burst, granulocyte count etc. Typing error in abstract (p< 0.05 should be p>0.05)


De Lalla 2001 [19]

RCT Single centre Observerblinded

Study quality 6/9

Severe limb threatening foot infection, all with osteomyelitis in diabetes N=40

Intervention: conventional treatment plus G-CSF 263µg sc daily for 21 days versus conventional

1 Cure (complete closure of the ulcer without signs of bone infection)

At 3 weeks - Intervention 0 vs Controls 0

At 9 weeks -

1+ No effect of GCSF on eradication of infection, in contrast to [21].

Patients with ABPI <0.5 or ankle systolic pressure <50mmHg, and patients with serum creatinine >1.6mg/100mL were excluded. 20 subjects in each treatment group

treatment (no placebo). Mean duration of antibiotics 68.9 ±29.2 days for G-CSF patients and 58.7± 23.7 for controls (not significant)

2 improvement (eradication of pathogens in addition to marked or complete reduction of cellulitis but incomplete ulcer healing, or ulcer healing but persistent osteomyelitis

3 failure (absence of any clinical improvement) or amputation for persistent infection

Intervention 7 vs Controls 7, p=1.0

At 3 weeks - Intervention 12 vs Controls 9, p=0.34




Differences with [21] study relating to prevalence of osteomyelitis and choice of outcome measures


Kästenbauer 2003 [20]

RCT Single centre Patient blinded

Study quality 7/9

Soft tissue infection of DFU, 20 subjects in intervention group, 17 in placebo group.

The patients in the intervention group received daily an initial dose of either 5 µg/kg G-CSF or

Infection outcomes: Infection scores pre vs post treatment, putrid, erythema, oedema

Patients who received G-CSF did not have an earlier resolution of clinically defined infection

1+ Infection score non-validated

No differences, like [18], whereas significant differences

placebo (0.9% sterile saline solution), s.c.. Subjects were treated with i.v. antibiotics (clindamycin and ciprofloxacin) until the inflammation had visibly improved. Oral antibiotics were administered 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

than placebo patients

in resolution of signs of infection contrast with [21]

Sponsored by Amgen

Viswanathan 2003 [6]

RCT Single centre Double blind

Study quality Not scored

N=20, with extensive cellulitis, Wagner II-III ulcers, 10 subjects in each treatment arm

The patients received daily initial dose of either 5 µg/kg body weight G-CSF or placebo (0.9% sterile saline

Eradication of infection:

Surgery:

Hospital length of stay:

Intervention: 9 Control 3 (N.S.)

Intervention:0 Control 3 (N.S.)

Intervention 7.4 Control 8.8

'Foot ulcers excluded'

Sponsored by Amgen

solution), injected subcutaneously. Duration of treatment with GCSF 10 days

(p=0.02)

Open in new window

Procaine plus polyvinylpyrrolidone

Reference

Study design

and score

Population

Intervention and control

management Outcomes

Differences and

statistical results

Level of

evidence (sign)

Comments

Duarte 2009 [23]

RCT, Single centre Assessor blinded,

Study quality 7/9

118 patients with ischemic diabetic foot infection, of which Ischemic gangrene n=63, ischemic ulcer n=55. 59 subjects in each treatment arm

59 patients treated with De Marco Formula 0.15 ml/ day intramuscular injection (DMF = combination of procaine HCl and polyvinylpyrrolidone), for ten days, then twice weekly until wound healing or completion of a 6-week period. 59 patients treated with standard care

Infection outcomes: Amputation

Amputation rate 45.8% vs 25.4% (toes 30.4% vs 28.8%, transmetatarsal amputation 18. 6% vs 8.5%) in the control group and DMF group, respectively (N.S.)

1+ Unknown risk of bias, unclear criteria for reason of amputation or level of amputation. Little obvious evidence of benefit

Sponsored by Gen Cell

Open in new window

Hyperbaric oxygen therapy

Reference

Study design

and score

Population Intervention and control

management Outcomes

Differences and

statistical results


Comments

Doctor 1992 [26]

RCT, Single centre Open label.

30 patients with chronic diabetic foot ulcers,

All patients treated with systemic antibiotic therapy and

Infection outcome: positive wou nd cultures.

Hospital stay 41 vs 47 days, major amputation

1- It was not described how many diabetic foot ulcers were infected, but

Study quality 3/9

15 subjects in both intervention and control

wound debridement, 15 patients treated with hyperbaric oxygen treatment (HBOT), 15 treated conservatively. 4 HBOT sessions of 45 minutes over 2 weeks. Antibiotic duration 3 days

Non-infection outcomes: hospital days, amputation and level

2 vs 7, minor amputations 4 vs 2, pre procedure positive wound culture 19 vs 16, post procedure positive wound culture 3 vs 12, in the HBOT group vs the control group, respectively. All differences were not significant

most received antibiotics. Method of randomisation was not described. Antibiotics used were based on sensitivity spectrum and included cephalosporins, aminoglycosides and metronidazole

No evidence of benefit

No sponsor identified.

Open in new window

Comparison of antibiotic regimens - skin and soft tissue infection alone

Reference

Study design

and score

Population

Intervention and

control manageme

nt

Outcomes Differences and

statistical results

Level of

evidence

(sign)

Comments

Bradsher 1984 [28]

RCT, Multicentre Open label,

Study quality 4/9

Subset of RCT in 84 patients with soft tissue infection. Of these 84, 20 patients had diabetic foot infection, 10 subjects in each treatment arm.

10 patients with DFI treated with ceftriaxone, 10 with cefazolin. Duration of antibiotic treatment unknown

Infection outcomes: only microbiological evaluation: elimination, reduction, persistence, relapse, reinfection

Elimination of infection: 6 vs 4, reduction: 3 vs 2, persistence: 1 vs 4 In ceftriaxone and cefazolin, respectively.

1- Insufficient data available for the diabetic foot infection subgroup. No clinical assessment in diabetic foot infection subgroup


Lipsky 1990 [34]

RCT, Single centre Open label

Study quality 4/9

Outpatient infected diabetic foot ulcers N=56, 27 vs 29 subjects in each treatment arm.

Oral clindamycin hydrochloride (n=27) or cephalexin (n=29). Duration of therapy 2 weeks. Additionally, 3 patients received an additional 2 weeks of antiobiotic treatment after their initial course

Infection outcomes: Eradication of bacteria by wound culture, clinical cure

No difference in eradication, clinical response or wound healing response between the two antibiotic. Fifty-one infections (91%) were eradicated, 42 (75%) after 2 weeks of treatment; only 5 (9%) were initially treatment failures, and 3 (5%) were subsequently cured with further outpatient oral antibiotic treatment. After a mean follow-up of 15 months, no further treatment was required in 43 (84%) of the cured patients

1- No ITT analysis. No data on blinding of patient/clinician/ assessor

Only study on clindamycin monotherapy.

First treatment trial of out-patients

Sponsored by the Dept of Veterans Affairs and Upjohn Company

Siami 2001 [29]

RCT, multicentre Investigator blinded,

Study quality 5/9

409 patients with skin and soft tissue infection, of which 279 patients clinically evaluable, 54 patients with diabetic foot infection, 25 subjects in each of the

29 patients treated with clinafloxacin IV, 25 with piperacillin/ tazobactam IV with or without vancomycin (in case of MRSA). Duration of

Infection outcomes: Clinical cure

Microbiological eradication

15/29 clinically cured in clinafloxacin group vs 12/25 in pip/tazo group.

Microbiological eradication: 32/73 and 15/47 isolates eradicated for clinafloxacin

1+ Approximately one third of patients not clinically or microbiologically evaluable

Short duration of treatment, also

two treatment arms. Patients with osteomyelitis were excluded.

treatment for whole group (including group with 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)

and piperacillin/ tazobactam groups, respectively

relatively low rate of clinical cure

Sponsored by Parke-Davis.

Clay 2004 [14]

RCT Single centre Open label. (Veterans Admin.)

Study quality 3/9

DFU N=70, only men with diabetes and lower extremity infection were included, 36 vs 34 subjects in each treatment arm

Group 1 n=36 Metronidazole 1g and 1g ceftriaxone IV each day for a mean of 6.7 ± 3.3 days in patients with successful outcome. 15 protocol violations

Group 2 n=34 Ticarcillin/

Temperature:

WCC:

Finger stick blood glucose:

Improvement of wound stage:

Creatinine clearance:

Costs:

No statistically significant differences (NS)

NS

NS

Stage changed "minimally" - details not shown

NS

Cost saving of $61 per hospital admission in

1- Men only 27 patients had antibiotics changed and no indication of whether the analysis was strictly per protocol. No stated time of day for blood glucose measurement, and only undertaken in 39/70. Creatinine clearance assessed in

clavulanate 3.1g IV each 6 hours for a mean of 6.1 ± 4.3 days in patients with successful outcome.

12 protocol violations

metronidazole/ ceftriaxone group

only 31/70 "Treatment success" achieved in 29 patients in Cef/Met and in 29 in the Tic/clav group p=NS. Inappropriate measures of treatment success besides clinical staging (which is not standardized). 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

Lobmann 2004 [27]

Cohort. Prospective

Study quality

180 diabetic patients with severe, limb-threatening foot infection were

90 ceftriaxone vs 90 quinolones in addition to standard

Non-infection outcomes Wound healing, amputation

Treatment with a third generation cephalosporin is as effective as a treatment with

2- Clindamycin could be added in both groups (added in 27%). Not

4/8 consecutively enrolled. 300 patients were screened, 90 vs 90 subjects in each treatment arm

treatment of foot infection. Mean duration of treatment in ceftriaxone group 18.7 days, in quinolone group 23.8 days. Median duration of treatment in ceftriaxone group 11.5 days, and 16.5 days in the quinolone group

rate, length of stay Infectious: clinical (reaching Wagner I or 0) and microbiological cure rate of infection, duration of antibiotic therapy, need to change antibiotic therapy

quinolones. Clinical response was achieved in 58.0% in the ceftriaxone group and in 51.1% in the quinolone group (NS.). Fourteen days after initiation of treatment, the number of patients with microbiological isolates decreased in both groups (52 to 5 in the ceftriaxone group and 60 to 12 in the quinolone group). At hospital disch arge, 66.0% of ceftriaxone and 64.4 of quinolonetreated 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

clear how many patients in each group received clindamycin. Definition of clinical response is unusual (change in Wagner grades)

Sponsored by Hoffmann La Roche

Harkless 2005 [30]

RCT Multicentre Open label

Study quality 2/9

314 Patients with polymicrobial infections involving methicillinresistant Staphylococcus aureus also received vancomycin 1 g q12h, n=155 vs n=159 subjects in each of two treatment arms

155 adult patients with moderateto- severe infected diabetic foot ulcers received piperacillin/ tazobactam (P/T) (4 g/0.5 g q8h) and 159 received ampicillin/ sulbactam (A/S) (2 g/1 g q6h) as a parenteral treatment. Median duration of treatment 8.0 days P/T vs 8.5 days A/S

Clinical success (resolution of ulcer and of symptoms of infection, no additional antibiotics needed) Bacteriological success (end of cure or end of treatment eradication or presumed eradication)

Clinical efficacy rates (cure or improvement) were statistically equivalent overall (81% for P/T vs. 83% for A/S), and median duration of treatment was similar in the clinically evaluable populations (nine days for P/T, 10 days for A/S). Drugrelated adverse events for both study drugs were comparable in frequency and type

1- Very large number of dropouts (38 and 44% non evaluable)

Sponsored by Wyeth

Lipsky 2005 [31]

RCT Subset analysis of multicentre trial Investigator blinded,

Study quality 4/9

N=133, all subjects had a DFU with infection, 47 vs 56 subjects in each of two treatment arms

Patients with a diabetic ulcer nfection were prospectively stratified to ensure they were equally represented in the treatment groups, then randomized to either

Infection outcomes: Success rates microbiological adverse events

Of 133 subjects, 103 were clinically evaluable. Most infections were monomicrobial, and Staphylococcus aureus was the predominant pathogen. Success rates for patients treated with daptomycin or the comparators were not statistically

1- Infection presumptively caused by Gram-positive organisms. 30 of 133 subjects were not clinically evaluable. 8 patients had MRSA infections: 1 in daptomycin group, 7 in vancomycin

daptomycin (n=47) [4 mg/kg every 24 h intravenously (iv)] or a pre-selected comparator (n=56) (vancomycin or a semi-synthetic penicillin) for 7-14 days. Exact duration of treatment not given

different for clinical (66% versus 70%, respectively; 95% CI, -14.4, 21.8) or microbiological (overall or by pathogen) outcomes. Both treatments were generally well tolerated, with most adverse events of mild to moderate severity

group.

Note: No ITT analysis

Sponsored by Cubist

Lipsky 2008 [8]

2 RCTs consecutive, multicentre doubleblind

Study quality 8/9

Mildly infected diabetic foot ulcers. N=835 subjects, of whom 418 in the intervention group, and 417 in the control group

2 studies: 303 and 304: 418 subjects received the active topical agent pexiganan plus an oral placebo vs 417 subjects that received oral ofloxacin plus a topical placebo. Mean duration 23 days in study 303 and 25 days in study 304. Median

Infection outcomes: clinical cure or improvement of the infection, eradication of wound pathogens, bacterial resistance, adverse events. Non-infection outcomes: wound healing

Although study 303 failed to demonstrate equivalence, study 304 and the combined data for the 2 trials demonstrated equivalent results (within the 95% confidence interval) for topical pexiganan and oral ofloxacin in clinical i mprovement rates (85%-90%), overall microbiological eradication rates (42%- 47%), and wound healing rates. The incidence of worsening

1++ Mild infection not adequately defined. Development of resistance in the oral antibiotic group.

Only study of oral vs topical treatment

Low incidence of pexiganin resistance

Sponsored by Magainin and SKB

duration 27 days in study 303 and 22 days in study 304

cellulitis (2%-4%) and amputation (2%-3%) did not differ 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 2008 [32]

RCT Multicentre Double blind

Study quality 6/9

Subgroup analysis of 257 people with DFI in a larger study of skin and skin structure infections: total N=828 (31% patients with DFI) 169 vs 89 subjects in each of the two treatment arms. Group allocation 2:1, only 222/257 were clinically evaluable

Group 1: 169 subjects: Ceftobiprole 500mg IV 8 hourly

Group 2: 89 subjects: Vancomycin 1g each 12 hours and ceftazidime 1g each 8 hours

Both for 7-14 days. Mean duration of

Clinical outcomes assessed at TOC visit (7-14 days after EOT) and defined as: cure, failure and not evaluable

Microbiological outcomes assessed at test-of-cure visit (7-14 days after end of

Clinically cured: Group 1 86.2% Group 2 81.8% (CI of comparison -5.4 - 15.7)

No further details given for the DFI group

1+ No baseline details of the DFI patients. Only outcome measure available for the DFI patients is the proportion of clinically cured in the clinically evaluable patients at TOC visit. Efficacy of the two groups seemingly

total population 9.0 days for ceftobiprole and 9.1 days for control group (per protocol analysis of N=828)

treatment): Eradication, presumed eradication, persistence, resumed persistence, colonisation, superinfection, not evaluable

equivalent. Drug is currently not FDA or EMA approved. Centres targeted had high prevalence of MRSA

Sponsored by Johnson & Johnson

Vick-Fragoso 2009 [33]

RCT Multinational Randomised Open label

Study quality 4/9

Large multinational study of skin and soft tissue infections, N=804. Subset with diabetic foot infection n=134. Group 1 63 subjects vs group 2 71 subjects. Total withdrawal 22/134

Group 1 Sequential IV/ oral moxifloxacin 400mg/day Group 2 : Sequential IV/oral amoxicillin/ clavulanic acid 1000/200mg three times daily. Mean duration of antibiotic treatment 14.1 ± 5.5 days for moxifloxacin and 15.2±5.4 days for amoxicillin/ clav (i.v. and oral combined)

Clinical success rate (success= otal resolution or marked improvement of all symptoms and signs; no additional or alternative antimicrobial treatment)

Group 1 : 25/49 (51.0%)

Group 2 : 42/63 (66.7%)

(5%CI for difference -34 to 2.7, formal statistical significance not calculated)

1- No apparent difference in the subset with diabetic foot infection. No difference observed in the total population.

Sponsored by Bayer

Graham 2002

RCT Multicent

540 adults with

53 subjects received 1

Clinical cure

Clinical cure in evaluable

1- Very limited demographic

Ertapenem vs piperacillin/ tazobactam [4]

re Double blind Study quality 5/9

complicated skin and skin-structure infections. Of these, 98 had a lower extremity infection with diabetes, of which the data of 66 patients were evaluable. Subjects with osteomyelitis were excluded

g daily ertapenem with TID placebo infusions, compared with 45 subjects who received 3.375 g QID piperacillin/ tazobactam

Mean duration of therapy was 9.1±3.1 days for ertapenem and 9.8±3.3 days for piperacillin/ tazobactam

patients (modified intention to reat analysis): Ertapenem group: 23/35 (66%) cure, Piperacillin/tazobactam group: 22/31 (71%) cure (no significant difference)

al and baseline data on the subjects of the subgroup with diabetes. Only data of 66 of 98 subjects were available for review and analysis. More outcome measures are available for the total studied group, but not for the subgroup of patients with diabetes related lower extremity infection

Sponsored by Merck

Graham 2002 Levofloxacin vs ticarcillin [7]


Study quality 1/9

399 adults with complicated skin and skin structure infections. Of these, 66 had an infected diabetic foot ulcer. Subjects with osteomyelitis or who needed emergency

Patients were randomised to 1 of the 2 study arms:Ticarcillin/ clavulanate (3.1 g given iv every 4-6 h) with a switch to oral amoxicillin/ clavulanate

Clinical cure

Clinical cure in evaluable patients in ticarcillin/ clavulanate group 18/26 (69%) versus 16/28 (57%) in the levofloxacin group (no significant difference) Seven patients taking levofloxacin and

1- Very limited demographical and baseline data on the subjects of the subgroup with diabetes Only data of 54 of 66 subjects were available for review and

surgery were excluded

(875 mg BID) at the investigator's discretion, or levofloxacin (750 mg given by mouth and/or iv QD). Subjects in both groups received 7-14 days of therapy. The randomization schedule was stratified by study centre and by diagnosis of diabetic ulcer.

Mean duration of therapy was 12.1±4.9 days in the levofloxacin group and 12.1±4.9 days in the ticarcillin/ clavulanate group

2 taking TC/AC had osteomyelitis diagnosed after admission to the study, resulting in 4 amputations. Five of 9 of the osteomyelitis cases were due to diabetic ulcers

analysis. More outcome measures are available for the total studied group, but not for the subgroup of patients with diabetes related lower extremity infection. Not reported to which group the subjects with osteomyelitis were randomised

Sponsored by Johnson & Johnson Research and Development

Open in new window

Comparison of antibiotic regimens - studies including patients with osteomyelitis

Refere Study Population Intervention Outcomes Differences and Level Comments

nce design

and score

and control management

statistical results

of evidence

(sign) Grayson 1994 [39]

RCT Single centre Double blind Study quality 9/9

Limbthreatening infection of the foot in 93 hospitalised subjects with 96 episodes of DFI, some despite previous antibiotic therapy. Prevalence of osteomyelitis 68% vs 56% episodes in the ampicillin/ sulbactam and imipenem/cilastatin group, respectively. Group 1: 48 episodes in 47 participants, group 2: 48 episodes in 46 participants. One person was randomised in error

Group 1: Ampicillin/ sulbactam 2g/1g (AS) IV 6-hourly

Group 2: Imipenem/ cilastatin (I/c) 500mg IV every 6 hours Doses adjusted to renal function. Mean duration of treatment in A/S group 13 ± 6.5 days, vs 15 ±8.6 days in the I/c group, folllow up period 1 year

Eradication of infection at 5 days:

Eradication of infection at End of Therapy (EOT):

Microbiological eradication:

Failure at EOT:

Adverse reactions:

Group 1 28/48 vs Group 2 29/48

Group 1 39/48 vs Group 2 41/48 (p=0.78)

Group 1 32/48 vs group 2 36/48 (p=0.5)

Group 1 8/48 vs Group 2 6/48

Group 1 16 vs Group 2 17

1++ High quality RCT

No difference between two intravenous regimens in terms of resolution of signs of STI and of systemic signs. There was a very high incidence of amputation 69 vs 58% for amp/ sul and imi/cil, respectively

Osteomyelitis - cannot be assessed in this way although did have follow-up for one year in this study, but they have also treated surgically

High prevalence

of osteomyelitis. 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 1997 [35]

RCT, Single centre Double blind

Study quality 6/9

36 patients with DFI, majority superficial infection (56%). 18 patients in each of 2 treatment arms. 44% vs 28% suspected or proven osteomyelitis in the

18 patients treated with ampicillin/ sulbactam 3 g QID (AS), 18 treated with cefoxitin, 2 g QID (Cef) for at least 5 days, in both groups combined with surgical intervention. Mean duration of

Infection outcomes: Cure (= complete alleviation of signs or symptoms of infection), improvement, bacteriological response, amputation

Cure 6% vs 39% (p=0.03), improvement in 78% vs 50%, cure + improvement 15/17 vs 16/17, bacteriological response in 100% vs 73%, toe/ray amputation n=7 vs n=7, below knee amputation n=1 vs =1 and

1+ Unclear what day of treatment the assessment of clinical outcome was made

Note: higher cure rate. Difficult to see why there is a

ampicillin/ sulbactam group vs the cefotixin group, respectively

hospitalization 21.1 (range 6-58) days in A/S group, 12.1 (range 4-39) days in Cef group (p=0.06)

, duration of hospitalization

days of hospitalization 21.1 vs 12.1 in the ampicllin/ sulbactam and cefotixin group, respectively

difference in cure as opposed to cure plus improvement

Sponsored by Pfizer

Lipsky 1997 [36]


Study quality 5/9

N=108, 55 vs 53 subjects in the treatment arms. Prevalence of osteomyelitis 4/55 vs 1/53 in the ofloxacin and Amoxicillin/ sulbactam group, respectively. Subjects with osteomyelitis included if the infected bone was removed

55 subjects IV then oral ofloxacin vs 53 subjects ampicillin/ sulbactam (A/S), then oral amoxicillin/ clavulanate (A/C). Mean duration of treatment iv ofloxacin 7.8 days, oral 13.2 days, A/S iv 7.1, oral 12.0 days, duration of treatment in osteomyelitis: ofloxacin iv 9.2 days oral 11.5 days, A/S i.v. 7.0, days, 12.9 days oral A/C

Infection outcomes: Treatment of infection: Cured or improved, mean duration of therapy

No differences in outcomes between groups. Cured or improved 85% Ofloxacin vs 83% A/S. The mean duration of therapy with the ofloxacin regimen was 7.8 days (range, 1-25 days) intravenously and 13.2 days (range, 3-25 days) orally. The mean duration of therapy with the aminopenicillin regimen was 7.1 days (range, 1-20 days) intravenously and 12.0 days (range, 1-24 days) orally. Patients with osteomyelitis received a somewhat longer course of intravenous therapy (mean duration, 9.2 vs. 7.0 days,

1+ 20 Subjects non evaluable. Persistence of streptococci in ofloxacin treatment group. Infected bone was supposed to be removed, but in the results it turned out that it was only removed in 71%. Numbers of osteomyelitis do not seem to match in the tables

Sponsored by Johnson Pharmaceuticals

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 2004 [37]

RTC Multicentre Open label

Study quality 4/9

371 enrolled, of whom 10 were not treated, 241 vs 120 in each treatment arm. Prevalence of osteomyelitis 24% vs 17% in the linezolid and ampicillin/ sulbactam group, respectively

241 linezolid, 120 ampicillin/ sulbactam, and amoxicillin/ clavulanate. Mean duration linezolid 17.2 ±7.9 days, ampicillin/ sulbactam 16.5 ± 7.9 days. Duration of i.v linezolid therapy 7.8 ±5.5 days, oral linezolid therapy 15.9±7.4 days, duration of ampicillin/ sulbactam therapy 10.4 ±5.7 days, oral amoxicillin/ clavulanate therapy 15.0 ±7.8 days

Infection outcomes: clinical cure and safety data.

Overall, the clinical cure ra tes were statistically equivalent (linezolid 81% vs. ampicillin/ sulbactam 71%,). Subjects with linezolid had a higher cure rate for infected DFU (81% vs. 68%; p=0.018) and in cases without osteomyelitis (87% vs. 72%; p=0.003). Significantly more anaemia, thrombocytopenia and discontinuation of therapy in the linezolid group. Any event 26.6% vs 10.0% in the linezolid group vs the ampicillin/ sulbactam group, respectively (p<0.01)

1- Investigators diagnosed osteomyelitis in 77 patients. The analysis of clinical outcome by pathogen is a modified intent-totreat population which consisted of patients in the intent-totreat population with a baseline pathogen and evaluable clinical response of success or failure). The clinical 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 2005 [13]

RCT Multicentre Double blind

Study quality 7/9

586 subjects with a diabetic foot infection classified as moderateto- severe and requiring intravenous antibiotics, 295 vs 291 subjects in each treatment arm. 12% of subjects had leg ulcers. Prevalence of osteomyelitis 8% vs 6% in the ertapenem and piperacillin/ tazobactam group, respectively. Osteomyelitis was surgically removed <48 hours

Intravenous ertapenem (1 g daily; n=295) or piperacillin/ tazobactam (P/T) (3.375 g every 6 h; n=291) given for a minimum of 5 days, after which oral amoxicillin/ clavulanic acid (875/125 mg every 12 h) could be given for up to 23 days. Mean duration of treatment 11.1 days for ertapenem and 11.3 days for P/T. Mean duration of oral follow up therapy 9.7 days

Infection outcomes: Clinical cure, bacteria eradication, safety data

Of the 576 treated subjects, 445 were available for assessment at the end of intravenous therapy. Both baseline characteristics and favourable clinical response rates were similar for the 226 who received ertapenem and the 219 who received piperacillin/ tazobactam (94%vs 92%, respectively. Rates of favourable microbiological responses (eradication rates and clinical outcomes, by pathogen) and adverse events

1+ Drop out rate 23% analyzed by modified ITT. 12% were leg ulcers. Data on site missing in n=174. Proportion of cure for organisms resistant to ertapenem (pseudomonas and enterococci) was similar to success rates of P/T. Number of patients that received additional antibiotics is not mentioned

Only 11

did not differ between groups. No differences in number of adverse events

days treatment duration

Sponsored by Merck

Lipsky 2007 [38]

RCT, Subanalysis of multicentre double blind, double dummy study. Study quality 8/9

617 Subjects, hospitalized for DFI, 78 patients with DFIs available for treatment efficacy. Prevalence of osteitis 11% vs 20% in moxifloxacin vs piperacillin/ tazobactam group, respectively. Bone infection was surgically "fully or partially resected"

Moxifloxacin (400 mg/day) or piperacillintazobactam (3.0/0.375 g every 6 h) for at least 3 days, followed by moxifloxacin (400 mg/day orally) or amoxicillinclavulanate (800 mg every 12 h orally). Duration of treatment: moxifloxacin iv 6.7 days, oral 7.4 days, amoxicillinclavulanate 6.3 days iv, 7.9 days oral

Infection outcomes: clinical response of the infection at test-ofcure (TOC), 10-42 days post-therapy, pathogen eradication, safety data

Among 617 patients enrolled in the original study, 78 with DFIs were evaluable for treatment efficacy. Clinical cure rates at TOC were similar for moxifloxacin and piperacillintazobactam/ amoxicillinclavulanate (68% versus 61%) for patients with infection (p=0.54). Overall pathogen eradication rates in the microbiologicallyvalid population were 69% versus 66% for moxifloxacin and comparator, respectively (p=1.0). No differences in safety outcomes

1++ Patients with osteomyelitis were excluded if the bone could not be fully or partially resected

Short duration of total treatment

Sponsored by Bayer

Senneville 2008 [9]

Cohort Multicentre Investig

50 patients with diabetic foot osteomyelitis

Bone culture based antibiotic therapy. Duration of

Infection outcomes: Failure 18 (36%), 32

Positive association: Bone culture based antibiotic

2+ 9 patients lost to follow up. There was

ator blinded.

Study quality 4/7

treated in different centres, of whom 16 (32%) had already been treated for osteomyelitis of the foot

treatment 11.0 ± 4.1 weeks for success group and 12.4 ± 4.2 week for failure group (p=0.19). In the two groups combined : 11.5 ± 4.2 weeks

remission (64%). 20 predictive criteria were evaluated

therapy 4 (22.2%) in failure group, 18 (56.3%) in remission group (p=0.02). Multivariate analysis OR 4.78, CI 1.02- 22.7, p=0.04)

variability in practice and antibiotic therapy among centres


Saltoglu 2010 [5]

RCT Single Centre Open label Study quality 5/9

In-patients with diabetes and severe DFI, and who were known to have organisms sensitive to study drugs. Total number randomised N=64, but two withdrawn early and not included in analysis. Group 1 n=30 (Osteomyelitis 73%), group 2 n=32 (Osteomyelitis 81%) p=0.05

Group 1 IV piperacillin/ tazobactam 4.5g 8 hourly, group 2: IV imipenem/ cilastatin 0.5g 6 hourly, with glycopeptide added if MRSA positive (n=3), with excision of infected bone and with negative pressure therapy if necessary. Intended duration of treatment: 14 days for soft tissue infection; 28 days for soft tissue plus bone, but only 5 days if all infected bone removed surgically

Clinical success rate (success= total resolution of all symptoms and signs , without amputation)

Relapse within two months of hospital discharge

Treatment duration

Microbiological response

Total amputations

Major amputations

Adverse

Group 1: 14 (46.7%) Group 2 9 (28.1%) p=0.13

0/14 versus 2/9

21days versus 24 days

Complete in 96% in both groups

18 total amputations versus 22 total p=0.739

22.5% of the whole group had a BKA

No difference between groups (p=0.55)

1- Total number recruited was 64 and yet analysis conducted on only 62: technically per protocol analysis. Despite inclusion criteria, microbiological data available in only "approximately 80%". 57% isolated organisms were Gram negative, reflecting disease duration and previous treatment. Mean duration of infection was 30 days and

events 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)

Clinical classification of infection (IDSA), with definitions IWGDF grade [4,81] (IDSA

classification) [16]

Uninfected: No systemic or local symptoms or signs of infection 1 (Uninfected)

Infected

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)

2 (Mild infection)

Infection involving structures deeper than skin and subcutaneous tissues (e.g., bone, joint, tendon) or erythema extending >2 cm* from the wound margin.

No systemic signs or symptoms of infection (see below)

3 (Moderate infection)

Any foot infection with the following signs of a systemic inflammatory response syndrome (SIRS). This response is

4 (Severe infection)

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 support 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 underlying 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 signs

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

Presence of a foreign body (accidental or surgically implanted), puncture wound, abscess, arterial or venous insufficiency, lymphedema

Current treatment Progression while on apparently appropriate antibiotic therapy

(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 uninfected 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

infection in the diabetic foot

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