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

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 costminimisation 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 g/kg or a fixed dose 263 g 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 GCSF, but this was not observed in another [18]. Hospital length of stay was shorter for the GCSF group in two studies [6,21], but not in a third [18]. The need for surgical intervention was not statistically different between the two groups in the three studies that examined it [6,19,21], and neither was the time to eliminate pathogens from the wound [19,21]. The results of these studies are inconsistent and provide no clear evidence to support the use of G-CSF in diabetic foot infections. A meta-analysis of these five studies also concluded that adding G-CSF did not significantly affect the likelihood of resolution of infection or wound healing, although it was associated with a reduced likelihood of lower extremity surgical interventions, including amputation [22]. The use of G-CSF also reduced the duration of hospital stay, although it did not significantly affect the duration of systemic antibiotic therapy. e. Procaine plus polyvinylpyrrolidone One study was identified in which the use of intramuscular injection of 0.15 ml/day of procaine and polyvinylpyrrolidone for ten days was assessed in 118 patients with a diabetic foot infection affecting an ischaemic limb [23]. The study was an observer blinded, single centre, RCT. No significant difference was observed between groups. f. Hyperbaric oxygen therapy Although there have been a number of trials that have examined the effect of hyperbaric oxygen therapy (HBOT) in patients with diabetic foot complications, including two double-blind randomised controlled trials [24,25], we could identify only one study that investigated diabetic foot infection as an outcome [26]. This was a single-centre, open label, study comparing the use of HBOT in 15 patients with 15 control subjects, with both groups receiving standard antibiotic treatment and wound debridement. Although it was not explicitly stated that the subjects had a foot infection, this was implied by the use of antibiotics. There were no significant differences in the numbers of positive wound cultures, major and minor amputations, and hospital stay between the intervention and control groups. g. Antibiotic choice based on bone biopsy A single cohort study attempted to explore the effect of basing antibiotic selection on the results of culture of a bone biopsy specimen in patients with osteomyelitis [9]. Among 50 subjects, 32 had had previous unsuccessful treatment for osteomyelitis. The rate of remission of infection was significantly higher in the group for whom antibiotic choice was based on bone culture than in those in whom therapy based on wound swab culture (82% versus 50%, respectively [p=0.02]). Nevertheless, it is possible that this difference was the result of confounding variables: especially the fact that patients in one of the highest enrolling centres only received a rifampicin-containing regimen if they had a bone culture.

h. Comparison of antibiotic regimens - skin and soft tissue infection alone Eleven of the available studies on antibiotic treatment of skin and soft tissue infections were RCTs, and one was a prospective cohort study [27]. Of the randomised trials, nine were multicentre trials [4,7,8,28-33], and two were single centre trials [14,34].Furthermore, three were double blind [4,8,32], two were investigator blinded [29,31], and six were non-blinded [7,14,28,30,33,34]. Three studies were subset analysis of larger trials [4,7,32]. One report consisted of two consecutive studies of the topical antibiotic peptide, pexiganan [8]. The other studies compared systemic antimicrobial regimens: one compared two oral antibiotic regimens [34], while the majority involved a switch from parenteral to oral antibiotic therapy. Classes of antibiotics that were compared were: 1st and 3rd and 5th generation cephalosporins (cephalexin, ceftriaxone and ceftobiprole, respectively), fluoroquinolones (ofloxacin, levofloxacin, ciprofloxacin and moxifloxacin), lincosamides (clindamycin), extended-spectrum penicillins and beta lactamase inhibitors (piperacillin/tazobactam, ticarcillin/clavulanate, amoxicillin/clavulanate), carbapenems (ertapenem), nitroimidazoles (metronidazole), lipopeptides (daptomycin), and glycopeptides (vancomycin). Each of these agents is in widespread use, except ceftobiprole, which is not currently available in North America or Europe. The mean duration of antibiotic administration in patients with skin and soft tissue infection ranged from 6 days to 27 days [8,14], but the duration of antibiotic treatment was not mentioned in two studies [28,31]. In the study of oral regimens, the duration of administration was only two weeks, although three patients were actually treated for longer [34]. No differences were observed in the ten studies with regard to infection outcome, length of hospital admission or amputation. Clinical cure rates in all studies without osteomyelitis ranged from 48% [29] to 90% [8]. One RCT of mildly infected diabetic foot ulcers reported that a topical antibiotic, pexiganan, was similar in clinical and microbiological effectiveness to the oral fluoroquinolone, ofloxacin, with fewer adverse effects [8]. We identified no studies that demonstrated a benefit of any specific antibiotic agent, route of administration, or duration of treatment. i. Comparison of antibiotic regimens - studies including patients with osteomyelitis In addition to the previously mentioned cohort study of the use of bone biopsy in selecting an antibiotic in patients with osteomyelitis [9], we identified seven studies of antibiotic treatment of diabetic foot infection in which a proportion the study population had infection of underlying bone [5,13,35-39]. All other seven studies were RCTs: three were double blind, one was single blind, three were open label; four were multicentre and three were single centre trials. The prevalence of osteomyelitis varied from 6 % [8,13,29,36] to 81% [5]. The groups of antibiotics that were compared were: penicillins with beta lactamase inhibitors (parenteral ampicillin/ sulbactam and oral amoxicillin/clavulanate), extended-spectrum penicillins and beta lactamase inhibitors (piperacillin/tazobactam), carbapenems (imipenem/ cilastatin, ertapenem), 2nd generation cephalosporins (cefoxitin), fluoroquinolones (ofloxacin, moxifloxacin) and oxazolidinones (linezolid). Outcomes included clinical cure [5,13,36-39], adverse drug reactions [5,13,37- 39], and duration

of therapy [5,36]. Only one study reported a difference in clinical and microbiological outcomes, and this was a comparison of ampicillin/sulbactam with cefoxitin [35]. The clinical cure rates in this study were significantly different (p=0.03) but were exceptionally low, and there were no significant differences between groups in bacteriological response (100% versus 73%), amputations (8 versus 8), and duration of hospitalisation (21 versus 12 days). In the other studies in which patients with osteomyelitis were included, clinical cure rates ranged from 61% [38] to 94% [13,39]. The mean duration of antibiotic treatment in the six studies was short, ranging from 6 days [35] to 28 days [5]. We found no studies that demonstrated a significant advantage of a particular antibiotic agent or route of administration in diabetic foot osteomyelitis. V. Discussion In planning this review, a search was made only for studies in which a treatment of diabetic foot infection was compared with a contemporaneous control group, but this led to the identification of only a very small number of suitable publications. Studies were only included if at least the outcome data of the (sub)population of subjects with diabetes were reported. It has to be accepted that trial design can pose problems in attempts to determine the effectiveness of different treatments in this field, and this is especially true for studies intended to evaluate the role of surgical interventions. Early surgery is accepted as essential in some cases of foot infection and yet the trial evidence to substantiate the benefit is weak, and based on just two studies - each of which had a very a high chance of bias. Another caution attaches to the use of the SIGN criteria for documenting study quality. This system ranks work mainly on the quality of study design, rather than study conduct, and this can result in apparent anomalies - with weaker studies occasionally achieving higher scores. For most clinical trials evaluating the efficacy of antimicrobial agents, patients with diabetic foot infections are either excluded or comprise a small proportion of the study population. Some clinical trials have allowed a post hoc analysis focusing on the subset of patients with a diabetic foot infection, but the small number of subjects limits their usefulness. Not only is the number of reasonably designed studies in this field remarkably small, but most had a low score for study design, were marred by the use of small and heterogeneous populations, were poorly described, or had a high risk of bias. Thus, readers should be cautious in interpreting the results of the available published work. Furthermore, circumstances dictating the choice of treatment in different countries and settings will vary according to the behaviours of affected population, nature of the presentation of infection, prevalence of different microorganisms and their antibiotic sensitivities. Selection of treatment is also severely restrained by limitation of resources in many parts of the world, and poses particular problems in the management of those who live far from urban centres. The available data suggest that it is possible to treat selected patients with a diabetic foot infection in an outpatient setting with an oral antibiotic regimen, either initially or after switch from parenteral therapy. The study of a topical antibiotic, pexiganan, is promising, but this agent will need to undergo further testing before it can be evaluated for approval. We identified few new data on the management of diabetic foot osteomyelitis since our relatively recent systematic review [1].

The reported data on skin and soft tissue infection confirmed earlier observations suggesting that Gram-positive microorganisms play a large role in infection of the foot in diabetes. Despite this, there is emerging observational evidence that Gram-negative species might be of greater significance in some populations, and in South Asia, in particular [40-42]. If confirmed, this would have an important impact on the selection of antibiotic regimens and the rates of clinical success. In the studies reported here it was also of note that no great difference was observed in comparisons between regimens with a relatively broader or a narrower spectrum of activity. It was also noteworthy that the randomised comparisons of antibiotic regimens were generally based on a shorter duration of treatment - even when bone infection was present - and reported good outcomes. These observations conflict with current understanding regarding the use of antibiotics in osteomyelitis and need to be formally tested. This systematic review makes clear the need for more robust, well-designed comparative studies to help clinicians make an optimal choice of antibiotic regimen in various situations, as well as of route of therapy and duration of administration. Such studies should use a validated system for defining and classifying infections [43,44], and look at all relevant clinical and microbiological, as well as other, outcomes. Furthermore, future studies should make a clear distinction between patients whose infection is limited to soft tissue and those with accompanying osteomyelitis. VI. Acknowledgements We thank Dr. Oleg Udovichenko, Russia, and Prof. Zhangrong Xu, China, for their help in the assessment of papers published in languages other than English. Furthermore, we would like to thank the following corresponding members of the expert panel: Dr ZG Abbas, Tanzania Dr. F. Javier Aragn Snchez, Spain Dr BM Ertugrul Turkey Prof Hanan Gawish, Egypt Dr Irina Gurieva, Russia Dr Shigeo Kono, Japan Dr A Nather, Singapore Dr. J.-L. Richard, France Dr Nina Rojas, Chile Dr Lynn Tudhope, South Africa Dr Steven Twigg , Australia Dr Vijay Viswanathan, India 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;

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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. Martnez-De Jess FR, Ramos-De la Medina A., Remes-Troche JM, Armstrong DG, Wu SC, Lzaro-Martnez JL, Beneit-Montesinos JV. Efficacy and safety of neutral pH superoxidised solution in severe diabetic foot infections. Int Wound J 2007; 4(4): 353362. 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. Ynem 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 colonystimulating factor as adjunctive therapy for limbthreatening diabetic foot infection. Antimicrob Agents Chemother 2001; 45(4): 1094-1098. 20. Kstenbauer 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, Fernndez Montequin JI, Fors Lpez 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. Lndahl 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, Hernndez-Oliva G, Cruz-Alczar J, Ambile-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 (betaLactams) OR (Cephalosporins) OR cefuroxime OR ceftazidime OR cephalexin OR ceftriaxone OR cefpirome OR (Clavulanic Acids) OR (Clavulanic Acid*) OR (Moxalactam) OR (Penicillins) OR penicillin OR flucloxacillin OR oxacillin OR Methicillin OR nafcillin OR ampicillin OR penicillin OR piperacillin OR (Tetracyclines) OR tetracycline OR minocycline OR doxycycline OR (Macrolides) OR erythromycin OR azithromycin OR clarithromycin OR (Lincomycin) OR clindamycin OR (Trimethoprim-Sulfamethoxazole Combination) OR cotrimoxazole OR co-trimoxazole OR (Quinolones) OR ciprofloxacin OR ofloxacin OR moxifloxacin OR levofloxacin OR (Anti-Infective Agents, Local) OR (Silver OR Silver Sulfadiazine OR iodine) OR honey OR larvae OR maggots OR larval OR (hyperbaric oxygen therapy OR hyperbaric OR (vacuum assisted wound therapy) OR (VAC therapy) OR (negative pressure therapy) OR (growth factors) OR (G-CSF) OR (granulocyte colony stimulating growth factor))) B. Literature search strings for Embase Map to preferred terminology (with spell check) Also search as free text Include sub-terms/derivatives (explosion search) (Diabetes Mellitus) OR diabetic AND (Clinical Trials) OR (comparative study) OR (epidemiologic study characteristics) OR (Clinical Trial*) OR (case-control stud*) OR (case control stud*) OR (cohort stud*) OR (Comparative stud*) OR (case control study) OR (Comparative study) OR (RCT) OR (Randomised controlled trial) OR (Costs and Cost Analysis) AND

Infection OR infected OR cellulitis OR abscess OR (necrotizing fasciitis) OR osteomyelitis OR gangrene OR erysipelas OR osteitis OR (Bone Diseases, Infectious) OR (Diabetic Foot) AND (Wound Healing) OR (Anti-Bacterial Agents) OR (Anti-Infective Agents) OR (administration and dosage) OR (Drug Administration Routes) OR parenteral OR oral OR topical OR duration OR cement OR Methylmethacrylate OR (Calcium Sulfate) OR implant OR collagen OR ceramic OR Aminoglycosides OR gentamicin OR amikacin OR tobramycin OR Glycopeptides OR vancomycin OR Oritavancin OR dalbavancin OR teicoplanin OR Metronidazole OR Linezolid OR (Fusidic Acid) OR Daptomycin OR Monobactam OR Carbapenem OR imipenem OR meropenem OR (beta-Lactams) OR Cephalosporins OR cefuroxime OR ceftazidime OR cephalexin OR ceftriaxone OR cefpirome OR (Clavulanic Acids) OR (Clavulanic Acid*) OR Moxalactam OR Penicillins OR penicillin OR flucloxacillin OR oxacillin OR Methicillin OR nafcillin OR ampicillin OR penicillin OR piperacillin OR Tetracyclines OR tetracycline OR minocycline OR doxycycline OR Macrolides OR erythromycin OR azithromycin OR clarithromycin OR Lincomycin OR clindamycin OR (Trimethoprim-Sulfamethoxazole Combination) OR cotrimoxazole OR (co-trimoxazole) OR Quinolones OR ciprofloxacin OR ofloxacin OR moxifloxacin OR levofloxacin OR (Anti-Infective Agents, Local) OR Silver OR (Silver Sulfadiazine) OR iodine OR honey OR larvae OR maggots OR larval OR (hyperbaric oxygen therapy) OR hyperbaric OR (vacuum assisted wound therapy) OR (VAC therapy) OR (negative pressure therapy) OR (growth factors) OR (G-CSF) OR (granulocyte colony stimulating growth factor) C. Evidence tables Open in new window Early surgery Interventio Study n and Referenc desig Population control e n and manageme score nt Tan 1996 Cohor Cohort 87 [10] t study of 112 infections Single patients with treated centre 164 diabetic without . foot surgery in infections, the first 3 Study hospitalized days vs 77 qualit for treated with y 3/8 treatment of antibiotics + the foot surgery (of Difference Level s and of statistical evidenc results e (sign) Amputatio 2n rate 27.6% vs 13.0% antibiotic group and antibiotic and surgical interventio

Outcomes

Comments

Infection outcome: Above ankle amputation

No information regarding (appropriatene ss of) antibiotic treatment. High risk of bias as there is no assessment

infection. Of which 46 these, 76 antibiotics had a deep and infection, 65 debridement had and 31 osteomyeliti antibiotic s. No early and early surgery and local antibiotics amputation) in 87 . Duration subjects vs of treatment early with surgery and antibiotics antibiotics unknown in 77 subjects Faglia Cohor Diabetes Group 1: 2006 [11] t and deep Immediate Single foot space surgical centre abscess debridement N=106, , group 2: Study group 1: 43 Referred qualit subjects, from y 5/8 group 2: 63 another subjects hospital after a mean delay of 6.2 7.5 days without debridement . Duration of treatment with antibiotics unknown

n groups, respectivel y (p<0.01)

of severity and there is a high chance of indication bias Provides no evidence to confirm the role of surgery, as opposed to timing of intervention No sponsor identified. 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

Drainage without amputation: One or more ray amputations:

Group 1: 9 2vs Group 2: 4 Group 1: 21 vs Group 2: 21

Transmetatars al amputation: Group 1: 12 vs Chopart: Group 2: 10 Major amputation: Group 1: 1 vs Group 2: 23 Group 1: 0 vs Group 2: 5 p<0.001 X2 24.4

Open in new window Health economics

Interventio Study n and Referenc design Population control e and score managemen t Tice 2007 RCT, 99 patients Substudy of [12] Subset with DFI, SIDESTEP analysis including [13], costbased on osteomyeliti minimisatio multicentr s provided n e, double all infected assessment blinded bone was of study. surgically ertapenem removed. 56 vs Study subjects in piperacillin/ quality 6/9 ertapenem tazobactam. group vs 43 No duration in of treatment piperacillin/ given tazobactam group

Difference Level of Comment s and evidenc Outcomes s statistical e (sign) results Infection outcomes: Mean days of I7.6 vs 7.4 treatment: (p=0.8) days of treatment, 7.5 vs 25.5 (p<0.0001) Total i.v. drug doses: total i.v. doses 8.6 vs 26.8 Total (p<0.0001) antibiotic dosages: total i.v and oral doses, $356 vs Mean drug $503 preparation (p<0.001) and administratio total cost n cost: of treatment for ertapenem and pip/tazo, respectivel y 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 Study Differences Intervention Level of design and evidence Comments Reference Population and control Outcomes and statistical management (sign) score results Martinez- RCT Type 2 n=21 Odour, Odour 1Alternate

De Jesus Single diabetes intervention periwound reduction 2007 [15] centre and group: cellulitis was Patient infected, neutral pH and achieved in blinded. deep superoxidised granulation all diabetic aqueous tissue superoxide Study foot ulcers, solution. patients quality 21 subjects (100% 4/9 in n=16 control versus 25%; intervention group: p< 0.01) and group vs 16 disinfectant surrounding in control such as soap cellulitis group or povidone diminished iodine. (p<0.001) in 17 patients Duration of (80.9% antibiotic versus treatment 43.7%) more than 10 days Chen RCT 30 patients 10 diabetic Infection Number of 1+ 2008 [17] Single with foot ulcers outcomes: colonies centre diabetic treated with Bacteria after 24 Patient foot ulcers, iodophor, 10 number in hours / blinded. 10 patients with rivanol, wound number of in each 10 controls. colonies at Study subgroup One single t=0 was quality application of 0.961, 0.918 6/9 topical and 0.986for treatment the control after ulcer group, debridement iodophor group and rivanolol, respectively. Significantly less growth of bacteria after 24 hours in the iodophor group compared with the rivanol and control group

patient group allocation, yet different numbers in each group. Nonstandardized wound classification criteria No sponsor identified

Use of systemic antibiotics not mentioned. Study only looked at bacterial growth after 5 minutes and 24 hours No sponsor identified

Piaggesi RCT 2010 [16] Single centre Open label.

40 patients with diabetes with postsurgical wounds, Study who had quality surgery for 6/9 a diabetic foot infection, 20 subjects in each treatment group

Dermacyn vs povidone iodine. All patients had systemic 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

Infection outcomes: use of antibiotics. Noninfection outcomes: Healing rate at 6 months and healing time

Duration of 1+ antibiotic use: 10.1 6.1 weeks 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)

2 patients lost to follow up. Details of the interventions 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 Interventio Level Difference n and of Study Referenc Comment s and Outcomes eviden design and Population control e s statistical manageme ce score results nt (sign) Gough RCT Single 40 patients Intervention Infection 1++ Well

1997 [21] centre with Double blind diabetes with Study moderate quality 9/9 (Internation al Consensus Guidelines Grade 3) infection of DFU, n=20 subjects in both treatment arms

: G-CSF 5g/kg adjusted on basis of WCC, for 7 days versus 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 g/kg, duration of antibiotic treatment 22.9 2.0 days in GCSF 23.3 1.9 days in control group, standard treatment with GCSF

outcome measures: 1 Time to resolution of infection: Interventio n: 7 (5-20) days versus Control 12 (5-93) p=0.03 Interventio n: 8.5 (530) versus Control 14.5 (8-63) days p=0.02

designed RCT showing significant benefit in moderate infection. See metaanaly sis [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

2 Total time of intravenous antibiotics:

3 Hospital length of Interventio stay: n: 10.0 (731) days versus 17.5 (9-100) p=0.02 4 Need for surgery: Interventio n: 0 versus 4/20 (20%) p=0.114 5 Time taken to Interventio eliminate n: 4 (2-10) pathogens days versus from control:8 wound (2-75) days Nonp=0.02 infection outcome: Interventio 6 Effect of n: 16.1 GCSF on (4,2-24.2) generation nmol per of 106 neutrophil neutrophils/ superoxide: 30 mins versus 7.3

3 days. Duration of antibiotic treatment 22.9 2.0 days in GCSF 22.3 1.9 days in control group Ynem, RCT, Single 15 subjects 15 patients 2001 [18] centre, with treated with Blinding cellulitis or standard unknown Wagner 2 or treatment less in each (antibiotics Study of the two and wound quality 2/9 treatment care), 15 arms patients treated with standard t reatment + G-CSF 5 g/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 De Lalla RCT Single Severe limb Intervention

(2.1-11.5) p<0.0001

Infection No 1outcomes: significant Time to differences resolution in time to of resolution infection, of duration of infection, hospitalisati duration of on, duration hospitalisat of ion parenteral duration of antibiotic parenteral administrati antibiotic on, need for administrati surgical on, intervention amputation in the GCSF treated group compared to the standard group

Also includes results of respirator y burst, granulocy te count etc. Typing error in abstract (p< 0.05 should be p>0.05) No sponsor identified

1 Cure

At 3 weeks 1+

No effect

2001 [19] centre threatening : (complete Observerblin foot conventiona closure of Interventio ded infection, l treatment the ulcer n 0 vs all with plus G-CSF without Controls 0 Study osteomyeliti 263g sc signs of quality 6/9 s in diabetes daily for 21 bone At 9 weeks N=40 days versus infection) conventiona Interventio Patients l treatment n 7 vs with ABPI (no 2 Controls 7, <0.5 or placebo). improveme p=1.0 ankle Mean nt systolic duration of (eradication At 3 weeks pressure antibiotics of <50mmHg, 68.9 29.2 pathogens Interventio and patients days for G- in addition n 12 vs with serum CSF patients to marked Controls 9, creatinine and 58.7 or complete p=0.34 >1.6mg/100 23.7 for reduction of mL were controls (not cellulitis At 9 weeks excluded. significant) but 20 subjects incomplete Interventio in each ulcer n 8 vs treatment healing, or Controls 4, group ulcer p=0.17 healing but persistent osteomyelit is 3 failure (absence of any clinical improveme nt) or amputation for persistent infection At 3 weeks Interventio n 8 vs Controls 11, p=0.34 At 9 weeks Interventio n 5 vs Controls 9, p=0.19 Patients 1+ who received G-

of GCSF on eradicatio n of infection, in contrast to [21]. Difference s with [21] study relating to prevalenc e of osteomyel itis and choice of outcome measures No sponsor identified

Kstenba RCT Single Soft tissue The patients Infection uer 2003 centre infection of in the outcomes: [20] Patient DFU, 20 intervention Infection

Infection score nonvalidated

group scores pre received vs post Study daily an treatment, quality 7/9 initial dose putrid, of either 5 erythema, g/kg Goedema CSF or placebo (0.9% sterile saline solution), s.c.. Subjects were treated with i.v. antibiotics (clindamyci n and ciprofloxaci n) until the inflammatio n had visibly improved. Oral antibiotics were administere d thereafter if necessary. Duration of treatment with GCSF 10 days. Mean antibiotic treatment duration 5.6 2.5 days in G-CSF group, 5.8 2.3 days in placebo group Viswanat RCT Single N=20, with The patients Eradication han 2003 centre extensive received of

blinded

subjects in intervention group, 17 in placebo group.

CSF did not have an earlier resolution of clinically defined infection than placebo patients

No difference s, like [18], whereas significant difference s in resolution of signs of infection contrast with [21] Sponsored by Amgen

Interventio n: 9

'Foot ulcers

[6]

Double blind cellulitis, Wagner IIStudy III ulcers, quality Not 10 subjects scored in each treatment arm

daily initial infection: dose of either 5 Surgery: g/kg body weight G- Hospital CSF or length of placebo stay: (0.9% sterile saline solution), injected subcutaneou sly. Duration of treatment with GCSF 10 days

Control 3 (N.S.) Interventio n:0 Control 3 (N.S.) Interventio n 7.4 Control 8.8 (p=0.02)

excluded' Sponsored by Amgen

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

Hyperbaric oxygen therapy Study Referenc desig n and e score Doctor RCT, 1992 [26] Single centre Open label. Differences Intervention Level of and and control Outcomes evidenc statistical management e (sign) results All patients Infection Hospital 1treated with outcome: stay 41 vs systemic positive 47 days, antibiotic wou nd major therapy and cultures. amputation wound Non2 vs 7, debridement, infection minor 15 patients outcomes: amputations treated with hospital 4 vs 2, pre hyperbaric days, procedure oxygen amputatio positive treatment n and wound (HBOT), 15 level culture 19 treated vs 16, post conservatively procedure . 4 HBOT positive sessions of 45 wound minutes over culture 3 vs 2 weeks. 12, in the Antibiotic HBOT duration 3 group vs days the control group, respectively . All differences were not significant

Populatio n

Comments It was not described how many diabetic foot ulcers were infected, but most received antibiotics. Method of randomisation was not described. Antibiotics used were based on sensitivity spectrum and included cephalosporins, aminoglycoside s and metronidazole No evidence of benefit No sponsor identified.

30 patients with chronic diabetic foot ulcers, 15 subjects Study in both qualit interventio y 3/9 n and control

Open in new window Comparison of antibiotic regimens - skin and soft tissue infection alone Study design and score Interventi on and Differences Population control Outcomes and statistical manageme results nt Subset of 10 patients Infection Elimination of Level of evide Comments nce (sign) 1Insufficient

Referen ce

Bradsher RCT,

1984 [28]

Multicen RCT in 84 tre Open patients with label, soft tissue infection. Of Study these 84, 20 quality patients had 4/9 diabetic foot infection, 10 subjects in each treatment arm.

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

outcomes: only microbiolo gical evaluation: eliminatio n, reduction, persistence , relapse, reinfection

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

data available for the diabetic foot infection subgroup. No clinical assessment in diabetic foot infection subgroup No sponsor identified No ITT analysis. No data on blinding of patient/clini cian/ assessor Only study on clindamycin monotherap y. First treatment trial of outpatients Sponsored by the Dept of Veterans Affairs and Upjohn Company

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 Infection clindamyci outcomes: n Eradicatio hydrochlori n of de (n=27) bacteria by or wound cephalexin culture, (n=29). clinical Duration of cure therapy 2 weeks. Additionall y, 3 patients received an additional 2 weeks of antiobiotic treatment after their initial course

No difference in 1eradication, clinical response or wound healing response between the two antibiotic. Fiftyone 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 followup of 15 months, no further treatment was required in 43

Siami 2001 [29]

RCT, multicent re Investiga tor 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 two treatment arms. Patients with osteomyelitis were excluded.

Clay 2004

RCT Single

DFU N=70, only men

(84%) of the cured patients 29 patients Infection 15/29 clinically 1+ treated outcomes: cured in with Clinical clinafloxacin clinafloxac cure group vs 12/25 in IV, 25 in pip/tazo with Microbiolo group. piperacillin gical / eradication Microbiological tazobactam eradication: IV with or 32/73 and 15/47 without isolates vancomyci eradicated for n (in case clinafloxacin of MRSA). and piperacillin/ Duration of tazobactam treatment groups, for whole respectively 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) Group 1 Temperatu No statistically 1n=36 re: significant

Approximat ely one third of patients not clinically or microbiolog ically evaluable Short duration of treatment, also relatively low rate of clinical cure Sponsored by ParkeDavis.

Men only 27 patients

[14]

centre Open label. (Veteran s Admin.) Study quality 3/9

with diabetes and lower extremity infection were included, 36 vs 34 subjects in each treatment arm

Metronidaz ole 1g and 1g ceftriaxone IV each day for a mean of 6.7 3.3 days in patients with successful outcome. 15 protocol violations

differences (NS) NS WCC:

Finger NS stick blood glucose: Stage changed "minimally" Improvem details not ent of shown wound stage: NS Creatinine clearance: Cost saving of Group 2 $61 per hospital n=34 Costs: admission in Ticarcillin/ metronidazole/ clavulanate ceftriaxone 3.1g IV group each 6 hours for a mean of 6.1 4.3 days in patients with successful outcome. 12 protocol violations

had antibiotics changed and no indication of whether the analysis was strictly per protocol. No stated time of day for blood glucose measureme nt, and only undertaken in 39/70. Creatinine clearance assessed in only 31/70 "Treatment success" achieved in 29 patients in Cef/Met and in 29 in the Tic/clav group p=NS. Inappropriat e measures of treatment success besides clinical staging (which is not standardize d). Treatment duration is only assessed in

those who achieved treatment success. This causes some doubt on the cost analysis No conclusions can be drawn from the study Pharmacistled study Sponsored by Roche Clindamyci n could be added in both groups (added in 27%). Not clear how many patients in each group received clindamycin . Definition of clinical response is unusual (change in Wagner grades) Sponsored by Hoffmann La Roche

Lobman Cohort. 180 diabetic 90 n 2004 Prospecti patients with ceftriaxone [27] ve severe, limb- vs 90 threatening quinolones Study foot infection in addition quality were to standard 4/8 consecutivel treatment y enrolled. of foot 300 patients infection. were Mean screened, 90 duration of vs 90 treatment subjects in in each ceftriaxone treatment group 18.7 arm days, in quinolone group 23.8 days. Median duration of treatment in ceftriaxone group 11.5 days, and 16.5 days in the

NonTreatment with 2infection a third outcomes generation Wound cephalosporin is healing, as effective as a amputation treatment with rate, length quinolones. of stay Clinical Infectious: response was clinical achieved in (reaching 58.0% in the Wagner I ceftriaxone or 0) and group and in microbiolo 51.1% in the gical cure quinolone group rate of (NS.). Fourteen infection, days after duration of initiation of antibiotic treatment, the therapy, number of need to patients with change microbiological antibiotic isolates therapy decreased in both groups (52 to 5 in the ceftriaxone group and 60 to

quinolone group

Harkless RCT 2005 Multicen [30] tre Open label Study quality 2/9

314 Patients 155 adult with patients polymicrobia with l infections moderateto involving - severe methicillinre infected sistant diabetic Staphylococc foot ulcers us aureus received also received piperacillin vancomycin / 1 g q12h, tazobactam n=155 vs (P/T) (4 n=159 g/0.5 g subjects in q8h) and each of two 159 treatment received arms ampicillin/ sulbactam (A/S) (2 g/1 g q6h)

12 in the quinolone group). At hospital disch arge, 66.0% of ceftriaxone and 64.4 of quinolonetreate d diabetic ulcers were cured or improved. Median duration of antibiotic therapy 11.5 days for ceftriaxone vs 16.5 days for quinolone (p<0.01). Need to change antibiotic therapy 7.8% ceftriaxone vs 16.7% for quinolones Clinical Clinical efficacy 1success rates (cure or (resolution improvement) of ulcer were and of statistically symptoms equivalent of overall (81% for infection, P/T vs. 83% for no A/S), and additional median duration antibiotics of treatment was needed) similar in the Bacteriolo clinically gical evaluable success populations (end of (nine days for cure or end P/T, 10 days for of A/S). treatment Drugrelated eradication adverse events or for both study

Very large number of dropouts (38 and 44% non evaluable) Sponsored by Wyeth

Lipsky 2005 [31]

RCT Subset analysis of multicent re trial Investiga tor blinded, Study quality 4/9

as a presumed parenteral eradication treatment. ) Median duration of treatment 8.0 days P/T vs 8.5 days A/S N=133, all Patients Infection subjects had with a outcomes: a DFU with diabetic Success infection, 47 ulcer rates vs 56 nfection microbiolo subjects in were gical each of two prospective adverse treatment ly stratified events arms to ensure they were equally represented in the treatment groups, then randomize d to either daptomyci n (n=47) [4 mg/kg every 24 h intravenous ly (iv)] or a preselected comparator (n=56) (vancomyc in or a semisynthetic penicillin) for 7-14 days. Exact duration of treatment

drugs were comparable in frequency and type

Of 133 subjects, 1103 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 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

Infection presumptive ly caused by Grampositive organisms. 30 of 133 subjects were not clinically evaluable. 8 patients had MRSA infections: 1 in daptomycin group, 7 in vancomycin group. Note: No ITT analysis Sponsored by Cubist

not given Lipsky 2 RCTs Mildly 2 studies: Infection 2008 [8] consecuti infected 303 and outcomes: ve, diabetic foot 304: 418 clinical multicent ulcers. subjects cure or re N=835 received improvem doublebli subjects, of the active ent of the nd whom 418 in topical infection, the agent eradication Study intervention pexiganan of wound quality group, and plus an oral pathogens, 8/9 417 in the placebo vs bacterial control group 417 resistance, subjects adverse that events. received Nonoral infection ofloxacin outcomes: plus a wound topical healing placebo. Mean duration 23 days in study 303 and 25 days in study 304. Median duration 27 days in study 303 and 22 days in study 304

Although study 1++ 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 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

Mild infection not adequately defined. Developme nt of resistance in the oral antibiotic group. Only study of oral vs topical treatment Low incidence of pexiganin resistance Sponsored by Magainin and SKB

Noel 2008 [32]

RCT Multicen tre Double blind Study quality 6/9

Subgroup Group 1: analysis of 169 257 people subjects: with DFI in a Ceftobiprol larger study e 500mg of skin and IV 8 hourly skin structure infections: Group 2: total N=828 89 (31% subjects: patients with Vancomyci DFI) 169 vs n 1g each 89 subjects 12 hours in each of the and two ceftazidime treatment 1g each 8 arms. Group hours allocation 2:1, only Both for 7222/257 14 days. were Mean clinically duration of evaluable total population 9.0 days for ceftobiprol e and 9.1 days for control group (per protocol analysis of N=828)

Clinical outcomes assessed at TOC visit (7-14 days after EOT) and defined as: cure, failure and not evaluable Microbiolo gical outcomes assessed at test-ofcure visit (7-14 days after end of treatment): Eradicatio n, presumed eradication , persistence , resumed persistence , colonisatio n, superinfect ion, not evaluable Clinical

pexiganan emerged among patients who received pexiganan. More adverse effects in the ofloxacin group Clinically 1+ cured: Group 1 86.2% Group 2 81.8% (CI of comparison -5.4 - 15.7)

No further details given for the DFI group

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 equivalent. Drug is currently not FDA or EMA approved. Centres targeted had high prevalence of MRSA Sponsored by Johnson & Johnson No apparent

Vick-

RCT

Large

Group 1

Group 1 : 25/49 1-

Fragoso Multinati multinational 2009 onal study of skin [33] Randomi and soft sed Open tissue label infections, N=804. Study Subset with quality diabetic foot 4/9 infection n=134. Group 1 63 subjects vs group 2 71 subjects. Total withdrawal 22/134

Sequential IV/ oral moxifloxac in 400mg/day Group 2 : Sequential IV/oral amoxicillin / clavulanic acid 1000/200m g three times daily. Mean duration of antibiotic treatment 14.1 5.5 days for moxifloxac in and 15.25.4 days for amoxicillin / clav (i.v. and oral combined) Graham RCT 540 adults 53 subjects 2002 Multicen with received 1 Ertapene tre complicated g daily m vs Double skin and ertapenem piperacil blind skinwith TID lin/ Study structure placebo tazobact quality infections. infusions, am [4] 5/9 Of these, 98 compared had a lower with 45 extremity subjects infection who with received diabetes, of 3.375 g which the QID data of 66 piperacillin patients were / evaluable. tazobactam Subjects with

success rate (success= otal resolution or marked improvem ent of all symptoms and signs; no additional or alternative antimicrob ial treatment)

(51.0%) Group 2 : 42/63 (66.7%) (5%CI for difference -34 to 2.7, formal statistical significance not calculated)

difference in the subset with diabetic foot infection. No difference observed in the total population. Sponsored by Bayer

Clinical cure

Clinical cure in 1evaluable patients (modified intention to reat analysis): Ertapenem group: 23/35 (66%) cure, Piperacillin/tazo bactam group: 22/31 (71%) cure (no significant difference)

Very limited demographi cal and baseline data on the subjects of the subgroup with diabetes. Only data of 66 of 98 subjects were available for review and analysis.

osteomyelitis Mean were duration of excluded therapy was 9.13.1 days for ertapenem and 9.83.3 days for piperacillin / tazobactam

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 Very limited demographi cal and baseline data on the subjects of the subgroup with diabetes Only data of 54 of 66 subjects were available for review and analysis. More outcome measures are available for the total studied group, but

Graham 2002 Levoflox acin vs ticarcilli n [7]

RCT Multicen tre Open label Study quality 1/9

399 adults Patients Clinical with were cure complicated randomised skin and skin to 1 of the structure 2 study infections. arms:Ticar Of these, 66 cillin/ had an clavulanate infected (3.1 g diabetic foot given iv ulcer. every 4-6 Subjects with h) with a osteomyelitis switch to or who oral needed amoxicillin emergency / surgery were clavulanate excluded (875 mg BID) at the investigato r's discretion, or levofloxaci n (750 mg given by

Clinical cure in 1evaluable patients in ticarcillin/ clavulanate group 18/26 (69%) versus 16/28 (57%) in the levofloxacin group (no significant difference) Seven patients taking levofloxacin and 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

mouth and/or iv QD). Subjects in both groups received 714 days of therapy. The randomizat ion schedule was stratified by study centre and by diagnosis of diabetic ulcer. Mean duration of therapy was 12.14.9 days in the levofloxaci n group and 12.14.9 days in the ticarcillin/ clavulanate group Open in new window

to diabetic ulcers

not for the subgroup of patients with diabetes related lower extremity infection. Not reported to which group the subjects with osteomyeliti s were randomised Sponsored by Johnson & Johnson Research and Developme nt

Comparison of antibiotic regimens - studies including patients with osteomyelitis Study Refere design and nce score Level Intervention Differences of Comment and control Outcomes and statistical evide s management results nce (sign)

Population

Grayso RCT n 1994 Single [39] centre Double blind Study quality 9/9

Limbthreaten ing 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/cil astatin 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

Eradicatio Group 1 28/48 1++ n of vs Group 2 infection at 29/48 5 days:

High quality RCT No difference between two intravenou s 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, respectivel y Osteomyel itis 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

Eradicatio Group 1 39/48 Group 2: n of vs Group 2 Imipenem/ infection at 41/48 (p=0.78) cilastatin (I/c) End of 500mg IV Therapy every 6 hours (EOT): Doses adjusted Group 1 32/48 to renal Microbiolo vs group 2 function. Mean gical 36/48 (p=0.5) duration of eradication treatment in : Group 1 8/48 vs A/S group 13 Group 2 6/48 6.5 days, vs 15 Failure at 8.6 days in the EOT: Group 1 16 vs I/c group, Group 2 17 folllow up Adverse period 1 year reactions:

osteomyeli tis. Osteo also treated with resection of bone. 1 year follow up. No diff narrow (G+ve targeted) versus broad spectrum antibiotics Research question must be to isolate osteo. But if included, need one year follow-up Sponsored by Pfizer Unclear what day of treatment the assessment of clinical outcome was made Note: higher cure rate. Difficult to see why there is a

Erstad RCT, 1997 Single [35] centre Double blind

36 patients with DFI, majority superficial infection (56%). 18 Study patients in quality each of 2 6/9 treatment arms. 44% vs 28% suspected or proven osteomyelitis in the ampicillin/

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 hospitalization

Infection Cure 6% vs 1+ outcomes: 39% (p=0.03), Cure (= improvement in complete 78% vs 50%, alleviation cure + of signs or improvement symptoms 15/17 vs 16/17, of bacteriological infection), response in improvem 100% vs 73%, ent, toe/ray bacteriolog amputation n=7 ical vs n=7, below response, knee amputation amputation n=1 , duration vs =1 and days

sulbactam group vs the cefotixin group, respectively

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

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

difference in cure as opposed to cure plus improveme nt Sponsored by Pfizer 20 Subjects non evaluable. Persistence of streptococc i 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 osteomyeli tis do not seem to match in the tables Sponsored by Johnson Pharmaceu ticals

Lipsky RCT 1997 Multice [36] ntre Open label

N=108, 55 vs 55 subjects IV 53 subjects in then oral the treatment ofloxacin vs 53 arms. subjects Prevalence of ampicillin/ osteomyelitis sulbactam Study 4/55 vs 1/53 (A/S), then oral quality in the amoxicillin/ 5/9 ofloxacin and clavulanate Amoxicillin/ (A/C). Mean sulbactam duration of group, treatment iv respectively. ofloxacin 7.8 Subjects with days, oral 13.2 osteomyelitis days, A/S iv included if 7.1, oral 12.0 the infected days, duration bone was of treatment in removed 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 1+ 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, 125 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, 120 days) intravenously and 12.0 days (range, 1-24 days) orally. Patients with osteomyelitis received a somewhat longer course of intra- venous therapy (mean duration, 9.2 vs. 7.0 days,

Lipsky RTC 2004 Multice [37] ntre Open label

371 enrolled, of whom 10 were not treated, 241 vs 120 in each Study treatment quality arm. 4/9 Prevalence of osteomyelitis 24% vs 17% in the linezolid and ampicillin/ sulbactam group, respectively

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 241 linezolid, Infection Overall, the 1120 ampicillin/ outcomes: clinical cure ra sulbactam, and clinical tes were amoxicillin/ cure and statistically clavulanate. safety equivalent Mean duration data. (linezolid 81% linezolid 17.2 vs. ampicillin/ 7.9 days, sulbactam ampicillin/ 71%,). Subjects sulbactam 16.5 with linezolid 7.9 days. had a higher Duration of i.v cure rate for linezolid infected DFU therapy 7.8 (81% vs. 68%; 5.5 days, oral p=0.018) and in linezolid cases without therapy osteomyelitis 15.97.4 days, (87% vs. 72%; duration of p=0.003). ampicillin/ Significantly sulbactam more anaemia, therapy 10.4 thrombocytopen 5.7 days, oral ia and amoxicillin/ discontinuation clavulanate of therapy in the therapy 15.0 linezolid group. 7.8 days Any event 26.6% vs 10.0% in the linezolid group vs the ampicillin/ sulbactam group, respectively

Investigato rs diagnosed osteomyeli tis in 77 patients. The analysis of clinical outcome by pathogen is a modified intenttotreat population which consisted of patients in the intenttotreat population with a baseline pathogen and evaluable clinical response of success or failure). The clinical

(p<0.01)

cure rate is actually a per protocol analysis instead of an ITT analysis Only study to show higher incidence of AEs in one group Sponsored by Pfizer. 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 (pseudomo nas and enterococc i) was similar to success rates of P/T. Number of patients that

Lipsky RCT 2005 Multice [13] ntre Double blind

586 subjects with a diabetic foot infection classified as moderatetoStudy severe and quality requiring 7/9 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. Osteomyeliti

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 1+ 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

s was surgically removed <48 hours

rates and clinical outcomes, by pathogen) and adverse events did not differ between groups. No differences in number of adverse events

received additional antibiotics is not mentioned Only 11 days treatment duration Sponsored by Merck Patients with osteomyeli tis were excluded if the bone could not be fully or partially resected Short duration of total treatment Sponsored by Bayer

Lipsky RCT, 2007 Subanal [38] ysis of multice ntre 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 Infection Among 617 1++ (400 mg/day) outcomes: patients or clinical enrolled in the piperacillintazo response original study, bactam of the 78 with DFIs (3.0/0.375 g infection at were evaluable every 6 h) for test-ofcure for treatment at least 3 days, (TOC), 10- efficacy. followed by 42 days Clinical cure moxifloxacin postrates at TOC (400 mg/day therapy, were similar for orally) or pathogen moxifloxacin amoxicillinclav eradication and ulanate (800 , safety piperacillintazo mg every 12 h data bactam/ orally). amoxicillinclav Duration of ulanate (68% treatment: versus 61%) for moxifloxacin iv patients with 6.7 days, oral infection 7.4 days, (p=0.54). amoxicillinclav Overall ulanate 6.3 pathogen days iv, 7.9 eradication rates days oral in the microbiological lyvalid population were 69% versus 66% for moxifloxacin and comparator, respectively

Sennev ille 2008 [9]

Cohort Multice ntre Investig ator blinded.

50 patients with diabetic foot osteomyelitis treated in different centres, of Study whom 16 quality (32%) had 4/7 already been treated for osteomyelitis of the foot

Saltogl RCT u 2010 Single [5] 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 (Osteomyeliti s 73%), group 2 n=32 (Osteomyeliti s 81%) p=0.05

Bone culture Infection based antibiotic outcomes: therapy. Failure 18 Duration of (36%), 32 treatment 11.0 remission 4.1 weeks for (64%). 20 success group predictive and 12.4 4.2 criteria week for failure were group (p=0.19). evaluated In the two groups combined : 11.5 4.2 weeks Group 1 IV Clinical Group 1: 14 1piperacillin/ success (46.7%) Group tazobactam rate 2 9 (28.1%) 4.5g 8 hourly, (success= p=0.13 group 2: IV total imipenem/ resolution cilastatin 0.5g 6 of all hourly, with symptoms glycopeptide and signs , added if MRSA without positive (n=3), amputation 0/14 versus 2/9 with excision ) of infected bone and with Relapse negative within two pressure months of 21days versus therapy if hospital 24 days necessary. discharge Intended duration of Treatment Complete in treatment: 14 duration 96% in both days for soft groups tissue infection; Microbiolo 28 days for soft gical 18 total tissue plus response amputations bone, but only versus 22 total 5 days if all Total p=0.739 infected bone amputation

(p=1.0). No differences in safety outcomes Positive 2+ association: Bone culture based antibiotic therapy 4 (22.2%) in failure group, 18 (56.3%) in remission group (p=0.02). Multivariate analysis OR 4.78, CI 1.0222.7, p=0.04)

9 patients lost to follow up. There was variability in practice and antibiotic therapy among centres No sponsor identified Total number recruited was 64 and yet analysis conducted on only 62: technically per protocol analysis. Despite inclusion criteria, microbiolo gical data available in only "approxim ately 80%". 57% isolated organisms were Gram negative, reflecting disease

removed surgically

22.5% of the whole group had a BKA

Major amputation No difference s between groups (p=0.55) Adverse events

duration and previous treatment. Mean duration of infection was 30 days and 40.5 days in the two groups and yet all had had no antibiotics for 48h prior to inclusion which is surprising in people with severe infection Not sponsored

Expert Opinion on the Management of Infections in the Diabetic Foot Contents Chapters Introduction Pathophysiology Classification Diagnosis Soft tissue infection Osteomyelitis Clinical evaluation Probe-to-bone test Blood tests Imaging studies Plain radiography Magnetic resonance imaging Nuclear medicine Radiological studies - other techniques Bone biopsy Assessing severity Microbiological considerations When to send specimens for culture Obtaining specimens for wound cultures Interpreting wound culture results Bone infection Treatment Antimicrobial therapy Indications for therapy Route of therapy Choice of antibiotics Duration of therapy

Wound care Treating osteomyelitis Adjunctive therapies Outcome of treatment Issues of particular importance in developing countries References I. Introduction This report from the expert panel on infectious diseases of the International Working Group on the Diabetic Foot (IWGFD) is an update of the one published in 2004 [1], incorporating some information from a related IWGDF 2008 publication on osteomyelitis [2] and from the concurrently published "Systematic Review of the Effectiveness of Interventions in the Management of Infection in the Diabetic Foot"[3]. Our intention is to present a brief overview to assist clinicians worldwide in diagnosing and treating foot infections in persons with diabetes. Separately, we have proposed "Specific Guidelines on the Management of Diabetic Foot infections," also published concurrently in this journal. The development of a foot infection is associated with substantial morbidity, including discomfort, the need for visits to health care providers, antibiotic therapy, wound care and often surgical procedures. Furthermore, foot infection is now the most frequent diabetic complication requiring hospitalization and the most common precipitating event leading to lower extremity amputation [4-6]. Managing infection requires careful attention to properly diagnosing the condition, obtaining specimens for culture, selecting empirical and definitive antimicrobial therapy, determining when surgical interventions are needed and caring for the wound. A systematic and, to the extent possible, evidence-based approach to diabetic foot infections (DFIs) should result in better outcomes. II. Pathophysiology In diabetic persons, foot infection is a common problem. Infection is best defined as invasion and multiplication of microorganisms in host tissues that induces a host inflammatory response, usually followed by tissue destruction. DFI is defined clinically as a soft tissue or bone infection anywhere below the malleoli. These infections usually occur in a site of skin trauma or ulceration [7]. Peripheral neuropathy is the main factor leading to skin breaks and ulcerations, which then become colonized with skin flora, and ultimately infected. Foot ischemia, related to peripheral arterial disease, is also common in patients with a DFI; while rarely the primary cause of foot wounds, the presence of limb ischemia increases the risk of a wound becoming infected [8], and adversely affects the outcome of infection [9]. Factors that predispose to foot infection include having a wound that is deep, long-standing or recurrent, as well as ill-defined diabetesrelated 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 Uninfected: No systemic or local symptoms or signs of infection Infected
y

IWGDF grade [4,81] (IDSA classification) [16] 1 (Uninfected) 2 (Mild infection)

At least 2 of the following items are present:

o o o o o

Local swelling or induration Erythema > 0.5 cm* around the ulcer Local tenderness or pain Local warmth Purulent discharge

Other causes of an inflammatory response of the skin should be excluded (e.g. trauma, gout, acute Charcot neuroosteoarthropathy, fracture, thrombosis, venous stasis) Infection involving the skin /or subcutaneous tissue only (without involvement of deeper tissues and without systemic signs as described below). Any erythema present extends < 2 cm* around the wound No systemic signs or symptoms of infection (see below) Infection involving structures deeper than skin and 3 (Moderate

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

infection)

No systemic signs or symptoms of infection (see below) Any foot infection with the following signs of a systemic inflammatory response syndrome (SIRS). This response is manifested by two or more of the following conditions:
o o o o

4 (Severe infection)

Temperature > 38 or < 36 Celsius Heart rate > 90 beats/minute Respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg White blood cell count > 12,000 or < 4,000 cu/ mm or 10% immature (band) forms

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

Accurately diagnosing bone infection can be difficult, but is essential to ensure appropriate treatment. A definite diagnosis of osteomyelitis requires both the presence of histological findings consistent with bone infection (inflammatory cells, necrosis) and isolation of bacteria from an aseptically obtained bone sample [2]. Because these procedures are not routinely available in many settings, clinicians must use surrogate diagnostic markers, including clinical, laboratory and imaging findings. The clinical presentation of osteomyelitis in the diabetic foot can vary with the site involved, the extent of infected and dead bone, the presence of associated abscess and soft tissue involvement, the causative organism(s) and the adequacy of limb perfusion. The main problems in diagnosing osteomyelitis are the delay in detecting bony changes early in infection on plain radiographs and the difficulty in distinguishing bony changes caused by infection from those related to neuroosteo (Charcot) arthropathy on most imaging studies. As discussed below, analyses from recent expert publications [2,23] and systematic reviews [2,24,25] provide guidance on the best diagnostic studies. 1. Clinical evaluation: Clinicians should suspect osteomyelitis when an ulcer overlying a bony prominence fails to heal despite adequate off-loading, or when a toe is erythematous and indurated. The likelihood ratio (LR) of a clinician's suspicion of osteomyelitis is surprisingly good: positive LR 5.5 and negative LR 0.54 [24,25]. The presence of exposed bone has a positive LR for osteomyelitis of 9.2; large ulcers (area > 2 cm2) are much more likely to have underlying bone infection than smaller ones [24-27]. Certainly, osteomyelitis can also occur in the absence of overlying local signs of inflammation [26]. 2. Probe-to-Bone Test: This is another useful clinical diagnostic tool. Striking bone with a sterile metal probe gently inserted through a wound increases the likelihood that the patient has osteomyelitis if the prevalence of bone infection is high (i.e., >60%) in the population under scrutiny [28,29]. Conversely, a negative probe to bone test in a patient at low risk (i.e., 20%) essentially rules out osteomyelitis [30-32]. 3. Blood tests: An erythrocyte sedimentation rate (ESR) is diagnostically useful; when elevated (usually defined as > 70 mm/hour) it increases the likelihood of osteomyelitis un- derlying a diabetic foot wound (positive LR 11) while lower levels reduce the likelihood (negative LR of 0.34) [24,26,33,34]. Based on fewer data, an elevated C-reactive protein, procalcitonin, or blood leukocyte count (or a positive swab culture of an ulcer) may also be predictive of osteomyelitis [34,35]. 4. Imaging studies: A. Plain radiography

Characteristic features of osteomyelitis on plain X-rays of the foot (usually 2 or 3 views) are summarized in Table 2 [26,36-38]. Among the many studies that have assessed the accuracy of plain radiography in diagnosing osteomyelitis [26,36,38-53]7, nine were prospective in design [26,36,38- 41,44,45,52]. Overall, the sensitivity varied from 28% to 75%. The timing of the imaging greatly influences its usefulness, as longer-standing cases are more likely to show bony abnormalities on plain radiographs than those present for less than a couple of weeks. In the systematic review by Dinh et al [25], the pooled sensitivity of the four eligible studies was 0.54 and the pooled specificity was 0.68, with a diagnostic odds ratio of 2.84 and a Q statistic of 0.60 [26,36,38,52]. In the systematic review by Butalia [24], analyzing 7 studies of plain radiographs the summary positive likelihood ratio was 2.3 (95% confidence intervals 1.6-3.3) while the negative likelihood ratio was 0.63 (95% CI 0.5-0.8) [26,36,38,43,47,48,50]. These results suggest that radiographic findings are only marginally predictive of osteomyelitis if positive and even less predictive of the absence of osteomyelitis if negative. Of note is that neither review identified a study that obtained sequential plain radiographs of the foot over time. Changes in radiological appearance over an interval of at least 2 weeks are far more likely to predict the presence of osteomyelitis than a single study, although correctly targeted antibiotic therapy may prevent these changes. B. Magnetic resonance imaging MRI is a valuable tool for diagnosing osteomyelitis, as well as helping define the presence and anatomy of deep soft tissue infections [16]. The key features suggestive of osteomyelitis on MRI are listed in Table 2. In their meta-analysis, Dinh and coworkers [25] identified four trials using MRI, all of which were prospective [27,36,38,54] and two of which used a consecutive recruitment method [36,38] Only one study, however, was conducted within the past 10 years [27]. The prevalence of osteomyelitis in the four studies ranged from 44% to 86%. The pooled sensitivity of MRI for diabetic foot osteomyelitis was 0.90 (CI 0.82-0.95) and the diagnostic odds ratio was 24.4. In 16 trials identified in the meta-analysis by Kapoor et al. [55], 9 were prospective studies and 11 included only subjects with diabetes, although enrollment criteria were quite varied. The prevalence of standard defined osteomyelitis was 50% (range 32% to 89%), the pooled sensitivity was 77%- 100%, and the specificity was 40%-100%. In subjects with diabetes the diagnostic odds ratio was 42 (CI 15-120), the summary positive likelihood ratio was 3.8 (CI 0.2.5-5.8), and the summary negative likelihood ratio was 0.14 (CI 0.08-0.26) [27,36,38,41,45,49,51,56-64]. More recently performed studies reported lower diagnostic odds ratios (25, CI 6-117) compared to older ones, perhaps because their study designs were better. The subgroups of patients with other diagnoses (e.g., Charcot arthropathy) were too small to analyze any differences among the studies. C. Nuclear medicine Three recent meta-analyses reviewed nuclear medicine techniques for evaluating the diabetic foot [25,55,65]. Capriotti and coworkers reviewed 57 papers, including 7 reviews on the clinical value of several nuclear medicine methods [65]. Among the several types of nuclear imaging scans, a bone scan, usually performed with 99mTc-methylene diphosphate and done in timesequence phases, is considered suggestive of osteomyelitis when it discloses increased blood-pool activity and radionuclide intensity localized to the bone[25]. Three-phase bone scans

are sensitive (90%), but not specific (46%) [65], with a calculated summary negative predictive value of 71% and positive predictive value of 65%. Among six studies with 185 subjects that qualified for the meta-analysis by Dinh and coworkers [25], the pooled sensitivity was 80% but the specificity was only 28% [26,36,38,52,66,67]. The pooled diagnostic odds ratio was 2.1, indicating poor discriminating ability, while the Q-statistic was 0.6, indicating moderate accuracy for the diagnosis of osteomyelitis [25]. Based on seven studies, Kapoor et al. [55] found the performance characteristics of to a triple-phase bone scan were markedly inferior to MRI [38,41,45,49,58,63,64], with a diagnostic odds ratio 3.5 of (CI 1.0-13) compared to 150 (CI 55-411) [55]. Healthy bone may also have an increased uptake of the radiopharmaceutical, especially in the forefoot [65] While a positive bone scan is certainly not specific for osteomyelitis (or Charcot neuro-osteoarthropathy), a negative one largely rules it out. Radiolabelled white blood cells (usually using either 99mTechnetium or 111Indium) are generally not taken up by healthy bone, making positive leukocyte scans more specific than bone scans for diagnosing osteomyelitis (and excluding Charcot osteoarthropathy) [65]. In a review of these scans by Capriotti et al, the summary positive predictive values for osteomyelitis were 90% and 72%, respectively, the negative predictive values were 81% and 83%, respectively[65]. 99mTc labeling appears to provide superior physical characteristics, leading to better spatial resolution than 111In [65]. In another recent review, Palestro and Love concluded that among radionuclide procedures, labeled leukocyte imaging is the best choice for evaluating diabetic pedal osteomyelitis, with a sensitivity of 72% to 100% and specificity of 67% to 98% [68]. Dinh and coworkers [25] identified 6 studies using 111Indium radiolabel leukocytes, with a pooled sensitivity of 74% and a specificity of 68% [26,36,38,52,66,67].The pooled diagnostic odds ratio was 10, indicating moderately good discriminating characteristics, while the Q-statistic of 0.59 suggests a low to moderate accuracy for the diagnosis of osteomyelitis [25]. Kapoor et al. [55] found that in three studies MRI outperformed leukocyte scanning (with 99mTc [64] or 111In [45,49]) with diagnostic odds ratios of 120 (CI 62-234) and 3.4 (CI 0.2-62), respectively. The combination of labeled leukocytes with a bone scan (dual tracer technique) does not substantially improve diagnostic accuracy [46]. Other available nuclear medicine techniques include in vivo methods of labeling leukocytes, radiolabeled polyclonal IgG, and radiolabeled antibiotics. Results of studies using these techniques have varied and most of the methods are unavailable in many countries. 99mTc/111In labeled human immunoglobin G uptake is related to vascular permeability, not inflamed tissue, and thus not as specific as radiolabeled leukocytes [50,69]. The pooled positive and negative predictive values for this technique, calculated from 97 lesions were 72 and 88%, respectively [65]. D. Other imaging techniques Two published studies of computer tomography (CT) and CT combined with positron emission tomography (PET) scans for the diagnosis of osteomyelitis [25] did not include histopathological examination of bone [70,71]. A recent prospective study that enrolled 110 patients reported that PET/CT scan had a sensitivity of 81%, specificity of 93%, positive predictive value of 78%, negative predictive value 94%, and accuracy of 90%, somewhat better than a simultaneous MRI [72]. While the data on this new procedure are limited, there seems to be place for CT

(especially if combined with PET) scans when MRI is unavailable or contraindicated. 5. Bone biopsy: The weight of current evidence supports bone biopsy as the best available diagnostic technique for both diagnosing bone infection and providing reliable data on the responsible organisms and their antibiotic susceptibility profile [3]. Soft tissue or sinus tract cultures are not sufficiently accurately in predicting bone pathogens [73,74]. Ideally, it would be best to process a bone specimen for both culture and histopathology. While infected bone usually has inflammatory cells (granulocytes early and mononuclear cells later), the histomorphology of uninfected bone is normal in diabetic patients, including in those with neuropathy or vasculopathy [75]. Unfortunately, both histology and culture may lead to misleading results. Culture of a bone specimen may be falsely negative because of sampling errors, prior antibiotic therapy or a failure to isolate fastidious organisms. It may also be falsely positive because of contamination by wound-colonizing flora not involved in bone infection. Similarly, bone histopathology may be falsely negative due to sampling error or potentially falsely positive due to some non-infectious inflammatory disorder. In a recent analysis of 44 patients, a comparison of microbiological and histopathological testing demonstrated that they performed similarly in identifying the presence of pedal osteomyelitis in the diabetic foot [76]. In one retrospective multicenter study, using bone culture-guided antibiotic treatment was associated with a significantly better clinical outcome than using soft tissue culture results [77]. While success rates of 75% or higher have been reported with empiric treatment of DFO, it is difficult to compare the results of available published studies because of their differences in the populations, in the criteria for both diagnosis and remission of infection they used, and in their durations of followup [78]. Bone culture is not always needed when DFO is suspected, but clinicians should consider this procedure when the diagnosis of osteomyelitis remains uncertain despite clinical and imaging evaluations, in cases of non-informative data from soft tissue cultures, when the infection has failed to respond to an initial empiric antibiotic therapy, or when considering an antibiotic regimen with a high potential for selecting resistant organisms (e.g., rifampin, fluoroquinolones, fusidic acid or clindamycin) [2]. To reduce the likelihood of false-negative culture results, it is presumably best to perform bone biopsy after an antibiotic-free period in clinically stable patients. As certain antibiotic agents have a prolonged release from bone tissue, holding antibiotics for two-weeks is ideal, but even a couple of days may be helpful [79]. Because DFO (in the absence of substantial soft tissue infection) is typically a slowly progressive disease, such a delay is usually safe. Percutaneous biopsy of bone through clinically uninvolved skin reduces the likelihood of false positive culture, although one study found good results (based on favourable clinical outcome) using a simpler per-wound bone biopsy after careful debridement [79]. Similarly, while there are potential risks of bone biopsy, e.g., tracking contaminating organisms into the bone or causing a bone fracture, several large series have shown that complications from percutaneous (and surgical) procedures are very rare [26,80]. Any properly trained physician (e.g., an orthopedic surgeon, podiatrist or interventional radiologist) can perform the biopsy. Percutaneous biopsy should preferably be done under fluoroscopic or CT guidance, traversing intact and uninfected skin. Patients with sensory neuropathy often do not need anaesthesia. If possible, the operator

should attempt to obtain at least 2 specimens-- one for culture and the other for histological analysis. With small toe bones, it may only be possible to aspirate a few bony spicules. Table 2 Common imaging features of diabetic foot osteomyelitis Plain Radiographs
y y y y y y

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)

y y y y

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 o o o o

Cortical disruption Adjacent cutaneous ulcer Soft tissue mass Sinus tract 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 Cellulitis Local signs General Presentation Systemic signs Laboratory tests Complicating features Acute or rapidly progressive Fever, chills, hypotension, confusion, volume depletion Leukocytosis, severe or worsening hyperglycemia, acidosis, azotemia, electrolyte abnormalities Presence of a foreign body (accidental or surgically implanted), puncture wound, abscess, arterial or venous insufficiency, lymphedema Penetrates into subcutaneous tissues, e.g. fascia, tendon, muscle, joint, bone Extensive (>2 cm), distant from ulceration, or rapidly progressive Severe inflammation, crepitus, bullae, marked induration, discoloration, necrosis/gangrene, ecchymoses, or petechiae

Current treatment

Progression while on apparently appropriate antibiotic therapy

(B) Factors suggesting hospitalization may be necessary

y y y y y y y y y

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 antibioticresistant 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 -hemolytic, and others) are also important pathogens. Enterococci are relatively frequent isolates, but usually of secondary clinical importance. Infections requiring hospitalization are often polymicrobial, including aerobes and anaerobes [16,92]. gram-negative bacilli (mainly Enterobacteriaceae, sometimes Pseudomonas aeruginosa or other non-fermentative species) are usually isolated in conjunction with gram-positive cocci from patients with chronic or previously treated infections; they are often, but not always, true pathogens. Many recent studies have reported that gram-negative organisms are the most frequent isolates in DFIs occurring in patients in warm climates, especially in developing countries [93-96]. It is unclear if this is related to environmental factors, footwear practices, personal hygiene habits, antimicrobial pretreatment, or other factors. Obligate anaerobic species are most frequent in wounds with ischemic necrosis or those that involve deep tissues; they are rarely the sole pathogen and most often are part of a mixed infection with aerobes [97]. Multi-drug resistant organisms (MDROs), especially methicillin-resistant S. aureus (MRSA), are more frequently isolated from patients who have recently received antibiotic therapy, have been previously hospitalized, or reside in a chronic care facility[98]. After the rates of MRSA dramatically increased in many countries starting in the late 1990s, they have begun to decline in most recent reports, concomitant with improved hospital (and outpatient) infection control measures [99-101]. The previously useful distinction of community-acquired (more-resistant) versus healthcare-associated strains has become blurred in recent years. In some, but not all, reports on DFIs, those caused by MRSA have been associated with worse outcomes, e.g., higher clinical failure and amputation rates [102-104]. In the past decade other multidrug-resistant organisms, especially gram-negatives with extended-spectrum beta-lactamases (ESBL) and occasionally vancomycinresistant enterococci, have been more commonly isolated from DFIs [96,105,106]. ESBL-producing organisms usually require treatment with very broad-spectrum antibiotics, e.g., carbapenems. Fungi may be isolated from both infected and uninfec- ted foot wounds, but rarely require systemic antifungal therapy [107]. They are, however, a frequent cause of onychomycosis. D. Bone infection

DFO can present the clinician with formidable diagnostic and therapeutic challenges [78]. It complicates about 50% to 60% of serious, and 10% to 20% of apparently less severe, foot infections in patients presenting to diabetic foot clinics. Bone infection typically occurs by contiguous spread from overlying soft tissue, which may penetrate through the cortex into the marrow. Bone destruction caused by neuroarthropathy (Charcot foot) may be difficult to distinguish from that caused by infection, although the former is less common, tends to occur in patients with profound peripheral neuropathy but adequate arterial perfusion, more frequently involves the midfoot and often occurs in the absence of a skin break [108,109]. Many cases of osteomyelitis are monomicrobial, but most are polymicrobial; S. aureus is the most commonly isolated agent (~50% of cases), while S. epidermidis (~25%), streptococci (~30%), and Enterobacteriaceae (~40%) are also frequent isolates [108]. VII. Treatment Patients with a severe infection (Table 3A) should usually be hospitalized, as they often require surgical interventions, fluid resuscitation, and control of metabolic derangements. Also consider admitting patients with moderate infections if they are unable or unwilling to be adequately involved in wound care, can or will not be able to off-load the affected area, are unlikely to comply with antibiotic therapy, require parenteral antibiotic therapy (that is not available as an outpatient), or need close monitoring of treatment response (see Table 3B). Most other patients with a moderate infection, and almost all with a mild infection, can cautiously be treated as outpatients, with instructions to return if the infection worsens or in-office reevaluation every few days initially [91]. Surgery is the cornerstone of treating many deep soft tissue infections [86], and early intervention might be associated with better outcomes [22,110-112]. Intervening emergently, however, is only needed in specific circumstances, such as: severe infection in an ischemic limb; an abscess accompanied by compartment syndrome or necrosis; systemic sepsis syndrome; or, local infection with bullae, ecchymoses, extreme pain, or unexpected anesthesia. The treating clinician should consider the need for surgery in every infection, which may range from minor debridement or drainage to extensive resections or major amputation. When the wound has a dry eschar, especially in an ischemic foot, it is often best to avoid debriding the necrotic tissue. Major amputation should, and usually can, be avoided except when the limb is non-viable, is affected by life-threatening infection (e.g., gas gangrene or necrotizing fasciitis), or is functionally useless. Revascularization may be needed for an infected ischemic limb. Surgeons operating on a patient with a DFI should have adequate knowledge of the complex anatomy of the foot [22,113]. Figure 1 shows an algorithmic overview of the approach to treating a diabetic patient with a foot lesion. Figure 1 Open in new window Approach to a diabetic patient with a potentially infected foot wound

MDRO= multi-drug resistant organism A. Antimicrobial therapy