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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 footExpert opinion on the management of infections in the diabetic footSpecific 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

AbstractIntroductionMethodsResultsTypes of studyIndividual topicsEarly surgical interventionHealth economicsTopical treatment with antiseptic agentsGranulocyte-colony stimulating factorProcaine plus polyvinylpyrrolidoneHyperbaric oxygen therapyAntibiotic choice based on bone biopsyComparison of antibiotic regimens - skin and soft tissue infection aloneComparison of antibiotic regimens - studies including patients with osteomyelitisDiscussionAcknowledgementsReferences

Appendices

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


I. Abstract

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

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

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

II. Introduction

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

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

III. Methods

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

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

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

IV. Results

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

Types of study

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

Individual topics


a. Early surgical intervention

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

b. Health economics

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

c. Topical treatment with antiseptic agents

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

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

d. Granulocyte-colony stimulating factor

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

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

e. Procaine plus polyvinylpyrrolidone

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

f. Hyperbaric oxygen therapy

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

g. Antibiotic choice based on bone biopsy

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

h. Comparison of antibiotic regimens - skin and soft tissue infection alone

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

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

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

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

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

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

V. Discussion

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

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

The available data suggest that it is possible to treat selected patients with a diabetic foot infection in an outpatient setting with an oral antibiotic regimen, either initially or after switch from parenteral therapy. The study of a topical antibiotic, pexiganan, is promising, but this agent will need to undergo further testing before it can be evaluated for approval. We identified few new data on the management of diabetic foot osteomyelitis since our relatively recent systematic review [1].

The reported data on skin and soft tissue infection confirmed earlier observations suggesting that Gram-positive microorganisms play a large role in infection of the foot in diabetes. Despite this, there is emerging observational evidence that Gram-negative species might be of greater significance in some populations, and in South Asia, in particular [40-42]. If confirmed, this would have an important impact on the selection of antibiotic regimens and the rates of clinical success.

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

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

VI. Acknowledgements

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

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

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  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.
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  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.
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  43. Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, LeFrock JL, Lew DP, Mader JT, Norden C, Tan JS. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004; 39(7): 885-910.
  44. International Working Group on the Diabetic Foot. International Consensus on the Diabetic Foot and Supplements. 2007; : DVD.

APPENDIX


A. Literature search string for Pubmed

((Diabetes Mellitus OR diabetic))

AND

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

AND

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

B. Literature search strings for Embase

Map to preferred terminology (with spell check)
Also search as free text
Include sub-terms/derivatives (explosion search)

(Diabetes Mellitus) OR diabetic

AND

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

AND

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

AND

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

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