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STUDY DESCRIPTION

Diabetes Osteomyelitis Managment and Outcome (DOMO) Study

Background

Bone infections in persons with diabetes generally occur by direct extension of infection from contiguous soft tissue (1,2) and available data suggest that outcomes for foot infections in diabetic patients are worse when bone is involved. Thus, recent studies of soft tissue infections have reported clinical cure rates of 85-90% (3,4), whereas those observed following antibiotic treatment for osteomyelitis of the foot in diabetes are in the region of 65-70% (5-7). Compared with soft tissue infection alone, osteomyelitis is also associated with a higher risk of lower extremity amputation (8,9). In a recent report by Henke and colleagues, management of osteomyelitis of the lower limb in 237 individuals (80% with diabetes) by aggressive debridement and revascularisation resulted in wound healing in just 56% and limb salvage in only 80% (10). Diabetic foot complications are now the most frequent cause of non-traumatic lower extremity amputation, and osteomyelitis is the commonest precipitating factor.

Osteomyelitis of the foot thus represents a major clinical threat in diabetes. Despite this, many medical centres lack formal guidelines for management of this problem. Those that exist vary widely and are not based on data from prospective studies. Many authorities emphasise the importance of early removal of infected bone (1,2,11), while others rely primarily on the long-term administration of antibiotics (6,7,12-14). Opinions on the route and duration of antibiotic therapy also vary widely (15,16). These and other uncertainties demonstrate the need for further data upon which to base clinical management. Properly designed studies can provide evidence on which to formulate strategies for best practice, with the aim of achieving the optimal outcome for the patient while minimising inappropriate surgery, use of antibiotics and other resources. While the trials necessary to address these questions are difficult to design (6), the difficulties are not insuperable (17).

A recent survey undertaken by the Emerging Infections Network (EIN) of the Infectious Diseases Society of America (IDSA) asked members what rates of primary treatment failure they regarded as acceptable (18). Of the 356 who responded, 75% would accept a failure rate of 7.8%, while only 25% felt that a rate 28.4% was acceptable. However, the evidence from such published data as there are, suggests that a failure rate of 25% or more may be more usual than exceptional. While a recent single centre study of primarily non-surgical therapy in 93 cases (7) reported a remission rate of just over 80%, the collated results of over 500 patients treated mostly medically indicated a somewhat lower response rate (6). Similarly, the incidence of apparent cure in a series of 147 patients managed in a single UK centre between 2000 and 2004 was only just over 60% (19). The response to primarily surgical management is less well documented, but Henke and colleagues recently reported an apparent cure rate of just over 50%, while earlier retrospective observations of digit amputation (principally for infection, and largely in patients with diabetes) indicated that the primary intervention was associated with persistent or recurrent infection in the majority of patients (20,21).

It is clear that further evidence is required to underpin strategies for routine care. The first step is to document the outcomes of current practices and their associated success rates. Hence, the aim of the proposed study is to determine the actual response to management of diabetic foot osteomyelitis in routine clinical practice in a large number of clinical centres world wide. If the observed rates of remission or apparent cure fall short of the predetermined target, the next stage will be to identify both features of individual cases and their methods of treatment that may be associated with clinical failure. The identification of such factors will help generate hypotheses that will form the basis of future prospective research.


 

Outline proposal

This will be an internet-based survey of the response to routine management in a large number of centres in different countries. We will approach clinicians in North America (through EIN, American Diabetes Association, American Podiatric Medicine Association), the UK (through the Diabetes UK, the Federation of Infection Societies), continental Europe (through the Diabetic Foot Study Group of the European Association for the Study of Diabetes), and the rest of the world (through the International Working Group on the Diabetic Foot, IWGDF, of the International Diabetes Federation) and invite them to participate in the study. Clinicians will be asked initially to express their interest and to give anonymised information on their professional training, their place of work and their usual approach to management. They will be given ID and PIN numbers, allowing them access to the secure DOMO website.

Clinicians will then be asked to enter details of the next newly presenting eligible case of osteomyelitis of the foot in a patient with diabetes that presents, or is referred, to them. Eligible cases will be those with probable (where the probability is sufficient to initiate immediate treatment) or definite infection of bone in the foot (including the malleoli), which is newly diagnosed by the registering clinician, which has not been previously managed by clinical staff in other departments or institutions with any intervention other than intravenous or oral antibiotics, and the total duration of any previous antibiotic therapy should not exceed 14 days. The option to enroll a first case will remain open for only 6 months from the start of the recruitment phase of the project. Once the clinician enrolls a case, he/she will be also asked to register every other case that presents or is referred to him/her in the succeeding 4 weeks. This design is intended to minimise the potential problem of case selection.

Anonymised details of each case will be entered by the clinician onto a specially constructed database located on a secure website, with cases being identified only by study number. We will record the site of registration, gender and date of birth to eliminate the possibility of duplicate entry. Following initial registration, participants will be invited through the use of structured questionnaires to provide details on the results of further test, of interventions and outcomes at intervals up to 12 months after case enrollment. Participants will be able to gain access to the details of cases which they themselves have entered, but not to any other cases.

Analyses will be directed towards determining the actual rates of clinical success and failure of the primary intervention, as well as differences observed among various centres, communities and countries, among different pre-defined patient groups and among patients managed in different ways. Apart from determining the overall incidence of apparent cure or remission, the principal aim will be to determine whether the outcome in those whose management is primarily non-surgical is different from that in those who undergo early surgical excision of infected bone. We will also seek differences in outcomes by specific agent and duration of antibiotic therapy, by routes of antibiotic therapy (intravenous or oral) and by whether or not the antibiotic regimen was selected by the results of microbiological studies. We will also determine if outcome of treatment correlates with any adjunctive treatments, such as hyperbaric oxygen or granulocyte-colony stimulating factor.


 

Diagnosis of osteomyelitis

There are no universally agreed criteria for the diagnosis of osteomyelitis of the foot in persons with diabetes. For this reason, the diagnosis of osteomyelitis made using the methods normally employed by the participating clinicians and centres and which would lead the clinician to initiate treatment. The diagnostic process may include using one or any combination of: clinical findings (e.g. depth of ulcer, visible bone, probe-to-bone test, long term clinical follow-up), hematological tests (e.g., erythrocyte sedimentation rate, C-reactive protein), imaging tests (e.g. plain radiographs, nuclear medicine studies, computed tomography, magnetic resonance and other scans), or bone biopsy (for histology or culture). Investigators will be asked to rate their diagnosis of osteomyelitis as "definite" or "probable" or "possible" and they will have the option to revise this diagnosis when further evidence becomes available.


 

Dataset

The details of the data to be recorded are shown on the attached print-outs from the website (www.domo.org.uk). It should be noted that the website also includes drop-down menus to facilitate completion, but the details of these are not displayed.

1 Clinician details
Table 2 lists the details of professional practice collected when a clinician initially expresses interest, and which is required before the clinician is issued with the password and PIN necessary to register clinical details. These details include identification details, primary specialty training and a summary of usual approaches to management of osteomyelitis of the foot in diabetes.

2 Case details
The details recorded on each individual are those of gender, data of birth, diabetes type, type of clinical care (private, insurance, state etc), diabetes complications and the clinical signs at presentation. The date of birth is recorded only to provide a check against the same patient being entered twice. No other patient-identifiable details will be collected. Data retrieved at Week 0 include detail on the criteria used as the basis of diagnosis: the extent of bone infection, the diagnostic criteria the clinician used for infection, and details of the primary and any adjunctive treatment. Other pages include options to enter detailed information on any amputations undertaken, on the results of confirmatory blood tests and on antibiotics administered.

Clinicians will receive acknowledgement of case details by return electronic mail, and the case will be identified by study number. After two weeks the registering clinician (or nominated deputy) will be approached for further information available at that time, concerning confirmation of diagnosis, results of diagnostic studies, interventions, adverse events and clinical outcomes. Further information will be requested at 4, 8, 12 and 26 weeks after enrollment, including details of continuing treatments and outcomes. There will be no requirement for the patient to be seen at these intervals - only that the clinician completes the form on the basis of information that would have been available at each of these time intervals. The usual management of the patient will not be affected in any way. Final outcome will be documented at 12 months.

3 Other cases
During the 4 weeks following registration of their first case, each professional will be asked to register every other case of newly presenting osteomyelitis of the foot in diabetes that is managed by the same unit. Follow up information will also be required for each of these patients. We will provide clinicians with regular feedback on the numbers of registrations worldwide.


 

Analyses

The expectation is that up to 1000 cases may be registered during the 6 month active recruitment phase. Data will be analysed to determine the success and failure of the primary treatment, and to see whether a greater or lesser incidence of clinical failure is associated with any specific case type or management strategy. The primary outcome measure will be the preservation of the affected foot (with or without resection of bone, but avoiding major [above the ankle] amputation) with clinical resolution of infection and without the need for continued antibiotic treatment (except for unrelated reasons) for at least 6 months.

Secondary outcome measures will include: time to apparent eradication or arrest of bone infection; percentage of patients with no apparent bone infection at 3, 6 and 12 months; rates of minor amputation, major amputation, other elective surgical procedures; percent requiring hospital admission; days of intravenous antibiotic therapy and/or oral antibiotic therapy; rates of clinically significant adverse events (e.g., post-operative complications, antibiotic-associated toxicity); percentage with healing of associated ulcer; antibiotic free days to 12 months; development of new foot lesions (ulcers or infections) and survival. The data may also be used to help validate the definitions of diabetic foot osteomyelitis which have been newly formulated by the IWGDF.

 

Ethical Issues 

 
We sought clarification about the need for ethical approval from the National Research Ethics Service in UK, and received the following reply, dated 18th January 2008. Participants should consider whether or not to seek approval of their own ethical committees or IRBs, or whether they are confident that criteria adopted by the NHS in UK apply also to their own site of working.
 

Response by the National Research Ethics Service in UK concerning the need to apply for ethical approval of the DOMO project:

Our leaflet “Defining Research”, which explains how we differentiate research from other activities, is published at:

http://www.nres.npsa.nhs.uk/applicants/help/guidance.htm#audit

Based on the information you provided, our advice is that the project is not considered to be research according to this guidance.  Therefore it does not require ethical review by a NHS Research Ethics Committee.

If you are undertaking the project within the NHS, you should check with the relevant NHS care organisation(s) what other review arrangements or sources of advice apply to projects of this type.  Guidance may be available from the clinical governance office.

Although ethical review by a NHS REC is not necessary in this case, all types of study involving human participants should be conducted in accordance with basic ethical principles such as informed consent and respect for the confidentiality of participants.  When processing identifiable data there are also legal requirements under the Data Protection Act 2000.  When undertaking an audit or service/therapy evaluation, the investigator and his/her team are responsible for considering the ethics of their project with advice from within their organisation.  University projects may require approval by the university ethics committee.

This response should not be interpreted as giving a form of ethical approval or any endorsement of the project, but it may be provided to a journal or other body as evidence that ethical approval is not required under NHS research governance arrangements.

However, if you, your sponsor/funder or any NHS organisation feel that the project should be managed as research and/or that ethical review by a NHS REC is essential, please write setting out your reasons and we will be pleased to consider further. 

 

 

Implications

This survey is likely to reveal widely varying practices and rates of apparent success of the primary therapy used at different centres. We anticipate that the rates of treatment success will mostly fall below the "acceptable" rates in the criteria published in the EIN survey. These data will allow the construction of a programme of research that addresses the key clinical questions concerning the management of osteomyelitis of the foot in diabetes, which need to be answered. The aims of such research will be to determine: the need for, and type of, microbiological and histological studies required in routine care; the benefit of culture-based targeting of antibiotic therapy; the need for and optimal duration of intravenous therapy; the total duration of antibiotic therapy required; the value of any adjunctive treatments; and the benefits and risks of early surgical resection of infected bone.


 

Study Plan

Planned start date 1 May 2008

Month 0 Project start. Disseminate information about the study through DFSG, IWGDF, EIN, American Diabetes Association, Diabetes UK, IDSA, FIS and other national diabetes and infectious diseases associations, and societies of podiatric medicine, wound care specialists and other relevant professional bodies.
Months 1-3 Appointment of administrative staff. Agree intended analyses. Refine dataset and mechanisms for data capture. Trial data entry and analysis using a small number of selected sites both on paper and electronically. Finalise data entry programme. Potential participants invited to express interest and to complete Professional details form (Table 1). Initiate regular feedback on progress.
Month 4 Launch of active phase of recruitment.
Month 10 End of active phase of recruitment.
Months 22-23 Last 12 month questionnaires sent out and returned.
Months 23-24 Completion of analysis and presentation of final results.
     
 

References

  1. Lipsky, B. A., A. R. Berendt, et al. (2004). "IDSA Guidelines: Diagnosis and treatment of diabetic foot infections." Clinical Infectious Diseases 39: 885-910.
  2. Norden, C. (1994). Infections of bone in patients with diabetes. Infections in Bones and Joints. C. Norden, W. J. Gillespie and S. Nade. Boston, Blackwell Scientific Publications: 181-197.
  3. Lipsky, B. A., K. Itani, et al. (2004). "Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate." Clin Infect Dis 38(1): 17-24
  4. Lipsky, B. A., D. G. Armstrong, et al. (2005). "Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial." Lancet 366(9498): 1695-703.
  5. Lipsky, B. A. (1997). "Osteomyelitis of the foot in diabetic patients." Clin Infect Dis 25(6): 1318-26.
  6. Jeffcoate, W. J. and B. A. Lipsky (2004). "Controversies in diagnosing and managing osteomyelitis of the foot in diabetes." Clin Infect Dis 39 Suppl 2: S115-22.
  7. Embil, J. M., G. Rose, et al. (2006). "Oral antimicrobial therapy for diabetic foot osteomyelitis." Foot Ankle Int 27(10): 771-9
  8. Balsells, M., J. Viade, et al. (1997). "Prevalence of osteomyelitis in non-healing diabetic foot ulcers: usefulness of radiologic and scintigraphic findings." Diabetes Res Clin Pract 38(2): 123-7
  9. Lavery, L. A., Armstrong D.G., Wunderlich R.P., Mohler M.J., Wendel C.S., Lipsky B.A. (2006). "Risk factors for foot infection in individuals with diabetes." Diabetes Care 29(6): 1288-93.
  10. Henke, P. K., S. A. Blackburn, et al. (2005). "Osteomyelitis of the foot and toe in adults is a surgical disease: conservative management worsens lower extremity salvage." Ann Surg 241(6): 885-92;
  11. Ha Van, G., H. Siney, et al. (1996). "Treatment of osteomyelitis in the diabetic foot. Contribution of conservative surgery." Diabetes Care 19(11): 1257-60.
  12. Bamberger, D. M., G. P. Daus, et al. (1987). "Osteomyelitis in the feet of diabetic patients. Long-term results, prognostic factors, and the role of antimicrobial and surgical therapy." Am J Med 83(4): 653-60.
  13. Venkatesan, P., S. Lawn, et al. (1997). "Conservative management of osteomyelitis in the feet of diabetic patients." Diabet Med 14(6): 487-90.
  14. Pittet, D., B. Wyssa, et al. (1999). "Outcome of diabetic foot infections treated conservatively: a retrospective cohort study with long-term follow-up." Arch Intern Med 159(8): 851-6.
  15. Lazzarini, L., B. A. Lipsky, et al. (2005). "Antibiotic treatment of osteomyelitis: what have we learned from 30 years of clinical trials?" Int J Infect Dis 9(3): 127-38
  16. Bonham, P. (2001). "A critical review of the literature: part II: antibiotic treatment of osteomyelitis in patients with diabetes and foot ulcers." Journal of Wound, Ostomy and Continence Nursing 28(3): 141-149.
  17. Jeffcoate, W. J. (2006). "The evidence base to guide the use of antibiotics in foot ulcers in people with diabetes is thin, but what are we going to do about it?" Diabet Med 23(4): 339-40
  18. Perencevich, E. N., K. S. Kaye, et al. (2004). "Acceptable rates of treatment failure in osteomyelitis involving the diabetic foot: a survey of infectious diseases consultants." Clin Infect Dis 38(4): 476-82
  19. Game, F.
  20. Murdoch, D. P., D. G. Armstrong, et al. (1997). "The natural history of great toe amputations." J Foot Ankle Surg 36(3): 204-8; discussion 256.
  21. Nehler, M. R., T. A. Whitehill, et al. (1999). Intermediate-term outcome of primary digit amputations in patients with diabetes mellitus who have forefoot sepsis requiring hospitalization and presumed adequate circulatory status. J Vasc Surg 30(3): 509-17.

 

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Last modified: 05/01/08