Review: Role of Inflammatory Markers in the Healing Time of Diabetic Foot Osteomyelitis Treated by Surgery or Antibiotics

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By Temple University School of Podiatric Medicine Journal Review Club
Editor's note: This post is part of the Temple University School of Podiatric Medicine (TUSPM) journal review club blog series. In each blog post, a TUSPM student will review a journal article relevant to wound management and related topics and provide their evaluation of the clinical research therein.

Article: Role of Inflammatory Markers in the Healing Time of Diabetic Foot Osteomyelitis Treated by Surgery or Antibiotics
Authors: Tardáguila-García A, García-Álvarez Y, Sanz-Corbalán I, Álvaro-Afonso FJ, Molines-Barroso RJ, Lázaro-Martínez JL
Journal: J Wound Care. 2020;29(1):5-10
Reviewed by: Ifeoma Nwaedozie, class of 2022, Temple University School of Podiatric Medicine

Introduction

One of the most severe complications of the diabetic foot is diabetic osteomyelitis.1 The diagnosis of diabetic foot osteomyelitis requires clinical suspicion of infection, and an associated soft tissue infection only increases the likelihood of confirming diabetic foot osteomyelitis.3 That said, there are still challenges in the diagnosis of osteomyelitis, such as a bone infection without the clinical manifestations of infection. This occurs in approximately half of all hard-to-heal osteomyelitis cases.4 Currently, the tests used to confirm a diagnosis of diabetic foot osteomyelitis include a probe-to-bone test, radiography, magnetic resonance imaging (MRI), and bone biopsy. Laboratory tests are also used to confirm the diagnosis of diabetic foot osteomyelitis, with the most important biomarker being erythrocyte sedimentation rate (ESR).5-8

Just as there are many ways to diagnose osteomyelitis, there are also many approaches to the treatment of diabetic foot osteomyelitis. Some clinicians prefer the surgical approach alone, and others prefer antibiotics alone.12-19 To date, only one randomized clinical trial has highlighted the outcomes of patients with osteomyelitis secondary to a neuropathic forefoot ulcer who were treated with antibiotics versus surgical treatments.16


Diabetic Foot Ulcer Classification and AssessmentDiabetic Foot Ulcer Classification and Assessment

This study was conducted to analyze the predictive role of initial inflammatory markers in the healing time of diabetic foot osteomyelitis managed by surgical or antibiotic treatment.

Methods

This study took place between September 2014 and December 2017. During this time, patients with a diagnosis of diabetic foot osteomyelitis were chosen to be placed in an observational cohort study based on a myriad of inclusion and exclusion criteria.

Inclusion criteria:

  • The presence of diabetes
  • Age older than18 years
  • Ulcers with an area of less than 5cm2
  • Previous surgical or antibiotic treatment for management of diabetic foot osteomyelitis and demonstrated healing of the ulcer
  • Written consent to participate in the study

Exclusion criteria:

  • Diabetic foot osteomyelitis in a patient with critical limb ischemia
  • Soft tissue infection only
  • Treatment that modified a patient’s biochemical profile (oral or parenteral corticosteroids, immunosuppressive agents, or cytotoxic agents)
  • Acute Charcot foot
  • Pregnancy or lactation
  • Inability or failure to understand the purpose of the study or refusal to be included

Of the 136 eligible patients, 116 were actually included in the study.

Diagnosis of diabetic foot osteomyelitis

For the study, the patients included had a diagnosis of diabetic foot osteomyelitis based on two criteria: probe-to-bone testing and plain radiography.20 The probe-to-bone test, performed with metal forceps, was considered to have a positive result if the clinician could feel a hard or gritty surface. The plain radiographs were positive for osteomyelitis if they showed cortical disruption, periosteal elevation, a sequestrum or involucrum, or gross bone destruction. Some other baseline data collected from the subjects included information on neuropathy status, peripheral arterial disease, and critical limb ischemia.

All subjects who were approved for inclusion in the study then had to have a blood test to gather information on inflammatory markers present at the time of their diabetic foot osteomyelitis diagnosis. These markers included the following: leukocytosis, defined as a white blood cell (WBC) count greater than 11×109/L; an elevated ESR, defined as an ESR greater than 20 mm/ hour; and an elevated C-reactive protein (CRP) count, defined as a CRP level greater than 47.6 nmol/L.
In study by Michail et al,21 the researchers set out to find the most important biomarkers for the diagnosis of diabetes. Serum inflammatory markers, CRP, ESR, WBCs, and procalcitonin (PCT),are common markers in the diagnosis of foot infections in patients with diabetes. Patients with osteomyelitis usually have higher CRP, ESR, WBC, and PCT values than patients with soft tissue infections. Michail et al21 found that all values declined after the start of treatment with antibiotics. It is not clear why these investigators decided on ESR, CRP, and WBC as the most relevant biomarkers in the diagnosis of diabetic foot osteomyelitis, while disregarding the role of PCT.

Treatment groups: surgical versus antibiotic

Patients included in the study were divided into one of two groups (group A: surgical treatment; or group B: antibiotic treatment) based on published recommendations.22

Surgical procedures used in patients with diabetic foot osteomyelitis generally consist of removal of infected bone and tissue without amputation of the foot.23 All of the surgical procedures were performed by the same surgeon, and the bone samples were sent for microbiological and pathological studies to further confirm the diagnosis of diabetic foot osteomyelitis. After each surgical procedure, an antibiogram was performed, and the results dictated the postoperative antibiotic treatment for each patient. Patients with negative culture results received antibiotics according to the Infectious Diseases Society of America (IDSA) guidelines24 for one week after surgery.

Patients in the antibiotic group started their treatment on empiric antibiotic therapy,24 with modifications based on the results of their antibiogram.25 If the results of the culture obtained from the wound was negative, IDSA guideline recommended maintenance of the empiric antibiotic therapy.24 Antibiotic treatment lasted 90 days,16,26 and it was discontinued in patients whose wounds healed sooner than 90 days.

Treatment of the ulcer was the same for both groups, and the patients were treated according to the wound care protocol of the research facility. Treatment consisted of an antimicrobial dressing for two weeks, and offloading was conducted using a removable cast walker. The patients were evaluated twice per week.

Results

There was no significant difference found between groups A and B in terms of elevated value of inflammatory markers.

chart_1_-_ifeoma.png

The main outcome was the time to healing, defined as the complete re-epithelialization of the ulcer.

chart_2_-_ifeoma.png

Discussion

The results of the study showed that healing time is not associated with the value of inflammatory markers regardless of the treatment administered (surgical vs. antibiotic), and both groups had similar data in terms of healing time. The results further demonstrated the importance of an effective treatment regimen for diabetic osteomyelitis, regardless of the severity because even in the presence of a systemic inflammatory response, time to healing was more or less the same with optimal treatment.

There are many factors that determine healing and healing time; however, no evidence was found to support the role of inflammatory markers in the treatment of diabetic foot osteomyelitis. One of the most effective therapeutic strategies consists of early diagnosis and treatment of the bone infection.

Conclusion

There was not enough evidence to confirm the role of inflammatory markers in the healing time of osteomyelitis secondary to diabetic foot ulcers, regardless of the treatment administered.

References

  1. Shahbazian H, Yazdanpanah L, Latifi SM. Risk assessment of patients with diabetes for foot ulcers according to risk classification consensus of international working group on diabetic foot (IWGDF). Pak J Med Sci. 2013;29(3):730-734. https://doi.org/10.12669/pjms.293.3473
  2. Lavery LA, Peters EJ, Armstrong DG, et al. Risk factors for developing osteomyelitis in patients with diabetic foot wounds. Diabetes Res Clin Pract. 2009;83(3):347-352. https://doi.org/10.1016/j.diabres.2008.11.030
  3. Lázaro-Martínez JL, Tardáguila-García A, García-Klepzig JL. Diagnostic and therapeutic update on diabetic foot osteomyelitis. Endocrinol Diabetes Nutr. 2017;64(2):100-108. https://doi. org/10.1016/j.endinu.2016.10.008
  4. Cecilia-Matilla A, Lázaro-Martínez JL, Aragón-Sánchez J, et al. Histopathologic characteristics of bone infection complicating foot ulcers in diabetic patients. J Am Podiatr Med Assoc. 2013;103(1):24-31. https:// doi.org/10.7547/1030024
  5. Malabu UH, Al-Rubeaan KA, Al-Derewish M. Diabetic foot osteomyelitis: usefulness of erythrocyte sedimentation rate in its diagnosis. West Afr J Med. 2007;26(2):113-116.
  6. Ertugrul BM, Savk O, Ozturk B, et al. The diagnosis of diabetic foot osteomyelitis: examination findings and laboratory values. Med Sci Monit. 2009;15(6):CR307–CR312
  7. Lipsky BA, Aragón-Sánchez J, Diggle M, et al.; International Working Group on the Diabetic Foot (IWGDF). IWGDF guidance on the diagnosis and management of foot infections in persons with diabetes. Diabetes Metab Res Rev. 2016;32(Suppl 1):45-74. https://doi.org/10.1002/ dmrr.2699
  8. van Asten SAV, Peters EJG, Xi Y, Lavery LA. The role of biomarkers to diagnose diabetic foot osteomyelitis. A meta-analysis. Curr Diabetes Rev. 2016;12(4):396-402. https://doi.org/10.2174/1573399811666150713104401
  9. Markanday A. Diagnosing diabetic foot osteomyelitis: narrative review and a suggested 2-step score-based diagnostic pathway for clinicians. Open Forum Infect Dis. 2014;1(2):ofu060. https://doi.org/10.1093/ofid/ ofu060
  10. van Asten SA, Jupiter DC, Mithani M, et al. Erythrocyte sedimentation rate and C-reactive protein to monitor treatment outcomes in diabetic foot osteomyelitis. Int Wound J. 2017;14(1):142-148. https://doi.org/10.1111/ iwj.12574
  11. Lipsky BA. Bone of contention: diagnosing diabetic foot osteomyelitis. Clin Infect Dis. 2008;47(4):528-530. https://doi.org/10.1086/590012
  12. Aragón-Sánchez J. Treatment of diabetic foot osteomyelitis: a surgical critique. Int J Low Extrem Wounds. 2010;9(1):37-59. https://doi. org/10.1177/1534734610361949
  13. Aragón-Sánchez FJ, Cabrera-Galván JJ, Quintana-Marrero Y, et al. Outcomes of surgical treatment of diabetic foot osteomyelitis: a series of 185 patients with histopathological confirmation of bone involvement. Diabetologia. 2008;51(11):1962-1970. https://doi.org/10.1007/ s00125-008-1131-8
  14. Karchmer AW, Gibbons GW. Foot infections in diabetes: evaluation and management. Curr Clin Top Infect Dis. 1994; 4:1-22.
  15. Aragón-Sánchez J, Lázaro-Martínez JL, Quintana-Marrero Y, et al. Super-oxidized solution (Dermacyn Wound Care) as adjuvant treatment in the postoperative management of complicated diabetic foot osteomyelitis: preliminary experience in a specialized department. Int J Low Extrem Wounds. 2013;12(2):130-137. https://doi.org/10.1177/1534734613476710
  16. Lázaro-Martínez JL, Aragón-Sánchez J, García-Morales E. Antibiotics versus conservative surgery for treating diabetic foot osteomyelitis: a randomized comparative trial. Diabetes Care. 2014;37(3):789-795. https:// doi.org/10.2337/dc13-1526
  17. Embil JM, Rose G, Trepman E, et al. Oral antimicrobial therapy for diabetic foot osteomyelitis. Foot Ankle Int. 2006;27(10):771-779. https:// doi.org/10.1177/107110070602701003
  18. Senneville E, Lombart A, Beltrand E, et al. Outcome of diabetic foot osteomyelitis treated nonsurgically: a retrospective cohort study. Diabetes Care. 2008;31(4):637-642. https://doi.org/10.2337/dc07-1744
  19. Game FL, Jeffcoate WJ. Primarily non-surgical management of osteomyelitis of the foot in diabetes. Diabetologia. 2008;51(6):962-967. https://doi.org/10.1007/s00125-008-0976-1
  20. Aragón-Sánchez J, Lipsky BA, Lázaro-Martínez JL. Diagnosing diabetic foot osteomyelitis: is the combination of probe-to-bone test and plain radiography sufficient for high-risk inpatients? Diabet Med. 2011;28(2):191-194. https://doi.org/10.1111/j.1464-5491.2010.03150.x
  21. Michail M, Jude E, Liaskos C, et al. The performance of serum inflammatory markers for the diagnosis and follow-up of patients with osteomyelitis. Int J Low Extrem Wounds. 2013;12(2):94-99. https://doi.org/10.1177/1534734613486152
  22. Lipsky BA. Treating diabetic foot osteomyelitis primarily with surgery or antibiotics: have we answered the question? Diabetes Care. 2014;37(3):593-595. https://doi.org/10.2337/dc13-2510.
  23. Aragón-Sánchez J. Treatment of diabetic foot osteomyelitis: a surgical critique. Int J Low Extrem Wounds. 2010;9(1):37-59. https://doi. org/10.1177/1534734610361949
  24. Lipsky BA, Berendt AR, Cornia PB, et al.; Infectious Diseases Society of America. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54(12):e132-e173. https://doi.org/10.1093/cid/cis346
  25. Malone M, Bowling FL, Gannass A, et al. Deep wound cultures correlate well with bone biopsy culture in diabetic foot osteomyelitis. Diabetes Metab Res Rev. 2013;29(7):546-550
  26. Tone A, Nguyen S, Devemy F, et al. Six-week versus twelve-week antibiotic therapy for nonsurgically treated diabetic foot osteomyelitis: a multicenter open-label controlled randomized study. Diabetes Care. 2015;38(2):302-307. https://doi.org/10.2337/dc14-1514

About The Authorifeoma_nwaedozie.jpg
Ifeoma Nwaedozie is a second-year podiatric medical student at Temple University School of Podiatric Medicine (TUSPM) in Philadelphia, PA. Following graduation, Ifeoma completed her post-baccalaureate sciences for medical school in New York City’s CUNY educational system, before matriculating at Liberty University’s Master of Biomedical Sciences program in 2014. At Liberty University, Ifeoma worked as a Graduate Student Assistant, teaching Anatomy and Physiology labs for Liberty’s nursing program. On graduating her Master’s program in 2016, Ifeoma moved back to New York and began teaching in the city’s biggest charter school network as an 11th and 12th grade Biology and Physics teacher. During this time Ifeoma shadowed doctors of various specialties, but eventually she gravitated towards podiatric medicine because of the hands-on and broad approaches (biomechanical, medical, surgical) to treating patients. In the fall of 2018, Ifeoma matriculated at TUSPM. Although she enjoys all of her classes, Ifeoma has found particular interest in classes emphasizing diabetic limb salvaging and wound care. She hopes to marry her background in education with her future as a podiatrist to educate at-risk communities on the importance of foot care.

Dr. James McGuire is the director of the Leonard S. Abrams Center for Advanced Wound Healing and an associate professor of the Department of Podiatric Medicine and Orthopedics at the Temple University School of Podiatric Medicine in Philadelphia.

The views and opinions expressed in this blog are solely those of the author, and do not represent the views of WoundSource, Kestrel Health Information, Inc., its affiliates, or subsidiary companies.

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