Emerging Insights In Diagnosing And Treating Osteomyelitis

Is the probe to bone test losing its gold standard luster? Will nuclear medicine imaging reinvent the diagnostic approach to osteomyelitis? Can antibiotic beads have an impact in treatment? Offering insights from the literature as well as their own clinical experience, these authors answer those questions and many more.

One of the greatest threats to the population of patients with diabetes is osteomyelitis, which may ultimately lead to amputation and limb loss. As podiatric physicians, we spend a large portion of our time in the prevention and management of such infections.

   Accurate diagnosis and early intervention of osteomyelitis is imperative due to the complex and lengthy nature of current treatment regimens.1 Advances in diagnostic modalities and treatment options will hopefully modify the standard of care to maximize successful patient outcomes and prevent the recurrence of infection.

   Osteomyelitis is a disease characterized by bone infection leading to inflammation and bone destruction in the presence of necrosis and new bone formation.2 Vasodilation in the acute inflammatory phase of osteomyelitis accelerates the breakdown of bone, resulting in bone necrosis caused by developing tissue pressure. Bone necrosis subsequently causes the development of abscesses, cloacae and sequestra, which various imaging modalities can commonly detect.2 Nevertheless, the presence of comorbidities that mask obvious signs of infection or limit diagnostic modalities makes the diagnosis of osteomyelitis challenging in all patients.

   Research has overwhelmingly proven that patients suffering from diabetes have at least a 10-fold greater risk of being hospitalized for bone and soft tissue infection in the lower extremity.3 Over the span of two decades, osteomyelitis affects the lower extremity more than any other site in the human body.4 Yet the diagnosis and treatment still prove to be problematic given the lack of a single imaging modality or treatment plan to correctly diagnose or cure osteomyelitis in all cases.5

   Wound history including initial presentation of pedal ulcers, examination of dermatological changes and wound exploration are mandatory for every foot ulcer.6 The typical human response to bacterial invasion and infection involves erythema (vasodilation), edema (increased vessel permeability) and pain (nerve impingement from expanding tissue).7 However, the clinical presentation of infection can often be misleading in the presence of diabetes mellitus, peripheral vascular disease or Charcot neuroarthropathy, all of which compromise local and systemic reactions to infection.7

Questioning The ‘Gold Standard’ Of Osteomyelitis Diagnosis

The clinical diagnosis of bone infection has long weighed heavily in favor of the probe to bone test as an indicator for osteomyelitis. Multiple studies have concluded that palpating or probing to bone through a pedal ulcer is both highly sensitive (66 percent) and specific (85 percent) for osteomyelitis.8 Lavery and colleagues in 2007 suggested using the probe to bone test as a negative predictor of osteomyelitis.9 They determined that diabetic wounds that did not probe to bone in the presence of pedal ulcers were negative for osteomyelitis 98 percent of the time.

   It is important to consider both clinical and laboratory tests when assessing and diagnosing osteomyelitis. Laboratory tests, including complete blood count with differential, basic metabolic panel, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), can often be ambiguous or within normal limits despite the presence of infection. The clinical presentation of osteomyelitis can be subtle. Less than 50 percent of patients with diabetes admitted to the hospital with acute osteomyelitis exhibited leukocytosis or systemic symptoms.10

   Emerging research advocates the use of clinical findings in conjunction with laboratory test as an effective predictor of osteomyelitis. Fleischer and co-workers demonstrated that elevated levels of CRP in combination with an ulceration depth of greater than 3 mm were the most accurate variables when diagnosing osteomyelitis without advanced modalities.11

   The gold standard of diagnosing osteomyelitis continues to be the histological analysis of bone specimens.6 This has allowed physicians to determine the route and duration of antibiotics, or the level of debridement and/or amputation necessary.12 However, the bone biopsy does not come without pitfalls and limitations. A bone biopsy is an invasive procedure that may cause bacterial seeding in the presence of contaminated or infected soft tissue commonly present in diabetic foot ulcers.13

   Meyr and colleagues questioned the acceptance of this “gold standard.”1 The authors performed a retrospective study, submitting 39 tissue specimens to four independent pathologists for analysis. All four pathologists diagnosed osteomyelitis in only 13 of 39 cases or 33 percent of the time. Is it possible the medical community has invested too much faith in the bone biopsy to confirm or exclude the presence of osteomyelitis?

Pertinent Insights On Less Invasive Imaging Modalities

A variety of less invasive imaging modalities can aid in diagnosing osteomyelitis. These modalities include plain radiographs, magnetic resonance imaging (MRI), computed tomography (CT) and nuclear medicine imaging. The modalities are useful in the early detection of osteomyelitis in order to prevent the further spread of infection and promote optimal patient outcomes with prompt intervention.14

   Despite all the advanced imaging options available, plain radiographs remain the preferred modality for the initial assessment of osteomyelitis. Plain radiographs are capable of differentiating infection from trauma or tumor, which all present with similar clinical findings.15 On the other hand, plain radiographs have a limited role in diagnosing acute osteomyelitis due to the “lag time” associated with radiolucency and cortical destruction.16 However, in the presence of chronic infection, defined as a bone infection present for more than 28 days, radiographic changes confirming the diagnosis of osteomyelitis are present 90 percent of the time.17 Therefore, despite all the emerging advances in the diagnosis of osteomyelitis, plain radiographs will remain relevant as an initial modality.

   Magnetic resonance imaging has become a prominent imaging modality in diagnosing osteomyelitis in the foot and ankle. Studies report diagnostic sensitivities of MRI for osteomyelitis in the lower extremity as high as 90 to 95 percent.19 A MRI allows early detection of bone, bone marrow and soft tissue abnormalities with a higher specificity than other advanced imaging modalities.19 Primary MRI findings for osteomyelitis include bone marrow signal abnormalities representing a decreased T1 signal and increased T2 signal.22 Secondary MRI findings involve adjacent soft tissue defects, cellulitis, sinus tracts or cortical bone erosion.20

   However, advances in the evaluation of the MRI of the foot and ankle are still occurring. Collins and colleagues recently established that T1 weighted imaging that demonstrates a decreased marrow signal is superior in diagnosing osteomyelitis in comparison to T2 weighted imaging abnormalities.19

   Limitations of MRI do exist aside from the well-documented contraindications (i.e. pacemaker/automated implantable cardioverter defribrillator). Gadolinium contrast enhanced MRI is not suitable for patients with peripheral vascular disease or chronic kidney disease, comorbidities commonly occurring in those with diabetes.21 Gout, arthritis, trauma and neuropathic osteoarthropathy can also mimic bone marrow signal abnormalities as those abnormalities are indistinguishable from those of osteomyelitis. Therefore, these conditions can drastically diminish the effectiveness and diagnostic capabilities of MRI in assessing osteomyelitis.22

Exploring The Diagnostic Efficacy Of Nuclear Medicine

Nuclear medicine imaging technology, which involves radiolabeled leukocytes and antibody imaging, has developed into an emerging and insightful tool in diagnosing infection, particularly osteomyelitis of the lower extremities.23 Nuclear medicine imaging differs from other diagnostic modalities in that it represents metabolic information, not anatomic information (i.e. CT or MRI), occurring within the human body.24

   Technetium (99mTc), indium (111In), gallium (67Ga) and fluorine (18F) are the most widely available isotopes used in nuclear medicine infection imaging. Technetium in particular is advantageous in nuclear medicine imaging because it emits low-energy gamma radiation, which minimizes patient exposure, maintains a short half-life within the human body and displays better imaging quality than most isotopes.23

   Due to these qualities, technetium was the optimal choice in the development of technetium-99m-d,l hexamethyl propylene amine oxime (Tc-HMPAO), better known by the trade name Ceretec (GE Healthcare).23 The Tc-HMPAO imaging combines the superior imaging noted with the 99mTc triple phase bone scan with the ability to precisely identify localized regions of white blood cell accumulation commonly visible in osteomyelitis.23 Tc-HMPAO has become more commonly used than other white blood cell labeled isotopes for these reasons. The Tc-HMPAO has gained popularity due to its unique advantage in differentiating aseptic inflammation (i.e. Charcot neuroarthropathy) versus infection (i.e. osteomyelitis).25 Smaller prospective studies confirm that white blood cell labeled scintigraphy is comparable to that of MRI in sensitivity and specificity in the diagnosis of osteomyelitis.26

   Similar to 111In-labeled leukocyte imaging, Tc-HMPAO is a timely process delivered to the patient in vitro, typically 24 hours prior to imaging.27 Emerging alternatives to in vitro delivery have occurred by way of using monoclonal antibodies in conjunction with technetium, both of which are delivered in vivo.26 The 99mTC-labeled murine IgM antigranulocyte monoclonal antibody (MoAb) binds to the human polymorphonuclear leukocyte CD15 antigen, which is present in high concentrations in areas of suspected infection or inflammation.28

   Preliminary studies utilizing this technique confirm that MoAb achieves comparable sensitivity and better specificity than 111In-labeled leukocyte imaging in the diagnosis of skeletal osteomyelitis.28 MoAb studies are unique in that they possess the potential to differentiate between Charcot and osteomyelitis. In theory, the destructive changes occurring in Charcot do not elicit the same accumulation of MoAb as osteomyelitis upon imaging.23 Further research is necessary to explore the capability of this imaging modality.

   Single positron emission computed tomography (SPECT) is a nuclear medicine imaging technique that produces a multi-axial image based upon the distribution of gamma-emitting radionuclides within the human body.29 This modality affords better representation and detail of lower extremity anatomy than traditional bone scintigraphy by providing sagittal, coronal and axial views. In addition, SPECT is often constructed to operate with a traditional CT scanner, resulting in what is known as a SPECT/CT.29 The SPECT/CT combines multiphase images visible with bone scintigraphy superimposed over the detailed, high resolution anatomic structures visualized with conventional CT for improved diagnostic capabilities.

   The specificity of diagnosing osteomyelitis in the lower extremity with the use of SPECT alone versus SPECT/CT improves from 50 to 86 percent respectively.30 Previously, a major disadvantage of using nuclear medicine imaging was a lack of specificity of diagnosing osteomyelitis due to poor imaging quality, requiring further modalities to confirm the diagnosis. However, by improving specificity with the combined use of CT imaging, nuclear medicine is emerging as a suitable alternative to MRI.

   The 18F-fluorodeoxyglucose (FDG) is a radiolabeled glucose analogue most commonly paired with positron emission tomography (PET). The FDG-PET is an imaging modality that oncologists traditionally employ in the monitoring and diagnosis of malignancy and metastases.31 Recently, this imaging technique has shown diagnostic capabilities beyond that of cancer, particularly showing promise in the realm of diagnosing inflammation and infection.31 Activated inflammatory cells within the human body possess cell surface glucose transporters. Glucose transporters amplify due to cytokine cell stimulation, resulting in the increased uptake of FDG by macrophages, lymphocytes and other inflammatory cells.32 The usefulness of 18F-FDG in regard to detecting increased glucose metabolic activity, commonly occurring in osteomyelitis, makes this a promising modality to aid in diagnosing osteomyelitis in the future.33

   A meta-analysis by Termaat and co-workers concluded that FDG-PET maintained the highest accuracy in properly diagnosing osteomyelitis in comparison to all other imaging modalities (plain radiographs, MRI, CT, bone scintigraphy).22 Most recently, Nawaz and colleagues compared sensitivity, specificity, positive and negative predictor values, as well as the accuracy of various imaging modalities in diagnosing osteomyelitis in the diabetic foot. The study demonstrated FDG-PET scans to be more specific and accurate in the diagnosis of osteomyelitis in comparison to MRI (see “Comparing The Efficacy Of FDG-PET Scans To Other Modalities” at left).34

   Similar to using SPECT scans, one can combine the FDG-PET scan with CT scans to further improve accuracy and spatial resolution to verify the exact anatomic location of bone infection.35 Although more research is necessary, FDG-PET scans are becoming an acceptable, accurate alternative for diagnosing osteomyelitis.

   Neutropenia, peripheral vascular disease and chronic kidney disease are comorbidities associated with diabetes mellitus that limit the effectiveness and value of nuclear medicine imaging.23 With respect to white blood cell labeled SPECT/CT, the in-vitro process employed not only takes time and effort to perform, but also may delay diagnosis.27 Furthermore, the additional use of CT exposes patients to larger amounts of radiation than other imaging modalities.36

   Certain limitations also exist when considering FDG-PET as an imaging modality. The pre-examination checklist for patients to receive FDG-PET scans is meticulous. Preparation involves strict N.P.O. (except water) four to six hours before examination, avoidance of rigorous activity before and after injection of the radioisotope to minimize muscular uptake by FDG, and strict glycemic control.23 Research has shown the presence of hyperglycemia to reduce the uptake of FDG, which significantly diminishes imaging resolution and diagnostic efficacy.26 Ideal blood glucose levels prior to FDG-PET imaging are less than or equal to 150 mg/dL. Financial costs and restricted availability also limit the application or consideration of SPECT or PET scans in today’s clinical and hospital settings.31

   As emerging research continues to explore the capability of these modalities in the accurate diagnosis of osteomyelitis, the paradigm may ultimately change in favor of nuclear medicine. This is largely due to the fact that nuclear medicine continues to establish the ability to both diagnose and differentiate osteomyelitis from other similarly presenting pedal diseases, largely Charcot neuroarthropathy.

Key Pearls On Antibiotic Treatment

One can approach the treatment of osteomyelitis with a variety of different therapy options. Throughout the years, the standard treatment options have included debridement of all necrotic and non-viable bone and soft tissue with an adjunct of antimicrobial therapy.37-38 More severe cases of osteomyelitis may warrant amputation of the affected digit or limb. It is vital to ensure one has eradicated all remaining infection from the site.

   The current recommendations are that during surgical debridement, one should obtain cultures of the soft tissue and drainage in order to better select specific antibiotic therapy and an appropriate dose.38 Oral and parenteral therapies can achieve similar cure rates, but oral therapies are less expensive and avoid the risks associated with intravenous catheters.38

   Recently, there has been more discussion regarding the use of oral antibiotics as well as the duration of treatment. Spellberg and Lipsky revealed there is no hardcore evidence proving that antibiotic therapy for four to six weeks improves the overall outcome in comparison to shorter treatment regimens.37 One deciding factor in the efficacy of the medication is based on the antibiotic’s ability to penetrate bone. Each antibiotic has a specific ability to permeate bone and this can be greatly decreased in patients with vasculopathy and other peripheral vascular disorders.39

   Keep in mind several other considerations when administering antimicrobial therapy. Patients can be on intravenous medication long-term on an outpatient basis under the proper supervision. Consider close monitoring of several markers such as renal function, liver function, hematologic function and serum drug levels.38 These can include ESR and/or CRP. Trampuz and co-workers state that if these test results have not normalized by the end of the proposed treatment plan, further clinical and diagnostic imaging must occur.38

   The efficacy of antibiotic therapy is clearly dependent on its ability to penetrate bone. One adjunctive way to increase this variable is to utilize hyperbaric oxygen therapy (HBOT), which can help increase intraosseous blood flow. While HBOT is by no means a new modality, there do not seem to be many publications about its adjunctive capability. Hyperbaric oxygen therapy induces neovascularization, which can occur after 14 treatments and continues on for years after therapy has concluded.40 Chen and co-workers demonstrated that HBOT is an effective and safe adjunctive therapy for the management of osteomyelitis in patients who had received adequate surgical debridement or resection and antibiotic therapy.39

What The Literature Reveals About Antibiotic Beads

Initially, the focus of treating bone infection was debridement of infected tissue and/or bone, and to leave the wound “open” to heal once the risk of infection had decreased.37-38

   There are a few minor modifications one can make to increase the effectiveness of antibiotics. There is an emerging method to infuse antibiotics within bone or soft tissue while closing an infected surgical site. The use of antibiotic-impregnated beads arose from an earlier trend of mixing antibiotics with bone cement. Using this same thought process, one would fashion the active antibiotic into several 7.0 mm beads, which can possess a very high surface to volume ratio of the active antibiotic ingredient. Studies have shown prolonged elution rates and a much higher concentration, approximately 50 to 100 times higher, in comparison to conservative treatment when researchers left the antibiotic beads in for a prolonged period of time.41

   Despite this great advancement in treatment, there is one downside. The antibiotic impregnated polymethyl methacrylate (PMMA) bead, which one inserts into the surgical site, later requires surgical removal. This clear disadvantage can occur when evaluating the drug’s elution profile, which shows efficacy of only 50 percent at week four of treatment.42

   Buchholz and colleagues state that since 1969, clinicians have mixed antibiotic powder with a bone cement polymer and by 1972, research showed that acrylic cement with an aminoglycoside was the best combination.43 Mader and co-workers demonstrated that the concentration of clindamycin and tobramycin mixed with PMMA was adequate up until week four while the effectiveness of vancomycin dropped rapidly at day 12.42 Research has now proven biodegradable beads to have the same or better effectiveness as their PMMA predecessor but they do not require the need for a second surgery.42 In comparison to past research with PMMA beads and their antibiotic concentration, biodegradable beads with vancomycin maintained their concentration for well over 32 days and up to 70 days depending on the composition.42

In Conclusion

As research and technology continue to develop new and innovative ideas, the medical field must adapt to the myriad of new products and thoughts. In just a short period of time, the standard of diagnosing and treating osteomyelitis is transforming to incorporate all of the most cutting edge technological advances. These advances include SPECT-CT and FDG-PET to help diagnose bone infection. The continuation of antibiotic therapy in conjunction with HBOT and a new bioabsorbable antibiotic delivery system may help redefine the standard of treatment.

   Dr. Hanft is the Director of Podiatric Medical Education at Baptist Health in South Florida. He is a Fellow of the American College of Foot and Ankle Surgeons.

   Dr. Moskovits is a third-year resident at South Miami/Baptist Hospital.

   Dr. Hall is a second-year resident at South Miami/Baptist Hospital.

References
1. Meyr AJ, Singh S, Zhang X, et. al. Statistical reliability of bone biopsy for the diagnosis of diabetic foot osteomyelitis. J Foot Ankle Surg. 2011; 50(6):663-667.
2. Mader JT. Clinical Features and Microbiology of Osteomyelitis. Up-To-Date, MA, 2003
3. Lavery LA, Armstrong DG, Wunderlich RP, et al. Risk factors for foot infections in individuals with diabetes. Diabetes Care. 2006; 29(6):1288-1293.
4. Lipsky BA. Osteomyelitis of the foot in diabetic patients. Clin Infect Dis. 1997; 25(6):1318-1326.
5. Capriotti G, Chianelli M, Signore A. Nuclear medicine imaging of diabetic foot infection: results of meta-analysis. Nucl Med Commun. 2006; 27(10):757-764.
6. Snyder RJ, Kirsner RS, Warriner RA 3rd, et. al. Consensus recommendations on advancing the standard of care for treating neuropathic foot ulcers in the diabetic patient. Ostomy Wound Manage. 2010; 56(4 Suppl):S1-24.
7. Williams DT, Hilton JR, Harding KG. Diagnosing foot infections in diabetes. Clin Infect Dis. 2004; 39(Suppl2):S83-86.
8. Grayson, ML, Gibbons GW, Balogh K, et. al. Probing to bone in infected pedal ulcers. A clinical sign of underlying osteomyelitis in diabetic patients. JAMA. 1995. 273(9):721-723.
9. Lavery LA, Armstrong DG, Peters EJ, Lipsky BA. Probe-to-bone test for diagnosing diabetic foot osteomyelitis, reliable or relic? Diabetes Care. 2007; 30(2):270-274.
10. Armstrong DG, Lavery LA, Sariaya M, Ashry H. Leukocytosis is a poor indicator of acute osteomyelitis in the diabetic foot. J Foot Ankle Surg. 1996; 35(4):280-283.
11. Fleischer AE, Didyk AA, Woods JB, et. al. Combined clinical and laboratory testing improves diagnostic accuracy for osteomyelitis in the diabetic foot. J Foot Ankle Surg. 2009; 48(1):39-46.
12. Berendt AR, Peters AJ, Bakker K, et. al. Diabetic foot osteomyelitis: a progress report on diagnosis and systematic review of treatment. Diabetes Metab Res Rev. 2008; 24(Suppl1):145-161.
13. Wheat J. Diagnostic strategies in osteomyelitis. Am J Med. 1985; 78(6B):218-224.
14. Caputo GM, Cavanagh PR, Ulbrecht JS, et. al. Assessment and management of foot disease in patients with diabetes. N Eng J Med. 1994; 331(13):854-860.
15. Marx J, Hockberger R, Walls R. Rosen’s Emergency Medicine - Concepts and Clinical Practice, 2-Volume Set, 7th Edition. 2010.
16. Croll SD, Nicholas GG, Osborne MA, et. al. Role of magnetic resonance imaging in the diagnosis of osteomyelitis in diabetic foot infections. J Vasc Surg. 1996; 24(2):266-270.
17. Kothari NA, Pelchovitz DJ. Meyer JS. Imaging of musculoskeletal infections. Radiol Clin North Am. 2011; 39:653-71.
18. Enderle MD, Coerper S, Schweizer HP, et. al. Correlation of imaging techniques to histopathology in patients with diabetic foot syndrome and clinical suspicion of chronic osteomyelitis. The role of high-resolution ultrasound. Diabetes Care. 1999; 22(2):294-299.

19. Collins AS, Schaar MM, Wenger DE, et. al. T-1 weighted MRI characteristics of pedal osteomyelitis. AJR Am J Roentgenol. 2005; 185(2):386-393.
20. Unger E, Moldofsky P, Gatenby R, et al. Diagnosis of osteomyelitis by MR imaging. AJR Am J Roentgenol. 1988; 150(3):605-610.

21. Jeffcoate WJ, Lipsky BA. Controversies in diagnosing and managing osteomyelitis of the foot in diabetes. Clin Infect Dis. 2004: 39(Suppl2):S115-S122.
22. Termaat MF, Raijmakers PG, Scholten HJ, et. al. The accuracy of diagnostic imaging for the assessment of chronic osteomyelitis: a systematic review and meta-analysis. J Bone Joint Surg Am. 2005; 87(11):2464-2471.
23. Schnirring-Judge MA. Utility of nuclear medicine imaging in the diabetic foot. In: Zgonis T (ed.): Surgical Reconstruction of the Diabetic Lower Extremity. Lippincott, Williams and Wilkins, Philadelphia, 2009, pp. 17-18.
24. Eubank WB, Mankoff DA, Schmiedl UP, et. al. Imaging of oncologic patients; benefit of combined CT and FDG PET in the diagnosis of malignancy. AJR Am J Roentgenol. 1998; 171(4):1103-1110.
25. Unal SN, Birinci H, Baktiroglu S, Cantez S. Comparison of Tc-99m methylene diphosphonate, Tc-99m human immune globulin, and Tc-99m-labeled white blood cell scintigraphy in the diabetic foot. Clin N Med. 2001; 26(12):1016-1021.
26. Ertugral MB, Baktiroglu S, Salman S, et. al. The diagnosis of osteomyelitis of the foot in diabetes: microbiological examination vs. magnetic resonance imaging and labeled leukocyte scanning. Diabetic Medicine. 2006; 23(6):649-653.
27. Rubello D, Casara D, Maran A, et al. Role of antigranulocyte Fab’ fragment antibody scintigraphy (LeukoScan) in evaluating bone infection. Nucl Med Commun. 2004; 25(1):39-47.
28. Palestro CJ, Kipper SL, Weiland FL, et. al. Osteomyelitis: Diagnosis with 99mTc-labeled antigranulocyte antibodies compared with diagnosis with 111In-labeled leukocytes – initial experience. Radiology. 2002; 223(3):758-764.
29. Single Positron Emission Computed Technology. MesH Heading. National Library of Medicine. 2011.
30. Horger M, Eschmann SM, Pfannenberg C, et. al. Added value of SPECT/CT in patients suspected of having bone infection: preliminary results. Arch Orthop Trauma Surg. 2007; 127(3):211-221.
31. Markowitz HC, Kantor HB, Cohen R, Khan KH. Is FDG-PET a better imaging option for diabetic osteomyelitis? Podiatry Today. 2010; 23(6)18-22.
32. Kumar R, Basu S, Torgian D, et. al. Role of modern imaging techniques for the diagnosis of infection in the era of 18F-Fluorodeoxyglucose positron emission tomography. Clin Microb Rev. 2008; 21(1):209-224.
33. Keidar Z, Militianu D, Melamed E, et. al. The diabetic foot: initial experience with 18F-FDG PET/CT. J Nucl Med. 2005; 46(3):444-449.
34. Nawaz A, Torigian DA, Siegelman DS, et al. Diagnostic performance of FDG-PET, MRI and plain film radiography (PFR) for diagnosis of osteomyelitis in the diabetic foot. Mol Imaging Biol. 2010; 12(3):335-342.
35. Israel O, Keider Z. Fusion of anatomic and physiologic imaging in the management of patients with cancer. Semin Nucl Med. 2001; 31(3):191-205.
36. Semelka RC, Armao DM, Elias J Jr., Huda W. Imaging strategies to reduce the risk of radiation in CT studies, including selective substitutions with MRI. J Magn Reson Imaging. 2007; 25(5):900-909.
37. Spellberg B, Lipsky BA. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis. 2012; 54(3):393-407.
38. Trampuz A, Zimmerli W. Diagnosis and treatment of infections associated with fracture-fixation devices. J Injury. 2006; 37(Suppl 2):59-66.
39. Chen CE, Ko JY, Fu TH, Wang CJ. Results of chronic osteomyelitis of the femur treated with hyperbaric oxygen: a preliminary report. Chang Gung Medical J. 2004; 27(2):91-97.
40. Marx RE, Johnson RP. Problem wounds in oral and maxillofacial surgery: The role of hyperbaric oxygen. In: Davis JC, Hunt TK (eds.) Problem Wounds - the role of oxygen. Elsevier, New York, 1988, pp. 65-123.
41. Salvati EA, Callaghan JJ, Brause BD, Klein RF, Small RD. Reimplantation in infection: Elution of gentamicin from cement and beads. Clinical Orthopaedics. 1986; 207:83–93.
42. Mader J, Calhoun J, Cobos J. In vitro evaluation of antibiotic diffusion from antibiotic-impregnated biodegradable beads and polymethylmethacrylate beads. Antimicrob Agents Chemother. 1997; 41(2):415-418.
43. Buchholz HW. Management of deep infection of total hip replacement. J Bone Joint Surg. 1981; 63-B(3):342-353.