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Case report.

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Case Report: Treatment of Chronic Osteomyelitis

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Cameron R. Wolfe, Case Report: Treatment of Chronic Osteomyelitis, Clinical Infectious Diseases , Volume 52, Issue suppl_7, June 2011, Pages S538–S541, https://doi.org/10.1093/cid/cir169

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Presented is a case of chronic methicillin-resistant Staphylococcus aureus osteomyelitis, which was unsuccessfully treated with multiple courses of debridement and potent antibiotic therapies. Amputation of the patient's lower limb was believed to be the only option remaining. A compassionate access program, with approval from the US Food and Drug Administration and the institutional review board, enabled the patient to undergo a course of treatment with oral fusidic acid (CEM-102). The patient tolerated the drug well, with no significant toxicities noted to date. His infection improved rapidly, his flap healed, he has returned to work part-time, and he continues to take daily suppressive doses of oral CEM-102.

Reported is a case of chronic methicillin-resistant Staphylococcus aureus (MRSA) femoral osteomyelitis. Despite multiple debridements and failed curative antibiotic courses, the use of suppressive fusidic acid (CEM-102) resulted in the sparing of the lower limb and resolution of acute infective symptoms. Although presently not registered in the United States, fusidic acid offers an attractive alternative for difficult-to-treat cases of MRSA infection as a well-tolerated, oral agent. It has been used widely since the 1960s and is currently available in Europe, Australia, New Zealand, and Israel, where it is available in oral and topical form. Increasing drug resistance, noted especially in staphylococcal isolates, has lead to revitalized interest in its use in countries where it is currently unavailable, such as the United States [ 1 ], as well as cautious attempts at restriction in places where it is widely used [ 2 ].

In 2008, a 49-year-old man presented with a myxoid/round cell liposarcoma (T2b, N0, and M0), emanating from the lateral head of the gastrocnemius, posterior to the left knee. He had a past medical history notable for smoking, coronary artery disease status after coronary artery stent placement, insulin-requiring diabetes mellitus, and hypertension. After 36 days of neoadjuvant external beam radiotherapy, the patient underwent a wide local excision, neuroplasty of the peritoneal and sciatic nerves, and complex exploration and repair of the popliteal artery. He required subperiosteal dissection to free the tumor capsule. He has been clinically and radiologically free of tumor for >48 months.

He was readmitted to the hospital 4 weeks after the operation with increasing pain, decreased range of movement, fever, and serosanguinous drainage from the wound. During 4 sequential operative joint washouts, he was noted to have copious deep purulence extending into the posterior compartments of the knee joint. Two of 2 blood cultures and numerous operative cultures grew MRSA. Minimum inhibitory concentration data for the MRSA isolate are presented in Table 1 . His subsequent treatment consisted of intravenous vancomycin, achieving plasma drug levels approximating 20 μg/mL. This treatment was extended for 8 weeks, given the clinical concern for possible osteomyelitis in an area with impaired vascular supply after radiotherapy and popliteal artery damage. Treatment was complicated by significant tinnitus and a decline in hearing.

Susceptibility Testing for Final Staphylococcus aureus Isolate

NOTE.  Isolates were tested at JMI Laboratories, and with exception of CEM-102, which was verified at my institution. Criteria were based on CLSI interpretive guidelines. MIC, minimum inhibitory concentration; R, resistant; S, susceptible.

The patient experienced relapse with recurrent septic arthritis 2 months later; MRSA was again isolated. On this occasion, he was treated with 6 weeks of intravenous daptomycin (6 mg/kg per day), followed by oral trimethoprim-sulfamethoxazole suppressive therapy. Oral therapy was complicated by the development of persistent fever and a diffuse allergic rash; oral antibiotics were discontinued.

The patient then remained well for almost 5 months, with improving mobility and decreasing pain, although his wound was healing slowly. Of note, his Erythrocyte Sedimentation Rate had decreased from a peak of 107 mm/h to 26 mm/h. Unfortunately, the patient experienced clinically relapse once more, with MRSA again isolated from purulence found in deep radiation–affected tissues and bone. After repeated debridements, a pedicle lateral gastrocnemius muscle flap with split-thickness skin graft was applied in an attempt to improve the local vascular flow and close an increasing skin defect (see Figure 1 ). He was treated again with 6 weeks of intravenous daptomycin (6 mg/kg per day), followed by attempted suppression with both rifampicin and doxycycline, to allow tissues to heal; however, intractable nausea and vomiting occurred while the patient was receiving these 2 drugs, both in combination and independently. Despite the flap, a fourth relapse occurred 2 months later. After additional femoral debridement, the patient was given daptomycin (10 mg/kg/day for 10 weeks), during which time he also underwent daily hyperbaric oxygen therapy.

Large skin defect after multiple courses of antibiotic therapy.

When a fifth clinical failure occurred, a final attempt at curative treatment was constructed with intravenous telavancin (10 mg/kg per day) and implantable vancomycin beads in the femoral shaft after debridement and sequestrectomy. Three days into the course of telavancin, the patient experienced a precipitous decline in renal function, with his serum creatinine level increasing from 1.0 to 2.3 mg/dL. The medication was discontinued, and although the patient’s renal function stabilized, no additional curative antibiotic treatments were deemed appropriate. The patient was informed amputation would be necessary. Two chronic sinuses had formed adjacent to his flap, his range of movement at the knee was restricted to 10 degrees of flexion, he had become wheelchair-bound, and he required a combination of analgesic therapies. Ultimate failure to cure was attributed to a combination of inadequate debridement and poor vascular supply (ie, irradiated, scarred tissue, with restricted popliteal artery flow, in a patient with preexisting peripheral vascular disease).

Before amputation, oral fusidic acid (CEM-102) was made available through an expanded-access program, with the approval of the hospital institutional review board. The investigational drug (CEM-102) was supplied by Cempra Pharmaceuticals. A loading dose of 1500 mg twice per day of CEM-102 was given for 24 h, followed by 900 mg twice per day thereafter. During the first week of therapy, fusidic acid was combined with oral linezolid (600 mg twice per day) to reduce the microbiologic burden. The patient tolerated the medication well, although during the first week, he developed moderate anemia requiring transfusion (nadir hemoglobin concentration, 6.8 g/dL; hematocrit, 0.22 L/L) that was believed to be secondary to chronic inflammation and linezolid.

At last clinical review, the patient has now been receiving CEM-102 for almost 9 months without clinical relapse. His anemia has steadily resolved (the most recent hemoglobin concentration was 12.1g/dL), his mobility has improved such that he is able to mobilize with a single-point stick, and his analgesic requirement has been reduced. Both of his draining sinuses have closed, and his Erythrocyte Sedimentation Rate has once again decreased from 120 to 15 mm/hr (see Figure 2 ). He returned to part-time work for the first time in >2 years.

Defect after 2.5 weeks of fusidic acid therapy. The bulge is the healed flap.

Chronic adult-onset staphylococcal osteomyelitis is an illness with significant morbidity, and often the only cure is through amputation. Our patient was prepared to explore multiple suppressive options, given that he had already survived limb-sparing surgery for his original liposarcoma. By the end of 2 long years, he was intolerant to vancomycin, telavancin, trimethoprim-sulfamethoxaole, linezolid, doxycycline, and rifampicin, and high-dose, prolonged daptomycin infusions had failed twice. Fusidic acid (CEM-102) provided a well-tolerated oral alternative for long-term suppression, without any significant toxicities to date.

S. aureus is the leading cause of osteomyelitis; not only does it adhere to bone, but it resists immune-modulated clearance and destruction through biofilm production and other microbiologic mechanisms [ 3 ]. Successful eradication therefore requires ample—and indeed, aggressive—surgical debridement to remove the bacterial load and devitalized bone. Removal of dead space, restoration of blood flow, and adequate soft-tissue coverage are also important, although as our case demonstrated, this can often be difficult to achieve. Furthermore, a prolonged course of antibiotics is usually recommended, with most clinicians favoring 4–6 weeks of treatment, depending on the organism involved, the adequacy of debridement, and the location [ 3 , 4 ]. The use of long-term suppressive antibiotic therapy is more controversial, although such treatments are often used when a cure cannot be attained.

For MRSA in particular, antibiotic options are limited. Intravenous vancomycin remains the most common first-line agent, although clinicians might expect more failures of osteomyelitis treatment, as have been seen in bacteremia, as minimum inhibitory concentrations increase to >2 [ 5 ]. Both hearing loss and renal impairment can result from longer courses of therapy, although both are uncommon [ 6 ]. Other agents have been used, although comparative trials are generally lacking [ 7 ], and attempted meta-analyses of studies have been hampered by the frequent use of concomitant antibiotics, small sample sizes, limited patient demographic characteristics, and disease characteristics [ 8 ]. Daptomycin is an intravenous agent available for the treatment of osteomyelitis, and both quinopristin-dalfopristin and tigecycline are additional options, although toxicity significantly limits the use of these agents [ 9–11 ]. Outside of North America, teicoplanin is an available alternative. Linezolid can be used for Staphylococcus isolates, although neurotoxicity and bone marrow suppression become more common as the duration of treatment increases, making it an unsuitable long-term option for osteomyelitis. Oral doxycycline, rifampicin, clindamycin, and trimethoprim- sulfamethoxazole all have variable in vitro activity against MRSA isolates and, therefore, lack the activity to be used as monotherapy in the curative intent treatment of osteomyelitis. Fusidic acid, in comparison, has a favorable adverse effect profile and excellent oral bioavailability, as described elsewhere in this supplement. In countries where it is available, clinicians should consider its use for suppression in cases of difficult-to-treat osteomyelitis.

Study drug (CEM-102) was supplied by Cempra Pharmaceuticals, Inc. I would like to acknowledge JMI Laboratories (North Liberty, IA) for their assistance in determining MICs.

Supplement sponsorship . This article was published as part of a supplement entitled “Fusidic Acid Enters the United States” sponsored by Cempra Pharmaceuticals.

Potential conflicts of interest. Author certifies no potential conflicts of interest.

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  • institutional review board
  • debridement
  • fusidic acid
  • osteomyelitis
  • united states food and drug administration
  • antibiotic therapy
  • osteomyelitis, chronic
  • toxic effect
  • methicillin-resistant staphylococcus aureus

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  • Primary chronic osteomyelitis in the mandible: a conservative approach
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  • Anuja Agarwal ,
  • Nishant Kumar ,
  • Amit Tyagi ,
  • ITS Dental College and Hospital , Greater Noida , India
  • Correspondence to Professor Anuja Agarwal, dranujaagar{at}yahoo.com

Primary chronic osteomyelitis of the jaw is an uncommon non-suppurative, chronic inflammatory disease of unknown origin. It can manifest as early or adult onset and is characterised by lack of pus formation, fistula or bony sequestra formation. A 28-year-old woman presented with swelling on the left side of her mandible. On the basis of clinical, radiological and histological findings, primary chronic osteomyelitis was diagnosed. Surgical decortication and contouring of the affected bone was performed and no signs of recurrence were seen at 2-year follow-up. Hence we emphasise the importance of decortication over peripheral or segmental resection of the jaw for the treatment of primary chronic osteomyelitis since this procedure is less aggressive and more functionally and aesthetically acceptable.

https://doi.org/10.1136/bcr-2013-202448

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Osteomyelitis is defined as an inflammatory condition of the bone that begins as an infection of the medullary cavity, rapidly spreads to the Haversian systems, and eventually involves the periosteum of the infected areas. 1 Primary chronic osteomyelitis (PCO) is a rare but well-known, non-suppurative inflammatory disease of unknown aetiology. Marx and Mercuri defined acute osteomyelitis as lasting for less than 4 weeks and chronic osteomyelitis as lasting for more than 4 weeks. 2

PCO exclusively affects the mandible with no special age preference. 3 Clinical features range from restricted mouth opening and regional lymphadenopathy to decreased inferior alveolar nerve sensation (Vincent's symptom). The absence of pus, intra- or extra-oral fistula, or sequestration strictly characterises PCO and differentiates primary from acute and secondary chronic osteomyelitis. Sometimes PCO may be associated with chronic recurrent multifocal osteomyelitis and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome. 4

Marx in his radiological study showed a mixed radiodensity in the early stages of PCO followed by only sclerotic changes in the later stages. 5 In the early stages, mixed radiodensity is suggestive of areas of sclerosis and osteolysis with varying degrees of periosteal reactions. Immununological investigation shows only mild to moderate elevation of C-reactive protein, erythrocyte sedimentation rate and lymphocyte count. 6 Histopathological features include the presence of pagetoid bone formation, lymphocytes, plasma cells (suggestive of chronic inflammation) and varying amounts of medullary fibrosis. 7 , 8

We treated PCO of the mandible by decortication of the bone. Although surgical treatment alone cannot guarantee an absolute cure, decortication with removal of necrotic tissue in the early stages is proposed and has a good prognosis. 9–11

Case presentation

A 28-year-old woman reported to the department with complaints of recurring episodes of swelling in the left lower jaw ( figure 1 ), intermittent mild pain in the entire left side and paresthaesia of the left lower lip for 1 month. She was apparently asymptomatic 3 years previously when she noticed a small diffuse swelling on the left side of her lower jaw. The swelling had recurred intermittently over the last 3 years. She had no history of trauma, infection or systemic disease. She had undergone drug therapy many times for her complaint but with little benefit. On clinical examination, a firm, hard, diffuse and mildly tender swelling extending from angle of the mouth to the angle of the mandible on the left side was noticed. On intra-oral examination, the buccal cortical plate was increased in size from the left mandibular canine to the second molar region and the buccal vestibule was obliterated. There were no signs of infection, periodontitis or caries.

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Mild extra-oral swelling on the left side of the face.

Investigations

Cone beam CT (CBCT) scans of the region involved revealed a mixed pattern with partial loss of normal bone structure along with sclerosis and subperiosteal bone formation suggestive of chronic osteomyelitis. A large expansion of the mandibular body and periosteal apposition was evident on CBCT ( figures 2 and 3 ).

Pre-operative three-dimensional CT scan showing a large increase in the size of the mandible.

CT scan showing a mixed pattern with absence of any sequestrate.

Blood investigation revealed a raised erythrocyte sedimentation rate. Incisional biopsy was carried out and histopathological finding revealed various stages of chronic inflammation, lymphocytosis and some areas of subperiosteal bone formation.

Differential diagnosis

PCO was diagnosed on the basis of mandibular involvement, the hard swelling, the absence of pus and extra- or intra-oral fistula, the insidious course and the full complement of teeth without any caries or pathology, or any other intra-oral foci of infection. Benign tumours such as ossifying and non-ossifying fibroma, and fibrous dysplasia were ruled out by clinical, radiological and histopathological evaluation.

Surgical management was planned and bone decortication was carried out from the left mandibular premolar to the second molar area with extraction of the first and second molars due to poor bone support in the region ( figure 4 ). The patient was prescribed antibiotics and attended regular follow-up visits.

Intra-operative photograph showing decortication with preservation of the mental nerve.

Outcome and follow-up

The patient was asymptomatic 2 years after surgery and a CBCT scan ( figure 5 ) revealed mild areas of radiolucency and reparative bone formation below the premolar area and comparative normal dense bone in the molar region, suggestive of incomplete bone healing although clinically there was no sign of disease.

Cone beam CT scan 2 years after surgery demonstrating regression of the pathology.

PCO of the jaws is a complex clinical entity which presents both a diagnostic and a therapeutic challenge, especially in young patients. The Zurich classification system subdivides PCO into adult onset, early onset (depending upon age at presentation) and syndrome associated. It is characterised as a strictly non-suppurative chronic inflammation of the jaw bones with the absence of pus formation, extra- or intra-oral fistula, or sequestration. The absence of these symptoms clearly differentiates primary from acute and secondary chronic osteomyelitis in most cases. Our case perfectly fits into the early onset subcategory of PCO. Mandibular involvement, a hard swelling, the absence of pus and extra- or intra-oral fistula, the insidious course and full complement of teeth without any caries or pathology, or any other intra-oral foci of infection strongly suggested PCO. Benign tumours such as ossifying and non-ossifying fibroma, and fibrous dysplasia were ruled out by clinical, radiological and histopathological evaluation.

Both orthopantomogram and CBCT showed mixed radiodensity in the early stages followed by only sclerotic changes in the later stages. Immununological investigation revealed only mild to moderate elevation of C-reactive protein, erythrocyte sedimentation rate and lymphocyte count, which was similar to the findings of the study by Erich. 12 On histopathological examination, variable amounts of chronic inflammatory cells were seen with numerous lymphocytes and absence of sequestrum. Surgical treatment in conjunction with antibiotics and non-steroid anti-inflammatory drugs is beneficial and considerably improves the patient's quality of life. 13 In our case, intra-oral decortication was carried out, antibiotics were prescribed and the patient was called for routine follow-up examinations. The patient was completely relieved of symptoms and had no complaint after 2 years of follow-up. We recommend that surgical decortication and empirical antibiotic therapy should be considered as the treatment of choice as compared to antibiotics alone or peripheral/segmental osteotomy. Patients should be followed up as recurrence is common.

Learning points

Surgical decortication and empirical antibiotic therapy should be considered as the treatment of choice for primary chronic osteomyelitis since this is less aggressive and more functionally and aesthetically acceptable.

Following decortications, implants can be used for the rehabilitation of patients.

Patients should be followed up as recurrence is common.

  • Prasad KC ,
  • Prasad SC ,
  • Eisenbud L ,
  • Baltensperger M ,
  • Chamot AM ,
  • Malmström M ,
  • Fyhrquist F ,
  • Kosunen TU ,
  • Van Merkesteyn JP ,
  • Griffin JE ,
  • Tanimoto K ,
  • Taguchi A ,
  • Theologie-Lygidakis N ,
  • Schoinohoriti O ,

Competing interests None.

Patient consent Obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

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Osteomyelitis (nursing).

Ifeanyi I. Momodu ; Vipul Savaliya ; Chaddie Doerr .

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  • Learning Outcome
  • Recall the causes of osteomyelitis
  • Describe the presentation of osteomyelitis
  • Summarize the treatment of osteomyelitis
  • List the nurse's role in the management of a patient with osteomyelitis
  • Introduction

Bone infection is called osteomyelitis. It is an acute or chronic inflammatory process involving the bone and its structures secondary to infection with pyogenic organisms, including bacteria, fungi, and mycobacteria. Interestingly, archeological finds showed animal fossils with evidence of bone infection, making this a relatively old disease. [1]  Various terms were used to describe infected bone over the years until Nelaton came up with the term osteomyelitis in 1844. [1]  Before the introduction of penicillin in the 1940s, management of osteomyelitis was mainly surgically consisting of extensive debridement, saucerization, and wound packing following which affected area is left to heal by secondary intention [1]  resulting in high mortality from sepsis. Since the availability of antibiotics, mortality rates from osteomyelitis, including staphylococcal osteomyelitis, has improved significantly.

  • Nursing Diagnosis
  • Disturbed body image
  • Impaired skin integrity
  • Ongoing infection
  • Drainage from wound

Healthy intact bone is resistant to infection. The bone becomes susceptible to disease with the introduction of a large inoculum of bacteria, from trauma, ischemia, or the presence of foreign bodies because bone sites to which microorganisms can bind are exposed. [2]  Certain bacteria such as  Staphylococcus aureus  adhere to the bone by expressing receptors, called adhesins, for some components of the bone matrix, including laminin, collagen, fibronectin, and bone sialoglycoprotein.  S. aureus  expresses a collagen-binding adhesin, which permits its attachment to bone cartilage while the fibronectin-binding adhesin's role in attachment of bacteria to surgically implanted devices in bone was recently discovered. [2]  Also interesting to note is that  S. aureus  can survive intracellularly after being internalized by cultured osteoblasts. Some bacteria create a protective biofilm coating around themselves and underlying surfaces. This characteristic of some bacteria to adhere to the bone and surgically implanted devices following which they express phenotypic resistance to antibiotic therapy and their ability to survive intracellularly may explain the persistence of bone infections and high failure rates of shorter courses of antimicrobial treatment. [2]

  • Risk Factors

The overall incidence of osteomyelitis in the United States is mostly unknown, but reports show it to be as high as 1 in 675 US hospital admissions each year or about 50,000 cases annually. [3]  Other studies show an overall incidence of osteomyelitis of 21.8 cases per 100,000 person-years. [4]  The incidence was higher in men for unknown reasons but increases with age, mainly due to an increase in the prevalence of comorbid factors such as diabetes mellitus and peripheral vascular disease. [4]  Also, an increase in the availability of sensitive imaging tests, such as magnetic resonance imaging (MRI) and bone scintigraphy has improved diagnostic accuracy and the ability to characterize the infection. [5]

The clinical presentation of osteomyelitis depends on the etiology. Sometimes diagnosis in adults can be tricky, and it requires a high index of suspicion. A good history and physical is always the right place to start and are essential parts of the initial evaluation. Some patients are at high risk for osteomyelitis, and these include those with bacteremia, endocarditis, intravenous drug use, trauma, and open fractures. Also, patients with chronic poorly healing wounds in the setting of diabetes mellitus, peripheral vascular disease, peripheral neuropathy, or orthopedic hardware are at increased risk. [1]  Acute osteomyelitis may present gradually with onset over a few days but usually manifests within two weeks. Patients may have local symptoms such as erythema, swelling, and warmth at the site of infection. There may be a dull pain with or without motion and sometimes constitutional symptoms such as fever or chills. In subacute presentations, some patients may have generalized malaise, mild pain over several weeks with minimal fever, or other constitutional symptoms. Acute osteomyelitis may also present as septic arthritis, especially if the metaphyses of the bone is within the infected joint capsule. Septic arthritis of the elbow, shoulder, and hip joints may complicate osteomyelitis of the proximal radius, humerus, and femur, respectively. New or worsening neck or back pain in a patient with fever, elevated inflammatory markers (CRP, erythrocyte sedimentation rate [ESR]), [6]  bacteremia or endocarditis should raise the suspicion for native vertebral osteomyelitis (NVO). [7]

In chronic osteomyelitis, symptoms may occur over a longer duration of time, usually more than two weeks. As with acute osteomyelitis, patients may also present with swelling, pain, and erythema at the site of infection, but constitutional symptoms like fever are less common.  Patients who have deep or extensive ulcers that do not heal after several weeks of appropriate therapy, especially in people with diabetes or debilitated patients, should raise the suspicion for osteomyelitis. Physical examination should focus primarily on finding a possible nidus of infection, assessing sensory function, and peripheral vasculature. Tenderness to palpation over vertebral bone may be a significant finding in vertebral osteomyelitis. The ability to probe an ulcer to the bone with a blunt sterile instrument is highly suggestive of osteomyelitis. [2]  The probe to bone test is a screening tool in conjunction with the patient's pretest probability for osteomyelitis to determine whether additional diagnostic tests such as radiographic imaging or bone biopsy are required for therapeutic decisions. [8]

Laboratory data can be useful in the assessment of osteomyelitis but are usually nonspecific for osteomyelitis. There may or may not be leukocytosis, elevation of ESR, and C-reactive protein (CRP). The CRP level correlates with clinical response to therapy and may be used to monitor treatment. Blood cultures may be positive, especially in hematogenous osteomyelitis involving the vertebrae, clavicle, or pubis.  

Radiographic imaging is an essential component of the evaluation of a patient with suspected osteomyelitis. Clinically, the most useful studies are plain radiographs, magnetic resonance imaging (MRI), and technetium-99 bone scintigraphy. [5]  A plain radiograph is usually the initial imaging of choice but may have a delay of about 14 days before the appearance of findings suggestive of osteomyelitis. [1] [5]  They are, however, used to rule out other potential causes of symptoms such as metastasis or osteoporotic fractures. Typically seen are soft tissue swelling, osteopenia, osteolysis, bony destruction, and nonspecific periosteal reaction. Lytic lesions are detectable on plain radiographs after approximately 50% to 75% of the bone matrix has been lost, making this modality inadequate for the detection of early bone disease. [5]  Rarely, Brodie's abscess, which is a well-circumscribed lytic lesion, may be seen in a child who has been in pain for months without fever. 

Of all the imaging modalities currently in use, MRI has the highest combined sensitivity and specificity (78% to 90% and 60 % to 90% respectively) for detecting osteomyelitis. It can detect early bone infection within 3 to 5 days of disease onset  [5] [6] , but its use is limited in the setting of surgical hardware. MRI has a high negative predictive value, so a negative result is sufficient for the exclusion of disease if symptoms have been present for at least one week. The use of intravenous contrast does not improve the detection of disease but helps provide the distinction between a phlegmon, necrotic tissue, and abscess. Nuclear imaging has a high sensitivity for detecting early evidence of bone disease but has very poor specificity. It is especially useful if metal hardware prevents the use of MRI. Three-phase technetium-99 bone scan and tagged white blood cell scans are the modalities commonly used.

Other imaging modalities less commonly used are positron emission tomography (PET), which is expensive and not routinely available, leukocyte scintigraphy, gallium scan, and computed tomography (CT scan). A CT scan is more sensitive than plain radiograph for assessing cortical and trabecular integrity, periosteal reaction, intraosseous and soft tissue gas, the extent of a sinus tract, and is superior to MRI in detecting necrotic bone fragments. However, though the CT scan is readily available compared to the MRI, it is more expensive than plain radiograph and has a limited role in the diagnosis of osteomyelitis. It should be used mainly to determine the extent of bony destruction (especially in the spine) to guide biopsies or in patients with contraindications to MRI. 

Bone biopsy (either open or percutaneously) is essential to establish the histopathological diagnosis in osteomyelitis, identify the causative pathogen, and provide susceptibility data that helps direct antibiotic therapy. Superficial wound cultures or material from needle puncture or sinus tracts should not be used in diagnosis as these specimens do not correlate well with bone biopsy results. [1]  In patients with positive blood cultures and radiographic evidence of osteomyelitis, a bone biopsy may not be very useful [7] . An open bone biopsy is preferred over percutaneous biopsy, if possible. Cessation of antibiotics 48 to 72 hours before open bone biopsy may increase microbiological yield but is not routinely necessary as bone cultures are often positive regardless of prior antibiotic therapy because these infections occur in areas of infection-induced infarction or necrosis. Percutaneous biopsy should be done through intact skin to prevent sampling errors, and fluoroscopic or CT guidance is preferable. Percutaneous biopsy should be done ideally before initiation of antibiotic therapy, if possible, to increase the microbiological yield. Usually recommended are the collection of 2 samples, one for histopathology and the other for culture and gram stain.

  • Medical Management

Hematogenous osteomyelitis is primarily monomicrobial, while osteomyelitis due to contiguous spread or direct inoculation is usually polymicrobial or monomicrobial. [1]  The most common pathogens in osteomyelitis depend on the patient's age. Staphylococcus aureus is the most common cause of acute and chronic hematogenous osteomyelitis in adults and children. [1] [5]  Increasingly isolated from patients with osteomyelitis is methicillin-resistant  Staphylococcus aureus  (MRSA). In some studies, MRSA accounted for over one-third of all staphylococcal isolates. [5]  Other common pathogens are coagulase-negative  staphylococcus , beta-hemolytic streptococcus, enterococci, aerobic gram-negative bacilli (including  Pseudomonas  species,  Enterobacter  species,  Escherichia coli ) and anaerobic gram-negative bacilli (such as  Peptostreptococcu s,  Clostridium  species,  Bacteroides ). 

It is crucial to consider less common pathogens in the appropriate epidemiological setting and immunocompromised patients. These include  Mycobacterium tuberculosis,  which may spread to the spine from the lungs; nontuberculous mycobacteria (Mycobacterium avium intracellulare, Bacille Calmette-Guerin which may complicate intravesical therapy for bladder cancer);  Candida  species; fungi such as  Blastomyces , Coccidiodes,  Cryptococcus , and Aspergillus. Infection with  Actinomyces  and  Sporothrix  usually follow traumatic inoculation,  Salmonella  and  S. aureus  are implicated in hematogenous osteomyelitis in sickle cell disease while  Brucella  and  Salmonella  occur in spinal infections. [1] [2]   Bartonella henselae  may be associated with HIV related osteomyelitis and  Pasteurella multocida  or  Eikenella corrodens  seen in human or animal bites.

Effective treatment of osteomyelitis involves a collaborative effort among various medical and surgical specialties. The two main aspects of therapy are surgical containment of the infection and prolonged antibiotics. Surgical debridement of all diseased bone is often required as antibiotics penetrate poorly into infected fluid collections such as abscesses and injured or necrotic bone. [1]  Thus, the removal of necrotic tissue and bone is usually indicated where feasible. [2] [1]  Preoperative use of imaging modalities such as MRI allows for delineation of the extent of the infection, but intraoperatively it is still difficult for the surgeon to determine if all necrotic bone and tissue have been successfully removed. Examination of the pathology report helps determine if repeat debridement is necessary. In osteomyelitis associated with prosthetic joints, removal of the hardware is indicated. [2]  However, if the infected prosthesis is in a stable joint such as the hip and is infected with a very susceptible organism such as streptococci, therapy with an extended antibiotic course for several months without removing the device has been successful. [2]  When the prosthesis has to be removed, a two-stage exchange arthroplasty is more commonly used as this carries less risk of recurrent infection compared to the 1-stage arthroplasty, especially if more virulent bacteria such as  S. aureus  is involved. [2]  If surgical debridement is not feasible based on the location of the infection, e.g., some cases of pelvic osteomyelitis, then extended antibiotic therapy for months may be used. NVO rarely requires surgical debridement except if there are associated neurological complications necessitating relief of spinal cord compression, failure of medical treatment, or need to drain epidural or paravertebral abscesses. [2]  Debridement, however, is needed in cases of osteomyelitis associated with spinal implants. [6]

Also important is the need for revascularization of the affected limb before surgical intervention if there is evidence of significant peripheral vascular disease, control diabetes mellitus and address other host factors that may impede wound healing including tobacco use, malnutrition, chronic hypoxia, immunodeficiency states, chronic lymphedema and peripheral neuropathy [2] . 

Prolonged antibiotic therapy is the cornerstone of treatment for osteomyelitis. Results of culture and sensitivity should guide antibiotic treatment if possible, but in the absence of this data, it is reasonable to start empiric antibiotics. A commonly used broad-spectrum empiric antibiotic regimen against both gram-positive and negative organisms including MRSA is vancomycin (15 mg/kg intravenously [IV] every 12 hours) plus a third a generation cephalosporin (e.g., ceftriaxone 2 gm IV daily) or a beta-lactam/beta-lactamase inhibitor combination (e.g., piperacillin/tazobactam 3.375 IV every 8 hours). [1]  Once sensitivity data becomes available, then the antibiotic therapy should be narrowed for targeted coverage of the susceptible organisms.

Pathogen-Specific Antibiotic Therapy for Osteomyelitis in Adults [1] [5] [2] [6]

Staphylococcus aureus  penicillin-sensitive

Treatment of choice is penicillin G 4 million units every 6 hours

Alternative regimens are a first-generation cephalosporin, e.g., cefazolin 2 g IV every 8 hours, clindamycin 900 mg IV every 8 hours, vancomycin 15 mg/kg IV every 12 hours, oxacillin or nafcillin 2 g IV every 4 hours

Staphylococcus aureus  penicillin-resistant

Treatment of choice is nafcillin 2 gm IV every 4 hours

Alternative therapies are cefazolin, clindamycin or vancomycin (doses as above)

Staphylococcus aureus  methicillin-resistant

Treatment of choice is vancomycin IV

An alternative regimen is linezolid 600 mg IV every 12 hours.

Streptococci  (group A, B, Beta hemolytic,  Streptococcus  pneumoniae)

Alternative regimens include ceftriaxone 2 gm IV daily, clindamycin IV, vancomycin IV, cefazolin IV (doses as above)

Enterobacteriaceae  quinolone sensitive

Treatment of choice is ciprofloxacin 400 mg IV twice per day (bid) or 750 mg orally (PO) bid, levofloxacin 500 to 750 mg PO or IV daily

Alternative regimens include ceftriaxone 2g IV daily, cefepime 2 gm IV every 12 hours, ceftazidime 2 gm IV every 8 hours

Enterobacteriaceae,  quinolone-resistant  (Escherichia coli)

Treatment of choice is piperacillin/tazobactam 3.375 g IV every 8 hours, Ticarcillin/clavulanate 3.1 gm IV every 4 hours

An alternative regimen is ceftriaxone 2 g IV daily

Pseudomonas aeruginosa

Treatment of choice is cefepime 2 gm IV every 12 hours, ceftazidime 2 gm IV every 8 hours

Alternative regimens include meropenem 1 gm IV every 8 hours, Imipenem 500 mg IV every 6 hours, ciprofloxacin 400 mg IV every 12 hours or 750 mg PO daily

Enterococci

Treatment of choice is penicillin G 4 million units every 6 hours

Alternatively vancomycin 15 mg/kg every 12 hours, daptomycin 6 mg/kg IV daily, linezolid 600 mg IV or PO every 12 hours

Treatment of choice is clindamycin 900 mg IV every 8 hours, ticarcillin/clavulanate 3.1 gm IV every 4 hours

Alternatively, metronidazole 500 mg IV every 8 hours (for gram-negative anaerobes) [1] [2] [5]

The recommended duration of treatment for osteomyelitis in adults is 4 to 6 weeks of parenteral antibiotic therapy to achieve acceptable cure rates with a decreased risk of recurrence. [7] [6] [2]  In cases where the infected bone is wholly debrided or amputated with clean disease-free margins documented, a shorter duration of antibiotic therapy is acceptable. A 2-week course of antibiotics postoperatively is sufficient to allow for the treatment of any residual tissue infection and wound healing of the surgical site. [1]

Vacuum-assisted wound closure devices are used in the right clinical setting, especially where large or deep wounds are left after extensive debridement. These devices have been shown to promote healing by both direct and indirect effects on the wound. [9]  Hyperbaric oxygen therapy is not routinely recommended in the treatment of osteomyelitis.

  • Nursing Management
  • Promote bed rest
  • Assess nutritional needs
  • Administer antibiotics as ordered
  • Administer pain medications as ordered
  • Monitor and dress wound as ordered
  • Encourage out of bed activity
  • Provide deep venous thrombosis and pressure sore prophylaxis
  • Educate patient about medication compliance
  • Improve muscle strength and functioning
  • Involve social work for home care
  • Provide techniques to improve self-care
  • Ensure wound care nurse is following the patient
  • When To Seek Help
  • Persistent fever
  • Foul drainage
  • Increasing pain
  • Unstable vital signs
  • Outcome Identification
  • No drainage
  • Normal appetite
  • Skin intact
  • Coordination of Care

Osteomyelitis is a complicated infection to treat. In most cases, management involves a multifaceted, interprofessional approach, including the primary care provider, radiologist, surgeons (orthopedic, vascular), a podiatrist, an infectious disease specialist, pharmacist, nurse wound care team, and sometimes a plastic surgeon, a pain specialist or interventional radiologist. The primary care provider often plays a vital role in the initial diagnosis and coordination of care across these medical and surgical specialties. 

The therapeutic approach to management is guided sometimes by the site of infection and the presence of vascular insufficiency. Minimally invasive CT or fluoroscopically guided aspiration of the disc space (usually by interventional radiology) for microbiological and histopathological testing is recommended for the diagnosis of suspected NVO if clinical, imaging and other laboratory data suggest osteomyelitis in the absence of positive blood cultures with an organism known to cause osteomyelitis ( S. aureus ,  Staphylococcus lugdunensis ,  Brucella ). [7]  However, in patients with suspected subacute NVO and strongly positive Brucella serology or those with suspected NVO based on available clinical, radiological, laboratory data and positive blood cultures involving an organism known to cause osteomyelitis, image-guided aspiration biopsy is not recommended. A 6-week course of parenteral antibiotics is reserved for cases with neurological complications or failure of medical therapy. [7]

Once again, a strong collaboration between the surgical and vascular teams is essential for effective management of osteomyelitis due to vascular insufficiency, especially if associated with diabetes mellitus. Revascularization of the affected limb is critical for proper wound healing. Procedures to restore adequate blood flow, including therapeutic angiogram by either interventional radiology or vascular surgery and even femoral to popliteal by-pass, are used before amputation depending on the severity of vascular insufficiency. Surgical revascularization procedures that use local pedicle muscle flaps and myocutaneous flaps maintain vascular supply to the surgical site, fill the space left by surgical debridement, and also fight infection. [2]

Following surgical debridement, the need for close follow-up with prolonged antibiotics and meticulous wound care cannot be overemphasized. Infectious disease specialists involved in the patient's care often monitor response to therapy and adjust antibiotics regimens where needed. Many patients can continue with parental antibiotics outpatient via peripherally inserted intravenous access to complete their antibiotic course while others can transition to highly bioavailable oral antibiotic therapy such as quinolones when feasible based on microbiological results. Qualified home-bound patients benefit from home health wound nurse visits several times a week, while those who are ambulatory are encouraged to use wound care clinics if available. Family members and caregivers are also an integral part of the care team, providing support and care between healthcare provider visits. Only through such an approach can the morbidity of osteomyelitis be decreased. [10]  (Level 5)

  • Health Teaching and Health Promotion

Patient education about the prolonged nature of therapy and the need for compliance with treatment recommendations to ensure adequate wound healing thereby reducing the risk for recurrence is an essential part of the care in these patients.

  • Discharge Planning
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MRI T1-Weighted Postcontrast Knee Osteomyelitis Contributed by Scott Dulebohn, MD

Digital Amputation Surgical amputation of the right hallux secondary to osteomyelitis. Not the Exposed 1st metatarsal head within the wound. Contributed by Mark A. Dreyer, DPM, FACFAS

Osteomyelitis CT Scan of Chronic osteomyelitis of the leg demonstrating classic cloaca, sequestrum and involucrum Contributed by Mark A. Dreyer, DPM, FACFAS

Osteomyelitis CT Scan of chronic osteomyelitis of the leg demonstrating classic cloaca, sequestrum, and involucrum Contributed by Mark A. Dreyer, DPM, FACFAS

T2-weighted MRI image of a patient's right foot. Patient had history of uncontrolled diabetes, peripheral neuropathy and a long-standing ulceration under the 5th metatarsal head resulting in osteomyelitis of the 5th metatarsal head and shaft. Patient (more...)

Disclosure: Ifeanyi Momodu declares no relevant financial relationships with ineligible companies.

Disclosure: Vipul Savaliya declares no relevant financial relationships with ineligible companies.

Disclosure: Chaddie Doerr declares no relevant financial relationships with ineligible companies.

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  • Cite this Page Momodu II, Savaliya V, Doerr C. Osteomyelitis (Nursing) [Updated 2023 May 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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  • [Vacuum-assisted closure therapy for the treatment of acute postoperative osteomyelitis]. [Z Orthop Unfall. 2011] [Vacuum-assisted closure therapy for the treatment of acute postoperative osteomyelitis]. Diefenbeck M, Mennenga U, Gückel P, Tiemann AH, Mückley T, Hofmann GO. Z Orthop Unfall. 2011 Jun; 149(3):336-41. Epub 2011 Apr 27.
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  • Published: 29 January 2024

Chronic osteomyelitis risk is associated with NLRP3 gene rs10754558 polymorphism in a Chinese Han Population

  • Yu-dun Qu 1   na1 ,
  • Nan Jiang 2 ,
  • Jia-xuan Li 1 ,
  • Wei Zhang 1 ,
  • Chang-liang Xia 1 ,
  • Shuan-ji Ou 1 ,
  • Yang Yang 1 ,
  • Yun-fei Ma 2 ,
  • Yong Qi 1 &
  • Chang-peng Xu 1  

BMC Medical Genomics volume  17 , Article number:  38 ( 2024 ) Cite this article

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Metrics details

Single nucleotide polymorphisms (SNPs) in the nucleotide-binding domain leucine-rich repeat protein-3 ( NLRP3 ) gene are reported to be linked to many inflammatory disorders. However, uncertainty persists over the associations between these SNPs and susceptibilities to chronic osteomyelitis (COM). This study aimed to investigate potential relationships between NLRP3 gene SNPs and the risks of developing COM in a Chinese Han cohort.

The four tag SNPs of the NLRP3 gene were genotyped in a total of 428 COM patients and 368 healthy controlsusing the SNapShot technique. The genotype distribution, mutant allele frequency, and the four genetic models (dominant, recessive, homozygous, and heterozygous) of the four SNPs were compared between the two groups.

A significant association was found between rs10754558 polymorphism and the probability of COM occurence by the heterozygous model ( P  = 0.037, odds ratio [OR] = 1.541, 95% confidence interval [CI] = 1.025–2.319), indicating that rs10754558 may be associated with a higher risk of developing COM.In addition, possible relationship was found between rs7525979 polymorphism and the risk of COM development by the outcomes of homozygous ( P  = 0.073, OR = 0.453, 95% CI = 0.187–1.097) and recessive ( P  = 0.093, OR = 0.478, 95% CI = 0.198–1.151) models, though no statistical differences were obtained.

Conclusions

Outcomes of the present study showed, for the first time, that rs10754558 polymorphism of the NLRP3 gene may increase the risk of COM development in this Chinese Han population, with genotype CG as a risk factor. Nonetheless, this conclusion requires verification from further studies with a larger sample size.

Peer Review reports

Chronic osteomyelitis (COM) is a frequent and challenging complication of trauma, affecting up to one third of patients during recovery from severe limb injury or open fracture [ 1 , 2 ]. In addition, hematogenous seeding and soft tissue infections, especially in patients with diabetes and pressure ulcers, can also lead to osteomyelitis (OM) [ 3 ]. Staphylococcus aureus remains to be the primary pathogen of COM [ 4 , 5 ]. Owing to insufficient blood supply to the infected bone, patients with COM often require both surgical debridement and antibiotic treatment [ 6 , 7 ]. COM has been shown to substantially increase the long-term mortality risk [ 8 ]. Approximately 30% of the acute OM cases progress into chronic phase [ 9 ], causing anincreased risk of mortality, perpetuating disability, and worsened quality of life [ 8 , 10 , 11 ]. Previous epidemiological studies have reported that COM elevates the risk of coronary heart disease [ 12 ], stroke [ 13 ], diabetes mellitus [ 14 ], renal disease [ 15 ], and even depression [ 10 ]. To comprehensively tackle COM-related issues, substantial efforts should be devoted to investigate the pathophysiology of the condition as well as to conduct clinical studies. The pathogenesis of OM is related to both environmental factors and genetic factors, and contemporary evidence suggests that genetic susceptibility may also play a crucial role in this process [ 16 , 17 ]. With the rapid development and application of sequencing and genetic association analysis, genetic variants that may cause OM have been extensively explored.

Numerous genetic studies examining nucleotide-binding domain leucine-rich repeat protein-3 ( NLRP3 ) polymorphisms have demonstrated the involvement of this gene in a range of inflammatory conditions, including Parkinson’s and Alzheimer’s diseases [ 18 ], type 2 diabetes, atherosclerosis [ 19 ], inflammatory bowel disease [ 20 ], gout, and recurrent fever [ 21 ]. Genetic differences in the NLRP3 have been hypothesized to have a substantial role in determining the severity of inflammatory responses, thereby predisposing susceptibility to disease [ 22 ]. However, the association between NLRP3 and COM, as well as the underlying mechanisms remain unclear. Previous studies had reported that several single nucleotide polymorphisms (SNPs), such as TaqI (rs731236) and FokI (rs2228570) in the vitamin D receptor ( VDR ) gene [ 23 ], rs689466 in the cyclooxygenase-2 ( COX-2 ) gene [ 24 ], the Alu insertion/deletion (rs4646972) in the tissue plasminogen activator ( tPA ) gene [ 25 ], and rs1799750 in the matrix metalloprotease 1 ( MMP-1 ) gene [ 26 ], may be associated with the risk of developing COM. In the HaploReg v4.2-Broad Institute (HaploReg v4.2 (broadinstitute.org)), we found that rs10754558, rs7525979, rs35829419, and rs4612666 were all involved in inflammatory responses and all played key roles in the mouse OM model (Supplementary Table S1 ).

To better understand potential role of genetic factor in the pathogenesis of COM, this study examined potential links between NLRP3 SNPs and susceptibilities to COM in a Chinese Han population.

Materials and methods

Study design and patient enrollment.

This investigation was designed as a case-control study and conducted in a Chinese Han population. Patients undergoing treatment for COM between 2016 and 2019 at the Nanfang Hospital, Southern Medical University, a tertiary healthcare facility in Southern China, were screened for enrollment. COM was defined by symptoms persisting for at least 10 weeks and/or radiological appearances suggestive signs of bone infection. In addition, at least one of the following operative findings was required to be present for inclusion: (i) two or more positive culture sterile site specimens with an indistinguishable organism; (ii) histology suggestive of COM (a mean of > 5 neutrophils per high power field, averaged over at least 5 fields); or (iii) sinus abscess or purulence, present during surgery. These criteria align with established methods of confirming the diagnosis of COM. Healthy controls were individuals without abnormalities or a history of any disorders, as determined by thorough examinations in the physical examination center. Informed consent forms were completed by all the participants or their guardians, and the medical ethics committee of the Southern Medical University Nanfang Hospital approved the study (approval no. NFEC-2019-087).

SNP selection and genotyping

Data regarding NLRP3 gene expression in osteoblasts were obtained through gene sequencing (BioProject number: PRJNA1001643). The model included a normal osteogenic differentiation group (tumor necrosis factor [ TNF-α ] = 0 ng/mL) and an inflammasome group ( TNF-α  = 5 ng/mL). The expression of the NLRP3 gene was then compared between the samples belonging to these two groups. We analyzed four selected SNPs (rs35829419, rs10754558, rs7525979, and rs4612666) in the NLRP3 inflammasome gene. Previous studies on inflammasome gene polymorphisms related to infection were referred. The expressions of these four SNPs in tissues were verified in the Genotype-Tissue Expression (GTEx) database. The GTEx project is an ongoing effort to build a comprehensive public resource to study tissue-specific gene expression and regulation. It provides open access to information, including gene expression, quantitative trait loci data, and histology images.

Peripheral blood samples (2 mL) were collected from each participant in tubes containing ethylenediaminetetraacetic acid. Polymerase chain reaction (PCR) was performed in a total reaction volume of 15 µL, which contained 1.0 µL of template DNA, 1.5 µL of 10× PCR buffer, 1.5 µL of 25 mmol/L MgCl 2 , 0.3 µL of 10 mmol/L dNTP mix, 0.15 µL of 10 µmol/mL primers, and 0.3 µL of 5 µ/µL Taq DNA polymerase (Fermentas, Waltham, MA, USA). Table  1 lists the forward, reverse, and extension primers used [ 23 ]. Reactions were performed using a PCR machine (model no. EDC-810, Dongsheng Co., Ltd., Beijing, China) with the following settings: initial denaturation at 94 °C for 3 min, followed by 35 cycles of denaturation at 94 °C for 15 s, annealing at 55 °C for 15 s, extension at 72 °C for 30 s, and a final extension step at 72 °C for 3 min. PCR products were purified in the following mixture: 3.0 µL of PCR products, 0.2 µL of 20 µ/µL Exonuclease I (ExoI; Fermentas), 0.8 µL of 1 µ/µL FastAP thermosensitive alkaline phosphatase (Fermentas), 0.7 µL of ExoI buffer, and 2.3 µL of ddH 2 O. Reactions were conducted at 37 °C for 15 min and 80 °C for 15 min.

Using the Multiplex SNaPshot technique, the four SNPs of the NLRP3 gene were genotyped. SNaPshot extension reactions were performed following the instructions of the ABI SNaPshot Multiplex PCR Kit (Applied Biosystems, Waltham, MA, USA) with slight revisions. The total reaction volume (6.0 µL) included 2.0 µL of purified PCR products, 1.0 µL of SNaPshot Multiplex Ready Reaction Mix, 0.2 µL of 10 µmol/mL pooled extension primer, and 2.8 µL of ddH 2 O. Extension reactions were performed as follows: pre-denaturation at 96 °C for 1 min, followed by 30 cycles of denaturation at 96 °C for 10 s, annealing at 52 °C for 5 s, and extension at 60 °C for 30 s. The product of this reaction (1.0 µL) was mixed with 9.0 µL of formamide and denatured at 95 °C for 3 min. The fluorescently labeled fragments were separated by capillary electrophoresis on an ABI PRISM 3730 XL Genetic Analyzer (Applied Biosystems). The results of the SNaPshot genotyping method are shown in Fig.  1 .

figure 1

SNaPshot genotyping. The rs10754558, rs7525979, rs35829419, and rs4612666 single nucleotide polymorphisms of the nucleotide-binding domain and leucine-rich repeat protein-3 gene were analyzed using the SNaPshot technique (Supplementary Table S2 )

Comparative analysis of NLRP3 gene polymorphisms and clinical indicators

Genotype distribution, mutant allele frequency, and the four genetic models (dominant, recessive, homozygous, and heterozygous) of the four NLRP3 SNPs were compared between the COM patients and healthy controls. Age, sex ratio, culture-positive rate, polymicrobial infection rate, and preoperative serum levels of two inflammatory biomarkers, interleukin ( IL )-6 and TNF-α , were compared between the four genotypes of NLRP3 gene polymorphisms among the patient group. Serum levels of IL-6 and TNF-α were detected using electrochemiluminescence immunoassay (Roche cobas e601, Basel, Switzerland). The upper limit of normal values, provided by the Medical Clinical Laboratory of Nanfang Hospital, were 7.0 and 8.1 pg/mL for IL-6 and TNF-α, respectively.

Statistical analysis

The Kolmogorov–Smirnov test assessed data normality. Normally distributed continuous variables are reported as the mean ± standard deviation, and a one-way analysis of variance or the student’s t-test was used to compare between the two or among over two groups. Continuous variables with a non-normal distribution were reported as the median withinterquartile range (IQR), and the Kruskal–Wallis or Mann–Whitney U tests were used for group comparisons. Dichotomous variables with percentage-based data were compared using the Chi-square or the Fisher’s exact test.

Analysis of the linkage disequilibrium at different loci of NLRP3 genotypes was performed. The genotype distributions of the healthy controls were examined using the Chi-square test to determine whether Hardy–Weinberg equilibrium (HWE) were sustained. The Chi-square test or Fisher’s exact test was used to examine the genotype distributions and mutant allele frequencies between the two groups. Sex, age, and genotype distribution were covariates. Binary logistic regression analysis was performed to examine the potential relationships between the four gene polymorphisms and the likelihood of developing COM using four genetic models with matching odds ratios (ORs) and 95% confidence intervals (CI). Statistical analyses were performed using R software (Version 4.2.3, LD-heatmap package) and SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Statistical significance was established as a P -value < 0.05.

Clinical characteristics of the participants

This study included 368 healthy controls (268 men and 100 women) and 428 COM patients (337 men and 91 women). There was no statistically significant difference in the sex ratio between the two groups (3.70 vs. 2.68, χ 2  = 3.792, P  = 0.051). The median ages of the two groups were not significantly different (patient group: 47 years, IQR, 33.00–59.00; control group: 46 years, IQR, 37.00–52.00; Z  = 0.114, P  = 0.662). Figure  2 shows clinical characteristics of COM of this Chinese cohort. The most prevalent type of COM was post-traumatic OM (PTOM)(58.35%), which often occurred after open injury (61.96%). The most typical infection location was the tibia (38.31%), followed by the foot (21.03%) and the femur (11.68%). Of all the intraoperative specimen cultures, 27.46% were tested positive, with monomicrobial infection accounting for 71.67%. The most commonly detected pathogen was Staphylococcus aureus (34.17%).

figure 2

Distribution map of infection sites of the COM patients. The number of patients involved is given at each site, along with the percentage of the total number of 428 patients

Expression of NLRP3 in different states and linkage disequilibrium analysis

The expression of the NLRP3 gene under inflammatory microenvironment was significantly higher than that under normal microenvironment ( P  = 0.015) (Fig.  3 ). However, according to the GTEx database, the expression of NLRP3 gene variants (rs10754558, rs7525979, rs35829419, and rs4612666) in the whole-blood and the musculoskeletal tissues did not show significant differences. The r 2 values of the NLRP3 gene SNPs were calculated using R software (Version 4.2.3). The results of the linkage disequilibrium analysis were shown in the r 2 hot graph in Fig.  4 . Deep-blue blocks represent high linkage disequilibrium (r 2  = 0.8–1), and light-blue blocks represent low linkage disequilibrium (r 2  = 0–0.2). There was no linkage disequilibrium among the three SNPs of NLRP3 (rs10754558, rs7525979, and rs35829419).

figure 3

Expression of the NLRP3 gene in osteoblasts. NLRP3 gene expression was analyzed in osteoblasts cultured under normal conditions (control) and those cultured in the presence of TNF-α (inflammatory microenvironment). NLRP3 , nucleotide-binding domain and leucine-rich repeat protein-3; TNF-α, tumor necrosis factor-α, * P  = 0.015

figure 4

Linkage disequilibrium analysis. The r 2 hot graph for the single nucleotide polymorphisms of the nucleotide-binding domain and leucine-rich repeat protein-3 gene: rs10754558, rs7525979, and rs35829419

Frequency of the four NLRP3 gene SNPs in COM patients and healthy controls

In the healthy controls, all the four genotyped NLRP3 gene SNPs were in HWE: P (HWE) for rs35829419 = 0.979, P (HWE) for rs10754558 = 0.377, P (HWE) for rs7525979 = 0.386, and P (HWE) for rs4612666 = 0.607. As shown in Table  2 , the heterozygous model of the rs10754558 SNP and susceptibility to COM were significantly associated ( P  = 0.037, OR = 1.541, 95% CI = 1.025–2.319), indicating that individuals with the CG genotype may be at a higher risk in developing COMin this Chinese Han population.

Although no significant association was identified between rs7525979 and the risk of developing COM, results of the recessive ( P  = 0.093) and homozygous ( P  = 0.073) models suggested that this SNP site may be linked to a decreased risk of COM development, with genotype TT as a possibly protective factor. However, this results need to be further tested. No significant correlations were found between rs35829419 or rs4612666 and the risks of COM development among these participants (Table  2 ).

IL-6 and TNF-α levels among different genotypes of rs10754558 and rs7525979 in the COM patients

Serum levels of IL-6 and TNF-α in the COM patients showed no significant differences among different genotypes of rs10754558 ( P  = 0.213 and 0.662, respectively; Table  3 ). Additionally, multiple comparisons showed that no significant differences were found regarding serological IL-6 or TNF-α levels between CG and GG ( P  = 0.180), CG and CC ( P  = 0.158), or CG and CC + GG ( P  = 0.072) genotype groups (Fig.  5 ). Moreover, serum levels of IL-6 and TNF-α did not differ significantlyamong different genotypes of rs7525979 ( P  = 0.900 and 0.843, respectively; Table  3 ) (Fig.  6 ).

figure 5

Cytokine levels in patients with chronic osteomyelitis. Serum levels of a IL-6 and b TNF-α were compared among different genotypes of the single nucleotide polymorphism rs10754558. IL-6, interleukin-6; TNF-α, tumor necrosis factor-α

figure 6

Cytokine levels in patients with chronic osteomyelitis. Serum levels of a IL-6 and b TNF-α were compared among different genotypes of the single nucleotide polymorphism rs7525979. IL-6, interleukin-6; TNF-α, tumor necrosis factor-α

DOur study results showed that, in this ChineseHan cohort, NLRP3 SNP rs1074558 may increase the risk of COM development, with CG genotype in a higher risk to develop COM. Despite the current study being unable to obtain statistical evidence supporting this association between the COM patients and healthy controls, the results of the recessive and homozygous models suggested that rs7525979 polymorphism may hinder COM development. Nonetheless, this conclusion requires verification from further studies with a larger sample size.

COM, which often develops following trauma and orthopaedic surgery, still poses great challenges tophysicians. The frequency of infection in the long bones after open fractures varies between 4% and 64%, with infection recurrence rates ranged between 20% and 30% [ 27 ]. Among the 428 COM patientsincluded in our study, PTOMaccounted for 58.35%, with infection following open injury occupying 61.96% and the positive rate of culture as27.46%. The physical and psychological well-being of patients is severely affected by the protracted course of the disease and inflammatory bone disintegration. Huang et al. [ 28 ] found that COM significantly increased the risk of death in the older population. Along with the aforementioned comorbidities, patients with COM also suffer fromhigher rates of deep vein thrombosis [ 15 ], erectile dysfunction [ 29 ], dementia [ 30 ], and end-stage renal disease [ 31 ], as well as mental health disorders, including depression [ 10 ]. In addition, while rare, there is a risk of malignant change in patients with COM [ 32 ].Consequently, COM is accompanied by an enormous healthcare and economic burdens [ 33 ].

Previous studies have found that IL-1β secretion and mRNA expression levels of key inflammasome components, namely apoptosis-associated speck-like protein containing a CARD and Caspase-1, are abnormally increased in patients with chronic recurrent multifocal osteomyelitis [ 34 , 35 ]. The release of IL-1β can lead to autocrine stimulation and production of other cytokines, such as IL-6 . In the present study, we did not detect the serological level of IL-1β . Thus, the potential influences of such SNPs on serological levels of IL-1β cannot be assessed. Instead, we evaluated the impact of genotype by comparing readily available serum inflammatory markers, IL-6 and TNF-α .

Studies have shown that genetic variables, with SNP as a key component, may play a role in the etiology of infection. According to several clinical studies, the VDR [ 23 ], tPA [ 25 ], COX-2 [ 24 ], and MMP-1 [ 26 ] genes, and the most frequently reported members of the IL family, have been implicated in the associations between SNPs and COM risk across various ethnicities. Previous investigations reported that IL - 1 (rs1800587) [ 36 , 37 ], IL - 4 (rs2243250, rs2243248) [ 37 ], and IL - 6 (rs1800795) [ 37 ] gene polymorphisms are positively correlated with the development of COM and raise the risk of developing OM. And we found that these SNPs pathways are associated with inflammation. As a crucial component of the inflammatory system, the NLRP3 inflammasome may also be linked to the incidence and progression of COM [ 38 ]. More importantly, our team investigated a possible association between NLRP3 gene polymorphisms and the risks of developing PTOM in a Chinese population. The results suggested that NLRP3 SNPs, rs10754558 (P =  0.047) and rs7525979 (P  = 0.048), were significantly different between patients and healthy controls. However, this study only discussed the susceptibility to PTOM and NLRP3 gene expressions, and could not clarify whether this gene susceptibility was related to COM. At the same time, we summarized the SNPs that are associated with COM, as well as the mechanistic pathways involved and the action (cis or trans) and location of SNPs (Table  4 ). Therefore, we conducted a more detailed study [ 39 ].

The rs10754558 polymorphism of the NLRP3 gene may be associated with an increased risk of COM in this Chinese Han population; to the best of our knowledge, no study has reported on this association to date. Although we did not find a difference in the frequency of the mutant alleles, C and G, of rs10754558 in the patient group, the heterozygous model of rs10754558 showed a statistical association of this polymorphism with COM, indicating that individuals with the CG genotype of this polymorphism are in an increased risk of COM development. Other genotypes did not significantly associated with COM. In addition, although there was no statisticalcorrelation between the results of the recessive and homozygous models of rs7525979 ( P  = 0.093 and 0.073, respectively), the frequency of the TT genotype was higher in the COM patients than that in healthy controls. Further research is required to verify whether patients with TT genotype of rs7525979 are in a lower risk to develop thisdisease. Several possible reasons may help explain why only the rs10754558 variants showed significant results while the others failed. The first reason may rest with the specificity of rs10754558 itself. Aside from the present findings, we also found that this SNP is associated with the development of several disorders, such as chronic kidney disease [ 40 ], acne vulgaris [ 41 ] and autoimmune diseases [ 42 ]. Second, the limited sample size of our study may have masked the correlations between the other SNPs and COM susceptibilities. Therefore, we will explore whether and how these genetic variants play roles in epigenetics in the future. Moreover, no significant differences were found among different genotypes of rs10754558 or rs7525978 SNPs, neither regarding clinical characteristics, nor regarding serological levels of IL-6 or TNF-α. These results suggest that further studies are required to investigate the potential influences of NLRP3 polymorphisms on clinical features and serum levels of the inflammatory biomarkers as well. Nonetheless, outcomes of the present study also need to be confirmed by a larger cohort.

Our study had several limitations. Firstly, despite a larger sample size of the current report compared to the majority of the previously published studies, it remains inadequate for an SNP analysis. Additionally, a broader pool of participants should be applied in future research since the pathogenic process for the development of COM is multifactorial. Secondly, a few participants could not be genotyped using the SNapShot method. Owing to the limited volume of blood collection from each participant, genotyping could not be repeated using alternative methods, resulting in a reduced number of samples with sequencing outcomes. However, this did not affect the final results. Thirdly, we did not detect serum level of IL-1β , thus, IL-1β levels among patients with different genotypes could not be compared, and correlations between the NLRP3 gene polymorphisms and serum IL-1β levels remain unclear. Fourthly, the environmental variables may play a role in the pathophysiology of COM in addition to the genetic factors. The majority of the patients in this study were transferred from neighboring hospitals; thus, it was difficult to determine their precise medical history prior to bone infection (e.g., the severity of the original injury and treatment approach). As a result, we were unable to further investigate how these external factors affected the development of COM. Finally, we found that NLRP3 gene polymorphisms are associated with an increased risk of COM; however, the function of the genetic variants has not been analyzed. Therefore, further functional validations of NLRP3 gene polymorphisms are needed.

This study confirmed that NLRP3 gene rs10754558 polymorphism is significantly associated with the prevalence of COM in a Chinese Han population. Nonetheless, this conclusion requires validation by future studies with a larger sample size. Based on our findings, detecting overexpression of the NLRP3 mutant gene may be a promising strategy to identify risk group for COM development. Future studies exploring this association that include a larger population of COM patients are essential, especially if genetic screening is to be employed as a prediction tool for the risk of disease development. Further, determining whether pharmacological inhibition of the NLRP3 pathway should be incorporated into the treatment regimen for COM may be beneficial.

Data availability

The datasets generated and analyzed during the current study are not publicly available to respect and protect the privacy of the patients; however, they are available from the corresponding author upon reasonable request.

Abbreviations

NOD-like receptor thermal protein domain associated protein 3

  • Chronic osteomyelitis

Osteomyelitis

Confidence interval

Interquartile range

Interleukin

  • Single nucleotide polymorphisms

Tumor necrosis factor-α

Hardy-Weinberg equilibrium

Post-traumatic osteomyelitis

Vitamin D receptor

Tissue plasminogen activator

Cyclooxygenase-2

Matrix metalloproteinase-1

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Acknowledgements

The authors thank all participants and staff who made this study possible. We would like to thank Editage ( www.editage.cn ) for English language editing.

This work was supported by the National Natural Science Foundation of China (grant numbers: 81972083, 82172197), Guangdong Provincial Science and Technology Project (grant number: 2020A0505100039), Guangdong Basic and Applied Basic Research Foundation (grant number: 2022A1515012385), the Science and Technology Planning Project of Guangzhou (grant numbers 202201020303, 202102080052, 202102010057, 201804010226); and the Science Foundation of Guangdong Second Provincial General Hospital (grant numbers 3D-A2020004, 3D-A2020002, YQ2019-009, C2020019).

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Yu-dun Qu and Nan Jiang contributed equally to the study.

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Department of Orthopaedics, Guangdong Second Provincial General Hospital, 466 Xingang Road, Haizhu District, 510317, Guangzhou, China

Yu-dun Qu, Jia-xuan Li, Wei Zhang, Chang-liang Xia, Shuan-ji Ou, Yang Yang, Yong Qi & Chang-peng Xu

Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China

Nan Jiang & Yun-fei Ma

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YDQ and NJ contributed equally to this study. YDQ, NJ, and CPX designed the study; YDQ, NJ, and CPX managed and analyzed the data; YDQ and CPX drafted the initial study protocol; YD Q wrote the first draft of the manuscript; JXL, WZ, CLX, YFM, SJO, YY, and YQ contributed to the data interpretation and preparation of the report. All authors contributed ideas to the paper and gave their consent for submission. The corresponding authors attest that all authors in the text meet the criteria for authorship and that no other authors who meet the criteria have been left out. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Yong Qi or Chang-peng Xu .

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Qu, Yd., Jiang, N., Li, Jx. et al. Chronic osteomyelitis risk is associated with NLRP3 gene rs10754558 polymorphism in a Chinese Han Population. BMC Med Genomics 17 , 38 (2024). https://doi.org/10.1186/s12920-024-01799-6

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