Infectious Diseases

Osteomyelitis

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OVERVIEW: What every practitioner needs to know

Osteomyelitis in adults is usually a chronic infection and difficult to heal. Treatment consists of a combined surgical and medical approach, including long-duration antibiotic therapy, except in the case of amputation of the entire area of infected bone with residual uninfected proximalmargins.

Are you sure your patient has osteomyelitis? What should you expect to find?

  • As an example, we present the case of Mr. A, a 44-year-old man who underwent osteosynthesis for an open tibia fracture 23 years ago. Three months after osteosynthesis, his scar spontaneously discharged a purulent liquid while the patient was febrile. An implant-related infection due to Staphylococcus aureus was diagnosed, the osteosynthesis material was removed, and the underlying osteomyelitis debrided. The patient received a course of antibiotic treatment with a penicillin-based agent for 3 months. Twenty-three years later, he fell down the stairs on the same place he had his infection. This time there is no fracture, but the pain did not subside despite antalgic medication for 2 months. With time, this pain began to be prevalent not only during exercise, but also during rest (e.g., during the night). Moreover, after 2 months, a sinus tract developed with occasional discharge of a white-yellow liquid. He had no fever.

  • We can expect to find the presence of a sinus tract (Figure 1), eventually with purulent discharge. We expect also pain, eventually fever, and a history of past (open fracture) trauma or surgery.

Figure 1.

Photo of a sinus tract; also named fistula (in other languages).

How did the patient develop osteomyelitis? What was the primary source from which the infection spread?

  • Osteomyelitis is very often a chronic bone infection. Acute forms of bone infections are: vertebral osteomyelitis, early onset or hematogenous arthroplasty infections, osteomyelitis accompanying septic arthritis, or osteomyelitis in children with a known hematogenous acquisition. Chronic forms of osteomyelitis are long bone, sacral, and foot osteomyelitis among adult patients often arising secondary to contiguous focus of infection (Figure 2).

  • Chronic osteomyelitis is often acquired by direct spread from contiguous infection that follows trauma, surgery, or soft tissue ulceration (e.g., in diabetic patients or patients with neurologic disorders who are prone to decubitus). Adult patients rarely develop osteomyelitis after hematogenous seeding of long bones during bacteremia.

Figure 2.

Different possible anatomic localizations of osteomyelitis in adult patients.

Which individuals are of greater risk of developing osteomyelitis?

The pathogenesis of osteomyelitis includes three processes which in turn dictates who develops this infection. Those individuals who are at greater risk of developing osteomyelitis are:

  • patients with polyneuropathy and/or peripheral arterial disease (e.g., patients with diabetes mellitus) develop skin ulcers which become infected with subsequent extension to adjacent bone. Other infections can extend to adjacent bone (direct extension).

  • patients undergoing surgery or suffering trauma that extends to the bone (direct introduction).

  • patients with S. aureus bacteremia are at unique risk for developing vertebral osteomyelitis or seeding of implanted prosthetic joints with subsequent paraprosthesis bone infection. Bacteremia due to other organisms can seed these sites as well but does so less frequently than that due to S. aureus (hematogenous seeding).

Beware: there are other diseases that can mimic osteomyelitis:

Osteomyelitis is a common term for bacterial bone and marrow infection with structural deformation of bone, although nonbacterial and non-infectious inflammation of bones and adherent structures exist. Mimics of bone infection include: SAPHO syndrome is a rare immunologic disorder that results in synovitis, acne, pustulosis, hyperostosis, and osteitis. Other immunologic diseases, such as chronic recurrent multifocal osteomyelitis, palmoplantar pustulosis, charcot foot or idiopathic bone marrow oedema can also present with non-infectious osteomyelitis.

Most importantly, clinicians must recognize the main differential diagnoses of diabetic foot osteomyelitis, which are the Charcot foot (neuropathic bone injury), gout, and inflammation due to ischemia itself.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Apart from microbiologic examinations, no routine laboratory tests are required for diagnosis, in particular, no chemistry or hematology. Inflammatory markers – erythrocyte sedimentation rate and C-reactive protein are often elevated but are not diagnostic. Radiography and biopsy are more important than laboratory parameters.

Results that confirm the diagnosis

Clinical signs and standard radiographs are suggestive for diagnosis, but non-invasive tests cannot definitively establish or exclude osteomyelitis. The ultimate proof of infection requires growth of the same pathogens in several (at least two) bone samples. Histopathology of bone may confirm the diagnosis.

Eubacterial (nonspecific) polymerase chain reaction (PCR) to detect bacteria genetic material has relatively low sensitivity and is relatively expensive, features which exclude its routine application. Furthermore, in polymicrobial colonization or infection, PCR interpretation can be difficult. However, specific or multiplex PCR can be beneficial in special circumstances when very slow or difficult to grow bacteria are suspected, such as Kingella kingae, Brucella spp, Coxiella burnetii, Bartonella henselae, Mycobacterium tuberculosis, or M. ulcerans, or if prior antibiotic therapy is likely to confound cultures.

In diabetic patients with a chronically infected foot ulcer, palpating or probing bone at the base of a non-debrided ulcer with a blunt steel probe had a sensitivity of 66% for diabetic foot osteomyelitis, a specificity of 85%, a positive predictive value of 89%, and a negative predictive value of 56%. Using cotton tipped swabs for probing does not allow distinguishing exposed bone from that covered by soft tissue. The value of bone surface swabs for specific pathogen identification is not clear. Similarly, culture of drainage from a sinus tract (Figure 1) is not a reliable technique for defining agent causing bone infection. When sinus-tract cultures were compared with cultures of operative specimens from patients with chronic osteomyelitis, only 44% of sinus-tract cultures contained the pathogen identified by culture of a deep surgical specimen.

What imaging studies will be helpful in making or excluding the diagnosis of osteomyelitis?

On standard X-rays, the earliest visible changes include swelling of soft tissue, periostal thickening or elevation, and focal osteopenia. Before the radiographs show lytic changes, probably 50 to 75% of the bone matrix must be destroyed, which takes at least 2 weeks.

Today, computed tomography (CT) scans are better for the visualization of sequestra and are less expensive than magnetic resonance imaging (MRI). MRI is very sensitive and can show tissue edema, including bone marrow edema, and increased regional perfusion. Therefore, it is useful to evaluate soft tissue infections adjacent to bone. However, these changes can last a long time after surgery and trauma. The distinction between fibrovascular scarring, “overuse syndromes,” gout, neuropathic osteoarthropathy Charcot arthropathy in the feet of diabetic patients, and reactive infection is often difficult. Thus, MRI lacks specificity, particularly in the post-surgery setting or in diabetic foot alterations. Kaim et al. reported a sensitivity, specificity, and accuracy of 100%, 69%, and 78%, respectively, for MRI in posttraumatic osteomyelitis.

Positron emission tomography (PET) could become the most accurate radiologic examination for osteomyelitis. When combined with a CT scan, its sensitivity, specificity, and accuracy for human osteomyelitis are 94%, 87%, and 91%, respectively. However, PET is the most expensive radiologic examination, thus, precluding its routine use in the clinical evaluation for osteomyelitis.

Scintigraphy has become less important because of its low specificity for implant-associated infections. Moreover, bone scintigraphy alone in the assessment for prosthetic joint infection cannot distinguish between aseptic loosening and infection and needs to be used in combination with leukocyte scintigraphy. The sensitivity, specificity, and accuracy for a leucocyte-labeled scintigraphy are 63%, 97%, and 77%, respectively, for implant-related osteomyelitis.

Scintigraphy is similarly nonspecific in the search for infection in the setting of bone trauma—after compound fracture with or without internal fixation and in the diabetic foot. Bone scintigraphy has been used to localize focal bone infection after bacteremia, but again suggests osteomyelitis but does not establish the diagnosis. This demands more discriminatory imaging or biopsy.

In the presence of a sinus tract extending to bone, foot ulcer, involucrum, or osteolysis observed on standard X-rays, these sophisticated images are unnecessary, except when the orthopedic surgeon might request a CT scan for surgical planning purposes.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

A multifaceted team is necessary for optimal treatment. In large centers, patients with osteomyelitis are treated by a team including orthopedic surgeons, infectious diseases specialists, diabetologists (when there is diabetic foot infection), nurses, and specialized physiotherapists.

If you decide the patient has osteomyelitis, what therapies should you initiate immediately?

The assessment of the patient’s general condition and comorbidities is of great importance. Not every osteomyelitis episode has to be treated or can be removed surgically. The key question is how much the patient will benefit from a long-lasting and perhaps complicated treatment. Today, millions of individuals in resource-poor, and even resource-rich countries, have chronic osteomyelitis that discharges from time to time but does not interfere substantially with daily life activities. When the surgical treatment could be more deleterious than the disease, an intermittently short and suppressive antibiotic therapy should be considered with the aim of controlling, but not curing, osteomyelitis.

Chronic bacterial osteomyelitis is a surgical disease. Antibiotics alone are very rarely successful because of sequester (devitalized bone) formation. Sequestra act as foreign bodies and are relatively impenetrable to antibiotics. There are only a few exceptions where antibiotic administration without surgery may eradicate bone infection. These include acute infections treated early, such as hematogenous osteomyelitis in children prior to sequestra formation, spondylodiscitis (with adjacent vertebral osteomyelitis), tuberculous osteomyelitis, and in selected diabetic patients with toe osteomyelitis.

Surgical treatment

The optimal management of chronic osteomyelitis includes sequestrectomy, intramedullar reaming, resection of scarred and infected bone, as well as soft tissue, obliteration of dead space, appropriate bone mechanical stability, adequate soft tissue coverage, and restoration of an effective blood supply. Adequate soft tissue coverage of the bone is considered necessary to arrest osteomyelitis. In the case of vascular insufficiency, restoration of a good blood flow is performed by vascular bypass or endovascular stenting. Tissue flaps with their vascular supply may be used effectively to eliminate defects in overlying soft tissue and to bring vascular supply to the bone surface. Amputation is infrequent for long bone osteomyelitis, in contrast to toe osteomyelitis of the diabetic foot.

Treatment of infection at the site of a fracture must integrate efforts to achieve fracture healing and treatment of the infection. Fracture healing requires both stabilization and at least suppression of infection. Eradication of infection may require removal of a foreign body that was required for stabilization. As a result, effective treatment of these complex infections often requires a multi-staged effort.

If the stability of the bone is compromised, a two-stage procedure might be required. The first stage consists of extensive debridement, dead space management with antibiotic-containing beads or cement, bone stabilization with external fixation, and coverage with dressings. After 3 weeks of antibiotic treatment, the second stage is performed: new debridement, removal of the beads or cement, filling in of the dead space with bone graft, bone stabilization with internal fixation (plate and/or intramedullary nail), and soft tissue coverage. The delay of 3 weeks is arbitrary and not evidence-based.

Alternatively, and particularly when infection arises after internal fixation and is not threatening and systemic, physicians and surgeons may try to suppress the infection with long-term oral agents until the fracture unites. If there is evidence of residual infection, the surgeon may remove the fixation device and debride the site. Small dead space is left unchanged if the soft tissue coverage is good. Large dead spaces are filled to reduce the likelihood of continued infection and stability loss. If a cavity cannot be filled by surrounding soft tissue, a local muscle flap or free tissue transfer can be used to obliterate the dead space.

The optimal choice of soft tissue coverage (usually Tiersch graft, local rotational flap, brachialis fasciocutaneous free flap, or latissimus dorsi free flap) is left to the plastic surgeon. Coverage with a vacuum-assisted closure (VAC) dressing is discouraged by some surgeons yet used by others. Tan et al. compared 35 patients treated by VAC therapy with 33 patients treated by conventional wound management. VAC patients had a significantly reduced recurrence (one wound versus seven wounds), a decreased rate of flap surgery, and increased bacterial clearance, and it was also a cost-effective approach.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Efforts to establish a microbiologic diagnosis should precede starting antibiotic therapy, especially since osteomyelitis is rarely acutely life-threatening. Empirical therapy should be avoided as much as possible. If pathogen identification is not possible, the most likely pathogens of each individual case should be covered. The most prevalent microorganism causing osteomyelitis is S. aureus, but the local antibiotic susceptibility pattern of S. aureus may change according to the geographical region. In many countries, an empirical regimen for methicillin-susceptible S. aureus—a quinolone and rifampicin, or co-trimoxazole and rifampicin—will likely be effective. In areas in which methicillin-resistant S. aureus (MRSA) is prevalent, empiric cover needs to address that organism.

The optimal antibiotic duration after effective debridement osteomyelitis (in the absence of implanted foreign material) among adults remains unknown. There are no randomized trials. International consensus guidelines are lacking.

Parenteral antibiotic therapy

Formerly, experts usually recommended an intravenous (IV) therapy for 4 to 6 weeks followed by an oral course of additional weeks or months. Prolonged IV therapy was preferred to ensure high serum antibiotic concentrations. Today, when feasible, many prefer IV treatment during the initial 2 weeks followed by prolonged therapy with oral agents that are highly bioavailable when ingested. When active, orally bioavailable agents are not an option; prolonged IV therapy is required. This duration of IV medication is based on expert opinion, rather than clinical trials. In the case of concomitant endocarditis, this intravenous therapy is usually prolonged to 4 to 6 weeks.

Oral antibiotic therapy

Recent retrospective data suggest that regimens with an early switch to oral antibiotics are as effective as prolonged parenteral regimens for osteomyelitis. A Cochrane review included five trials comparing oral versus IV antibiotics for chronic osteomyelitis in adults. There was no statistically significant difference in the remission rate by route of administration. Several orally administered antibiotic agents have demonstrable clinical efficacy: quinolones, linezolid, clindamycin, and fusidic acid combined with rifampicin. These drugs have an oral bioavailability of more than 90% and can be used to provide cost-effective prolonged therapy for patients with osteomyelitis caused by susceptible organisms.

Duration of antibiotic therapy

Total duration of antibiotic treatment, following effective debridement surgery, can be limited to 6 weeks for osteomyelitis in the absence of implanted material. When an osteosynthetic device is used or prosthesis retention is attempted, the current guideline advised therapy for 3 to 6 months. Nonrandomized trials of longer courses of IV or oral antibiotics (6 months or more) do not suggest any improved outcomes compared with 6 weeks of therapy. Two prospective randomized multicenter trials compared 6 weeks’ versus 12 weeks’ of antibiotic administration; one for non-amputated diabetic foot osteomyelitis, the other for spondylodiscitis with vertebral osteomyelitis. Both trials identified the 6 weeks’ regimens as non-inferior to the 12 weeks’ regimens. Important, however, was the selection of patients enrolled into these trials. In particular, patients with S. aureus infection, especially MRSA, and those with more complicated infections (soft tissue collections) were under-represented in the trial focused on spondylodiscitis and vertebral osteomyelitis. Of note, a large retrospective series examining treatment of hematogenous vertebral osteomyelitis, especially complicated S. aureus and MRSA infection, suggests that longer courses of treatment (8-12 weeks) yields higher cure rates than 6 weeks of therapy.

Choice of antibiotic agents

Contrary to common belief, the specific choice for bactericidal agents is not necessary for the long-term treatment of chronic bone infection. Studies investigating the use of bacteriostatic antibiotics reveal the same success rates when compared to so-called bactericidal drugs. Probably, when it comes to long-term treatment, the oral bioavailability and bone penetration of the agent could be more important than its formal bactericidal properties.

The most frequently used class of drugs in osteomyelitis is beta-lactam antibiotics given intravenously, particularly for S. aureus, which is the most frequent pathogen in osteomyelitis. Beta-lactams have important drawbacks: the low oral bioavailability and low intraosseous and synovial penetration. Therefore, although frequently recommended for first-line therapy intravenously in osteomyelitis, alternative agents are often proposed for an oral switch.

Vancomycin is a glycopeptide that must be administered intravenously and has a serum half-life of 6 hours. It is the most frequently used antibiotic for the treatment of osteomyelitis caused by MRSA. It is not removed efficiently by standard dialysis techniques. According to individual pharmacokinetics, bone penetration of vancomycin is only about 15 to 30% of the serum concentration; minimal serum through levels of 20mg/mL is believed to be necessary to treat bone infections. Fortunately, penetration in infected bone is higher than in uninfected bone.

The nephrotoxicity associated with the high vancomycin doses required to achieve the desired serum trough concentrations is a concern. As a result, monitoring of both serum vancomycin trough concentration and renal function is recommended. In continuous infusion, abrupt changes in serum concentrations are much lower than in intermittent application. Although popular in some European countries (i.e., France, Italy) because target concentrations are achieved more quickly and there are fewer adverse drug effects, continuous infusion is not widely accepted. Continuous infusion does not guarantee a better clinical outcome.

Teicoplanin is available in Europe and elsewhere, but not in the United States. It is a glycopeptide with a serum half-life of 72 hours. It is infused intravenously over 30 minutes, generally as a single dose of 400mg once a day. A loading dose 400mg given twice on the first day is advised.

Rifampicin can penetrate cells and phagocytes and kill intracellular bacteria; however, if used as monotherapy, there is rapid emergence of rifampicin-resistance among staphylococci. Hence, rifampicin should never be used alone, but rather always in combination with another antimicrobial agent to which the Staphylococcus is susceptible. The classical indication for combination therapy including rifampicin is staphylococcal implant-related bone infection. However, a recent meta-analysis found very few human studies addressing the role of adjunctive rifampicin therapy. Benefits were not always seen in vivo or in vitro.

Daptomycin yields a dose-dependent bactericidal effect. The serum half-life is 9 hours. It is only available in parenteral form and administered once a day at a dose of 6 to 8mg/kg in the absence of renal dysfunction. Few adverse events are known, among them muscular toxicity with an elevation of creatinine-phosphokinases and rare episodes of an eosinophilic pneumonitis. Clinicians should keep in mind that emergence of a daptomycin-resistant S. aureus isolate during treatment of initially daptomycin-susceptible osteomyelitis has been described.

Dalbavancin is an intravenous lipoglycopeptide with activity against Gram-positive pathogens. With a terminal half-life of >14 days, dosing regimens with infrequent parenteral administration become available to treat infectious diseases such as osteomyelitis that otherwise require daily dosing for many weeks. Dalbavancin concentrations in cortical bone 12 h after infusion of a single 1,000 mg intravenous infusion were 6.3 μg/g and 2 weeks later were 4.1 μg/g. Dalbavancin for Staphylococcus aureus osteomyelitis that maximizes exposure to treatment while minimizing the frequency of intravenous therapy, has been proposed. Currently, however, reports of dalbavancin treatment of osteoarticular infections are limited.

Aminoglycosides might be indicated in combination therapy for sustained bacteremia, but are not indicated for osteoarticular infections. They are less active in bone. Furthermore, staphylococcal small-colony variants, a hallmark of chronic osteoarticular S. aureus infections, are generally resistant to aminoglycosides and may even be a cause of recurrence. However, in desperate situations and in low-income countries, aminoglycosides might be an option (IV or intramuscular).

Linezolid inhibits ribosomal protein synthesis and can be administered parenterally or orally at a dose of 600 mg twice daily, without adjustment for renal insufficiency. It is bacteriostatic with no cross-resistance to other antibiotics and is primarily active against gram-positive bacteria. Because of its excellent oral bioavailability (approximately 100%), it is a good choice for outpatient treatments. Many patients with osteomyelitis have demonstrated a successful treatment with linezolid. Almost 50 publications highlight its efficacy in monotherapy or combination therapy with rifampicin. Nevertheless, apart from its high cost, concern regarding adverse events with longer duration courses has limited its use in osteomyelitis. Linezolid is associated with reversible bone marrow suppression, particularly thrombocytopenia, during administration of more than 2 weeks. Regular monitoring of the hematogram is mandatory. Optic neuropathy and nonreversible peripheral neuropathy have been reported in 2 to 4% of patients with prolonged administration. A severe serotonin syndrome when given concomitantly with certain antidepressive drugs, such as serotonin reuptake inhibitors and monoamine oxidase inhibitors, has been described.

Co-trimoxazole (trimethoprim-sulfamethoxazole) is an inexpensive folate antagonist that has provided effective therapy for small soft tissue infections. One reason for failure of co-trimoxazole in severe infections might be the amount of thymidine released from damaged host tissues and bacteria, a concept strengthened by the fact that S. aureus thermonuclease releases thymidine from DNA. Thymidine antagonizes the anti-staphylococcal effects of both trimethoprim and sulfamethoxazole. Thus, failure with co-trimoxazole may well depend on the amount of tissue damage and organism burden. We recommend its use only in combination with rifampicin for osteomyelitis.

Tetracyclines (doxycycline and minocycline; both 100 mg twice daily) are lipophilic, thus, facilitating the passage into tissues. Evidence of efficacy is primarily in the treatment of skin and soft tissue infections and, to a lesser extent, for osteomyelitis. Tetracyclines are often combined with rifampicin, although firm data regarding the efficacy of this combination are lacking. Whether the combination is also superior to minocycline or doxycycline alone has been questioned. Main adverse events are nausea and the danger of photosensitivity during summer.

Tigecycline belongs to the glycylcyclines and inhibits ribosomal protein synthesis. It is only available in parenteral form: a loading dose of 100mg followed by 50mg twice daily intravenously is standard. Currently, it should be considered as an experimental drug for osteoarticular infections and experiences are few.

Oral fusidic acid 500 mg three times daily has demonstrated efficacy in chronic osteomyelitis, vertebral infection, septic arthritis, and prosthetic and other device-related infections. Most experts do not recommend monotherapy because of the development of (potentially reversible) resistance. The time delay under current therapy until the appearance of resistance is unknown and might be variable. The antibiotic can be combined with rifampicin and the association is becoming popular for oral therapy, although the serum levels of fusidic acid may be decreased to 40% when administered in combination with rifampin. This drug-drug interaction may result in ineffective therapy as well as the emergence of rifampin-resistance during therapy. Hepatic failure has been reported with use of fusidic acid and rifampicin combinations, so monitoring liver function is advisable. Fusidic acid is available in some European countries, but not in the United States.

For some anaerobic gram-negative bacteria, streptococci and staphylococci causing osteomyelitis, clindamycin 600-900 mg three times daily may be an option. The clinical efficacy of clindamycin in bone infection, which has been demonstrated particularly in children, can be explained by its excellent oral bioavailability and bone penetration despite its classification as a bacteriostatic agent. However, when isolates routinely tested as susceptible for clindamycin are resistant to erythromycin, clindamycin resistance may be inducible and arise during clindamycin treatment. To detect this relatively frequent inducible clindamycin resistance, a so-called "D test" should be performed by the laboratory. However, the relationship between inducible resistance to clindamycin and treatment failure is poorly defined.

Although staphylococci may be susceptible to fosfomycin and chloramphenicol, these antibiotics have not been approved for osteoarticular infections and should be avoided. For osteomyelitis caused by anaerobic gram-negative bacteria, clindamycin, metronidazole, beta-lactam/beta lactamase inhibitor combinations, or carbapenems are the drugs of choice. High-dose metronidazole may cause peripheral (irreversible) neuropathy.

Quinolones are one of the few and preferred orally bioavailable classes of antibiotics effective in the treatment of bone infection caused by susceptible gram-negative bacteria. Pseudomonas aeruginosa and other non-fermenting gram-negative rods may rapidly develop resistance to quinolones during monotherapy. Therefore, combining a quinolone with another parenteral antispeudomonal beta-lactam drug for prolonged IV treatment in pseudomonal osteomyelitis is advised. Of note, the optimal oral dose for ciprofloxacin for bone and synovial infections is set at 750 mg twice daily for patients with a good renal function. Ciprofloxacin can “cure” staphylococcal osteomyelitis also in monotherapy but is probably less effective as treatment of streptococcal infection. However, there are antibiotic alternatives for gram-positive infection. Therefore, we suggest quinolones be limited to use in combination with rifampin for treatment of staphylococcal osteomyelitis or used for treatment of osteomyelitis due to susceptible gram-negative bacteria.

Different antibiotics for different pathogens of osteomyelitis are summarized in Table I.

Table I.

Antibiotic choices stratified upon pathogens of osteomyelitis. Experts' recommendations.

2. Next list other key therapeutic modalities.

Controversial or evolving therapies

Hyperbaric oxygen therapy

Hyperbaric oxygen therapy consumes very substantial resources. It provides oxygen to promote collagen production, angiogenesis, osteogenesis, and healing in the ischemic or infected wound. Several authors have suggested that adjunctive hyperbaric oxygen therapy might be useful in the treatment of human chronic osteomyelitis, even although the results are not consistent. Today, although recognized for reimbursement by some health insurers, the evidence base for hyperbaric oxygen therapy for diabetic foot care remains weak.

Local antibiotic-releasing delivery systems

The ideal local antibiotic delivery system is lacking. Antibiotic-containing cement is used for treatment and prophylaxis of bone and prosthetic joint infections, but remains controversial in terms of additional benefit. Spacers for knee joint surgery may also contain antibiotics. All of these systems release antibiotics locally at concentrations exceeding up to 1,000 times the threshold for local treatment, which would be necessary. However, the duration of time over which these antibiotics continue to be active and released is less certain. Similarly, whether the local delivery provides an incremental benefit beyond concurrent system antibiotic therapy has not been established. Moreover, the advantage appears minimal in two-stage procedures for arthroplasty infections.

What complications could arise as a consequence of osteomyelitis?

One very rare, but potentially fatal, late-term complication is squamous cell carcinoma complicating a chronically discharging sinus tract, also called Marjolin ulcer. The pathophysiological mechanism of this transformation is unknown, and overall incidence is believed to be approximately 0.2% among all chronic cases of osteomyelitis. The duration of the discharge before oncologic transformation ranges between 12 and 43 years. This neoplasm can also disseminate.

What should you tell the family about the patient’s prognosis?

In general, remission rates after a combined surgical and medical approach for osteomyelitis vary considerably and may reach 80%. High remission reports are often seen in short follow-up times or among children. However, comparison of treatment modalities in osteomyelitis should be viewed with precaution, because reports are not based on standardized treatments and the osteomyelitis episodes vary from study to study in definition, bones involved, host factors, and different chronicity of drainage. Some reports also mix up remission following first therapy with a “final remission” after a second or third treatment episode.

In contrast to implant-associated osteomyelitis, there are few epidemiological studies that exist assessing the risk of recurrence of osteomyelitis involving bones in absence of implants. Inadequate debridement may be the most important reason for failure. Staphylococcal small-colony variants that may survive intracellularly are also considered a risk for relapse. Previously infected bone should be considered a lifetime focus of diminished resistance, thus, prior osteomyelitis should be considered as a risk factor for a second episode at the same site due to pathologically-altered bone surfaces. Further clinical variables associated with treatment failure are smoking, older age, or duration of discharge before treatment.

It is not clear whether culture-negative osteomyelitis or empirical therapy without cultures leads to increased failure rates. In arthroplasty infections, empirical antibiotic treatment directed at the common bacteria causes of these infections has not been associated with decreased cure rates. It is equally unresolved whether methicillin-resistant staphylococcal infection increases the likelihood of treatment failure.

How do you contract osteomyelitis and how frequent is this disease?

The epidemiology of osteomyelitis is heterogeneous with variability among the bones involved, pathogens, and settings. For example, patients in resource-poor countries may experience a higher incidence of tuberculous osteomyelitis or chronic osteomyelitis following trauma compared to resource-rich countries. Recurrences of osteomyelitis after several years, if not decades, have been reported, and there is no internationally accepted minimal follow-up duration. Some authors suggest that the term “arrest” or “remission” is more appropriate than “cure” for defining outcome in chronic osteomyelitis.

The incidence of vertebral osteomyelitis is estimated at 0.2 to 2 cases per 100,000 patients per year. This occurs largely in middle-aged patients with a male to female ratio of 2:1. The incidence of pediatric hematogenous osteomyelitis ranges from 3 to 76 cases per 100,000 children per year, with a male predominance. Osteomyelitis complicates approximately 15 to 20% of diabetic patients with infected foot ulcers.

A large proportion of osteomyelitis is either trauma-related or surgery-related. Most surgical site infections are believed to be acquired at the time of surgery and are caused by endogenous flora. Arguments for this hypothesis are the efficacy of preoperative antibiotic prophylaxis, together with the similarity of skin flora and pathogens. Postoperative osteomyelitis, in terms of surgical site infections, occurs in roughly 1 to 4% of orthopedic and trauma-related interventions.

Because osteomyelitis is a heterogeneous infection with an enormous worldwide variability among involved bones, pathogens, and settings, meaningful epidemiologic studies would be difficult to perform.

No zoonotic transmission is reported for osteomyelitis pathogens, with the exception of Echinococcus, which is a very rare disease.

What pathogens are responsible for this disease?

Almost every bacterial and fungal pathogen can cause osteomyelitis. Among all bacteria and types of osteomyelitis, except the jaw, S. aureus is the predominant pathogen and accounts for 66 to 75% of reported cases, followed by streptococci and gram-negative pathogens, such as P. aeruginosa. Polymicrobial infection is frequently when osteomyelitis is secondary to trauma or to adjacent chronic ulcerations, but not in hematogenous infection. Anaerobes are seldom observed. Kingella kingae is responsible for osteoarticular infections, including osteomyelitis, in children younger than 4 years of age. Sickle-cell disease leads to bone necrosis caused by microvascular occlusion. Osteomyelitis in these patients is often caused by gram-negative pathogens (e.g., Salmonella spp). The life-time incidence of osteoarticular infection in severe homozygote sickle cell disease is estimated at 3%.

Tuberculous osteomyelitis is a frequent disease in endemic regions (e.g., developing countries). The vertebrae are the most frequently affected bones. The antituberculosis agents used for treatment are similar to those used for treatment of pulmonary tuberculosis and depend on the susceptibility patterns. The multidrug treatment is continued for 1 year.

Infection is almost exclusively of bacterial origin; bone infections due to fungi or echinococcus are much less common (e.g., Candida spp. in intravenous drug abusers or zygomycetes in skull osteomyelitis).

No case of viral chronic osteomyelitis with bone destruction has been described to the best of our knowledge.

How do these pathogens cause osteomyelitis?

Bacterial surface adhesins allow organisms to adhere to bone matrix and orthopedic implants coated with fibronectin and other extracellular matrix proteins. Adherence to bone appears mediated by the collagen adhesion protein. Bacteria elude host defenses and antibiotics by hiding intracellularly and by developing a biofilm (Figure 3).

Figure 3.

Electron microscopic imaging of a biofilm. Note the dense matrix in which bacteria remain dormant and/or divide at a very low frequency.

Biofilms are the hallmark of implant-related osteomyelitis but are also important in the absence of a foreign body.

Patchy ischemic bone necrosis occurs when the inflammation occludes the vascular tunnels. Segments of bone devoid of blood supply can become separated from viable bone. These bone fragments are called sequestrate. Abscesses are formed in the medullary cavity within 48 hours of seeding. At the infarction edge, there is reactive hyperemia associated with increased osteoclastic activity resulting in bone loss. Meanwhile, bone apposition occurs, in some cases exuberantly, causing periosteal elevation and new bone formation, named involucrae (Figure 4).

Figure 4.

New bone formation central inside the bone shaft. Bone apposition occurs, in some cases exuberantly, causing periosteal elevation and new bone formation, named involucrae.

There is much evidence that growth factors, cytokines, hormones, and drugs regulate the proliferation and activity of osteoblasts and osteoclasts. Infection may also extend into the surrounding soft tissue. When a sequestrum or involucrum becomes fibrotic, sclerosis may result. Bone sclerosis usually indicates infection present for more than 1 month.

What other clinical manifestations may help me to diagnose and manage osteomyelitis?

Another clinical manifestation that may help to diagnose and manage osteomyelitis is a history of past trauma or surgery. The only sure clinical sign for osteomyelitis from outside the body is a sinus tract or the visualization of the exposed infected (and fragmented) bone.

How can osteomyelitis be prevented?

Prevention is difficult. Only the subgroups of osteomyelitis due to surgical site infections and skin ulcers (decubitus ulcers, diabetic foot ulcers) can really be prevented. For the various aspects of prevention of surgical site infection, we recommend consulting the vast literature on this topic. For diabetic patients, education about foot health and regular foot inspections are strongly recommended. Proper shoes and efforts to avoid points of pressure, especially in those patients with significant sensory neuropathy are important steps to prevent ulcer formation and subsequent osteomyelitis. When ulcers do occur, proper wound cleansing, debridement of callus and necrotic tissue, and off-loading of pathologic pressure (weight bearing) to insure prompt healing are essential. In those patients with peripheral vascular disease and threatening ischemia, revascularization should be considered.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Bernard, L, Dinh, A, Ghout, I, Simo, D, Zeller, V, Issartel, B, Le Moing, V, Belmatoug, N, Lesprit, P, Bru, JP, Therby, A, Bouhour, D, Dénes, E, Debard, A, Chirouze, C, Fèvre, K, Dupon, M, Aegerter, P, Mulleman, D. "Duration of Treatment for Spondylodiscitis (DTS) study group. Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial". Lancet. vol. 385. 2015. pp. 875-82.

(Prospective randomized multicenter trial on the duration of antibiotic treatment for spondylodiscitis and vertebral osteomyelitis. 6 weeks are not inferior to 12 weeks.)

Betz, M, Landelle, C, Lipsky, BA, Uçkay, I. "Letter to the Editor concerning the review of Prof. Sheldon L. Kaplan "Recent lessons for the management of bone and joint infections" - Bacteriostatic or bactericidal agents in osteoarticular infections". J Infect. vol. 71. 2015. pp. 144-6.

(Retrospective trial comparing the performance of bactericidal versus bacteriostatic antibiotic agents in the treatment of osteoarticular infections.)

Cierny, G, Mader, JT, Penninck, JJ. "A clinical staging system of adult osteomyelitis". Clin Orthop Relat Res. vol. 414. 2003. pp. 7-24.

(Classic paper about the most frequently used surgical staging system of chronic osteomyelitis: the Cierny classification.)

Conterno, LO, da Silva Filho, CR. "Antibiotics for treating chronic osteomyelitis in adults". Cochrane Database Syst Rev. vol. 3. 2009. pp. CD004439.

(Available evidence of antibiotic prescription for chronic osteomyelitis in adults.)

Cui, Q, Mihalko, WM, Shields, JS, Ries, M, Saleh, KJ. "Antibiotic-impregnated cement spacers for the treatment of infection associated hip or knee arthroplasty". J Bone Joint Surg Am. vol. 89. 2007. pp. 871-82.

(Role and performance of local antibiotic delivery for chronic osteomyelitis in humans.)

Dunne, MW, Puttagunta, S, Sprenger, CR, Rubino, C, Van Wart, S, Baldassarre, J. "Extended-duration dosing and distribution of dalbavancin into bone and articular tissue". Antimicrob Agents Chemother. vol. 59. 2015. pp. 1849-55.

(Experiences and pharmacokinetics of dalbavancin in bone.)

Grayson, ML, Gibbons, GW, Balogh, K, Levin, E, Karchmer, AW. "Probing to bone in infected pedal ulcers. A clinical sign of underlying osteomyelitis in diabetic patients". JAMA. vol. 273. 1995. pp. 721-3.

(Landmark study concerning the accuracy of bone probing for the diagnosis of chronic osteomyelitis diabetic foot. Useful for clinical practice.)

Griffin, AT, Harting, JA, Christensen, DM. "Tigecycline in the management of osteomyelitis: a case series from the bone and joint infection (BAJIO) database". Diagn Microbiol Infect Dis. vol. 77. 2013. pp. 273-7.

(Experiences with tigecycline is osteomyelitis.)

Hartmann, A, Eid, K, Dora, C, Trentz, O, von Schulthess, GK, Stumpe, KD. "Diagnostic value of 18F-FDG PET/CT in trauma patients with suspected chronic osteomyelitis". Europ J Nucl Med Mol Imaging. vol. 34. 2007. pp. 4444-14.

(The value of a PET-Scan in the diagnosis of osteomyelitis. Promising research, but expensive.)

Jansson, A, Renner, ED, Ramser, J. "Classification of non-bacterial osteitis: retrospective study of clinical, immunological, and genetic aspects in 89 patients". Rheumatology (Oxford). vol. 46. 2007. pp. 154-60.

(A good review about chronic bone inflammation of non-infectious origins. Differential diagnosis to infectious osteomyelitis.)

Kaim, A, Ledermann, HP, Bongatz, G, Messmer, P, Müller-Brand, J, Steinbrich, W. "Chronic post-traumatic osteomyelitis of the lower extremity: comparison of magnetic resonance imaging and combined bone scintigraphy/immunoscintigraphy with radiolabelled monoclonal antigranulocyte antibodies". Skeletal Radiol. vol. 29. 2000. pp. 378-86.

(The roles of MRI and scintigraphy in the diagnosis of osteomyelitis.)

Lew, DP, Waldvogel, FA. "Use of quinolones in osteomyelitis and infected orthopaedic prosthesis". Drug. vol. 58. 1999. pp. 85-91.

(Role of old and new quinolones for the treatment of osteomyelitis.)

Lew, DP, Waldvogel, FA. "Osteomyelitis". Lancet. vol. 364. 2004. pp. 360-79.

(Landmark review of epidemiology, clinical presentation, and treatment of different forms of osteomyelitis in the adult patient.)

Park, K, Cho, O, Lee, JH. "Optimal Duration of Antibiotic Therapy in Patients with Hematogenous Vertebral Osteomyelitis at Low Risk and High Risk of Recurrence". Clin Infect Dis. vol. 62. 2016. pp. 1262-1269.

(This retrospective study suggests that prolonged antibiotic therapy ( >8 weeks) should be given to patients at high-risk of recurrence, particularly those with MRSA infection, undrained saft tissue infection and end-stage renal disease.)

Perlroth, J, Kuo, M, Tan, J, Bayer, AS, Miller, AG. "Adjunctive use of rifampin for the treatment of Staphylococcus aureus infections: a systematic review of the literature". Arch Intern Med. vol. 168. 2008. pp. 805-19.

(A review concerning the accuracy of combined antibiotic treatment with rifampin for staphylococcal implant-associated infections.)

Proctor, RA. "Role of folate antagonists in the treatment of methicillin-resistant Staphylococcus aureusinfection". Clin Infect Dis. vol. 46. 2008. pp. 584-93.

(Pitfalls of co-trimoxazole for long-term antibiotic treatment of osteomyelitis.)

Pushkin, R, Iglesias-Ussel, M, Kara, K, MacLauchlin, C, Mould, DR, Berkowitz, R, Kreuzer, S, Darouiche, R, Oldach, D, Fernandes, P. "A Randomized Study Evaluating Oral Fusidic Acid (CEM-102) in Combination with Oral Rifampin Compared with Standard of Care Antibiotics for Treatment of Prosthetic Joint Infections: A Newly Identified Drug-Drug Interaction". Clin Infect Dis. vol. pii. 2016 Sep 28. pp. ciw665.

(Study investigating the in vivo interaction of fusidic acid with rifampin.)

Salvana, J, Rodner, C, Browner, BD, Livingston, K, Schreiber, J, Pesanti, E. "Chronic osteomyelitis: results obtained by an integrated team approach to management". Conn Med. vol. 69. 2005. pp. 195-207.

(Description of a multidisciplinary approach to treatment of osteomyelitis.)

Smith, SL, Wastie, ML, Forster, I. "Radionuclide bone scintigraphy in the detection of significant complications after total knee joint replacement". ClinRadiol. vol. 56. 2001. pp. 221-4.

(Pitfalls and performance of scintigraphy regarding diagnosis of osteomyelitis.)

Steinmetz, S, Racloz, G, Stern, R, Dominguez, D, Al-Mayahi, M, Schibler, M, Lew, D, Hoffmeyer, P, Uçkay, I. "Treatment challenges associated with bone echinococcosis". J Antimicrob Chemother. vol. 69. 2014. pp. 821-6.

(The most extensive clinical review on bone echinococcosis.)

Tan, Y, Wang, X, Li, H. "The clinical efficacy of the vacuum-assisted closure therapy in the management of adult osteomyelitis". Arch Orthop Trauma Surg. vol. 131. 2011. pp. 255-9.

(The role of vacuum-assisted closure therapy in the management of adult osteomyelitis.)

Tone, A, Nguyen, S, Devemy, F. "Six-week versus twelve-week antibiotic therapy for nonsurgically treated diabetic foot osteomyelitis: a multicenter open-label controlled randomized study". Diabetes Care. vol. 38. 2015. pp. 302-307.

(Prospective randomized multicenter trial on the duration of antibiotic treatment for diabetic foot osteomyelitis. 6 weeks are not inferior to 12 weeks.)

Uçkay, I, Pittet, D, Vaudaux, P, Sax, H, Lew, D, Waldvogel, F. "Foreign body infections due to Staphylococcus epidermidis". Ann Med. vol. 41. 2009. pp. 109-19.

(Review of the mechanisms and clinical consequences of biofilm formation.)

Vaudaux, P, Kelley, WL, Lew, DP. "Staphylococcus aureussmall colony variants: difficult to diagnose and difficult to treat". Clin Infect Dis. vol. 43. 2006. pp. 968-70.

(Identification and role of small colony variants in osteomyelitis.)

DRG Codes and expected length of stay

Because osteomyelitis is often chronic in adults and principally a surgical disease, length of hospital stay is largely influenced by the number of surgical interventions needed and may be well beyond 1 month in resource-rich countries. In resource-poor settings, the length of hospital stay is largely influenced by the financial and organizational resources.

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