Chronic Osteomyelitis




Background


Bone infections have long been a source of challenge, and too often frustration, for patients and physicians alike. Despite significant advances over the past century in the diagnosis and treatment of osteomyelitis, multiple surgeries are often necessary and recurrence is not uncommon. The purpose of this chapter is to review our current knowledge of osteomyelitis along with methods of examination, diagnosis, and treatment of the disease. To appreciate the present understanding of osteomyelitis, a brief review of the history of bone infections is helpful.


The Edwin Smith Papyrus (3000–2500 bc ) is often cited as the earliest written evidence of bone infection. Review of the translated hieroglyphic text reveals recognition by its author of the challenges and uncertain outcomes associated with wounds extending to bone with accompanying inflammation. The unknown author describes clearly outlined management of closed fractures but in the case of an open humerus fracture instructs, this is an “ailment not to be treated.” Although the severity of the sequelae of open fractures appears to be recognized, limited treatment options seem to have been available.


Hippocrates (460–370 bc ) is credited as the first author to describe necrosis of the bone occurring after open fractures. His treatment involved cleaning the wound and reducing the fracture, or sawing off the protruding segment, followed by splinting. At the time, dead bone was allowed to “exfoliate” from the wound. Historical texts reveal that removal of the necrotic bone was advocated as early as the third century ad . Around the turn of the eleventh century, Avicenna wrote of the importance of “curetting … cutting … or sawing” bone to completely remove “corruption of the bones.”


Several centuries later, eighteenth-century physicians provided more complete descriptions of the characteristics and management of bone infection. Various terms were used for bone infections including “caries of the bone,” “abscessus in medulla,” and “boil of the bone marrow.” In 1844, Auguste Nélaton is believed to have introduced the term “osteomyelitis.” Additionally, following this period, the terms sequestrum and involucrum came into usage describing the fragment of necrotic bone and surrounding sheath of reactive bone formation, respectively.


In 1867, following Louis Pasteur’s identification of a microbial basis of infection, Joseph Lister described his aseptic technique for surgery using carbolic and phenic acid. He also discussed applying these agents to open fractures. In a case series, several cases of osteomyelitis were successfully treated with excision of the infected bone combined with application of antiseptic agents. This was a significant advancement in reducing gangrene and septicemia that were exceedingly common following open fractures.


Much of the early twentieth-century literature describes treatment of osteomyelitis based on the Orr method. H. Winnett Orr provided detailed descriptions of his surgical protocol, postoperative management, and outcomes. His treatment approach included “saucerizing” the infected area, removing foreign and dead tissue, cleaning with iodine and alcohol, filling the defect with Vaseline gauze packs, and applying a splint. Although he was not the first to describe the surgical procedure, unique to Orr’s treatment was that no dressing changes were performed for several weeks in order to avoid manipulating the fracture by opening the splint. In 76 cases of chronic osteomyelitis due to open fractures, Orr reported 62% healed, 9 did not heal, 3 required amputation, and 2 deaths occurred. Other authors using the Orr method reported similar results. However, examining photos of successfully treated patients reveals a level of persistent deformity that would not likely be tolerated by today’s standards.


Attempts to better characterize the differing presentations of osteomyelitis are evident from early twentieth-century literature. Chappel differentiated between primary and secondary osteomyelitis. According to Chappel, primary osteomyelitis was due to direct inoculation of bone from an exogenous source. Secondary osteomyelitis occurred from hematogenous bacterial seeding. He theorized that microtrauma to bony trabeculae resulting in microvascular compromise predisposed patients to this infection. He also differentiated between acute, subacute, and chronic osteomyelitis, as well as specific forms including Brodie abscess and nonsuppurative hemorrhagic osteomyelitis. Orr also cited early classification of osteomyelitis including acute, chronic, idiopathic, fulminating, and postoperative. Although these early physicians recognized that various presentations of the disease were possible, in the period prior to the introduction of antibiotics, the type of bone infection had no relevance as surgical excision was the only treatment option.


The discovery of penicillin was a pivotal point in the evolution of osteomyelitis treatment. In the 1930s, as is the case today, Staphylococcus aureus was recognized as the primary pathogen responsible for most cases of osteomyelitis. Despite having a better understanding of the disease than their predecessors, physicians of the early twentieth century remained limited in their treatment options and control of the infection, following débridement, was purely dependent on host immune function. In 1940, Chain and colleagues proved the effectiveness of penicillin in eradicating systemic staphylococcal infections in animal models. Over the course of the next decade, penicillin became widely available and was used for prevention and treatment of osteomyelitis. Suddenly, the pathophysiologic differences of acute and chronic osteomyelitis became significant.


Historically, the distinction between acute and chronic osteomyelitis was based on an ill-defined chronicity of infection. Acute osteomyelitis has been described as bone infection present for a few days to weeks. Chronic osteomyelitis has in some cases been arbitrarily defined as infection lasting months to years. However, the time frame is not as helpful as the character of the infection in determining treatment. Acute osteomyelitis is most often due to bacterial seeding of bone from a hematogenous source. It predominantly affects adolescents with open physes. Conservative treatment with appropriate antibiotics is the mainstay of treatment. In the majority of cases, acute hematogenous osteomyelitis can be arrested with antibiotics and without the need for surgical intervention. In contrast, chronic osteomyelitis is marked by sequestrum formation that may be infected by an endogenous or exogenous source. It is the presence of this necrotic tissue that defines the disease rather than chronicity. This necrotic tissue allows the formation of a bacterial environment resistant to antibiotics and is the reason surgical intervention remains necessary.


Where the early part of the twentieth century was marked by tremendous progress in understanding the etiology of osteomyelitis and developing different methods of débridement and postoperative care, the second half of the century was marked by improvement in diagnosis and fine-tuning of the surgical approach to create more options for limb salvage. The development and improvement of advanced imaging techniques, including magnetic resonance and nuclear medicine imaging techniques, has facilitated diagnosis and allowed precise localization of infection. The use of external fixators allowed stabilization of open fractures while maintaining exposure of wounds for better soft tissue management. The development of antibiotic-impregnated cement beads has allowed local delivery of antibiotics with control of dead space. In addition, advances in soft tissue closure techniques, including myocutaneous and free flap procedures, have allowed improved vascularity for systemic antibiotic delivery as well as a better opportunity for wound healing with the potential for immediate closure of wounds. The introduction, and now wide usage, of negative pressure wound therapy devices has allowed temporary coverage of open wounds and facilitated multistage intervention. The combined effects of these advances in the treatment of chronic osteomyelitis has allowed successful treatment of infection in 90% of patients. However, even with current advances in treatment, remission rather than cure is often regarded as a successful outcome and recurrence following several years without signs or symptoms of infection is not unusual.




Epidemiology


Although the true incidence and prevalence of osteomyelitis is unknown, it has been reported that 50,000 hospital admissions occur annually due to the disease. Additionally, bone and joint infections have been reported to be present in 1% of hospitalized patients. The vast majority of cases of chronic osteomyelitis occur from an exogenous source, open fractures being the most commonly reported.


Posttraumatic osteomyelitis is one of the few infectious diseases that have become more prevalent over the past century, probably due to improved survival following catastrophic injury. There are two reasons infection is so closely linked with such injuries. First, they provide ubiquitous microbes with an opportunity for breaching host defenses by exposing bone to the contamination of an accident scene. Second, once the microbes have bypassed external defenses, the trauma setting offers an ideal environment for adherence and colonization, namely, devitalized hard and soft tissues. When presented with these conditions, bacteria are able to form a biofilm layer making eradication of infection challenging.


A review by Gustilo showed the deep infection rate in the setting of open fractures to be anywhere from 2% to 50%. The infection rate is influenced, to a large extent, by the severity of the injury. Grade I and II open fractures are associated with around a 2% risk of infection as compared with 10% to 50% in grade III injuries. In addition, type IIIC fractures have a significantly greater risk of infection compared to type IIIa and IIIb. It intuitively seems reasonable that lack of bone coverage, massive contamination of the wound, compromised perfusion, and instability of the fracture would lead to an increased risk of infection in more severe injuries.


Because of the limited anterior soft tissues, the tibia is the most frequent location of open fractures ( Fig. 24-1 ). Accordingly, the tibia is the most frequent site of osteomyelitis. One retrospective study of 948 high-energy open tibial fractures reported a 56% posttraumatic infection rate. Although not involved so often as the lower extremity, the upper extremity also is vulnerable to accidental trauma and subsequent infection.




Figure 24-1


Open tibia fracture. The limited soft tissue coverage of the anteromedial tibia makes this area particularly susceptible to osteomyelitis.


In addition to accidental trauma, surgery itself poses a risk for the development of bone infection. Even when attempting to provide the most sterile conditions, there is an estimated 1% to 3% risk of surgical site infection. In addition to the risk posed by violating the integrity of the skin, soft tissues and potentially bone, orthopaedic implants may allow bacteria to colonize and form an environment secure from immune surveillance. Joint replacement and spine surgery was shown in one study to have the highest association with nosocomial infection. Although the risk of prosthetic joint infection is greatest within 2 years of implantation, the potential for colonization from hematogenous invasion remains elevated throughout the life of the prosthesis.


Pressure ulcers, a common occurrence in the bedridden multitrauma patient, are another frequent source of osteomyelitis. Despite the limited literature on decubitus ulcers and the development of osteomyelitis, this population (with limited mobility and often multiple comorbidities) comprises a significant portion of the patients with pelvic and calcaneal osteomyelitis. Typically, the pressure ulcer is contaminated with various organisms from the external environment. In the case of pelvic osteomyelitis, this includes enteric bacteria. The infected soft tissue, combined with an often compromised vascular and immune system, allows for bone involvement through contiguous spread.


In addition to multiple potential sources of infection, a number of host factors are associated with the development of osteomyelitis. Although quality evidence is often lacking, malnutrition, obesity, drug abuse, smoking, diabetes, malignancy, and immune system compromise and/or suppression are believed to be predisposing conditions for the development of osteomyelitis. Diabetic patients are particularly susceptible to soft tissue and bone infections. In fact, roughly 25% of diabetic patients will develop a foot ulcer in their lifetime. The combination of peripheral neuropathy, which leads to loss of protective sensation, combined with microvascular disease, which impairs the ability to heal and fight infection, sets the stage for nonhealing soft tissue lesions that may quickly spread to bone. Furthermore, hyperglycemia leads to altered cellular and humeral response to infection, thus weakening the host defenses.


Patients with peripheral vascular disease from causes other than diabetes are also at increased risk of osteomyelitis. Impaired bone perfusion in these patients not only functions as a barrier to immune surveillance but also impairs access to the infected tissue by systemic antibiotics. Additionally, vasoocclusive disorders such as sickle cell anemia may lead to bone ischemia and necrosis predisposing these patients to opportunistic infection.


As one would anticipate, immunocompromised individuals are at high risk for developing osteomyelitis. Whether immune system impairment is due to disease or medications, the host becomes susceptible to microbial invasion and spread. Patients suffering from a disorder of polymorphonuclear leukocytes, for example, have been shown to be at significantly elevated risk for the development and progression of osteomyelitis. Other immunocompromised individuals, such as organ transplant recipients, patients with end-stage renal disease on hemodialysis, and those receiving chemotherapy, also are at an increased risk. With the development and widespread use of immune-modulating medications, such as tumor necrosis factor (TNF)-α inhibitors, patients undergoing treatment for various autoimmune diseases may be predisposed. Although human immunodeficiency virus infection has not been identified as an independent risk factor in developing osteomyelitis, skeletal infection in this population is clearly associated with a more severe clinical course with elevated morbidity and mortality. Furthermore, behaviors that may be associated with human immunodeficiency virus (HIV) infection, particularly intravenous (IV) drug abuse, has been shown to increase a patient’s risk of osteomyelitis.


In addition to risk factors for the development of osteomyelitis, the disease itself may pose a risk for the development of certain malignancies. Patients with chronic draining sinuses often present with metaplastic changes of the sinus tract epithelium. These lesions have been reported to undergo malignant transformation in 0.2% to 1.6% of cases. Squamous cell carcinoma is the most frequently reported and should be suspected in patients with the triad of elevated symptoms, foul discharge, and hemorrhage.




Pathogenesis


The initial step in the pathogenesis of osteomyelitis involves bacterial penetration of the host’s external barriers. An open fracture and deep wound provide guaranteed access, but bacteria may also enter through an infection at a remote site. The bacteria must then find their way to the bone. In the case of an open fracture, this typically involves direct inoculation, and with an open wound, it is from spread of the adjacent soft tissue infection. In the case of a remote infection, the bacteria infiltrate the adjacent blood vessels and are carried with the blood to the osseous microvasculature.


Next, bacteria must be presented with an environment conducive to proliferation. This is not easily found in a healthy host as a functioning immune system renders bone quite resistant to bacterial colonization. It is only under certain conditions, such as a very large inoculum (>10 5 organisms), ischemic bone and soft tissue, or the presence of a foreign body that infectious pathogens may have an opportunity to take a stand. The accumulation of bacteria results in local edema, changes in pH, and the release of inflammatory mediators and catabolic enzymes causing destruction of bony trabeculae. Although the steps involved differ slightly between the different routes of infection, the common feature in chronic osteomyelitis is the creation of devitalized bone, the sequestrum ( Fig. 24-2 ). Around the necrotic bone forms a sheath of reactive bone, the involucrum, which effectively shields the area from the bloodstream much like a walled-off abscess.




Figure 24-2


A, Radiograph of tibia and fibula chronic osteomyelitis showing sclerotic dead bone and ( B ) sequestrum removed at time of débridement.


When microorganisms are transmitted to bone via a hematogenous route, the pathogens have a predilection for infiltration of metaphyseal end arteries, especially in the skeletally immature, and the highly vascular vertebral bodies. This instigates a robust inflammatory response with an influx of inflammatory cells. This increased volume within the inelastic walls of the haversian system results in increased intraosseous pressure and an occlusion of normal blood flow. The resulting ischemic condition sets the stage for the development of chronic osteomyelitis. However, in this instance, it is possible to interrupt the progression with early administration of antibiotics. As a result, in regions where modern medical care is readily available, acute hematogenous infection can be arrested before it evolves into chronic osteomyelitis.


In contrast, the patient with an open fracture often presents with a high level of bacterial contamination, foreign debris, and ischemic bone due to the trauma. Surprisingly, not all of these situations actually progress to osteomyelitis. For osteomyelitis to develop, the microbe must not only penetrate the host’s external defenses but actually become adherent to the underlying bone. This involves a complex interplay of intermolecular forces that allows binding of bacterial glycoproteinaceous structures (adhesins) to cell surface receptors and the extracellular matrix of the host tissue. The bacteria-host interaction is strain specific with bacteria showing varied expression of adhesins for multiple host proteins and glycoproteins, including collagen, bone sialoprotein, elastin, fibronectin, laminin, albumin, and fibrinogen, among others. These molecules are exposed to a greater degree with bone injury facilitating bacterial colonization.


Furthermore, necrotic bone fragments act as avascular foci for further bacterial adherence. Thus, as the osteonecrotic area expands, the disease is perpetuated by exposure of an increasing number of sites to which opportunistic bacteria can bind. In cases of chronic osteomyelitis secondary to internal fixation, the hardware itself serves as a surface for adhesion.


Once anchored to the substratum, bacteria aggregate and proliferate within an extracellular polysaccharide matrix, known as a biofilm or “slime” layer. The microbial inhabitants of this biofilm-protected environment undergo complex changes in behavior regulated through intercellular signaling. This cell-to-cell communication occurs through the release of simple hormone-like molecules and is known as quorum sensing . The effects include altered gene expression, regulated cell growth and division, as well as lowered metabolic rate. This interaction is likely an adaptation that allows bacterial colonies the ability to manage their nutritional resources. The biofilm also provides resistance to antimicrobials resulting in a significantly elevated minimum inhibitory concentration (MIC) of antibiotics necessary for controlling the infection, usually exceeding the capabilities of systemic antibiotics. In addition, the biofilm has a direct impact on immune function by inhibiting the activity of B and T lymphocytes and resisting phagocytosis of bacterial cells.


After bacteria successfully adhere to bone, they are able to aggregate and replicate in the devitalized tissue. Effectively sealed off from the host immune system, as well as from antibiotics, the organisms at the avascular focus of infection proliferate undeterred in a medium of dead bone, clotted blood, and dead space. Eventually, the bacteria disperse to adjacent areas of bone and soft tissue and the infection expands. The rapid growth of bacteria can lead to abscess and sinus tract formation. As pus accumulates and abscesses form within the soft tissues adjacent to the necrotic tissue, the patient experiences cyclic episodes of pain followed by drainage. A chronic course ensues without aggressive surgical débridement of all avascular tissue.




Microbiology


Although cases of fungal and parasitic bone infections have been reported, the vast majority of osteomyelitis is due to bacterial infection. In contrast to acute hematogenous osteomyelitis, which is typically monomicrobial, chronic osteomyelitis involves a polymicrobial infection in a substantial proportion of patients. Given that trauma is the most common cause of adult osteomyelitis, it is no surprise that a combination of bacteria from exposure to water, soil, foreign bodies, and skin flora result in most adult musculoskeletal infections. Despite this, it is important to recognize that certain bacteria may predominate in the pathogenesis of osteomyelitis for a given patient under certain conditions.


Staphylococcus aureus is the most common isolate in all types of bone infection and is implicated in 38% to 67% of chronic osteomyelitis cases. Although coagulase-positive staphylococci (S. aureus) are often cultured from the wound at the time of initial inspection, superinfection with multiple other organisms, such as coagulase-negative staphylococci (Staphylococcus epidermidis) and aerobic gram-negatives ( Escherichia coli and Pseudomonas species), also occurs. In bone cultures obtained from 100 patients with osteomyelitis, Zuluaga and colleagues found gram-positive aerobes in 89%, gram-negative aerobes in 45%, and anaerobes in 16% of cultures. Staphylococcus aureus was found in 43% followed by Enterococcus faecalis in 19% and Pseudomonas in 14%. Similarly, Cierny and coworkers found staphylococci to be the most common microbiologic finding in cultures from patients with infected tibia nonunions. This was followed by gram-negative rods and anaerobes. In their review, the distribution of bacteria found remained relatively constant from 1981 to 1995, but an increased incidence of methicillin-resistant S. aureus (MRSA) was seen in more recent years. Patzakis and colleagues grew 20 different organisms from 36 patients with posttraumatic osteomyelitis. The most frequently occurring isolates in decreasing order of frequency were S. aureus, Pseudomonas aeruginosa , Bacteriodes spp., and S. epidermidis . Interestingly, data from the University of Connecticut Multidisciplinary Bone Infection Clinic collected over the past 20 years has shown differences in the prevalence of certain organisms depending on the location of chronic osteomyelitis (unpublished data). Although S. aureus was the most frequently cultured organism, Corynebacterium and P. aeruginosa were found more frequently in the pelvis and proximal femur. In contrast, patients with osteomyelitis of the tibia were more likely to be infected with coagulase-negative staphylococci and enterococci.


Staphylococci are so frequently cultured in bone infection partly because they are ubiquitous organisms and are elements of normal skin flora. Any traumatic event gives these bacteria a conduit to internal tissues. In addition, staphylococci have adapted through natural selection to be particularly virulent in regard to bone and soft tissue infection. For one, S. aureus has been shown to express multiple adhesins, including fibronectin-binding proteins and collagen-binding proteins, facilitating attachment to wounded tissue. Both S. aureus and S. epidermidis also produce biofilm-associated protein and polysaccharide intercellular adhesins that facilitate aggregation and the production of a biofilm layer. As discussed, the cells protected in this glycocalyx layer are resistant to humoral and cell-mediated immunity, as well as antimicrobial agents, allowing for chronic and recurrent infection.


Another important virulence factor designed to protect S. aureus is the ability to gain intracellular access to host cells. Both S. aureus and S. epidermidis have been shown to invade osteoblasts. Surface proteins, specifically fibronectin-binding protein, allow staphylococci to complex with osteoblast integrins. This results in a series of enzymatic reactions resulting in internalization of the bacterium. Once intracellular, the pathogens can survive and replicate free from the danger of host immunity and antibiotics.


Furthermore, staphylococci are highly invasive and destructive when attached to bone. Staphylococcus surface-associated material (SAM) has been shown to stimulate osteoclast activity, likely through interaction with host cell receptors and provoking a release of interleukin-1 (IL-1), interleukin-6 (IL-6), and TNF-α. One surface protein, S. aureus protein A (SpA), has recently been shown to have an important role in mediating bone destruction. Widaa and colleagues showed that binding of SpA to receptors on osteoblasts interferes with normal metabolic activity and proliferation. Furthermore, the interaction was shown to induce expression of receptor activator of nuclear factor kappa B ligand (RANKL) and secretion of proinflammatory cytokines leading to stimulation of osteoclastogenesis and bone resorption.


Although staphylococci are most commonly involved in musculoskeletal infections, and as a result happen to be the most extensively studied, it is important to recognize that many other organisms are frequently involved. As can be seen in Table 24-1 , both the mechanism of inoculation and the status of the host influence the microbiologic makeup of the infection. This is important to recognize when choosing empiric antibiotics for a given patient.



TABLE 24-1

MICROORGANISMS AND CLINICAL ASSOCIATION


































Clinical Scenario Microorganism
Most common in any type of osteomyelitis Staphylococcus aureus (methicillin sensitive or resistant)
Foreign body associated Coagulase-negative staphylococci or Propionibacterium spp.
Soil contamination Pseudomonas aeruginosa, Clostridium spp., Bacillus spp., Nocardia spp.
Fresh water Pseudomonas spp., Aeromonas spp., Plesiomonas spp.
Bite wounds Pasteurella multocida, Eikenella corrodens
Diabetic foot lesions Streptococci, enterococci, Corynebacterium, and/or other anaerobic bacteria
Sickle cell disease Salmonella spp., Streptococcus pneumoniae, Proteus mirabilis, Haemophilus influenzae, Mycobacterium tuberculosis
HIV infection and immunocompromised patients Bartonella henselae, Bartonella quintana, Mycobacteria spp. , Aspergillus spp. , Candida albicans
Vertebral osteomyelitis Group B and G streptococci, gram-negative bacilli, M. tuberculosis

HIV, Human immunodeficiency virus.

Source: Adapted with permission from Lew DP, Waldvogel FA: Osteomyelitis, Lancet 364:369–379, 2004.


Like staphylococci, P. aeruginosa is a ubiquitous organism, with soil and fresh water serving as its primary reservoirs. Puncture wounds of the foot involve P. aeruginosa in about 95% of cases, probably because of its prevalence in soil and moist areas of skin. In addition, a soiled, sweaty shoe can serve as a repository of bacteria that are carried on a penetrating object into the patient’s foot. Clostridium, Bacillus, and Nocardia species are also present in soil and have been implicated in certain cases of osteomyelitis following open fracture. Conversely, Aeromonas and Plesiomonas species are more likely to be present in fresh-water infections. In the event of inoculation through bite wounds, multiple organisms are often found but Pasteurella multocida and Eikenella corrodens infections may be uniquely involved.


Intravenous drug use has long been associated with osteomyelitis likely due to the high frequency of skin puncture, lack of sterile conditions, and the presence of comorbidities commonly found in this population. Allison and coworkers found bone and joint infections of injection drug abusers, as with other causes of osteomyelitis, to be primarily because of S. aureus . However, the frequency of infection with S. epidermidis, P. aeruginosa, Streptococcus, and anaerobic infections are higher than in studies of nondrug abusers. Surprisingly, despite the expected hematogenous route of infection in these patients, 46% with osteomyelitis were found to have a polymicrobial infection.


Although HIV has not been clearly linked to an increased incidence of osteomyelitis, the microbiologic profile of the infection in those with HIV appears to be slightly different compared to those without HIV. In a sample of 23 HIV infected patients with osteoarticular infections, Busch and colleagues found an increased incidence of mycobacterial and streptococcus species, although S. aureus remained the most frequently identified organism. Other organisms reported in patients with HIV are Bartonella henselae and Bartonella quintana . Both HIV-infected and immunosuppressed patients are also more susceptible to fungal infections including Aspergillus and Candida .


Diabetic foot infections often involve a broad range of bacteria. Staphylococcus , Streptococcus, Pseudomonas, Enterococcus, and Corynebacterium have been found in a high percentage of patients. However, this is not consistent across all studies. Parvez and coworkers took bone cultures from 35 subjects with diabetic foot lesions. The most common organism identified was E. coli occurring in 22.7% followed by Proteus species in 18.2%. Other bacteria identified in a high number of patients included Klebsiella pneumoniae, P. aeruginosa, Peptostreptococcus, and Clostridium species. The difference in bacterial makeup found in various studies of diabetic foot infections may be in part due to regional differences, but what is important to recognize is that these infections can involve a wide range of pathogens necessitating broad empiric antibiotic coverage.


Patients with sickle cell disease represent another population at elevated risk for osteomyelitis. There appears to be a predisposition to Salmonella infection in these patients. Other frequently found organisms include S. aureus , Proteus mirabilis, Haemophilus influenzae, E. coli, and Mycobacterium tuberculosis .


Surgical site infections most commonly involve skin flora. Coagulase-positive and coagulase-negative staphylococci tend to predominate, but other organisms, including fungi, may be involved. Similarly, prosthetic-related infections most commonly involve staphylococci. In a review of 81 total knee arthroplasty infections, gram-positive cocci including Staphylococcus, Streptococcus, and Enterococcus predominated. In contrast, Propionibacterium acnes is a commonly recognized cause of infection after shoulder arthroplasty. This organism may be easily missed as clinical signs are often subtle and growth on culture takes longer than many other organisms.


Vertebral osteomyelitis is most commonly caused by hematogenous seeding. As in other infections of hematogenous route, S. aureus is the most common pathogen. Other bacteria include group B and G streptococci and various gram-negative bacilli. In addition, M. tuberculosis involves the spine in approximately 50% of musculoskeletal tuberculosis.


Other atypical causes of osteomyelitis have been reported in the literature. Cryptococcal osteomyelitis has been reported in both long bone and spine infections. These infections have been shown to produce lytic bone lesions similar to bacterial infections. In addition, musculoskeletal brucellosis because of Brucella infection is a rare cause of osteomyelitis that produces an inflammatory response and subsequent osteolysis. This most commonly involves the sacroiliac joint. Q fever is caused by an infection by Coxiella burnetii and has been reported to be a potential cause of osteomyelitis.


Widespread use of antibiotics leading to the development of multidrug-resistant organisms is creating ongoing challenges in the treatment of osteomyelitis. A dramatic rise in the frequency of MRSA infections has occurred in the past 20 years. The presence of MRSA in patients with osteomyelitis ranges from 33% to 55%. Vancomycin-resistant enterococci have also been on the rise over the past 15 years. This is especially evident in military data of wartime injuries. In a study of 137 Iraqi civilians with combat-related injuries, 55% were found to be infected with multidrug-resistant organisms. Resistant organisms found in this study included Enterobacteriaceae, MRSA, and Acinetobacter baumannii .




Classification


Several systems exist for classifying osteomyelitis. First, a distinction is often made between acute and chronic osteomyelitis. A precise definition is lacking for what constitutes acute osteomyelitis, but this is typically used to represent infection occurring within days to weeks of inoculation and presenting with systemic signs and symptoms of infection. In contrast, as was previously discussed, chronic osteomyelitis describes a bone infection in the presence of necrotic bone. It has been reported that chronic osteomyelitis is the consequence of untreated acute osteomyelitis. However, although this may occur in some cases, most cases of adult osteomyelitis occur because of inoculation of injured bone at the time of a traumatic event. In this case, the initial injury is likely to lead to bone ischemia and subsequent necrosis prior to the development of signs and symptoms of osteomyelitis. As a result, osteomyelitis following trauma is usually considered “chronic” from the start.


Another method of distinguishing between forms of osteomyelitis is by the route of inoculation. Pathogens may be delivered to bone by hematogenous seeding, direct inoculation, or spread from a contiguous focus. Contiguous-focus osteomyelitis can be further divided into that occurring with and without vascular insufficiency. Hematogenous osteomyelitis occurs most commonly in the pediatric population, but has been reported to account for up to 20% of adult bone infections. Direct inoculation occurs when an open fracture exposes bone to the external environment. Contiguous-focus osteomyelitis is the result of direct spread from local soft tissue infection or due to a nosocomial infection occurring from a postoperative wound infection. When vascular insufficiency is present, as is often the result in diabetics and those with peripheral vascular disease, the patient’s ability to fight soft tissue infection is compromised resulting in a predisposition to chronic osteomyelitis.


Although differentiating between routes of infection can be helpful for communication and helping to predict the microbiologic profile, it provides little help with determining the most appropriate treatment. It is well accepted that chronic osteomyelitis will almost invariably persist without surgical intervention. However, deciding the best treatment for the patient is based on multiple factors including the status of the host, the location of infection, and the effect of the disease on patient function. For this reason, the Cierny-Mader classification is helpful for guiding treatment.


The Cierny-Mader staging system classifies bone infection on the basis of two independent factors: (1) the anatomic area of bone involved and (2) the physiologic status of the host. By combining one of the four anatomic types of osteomyelitis (I, medullary; II, superficial; III, localized; or IV, diffuse) ( Fig. 24-3 ) with one of the three classes of host immunocompetence (A, B, or C), this system arrives at 12 clinical stages. As described by Cierny and colleagues, the primary lesion in medullary osteomyelitis (type I) is endosteal and confined to the intramedullary (IM) surfaces of bone (e.g., a hematogenous osteomyelitis or an infection of an IM rod). S uperficial osteomyelitis (type II) is a true contiguous-focus infection in which the outermost layer of bone becomes infected from an adjacent source, such as a decubitus ulcer or a burn. Localized osteomyelitis (type III) produces full-thickness cortical cavitation within a segment of stable bone. It is frequently observed in the setting of open fractures or when bone becomes infected from an adjacent implant. When the infected fracture does not heal and there is through-and-through disease of the hard and soft tissue, the condition is called diffuse osteomyelitis (type IV). Patients with posttraumatic osteomyelitis almost always have type III or type IV disease.




Figure 24-3


Anatomic types of osteomyelitis as they relate to the osseous location.

(Redrawn from Cierny G 3rd, Mader J, Penninck J: Adult osteomyelitis, Contemp Orthop 10(5):21, 1985.)


The host condition portion of the Cierny-Mader classification stratifies patients according to their ability to mount an immune response and heal surgical wounds. A patient with a normal physiologic response is labeled an A host, a compromised patient a B host, and a patient who is so compromised that surgical intervention poses a greater risk than the infection itself is designated a C host. A further stratification is made in B hosts on the basis of whether the patient has a local ( B L ), systemic ( B S ), or combined ( B S,L ) deficiency in wound healing. An example of a local deficit in wound healing would be venous stasis at the site of injury, whereas systemic deficits would include malnutrition, renal failure, diabetes, tobacco or alcohol use, or acquired immunodeficiency syndrome.


The physiologic classification also includes an assessment of the level of disability caused by the infection. This is an important variable in treatment planning for patients with compromised health. Although eradication of chronic osteomyelitis requires surgery, the morbidity and mortality risk associated with a major operation may outweigh the benefit if limited improvement in quality of life is expected. Even though systemic spread of infection is a constant concern, antibiotic suppression of infection may be a reasonable goal for select patients.


Each classification system has strengths and limitations. They are all useful for communication and, to some extent, treatment planning. For chronic osteomyelitis, classification based on the route of inoculation is simple and easy to remember. The Cierny-Mader classification is more comprehensive and is more useful in terms of operative planning. However, as with all classification systems, it is impossible to capture the complexities of each individual with a few categories. Therefore, to optimize outcomes, it is necessary to follow a systematic approach, which is detailed in the next section, to gain a complete understanding of the patient’s overall condition.




Diagnosis


History


A detailed history not only facilitates making the diagnosis but also provides important information for planning treatment and predicting outcomes. Osteomyelitis should be suspected in anyone with bone pain who has a past history of trauma or orthopaedic surgery. Complaints often include persistent pain, erythema, swelling, and drainage of the involved area. Walenkamp and coworkers described cyclical pain, increasing to “severe deep tense pain with fever,” that often subsides when pus breaks through in a fistula. Although these symptoms are present for some, they certainly do not occur in everyone with the disease. Most often, symptoms are vague and generalized (e.g., “my leg is red and sore”), making it difficult to differentiate between cellulitis and a true bone infection.


In addition to patient symptoms, it is important to collect details regarding past trauma and surgery. In cases of prior trauma to the involved bone, it is important to establish the mechanism of injury and the treatment provided. If there was a previously diagnosed soft tissue or bone infection, the culture results should be reviewed along with previous antibiotics given. Furthermore, the ability of a host’s soft tissues to heal and clear infection are largely dependent on the presence of comorbid conditions. Vascular compromise, extremity edema, extensive scarring, and a history of radiotherapy impact soft tissue healing. In addition, systemic factors including diabetes, poor nutritional status, chronic kidney disease, and immune deficiency may impact outcomes of surgery and must be considered in weighing the decision to attempt limb salvage versus amputation.


Physical Examination


Inspection of the soft tissues is the first step in a comprehensive physical examination. Erythema, open wounds, and draining sinuses strongly suggest an underlying infection. In the presence of exposed soft tissue or bone, the diagnosis is confirmed ( Fig. 24-4 ). However, signs of osteomyelitis are often subtle. Fever is often absent and in cases of infected nonunions, the skin may appear benign. Even small trivial-appearing skin lesions should be probed to determine depth, as a sinus tract extending to bone is pathognomonic for osteomyelitis ( Fig. 24-5 ), The involved site should be palpated for tenderness, swelling, and structural abnormalities. Old fracture sites should be stressed and adjacent joints must be thoroughly examined. In addition, the length and alignment of the limb along with general functional limitations should be assessed.




Figure 24-4


Exposed bone is an obvious sign that an underlying skeletal infection is present.



Figure 24-5


Even benign-appearing lesions must be carefully inspected and probed as is the case of this slow-draining sinus from a patient with osteomyelitis.


Cultures


Culturing drainage fluid and swabbing open wounds is often performed in the office setting. Although potentially helpful in identifying causative bacteria and guiding antibiotic choice, these results must be interpreted with caution, because such specimens often yield opportunistic organisms that have simply colonized the nutrient-rich exudate. In a prospective study of 100 patients with chronic osteomyelitis, cultures taken from nonbone specimens agreed with bone cultures in only 30% of patients. Other studies also showed significant discrepancies in the results of cultures taken from drainage and soft tissue cultures when compared with bone cultures. As a result, conclusive microbiologic diagnosis should be based on deep intraoperative cultures rather than needle or swab cultures taken in a nonsterile environment. Multiple intraoperative cultures are recommended including sinus tracts, deep purulent material, and, of course, bone.


It is important to recognize that although culture has long been the gold standard for definitive diagnosis of osteomyelitis, it is not without limitations. In order for an organism to be identified on culture, it must be able to grow on the media provided. An ideal medium is not available for all bacteria in the clinical laboratory setting and may partly explain the culture-negative cases of osteomyelitis found in some studies. Newer methods of identifying microbes are currently being investigated. For example, bacterial identification through DNA analysis has been found to have greater sensitivity than traditional cultures of infected wounds. Further study is needed to evaluate the clinical utility of alternative methods of microbe identification.


Laboratory Values


White blood cell (WBC) counts, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels have traditionally been part of the workup of any patient with suspected musculoskeletal infection. In an immunocompetent individual, elevated levels of these laboratory values are fairly sensitive indicators of some sort of acute infection. However, there is a paucity of studies showing a correlation between laboratory values and the presence of bone infection, although one group of investigators has shown CRP to be useful in the early detection of sequelae-prone acute osteomyelitis. Most laboratory values are rather nonspecific to skeletal infection and, thus, add little to the clinician’s ability to distinguish a superficial inflammatory process, such as a cellulitis, from a deeper, osteomyelitic one. Furthermore, although theoretically helpful in screening for an acute infection, the WBC count, ESR, and CRP are frequently normal in the setting of chronic osteomyelitis and, thus, are neither sensitive nor specific for it.


Nutritional parameters, such as albumin, prealbumin, and transferrin, are helpful to obtain in the workup of a patient with suspected chronic osteomyelitis so that malnutrition can be identified and reversed before taking the patient to the operating room. Orthopaedic surgery patients who are malnourished have significantly higher infection rates than those who have a normal nutritional status. Presumably, it would follow that patients who already have infection present would be more likely to respond to therapy if their nutrition were optimized beforehand.


Imaging


Diagnostic imaging plays an integral role in evaluating patients with known or suspected osteomyelitis, facilitating disease localization and preoperative planning. Early diagnosis is critical, allowing timely therapy and preventing many of the unfortunate complications.


Plain radiographs are the most appropriate initial imaging modality for patients with suspected or confirmed osteomyelitis. Radiographs are inexpensive, readily available, and can reveal periosteal reaction, cortical erosion, endosteal scalloping and radiolucent or osteolytic lesions, as seen in Brodie abscess ( Fig. 24-6 ). Radiographs may demonstrate involucrum (layer of new living bone formed about necrotic bone), sequestrum (fragment of dead bone separated from viable parent bone by granulation tissue), and cloaca (opening in the involucrum through which granulation tissue and/or sequestra can be discharged), all hallmarks of subacute to chronic osteomyelitis. Additional radiographic findings may indicate septic arthritis (loss of joint space and osseous erosions) and soft tissue infection (swelling, radiolucent streaks, and periostitis). However, radiographs have been shown to have a sensitivity and specificity of only 0.60 and 0.67, respectively, in diagnosing chronic osteomyelitis limiting their usefulness as an isolated study. Other imaging modalities, namely magnetic resonance imaging (MRI) and nuclear scintigraphy, provide an accurate diagnosis at an earlier stage of disease.




Figure 24-6


Osteomyelitis of the femur showing characteristic radiolucent lesions with cortical erosion and periosteal reaction.


The now widespread availability of MRI has greatly facilitated the diagnosis and localization of bone infection, particularly in the acute stage. MRI offers superior soft tissue contrast, delineating soft tissue infection and abscess as well as sinus tract communication with bone and/or joints. Abnormal bone marrow signal, manifesting as low signal on T1-weighted fast spin echo and high signal on T2-weighted images, is typical for acute osteomyelitis. Subacute and chronic osteomyelitis have a more variable MRI appearance, although chronic active cases do show similar signal characteristics. Short tau inversion recovery (STIR) sequences show markedly increased fluid signal in areas of osteomyelitis and soft tissue infection.


Following IV administration of gadolinium contrast, areas of vascularized inflammatory tissue will enhance. Nonvascularized soft tissue abscesses will typically demonstrate peripheral and/or marginal enhancement. Brodie abscesses appear as well-defined regions of intraosseous low-signal intensity on T1-weighted images with corresponding high-signal intensity on T2-weighted images; they may be further delineated with IV gadolinium contrast ( Fig. 24-7 ). Sequestra, although more clearly identified on computed tomography (CT), appear as regions of low to intermediate signal on both T1- and T2-weighted images and are notable for their lack of gadolinium enhancement. In cases of septic arthritis, inflamed synovium will enhance with gadolinium. Despite the high sensitivity of MRI in identifying osteomyelitis, challenges remain. Distinguishing osteomyelitis from surrounding bone marrow edema remains difficult. Similarly, distinguishing soft tissue extension of infection from soft tissue edema is also a challenge. In cases of chronic osteomyelitis, differentiating active from inactive disease can be problematic. MRI resolution is also limited by metal artifact, making it less useful in cases of suspected periprosthetic infection.




Figure 24-7


A, Coronal T1-weighted magnetic resonance imaging (MRI) with fat saturation showing low signal intensity in femoral diaphysis. B, Coronal T1-weighted MRI with fat saturation postcontrast showing enhancement of femoral diaphysis with nonenhancing abscess.


The primary utility of CT in musculoskeletal infection is in delineating extent of osseous and soft tissue disease. Many of the CT abnormalities in osteomyelitis are shared by both primary bone and metastatic tumors, including cortical bone destruction, new bone formation, and soft tissue mass. Gas within the medullary canal, best visualized with CT, is an uncommon but highly specific feature of osteomyelitis, analogous to the presence of gas within soft tissue abscesses. CT may also reveal cortical sequestra and cloacae, as well as bone and soft tissue abscesses. In addition, CT is useful for gauging the amount of bony bridging in fracture healing to guide the timing of fixation removal.


Three-phase nuclear medicine bone scans using 99m technetium ( 99m Tc)-methylenediphosphonate (MDP) is a mainstay of musculoskeletal infection imaging, particularly for those patients without underlying bone disease, fractures, or orthopaedic prostheses. 103 99m Tc phosphonates are readily available. They provide a short physical half-life (6 hours) and a gamma energy of 140 keV, ideal for the gamma camera. Following injection, 99m Tc-MDP flows through arteries and into capillaries, with leakage into the extracapillary space. Increased capillary permeability may be seen in infection, trauma, and tumors. 103 99m Tc-MDP also localizes to new bone formation, depositing in bone mineral and/or bone matrix. Increased tracer uptake on early blood flow and blood pool phases with absent or only mild uptake on the delayed phase is consistent with soft tissue infection. A fourth phase 24-hour scan may be helpful if the initial three-phase scan is nondiagnostic; increased uptake on all three or four phases of the bone scan is consistent with osteomyelitis. It is important to note that three-phase bone scan positivity is nonspecific; that is, fractures, tumors, and other bone abnormalities may show a similar scintigraphic appearance ( Fig. 24-8 ). Yet, in intact bone (i.e., normal radiographs), the sensitivity and specificity for osteomyelitis with three-phase bone scan is well over 90%. In the presence of fracture or prior surgery, specificity drops substantially. Septic arthritis is characterized by hyperemia on early phase imaging and diffusely increased tracer uptake on delayed images. Again, these findings are nonspecific and may be seen with noninfectious inflammatory arthritis.




Figure 24-8


99m Technetium-methylenediphosphonate (MDP) showing increased uptake at the left ankle. On further imaging, this patient was found to have a fracture of the distal tibia.


Indium 111 ( 111 In)-labeled leukocyte scintigraphy is often used for confirmation or exclusion of musculoskeletal infection in patients with underlying bone disease and/or hardware. The radiotracer (labeled WBC) localizes to areas of infection rather than remodeled bone, as infection and/or abscess consists primarily of leukocytes. The labeling process is labor intensive; roughly 50 mL of autologous blood is drawn into a syringe, red blood cells and platelets are separated, and leukocytes are then labeled with radiotracer and subsequently injected via a peripheral vein within 2 to 4 hours. Images are typically acquired 18 to 24 hours after radiotracer injection, allowing sufficient time for WBC localization and blood pool clearance. Focal uptake greater than or equal to that in the liver or spleen is typical for an abscess. Potential sources for false-negative studies include nonpyogenic abscess, chronic low-grade infection, and vertebral osteomyelitis. False-positive results may be caused by healing fractures and surgical wounds. In cases where marrow distribution is not normal, that is, cases of previous disease, orthopaedic hardware or tumor, determining whether focal uptake represents infection versus atypical normal distribution is difficult. In these equivocal cases, combining the 111 In-labeled leukocyte study with a 99m Tc sulfur colloid bone marrow study can improve specificity. In the absence of infection, radiotracer distribution in the two studies is similar. If localized infection is present, osteomyelitis will appear as a photopenic defect on sulfur colloid owing to marrow displacement by underlying infection. Discordance between 111 In-labeled leukocyte and 99m Tc sulfur colloid studies is consistent with osteomyelitis.


There are disadvantages to using 111 In-labeled leukocytes. As 111 In is cyclotron produced, many hospitals, lacking facilities and personnel for radiolabeling, send the patient’s blood to an outside commercial radiopharmacy. The handling of patient’s blood is also not without risk; misadministration to the wrong patient has unfortunately been reported. The rather long (18 to 24 hour) time delay between reinjection of labeled WBCs and imaging may be suboptimal for clinical decision making. Also, the relatively high radiation dose to the spleen (the target organ) is of particular concern for pediatric patients, whose smaller blood volume distribution means a higher radiation dose.


Leukocyte labeling may be alternatively performed with 99m Tc hexamethylpropyleneamine oxime (HMPAO) ( Fig. 24-9 ). 99m Tc-HMPAO offers a lower radiation dose and thus, allows a higher administered activity. As it is a technetium-based compound, imaging also begins much sooner, typically 1 to 2 hours after administration. Although this shortened examination time does provide images much sooner than with indium, the 18- to 24-hour window between injection and imaging with indium allows more time for leukocytes to migrate to sites of infection. Again, there are trade-offs. An important downside to using 99m Tc HMPAO–labeled leukocytes is the inability to perform dual isotope imaging.


Jun 11, 2019 | Posted by in ORTHOPEDIC | Comments Off on Chronic Osteomyelitis

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