Unraveling Orthopaedic Infections and Osteomyelitis: History & Treatment

INTRODUCTION The first descriptions of infections date back to the early Sumerian carvings, when the tenets of treatment were irrigation, immobilization, and bandaging.82 In these early times, the practice of infection and wound care was essentially an art and there was very little science applied to it. Treatment included the use of honey, wine, and donkey feces, and there were a number of philosophies regarding the value of purulence. Dominant personalities had a significant influence over medical practice and the value of purulence persisted because of the writings of Galen of Pergamum (120-201 A.D.). It was not until the latter third of the second millennium that the concept of the value of purulence would be challenged.82 In the past three centuries, the treatment of infection has involved the use of local ointments or salves and the maintenance of an open wound that permitted purulence to exit the body. Some important terms were adopted into medical parlance. A sequestrum was defined as “a fragment of dead bone separated from the body.” The word sequestrum is derived from the Latin words sequester meaning “depositary” and sequestrate meaning “to give up for safe keeping.” The word sequestrum is used to describe a detached piece of bone lying within a cavity formed by necrosis. The term involucrum derives from the Latin word involucrum meaning “enveloping sheath or envelope.” This term describes the effects of the body’s inflammatory response when trying to envelope and isolate the sequestrum from the host. The natural history of osteomyelitis was seen as the process of isolation of the infective material followed by a slow attempted resorption of the material by the immune system. However, the term osteomyelitis was not coined until the mid-1800s, when it was adopted by Nelaton.98 In his book The Story of Orthopaedics, Mercer Rang describes the three pivotal discoveries that allowed orthopaedic surgery to be successful:98 anesthesia, antisepsis, and radiography. The first two were important in all surgical specialties. Anesthesia made surgery tolerable, but there was still considerable morbidity secondary to infection. It was not until the mid-1800s that progress with antisepsis permitted infection control and more effective surgical intervention. As a result of this, infection issues became an integral part of medicine and were studied in a more formal basis. However, descriptions of the first sequestrectomies of the tibia had been illustrated as early as 1593 by Scultetus.98 Prior to anesthesia, most operative procedures were performed using forced immobility and inebriation. Operating rooms were created because procedures undertaken in the wards horrified patients who witnessed them and the screams of agony did nothing to encourage other patients to seek surgical treatment. Thus, the patients were isolated from the rest of the ward. In the same era, many modern drugs were developed, including morphine, heroin, nitrous oxide, and ether. Ether was in fact serendipitously identified as an anesthetic agent during one of the drug parties that were common at this time. However, it was first used for anesthesia in Massachusetts General Hospital in 1846 by William T. G. Morton, and its use quickly caught on around the world. This increased the incentive to undertake surgical procedures. The ensuing increase in the number of surgical procedures, together with the lack of antisepsis, meant that the morbidity and mortality of surgery also increased.98 Pasteur and Lister are most commonly credited as being the forerunners of antisepsis, but the most notable achievement in demonstrating the efficacy of bacterial transmission is the work of Semmelweiss, who, in 1848, demonstrated that hand washing between obstetric deliveries reduced maternal mortality from 18% to about 1%. Lister read Pasteur’s work on fermentation and likened tissue putrefaction to the same process. He subsequently developed carbolic acid, which reduced mortality from amputation from 43% in an untreated cohort of patients to 15% in a treated cohort. Despite this significant discovery, his findings were resisted for decades. Even when his concepts were adopted, the remaining pieces of the puzzle required for successful aseptic surgery did not come together for another 100 years. The initial use of antibiotics was just as serendipitous as the use of anesthesia and antisepsis. Some antibacterial treatments were introduced, but it was not until the discovery of penicillin by Alexander Fleming in 1928 that the proven usefulness of antibiotics became understood. Even Fleming did not vigorously pursue his discovery. However, when Florey and Chain read Fleming’s initial report, they pursued and found the true impact of penicillin, which was effective against streptococci. Since then, many antibiotics have been developed, but the number of resistant bacteria has also increased. Hand washing, gloves, hats, enclosed rooms, aseptic techniques, and early antibiotics all slightly decreased the incidence of surgical infection. However, the operating theaters in the early 1900s still admitted observers who coughed, did not use masks, and wore street clothes. It was not until the mid-20th century that surgeons began to integrate all the controllable aspects of patient exposure to infectious agents by attempting to standardize the contributive effects of the environment, patient, surgeon, wound, antisepsis, antibiotics, and surgical techniques. It is likely, though, that many of the answers to the problem of infection remain undiscovered, and it seems likely that at the moment we do not fully understand the complex symbiosis between bacteria and humans. This chapter will concentrate on the description, etiology, diagnosis, and management of orthopaedic infections but will have a specific focus on posttraumatic conditions. Historically, the treatment of orthopaedic infection was either ablative, when an amputation was performed, or temporizing with treatment of a chronic wound or sinus. There was little chance of limb salvage as we know it today, and infections that were not adequately treated would occasionally become systemic and fatal. Certainly the high mortality of open gunshot wounds to the femur in the American Civil War and World War I were largely due to sepsis. In every war, the science of surgery and medicine advances, and this is particularly true for trauma surgery and extremity injuries, which still account for approximately 65% of all war-related injuries.83 Thus, many advances in infection treatment and extremity injuries have ironically come about as a result of war. To treat orthopaedic infection, one must first understand the basics of the interdependence of humans and bacteria. Bacteria are a necessary part of our existence and normal flora live in abundance on our bodies. It is worth considering that an individual’s skin can contain up to 180 different types of bacteria at any given time.45 There are up to 10 colony-forming units (CFUs) of bacteria in the mouth and perineum. Nearly 95% of bacteria found in the hands exist under the fingernails. The average human is composed of 100 trillion cells, but it is thought that we harbor over a 1000 trillion bacteria in or on our bodies. Our blood is constantly infiltrated with bacteria from breaks in the skin, translocation across mucous membranes, and other roots. However, nearly all of these bacteria are quickly and efficiently eradicated by our host defense mechanisms. It is the disruption of our own homeostasis that provides an opportunity for either external contaminant or opportunistic host bacteria to become pathogenic and cause infection. While colonization necessarily precedes infection, the presence of bacteria by itself does not constitute infection. This is highlighted by the findings of one study of hardware removal in which 50% of cultures were positive in patients with no signs of symptoms or infection.80 Thus, there is an important distinction between colonization and infection. Understanding the factors that have changed the local or systemic environment with resultant bacterial infection is the key to effective prophylaxis, treatment, and improved outcomes in orthopaedic surgery. CLASSIFICATION Historically, osteomyelitis was classified as either acute or chronic depending on the duration of symptoms. Kelly documented a classification system based on the etiology of the osteomyelitis.61 There were four types with type I being hematogenous osteomyelitis. Type II was osteomyelitis associated with fracture union, while type III was osteomyelitis without fracture union and type IV was postoperative or posttraumatic osteomyelitis without a fracture. Weiland et al.123 in 1984 suggested another classification scheme based on the nature of the bony involvement. In this classification system, there were three types, with type I being characterized by open exposed bone without evidence of osseous infection but with evidence of soft tissue infection. In type II fractures, there was circumferential cortical and endosteal infection, and in type III fractures, the cortical and endosteal infection was associated with a segmental defect. In 1989, May et al.71 proposed another classification scheme for osteomyelitis focusing on the tibia. This system was based on the nature of the bone following soft tissue and bony débridement. They proposed that there were five different categories. Type I posttraumatic tibial osteomyelitis was defined as being present when the intact tibia and fibula were able to withstand functional loads and no reconstruction was required. In type II osteomyelitis, the intact tibia was unable to withstand functional loading and required bone grafting. In type III osteomyelitis, there was an intact fibula but a tibial defect that measured no more than 6 cm. The tibial defect required cancellous bone grafting, tibiofibular synostosis, or distraction histogenesis. Type IV osteomyelitis was characterized by an intact fibula but with a defect of more than 6 cm in length, which required distraction osteogenesis, tibiofibular synostosis, or a vascularized bone graft. Type V osteomyelitis was characterized by a tibial defect of more than 6 cm without an intact fibula, which often required amputation. The Waldvogel classification121 categorized osteomyelitis into three primary etiologies—hematogenous, contiguous (from an adjacent root such as an open fracture or a seeded implant), or chronic, this being a longstanding osteomyelitis with mature host reaction. These various classification systems were predicated on the beliefs and treatment options of the times, and they have all become less relevant with current diagnostic and treatment modalities. However, each classification represented an important effort to categorize the pathophysiology of bone infection to facilitate the choice of an effective treatment. The currently accepted classification remains the Cierny-Mader classification,21 which not only describes the pathology in the bone but, more importantly, also classifies the host or patient (Tables 24-1 and 24-2). The usefulness of the Cierny-Mader system is its applicability to clinical practice and the wealth of experience and data gleaned from a single surgeon’s practice with meticulous records. The hallmark of Cierny’s approach is the use of oncologic principles for treatment. In fact, osteomyelitis behaves very similarly to a benign bone tumor in that it is rarely lethal but has a tendency to return without complete eradiation. Interestingly, the outcome data reported by Cierny et al.21 indicate that once appropriate surgical treatment is undertaken, the host may be the most important variable affecting treatment and outcome. A novel aspect of the Cierny-Mader classification is its analysis of the physiologic state of the patient or host. The host is classified by the number of systemic and local comorbidities. An A host has a healthy physiology and limb with little systemic or local compromise. The B host is further divided into one with local compromise (B local), systemic compromise (B systemic), or both (B systemic/local systemic compromise, which includes any immunocompromised condition, poor nutrition, diabetes, old age, multiple trauma, chronic hypoxia, vascular disease, malignancy, or organ failure such as renal insufficiency or liver failure). Local compromise includes conditions such as previous surgery or trauma, cellulitis, radiation fibrosis, scarring from burns or trauma, local manifestations of vascular disease, lymphoedema, or zone-of-injury issues. We believe that a new variable of compromise can be identified in the trauma patient where systemic compromise is due to multiple organ damage and the consequent systemic response to trauma and local compromise is defined by the zone-of-injury effects on local tissues. The C host is a patient in whom the morbidity of treatment is greater than the morbidity of disease because of multiple and severe comorbid conditions that cannot be treated safely. In these patients, the risks of curative treatment such as extensive surgery, as might be used with free flaps, or prolonged reconstruction with bone transport would be greater than that caused by the infective condition itself. Type C hosts are often better treated with limited nonablative surgery and suppression or, if appropriate, by an amputation. In the Cierny-Mader classification21, the bone lesion is classified by the extent of involvement and stability. Type I is a medullary or endosteal infection without penetration through cortex. This is the type of infection that occurs after intramedullary nailing. Type II is a superficial osteomyelitis that involves only the outer cortex and is frequently contiguous with a pressure ulcer or adjacent abscess. Type III is permeative in that there is involvement of both cortical and medullary bone but, importantly, there is no loss of axial stability of the bone. Type IV also involves cortical and medullary bone but in a segmental fashion such that axial stability is lost. Types III and IV would be typical infections related to open fractures. In type IV lesions, the segmental resection that is required necessitates reconstruction of the bone, whereas in type III lesions, additional stabilization may not be required (Tables 24-1 and 24-2). The pairing of the four types of osteomyelitis with the three host classes allows for the development of practical treatment strategies. Cierny et al.21 proposed a detailed treatment regimen defining optimal treatment modalities for each stage. They achieved an overall clinical 2-year success rate of 91% for all states. As one would expect, when their results were broken down by class of host and type of lesion. Class A hosts fared the best. In class A hosts, success rates of 98% were achieved even with type IV osteomyelitis. The compromised class B host success rates were far lower, ranging from 79% to 92% depending on anatomic type. In his series Cierny found that the host class seemed to be more important than the type of infection. A cumulative success rate of greater than 90% was achieved with most of the failures being in B hosts. C hosts were recommended for amputation or suppressive treatment.22 The lessons that stem from their findings are that it is important not just to treat the disease but also the host and that the patient’s physiologic condition should be optimized. Thus, a B systemic-local host who has had a previous open fracture but also smokes and has uncontrolled diabetes, renal insufficiency, and malnutrition should have all of these problems treated together with the bone disease. Improving host status would appear to be a fruitful endeavor when one | considers Cierny et al.’s21,22 findings. TABLE 24-1 Cierny-Mader Classification of Bone --- | Type I—Medullary | Osseous location | Involvement | | --- | --- | --- | | Infection is limited to the medullary canal. Typically seen after intramedullary nailing. | | Type II—Superficial Infection is limited to the exterior of the bone and does not penetrate the cortex. Typically seen from pressure ulcers. | | Type III—Permeative/Stable Infection penetrates cortex but bone is axially stable and generally will not require supplemental stabilization. Typically seen after internal fixation with plates. | | Type IV—Permeative/Unstable Infection is throughout the bone in segmental fashion and results in axial instability. Typically seen in extensive infections or after aggressive débridement of type III infections that results in loss of axial stability. | | It should be noted that Cierny et al.’s21,22 results used outcome criteria that were commonly used at that time. Current outcome studies focus more on subjective patient-based assessments than on surgeon-based assessments. We do not have much data on the functional outcomes in the scenarios described by Cierny and colleagues, and it is possible that some of the patients whom they salvaged would have fared better with prosthetic replacement and vice versa. The findings of the LEAP study for acute limb salvage have raised new questions about the true nature of outcome and success.65 PATHOGENESIS Before a discussion of diagnosis and treatment, it is vital to understand the mechanisms by which infections occur. Most infections encountered in orthopaedics are related to biofilm-forming bacteria. Much of our understanding of biofilm bacteria has come from the Centre for Biofilm Engineering in Bozeman, Montana. Biofilm bacteria are also important in the oil, food processing, naval, paper manufacturing, and water processing industries. Biofilm bacteria exist in one of two states—the planktonic state or the stationary state (Fig. 24-1). Planktonic state bacteria are free floating in the extracellular matrix and are isolated and relatively small in quantity. In this state, the body host defenses can easily eradicate the organism through the usual immunologic mechanisms. It is rare for planktonic bacteria to survive long in the extracellular matrix despite numerous and repeated occurrences of entry. However, if the bacterial load is large and sustained, they can overwhelm the host defenses and escape the effects of antibiotics. They can then invade tissue and blood, leading to septicemia and death. Planktonic bacteria are also metabolically active and reproductive. This is an important consideration for antibiotic treatments that work by either interfering with cell wall or protein synthesis or with reproduction. If planktonic bacteria encounter a suitable inert surface such as dead or necrotic tissue, foreign bodies, or any avascular body part by either direct contamination, contiguous spreading, or hematogenous seeding, they can attach and begin the process of colonization. Juxtaposition of the bacteria with a surface or biomaterial is accomplished by Van der Waals forces, which allow bacteria to develop irreversible cross-links with the surface (adhesion-receptor interaction).27 Adhesion is based on time-dependent specific protein adhesion-receptor interactions, as well as carbohydrate polymer synthesis in addition to | charge and physical forces.61 Following adhesion to a surface, bacteria begin to create a TABLE 24-2 Cierny-Mader Classification of the Host --- | Host Class | Description | | --- | --- | | A host | Healthy physiology and limb | | B host: systemic | Diabetes, | stable multiple organ disease, nicotine use, substance abuse, immunologic deficiency, malnutrition, malignancy, old age, vascular disease Trauma context: Multiple injuries B host: local | Previous trauma, burns, previous surgery, vascular disease, cellulitis, scarring, previous radiation treatment, lymphedema Trauma context: Zone of injury B host: systemic/ local | Combinations of systemic and local conditions C host | Multiple uncorrectable comorbidities. Unable to tolerate extent of surgical reconstruction required. Treatment of the disease is worse than the disease itself FIGURE 24-1 Illustration of bacterial attachment to a surface followed by colonization and detachment. (Redrawn with permission after P. Dirckx, MSU Center for Biofilm Engineering, Bozeman, MT.) mucopolysaccharide layer called biofilm or slime. They then develop into colonies. These colonies exhibit remarkably resilient behavior. Figure 24-2 illustrates mature biofilm colonies where pillars of a mature biofilm are visible distributed on top of a monolayer of surface-associated cells. In addition to fixed cells, there are motile cells, which maintain their association with the biofilm for long periods, swimming between pillars of biofilm-associated bacteria.122 The interaction of the colonies and bacteria demonstrates complex communication via proteins or markers that can alter bacterial behavior. In the early stages of colonization, sessile bacteria can be killed or neutralized by the host defenses. However, some of these bacteria may escape destruction and potentially act as a nidus for future infection. Transition from colonization to infection usually requires other conditions to exist. This might occur if there was an inoculum that was larger than threshold levels, impaired host immune defense mechanisms, traumatized or necrotic tissues, foreign body, or an acellular or inanimate surface such as dead bone, cartilage, or biomaterials. As previously discussed, the first step in the transition from colonization to infection requires bacterial adhesion, which will usually not occur on viable tissue surfaces. Thus, when foreign material or dead tissue is found in the body, a “race for the surface” begins. Host cells will attempt to incorporate nonliving material or sequester nonviable tissue via encapsulation so that a well-incorporated biomaterial implant that has such a tissueintegrated neocapsule will be resistant to bacterial adhesion. Furthermore, the same tissue integration can often isolate bacteria that have become sessile on an implant surface by sequestering the bacteria from necessary nutrients until host mechanisms can act. However, if bacteria encounter the surface and develop mature colonies, tissue integration by the host may be impaired and the process of infection may proceed. Damaged bone, being relatively acellular, acts as a suitable surface for bacterial adhesion and colonization.69 Devitalized bone devoid of normal periosteum presents a collagen matrix to which bacteria can bind. Moreover, it has been suggested that bone sialoprotein can act as a ligand for bacterial binding to bone.69 Biomaterials and other foreign bodies are usually inert and susceptible to bacterial colonization because they are inanimate. Regardless of how inert a metal is, it may still modulate molecular events on its surfaces, these being receptor-ligand interactions, covalent bonding, and thermodynamic interactions.44,50 The most important feature of any particular method is the interaction between its outer surface atomic layer and the glycoproteins of prokarytotic and eukaryotic cells. Stainless steel and cobalt-chromium and titanium alloys are resistant to corrosion because of several mechanisms including surface oxide passivates. These surface oxides form a reactive interface with bacteria that can promote colony formation. There is therefore a balance between implanting devices with surface structures that lower corrosion rates but might increase the likelihood of surface binding by bacteria. Thus, a large surface area and bacteria inoculum, combined with local tissue damage and a compromised or insufficient host response, can collectively create the necessary conditions for infection. --- FIGURE 24-2 Mature biofilm colonies showing potential intercolony communication. (Redrawn with permission after P. Dirckx, MSU Center for Biofilm Engineering, Bozeman, MT.) Following bacterial adherence and colonization, the resistance to antibiotics appears to increase.84,86 This resistance is dependent on the type of surface to which the organisms are attached. Organisms that adhere to hydrocarbon polymers are extremely resistant to antibiotics. These same organisms, when attached to metals, do not resist antibiotic therapy to the same extent. Bacterial colonies can undergo phenotypic changes and appear to hibernate. They can survive in a dormant state without causing infection, and this can explain the recovery of bacteria from asymptomatic hardware removal.80 So while colonization is a necessary antecedent for infection, colonization alone does not necessarily lead to infection. Two characteristics of colonized bacteria may help understand and explain this pseudo-resistance. Because the passage of antibiotics through tissues is based on a diffusion gradient, colonized bacteria are insulated with a natural barrier of glycocalyx, often referred to as a slime, through which the circulating antibiotic must diffuse before arriving at the bacterial cell wall (Fig. 24-3). The antibiotic molecules must then diffuse into the bacterial cell or be transported by metabolically active bacterial cell membranes. Because it is theorized that bacteria within biofilms have a decreased metabolic rate and undergo phenotypic changes, active processes such as cell membrane formation, which are targeted by antibiotics, would be similarly decreased (Fig. 24-3).116 Consequently, antibiotic concentrations of 1500 times normal may be required to penetrate both the biofilm and the bacterial cell wall. Even then, most antimicrobials work via interference with cell wall synthesis or cellular reproduction, and they therefore require metabolically active bacteria to be effective. Thus, bacteria in the biofilm may be dormant and appear to be pseudoresistant. The more metabolically inactive the bacteria, the less bactericidal will be the antibiotic therapy, which is why mature or chronic infections can rarely be cured with antibiotics alone. Table 24-3 outlines the major antibiotic classes and their mechanisms of action, all of which may be limited by the bacterial state in biofilm. --- FIGURE 24-3 Biofilm creates a diffusion barrier that interferes with the ability of antibiotics to reach bacterial organisms. Biofilm bacteria are metabolically inactive and therefore not subject to the mechanism of action of most antibiotics. They appear as “pseudoresistant.” (Redrawn with permission after P. Dirckx, MSU Center for Biofilm Engineering, Bozeman, MT.) Once colonization occurs, body defenses continue to identify bacteria as foreign. There may be chemotactic mechanisms that keep immune cells active. The subsequent collection of inflammatory cells brought in to wall off the bacteria via chemotaxis manifests as purulence, which is a symptom of the host’s attempt to isolate and destroy the infection. The acute inflammatory cells will also release a spectrum of oxidative and enzymatic products in an attempt to penetrate the glycocalyx. These mediators and enzymes are nonspecific and may be toxic to host tissue. Increased host tissue damage can lead to more surface substrate for local bacteria, creating a cycle of tissue damage, host response, and exacerbation of infection (Fig. 24-4). The host tissues will eventually react to limit the spread of infection macroscopically as well as microscopically. The clinical manifestation of a sequestered infection is an abscess or involucrum. Alternatively, if the infection grows and reaches the skin or an internal epithelial surface, a sinus tract forms as a route to dispel detritus. While the appearance of a sinus tract is a manifestation of a locally devastating disease process and indicates severe underlying infection, it should be remembered that it may also prevent the accumulation of internal | fixation, which can lead to bacteremia and septicemia. TABLE 24-3 Major Antibiotic Classes and Their Mechanism of Action --- | Inhibition of cell wall synthesis/development | Penicillin, cephalosporins, vancomycin, bacitracin, chlorhexidine | | --- | --- | | Inhibition of protein synthesis | Chloramphenicol, macrolides, lincosamides, tetracyclines | | Inhibition of RNA synthesis | Rifampin | | Inhibition of DNA synthesis | Quinolones, macrolides | | Inhibition of enzymatic/metabolic activity | Trimethoprim-sulfamethoxazole (blocks folic acid production) | Source: www.sigmaaldrich.com/Area_of_Interest/Biochemicals/Antibiotic_Explorer/Mechanism_of_Action.html. FIGURE 24-4 Autoinjury mechanism of host white cells in response to biofilm bacteria. A. Host white cell engulfs planktonic bacteria and then B. moves to engulf a bacterial colony that has developed but is unable to do so. C. Host white cell’s next response to engulfed bacteria is to release oxidative enzymes, but those enzymes also cause damage to local host cells. D. Unsuccessful eradication of bacteria and colony growth attracts more host white cells, resulting in increased damage to host tissue. Eventually, an equilibrium may exist in the form of a chronic infection, which is what many surgeons see in practice. There is usually a history of intermittent symptoms and drainage that has responded to some type of antibiotic regimen. What this probably represents is the inhibition of colony expansion at the borders of the infectious site. Clinically harmful manifestations of infection are generally caused by the release of bacteria into the bloodstream that are metabolically active and release toxins in addition to the release of oxidative enzymes by the host cell. Although the bacteria remain susceptible to the body’s host defenses and to antibiotics, their numbers and continued release into the bloodstream represent a chronic debilitating disease. Any acute stress on the host environment from trauma, disease, or immunosuppression can allow the infection to strengthen and spread. Thus, longstanding infections that were tolerated by young healthy individuals may suddenly become limb or life threatening as the individual’s age. New developments stemming from the work of the Bozeman group provide novel opportunities to treat bacterial infection of orthopaedic implants. These include surface coatings, agents that inhibit colonization or promote dissolution of colonies, small electric fields, and low pH and acidic and negatively charged surfaces that are resistant to biofilms. Surface properties of implants or local or systemic drugs may help decrease the risk to infection, particularly in the elderly population, who have decreased immune system activity.17 INFECTION AFTER FRACTURE Infection after fracture is most likely to be associated with open fractures or invasive surgical procedures. Few closed fractures treated nonoperatively develop osteomyelitis. To improve the diagnosis of posttraumatic bone infection, it is necessary to understand the mechanisms of infection, particularly for open fractures. --- FIGURE 24-5 Operative photographs of a severe open fracture. A. The appearance before surgical débridement. B. The appearance after surgical débridement. Note that after débridement, the tissues and wound appear as if they were surgically created. While it is unlikely that all bacteria have been removed, a thorough exploration and débridement leaving behind only viable tissues will minimize the risk of subsequent infection. Approximately 60% to 70% of open fractures are contaminated by bacteria, but a much small percentage develop infection. The risk of infection correlates significantly with the degree of soft tissue injury.117 If one remembers that merely the presence of bacteria in an open wound is not sufficient to cause infection, it is important to recognize that a severely contaminated fracture can rarely be débrided to the point of achieving a sterile or bacteria-free tissue bed. We believe that next to removing the majority of bacteria from the contaminated tissue bed, the second major goal of a wide and aggressive débridement is to leave behind a viable tissue bed with minimal necrotic or inert surfaces for the remaining bacteria to colonize. By minimizing the bacterial contamination by eliminating adhesions and nutrition, the host gains an opportunity to eradicate any remaining contaminants in the zone of injury. Figure 24-5 demonstrates the concept of open fracture débridement where a contaminated wound is débrided until the remaining wound looks as if it is created surgically, with residual tissue being healthy with little evidence of contamination. It is important to remember that contamination can penetrate into tissue planes or locations that are not obvious in the initial wound. The use of pulsatile irrigation before surgical exploration and débridement may in fact push the initial contaminants deeper into the tissues and result in contaminants being left behind in a locally compromised tissue bed. This will increase the likelihood of both acute and delayed infection. An important fact that is often unrecognized is that the bacteria recovered from clinical infections are not necessarily the bacteria found acutely in the contaminated tissue bed. Several studies have found that routine cultures of open fractures are not useful because the predominant organism recovered from acute cultures is frequently not the organism recovered if and when an infection occurs. Antibiotic treatment based on the acute culture, whether before or after débridement, may be detrimental because the antibiotic that is chosen may not be specifically indicated and has the potential to promote changes and overgrowth in the bacterial flora. In the worst case scenario, routine antibiotic treatment based on initial wound cultures may promote the development of resistant bacterial strains.63,92,118 Many of the organisms responsible for eventual osteomyelitis are often hospital-acquired pathogens such as resistant Staphylococcus aureus or gram-negative bacilli, including Pseudomonas aeruginosa,51,67 which are not initially present in a traumatic wound. This does not mean that other bacteria should not be considered and these may depend on the environment. Clostridium perfringens must be considered if there is soil contamination and Pseudomonas, and Aeromonas hydrophila may be present following a freshwater injury. Vibrio and Erysipelothrix may be present in saltwater injuries. One possible explanation for the lack of correlation between acute cultures and the eventual infection may be that the initial contaminants are of low virulence and easily neutralized by a combination of débridement and antibiotics but that the locally and, in polytrauma, the systemically, compromised tissue bed is susceptible to the more aggressive nosocomial organisms. ACUTE POSTTRAUMATIC OSTEOMYELITIS Acute posttraumatic osteomyelitis is a bone infection that results in traumatic injury that allows pathogenic organisms to make contact with damaged bone and soft tissues, with a proliferation and expression of infection.74 In a patient with traumatic injuries, additional factors that contribute to the subsequent development of osteomyelitis are the presence of hypotension, inadequate débridement of the fracture site, malnutrition, sustained intensive care unit hospitalization, alcoholism, and smoking.42,115 Trauma may lead to interference with the host response to infection. Tissue injury or the presence of bacteria triggers activation of the complement cascade that leads to local vasodilatation, tissue edema, migration of polymorphonuclear leukocytes (PMNs) to the site of the injury, and enhanced ability to phagocytes to ingest bacteria.56 Trauma has been reported to delay the inflammatory response to bacteria as well as to depress cell-mediated immunity and to impair the function of PMNs, including chemotaxis, superoxide production, and microbial killing.56 The commonly used system of Cierny-Mader21 has been shown to have a close correlation with the general condition of the patient rather than the specifics of bone involvement. CHRONIC OSTEOMYELITIS This condition is often the result of an acute osteomyelitis that is inadequately treated. General factors that may predispose to chronic osteomyelitis include the degree of bone necrosis, poor nutrition, the infecting organism, the age of the patient, the presence of comorbidities, and drug abuse.26 The infecting organism generally varies with the cause of the chronic osteomyelitis. Chronic osteomyelitis results from acute osteomyelitis and is frequently caused by S. aureus, although chronic osteomyelitis that occurs after a fracture can be polymicrobial or gram negative. Intravenous drug users are commonly found to have Pseudomonas as well as S. aureus infections. Gram-negative organisms are now seen in up to 50% of all cases of chronic osteomyelitis, and this may be due to variables such as surgical intervention, chronic antibiotics, nosocomial causes, or changes in the bacterial flora of the tissue bed.26 The fundamental problem in chronic osteomyelitis is a slow progressive revascularization of bone that leaves protected pockets of necrotic material to support bacterial growth that are relatively protected from systemic antibiotic therapy. This collection of necrotic tissue, bone, and bacteria is what becomes termed a sequestrum, and the body’s attempt to wall off the offending material with reactive inflammatory tissue, whether this is bone or soft tissue, is termed the involucrum. The involucrum can be highly vascular and may be viable and structural, and this should be taken into consideration during surgical débridement. FUNGAL OSTEOMYELITIS Fungal osteoarticular infections are caused by two groups of fungi. The dimorphic fungi, which include Blastomyces dermatitidis, Ciccidioides sp., Histoplasma capsulatum, and Sporothrix schenckii, typically cause infections in healthy hosts in endemic regions, while Candida sp., Cryptococcus, and Aspergillus cause infections in immunocompromised hosts. Infection is introduced by direct trauma or injury but may be associated with a penetrating foreign body or hematogenous spread. Candida sp. is the most common fungus seen in osteomyelitis. It affects both native and prosthetic joints, vertebrae, and long bones. Risk factors include loss of skin integrity, diabetes, malnutrition, immunosuppressive therapy, intravenous drug use, hyperalimentation, the use of central venous catheters, intra-articular steroid injections, and the use of broad-spectrum antibiotics. A combined approach to therapy using medical and surgical modalities is necessary for optimal results. Azole antifungals and lipid preparations of Amphotericin B have expanded the therapeutic options in fungal osteomyelitis as there is reduced toxicity associated with long-term therapy.74 CLINICAL AND LABORATORY DIAGNOSTIC TESTS A history of infection or intercurrent illness as well as of remote surgery or trauma should raise the clinical suspicion of osteomyelitis. Normal signs of inflammation may be absent and thus the diagnosis of infection may be difficult. Patients may have a history of infection at another site, such as the lungs, bladder, or skin in conjunction with a history of trauma. They usually complain of pain in the affected area and feel generally unwell. Moreover, reduced activity, malaise, anorexia, fever, tachycardia, and listlessness may be present. Local findings include swelling and warmth, occasional erythema, tenderness to palpation, drainage, and restricted range of motion in adjacent joints. Aspects of the clinical history that should alert the surgeon to look for infection include a history of open fracture, severe soft tissue injury, a history of substance abuse and smoking, inadequate previous treatment, or an immunocompromised state. These are all factors that contribute to a B host. Factors affecting treatment that need to be assessed include the time of onset of the infection, the status of the soft tissues, the viability of the bone, the status of fracture healing, implant stability, the condition of the host, and the neurovascular examination (Fig. 24-6). --- FIGURE 24-6 Typical appearance of a postoperative wound. The limb looks relatively benign. This patient had an extensive type III infection and had been treated with attempted débridement on several occasions before referral. Poor nutrition and nicotine use together with her previous multiple surgeries made her a B systemic/local host. Routine blood cultures are of little help unless patients show manifestations of systemic disease, but they may be positive in up to 50% to 75% of cases where there is concomitant bacteremia or septicemia.124 Blood cultures that yield coagulasenegative staphylococci, a common contaminant and pathogen, must be correlated with other clinical findings before attribution of clinical significance. Blood results that are suggestive of infection include an elevation of the white blood cell (WBC) count and elevations in the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels. The ESR may be normal in the first 48 hours but rises to levels about 100 mm/hr and may remain elevated for several weeks. It is, however, a nonspecific marker.124 Combination of the ESR with the CRP improves specificity such that if both are negative, the specificity is 90% to 95% for acute osteomyelitis. In other words, a negative CRP and ESR makes osteomyelitis unlikely. Their values are also age dependent, and there is a steady increase in normal values with aging. In one recent study, the ESR and CRP were found to be useful diagnostic tools for the detection of an infected arthroplasty. While they had low sensitivities and positive predictive values and therefore were of little value for screening, they had high specificity and negative predictive value and therefore were useful for treatment decisions.49 These studies and other diagnostic studies may not be as useful in acute postoperative and chronic infections. In the acute setting, the ESR and CRP are expected to be elevated due to local and systemic inflammation from the surgical procedure. In chronic infections, the host has had time to adapt to the offending condition and thus may not mount the response required to trigger an elevation in these tests. Once osteomyelitis treatment is initiated, the CRP and ESR are useful in following the response to treatment. We use the ESR and CRP to establish a baseline value before débridement and initiation of antibiotic therapy and to monitor the subsequent response to treatment. Radiographic Imaging Radiologic findings in the initial presentation of acute osteomyelitis are often normal. The most common radiographic signs of bone infection are rarefaction, which represents diffuse demineralization secondary to inflammatory hyperemia; soft tissue swelling with obliteration of tissue planes; trabecular destruction; lysis; cortical permeation; periosteal reaction; and involucrum formation. Radiologically detectable demineralization may not be seen for at least 10 days after the onset of acute osteomyelitis.124 When present, mineralization usually signifies trabecular bone destruction. If the infection spreads to the cortex, usually within 3 to 6 weeks, a periosteal reaction may be seen on radiographs. One study reported that in cases of proven osteomyelitis, 5% of radiographs were abnormal initially, 33% were abnormal by 1 week, and 90% were abnormal by 4 weeks.6 In trauma and fracture treatment, the nature of callus formation and the obfuscation of bone by hardware may make radiologic changes difficult to recognize in the early or middle states of infection. Often it is not until there is a clear sequestrum, sinus, or involucrum that parallels the clinical findings that specific radiographic changes are recognized (Fig. 24-7). Bone Scintigraphy Scintigraphy has been widely used and remains a very useful diagnostic tool. There are numerous types of scintigraphy, but three scan types are commonly used to diagnose musculoskeletal infection. These are the bone scan, which uses tagged red cells; the leukocyte scan, which uses tagged white cells; and the bone marrow scan, which investigates marrow cell activity. Recently, positron emission tomography (PET) has shown promise and is undergoing increased investigation and use. Technetium-99m is the principal radioisotope used in most whole body red cell bone scans.28,32,43 Technetium is formed as a metastable intermediate during the decay of molybdenum-99. It has a 6-hour half-life and is relatively inexpensive and readily available.28 After intravenous injection, there is a rapid distribution of this agent throughout the extracellular fluid. Within several hours, more than half the dose will accumulate in bone, while the remainder is excreted in the urine. Technetium phosphates bind to both the organic and inorganic matrix. However, the key characteristic that makes technetium scanning useful is that there is preferential incorporation into metabolically active bone. Bone images are usually acquired 2 to 4 hours following intravenous injection of the isotope. A triple-phase bone scan is one that is useful for examining general inflammation and related processes. Following the initial injection, dynamic images are captured over the specified region. These are followed by static images at later time points. The first phase represents the blood flow phase, the second phase immediately postinjection represents the bone pooling phase, and the third phase is a delayed image made at 3 hours when there is decreased soft tissue activity. Classically, osteomyelitis presents as a region of increased blood flow, and it should appear “hot” in all phases with focal uptake in the third phase (Fig. 24-8). Other processes such as healing fractures, loose prostheses, and degenerative change do not appear hot in the early phase despite a hot appearance in the delayed phase. Reported sensitivities of bone scintigraphy for the detection of osteomyelitis vary considerably from 32% to 100%. Reported specificities have ranged from 0% to 100%.103,120 --- FIGURE 24-7 Radiograph of patient in Figure 24-6. The arrow points to periosteal reaction. Gallium-67 citrate binds rapidly to serum proteins, particularly Transferrin.10,100 There is also uptake in the blood, especially by leukocytes. Gallium has been used in conjunction with technetium-99 to increase the specificity of the bone scanning.40,52 Several mechanisms have been postulated to explain the increased activity at sites of inflammation. Enhanced blood flow and increased capillary permeability cause enhanced delivery. Bacteria have high iron requirements and thus take up gallium. Gallium is strongly bound to bacterial siderophores and leukocyte lactoferrins. In regions of inflammation, these proteins are available extracellularly and can bind with gallium avidly. Chemotaxis also acts to localize gallium-labeled WBCs at the sites of infection. In a typical study, gallium is injected intravenously and delayed images are acquired at 48 to 72 hours. The hallmark of osteomyelitis is the focal increased uptake of gallium. Unfortunately, gallium’s nonspecific bone uptake can be problematic because any processes causing reactive new bone formation will appear hot. In patients with fractures or a prosthesis, osteomyelitis cannot be easily diagnosed with gallium alone. Gallium images are usually interpreted in conjunction with a technetium bone scan. Gallium activity is interpreted as abnormal either if it is incongruous with the bone scan activity or if there is a matching pattern with gallium activity. Reported sensitivities and specificities for the diagnosis of osteomyelitis range from 22% to 100% and 0% to 100%, respectively.2,52,76,103 Despite its lower-than-optimal diagnostic value, gallium still has some advantages. It is easily administered and it is the agent of choice in chronic soft tissue injection, although it is less effective in bone infections. It has also proved useful in following the resolution of an inflammatory process by showing a progressive decline in activity. --- FIGURE 24-8 Red cell scan of patient in Figure 24-6 demonstrating increased activity in distal femur. An indium-111 or 99mTc-hexamethylpropyleneamine osime (99mTc-HMPAO) (Ceretec; GE Healthcare) -labeled leukocyte scan is the most common scan used in conjunction with a standard bone scan. The labeled leukocytes migrate to the region of active infection resulting in a hot white cell scan over the area of active inflammation. The use of a combined red cell and white cell scan significantly increases both the sensitivity and specificity and now represents the g