Osteomyelitis

Osteomyelitis usually results from open fractures or open fracture repair. The term simply means inflammation of the bone and marrow contents, but bacterial infection is often implied when the word is used. Endogenous and exogenous modes of infection occur, with exogenous being more frequent. Treatment varies depending on the source of infection, the organism involved, and duration of infection.

Etiology

A variety of organisms has been implicated in bone infections. A single organism is usually involved [1]. Beta-lactamase-producing staphylococcal species, streptococcal species, and gram-negative aerobic bacteria are most commonly isolated [2-4], with staphylococcal species, usually Staphylococcus intermedius, isolated 46 to 74% of the time [2,4,5]. Multiple organisms are isolated 33 to 66% of the time [4,6].

Isolation of anaerobic bacteria can be difficult, but isolation rates as high as 70% have been reported.1 Isolation of anaerobes is site–dependent, with the radius/ulna, mandible, and tympanic bulla commonly involved [1]. Anaerobic bacteria should be suspected in cases of apparent infection but lack of growth on culture, infection secondary to disruption of tissue normally inhabited by anaerobic bacteria, or when infection from an external source has occurred [1,7-9]. Common anaerobic isolates include Bacteroides, Fusobacterium, Actinomyces, Clostridium, Peptococcus, and Peptostreptococcus species [1,8,10].

Mycotic bone infection also occurs, but usually results from hematogenous spread.9 Isolated fungal organisms include Cryptococcus neoformans, Coccidioides immitis, Aspergillus species, Penicillium species, Blastomyces dermatitidis, Histoplasma capsulatum, and Phialemaenium [11-16].

Pathophysiology

Osteomyelitis comes from endogenous or exogenous sources. Acute hematogenous osteomyelitis is the endogenous form; bone infection develops from an infectious focus at a distant site within the body such as the skin, respiratory system, heart, oral cavity, or genitourinary tract. Alternatively, exogenous bone infection (infection from nonhematogenous routes) may occur from direct inoculation (e.g., bites, punctures, or surgery), open fractures, foreign body migration, or gunshot wounds. Osteomyelitis from exogenous sources is divided into acute and chronic forms.

Acute hematogenous osteomyelitis typically affects the metaphyseal region of long bones, but diaphyseal infections can occur.2,17 Bacteria lodge in the metaphysis where the capillary endothelium is discontinuous and blood flow slows in the veins [18,19]. After localizing in the metaphysis, bacteria and activated platelets cause inflammation and thrombus formation, producing an ischemic environment that is conducive to bacterial proliferation [19]. Infection either progresses or is walled off by the immune response.20 Cellular debris, inflammatory by-products, and bacteria cause thrombosis, abscessation, and compromise of blood supply to the bone. Sequestration, formation of a walled off, devitalized portion of bone, can occur when exudate reaches the outer cortex and elevates the periosteum, compromising cortical blood supply to that area of bone [19]. The isolated bone fragment is usually surrounded by purulent debris (lacuna) and can form an opening for escape of purulent material outside the walled off area (cloaca). Chronic osteomyelitis can result when the infection is walled off, but not eliminated by the body.

Fungal organisms typically gain entrance to the body via inhalation or spread from the gastrointestinal tract. Hematogenous dissemination occurs after localization of the organisms in areas away from the bone [11,14-16,21-23]. Hence, fungal osteomyelitis is usually considered hematogenous in origin, although primary fungal osteomyelitis and direct bone inoculation occur on occasion [15].

Nonhematogenous acute and chronic osteomyelitis occur when an organism invades osseous tissue by overwhelming the immune system or by seeding compromised tissue. Normal bone is resistant to infection, but soft-tissue injury, bone devitalization, surgical implants, instability of bone fragments, prolonged wound exposure, and immunosuppression increase the risk of infection [24,25].

Acute nonhematogenous osteomyelitis is usually a complication of surgical fracture repair and clinical signs are typically apparent 5 to 7 days after surgery. Long bones are more often affected than axial bones, probably owing to increased occurrence of fracture in long bones [2,4,6]. The degree of soft-tissue devitalization, fracture stability, type of fracture repair, organism virulence, and immune system competence influence development of fracture site infection [6,9,24]. Trauma from fracture generation and/or surgery and implants applied during fracture repair disrupt blood supply and provide foreign material for bacterial adherence and proliferation [24]. Implants decrease the quantity of bacteria needed to establish an infection and provide a site for bacterial adherence that can escape immunosurveillance and antibiotics [24,26]. Moreover, devitalized bone fragments increase the risk of infection for both virulent and nonvirulent strains of bacteria [27]. Bullet penetration and bites cause soft-tissue injury and are a means of bacterial inoculation. Shrapnel, migrating foreign bodies, and occasionally bites leave material behind that allow bacteria to evade host immune responses and proliferate [9].

Nonhematogenous, chronic osteomyelitis develops from inadequate treatment of acute osteomyelitis, hidden infections associated with implants or other foreign material, and/or isolation of bacteria from the immune system [24,28,29]. In fractures with prolonged infection, granulation and fibrous tissue isolate devitalized bone (sequestration) and cause delayed healing and/or persistent infection [19,27]. The sequestration of fracture fragments occurs because the fragment of bone is devitalized at the time of fracture owing to trauma and is walled off instead of being resorbed or incorporated into the fracture callous. However, devitalization and sequestration of bone after fracture can also occur through the same mechanism as with acute hematogenous osteomyelitis. Persistent, chronic infection is enhanced by the presence of metallic implants/foreign material and through bacterial biofilm production, which protects bacteria from immunosurveillance[24,26,30].

Clinical Findings

Acute hematogenous osteomyelitis is not common but most often affects young animals [2,4]. Findings can include soft-tissue swelling over the affected site, moderate to severe lameness, inappetence, malaise, fever, and debilitation. The source of bone infection may or may not be found during initial examination, but the animal should be examined for such. The oral cavity, integument system, urogenital tract, lungs, and heart should be carefully examined. Draining tracts occur uncommonly [19].

Acute osteomyelitis of nonhematogenous sources has no breed or sex predilection and typically occurs after fracture repair. In such cases, the surgical wound may be edematous, erythematous, and warm, and the limb is painful during manipulation. Animals are often febrile and have a substantial lameness. Draining tracts are not common during the acute phase, but incisional drainage might be obvious. Signs of systemic illness such as inappetence and lethargy might also be apparent [9].

Animals suffering from chronic nonhematogenous osteomyelitis usually present with an insidious lameness and varying degrees of pain at the fracture site. If the fracture is not healed, the degree of fracture instability can influence the degree of pain and lameness. Moderate to severe muscle atrophy is usually present in the affected limb and a draining tract might be apparent. It is common for drainage to dissipate with antimicrobial administration only to return once antimicrobials are discontinued. Muscle fibrosis and contracture owing to the effects of long-standing infection on the soft tissues might contribute to the lameness [9]. Signs of systemic involvement, such as fever and inappetence, are less likely to be present than with acute infections.

The clinical presentation of animals suffering from fungal osteomyelitis is similar to those suffering from bacterial osteomyelitis. Signs include lameness, swelling, and pain associated with the affected area, and the presence of draining tracts. However, animals with fungal osteomyelitis often have disseminated disease and systemic signs such as general malaise, inappetence, respiratory compromise, lymphadenopathy, weight loss, and fever [11,31]. Any age, breed, and sex can be affected, but German shepherd dogs may be overrepresented, possibly owing to genetic factors involving altered immune function [11].

Diagnosis

History and signalment play a role in diagnosis of bone infection. Concurrent or prior infection elsewhere in the body in conjunction with sudden lameness, pain, heat, and swelling over the affected bone is suggestive of acute hematogenous osteomyelitis. For acute nonhematogenous osteomyelitis, a history of recent fracture repair, animal bite, evidence of foreign body migration, or puncture wound is more suggestive. Chronic osteomyelitis is usually associated with a history of previous fracture repair or implantation of foreign material and may also be linked to a previous diagnosis of osteomyelitis

Radiography is commonly employed in the evaluation of suspected osteomyelitis. Radiographs alone have a sensitivity of only 62.5% and a specificity of 57.1% for diagnosis of osteomyelitis, but are commonly used in conjunction with clinical signs to make a diagnosis [32]. For an acute infection, soft-tissue swelling without alteration in bone architecture predominates,9,33 but with chronic infection, periosteal new bone proliferation, cortical bone resorption, cortical thinning, implant loosening, and bone sequestration might be apparent (Fig. 93-1) [2,4,33,34]. Osteolytic and proliferative changes generally lag behind the actual time of infection by 10 to 14 days, so obtaining a second radiograph several days later may aid in diagnosis of questionable cases [35]. Radiographic evidence of sequestration may be delayed by several weeks, but in chronic situations, the presence of a sequestrum can be common (Fig. 93-2) [36]. Contrast radiography (fistulography) of draining tracts might help identify sequestra or foreign bodies.9 Scintigraphy with Technetium-99 methylene diphosphonate can provide early information regarding active bone and joint remodeling; however it is not specific for infection [33,37]. New scintigraphic techniques offer distinction between infection and other inflammatory processes and might hold some benefit in the future [38]. Magnetic resonance imaging and computed tomography can also aid in early diagnosis of osteomyelitis [34,39,40].

Figure 93-1. Chronic Osteomyelitis. This is a radiograph from a 2-year-old dog that developed osteomyelitis from an open fracture sustained 1 month earlier. Note the periosteal proliferation (solid white arrow) and the radiolucent line along the fixators pin (small line arrow) indicating implant loosening.

Figure 93-2. Sequestrum. This is a radiograph from a 2-year-old dog that developed osteomyelitis from an open fracture sustained 1 month earlier. Note the lack of periosteal reaction and remodeling of the devitalized portion of bone (solid white arrow).

To obtain a definitive diagnosis, tissue samples, direct swabs, and/or needle aspirates should be aseptically collected from the affected area for cytology, aerobic and anaerobic culture, and antimicrobial susceptibility testing. Gram staining of samples can provide early information for empiric treatment while awaiting culture results. Percutaneous aspiration of tissues around and in the affected site can have isolation rates as high as 86% [41], although some reports do not concur with that high a rate [2,4]. If an abscess is present, the chances of obtaining organisms is likely higher. Tissue culture or direct swabbing through a surgical approach might be more likely to result in a positive culture. In chronic cases, needle aspiration might be less rewarding because bacteria can adhere tightly to surrounding structures with minimal exfoliation [24,29,42]. Ideally, antibiotics should be withheld for at least 24 hours before sample collection to improve yield in chronic cases and should be initiated after sample collection in acute cases unless the animal’s condition dictates otherwise [43]. Culturing draining tracts should be avoided because contaminants rather than the causative organism are often isolated [44]. If systemic involvement or hematogenous osteomyelitis is suspected, blood cultures should be performed.45 In people with hematogenous osteomyelitis, approximately 50% of blood cultures grow the causative organism [46].

Supportive diagnostics including a complete blood count, biochemistry panel, and urinalysis might show other organ-system involvement, be suggestive of infection, or not reveal anything of significance. For acute infections, especially hematogenous osteomyelitis, thoracic and abdominal radiographs, abdominal ultrasound, and/or echocardiogram can elucidate the source of infection and determine the animal’s systemic condition.

A diagnosis of fungal osteomyelitis is often made from cytologic or histologic evaluation of affected tissues. Cytology of affected areas mostly consists of pleocellular infiltration, including macrophages, lymphocytes, plasma cells, neutrophils, and multinucleated giant cells; lesions are pyogranulomatous in nature [31]. Fungal hyphae or intracellular organisms are often apparent on preparations [11,14-16,21-23]. Special stains such as India ink, periodic acid-Schiff, and silver nitrate stains, or treatment of preparations with 10% potassium hydroxide can improve visualization of organisms [21,31]. Serologic testing is helpful to identify exposure [31]. Fungal culture is necessary for definitive diagnosis. In cases of aspergillosis, fungal hyphae can be seen in the urine sediment and can be cultured from urine of some infected animals.11 Bone biopsy should be performed to rule out neoplasia and to obtain samples for culture and histopathology. Radiographic changes include soft-tissue swelling, periosteal and endosteal bone proliferation, and bone lysis. Lesions are typically below the elbow and stifle, but may be anywhere and must be differentiated from bone tumors [11,14-16,21-23]. Complete blood count and biochemistry profiles are not specific for fungal disease, but findings include nonregenerative anemia, leukocytosis, hyperglobulinemia, and eosinophilia [11,14-16,21-23].

Treatment

Antibiotic penetration into bone and efficacy against the causative organism are necessary for resolution of infection. Ultimately, antibiotic choice is based on culture and antimicrobial susceptibility testing. Empiric therapy is initiated while culture and antimicrobial susceptibility are pending or when cultures fail to offer an appropriate therapeutic strategy. If the causative organism cannot be identified, continued antimicrobial administration is based on appropriate response to the initial therapeutic regimen. Intravenous therapy is always initiated for acute infections, and a favorable initial response permits a change to oral antimicrobial administration within the first 3 to 5 days of therapy. Oral therapy is appropriate in chronic cases, but is typically combined with surgical intervention. In cases of severe soft-tissue destruction, microvascular muscle flaps can provide increased blood supply and improved delivery of antibiotics and healing factors to the wound bed.47

Care should be taken in antibiotic selection because antimicrobial resistance of commonly isolated organisms is constantly changing and antibiotic effectiveness is dependant on many factors. Penicillins and penicillin-combination drugs, cephalosporins, and aminoglycosides readily penetrate normal and infected bone [48-52]. Staphylococci isolated from canine infections are often resistant to pure penicillins because of β-lactamase production, so β-lactamase-resistant drugs are preferred [53]. Staphylococci showed 18% resistance to first generation cephalosporins in one report [54], although cephalosporins are a commonly used antibiotic in the first line of defense against bone infections.54 Aminoglycosides lose some effectiveness in hypoxic or acidotic conditions and in the presence of white blood cells, so efficacy should be monitored during treatment [55]. Fluoroquinolones have good bone penetration and are beneficial for many gram-negative infections [56]. However, fluoroquinolones are not effective under anaerobic conditions and should be avoided in immature animals owing to potential deleterious effects on cartilage [57,58]. Clindamycin penetrates normal bone and is useful for gram-positive and anaerobic osteomyelitis [59-61].

Duration of antimicrobial therapy depends on the severity of the infection, but antibiotics should be continued for at least 2 weeks beyond radiographic and clinical resolution of infection, which typically requires weeks to months of therapy [55,62-66]. Recurrence is lower in people with acute osteomyelitis if antibiotics are continued for a minimum of 30 days [63]. Owners should be warned that treatment will likely require long-term commitment and can be expensive.

Surgery is a necessary component of treatment in some cases of osteomyelitis. Palpable abscesses must be drained, cultured, debrided, and lavaged. In animals with nonhematogenous osteomyelitis, loose implants and foreign material must be removed [64]. For chronic osteomyelitis, surgery is often necessary to promote resolution of infection and involves aggressive debridement of devitalized bone fragments and necrotic soft tissue, removal of sclerotic bone occluding the medullary canal, and removal of loose implants or foreign material [65]. If debridement is adequate and the wound bed is healthy, closure over an active drain can be considered, otherwise the wound should be left open and closed at a later time once the tissues appear healthy. Multiple operations might be necessary to resolve infection in refractory cases of osteomyelitis [6].

Stabilization of an unstable fracture is essential in nonhematogenous osteomyelitis. For amendable fractures, external fixators can be applied with minimal disruption of blood supply and have an added advantage of being easily removed [66]. If the soft tissues are healthy and the surgical procedure has consisted primarily of sequestrectomy and debridement of a fistulous tract, internal fixation can be considered [67,68]. However, all implants should be removed once the fracture is healed because they can harbor organisms and lead to recurrent osteomyelitis [26]. In fracture cases, bone grafting should be considered, but delayed grafting might be necessary in excessively exudative wounds because graft resorption can occur [5,20].

Fluid therapy, nutritional supplementation, and analgesics should be instituted as needed and when systemic involvement is present. The inciting cause in cases of hematogenous osteomyelitis must be found and treated appropriately. Rehabilitation of the affected limb is also important, especially in chronic osteomyelitis, because inflammation of the soft tissues secondary to infection can lead to considerable muscle atrophy, fibrosis, and contracture, and prevent return to function. In severe cases that have not responded to antibiotic therapy or surgery and in cases with irreversible muscle damage and excessive joint stiffness, amputation might be necessary.

Although systemic antibiotic therapy is essential in the treatment of orthopedic infections, local antibiotic therapy provides another means of treatment that has some advantages when combined with systemic therapy [41,69-71]. Local antibiotic administration maintains a higher local drug concentration at the site of infection for a prolonged period of time with reduced systemic toxicity [72-75]. Local delivery of antibiotics usually involves temporary implantation of antibiotic-impregnated polymethylmethacrylate (AIPMMA) at the site of infection, but biodegradable delivery systems have also been investigated.76-79 Local antibiotic delivery systems work by gradual release of antibiotics to the site of infection via antibiotic elution out of the implanted material. Tissue antibiotic concentration and elution rate depend on multiple factors including the antibiotic used, cement configuration, type of antibiotic carrier, and tissue environment [69,73-75,80-83]. AIPMMA is most often used in the form of preformed beads that are bought or handmade. The beads are placed at the site of infection and are left there for a duration based on the expected elution rate of the impregnated antibiotic.

Beads can be replaced serially to maintain an adequate local antibiotic concentration, but implanted cement should ultimately be removed from the infected site because it can harbor bacteria and result in recurrent osteomyelitis [84].

Treatment of fungal osteomyelitis is difficult and expensive. Animals require long-term antifungal therapy (months) and are treated at least a month beyond resolution of clinical signs [85]. Some animals require life-long therapy [85] or amputation [21]. Antifungals include fluconazole, ketoconazole, amphotericin B, and itraconazole, but itraconazole is associated with fewer side effects [85]. Amputation is a reasonable alternative to therapy for fungal osteomyelitis if the systemic fungal disease is under control but the local bone infection cannot be cured.

Prognosis

Osteomyelitis typically carries a favorable prognosis unless fungal organisms are involved. Most animals respond favorably to treatment if antibiotic therapy is appropriate and the inciting cause is treated. Most infected fractures will heal in the face of infection so long as appropriate antibiotic therapy is used and the fracture is stable. For acute osteomyelitis, aggressive early intervention is necessary for resolution and prevention of chronic osteomyelitis. The inciting cause must be eliminated in cases of hematogenous spread or foreign body migration for complete resolution of disease [6,62]. In chronic cases, a favorable response to treatment occurs in up to 90% of affected dogs, but recurrence is possible [6,62].

For fungal disease, prognosis is guarded to poor, although some animals respond to therapy. Systemic disease worsens the prognosis. Recurrence is possible [16,85] and varies from 20 to 25% in cases of blastomycosis [85]. On the other hand, histoplasmosis infection in cats often responds favorably to itraconazole [85].

Although uncommon, complications can also affect the ultimate prognosis in cases of osteomyelitis. For acute cases, recurrence and progression to chronic disease can occur. Infections near the epiphysis can rarely lead to concurrent joint infection, and septicemia can result from inappropriate local bacterial control. Finally, chronic osteomyelitis, and some cases of acute osteomyelitis, can lead to refractory or recurrent osteomyelitis, nonunion, restricted joint motion, and loss of limb function.

In summary, many factors contribute to the formation, progression, and prognosis of osteomyelitis. The cause must be identified and treated appropriately. Diagnosis is based on culture and suspicion of disease, whereas treatment depends on the severity and type of infection present. For bacterial infections, the prognosis is favorable as long as treatment is appropriate for the type of disease, but fungal osteomyelitis carries a guarded to poor prognosis.