ACP medicine, 3rd Edition

Infectious Disease

Osteomyelitis

Layne O. Gentry MD1

1Clinical Professor of Medicine, Baylor College of Medicine, Chief, Infectious Disease Section and Medical Director, Infection Control, St. Luke's Episcopal Hospital

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

November 2004

Osteomyelitis is an infection of bone characterized by progressive inflammatory destruction of bone, bone necrosis, and new bone formation. Osteomyelitis poses a challenge because it is often difficult to diagnose and treat. Even when appropriate antibiotic therapy is instituted promptly, osteomyelitis can cause serious morbidity. Chronic cases are often refractory to treatment. In diabetic patients, amputation to remove the site of infection is often necessary. The etiology of osteomyelitis has evolved considerably over the past 2 decades. Twenty years ago, most cases of osteomyelitis were caused by susceptible strains of Staphylococcus aureus and were cured with surgical debridement and 4 to 6 weeks of methicillin therapy. Although S. aureus is still a common cause of osteomyelitis, an increasing number of infections are caused by gram-negative organisms, such as Pseudo mon as aeruginosa, or are polymicrobial. Coagulase-negative staphylococci, once regarded as contaminants, are now considered significant pathogens. Increasingly, osteomyelitis is a complication of reconstructive orthopedic surgery; it is also a complication of median sternotomy after cardiothoracic surgery. The growing incidence of diabetes in the population is also responsible for increasing numbers of osteomyelitis diabetes foot infections. These changes, together with improvements in diagnosis and therapy, indicate a need to reexamine traditional management of osteomyelitis.

Classification

Osteomyelitis is classified on the basis of pathogenesis, duration of disease, extent or type of bone involvement, anatomy of the bone infection, and host characteristics. Osteomyelitis can present as either an acute condition or a chronic infection. Acute osteomyelitis is usually defined as the first clinical episode, complete with the signs, symptoms, and radiographic and histologic findings associated with bone infection. Acute infections often occur soon after an episode of bacteremia and are usually accompanied by fever and bone pain. Chronic osteomyelitis is defined as bone infection that has failed to resolve after one or more treatment attempts. Retained foci of dead bone, or sequestra, are characteristic of chronic osteomyelitis.

Waldvogel and coworkers described three types of osteomyelitis: hematogenous osteomyelitis, osteomyelitis secondary to contiguous focus of disease, and osteomyelitis associated with vascular insufficiency.1 In hematogenous osteomyelitis, infection is introduced through the bloodstream and usually affects the metaphyses of long bones. Hematogenous osteomyelitis is diagnosed in about 20% of cases of osteomyelitis; it is the most common type of osteomyelitis in children. In osteomyelitis secondary to a contiguous focus of disease, the bone becomes infected from an external source (e.g., penetrating trauma or open fracture) or from the spread of infection from adjacent soft tissue (e.g., abscess or skin infection). Contiguous-focus disease is usually seen in older persons and accounts for 50% of cases of osteomyelitis. Osteomyelitis associated with vascular insufficiency, which is responsible for about 30% of cases, is usually seen in patients with diabetic neuropathy.

Clinical Syndromes

HEMATOGENOUS OSTEOMYELITIS

Hematogenous osteomyelitis is usually seen in children between 1 and 15 years of age and adults older than 50 years or in persons who abuse I.V. drugs. In children, infection usually occurs as a single focus in the metaphyseal area of long bones (particularly the tibia and femur). In older persons, infection of the vertebral bodies is more common. When osteomyelitis is seen in young adults, it is often associated with I.V. drug abuse or sickle cell anemia. Several predisposing factors are associated with the development of hematogenous osteomyelitis. Children may be predisposed to infection by minor trauma that causes a small hematoma, vessel obstruction, and bone necrosis. Thus, hematogenous osteomyelitis may be seen in teenagers who play contact sports. About one third of patients have a history of trauma to the site of osteomyelitis. Some children with local trauma may have a history of infection at a distant site. In adults, predisposing factors include advanced age, immunodeficiency, chronic bacteremia, I.V. drug abuse, long-term indwelling catheters, and sickle cell anemia.

Etiology

Most cases of hematogenous osteomyelitis are monomicrobial. Although S. aureus causes 60% to 90% of cases of hematogenous osteomyelitis, certain organisms tend to cause infections in certain age groups. In newborns, group B streptococci and gram-negative bacilli are common. In children, streptococci and Haemophilus influenzae are often seen. However, evidence from a retrospective study in Canada showed that vaccination of infants and children succeeded in eliminating H. influenzae type b as an infective agent in hematogenous osteomyelitis.2 Polymicrobial hematogenous osteomyelitis is usually caused by S. aureus and a streptococcus.

The incidence of hematogenous osteomyelitis caused by gram-negative organisms is about 25%. Escherichia coli is the most common gram-negative organism isolated from hematogenous bone infections. P. aeruginosa, which has a predilection for the cervical vertebrae, andSerratia species are common pathogens in I.V. drug abusers. Furthermore, P. aeruginosa can be isolated from patients with long-term indwelling catheters.3 Salmonella species are frequently associated with osteomyelitis in patients with sickle cell anemia4 and may also be seen in patients with AIDS and other hemoglobinopathies.

Tuberculous infection of bone may be seen in patients from areas endemic for tuberculosis and in patients with AIDS. Fungal osteomyelitis, usually caused by opportunistic organisms, is found in patients who are severely immunodeficient or neutropenic or who have indwelling venous catheters. Because of their increasing frequency in all types of infection, Candida species may be seen more often in bone infections. Recent case reports reviewed 58 cases of candidal vertebral osteomyelitis5 and 11 cases of deep sternal wounds caused by C. albicans after coronary artery bypass grafting.6 Treatment of these infections is difficult, and therapy needs to be individualized against the specific organism.

Clinical Features

Children with acute hematogenous osteomyelitis usually present with fever and localized pain. Leukocytosis may be present. A decreased range of motion and signs of local infection may be seen in the affected area. Drainage is not usually seen. Blood cultures are positive in more than half of patients.3 Although in most children symptoms are present for 3 weeks or less, some children may present with vague symptoms of 1 to 3 months' duration.

Vertebral osteomyelitis is a form of hematogenous osteomyelitis most commonly seen in older persons and I.V. drug abusers. Most patients present with a constant dull pain that progresses slowly. Percussion over the affected area usually causes intense pain. Neurologic signs are generally absent but, when present, may indicate an epidural abscess. Fewer than half of patients are febrile. Vertebral infection typically involves the vertebral body rather than the spinous or transverse processes; often, two adjacent vertebrae and the disk space between them are affected. The lumbar region is most frequently involved in pyogenic hematogenous osteomyelitis. Thoracic vertebrae are often infected in spinal tuberculosis (Pott disease), and the cervical spine is often the site of infection in patients who abuse I.V. drugs.7

In about 10% of patients with acute hematogenous osteomyelitis, the disease progresses to a chronic condition. These patients have recurrent episodes of clinical exacerbations that are usually more indolent than those seen in the acute episode. Patients who are more susceptible to chronic osteomyelitis include those for whom therapy was delayed and those with compound fractures.

Despite the serious nature of hematogenous osteomyelitis, the prognosis is good for most patients. In a retrospective review of 69 children with acute hematogenous osteomyelitis, major sequelae were seen in only 3% of patients and minor problems in 2%. A favorable long-term outcome was associated with early hospitalization and initiation of appropriate antibiotic therapy.8 Patients with severe underlying conditions have a worse prognosis.

Special Presentations of Hematogenous Osteomyelitis

Brodie abscess

In patients with Brodie abscess, the infected portion of bone is completely replaced by pus and forms an intraosseous abscess. The infection, which is contained within a sclerotic membrane, may become quiescent. However, the risk of recurrence is high, and infection may spread. Patients are usually afebrile and may present only with local pain or swelling. Brodie abscess may be misdiagnosed as a bone tumor; the diagnosis of Brodie abscess is confirmed by histologic examination and culture. S. aureus is usually the etiologic agent, although S. epidermidis is occasionally implicated. Although seemingly benign, Brodie abscess should be aggressively treated. Pus may accumulate and spread through the tissues, causing a draining sinus; if near the joint surface of an intracapsular bone, infection can cause pyogenic arthritis.

Osteomyelitis in patients with sickle cell anemia

There are two main differences between hematogenous osteomyelitis in children with sickle cell anemia and that in children who are otherwise healthy. First, infection in children with sickle cell anemia usually localizes in the diaphysis rather than the metaphysis. Second,Salmonella species frequently cause infection in this group, although staphylococci are also common.4 Differentiating between osteomyelitis and thrombotic crisis in patients with sickle cell anemia may be difficult. In both situations, patients may present with bone pain and fever, and the erythrocyte sedimentation rate (ESR) and leukocyte count may be elevated. A bone biopsy is usually required for diagnosis of osteomyelitis. Multiple sites of bone may be infected. Antibiotics for empirical therapy should be effective against both Salmonella and staphylococci. A regimen of a semisynthetic penicillin and an aminoglycoside is recommended [see Treatment Overview, below].

Hematogenous osteomyelitis in I.V. drug abusers

In I.V. drug abusers, hematogenous osteomyelitis is associated with subtle clinical signs and symptoms. Patients may present with localized pain, but fever is usually absent. Although vertebral osteo myelitis is common, infection of the pubis and the clavicle is also seen. Culture of the infected site usually yields S. aureus or S. epidermidis, although P. aeruginosa is often seen. Serial radio graphs may be necessary, and surgery may be required to confirm the microbiologic diagnosis.

OSTEOMYELITIS SECONDARY TO A CONTIGUOUS FOCUS OF INFECTION

Osteomyelitis in adults almost always derives from a contiguous source of infection. These bone infections are often complex and heterogeneous. Organisms may be inoculated directly into the bone after an open fracture, a penetrating wound, or a surgical procedure; or they may spread from an adjacent soft tissue infection. Because techniques for joint replacement have improved, the number of artificial joints inserted has increased and so has the number of infections associated with prosthetic joints.

Etiology

The cause of osteomyelitis depends, in part, on the route of entry, the phenotypic characteristics of organisms, and the epidemiologic background of the patient. Thus, the bacteriology of osteomyelitis in a diabetic patient who has had multiple hospital admissions and has been treated with multiple antibiotics over several years differs from that in a patient with a community-acquired infection. Organisms with common clinical associations are listed [see Table 1].

Table 1 Common Clinical Associations in Osteomyelitis

Organism

Common Clinical Associations

Staphylococcus aureus

Found in 50%–70% of cases

Coagulase-negative staphylococci

Infections of prosthetic devices

Gram-negative bacilli

Decubitus ulcers, vascular insufficiency

Pseudomonas aeruginosa

Puncture wounds

Streptococci and anaerobes

Diabetic foot lesions, decubitus ulcers, bite wounds

Pasteurella multocida

Cat bites

Actinomyces

Periodontal infection or sinusitis

Eikenella corrodens

Mandibular osteomyelitis

Because of virulence factors and adherence characteristics, S. aureus is the most common single pathogen in contiguous-focus osteomyelitis and accounts for 50% to 70% of cases.9 In contrast to hematogenous osteomyelitis, contiguous-focus disease is often polymicrobial; multiple organisms may be isolated from 30% to 50% of such patients. The incidence of osteomyelitis caused by gram-negative bacilli is increasing. Gram-negative pathogens are important in patients who have undergone multiple hospital procedures, have had an extended hospital stay, are in intensive care units, or have had an open fracture. P. aeruginosa is often responsible for osteomyelitis associated with comminuted fractures and puncture wounds to the heel.10 S. epidermidis is another common pathogen in contiguous-focus osteomyelitis, particularly in patients who have infected orthopedic prostheses.

Osteomyelitis caused by anaerobic bacteria usually results from contiguous spread of a polymicrobial infection. Anaerobes should be suspected when osteomyelitis is associated with a human bite or is contiguous to a dental infection, intra-abdominal abscess, decubitus ulcer, or otorhinolaryngologic infection.

Clinical Features

In the initial stages of contiguous-focus osteomyelitis, patients may have pain, fever, swelling, and erythema. However, during recurrent episodes of chronic infection, fever subsides, and pain and drainage from a sinus tract or ulcer are often seen. In patients with generalized vascular insufficiency, the disease starts insidiously in an area of traumatized skin. The patient may present with an ingrown toenail, a perforating foot ulcer, cellulitis, or a superficial or deep wound infection. Fever and systemic signs of infection are not usually present.

Osteomyelitis after replacement of the hip joint may occur soon after surgery or later. Often evident within the first few days or weeks after surgery, acute contiguous infections result directly from infected skin, subcutaneous tissue, or muscle. Fever, pain, erythema, edema, and purulent drainage are often present when early infections are caused by pyogenic organisms such as S. aureus, streptococci, or enteric gram-negative bacilli. When early infections are caused by less pathogenic organisms, such as S. epidermidis or diphtheroids, the disease presents more insidiously. Chronic contiguous infections are usually diagnosed 6 to 24 months after surgery. The patient usually presents with persistent pain. Most infections are probably introduced during surgery but remain quiescent for a long time.

Sternal osteomyelitis, a serious complication of median sternotomy after cardiothoracic surgery, occurs in 1% to 5% of patients. Patients have fever, a slightly erythematous wound, and persistent pain. Frequent pathogens include S. epidermidis, S. aureus, gram-negative bacilli, and, more recently, Candida species. The presence of sternal wires, used to approximate the sternum, is a major risk factor for chronic recurrent osteomyelitis. Surgical removal of the wires is essential for recovery. The risk of death may be high in complicated cases.10

OSTEOMYELITIS ASSOCIATED WITH VASCULAR INSUFFICIENCY

Osteomyelitis secondary to vascular insufficiency occurs most frequently in older patients with diabetes mellitus or severe vascular impairment. In these patients, osteomyelitis usually develops by contiguous spread of infection from soft tissue to underlying bone; often, it occurs in the small bones of the feet in patients in whom soft tissue breaks down over weight-bearing or pressure-bearing areas. Bone infections develop in about 25% of diabetic patients with superficial mild to moderate foot infections; however, of those patients with serious foot infections, over 50% will have osteomyelitis.11 Extensive debridement is necessary, and about two thirds of cases require bone resection or partial amputation.12

Complex foot lesions in diabetic patients result from a combination of neuropathy, atherosclerotic peripheral vascular disease, and repetitive trauma to the area. Atherosclerosis of the tibial and peroneal arteries of the lower leg is common in diabetic patients.13 Limb ischemia, combined with poor collateral circulation, impairs wound healing in foot ulcers and allows for the contiguous spread of infection to bone. In addition, this anoxic environment contributes to the development of gangrenous changes and anaerobic infections. Furthermore, peripheral vascular disease may compromise the efficacy of antibiotic therapy by preventing the accumulation of adequate drug levels in the infected tissues.

Osteomyelitis should be considered in all diabetic patients with deep or chronic foot ulcers or infections. The Group Health Cooperative of Puget Sound conducted a study to determine the incidence of foot ulcers and the risk of developing serious complications among 8,905 patients with type 1 or type 2 diabetes. Over a period of 3 years, 5.8% developed a foot ulcer, and of those, 15% developed osteomyelitis.14 Distinguishing between true bone infection and noninfectious destructive neuropathic bone changes in patients with diabetes is challenging and requires diagnostic imaging tests. Although S. aureus is the most common pathogen isolated from patients with osteomyelitis associated with vascular insufficiency, multiple organisms, including both anaerobes and aerobes, may be present, especially in hospitalized patients. Mixed gram-positive and gram-negative infections are often seen in patients with chronic or previously treated infections.

Pathogenesis

Pathogens gain access to bone in humans by three methods: direct inoculation, extension from contiguous sites, and hematogenous dissemination. Each type of infection may be further complicated by the presence of a prosthesis.

The sequelae associated with the hematogenous dissemination of bacteria to the bone vary with the age of the patient.3 In infants, infection can spread via transphyseal vessels to the epiphysis and then to the joint space. Concurrent septic arthritis and epiphyseal destruction may be seen. In children older than 1 year, the growth plate is avascular, and osteomyelitis usually begins in the metaphyseal region of the long bones. Capillary loops do not anastomose in this region, and bacterial emboli can settle in this area and cause a microinfarction. Microscopic metaphyseal hemorrhage and necrosis, caused by insignificant trauma, provide a favorable environment for infection. Once infection is established, it can spread to the periosteum. If pus reaches the subperiosteal space, the periosteum becomes elevated. Osteoblasts beneath the detached periosteum gradually produce new bone.

The pathogenesis of hematogenous osteomyelitis in adults differs from that in children.8 After growth ceases and the epiphyses close, organisms causing osteomyelitis no longer have a predilection for the metaphyseal area of long bones. The vertebrae, sternoclavicular and sacroiliac joints, and symphysis pubis are often affected. Infection may spread from the subchondral bone to the joint space. Sites of previous injury or trauma often provide the point of seeding of infectious organisms.

Unlike hematogenous osteomyelitis, contiguous-focus disease may invade any traumatized bone. Local inflammatory response or injury can devitalize bone and tissue. Microbes can multiply in these areas of dead bone. Osteomyelitis often complicates decubitus ulcers or cutaneous ulcerations in diabetic patients. Undetected trauma in diabetic patients with neuropathy provides a portal of entry for bacteria. Moreover, compromised blood flow impairs wound healing and allows unchecked bacterial proliferation.

Histologic findings in acute osteomyelitis include microbes, neutrophils, and congested or thrombosed blood vessels [see Figures 1a and 1b]. The local inflammatory reaction contributes to further bone necrosis, which is a distinguishing feature of chronic osteomyelitis. As necrosis progresses, new bone gradually surrounds the infected area of dead bone (sequestrum). The formation of a functionally inert, nonresorbable substratum—either a sequestrum or a foreign body—upon which bacteria can attach and multiply marks the transition from acute to chronic disease.

 

Figure 1a. Bone Biopsy in Acute Osteomyelitis

Photomicrograph of a specimen from bone biopsy shows acute osteomyelitis (magnification: × 40). Note missing osteoclastic cells (signifying bone death) and intense inflammatory reaction adjacent to bone fragment.

 

Figure 1b. Biopsy Showing Polymorphonuclear Infiltration

Higher magnification (× 100) shows intense polymorphonuclear infiltration at same site.

Diagnosis

The diagnosis of osteomyelitis should be considered in patients with fever and localized skeletal pain, positive blood cultures, persistently draining wounds, and radiologic findings that suggest a localized inflammatory process. The diagnosis can then be confirmed by the histologic examination and bacteriologic culture of bone specimens obtained either by surgery or by multiple percutaneous needle biopsies. A detailed history with emphasis on previous trauma or surgery is important. Although no laboratory test specifically indicates the diagnosis of osteomyelitis, a complete blood cell count, ESR, and C-reactive protein test may be useful. The white blood cell count is usually elevated only in early stages of the disease. The ESR may be helpful in diagnosing acute hematogenous osteomyelitis in children but is less useful in newborns and children with sickle cell anemia. C-reactive protein is an acute-phase reactant, and although the C-reactive protein test is relatively insensitive and nonspecific, it may be more specific for infection than the ESR.

RADIOLOGIC AND NUCLEAR FINDINGS

There is a plethora of imaging techniques for diagnosing osteomyelitis [see Table 2]. The accuracy of imaging studies is affected by the extent of inflammation, the duration and site of infection, the vascularity of the site, and associated pathologic conditions. Osteomyelitis cannot be absolutely confirmed or excluded on the basis of results from any one test.

Table 2 Radiographic and Radionuclide Techniques for Diagnosing Osteomyelitis

Test

Sensitivity

Specificity

Indications/Comments

Radiograph

Good after 3 weeks

Poor

Initial test for most patients

99mTc bone scan

Good in first 2 weeks

Poor

Use in patients with suspected osteomyelitis who have a negative result on radiograph

Gallium

Moderate after 2 weeks

Poor

Use in infants and children with a negative result on bone scan

Indium

Moderate

Moderate

May be used in patients with a recent fracture; may be useful in diagnosis of infected joint prosthesis 2–4 months after implantation

CT

Excellent

Moderate

Useful in osteomyelitis of the skull, pelvis, and sternoclavicular junction

MRI

Excellent

Excellent

Reliability distinguishes tumor of infarction from osteomyelitis; useful in surgical planning for diabetes; good for vertebral disease; very expensive

PET

Excellent

Moderate

May be useful in chronic osteomyelitis in patients with negative results on other tests

CT—computed tomography  MRI—magnetic resonance imaging  PET—positron emission tomography  99mTc—technetium-99m

Radiograph

Radiographs, which are relatively inexpensive, should be the initial diagnostic technique for almost all patients suspected of having osteomyelitis. However, findings on conventional radiographs are often normal until at least 2 weeks after the onset of symptoms. Furthermore, radiographic changes can be subtle and nonspecific. In children with hematogenous osteomyelitis, the earliest changes are deep soft tissue swelling, which may be difficult to detect; periosteal elevation; and radiolucent areas of bone destruction, which are not usually detected until 50% to 75% of bone density has been lost.15 In contiguous-focus disease, the initial radiologic manifestation is periosteal reaction. Radiographs may show the presence of sequestra, sclerosis, and significant bone lysis in patients with chronic disease.

Bone Scan

The technetium-99m (99mTC) methylene diphosphonate three-phase bone scan is often used to identify osteomyelitis, because it is more sensitive than conventional radiography and can confirm a suspected diagnosis of osteomyelitis within 48 hours after onset of symptoms. The bone scan should be the next imaging study performed in patients with normal radiographs. Classic findings on bone scan are increased blood flow, pooling, and reactive new bone formation. Although sensitivity is good, specificity is poor [see Table 2]. Cellulitis and septic arthritis cannot be differentiated from osteomyelitis on bone scan. False positive results may be seen in patients with previous bone injury, tumor, or infarction. Furthermore, bone scans may remain positive for 6 weeks to 6 months after therapy because of bone metabolism and remodeling. In children with uncomplicated hematogenous osteomyelitis, the bone scan has a high sensitivity and specificity; a positive bone scan strongly suggests osteomyelitis, and a negative scan in children older than 3 years excludes the diagnosis.16 Sensitivity, however, is lower in neonates and in patients with sickle cell anemia.

Gallium Scan

Gallium scans may be useful in infants and in children in whom bone scans are negative. The low specificity of gallium imaging may be improved if it is combined with bone scans. When interpreted in combination with a bone scan, the gallium scan can in some cases be used to differentiate acute cellulitis from acute osteomyelitis. Disadvantages associated with gallium scans include higher doses of radiation and a 1- to 2-day waiting period for results.

Leukocyte Scan

Indium-111 (111In)-labeled and 99mTC-labeled leukocyte scans, which are more specific but less sensitive than bone scans, have been used to evaluate patients with osteomyelitis. Leukocyte scans are not useful in patients with chronic, indolent infections. In a patient who is suspected of having osteomyelitis and has recently had a fracture, a leukocyte scan may be the study of choice because results from a bone scan will be equivocal. The cumbersome and expensive technique of leukocyte scanning requires in vitro cell isolation and radiolabeling, which is time-consuming and potentially biohazardous. However, leukocyte scans, especially in combination with bone scans, may be sensitive and specific in detecting osteomyelitis in diabetic patients.17,18,19 In a study of 52 diabetic patients with chronic foot ulcers, both specificity and accuracy were significantly higher with leukocyte scans than with bone scans.17 The combined use of leukocyte scans and bone scans has effectively differentiated osteomyelitis from soft tissue infections in patients with diabetes; the sensitivity of the combination has ranged from 93% to 100%, and the specificity has ranged from 80% to 83%. 111In-labeled and 99mTC-labeled leukocyte scanning have been shown to be useful in the diagnosis of prosthetic joints 2 to 6 months after implantation. Biopsy confirmation is necessary for diagnosis.

Computed Tomography and Magnetic Resonance Imaging

Both CT and MRI have excellent sensitivity and resolution and allow simultaneous evaluation of bone and surrounding soft tissues. CT reliably detects sequestra and devitalized bone and is useful for evaluating patients with osteomyelitis of the skull. However, CT is prone to image degradation and is less specific than other tests. MRI, with its excellent specificity, is helpful in distinguishing bone tumor or infarction from osteomyelitis.20 Furthermore, MRI is particularly reliable in distinguishing normal areas from abnormal areas when surgery is being planned for diabetic patients with osteomyelitis.21 In addition, MRI is the technique of choice for detecting and assessing the site and extent of infection in the spine. However, the expense of MRI precludes its use on a routine basis. A limited MRI scan with specialized views and minimal use of gadolinium contrast can be used to control costs.22 Metallic prostheses exclude the use of MRI and distort image reflection on CT, thereby obscuring early changes of infection.

Positron Emission Tomography

Positron emission tomography (PET) has been used as an imaging tool for infections of the bone and osteosynthetic material.23 PET with fluorodeoxyglucose (FDG) was shown to be superior to bone scans in diagnosing chronic osteomyelitis of the central skeleton.24 Because of its excellent sensitivity, FDG PET may be an effective technique for excluding chronic osteomyelitis when a bone scan is negative.25

CULTURES

The gold standard for diagnosis of osteomyelitis is aerobic and anaerobic culture of a biopsy specimen obtained under direct vision during surgery. Alternatively, culture of multiple specimens obtained by needle biopsy under ultrasound or radiographic guidance has been a reliable, cost-effective means of diagnosing osteomyelitis at our center. Combining surgical debridement with the obtaining of culture specimens is also cost-effective. Blood cultures should also be obtained, especially from patients suspected of having hematogenous osteomyelitis. Results of swab cultures of the sinus tract are usually inaccurate. Studies have shown that the results of cultures of sinus tract and bone biopsy specimens match in only 44% to 57% of patients with chronic osteomyelitis.26,27

Treatment Overview

Optimal management of the patient with osteomyelitis entails microbiologic confirmation of the diagnosis by biopsy and complete surgical debridement, followed by institution of antibiotic therapy that is based on culture and sensitivity results [see Table 3]. When debridement is inadequate, therapy often fails, despite appropriate antimicrobial therapy; therefore, “a subtle balance between medical and surgical therapy is necessary if a potentially curative outcome is to be achieved.”28

Table 3 Choices for Antibiotic Treatment of Bacterial Osteomyelitis

Organism

Antibiotic

Dosage

 

 

Children

Adults

Staphylococcus aureus

 

 

 

  Methicillin-sensitive

Nafcillin or oxacillin

150 mg/kg I.V., q. 4 hr

2 g I.V., q. 6 hr

 

Cefazolin

2 g I.V., q. 8 hr

 

Cephalexin

100 mg/kg p.o., q. 6 hr

  Methicillin-resistant or S. epidermidis

Vancomycin*

40 mg/kg I.V., q. 6 hr

1 g I.V., q. 12 hr

Streptococci

Ampicillin

150 mg/kg I.V., q. 6 hr

2 g I.V., q. 6 hr

 

Ceftriaxone

50 mg/kg I.V., q. 24 hr

2 g I.V., q. 24 hr

Enterococci

Ampicillin + gentamicin

2 g I.V., q. 6 hr

 

 

 

1 mg/kg q. 8 hr

Enterobacteriaceae

Ciprofloxacin

750 mg p.o., q. 12 hr

 

Ceftriaxone

50mg/kg I.V., q. 24 hr

2 g I.V., q. 24 hr

Pseudomonas aeruginosa

Ceftazidime

2 g I.V., q. 12 hr

 

Ciprofloxacin

750 mg p.o., q. 12 hr

 

Semisynthetic penicillin

 

 

 

  Piperacillin

3 g I.V., q. 6 hr

 

 with

 

 

 

Aminoglycoside

 

 

 

  Amikacin

15 mg/kg q.d.

 

  Gentamicin

5 mg/kg q.d.

Mixed infections (diabetic foot)

Ticarcillin-clavulanate§

3.1 g I.V., q. 6 hr

 

Clindamycin + ciprofloxacin

0.9 g I.V., q. 8 hr

 

 

 

750 mg p.o., q. 12 hr

 

Imipenem-cilastatin||

1 g I.V., q. 6 hr

*Adding rifampin may increase efficacy.
Use combination for the first 2 wk, followed by ampicillin alone.
Use a semisynthetic penicillin in combination with an aminoglycoside.
§Use in limb-threatening infections.
||Use in life-threatening infections.

SURGICAL THERAPY

The type of surgical therapy depends on the extent of infection. Surgical management of acute infection requires debridement of dead tissue, whereas chronic osteomyelitis requires surgical debridement of all devitalized bone and soft tissue and removal of foreign bodies. Adequate surgical management is essential for successful treatment. Inadequate surgical debridement, regardless of antibiotic therapy, is the most common cause of treatment failure. Sequestered dead bone can serve as a nidus for persistent infection. In some cases, a two-staged debridement protocol may be necessary to sterilize the wound.29

Surgical therapy entails filling the dead space created by debridement and reestablishing blood supply to the poorly perfused area. Skin, bone, or muscle grafts are used to cover the wound. Cancellous bone grafts can be used to fill the dead space. Revascularization procedures include the use of local pedicle muscle flaps and myocutaneous flaps. In patients with very large bone defects, the Ilizarov technique has been used to reconstruct large defects in bone and soft tissue. In this procedure, major segmental resections of infected bone are performed, followed by realignment of opposing ends of now noninfected bone so that new bone growth fills in the defect. Each salvage procedure has associated morbidity and expense.

ANTIBIOTIC THERAPY

Oral and I.V. Antibiotic Therapy

The standard treatment for chronic osteomyelitis is I.V. antimicrobial therapy targeting the causative organism. Because of rising hospital costs, alternatives to an extended hospital stay for parenteral treatment of osteomyelitis in otherwise healthy patients are being sought. The economic benefits of oral therapy are obvious: decreased hospital stay, reduced pharmacy and supply costs, no need for surgical insertion of a catheter, and decreased catheter-related complications. For patients who require a complete regimen of I.V. antibiotics, outpatient therapy should be considered. Patients should be educated in the care and use of the catheter while they are still in the hospital. Furthermore, drug toxicity and clinical response should be closely monitored by the physician. Administration of I.V. antibiotics during clinic visits or by a home health agency can substantially reduce costs over in-hospital care.

Alternative Delivery of Antibiotics

Antibiotic-impregnated acrylic beads have been used for local treatment of bone infections; however, they have not been approved for use in the United States. Although the beads deliver a high concentration of antibiotic to the area of infection, bacteri- cidal levels of antibiotic are present locally for only 2 to 4 weeks. Thus, the beads should be used in conjunction with systemic antibiotics. Both biodegradable and nonbiodegradable beads have been used, and both require surgical placement. Nonbiodegradable beads, such as the polymethylmethacrylate beads, must be surgically removed after 2 to 4 weeks. Biodegradable antibiotic beads do not require surgical removal and provide local bactericidal concentrations for extended periods.30,31

Choice of Antimicrobial Agents

Staphylococcal infections

Methicillin-resistant S. aureus infections represent nearly 60% of nosocomial S. aureus isolates detected in hospitals and reported to the CDC.32 For infections caused by susceptible S. aureus, a β-lactamase-resistant semisynthetic penicillin is the drug of choice because most strains of S. aureus are resistant to penicillin. At our center, only 45% of S. aureus organisms are methicillin susceptible, but more than 70% of coagulase-negative staphylococci are resistant to methicillin. The problem of methicillin-resistant S. aureus is worsening, especially in tertiary medical centers. Although vancomycin is the preferred agent for treatment of methicillin-resistant staphylococcal infections, its use as monotherapy has come into question. At our center, the use of vancomycin alone to treat osteomyelitis caused by methicillin-resistant S. aureus has failed in the standard 4- to 6-week treatment regimen, and rifampin (300 mg p.o. twice daily) is now routinely added to the regimen, unless there is a contraindication to its use. Similar regimens are used to treat methicillin-resistant S. epidermidisinfections, especially sternal bone infections after median sternotomy. Unfortunately, because failure of vancomycin alone has been observed with increasing frequency, objective clinical trials to determine efficacy are not likely to be performed, for ethical reasons.

In selected cases, after 2 weeks of parenteral therapy with vancomycin, patients can be switched to oral therapy if the appropriate requirements are met. Those requirements include good response to I.V. therapy, strict patient compliance, microbiologic diagnosis, isolated pathogen highly susceptible to the proposed antibiotic, and a high level of bioavailability of the oral agent (serum bactericidal titers may be useful).

Although oral therapy with ciprofloxacin has been effective in treating staphylococcal osteomyelitis,33,34 reports of variable efficacy and the development of resistance indicate that ciprofloxacin should not be used as monotherapy in osteomyelitis caused by staphylococci.35However, long-term treatment with the combination of ciprofloxacin and rifampin has been successful for implant-related staphylococcal infections in patients who have stable implants and symptoms of short duration.36 A recent study of 17 diabetic patients with mild to moderate foot lesions associated with 20 osteomyelitic bones received rifampin plus ofloxacin for 6 months; 88.2% of the patients were cured, and cure was maintained by 76.5% at the end of a 22-month follow-up.37 Quinolones are contraindicated in children and pregnant women.

Enterococcal infections

Enterococcus faecalis is an increasingly troublesome pathogen, especially in patients with infected prostheses and patients with diabetes who have osteomyelitis in the diabetic foot. Fortunately, E. faecalis does not usually cause osteomyelitis of long bones in the absence of prostheses. Because of the serious nature of a possible associated bacteremia in acute infections, aggressive therapy is necessary until acute symptoms resolve and blood cultures become negative.

  1. faecalisis becoming a problem in postoperative orthopedic patients and in diabetic patients. The isolation of vancomycin-resistantEnterococcusspecies in tertiary medical centers has increased over the past few years. In a recent study, 89 patients with osteomyelitis were treated with linezolid and were evaluated for clinical efficacy, safety, and tolerability.

The clinical cure rate of 22 evaluable patients was 81.8%. The authors concluded that linezolid (administered either intravenously or by mouth) was successful in treating osteomyelitis caused by resistant gram-positive organisms.38 However, hematologic complications have been found to be a limiting factor in long-term use of linezolid.39 More experience is necessary before the ultimate use of linezolid in these patients is determined.

Gram-negative infections

Treatment of gram-negative osteomyelitis requires an accurate identification of the organism and antimicrobial susceptibility. Oral ciprofloxacin is an effective and inexpensive choice for treating bone infections caused by Enterobacteriaceae.22,33,34 Furthermore, studies have shown that ciprofloxacin and ofloxacin have been effective in treating osteomyelitis caused by multiresistant gram-negative bacteria.40Because of reports of the development of resistance, however, patients should be carefully monitored when either agent is used as monotherapy in pseudomonal osteomyelitis. Ceftazidime and cefepime are other potent antipseudomonal agents, although neutropenia has been associated with cefepime.41 In cases of resistant strains of Pseudomonas, a regimen of an extended-spectrum penicillin and an aminoglycoside may be used; however, efficacy is not definitive in cases of osteomyelitis, and the toxicity of an extended regimen of I.V. aminoglycosides is a serious concern.

Treatment of Clinical Syndromes

HEMATOGENOUS OSTEOMYELITIS

In children with acute hematogenous osteomyelitis, antibiotic therapy alone may be sufficient. When the disease is recognized early and treated promptly, cure can be anticipated. Surgery should be considered for patients who do not respond to antibiotic therapy. For compliant children with a documented microbiologic infection who respond initially to parenteral therapy and who have no complications, the course of therapy may be completed with oral agents.42 Cure rates of 95% have been obtained with this regimen. The suggested duration of I.V. therapy ranges from 4 to 14 days, and oral therapy is continued for 14 to 26 days.43 Although some investigators have suggested that monitoring blood concentrations of antibiotics may be unnecessary,42 most agree that adequate gastrointestinal absorption of the antibiotic should be confirmed by repeated measurements of serum bactericidal activity.44 Close outpatient follow-up is essential.

In adults with hematogenous osteomyelitis, surgical debridement and drainage of soft tissue abscesses are often necessary. Antibiotic therapy is usually maintained for 4 to 6 weeks. I.V. administration is used most often; however, oral ciprofloxacin is used to treat gram-negative infections.

OSTEOMYELITIS SECONDARY TO A CONTIGUOUS FOCUS OF INFECTION

The diagnosis of osteomyelitis secondary to a contiguous focus of infection is based on a biopsy of the bone and not of the contiguous lesion. Once bone infection is confirmed by biopsy, treatment should proceed according to general principles of osteomyelitis management [see Treatment Overview, above].

OSTEOMYELITIS ASSOCIATED WITH VASCULAR INSUFFICIENCY

Prompt, aggressive surgical and antibiotic therapy and proper wound care are the best means of preserving a functional limb and optimizing outcome in patients with osteomyelitis associated with vascular insufficiency. Hyperbaric oxygen therapy, by increasing oxygen levels in ischemic tissues, has improved wound healing and reduced the amputation rate in high-risk patients. Revascularization of lesions in the lower-extremity vasculature by angioplasty and bypass grafting may help oxygenate tissue with critical ischemia, thereby preventing limb amputations. Prognosis for wound healing improves when the tissue oxygen level is greater than 40 mm Hg and when the popliteal pulse is palpable.11

References

  1. Waldvogel FA, Medoff G, Swartz MM: Osteomyelitis: a review of clinical features, therapeutic considerations, and unusual aspects. N Engl J Med 282:198, 1970
  2. Howard AW, Viskontas D, Sabhagh C: Reductions in osteomyelitis and septic arthritis related to Haemophilus influenzaetype B vaccination. J Pediatr Orthop 19:705, 1999
  3. Lew DP, Waldvogel FA: Osteomyelitis. N Engl J Med 336:999, 1997
  4. Sadat-Ali M: The status of acute osteomyelitis in sickle cell disease: a 15-year review. Int Surg 83:84, 1998
  5. Miller DJ, Mejicano GC: Vertebral osteomyelitis due to Candidaspecies: case report and literature review. Clin Infect Dis 333:523, 2001
  6. Malani PM, McNeil SA, Bradley SF, et al: Candida albicanssternal wound infections: a chronic and recurrent complication of median sternotomy. Clin Infect Dis 35:1316, 2002
  7. Endress C, Guyot DR, Fata J, et al: Cervical osteomyelitis due to I.V. heroin use: radiologic findings in 14 patients. Am J Roentgenol 155:333, 1990
  8. Christiansen P, Frederiksen B, Glazowski J, et al: Epidemiologic, bacteriologic, and long-term follow-up data of children with acute hematogenous osteomyelitis and septic arthritis: a ten-year review. J Pediatr Orthop B 8:302, 1999
  9. Gentry LO: Osteomyelitis and other infections of bones and joints. The Staphylococci in Human Disease. Crossley KB, Archer GL, Eds. Churchill Livingstone, New York, 1997, 455
  10. Laughlin TJ, Armstrong DG, Caporusso J, et al: Soft tissue and bone infections from puncture wounds in children. West J Med 166:126, 1997
  11. Lipsky BA: Osteomyelitis of the foot in diabetic patients. Clin Infect Dis 25:1318, 1997
  12. Ramsey SD, Newton K, Blough D, et al: Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care 22:382, 1999
  13. Hill SL, Holtzman GI, Buse R: The effects of peripheral vascular disease with osteomyelitis in the diabetic foot. Am J Surg 177:282, 1999
  14. Ramsey SD, Newton K, Blough D, et al: Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diab Care 22:382, 1999
  15. Jaramillo D, Treves ST, Kasser JR, et al: Osteomyelitis and septic arthritis in children: appropriate use of imaging to guide treatment. AJR Am J Roentgenol 165:399, 1995
  16. Sutter CW, Shelton DK: Three-phase bone scan in osteomyelitis and other musculoskeletal disorders. Am Fam Physician 54:1639, 1996
  17. Harvey J, Cohen MM: Technetium-99-labeled leukocytes in diagnosing diabetic osteomyelitis in the foot. J Foot Ankle Surg 36:209, 1997
  18. Johnson JE, Kennedy EJ, Shereff MJ, et al: Prospective study of bone, indium-111 labeled white blood cell, and gallium-67 scanning for the evaluation of osteomyelitis in the diabetic foot. Foot Ankle Int 17:16, 1996
  19. Crerand S, Dolan M, Laing P, et al: Diagnosis of osteomyelitis in neuropathic foot ulcers. J Bone Joint Surg Br 78:51, 1996
  20. Umans H, Haramati N, Flusser G: The diagnostic role of gadolinium enhanced MRI in distinguishing between acute medullary bone infarct and osteomyelitis. Magn Reson Imaging 18:255, 2000
  21. Sammak B, Abd El Bagi M, Al Shahed M, et al: Osteomyelitis: a review of currently used imaging techniques. Eur Radiol 9:894, 2000
  22. Gentry LO, Clint B: Adult osteomyelitis. Current Practice of Medicine. Bone RC, Ed. Churchill Livingstone, New York, 1996, 15.6
  23. Robiller FC, Stumpe KD, Kossmann T, et al: Chronic osteomyelitis of the femur: value of PET imaging. Eur Radiol 10:855, 2000
  24. Guhlmann A, Brecht-Krauss D, Suger G, et al: Fluorine-18-FDG PET and technetium-99m antigranulocyte antibody scintigraphy in chronic osteomyelitis. J Nucl Med 39:2145, 1998
  25. Zhuang H, Duarte PS, Pourdehand M, et al: Exclusion of chronic osteomyelitis with F-18 fluorodeoxyglucose positron emission tomographic imaging. Clin Nucl Med 25:281, 2000
  26. Patzakis MJ, Wilkins J, Kumar J, et al: Comparison of the results of bacterial cultures from multiple sites in chronic osteomyelitis of long bones: a prospective study. J Bone Joint Surg Am 76:664, 1994
  27. Mackowiak PA, Jones SR, Smith JW: Diagnostic value of sinus-tract cultures in chronic osteomyelitis. JAMA 239:2772, 1978
  28. Snyder RJ, Cohen MM, Sun C, et al: Osteomyelitis in the diabetic patient: diagnosis and treatment: part 2. Medical, surgical, and other alternatives. Ostomy Wound Manage 47:24, 2001
  29. Patzakis MJ, Greene N, Holtom P, et al: Culture results in open wound treatment with muscle transfer for tibial osteomyelitis. Clin Orthop 360:66, 1999
  30. Calhoun JH, Mader JT: Treatment of osteomyelitis with a biodegradable antibiotic implant. Clin Orthop 341:206, 1997
  31. Kanellakopoulou K, Giamarellos-Bourboulis EJ: Carrier systems for the local delivery of antibiotics in bone infections. Drugs 59:1223, 2000
  32. Kaye K, Lynfield R, Kreiswirth B: Methicillin-resistant Staphylococcus aureus. Paper presented at the International Conference on Emerging Infectious Diseases, February 29 to March 3, 2004, Atlanta, Georgia
  33. Gentry LO, Rodriguez GG: Oral ciprofloxacin compared with parenteral antibiotics in the treatment of osteomyelitis. Antimicrob Agents Chemother 34:40, 1990
  34. Lew DP, Waldvogel FA: Use of quinolones in osteomyelitis and infected orthopaedic prosthesis. Drugs 58(suppl 2):85, 1999
  35. Trucksis M, Hooper DC, Wolfson JS: Emerging resistance to fluoroquinolones in staphylococci: an alert editorial. Ann Intern Med 114:424, 1991
  36. Zimmerli W, Widmer AF, Blatter M, et al: Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA 279:1537, 1998
  37. Senneville E, Yazdanpanah Y, Cazubiel M, et al: Rifampin-ofloxacin oral regimen for the treatment of mild to moderate diabetic foot osteomyelitis. J Antimicrob Chemother 48:927, 2001
  38. Rayner CR, Baddour LM, Birmingham MC, et al: Linezolid in the treatment of osteomyelitis: results of compassionate use experience. Infection 32:8, 2004
  39. Kuter DJ, Tillotson GS: Hematologic effects of antimicrobials: focus on the oxazolidinone linezolid. Pharmacotherapy 21:1010, 2001
  40. Galanakis N, Giamarellou H, Moussas T, et al: Chronic osteomyelitis caused by multi-resistant gram-negative bacteria: evaluation of treatment with newer quinolones after prolonged follow-up. J Antimicrob Chemother 39:241, 1997
  41. Wong BB, Ko GJ: Neutropenia in patients receiving long-term cefepime therapy for osteomyelitis. Am J Health Syst Pharm 60:2229, 2003
  42. Tetzlaff TR, McCracken GH Jr, Nelson JD: Oral antibiotic therapy for skeletal infection of children: II. Therapy of osteomyelitis and suppurative arthritis. J Pediatr 92:485, 1978
  43. Peltola H, Unkila-Kallio L, Kallio MJ: Simplified treatment of acute staphylococcal osteomyelitis of childhood. Finnish Study Group. Pediatrics 99:846, 1997
  44. Nelson JD: Toward simple but safe management of osteomyelitis. Pediatrics 99:883, 1997

Editors: Dale, David C.; Federman, Daniel D.