Version May 2024
INTRODUCTION — Nontuberculous mycobacteria (NTM) are a large group of organisms that are widespread in the environment. They have been isolated from numerous environmental sources, including water and soil. NTM can cause a broad range of infections that vary depending on the particular NTM species and on the host’s immune status. In immunocompetent individuals, disease can present as pneumonia, lymphadenitis, or skin, soft tissue, and/or bone infection. Immunocompromised individuals can also present with any of these findings, but disease in such patients may also manifest as disseminated infection. Since NTM are seldom considered as a possible etiology in infections of the soft tissues and/or bones, delays in diagnosis are common.
The epidemiology, pathogenesis, clinical manifestations, and diagnosis of osteomyelitis due to NTM will be reviewed here. The treatment of osteomyelitis due to NTM is discussed separately. (See "Treatment of osteomyelitis due to nontuberculous mycobacteria in adults".)
Other manifestations of NTM infections, as well as osteomyelitis due to bacteria and Mycobacterium tuberculosis are also discussed separately. (See "Epidemiology of nontuberculous mycobacterial infections" and "Microbiology of nontuberculous mycobacteria" and "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV" and "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum" and "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis" and "Pathogenesis of osteomyelitis" and "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis" and "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology" and "Vertebral osteomyelitis and discitis in adults" and "Bone and joint tuberculosis".)
EPIDEMIOLOGY — Osteomyelitis is a rare manifestation of nontuberculous mycobacteria (NTM) infection, which may occur in immunocompetent and immunocompromised hosts. A wide range of NTM species can cause osteomyelitis, including both rapidly and slowly growing mycobacteria. Osteomyelitis caused by NTM can result from environmental exposure or nosocomial exposure and has involved either penetrating injuries or postsurgical infections, such as sternal wound infections; such cases typically occur in immunocompetent hosts [1-3].
NTM infections are commonly associated with HIV infection. Mycobacterium avium complex, Mycobacterium haemophilum, and Mycobacterium kansasii have been the most common pathogens reported in cases of HIV-associated NTM osteomyelitis, and usually occur in the setting of disseminated disease [4]. Most cases have occurred in the setting of advanced AIDS and a CD4 count <100 cells/microL.
Other risk factors for NTM osteomyelitis are discussed below. (See 'Risk factors' below.)
Vertebral osteomyelitis — Vertebral osteomyelitis due to NTM is rare. One review noted only 31 cases and 1 health care-associated outbreak of vertebral osteomyelitis due to NTM reported in the literature between 1965 and 2003 [5]. Most of these cases were due to M. avium complex (in 13), followed by Mycobacterium xenopi (in 7), Mycobacterium fortuitum (in 5), and Mycobacterium abscessus (in 3). The outbreak involved over 50 patients who developed M. xenopi spinal infection after vertebral surgery in the 1990s in France [6]. A subsequent review of 69 cases (63 reported between 1961 and 2004 and 6 subsequent cases) noted predisposing trauma or surgery in only 14.5 percent of cases [7]. A variety of immunosuppressive conditions were observed in 49 percent of the cases, including 10 patients with HIV infection and 28 percent with corticosteroid use. Other cases have been reported in intravenous drug users [8,9], patients with diabetes mellitus [7], and immunocompetent patients without risk factors [10,11].
Unlike NTM osteomyelitis in other anatomic locations, vertebral osteomyelitis due to NTM is not often the result of direct inoculation from penetrating trauma or surgery, although some patients with M. avium complex and M. fortuitum had spinal glucocorticoid injections that likely introduced mycobacteria into the vertebrae [5]. There have been sporadic outbreaks due to contamination of equipment used in surgical procedures. One example involved 58 cases of M. xenopi spine infections in France where contaminated tap water used for rinsing surgical devices after disinfection was identified as the source of the outbreak [6]. Two case reports have described thoracic vertebral osteomyelitis developing after pulmonary infection, suggesting contiguous spread of the infection from the thoracic cavity into the vertebral bodies [12,13].
Causative species
Rapidly growing mycobacteria — The most common rapidly growing NTM pathogens to cause osteomyelitis are M. abscessus, M. chelonae, and M. fortuitum (table 1). M. abscessus, the most common rapidly growing mycobacterial species to cause chronic lung disease, includes three subspecies: M. abscessus, M. massiliense, and M. bolletii [14]. M. fortuitum complex includes 12 species, of which M. fortuitum is the most common [15].
Most cases of osteomyelitis caused by rapidly growing NTM have followed trauma, including penetrating injuries and open fractures, or cardiac surgery [1,2,16-25]. As an example, in a series that included 76 cases of extrapulmonary infections due to M. fortuitum, 15 cases of osteomyelitis were described [1]. Six cases were characterized as post-traumatic and nine were described as postsurgical sternal osteomyelitis.
Slowly growing mycobacteria — The most common slowly growing NTM to cause disease are M. avium complex (MAC), M. haemophilum, M. kansasii, M. marinum, M. ulcerans, and M. xenopi (table 1). Less commonly encountered pathogens include M. scrofulaceum, M. simiae, M. szulgai, and M. terrae complex.
Between 1982 and 2018, there were 16 cases of MAC-related vertebral osteomyelitis reported in individuals without HIV [26]. In patients with HIV, most reports of osteomyelitis are due to disseminated MAC [4]. Immunosuppressive medications, such as glucocorticoids, also increase the risk of NTM infections [27]. MAC osteomyelitis can also occur following penetrating injury in immunocompetent or immunocompromised patients [28,29]. Disseminated infection associated with MAC osteomyelitis has been reported rarely in immunocompetent patients, although a global outbreak of M. chimaera associated with contaminated heater-cooler units involved several cases of vertebral osteomyelitis with disseminated infection in a largely immunocompetent population [30,31].
There are reports of apparently immunocompetent children with MAC osteomyelitis [32-34]. It is possible that some of these cases could have involved a defect in the interferon-gamma/interleukin-12 pathway, since they were reported before the association between this defect and mycobacterial infections had been recognized. (See 'Risk factors' below.)
Although M. kansasii is one of the most common causes of pulmonary NTM infection in the United States, it causes osteomyelitis and septic arthritis rarely. M. kansasii has been reported to cause osteomyelitis in immunocompromised (particularly those with HIV) and immunocompetent patients [35-38].
Several slowly growing NTM species have a predilection for causing skin and soft tissue infections, which in some cases can progress to cause osteomyelitis and/or septic arthritis. Each species has different epidemiologic associations:
●M. haemophilum – Infection is often associated with immunocompromising conditions, such as HIV infection [39,40]. In a 2011 review, 26 cases of M. haemophilum osteomyelitis were reported; 17 cases occurred in patients with HIV and 7 cases in solid organ transplant recipients [40]. Other underlying conditions included lymphoma, stem cell transplantation for aplastic anemia, and glucocorticoids for rheumatoid arthritis.
●M. marinum – Infection due to M. marinum is often referred to as "swimming pool granuloma" or "fish tank granuloma." Infection presents as nodular soft tissue disease after exposure of an open wound (especially the hand) to an aquatic environment, especially a fish tank [41]. Median time from onset of symptoms to diagnosis was 3.5 months in one series of 28 patients [42]. Such infections rarely progress to involve bone [43-47]. As an example, in a series of 63 cases of M. marinum soft tissue infection, only three cases caused osteitis (4.7 percent) [48]. A review of the literature reported 11 cases of osteomyelitis due to M. marinum between 1972 and 2014, which typically involved the fingers [49].
●M. ulcerans – Cutaneous disease due to M. ulcerans is called Buruli ulcer. Infection begins as a painless nodule or plaque and progresses to become an ulcer with central necrosis. M. ulcerans is endemic to tropical rainforests, particularly in West Africa [50]. M. ulcerans produces reactive osteitis, localized osteomyelitis, or metastatic osteomyelitis due to hematogenous spread [51-53]. One report from Africa noted that 13 percent of Buruli ulcer cases were complicated by osteomyelitis [54]. (See "Buruli ulcer (Mycobacterium ulcerans infection)".)
Other species that rarely cause osteomyelitis include M. scrofulaceum [55,56], M. simiae [57-60], M. xenopi [61-63], M. szulgai [64-68], M. aubagnense [69] and members of the M. terrae complex [70,71]. The most common presentation of disease due to M. terrae complex is tenosynovitis of the hand [72]. Osteomyelitis has been reported rarely in immunocompetent hosts in association with tenosynovitis or septic arthritis [70,71].
Mixed infections — Although extremely rare, there have been reports of osteomyelitis due to more than one NTM species or NTM in combination with bacteria (most commonly gram-negative bacilli) or M. tuberculosis [2,73,74]. Most reported cases of mixed infections with more than one NTM species or NTM in combination with bacteria have occurred in the setting of open injuries, such as open fractures or penetrating injuries [2,74,75]. One case of chronic osteomyelitis of the ankle caused by M. tuberculosis and M. fortuitum complex occurred in a patient with no history of penetrating injury [73].
RISK FACTORS — As noted above, osteomyelitis due to nontuberculous mycobacteria (NTM) can result from either direct inoculation or disseminated infection. Patients who acquire NTM infection via direct inoculation are more likely to be immunocompetent, whereas patients who have disseminated infection are typically immunocompromised.
The most well-established risk factor for disseminated NTM infection, which may result in osteomyelitis, is advanced HIV infection, particularly with a CD4 count <100 cells/mm3 [4,39,40,60] (see "Mycobacterium avium complex (MAC) infections in persons with HIV"). A defect in the interferon-gamma/interleukin-12 pathway has also been associated with NTM infections [76-79]. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)
In addition, cases of osteomyelitis have been reported in patients with the following risk factors:
●Traumatic injury, such as a puncture wound [1,2,22]
●Systemic glucocorticoids [27,40]
●Cardiac surgery requiring sternotomy, resulting in sternal osteomyelitis [16-18,80]
●For M. ulcerans (the cause of Buruli ulcer), inhabiting a tropical rainforest, particularly in West Africa (see "Buruli ulcer (Mycobacterium ulcerans infection)")
As noted above, cases of NTM osteomyelitis have been reported rarely in patients with no obvious immunosuppression or other risk factors. (See 'Epidemiology' above.)
PATHOGENESIS — Any nontuberculous mycobacteria (NTM) can cause osteomyelitis. However, in contrast to tuberculous osteomyelitis, infection with NTM does not appear to have stages of primary infection followed by latent infection and then reactivation (see "Bone and joint tuberculosis"). Instead, the route of infection is either through direct inoculation [81] or via hematogenous spread in a patient with disseminated infection [82].
One report described vertebral osteomyelitis in three patients with blunt trauma to the vertebrae [10]. The authors suggested that seeding of NTM into an area of recent trauma illustrates the principle of locus minoris resistentiae, in which damaged or devitalized tissue becomes vulnerable to invasive infection.
CLINICAL FINDINGS — The clinical manifestations of osteomyelitis caused by nontuberculous mycobacteria (NTM) depend on whether the bone involvement results from direct inoculation or from disseminated infection. The clinical findings also differ based upon the infecting species and on the immune status of the patient.
Signs and symptoms — Osteomyelitis due to NTM resulting from direct inoculation often presents in an indolent manner [83]. Patients may complain of dull pain at the involved site, with or without movement. Local findings (tenderness, warmth, erythema, and swelling) may also be present. Patients may or may not present with fever. Symptoms generally present within weeks of the inciting trauma [39], but in some cases have occurred years later [30,84]. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)
Patients with vertebral osteomyelitis due to NTM almost always present with back pain. Neurologic deficits have been reported in approximately 30 percent of patients. Fever is relatively uncommon, occurring in about 20 percent of cases in one review of 69 cases [7]. In that review, 90 percent of patients without HIV had thoracolumbar spinal involvement, whereas 90 percent of patients with HIV had thoracic involvement. The median interval between previous spinal surgical procedure or trauma and the onset of osteomyelitis was about 6.5 and 9 months, respectively (with a range from 1 to 72 months). (See 'Vertebral osteomyelitis' above.)
The majority of patients with disseminated infection have advanced HIV infection; most have a CD4 count <100 cells/microL [4]. The anatomic sites of osteomyelitis have varied widely and many patients have involvement of multiple sites [4,85]. As an example, in a case series and literature review of 25 skeletal infections caused by NTM in patients with HIV, sites of osteomyelitis included the arm, wrist, ankle, calvarium, tibia, fibula, and fingers [4]. Several patients had concomitant septic arthritis of adjacent or distant sites.
The clinical course in patients with HIV ranges from indolent to rapidly progressive [84]. Patients may or may not have signs of systemic illness, such as fever.
In patients with HIV, NTM may also present as an immune reconstitution syndrome (IRIS); IRIS typically presents as localized disease in patients recently initiated on antiretroviral therapy [86-89]. (See "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV" and "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Immune reconstitution inflammatory syndrome", section on 'IRIS associated with mycobacterial infections'.)
Certain NTM species have a predilection for causing skin and soft tissue infections. Such species include M. haemophilum, M. marinum, and M. ulcerans. The skin and soft tissue infection may precede or coincide with the onset of osteomyelitis. Findings in patients with NTM skin and soft tissue infections may include erythema, nodules, and ulcers. In one series, disseminated infection due to M. haemophilum presented with tender ulcerating cutaneous or subcutaneous lesions [39]. Infection with M. marinum presents as nodular soft tissue disease that moves progressively up an extremity ("sporotrichoid presentation") after an open wound is exposed to an aquatic environment, most commonly a fish tank [41]; M. marinum infection rarely progresses to involve bone [43-47]. M. ulcerans typically presents with ulceration.
Laboratory findings — Laboratory findings are nonspecific and may include leukocytosis and elevated serum inflammatory markers (erythrocyte sedimentation rate [ESR] and/or C-reactive protein). In one review of vertebral osteomyelitis, the mean ESR was higher among patients without than in patients with HIV (58 versus 46 mm/hour) [7].
Imaging — Imaging studies typically reveal well-marginated osteolysis, cortical bone destruction, and adjacent soft tissue inflammation (image 1) [39,90]. Other findings may include bone abscesses, sequestrum formation, mature periosteal reaction with involucrum formation (a zone of living bone surrounding sequestered bone), and sinus tracts [91]. The characteristic imaging findings are not specific to NTM osteomyelitis, and are similar to those seen with tuberculous osteomyelitis and bacterial osteomyelitis (image 2).
Vertebral osteomyelitis due to NTM species shares imaging findings with tuberculous spondylitis (Pott disease) [91]. It may also be difficult to distinguish between mycobacterial and bacterial causes based on imaging alone. Imaging findings may include involvement of one or several contiguous (or sometimes non-contiguous) vertebral bodies that may result in kyphosis, destruction of adjacent discs, absence of reactive sclerosis, and formation of adjacent abscesses, often containing calcifications (image 3) [91]. Approximately 50 percent of patients have radiographic evidence of paravertebral abscess formation [7]. Some cases involve only a single end plate.
On magnetic resonance imaging (MRI), involved areas demonstrate decreased signal intensity on T1-weighted sequences and increased signal intensity on T2-weighted images and short inversion time inversion-recovery sequences [91]. MRI also shows a periosteal reaction and enhanced fat-suppressed images provide delineation of associated cellulitis, abscesses, and sinus tracts and may enable distinction between sequestered and living bone [91,92]. (See 'Diagnosis' below and "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".)
Histopathology — When present, necrotizing granulomas with positive acid-fast bacillus staining are highly suggestive of mycobacterial infection, but these findings can be found with both tuberculosis and infection caused by various NTM species and neither finding appears to be highly sensitive for NTM infection [10,84,93]. A case series of eight patients with osteomyelitis, tenosynovitis, or synovitis caused by NTM revealed a spectrum of histopathologic findings, including virtually no inflammation, mild to severe non-specific chronic inflammation, non-necrotizing granulomas, and necrotizing epithelioid granulomas [93].
DIAGNOSIS — The diagnosis of osteomyelitis is considered in patients presenting with pain localized to the bone, particularly when tenderness, warmth, erythema, and/or swelling are present. The diagnosis is established based upon the combination of consistent clinical and radiographic findings plus the isolation of a nontuberculous mycobacteria (NTM) from the involved bone by culture. When an NTM infection is suspected, bone biopsy should be performed and specimens should be sent for histopathology with acid-fast bacillus (AFB) staining (as well as staining for bacteria and fungi). Specimens should also be sent to the microbiology laboratory for AFB staining and mycobacterial culture (as well as Gram stain and bacterial culture and fungal stain and culture).
AFB staining cannot distinguish among NTM species or between NTM and M. tuberculosis. AFB staining is not highly sensitive, and therefore may result in a false-negative result. Mycobacterial culture is used to determine the causative species. Some of the organisms reported to cause osteomyelitis may be difficult to grow in the laboratory. For example, M. haemophilum and M. marinum grow best at lower incubation temperatures, and the former requires supplementation of the media with iron for growth. (See "Microbiology of nontuberculous mycobacteria".)
Identification of the species, even to the subspecies level in cases of M. abscessus, is imperative, and we recommend sending the isolate to a specialized lab to obtain this information. Species and subspecies identification are critical to management decisions. As an example, most strains of M. abscessus subspecies abscessus and subspecies bolletii have a functional erm(41) (erythromycin ribosomal methylase gene) that results in inducible macrolide resistance in the presence of macrolides. In contrast, M. abscessus subspecies massiliense has a truncated, nonfunctional erm(41), so the organism retains susceptibility to the macrolides, which is associated with improved outcomes in both pulmonary and extrapulmonary disease [94,95]. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)
Line probe assays can identify some of the more common slowly and rapidly growing species, as well as identify mutations associated with macrolide and aminoglycoside resistance. In a study from South Korea that evaluated a line probe assay for MAC species and M. abscessus subspecies identification, accuracy was 92 and 100 percent, respectively [96]. The assay was able to detect the presence of clarithromycin and aminoglycoside resistance in approximately 99 percent of isolates.
We check serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) at the time of diagnosis in order to have baseline results to compare with subsequent results to assess the response to therapy. (See "Treatment of osteomyelitis due to nontuberculous mycobacteria in adults", section on 'Monitoring during therapy'.)
Although plain radiography, computed tomography (CT), and bone scanning are sometimes used in the evaluation of osteomyelitis, we favor magnetic resonance imaging (MRI) since it is the most sensitive imaging method for the detection of osteomyelitis, including during early infection [91]. It is also the best modality for obtaining detailed anatomic delineation of the extent of bone marrow and soft tissue inflammation. CT can provide excellent anatomic delineation of areas involved by infection, and it is the modality of choice in circumstances in which MRI cannot be obtained.
NTM are rarely considered as possible etiologies of osteomyelitis since bacterial causes (eg, Staphylococcus aureus) are far more common. Therefore, delays in presentation and diagnosis are common. In an outbreak of M. xenopi spine infections post-discectomy, there was a prolonged time from surgery to diagnosis (mean 5.6 years) [6].
The general approach to the diagnosis of osteomyelitis and the approach to imaging modalities for osteomyelitis are discussed in detail separately. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis' and "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".)
DIFFERENTIAL DIAGNOSIS — As noted above, nontuberculous mycobacteria (NTM) are rarely considered when patients first present with osteomyelitis. Bacteria, such as Staphylococcus aureus, are the most common causes of osteomyelitis and typically cause a more acute infection than the NTM species. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)
M. tuberculosis can also cause osteomyelitis, particularly of the lumbar and lower thoracic spine, and is often considered when histopathology reveals necrotizing granulomas with or without visualization of acid-fast bacilli. Risk factors for and other signs and symptoms of tuberculosis (TB) should be considered when the histopathology is suggestive of TB. A history of residence in a TB-endemic area, a positive tuberculin skin reaction or interferon-gamma release assay, and/or evidence of apical scarring on chest imaging would make TB more likely. The diagnosis of TB is established by culture. (See "Bone and joint tuberculosis", section on 'Osteomyelitis' and "Epidemiology of tuberculosis".)
Certain fungal infections can also cause osteomyelitis. Examples include endemic fungi (Blastomyces dermatitidis, Coccidioides spp, Histoplasma capsulatum) and Candida spp. (See "Clinical manifestations and diagnosis of blastomycosis", section on 'Bone and joint' and "Pathogenesis and clinical manifestations of disseminated histoplasmosis", section on 'Other' and "Candida osteoarticular infections".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nontuberculous mycobacteria".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Osteomyelitis is a rare manifestation of NTM infection but it can be caused by various NTM species. Most cases involve either penetrating injuries or postsurgical infections, such as sternal wound infections; such cases typically occur in immunocompetent hosts. HIV-associated NTM osteomyelitis usually occurs in the setting of disseminated disease. (See 'Epidemiology' above.)
●Clinical features:
•Infection from direct inoculation – Osteomyelitis due to NTM resulting from direct inoculation often presents in an indolent manner. Patients may complain of dull pain at the involved site, with or without movement. Local findings (tenderness, warmth, erythema, and swelling) may also be present. Patients may or may not have signs of systemic illness, such as fever. (See 'Signs and symptoms' above.)
•Osteomyelitis associated with disseminated infection – The majority of patients with disseminated infection have advanced HIV infection. Many patients have involvement of multiple sites. The clinical course in patients with HIV ranges from indolent to rapidly progressive. Patients may or may not have signs of systemic illness, such as fever. In patients with HIV, NTM may also present as an immune reconstitution syndrome (IRIS); IRIS typically presents as localized disease in patients recently initiated on antiretroviral therapy. (See 'Signs and symptoms' above.)
●Imaging – For the detection of osteomyelitis, we favor magnetic resonance imaging since it is the most sensitive imaging method. The characteristic imaging findings are not specific to NTM osteomyelitis, and are similar to those seen with tuberculous osteomyelitis and bacterial osteomyelitis. Imaging studies typically reveal well-marginated osteolysis, cortical bone destruction, and adjacent soft tissue inflammation (image 1 and image 2 and image 3). (See 'Diagnosis' above and 'Imaging' above.)
●Bone biopsy – When an NTM infection is suspected, bone biopsy should be performed and specimens should be sent for histopathology with acid-fast bacillus (AFB) staining (as well as staining for bacteria and fungi). When present, necrotizing granulomas with positive AFB staining are highly suggestive of mycobacterial infection, but these findings can be found with both tuberculosis and infection caused by various NTM species and neither finding appears to be highly sensitive for NTM infection. Specimens should be sent to the microbiology laboratory for AFB staining and mycobacterial culture (as well as Gram stain and bacterial culture and fungal stain and culture). (See 'Diagnosis' above and 'Histopathology' above.)
●Diagnosis – The diagnosis of osteomyelitis is considered in patients presenting with pain localized to the bone, particularly when tenderness, warmth, erythema, and/or swelling are present. The diagnosis of NTM osteomyelitis is established based upon the combination of consistent clinical and radiographic findings plus the isolation of an NTM from the involved bone by culture. (See 'Diagnosis' above.)
●Differential diagnosis – NTM are rarely considered as possible etiologies of osteomyelitis since bacterial causes (eg, Staphylococcus aureus) are far more common. (See 'Differential diagnosis' above.)
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