atypical mycobacterial infection skin

Atypical mycobacterial infections

Atypical mycobacterial infections also called non-tuberculous mycobacterial infections or non-tuberculous mycobacterium infections are infectious diseases that are caused non-tuberculous mycobacteria which are aerobic acid-fast bacilli that are resistant to acid and alcohol 1), 2), 3), 4), 5), 6). Atypical mycobacteria include all mycobacteria other than “typical” mycobacteria which are Mycobacterium tuberculosis that commonly cause tuberculosis (TB) in human, Mycobacterium bovis another mycobacterium that can cause tuberculosis (TB) disease in people, and Mycobacterium leprae that cause leprosy or Hansen disease 7).

Atypical mycobacterial infections may cause life-threatening disease in people with weakened immune systems (immunocompromised individuals). Atypical mycobacteria or nontuberculous mycobacteria can cause various diseases such as skin and soft tissue infection, lymphadenitis (infection or inflammation of lymph node), lung infection, disseminated infection, and a wide range of more rarely encountered infections 8). Infections with atypical mycobacteria (non-tuberculous mycobacteria) frequently occur after surgical procedures, penetrating accidental trauma, acupuncture, intravenous catheter use, intramuscular injections, subcutaneous injections, mesotherapy (alternative medicine therapy that uses micro-fine needles to inject vitamins into the middle layer of the skin or the mesoderm) and superficial skin abrasions 9), 10), 11). Several cases of atypical mycobacterial infections are caused by tattoos 12)13), 14), 15), 16), cosmetic treatments 17), 18), 19), botulinum toxin injections 20), implant surgeries 21)., have been described. Also, outbreaks of atypical mycobacterial infections related to contaminated instruments have been described in hospitals 22).

The non-tuberculous mycobacteria that most commonly cause atypical mycobacterial infection are most commonly found in the soil, indoor and outdoor water sources, and are recognized to colonize poorly sterilized medical equipment 23). Atypical mycobacteria (non-tuberculous mycobacteria) most commonly infect young children, immunocompromised individuals, individuals with indwelling medical equipment, and those who have recently undergone surgical or non-surgical procedures 24).

Atypical mycobacteria (non-tuberculous mycobacteria) bacteria can be further categorized into slow and rapidly growing organisms and grouped by the organ systems they commonly affect. Due to their size, shape and growth patterns, atypical mycobacteria are difficult to identify on diagnostic testing 25).

Atypical mycobacterium treatment often requires extended courses of combination antibiotic therapy, frequently with surgical intervention 26), 27). There are specific antibiotics for each family of atypical mycobacteria, because they are resistant to most antibiotic drugs and single therapy may be inadequate 28). This difficulty in treating atypical mycobacterial infections can lead to serious health complications, including death 29).

Figure 1. Atypical mycobacterial infection after skin tattoos

atypical mycobacterial infection after skin tattoo

Footnote: Atypical mycobacterial infection after skin tattoos. Tattooed area of the right lower leg showing (A) thickened reddish bumps (indurated erythematous papules) and crust involving the tattoo on presentation (note the eruption appears to conform to the areas of soft shading through the rose design, sparing the distal lettering) and (B) clearing of skin bumps (papules) and reduced redness (erythema) after 4 months of combination antibiotic therapy, leaving some areas of residual post inflammatory hyperpigmentation and an area of hypopigmented scarring

[Source 30) ]

Figure 2. Atypical mycobacterial infection tattoo

Atypical mycobacterial infection after skin tattoo

Footnote: Atypical mycobacterial infection after skin tattoos. Pustules located in the black- and gray-shaded areas of a patient’s tattoo (culture positive for Mycobacterium abscessus).

[Source 31) ]

Figure 3. Atypical mycobacterial infection skin histopathology

Atypical mycobacterial infection skin histopathology

Footnotes: Histopathology of tattoo-associated atypical mycobacterial infection. (A) Low-power photomicrograph of skin biopsy showing mixed acute and chronic inflammation with focal granulomatous areas as seen using hematoxylin and eosin (H&E) stain. (B) Higher-power magnification showing granulomatous inflammation with deposits of tattoo pigment (arrow) as seen by H&E stain. (C) Cluster of mycobacteria (arrow) as seen by Ziehl–Neelsen acid-fast stain. (D) Immunostaining (arrows) of mycobacteria as seen using Mycobacterium species immunohistochemical assay and brownish tattoo pigment (arrowheads). Original magnifications: 12.5× 100× 158× 158×.

[Source 32) ]

Figure 4. Buruli ulcer caused by Mycobacterium ulcerans

Buruli ulcer
[Source 33) ]

Atypical mycobacterial infection cause

The most commonly encountered atypical mycobacteria that cause the majority of infection in humans are the Mycobacterium avium complex bacteria (MAC), Mycobacterium avium, and Mycobacterium intracellulare also known as Mycobacterium avium-intracellulare (MAI), Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium ulcerans, Mycobacterium abscessus complex bacteria (abscessus, massiliense, and bolletii), Mycobacterium chelonae, and Mycobacterium fortuitum 34). These atypical mycobacteria (non-tuberculous mycobacteria) are most commonly found in the soil, indoor, and outdoor water sources and are recognized to colonize poorly sterilized medical equipment. Atypical mycobacteria most commonly infect young children, immunocompromised individuals, individuals with indwelling medical equipment, and those who have recently undergone surgical or non-surgical procedures. The type of disease caused by atypical mycobacteria is dependent on the mode of inoculation and the susceptibility of the host to infection. Lung infection occurs via inhalation of aerosolized material containing the bacteria, whereas lymphadenitis is often caused by ingestion or penetration through the soft tissues, and skin and soft tissue infection by access through skin breakdown or by indwelling medical equipment 35), 36).

Mycobacterium avium complex bacteria (MAC) or Mycobacterium avium-intracellulare (MAI) infection of lung is most commonly found in adults and those with impaired host defense of the lung, such as human immunodeficiency virus (HIV), patients on TNF-alpha inhibitors, and cystic fibrosis (CF) 37). Adult with atypical mycobacterial infection of the lung preferentially impacts White, middle-aged, or older men, who often have comorbid conditions such as chronic obstructive pulmonary disease (COPD), alcohol use, or tobacco use 38). A less common presentation referred to as “hot tub lung” can be seen as part of a hypersensitivity syndrome following mycobacterium avium complex bacteria (MAC) exposure related to bathing or recreational water exposure. Disseminated mycobacterium avium complex bacteria (MAC) or mycobacterium avium-intracellulare (MAI) is primarily observed in patients with significantly immunocompromised states such as acquired immunodeficiency syndrome (AIDS) 39), 40), 41), 42).

One important feature of most atypical mycobacteria is that they are acid-fast bacilli (AFB) 43). This staining property detected via the Kinyoun method is due to its hydrophobic mycolic acid outer layer. This mycolic acid layer allows them to form thick biofilms, enabling their survival in harsh environments that are not as well tolerated by other bacteria 44). These biofilms stunt the ability of antibiotics to penetrate the atypical mycobacteria effectively. The biofilms allow the atypical mycobacteria to survive in varying temperatures and protect the bacteria from being killed by water purifying chemicals such as chlorine, disinfectants, and cleaning products 45). The biofilms also allow these atypical mycobacteria to survive in oxygen-rich and anaerobic environments. Another defining characteristic of mycobacteria is their slow rate of growth.

Atypical mycobacteria are divided into rapid and slow-growing categories 46). The rapid-growing atypical mycobacteria take 7 to 30 days to grow on culture. The slow-growing atypical mycobacteria will take several weeks to months to demonstrate growth.

Atypical mycobacterial infection of lymph node (atypical mycobacterial lymphadenitis)

According to the American Thoracic Society and Infectious Disease Society of America, Mycobacterium avium complex (MAC) bacteria cause approximately 80% of atypical mycobacterial infections in children 47). Mycobacterial cervical lymphadenopathy is caused by tuberculous mycobacteria in 64% and by atypical mycobacteria in 36% of cases 48). The progression of atypical mycobacterial lymphadenitis has been described in four stages by Toretta et al. 49). The first stage describes a unilateral submandibular, preauricular, or cervical chain lymph node that slowly and painlessly enlarges over several days to months. Stage one was noted by the author to be unlikely to show systemic symptoms. Stage two describes the presence of tenderness indicative of necrosis within the lymph node. Stage three describes erythematous discoloration of the overlying skin. Stage four describes the progression of skin breakdown to the formation of sinus tracts.

Atypical mycobacterial infection of lung

The three species that make up the vast majority of atypical mycobacterial lung infections are the Mycobacterium avium complex bacteria (approximately 80%), Mycobacterium kansasii, and Mycobacterium abscessus 50). Mycobacterium avium complex infections can be further grouped into two different presentations. The first presentation is found more commonly in middle-aged males with the risk factors of long term alcohol and tobacco abuse. In these patients, the MAC bacteria tend to form large fibrocavitary lesions in the apex of the lung. These lesions can rapidly progress to encompass significant areas of the lung within 1 to 2 years and generally result in morbidity and mortality at a much faster rate. The second type of presentation of Mycobacterium avium complex lung disease more commonly affects postmenopausal caucasian women. In this presentation, the bacteria form small pulmonary nodules and cylindrical bronchiectasis with a concentration of nodules in the right middle lobe and ligula of the left upper lobe of the lungs. Similar presentations to Mycobacterium avium complex lung disease are seen with Mycobacterium kansasii and Mycobacterium abscessus. Mycobacterium kansasii tends to form large fibrocavities in the apex of the lung, similar to the first type of Mycobacterium avium complex disease presentation. A much smaller proportion of infections resemble the nodular and bronchiectatic type of presentation 51). Mycobacterium abscessus infection presents the majority of the time with a nodular and bronchiectatic presentation concentrated in the upper lung fields. Mycobacterium abscessus will form fibrocavities in approximately 15 percent of infections.

Atypical mycobacterial infection of skin and soft tissue

Atypical Mycobacteria enter the skin and soft tissue through trauma, surgical procedures, or via indwelling medical equipment 52). All species of atypical mycobacteria can cause skin and soft tissue infection 53). The most common species to cause skin and soft tissue infection are Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium fortuitum, Mycobacterium ulcerans, and Mycobacterium marinum.

Mycobacterium marinum infection is also known as the fish tank granuloma, after originally being discovered to cause soft tissue infection in fish tank workers or enthusiasts. It most commonly causes localized erythema and granuloma formation of the digits, which can progress to nodular lymphangitis of the hands and forearms similar in appearance to sporotrichosis. These bacteria more rarely can affect tendons, joint spaces and cause osteomyelitis. Immunocompromised patients have had recorded cases of disseminated infection.

Mycobacterium ulcerans is also known as the Buruli ulcer (Figure 4). Buruli ulcers are known for their large areas of destructive lesions of skin, deep ulceration, and soft tissue and even bone involvement. Buruli ulcers most commonly begin as a small, painless nodule, which slowly begins to ulcerate. Buruli ulcers are characterized by poorly defined and irregular borders and can cover extensive sections of the body. Other variations of these lesions may also begin as localized erythema, subcutaneous edema, or a violaceous skin rash. Of note, approximately 15% of Mycobacterium ulcerans infections cause osteomyelitis.

Mycobacterium fortuitum most commonly presents as a solitary subcutaneous nodule. The majority of cases of Mycobacterium fortuitum infection have low morbidity and limited infection. Immunocompromised patients, however, have been known to suffer from the more serious and disseminated infection.

Mycobacterium abscessus most commonly forms an abscess under the site of skin trauma/penetration. These abscesses are painful to the touch, may form draining sinus tracts, and may progress to ascending lymphadenitis. Disseminated disease can occur in immunocompromised individuals and produce diffuse subcutaneous nodules with lymphadenitis.

Mycobacterium chelonae presents in the majority of cases as small disseminated cutaneous nodules that are painful to the touch. The skin surrounding these lesions is often hyperpigmented. Lesions may also drain, form sinus tracts, appear as cellulitis or non-healing ulcers. Infection is most common in immunocompromised patients. Mycobacterium chelonae has also been known to cause osteomyelitis 54), 55), 56), 57).

Atypical mycobacterial infection signs and symptoms

Atypical mycobacterial lymph node infection (atypical mycobacterial lymphadenitis)

The majority of atypical mycobacterial lymphadenitis cases will present in children under the age of five whose parents have noticed one or more soft but firm, unilateral, subcutaneous masses, usually in the submandibular or cervical chain regions. The masses are usually non-tender at the beginning of the disease, followed by the later development of fluctuance and even purulent discharge from fistulizing tracts. A diagnosis of mycobacterial lymphadenitis is frequently suspected after enlarged cervical nodes in children fail to respond to empiric antibiotic therapy directed at Staphylococcus and Streptococcus or fail to resolve under watchful-waiting for a presumed viral process.

Atypical mycobacterial lung infections

Atypical mycobacterial lung infection typically presents in patients with impaired host defense of the lung. This includes patients with cystic fibrosis, chronic obstructive pulmonary disease (COPD), HIV, and other immunodeficiency syndromes 58). In patients without known immunodeficiency syndromes, patients are more often male, middle-aged or older, and have a history of comorbid alcohol and/or tobacco abuse. These patients present with cough and worsening lung function in all cases but can also present with pneumonia, hemoptysis, persistent fever, and weight loss 59). These patients tend to have a much more rapidly progressing disease. Another subset of patients with a more slowly progressing disease and similar symptoms has been identified as women who have undergone menopause, have a lower body mass index (BMI), scoliosis, or rib cage abnormalities 60), 61).

Atypical mycobacterial skin and soft tissue infections

Atypical mycobacterial skin and soft tissue infections can result from localized or disseminated infection and occur in patients of all ages 62). Patients with localized lesions may give a history in which they experienced trauma to their skin while swimming (freshwater, saltwater, swimming pool, hot tubs). Other risk factors for skin and soft tissue infections include patients who are currently immunosuppressed or have had recent surgical procedures. Skin lesions can range from erythematous papules/nodules that progressively ulcerate, to ecthyma, resembling cellulitis. A separate category of skin lesion, the Buruli ulcer, is characteristic of a painless area of soft tissue swelling that slowly begins to ulcerate with poorly defined and irregular borders. Untreated, they can grow from a few centimeters to span large areas of the body. Patients with these lesions are usually from West Africa, Central, and South America, Australia, and Japan 63).

Atypical mycobacterial infection complications

Atypical mycobacterial lymphadenitis can result in fistula formation and repeated need for surgical intervention 64). Excision of preauricular lymph nodes risks paralysis of the facial nerve as it courses through the underlying parotid gland 65). Repeated surgical procedures and scarring from the skin and soft tissue infection can result in cosmetic disfiguration 66). Since most lymphadenitis cases occur in the neck and facial region lymph nodes in young children, careful consideration of the psychosocial consequences of cosmetic disfiguration from repeated surgical procedures must be weighed against the chances of improved outcomes. The curative rate with antibiotics alone ranges from approximately 66% to 73%, which increases to around 95% with surgical intervention.

The ability of patients with advanced age and multiple comorbidities to tolerate the prolonged combination of antibiotic therapy or possible surgical intervention required to treat atypical mycobacterial lung infection necessitates the discussion of chronic suppressive therapy vs. curative therapy. Clarithromycin can cause gastrointestinal upset and may need to be divided into twice-daily dosing. Azithromycin can prolong the QT interval and might have to be avoided due to other medications previously prescribed to patients. Rifabutin can cause leukopenia and uveitis. Ethambutol can cause optic neuritis, and patients should be screened for decreases in visual acuity and color blindness. Severe atypical mycobacterial lung infection resulting in lobectomy can result in chronic respiratory complications even when the intervention is curative 67), 68), 69).

Atypical mycobacterial infection diagnosis

Atypical mycobacteria are difficult to identify detect by laboratory testing 70). Atypical mycobacteria contain a hydrophobic mycolic acid layer in their cell wall. Due to this property, they are not typically seen using Gram staining 71). The best method for detecting atypical mycobacteria is fluorochrome staining, a type of acid-fast staining where these bacteria will appear as yellow to orange bacilli 72). Rapidly growing mycobacteria are frequently not seen even with fluorochrome staining, and atypical mycobacteria overall are visualized in only 30% to 60% of cases 73). Rapidly growing atypical mycobacteria are noted to be more sensitive to the decolorization process in acid-fast staining. It is thought that using more delicate methods for decolorization can increase the chance of visualizing these bacteria. Other less sensitive staining methods that may also be used include the Ziehl-Neelsen method and the Kinyoun stain 74).

The initial workup for most infections begins with a complete blood count (CBC), which can show a normal to elevated white blood cell count. Inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can also be normal or elevated 75). Samples from fluid cultures obtained from soft tissue lesions or excised lymph nodes should undergo acid-fast or fluorochrome staining 76). Organisms are visualized in around 30% to 60% of cases 77). Culture of fluid and tissue samples should be obtained and yields an organism in approximately 65% of cases 78). 90% of patients diagnosed with a disseminated atypical mycobacterial infection will have positive blood cultures. Unlike the growth of common bacteria on culture, rapidly growing mycobacteria will take approximately 1 week or more to grow, and slow-growing mycobacteria will take several weeks to months to show growth 79).

Polymerase chain reaction (PCR) is frequently used on samples to obtain faster results and is more sensitive in diagnosis, yielding an organism around 91% of the time 80). Tuberculin skin testing can also be used as a nonspecific method to confirm suspected atypical mycobacterial infection 81). It will result in a greater than 10 mm area of induration between 30% to 60% of the time 82). Diagnosis of lung infection is currently based on clinical suspicion of an active infection given active pulmonary symptoms, findings on chest X-ray or CT, and growth on 2 or more sputum cultures (also accepted is tissue biopsy or lavage cultures) 83), 84).

Atypical mycobacterial lung disease diagnostic criteria

The minimum evaluation of a patient suspected of atypical mycobacterial lung disease should include the following 85):

  1. Chest radiograph or, in the absence of cavitation, chest high-resolution computed tomography (HRCT) scan;
  2. Three or more sputum specimens for acid-fast bacilli (AFB) analysis; and
  3. Exclusion of other disorders, such as tuberculosis (TB).

Clinical, radiographic, and microbiologic criteria are equally important and all must be met to make a diagnosis of atypical mycobacterial lung disease. The following criteria apply to symptomatic patients with radiographic opacities, nodular or cavitary, or an high-resolution computed tomography (HRCT) scan that shows multifocal bronchiectasis with multiple small nodules. These criteria fit best with Mycobacterium avium complex (MAC), Mycobacterium kansasii, and Mycobacterium abscessus. There is not enough known about most other atypical mycobacteria to be certain that these diagnostic criteria are universally applicable for all atypical mycobacteria respiratory pathogens.

Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or an high-resolution computed tomography (HRCT) scan that shows multifocal bronchiectasis with multiple small nodules.

Positive culture results from at least two separate expectorated sputum samples. If the results from the initial sputum samples are nondiagnostic, consider repeat sputum AFB smears and cultures. Or positive culture results from at least one bronchial wash or lavage. Or transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for atypical mycobacteria or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive for atypical mycobacteria.

Expert consultation should be obtained when atypical mycobacteria are recovered that are either infrequently encountered or that usually represent environmental contamination.

Patients who are suspected of having atypical mycobacteria lung disease but who do not meet the diagnostic criteria should be followed until the diagnosis is firmly established or excluded.

Making the diagnosis of atypical mycobacteria lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients.

Atypical mycobacterial infection treatment

Atypical mycobacterium treatment often requires extended courses of combination antibiotic therapy, frequently with surgical intervention 86), 87). There are specific antibiotics for each family of atypical mycobacteria, because they are resistant to most antibiotic drugs and single therapy may be inadequate 88). This difficulty in treating atypical mycobacterial infections can lead to serious health complications, including death 89).

Atypical mycobacterial lung infection treatment

Recommended treatment for adults and children with Mycobacterium avium complex bacteria (MAC) infections includes azithromycin, rifampin, and ethambutol. Additional drug options are available for each drug class 90). Three times per week dosing is used in adult nodular or bronchiectatic disease with recommended regimens of azithromycin 500 to 600 mg, or clarithromycin 1000 mg, plus ethambutol 25 mg/kg, plus rifampin 600 mg 91). Daily dosing is required in cavitary disease with the additional option of three times weekly streptomycin or amikacin. Recommended daily dosages are: clarithromycin 500 to 1000 mg or azithromycin 250 to 300 mg, plus rifampin 450 to 600 mg, with either amikacin or streptomycin 92). The American Thoracic Society and Infectious Disease Society of America cite a study that suggests tolerated dosages of 25 mg/kg three times weekly for both drugs 93). They also state that certain experts recommend considering decreasing dosages to 8 to 10 mg/kg (maximum 500 mg) for patients older than 50 years or receiving treatment longer than 6 months 94). Antibiotics are continued until the patient has had 12 months of negative sputum cultures. The typical time to the first negative sputum culture is 3 to 6 months, with most patients obtaining negative sputum cultures within 12 months. Treatment failure is defined as the lack of sputum conversion after 12 months or the lack of sputum conversion within 6 months without any improvement clinically or on imaging. In cases of progressively worsening respiratory status where patients continue to fail sputum conversion, surgical resection of the lung parenchyma containing the cavitary disease may be required 95), 96).

Mycobacterium avium-intracellulare (MAI) has demonstrated rising minimum inhibitory concentrations and overall increased resistance to anti-mycobacterial agents compared to Mycobacterium avium, making it more complicated to treat at times.

Alternative agents utilized to treat Mycobacterium avium complex bacteria (MAC) or Mycobacterium avium-intracellulare (MAI) lung disease includes inhaled amikacin, clofazimine (as a substitute for rifampin), and moxifloxacin 97).

Several other atypical mycobacterial species have been shown to cause pulmonary disease and are generally susceptible to macrolides, rifampin/rifabutin, streptomycin, amikacin, doxycycline, and fluoroquinolones. Of note, the pulmonary disease caused by Mycobacterium abscessus is resistant to most antibiotics and can only be cured in a minority of patients by surgical resection. Those that are not cured are administered chronic intermittent antibiotic therapy to attempt to slow disease progression 98), 99).

Atypical mycobacterial lymphadenitis treatment

Treatment for atypical mycobacterial lymphadenitis is based on a two-drug regimen of one macrolide, azithromycin, or clarithromycin, combined with rifampin or ethambutol 100). Antibiotics are dosed daily and taken until the resolution of symptoms. Surgical resection of infected lymph nodes and tissue is typically used in combination with antibiotic therapy with significantly increased cure rates. The initial antibiotic regimen may be adjusted based on culture susceptibility results 101).

Atypical mycobacterial skin and soft tissue infection treatment

Skin and soft tissue atypical mycobacterium infections are treated with combination antibiotic therapy with a variety of options available, including macrolides, doxycycline, fluoroquinolones, trimethoprim/sulfamethoxazole, cephalosporins, or linezolid 102). Empiric therapies are adjusted once susceptibility testing yields results; however, combination antibiotic therapy is continued due to inducible antibiotic resistance 103). Surgical debridement is required for infections that are extensive and associated with necrosis 104).

Atypical mycobacterial infection prognosis

  • Atypical mycobacterial lung infection: Treatment of Mycobacterium avium lung disease is successful in approximately 39% of patients with a 12% 5-year mortality rate 105). High levels of morbidity and mortality are seen in strains that exhibit macrolide resistance with a significantly higher 47% mortality rate at 5 years 106). Outcomes of pulmonary Mycobacterium abscessus infection are poor, with only around 41% of patients achieving sputum conversion with surgical and antibiotic intervention. Approximately 34% of patients achieve sputum conversion with antibiotics alone 107), 108).
  • Atypical mycobacterial lymphadenitis: Children with lymphadenitis caused by Mycobacterium avium are cured in 95% of cases where both surgical excision and antibiotic therapy are used 109).
  • Atypical mycobacterial skin and soft tissue infection: Resolution of infection is achieved in the vast majority of patients with Mycobacterium marinum, abscessus, ulcerans, fortuitum, and other skin and soft tissue infections when proper antibiotic and surgical treatments are utilized 110), 111), 112).

References   [ + ]

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