Atypical Mycobacterial Diseases

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Practice Essentials

Mycobacteria are a large group of aerobic bacteria that produce filamentous pellicles similar to molds when grown in liquid media. The family Mycobacteriaceae consists of a single genus, Mycobacterium, which are thin, slightly curved-to-straight, non–spore-forming, nonmotile acid-fast bacilli. The genus consists of more than 190 species,[1] many of which are ubiquitous and can be found in water (including tap water), soil, animals, birds, plants, food (dairy products), vegetation, and human feces.[2] Mycobacterium fortuitum has been reported as a commensal on human skin. They can also be found as colonizers of medical equipment[3] such as endoscopes and surgical solutions. Mycobacterial species other than Mycobacterium tuberculosis and Mycobacterium leprae are classified as atypical mycobacteria, nontuberculous mycobacteria (NTM), or environmental mycobacteria.

Background

Nontuberculous mycobacteria (NTM) are aerobic, generally free-living organisms that do not form spores. Mycobacterial species reside in a wide variety of environments, owing to multiple adaptations. More than 190 species of NTM have been identified, most of which are not pathogenic to humans. These environmental, ubiquitous bacteria are transmitted by inhalation, ingestion, and percutaneous penetration.

Four distinct clinical syndromes account for most infections with NTM[4] and include (1) pulmonary disease, (2) lymphadenitis, (3) skin or soft-tissue infections (SSTIs),[5] and (4) disseminated disease. As reported in 2019, NTM are being implicated in a few challenging cases of eye infections.[6] Person-to-person spread is extremely uncommon, although in 2012 the first known outbreak of respiratory Mycobacterium abscessus subsp massiliense disease occurring in a population of patients with cystic fibrosis (CF) was reported.[7] Studies from multiple countries indicate that the incidence of NTM infection is increasing globally[8] and that Mycobacterium avium and Mycobacterium intracellulare (known together as M avium complex [MAC]) infections are the main driver of this increase.[9] Meanwhile, Mycobacterium marinum, the causative organism of the fish-tank granuloma as well as swimming pool granuloma, given its resistance to chlorine,[10] remains the most common atypical bacteria causing skin involvement. See the image below.



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Mycobacterium marinum is an atypical mycobacteria found in water with a wide range of temperatures and salinities

The type of disease depends on the species of mycobacteria, the route and degree of exposure, and the immune status of the host.

Classification

Traditionally, NTM have been classified according to the Runyon system, into four broad categories based on their growth rates, pigment production, and colony morphology. Groups I-III are categorized as slow-growing NTM and group IV is known as the fast growers (detectable in culture within 7 days).

NTM have been known since the time of Robert Koch, but historically they have been overshadowed by tuberculosis and dismissed as contaminants. NTM were first isolated by Pinners in 1931, who found that these organisms were different from M tuberculosis in their lack of virulence for guinea pigs and poor response to antituberculous therapy. The importance of NTM as human pathogens was not generally appreciated until the 1950s.[11] In 1996, Horsburgh[12] noted clinically important NTM, including M avium, M intracellulare, M kansasii, M marinum, M scrofulaceum, M haemophilum, M ulcerans, M abscessus, M chelonae, M fortuitum, M genavense, M xenopi, M malmoense, M simiae, M szulgai, and M smegmatis. Approximately 60 species of NTM are now recognized as true pathogens and important causes of human infection.[13]

Disseminated NTM infections occur almost exclusively in immunocompromised patients. Disease in patients who are immunocompetent usually consists of localized SSTIs.

Tap water is considered the major reservoir for NTM pathogens in humans and, as such, is of increasing public health concern.[14]

NTM develop and are protected within biofilms, which makes them difficult to eradicate with common decontamination techniques and relatively resistant to standard disinfectants such as chlorine, glutaraldehyde, gigasept, and Virkon.[15] They can grow in hot and cold water systems.

Pathophysiology

In the human host, mycobacterial infections may affect multiple anatomical sites, but since they enter through the skin and mucosal barriers, they lead mostly to pulmonary or cutaneous infections.[16, 17] Infections with atypical mycobacteria usually occur mostly in immunocompromised hosts (eg those with HIV, transplant recipients, those on tumor necrosis factor [TNF]–alpha inhibitors). Normal host defense mechanisms are sufficient to prevent NTM infection.

While the lungs are the most common site of infection, NTM can colonize and infect any other organ systems, including lymph nodes, skin, sinuses, eyes, ears, bones, the CNS,[18] and the urinary tract. The main host-derived risk factor for pulmonary NTM infection is a preexisting lung disease such as chronic obstructive pulmonary disease, asthma, alpha-1 antitrypsin deficiency, cystic fibrosis (CF), non-CF bronchiectasis, primary ciliary dyskinesia, or allergic bronchopulmonary aspergillosis, which may predispose to NTM infection by causing chronic epithelial cell inflammation and impaired mucociliary clearance.[19]

The most common cutaneous forms of acquisition of NTM involve direct inoculation through skin barrier breaks, trauma,[20] postsurgical infections, iatrogenic acquisition with indwelling medical devices, plastic surgery, cosmetic procedures, prosthetic implants, tattoos, acupuncture, and body piercings.[21]

In current practice, immunodeficiency remains a known risk factor for all NTM infections. A number of immunodeficiencies have been associated with NTM infection,[22] including inherited disorders of interferon (IFN)γ-IL12 pathway (eg, IFNγR1 mutations),[23] other cytokine signalling (eg, STAT mutations),[24] and macrophage and dendritic cell function (eg, GATA2[25] , NRAMP1[26] ), as well as acquired immunodeficiencies including HIV infection[27] and functional anti–interferon-gamma autoantibodies.[28] Patient with the above disorders are predisposed to severe and disseminated infections with NTM.

Common immunosuppressive drugs have been associated with acquisition of NTM infection, and these include oral and inhaled corticosteroids,[29] TNF-alpha inhibitors,[30] immunosuppression used in solid organ transplantation,[31] and cancer chemotherapy.[27]

The ability of some NTM to survive sterilization procedures and to even contaminate antiseptic solutions can lead to infections in surgical patients.[32]

Etiology

Tap water is considered the major reservoir for nontuberculous mycobacteria (NTM) pathogens in humans and, as such, is of increasing public health concern.[14] Mycobacteria were found in up to 90% of samples taken from piped water systems in 1992.[33]

Exposure to contaminated water, injections, surgical and cosmetic procedures, and trauma have been linked to infection with atypical mycobacteria.

Immunodeficiency is a known risk factor for all NTM infections, and it usually predisposes to severe localized forms or disseminated visceral disease. A number of immunodeficiencies have been associated with NTM infection,[22] including inherited disorders of IFNγ-IL12 pathway (eg, IFNγR1 mutations),[23] other cytokine signalling (eg, STAT mutations),[24] and macrophage and dendritic cell function (eg, GATA2[25] , NRAMP1[26] ), as well as acquired immunodeficiencies including HIV infection[27] and functional anti–interferon-gamma autoantibodies.[28] Patients with the above disorders are predisposed to severe and disseminated infections with NTM.

Common immunosuppressive drugs have been associated with acquisition of NTM infection, including oral and inhaled corticosteroids,[29] TNF-alpha inhibitors,[30] immunosuppression used in solid organ transplantation,[31] and cancer chemotherapy.[27]

In a hospital in Taiwan,[34] 12 cockroaches (Periplaneta americana) were found to be infected with the following organisms:

Because cockroach infestation commonly occurs in the hospital environment, cockroaches might be implicated as a cause of hospital-acquired infections due to atypical mycobacteria.

Epidemiology

Frequency

The most common nontuberculous mycobacteria (NTM) species causing human disease are the slowly growing species of the M avium complex (MAC) and M kansasii and the rapidly growing mycobacteria, M abscessus subsp abscessus.

Determining the incidence and prevalence of NTM lung disease remains difficult because disease reporting to health authorities is not mandatory. M kansasii, although the second most common cause of lung disease after MAC, has been considered the most virulent NTM species, and the presence of a single M kansasii isolate in a sputum sample has been believed to be clinically significant.[4]

Approximately 85% of NTM infections involve the pulmonary system; the remaining 15% involve lymph nodes, skin and soft tissue, bones, and, less frequently, eye, ears, and disseminated infection.[35, 36, 37]

Cutaneous infections with atypical mycobacteria are rare in the United States and worldwide. They are mostly seen in immunocompromised hosts, in particular those with HIV infection, leukemia, or undergoing immunosuppressive therapy.

Race

No apparent difference in race exists with regard to the course of atypical mycobacteria infection.

Sex

Atypical mycobacteria infection is more common in men than in women. Middle-class, middle-aged, white men of urban origin are most commonly affected from pulmonary and skin and soft tissue disease.[38]

Age

Atypical mycobacteria infections are more commonly reported in older patients. This probably relates to the decline in health and the presence of other predisposing conditions.

The predominant NTM disease in children is cervical lymphadenitis due to MAC and M scrofulaceum and less common cutaneous disease due to M marinum and M ulcerans, although rare cases of disseminated disease have been reported.[39] NTM lymphadenitis usually affects children younger than 5 years.[40]

Prognosis

The prognosis is good with proper medical and surgical treatment. Atypical mycobacteria infections cause little mortality. They can cause morbidity, especially when they are not diagnosed and not treated effectively. Often times, cutaneous atypical mycobacteria infection can resolve on its own without intervention. In children, cervical lymphadenitis caused by atypical mycobacteria can result in facial nerve injury, and the incidence of hypertrophic scarring varies among the different treatments.

Patient Education

Patients should avoid exposure to atypical mycobacteria by contaminated injections or materials.

History

Known underlying diseases that contribute to nontuberculous mycobacteria (NTM) infections include chronic obstructive pulmonary disease, asthma, pulmonary emphysema, alpha-1 antitrypsin deficiency, cystic fibrosis (CF), non-CF bronchiectasis, primary ciliary dyskinesia, allergic bronchopulmonary aspergillosis, diabetes mellitus, leukemia, collagen diseases, systemic lupus erythematosus,[41, 42, 43] lung cancer, chronic kidney diseases, carcinomatous pleurisy, and previously treated tuberculosis.

Tumor necrosis factor (TNF)–alpha inhibitor therapy, as well as other immunosuppressive drugs such as azathioprine, mycophenolate mofetil, and cyclosporine, remain potential risk factors for atypical mycobacteria infections.[44]

Cases of cutaneous M chelonae infection, pulmonary M kansasii infection[45] occurring after liver transplantation, and disseminated M kansasii infection after renal transplantation[46] have been reported.

Drug abuse even in immunocompetent patients can present a risk factor for atypical mycobacteria infections.[47] Bilateral sporotrichoid lymphocutaneous dermatosis due to M fortuitum in a drug-abusing patient and cured by clarithromycin and ciprofloxacin has been noted.[47]

An outbreak of tattoo-associated NTM skin infections was recently reported in Florida. The investigators concluded that the open and unopened bottles of ink tested positive for mycobacteria and other contaminants.[48]

A case of breast infection with combined Prevotella melaninogenica and M fortuitum infections following nipple piercing has been reported.[49]

NTM infections after trauma, surgery, or cosmetic procedures should be considered especially if the infection is not responding to standard antibiotic regimens.[50] Surgery can provide a portal of entry for atypical mycobacteria. Procedures include cosmetic liposuction,[51] liposculpture,[51] breast augmentation mammoplasty, or median sternotomy.

Breast prostheses can be the site of atypical mycobacterial infections.[52] Cases of M fortuitum infection occurring after prosthetic breast reconstruction have been reported.[53] In 2017, three cases of NTM infection after silicone breast implant placement were reported.[54]

With an ever-increasing prevalence of cosmetic treatments, there also have been increasing rates of skin and soft-tissue infections (SSTIs) due to cosmetic procedures and other popular procedures such as acupuncture. In 2007, Sañudo et al[55] described NTB infection after mesotherapy in 15 patients. While in 2019, a case of M abscessus infection following home dermabrasion was reported.[56]

In 2007, Murdoch and McDonald[57] reported M avium-intracellulare cellulitis occurring with septic arthritis after joint injection. In 2014, Mycobacterium arupense was noted to cause large-joint osteoarticular infection.[58] Whenever a case of chronic granulomatous infection is encountered that does not respond to standard antituberculous treatment, with a history of open trauma, surgical intervention, or injection, a possible NTM infection should be considered and managed appropriately.[59]

Nosocomial disease has become increasingly important; pseudoepidemics associated with contaminated, automated endoscopic washing machines are the most recently described manifestation. M chelonae has been found in the colonic mucous membranes, the respiratory tracts, and as a contaminant in the tap water used for diluting concentrated chlorhexidine. The organism happened to be isolated with the mucous membranes that were picked up while using the washed fiberscope in the colons of six patients. These findings suggest that M fortuitum and M chelonae groups, in spite of the fact that they rarely cause infection, have a significant risk of infecting older patients (those >60 y) in general hospitals with various underlying diseases attributable to infections.

In 2014, atypical mycobacterial infections were noted in Louisiana in the exit sites of peritoneal dialysis catheters.[60]

Patients can report systemic and constitutional symptoms that include productive cough/purulent sputum, hemoptysis, weight loss, weakness, fever, and night sweats.

Injection abscesses due to M abscessus have been reported in a patient with diabetes. M chelonae wound infections after plastic surgery using contaminated gentian violet skin-marking solution[61] and infection with M abscessus associated with intramuscular injection of adrenal cortex extract have been reported.[62] M chelonae often occurs after puncture wounds and is a community-acquired disease. Infection can occur from scratches, road traffic accidents, and other trauma, such as from nails or wire.

In 2003, Sungkanuparph et al[63] reported a retrospective study of a series of patients infected with rapidly growing mycobacteria in Ramathibodi Hospital (Bangkok, Thailand) from January 1993 to June 1999. Eighteen patients had no underlying disease, and two were infected with HIV. Reported physical findings were lymphadenitis (7), skin and subcutaneous abscess (7), eye infection (4), pulmonary infection (1), and chronic otitis media (1). Sweet syndrome manifested in 4 of 7 patients with lymphadenitis. The organisms isolated included M chelonae/M abscessus group (17 cases) and M fortuitum group (3 cases). The atypical mycobacteria were susceptible to amikacin, netilmicin, and imipenem. The M fortuitum group was susceptible to more antibiotics than the M chelonae/M abscessus group. Histology findings demonstrated pathology that ranged from nonspecific to suppurative or caseous granulomas. Antimicrobial susceptibility defined the clinical response, which was good. A combination of two or more drugs provided effective therapy. Surgical resection was performed in apposite cases to reduce the load of the organism. Surgery was almost always used in cases with infections involving pan-resistant atypical mycobacteria.

Physical Examination

Humans encounter atypical mycobacterial species because of their ubiquity in the environment. Pathogenic mycobacterial species may breach the first-line barrier defenses of the innate immune system and modulate the activation of phagocytes to cause disease of the respiratory tract or the skin and soft tissues, sometimes resulting in disseminated infection. At one end of the spectrum, skin and soft-tissue infections (SSTIs) are almost always the result of iatrogenic or accidental inoculation of nontuberculous mycobacteria (NTM). Patients with NTM lung disease not uncommonly have a primary lung disorder or a systemic condition that predisposes them to these infections. At the other end of the spectrum, visceral and disseminated NTM disease invariably occurs in immunocompromised hosts.

Four clinical syndromes account for most infections with NTM: pulmonary disease, lymphadenitis, disseminated disease, and SSTIs.

Pulmonary disease

The most common form of localized NTM infection is chronic pulmonary disease in HIV-negative hosts. Diagnosis of NTM lung disease requires the integration of clinical, radiographic, and microbiological data, particularly as the symptoms, such as chronic cough, sputum, hemoptysis, fatigue, malaise, and weight loss, are often nonspecific and may also reflect underlying lung disease. Lung NTM infection remains a challenging diagnosis that requires extensive laboratory and imaging workup. M avium complex (MAC) followed by M kansasii and M abscessus are the most common responsible pathogens.

NTM lung disease has the following two major different radiographic manifestations[4] :

Microbiological criteria include two positive sputum cultures, one positive bronchial wash or lavage sample, or other evidence of NTM, such as lung biopsy samples that are culture-positive for NTM and that have histological features consistent with the presence of mycobacteria.

Lymphadenitis

It typically affects immunocompetent children aged 1-5 years, with a female predominance. Isolated unilateral cervical adenitis is the most common form of presentation. It is important to differentiate it from tuberculous lymphadenitis,[64] as inappropriate management can lead to complications such as fistulas, sinus tracts, and scarring. The definitive diagnosis is established by recovery of the causative organism in tissue cultures. Approximately 80% of culture-proven NTM lymphadenitis is due to MAC.[65]

M scrofulaceum is the second most common cause of local lymphadenitis,[66] primarily in the submandibular and submaxillary regions. It usually has a benign, self-limited course with no systemic symptoms, although in some cases the involved lymph nodes may slowly enlarge and eventually result in ulceration and drainage with fistula formation.

Treatment of uncomplicated NTM lymphadenitis involves complete surgical resection of the involved lymph nodes.[36]

Visceral disseminated disease

It occurs almost exclusively in immunocompromised patients. Although a number of different species of NTM have been reported, the majority (90%) of these infections are caused by MAC. In HIV patients, MAC remains the most commonly implicated NTM. Disseminated disease in patients without HIV infection is seen in the setting of significant immunosuppression (eg, transplant recipients, long-term corticosteroid use, TNF-alpha inhibitor use, leukemia). Systemic dissemination of a primary cutaneous NTM can occur. In most cases, disseminated disease presents with disseminated cutaneous lesions. The rapidly growing mycobacteria species, as well as M kansasii and M haemophilum, are the most commonly isolated causative organisms.

Skin and soft-tissue disease

SSTIs caused by NTM typically present in the form of isolated or multiple nodules, commonly in a linear distribution following the local blood or lymphatic vessels.

SSTIs caused by NTM include two distinctive species-specific clinical entities: (1) fish-tank granuloma caused by M marinum and (2) Buruli ulcer caused by M ulcerans. However, most SSTIs caused by NTMs are nonspecific in their clinical presentations and may present as papules, plaques, abscesses, cellulitis, folliculitis, subcutaneous nodules with or without violaceus discolorations, sporotrichoid nodules, ulcerations, panniculitis, or draining sinus tracts.

M marinum

M marinum skin infections (also known as fish-tank granuloma or swimming-pool granuloma) are typically seen in immunocompetent persons with an extensive history of exposure to fresh, salt, or brackish water. Cutaneous infection requires a port of entry and the presence of breaks in skin barrier.[67] The clinical spectrum includes a solitary inflammatory papule or nodule that may later ulcerate and even spread in a sporotrichoid pattern (lymphangitic spread).[67] Because its optimal temperature for growth is around 30°C (86°F), cutaneous lesions most frequently occur in the upper or lower extremities and sometimes in the tip of the nose. It is not associated with marked regional lymphadenitis. Occasionally, deeper infections can be complicated by tenosynovitis, septic arthritis, or, rarely, osteomyelitis.

M ulcerans

M ulcerans, a toxin-producing NTM, is the causative organism of Buruli ulcer, considered a neglected tropical disease.[68] It is the third most common mycobacteriosis in immunocompetent hosts worldwide, after tuberculosis and leprosy. M ulcerans typically produces an exotoxin that is able to decrease inflammation, inhibit pain perception, and induce cell death. Children younger than 15 years are predominantly affected in western and central Africa.

Clinically, Buruli ulcer tends to affect predominantly the lower extremities and, to a lesser extent, the upper extremities and the face. The initial lesion presents as a single, small, firm, painless nodule that ulcerates and evolves into a painless ulcer over the course of 4-8 weeks. There is little to no regional lymphadenopathy or systemic manifestations. The ulcer itself is shallow, with an undermined edge and a base composed of necrotic fat. Ulcers can expand to 15 cm and more in diameter, and, if untreated, they may persist over many months and cause extensive scarring and deformity. Buruli ulcer may present in an atypical fashion, with manifestations of septic arthritis or osteomyelitis.[69]

M kansasii

Although M kansasii typically causes pulmonary disease that resembles tuberculosis, it has been recovered consistently from municipal water systems in endemic areas, including the United States. To date, it has not been recovered from soil or natural water supplies.

Cutaneous involvement usually presents in immunocompromised hosts and sometimes with concomitant pulmonary disease or disseminated disease.[70] It may present as nodules, pustules, verrucous lesions, erythematous plaques, ulcers, or abscesses. The lesions may be arranged in a sporotrichoid pattern. Deep lesions may also be associated with osteomyelitis and septic arthritis.

M. haemophilum

M haemophilum is a fastidious organism that requires iron and hemin to grow. It has structural similarities with M leprae. The cutaneous clinical spectrum includes a variety of skin lesions.

Most often, it presents with erythematous or violaceous papules, pustules, nodules, or plaques, some of which evolve into necrotic abscesses or deep-seated ulcerations.[71]

This organism preferentially grows at 30°C (86°F), explaining the predilection of lesions to locate on the extremities, particularly over joints. In immunosuppressed hosts, contiguous spread of the infection can be complicated with septic arthritis and osteomyelitis. In immunocompetent children, this infection usually presents as isolated cervical, submandibular, or inguinal lymphadenitis.[72]

M avium-intracellulare (MAC)

It is an opportunistic infection in patients with AIDS, occurring during the terminal stage and causing disseminated disease. Cutaneous infections are rarely reported in immunocompetent hosts.[73] It can present with primary cutaneous manifestations after trauma, surgery, or secondary to a disseminated infection. The clinical spectrum includes papulopustular, nodular lesions with a sporotrichoid pattern, which can progress to verrucous ulcers, inflammatory pseudotumors, sinus tracts, and abscesses.[74]

Rapidly growing mycobacteria

This group of NTM includes M chelonae, M abscessus, and M fortuitum, often referred together as the fortuitum complex. M abscessus was first identified in a patient with a knee infection and subcutaneous abscesses in 1950.[75] Posttraumatic infections, catheter-associated infections, postsurgical infections (breast implants, liposuction), and infections post cosmetic procedures (mesotherapy, fillers injections) can result in localized cutaneous infection.[76]

The clinical manifestations of cutaneous involvement include papules, violaceous nodules, abscesses, cellulitis, sinus tracts, subcutaneous nodules (pseudoerythema nodosum), and ulcerations. M chelonae and M abscessus usually present with multiple skin lesions, while M fortuitum tends to present as a single lesion.[77]

Less common forms of presentation

Gastrointestinal tract disease caused by MAC is well-described in the literature and can present as part of a disseminated illness. Findings can include hepatosplenomegaly, colonic ulcers, mesenteric involvement, and abscess formation.[78]

Musculoskeletal disease is not a common presentation for NTM, but all atypical mycobacteria have the potential to cause musculoskeletal infection and it is important to recognize this possibility if clinically plausible.[79]

Complications

Scarring and nerve damage can occur from long-standing untreated infections. Deep-seated infections, if left untreated, can progress to bone involvement with osteomyelitis as a consequence.

Approach Considerations

Diagnosis of infections due to atypical mycobacteria differs depending on the site of infection. Patients with nontuberculous mycobacteria (NTM) infections usually present with an indolent or subacute course. Fever is the most common symptom reported. The isolation of NTM remains a challenge for clinicians.

Diagnostic criteria for pulmonary NTM infection are established in the guidelines published by American Thoracic Society and involve clinical, radiographic, and microbiologic criteria. The three components are equally important and all must be met to establish the diagnosis. The minimum evaluation of a patient suspected of NTM lung disease should include (1) a chest radiograph or, in the absence of cavitation, chest high-resolution CT scan; (2) three or more sputum specimens for acid-fast bacilli analysis; and (3) exclusion of other disorders, such as tuberculosis.[4]

If lymphadenitis due to NTM is suspected acid-fast stain and culture of surgically excised tissue must be ordered in order to rule out other organisms or typical mycobacteria as causative agents.

Skin and soft-tissue infection (SSTI) presumptive diagnosis is made based on signs and symptoms, clinical presentation, and history of exposure and geographic location. It requires a low threshold of clinical suspicion given the broad spectrum of potential clinical presentations. Definitive diagnosis is confirmed by tissue culture of biopsy material and real-time polymerase chain reaction detection, which enables a more rapid diagnosis.

Disseminated disease diagnosis relies on isolation of the offending organism from normally sterile sites such as blood, bone marrow, or affected lymph nodes.

Laboratory Studies

Diagnosis of infection due to nontuberculous mycobacteria (NTB) is not easy, as it must be distinguished from colonization or contamination by other NTB. Acid-fast bacilli staining and culture for mycobacteria remain the core diagnostic processes.

Culture

The optimal way to diagnose atypical mycobacteria is by performing a culture of a tissue specimen (skin, lymph node, blood). This should be performed at multiple temperatures (28°C [82.4°F], 30°C [86°F], 31°C [87.8°F], 35°C [95°F], 37°C [98.6°F], and 42°C [107.6°F]) to ensure that the cultures grow out all possible pathogens. Specimens should be cultured on both liquid and solid media.

Smear microscopy

Since the culture needs to be incubated for a long time, sometimes weeks, smear microscopy remains an important technique for preliminary results.

The recommended staining method for clinical specimens for acid-fast bacilli is the fluorochrome technique, although the Ziehl-Neelsen staining method remains still an acceptable option. It is important to note that acid-fast bacilli staining cannot differentiate between M tuberculosis and NTMs.

High-performance liquid chromatography for NTM identification

This method analyzes an organism’s mycolic acids (fatty acids found in the cell walls of mycobacteria) and is highly species specific.[80]

Imaging Studies

In 1999, Erasmus et al[81] noted that the radiologic manifestations of pulmonary atypical mycobacteria infection are protean and include consolidation, cavitation, fibrosis, nodules, bronchiectasis, and adenopathy. Pulmonary atypical mycobacteria infection has five distinct clinicoradiologic manifestations: (1) classic infection, (2) nonclassic infection, (3) nodules in patients who are asymptomatic, (4) infection in patients with achalasia, and (5) infection in patients who are immunocompromised. Although classic atypical mycobacteria infection may be indistinguishable from active tuberculosis, it is usually more indolent. The characteristic radiologic features of nonclassic atypical mycobacteria infection include bronchiectasis and centrilobular nodules isolated to or most severe in the lingula and the middle lobe. In patients with acquired immunodeficiency syndrome, mediastinal or hilar adenopathy is the most common radiographic finding.

Other Tests

Molecular techniques

Molecular identification of species by using polymerase chain reaction (PCR) restriction fragment length polymorphism analysis, real-time PCR, line probe hybridization, DNA sequencing, and matrix-assisted laser desorption ionization–time of flight spectrometry aid in detecting the diagnosis earlier.[82] Sequencing of the 16S rRNA gene, hsp65, and rpoB allows discrimination at the species and subspecies level.[83]

Purified protein derivative

The purified protein derivative test result is usually negative in infections with atypical mycobacteria.

Procedures

Biopsy of the skin, involved lymph nodes, and lung can be used to diagnose atypical mycobacteria. The tissue obtained can be used for cultures of the tissue and for histopathologic examination.

Histologic Findings

Histopathologic examination of tissue based on the causative species can reveal tuberculoid, palisading, and sarcoidlike granulomas; a diffuse infiltrate of histiocytic foamy cells; acute and chronic panniculitis; nonspecific chronic inflammation; cutaneous abscesses; suppurative granulomas; and necrotizing folliculitis. Suppurative granulomas are the most characteristic feature in skin biopsy specimens from cutaneous atypical mycobacteria infections. The evolution of the disease and the immunologic status of the host may explain this spectrum of morphologic changes. In Buruli ulcer, mature lesions can show extensive necrosis with destruction. of nerves, appendages, and blood vessels.[10]

Some authorities note severe inflammatory lesions involved with the dermis and the hypodermis; these can have three main histopathologic patterns: (1) granulomatous nodular or diffuse inflammation with mixed granulomas, (2) prevailing abscesses with mild granulomatous reaction, and (3) deep dermal and subcutaneous granulomatous inflammation with no neutrophil component.

Approach Considerations

A diagnosis of nontuberculous mycobacteria (NTM) lung disease does not necessitate prompt initiation of antibiotic therapy. This decision should be made based on the potential risks and benefits of a prolonged course of treatment with multiple antibiotics. Initiation of NTM treatment should be individualized based on disease type, comorbid conditions, and patient age.[4]

Therapy of skin and soft-tissue NTM infections varies depending on the causative organism.[84] Initial empiric treatment with clarithromycin can be considered while awaiting culture and sensitivity results in patients with high suspicion and clinical presentations suggestive of cutaneous NTM infection. The optimal treatment regimen and length are not well established. As a general rule, deeper infections may require 6 or more months of treatment.

Patients with atypical mycobacteria infections can be treated as outpatients after appropriate surgery has been performed.

Medical Care

Infections with atypical mycobacteria can be treated with a variety of antibiotics. It is important to note that the choice of the regimen reflects more the personal experience and preference of the physician. Since most of the nontuberculous mycobacteria (NTM) species demonstrate strong resistance to multiple antimicrobial agents, treatment of NTM infections and establishment of an effective regimen remain challenging.[85] In specific cases, the results of susceptibility tests help guide the decision.

M avium complex lung disease

American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) clinical guidelines recommend an initial regimen of three drugs: a macrolide (clarithromycin or azithromycin), ethambutol, and rifampin. The ideal duration of treatment is 12 months after achieving culture conversion.[4]

M avium complex prevention of disseminated infection in HIV-infected patients

Recommended therapy is azithromycin at 1200 mg orally weekly. Alternatives are clarithromycin at 500 mL orally twice daily or rifabutin at 300 mg orally daily.

M kansasii infection

In rifampin-susceptible strains, a four-drug regimen is recommended, including rifampin, ethambutol, isoniazid, and pyridoxine. The ideal duration is 12 months after achieving culture conversion.

In rifampin-resistant strains, a three-drug regimen is recommended, combining in higher doses clarithromycin or azithromycin, moxifloxacin, isoniazid, ethambutol, sulfamethoxazole, or streptomycin.

M marinum infection

This organism is susceptible to clarithromycin, minocycline, trimethoprim-sulfamethoxazole, rifampin, rifabutin, and ethambutol. It is resistant to isoniazid and pyrazinamide.

Excellent outcomes in deep infections have been reported with clarithromycin plus rifampin or ethambutol.[67]

M ulcerans infection

Medical therapy for M ulcerans infection has been disappointing. Rifampin in combination with clarithromycin for at least 6-8 weeks may be the best choice for controlling complications of the ulcer.

M haemophilum infection

Currently, there exists no standardized susceptibility test for M haemophilum. Even though there is no optimal therapy, multidrug regimens including clarithromycin, rifampin, rifabutin, ciprofloxacin, or amikacin have proven to be efficacious.

M scrofulaceum

There is no standard treatment regimen, but the most effective proven regimen is the combination of isoniazid with clarithromycin or rifampin.

Rapidly growing mycobacteria infections (M fortuitum, M chelonae, M abscessus)

M fortuitum is susceptible to ciprofloxacin and ofloxacin, amikacin, sulfonamides, imipenem, clarithromycin, cefoxitin, and doxycycline. For serious infections, use at least two agents.

M chelonae can be treated with clarithromycin and a second agent chosen from linezolid, imipenem, tobramycin, or amikacin.

M abscessus complex group bacteria are the most difficult rapidly growing mycobacteria to treat, owing to their resistance to multiple standard antituberculous drugs. Treatment options include clarithromycin or azithromycin, with the addition of amikacin, cefoxitin, or imipenem for serious and complicated infections.

Surgical Care

A combined therapeutic approach, including surgical drainage, debridement, excision, and a prolonged (>3 mo) treatment with combined antimicrobial agents, remains a mainstream in some cases of atypical mycobacteria infection.

A 2019 retrospective study in Taiwan concluded that surgical resection of nontuberculous mycobacteria (NTM) solitary pulmonary nodules is curative in asymptomatic patients without positive culture of the same NTM species from respiratory specimens and a history of NTM pulmonary disease. Further medical treatment for NTM will probably not be necessary.[86]

Selective cervical lymphadenectomy leads to a quick resolution of NTM cervicofacial lymphadenitis in children.[87]

Split-thickness skin grafting has been successfully used to cover large wounds. Grafting did not appear to foster recurrent infection.

Consultations

Consultations with infectious disease specialists, surgeons, dermatologists, clinical microbiologists, and pulmonary specialists may be necessary.

Prevention

Patients should avoid contaminant material and injections with contaminated materials. Patients should also avoid contaminated water.

Long-Term Monitoring

Patients must be aware of the needed prolonged courses of antibiotics and the importance of compliance. Lack of the compliance results in treatment failure and higher resistance and a more prolonged course of further therapy.

Medication Summary

When possible, sensitivity testing should be performed to guide the selection of drugs and optimize the therapy outcome. Treatment requires good adherence to potentially toxic drug regimens over a prolonged period.

Tigecycline was administered in a 2014 series of 52 patients with M abscessus and M chelonae infections resistant to standard regimens. These patients received tigecycline for at least a month as part of a multidrug regimen.[88] Improvement was seen in more than 60% of patients, even those with underlying cystic fibrosis, regardless of failure of prior antibiotic therapy. The authors of this study noted adverse events in more than 90% of cases, with nausea and vomiting being the most common adverse effects.

Bedaquiline is approved by the US Food and Drug Administration (FDA) for macrolide-resistant, multidrug-resistant, and extremely drug-resistant tuberculosis. It has in vitro activity against M avium complex, M abscessus, and M ulcerans, making it a potential alternative agent for the treatment of pulmonary NTM disease.[89]

Delamanid is a dihydro-nitroimidazooxazole derivative that inhibits mycolic acid synthesis. The molecule is approved in Europe, Japan, and South Korea for multidrug-resistant tuberculosis. Delamanid has shown some in vitro inhibitory activity against M kansasii and other slow-growing mycobacteria.[90] More experience is needed to firmly establish its efficacy and safety in treatment of nontuberculous mycobacteria (NTM) infections.

Regarding oxazolidinones, both linezolid and tedizolid are active against NTM, but prolonged use of linezolid is associated with myelosuppression and neuropathies. Tedizolid is emerging as a more tolerable alternative to linezolid.[91] Newer members of the class, such as sutezolid, contezolid, and delpazolid, are currently in clinical trials for activity against M tuberculosis.[92]

Isoniazid (Nydrazid, Laniazid)

Clinical Context:  Isoniazid is used in isolation for prevention of tuberculosis and in combination to treat tuberculosis and mycobacterial infections.

Clarithromycin (Biaxin)

Clinical Context:  Clarithromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Streptomycin

Clinical Context:  Streptomycin is used in combination with other drugs in the treatment of M avium-intracellulare infections.

Ciprofloxacin (Cipro)

Clinical Context:  Ciprofloxacin is used in combination with other agents in the treatment of M avium-intracellulare infections.

Rifabutin (Mycobutin)

Clinical Context:  Rifabutin is used for the prevention of disseminated M avium-intracellulare infections in patients with HIV infection.

Minocycline (Dynacin, Minocin)

Clinical Context:  Minocycline treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible Chlamydia, Rickettsia, and Mycoplasma species and atypical mycobacteria.

Amikacin (Amikin)

Clinical Context:  Amikacin is used for gram-negative bacterial coverage of infections resistant to gentamicin and tobramycin. It is effective against Pseudomonas aeruginosa. It irreversibly binds to the 30S subunit of bacterial ribosomes, blocks the recognition step in protein synthesis, and causes growth inhibition. Use ideal body weight of the patient for dosage calculation.

Cefoxitin (Mefoxin)

Clinical Context:  Cefoxitin is a second-generation cephalosporin indicated for gram-positive cocci and gram-negative rod infections. Infections caused by cephalosporin- or penicillin-resistant gram-negative bacteria may respond to cefoxitin. Higher doses are required for severe or serious infections.

Bedaquiline (Sirturo)

Clinical Context:  It is a novel oral agent that inhibits ATP synthase with bactericidal activity against M tuberculosis. It is approved by the FDA for macrolide-resistant, multidrug-resistant, and extremely drug-resistant tuberculosis. It has in vitro activity against M avium complex, M abscessus, and M ulcerans, making it a potential alternative agent for the treatment of pulmonary NTM disease.

Class Summary

Therapy must cover all likely pathogens in the context of the clinical setting.

Author

Erisa Alia, MD, Clinical Trials Research Fellow, Department of Dermatology, University of Connecticut School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Jun Lu, MD, FAAD, Associate Professor, Director of Clinical Trial Unit, Director of Connective Tissue Disease Multispecialty Clinic, Farmington Site Director of Dermatology Residency Program, Department of Dermatology, University of Connecticut Health Center

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Disclosure: Received honoraria from UpToDate for author/editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Allergen; Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Takeji Nishikawa, MD, Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc

Disclosure: Nothing to disclose.

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Mycobacterium marinum is an atypical mycobacteria found in water with a wide range of temperatures and salinities

Mycobacterium marinum is an atypical mycobacteria found in water with a wide range of temperatures and salinities