Are You Confident of the Diagnosis?
Atypical mycobacteria (ATM) are mycobacteria other than Mycobacterium tuberculosis and M leprae. MOTT (mycobacteria other than tuberculosis) is sometimes used to refer to this group.
Often, ATM infections are not considered initially. The variable presentations, lack of appropriate culture media, delay in culture growth, or paucity of organisms on histopathologic sections may delay diagnosis.
A high index of suspicion is required. Exposure to medical and aesthetical procedures, contaminated water and trauma should prompt consideration of infection with ATM. Immunosuppression, including use of tumor necrosis factor inhibitors, is also a predisposing factor.
M marinum infection is suspected in fish enthusiasts and fisherman with granulomatous cutaneous lesions. M ulcerans typically enters the skin through cuts or scrapes from vegetation in tropical and warm temperate water bodies of Australia, Mexico, and Western and Central Africa. Therefore, suspicion of this infection requires a travel history.
Infection with rapid growing ATM (M fortuitum, M chelonae, and M abscessus) has been associated with liposuction, acupuncture, breast augmentation, tattoos, mesotherapy, dialysis, contaminated skin marking solutions, catheters, laser resurfacing, foot baths at nail salons, body piercing, and contaminated injection solutions. Unlike the other rapid growing ATM, M fortuitum infection most commonly involves immunocompetent patients. Many of the other ATM are primary pulmonary pathogens, but cutaneous dissemination occasionally occurs.
Characteristic features on physical examination
The clinical presentation of ATM infection differs based on the specific organism and method of transmission with involvement most commonly of the skin, lungs, and lymph nodes.
M marinum infection typically presents with an erythematous nodule at the site of inoculation, 2 to 8 weeks after exposure (Figure 1). Patients may not recall the trauma and/or water exposure because of this delay. Due to the association with trauma and optimal growth below body temperature, there is a predilection for the hand. The lesions may become verrucous, ulcerate, or expand into plaques. Twenty to forty percent of patients will develop additional similar lesions along the lymphatic drainage mimicking sporotrichosis.
Unlike ulceroglandular processes, the nodular lymphangitis associated with this infection generally lacks adjacent adenopathy, unless there is secondary bacterial infection. This sporotrichoid pattern is classically associated with M marinum; however, it has been reported with M kansasii and M avium-intracellulare (MAI). Tenosynovitis or bursitis may be associated with progression to septic arthritis or osteomyelitis. Systemic symptoms and disseminated disease are very rare but can occur in immunocompromised patients.
M ulcerans enters the skin at sites where the protective barrier is impaired but requires 2 to 3 months to produce the characteristically painless nodules. Infection is most common on the leg, usually with extension, ulceration and necrosis (Buruli ulcer). Infection occurs primarily in children. The course is prolonged with healing and scarring in one area while progression occurs in other areas. Severe scarring can result in contracture. Constitutional symptoms are typically lacking. Deep extension with involvement of the fascia, muscle, and bone can occur.
Infection with M fortuitum is usually the result of surgery or trauma and presents as painful erythematous nodules, ulcers, abscesses, draining sinuses, or cellulitis 4 to 6 weeks after inoculation. The presentation is usually that of a solitary lesion in an immunocompetent patient.
Infection with the other rapid growing ATM, M chelonae and M abscessus, similarly present as localized cellulitis or abscesses at surgical or catheter sites or as multiple erythematous draining nodules in patients on corticosteroids, usually on an extremity (Figure 2). Most patients have no constitutional complaints or systemic disease with M chelonae, but M abscessus can cause chronic pulmonary disease.
M scrofulaceum rarely results in cutaneous infection. The most common presentation is unilateral cervical lymphadenitis with or without cutaneous fistula in children and pulmonary disease in adults. The disease is contracted by inhalation or ingestion.
M avium-intracellulare (MAI) primarily is a pulmonary infection with rare cases of cutaneous dissemination or direct inoculation resulting in painful subcutaneous nodules that ulcerate and drain. MAI has surpassed M scrofulaceum as the most common cause of lymphadenitis in children.
M haemophilum infection is most common in immunosuppressed patients with constitutional symptoms and involvement of the lung, bone, and skin. The cutaneous lesions consist of multiple violaceous tender papules, plaques, or nodules, especially on the extremities over joints. Lesions may develop into ulcers or abscesses. Children may present with lymphadenitis.
M kansasii clinically resembles pulmonary tuberculosis in middle age to elderly patients with preexisting lung disease. Cutaneous disease is rare, manifesting as ulcers, cellulitis, verrucous sporotrichoid nodules, papulopustules, or plaques.
Expected results of diagnostic studies
Diagnosis requires skin biopsy for histopathologic examination and tissue culture.
The histopathologic features of ATM infection are not species specific. Although suppurative granulomas (Figure 3) are the most characteristic pattern, the pathology is variable and includes tuberculoid, palisading, and sarcoidal granulomas. Necrosis, when present, is rarely caseous. Diffuse foamy histiocytes, panniculitis, abscesses, and necrotizing folliculitis have been reported. Pseudoepitheliomatous hyperplasia, papillomatosis and hyperkeratosis can be seen.
The immunologic status of the patient, the evolution of the disease, and organism specific features may explain this spectrum of pathology. Immunosuppressed patients typically show a more diffuse infiltrate that involves the subcutaneous fat with abscess formation. M ulcerans is associated with significant necrosis with surprisingly limited adjacent inflammatory infiltrate and involvement of the subcutaneous fat. Identification of the acid fast bacilli is more common in acute lesions and in immunosuppressed patients in and around the necrotic tissue.
Ziehl–Neelsen, Kinyoun’s method and its modification, the Fite stain, highlight the mycobacteria red in tissue sections (Figure 4) while they fluoresce when stained with auramine-rhodamine and viewed under fluorescence microscopy. The bacilli of ATM infections typically are longer and wider than those of M tuberculosis. The number of bacilli in tissue can vary depending on the species and the host immune status. When frequent, organisms may fill vacuoles within the area of infection.
Growth of ATM in culture requires special knowledge of the growth characteristics. Special media such as Lowenstein-Jensen is required and depending on the organism, incubation at specific temperatures is required for growth. Clinicians should communicate their suspicion with the laboratory so that they culture under the appropriate conditions. Sensitivity testing, although often prolonged, can be invaluable in treatment.
ATM can be identified by culture growth characteristics and biochemical tests. M marinum and M haemophilum grow best at 30oC to 32oC in 2 to 5 weeks. Growth is poor or absent when incubated at 37oC. M haemophilum must be grown on media that is supplemented with iron. M ulcerans has optimal growth at a similar temperature, 32oC to 33oC, but requires 2 to 3 months to see growth. Most other ATM grow at temperatures closer to body temperature, at 35oC to 37oC.
Colonies of M chelonae, M abscessus, and M fortuitum grow at temperatures ranging from 22oC to 40oC in as few as 7 days, thus the name rapid growers.
Molecular methods such as genetic sequencing and polymerase chain reaction (PCR) based techniques, can be used to identify the different species of ATM. In the case of slow-growing mycobacteria, direct sequencing of the gene coding the 16S ribosomal RNA can be used and in rapid growing mycobacteria PCR restriction analysis length polymorphisms of the heat shock protein 65 gene is available.
Intradermal skin tests of many ATM extracts have been prepared similar to the purified protein derivative (PPD) test for M tuberculosis but cross reactivity is high and therefore testing is not of practical use.
The differential diagnosis of ATM infection includes the following:
Sporotrichosis (nodular lymphangitis, consisting of nodular lesions progressing along the lymphatic drainage, can be seen in sporotrichosis, leishmaniasis, ATM or Nocardia infection, but sporotrichosis can be distinguished by the presence of yeast in tissue)
Leishmaniasis (distinguished by presence of amastigotes in Giemsa stained sections)
Nocardiosis (is due to filamentous bacteria that grow within days in routine bacterial culture and although weakly acid fast in tissue, also stain with Gram and Gomori methenamine silver)
Cellulitis (bacterial cellulitis typically becomes apparent rapidly after inoculation and responds quickly to typical antimicrobials)
Actinomycosis (can mimic M scrofulaceum infection but draining sinuses discharge sulfur granules composed of Gram-positive, non–acid-fast filamentous bacteria)
Pyoderma gangrenosum (diagnosis of this ulcerative process requires exclusion of possible infectious causes)
Sarcoidosis (the protean manifestations of this granulomatous disease can mimic ATM infection and many organisms, including mycobacteria, have been suggested, without supporting data, in the pathogenesis but organisms are not identified in tissue and sarcoidosis responds to steroids which typically worsen ATM infection)
Cutaneous tuberculosis (can be differentiated from other mycobacteria by culture, PCR, and interferon gamma release assays that tend not to react with ATM)
Majocchi’s granuloma (differentiated by identification of fungi in the fair follicle)
Who is at Risk for Developing this Disease?
There is no apparent racial or gender predilection with ATM infection. The primary affected age group differs based on the species. Most species of ATM are ubiquitous and found worldwide, whereas some (M ulcerans) have a limited geographic distribution.
M marinum is found worldwide in salt water, fresh water, or brackish water and swimming pools or aquariums, thus the name swimming pool or fish tank granuloma. Because of the use of chlorination, infection currently is rare in association with swimming pools. In addition, shrimp, dolphins, snails, and fish have been reported vectors. The organism lacks the ability to penetrate intact skin; therefore, trauma (abrasion or puncture) is typically associated with infection. Fish-related occupations or hobbies increase risk of exposure and infection.
M ulcerans is the most common ATM infection worldwide but is not endemic to the United States. Tropical and warm temperate water bodies in Australia, Mexico, and Western and Central Africa are the primary source. Infection usually follows inoculation through an abrasion and is more common in children 5 to 15 years of age.
M fortuitum is found in soil, water, milk, biofilm, and human saliva. Infection has been associated with medical and surgical procedures, including cosmetic procedures, dialysis, acupuncture, tattooing, piercing, and nail salons. Unlike the other rapid growing ATM, M fortuitum most commonly involves immunocompetent patients.
M chelonae is found in ponds, hot springs, rivers, soil, and house dust. Similar to M fortuitum, M chelonae can contaminate injection solutions and cause infection after medical or surgical procedures.
M abscessus is also found in soil, dust, and water, as well as body secretions. Similar to the other rapid growing ATM, infection has occurred after injections and surgical procedures. Disseminated skin lesions can be seen in immunosuppressed patients.
M scrofulaceum is most prevalent in southeast United States and has been isolated in dairy products, pooled oysters, soil and tap water. Lymphadenitis is primarily identified in children while pulmonary infection is more common in adults.
MAI is ubiquitous in the environment and survives in soil, water, house dust, vegetables, eggs, and milk. Inhalation and ingestion are thought to be the primary modes of infection with MAI.
The reservoir and route of infection for M haemophilum is unknown, but most cases have occurred in proximity to large water bodies.
M kansasii is found in fresh water, particularly in temperate regions with the highest incidence in the central and southern United States.
Immunosuppression is a significant risk factor for ATM infection. Infection has been increasingly reported in patients on tumor necrosis factor inhibitors, such as etanercept and infliximab.
What is the Cause of the Disease?
ATM lacks the ability to pass through intact skin therefore, infection requires inoculation, inhalation, or rarely ingestion. Secondary cutaneous dissemination can occur in systemic infection.
ATM infections occur in immunocompromised patients due to poor host immunity and commonly are disseminated in nature.
Human to human transmission of ATM has not been reported.
Runyon divided ATM into groups by growth rate, ability to produce pigment, and optimal temperature for culture, as follows:
Group I. Photochromogens
The ATM in this group are slow growing and produce pigment only when exposed to light. The organism in this group that most commonly causes cutaneous infection is M marinum. This group also includes M kansasii.
Group II. Scotochromogens
These slow growing ATM produce pigment in culture regardless of light exposure and rarely cause skin infection. M scrofulaceum belongs to this group.
Group III. Nonchromogens
Group III ATM are slow growing and fail to produce pigment in culture. These organisms include M avium-intracellulare, M ulcerans, and M haemophilum. M ulcerans produces the toxin, mycolactone, that is likely responsible for the ulceration and evasion of the immune system.
Group IV. Rapid Growers
M fortuitum, M chelonae, and M abscessus (formerly M chelonae, subspecies abscessus) grow in culture within 5 to 7 days. These organisms are found in soil, dust, bio-aerosols, water, some animals (both wild and domestic), fish, and biofilms that can resist common disinfectants such as chlorine, alkaline glutaraldehyde, and organomercurials and thus can infect catheters and vascular shunts.
Systemic Implications and Complications
ATM, particularly those that are capable of growing at core body temperature, can result in disseminated infection, typically from a respiratory source. Infection can result in osteomyelitis, lymphadenitis, endocarditis, meningitis and keratitis.
Systemic symptoms are rare with M marinum and M ulcerans however, infection can be complicated by tenosynovitis, septic arthritis, and osteomyelitis.
Treatment options for ATM are summed up in the Table I.
|Treatment options for atypical mycobacterial infections|
Optimal Therapeutic Approach for this Disease
On occasion spontaneous resolution of ATM infection can occur in immunocompetent patients but can take years and result in significant scarring.
A standardized treatment regimen is lacking for ATM infections due to limited randomized controlled trials comparing the treatment alternatives. Antibiotics are the mainstay of treatment, commonly in a multidrug approach to avoid resistance. In general, therapy should be prolonged with continuation 1 to 2 months after apparent clinical cure to prevent relapse. Disseminated cutaneous infection should be treated at least 6 months.
Tetracyclines, antituberculoid drugs, macrolides, quinolones, and trimethoprim-sulfamethoxazole are the most commonly used agents. Clarithromycin is emerging as the first line empiric therapy while cultures are pending but, because sensitivities vary, the drug(s) of choice ultimately depends on the susceptibility testing of the causative organism.
Surgical debridement or excision, with or without antibiotics, may be necessary for deep infection or infection involving multiresistant ATM.
Skin and soft tissue M marinum infections are typically treated with monotherapy: clarithromycin 500mg twice daily, minocycline 100mg twice daily, doxycycline 100mg twice daily, trimethoprim-sulfamethoxazole 160-800mg twice daily, or ciprofloxacin 500mg twice daily. Severe and deeper infection has been treated with a combination of clarithromycin 500mg twice daily, rifampin 600mg daily, and ethambutol 25mg/kg daily. Treatment lasts 3 to 6 months with at least 4 to 8 weeks of treatment after resolution of the clinical lesion(s).
Debridement may be necessary for deeper infection however excision is usually not necessary and could precipitate spread of infection. Heat may also assist in healing because growth is inhibited at higher temperatures. X-ray treatment, cryotherapy, electrodesiccation, and photodynamic therapy have been reported alternatives.
Antimicrobials penetrate the necrotic avascular tissue of M ulcerans infection poorly; therefore, surgical debridement or excision forms the basis of treatment, often in combination with rifampin 600mg daily and amikacin 15mg/kg intramuscularly divided twice a day or streptomycin 15mg/kg intramuscularly daily for 4 to 8 weeks.
Local hyperthermia (to temperatures above 40 degrees Celsius at the base of the ulcer) has also been used with variable success. Hyperbaric oxygen therapy has been employed. BCG vaccination may result in short term protection from infection. Other preventive vaccines are under development.
M fortuitum has been treated with clarithromycin 500mg twice daily, azithromycin 200mg daily, doxycycline 100mg daily, levofloxacin 500 to 750mg daily, moxifloxacin 400mg daily, gatifloxacin 400mg daily, trimethoprim-sulfamethoxazole 800-160mg twice daily for 4 to 6 months depending on the severity of infection and immune status of the host. Ciprofloxacin resistance is emerging.
Serious infections may require intravenous amikacin 15mg/kg daily in divided doses, cefoxitin 12gm daily in divided doses, and clarithromycin. Surgical debridement in addition to chemotherapy is important to establish a cure in deep infection.
Surgical debridement may be necessary for M chelonae infection but usually requires antimicrobial therapy. The parenteral agents of choice, when necessary, are tobramycin and imipenem, whereas clarithromycin is the most effective oral agent but should be combined with another drug such as ciprofloxacin to prevent resistance. One quarter of isolates are susceptible to doxycycline or ciprofloxacin. Treatment typically continues for at least 6 months.
Complete resolution has been reported in patients with M abscessus infection treated over 12 months with clarithromycin 500mg twice daily. Extensive and disseminated disease requires clarithromycin in combination with high-dose cefoxitin or low-dose amikacin. Usually therapy involves antimicrobial therapy combined with surgical debridement
M scrofulaceum is generally not sensitive to antimicrobials and requires surgical removal, although clarithromycin sensitivity has been shown in vitro.
Specific guidelines for cutaneous MAI infection are lacking but can be extrapolated from the recommendations from the American Thoracic Society: clarithromycin 500mg twice daily in combination with ethambutol 15-25mg/kg daily, with rifampin 600mg daily or rifabutin 300 mg daily and streptomycin for the first 3 months. The duration of therapy is unknown but pulmonary disease is treated until culture is negative for 1 year. Resistance occurs rapidly with monotherapy.
There are no clear guidelines for treatment of M haemophilum, but treatment with two active agents (amikacin, ciprofloxacin, clarithromycin, rifabutin, rifampin) for 6 to 9 months or longer in immunosuppressed patients has been effective. Excision of affected lymph nodes in healthy children may be all that is required.
M kansasii is susceptible to many antituberculosis drugs and like tuberculosis regimens consists of a combination of medications: rifampin 600mg daily, ethambutol 15mg/kg daily, and isoniazid 300 to 600mg daily for 18 months in disseminated disease and up to 9 months in cutaneous disease. Streptomycin, 1 gram intramuscularly twice weekly may be added in the first 3 months for patients with acquired immunodeficiency syndrome. Rifampin resistance has been reported while clarithromycin appears highly active in vitro and may be an option for purely cutaneous infection.
As always, care is warranted in treatment of immunosuppressed patients treated with other drugs due to the possibility of drug interactions and enhanced drug toxicities. For example, macrolides inhibit cytochrome p450 3A and can result in increased levels of calcineurin inhibitors such as tacrolimus and cyclosporine. Similarly, synergistic nephrotoxicity can occur with concurrent use of calcineurin inhibitors and aminoglycosides such as amikacin. Protease inhibitors enhance the metabolism of rifampin and should result in selection of an alternate ATM therapy.
Treatment often requires empiric therapy due to the slow rate of growth in culture. Clarithromycin has shown efficacy against a broad range of ATM and is therefore a reasonable option, but some organisms are resistant. Antimicrobial therapy should be tailored by sensitivity testing as soon as it is available. Patients should be educated that prolonged courses of antibiotics are typically necessary and should be continued up to 2 months after clinical resolution.
Consultation with a surgeon, infectious disease and/or pulmonary specialist may be necessary depending on the presentation.
Patients should avoid repeat exposure to any identifiable source, for example an aquarium.
Unusual Clinical Scenarios to Consider in Patient Management
The variable clinical presentations and complexity of laboratory techniques can lead to significant delay in diagnosis of ATM infection. Failure to diagnose may result in delayed treatment or inappropriate treatment with steroid that will exaggerate the infection.
A high degree of suspicion is required and ATM should be suspected when evaluating any persistent draining nodule, plaque, area of panniculitis or cellulitis. This is of paramount importance if the patient is immunosuppressed, had a history of previous trauma or surgery, especially if routine bacterial culture is negative and/or response to conventional antibiotics has been poor.
Remember to alert laboratory staff of the suspected organism(s) so they use appropriate isolation protocols.
Therapeutic response may ultimately confirm the diagnosis when other forms of isolation fail.
What is the Evidence?
Bartralot, R, Pujol, RM, García-Patos, V, Sitjas, D, Martín-Casabona, N, Coll, P. “Cutaneous infections due to nontuberculous mycobacteria: histopathological review of 28 cases. Comparative study between lesions observed in immunosuppressed patients and normal hosts”. J Cutan Pathol. vol. 27. 2000. pp. 124-9. (Detailed report of the histopathologic findings in ATM infections and how it differs between the normal host and immunosuppressed patients)
Bhambri, S, Bhambri, A, Del Rosso, JQ. “Atypical mycobacterial cutaneous infections”. Dermatol Clin. vol. 27. 2009. pp. 63-73. (Thorough review of the epidemiology, growth characteristics, clinical presentation, histopathology, and treatment of ATM infection divided by organism)
Elston, D. “Nontuberculous mycobacterial skin infections: recognition and management”. Am J Clin Dermatol. vol. 10. 2009. pp. 281-5. (Collective up-to-date review of cutaneous infections due to ATM.)
Fabroni, C, Buggiani, G, Lotti, T. “Therapy of environmental mycobacterial infections”. Dermatol Ther. vol. 21. 2008. pp. 162-6. (Concise review of most common ATM that cause cutaneous infection with attention to the differential diagnosis and treatments, including the dosing and principle side effects.)
Garrison, AP, Morris, MI, Doblecki Lewis, S, Smith, L, Cleary, TJ, Procop, GW. “Mycobacterium abscessus infection in solid organ transplant recipients: report of three cases and review of the literature”. Transpl Infect Di.. vol. 11. 2009. pp. 541-8. (This report details three organ transplant patients with M abscessus infection and discusses the complexities of treatment with respect to drug interactions and synergistic toxicities.)
Rallis, E, Koumantaki-Mathioudaki, E. “Treatment of Mycobacterium marinum cutaneous infections”. Expert Opin Pharmacother.. vol. 8. 2007. pp. 2965-78. (Extensive review of most common ATM infections that present to dermatologists, with detailed treatment discussion.)
Weitzul, S, Eichhorn, PJ, Pandya, AG. “Nontuberculous mycobacterial infections of the skin”. Dermatol Clin. vol. 18. 2000. pp. 359-77. (Slightly dated but comprehensive and provides a table of cutaneous and extracutaneous manifestations of infection of each organism, as well as a table detailing the growth characteristics of each of the mycobacterial species.)
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