Review
Cutaneous non-tuberculous mycobacterial infections Ruth C. Lamb1, MBChB, BMedSci, MRCP, and Goutam Dawn2, MBBS, MD, DNB, FRCP
1 Alan Lyell Centre for Dermatology, Southern General Hospital, Glasgow, UK, and 2Department of Dermatology, Monklands Hospital, Airdrie, UK
Correspondence Ruth C. Lamb, MBCHB, BMEDSCI, MRCP Alan Lyell Centre for Dermatology Southern General Hospital 1345 Govan Road, Glasgow G51 4TF, UK E-mail: [email protected]
Abstract Mycobacteria cause a range of diseases in both immunocompetent and immunosuppressed individuals and may affect many different organs. The most noticeable recent change in patterns of cutaneous mycobacterial infection refers to the increase in non-tuberculous mycobacterial (NTM) infections. This review focuses on the clinical manifestations, diagnosis, and treatment of cutaneous NTM infections. The MEDLINE, PubMed, and Cochrane Library databases were searched using the keywords “nontuberculous mycobacteria,” “atypical mycobacteria,” and “mycobacteria other than tubercle bacilli”. Publications on cutaneous NTM infections written in English were included in this review. Literature published by the World Health Organization was examined for further
Funding: None. Conflicts of interest: None
material. References in review articles were screened for other studies not already identified. The clinical features, diagnosis, and treatment of NTM infections were reviewed. Cutaneous mycobacterial disease may take many guises and may appear benign in nature. Chronic cutaneous lesions at the sites of trauma or surgical procedures, especially those that fail to respond to standard antibiotic therapy, should prompt the consideration of mycobacterial disease. The lack of rapid techniques for the identification of pathogens makes diagnosis challenging. The lack of randomized controlled trials on the efficacy of antimicrobial agents means that empiric therapy may fail, necessitate prolonged combinations of antibiotics, and increase the probability of side effects and diminished compliance.
Introduction
Materials and methods
Mycobacteria cause a range of diseases in both immunocompetent and immunosuppressed individuals and may affect many different organs. Despite a global decrease in tuberculosis, incidences of cutaneous mycobacterial infections seem to be increasing in developed countries.1,2 This is probably secondary to the increasing burden of immunocompromised individuals within the general population, immigration from endemic countries, improved laboratory identification techniques, and changes in human behavior that expose individuals to the culprit organisms. However, the most noticeable recent change in patterns of cutaneous mycobacterial infection is related to the increase in cutaneous non-tuberculous mycobacterial (NTM) infections.3 Cutaneous NTM infections are increasingly common among hospital-acquired infections and following cosmetic procedures, and thus the pathogens implicated are emerging as important in both primary and secondary care.3 This review focuses on the clinical manifestations, diagnosis, and treatment of cutaneous NTM infections.
The MEDLINE, PubMed, and Cochrane Library databases were
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searched using the keywords “non-tuberculous mycobacteria,” “atypical mycobacteria,” and “mycobacteria other than tubercle bacilli”. Publications on cutaneous NTM infections written in English were included in this review. Literature published by the World Health Organization was examined for further material. References in review articles were screened for other studies not already identified. The clinical features, diagnosis, and treatment of NTM infections were reviewed.
Results and discussion Background and classification
Non-tuberculous mycobacteria were not identified as human pathogens until the 1950s but are now thought to cause cutaneous infections more commonly than Mycobacterium tuberculosis.2,4 These non-motile acid-fast bacilli can be divided into slow-growing and rapidgrowing groups based on their culture characteristics.4 Runyon4 further classified the NTM group based on its International Journal of Dermatology 2014, 53, 1197–1204
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Table 1 Modified classification of non-tuberculous mycobacteria
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Runyon group4
Phenotype
Colony characteristics
Mycobacterium species
I II
Photochromogens Scotochromogens
Produce yellow pigment when exposed to light Produce yellow–orange pigment when exposed to light or in the dark
III
Non-chromogens
Slow growers No pigment production
IV
Rapid growers
Produce colonies in 3–5 days No pigment production
M. marinum, M. kansasii M. scrofulaceum M. gordonae M. avium M. intracellulare M. haemophilum M. ulcerans M. fortuitum group: M. fortuitum M. peregrinum M. septicum M. mageritense M. chelonae–abscessus group: M. chelonae M. abscessus M. immunogenum M. smegmatis group: M. smegmatis M. goodie M. wolinskyi M. massiliense
a
This list is not exhaustive.
members’ pigment-forming properties when cultured (Table 1). Recent advances have meant that these bacteria can now also be grouped according to genotypic characteristics.4,5 In addition, because of their similar clinical, etiologic, and antigenic characteristics, some groups of NTM are considered together as complexes; for example, Mycobacterium avium and Mycobacterium intracellulare produce identical disease and are found together endemically and are therefore grouped together as the M. avium–intracellulare complex. Likewise, Mycobacterium fortuitum and Mycobacterium chelonae are often grouped together as the M. fortuitum complex. How does a patient acquire infection with an NTM?
Non-tuberculous mycobacteria, especially the rapidly growing species, are hardy, environmental saprophytes found commonly in nature and can be isolated from soil, dust, water, vegetation, animals, and hospital environments.6,7 They may also colonize body surfaces, and thus multiple isolates may be required from non-sterile sites to establish disease, whereas one positive culture from a sterile site with supportive histopathology may suffice.2 Tap water is the main reservoir for most human NTM pathogens. Carson et al. found that 55% of incoming city water in hemodialysis centers throughout the USA contained rapidly growing mycobacteria.8 Thus, it seems logical that NTM infections are acquired by environmental exposure rather than by person-to-person spread as in tuberculous infections. Although contact with International Journal of Dermatology 2014, 53, 1197–1204
environmental mycobacteria is frequent, overt disease is uncommon because the organisms are relatively low in virulence. In addition, the organisms usually require the skin barrier to be broken in order to cause infection. Pulmonary disease is the most recognized NTM infection, but lymphadenitis, skin and soft tissue infections, catheter-related infections, disseminated infections, and chronic granulomatous infections of bursae, joints, tendon sheaths, and bones may also occur.2,9 Incubation periods can vary from two weeks to nine months and depend on the characteristics of the infecting mycobacterium, as well as on host-related factors.10 Almost all NTM can cause cutaneous disease. The most common species causing cutaneous NTM infections in Europe and the USA are Mycobacterium marinum (Fig. 1a), and the rapidly growing Mycobacterium abscessus, M. fortuitum, and M. chelonae (Fig. 1b).6 True incidences are difficult to determine because these are not communicable diseases and may be under-reported. Mycobacterium ulcerans has a more limited geographic distribution: the majority of cases occur in tropical and subtropical regions of West and Central Africa, Southeast Asia, South America, and the Western Pacific.6,11 Why is the incidence of NTM infections increasing?
Multiple cases and small case series of outbreaks of cutaneous NTM infections have been reported in the literature over the last 30 years. Although exact incidences are difficult to define, recent data presented at the annual ª 2014 The International Society of Dermatology
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(c)
Figure 1 (a) Clinical examination of a Mycobacterium marinum infection on the left hand demonstrates warty nodules with a sporotrichoid spread. (b) Mycobacterium chelonae infection on the right leg manifests as a furuncle-like lesion with evidence of pus and early surrounding cellulitis. (c) Mycobacterium chelonae contaminating gray tattoo ink: erythematous nodules can be seen between the blue claws in the tattoo
Scottish Dermatology Society meeting on NTM incidence between 2003 and 2013 identified 67 cases of cutaneous NTM infection, including 23 cases of M. chelonae infection and 15 cases of M. marinum infection.12 In the USA, a population-based study conducted in Minnesota found a local incidence of 1.3 per 100,000 person-years between 1980 and 2009 and a higher incidence in the period between 2000 and 2009 (2.0 per 100,000 person-years).13 The ability to identify NTM infections through more advanced laboratory techniques such as with polymerase chain reaction (PCR) is likely to have had some influence on the increasing incidence of infections.14 In addition, it is possible that the increased popularity of cutaneous surgery, particularly within the cosmetic industry, may be contributing. Some NTM are able to withstand sterilization and to colonize or contaminate antiseptics, resulting in infections in surgical patients. An example of such an event refers to an outbreak following the contamination of benzalkonium chloride with NTM, which caused infection in 12 patients following steroid injections.15 In Brazil, an epidemic of infections after video-assisted surgery gave rise to over 1050 probable cases of infection by Mycobacterium massiliense which had developed tolerance to 2% gluteraldehyde.16 Infections with NTM have also been described in association with skin surgery, acupuncture, cardiothoracic surgery, endoscopy, breast reconstruction, plastic surgery, laser resurfacing, laser eye surgery, liposuction, body piercing, and tattoos.17–26 Perhaps the most notable report cited an outbreak of 61 M. fortuitum infections that occurred after foot baths performed before pedicures at a spa in the USA.27 Although the increasing use of immunosuppressive treatments and acquired immunosuppression are also likely to have contributed to growth in incidence rates, many of the infections affect immunocompetent individuals. In keeping with this, several recent retrospective ª 2014 The International Society of Dermatology
studies of cutaneous NTM infections found that 72–86% of patients were immunocompetent.28,29 Infections in immunocompromised subjects have been noted to arise particularly in patients taking glucocorticoid therapy; this was also apparent in recent Scottish data, which showed that approximately 50% of all patients diagnosed with M. chelonae infections over a 10-year period were taking a concurrent systemic glucocorticoid.12 When should I suspect cutaneous infection with NTM?
Non-tuberculous mycobacterial infections should be considered when the clinician is confronted with a patient with persistent abscesses or cellulitis especially in the setting of recent surgery, trauma, or immunosuppression. The main clinical feature refers to painful erythematous nodules that may ulcerate and form abscesses; however, morphology is variable. Infections with M. marinum and M. ulcerans result in well-defined clinicopathologic entities, known as fish tank granuloma and Buruli ulcer, respectively.30,31 In Australia, the Buruli ulcer is also known as the Bairnsdale ulcer. Other NTM can have a wide range of clinicopathologic appearances that are not specific to the infecting mycobacterium (Table 2). Additional lesions may appear weeks after the development of the initial cutaneous NTM lesion; typically, further nodules or ulcers will emerge along the path of lymphatic drainage towards the lymph nodes in a manner reflecting the so-called sporotrichoid spread. In immunosuppressed individuals, infection tends to be more disseminated and may not be associated with trauma. Disseminated cutaneous infections are defined by the involvement of more than one body site. There is usually a delay in the seeking of medical attention because the lesions demonstrate an apparently benign and variable appearance. In addition, diagnosis is often delayed as a result of the medical practitioner’s lack of International Journal of Dermatology 2014, 53, 1197–1204
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SG
SG
M. marinum
M. kansasii
“Fish tank granuloma” or “swimming pool granuloma” Tender erythematous nodule or pustule at site of inoculation Several months of incubation Sporotrichoid spread Papules, pustules, sporotrichoid verrucous nodules, ulcers or cellulitis Commonly in the setting of immunosuppression Children often infected Classically lower limbs Painless subcutaneous nodule which ulcerates Indolent course often leading to scarring and deformity Rare in immunocompetent subjects Disseminated painful subcutaneous nodules, scaling plaques and ulcers which may drain pus
Erythematous nodules, abscesses and sinus tracts
Erythematous nodules, cellulitis, ulcers, sinus tracts and abscesses
Erythematous nodules, cellulitis, ulcers, sinus tracts and abscesses
Clinical features
Treatment length in an immunocompetent host. RG, rapid-growing; SG, slow-growing.
Ubiquitous
Tropical areas and Africa In water sources draining rainforests
Ubiquitous
Fresh water, salt water, swimming pools, aquariums
Ubiquitous
Ubiquitous
Ubiquitous
Natural habitat
Primary cutaneous infection is rare, primarily a pulmonary pathogen
None known but dissemination to distant sites reported
Primarily a pulmonary pathogen
Endocarditis Osteomyelitis Meningitis Keratitis Mediastinitis Catheter-related infections Regional lymphadenitis Catheter-related infections Osteomyelitis Otitis media Endocarditis Pulmonary disease Otitis media Osteomyelitis Catheter-related infections None known
Other manifestations
WHO recommend initial 4-week course with monitored response; may be repeated11 Up to 1 year and for several weeks after symptoms and signs have resolved
Antimicrobial: ethambutol + clarithromycin/ azithromycin + rifampicin2
9–18 months
4–38 weeks37,38
3–6 months
3–6 months
3–12 months
Treatment lengtha
Difficult Surgical debridement Possible antimicrobials: rifampicin PLUS streptomycin amikacin42
Antimicrobial: combination isoniazid PLUS rifampicin and ethambutol2,37
Antimicrobial: clarithromycin, minocycline, doxycycline or ethambutol + rifampicin6,41
Antimicrobials: usually sensitive to clarithromycin (resistance reported in disseminated disease40), doxycycline and ciprofloxacin Suggested regime: as for M. fortuitum34 Surgical debridement PLUS antimicrobials; avoid monotherapy, clarithromycin + amikacin/ cefoxitin, or imipenem2,41
Antimicrobial: usually susceptible to clarithromycin, doxycycline, levofloaxacin or moxifloacin, co-trimoxazole27 Suggested regime: Ciprofloxacin and an aminoglycoside or imipenem clarithromycin34 Consider surgical debridement
Initial treatment options
Cutaneous non-tuberculous mycobacterial infections
a
SG
RG
M. abscessus
M. avium complex
RG
M. chelonae
SG
RG
M. fortuitum
M. ulcerans
RG or SG
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Organism
Table 2 Selected non-tuberculous mycobacteria (NTM) causing cutaneous disease
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Table 3 Differential diagnoses to be considered in cutaneous non-tuberculous mycobacterial (NTM) infection Infectious
Infiltrative or autoimmune
Other dermatoses
Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) or Panton– Valentine leukocidin-positive S. aureus Deep cutaneous fungal infections (e.g. coccidiomycosis, blastomycosis, sporotrichosis, actinomycosis) Chronic bacterial osteomyelitis Cat scratch disease Syphilitic gummata Leishmaniasis Lymphogranuloma venereum Amoibiasis Cutaneous tubercule bacilli infection Pyoderma gangrenosum Pseudolymphoma Sarcoidosis Discoid lupus erythematosus Cutaneous malignancy (e.g. squamous cell carcinoma) Psoriasis Hidradenitis suppuritiva Hypertrophic lichen planus Lichen nitidus/lichen spinulosis/keratosis pilaris Pitriasis rubra pilaris Nodular vasculitis Erythema nodosum
suspicion and the wide number of differential diagnoses (Table 3). How do I diagnose a cutaneous NTM infection?
As with cutaneous tuberculous infections, the diagnosis of NTM infections from skin lesions can be challenging. The routine culture of exudates from lesions can be misleading and may give rise to the rapid overgrowth of skin contaminants compared with the more slow-growing mycobacteria. The identification of Mycobacterium species from culture of skin biopsy material is the reference standard.2 Polymerase chain reaction may be used to screen for mycobacterial material before culture and DNA sequencing may be used to identify the exact subtype isolated from culture.2,14 The lengthy time required for tissue culture can delay diagnosis. Acid-fast staining of lesion exudates and skin biopsy frequently yield false negative findings as a result of low numbers of organisms.32 It is perhaps worth noting that not all laboratories are able to carry out mycobacterial culture: in the UK, laboratories must be accredited to perform this service and will require warning of clinical suspicion in order to process samples correctly with respect to culture medium and the temperature of incubation.33 Skin biopsies should also be sent for histopathological examination. The typical histopathological appearance of ª 2014 The International Society of Dermatology
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a cutaneous NTM infection, which may be the first pointer towards a suspected NTM infection, resembles that of suppurative granulomas, but other patterns are described and may also reflect host immunity.2,32 How do I treat a cutaneous NTM infection?
The optimal treatment regimes for skin and soft tissue infection with NTM are not well established. No largescale clinical trials have compared different antibiotic regimens or defined the appropriate length of treatment. The majority of studies have been small and retrospective, resulting in a lack of overall consensus. In 2000 and 2007, respectively, the British and American thoracic societies produced recommendations for the management of NTM pulmonary infections, from which details are often extrapolated to guide treatment for cutaneous infections.2,34 Susceptibility testing for isolates should be performed. Results are known to be quite different from susceptibility profiles of M. tuberculosis; for example, rapidly growing NTM are often resistant to antituberculous agents.2 Some superficial infections can be self-limiting (10–20%).29,35 Tetracyclines, macrolides, quinolones, antitubercular drugs, and co-trimoxazole are the most commonly used drugs (Table 2).34,36,37 Frustratingly for physicians and patients, because the culture of NTM requires time and thus information on the available spectrum of antimicrobial susceptibility is delayed, an empiric choice of antibiotic is made and hence therapy may fail initially. The optimal length of treatment is also not well defined, but deeper infections may require six months or more of treatment. In some NTM infections, such as those with M. abscessus, surgical debridement is useful in addition to antimicrobial treatments.34,36 It may be reasonable to give dual-agent therapy to minimize potential for the development of resistance, and it is suggested that antimicrobial therapy be continued for 4–8 weeks after the resolution of lesions.37,38 Other additional therapies have been reported as effective for some NTM infections, including cryotherapy, photodynamic therapy, electrodesiccation, and local hyperthermic therapy, but these are not in wide use.39 In the developing world, both diagnosis and treatment may be challenging, and therefore in localized disease the excision of cutaneous lesions may be most effective given the lack of facilities in which to achieve antimicrobial susceptibility. Conclusions Cutaneous mycobacterial disease may take many guises and may often appear benign in nature. Changing patterns in mycobacterial disease mean that physicians, surgeons, and those in general practice should familiarize International Journal of Dermatology 2014, 53, 1197–1204
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themselves with presentations, and diagnostic and therapeutic options. Chronic cutaneous lesions at the sites of trauma or surgical procedures, especially those that fail to respond to standard antibiotic therapy, should prompt the consideration of mycobacterial disease. Diagnosis remains challenging as a result of the lack of simple and rapid techniques for the isolation and identification of pathogens and the testing of susceptibility to drugs. The lack of randomized controlled trials looking at the efficacy of antimicrobial agents means that empiric therapy may result in treatment failure, necessitate prolonged combinations of antibiotics, and thus increase the probability of side effects and diminished compliance. Acknowledgment We would like to thank our colleague Dr. Alex Holme, Consultant Dermatologist, Department of Dermatology, Royal Infirmary of Edinburgh, Edinburgh, UK, for kindly providing the image used in Figure 1(c) in this review. Questions (See answers after references) 1 The most recognized body site for non-tuberculous mycobacterial (NTM) infection is: a Skin and soft tissue b Joints and bursae c Catheter-related d Lung e Bone 2 The most common group of NTM causing cutaneous infection in hospitals in developed countries is: a Scotochromogens b Non-chromogens c Rapid growers d Photochromogens 3 The main reservoir for NTM pathogens known to affect humans is: a Soil b Tap water c Hospital environments d Animals e Dust 4 Mycobacterium ulcerans is not endemic in: a West Africa b Southeast Asia c South America d Europe e Western Pacific 5 Cutaneous NTM infections are rarely identified in immunocompetent hosts? a True b False
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6 What is the reference standard test for diagnosis of cutaneous NTM infection? a Staining exudates for acid-fast bacilli b Routine swab for microscopy and culture c Culture of exudate for NTM species d Culture of skin biopsy for NTM species e Histopathological appearances of skin biopsy 7 What name is given to cutaneous NTM infections with M. ulcerans in Australia? a Buruli ulcer b Bairnsdale ulcer c Fish tank granuloma d Photochromogens e Kangri ulcer 8 To which group of drugs may cutaneous NTM infections be resistant most often? a Tetracycline b Macrolide c Quinolones d Antitubercular 9 In which cutaneous NTM infection is surgical debridement most often required as part of treatment? a Mycobacterium kansasii b Mycobacterium abscessus c Mycobacterium avium complex d Mycobacterium marinum 10 What is the current World Health Organization-recommended antibiotic treatment approach to M. ulcerans infection? a Isoniazid + rifampicin + ethambutol for 3– 12 months. b Ciprofloxacin + aminoglycoside or imipenem clarithromycin for 9–18 months c Rifampicin + streptomycin amikacin for 4 weeks and review response d Antibiotics are contraindicated
References 1 Pinner M. Atypical acid-fast microorganisms. Am Rev Tuberc 1935; 32: 424–445. 2 Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of non-tuberculous mycobacterial diseases. Am J Resp Crit Care Med 2007; 175: 367–416. 3 Brown-Elliott BA, Griffith DE, Wallace RJ Jr. Newly described or emerging human species of nontuberculous mycobacteria. Infect Dis Clin North Am 2002; 16: 187– 220. 4 Runyon EH. Anonymous mycobacteria in pulmonary disease. Med Clin North Am 1959; 43: 273–290. 5 Brown-Elliot BA, Wallace RJ Jr. Clinical and taxonomic status of pathogenic nonpigmented or late-pigmenting
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rapidly growing mycobacteria. Clin Microbiol Rev 2002; 15: 716–746. Wagner D, Young LS. Nontuberculous mycobacterial infections: a clinical review. Infection 2004; 32: 257–270. Phillips MS, von Reyn CF. Nosocomial infections due to nontuberculous mycobacteria. Clin Infect Dis 2001; 33: 1363–1374. Carson LA, Cusick LB, Bland LA, et al. Efficacy of chemical dosing methods for isolating nontuberculous mycobacteria from water supplies of dialysis centers. Appl Environ Microbiol 1988; 54: 1756–1760. Petitjean G, Fluckiger U, Sch€ aren S, et al. Vertebral osteomyelitis caused by non-tuberculous mycobacteria. Clin Microbiol Infect 2004; 10: 951–953. Palenque E. Skin disease and nontuberculous atypical mycobacteria. Int J Dermatol 2000; 39: 659–666. World Health Organization. Buruli Ulcer (Mycobacterium ulcerans infection). Fact sheet No. 199. Geneva: WHO 2012. http://www.who.int/mediacentre/ factsheets/fs199/en/index.html, [Accessed November 30, 2012]. Scott-Lang V, Doherty V, Kavanagh GM, et al. A review of cutaneous Mycobacterium chelonae infection in South-East Scotland, 2003–2013. Scottish Dermatology Society Annual General Meeting, May 23, 2013, Inverness. Wentworth AB, Drage LA, Wendenack NL, et al. Increased incidence of cutaneous nontuberculous mycobacterial infection, 1980–2009: a population-based study. Mayo Clin Proc 2013; 88: 38–45. Ngan GJ, Ng LM, Jureen R, et al. Development of multiplex PCR assays based on the 16S–23S rRNA internal transcribed spacer for the detection of clinically relevant nontuberculous mycobacteria. Lett Appl Microbiol 2011; 52: 546–554. Tiwari TS, Ray B, Jost KC Jr. Forty years of disinfectant failure: outbreak of post-injection Mycobacterium abscessus infection caused by contamination of benzalkonium chloride. Clin Infect Dis 2003; 36: 954– 962. Duarte RS, Lourencßo MCS, Fonseca LS, et al. Epidemic of postsurgical infections caused by Mycobacterium massiliense. J Clin Microbiol 2009; 47: 2149–2155. Hutcheson AC, Lang PG. Atypical mycobacterial infections following cutaneous surgery. Dermatol Surg 2007; 33: 109–113. Guevara-Patino A, Sandoval de Mora M, Farreras A, et al. Soft tissue infection due to Mycobacterium fortuitum following acupuncture: a case report and review of the literature. J Infect Dev Ctries 2010; 4: 521– 525. Grange JM. Mycobacterial infections following heart valve replacement. J Heart Valve Dis 1992; 1: 102–109. Kressel AB, Kidd F. Pseudo-outbreak of Mycobacterium chelonae and Methylobacterium mesophilicum caused by contamination of an automated endoscopy washer. Infect Control Hosp Epidemiol 2001; 22: 414–418.
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21 Coney PM, Thrush S. Cutaneous Mycobacterium fortuitum complicating breast reconstruction. J Plast Reconstr Aesthet Surg 2007; 60: 1162–1163. 22 Pennekamp A, Pfyffer GE, Wuest J, et al. Mycobacterium smegmatis infection in a healthy woman following a face lift: case report and review of the literature. Ann Plast Surg 1997; 39: 80–83. 23 Rao J, Golden TA, Fitzpatrick RE. Atypical mycobacterial infection following blepharoplasty and full-face skin resurfacing with CO2 laser. Dermatol Surg 2002; 28: 768–771. 24 Kim MJ, Mascola L. Mycobacterium chelonae infection after liposuction. Emerg Infect Dis 2010; 16: 1173–1175. 25 Horii KA, Jackson MA. Images in clinical medicine. Piercing-related nontuberculous mycobacterial infection. N Engl J Med 2010; 362: 2012. 26 Drage LA, Ecker PM, Orenstein R, et al. An outbreak of Mycobacterium chelonae infection in tattoos. J Am Acad Dermatol 2010; 62: 501–506. 27 Winthrop KL, Albridge K, South D, et al. The clinical management and outcome of nail salon acquired Mycobacterium fortuitum skin infection. Clin Infect Dis 2004; 38: 38–44. 28 Song H, Lee H, Choi G, et al. Cutaneous nontuberculous mycobacterial infection: a clinicopathological study of seven cases. Am J Dermatopathol 2009; 31: 227–231. 29 Lee WJ, Kang SM, Sung H, et al. Non-tuberculous mycobacterial infections of the skin: a retrospective study of 29 cases. J Dermatol 2010; 37: 965–972. 30 Greenberg AE, Kupka E. Swimming pool injuries, mycobacteria and tuberculosis-like disease. Publ Health Rep 1957; 72: 902. 31 Meyers WM, Shelly WM, Connor DH, et al. Human Mycobacterium ulcerans infections developing at sites of traumatized skin. Am J Trop Med Hyg 1974; 23: 91. 32 Bartralot R, Pujol RM, Garcˇa-Patos V, et al. 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 2000; 27: 124–149. 33 Department of Health. Tuberculosis prevention and treatment: a toolkit for planning, commissioning and delivering high-quality services in England. London: DoH 2007. http://www.dh.gov.uk/en/Publicationsandstatistics/ Publications/PublicationsPolicyAndGuidance/ DH_075621. [Accessed November 30, 2012.] 34 Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Management of opportunistic mycobacterial infections: Joint Tuberculosis Committee guidelines 1999. Thorax 2000; 55: 210–218. 35 Woods GL, Washington JA. Mycobacteria other than Mycobacterium tuberculosis. Review of microbiological and clinical aspects. Rev Infect Dis 1987; 9: 275–294. 36 Wallace RJ Jr, Brown BA, Silcox VA, et al. Clinical disease and drug susceptibility, and biochemical patterns
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of unnamed third biovariant complex of Mycobacterium fortuitum. J Infect Dis 1991; 163: 598–603. Jogi R, Tyring SK. Therapy of nontuberculous mycobacterial infections. Dermatol Ther 2004; 17: 491– 498. Ang P, Rattana-Apiromyakij N, Goh CL. Retrospective study of Mycobacterium marinum skin infections. Int J Dermatol 2000; 39: 343–347. Rallis E, Koumantaki-Mathioudaki E. Treatment of Mycobacterium marinum cutaneous infections. Expert Opin Pharmacother 2007; 8: 2965–2978. Wallace RJ Jr, Tanner D, Brennan PJ, et al. Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae. Ann Intern Med 1993; 119: 482–486. Dodiuk-Gad R, Dyachenko P, Ziv M, et al. Nontuberculous mycobacterial infections of the skin: a retrospective study of 25 cases. J Am Acad Dermatol 2007; 57: 413–420.
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42 Sizaire V, Nackers F, Comte E, et al. Mycobacterium ulcerans infection: control, diagnosis, and treatment. Lancet Infect Dis 2006; 6: 288–296.
Answer key 1d 2c 3b 4d 5b 6d 7b 8d 9b 10 c
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Cutaneous non-tuberculous mycobacterial infections Ruth C. Lamb1, MBChB, BMedSci, MRCP, and Goutam Dawn2, MBBS, MD, DNB, FRCP
1 Alan Lyell Centre for Dermatology, Southern General Hospital, Glasgow, UK, and 2Department of Dermatology, Monklands Hospital, Airdrie, UK
Correspondence Ruth C. Lamb, MBCHB, BMEDSCI, MRCP Alan Lyell Centre for Dermatology Southern General Hospital 1345 Govan Road, Glasgow G51 4TF, UK E-mail: [email protected]
Abstract Mycobacteria cause a range of diseases in both immunocompetent and immunosuppressed individuals and may affect many different organs. The most noticeable recent change in patterns of cutaneous mycobacterial infection refers to the increase in non-tuberculous mycobacterial (NTM) infections. This review focuses on the clinical manifestations, diagnosis, and treatment of cutaneous NTM infections. The MEDLINE, PubMed, and Cochrane Library databases were searched using the keywords “nontuberculous mycobacteria,” “atypical mycobacteria,” and “mycobacteria other than tubercle bacilli”. Publications on cutaneous NTM infections written in English were included in this review. Literature published by the World Health Organization was examined for further
Funding: None. Conflicts of interest: None
material. References in review articles were screened for other studies not already identified. The clinical features, diagnosis, and treatment of NTM infections were reviewed. Cutaneous mycobacterial disease may take many guises and may appear benign in nature. Chronic cutaneous lesions at the sites of trauma or surgical procedures, especially those that fail to respond to standard antibiotic therapy, should prompt the consideration of mycobacterial disease. The lack of rapid techniques for the identification of pathogens makes diagnosis challenging. The lack of randomized controlled trials on the efficacy of antimicrobial agents means that empiric therapy may fail, necessitate prolonged combinations of antibiotics, and increase the probability of side effects and diminished compliance.
Introduction
Materials and methods
Mycobacteria cause a range of diseases in both immunocompetent and immunosuppressed individuals and may affect many different organs. Despite a global decrease in tuberculosis, incidences of cutaneous mycobacterial infections seem to be increasing in developed countries.1,2 This is probably secondary to the increasing burden of immunocompromised individuals within the general population, immigration from endemic countries, improved laboratory identification techniques, and changes in human behavior that expose individuals to the culprit organisms. However, the most noticeable recent change in patterns of cutaneous mycobacterial infection is related to the increase in cutaneous non-tuberculous mycobacterial (NTM) infections.3 Cutaneous NTM infections are increasingly common among hospital-acquired infections and following cosmetic procedures, and thus the pathogens implicated are emerging as important in both primary and secondary care.3 This review focuses on the clinical manifestations, diagnosis, and treatment of cutaneous NTM infections.
The MEDLINE, PubMed, and Cochrane Library databases were
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searched using the keywords “non-tuberculous mycobacteria,” “atypical mycobacteria,” and “mycobacteria other than tubercle bacilli”. Publications on cutaneous NTM infections written in English were included in this review. Literature published by the World Health Organization was examined for further material. References in review articles were screened for other studies not already identified. The clinical features, diagnosis, and treatment of NTM infections were reviewed.
Results and discussion Background and classification
Non-tuberculous mycobacteria were not identified as human pathogens until the 1950s but are now thought to cause cutaneous infections more commonly than Mycobacterium tuberculosis.2,4 These non-motile acid-fast bacilli can be divided into slow-growing and rapidgrowing groups based on their culture characteristics.4 Runyon4 further classified the NTM group based on its International Journal of Dermatology 2014, 53, 1197–1204
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Table 1 Modified classification of non-tuberculous mycobacteria
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Runyon group4
Phenotype
Colony characteristics
Mycobacterium species
I II
Photochromogens Scotochromogens
Produce yellow pigment when exposed to light Produce yellow–orange pigment when exposed to light or in the dark
III
Non-chromogens
Slow growers No pigment production
IV
Rapid growers
Produce colonies in 3–5 days No pigment production
M. marinum, M. kansasii M. scrofulaceum M. gordonae M. avium M. intracellulare M. haemophilum M. ulcerans M. fortuitum group: M. fortuitum M. peregrinum M. septicum M. mageritense M. chelonae–abscessus group: M. chelonae M. abscessus M. immunogenum M. smegmatis group: M. smegmatis M. goodie M. wolinskyi M. massiliense
a
This list is not exhaustive.
members’ pigment-forming properties when cultured (Table 1). Recent advances have meant that these bacteria can now also be grouped according to genotypic characteristics.4,5 In addition, because of their similar clinical, etiologic, and antigenic characteristics, some groups of NTM are considered together as complexes; for example, Mycobacterium avium and Mycobacterium intracellulare produce identical disease and are found together endemically and are therefore grouped together as the M. avium–intracellulare complex. Likewise, Mycobacterium fortuitum and Mycobacterium chelonae are often grouped together as the M. fortuitum complex. How does a patient acquire infection with an NTM?
Non-tuberculous mycobacteria, especially the rapidly growing species, are hardy, environmental saprophytes found commonly in nature and can be isolated from soil, dust, water, vegetation, animals, and hospital environments.6,7 They may also colonize body surfaces, and thus multiple isolates may be required from non-sterile sites to establish disease, whereas one positive culture from a sterile site with supportive histopathology may suffice.2 Tap water is the main reservoir for most human NTM pathogens. Carson et al. found that 55% of incoming city water in hemodialysis centers throughout the USA contained rapidly growing mycobacteria.8 Thus, it seems logical that NTM infections are acquired by environmental exposure rather than by person-to-person spread as in tuberculous infections. Although contact with International Journal of Dermatology 2014, 53, 1197–1204
environmental mycobacteria is frequent, overt disease is uncommon because the organisms are relatively low in virulence. In addition, the organisms usually require the skin barrier to be broken in order to cause infection. Pulmonary disease is the most recognized NTM infection, but lymphadenitis, skin and soft tissue infections, catheter-related infections, disseminated infections, and chronic granulomatous infections of bursae, joints, tendon sheaths, and bones may also occur.2,9 Incubation periods can vary from two weeks to nine months and depend on the characteristics of the infecting mycobacterium, as well as on host-related factors.10 Almost all NTM can cause cutaneous disease. The most common species causing cutaneous NTM infections in Europe and the USA are Mycobacterium marinum (Fig. 1a), and the rapidly growing Mycobacterium abscessus, M. fortuitum, and M. chelonae (Fig. 1b).6 True incidences are difficult to determine because these are not communicable diseases and may be under-reported. Mycobacterium ulcerans has a more limited geographic distribution: the majority of cases occur in tropical and subtropical regions of West and Central Africa, Southeast Asia, South America, and the Western Pacific.6,11 Why is the incidence of NTM infections increasing?
Multiple cases and small case series of outbreaks of cutaneous NTM infections have been reported in the literature over the last 30 years. Although exact incidences are difficult to define, recent data presented at the annual ª 2014 The International Society of Dermatology
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(c)
Figure 1 (a) Clinical examination of a Mycobacterium marinum infection on the left hand demonstrates warty nodules with a sporotrichoid spread. (b) Mycobacterium chelonae infection on the right leg manifests as a furuncle-like lesion with evidence of pus and early surrounding cellulitis. (c) Mycobacterium chelonae contaminating gray tattoo ink: erythematous nodules can be seen between the blue claws in the tattoo
Scottish Dermatology Society meeting on NTM incidence between 2003 and 2013 identified 67 cases of cutaneous NTM infection, including 23 cases of M. chelonae infection and 15 cases of M. marinum infection.12 In the USA, a population-based study conducted in Minnesota found a local incidence of 1.3 per 100,000 person-years between 1980 and 2009 and a higher incidence in the period between 2000 and 2009 (2.0 per 100,000 person-years).13 The ability to identify NTM infections through more advanced laboratory techniques such as with polymerase chain reaction (PCR) is likely to have had some influence on the increasing incidence of infections.14 In addition, it is possible that the increased popularity of cutaneous surgery, particularly within the cosmetic industry, may be contributing. Some NTM are able to withstand sterilization and to colonize or contaminate antiseptics, resulting in infections in surgical patients. An example of such an event refers to an outbreak following the contamination of benzalkonium chloride with NTM, which caused infection in 12 patients following steroid injections.15 In Brazil, an epidemic of infections after video-assisted surgery gave rise to over 1050 probable cases of infection by Mycobacterium massiliense which had developed tolerance to 2% gluteraldehyde.16 Infections with NTM have also been described in association with skin surgery, acupuncture, cardiothoracic surgery, endoscopy, breast reconstruction, plastic surgery, laser resurfacing, laser eye surgery, liposuction, body piercing, and tattoos.17–26 Perhaps the most notable report cited an outbreak of 61 M. fortuitum infections that occurred after foot baths performed before pedicures at a spa in the USA.27 Although the increasing use of immunosuppressive treatments and acquired immunosuppression are also likely to have contributed to growth in incidence rates, many of the infections affect immunocompetent individuals. In keeping with this, several recent retrospective ª 2014 The International Society of Dermatology
studies of cutaneous NTM infections found that 72–86% of patients were immunocompetent.28,29 Infections in immunocompromised subjects have been noted to arise particularly in patients taking glucocorticoid therapy; this was also apparent in recent Scottish data, which showed that approximately 50% of all patients diagnosed with M. chelonae infections over a 10-year period were taking a concurrent systemic glucocorticoid.12 When should I suspect cutaneous infection with NTM?
Non-tuberculous mycobacterial infections should be considered when the clinician is confronted with a patient with persistent abscesses or cellulitis especially in the setting of recent surgery, trauma, or immunosuppression. The main clinical feature refers to painful erythematous nodules that may ulcerate and form abscesses; however, morphology is variable. Infections with M. marinum and M. ulcerans result in well-defined clinicopathologic entities, known as fish tank granuloma and Buruli ulcer, respectively.30,31 In Australia, the Buruli ulcer is also known as the Bairnsdale ulcer. Other NTM can have a wide range of clinicopathologic appearances that are not specific to the infecting mycobacterium (Table 2). Additional lesions may appear weeks after the development of the initial cutaneous NTM lesion; typically, further nodules or ulcers will emerge along the path of lymphatic drainage towards the lymph nodes in a manner reflecting the so-called sporotrichoid spread. In immunosuppressed individuals, infection tends to be more disseminated and may not be associated with trauma. Disseminated cutaneous infections are defined by the involvement of more than one body site. There is usually a delay in the seeking of medical attention because the lesions demonstrate an apparently benign and variable appearance. In addition, diagnosis is often delayed as a result of the medical practitioner’s lack of International Journal of Dermatology 2014, 53, 1197–1204
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SG
SG
M. marinum
M. kansasii
“Fish tank granuloma” or “swimming pool granuloma” Tender erythematous nodule or pustule at site of inoculation Several months of incubation Sporotrichoid spread Papules, pustules, sporotrichoid verrucous nodules, ulcers or cellulitis Commonly in the setting of immunosuppression Children often infected Classically lower limbs Painless subcutaneous nodule which ulcerates Indolent course often leading to scarring and deformity Rare in immunocompetent subjects Disseminated painful subcutaneous nodules, scaling plaques and ulcers which may drain pus
Erythematous nodules, abscesses and sinus tracts
Erythematous nodules, cellulitis, ulcers, sinus tracts and abscesses
Erythematous nodules, cellulitis, ulcers, sinus tracts and abscesses
Clinical features
Treatment length in an immunocompetent host. RG, rapid-growing; SG, slow-growing.
Ubiquitous
Tropical areas and Africa In water sources draining rainforests
Ubiquitous
Fresh water, salt water, swimming pools, aquariums
Ubiquitous
Ubiquitous
Ubiquitous
Natural habitat
Primary cutaneous infection is rare, primarily a pulmonary pathogen
None known but dissemination to distant sites reported
Primarily a pulmonary pathogen
Endocarditis Osteomyelitis Meningitis Keratitis Mediastinitis Catheter-related infections Regional lymphadenitis Catheter-related infections Osteomyelitis Otitis media Endocarditis Pulmonary disease Otitis media Osteomyelitis Catheter-related infections None known
Other manifestations
WHO recommend initial 4-week course with monitored response; may be repeated11 Up to 1 year and for several weeks after symptoms and signs have resolved
Antimicrobial: ethambutol + clarithromycin/ azithromycin + rifampicin2
9–18 months
4–38 weeks37,38
3–6 months
3–6 months
3–12 months
Treatment lengtha
Difficult Surgical debridement Possible antimicrobials: rifampicin PLUS streptomycin amikacin42
Antimicrobial: combination isoniazid PLUS rifampicin and ethambutol2,37
Antimicrobial: clarithromycin, minocycline, doxycycline or ethambutol + rifampicin6,41
Antimicrobials: usually sensitive to clarithromycin (resistance reported in disseminated disease40), doxycycline and ciprofloxacin Suggested regime: as for M. fortuitum34 Surgical debridement PLUS antimicrobials; avoid monotherapy, clarithromycin + amikacin/ cefoxitin, or imipenem2,41
Antimicrobial: usually susceptible to clarithromycin, doxycycline, levofloaxacin or moxifloacin, co-trimoxazole27 Suggested regime: Ciprofloxacin and an aminoglycoside or imipenem clarithromycin34 Consider surgical debridement
Initial treatment options
Cutaneous non-tuberculous mycobacterial infections
a
SG
RG
M. abscessus
M. avium complex
RG
M. chelonae
SG
RG
M. fortuitum
M. ulcerans
RG or SG
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Organism
Table 2 Selected non-tuberculous mycobacteria (NTM) causing cutaneous disease
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Table 3 Differential diagnoses to be considered in cutaneous non-tuberculous mycobacterial (NTM) infection Infectious
Infiltrative or autoimmune
Other dermatoses
Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) or Panton– Valentine leukocidin-positive S. aureus Deep cutaneous fungal infections (e.g. coccidiomycosis, blastomycosis, sporotrichosis, actinomycosis) Chronic bacterial osteomyelitis Cat scratch disease Syphilitic gummata Leishmaniasis Lymphogranuloma venereum Amoibiasis Cutaneous tubercule bacilli infection Pyoderma gangrenosum Pseudolymphoma Sarcoidosis Discoid lupus erythematosus Cutaneous malignancy (e.g. squamous cell carcinoma) Psoriasis Hidradenitis suppuritiva Hypertrophic lichen planus Lichen nitidus/lichen spinulosis/keratosis pilaris Pitriasis rubra pilaris Nodular vasculitis Erythema nodosum
suspicion and the wide number of differential diagnoses (Table 3). How do I diagnose a cutaneous NTM infection?
As with cutaneous tuberculous infections, the diagnosis of NTM infections from skin lesions can be challenging. The routine culture of exudates from lesions can be misleading and may give rise to the rapid overgrowth of skin contaminants compared with the more slow-growing mycobacteria. The identification of Mycobacterium species from culture of skin biopsy material is the reference standard.2 Polymerase chain reaction may be used to screen for mycobacterial material before culture and DNA sequencing may be used to identify the exact subtype isolated from culture.2,14 The lengthy time required for tissue culture can delay diagnosis. Acid-fast staining of lesion exudates and skin biopsy frequently yield false negative findings as a result of low numbers of organisms.32 It is perhaps worth noting that not all laboratories are able to carry out mycobacterial culture: in the UK, laboratories must be accredited to perform this service and will require warning of clinical suspicion in order to process samples correctly with respect to culture medium and the temperature of incubation.33 Skin biopsies should also be sent for histopathological examination. The typical histopathological appearance of ª 2014 The International Society of Dermatology
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a cutaneous NTM infection, which may be the first pointer towards a suspected NTM infection, resembles that of suppurative granulomas, but other patterns are described and may also reflect host immunity.2,32 How do I treat a cutaneous NTM infection?
The optimal treatment regimes for skin and soft tissue infection with NTM are not well established. No largescale clinical trials have compared different antibiotic regimens or defined the appropriate length of treatment. The majority of studies have been small and retrospective, resulting in a lack of overall consensus. In 2000 and 2007, respectively, the British and American thoracic societies produced recommendations for the management of NTM pulmonary infections, from which details are often extrapolated to guide treatment for cutaneous infections.2,34 Susceptibility testing for isolates should be performed. Results are known to be quite different from susceptibility profiles of M. tuberculosis; for example, rapidly growing NTM are often resistant to antituberculous agents.2 Some superficial infections can be self-limiting (10–20%).29,35 Tetracyclines, macrolides, quinolones, antitubercular drugs, and co-trimoxazole are the most commonly used drugs (Table 2).34,36,37 Frustratingly for physicians and patients, because the culture of NTM requires time and thus information on the available spectrum of antimicrobial susceptibility is delayed, an empiric choice of antibiotic is made and hence therapy may fail initially. The optimal length of treatment is also not well defined, but deeper infections may require six months or more of treatment. In some NTM infections, such as those with M. abscessus, surgical debridement is useful in addition to antimicrobial treatments.34,36 It may be reasonable to give dual-agent therapy to minimize potential for the development of resistance, and it is suggested that antimicrobial therapy be continued for 4–8 weeks after the resolution of lesions.37,38 Other additional therapies have been reported as effective for some NTM infections, including cryotherapy, photodynamic therapy, electrodesiccation, and local hyperthermic therapy, but these are not in wide use.39 In the developing world, both diagnosis and treatment may be challenging, and therefore in localized disease the excision of cutaneous lesions may be most effective given the lack of facilities in which to achieve antimicrobial susceptibility. Conclusions Cutaneous mycobacterial disease may take many guises and may often appear benign in nature. Changing patterns in mycobacterial disease mean that physicians, surgeons, and those in general practice should familiarize International Journal of Dermatology 2014, 53, 1197–1204
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themselves with presentations, and diagnostic and therapeutic options. Chronic cutaneous lesions at the sites of trauma or surgical procedures, especially those that fail to respond to standard antibiotic therapy, should prompt the consideration of mycobacterial disease. Diagnosis remains challenging as a result of the lack of simple and rapid techniques for the isolation and identification of pathogens and the testing of susceptibility to drugs. The lack of randomized controlled trials looking at the efficacy of antimicrobial agents means that empiric therapy may result in treatment failure, necessitate prolonged combinations of antibiotics, and thus increase the probability of side effects and diminished compliance. Acknowledgment We would like to thank our colleague Dr. Alex Holme, Consultant Dermatologist, Department of Dermatology, Royal Infirmary of Edinburgh, Edinburgh, UK, for kindly providing the image used in Figure 1(c) in this review. Questions (See answers after references) 1 The most recognized body site for non-tuberculous mycobacterial (NTM) infection is: a Skin and soft tissue b Joints and bursae c Catheter-related d Lung e Bone 2 The most common group of NTM causing cutaneous infection in hospitals in developed countries is: a Scotochromogens b Non-chromogens c Rapid growers d Photochromogens 3 The main reservoir for NTM pathogens known to affect humans is: a Soil b Tap water c Hospital environments d Animals e Dust 4 Mycobacterium ulcerans is not endemic in: a West Africa b Southeast Asia c South America d Europe e Western Pacific 5 Cutaneous NTM infections are rarely identified in immunocompetent hosts? a True b False
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6 What is the reference standard test for diagnosis of cutaneous NTM infection? a Staining exudates for acid-fast bacilli b Routine swab for microscopy and culture c Culture of exudate for NTM species d Culture of skin biopsy for NTM species e Histopathological appearances of skin biopsy 7 What name is given to cutaneous NTM infections with M. ulcerans in Australia? a Buruli ulcer b Bairnsdale ulcer c Fish tank granuloma d Photochromogens e Kangri ulcer 8 To which group of drugs may cutaneous NTM infections be resistant most often? a Tetracycline b Macrolide c Quinolones d Antitubercular 9 In which cutaneous NTM infection is surgical debridement most often required as part of treatment? a Mycobacterium kansasii b Mycobacterium abscessus c Mycobacterium avium complex d Mycobacterium marinum 10 What is the current World Health Organization-recommended antibiotic treatment approach to M. ulcerans infection? a Isoniazid + rifampicin + ethambutol for 3– 12 months. b Ciprofloxacin + aminoglycoside or imipenem clarithromycin for 9–18 months c Rifampicin + streptomycin amikacin for 4 weeks and review response d Antibiotics are contraindicated
References 1 Pinner M. Atypical acid-fast microorganisms. Am Rev Tuberc 1935; 32: 424–445. 2 Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of non-tuberculous mycobacterial diseases. Am J Resp Crit Care Med 2007; 175: 367–416. 3 Brown-Elliott BA, Griffith DE, Wallace RJ Jr. Newly described or emerging human species of nontuberculous mycobacteria. Infect Dis Clin North Am 2002; 16: 187– 220. 4 Runyon EH. Anonymous mycobacteria in pulmonary disease. Med Clin North Am 1959; 43: 273–290. 5 Brown-Elliot BA, Wallace RJ Jr. Clinical and taxonomic status of pathogenic nonpigmented or late-pigmenting
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rapidly growing mycobacteria. Clin Microbiol Rev 2002; 15: 716–746. Wagner D, Young LS. Nontuberculous mycobacterial infections: a clinical review. Infection 2004; 32: 257–270. Phillips MS, von Reyn CF. Nosocomial infections due to nontuberculous mycobacteria. Clin Infect Dis 2001; 33: 1363–1374. Carson LA, Cusick LB, Bland LA, et al. Efficacy of chemical dosing methods for isolating nontuberculous mycobacteria from water supplies of dialysis centers. Appl Environ Microbiol 1988; 54: 1756–1760. Petitjean G, Fluckiger U, Sch€ aren S, et al. Vertebral osteomyelitis caused by non-tuberculous mycobacteria. Clin Microbiol Infect 2004; 10: 951–953. Palenque E. Skin disease and nontuberculous atypical mycobacteria. Int J Dermatol 2000; 39: 659–666. World Health Organization. Buruli Ulcer (Mycobacterium ulcerans infection). Fact sheet No. 199. Geneva: WHO 2012. http://www.who.int/mediacentre/ factsheets/fs199/en/index.html, [Accessed November 30, 2012]. Scott-Lang V, Doherty V, Kavanagh GM, et al. A review of cutaneous Mycobacterium chelonae infection in South-East Scotland, 2003–2013. Scottish Dermatology Society Annual General Meeting, May 23, 2013, Inverness. Wentworth AB, Drage LA, Wendenack NL, et al. Increased incidence of cutaneous nontuberculous mycobacterial infection, 1980–2009: a population-based study. Mayo Clin Proc 2013; 88: 38–45. Ngan GJ, Ng LM, Jureen R, et al. Development of multiplex PCR assays based on the 16S–23S rRNA internal transcribed spacer for the detection of clinically relevant nontuberculous mycobacteria. Lett Appl Microbiol 2011; 52: 546–554. Tiwari TS, Ray B, Jost KC Jr. Forty years of disinfectant failure: outbreak of post-injection Mycobacterium abscessus infection caused by contamination of benzalkonium chloride. Clin Infect Dis 2003; 36: 954– 962. Duarte RS, Lourencßo MCS, Fonseca LS, et al. Epidemic of postsurgical infections caused by Mycobacterium massiliense. J Clin Microbiol 2009; 47: 2149–2155. Hutcheson AC, Lang PG. Atypical mycobacterial infections following cutaneous surgery. Dermatol Surg 2007; 33: 109–113. Guevara-Patino A, Sandoval de Mora M, Farreras A, et al. Soft tissue infection due to Mycobacterium fortuitum following acupuncture: a case report and review of the literature. J Infect Dev Ctries 2010; 4: 521– 525. Grange JM. Mycobacterial infections following heart valve replacement. J Heart Valve Dis 1992; 1: 102–109. Kressel AB, Kidd F. Pseudo-outbreak of Mycobacterium chelonae and Methylobacterium mesophilicum caused by contamination of an automated endoscopy washer. Infect Control Hosp Epidemiol 2001; 22: 414–418.
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21 Coney PM, Thrush S. Cutaneous Mycobacterium fortuitum complicating breast reconstruction. J Plast Reconstr Aesthet Surg 2007; 60: 1162–1163. 22 Pennekamp A, Pfyffer GE, Wuest J, et al. Mycobacterium smegmatis infection in a healthy woman following a face lift: case report and review of the literature. Ann Plast Surg 1997; 39: 80–83. 23 Rao J, Golden TA, Fitzpatrick RE. Atypical mycobacterial infection following blepharoplasty and full-face skin resurfacing with CO2 laser. Dermatol Surg 2002; 28: 768–771. 24 Kim MJ, Mascola L. Mycobacterium chelonae infection after liposuction. Emerg Infect Dis 2010; 16: 1173–1175. 25 Horii KA, Jackson MA. Images in clinical medicine. Piercing-related nontuberculous mycobacterial infection. N Engl J Med 2010; 362: 2012. 26 Drage LA, Ecker PM, Orenstein R, et al. An outbreak of Mycobacterium chelonae infection in tattoos. J Am Acad Dermatol 2010; 62: 501–506. 27 Winthrop KL, Albridge K, South D, et al. The clinical management and outcome of nail salon acquired Mycobacterium fortuitum skin infection. Clin Infect Dis 2004; 38: 38–44. 28 Song H, Lee H, Choi G, et al. Cutaneous nontuberculous mycobacterial infection: a clinicopathological study of seven cases. Am J Dermatopathol 2009; 31: 227–231. 29 Lee WJ, Kang SM, Sung H, et al. Non-tuberculous mycobacterial infections of the skin: a retrospective study of 29 cases. J Dermatol 2010; 37: 965–972. 30 Greenberg AE, Kupka E. Swimming pool injuries, mycobacteria and tuberculosis-like disease. Publ Health Rep 1957; 72: 902. 31 Meyers WM, Shelly WM, Connor DH, et al. Human Mycobacterium ulcerans infections developing at sites of traumatized skin. Am J Trop Med Hyg 1974; 23: 91. 32 Bartralot R, Pujol RM, Garcˇa-Patos V, et al. 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 2000; 27: 124–149. 33 Department of Health. Tuberculosis prevention and treatment: a toolkit for planning, commissioning and delivering high-quality services in England. London: DoH 2007. http://www.dh.gov.uk/en/Publicationsandstatistics/ Publications/PublicationsPolicyAndGuidance/ DH_075621. [Accessed November 30, 2012.] 34 Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Management of opportunistic mycobacterial infections: Joint Tuberculosis Committee guidelines 1999. Thorax 2000; 55: 210–218. 35 Woods GL, Washington JA. Mycobacteria other than Mycobacterium tuberculosis. Review of microbiological and clinical aspects. Rev Infect Dis 1987; 9: 275–294. 36 Wallace RJ Jr, Brown BA, Silcox VA, et al. Clinical disease and drug susceptibility, and biochemical patterns
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of unnamed third biovariant complex of Mycobacterium fortuitum. J Infect Dis 1991; 163: 598–603. Jogi R, Tyring SK. Therapy of nontuberculous mycobacterial infections. Dermatol Ther 2004; 17: 491– 498. Ang P, Rattana-Apiromyakij N, Goh CL. Retrospective study of Mycobacterium marinum skin infections. Int J Dermatol 2000; 39: 343–347. Rallis E, Koumantaki-Mathioudaki E. Treatment of Mycobacterium marinum cutaneous infections. Expert Opin Pharmacother 2007; 8: 2965–2978. Wallace RJ Jr, Tanner D, Brennan PJ, et al. Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae. Ann Intern Med 1993; 119: 482–486. Dodiuk-Gad R, Dyachenko P, Ziv M, et al. Nontuberculous mycobacterial infections of the skin: a retrospective study of 25 cases. J Am Acad Dermatol 2007; 57: 413–420.
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42 Sizaire V, Nackers F, Comte E, et al. Mycobacterium ulcerans infection: control, diagnosis, and treatment. Lancet Infect Dis 2006; 6: 288–296.
Answer key 1d 2c 3b 4d 5b 6d 7b 8d 9b 10 c
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