Nontuberculous mycobacteria

Nontuberculous mycobacteria (NTM), also known as environmental mycobacteria, atypical mycobacteria[1] and mycobacteria other than tuberculosis (MOTT), are mycobacteria which do not cause tuberculosis or leprosy (also known as Hansen's disease). NTM do cause pulmonary diseases that resemble tuberculosis.[2] Mycobacteriosis is any of these illnesses, usually meant to exclude tuberculosis. They occur in many animals, including humans.

Introduction

Mycobacteria are a family of small, rod-shaped bacilli that can be classified into 3 main groups for the purpose of diagnosis and treatment:

Still images of mycobacterium abscessus growing in culture over a period of 60 hours. Courtesy of Dr. Y. Av-Gay at Division of Infectious Diseases at University of British Columbia, Vancouver, Canada.

Taxonomy

In 1959, botanist Ernest Runyon put these human disease-associated bacteria into four groups (Runyon classification):[3]

The number of identified and cataloged NTM species has been increasing rapidly, from about 50 in 1997 to over 125 by January 2007. The surge is mainly due to improved isolation and identification technique.[5]

However, even with these new techniques, the Runyon classification is still sometimes used to organize the mycobacteria into categories.[6]

Epidemiology

NTM are widely distributed in the environment, particularly in wet soil, marshland, streams, rivers and estuaries. Different species of NTM prefer different types of environment.[7] Human disease is believed to be acquired from environmental exposures, and unlike tuberculosis and leprosy, there has been no evidence of animal-to-human or human-to-human transmission of NTM, hence the alternative label "environmental bacteria".[8]

NTM diseases have been seen in most industrialized countries, where incidence rates vary from 1.0 to 1.8 cases per 100,000 persons. Recent studies, including one done in Ontario, Canada, suggest that incidence is much higher. Pulmonary NTM is estimated by some experts in the field to be at least ten times more common than TB in the U.S., with at least 150,000 cases per year.

Most NTM disease cases involve the species known as Mycobacterium avium complex or MAC for short, M. abscessus, M. fortuitum and M. kansasii. M. abscessus is being seen with increasing frequency and is particularly difficult to treat.[8]

Mayo Clinic researchers found a three-fold increased incidence of cutaneous NTM infection between 1980 and 2009 in a population-based study of residents of Olmsted County, Minnesota. The most common species were M. marinum, accounting for 45% of cases and M. chelonae and M. abscessus, together accounting for 32% of patients.[9] M. chelonae infection outbreaks, as a consequence of tattooing with infected ink, have been reported in the United Kingdom[10] and the United States.[11]

Rapidly growing NTMs are implicated in catheter infections, post-LASIK, skin and soft tissue (especially post-cosmetic surgery) and pulmonary infections.[12]

Pathogenesis

The most common clinical manifestation of NTM disease is lung disease, but lymphatic, skin/soft tissue, and disseminated disease are also important.[8]

Pulmonary disease caused by NTM is most often seen in post-menopausal women and patients with underlying lung disease such as cystic fibrosis, bronchiectasis, and prior tuberculosis. It is not uncommon for Alpha 1-antitrypsin deficiency, Marfan Syndrome and Primary ciliary dyskinesia patients to have pulmonary NTM colonization and/or infection. Pulmonary NTM can also be found in individuals with AIDS and malignant disease. It can be caused by many NTM species which depends on region, but most frequently MAC and M. kansasii.[13]

Clinical symptoms vary in scope and intensity but commonly include chronic cough, often with purulent sputum. Hemoptysis may also be present. Systemic symptoms include malaise, fatigue, and weight loss in advance disease [14]. The diagnosis of M. abscessus pulmonary infection requires the presence of symptoms, radiologic abnormalities, and microbiologic cultures.

Lymphadenitis can be caused by various species that is different from one place to another; but again, MAC is the main cause worldwide. Most patient are aged less than 5 years, but the incidence is rare for children having BCG vaccine. The disease has a high curability.[15]

Soft tissue disease due to NTM infection include post-traumatic abscesses (caused by rapid growers), swimming pool granuloma (caused by M. marinum) and Buruli ulcer (caused by M. ulcerans or M. shinshuense). Post-traumatic abscesses most commonly occur after injection.[15]

Disseminated mycobacterial disease was common in US and European AIDS patients in the 1980s and early 1990s, though the incidence has declined in developed nations since the introduction of highly active antiretroviral therapy. It can also occur in individuals after having renal transplantation.[13]

Diagnosis

A) Neck and chest of a 53-year-old woman 14 days after fractionated CO2 laser resurfacing, showing Nontuberculous Mycobacterial infection B) Neck of the patient after 5 months of multidrug therapy and pulsed dye laser treatment.

Diagnosis of opportunistic mycobacteria is made by repeated isolation and identification of the pathogen with compatible clinical and radiological features. Similar to M. tuberculosis, most nontuberculous mycobacteria can be detected microscopically and grow on Löwenstein-Jensen medium.[13] Many reference centres now use a nucleic acid-based method such as sequence differences detection in the gene coding for 16S ribosomal RNA to identify the species.[7]

Pulmonary NTM disease diagnosis requires both identification of the mycobacterium in the patient's lung(s) as well as a high resolution CT scan of the lungs.

Treatment

The management of NTM lung disease is a challenge due to antibiotic-resistance strains of NTM and toxicity and cost associated with combinations of multiple drugs. Of special concern are infections caused by [abscessus] (M. abscessus)complex, a group of rapidly growing, multidrug-resistant NTM species that are ubiquitous in soil and water [16]. Treatment guidelines for NTM issued by the American Thoracic Society recommends a multi-drug regimen that includes Clarithromycin (Biaxin) or Axithromycin (Zithromax), Rifampin (Rifadin) or Rifabutin (Mycobutin) and Ethambutol (Myambutol), and Streptomycin or Amikacin (Amikin). Click here for a summary of available medications and their side effects.

Unfortunately, drug-resistance is commonly observed in several rapidly growing NTM strains, leading to failure of conventional therapeutic drugs. This has led FDA to identify NTM as a Disease Area to be the focus of FDA in 2016/2017, with special attention to high-risk patients with underlying lung disease such as cystic fibrosis (link here).

A few promising investigational new drugs are currently in Clinical trials for the treatment of NTM lung disease:

1. AIT Therapeutics (AIT) is recruiting patients diagnosed with M. abscessus NTM lung infection for treatment with inhaled nitric oxide (NO) gas (Link to clinicaltrials.gov). NO is naturally produced by the body’s immune system against invading bacterial and viral pathogens. The pharmacology and toxicity of inhaled NO in humans is well defines and its application has been approved by the FDA mainly as a vasodilator in pulmonary hypertension (reviewed here). Nitric oxide has also been shown to be effective against most antibiotic resistant bacterial strains [17].

2. Insmed Incorporated is recruiting patients diagnosed with NTM lung infection that is caused by Mycobacterium avium complex (MAC) to enroll in the “CONVERT” study. The CONVERT study is evaluating the efficacy of a novel delivery method for Amikacin (Liposomal Amikacin for inhalation) (link to clinicaltrials.gov).

Research

French researchers finalized the genome sequence of M. abscessus in March 2008. The genome is available at http://www.ncbi.nlm.nih.gov/sites/entrez?db=genome&cmd=search&term=abscessus.

Notes

  1. ↑ Nontuberculous Mycobacteria at the US National Library of Medicine Medical Subject Headings (MeSH)
  2. ↑ American Thoracic Society (1997). "Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association". American Journal of Respiratory and Critical Care Medicine. 156 (2 Pt 2): S1–25. PMID 9279284. doi:10.1164/ajrccm.156.2.atsstatement.
  3. 1 2 3 Grange, p. 221
  4. 1 2 Grange, p. 222
  5. ↑ American Thoracic Society, p.369
  6. ↑ Tortoli E (April 2003). "Impact of genotypic studies on mycobacterial taxonomy: the new mycobacteria of the 1990s". Clinical Microbiology Reviews. 16 (2): 319–54. PMC 153139 Freely accessible. PMID 12692101. doi:10.1128/CMR.16.2.319-354.2003.
  7. 1 2 Grange, p. 226
  8. 1 2 3 American Thoracic Society, p. 370
  9. ↑ Wentworth, A.B.; Drage L.A.; Wengenack N.L.; Wilson J.W.; Lohse C.M. (4 December 2012). "Increased Incidence of Cutaneous Nontuberculous Mycobacterial Infection, 1980 to 2009: A Population-Based Study.". Mayo Clinic Proceedings. 88 (1): 38–45. PMID 23218797. doi:10.1016/j.mayocp.2012.06.029.
  10. ↑ Sergeant, A.; Conaglen P.; Laurenson I.F.; Claxton P.; Mathers M.E.; Kavanagh G.M.; Tidman M.J. (25 July 2012). "Mycobacterium chelonae infection: a complication of tattooing.". Clinical and Experimental Dermatology. 38 (2): 140–2. PMID 22831709. doi:10.1111/j.1365-2230.2012.04421.x.
  11. ↑ Centers for Disease Control and Prevention (CDC) (24 August 2012). "Tattoo-associated nontuberculous mycobacterial skin infections--multiple states, 2011-2012.". CDC - Morbidity and Mortality Weekly Report (MMWR). 61 (33): 635–6. PMID 22914227.
  12. ↑ De Groote, MA and Huitt G. Infections due to Rapidly Growing Mycobacteria. Clinical Infectious Diseases 2006;42:1756–1763.
  13. 1 2 3 Grange, p. 225
  14. ↑ Johnson & Odell (2014); Nontuberculous mycobacterial pulmonary infections. J Thorac Dis.; 6(3): 210–220. PMCID: 3949190
  15. 1 2 Grange, p. 223
  16. ↑ Lee et al., 2015
  17. ↑ Deppisch C et al. 2016

References


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