The growing threat of nontuberculous mycobacteria

Nontuberculous mycobacteria (NTM) present a growing threat – a number of species are drug resistant and little is understood about how and where infection with these organisms occurs. A meeting organised by Papworth Hospital NHS Foundation Trust, and sponsored by Insmed Inc, was held in London in March to consider the state of the art in diagnosis and treatment of NTM pulmonary disease.

There are more than 150 species of nontuberculous mycobacteria (NTM) – pulmonary infections are most commonly due to Mycobacterium avium complex (MAC), M. kansasii, and M. abscessus.1 They are rod-shaped organisms that have a thick waxy cell wall and they form biofilms that allow them to grow in nutrient- and oxygen-poor conditions. The cell wall confers resistance to rifamycin, beta-lactam and quinolone antibiotics. Other attributes such as efflux pumps and biotransformation provide resistance against tetracycline and aminoglycosides, explained Dr Jakko van Ingen, clinical microbiologist from Radboud University in the Netherlands.

Mycobacteria are present in the environment, in soil and all types of water sources, including domestic water systems, and they can also be found on plant leaves. They seem to prefer areas rich in organic acid such as peat. Some are heat resistant so can survive in hot water systems.

Dr Rebecca Prevots, chief of the Epidemiology Unit in the Laboratory of Clinical Infectious Diseases at the National Institute of Allergy and Infectious Diseases in the USA, said that in England, Wales and Northern Ireland, the incidence of NTM has continued to rise in recent years. However, the same trend has not been seen in Scotland, where no change was recorded from 2000 to 2010.2 The incidence of NTM in all sample types almost trebled between 1995 (0.9 per 100,000 population) and 2006 (2.9 per 100,000 population). Between 2007 and 2012, 21,118 individuals had NTM culture-positive isolates; the overall incidence of NTM increased from 5.6 per 100,000 (n=3126, 95% CI 5.4–5.7) to 7.6 per 100,000 (n=4454, 95% CI 7.4–7.9) (p<0.001). The most frequently cultured organism in pulmonary samples was MAC, found in 35.6% of 5800 samples.3

Risk factors and consequences of infection

NTM infection can result in progressive inflammatory lung damage. Equally, infection can be asymptomatic, presenting clinicians with a dilemma as to who and when to treat. People with lung disorders such as asthma, cystic fibrosis, bronchiectasis and chronic obstructive pulmonary disease (COPD) as well as people with rheumatoid arthritis taking therapy such as TNF inhibitors are at increased risk of disease from NTM infection, Dr Ken Olivier, senior clinician in the Pulmonary Clinical Medicine Section of the National Heart, Lung, and Blood Institute at the National Institutes of Health in the USA, told the meeting. People over the age of 65 years, or those with a lower BMI or severe vitamin D deficiency also seem to be at greater risk and there are a number of genetic disorders affecting immunological processes and responses that increase individual susceptibility to NTM infection.4 Table 1 lists some of the potential risk factors for infection.

Table 1. Factors associated with potential increased risk of nontuberculous mycobacterial infection1,4

Although still relatively rare, figures from Germany show that nontuberculous mycobacterial pulmonary disease (NTM-PD) can result in a significant health and economic burden (see Table 2).5 Mortality, direct costs and indirect costs due to loss of work were all higher among patients with NTM-PD compared with matched controls followed for 39 months. NTM-PD patients were admitted to hospital three times more often than control patients and hospital treatment accounted for 63% of the total costs for NTM-PD patients.

Table 2. Health and economic burden of nontuberculous mycobacterial pulmonary disease (NTM-PD) among patients in Germany5

Diagnosis

Dr Michael Loebinger, consultant respiratory physician at the Royal Brompton Hospital, explained that diagnosis of NTM-PD is made based on a culture from sputum, induced sputum, bronchoscopy wash or biopsy. Direct molecular detection, skin testing (in a similar way to tuberculosis) and serology using antibodies to detect NTM have been looked at but none are being used in mainstream practice as yet. However, because NTM are ubiquitous, a sputum sample does not necessarily indicate infection. It could be a contaminant, it could be a casual isolate – the organism may have been inhaled but is later coughed out – it could be colonisation or it could be disease. For a diagnosis, American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines require clinical, radiographic and microbiological criteria for diagnosis.6 Updated guidelines on the diagnosis and management of NTM-PD, following along similar lines, are expected from the British Thoracic Society (BTS) later in 2017.7

However, a number of NTM symptoms – cough, sputum, haemoptysis, sweats, fevers, weight loss, malaise and fatigue – are also seen with underlying co-morbid diseases such as COPD or bronchiectasis and it can be difficult to tease out what is due to NTM and what is due to underlying disease. Deterioration in a patient with co-morbidity would prompt a sputum culture as part of the annual surveillance in patients at risk, Dr Loebinger added.

The decision to treat is not always easy to make even in people with NTM disease. For example, managing an underlying condition such as bronchiectasis may be sufficient. So the decision is based on potential risks and benefits of therapy for individual patients. Dr Loebinger explained that he considers the extent, progression, significance and the patients themselves in treatment decisions. Patients with cavitary disease, progressive disease (as indicated by microbiology, radiology and symptoms), those infected with certain species of NTM who are known to have worse outcomes (such as MAC, M. abscessus and M. kansasii)8 and those with co-morbid disease are likely to be treated sooner or at least monitored closely.

Treatment of MAC

Professor David Griffith, interim director of the Pulmonary Division in the Department of Medicine and director of tuberculosis services at the University of Texas Health Science Center, USA, reminded the audience that people with MAC disease are lifetime patients: there is no right time to stop following patients with MAC in their sputum. In his experience, when he feels the time is right to start treatment, the patients themselves usually agree. The risk-benefit analysis that helps inform whether to treat is multifactorial and includes consideration of:

• How symptomatic the patient is
• Whether the NTM lung disease is associated with pulmonary cavities
• The patient’s pulmonary co-morbidities and whether they are compensated
• The patient’s short- and long-term prognosis and
• What the patient wants to do.

Innate resistance in NTM needs to be borne in mind and needs to be separated from acquired resistance, which can be avoided through good practice, Dr Griffith explained. So, for example, when using macrolides or amikacin, companion medication capable of preventing the emergence of isolates with mutational resistance that are naturally existing must also be prescribed.

ATS/IDSA guidelines detail the treatment regimens for MAC disease.6 Dr Griffith said that following these macrolide/azalide-based regimens for nodular/bronchiectatic MAC lung disease results in favourable microbiological outcomes for most patients. The regimens do not promote macrolide resistance and intermittent regimens have been shown to be as effective as daily treatment, so three-times-weekly regimens are favoured. However, Dr Griffith wondered whether anybody actually cared about the guidelines. For example, Adjemian et al. found that among a sample of 349 physicians treating 915 patients, only 13% of antibiotic regimens prescribed for MAC met ATS/IDSA guidelines, 56% did not include a macrolide, and 16% were for macrolide monotherapy. Among patients with M. abscessus, 64% of regimens prescribed did not include a macrolide.9,10 That said, there is some evidence that even the guideline-based therapy has its vulnerabilities with Moon et al. showing the development of macrolide-resistant MAC in 65% of patients treated with guideline-recommended therapy including macrolide/ethambutol and rifamycin.11

Treatment of M. abscessus pulmonary disease

Dr Charles Haworth, director of the Cambridge Centre for Lung Infection, and consultant in respiratory medicine at Papworth Hospital, said that genetic differences between subspecies of M. abscessus appear to confer different susceptibility to clarithromycin and affect outcomes. M. massiliense has partial erm(41) gene deletion that prevents inducible gene deletion so the bacterium is likely to respond well to macrolide therapy. In contrast, M. abscessus has a functional erm(41) gene that results in inducible macrolide resistance so patients with this subspecies may require a longer duration of treatment with antibiotics. In addition, just to complicate the picture further, any M. abscessus has a 23S rRNA mutation, which confers constitutive macrolide resistance that may again require a longer duration of antibiotic therapy.

The proposed updated BTS guidelines, expected to be published later in 2017, include advice on treatment taking account of these differences.10

Dr Haworth suggested that treatment can in some ways be likened to starting chemotherapy as the drugs are highly toxic and patients need to be fully aware of what is involved, including likely side-effects, as well as the pros and cons of treatment. Safety monitoring, including audiometry and ECG, is important, as is antiemetic therapy.

Treatment of other NTM infections

Professor Charles Daley, chief of the Division of Mycobacterial and Respiratory Infections at National Jewish Health and University of Colorado in Denver, USA, noted that there are over 170 species of NTM that have been reported to cause lung disease. Resistance to drug therapy varies, for example M. kansasii and M. malmoense are relatively susceptible to drug treatment whereas M. simiae is resistant to most antibiotics used to treat NTM. M. xenopi, on the other hand, appears susceptible to a number of antibiotics according to laboratory tests but that is not reflected in the clinical experience as outcomes tend to be poor.12

M. Kansasii responds well to therapy given for at least 12 months. M. malmoense tends to be seen in patients with underlying lung disease but treatment outcomes are relatively good. M. simiae does not appear to be associated with disease in most patients in whom the organism is isolated so it is important to be sure patients have progressive disease. In patients who have been treated, outcomes have varied. M. xenopi shows optimal growth at 45oC. Pulmonary disease associated with the organism is usually seen in patents with underlying lung disease and all-cause mortality is high.13

Future treatments

Professor Andres Floto, professor of respiratory biology at the University of Cambridge, said treatment success with NTM infection lags well behind that for tuberculosis (TB), for example. Therefore, there is a real need for new treatments and new approaches to treatment, and he outlined three potential strategies.

The first is to borrow from the TB pipeline. Antimycobacterial drugs target protein synthesis, cell wall biosynthesis (enhancing the permeability to other drugs) or bacterial energetics (reducing efflux pump activity). Some of these drugs have shown promising effects against MAC and M. abscessus. Combining these three approaches is being studied in the Nix-TB study.14,15

The second strategy is to attempt to make old drugs work better. For example, beta-lactamase inhibition to allow the use of beta-lactam antibiotics. Another approach being studied is delivering drugs encapsulated using a liposomal formulation, which may facilitate drug penetration into bacterial cells and biofilms. Such formulations may also reduce toxicity. Another way of encapsulating drugs is with nanoparticles by constructing the nanoparticle wall with polymerised drug, which is then cleaved by the acidic environment in the mycobacteria to slowly release the drug. Drugs can also be encapsulated inside nanoparticles. The work investigating this approach is being carried out by Professor Floto’s group in collaboration with Sir Mark Welland at the University of Cambridge.

Finally, developing new drugs to treat NTM presents a significant challenge, but one potential source is from the bacteria themselves, which produce antimicrobial compounds that are found in the soil where mycobacteria exist. Ling et al. have cultured bacteria found in soil to produce a new antimicrobial compound, which has shown activity in vitro against methicillin-resistant Staphylococcus aureus and M. tuberculosis.16

References

1. Johnson MM, Odell JA. Nontuberculous mycobacterial pulmonary infections. J Thorac Dis 2014;6(3):210–20.
2. Russell CD, et al. Non-tuberculous mycobacteria: a retrospective review of Scottish isolates from 2000 to 2010. Thorax 2014;69:593–5.
3. Shah NM, et al. Pulmonary Mycobacterium avium-intracellulare is the main driver of the rise in non-tuberculous mycobacteria incidence in England, Wales and Northern Ireland, 2007–2012. BMC Infect Dis 2016;16:195.
4. Lake MA, et al. ‘Why me, why now?’ Using clinical immunology and epidemiology to explain who gets nontuberculous mycobacterial infection. BMC Med 2016;14:54.
5. Diel R, et al. Burden of non-tuberculous mycobacterial pulmonary disease in Germany. Eur Respir J 2017;49(4):1602109.
6. Griffith DE, et al. An Official ATS/IDSA Statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Res Crit Care Med 2007;175:367–416.
7. British Thoracic Society. Guidelines for the diagnosis and management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Public consultation. February – March 2017. Available from: www.brit-thoracic.org.uk/document-library/clinical-information/non-tuberculous-mycobacteria/ntm-guideline/bts-guidelines-for-the-diagnosis-and-management-of-ntm-pd [accessed April 2017].
8. Jankovic M, et al. Microbiological criteria in non-tuberculous mycobacteria pulmonary disease: a tool for diagnosis and epidemiology. Int J Tuberc Lung Dis 2016 Jul;20(7):934–40.
9. Adjemian J, et al. Lack of adherence to evidence-based treatment guidelines for nontuberculous mycobacterial lung disease. Ann Am Thorac Soc 2014;11(1):9–16.
10. van Ingen J, et al. Poor adherence to management guidelines in nontuberculous mycobacterial pulmonary diseases. Eur Respir J 2017;49(2):1601855.
11. Moon SM, et al. Clinical characteristics, treatment outcomes, and resistance mutations associated with macrolide-resistant Mycobacterium avium complex lung disease. Antimicrob Agents Chemother 2016;60(11):6758–65.
12. van Ingen J, et al. In vitro drug susceptibility of 2275 clinical non-tuberculous Mycobacterium isolates of 49 species in The Netherlands. Int J Antimicrob Agents 2010;35(2):169–73.
13. Andréjak C, et al. Mycobacterium xenopi pulmonary infections: a multicentric retrospective study of 136 cases in north-east France. Thorax 2009;64(4):291–6.
14. Murray S, et al. TB Alliance regimen development for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2016;20(12):38–41.
15. TB Alliance. Nix-TB. Available from: www.tballiance.org/portfolio/trial/5089 [accessed April 2017].
16. Ling LL, et al. A new antibiotic kills pathogens without detectable resistance. Nature 2015;517:455–9.

Declaration of interests

Meeting sponsored by Insmed Inc.

Steve Titmarsh is a freelance medical writer

The growing threat of nontuberculous mycobacteria

 

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