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Combatting The Rising Rates Of NTM Pulmonary Disease

Updated NTM pulmonary disease estimates in U.S. Medicare beneficiaries revealed rising incidence, demographic disparities, and associated comorbidities.

Rates of nontuberculous mycobacteria pulmonary disease (NTM PD) have increased globally over the past two decades. However, national estimates of NTM PD incidences in the United States have not been assessed since 2015.

Using a population-based data set of Medicare beneficiaries at least 65 years of age, Samatha J. Bents and colleagues provided updated estimates of NTM PD trends in the United States and insight into demographic heterogeneity in disease burden in high-risk populations. They also evaluated the relative prevalence of various comorbid conditions previously found associated with NTM PD. They published their findings in BMC Infectious Diseases.

The researchers identified 59,724 cases of NTM PD from 2010 to 2019 from an annual mean population of 29,687,097 beneficiaries, with an average annual incidence of 20.1 per 100,000 population for the study period.

Overall, the NTM PD rate was highest in the South and among women, Asian people, and people aged 80 years and older. In the South, rates of NTM PD rose from 17.8 to 28.6 per 100,000 people from 2010 to 2019. Women had higher rates of disease than men, with an average annual 1.4- to 2.0-fold higher prevalence across age groups.

Among all racial and ethnic groups in 2019, NTM PD incidence among Asian people was 1.4-fold higher versus White people, 3.1-fold higher versus Hispanic people, and 4.3-fold higher versus Black people. In the same year, incidence among people aged at least 80 years was 3.3-fold higher compared with people aged 65-69 years and 1.3-fold higher compared with people aged 70-79 years.

Data showed that the annual percent change in NTM PD incidence was highest in the Northeast (6.5%) and Midwest (5.9%) but increased significantly across all regions. The relative prevalence (RP) of several comorbid conditions was strongly associated with concurrent NTM PD diagnosis, including allergic bronchopulmonary aspergillosis (RP=93.6), pulmonary tuberculosis (RP=87.8), bronchiectasis (RP=74.6), and cystic fibrosis (RP=34.2). The researchers also observed associations between NTM PD and other common conditions that increase the risk of NTM PD, including COPD (RP=5.6) and GERD (RP=2.4).

"Our study, taken together with several prior population-based studies similarly showing increased infection and disease trends, suggests a concurrent increased need for improved healthcare planning to handle an increased future caseload, as well as improved diagnostics and therapeutics to better detect and treat NTM PD," the investigators concluded.

They underscored the importance of increased awareness of NTM PD diagnosis and treatment guidelines to help improve disease management.

Paratek's Antibiotic Succeeds In Phase IIb Lung Disease Trial

Boston-based Paratek Pharmaceuticals has released positive topline data from a Phase IIb trial evaluating its oral antibiotic Nuzyra (omadacycline) in adult patients with nontuberculous mycobacterial (NTM) pulmonary disease.

The therapy showed an improvement in at least 50% of the NTM symptoms present at baseline and no worsening of any baseline symptom. The company was quick to note that "while the study was not designed to formally test for statistical differences between treatment arms, a trend favouring omadacycline was consistently observed across top line primary and secondary endpoints."

Paratek was acquired by Novo Holdings and Gurnet Point in a deal worth approximately $462m in September 2023. Nuzyra is Paratek's lead therapy and is approved by the US Food and Drug Administration (FDA) as a treatment for community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI). GlobalData expects the therapy to generate $119m in 2030.

GlobalData is the parent company of Clinical Trials Arena.

The placebo-controlled Phase IIb trial (NCT04922554) enrolled 66 patients with NTM pulmonary disease caused by mycobacterium abscessus. The study evaluated the primary efficacy endpoint of treatment response on the NTM Symptom Assessment Scale at Day 84 in two ways.

The first evaluation defined a positive response as an improvement in at least 50% of the NTM symptoms present at baseline. The second approach required an improvement in at least 50% of the NTM symptoms present at baseline along with no worsening of any baseline symptom.

In the first evaluation, 34.1% of the participants demonstrated a favourable trend towards higher response rates compared with 20% of the placebo treated subjects. The second evaluation saw 34.1% of the treatment participants showing a favourable trend towards higher response rates compared with 12% of the placebo group.

Nuzyra also showed improvement in microbiological endpoints, with 56.4% of treatment group patients having negative sputum cultures for mycobacterium abscessus compared to 29.2% of the placebo group. At 84 days, 76.5% of the Nuzyra group saw a reduction in semi-quantitative sputum culture scores compared to 45.8% of placebo treated patients.

The common treatment emergent adverse events were gastrointestinal symptoms, with four patients discontinuing treatment due to these. Paratek noted that the study data analysis is ongoing, with the company intending to present and publish complete data at a later date.

"Paratek's antibiotic succeeds in Phase IIb lung disease trial" was originally created and published by Clinical Trials Arena, a GlobalData owned brand.

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Nontuberculous Mycobacteria – An Emerging Public Health Problem

Sessions on nontuberculous mycobacterial pulmonary disease (NTM-PD) were particularly well attended at the recent 27th International Congress of the European Respiratory Society, reflecting the rising incidence and prevalence of these infections, and the growing interest of clinicians and researchers. Professor James Chalmers explains the current situation and the challenge of treating NTM-PD effectively.   

Nontuberculous mycobacteria (NTM) are everywhere – in the ground we walk over, the water we drink, the air we breathe. There are more than 150 species of these tiny, rod-shaped pathogens and they are ubiquitous in the environment.

Most of the time they cause no trouble, but for people who are immunocompromised or who have damaged airways, NTM can cause serious, and sometimes fatal, lung infections. For example, a large Danish study reported a five-year mortality of 40% in definite NTM disease [1].

Pulmonary NTM infections are also being reported in people without immune deficiency. Reports from several countries show a rising prevalence. This may be due to both increased awareness and improved diagnosis [2].

In England, Wales and Northern Ireland, the reported rate of NTM more than doubled between 1996 and 2006. An updated analysis has shown that the incidence of NTM has continued to rise – overall, an almost tenfold increase since 1995. Pulmonary Mycobacterium avium complex (MAC) in older people is responsible for the majority of this increase. [2]

The causative pathogens in NTM infections can be notoriously difficult to kill. They are shielded by an unusually thick cell wall, can 'hide' inside other cells or within biofilms where they cannot be reached by antibiotics and disinfectants, can grow under nutrient- and oxygen-poor conditions and thrive at temperatures that would disable many other bacteria. Additional NTM defence mechanisms include both innate and acquired antibiotic resistance, plus highly efficient efflux pumps that can swiftly remove antibiotics from the bacterial cell [3].

Furthermore, because these bacteria evolved in the soil – alongside the moulds which became the source of many widely-used antibiotics – they can be stubbornly resistant to standard antibiotics.  Lung infections caused by NTM therefore pose a major clinical challenge, requiring lengthy treatment with combination antibiotics – regimens that frequently fail and that can cause significant side effects for patients [4].  New treatments are urgently needed.

To add to the clinical challenge, NTM infections can be notoriously difficult to diagnose – sometimes meaning that the patient has suffered significant lung damage before diagnosis. Accurate diagnosis requires clinical, microbiological and radiological criteria – a full medical history, sputum culture for acid fast bacilli (AFB), or bronchoscopy in patients unable to produce sputum. A chest CT scan is also an important diagnostic tool. The American Thoracic Society criteria for diagnosis of NTM pulmonary disease requires clinical, microbiological and radiological evidence of NTM-PD to be present before a diagnosis can be made.

A clear sign of the growing importance of NTM was the number of sessions, posters and other abstracts devoted to NTM research at the recent meeting of the European Respiratory Society (ERS), held in Milan, Italy.

In one symposium, Dr Felix Ringhausen from Hannover, Germany, reviewed the latest epidemiological data for NTM, including a German study which interrogated national databases to define the current burden of NTM-PD-associated hospitalisations in Germany [5].  The results showed an incidence rate of 2.6 per 100,000 insured persons, with a mean direct expenditure per patient of €39,559.60 – four-fold higher than costs for matched controls, largely due the need for repeat hospital admissions.

Elsewhere, the burden of infection appears to be even higher. Dr Ho Namkoong, of Keio University School of Medicine, Tokyo, Japan, reported results from a nationwide survey of Japanese hospitals showing an incidence estimated at 14.7 cases per 100,000 person-years – almost three times higher than that found in the last survey (2007) –  an incidence that he acknowledged to be one of the highest in the world (Oral abstract 1973 Session 264).

Ringhausen also reported that one-in-four patients had not been prescribed antibiotic treatment. And among those who were given antibiotics, 12% received the wrong regimen, despite well publicised guidelines. In the UK, new guidelines on the diagnosis and management of NTM‐PD have recently been published by the British Thoracic Society [6].

However, according to Professor David Griffith, Department of Medicine, University of Texas Health Science Center, Tyler, USA, adherence to existing guidelines is poor, with one study showing that only 13% of patients with pulmonary MAC infection were prescribed the guideline regimen [7]. He urged clinicians to treat patients aggressively and to stick to guideline-recommended regimens.

There is probably no other respiratory disease with such a low guideline compliance rate. We need to understand why compliance is so poor and we need to do better.

In summary, current epidemiological data, mortality statistics and sub-optimal treatment regimens clearly point to an unmet need when treating NTM. In the immediate future there should be some improvement with better antibiotics and reformed treatment protocols. Some studies also show hope for better prevention via modification of environmental and host factors. Longer term, there are promising areas of research such as biofilm-disrupting drugs, patient microbiome modification, candidate virulence blockers, novel immunomodulators and the use of genetic sequencing to provide targeted therapy for individual patients.

References:

1 Andréjak C, et al (2010). Nontuberculous pulmonary mycobacteriosis in Denmark: incidence and prognostic factors. Am J Respir Crit Care Med; 181 (5): 514-21.

2 Shah N M, et al (2016). 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 Infectious Diseases; 16: 195

3 van Ingen J, Boeree M J, van Soolingen D, & Mouton J W. (2012). Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria. Drug Resist Updat.; 15(3): 149-61.

4 Loebinger M R, & Welte T. (2016). Current Perspectives in the Diagnosis and Treatment of Nontuberculous Mycobacterial Pulmonary Disease. European Respiratory & Pulmonary Diseases; 2(2): 54-57.

5 Diel R, et al (2017). Burden of non-tuberculous mycobacterial pulmonary disease in Germany. Eur Respir J.; 49(4): DOI: 10.1183/13993003.02109-2016.

6 Haworth S, et al (2017). British Thoracic Society Guideline for the management of non-tuberculosis mycobacterial pulmonary disease (NTM-PD). BMJ Open Resp Res; 4: e000242. Doi:10.1136/bmjresp-2017-000242.

7 Adjemian J, et al (2014). Lack of adherence to evidence-based treatment guidelines for nontuberculous mycobacterial lung disease. Ann Am Thorac Soc.; 11(1): 9-16.

About the author:

Professor James D Chalmers chaired the symposium 'The challenge of nontuberculous mycobacterial lung disease' at the European Respiratory Society meeting 2017.

He is GSK/British Lung Foundation Chair of Respiratory Research at the University of Dundee, UK. He is also Chair of EMBARC, The European Bronchiectasis Registry.

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