Rapid, whole genome sequencing-based diagnosis of drug-resistant Mycobacterium abscessus complex and new options for treatment

Nontuberculous mycobacteria (NTM) are mycobacterial species other than the Mycobacterium tuberculosis complex and Mycobacterium leprae. They are ubiquitous in the environment and often isolated from water, soil, and hospital wards. With increasing numbers of immunocompromised patients (including those with HIV infection and haematological disorders), as well as patients with cystic fibrosis and chronic lung disorders, the role of NTM as a cause of human, and in particular pulmonary, disease has become apparent, with recent reports indicating a worldwide increase.

In particular, Mycobacterium abscessus complex comprises a group of rapidly growing, multidrug-resistant, nontuberculous mycobacteria that are responsible for a wide spectrum of skin and soft tissue diseases, central nervous system infections, bacteraemia, and ocular and other infections.

Current treatment guidelines are based on limited data derived mostly from expert opinion, case series, and few randomized clinical trials. Infections caused by M. abscessus complex are notoriously difficult to treat. Although there is no standard treatment, the guidelines suggest the administration of macrolide-based therapy in combination with other antimicrobial agents administered intravenously; however, this regimen has been shown to have substantial side effects for patients.

Additionally, susceptibility testing is problematic and there is still no consensus on a standardized method and there are important discrepancies between drug susceptibility measured in the laboratory and the activity of the drug observed in patients. New antimycobacterial drugs (i.e. bedaquiline, delamanid) and other compounds used in case of drug resistant tuberculosis (i.e. cloafazimine) are not routinely tested against NTM in the reference laboratory, despite recent research studies suggesting some excellent activity.

Whole genome sequencing (WGS) has been applied to a wide range of clinical scenarios and England is the first country in the world to pioneer its use on a national scale for the diagnosis of M. tuberculosis, detection of drug resistance, and typing. This has drastically reduced the time to final diagnosis with first line susceptibilities data available in only 8 days (from weeks and sometime months).

However, NTM have long been under investigated and much work still needs to be done to allow a rapid diagnosis with susceptibility testing. The advancement of subspecies differentiation has allowed for more effective management of pulmonary disease caused by M. abscessus complex. For example, unlike M. abscessus subsp. abscessus, M. abscessus subsp. massiliense does not have inducible resistance to clarithromycin.

The discovery of the erm gene, which is responsible for macrolide resistance, is an example of how rapid diagnosis would enable the physician to confidently administer clarithromycin and optimize treatment early. However, M. abscessus subsp. abscessus still remains both a diagnostic and treatment challenge as 80% of isolates are macrolide resistant.

There is no current test to allow a rapid diagnosis and there is a lack of consensus on the optimal antimicrobial agents and combination therapy, combined with the paucity of available drugs. Hence, further research in both rapid diagnosis and treatment options of M. abscessus is needed. The main aim of this research project is to investigate the utility of WGS applied to M. abscessus complex, with a particular focus on rapid detection of drug resistance mutations (thus, allowing early optimization of treatment).

The secondary aim is to investigate the antimicrobial activity of various compounds against M. abscessus complex, including anti-microbial peptides and bacteriophages (thus, providing additional options to treat drug resistance).