Geneva, 11 July 2016 – The first ever multi-country population-based survey investigating levels of the resistance to essential tuberculosis (TB) drugs was published last week in The Lancet Infectious Diseases. This work was led by the World Health Organization (WHO), in collaboration with National TB Programmes, National TB Reference Laboratories and Supranational Reference Laboratories.
Over the past 20 years, levels of resistance to rifampicin and isoniazid have been monitored in more than 150 countries worldwide by WHO. However, susceptibility testing to fluoroquinolones and pyrazinamide is not routinely performed on all tuberculosis cases as part of drug resistance surveillance efforts. Testing is usually restricted to specific patient groups, such as those with rifampicin resistance or a history of previous TB treatment, and little data exist regarding the levels of resistance of these drugs at the population level.
In this study, an estimated 5,000 patients were tested in Azerbaijan, Bangladesh, Belarus, Pakistan and South Africa to investigate resistance to pyrazinamide and fluoroquinolones among TB patients in high TB burden countries.
Pyrazinamide is a key component of the most commonly used short-course regimen for TB recommended by WHO, and also of second-line regimens for the treatment of multidrug-resistant TB (MDR-TB). The survey findings indicate that the vast majority of the burden of pyrazinamide resistance is among patients with rifampicin resistance. However, depending on the setting, pyrazinamide may still be effective in 19-63% of patients with rifampicin-resistant TB.
It is crucial to rapidly distinguish between patients who could benefit from a pyrazinamide-containing regimen and those for whom inclusion of pyrazinamide would not be effective. This distinction requires rapid molecular tests to diagnose pyrazinamide resistance, which do not currently exist.
As with pyrazinamide, levels of resistance to fluoroquinolones were closely associated with rifampicin resistance in all settings, with notable geographical differences. Levels of resistance to fluoroquinolones were significantly lower than that of rifampicin in Azerbaijan and Belarus, but significantly higher in Pakistan. Resistance to the later generation fluoroquinolones, moxifloxacin and gatifloxacin, were low in all settings.
The study findings show that rifampicin resistance, which can be easily diagnosed with rapid molecular tests, can be an indicator for the possibility of simultaneous resistance to pyrazinamide and, in some settings, earlier-generation fluoroquinolones. These data provide insight into the background proportions of resistance to these drugs at the population level and the feasibility of introducing new tuberculosis treatment regimens and strategies for drug-susceptibility testing in these settings.
“We need to rethink our surveillance approaches so as to improve our understanding of levels of resistance to pyrazinamide and fluoroquinolones in different settings and patient groups,” said Dr Matteo Zignol of WHO’s Global TB Programme and lead author of the study. “Without this information, we risk introducing ineffective TB treatment regimens that may amplify the development of drug resistance.”
The survey was funded by The Bill & Melinda Gates Foundation, the US Agency for International Development and the Global Alliance for TB Drug Development.