Concern over pyrazinamide resistance
is an important drug for the treatment of tuberculosis (TB). Together with three other drugs, it makes up the four-in-one pill that people with drug-susceptible (DS) TB are treated with in South Africa. The other three drugs are rifampicin, isoniazid and ethambutol. Apart from its existing use, pyrazinamide also forms part of almost all experimental regimens currently in phase II and III TB trials.
A systematic review recently published in the journal PLOS One has found that resistance to pyrazinamide is worryingly widespread. It estimated that globally 16.2 percent of new TB cases are pyrazinamide resistant – 1.4 million of the estimated 9 million new cases per year. The picture is worse in people who are also resistant to other first-line TB drugs, with an estimated 60.5 percent of people with confirmed multi-drug resistant (MDR) TB being resistant to pyrazinamide. These findings suggest that many people now receiving pyrazinamide are likely resistant to the drug. The findings are also worrying given how widely pyrazinamide is used in experimental treatment regimens for both DS- and MDR-TB. For example, a high-profile phase III trial called STAND is testing a three-drug combination of pyrazinamide, moxifloxacin and pretomanid for both DS-TB and MDR-TB. In people with prazinamide resistance this regimen would effectively be reduced to a two-drug regimen.
As pyrazinamide forms part of many existing and experimental treatment regimens, resistance testing for the drug should become more important in future to ensure it is not given to people who are resistant to it. Unfortunately we don’t yet have fast, affordable, and accurate tests for pyrazinamide resistance. The development of such tests must be a high priority. It’s noteworthy that since the introduction of the GeneXpert machine in South Africa, testing for rifampicin resistance has become widespread because the machine tests specifically for this condition. People who are resistant to rifampicin are typically also resistant to isoniazid.