By IDSE News Staff
Resistance to the new multidrug-resistant TB (MDR-TB) treatment regimen recently recommended by the WHO is already spreading among patients, according to researchers at the Swiss Tropical and Public Health Institute (Swiss TPH) (N Engl J Med 2025;392[1]:97 doi:10.1056/NEJMc2404644).
The findings highlight the urgent need for better surveillance and infection control to counteract the rise in antimicrobial resistance, they said.
Found in every country-but with India, Central Asia and Southern Africa bearing a particularly high burden-TB remains the world's biggest infectious disease killer with an estimated 1.25 million deaths annually. More than 10 million people develop TB every year.
The traditional treatment regimen for MDR-TB is lengthy, expensive and comes with severe adverse events. In 2022, the WHO endorsed BPaL(M), based on evidence of its improved safety and efficacy from numerous clinical studies, including TB-PRACTECAL. BPaL(M) is a novel, oral, six-month regimen comprising bedaquiline, pretomanid and linezolid that can be used with moxifloxacin, when fluoroquinolones prove resistant.
“While this new regimen is a game changer for patients suffering from MDR-TB, we knew that it will be difficult to outsmart Mycobacterium tuberculosis, the bacteria causing TB,” said Sébastien Gagneux, PhD, the head of the Department of Medical Parasitology and Infection Biology at Swiss TPH and senior author of the study. “It was therefore crucial to study how the TB bacteria would react to the global rollout of this new regimen.”
In collaboration with the National Centre for Tuberculosis and Lung Diseases in Tbilisi, Georgia, the researchers examined whether resistance to the drugs in the new regimen has already emerged since its introduction, and whether this resistance is transmitting between patients.
The researchers analyzed the genomes of close to 90,000 M. tuberculosis strains from Georgia and many other countries around the world. They identified a total of 514 strains that were resistant to TB drugs, including both the old and the new treatment regimens. These highly drug-resistant strains were found in 27 countries across four continents.
Alarmingly, 28% of these strains were transmitted directly from one patient to another. "We already had anecdotal evidence of resistance emerging to the new regimen, but we did not know to what extent transmission was responsible for the spread of these highly drug-resistant strains," said Galo A. Goig, PhD, a postdoctoral collaborator at Swiss TPH and first author of the study.
“The good news is that the total number of these cases is still low. However, the fact that more than a quarter of these highly drug-resistant cases are due to patient-to-patient transmission, only two years after WHO endorsed the new regimen, is worrying,” Dr. Goig added.
These findings have important implications for public health policy and interventions. The authors emphasize the need for improved diagnostic tools, better infection control and robust surveillance systems to curb the spread of these highly drug-resistant strains, and to safeguard the efficacy of the new treatment regimen.
While there are already new TB drugs in the pipeline, experts worry that M. tuberculosis will continue to develop resistance. “The example of these highly drug-resistant TB strains further illustrates that antimicrobial resistance is one of the most critical threats to global health today,” Dr. Gagneux said. “We must stay ahead in this constant race between drug development and bacterial resistance, and take proactive steps to prevent a 'post-antibiotic era' for TB and other diseases.”
In related news, Harvard researchers found three new safe and effective drug regimens for TB that is resistant to rifampin (N Engl J Med 2025;392[5]:468. doi:10.1056/NEJMoa2400327).mThe newly identified regimens take advantage of recently discovered drugs to expand the treatment arsenal and give physicians new ways to shorten and personalize treatment, minimize side effects and treat patients using only pills instead of daily injections. They also offer alternatives in case of drug intolerance, medication shortages or unavailability, or drug resistance, the researchers said.
The endTB trial is one of four efforts to use randomized controlled trials to test new, shorter and less toxic regimens for drug-resistant TB. The trial uses two new drugs—bedaquiline and delamanid—which, when brought to market in 2012-2013, were the first new TB medicines developed in nearly 50 years.
To find shorter, injection-free drug combinations for people infected with TB that is resistant to rifampin, endTB tested five new, all-oral, nine-month regimens using the two new drugs in combination with older medications.
A third drug, pretomanid, received emergency authorization from the FDA for specific use within a regimen against highly drug-resistant TB in 2019, after the endTB clinical trial was underway, and is not included in the regimens used in these trials.
Trial regimens were considered effective if they performed at least as well as the control group, which received a well-performing standard of care composed in accordance with a stringent interpretation of recommendations by the WHO. The three new regimens were successful for between 85% and 90% of patients, compared with 81% success for people in the control group. The control group was treated with longer treatments, which also included the recently discovered medicines.
The trial launched in 2017 and enrolled 754 patients in seven countries: Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru and South Africa. The goal was to improve treatment for patients with TB resistant to rifampin. The WHO estimates that some 410,000 people become sick with rifampin-resistant TB each year, including people with MDR-TB. Only 40% are diagnosed and treated, 65% of them successfully.
The study population included children as well as people infected with HIV or hepatitis C, both common in populations with high rates of TB. In another innovation, people who became pregnant while on treatment were included in the endTB trial. These groups are often excluded from clinical trials. In a special report published in August 2024, the WHO added the three noninferior regimens from the endTB trial to the list of treatment options for rifampin-resistant TB and MDR-TB treatment; the recommendations extend to these neglected groups as well as to pregnant women.
With recent efforts to end patent exclusivity on bedaquiline, two of the endTB regimens and the WHO-recommended pretomanid-containing regimen can all be purchased for less than $500, an access target set by activists more than 10 years ago, which has only just now been achieved. All these innovations together mean the new shortened, all-oral regimens are available to more people than ever.
The endTB trial is part of a major transformation in how the world treats TB, said the trial's co-principal investigator Carole Mitnick, ScD, a professor of global health and social medicine at the Blavatnik Institute at Harvard Medical School, in Boston, and the Partners in Health director of research for the endTB project.
“This Harvard-led partnership among NGOs [non-governmental organizations], ministries of health and other academic partners identified three new regimens that will make lifesaving care dramatically more accessible,” Dr. Mitnick said. “We also resolved a critical question left open by pharmaceutical industry trials that brought bedaquiline and delamanid to market: How can these new drugs be used to shorten and simplify treatment while retaining efficacy?”
