Updates in the Treatment of Mycobacterium Tuberculosis
The latest Bench to Bedside column reviews new guidance on the treatment of drug-susceptible and drug-resistance Mycobacterium tuberculosis infections.
Tuberculosis (TB) continues to be a significant source of morbidity and mortality. In 2023, 10.9 million people globally contracted TB, and 1.25 million people worldwide died from TB.1 In the United States, in 2023, 9,633 cases of TB were reported, a 15.6% increase compared to 2022.2 TB can be divided into drug-susceptible TB and drug-resistant TB. Based on recent clinical trials, the ATS/CDC/ERS/IDSA 2025 guidelines have updated treatment guidance for both drug-susceptible and drug-resistant TB. Below is a brief summary of study findings and the guideline updates.
Drug-Susceptible TB (DS-TB)
DS-TB is denoted by TB isolates that are susceptible to isoniazid and rifampin. Drug-susceptible pulmonary TB has traditionally been treated with at least six months of a four-drug regimen, comprised of isoniazid, rifampin, pyrazinamide, and ethambutol for the first two months, followed by at least four months of isoniazid and rifampin.3 Shorter durations of equally efficacious drug therapy are preferable in terms of drug costs, regimen adherence, and patient quality of life.
To this end, Study 31/A5349 was a randomized, open-label, phase III, non-inferiority study that compared the standard-of-care 6-month treatment regimen to two 4-month regimens, one containing isoniazid, rifapentine, and moxifloxacin with two months of pyrazinamide and the other substituting rifapentine for rifampin in the standard-of-care regimen. Participants were at least 12 years of age with drug-susceptible pulmonary TB. The 4-month regimen containing moxifloxacin was found to be non-inferior with regard to cure, but the 4-month regimen substituting rifapentine for rifampin was not (85.4% 6-month regimen, 84.5% 4-month regimen with moxifloxacin, 1% difference [95% CI, -2.6 to 4.5]; 82.3% 4-month regimen with rifapentine instead of rifampin, 3% difference [95% CI, -0.6 to 6.6]). The grade three or higher adverse events were also similar between the 6-month regimen and the 4-month regimen with moxifloxacin (19.3% 6-month regimen, 18.7% 4-month regimen with moxifloxacin, -0.6% difference [95% CI, -4.3 to 3.2]). Fewer patients receiving the 4-month regimen substituting rifapentine for rifampin had grade three or higher adverse events compared to standard-of-care (14.3%, -5.1% difference [95% CI, -8.7 to -1.5]).4 Based on the results of this study, the 2025 ATS/CDC/ERS/IDSA guidelines conditionally recommend the 4-month regimen of isoniazid, rifapentine, pyrazinamide, and moxifloxacin for patients at least 12 years old with DS-TB (Table 1).5 Since the study enrolled relatively young patients (65% under the age of 35 years), there may be additional considerations in areas where TB is lower in prevalence and those patients with TB who are older in age with comorbidities and concomitant medications that make the 4-month regimen less ideal.
The SHINE trial was a randomized, open-label, non-inferiority study that compared a 4-month regimen including two months of rifampin, isoniazid, pyrazinamide, and ethambutol, followed by two months of isoniazid and rifampin with the standard 6-month regimen including the same drugs in children under the age of 16 years with non-severe, DS-TB. For the primary efficacy outcome of unfavorable status by 72 weeks (defined as treatment failures, TB recurrences, loss to follow-up on treatment, or all-cause mortality by 72 weeks), the 4-month regimen was found to be non-inferior to the 6-month regimen (risk difference -0.3% [95% CI, -2.3 to 1.6]). For the primary safety outcome of grade three or higher adverse events, the rates in both groups were 8%.6 Based on the results of this study, the 2025 ATS/CDC/ERS/IDSA guidelines recommend the 4-month regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for children under 16 years old with non-severe, DS-TB (Table 1).5
Drug-Resistant TB (DR-TB)
DR-TB poses a significant public health threat given the rise in cases globally, poorer outcomes compared to DS-TB, and the historical lack of effective, safe, and affordable treatment options.7 DR-TB can be classified into the following categories: rifampin-resistant TB (RR-TB), multidrug-resistant TB (MDR-TB), pre-extensively drug-resistant TB (pre-XDR-TB), and extensively drug-resistant TB (XDR-TB). Table 2 below provides a summary of definitions adopted by the World Health Organization (WHO).8
Prior to the approval of new drugs for DR-TB, treatment often required the use of a combination of second-line agents such as intravenous aminoglycosides, clofazimine, and others. However, new studies in the DR-TB space show promising results with the use of novel regimens including bedaquiline, pretomanid, linezolid, and/or moxifloxacin. The NIX-TB study was an open-label, single group study of patients in South Africa who received 26 weeks of bedaquiline, pretomanid, and linezolid (BPaL) for the treatment of XDR- and non-responsive/intolerant MDR-TB. 90% of patients had favorable outcomes assessed at 6 months after the end of BPaL treatment [95% CI, 83 to 95], but linezolid dosed at 1200 mg daily was associated with significant peripheral neuropathy (81%) and myelosuppression (48%).9 Therefore, the ZeNix trial compared linezolid dosed at 1200 mg daily versus 600 mg daily for 26 weeks or 9 weeks as part of the BPaL regimen for patients with RR-, pre-XDR-, and XDR-TB. BPaL with linezolid 600 mg daily dosing for 26 weeks demonstrated favorable outcomes in 91% of cases [95% CI, 79 to 98] and was better tolerated compared to 1200 mg daily dosing.10
Lastly, TB-PRACTECAL was an open-label, multicenter, randomized study of patients with RR-TB. Following an initial stage to evaluate the safety and efficacy of BPaL, stage 2 of the trial compared the combination of an all-oral regimen, bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) for 24 weeks versus standard-of-care administered for 9-20 months. Unfavorable outcomes occurred in 11% of patients in the BPaLM arm versus 48% receiving standard of care [-37% risk difference; 96.6% CI, -53 to -22] with fewer serious adverse events.11
Based on these new data, the 2025 ATS/CDC/ERS/IDSA guidelines strongly recommend 6-month BPaL regimen for patients aged 14 years and older for the treatment of RR-, fluoroquinolone-resistant pulmonary TB. Guidelines also recommend 6-month BPaLM regimen for patients aged 14 years and older for the treatment of RR-, fluoroquinolone-susceptible pulmonary TB (Table 1). 5
The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.
