Multidrug-resistant and rifampicin-resistant tuberculosis, collectively known as MDR/RR-TB, remains one of the most formidable challenges in global infectious disease control. When the bacteria that cause tuberculosis become resistant to isoniazid and rifampicin, the two most powerful first-line antibiotics, treatment options narrow dramatically and the regimens that remain are longer, more toxic, and less effective. For patients whose disease progresses to pre-extensively or extensively drug-resistant tuberculosis, the therapeutic arsenal shrinks even further, making every usable drug precious.

Delamanid, a nitroimidazo-oxazole derivative, was developed specifically to address this gap. The drug works through a mechanism distinct from most classical anti-tuberculosis agents: it blocks the synthesis of mycolic acids, essential components of the mycobacterial cell wall, thereby killing the bacillus while interfering with its energy metabolism. Controlled clinical trials demonstrated its therapeutic benefit, and it has since become a cornerstone of optimized background regimens, the individually tailored combinations of drugs assembled around core agents for each resistant case. Yet despite its growing importance, large-scale real-world safety data have remained limited, particularly for Chinese patients, who represent a substantial share of the global burden of drug-resistant tuberculosis.

To close this evidence gap, researchers led by teams at Beijing Chest Hospital, Capital Medical University, conducted a prospective observational study at 26 hospitals across China between July 2020 and August 2023. They enrolled 608 patients with microbiologically confirmed MDR/RR-TB, pre-XDR-TB, or XDR-TB, all of whom received delamanid alongside optimized background regimens. The study was registered at clinicaltrials.gov under identifier NCT04421495 on June 9, 2020, and was conducted in accordance with the Declaration of Helsinki, with ethics approval from the leading center and written informed consent from all participants.

The safety evaluation was comprehensive, encompassing adverse events, serious adverse events, and adverse drug reactions, together with targeted cardiac monitoring. Because delamanid is known to prolong the QT interval, the portion of the electrocardiographic cycle representing ventricular repolarization, the investigators systematically measured the QT interval corrected using Fridericia’s formula, abbreviated QTcF. Prolongation of this interval matters because extreme QT stretching can predispose patients to torsades de pointes, a potentially life-threatening arrhythmia. All data were captured through a standardized electronic data management system and analyzed with SAS 9.4, ensuring consistency across the many participating centers.

The headline numbers paint a picture of tolerability broadly consistent with prior knowledge. Among the 608 participants, 352 patients, or 57.9 percent, reported at least one adverse event, while 331 patients, or 54.4 percent, experienced adverse drug reactions. Serious adverse events were documented in 39 patients, representing 6.4 percent of the cohort. When adverse events were grouped by system organ class, the most frequently affected categories were blood and lymphatic system disorders at 24.5 percent, investigations at 22.7 percent, driven mainly by electrocardiographic QT prolongation, and hepatobiliary disorders at 15.6 percent. These patterns reflect the cumulative toxicity of multidrug regimens rather than delamanid alone, since patients typically take five or more medications for many months.

Drilling down to reactions specifically attributed to delamanid, the investigators found that 167 patients, or 27.5 percent, experienced at least one. The most common was QT prolongation, affecting 17.1 percent of the cohort, followed by gastrointestinal disturbances at 3.3 percent and hepatotoxicity at 3.1 percent. QTcF prolongation, defined either as an increase of at least 60 milliseconds from baseline or as an absolute value of at least 500 milliseconds, was observed in 138 individuals, or 22.7 percent of participants. This rate falls within the range documented in earlier trials, reinforcing the message that cardiac monitoring, rather than avoidance of the drug, is the appropriate clinical response.

Perhaps the most intriguing analytical finding concerned who develops QT prolongation. Using multivariable logistic regression, the researchers identified age as the only significant factor associated with QTcF prolongation, and the direction of the effect ran counter to many clinicians’ intuitions. Compared with patients younger than 25 years, those aged 25 to 44 years had significantly lower odds of developing QTcF prolongation, with an adjusted odds ratio of 0.232 and a 95 percent confidence interval of 0.150 to 0.361. Patients aged 45 years or older also had lower odds, with an adjusted odds ratio of 0.386 and a 95 percent confidence interval of 0.243 to 0.614. In other words, the youngest patients in the cohort were the most likely to experience electrocardiographic changes, a pattern that suggests heightened vigilance and more frequent ECG surveillance may be warranted for adolescents and young adults receiving delamanid.

The study’s scale and design give its conclusions considerable weight. By enrolling more than 600 patients across 26 hospitals in a routine care setting, the investigators captured a far broader spectrum of patients than typical randomized trials do, including individuals with comorbidities, varying disease severity, and diverse background regimens that would often exclude trial participants. The prospective structure and standardized electronic data capture minimized the reporting inconsistencies that plague retrospective pharmacovigilance studies. The result is one of the clearest real-world portraits to date of how delamanid behaves outside the controlled environment of a clinical trial.

For global tuberculosis programs, the implications are practical and timely. The World Health Organization has encouraged the adoption of shorter, all-oral regimens for drug-resistant tuberculosis, and combinations that include both delamanid and bedaquiline, another QT-prolonging agent, are increasingly used despite theoretical concerns about additive cardiac effects. The Chinese cohort’s finding that no new safety signals emerged during available follow-up supports the continued expansion of delamanid-containing therapy, provided that the established monitoring framework, periodic electrocardiography and serum potassium assessment, is maintained. The authors conclude that the observed tolerability provides supportive real-world safety evidence for delamanid use in patients with MDR/RR-TB, while emphasizing that careful QT interval monitoring remains essential. As drug-resistant tuberculosis continues to pose a substantial public health threat, evidence of this kind, generated in the clinics where patients are actually treated, is what ultimately transforms a promising experimental drug into a dependable public health tool.

Subject of Research: Real-world safety of delamanid-containing regimens in patients with multidrug-resistant tuberculosis in China

Article Title: Delamanid-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety

Article References: Zhu, Y.-Q., Gao, M.-Q., Du, J., Liang, R.-X., Wu, G.-H., Pei, Y., Yan, X.-F., Cai, Q.-S., Huang, Y.-P., Huang, Z.-F., Wu, Y.-Q., Li, X.-J., Liu, Q.-Q., Jin, L., Wu, Q.-H., Xiong, Y., Li, M.-W., Wang, J.-Y., Kuang, H.-B., … Gao, J.-T. (2026). Delamanid-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14540-8

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14540-8

Keywords: delamanid, multidrug-resistant tuberculosis, MDR/RR-TB, QT prolongation, drug safety, tuberculosis treatment, China, adverse drug reactions, pharmacovigilance, XDR-TB, optimized background regimens, cardiac monitoring

The research, led by Liang-rui Qin and Can Hu of the State Key Laboratory of Ultrasound in Medicine and Engineering at Chongqing Medical University, together with colleagues including corresponding authors Yong-hong Du and Dai-rong Li, focused on a deceptively straightforward therapeutic idea: deliver oxygen-generating capacity directly into the granuloma microenvironment. Catalase is an enzyme that breaks down hydrogen peroxide into water and molecular oxygen. By injecting catalase locally into tuberculous granulomas at defined stages of infection, the team hoped to relieve the hypoxia, the severe oxygen depletion, that characterizes these lesions and that has long been suspected of undermining both immune function and drug efficacy.

To test the concept, the researchers established a murine subcutaneous tuberculous granuloma model using Bacillus Calmette-Guérin, or BCG, the attenuated mycobacterial strain best known as the tuberculosis vaccine. Mice were divided into treatment groups receiving either catalase, cobalt chloride, a chemical that mimics hypoxia, or a saline control. Crucially, the interventions were timed: one group received treatment at day six after infection, representing an early stage of granuloma formation, while another received it at day twelve, when lesions were more established. The team then assessed outcomes using a battery of techniques including histopathology, immunohistochemistry, immunofluorescence, enzyme-linked immunosorbent assays, and lipidomics, an analytical approach that profiles the full repertoire of lipid species in tissue.

The baseline findings were sobering. As BCG infection progressed, the granulomas became progressively more hypoxic, and this deterioration was accompanied by vascular dysfunction, visible as reduced expression of CD31, a marker of endothelial cells, and alpha-smooth muscle actin, a marker of vascular mural cells. Collagen deposition increased, scarring the lesions and further restricting blood flow. Lipid accumulated within the tissue, and bacterial load, measured as colony-forming units, climbed in parallel. In other words, the granuloma behaves like a self-reinforcing vicious cycle: poor vasculature starves the tissue of oxygen, hypoxia damages vessels further and promotes fibrosis and fat buildup, and the worsening microenvironment favors bacterial persistence.

Against this backdrop, the results of early catalase intervention stood out sharply. When catalase was administered at day six, the treatment downregulated hypoxia inducible factor-1 alpha, the master molecular switch that cells activate under low oxygen, along with vascular endothelial growth factor, a signaling protein that hypoxic tissues produce to stimulate new but often dysfunctional blood vessel growth. With the hypoxic burden lifted, the vascular structure inside the granulomas improved, as did vessel permeability, potentially opening a window for drugs that would otherwise fail to reach the bacteria. Collagen and lipid deposition both declined, indicating that the fibrotic and metabolic deterioration of the lesion had been blunted.

Perhaps the most technically intriguing finding came from the lipidomics analysis. Early catalase treatment did not simply reduce lipid accumulation indiscriminately; it specifically reshaped the lipid profile of the granuloma. The phospholipid species phosphatidylserine 18:0/18:0 was downregulated, while multiple subtypes of phosphatidylinositol and phosphatidylethanolamine were upregulated. This specificity matters because mycobacteria are notorious lipid manipulators: they co-opt host lipid metabolism to build their own protective niches inside macrophages, and aberrant lipid handling within granulomas has been linked to bacterial persistence and lesion necrosis. The finding suggests that oxygen restoration does not merely improve tissue plumbing but actively recalibrates the metabolic landscape on which the bacteria depend.

Timing, however, proved to be everything. When catalase was given at day twelve, well after the granulomas had matured, the therapeutic benefit was markedly limited. The late-stage lesions, already entrenched in hypoxia, fibrosis, and lipid dysregulation, apparently could not be rescued by a single round of oxygen-generating enzyme therapy. Conversely, when the researchers injected cobalt chloride to chemically induce hypoxia, every pathological measure worsened: vascular markers fell further, collagen and lipid deposition increased, and the lesions deteriorated across the board. This reciprocal experiment strengthens the causal argument that hypoxia is not merely correlated with granuloma progression but actively drives it.

The implications for tuberculosis therapy are potentially significant. Current drug regimens for tuberculosis require months of multidrug therapy, and treatment failure is often attributed to poor drug penetration and the metabolically dormant state that bacteria adopt in hypoxic lesions. If restoring oxygenation can normalize granuloma vasculature and reverse the metabolic conditions that shelter persistent bacteria, catalase-based local oxygen therapy could, in principle, serve as an adjunct that makes existing antibiotics work better, rather than a replacement for them. The study’s authors note that their findings suggest a potential application prospect in animal models that more closely recapitulate human tuberculosis, an important caveat, since the subcutaneous BCG model, while tractable and ethically manageable, differs in key respects from pulmonary infection with virulent M. tuberculosis in humans.

Those caveats deserve emphasis. BCG is an attenuated organism, and the granulomas in this model form in the skin rather than the lung, where the architecture of human tuberculous lesions, including caseous necrosis and cavitation, presents additional barriers. The dosing, delivery route, and safety profile of local catalase administration would all need to be established in more faithful models before any translation toward patients could be contemplated. Nonetheless, the study offers a mechanistically grounded proof of concept that the pathological microenvironment of a granuloma is a druggable target in its own right, and that the window for intervening is early, before fibrosis and lipid derangement become irreversible.

What makes the work resonate beyond tuberculosis is its broader message about infectious disease: the battlefield matters as much as the combatants. Rather than attacking the bacteria directly, this approach remodels the tissue ecosystem in which the bacteria survive, targeting hypoxia signaling, vascular integrity, and lipid metabolism simultaneously. As researchers increasingly recognize that chronic infections are sustained by microenvironmental niches, strategies that restore normal tissue physiology, whether through oxygen-generating enzymes, vascular repair, or metabolic modulation, may complement the antibiotic arsenal in ways that new drugs alone cannot. For a disease that still kills well over a million people each year, even a modest improvement in drug penetration and bacterial clearance inside granulomas could translate into shorter cures and fewer treatment failures. The Chongqing team’s catalase experiments are an early step, but they point toward a reframing of tuberculosis therapy: treat the lesion, not just the microbe.

Subject of Research: Catalase-based local oxygen therapy targeting hypoxia and lipid metabolism in tuberculous granulomas

Article Title: Therapeutic effects of early catalase intervention in tuberculous granulomas: targeting hypoxia and lipid dysregulation

Article References: Therapeutic effects of early catalase intervention in tuberculous granulomas: targeting hypoxia and lipid dysregulation. (n.d.). https://doi.org/10.1186/s12879-026-14516-8

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14516-8

Keywords: tuberculosis, granuloma, catalase, hypoxia, HIF-1alpha, oxygen therapy, BCG, lipidomics, vascular dysfunction, fibrosis, mouse model, BMC Infectious Diseases