pretomanid (PA-824) / Global Alliance for TB Drug Development - LARVOL DELTA

The pharmacokinetics (PK) / pharmacodynamics (PD) of pretomanid, delamanid and bedaquiline in the BALB/c mouse model of central nervous system tuberculosis. (PubMed, BMC Infect Dis) - No abstract available

Journal • PK/PD data • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Advances in Five-Membered Heterocyclic Scaffolds as Anti-Tuberculosis Agents: A Decade of Discovery. (PubMed, Arch Pharm (Weinheim)) - "Clinical candidates such as pretomanid (nitroimidazole), linezolid (oxazolidinone), and delamanid (imidazo-oxazole ring) approved by the FDA provide evidence for their significance against TB. This review addresses the global challenge of tuberculosis by highlighting the strategic design of five-membered heterocyclic scaffolds. It provides a comprehensive overview of the evolution of clinical candidates and recent advancements in pyrrole-, furan-, thiophene-, pyrazole-, imidazole-, thiazole-, oxadiazole-, thiadiazole-, and tetrazole-based scaffolds and their hybrid derivatives developed over the past decade, and further offers insights into their SAR analyses and molecular docking aspects."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Predicting early bactericidal activity of tuberculosis drug combinations using a translational pharmacokinetic-pharmacodynamic modeling approach. (PubMed, bioRxiv) - "Interactions between bedaquiline, pretomanid, linezolid, and pyrazinamide were characterized using two modeling approaches: the empirical SUPER method and the mechanistic General Pharmacodynamic Interaction model. Our study demonstrated that the translational PK-PD platform reliably predicts both short- and long-term outcomes for combinations, regardless of the interaction model. This supports its application across drug development stages to inform dose selection and effective companion drugs for anti-TB therapies."

Journal • PK/PD data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Treatment Outcomes and Drug-Related Adverse Events Across Four Short-Course RR-TB Regimens in South Africa: A Retrospective Analysis. (PubMed, Int J Infect Dis) - "Under programmatic conditions, the BPaL-L regimen achieved the highest treatment success while maintaining manageable safety profiles. These findings provide valuable evidence to guide patient management and support implementation of novel MDR/RR-TB regimens in high-burden settings."

Adverse events • Journal • Retrospective data • Hematological Disorders • Infectious Disease • Otorhinolaryngology • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Identifying optimal combination regimens for therapy of Mycobacterium tuberculosis with an algorithmic approach: prospective predictions and validations. (PubMed, PLoS One) - "We conclude that this provides a way forward for the future to identify the most promising regimens to shorten therapy for tuberculosis and suppress emergence of resistance."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A bactericidal tuberculosis drug regimen driven by inhibition of the terminal oxidases by pretomanid. (PubMed, EMBO Mol Med) - "This property leads to a pronounced synergy with telacebec (Q203), a clinical-stage drug targeting the cytochrome bcc:aa3, while concurrently curtailing the emergence of resistance to pretomanid. Furthermore, the incorporation of the cytochrome bd oxidase inhibitor ND-011992 resulted in a triple drug combination highly bactericidal against antibiotic-tolerant, non-replicating as well as replicating M. tuberculosis. The combination of pretomanid and drugs targeting the terminal oxidases holds the potential to serve as the cornerstone for an efficacious sterilizing drug regimen against tuberculosis."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

The microevolutionary trajectory of endemic multidrug-resistant tuberculosis strains in Portugal toward increased drug resistance levels and its clinical significance. (PubMed, Front Microbiol) - "The PK models for isoniazid and moxifloxacin suggest an increase in dosage to be ineffective against strains harboring high-level resistance-conferring double inhA mutations and gyrA/B mutations. Cycloserine and para-aminosalicylic acid are the only drugs predicted to remain efficacious against the majority of tested strains, while the effectiveness of newer drugs like bedaquiline, pretomanid and delamanid have yet to be uncovered. Proper diagnosis of drug resistance-associated mutations provides invaluable insights into the treatment of TB, as different allelic configurations lead to differing drug resistance levels, often rendering drugs ineffective."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Preserving the Antimycobacterial Drug Arsenal: A Case Report of Disseminated Mycobacterium Avium Disease (IWLH 2026) - "The patient was treated with clarithromycin, ethambutol, rifabutin, moxifloxacin, and cycloserine for two years, with amikacin added for the first six months, inducing ototoxicity...A salvage regimen was initiated, including amikacin, tedizolid, clofazimine, ceftazidime/avibactam, isoniazid, delamanide, and ethambutol, as well as antiepileptic treatment and IFNγ administration...Intravenous dexamethasone was administered with intensified NTM treatment, but blood cell counts continued to decline, and inflammatory markers (CRP, PCT) remained high. Due to previous Gram-negative infections, his regimen was modified to include daptomycin, meropenem/vaborbactam, and colistimethate. Candida glabrata was identified in port cultures, necessitating port removal and initiation of isavuconazole. He was placed on dual beta-lactam therapy (meropenem and ceftriaxone) combined with clofazimine, isoniazid, linezolid, cycloserine, bedaquiline, and pretomanid...Conclusions This case..."

Case report • Clinical • CNS Disorders • Epilepsy • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hemophagocytic lymphohistiocytosis • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • Pulmonary Disease • Respiratory Diseases • Septic Shock • IFNG • IL12A

Relapse and Emergent Resistance With Novel Short-Course Regimens for Multidrug-Resistant Tuberculosis, United States, 2022-2024. (PubMed, Open Forum Infect Dis) - "Bedaquiline, pretomanid, and linezolid with or without moxifloxacin (BPaL/M) are recommended oral 6-month treatment regimens for multidrug- or rifampin-resistant (MDR/RR) tuberculosis (TB)...Despite the advent of shorter and better tolerated bedaquiline-based regimens, US clinicians continue to face challenges in managing drug-resistant TB. These data support the need for expert management of these patients beyond routine TB care, as well as the need for close monitoring and follow-up months after treatment completion."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Tuberculosis diagnosis and the complete drug resistance pattern from a single sample within a single day by use of a composite platform of MAX MDR-TB and AmPORE-TB. (PubMed, J Clin Microbiol) - "Resistance profiling most frequently (up to 11.3%) failed for clofazimine, pretomanid, and delamanid. This approach is expected to markedly reduce morbidity, drop-out rates, and transmission. The necessary instruments and technologies are already available in many high-prevalence countries and are currently being rapidly scaled up worldwide."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Cost-effectiveness of BPaL/BPaLM as compared to mixed standard of care bedaquiline containing regimen for MDR/RR-TB. (PubMed, Indian J Med Res) - "Background & objectives Current options for treating tuberculosis (TB) that is resistant to rifampicin (RR-TB) are limited and available regimens are often lengthy and poorly tolerated. However, following recent evidence from the TB PRACTECAL trial, countries are considering programmatic adoption of six-month, all-oral treatment regimen such as bedaquiline, pretomanid, linezolid (BPaL) and BPaL with moxifloxacin (BPaLM)...Interpretation & conclusions Our findings indicate that BPaL based regimens are likely to be cost-saving and more effective than the current mixed SoC in a range of settings. Countries should consider programmatic uptake of BPaL based regimens to treat MDR/RR-TB."

HEOR • Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Preparation and in vitro sustained release performance of thermosensitive gel microsphere composite loaded with Anti-Tuberculosis drug PaMZ/BMP-2. (PubMed, J Orthop Surg Res) - "This study successfully prepared PaMZ/BMP-2 microspheres with good morphology and drug loading capacity, achieving controlled sustained release through thermosensitive gel. This offers a potential formulation approach for future localized therapy of spinal tuberculosis and lays the foundation for subsequent in vivo experiments and clinical translation."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • BMP2

Identification of Novel Leads as Antitubercular Agents that Target Mtb-DHFR by using Virtual Screening. (PubMed, Curr Med Chem) - "On the basis of cell-based and enzymatic results, we concluded that Ansh- 04 is a promising, selective Mtb-DHFR inhibitor with potential as an anti-TB lead candidate."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • DHFR

Delamanid and pretomanid have comparable bactericidal activity but pretomanid potently inhibits Mycobacterium tuberculosis ribosomal rRNA synthesis. (PubMed, bioRxiv) - "This information deepens understanding of differences between two clinically important antibiotics. It also shows that antibiotics testing should consider not only bacterial burden but also new tests of bacterial health."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

[Fe(phen) 3 ] 2+ and [Fe(phen) 3 ] 2+ -Loaded Nanostructured Lipid System: In Silico, In Vitro, and In Vivo Efficacy against Mycobacterium tuberculosis. (PubMed, ACS Omega) - "FEP combination with rifampicin or pretomanid significantly reduced the MIC90, with fractional inhibitory concentration index (FICI) of 0.27 and 0.103, respectively. FEP-loaded nanostructured lipid system (NLS@FEP) was designed to optimize FEP activity, which improved its stability and bioavailability. In a murine model infected with Mtb H37Rv, free FEP and NLS@FEP achieved complete elimination of pulmonary infection."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

The power of resistance: mechanisms of antimicrobial resistance in Mycobacterium tuberculosis and its impact on tuberculosis management. (PubMed, Clin Microbiol Rev) - "We highlight the emerging role of therapeutic drug monitoring and pharmacokinetic/pharmacodynamic modeling in optimizing individualized therapy, particularly for novel regimens incorporating bedaquiline, pretomanid, and linezolid. Finally, we propose a paradigm shift toward integrated, precision-based TB management, leveraging host-directed therapies, biofilm-disrupting agents, and real-time pharmacokinetics-guided dosing to preempt resistance emergence and improve clinical outcomes. This review provides a translational framework for addressing the biological and operational complexities of DR-TB in the era of AMR."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Protocol for a phase 2, partially blinded, randomized trial assessing the safety and efficacy of sorfequiline or bedaquiline in combination with pretomanid and linezolid in adult participants with newly diagnosed, drug-sensitive, smear-positive pulmonary tuberculosis (NC-009). (PubMed, Trials) - P2 | "NC-009 is a first in-patient, dose-ranging, phase 2 trial of sorfequiline, with an innovative design combining ph2a, ph2b, and ph2c elements that simultaneously allow for dose selection, preliminary evaluation of treatment duration, robust collection of safety data, evaluation of drug-drug interaction with antiretroviral medications, and pharmacokinetic assessment of study drugs. The study is currently ongoing. TRIAL REGISTRATION NUMBER {4}: ClinicalTrials.gov NCT06058299. Registered on 09 September 2023."

Clinical • Journal • P2 data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A novel antituberculosis agent exhibits potent clinical efficacy and good safety profile: an open-label, randomized-controlled, multicenter, phase 2a trial. (PubMed, Signal Transduct Target Ther) - P2 | "Recently, 2 nitroimidazole-based agents, namely, delamanid and pretomanid, have been approved by regulatory agencies. Ninety-one adverse events (AEs), including no serious AEs, were attributed to JDB0131 in 30 patients. This trial identified a promising new drug for the increasing TB burden worldwide."

Clinical • Journal • P2a data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Mind the gap: Understanding discordance between culture- and a non-culture-based measure of bacterial burden in murine tuberculosis treatment models. (PubMed, bioRxiv) - "For all regimens, CFU fell more than 16S rRNA, ranging from isoniazid-rifampin-pyrazinamide-ethambutol (CFU decreased 39-times more than 16S rRNA at week 4) to bedaquiline-pretomanid-moxifloxacin-pyrazinamide (CFU decreased >500,000-times more). CFU-16S gap is only partially explained by slow decay of residual 16S, suggesting development of a VBNC SA population. However, continued decrease in 16S rRNA after treatment cessation and its limited association with relapse suggests VBNC SA may be a transient rather than persistent state."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Hepatic Safety of Bedaquiline, Delamanid, and Pretomanid: A Systematic Review and Meta-analysis. (PubMed, Int J Mycobacteriol) - "Among all the studied drugs, DLM alone demonstrated the highest hepatic safety, while regimens containing BDQ, Pa, or their combination showed higher hepatotoxic risks compared to SOC. We recommend regular liver function monitoring for DR-TB patients receiving these novel anti-TB drugs."

Clinical • Journal • Retrospective data • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Biodistribution and Pharmacokinetics of Pretomanid in Tuberculosis Patients Using 18F-Pretomanid PET (clinicaltrials.gov) - P=N/A | N=10 | Completed | Sponsor: Johns Hopkins University | Recruiting ➔ Completed | N=20 ➔ 10 | Trial completion date: Feb 2027 ➔ Oct 2025 | Trial primary completion date: Feb 2026 ➔ Oct 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Pretomanid: The life-saving drug to combat Pakistan's TB crisis. (PubMed, J Pak Med Assoc) - No abstract available

Journal

Laboratory strengthening strategies to advance drug susceptibility testing for BPaL regimens in TB treatment. (PubMed, Public Health Action) - "Our study highlights the need for continued investment in training and infrastructure to integrate DST into routine diagnostics and to support scale-up of BPaL regimens in high TB-burden settings."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

QUANTUM: A Study of Quabodepistat-containing Regimens for the Treatment of Drug-resistant Pulmonary Tuberculosis (clinicaltrials.gov) - P3 | N=532 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Whole-Genome and Targeted Sequencing of 75 Drug-Resistant Mycobacterium tuberculosis Clinical Isolates in South Korea. (PubMed, Ann Lab Med) - "Specifically, we analyzed mutations associated with resistance against isoniazid (INH), rifampicin (RIF), moxifloxacin (MFX), pyrazinamide (PZA), pretomanid (PMD), delamanid (DLM), linezolid (LZD), and bedaquiline (BDQ) and compared them with those in the 2023 WHO mutation catalog. However, PZA results were discrepant for 16 isolates. Our findings highlight the potential of WGS and targeted sequencing as powerful tools for diagnosing TB drug resistance and emphasize the need for further validation before their routine implementation in clinical settings."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis