- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development
Determination MIC Distribution and Interim Breakpoints for Pretomanid in Mycobacterium Tuberculosis in South Korea (SAPPHIRE; B1F) - Oct 21, 2024 - Abstract #KATRDIC2024KATRDIC_487;
Our findings provide molecular insights into how nutritional competition drives a novel antibiotic resistance mechanism and its ensuing fitness tradeoffs. In South Korea, the BPaLM 6-month short-course regimen, which includes pretomanid, linezolid, bedaquiline, and moxifloxacin, has shown effectiveness, but antimicrobial susceptibility testing for this drug has not yet been established...The MIC distribution of pretomanid was then determined using a microplate panel with both 100 pan- susceptible and 98 rifampicin and/or isoniazid resistant isolates, characterized by the absolute method using L
- |||||||||| Treatment of drug-susceptible tuberculosis (EMERALD; 3F) - Oct 21, 2024 - Abstract #KATRDIC2024KATRDIC_188;
this In the trial, BPaMZ therapy (bedaquiline, pretomanid, moxifloxacin, pyrazinamide) was administered to a group of drug-susceptible tuberculosis patients for 4 months...Another major clinical study currently underway includes BCZD therapy (bedaquiline, clofazimine, pyrazinamide, There is a Phase IIc open-label randomized PRESCIENT trial comparing a group receiving delamanid for 12 weeks and a standard treatment group...that Among these, securing universal accessibility to new drugs and their susceptibility testing methods is essential for the successful application of new short-term therapies. also, Additional research is needed to resolve concerns about the risk of drug resistance and occurrence of serious adverse reactions.
- |||||||||| New Paradigm Shift: The Novel Approach to Tuberculosis Treatment (CRYSTAL 3; 3F) - Oct 21, 2024 - Abstract #KATRDIC2024KATRDIC_54;
also, Additional research is needed to resolve concerns about the risk of drug resistance and occurrence of serious adverse reactions. The emergence of multidrug/rifampin-resistant tuberculosis (MDR/RR-TB) has become a significant global health challenge...Notably, new drugs such as bedaquiline, delamanid, and pretomanid have shown promising results, offering high efficacy and tolerability in treating drug-resistant TB...The recommended 6-month BPaLM regimen
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: Novel Treatment for Pre-XDR Tuberculosis Linked to a Lethal Case of Acute Myocarditis. (Pubmed Central) - Oct 16, 2024
To our knowledge, this is the first case of myocarditis in such a patient, the clinical features of which raised a high suspicion of drug induction that could be attributed to the treatment regimen that was administered. Clinicians who manage cases of drug-resistant tb should be aware of this newly reported, potentially lethal, adverse event.
- |||||||||| linezolid oral / Generic mfg.
Journal: A modified BPaL regimen for tuberculosis treatment replaces linezolid with inhaled spectinamides. (Pubmed Central) - Oct 8, 2024
The Nix-TB clinical trial evaluated a new 6 month regimen containing three oral drugs; bedaquiline (B), pretomanid (Pa), and linezolid (L) (BPaL regimen) for the treatment of tuberculosis (TB)...Moreover, the BPaL also increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. These combined data suggest that inhaled spectinamide 1599 combined with BPa is an effective TB regimen without L-associated AEs.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
P2/3 data, P2b data, Preclinical, Journal: Prospectively predicting BPaMZ phase IIb/III trial outcomes using a translational mouse-to-human platform. (Pubmed Central) - Oct 8, 2024
We predicted the addition of B to PaMZ to shorten treatment duration by 2 months and to have similar bacteriological success to standard HRZE treatment (considering only treatment success but not withdrawal from side effects and other adverse events), both at the end of treatment for treatment efficacy and 6 months after treatment has ended in relapse prevention. Using BPaMZ as a case study, we have demonstrated our translational platform can predict Phase II and III outcomes prior to actual trials, allowing us to better prioritize the regimens most likely to succeed.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: BPaLM Regimen Against Drug-Resistant Tuberculosis in India: A Need of the Hour. (Pubmed Central) - Oct 3, 2024
One such remarkable development is the introduction of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM)-based regimens to fight against two of the most severe forms of tuberculosis, i.e., multidrug- and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB). This editorial throws light on this newer regimen and discusses the same in the Indian context.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: Progress in programmatic management of drug-resistant TB, WHO Eastern Mediterranean Region, 2018-2023. (Pubmed Central) - Sep 21, 2024
Eastern Mediterranean Region countries progressed in PMDT using Xpert MTB/RIF, increased diagnosis and treatment of MDR/RR-TB patients using all-oral regimens, and improved treatment success. They must now enhance diagnostic capacity using WHO-recommended diagnostics, decentralise services while integrating them into primary health care, and prioritise the BPaL(M) regimen.
- |||||||||| Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: Impact of bedaquiline resistance probability on treatment decision for rifampicin-resistant TB. (Pubmed Central) - Sep 21, 2024
They must now enhance diagnostic capacity using WHO-recommended diagnostics, decentralise services while integrating them into primary health care, and prioritise the BPaL(M) regimen. Given the uncertainty of genotype-phenotype associations, physicians valued prBDQR for BDQ decision-making in rifampicin-resistant TB treatment.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, TBAJ-876 / Global Alliance for TB Drug Development
Enrollment closed, Combination therapy: Phase 2 Trial Assessing TBAJ876 or Bedaquiline, with Pretomanid and Linezolid in Adults with Drug-sensitive Pulmonary Tuberculosis (clinicaltrials.gov) - Sep 20, 2024
P2, N=309, Active, not recruiting,
Given the uncertainty of genotype-phenotype associations, physicians valued prBDQR for BDQ decision-making in rifampicin-resistant TB treatment. Recruiting --> Active, not recruiting
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Fexinidazole Winthrop (fexinidazole) / Sanofi
Journal: Free Radical Production Induced by Nitroimidazole Compounds Lead to Cell Death in Leishmania infantum Amastigotes. (Pubmed Central) - Sep 14, 2024
These molecules showed good efficacy in both axenic and intramacrophage amastigotes and were poorly cytotoxic in RAW 264.7 and HepG2 cultures. Fexinidazole and pretomanid induced the production of ROS in axenic amastigotes but were not able to inhibit trypanothione reductase (TryR), thus suggesting that these compounds may target thiol metabolism through a different mechanism of action.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development
Journal: Phenotypic-based Discovery and Exploration of a Resorufin Scaffold with Activity against Mycobacterium Tuberculosis. (Pubmed Central) - Sep 9, 2024
Exploration of the structure-activity relationship led to the discovery of novel resorufin analogues that do not rely on the deazaflavin-dependent nitroreductase (Ddn) bioactivation pathway for their antimycobacterial activity. These analogues are of interest as they work through an alternative, currently unknown mechanism that may expand our chemical arsenal towards the treatment of this devastating disease.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Lamprene (clofazimine) / Novartis, Sirturo (bedaquiline) / J&J, Pharmstandard
A CASE SERIES OF MULTIDRUG-RESISTANT TUBERCULOSIS () - Aug 27, 2024 - Abstract #MTS2024MTS_229;
Two patients had an all-oral regimen where amikacin was replaced with bedaquiline...Conclusions Even though the WHO all-oral recommendation regimen is shorter, more acceptable and easier to administer, it remains a challenge for full implementation. Individualized MDRTB treatment based on resource availability and patient characteristics should be considered.
- |||||||||| Review, Journal: Pharmacology of emerging drugs for the treatment of multi-drug resistant tuberculosis. (Pubmed Central) - Aug 27, 2024
The introduction of treatment regimens containing the novel agents bedaquiline, pretomanid, and linezolid, with or without moxifloxacin (BPaL-M or BPaL, respectively) have substantially reduced TB-related morbidity and mortality and are associated with favorable rates of treatment completion and cure. This review summarizes key information on the pharmacology and treatment principles for moxifloxacin, bedaquiline, delamanid, pretomanid, linezolid, and tedizolid in the treatment of multi-drug resistant TB, with recommendations provided to address and attenuate common adverse effects during treatment.
- |||||||||| TBI-223 / Global Alliance for TB Drug Development
Clinical, Journal: Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen. (Pubmed Central) - Aug 26, 2024
P1, P1/2,
TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200-2400?mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: Experiences in the introduction of bedaquiline pretomanid linezolid for drug-resistant tuberculosis in Kyrgyzstan. (Pubmed Central) - Aug 23, 2024
The experiences, successes, and lessons from the BPaL operational research, along with the programmatic introduction, offer valuable guidance for global drug-resistant TB control strategies. This initiative becomes a resource for countries with similar drug-resistant TB burdens, promoting a collaborative global approach to address drug-resistant TB challenges.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: Availability of drugs and resistance testing for BPaLM regimen for rifampicin-resistant tuberculosis in Europe. (Pubmed Central) - Aug 15, 2024
A complete DST for the BPaL(M) medicines was possible in less than half of the countries, because of the low accessibility of DST for pretomanid. Equal access to new regimens is urgently needed in Europe and a rapid scale up of DST, especially for pretomanid, is important to prevent unnoticed spread of drug resistance.
- |||||||||| Review, Journal: Recent advances in the treatment of tuberculosis. (Pubmed Central) - Aug 15, 2024
Equal access to new regimens is urgently needed in Europe and a rapid scale up of DST, especially for pretomanid, is important to prevent unnoticed spread of drug resistance. Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centred access to new treatment options for all people affected by TB.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
A CASE OF MULTIDRUG-RESISTANT TUBERCULOSIS COMPLICATED BY PNEUMOTHORAX (Convention Center Exhibit Hall: Poster Area 2) - Jul 31, 2024 - Abstract #CHEST2024CHEST_1228;
This case highlights the challenges in managing MDR-TB, especially when complicated by pneumothorax and nutritional issues. MDR-TB requires a comprehensive approach, addressing not only drug resistance but also associated complications.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: TB drug susceptibility testing in high fluoroquinolone resistance settings. (Pubmed Central) - Jul 18, 2024
Improving readability of PILs should be an important objective when preparing patient-facing written materials, thereby improving patient health/treatment literacy. The obtained results allowed designing the proposed diagnostic algorithm for rapid identification of DR-TB, ensuring rapid and equitable access to drug susceptibility testing for TB, ultimately improving TB care and control.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: Successful Multidisciplinary Treatment of Small Bowel Obstruction With an Ileal Stricture Resulting in Bowel Perforation in the Setting of Multidrug-Resistant Gastrointestinal Tuberculosis: A Case Report. (Pubmed Central) - Jul 15, 2024
The obtained results allowed designing the proposed diagnostic algorithm for rapid identification of DR-TB, ensuring rapid and equitable access to drug susceptibility testing for TB, ultimately improving TB care and control. We present the case of a male in his 40s who recently emigrated from Russia and was actively undergoing treatment for multidrug-resistant (MDR) pulmonary tuberculosis (TB) with the BPaL-M (bedaquiline, pretomanid, linezolid, moxifloxacin, and pyridoxine) regimen who presented to the emergency department (ED) with abdominal pain, vomiting, and no bowel movements...An oral BPaL-M regimen was held and an intravenous (IV) regimen consisting of linezolid, moxifloxacin, meropenem, and ampicillin/sulbactam was started per infectious disease (ID) recommendations...A
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development
Enrollment open: Single-Dose Study to Evaluate the PKs of Pretomanid in Participants With Renal Impairment Compared to Participants With Normal Renal Function (clinicaltrials.gov) - Jul 15, 2024
P1, N=36, Recruiting,
We present the case of a male in his 40s who recently emigrated from Russia and was actively undergoing treatment for multidrug-resistant (MDR) pulmonary tuberculosis (TB) with the BPaL-M (bedaquiline, pretomanid, linezolid, moxifloxacin, and pyridoxine) regimen who presented to the emergency department (ED) with abdominal pain, vomiting, and no bowel movements...An oral BPaL-M regimen was held and an intravenous (IV) regimen consisting of linezolid, moxifloxacin, meropenem, and ampicillin/sulbactam was started per infectious disease (ID) recommendations...A Not yet recruiting --> Recruiting
- |||||||||| Features of the BPaL triage routine practice algorithm in Bit-TB regions of Ukraine (PS-22; Poster board no. 11) - May 31, 2024 - Abstract #ERS2024ERS_2393;
a large part of the cohort consisted of patients with a normal BMI, without HIV infection, and a significant part of patients did not have fDST. Some patients were not prescribed B?aL/M according to inclusion criteria and for a significant part of patients BPaL/M were changed to another regimen during treatment.
- |||||||||| Journal: Multidrug-resistant tuberculosis in children: A practical update on epidemiology, diagnosis, treatment and prevention. (Pubmed Central) - May 17, 2024
Rapid molecular-based testing that provides information on rifampin susceptibility is increasingly globally available and recommended for all children suspected of TB disease--but remains limited by challenges obtaining appropriate samples and the paucibacillary nature of most pediatric TB...Several new or repurposed drugs including bedaquiline, delamanid, clofazimine and linezolid now allow most treatment regimens to be shorter and all-oral. Yet data to support short, all-oral, novel regimens for young children containing pretomanid remain insufficient at present, and there is a compelling need to conduct pediatric trials of promising therapeutics and MDR-TB treatment regimens.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
PK/PD data, Preclinical, Journal: Use of multiple pharmacodynamic measures to deconstruct the Nix-TB regimen in a short-course murine model of tuberculosis. (Pubmed Central) - May 2, 2024
Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness of in vivo systems for preclinical TB regimen development.
- |||||||||| sudapyridine (WX-081) / Guangzhou JOYO Pharma, Lamprene (clofazimine) / Novartis
Preclinical, Journal: Bactericidal and sterilizing activity of sudapyridine-clofazimine-TB47 combined with linezolid or pyrazinamide in a murine model of tuberculosis. (Pubmed Central) - May 1, 2024
Here, we found synergistic activities between C and sudapyridine (S), a structural analog of bedaquiline (B)...Compared to the BPa(pretomanid)L regimen, SCT and SCTL demonstrated similar bactericidal and sterilizing activities...Our findings emphasize the efficacy and the potential clinical significance of combination therapy with ETC inhibitors. Additionally, cross-resistance exists not only between S and B but also between S/B and C. This is supported by our findings, as spontaneous S-resistant mutants exhibited mutations in Rv0678, which are associated with cross-resistance to B and C.
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