By: Kevin Lee, PharmD Candidate c\/o 2028, Angela Yin, PharmD Candidate c\/o 2028<\/p>\n\n\n\n
The American Thoracic Society, Centers for Disease Control and Prevention (CDC), European Respiratory Society, and the Infectious Diseases Society of America recently published \u201cUpdates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS\/CDC\/ERS\/IDSA Clinical Practice Guideline\u201d in January 2025. This article will focus on the updated guidelines for multidrug-resistant and rifampin-resistant tuberculosis (MDR\/RR-TB), as the treatment regimen has dramatically improved from a 15-month parenteral regimen to a 6-month all-oral therapy, and it will give insight on the future direction of MDR\/RR-TB drugs that aim to overcome resistance issues and improve the safety profile.1<\/sup> Tuberculosis can be treated with antibiotics including isoniazid, rifampin, and pyrazinamide. However, in some cases M. tuberculosis<\/em> can develop resistance to this treatment, resulting in multidrug-resistant and rifampin-resistant tuberculosis (MDR\/RR-TB). This has proven to be extremely difficult to treat as bacterial resistance renders these drugs ineffective. With greater global availability and usage of TB drugs and concerns of resistance issues, this has emphasized the need to find effective therapy for MDR\/RR-TB before it becomes untreatable.2<\/sup> Shortening the duration of therapy while maintaining efficacy not only improves patient adherence by making it easier for the patient to take the full course of therapy, but reduces the risk of side effects associated with MDR\/RR-TB drugs by decreasing overall exposure. By having an all-oral therapy, this further improves adherence compared to IV or IM injections by simplifying the treatment. By reducing the therapy duration, this also minimizes the risk of drug resistance compared to a 15-month regimen because there is less time for the mycobacteria to develop resistance. The benefits of BPaL or BPaLM therapy largely stem from greater overall flexibility in the shorter duration treatment. For instance, if the therapy is ineffective, this will be inherently easier and faster to correct when compared to the previous therapy. By: Kevin Lee, PharmD Candidate c\/o 2028, Angela Yin, PharmD Candidate c\/o 2028 The American Thoracic Society, Centers for Disease Control and Prevention (CDC), European Respiratory Society, and the Infectious Diseases Society of America recently published \u201cUpdates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS\/CDC\/ERS\/IDSA Clinical Practice Guideline\u201d in January 2025.…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[7],"tags":[],"class_list":["post-4222","post","type-post","status-publish","format-standard","hentry","category-clinical"],"views":16,"_links":{"self":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts\/4222","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/comments?post=4222"}],"version-history":[{"count":1,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts\/4222\/revisions"}],"predecessor-version":[{"id":4223,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts\/4222\/revisions\/4223"}],"wp:attachment":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/media?parent=4222"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/categories?post=4222"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/tags?post=4222"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
What is multidrug-resistant and rifampin-resistant tuberculosis?
<\/strong>
Tuberculosis is the leading infectious cause of death, with an estimated 10.8 million new cases and 1.3 million deaths in 2023 alone. It is a chronic inflammatory disease characterized by the presence of Mycobacterium tuberculosis<\/em> bacteria, which cause severe inflammation in the lungs along with the development of necrotic plaques that drastically reduce lung function. M. tuberculosis<\/em> is extremely resistant to the body’s immune system, so when it is not cleared by macrophages or neutrophils, the immune system instead forms a granuloma to wall off the infection. However, these granulomas are only a stopgap, eventually being unable to contain the replicating bacteria in active TB, leading to tissue necrosis. Additionally, the presence of the granulomas themselves induce inflammation from the body’s attempt to eliminate them, such as excessive cytokine release, resulting in damage to the surrounding tissue.<\/p>\n\n\n\n
What are the new updated guidelines for treating MDR\/RR-TB?<\/strong>
According to the Updates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS\/CDC\/ERS\/IDSA Clinical Practice Guideline, the CDC recommends a 6-month treatment regimen (BPaLM) of bedaquiline (B) + pretomanid (P) + linezolid (L) + moxifloxacin (M) for patients aged 14 years or older with rifampin-resistant and fluoroquinolone-susceptible pulmonary TB disease. While for fluoroquinolone-resistant patients, the CDC recommends a 6-month treatment regimen (BPaL) of bedaquiline (B) + pretomanid (P) + and linezolid (L).1<\/sup>
Bedaquiline
\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Bedaquiline is a M. tuberculosis<\/em> ATP synthase inhibitor, demonstrating potent bactericidal and sterilizing activity against both actively replicating and nonreplicating bacilli. By blocking energy production of M. tuberculosis<\/em>, this outright kills both active and latent bacteria, making it an especially useful drug in the treatment of MDR\/RR-TB. However, with its widespread usage due to its high efficacy, an increase in bedaquiline resistance is expected and emerging data shows that treatment outcomes of bedaquiline-resistant TB are poor with bedaquiline essentially being useless in bedaquiline-resistant TB.3<\/sup>
Delamanid and pretomanid
\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Delamanid and pretomanid are nitroimidazole derivatives that inhibit mycolic acid synthesis, offering bactericidal activity by inhibiting the synthesis of the mycobacterial cell wall. They also demonstrate additional bactericidal activity by generating reactive nitrogen species, disrupting ATP production. Despite having promising effects, delamanid and pretomanid have their own issues involving high cost that decrease accessibility, as well as having the significant side effect of increasing QT interval prolongation and the associated risks of sudden cardiac death.
\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Because of their unique mechanism of action compared to bedaquiline, pretomanid is used in conjunction with bedaquiline in hopes of providing synergistic effects, such as disrupting M. tuberculosis <\/em>ATP synthesis in various ways. For instance, pretomanid is used in combination with bedaquiline in BPaL (bedaquiline + pretomanid + linezolid) and BPaLM (bedaquiline + pretomanid + linezolid + moxifloxacin) regimens, which are the updated first-line treatments for MDR\/RR-TB.
\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Delamanid was the first drug of the nitroimidazole antimycobacterial class, and modification for improved efficacy and better patient adherence led to the development of pretomanid. Moxifloxacin and linezolid are broad-spectrum antibiotics that were repurposed for TB treatment with moxifloxacin not being used in BPaL treatment for fluoroquinolone-resistant patients because it is a fluoroquinolone.3<\/sup>
Benefits of BPal and BPaLM therapy
<\/strong>\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Previous MDR\/RR-TB treatment utilized a combination of an injectable like amikacin, capreomycin, or kanamycin along with a fluoroquinolone like levofloxacin or moxifloxacin and additional oral agents like ethionamide or prothionamide over a 15-month period. Most notably, BPaL and BPaLM significantly shorten the treatment duration from 15 months to 6 months, a 60% reduction, revolutionizing the treatment of MDR\/RR-TB by allowing faster treatment. A shorter treatment duration will ultimately save the lives of TB patients that are in critical condition who do not have the time for a longer therapy duration.<\/p>\n\n\n\n
The future of MDR\/RR-TB therapy: Bedaquiline derivatives and DprE1 inhibitors<\/strong>
Bedaquiline derivatives
\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 TBAJ-876 and sudapyridine are next-generation antibiotics that are structurally related to bedaquiline, offering benefits in improved safety profile while maintaining efficacy. For instance, TBAJ-876 shows reduced risk for QT prolongation as well as has activity against bedaquiline-resistant strains, while sudapuridine similarly also has decreased risks of QT prolongation and cardiotoxicity. The efficacy and safety of these drugs are currently being evaluated, with the recently conducted NC-009 phase 2 trial determining the optimal dosing of TBAJ-876 in combination with pretomanid and linezolid and the ongoing NCT05824871 phase 3 trial testing sudapyridine for the treatment of rifampicin-resistant disease.3<\/sup>
DprE1 inhibitors
\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Additionally, there is also a new class of drugs for tuberculosis treatment, DprE1 (decaprenylphosphoryl-\u03b2-d-ribose 2\u0384-epimerase subunit 1) inhibitors, which target an enzyme involved in the synthesis of mycobacterial cell wall components. By decreasing the production of lipoarabinomannan and arabinogalactan, DprE1 inhibitors have a unique mechanism of action \u00a0\u00a0\u00a0\u00a0\u00a0that specifically disrupts mycobacterial cell wall synthesis while also having low risk for side effects. As there is no human protein analogue of DprE1, the inhibitors are selective towards mycobacterial cell wall synthesis and produce less side effects. DprE1 inhibitors, such as quabodepistat (OPC-167832), BTZ-043, and TBA-7371, are currently undergoing phase 2 trials.
\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Quabodepistat was tested in a phase 2 trial (NCT05221502) that evaluated the combination of quabodepistat, bedaquiline, and delamanid in a 4-month regimen compared to the standard 6-month HRZE regimen (isoniazid + rifampicin + pyrazinamide + ethambutol). The trial found that the combination was well tolerated with no serious treatment-emergent adverse events and had similar efficacy in reducing sputum culture conversion rates compared to the standard 6-month HRZE regimen while having a shorter treatment duration.
\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 BTZ-043 has demonstrated the promising effects of accumulation in necrotic lesions, which is significant because antibiotics are usually unable to penetrate the necrotic lesions to reach therapeutic concentrations. BTZ-043 overcomes this challenge, having unique benefits of being able to effectively treat patients with necrotic lesions that are prevalent in TB cases and also having a lower hepatotoxicity risk than isoniazid or pyrazinamide. The dosing of BTZ-043 is currently being evaluated in a phase 2 trial (NCT05926466) in combination with bedaquiline and delamanid compared to a control regimen of bedaquiline, delamanid and moxifloxacin. TBA-7371 has recently completed a Phase 1\u200a trial (NCT03199339), but the results have not been published.3<\/sup>
\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 To summarize, updated guidelines recommend that MDR\/RR-TB can be treated using
6-month BPaL (bedaquiline + pretomanid + linezolid) or BPaLM (bedaquiline + pretomanid + linezolid + moxifloxacin) all-oral regimens, dramatically reducing treatment duration from 15 months to 6 months while improving patient adherence. These new regimens specifically utilize bedaquiline and pretomanid, which have unique mechanisms of action that allow them to have high efficacy. However, with issues of bacterial resistance and side effects such as QT prolongation, further development of MDR\/RR-TB drugs is critical. New MDR\/RR-TB drugs that are currently in phase 2 or 3 trials include bedaquiline derivatives and DprE1 inhibitors, which have promising effects of addressing resistance issues and improving the safety profile to ensure that MDR\/RR-TB remains treatable.
References:<\/p>\n\n\n\n\n
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