What are the recent advancements in drugs for the treatment of tuberculosis (TB)?

Recent Drugs in Tuberculosis

The TB treatment landscape has been revolutionized by three new drugs—bedaquiline, delamanid, and pretomanid—which represent the first novel anti-TB compounds approved in nearly 50 years and have demonstrated significant improvements in mortality and treatment success rates for drug-resistant TB. 1

New Drugs Approved for TB Treatment

Bedaquiline (Diarylquinoline)

• Bedaquiline is now classified as a Group A drug by WHO, meaning it is strongly recommended for inclusion in all MDR-TB regimens and should be used as a core component of treatment. 1
• This drug works by inhibiting mycobacterial ATP synthase and is active against both replicating and non-replicating bacilli, regardless of intracellular or extracellular location. 2
• Bedaquiline received FDA conditional approval and WHO interim policy guidance, with demonstrated efficacy in improving treatment outcomes for MDR-TB and extensively drug-resistant TB (XDR-TB). 3
• The standard duration is 24 weeks (6 months), though WHO now recommends it can be extended beyond 6 months when needed with careful monitoring. 4

Delamanid (Nitroimidazole)

• Delamanid is a nitromidoxazole compound that has received stringent regulatory approval and WHO interim policy guidance for use in MDR-TB. 3
• This drug is typically administered for 24 weeks (6 months) as part of an optimized background regimen, achieving 91% favorable outcomes in the BEAT-India trial. 4
• After completing 6 months of delamanid, the regimen must maintain at least 3-4 effective drugs for the remainder of the 18-20 month treatment course. 4

Pretomanid

• Pretomanid is the third new drug to enter the TB treatment arsenal and is a key component of the BPaL regimen (bedaquiline, pretomanid, and linezolid). 1
• The BPaL regimen represents a 6-9 month all-oral treatment option for MDR/RR-TB and pre-XDR-TB patients who have not had prior exposure to bedaquiline or linezolid (defined as <2 weeks). 1

Repurposed Drugs with Enhanced Roles

Linezolid

• Linezolid is now a Group A drug alongside bedaquiline and fluoroquinolones, forming the backbone of modern MDR-TB regimens. 1
• Linezolid has demonstrated potential to cure refractory cases of MDR-TB and should continue at appropriate dosing (600 mg daily or 300 mg daily if toxicity develops). 4, 5
• Monthly complete blood counts are required to detect myelosuppression, and regular assessment for peripheral neuropathy is essential. 4

Fluoroquinolones (Levofloxacin/Moxifloxacin)

• Levofloxacin and moxifloxacin are Group A drugs with equal efficacy and safety in early-phase treatment of MDR-TB. 1, 5
• Levofloxacin is generally preferred over moxifloxacin due to fewer adverse events and less QTc prolongation. 1

Clofazimine

• Clofazimine is classified as a Group B drug and should be included when at least one Group B agent is needed alongside the three Group A drugs. 1

New Treatment Regimens

Shorter All-Oral Regimen for MDR-TB

• For eligible MDR/RR-TB patients, the recommended treatment is a 6-month all-oral, bedaquiline-containing regimen with a 4-6 month intensive phase followed by a 5-month continuation phase. 1
• Eligibility criteria include: no fluoroquinolone resistance, no extensive TB (spinal/CNS/miliary), not pregnant, and age >18 years. 1
• The intensive phase includes: bedaquiline (6 months), levofloxacin/moxifloxacin, clofazimine, pyrazinamide, ethambutol, high-dose isoniazid, and ethionamide. 1

Individualized Longer Regimen

• Patients with extensive pulmonary disease, severe extrapulmonary TB, fluoroquinolone resistance, or prior second-line drug exposure require an individualized 18-20 month regimen. 1
• The regimen must include at least three Group A agents (bedaquiline, levofloxacin/moxifloxacin, and linezolid) plus at least one Group B agent (cycloserine/terizidone and/or clofazimine). 4

BPaL Regimen

• The BPaL regimen (bedaquiline, pretomanid, linezolid) offers a 6-9 month treatment option for MDR/RR-TB and pre-XDR-TB under operational research conditions. 1
• This regimen may be considered as a last resort under programmatic conditions when an effective regimen based on existing recommendations cannot be designed. 1

Critical Monitoring Requirements

QTc Prolongation Monitoring

• ECG monitoring is required at 2,4,8, and 12 weeks, then monthly for QTc prolongation, with correction of electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia) before and during treatment. 4
• This is particularly important given that multiple new drugs (bedaquiline, delamanid, clofazimine, moxifloxacin) can prolong QTc interval. 6

Hematologic and Neurologic Monitoring

• Monthly complete blood counts are essential to detect linezolid-induced myelosuppression. 4
• Monthly visual acuity and color vision screening for optic neuropathy is required. 4
• Regular assessment for peripheral neuropathy (numbness, tingling, pain in extremities) must be performed. 4

Key Clinical Trials Demonstrating Efficacy

Drug-Susceptible TB Trials

• Study 31/A5349, TRUNCATE-TB, and SHINE trials have shown promising results toward shortening treatment duration for drug-susceptible TB. 1

Drug-Resistant TB Trials

• STREAM, NiX-TB, ZeNix, and TB-PRACTECAL trials have demonstrated that new drugs and regimens can significantly shorten treatment duration and improve outcomes for drug-resistant TB. 1

Common Pitfalls to Avoid

Drug Susceptibility Testing

• Drug susceptibility testing (DST) is essential for both shorter and longer regimens to guide appropriate therapy, given the estimated 450,000 new MDR/RR-TB cases in 2021. 7
• Never add a single drug to a failing regimen, as this creates monotherapy conditions and subsequent drug resistance. 7

Inadequate Drug Coverage

• Accepting fewer than 3 effective drugs after delamanid completion violates WHO guidelines and risks treatment failure. 4
• The regimen must maintain adequate drug coverage throughout the entire 18-20 month treatment course. 4

Premature Treatment Discontinuation

• Treatment should not be stopped early even though delamanid or bedaquiline has been completed at 6 months; the full treatment course is 18-20 months from initiation or 15-17 months after culture conversion, whichever is longer. 4

Implementation Considerations

Scale-Up Challenges

• Between 2016 and 2017, the number of patients started on shorter MDR-TB regimens globally increased from 2,400 to 10,000, with 62 countries reporting use by the end of 2017. 1
• Only 12,194 and 976 treatment courses were procured globally for bedaquiline and delamanid respectively in 2017, indicating significant implementation gaps. 1
• Barriers to adoption include regulatory processes for new drugs, requirement for new resources, and financial and political commitment from Ministries of Health. 1