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This article by infectious diseases pharmacist Aneeka Chavda outlines five key considerations for pharmacists in the treatment of Mycobacterium tuberculosis (TB), particularly drug-sensitive cases. It emphasizes the critical but potentially underdosed role of rifampicin, highlighting research into higher doses that may improve outcomes. Ethambutol’s ocular toxicity is addressed, especially in at-risk populations, underlining the need for early screening. The piece advocates for therapeutic drug monitoring (TDM) in specific high-risk groups to personalize treatment. It also explores rifapentine as a promising agent for shorter, effective regimens, despite current access barriers. Finally, the use of fluoroquinolones are discussed, especially for drug-resistant or intolerant patients, noting their potential in CNS TB and as part of shorter-course therapies.
Authored By: Aneeka Chavda, MRPharmS, MSc, MCMI, PgDipClinPharm
Posted 19 June 2025
Mycobacterium tuberculosis (TB) is one of the leading causes of death globally. The WHO reports that in 2023, around 10.8 million individuals contracted TB, leading to an estimated 1.25 million fatalities. While TB can be cured using a combination of antibiotics, the treatment typically spans 6 to 12 months; additionally, therapy for drug-resistant tuberculosis can extend beyond 18 months, often with significantly reduced chances of success. The protracted treatment durations and the range of potentially harmful side effects hinder the efficacy of existing regimens, raising the likelihood of treatment interruptions and further developing drug resistance.
Combination therapy is crucial for effective treatment, as TB exists in different subpopulations that exhibit different physiological responses in the host. TB can exist in both actively growing and dormant states, with each responding differently to antibiotics1. The standard treatment protocol includes an initial 2-month regimen of isoniazid, rifampicin, ethambutol, and pyrazinamide, followed by a continuation phase with isoniazid and rifampicin.
In this article, we will explore 5 things for pharmacists to know about the treatment for drug sensitive Mycobacterium tuberculosis.
1. Rifampicin is a critical component of TB treatment, but is it dosed optimally?
Rifampicin was introduced in the 1960s and has since become a pivotal component of TB treatment regimens due to its excellent sterilising effect2.
When introduced, it was dosed at 600 mg daily (10 mg/kg); however, the underpinning evidence for this dosing regimen is scant. Literature indicates that this was partly driven by a fear of toxic adverse effects at higher doses and financial considerations, as it was prohibitively expensive when first introduced3. Whilst preliminary pharmacokinetic studies indicated that a daily dose of 600 mg produced serum concentrations surpassing the typical minimum inhibitory concentration for M. tuberculosis4, more recent research implies that this dosage falls at the lower end of the dose-response curve5. This has led to several studies evaluating the safety and efficacy of higher doses of rifampicin, driven by emerging evidence indicating its potential for enhanced anti-mycobacterial activity, such as early conversion rates and relapse-free cure6.
High doses of up to 40 mg/kg have been evaluated in several clinical trials and have all demonstrated tolerability, with shortened time to sputum culture conversion and higher plasma concentrations for the duration of treatment7,8,9,10. All high-dose rifampicin trials have demonstrated favourable outcomes to date and do not show dose-limiting side effects; however, no progress has been made in implementing this dosing structure due to insufficient evidence to support shortened treatment duration. In the interim, there may be value in utilising high-dose rifampicin (>10 mg/kg) to treat high-risk patients who are severely ill, CNS disease or have low drug concentrations11.
The measurement of therapeutic drug levels may serve as a valuable tool to augment the increased dose of rifampicin in instances where reduced absorption or ineffective treatment outcomes are suspected.
2. Ethambutol ocular toxicity is rare, but caution should be exercised in certain populations
Ethambutol is part of the first-line TB regimen and shows modest anti-mycobacterial activity compared to other agents. It is the only drug with bacteriostatic properties, but its importance is often underestimated. Ethambutol helps prevent acquired resistance, so after confirming susceptibility to isoniazid and rifampicin through drug susceptibility tests, it can be safely stopped without affecting treatment outcomes12.
However, ethambutol is linked to significant side effects, particularly ethambutol-induced optic neuropathy (EON), characterised by bilateral, painless loss of central visual acuity and field. Studies demonstrate its role in partially reversible optic neuropathy, leading to varying vision loss13. Crucially, the effects depend on dosage, with EON incidence at a standard dose of 15 mg/kg/day ranging from 1% to 2.5%, increasing to 18% at 35 mg/kg/day14. Thus, higher doses should be avoided.
Patients stopping ethambutol promptly (before irreversible optic atrophy) can regain vision within weeks to months15. Other risk factors include age, hypertension, and renal insufficiency, since it’s mostly eliminated by the kidneys. Although rare, preventing EON requires a baseline eye examination before starting ethambutol and stratifying at-risk patients. Monthly visual loss screenings are essential to detect EON before significant changes occur, and patients should be informed about ocular toxicity symptoms.
Those with significant renal impairment should have adjusted doses of ethambutol for reduced clearance or consider alternative therapies.
3. Therapeutic drug monitoring has an emerging role for improving outcomes in TB
Therapeutic drug monitoring (TDM) is widely used in various conditions to ensure optimal dosing, maximising efficacy whilst minimising toxicity. However, it is not routine practice in the setting of active TB for various reasons.
As it stands, the majority of patients who receive the standard regimen for drug-susceptible TB will respond completely to treatment16. Approximately 90% of patients are completely cured by standard dosing of first-line agents of rifampicin, isoniazid, pyrazinamide and ethambutol. Despite advancements in treatment, certain patients may exhibit delayed responses, have drug-resistant TB, be at risk for drug-drug interactions, or have comorbid conditions that considerably complicate clinical management. There is growing evidence to suggest that such groups may benefit from TDM, allowing clinicians to make timely adjustments to drug therapy, impeding the development of drug resistance.
Studies now indicate that patients with low anti-tuberculosis drug levels had a longer time to culture conversion17, delayed treatment response and failures18. Current recommendations for maximum doses and fixed-dose preparations were historically informed by TB patients weighing 50 kg8, but it is now recognised that patients often present with considerably higher weights. Therefore, ensuring appropriate drug exposure for patients is crucial, and this requires a personalised dosing strategy tailored to each individual. Although TDM can be inconvenient and expensive, specific high-risk populations (see table 1) have experienced advantages with tailored dosing, suggesting a need for a prioritised strategy. The 2-h post-dose concentrations approach the peak for most TB drugs, and a 6-h sample allows the clinician to distinguish between delayed absorption and malabsorption, an approach supported by the British Thoracic Society – TB drug monographs19.
Table 1. Patient group that may benefit from TDM
| Critically ill patients |
| TB meningitis |
| HIV- co infected patients |
| Diabetic patients |
| Patients with gastrointestinal disease |
| Renal failure |
| Multiple drug-drug interactions |
It is important to note that TDM is one aspect of the care for patients with TB and should be combined with clinical and microbiological assessments, enabling even the most complicated patients to be treated successfully.
4. Rifapentine: A game changer for TB treatment?
Rifapentine, a synthetic derivative of rifampicin developed in 1965, has gained recent attention for its pharmacological differences, primarily a terminal half-life of 13 hours compared to rifampicin’s 2-3 hours, indicating enhanced activity20. This characteristic supports improved dosing structures, prompting trials to optimise its use in both latent and active TB settings.
Rifapentine is a compelling option for latent TB infection (LTBI), particularly where compliance issues exist. The PREVENT TB trial showed that a weekly regimen of isoniazid and rifapentine for 3 months was non-inferior to daily isoniazid for 9 months21. The rifapentine group had higher treatment completion rates (82.1% versus 69%) than the isoniazid group, mirroring findings from U.S. TB Control Programs21. In 2014, the US FDA approved this regimen, and it features in the latest WHO guidelines for LTBI treatment.
More recently, the WHO also endorsed a 30-day rifapentine and isoniazid regimen for LTBI based on positive trial outcomes22. Rifapentine’s benefits also extends to active disease; a phase III trial found a 4-month rifapentine-based regimen with moxifloxacin non-inferior to the standard 6-month treatment23. This landmark trial was the first successful attempt at shortening of TB treatment to under 6 months, which is now approved by the WHO as an alternative regimen.
Rifapentine could revolutionise TB management by simplifying treatment regimens, increasing completion rates, and improving patient outcomes. However, its adoption is currently limited by global availability, high costs, and preparation challenges. The WHO Global TB Programme is encouraging manufacturers to produce quality-assured rifapentine formulations to lessen the pill burden in treatment regimens, ultimately improving the chances of successful treatment completion. Unfortunately, until these challenges are resolved, widespread use of rifapentine will remain limited.
5. The fluoroquinolones: How does this antibiotic class contribute to TB treatment?
Fluoroquinolones are typically not used as first-line treatment for fully susceptible TB, but are considered crucial for managing drug-resistant cases. The WHO currently positions fluoroquinolones in the context of isoniazid-resistant TB and MDR/XDR-TB. Their importance is also growing in treating drug-sensitive TB, typically used as an alternative to first-line therapies if those treatments cause hepatotoxicity. The 2025 guidelines from the Infectious Diseases Society of America recommend isoniazid, rifapentine, pyrazinamide and moxiflxacin as first-line for the treatment of isoniazid-suscpetibel, rifampin-susceptible tuberculosis in adults. These guidelines also recommend moxifloxacin as a part of combination therapy when treating rifampin-resistant, fluoroquinolone-susceptible TB.
Research indicates that fluoroquinolones can improve sterilising activity and achieve sputum culture conversion within eight weeks, suggesting shorter treatment durations and less frequent dosing could yield similar results24. Until recently, no studies had conclusively shown improvements in outcomes like relapse, treatment failure, or treatment duration reduction25,26. In 2021, Dorman et al demonstrated non-inferiority when moxifloxacin was paired with high-dose rifapentine, isoniazid, and pyrazinamide, resulting in the first four-month regimen approved by both the WHO and the U.S CDC for treating pulmonary tuberculosis23. However, the adoption of this regimen has been hindered by the lack of rifapentine in appropriate formulations and worries about rare adverse effects associated with fluoroquinolones, such as tendinopathy, peripheral neuropathy, and aortic aneurysm.
Extra caution is warranted for at-risk groups, especially given the prolonged nature of TB therapy. Among available quinolones, levofloxacin and moxifloxacin are preferred due to their significantly enhanced effectiveness against M. tuberculosis compared to ciprofloxacin and ofloxacin, as well as their once-daily dosing and good tolerability. They have also been shown to penetrate the blood-brain barrier and achieve therapeutic levels in the cerebrospinal fluid27. They show significant promise as part of first-line therapy for CNS TB. Nevertheless, existing studies have not demonstrated a notable difference in clinical outcomes, such as mortality rates. Until further evidence emerges, fluoroquinolones remain as second-line options, used when first-line drugs fail or when there is concern regarding drug resistance.
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ABOUT THE AUTHOR
Aneeka Chavda, MRPharmS, MSc, MCMI, PgDipClinPharm is the senior lead pharmacist for Infection and Tuberculosis at Imperial College Healthcare NHS Trust in London. She was the consultation lead of the UK Clinical Pharmacy Association Infection Group from 2018 to 2025 and is currently a clinical advisor for the British Thoracic Society Multi-Drug Resistant Tuberculosis Clinical Advice Service. She presently serves on the NICE antimicrobial evaluation panel, drawing on her expertise to assess antimicrobials in accordance with the evaluation criteria of the new de-linkage subscription model established by NICE and NHS England.
Her postgraduate education includes an MSc in Pharmacy Practice, which focuses on unintended consequences of spurious penicillin allergy labels, non-medical independent prescribing, and a healthcare leadership fellowship. At present, she is undertaking the UK-Africa AMS leadership fellowship through the Commonwealth Pharmacists Association. Her areas of interest include data-driven quality improvements in antimicrobial stewardship, pharmacist-led penicillin allergy de-labelling, and the drug management of multidrug-resistant tuberculosis.
Disclosures: Nothing to disclose.
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