From Repurposing to Refinement: Optimizing Levofloxacin for Treatment of Multidrug-Resistant Tuberculosis

After the development of rifampicin in 1963, nearly 50 years passed before the U.S. Food and Drug Administration approved a new antituberculosis drug, bedaquiline, in 2012 (1). During this five-decade drought, antibiotics originally developed for other bacterial infections but later found to be effective against tuberculosis (TB) were repurposed to treat drug-resistant TB. Representative examples include fluoroquinolones, linezolid, and clofazimine.

Among the repurposed drugs, fluoroquinolones were the first to be widely adopted and became the most extensively used in TB treatment. Their anti-TB activity was potent enough that patients with TB who initially received incorrect diagnoses of bacterial pneumonia experienced temporary but noticeable clinical improvement when prescribed these drugs (2). With multiple studies confirming their positive impact on microbiological and clinical outcomes, fluoroquinolones have consistently been recognized as key components in multidrug-resistant (MDR) TB treatment (3, 4). A meta-analysis incorporating individual data from more than 12,000 patients with MDR TB further reinforced these findings, demonstrating that the use of levofloxacin or moxifloxacin was associated not only with treatment success but also with reduced mortality (5). On the other hand, the presence of fluoroquinolone resistance significantly worsens MDR TB treatment outcomes (6–8). Because of the significant clinical impact of fluoroquinolone resistance and their crucial role in MDR TB treatment, these drugs are not only considered defining criteria of extensive drug-resistant TB and pre–extensive drug-resistant TB, but they are also classified as group A essential anti-TB drugs, alongside linezolid and bedaquiline (9).

Among the newer generation fluoroquinolones, levofloxacin and moxifloxacin have been used in TB treatment. Gatifloxacin, another fluoroquinolone, was previously evaluated in experimental 4-month regimens for drug-susceptible TB (10). However, because of its association with dysglycemia, particularly in elderly patients, it was subsequently withdrawn from the market (11).

Choosing between levofloxacin and moxifloxacin for TB treatment requires careful consideration. Experimental and animal studies have shown that moxifloxacin has a lower minimum inhibitory concentration than levofloxacin (12, 13) and exhibits greater bactericidal activity (14). However, moxifloxacin is also more likely to cause QT interval prolongation compared with levofloxacin (15). Previously, we conducted a randomized controlled trial comparing the effectiveness of levofloxacin and moxifloxacin in patients with MDR TB. The negative sputum culture conversion rates at 3 months and overall treatment outcomes were not different between the two groups. Adverse events were more frequent in the levofloxacin group, particularly musculoskeletal pain (16, 17).

Both fluoroquinolones are currently recommended for the longer treatment of MDR/rifampin-resistant TB (9). For shorter treatment regimens, moxifloxacin is included in the BPaLM regimen (Bedaquiline, pretomanid, linezolid, and moxifloxacin) (18), while levofloxacin is part of the MDR-END regimen (delamnid, linezolid, levofloxacin, and pyrazinamide, which is used in South Korea (19). In addition, levofloxacin is recommended for the treatment of isoniazid-resistant TB (9) and for MDR TB contacts (20). However, the optimal doses of these drugs have not been well established.

In this issue of the Journal, Phillips and colleagues (pp. 1277–1287) propose the optimal dose of levofloxacin in combination regimens for MDR TB treatment, considering both efficacy and safety (18). They conducted a multicenter, randomized, placebo-controlled phase II trial (Qpti-Q) in South Africa and Peru, comparing various once-daily doses of levofloxacin: 11 mg/kg (750 mg), 14 mg/kg (750 mg or 1,000 mg), 17 mg/kg (1,000 mg or 1,250 mg), and 20 mg/kg (1,250 mg or 1,500 mg). The study assessed time to culture conversion and adverse events across different dose groups. No significant differences were observed in time to culture conversion by treatment arm, dose received, or ratio of area under the curve (AUC) to minimum inhibitory concentration (MIC). However, grade 3–5 adverse events were more common in higher dose groups compared with lower dose groups. Collectively, doses exceeding 1,000 mg did not improve time to culture conversion but were associated with a higher risk of grade 3 or more severe adverse events. On the basis of these findings, the authors recommend a daily dose of 1,000 mg of levofloxacin as the most optimal choice in combination regimens for MDR TB treatment.

This is a well-designed and carefully conducted study, but the authors’ conclusion merits further consideration. First, the authors provide no evidence that the 750-mg regimen was inferior to the 1,000-mg regimen in any of the evaluated parameters, including time to culture conversion, MIC, ratio of AUC to MIC, and adverse events. Therefore, it would be more reasonable to conclude that a 750-mg dose remains a viable option, at least for lean patients.

Second, it is worth noting that QT interval prolongation (Fridericia-corrected QT interval > 450 ms) was more common among patients in the higher dose group in this study. As the authors acknowledge as a limitation, the drugs used alongside levofloxacin in their study are not those currently prioritized for MDR TB treatment. When combined with newer anti-TB drugs, QT interval prolongation could be more pronounced, as both bedaquiline and delamanid can also prolong the QT interval (19). Considering these factors, the study’s findings supporting the use of a lower dose should be given greater significance.

In conclusion, the authors have conducted a well-designed study to determine the optimal dose of levofloxacin as an anti-TB drug. The study delivers a clear and straightforward message: for MDR TB treatment, a daily dose exceeding 1,000 mg of levofloxacin provides no additional benefit in terms of efficacy while increasing the risk of adverse effects. Levofloxacin, repurposed for MDR TB treatment, has now been refined for optimal dosing.