RCT: Levofloxacin for the Prevention of Multidrug-Resistant Tuberculosis in Vietnam
24 Dec, 2024 | 12:53h | UTCBackground:
Multidrug-resistant (MDR) and rifampin-resistant tuberculosis pose significant global health challenges. Preventing active disease among contacts exposed to resistant strains is critical, yet limited evidence exists on targeted chemopreventive interventions. This study investigated whether a six-month course of daily levofloxacin could reduce the incidence of bacteriologically confirmed tuberculosis among household contacts of individuals with confirmed MDR or rifampin-resistant tuberculosis in Vietnam.
Objective:
To assess if levofloxacin prophylaxis decreases the 30-month incidence of active tuberculosis among high-risk contacts. Primary endpoints included bacteriologically confirmed disease, and secondary outcomes encompassed adverse events, mortality, and development of fluoroquinolone-resistant Mycobacterium tuberculosis.
Methods:
Researchers conducted a double-blind, placebo-controlled, randomized trial. Eligible participants were household contacts of persons who had started MDR tuberculosis treatment within the previous three months, had a positive tuberculin skin test or immunosuppressive condition, and showed no clinical or radiographic signs of active disease. Enrolled individuals received weight-based oral levofloxacin (up to 750 mg/day) or an identical placebo for 180 days. Monthly visits supported adherence and monitored adverse events. Participants underwent follow-up visits every six months until 30 months for tuberculosis screening, chest radiography, and sputum testing where indicated.
Results:
Of 2041 randomized contacts, 1995 (97.7%) completed 30 months of follow-up or reached a primary endpoint. Confirmed tuberculosis was diagnosed in 6 participants (0.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95% CI, 0.19–1.62), a difference that did not achieve statistical significance. Severe (grade 3 or 4) adverse events were infrequent in both groups, while mild adverse events were more common with levofloxacin (31.9% vs. 13.0%). Acquired fluoroquinolone resistance was not detected.
Conclusions:
Daily levofloxacin for six months showed a numerically lower incidence of tuberculosis than placebo, but the difference was not statistically significant due to lower-than-expected case counts. Treatment was generally well tolerated; however, higher discontinuation rates occurred among levofloxacin recipients, often due to mild musculoskeletal complaints. Further studies may clarify the role of fluoroquinolone-based regimens in preventing MDR tuberculosis across diverse epidemiologic contexts.
Implications for Practice:
These findings suggest that levofloxacin prophylaxis could benefit contacts at high risk of MDR tuberculosis, albeit with caution regarding adherence challenges and low-grade side effects. Broader implementation would require diligent screening, consideration of background fluoroquinolone resistance, and strategies to manage mild adverse events that could undermine treatment completion.
Study Strengths and Limitations:
Strengths include a rigorous double-blind, placebo-controlled design, nearly complete follow-up, and thorough exclusion of prevalent tuberculosis at baseline. Limitations involve an unexpectedly low incidence of confirmed disease, limiting statistical power, and a study population with low HIV prevalence, which may reduce generalizability.
Future Research:
Further research is necessary to confirm these findings in diverse settings, explore alternative or shorter regimens (including newer agents like delamanid), and investigate optimal approaches for patients with fluoroquinolone-resistant strains. The long-term impact on transmission dynamics and microbiome shifts also warrants additional investigation.