Levofloxacin Prophylaxis in Children Exposed to MDR Tuberculosis

Source: Hesseling AC, Purchase SE, Martinson NA, et al. Levofloxacin preventive treatment in children exposed to MDR tuberculosis. N Engl J Med. 2024;391(24):2315-2326; doi: 10.1056/NEJMoa2314318.Investigators from multiple institutions conducted a randomized controlled trial to assess the efficacy and safety of levofloxacin in preventing tuberculosis (TB) in children who were household contacts of an adult with multiple drug resistant (MDR) TB. The study was conducted at 5 sites in South Africa between 2017 and 2023. Participants were children <17 years old who were household contacts of an adult with bacteriologically confirmed TB that was resistant to isoniazid (INH) and rifampin (RIF). Children <5 years old were eligible for enrollment regardless of interferon-gamma release assay (IGRA) results or human immunodeficiency virus (HIV) status; those 5–17 years of age who were IGRA positive, or who had HIV infection, were enrolled. Study participants were randomized by household to receive levofloxacin, 15–20 mg/kg once daily for 24 weeks, or placebo, and were followed for 72 weeks. Adherence to the treatment regimen was assessed by parental questionnaire. The primary study outcome was incident TB, either microbiologically confirmed or diagnosed clinically, by week 48 after randomization. Secondary outcomes included incident TB by week 72. The main safety outcome was a significant adverse event that was at least possibly related to the study medication during the 24 weeks of treatment. Cox regression was used to compare outcomes among children in the levofloxacin and placebo groups.Data were analyzed on 922 children who were household contacts of an adult with MDR TB, with 453 assigned to receive levofloxacin and 469 randomized to placebo. The median age of participants was 2.8 years, 91% were <5 years old, and 93.8% had received bacille Calmette-Guérin (BCG) vaccine. Adherence to the treatment regimen was 86% in >80% of participants in each group. By study week 48, 5 (1.1%) children in the levofloxacin group had developed TB compared to 12 (2.6%) of those assigned to placebo (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.15, 1.25; P = 0.12). Incident TB had occurred by 72 weeks in 6 (1.3%) participants assigned to levofloxacin and 13 (2.8%) in the placebo group (HR, 0.49; 95% CI, 0.18, 1.30). A significant adverse event that possibly was related to study medication occurred during the treatment period in 0.9% and 1.7% of participants randomized to levofloxacin or placebo, respectively. One child receiving levofloxacin had grade 2 tendonitis, which resolved within 21 days after stopping treatment.The authors conclude that levofloxacin treatment was not significantly associated with a reduced risk of TB in children with an adult household contact with MDR TB.Dr Brady has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.An estimated 2 million children worldwide are currently infected with MDR TB, often acquired from a household contact.1 Children recently exposed to a contagious contact with TB disease are recommended to have a tuberculin skin test (TST) or IGRA along with a history, physical examination, and chest radiograph, if symptomatic or positive TST or IGRA, to assess for TB disease.2 Once TB disease is excluded (See AAP Grand Rounds. 2018;39[6]:71),3 those with TB infection are treated, usually with an INH- or RIF-based regimen. Choice of treatment is difficult when the index case has MDR TB, because only low-quality evidence is available.4 Although the results of the current study were not statistically significant, it provides some support for consideration of levofloxacin preventive therapy for children exposed to MDR TB.Fox et al5 also assessed the use of levofloxacin for the prevention of MDR TB in Vietnamese household contacts assigned 1:1 to daily levofloxacin or placebo for 6 months. The primary outcome was incident TB by 54 weeks. Again, the incidence of TB was lower in the levofloxacin group than the placebo group, but the difference was not statistically significant.A meta-analysis6 of these 2 randomized trials showed that levofloxacin was associated with a 60% relative reduction in TB incidence among adult and child household MDR TB contacts. Musculoskeletal adverse events were more common in the levofloxacin group, but only among those ≥10 years of age. An editorial by Hodzic-Santor et al7 reminds the reader to examine many factors, including availability of other treatments, study design, and severity of the clinical condition. Solely focusing on P values or CI when determining whether a therapy works is an oversimplification.Levofloxacin prophylaxis leads to a lower incidence of TB than placebo among children with household exposure to MDR TB, although the difference is not statistically significant.