New York Presbyterian Hospital/Weill Cornell Medicine, New York.
Duke Clinical Research Institute, Duke University, Durham, North Carolina.
JAMA. 2021 May 11;325(18):1841-1851. doi: 10.1001/jama.2021.4956.
Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis.
To assess the effect of antimicrobial therapy on clinical outcomes.
DESIGN, SETTING, AND PARTICIPANTS: Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020).
Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group.
The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality.
Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%).
Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease.
ClinicalTrials.gov Identifier: NCT02759120.
肺部微生物的改变与特发性肺纤维化的疾病进展有关。
评估抗菌治疗对临床结局的影响。
设计、地点和参与者：这是在美国 35 个地点进行的一项实用、随机、非盲临床试验。共有 513 名年龄大于 40 岁的患者于 2017 年 8 月至 2019 年 6 月间被随机分组（最后随访时间为 2020 年 1 月）。
患者以 1:1 的比例随机分配接受抗菌药物（n = 254）或单独接受常规治疗（n = 259）。抗菌药物包括复方新诺明（甲氧苄啶 160 mg/磺胺甲恶唑 800 mg，每日 2 次，加叶酸 5 mg，每日 1 次，n = 128）或多西环素（体重<50 kg 时每日 100 mg，体重≥50 kg 时每日 100 mg 2 次，n = 126）。在单独常规治疗组中未给予安慰剂。
首次非择期呼吸住院或全因死亡率的时间。
在 513 名被随机分组的患者（平均年龄 71 岁；23.6%为女性）中，所有人（100%）均被纳入分析。由于疗效不佳，研究于 2019 年 12 月 18 日终止。在平均 13.1 个月（中位数 12.7 个月）的随访后，共有 108 例主要终点事件发生：常规治疗加抗菌治疗组有 52 例（100 例患者-年中有 20.4 例[95%CI，14.8-25.9]），常规治疗组有 56 例（100 例患者-年中有 18.4 例[95%CI，13.2-23.6]），两组之间无显著差异（调整后的 HR，1.04 [95%CI，0.71-1.53；P = 0.83）。预先指定的抗菌药物（复方新诺明与多西环素）对主要终点的影响之间无统计学显著的交互作用（复方新诺明组调整后的 HR 为 1.15 [95%CI，0.68-1.95]，多西环素组为 0.82 [95%CI，0.46-1.47]；P = 0.66）。在接受常规治疗加抗菌药物治疗与单独接受常规治疗的患者中，发生率为 5%或更高的严重不良事件包括呼吸系统事件（16.5%与 10.0%）和感染（2.8%与 6.6%）；特别关注的不良事件包括腹泻（10.2%与 3.1%）和皮疹（6.7%与 0%）。
在特发性肺纤维化成人患者中，与单独常规治疗相比，复方新诺明或多西环素联合常规治疗并未显著改善非择期呼吸住院或死亡的时间。这些发现不支持使用这些抗生素治疗潜在疾病。
ClinicalTrials.gov 标识符：NCT02759120。
