We investigated the preclinical efficacy and safety/tolerability of biodegradable polymeric particles containing isoniazid (INH) and rifabutin (RFB) dry powder for inhalation (DPI) as an adjunct to oral first-line therapy. Mice and guinea pigs infected with Mycobacterium tuberculosis H37Rv (Mtb) were treated with ∼80 and ∼300 μg of the DPI, respectively, for 3–4 weeks starting 3, 10, and 30 days post-infection. Adjunct combination therapy eliminated culturable Mtb from the lungs and spleens of all but one of 52 animals that received the DPI. Relapse-free cure was not achieved in one mouse that received DPI + oral, human-equivalent doses (HED) of four drugs used in the Directly Observed Treatment, Short Course (DOTS), starting 30 days post-infection. Oral doses (20 mg/Kg/day, each) of INH + RFB reduced Mtb burden from ∼10⁶ to ∼10³ colony-forming units. Combining half the oral dose with DPI prevented relapse of infection four weeks after stopping the treatment. The DPI was safe in rodents, guinea pigs, and monkeys at 1, 10, and 100 μg/day doses over 90 days. In conclusion, we show the efficacy and safety/tolerability of the DPI as an adjunct to oral chemotherapy in three different animal models of TB.

我们研究了含有异烟肼 (INH) 和利福布汀 (RFB) 干粉吸入 (DPI) 的可生物降解聚合物颗粒作为口服一线治疗的辅助药物的临床前疗效和安全性/耐受性。感染结核分枝杆菌的小鼠和豚鼠从感染后 3、10 和 30 天开始，H37Rv (Mtb) 分别用约 80 和 300 μg DPI 处理 3-4 周。除了接受 DPI 的 52 只动物中的一只之外，辅助联合疗法从所有的肺和脾脏中消除了可培养的 Mtb。在感染后 30 天开始，接受 DPI + 口服、人体等效剂量 (HED) 的四种药物的小鼠中未实现无复发治愈，这些药物用于直接观察治疗、短期治疗 (DOTS)。口服 INH + RFB 剂量（20 mg/Kg/天，每次）将 Mtb 负担从 ~10 ⁶降低到 ~10 ³ 菌落形成单位。将一半的口服剂量与 DPI 结合使用可在停止治疗 4 周后预防感染复发。DPI 在 90 天内以 1、10 和 100 μg/天的剂量在啮齿动物、豚鼠和猴子中是安全的。总之，我们在三种不同的结核病动物模型中展示了 DPI 作为口服化疗的辅助手段的有效性和安全性/耐受性。