Lanni Alessio, Iacobino Angelo, Fattorini Lanfranco, Giannoni Federico
Department of Infectious Diseases, Istituto Superiore di Sanità, Via Regina Elena 299, 00161 Rome, Italy.
Microorganisms. 2023 Jun 6;11(6):1511. doi: 10.3390/microorganisms11061511.
The lungs of tuberculosis (TB) patients contain a spectrum of granulomatous lesions, ranging from solid and well-vascularized cellular granulomas to avascular caseous granulomas. In solid granulomas, current therapy kills actively replicating (AR) intracellular bacilli, while in low-vascularized caseous granulomas the low-oxygen tension stimulates aerobic and microaerophilic AR bacilli to transit into non-replicating (NR), drug-tolerant and extracellular stages. These stages, which do not have genetic mutations and are often referred to as persisters, are difficult to eradicate due to low drug penetration inside the caseum and mycobacterial cell walls. The sputum of TB patients also contains viable bacilli called differentially detectable (DD) cells that, unlike persisters, grow in liquid, but not in solid media. This review provides a comprehensive update on drug combinations killing in vitro AR and drug-tolerant bacilli (persisters and DD cells), and sterilizing -infected BALB/c and caseum-forming C3HeB/FeJ mice. These observations have been important for testing new drug combinations in noninferiority clinical trials, in order to shorten the duration of current regimens against TB. In 2022, the World Health Organization, following the results of one of these trials, supported the use of a 4-month regimen for the treatment of drug-susceptible TB as a possible alternative to the current 6-month regimen.
肺结核（TB）患者的肺部存在一系列肉芽肿病变，从实性且血管丰富的细胞性肉芽肿到无血管的干酪样肉芽肿不等。在实性肉芽肿中，当前的治疗方法可杀死活跃复制（AR）的细胞内杆菌，而在血管化程度低的干酪样肉芽肿中，低氧张力会刺激需氧和微需氧的AR杆菌转变为非复制（NR）、耐药物且细胞外的阶段。这些阶段没有基因突变，通常被称为持留菌，由于药物在干酪样物质和分枝杆菌细胞壁内的渗透性低，难以根除。肺结核患者的痰液中还含有称为差异可检测（DD）细胞的活杆菌，与持留菌不同，它们在液体中生长，但在固体培养基中不生长。本综述全面更新了在体外杀死AR和耐药物杆菌（持留菌和DD细胞）以及对感染的BALB/c小鼠和形成干酪样物质的C3HeB/FeJ小鼠进行杀菌的药物组合。这些观察结果对于在非劣效性临床试验中测试新的药物组合很重要，以便缩短当前抗结核治疗方案的疗程。2022年，世界卫生组织根据其中一项试验的结果，支持使用4个月疗程治疗药物敏感型肺结核，作为当前6个月疗程的一种可能替代方案。
