Case Sudy Evolution of BDQ Resistance

Whole genome sequencing (WGS) based prediction of drug-resistance in Mycobacterium tuberculosis has the potential to guide clinical decisions in the design of optimal treatment regimens. We utilized WGS to investigate drug-resistant mutations in a 32-year-old Tanzanian male admitted to Kibong'oto Infectious Diseases Hospital (KIDH) with a history of interrupted MDR-TB treatments over three years. Before admission, he received various all-oral Bedaquiline-based MDR-TB treatment regimens with unfavourable outcomes. Drug susceptibility testing of serial M. tuberculosis isolates using MGIT culture and WGS revealed resistance to first-line anti-TB drugs, Bedaquiline, and fluoroquinolones but susceptibility to linezolid, clofazimine, and delamanid. WGS on serial cultured isolates identified the Beijing (Lineage 2.2.2) strain resistance against Bedaquiline, with mutations in the mmpR5 gene (Rv0678. An individualized regimen comprised of Bedaquiline, delamanid, pyrazinamide, ethionamide, and para-aminosalicylic acid was designed. The patient was discharged home at month 8 and is currently in the ninth month of treatment. He reports no cough, chest pain, fever, or chest tightness, but still experiences numbness in his lower limbs. We propose the incorporation of WGS in the diagnostic framework for optimal management of DR and XDR-TB patients.

基于全基因组测序（Whole Genome Sequencing, WGS）预测结核分枝杆菌（Mycobacterium tuberculosis）的耐药性，可为优化治疗方案的临床决策提供潜在指导价值。本研究利用全基因组测序技术，对一名因3年余耐多药结核病（Multidrug-Resistant Tuberculosis, MDR-TB）治疗中断病史而入住基邦戈托传染病医院（Kibong'oto Infectious Diseases Hospital, KIDH）的32岁坦桑尼亚男性患者的耐药突变展开分析。入院前，该患者曾接受多种以贝达喹啉（Bedaquiline）为基础的全口服耐多药结核病治疗方案，但疗效欠佳。采用分枝杆菌生长指示管（MGIT）培养联合全基因组测序对系列结核分枝杆菌分离株进行药物敏感性检测，结果显示其对一线抗结核药物、贝达喹啉及氟喹诺酮类药物耐药，但对利奈唑胺（linezolid）、氯法齐明（clofazimine）与德拉马尼（delamanid）敏感。对系列培养分离株的全基因组测序分析显示，该北京株（谱系2.2.2）对贝达喹啉耐药，且存在mmpR5基因（Rv0678）突变。研究团队为该患者制定了包含贝达喹啉、德拉马尼、吡嗪酰胺、乙硫异烟胺及对氨基水杨酸的个体化治疗方案。该患者于治疗第8个月出院，目前已处于治疗第9个月阶段。其自述无咳嗽、胸痛、发热及胸闷症状，但仍存在下肢麻木感。本研究建议将全基因组测序纳入耐药结核病（Drug-Resistant Tuberculosis, DR-TB）与广泛耐药结核病（Extensively Drug-Resistant Tuberculosis, XDR-TB）患者的诊疗框架，以实现最优临床管理。