2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/650502摘要：氟喹諾酮(Fluoroquinolones)，如ofloxacin，是治療多重抗藥結核病(multidrug-resistanttuberculosis, MDR-TB)最重要的藥物之一，ofloxacin抗藥MDR-TB的治療相當棘手。Moxifloxacin是新一代fluoroquinolones，具有更優異的抗結核菌效果，其最低抑菌濃度遠低於ofloxacin。依據藥物動力學的資料，WHO曾提出將moxifloxacin抗藥性MDR-TB區分為低度(low-level)及高濃度(high-level) moxifloxacin抗藥的草案；此一建議，似乎暗示moxifloxacin仍可能有助於治療低度抗藥性moxifloxacin-resistant MDR-TB患者，然而，尚無臨床研究加以證實。目前結核病實驗室，僅使用傳統瓊脂比例法進行ofloxacin抗藥檢查，對於moxifloxacin的交互抗藥程度(敏感、低度及高度抗藥) 缺乏了解。然而，要進行moxifloxain的抗藥程度檢測，非一般臨床實驗室所能負荷。我們過去的研究發現，特定的gyrase基因變異可能可以預測moxifloxacin的抗藥程度，運用分子檢定，能否預測抗藥程度及治療反應，需要進一步釐清。另一個問題是，過去研究也發現，傳統的sanger sequencing不夠敏感，只能在約64%的fluoroquinolones抗藥結核菌的基因體中，發現抗藥相關突變。我們計畫收集於台大醫院及衛生福利部胸腔病院治療之MDR-TB患者約100人，收集患者基本資料、治療過程、共病症、moxifloxacin的最低抑菌濃度，gyrase基因突變，菌株基因分型等，進行三大部分研究：(1)分析台灣地區ofloxacin抗藥 MDR-TB的moxifloxacin抗藥特性及相關基因變異(2)分析moxifloxacin抗藥程度及抗藥基因變異對使用moxifloxacin治療ofloxacin抗藥MDR-TB治療成效的影響，(3)利用全基因深度定序(whole genomic deep-sequencing)及驗證，分析探討結核菌產生fluoroquinolone抗藥之可能未知抗藥相關基因變異<br> Abstract: Due to promising activity against Mycobacteria tuberculosis (MTB), fluoroquinolones (FQs) havebeen recommend as the most important component of the treatment of multidrug-resistant (MDR)-TB.Thus, the emergence of ofloxacin (OFX)-resistant MDR-TB and extensively drug resistant TB (XDRTB)have further complicated patient care.Later-generation FQs, including moxifloxacin (MFX), having a more potent anti-tuberculosiseffect and do not have complete cross-resistance with OFX by in vitro drug susceptibility testing (DST)results. Recently, WHO proposed a updated interim suggestion to measure low- and high-level resistancein moxifloxacin-resistant MDR-TB, however, still lack of clinical evidences to support this suggestion.Our preliminary data showed moxifloxacin could improve time to culture conversion in ofloxacinresistantMDR-TB. However we did not know the prevalence of moxifloxacin-resistance amongofloxacin-resistant MDR-TB in Taiwan. Furthermore, the efficacy of moxifloxacin in low- and high-levelofloxacin-resistant MDR-TB also needed more investigation.In addition, the level of moxifloxacin resistance probably link to specific mutations in gyrase genes.It also should been investigated if the molecular test could predict the level of moxifloxacin resistanceand treatment outcomes. Although previous studies showed only two third of ofloxacin-resistant MDRTBhave mutations in gyrase genes, this may be attributed to low sensitivity of sanger’s sequencing.Using whole-genomic deep-sequencing, we expected to find heterogeneity or new unknown resistanceassociated mutations.We planned to enrolled about 100 ofloxacin-resistant MDR-TB in Taiwan and arm to investigate:(1) the prevalence of different levels of moxifloxacin-resistance and associated mutations in gyrasegenes among ofloxacin-resistant MDR-TB, (2) the association between different levels of moxifloxacinresistance and resistance associated mutations with treatment outcomes of MDRTB with/withoutmoxifloxacin, and (3) we will use whole-genomic deep-sequencing to find heterogeneity or new unknownresistance associated mutations among ofloxacin-resistant MDR-TB.