Hofmann-Thiel S, van Ingen J, Feldmann K, Turaev L, Uzakova G T, Murmusaeva G, van Soolingen D, Hoffmann H
IML, Institute of Microbiology & Laboratory Medicine, Supranational Reference Laboratory (SNRL), Asklepios Fachkliniken, Robert-Koch-Allee 2, D-82131 Gauting, Germany.
Eur Respir J. 2009 Feb;33(2):368-74. doi: 10.1183/09031936.00089808. Epub 2008 Oct 1.
Heteroresistance of Mycobacterium tuberculosis (MTB) is defined as the coexistence of susceptible and resistant organisms to anti-tuberculosis (TB) drugs in the same patient. Heteroresistance of MTB is considered a preliminary stage to full resistance. To date, no mechanism causing heteroresistance of MTB has been proven. Clinical specimens and cultures from 35 TB patients from Tashkent, Uzbekistan, were analysed using the Genotype MTBDR assay (Hain Lifescience, Nehren, Germany), which is designed to detect genetic mutations associated with resistance to rifampin and isoniazid. Cases of heteroresistance were further subjected to genotyping using mycobacterial interspersed repetitive unit-variable-number tandem repeat typing, spoligotyping and IS6110 fingerprinting. Heteroresistance to rifampin and/or isoniazid was found in seven cases (20%). In five of them, heteroresistance was caused by two different strains and in two by a single strain of the Beijing genotype. The latter cases had a history of relapse of their TB. For the first time, two different mechanisms of heteroresistance in tuberculosis have been proven using a stepwise molecular-biological approach: 1) superinfection with two different strains, which is of interest for clinical infection control practitioners; and 2) splitting of a single strain into susceptible and resistant organisms. The latter mechanism is most likely to be related to poor treatment quality and could serve as a quality marker for tuberculosis therapy programmes in the future.
结核分枝杆菌（MTB）的异质性耐药是指在同一患者体内同时存在对抗结核药物敏感和耐药的菌株。MTB的异质性耐药被认为是完全耐药的初级阶段。迄今为止，尚未证实导致MTB异质性耐药的机制。使用Genotype MTBDR检测法（德国内伦市海因生命科学公司）对来自乌兹别克斯坦塔什干的35例结核病患者的临床标本和培养物进行了分析，该检测法旨在检测与利福平及异烟肼耐药相关的基因突变。对异质性耐药病例进一步采用分枝杆菌散布重复单位可变数目串联重复序列分型、间隔寡核苷酸分型和IS6110指纹图谱法进行基因分型。发现7例（20%）患者存在对利福平和/或异烟肼的异质性耐药。其中5例的异质性耐药由两种不同菌株引起，2例由北京基因型单一菌株引起。后两例患者有结核病复发史。首次采用逐步分子生物学方法证实了结核病中两种不同的异质性耐药机制：1）两种不同菌株的重叠感染，这对临床感染控制从业者具有重要意义；2）单一菌株分裂为敏感菌和耐药菌。后一种机制很可能与治疗质量差有关，未来可作为结核病治疗方案的质量指标。
