Böttger Erik C, Springer Burkhard
Nationales Zentrum für Mykobakterien, Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 32, 8006, Zürich, Switzerland.
Eur J Pediatr. 2008 Feb;167(2):141-8. doi: 10.1007/s00431-007-0606-9. Epub 2007 Nov 7.
Directly observed standardized short-course chemotherapy (DOTS) regimes are an effective treatment for drug susceptible tuberculosis disease. Surprisingly, DOTS has been reported to reduce the transmission of multi-drug resistant tuberculosis, and standardized short-course chemotherapy regimens with first-line agents have been found to be adequate treatments for some patients with drug resistant tuberculosis, including multi-drug resistance. These paradoxical observations and the apparent heterogeneity in treatment outcome of multi-drug resistant tuberculosis when using standard regimens may be due in part to limitations of in vitro drug susceptibility testing based on unique but mistakenly used techniques in diagnostic mycobacteriology. Experimental data and mathematical models indicate that the fitness cost conferred by a resistance determinant is the single most important parameter which determines the spread of drug resistance. Chromosomal alterations that result in resistance to first-line antituberculosis agents, e.g. isoniazid, rifampicin, streptomycin, may or may not be associated with a fitness cost. Based on work in experimental models and from observations in clinical drug resistant isolates a picture emerges in which, among the various resistance mutations that appear with similar rates, those associated with the least fitness cost are selected in the population.
直接观察下的标准化短程化疗（DOTS）方案是治疗药物敏感型结核病的有效方法。令人惊讶的是，有报道称DOTS可减少耐多药结核病的传播，并且已发现使用一线药物的标准化短程化疗方案对包括耐多药结核病在内的一些耐药结核病患者是足够的治疗方法。这些看似矛盾的观察结果以及使用标准方案时耐多药结核病治疗结果明显的异质性，可能部分归因于基于诊断分枝杆菌学中独特但错误使用的技术进行的体外药敏试验的局限性。实验数据和数学模型表明，耐药决定因素赋予的适应性代价是决定耐药性传播的唯一最重要参数。导致对一线抗结核药物（如异烟肼、利福平、链霉素）耐药的染色体改变，可能与适应性代价有关，也可能无关。基于实验模型的研究工作以及对临床耐药菌株的观察，出现了这样一种情况：在以相似频率出现的各种耐药突变中，那些适应性代价最小的突变在群体中被选择出来。
