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Wild-Type MIC Distribution for Re-evaluating the Critical Concentration of Anti-TB Drugs and Pharmacodynamics Among Tuberculosis Patients From South India.
Frontiers in Microbiology ( IF 5.2 ) Pub Date : 2020-05-08 , DOI: 10.3389/fmicb.2020.01182
Azger Dusthackeer 1 , Shainaba A Saadhali 1 , Manonanthini Thangam 2 , Sameer Hassan 3 , Mahizhaveni Balasubramanian 1 , Angayarkani Balasubramanian 1 , Geetha Ramachandran 4 , A K Hemanth Kumar 4 , Kannan Thiruvenkadam 5 , Govindarajan Shanmugam 1 , Christy Rosaline Nirmal 1 , Sam Ebenezer Rajadas 1 , Sucharitha Kannappan Mohanvel 6 , Rajesh Mondal 1
Affiliation  

The World Health Organization (WHO) has developed specific guidelines for critical concentrations (CCs) of antibiotics used for tuberculosis (TB) treatment, which is universally followed for drug susceptibility testing (DST) of clinical specimens. However, the CC of drugs can differ significantly among the mycobacterial species based on the population, geographic location, and the prevalence of the infecting strain in a particular area. The association between CC and the minimal inhibitory concentration (MIC) of anti-TB drugs is poorly understood. In this study, we assessed the MICs of anti-TB drugs, including isoniazid (INH), rifampicin (RMP), moxifloxacin (MXF), ethambutol (ETH), and p-aminosalicylic acid (PAS) on drug-sensitive Mtb isolates from pulmonary TB patients in South India. The MIC assays performed using solid- and liquid-growth media showed changes in the CC of a few of the tested antibiotics compared with the WHO-recommended levels. Our observation suggests that the WHO guidelines could potentially lead to overdiagnosis of drug-resistant cases, which can result in inappropriate therapeutic decisions. To evaluate the correlation between drug-resistance and CC, we performed the whole-genome sequencing for 16 mycobacterial isolates, including two wild-type and 14 resistant isolates. Our results showed that two of the isolates belonged to the W-Beijing lineage, while the rest were of the East-African–Indian type. We identified a total of 74 mutations, including five novel mutations, which are known to be associated with resistance to anti-TB drugs in these isolates. In our previous study, we determined the serum levels of INH and RMP among the same patients recruited in the current study and estimated the MICs of the corresponding infected isolates in these cases. Using these data and the CCs for INH and RMP from the present study, we performed pharmacodynamics (PD) evaluation. The results show that the PD of RMP was subtherapeutic. Together, these observations emphasize the need for optimizing the drug dosage based on the PD of large-scale studies conducted in different geographical settings.



中文翻译:

野生型MIC分布,用于重新评估印度南部结核病患者中抗结核药物的临界浓度和药效学。

世界卫生组织(WHO)已为结核(TB)治疗中使用的抗生素的临界浓度(CCs)制定了具体指南,临床标本的药敏试验(DST)普遍遵循该指南。但是,根据特定地区的人口,地理位置和感染菌株的流行程度,在分枝杆菌物种之间,药物的CC可能有很大差异。CC和抗结核药物的最低抑菌浓度(MIC)之间的关联了解甚少。在这项研究中,我们评估了抗结核药物的MIC,包括异烟肼(INH),利福平(RMP),莫西沙星(MXF),乙胺丁醇(ETH)和p印度南部肺结核患者对药物敏感的Mtb分离物上的-氨基水杨酸(PAS)。使用固体和液体生长培养基进行的MIC分析显示,与WHO推荐的水平相比,几种测试抗生素的CC变化。我们的观察表明,WHO指南可能会导致对耐药病例的过度诊断,从而可能导致不合适的治疗决策。为了评估耐药性与CC之间的相关性,我们对16种分枝杆菌菌株(包括2种野生型和14种耐药菌株)进行了全基因组测序。我们的结果表明,其中的两个分离株属于W-Beijing谱系,其余则属于东非-印度类型。我们总共确定了74种突变,其中包括5种新颖的突变,已知与这些分离物中的抗结核药物耐药有关。在我们以前的研究中,我们确定了本研究中招募的相同患者的INH和RMP血清水平,并估计了这些病例中相应感染菌株的MIC。使用这些数据以及本研究中INH和RMP的CC,我们进行了药效学(PD)评估。结果表明,RMP的PD是亚治疗的。总之,这些观察结果强调需要基于在不同地理环境中进行的大规模研究的PD来优化药物剂量。我们确定了本研究中招募的相同患者的INH和RMP血清水平,并估计了这些病例中相应感染菌株的MIC。使用这些数据以及本研究中INH和RMP的CC,我们进行了药效学(PD)评估。结果表明,RMP的PD是亚治疗的。总之,这些观察结果强调需要基于在不同地理环境中进行的大规模研究的PD来优化药物剂量。我们确定了本研究中招募的相同患者的INH和RMP血清水平,并估计了这些病例中相应感染菌株的MIC。使用这些数据以及本研究中INH和RMP的CC,我们进行了药效学(PD)评估。结果表明,RMP的PD是亚治疗的。总之,这些观察结果强调需要基于在不同地理环境中进行的大规模研究的PD来优化药物剂量。

更新日期:2020-06-30
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