Drug resistance characteristics and cluster analysis of M. tuberculosis in Chinese patients with multiple episodes of anti-tuberculosis treatment

Yi Hu, Qi Zhao, Jim Werngren, Sven Hoffner, Vinod K. Diwan, Biao Xu

Tuberculosis (TB) patients with multiple episodes of anti-TB treatment represent an important source of TB transmission, as well as a serious threat to the control of drug resistant TB, due to the high risk of multidrug and extensively drug resistance (MDR/XDR) and elongating infectiousness of this patient group. In this study we analyzed the possible risk of development and transmission of MDR and XDR in TB patients with multiple episodes of previous treatment history. The study subjects were pulmonary TB patients who had at least two episodes of previous anti-TB treatment. A total of 166 eligible patients were identified from 10 counties/districts distributed in east, west, north, south and central China. Drug susceptibility test (DST) was performed by proportion method on LJ-media for the 1st line anti-TB drugs and a line probe assay was used to detect mutations related to resistance of the key 2nd-line drugs. Genotyping of M. tuberculosis (Mtb) was performed with MIRU-VNTR and Spoligotyping. Resistances to 1st-line drugs was observed in 122 (73.5 %) of the 166 Mtb isolates with 97 (58.4 %) being MDR-TB. Mutations relevant to 2nd-line drug resistance was seen in 63 isolates, including 35 MDR-TB isolates (30 pre-XDR, 5 XDR-TB). The Spoligotyping revealed 83.1 % Mtb isolates belonged to the Beijing family. The MIRU-VNTR based genotyping revealed 32 (19.3 %) of patients were infected with more than one strain. The number of previous TB treatment episode was found being significantly associated with the risk of MDR-TB and XDR-TB. Among the remaining 134 patients infected with a single Mtb strain, MIRU-VNTR revealed a high homogeneity of strain especially within Beijing family despite the polymorphic variations along with geographic locations. The high genetic relatedness and risk of MDR-TB and subsequent pre-XDR and XDR-TB among repeatedly treated patients suggest the establishment of M/XDR Mtb in this specific patient population. It highlights the urgent needs of providing DST of both 1st- and 2nd-line drugs before and during the medication in China's MDR-TB control program. Furthermore, the possibility of infection with multiple strains should also be considered to be associated with the drug resistance, which calls for the modification of treatment regimen.