EpidemiologyPrevalence and transmission of pyrazinamide resistant Mycobacterium tuberculosis in China
Introduction
Pyrazinamide (PZA) is a first-line drug and an important component used for the treatment of both drug-susceptible and drug-resistant tuberculosis (TB). Combined with other anti-TB drugs, PZA shows a remarkable therapeutic effect [1], [2], because of its unique sterilizing activity to kill semi-dormant or persistent Mycobacterium tuberculosis [3]. Specifically, in multidrug resistant (MDR) TB therapy, it has a strong effect on the success rates of treatment [4]. So, the absence of PZA in the regimens would lead to poor treatment outcome [5], [6], [7].
At present, there are two main methods for drug susceptibility testing (DST) of M. tuberculosis: the phenotypic DST by traditional culture, and the molecular drug susceptibility test (mDST) by detecting drug resistant mutations. However, both phenotypic DST and mDST have limitations to detect PZA-R. The accuracy and reproducibility of PZA phenotypic DST are not satisfactory [8], [9], because it must be conducted under acidic condition (pH 5.5–6). The growth of M. tuberculosis is inhibited at such a low pH and many factors such as inoculum size could lead to inaccurate results. For mDST, because the molecular mechanism of PZA-R is not completely understood, the PZA mDST based on detecting pncA mutations could provide only about 90% specificity and sensitivity [10]. According to studies conducted in different areas of China, the specificities of pncA sequencing to predict PZA-R were more than 90% [11], [12], [13]. Therefore, for large scale and multi-center PZA-R investigation in China, mDST is a more reliable and objective method.
China is one of the high drug resistant TB burden countries, but there are relatively few available data on PZA-R rates. Studies showed that PZA-R rates were 35.6% among drug resistant TB in Hong Kong [14] and 43.1% among MDR-TB in Zhejiang [13]. However these studies were based on samples collected from single hospital, which could not reflect the real prevalence of PZA-R in the general population. In this study, we used the pncA mutations to predict PZA-R among M. tuberculosis clinical isolates collected from a population based epidemiological study and estimated the prevalence and risk factors of PZA-R in China.
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Study population and isolates
In a previous study, we collected all M. tuberculosis isolates from five counties in different provinces of China (Songjiang in Shanghai, Wusheng in Sichuan, Pingguo in Guangxi, Wuchang in Heilongjiang, and Weishi in Henan provinces respectively) between June 2009 and June 2012 [15]. The data of patient information and isolates genotype (Beijing genotype and variable number tandem repeat (VNTR) genotype) was described in our previous study [15]. The isolates were considered to be clusters only
Characteristics of the patients and isolates
During the period from June 2009 to June 2012, 2274 culture-positive TB cases were diagnosed in the five settings [15]. With the exception of 60 isolates without DST data and 39 isolates with inconsistent results between phenotypic DST and mDST, there were 130 INH mono-resistant, 43 RIF mono-resistant and 124 MDR isolates (including 35 pre-XDR isolates). To estimate the proportion of PZA-R, we included all 297 drug-resistant isolates and randomly selected 196 isolates from 1878 pan-susceptible
Discussion
This study covered five settings located in different provinces of China. We selected all drug resistant and randomly selected drug susceptible M. tuberculosis isolates, to predict PZA-R prevalence by mDST. The results showed that 81.8% of PZA-R isolates were MDR-TB isolates; and that MDR, pre-XDR, RIF mono-resistance and retreatment were risk factors for PZA-R. Furthermore, we observed that 48.5% of the PZA-R was primary drug resistance. Clustered isolates with identical pncA mutations were
Conclusion
By detecting pncA mutation of M. tuberculosis isolates from five provinces of China, we have shown that the PZA-R rate was as high as 43.5% in MDR isolates. Our results also showed that MDR, pre-XDR, RIF mono-resistance and retreatment were risk factors for PZA-R. Finally, since transmission of PZA-R isolates play important role in emergence of PZA-R TB, it is necessary to regularly conduct PZA susceptibility testing among MDR-TB patient and modify the treatment regimens accordingly.
Acknowledgments
We thank the patients and the health-care workers of the Sichuan Wusheng CDC, Guangxi Pingguo CDC, Henan Weishi CDC, Shanghai Songjiang CDC and Heilongjaing Wuchang CDC, for their generous support and cooperation.
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These authors contributed equally to this work.