Molecular characteristics of second-line drug resistance in multidrug-resistant Mycobacterium tuberculosis
다제내성결핵에서 이차약제 내성의 분자생물학적 특성 규명
Dept. of Medicine/박사
Tuberculosis (TB) is an infectious disease that usually attacks the respiratory system. Almost 10 million people worldwide contract TB each year. In Korea, TB incidence is 97 cases per 100,000 populations, which is highest among the member countries of the Organisation for Economic Cooperation and Development. Although there have been many efforts and resources contributed to control TB worldwide, an increase in drug-resistant TB cases is one of the major obstacles. Multidrug-resistant TB (MDR-TB) is defined as TB that is resistant to both isoniazid and rifampicin, which are the most important first-line drugs for TB. It takes approximately two years to cure MDR-TB with second-line drugs. Moreover, some MDR-TB cases are resistant to second-line drugs, which are called extensively drug-resistant TB (XDR-TB). It is extremely difficult to select drugs to treat XDR-TB; thus, treatment outcomes are poor. For successful control of drug-resistant TB, assessment of drug resistance rates and rapid and accurate drug susceptibility testing (DST) are necessary. Since conventional DST has many drawbacks, molecular DST has been introduced for detecting MDR-TB. However, there is little evidence of feasibility for molecular DST to detect XDR-TB. Therefore, the present study aims to analyze drug resistance in Korea and to evaluate rapid molecular detection of second-line drug resistance. DST results in 2009 were collected and divided into six groups: smear-negative new cases of health centers (HCs), smear-positive new cases of HCs, previously treated cases of HCs, health examination, referred cases from hospitals, and patients of the Korean National TB Association clinics. Also, we collected MDR-TB isolates whose mutations in seven loci associated with second-line drug resistance were identified and compared with conventional DST results. The resistance rate to isoniazid was highest, and the MDR rate of smear-positive new cases was 3.5%. XDR-TB accounted for 1% of the total cases and 12% of the MDR-TB cases. Resistance rates in MDR-TB varied greatly based on the drug and group. First-line drugs other than isoniazid and rifampicin showed very high resistance rates, with injectable agents demonstrating the lowest resistance rates among the drugs tested. The rates of resistance to fluoroquinolones were 2-4-fold higher in the private sector than in the public sector. Mutations in rpsL, 16S rRNA gene, and gyrA and gyrB were common in TB isolates with resistance to streptomycin, aminoglycosides, and fluoroquinolones, respectively. On the other hand, mutations in eis and gidB were not only present in resistant isolates, but also in susceptible isolates. This study demonstrates an increasing trend in MDR-TB rate among new cases of Korea. Also, we found that the proportion of XDR in MDR-TB cases was lower than the previously reported rate of 15%. A higher resistance rate of fluoroquinolones in the private sector underlines cautious use of these drugs and need for improvement in the treatment success rate for MDR-TB cases. Detecting major mutations which confer resistance to second-line drugs would be a reliable and specific method of identifying these strains. In summary, these results will be useful in helping to establish a treatment strategy for MDR-TB, and the data suggest that molecular DST can be used as a surrogate for conventional DST.