MDR and XDR TB, Japan | CDC EID

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Volume 16, Number 6–June 2010
Research
Clonal Expansion of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis, Japan
Yoshiro Murase, Shinji Maeda, Hiroyuki Yamada, Akihiro Ohkado, Kinuyo Chikamatsu, Kazue Mizuno, Seiya Kato, and Satoshi Mitarai
Author affiliation: The Research Institute of Tuberculosis/Japan Anti-Tuberculosis Association, Tokyo, Japan

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Abstract
The emergence and spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has raised public health concern about global control of TB. To estimate the transmission dynamics of MDR and XDR TB, we conducted a DNA fingerprinting analysis of 55 MDR/XDR Mycobacterium tuberculosis strains isolated from TB patients throughout Japan in 2002. Twenty-one (38%) of the strains were classified into 9 clusters with geographic links, which suggests that community transmission of MDR/XDR TB is ongoing. Furthermore, the XDR M. tuberculosis strains were more likely than the non–XDR MDR strains to be clustered (71% vs. 24%; p = 0.003), suggesting that transmission plays a critical role in the new incidence of XDR TB. These findings highlight the difficulty of preventing community transmission of XDR TB by conventional TB control programs and indicate an urgent need for a more appropriate strategy to contain highly developed drug-resistant TB.
The epidemic of drug-resistant tuberculosis (TB) has raised public health concern about the global control of TB. The World Health Organization estimated that 0.5 million cases of multidrug-resistant TB (MDR TB) (i.e., Mycobacterium tuberculosis resistant to >2 of the most potent TB drugs, rifampin and isoniazid) occurred in 2007 (1). Some countries have extraordinarily high rates of this disease, but the problem is universal, and the extent varies from 1 country to another.

Another recent alarming issue is the emergence of extensively drug-resistant TB (XDR TB) (i.e., M. tuberculosis with MDR plus resistance to any fluoroquinolone and >1 injectable drug, thus posing even greater management challenges than MDR TB alone). The treatment outcome of XDR TB is worse than that of simple MDR TB, and the death rate is particularly high among HIV-infected patients (2). Also, because XDR TB is much more expensive to manage in terms of prolonged medication and prolonged period of infectivity to other persons (3), it has the potential to exhaust human and financial resources of the public health system for TB control. Although this new life-threatening disease had been reported from 49 countries as of June 2008 (4), its transmissibility among immunocompetent persons is not well known (5).

In Japan, TB remains a major infectious disease; in 2008, a total of 19.4 cases/100,000 population were reported (6), and Japan is generally classified as a country with intermediate TB incidence. According to the most recent nationwide drug-resistance survey, the prevalence of MDR TB and XDR TB were 1.9% and 0.5%, respectively (7). Approximately one third of MDR and XDR (MDR/XDR) M. tuberculosis strains were isolated from new TB patients, implying ongoing transmission of MDR/XDR TB in Japan.

Our purpose was to evaluate the transmission dynamics of MDR/XDR TB by using strains from the most recent (2002) nationwide drug-resistance survey in Japan, an industrialized country with low HIV incidence and intermediate TB incidence. We did so by analyzing the MDR/XDR strains by molecular genotyping methods, i.e., insertion sequence 6110 restriction fragment length polymorphism (IS6110-RFLP), spacer-oligonucleotide genotyping (spoligotyping), and variable number tandem repeats (VNTR).

Materials and Methods
We used data and culture isolates obtained in the 2002 nationwide drug-resistance survey, as previously reported (7). Briefly, during June–November 2002, a total of 3,122 clinical strains were collected from different patients who had started treatment in 99 hospitals throughout Japan. The number of patients enrolled represented 36.0% of all new reported TB cases during the study period. The sampling of the hospital was not randomized but was based on voluntary participation. The survey identified 60 MDR/XDR M. tuberculosis strains, 55 of which were analyzed in this study; the other 5 strains were unavailable for use in this study.

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MDR and XDR TB, Japan | CDC EID