Extensively Drug-resistant Tuberculosis
(XDR-TB) is the occurrence of TB in persons whose M.
tuberculosis isolates are resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line
drugs (i.e.,
amikacin, kanamycin, or capreomycin). XDR-TB is an extremely serious, emerging
threat to public health and TB control.
Magnitude of the Problem
In 1997, the first global report on
drug resistance, published by the World Health Organization (WHO) and the International Union Against
Tuberculosis and Lung Diseases (ILJATLD) Global Project on Anti-Tuberculosis
Drug Resistance
Surveillance, contained data from 35 countries. The 2nd and the 3d reports were
subsequently published in 2000 and 2004, respectively.
The third global report on antituberculosis drug resistance surveillance has documented that many areas of the world face endemic and epidemic MDR-TB, and in some areas resistance is alarmingly high. In patients never previously treated, the median prevalence of resistance to any of the first-line
drugs, most
commonly streptomycin and/or isoniazid, was 10.7% (range 0-57.1%); survey sites exceeded 20%. The median prevalence of MDR-TB was 1.2% (range 0-14.2%); 1 1 sites exceeded the 6.5% threshold for extreme values, including 7 in the former Soviet Union. In patients previously treated, the median prevalence of any resistance was 23.3% (range 0-82.1%) and of MDR-TB, 7.7% (range 0-58.3%)."
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Drug resistance
was strongly associated with previous treatment. In previously treated patients,
the probability of any resistance was over 4-fold higher, and of MDR-TB over
10-fold higher, than for untreated patients. The overall prevalence of drug
resistance was often related to the number of previously treated cases in the
country. Among countries with a high burden of TB, previously treated cases
ranged from 4.4% to 26.9% of all patients registered in DOTS programmes. In the
two largest high-TB burden countries (China and India), re-treatment cases
accounted for more than 20% of sputum smear-positive cases.
Many identified MDR-TB cases have resistance to drugs other than both isoniazid and rifampicin. In fact, one third of MDR-TB cases had resistance to all four of the first-line
drugs tested in the global survey. Moreover, MDR-TB patients often live for several years before succumbing to the disease. Prevalence of MDR-TB may therefore be three times greater than its incidence, suggesting that the true number of MDR-TB cases in the world today may approach or exceed one million."
A recent investigation by Zignol M ef al used data from the most recent national
surveys to evaluate a total of 184 countries that accounted for 99.9% of the
world's population. MDR-TB rates among new cases were available from 90
countries. Figure 1 shows the distribution of the proportions of MDR-TB cases
among new cases. Figure 2 shows the distribution of the proportions of MDR-TB
cases among previously treated cases.
In parts of Eastern Europe and Central Asia, TB patients are 10 times more
likely to have MDR-TB than those in the rest of the world, perhaps due to
mutations in the genetic material of mycobacteria.
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Genesis and Spread
Resistance to one or several forms of treatment occurs when the bacteria
develops the ability to withstand antibiotic attack and transfer that ability to
newly produced bacteria. Since that entire strain of bacteria inherits this
capacity to resist the effects of the various treatments, resistance can spread
from one person to another.
The three factors involved in the genesis and spread of drug-resistant TB are as follows:"
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Microbial factors
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Clinical factors
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Programmatic factors
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Microbial Factors
From a microbiological perspective, spontaneous chromosomally borne mutations occurring in M.
tuberculosis at a predictable rate are thought to confer resistance to anti-TB drugs. A characteristic feature of these mutations is that they are unlinked. A TB cavity usually contains 107 to 109 bacilli. If mutations causing resistance to isoniazid occur in about 1 in 106 replications of bacteria, and the mutations causing resistance to rifampicin occur in about 1 in 10s replications, the probability of spontaneous mutations causing resistance to both isoniazid and rifampicin would be 106 x 108 = 1 in 1 Ou replications. Given that this number of bacilli cannot be found even in patients with extensive cavitary
pulmonary TB,
the chance of the development of spontaneous dual resistance to rifampicin and
isoniazid is practically remote.
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Table 1 lists the perturbations in the individual drug target genes that are responsible for the genesis of anti-TB
drug resistance. Rifampicin resistance has been shown to be caused by an alteration of the (3-subunit of RNA polymerase, which is encoded by the rpop gene. On the contrary, resistance to isoniazid is more complicated, as mutations in several genes can lead to drug resistance.