Researchers find alarming global levels of drug-resistant TB

Aug 30, 2012 (CIDRAP News) – A large, eight-nation study today reported worrisome levels of tuberculosis (TB) resistant to first- and second-line drugs, along with higher-than-expected levels of extensively drug-resistant (XDR) TB.

The study, published in The Lancet, enrolled patients with multidrug-resistant (MDR) TB from Estonia, Latvia, Peru, the Philippines, Russia, South Africa, South Korea, and Thailand. The study design allowed researchers to sift out some risk factors for resistance, which the authors said could help global health officials design better strategies for preventing it.

The higher level of XDR-TB is alarming, the authors said, because that form of the disease is difficult and expensive to treat, two formidable obstacles. The trend also raises the threat of more cases of an untreatable form of the disease, which emerged in 2007 and was recently reported in four patients from India.

Those who have XDR-TB, like those with MDR-TB, are infected with Mycobacterium tuberculosis that is resistant to the first-line treatments isoniazid and rifampin. However, they are also resistant to second-line fluoroquinolone drugs and one of three injectable drugs (amikacin, capreomycin, or kanamycin).

The group focused its study on 1,278 patients with locally confirmed MDR-TB who started treatment with a second-line drug at the study sites from 2005 through 2008. Taiwan was also part of the study, but its findings weren't included in the overall results because drug-susceptibility data were not available in time for analysis.

The authors noted that all of the countries had well-established TB programs, including strategies aimed at MDR-TB, when the study launched.

Researchers collected demographic, socioeconomic, and clinical data for each patient, and baseline isolates were tested for susceptibility to 11 first-line and second-line TB drugs at the US Centers for Disease Control and Prevention (CDC).

Overall, resistance to a second-line drug was detected in 43.7% of patients, with levels that varied by country, from 33% in Thailand to 62% in Latvia. Isolates from 20% of the patients showed resistance to at least one second-line injectable drug, ranging from 2% in the Philippines to 47% in Latvia. Nearly 13% of the samples had resistance to fluoroquinolone, and that prevalence varied, as well, from 7% in the Philippines to 32% in South Korea.

Testing found XDR-TB in 6.7% of patients overall, with levels in South Korea (15.2%) and Russia (11.3%) that were more than double the World Health Organization (WHO) 5.4% global estimate for the same period. The WHO has since updated its global XDR-TB estimate to 9.4%.

When researchers explored patient records for clues about possible risk factors for resistance, they found the risk of XDR-TB quadrupled in previously treated patients, with earlier treatment with a second-line drug a consistently strong risk factor. Fluoroquinolone resistance and XDR-TB were more common in women than in men, and being in the hospital was also strongly connected to resistance.

Socioeconomic factors such as unemployment, alcohol abuse, and smoking were associated with resistance to second-line drugs across the different countries.

Tracy Dalton, PhD, a study coauthor and a microbiologist in the CDC's Division of TB Elimination, said today in a press release from The Lancet sent to reporters that social factors should be taken into account for managing TB. "Our country-specific results can be extrapolated to guide in-country policy for laboratory capacity and for designing effective treatment recommendations for MDR-TB," she said.

The researchers wrote that they saw the lowest levels of resistance in countries in which second-line drugs had been available for 10 years or less. Countries that had the drugs for 20 years or longer—South Korea and Russia—had the highest rates of resistance, they noted.

Higher rates of XDR-TB than what earlier WHO data showed could in part be related to differences in lab procedures, according to the researchers, who pointed out that they tested all three second-line injectable agents, though most countries test for one or two, which could underestimate the XDR-TB burden.

Resistance seen in hospitalized patients might reflect nosocomial transmission or disease severity, the group wrote.

In an editorial on the study that appeared in the same issue of The Lancet, Sven Hoffner, PhD, with the Department of Preparedness at the Swedish Institute for Communicable Disease Control, said that differences between countries in their use of TB drugs, along with their combinations and use in treating other bacterial infections, could lead to the different drug-resistance profiles seen in the study.

Greater transmission of MDR-TB in some countries and variations in the percentage of patients with HIV are among the differences in risk factors among countries that the researchers reported, he wrote. "Such local differences in drug-resistance and epidemiological characteristics should be taken into account when international guidelines for diagnostic algorithms, infection-control measures, and treatment recommendations for drug-resistant tuberculosis are adapted."

Though the rate of XDR-TB varies among countries, Hoffner wrote that the study's findings show the disease is increasingly concerning, especially in areas that have high MDR-TB prevalence.

He wrote that the study helps increase global understanding of the disease.

"Updated information on MDR tuberculosis and investigation of the trends are urgently needed, especially since the true scale of the burden of MDR and XDR tuberculosis might be underestimated and seem to be rapidly increasing," Hoffner said, adding that identifying the risk factors in certain settings will help guide the use of new diagnostic tools.

Dalton T, Cegielski P, Akksilp S, et al. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet 2012 (published online Aug 30) [Abstract]

Hoffner S. Unexpected high levels of multidrug-resistant tuberculosis present new challenges for tuberculosis control. Lancet 2012 (published online Aug 30) [Extract]

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