Dramatic Rise in Extensively Drug-Resistant Tuberculosis

Troy Brown

August 30, 2012

August 30, 2012 — Almost half (43.7%) of patients with multidrug-resistant (MDR) tuberculosis in 8 countries studied were resistant to at least 1 second-line drug, and 6.7% had extensively drug-resistant (XDR) tuberculosis, according to a study published online August 30 in the Lancet.

To determine the prevalence of XDR tuberculosis, Tracy Dalton, PhD, a senior service fellow in the Division of Tuberculosis Elimination at the Centers for Disease Control and Prevention in Atlanta, Georgia, and colleagues tested sputum cultures from 1278 adults with MDR tuberculosis for susceptibility to 11 first-line and second-line antituberculosis drugs. The sputum cultures came from patients in 8 countries: Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand.

The investigators also used the data to identify risk factors associated with resistance to second-line drugs among people with MDR tuberculosis.

"The global emergence of [XDR] tuberculosis heralds the advent of widespread, virtually untreatable tuberculosis," the authors write.

MDR tuberculosis is caused by Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampicin.

XDR tuberculosis is caused by M tuberculosis strains that are resistant to isoniazid, rifampicin, and at least 1 drug within the fluoroquinolones and 1 antituberculosis injectable drug. Fluoroquinolones and injectable drugs are second-line antituberculosis drugs.

"Most international recommendations for tuberculosis control have been developed for [MDR] tuberculosis prevalence of up to around 5%. Yet we now face prevalence up to ten times higher in some places, where almost half of the patients with infectious disease are transmitting MDR strains of Mycobacterium tuberculosis," Sven Hoffner, PhD, from the Department of Preparedness at the Swedish Institute for Communicable Disease Control in Solna, Sweden, writes in an accompanying comment.

Dr. Dalton and colleagues found MDR tuberculosis in 1278 of the 1540 baseline isolates. Of those 1278 patients, 1199 (93.8%) had a history of tuberculosis. Percentages ranged from 47.8% to 100.0% across countries. Most (70.6%) of the 1199 patients reported 1 or 2 previous tuberculosis episodes. Nearly all of the patients in the study (92.8%) had received first-line antituberculosis drugs before enrollment, but only 195 (15.3%) had received second-line drugs. The rate of second-line drug administration ranged from 2.7% in South Africa to 53.5% in South Korea.

There was substantial variation in the prevalence of resistance between countries. Of the 1278 isolates, 625 (49.0%) were resistant to ethambutol and streptomycin in addition to isoniazid and rifampicin. Almost half (43.7%) of the patients were resistant to at least one second-line drug, with country-specific rates ranging from 33.3% in Thailand to 62.0% in Latvia. The overall prevalence of fluoroquinolone resistance was 12.9%, with the lowest country-specific rate being in the Philippines (7.1%) and the highest rate being in South Korea (32.3%).

Overall, the prevalence of resistance to at least one second-line injectable drug was 20.0%, with the lowest prevalence found in the Philippines (2.0%) and the highest in Latvia (47.0%).

The Eastern Cape province of South Africa had a significantly higher prevalence of resistance to all 3 second-line injectable drugs than the other South African provinces (65 [48.9%] of 133 vs 10 [6.3%] of 160 patients; P < .0001).

All countries had resistance to other oral second-line drugs, with an aggregate prevalence of 27.1% (range, 13.0% - 38.0%). Of 1278 patients overall, XDR tuberculosis was found in 86 (6.7%); the prevalence of XDR tuberculosis was lowest in the Philippines and highest in South Korea.

According to data from the World Health Organization, 5.4% of patients with MDR tuberculosis have XDR tuberculosis. The higher rate detected in the current study may be a result of differences in laboratory tests, according to Dr. Dalton and colleagues. "We tested all three second-line injectable agents for this study, but most countries test one or two, which could underestimate the burden of XDR tuberculosis. The same may be said for fluoroquinolones," the authors write.

Prior treatment with second-line drugs increased the risk for XDR tuberculosis more than 4-fold. "The strongest, most-consistent risk factor was previous treatment for MDR tuberculosis with any second-line drug, and the risk remained significant when fluoroquinolones, second-line injectable drugs and other oral second-line drugs were assessed separately," the authors write.

"Dalton and colleagues' study increases awareness of the clinical and public health issues caused by resistant M tuberculosis and reveals differences in prevalence and risk factors between countries and settings. Hopefully, these findings will contribute to the identification of the tools needed for optimum control of MDR tuberculosis in specific epidemiological settings," Dr. Hoffner writes.

"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," he concludes.

The study was supported by the US Agency for International Development, Centers for Disease Control and Prevention, National Institutes of Health/National Institute of Allergy and Infectious Diseases, and Korean Ministry of Health and Welfare. The authors and the editorialist have disclosed no relevant financial relationships.

Lancet. Published online August 30, 2012. Article abstract, Comment extract

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