Global Surveillance For Antituberculosis-Drug Resistance

NEW YORK, NY, June 3, 1998 -- Drug resistance of Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is a global phenomenon but is worse in a number of recently identified "hot zones," reports the World Health Organization - International Union Against Tuberculosis and Lung Disease Global Project on Anti-Tuberculosis Drug Resistance Surveillance, in the June 4 New England Journal of Medicine. The project surveyed on average 555 patients in each of 35 nations, from 1994 to 1997, for resistance to any of four commonly used drugs.

The study is the first to standardize surveys, surveillance reports, reporting methods, laboratory tests, and definitions used in describing the prevalence of this common infectious disease. "In the past, we had isolated reports, with no way to compare how many cases occurred in which nations. This study provides, for the first time, a global look at the prevalence of drug resistance to tuberculosis," says Ariel Pablos-Mendez, M.D., M.P.H., an assistant professor of medicine and public health at the Columbia College of Physicians & Surgeons and lead author of the study.

The study reveals an uneven distribution of drug resistance to TB worldwide. Incidence was low in many countries, including the United States, Brazil, and several African nations, but elevated in the Dominican Republic, India, the former Soviet Union, and Argentina. "This is the first major report which confirms that TB "hot zones" are emerging around the world," says Mario Raviglione, M.D., of the WHO and co-author of the report. "In these "hot zones," multi-drug resistant TB is virtually incurable without expensive and sophisticated health care. The World Health Organization is taking a lead in coordinating international efforts to tackle this problem," he adds.

Bacteria naturally undergo mutations that confer drug resistance, but these are rare events. When a patient does not take anti-tuberculosis drugs regularly, as prescribed, those rare resistant bacteria can persist. Not only does this selection for pre-existing drug-resistant variants complicate treating the patient in whom the problem originates, but then that person can transmit the resistant bacterial strain. This acquisition of an already-drug-resistant strain is called primary multi-drug resistance. "If a patient takes just one drug, or three or four but once in awhile, the resistant strains are selected. The patient can transmit that resistant strain to others," says Dr. Pablos-Mendez.

History has played a role in the rise of multi-drug resistant strains of M. tuberculosis, which began to be widely seen in the early 1990s. "TB resistance was noted right after the first use of streptomycin in 1948. But other drugs became available in the 1950s and 1960s which made resistance to streptomycin a non-issue. In the 1970s and 1980s, there was a very effective multidrug regimen, so regulations relaxed. Then HIV came in. And these two factors combined to create an explosive problem with tuberculosis. Now we see multi-drug resistant cases," says Dr. Pablos-Mendez. People with HIV infection are highly susceptible to TB. The study distinguished between patients who had no prior treatment -- indicating transmission of drug resistance from another person -- from those who developed resistance after a month or more on drug therapy. Of the patients who had no prior treatment, almost 10 percent were resistant to at least one of the four drugs (isoniazid, streptomycin, rifampin, and ethambutol). Multi-drug resistance was seen in 1.4 percent of them. But of treated patients, 36 percent had resistance to at least one drug, and 13 percent showed multi-drug resistance. Also, resistance was higher to isoniazid and streptomycin than to the other two drugs, a prerequisite to developing multi-drug resistance. Dr. Pablos-Mendez cites several sources that might set the stage for increased incidence of drug-resistant TB -- patients who do not take their drugs regularly, doctors who fail to prescribe the optimal numbers and types of drugs, and control programs that do not effectively monitor patients and physicians.

The study will help guide health agencies to where they should concentrate their efforts in TB management. "While several hot spots of nearly untreatable multi-drug resistant TB were identified, many nations have very low incidence," says Dr. Raviglione. And recent history in New York City has shown that identifying the problem can lead to highly effective efforts to stem it. "The incidence of multi-drug resistant tuberculosis in New York City today is only 12 percent of what it was in 1991, because of improved measures," Dr. Pablos-Mendez says.


India, New York City, Pablos Mendez, TB