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FOR COMMENT: Peter M. Small, MD, (650) 725-7908

EMBARGOED FOR RELEASE: Sunday, March 12 at 1:00 p.m., PST to coincide with publication in the March 13 issue of Archives of Internal Medicine


STANFORD -- Drug-resistant tuberculosis is more deadly in developing countries than doctors previously recognized. One-third to one-half of patients suffering from drug-resistant tuberculosis are not cured despite treatment with standard antibiotics administered by an efficient tuberculosis control program, a team of Mexican and Stanford researchers has discovered. The findings, which will be published in the March 13 issue of Archives of Internal Medicine, show the limitations of a TB control strategy widely applied in developing countries, said Peter M. Small, MD, assistant professor of medicine at Stanford University Medical Center and senior author on the paper.

"This is extremely bad news for resource-poor countries," Small said. "Although affordable, increasingly available, and effective for most patients, the standard approach is inadequate for treating patients with drug-resistant tuberculosis. To confront this disease, new tactics are urgently needed in countries with high rates of drug-resistant tuberculosis."

Unfortunately, drug-resistant TB patients are common. A recent World Health Organization survey found drug-resistant TB in every country studied and in more than half of patients in some areas. Drug resistance emerges when patients are inadequately treated, clearing the way for the proliferation of resistant bacteria. To ensure completion of the full course of drugs, public health officials devised a strategy of testing, treatment and follow-up called DOTS, which stands for Direct Observed Therapy, Short-course. As the name implies, one of the requirements of DOTS is that patients take their medications in the presence of a health care worker.

In the United States and other developed countries, therapy goes one step further. All TB patients are tested to determine if the strain of bacteria they carry is resistant to antibiotics. With that information, the patient's doctor can tailor a treatment best suited to eradicating the bacteria.

Costing tens of thousands to hundreds of thousands of dollars per patient, such a strategy is too expensive for most developing countries, Small said. Instead, the World Health Organization recommends treating every patient with a standard, affordable regimen of drugs. Administration of these drugs under direct observation has been hailed as one of the most important recent public health interventions, and it has shown to prevent the emergence of drug resistance, Small said.

However, there is scant data about the effects of DOTS therapy where drug resistant TB is already a problem. Small and 11 Mexican colleagues set out to determine how well this strategy worked in a TB control program in Orizaba in southern Mexico. The team found that drug resistance among the participants was disturbingly common. Twenty-eight percent of the 232 patients were infected with bacteria resistant to one or more antibiotics, while 11 percent were infected with bacteria resistant to at least two drugs.

Whether a patient harbored drug-resistant strains had an important influence on the outcome of treatment. While 2 percent of patients infected with non-resistant bacteria weren't cured, treatment failed for 56 percent of the patients infected with strains resistant to multiple drugs. And though only 10 percent of the patients with antibiotic-susceptible strains died during the study, 28 percent of those with multi-drug resistant strains died.

"Administering standard regimens independent of the susceptibility of the infecting organisms did not work," Small said. "In settings where there are significant rates of resistant TB, standard DOTS therapy, while essential, may not be sufficient," he added. However, given the financial limitations of the developing countries, it is not clear what kind of treatment program would work better, Small said. "International collaborations will be essential to devising improved strategies. Tuberculosis does not respect national borders and neither should tuberculosis research and control efforts."

The researchers also found evidence to support the controversial idea that drug-resistant strains are less likely to spread from person to person. Using DNA fingerprinting, they sorted the patients into 20 groups, or clusters, according to the genetic characteristics of their bacteria. All the people in each cluster can trace their infections to the same ultimate source. Compared with patients infected with non-resistant strains, patients who had drug-resistant strains were less likely to belong to a cluster, which suggests that they are not transmitting the disease to as many other people. "The observation that the most highly drug-resistant bacteria were less transmissable is at best a very thin silver lining in a fairly dark cloud," Small said. "Drug-resistant tuberculosis had a profoundly negative impact on these patients."

Small's Mexican collaborators were from the Instituto Nacional de Salud Publica in Cuernavaca, the Instituto National de la Nutricion Salvador Zubiran in Mexico City and the Instituto Nacional de Diagnostico y Referencia Epidemiologicos in Mexico City.

A grant from the National Institute of Allergy and Infectious Diseases, a branch of the National Institutes of Health, supported the study.

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