Health
100 Years of Progress in Tuberculosis Treatment
By American Thoracic Society
Apr 1, 2005, 09:46

Over the past century, the use of antituberculosis drugs has changed tuberculosis from a disease with a 50 percent mortality rate which was treated by collapsing the affected lung and rest in a sanitarium to a condition successfully cured by chemotherapy.

Writing in the first issue for April 2005 of the American Thoracic Society�s peer-reviewed American Journal of Respiratory and Critical Care Medicine, Denis A. Mitchison, M.B., F.R.C.P., F.R.C.Path., of Medical Microbiology in the Department of Cellular and Molecular Medicine at St. George�s Hospital Medical School in London, United Kingdom, has provided a history of diagnosis and treatment for this previously fatal disease over the past 100 years.

Highlights of a 100 years of progress in respiratory medicine and critical care are being currently featured in American Thoracic Society (ATS) journals and at the ATS International Conference in San Diego, May 20 to 25, as the Society celebrates its 100th anniversary.

According to the author, the initial key step in the development of modern chemotherapy for tuberculosis was the demonstration in clinical trials (starting in 1946) that the antibiotic streptomycin might be a viable drug for the disease.

Prior to this development, the basis for treatment was rest for the patient in a sanitarium and rest for the affected lung by collapsing it. After the affected lung was pierced, air was injected into the pleural cavity.

The results of the early British trials showed a substantial benefit to the streptomycin arm of the trial; however, many patients soon developed antibiotic resistant strains and little ultimate benefit came to those treated.

The next big movement forward came with the introduction of a combination of drugs to prevent the emergence of drug resistant Mycobacterium tuberculosis.

Starting in 1952, isoniazid, a more potent drug than streptomycin, was combined with p-aminosalicylic acid (which was then currently in use) and became part of a series of randomized clinical trials. Isoniazid could be given safely at a dose level substantially above its minimal effective dose. Between 1952 and the mid-1960s, a series of random clinical trials took place in Great Britain, the United States and elsewhere.

In 1955, trials in Great Britain showed that almost all tuberculosis strains had primary resistance to only one drug. Treatment with a 2- to 3-month three-drug phase, followed by a continuation phase of two drugs, became the world standard. However, the regimen had to be given for 12 months and it was very expensive for countries in the developing world.

In 1956, researchers in Madras, India, found that patients who were treated with tuberculosis drugs at home compared equally well with patients treated at a sanitarium. Furthermore, they discovered that family members who were in contact with a tuberculosis case daily were no more liable to develop the disease than were relatives of those who were treated at a sanitarium.

Later, studies with animals showed that a drug called rifampin, also a potent sterilizing agent, could be given intermittently with excellent effects. However, the higher doses produced an immunologic �flu� reaction in certain patients.

Finally, U.S. researchers working with experimental tuberculosis in mice set up a model system using a drug called pyrazinamide, a compound which was discovered in 1952. They showed that as bacterial metabolism slows down from the action of other drugs, pyrazinamide acts with more bactericidal effect.

�In the mouse model, therapy with the standard drugs�isoniazid, streptomycin, and p-aminosalicylic acid, produced an initial fall in viable bacterial counts, but these then leveled out and it was difficult to sterilize the organ,� said Dr. Mitchison. �When pyrazinamide was added, the counts continued downwards and eventually a state was reached in which all organ cultures were negative. Pyrazinamid is thus a good sterilizing drug.�

Out of the multiplicity of random clinical trials that were carried out over the years, two regimens emerged. The first was a 6-month treatment in which rifampin (the potent sterilizing drug) was given throughout the time period. Patients began treatment with 2 months of streptomycin, isoniazid and pyrazinamide, followed by 4 months of isoniazid, with, of course, rifampin.

This regimen, developed in Singapore, has efficacy and low toxicity. (Today, ethambutol is widely substituted for streptomycin.) The second choice was an 8-month regimen of a combination of these drugs, which a recent randomized clinical trial has shown to be �distinctly inferior to the 6-month regimen with rifampin throughout.�

�In the absence of new drugs, little change has taken place in current regimens during the past 30 years,� said Dr. Mitchison. �However, there is current interest in the fluoroquinolones with at least three other potentially valuable drugs near or at early clinical development. New drugs would only benefit standard therapy if they could shorten the treatment period of 6 months to 4 months or less. Otherwise, their role would be confined to the treatment of patients with multidrug resistant tuberculosis. . .�

In the U.S. in 2004, the total number of new cases of tuberculosis was 14,511, which represented a 3.5 percent decline from the previous year. That figure resulted in the lowest rate for reported TB cases since national surveillance began in 1953. More than half of the cases (53.7 percent) were in persons born outside the U.S.

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