What do wolf’s liver, the touch of a king and millipede syrup have in common? These were all early treatments for tuberculosis before the advent of the TB hospitals called sanatoriums and then antibiotics.
You might be surprised to learn that there is still one operating tuberculosis sanatorium in the U.S., in Lantana, Florida, profiled this week in The New York Times. Treating up to 50 patients at a time, for the duration of the extended drug regime required to fight drug-resistant TB, it is a monument to the past, present and future of tuberculosis, as the “plague” that was almost cured continues to kill millions worldwide each year and resistant strains continue to evolve and attack not only in developing countries but here at home as well.
Much has been written about tuberculosis (also called consumption, wasting disease, scrofula, the White Plague, King’s Disease and many other names) and its devastating impact on entire families, generations, countries, and peoples throughout human history. There are a number of lively in-depth narratives of the missteps and breakthroughs in understanding the nature and spread of TB, identifying its cause and easing the suffering of patients. Many accounts focus on the poets, musicians, authors and artists who shared their experiences and shaped popular culture as they lived with and died of tuberculosis, to some degree romanticizing the experience for their peers.
However, because the focus of the Working Group on New TB Drugs is how tuberculosis has been and is treated, we are taking a look at the history of TB through this lens. This post launches a new series on www.NewTBDrugs.org called “The Sanatorium Files,” which will explore how medical practitioners, caregivers, society and governments have fought the ongoing TB epidemic and the impact these treatments had and have on the patients receiving them.
This first post in the series is a timeline showing the evolution of tuberculosis treatments, ranging from the harmless but useless to the painful, bizarre and dangerous, and ultimately leading to the antibiotics used to treat the disease for the last 30-40 years. Later posts will take a closer look at the sanatorium movement as a way to isolate TB patients and provide comfort, hope and whatever treatments were available prior to the discovery of the drugs that could cure the disease.
The sheer scope of these efforts to search for a cure were made possible by the nature of tuberculosis itself. Though it has been called “The White Plague,” it is not really a plague as the term is most commonly used, describing a disease that sweeps through populations killing many people relatively quickly (for example, the bubonic plague was fatal in 2-3 days).
In contrast, for much of the 19th and 20th centuries tuberculosis was a chronic disease that patients lived with often for years or decades, going about their daily life as best they could, with better periods and then relapses as part of an overall slow, steady decline. As a result, many people with TB focused on making sense of their condition and trying anything and everything for a cure.
A review of the timeline shows that the five drugs still used as first-line therapies to treat tuberculosis today (and their required 6- to 24-month daily regimens) were all introduced before 1965. Though other drugs have been introduced since 1965, all have significant toxicity and other issues, relegating them all to second-line status (see “Handbook of Anti-Tuberculosis Agents,” [.pdf download] published by the Global Alliance for TB Drug Development for details) and highlighting the urgent need for new approaches and new therapies to combat resistance to these existing drugs. See our Global TB Drug Pipeline, for information on new TB drugs now in development.
As we search for newer and better therapies for today’s millions of patients, a review of how far we’ve come shows how far we have yet to go. Our research in this area continues, and we’ll update the timeline as more TB treatment facts emerge. If you have additional information to share, please add a comment.
Historical Timeline of Tuberculosis Treatments
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____________ 3000 B.C. |
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Mummified remains uncovered in Egypt indicate that tuberculosis sanatoriums existed |
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____________ Ancient Rome |
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____________ Fourth Century B.C. |
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Greek physician Hippocrates prescribes “cleanliness and healthy diet” |
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____________ First Century A.D. |
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____________ Middle Ages |
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____________ Early 1800s |
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____________ 1800s |
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____________ 1840s |
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Iodine, taken by mouth, rubbed in, added to bath water, mixed with food or given in combination with mercurial pills |
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____________ 1850s |
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Cod-liver oil, used for centuries for other conditions, because a standard treatment for TB after its introduction for this purpose by Dr. D. J. Blasius Williams at the Brompton Hospital in London |
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____________ 1854 |
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Hermann Brehmer, a German doctor who had recovered from TB while on an expedition in the Himalaya mountains, opened the first modern sanatorium in Eastern Europe. At this part hospital, part open-air hotel, he prescribed fresh air and rest. |
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____________ 1865 |
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The firm Gobel of Gmunden is founded in Austria, selling bottled air from every famous spa in Europe. Recommended for consumption, Luft von Ischl (Ischl Air), from a charming Alpine spa near Salzburg that was the summer home of the Austrian emperor, is its best-selling line. Patients would open a bottle in their room at night before going to bed. |
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____________ Late 1800s |
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____________ Late 1800s |
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Hugh Owen Thomas, fourth-generation bone-setter, slowed the progression of and possibly cured many cases of TB of the bones with “enforced, uninterrupted and prolonged” rest of inflamed joints, made possible by the simple yet highly effective splint he invented. |
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Niels Ryberg Finsen in Denmark created a special lamp to concentrate and cool ultraviolet rays, and his research showed that ultraviolet irradiation proved very effective for treating lupus vilgaris (TB of the skin), making irradiation the first successful treatment of any kind for tuberculosis. He was awarded the Nobel Prize in 1903. |
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____________ 1882 |
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Robert Koch of Germany discovered the rod-shaped bacterium that causes tuberculosis, identifying the target for future yet-to-be-discovered antibiotics. Koch was awarded the Nobel Prize in 1905 for this and other discoveries. |
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____________ 1885 |
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Edward Livingston Trudeau, an American doctor who had planned to spend his final days in the Adirondack Mountains, opened the first American sanatorium in Saranac Lake, NY, after he found that his symptoms disappeared in the fresh air. |
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____________ 1900 |
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Robert Koch announced at the Tenth International Congress of Medicine in Berlin that he had discovered a substance that “in some cases” could protect against TB and even “under certain circumstances” cure the disease. The substance, called Koch’s Lymph or Old Tuberculin, contained proteins from killed bacteria originally harvested from infected guinea pigs and concentrated in a filtrate of the ox bile and glycerine medium in which the TB bad been cultured. However, the announcement was very premature and subsequent usage of the serum not only showed no such results but caused significant side effects and increased vulnerability to the influenza epidemic. Koch was able to salvage his reputation after several years, and his tuberculin later became the basis of the TB diagnostic skin test developed by Clemens von Pirquet. |
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____________ 1909 |
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Salvarsan, discovered by Paul Erlich and his team searching for a chemical compound that would be lethat to pathogenic organisms without killing the host, shows some effectiveness in treating syphilis but not tuberculosis. It was also unpredictably toxic. |
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____________ Early 1900s |
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– Silica and colloidal preparations of silver, copper, aluminum and antimony – Brass digested in a mixture of vegetable oil – Calcium supplements – Inhalations injected directly into the windpipe included:
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____________ 1920s |
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“Collapse Therapy,” surgical intervention to create an artificial pneumothorax or collapsed lung becomes the mainstay of the active treatment of for pulmonary TB. |
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____________ 1924 |
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Holger Mollgard, an animal psychologist at the University of Copenhagen, introduces Sanocrysin, a combination of gold and sodium, basing his claims of TB treatment on animal experiments that ultimately did not support his theory. |
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____________ 1930s |
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Gerhard Domagk discovers sulphonomides, including Prontosil, which raised hopes that it might be effective in TB; it was not. It did prove very useful in treating infections, including secondary infections resulting from invasive TB therapies. |
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____________ 1944: The Turning Point – Streptomycin |
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American soil biologist Selman Waksman and his assistant Alfred Schatz, identified a fungus in soil, Streptomyces griseus, that produced a chemical agent in the lab that slowed the growth of some disease-causing bacteria. Now known as streptomycin, it proved to be the first compound that effectively killed tuberculosis bacteria, and it is still a 1st line therapy for TB. Waksman was awarded the Nobel Prize for his discovery in 1952. |
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____________ 1946 – PAS, 2nd line therapy |
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Jorgen Lehmann, a Dane working at a hospital in Sweden discovered p-aminosalicylic acid (PAS), a compound similar to salicylic acid that proved to be a powerful inhibitor of benzoic and salicylic acid, which played a key role in the oxygen uptake of TB in order to grow. Trials of the drug 1948-50 showed that PAS not only significantly reduced the risk of resistant strains emerging during streptomycin therapy but also rendered streptomycin more effective. This was welcome news, because streptomycin caused significant and sometimes permanent side effects and the first streptomycin-resistant strains had already begun to emerge. |
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____________ Isoniazid, 1st line therapy – 1952 |
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Once the first two TB drugs were developed and were obvious commercial successes, three pharmaceutical companies began to develop the next drug. Hoffman La Roche, the Squibb Institute and Bayer’s came up with a similar compound simultaneously and began to negotiate the patent rights. However, it was then discovered that two Prague chemists had already discovered the molecule, isoniazid, derived from coal tar, in 1912 for their doctoral thesis in chemistry without knowing of its anti-TB properties. As a result, isoniazid could not be patented and became available at a much lower price per patient ($100 vs. $3,500 for streptomycin and PAS). |
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____________ Cycloserine, 2nd line therapy – 1955 |
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____________ 1955 – Triple Therapy |
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Cycloserine is an effective agent but severe toxicity has limited its use. |
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Soon after isoniazid reached patients, it became apparent that it would not actually replace streptomycin or PAS because of the ongoing emergence of resistant strains. Instead, by 1955 the consensus was to use all three drugs in a combination called Triple Therapy – streptomycin, PAS and isoniazid. The recommended course was two years. |
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____________ Rifampicin, 1st line therapy – 1959 |
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Professor Piero Sensi at the Lepetit Pharmaceuticals research lab in Milan, Italy identified a new bacterium producing a new class of molecules with antibiotic activity in 1957, and after two years of refining his team introduced rifampicin. It has the unusual side effect of causing certain bodily fluids, such as urine and tears, to become orange-red in color. In combination with isoniazid, a course of 9 months was shown to be as effective as the two-year course of Triple Therapy. |
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____________ 1961 – Ethambutol, 1st line therapy |
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Ethambutol is used in combination with other drugs in the treatment of pulmonary tuberculosis especially in cases of suspected drug resistance. It can’t be used alone due to the risk of resistant mutants. |
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____________ Pyrazinamide, 1st line therapy – 1962 |
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Another effective drug, pyrazinamide, had been tested in the 1950s but was abandoned because of its toxic side-effects. Wallace Fox and his team at the Medical Research Council showed that it was safe in lower doses and over shorter periods than had been originally tested. The treatment regimen with pyrazinamide was shortened to 6 months. |
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____________ 1992 – Rifabutin |
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A modified form of rifampicin, (approved in 1959), rifabutin can be taken in smaller doses, penetrates better into diseased tissues and remains active longer than its precursor. |
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____________ Rifater – 1994 |
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Rifater, developed by Marion Merrell Dow Inc., combines three of the TB drugs developed in the 1950s and 1960s – rifampin, isoniazid and pyrazinamide – into one pill, making it easier for patients to take their medicine as prescribed, daily for a course of six months. |
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____________ 2010 |
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Though no new first-line drugs for tuberculosis have been introduced since 1962, there are a number of drugs in late-stage development now (see our Global TB Drug Pipeline). The course of TB therapy is still a cocktail of the existing TB drugs for 6-9 months for TB and 18 months+ for drug-resistant TB. |
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Sources: “The White Death,” by Thomas L. Dormandy, 2000, New York University Press/1999, Hambledon Press. This extract is printed by kind permission of the Continuum International Publishing Group. (www.continuumbooks.com)
“Tuberculosis” by Diane Yancey. Text copyright © 2008 by Diane Yancey. Reprinted with the permission of Twenty-First Century Books, a division of Lerner Publishing Group, Inc. All rights reserved. No part of this text excerpt may be used or reproduced in any manner whatsoever without the prior written permission of Lerner Publishing Group, Inc. (www.lernerbooks.com)
“Drug-Resistant Tuberculosis: Inconsistent Results of Pyrazinamide Susceptibility Testing-Reply,” Journal of the American Medical Association, Vol. 273 No. 12, March 22, 1995