World Tuberculosis Day: new drugs for an old foe
World Tuberculosis Day is observed on March 24 each year and commemorates the date in 1882 when Robert Koch announced the discovery of Mycobacterium tuberculosis, the bacterium which causes TB. Worldwide, tuberculosis remains one of the leading causes of death from infectious disease. An estimated 2 billion people (one third of the world’s population) are infected with M. tuberculosis. Each year, approximately 9 million people become ill with TB and nearly 2 million die from the disease, with new infections occurring at a rate of one every second. Tuberculosis has plagued humans for as long as we’ve been on this planet, probably evolving alongside us. In the UK, the Health Protection Agency has just announced that tuberculosis has increased another 2% to over 8000 cases in 2006. Since the late 1980s the number of people in the UK diagnosed with TB has risen every year, although in the USA CDC has just reported a 3.2% decline in cases in 2006.
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Tuberculosis is spread by aerosol droplets expelled by people with infected lungs when they cough, sneeze, speak, or spit. The disease most commonly affects the lungs (pulmonary TB), but can also affect the central nervous system, most other organs, bones, and even the skin. Worldwide, TB is the leading cause of death in terms of curable infectious diseases.
Although there are several drug-resistant forms of the organism, such as multi-drug resistant or MDR-TB (strains which are resistant to at least two of the main first-line TB drugs such as isoniazid and rifampin) and the virtually untreatable extreme drug resistant XDR-TB (strains which are resistant to all the current the front-line drugs, and three or more of the six classes of second-line drugs), the majority of TB strains are not resistant to drugs in the way that other bacteria such as MRSA are resistant to most antibiotics.
Patients with TB typically have to take four different antibiotics for two months and then continue with two of these antibiotics for an additional four months. DOTS (Directly Observed Treatment Short-course), the WHO-recommended TB control strategy includes directly observed treatment for at least the first two months in order to ensure compliance. Poor adherence to therapy results in the emergence of MDR and XDR strains, hence the need for new drugs to shorten treatment of drug-sensitive TB, and for effective treatment of MDR- and XDR-TB.
Why is such long treatment needed? Traditionally the answer was thought to lie in the fact that Mycobacterium tuberculosis enters a dormant or non-replicating state in an infected person. Because most of antibiotics act only on replicating bacteria, the dormant state of TB was thought to render it resistant to treatment. But that notion has now been challenged by a paper in PLoS Medicine (Why is long-term therapy required to cure tuberculosis? 2007 PLoS Med 4: e120).
Soon after the discovery of streptomycin, the first effective drug against TB, it became clear that while many patients treated with this antibiotic initially improved dramatically, most subsequently developed streptomycin-resistant strains so that there was little improvement in mortality over untreated patients. The development of new antibiotics led to the realization that there were two requisites for an effective cure: treatment with multiple antibiotics and a long course of therapy.
TB displays multiple mechanisms of drug resistance when growing in vivo. Some of these are classic genetic mechanisms, but others are phenotypic and reversible, such as growth within enclosed granulomas and in biofilms. In tuberculosis, more than with other bacterial infections, these phenotypic mechanisms seems to be of great importance.
New drugs which target non-replicating bacteria are likely to revolutionize TB therapy. Such agents have the potential not only to treat MDR and XDR strains but also to dramatically shorten the duration of therapy, and shorter treatment times should allow higher patient adherence, reduced transmission of infection, and decreased drug resistance, leading in turn to fewer deaths and the ultimate prospect of controlling one of the human race’s oldest enemies, tuberculosis.
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