Tuberculosis is an infectious bacterial disease that affects the lungs or other organs. Until 50 years ago there were no treatments for it. Nowadays there are many. But, further research is required to overcome resistance and to eradicate this centuries old scourge.
Tuberculosis (TB) is a bacterial infectious disease caused by mycobacterium tuberculosis. It is characterised by the formation of granulomas. Primarily, the disease affects the lungs. Signs and symptoms include a cough for more than three weeks, chest pain, tiredness and fatigue, night sweats, coughing up blood and weight loss.
The disease is transmitted when an infected person coughs, spits or sneezes and sends microscopic droplets loaded with the bacteria into the air, which are inhaled by other people. Body fluids of patients, like saliva, blood and urine can also be a source of infection. TB thrives in conditions of poverty and overcrowding. A person with active tuberculosis can infect an average of 15 people a year.
Not everybody who is infected falls ill. One in three of the global population – about two billion people – have latent TB infection, but only about ten per cent of them will go on to develop the disease. In patients with a weakened immune system, the infection may generalise and lead to abscesses in other organs, including the brain and the skeletal system.
Every year, about eight million people contract TB and two million die from it. The World Health Organisation (WHO) estimated recently that, by 2020, nearly one billion people will be newly infected, 200 million will get sick and 35 million will die from the infection. This is largely due to the spread of HIV in Africa and to the economic difficulties affecting the states of Eastern Europe and Central Asia. Approximately 80 per cent of all TB cases are found in 22 “high burden” countries, with the largest numbers in Africa and south-east Asia.
Until approximately 50 years ago, there were no medicines to treat TB. Since the 1950s, the appearance of new therapies of different types has allowed TB epidemics to be brought rapidly under control. One of the difficulties of treatment is that TB bacteria have become resistant to medicines, though there is less danger of this when two, three or four medications are given together. Some bacterial strains are resistant to a single medicine or even a combination of them. Multi-drug-resistance is caused by inconsistent or partial treatment, when patients do not take their medicines regularly for the required period.
A problem with TB treatments is that they are lengthy and complicated. Multi-drug-resistant TB takes at least 18 to 24 months of treatment and has a poor chance of cure. A four-drug combination – isoniazid, rifampicin, pyrazinamide and ethambutol – preferably in one tablet, given over 6 to 9 month treatment periods is advised. The therapy must be under strict supervision, since patient compliance is crucial for the success of the treatment. Multi-drug-resistant cases may also be treated with rifapentin, which was introduced in 1998.
The strategy recommended by the WHO for the detection and cure of TB is known as DOTS (Directly Observed Treatment Short-course). DOT (Directly Observed Therapy) is a system of monitoring compliance of TB patients and their treatment regimens. The entire system is underpinned by trained volunteers and involves many health workers at health care facilities.
By 2020, WHO aims to detect 70 per cent of new TB cases and to cure 85 per cent of those. All 22 of the high burden countries have adopted DOTS. In 2005, 43 per cent of the global population had access to DOTS, double the amount reported in 1995. Also in 2005, 21 per cent of TB patients received treatment under DOTS, also double the amount reported ten years ago.
Fluoroquinolone antibiotics are increasingly being used in the treatment of TB. They act by inhibiting DNA gyrase through binding to the enzyme-DNA complex in M. tuberculosis. There is also clinical evidence that substituting a gyrase-blocking antibiotic in the regimen of medicines used to treat the highly contagious form of lung disease could dramatically shorten the time needed to cure the illness from six months to four.
Other interventions include BCG (Bacille Calmette-Guerin) vaccination of newborns or young people to prevent TB. Although BCG is efficacious against serious forms of the disease in children, the protection it offers is variable in adults. Why BCG vaccination has only modestly reduced disease prevalence, especially in the developing world, is not fully understood. Important contributing factors might include background immunity induced by non-TB environmental mycobacteria, diversity of BCG strains, and over-attenuation of the vaccine strains which are presently used.
A number of new candidate vaccines for tuberculosis have been tested in preclinical studies, under an EU project involving public and private research organisations and pharmaceutical companies. The project, called the TB Vaccine Cluster, was set up under the fifth research framework programme 1998-2002, which has allocated €15 million to vaccine research.
TBVac has established a joint academic-industrial consortium capable of taking TB vaccine candidates from the laboratory bench to Phase 1 trials. It involves 38 leading European research groups from 12 countries, including two large pharmaceutical companies. In addition, the EU is supporting additional vaccine projects, two of which are looking at the possibilities of intranasal or oral vaccination as an alternative to injection. Clinical studies have been started to test a recombinant vaccine containing two proteins of M. tuberculosis.
A new substance based on the natural product thiolactomycin has been found. This compound has shown activity against TB both in vitro and in vivo and efforts have begun to develop a compound with improved potency. The class of bicyclic nitroimidazoles which acts against M. tuberculosis is also in early clinical development. This class of compounds appears to kill anaerobic cells by acting as intracellular nitric oxide donors. The compounds also appear to be active against non-replicating organisms, suggesting they might be capable of significantly shortening TB treatment time.
The widely used beta-lactam class of antibiotics has been mainly ineffective against M. tuberculosis because the compounds are hydrolysed by a bacterial beta-lactamase (BlaC). A combination of approved beta-lactams and a BlaC inhibitor, was found to be active in vitro not only against both laboratory strains that mimic the persistent state of the infection but also against extensively drug-resistant strains.
Another new tool in the TB armoury could be a compound from a series of diarylquinolines. These have been shown to provide substantial selectivity and potency for several mycobacterial species, including M. tuberculosis, and to retain activity against strains that are resistant to commonly used medicines. In contrast to other anti-mycobacterial compounds, this class of molecules targets an adenosine triphosphate synthase. It is hoped that this new approach will allow the treatment of TB in as little as two months.
Research is also underway to look into new disease models. Scientists have developed a goldfish model of tuberculosis, which they hope to use to design an attenuated live M. tuberculosis vaccine. Goldfish play host to M. marinum, a species closely related to mycobacterium tuberculosis. The pathology of M. marinum infection in the model parallels that of human TB infection, with giant cell and granuloma formation.
It is projected by the scientific community that at least one new medicine against TB will be registered by 2010 and available in high-burden areas by 2012.
Much of the future scientific work will depend on improving knowledge of the genome of M. tuberculosis. Meanwhile, research groups have been able to decode the genome sequence of extensively drug-resistant (XDR) strains of M. tuberculosis. Initial comparisons of the genome sequences reveal that XDR and sensitive microbes differ at only a few dozen locations along the four-million-letter DNA code, revealing some known drug resistance genes as well as some additional genes that may also be important to the spread of TB. With the analysis of additional XDR strains, it should be feasible to systematically unravel the biological significance of each genetic variation.