Tuberculosis: The search for new drugs continues
Tuberculosis bacteria in the focus of research.
Every year on 24 March, we commemorate Robert Koch’s discovery of the tubercle bacillus. Almost 140 years later, tuberculosis is still the leading infectious disease with the most number of deaths worldwide. Antibiotic resistance is increasingly challenging treatment and an effective vaccine is still not available. However, promising approaches do exist: genome analysis, new agents and treatment regimens all contribute towards making progress in combatting this disease. We spoke Professor Stefan Niemann, a tuberculosis expert from the Research Center Borstel, about the current situation on tuberculosis research.
Tuberculosis has once again become a more frequently reported topic in the German media. Is the disease returning to Germany in the light of increasing globalisation?
Stefan Niemann:
In the past few years, the trend of decreasing tuberculosis incidence has indeed been reversed in Germany. This is mainly due to the fact that refugees account for more cases of tuberculosis. However, it is important to note that with approximately 5,400 new cases and an incidence of only 6.7 cases per 100,000 inhabitants in 2018, the incidence of tuberculosis in Germany is relatively low. Nevertheless, the disease certainly needs to be given more attention. With an average treatment success of approximately 80 percent, Germany has not yet achieved the WHO’s recommended goal, which is 90 percent. Late diagnosis of the disease continues to be a problem, as the disease is not identified early enough.
There is a particular danger of tuberculosis developing increasing antibiotic resistance, as is the case with other infectious diseases. What is the treatment prognosis in these cases?
Stefan Niemann:
Even in cases of drug-sensitive, i.e. non-resistant tuberculosis, we have to administer a combination treatment over a period of six months. For resistant pathogens, the duration of treatment increases to nine months and can last all the up to two years with markedly poorer treatment success. A major problem is ensuring that patients actually take the medication over such a long period of time. In the past few years, the number of cases of multidrug-resistant tuberculosis with resistance against two of the most important tuberculosis drugs has increased to approximately 550,000 cases worldwide. A major problem is that only a small proportion of patients with multidrug-resistant tuberculosis are actually diagnosed and treated and the success of treatment is only approximately 50 percent worldwide. Consequently, only a small proportion of patients with multidrug-resistant tuberculosis are treated successfully.
How do researchers react to these problems?
Stefan Niemann:
First of all, the DZIF is focusing on case finding and accurate diagnosis of resistance. Personalised treatment is subsequently based on these results, in order to achieve similar rates of treatment success with the available drugs compared to the success rates seen in drug-sensitive tuberculosis. Accurate diagnosis means that we decipher the pathogen’s entire genome using modern genome sequencing methods and use the results to comprehensively predict resistance. Based on these findings, we can subsequently select the medication for an individual patient in order to precisely tailor the treatment. This should happen as early as possible so as to avoid the development of new resistance and a further spread of multidrug-resistant pathogen strains. Currently, many countries with a high incidence of tuberculosis do not have these techniques available. Nonetheless, the DZIF has initiated pilot projects together with African partner laboratories and in Eastern Europe, which is how we succeeded in setting up a sequencing laboratory in Kirgizstan, for example.
Are new treatment approaches being researched, will there perhaps soon be a one-tablet-treatment available for tuberculosis?
Stefan Niemann
In order to avoid the development of resistance, tuberculosis has to be treated with several drugs and this is most likely not going to change. Here, the evolution of tuberculosis bacteria is the enemy of treatment and the likelihood of developing resistance becomes very high as soon as we treat a patient with one or two effective drugs only. However, we are currently also observing small “revolutions”: Instead of treating multidrug-resistant strains for a period 18 months, we now see short-term treatments of nine months becoming effective. This treatment regimen is recommended by the WHO and works very well in certain regions of the world. Changes have also been made in the combination of antibiotics for longer treatment regimens, in which bedaquiline, the only newly approved TB drug in recent years, has been included. However, resistance against this new drug has already been observed.
This means: Keep searching for new drugs?
Stefan Niemann
Yes, this is what it means. In order to tackle reoccurring resistance, we have set up a “Drug Discovery Pipeline” at the DZIF. It covers the different steps in drug development starting from the discovery of a new substance that is active against tuberculosis bacteria through to development and testing in clinical trials. Here, for example, we can search the DZIF’s Natural Compound Library in order to find completely new substances. We have already generated a series of hits which are currently being tested further. At the LMU in Munich, DZIF scientists are also investigating a promising substance that was discovered years ago and is effective against multidrug-resistant strains. It is called BTZ-043 and has already been tested for safety and tolerability in healthy volunteers and will soon be tested on patients in clinical trials. Up to now, we have the all clear, but this drug will have to be administered in combination with other drugs. Consequently, together with the European-African network “PANACEA”, the DZIF is developing strategies to find the most effective combination therapies.
The WHO has set the goal of completely ending tuberculosis by 2030. Do you believe this to be realistic?
Stefan Niemann
To achieve this by 2030 is a major challenge. In Germany alone this would mean that we have to significantly reduce the incidence of tuberculosis, which is very difficult due to the developments over the past few years. Worldwide, severe shortfalls exist in many areas particularly in countries that have a high incidence of tuberculosis, which is a big problem, of course. These shortfalls include case finding, diagnostics, treatment and transmission control. Germany, being a rich country with resources available, therefore has a high level of responsibility to be internationally active. Last year, a UN high-level meeting on ending tuberculosis took place in which participating countries set themselves the goal of developing a plan to end tuberculosis. This clearly shows that governments recognise that something needs to be done. The German Federal Government also dedicated itself to improving healthcare worldwide and established the Global Health Hub. In the field of tuberculosis, the “Global Health Protection” programme has funded a networking project in which Germany provides assistance with modern sequencing technology applications to support countries with high incidences of tuberculosis. An important aspect here is that many countries in the European region, for example Romania, have high rates of multidrug-resistant tuberculosis and the majority of patients with multidrug-resistant tuberculosis in Germany come from these regions. And independent of this, we also have a social responsibility to help other more severely affected countries.
Fact box:
Tuberculosis, also called TB, is the most deadly infectious disease worldwide. According to the WHO, three people die of tuberculosis each minute. In 2017, 10 million new cases of tuberculosis were reported. TB is spread by droplet transmission: Infections are usually contracted via the air that we breathe. Microdroplets from an infected person are exhaled and subsequently inhaled by a healthy person. Typical symptoms include coughing, low fever and weight loss. Tuberculosis can be treated well with drugs, but multidrug-resistant strains increasingly challenge treatment.
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