Tuberculosis drugs stop working. What to do with drug resistance?

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Tuberculosis drugs stop working. What to do with drug resistance?
Tuberculosis drugs stop working. What to do with drug resistance?
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Tuberculosis has been known since antiquity and has been a sentence for centuries. In the 18th century, almost every thousandth inhabitant of Western Europe died from tuberculosis every year, and in the next century, every fourth death in Europe and North America was caused by this disease. Tuberculosis was called the white plague, and at one time it even became fashionable to get sick: romantic natures were fascinated by pale, emaciated faces with a bright blush - the faces of the doomed.

Until medications appeared, patients were treated with rest, fresh air, sunbathing, and proper nutrition, but without much success. In the first half of the 20th century, patients were given isoniazid, and in the 1950s and 1960s, three more drugs appeared: pyrazinamide, ethambutol, and rifampicin. These four drugs are still the first line of defense against tuberculosis. But the causative agent of the disease is able to overcome it.

Tuberculosis is caused by mycobacteria-like bacteria (German Robert Koch discovered them on March 24, 1882). They enter the human body through the lungs, where they are met by eater cells - macrophages. Having absorbed the stranger, the macrophage tries to "digest" it, but it is beyond its power: the wall of the mycobacterium can withstand the attack. Then macrophages and other cells grow together into a nodule - a granuloma.

Granuloma for the time being delays the spread of mycobacteria throughout the body, but it also protects them from the immune system and drugs. Because of this, the treatment is delayed. If antibiotics usually cope with other bacterial infections in a matter of days, then it takes at least six months to get rid of active tuberculosis.

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The causative agent of tuberculosis mycobacterium tuberculosis (red) under a microscope

The longer the treatment period, the more chances mycobacteria have to escape. When they divide, random mutations constantly occur in them. Some are incompatible with life, others weaken the pathogen. But sometimes mutations provide benefits, such as drug resistance, and can become entrenched through selection.

“Imagine that 100 mycobacteria live in the lungs, and two of them have a mutation in their genome that makes them immune to isoniazid. If a person is treated with isoniazid, 98 bacteria will die from it, and these two will survive and continue to divide. there will be four bacteria resistant to isoniazid, another day - eight, etc. Treatment with this drug will be pointless, explains Irina Kontsevaya, a researcher at the Clinical Infectology Department of the Borstel Research Center and a member of the TBnet community steering committee.

Why drug resistance is developing

To prevent the development of resistance, patients are simultaneously prescribed all four first-line drugs. When mycobacteria are resistant to isoniazid, it can be substituted for levofloxacin. But it also happens that isoniazid and rifampicin, two main drugs, do not work at the same time. This is multidrug-resistant tuberculosis (MDR-TB) and needs to be treated with second-line drugs, which are more expensive, more difficult to tolerate and require a longer course of up to two years.

If mycobacterium is also resistant to second-line drugs, then they speak of extensively drug-resistant tuberculosis (XDR-TB). Such tuberculosis is more and more amenable to treatment, but so far only 41% of patients have been cured of it. Some just can't stand it because of the side effects.

Every second case of MDR-TB occurs in three countries: India, China and Russia. According to the World Health Organization (WHO), in 2019, 35% of newly diagnosed cases of tuberculosis in Russia were caused by mycobacteria resistant to isoniazid and rifampicin. In those who have not been cured the first time, such bacteria are found in two cases out of three.

According to Irina Kontseva, the high incidence of tuberculosis and the high level of drug resistance in Russia is associated with the so-called Peking genetic group of mycobacteria. "The strains of this group first appeared in China and have been evolutionarily very successful: they often have mutations, both associated with MDR-TB, and offset their 'cost', and are characterized by increased virulence and the ability to transmit to other people," she explains. …

But mutations do not guarantee success - suitable conditions for the spread of mycobacteria still need to be created. “This is a long-standing problem. In the 1980s, we did not comply with all WHO recommendations. Previously, we did not have controlled treatment. And in the 1990s, there was a lack of drugs: today they brought one - they started giving, tomorrow they brought another - they started giving another. Now the situation has changed fundamentally, says Andrei Maryandyshev, chief freelance phthisiatrician of the Northwestern Federal District and the Arkhangelsk Region.

How the treatment of tuberculosis in Russia has changed

Once resistant, mycobacteria can infect another person. It so happens that a patient is admitted to a hospital with a drug-susceptible strain, and already there he becomes infected with a more dangerous one. According to Andrei Maryandyshev, now they are trying to leave patients at home. They have already infected the family, and in order to protect strangers, patients are asked not to go anywhere while the bacteria are released (usually four weeks), and they organize social support for them.

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© TASS

Households and other contacts of the patient are trying to check for latent infection. Irina Kontsevaya notes that in these cases the transmission probability is relatively low and definitely less than 100%. Nevertheless, according to some estimates, a quarter of the people on the planet are carriers of mycobacteria. With a 5–15% probability, they will develop tuberculosis sooner or later. People who come into contact with the patient are prescribed one or two drugs in a short course to try to kill mycobacteria before they cause active tuberculosis.

Recently, new diagnostic methods have also emerged that detect drug resistance before starting treatment. But only about half of the cases can be checked: often tuberculosis is detected at an early stage, when there are no mycobacteria in the sputum, and sometimes the medical staff does not control the collection of sputum, and then it is impossible to carry out the analysis. But when tests for resistance are done, patients are prescribed not the same drugs, but only those that will definitely work. Even prisons that have had large outbreaks of tuberculosis have access to technology. "The devices have become simple, the laboratory is not needed. The patient donated sputum, put it in a cartridge, and two hours later received an answer," says Andrey Maryandyshev. According to him, the increase in the number of detected cases of MDR-TB is due to improved diagnostics. But Irina Kontsevaya writes that the reason, first of all, is not this, but in the transmission of resistant strains from person to person.

The National Medical Research Center for Phthisiopulmonology and Infectious Diseases maintains a single register of tuberculosis patients. According to the data from this register, they calculate how many and what drugs are needed in the regions of Russia. “All new drugs, except one, are registered with us. The only thing missing is clofazimine. MDR-TB is fully covered by the federal budget. XDR-TB is not fully covered: drugs are found by the local budget. There are territories that cannot find funds., but they may not immediately take you for treatment, says Andrey Maryandyshev.

However, not all patients seek help. Tuberculosis develops when the body is unable to keep mycobacteria under control. It can be related to HIV, alcoholism, poor diet, high stress, diabetes or other chronic diseases - vulnerable people are often sick: the homeless and those with addictions. They are also trying to help them. Andrei Maryandyshev gives an example from St. Petersburg, where a car with a fluorographic examination machine arrives at food distribution points for the homeless. So they can check the lungs.

Who wins the race: human or mycobacteria

Thanks to all these measures, in general, morbidity and mortality are decreasing in Russia, ahead of the WHO targets. Yesterday, Russian Health Minister Mikhail Murashko recalled that WHO considers Russia the first candidate to leave the list of countries with a high burden of tuberculosis.

However, the data on drug resistance are alarming. XDR-TB, the most dangerous type of disease, is being detected with increasing frequency: from 2016 to 2019, the number of cases increased by two-thirds, to 5,700 per year. According to Andrey Maryandyshev, the fact is that now almost all patients with MDR-TB are tested for susceptibility to the drug ofloxacin, that is, the reason is improved diagnostics. Be that as it may, in some regions, patients have to wait for the necessary drugs, and even when they are available, XDR-TB is difficult to cure.

Nevertheless, Andrei Maryandyshev looks to the future with optimism. "Our country has the fastest pace of improvement in the epidemiological situation in the world. WHO and we have a goal of eliminating tuberculosis by 2035. For Europe, we hope it will be 2030," he explains (more precisely, the goals of the WHO strategy - with 2015 to 2035 to reduce mortality by 95%, and morbidity by 90% and to make sure that no family has unbearable costs for treatment - TASS note).

Irina Kontsevaya thinks differently: “The fight against drug resistance can be imagined as a race: a person develops a drug, a bacterium develops a mechanism of resistance to it, the drug stops working, a person develops a new drug - and history repeats itself. If this is really a race, then humanity is in it so far, unfortunately, is losing."

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