Anti-tuberculosis

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A drug with which tuberculosis (TB, consumption) can be effectively treated is called an antituberculotic or tuberculostatic drug .

Since the pathogens divide very slowly and can also rest for a long time in the tubercular granulomas, the risk of developing resistance in mycobacteria is particularly high. In the case of confirmed tuberculosis or even high-grade suspicion of tuberculosis, all patients must therefore be treated with a combination therapy of several antibiotics , also known as antituberculotics, that are specifically effective against Mycobacterium tuberculosis . In addition, because of the slow division rate, the duration of the treatment must be long enough to avoid relapses.

therapy

Standard therapy

According to currently existing guidelines, the treatment of uncomplicated tuberculosis should consist of a four-fold combination of isoniazid , rifampicin or rifabutin , ethambutol and pyrazinamide and should initially be carried out for two months. Thereafter, treatment with isoniazid and rifampicin must be continued for another four months. So it takes a total of at least half a year. In children, only a triple combination (without ethambutol) is initially used. Exceptionally, this is also possible in particularly light forms in adults. Streptomycin is also available as a reserve drug for intolerance . Thiacetazone , a sixth substance, is not used in the industrialized nations due to an unfavorable side effect profile. It is not recommended for the treatment of co-infected patients with HIV. However, the majority of tuberculosis sufferers in some poor countries, where the substance is still used because of the low price, are also HIV-positive.

If resistance is found in the microbiological bacterial culture, which can only be assessed six to eight weeks after the start of therapy, a specific therapy can be used to switch to other antibiotics to which the specific bacterial strain is actually sensitive ( see also: antibiogram ).

Isoniazid, rifampicin and pyrazinamide can cause liver damage, ethambutol can damage the nerve of the eye, and streptomycin can damage the kidneys and inner ear . These organs should be monitored before and during therapy.

Since the patients often feel relatively healthy, many of them no longer take the tablets regularly after a certain time ( compare: compliance (medicine) ).

Therapy of multi-resistant tuberculosis

If there is resistance to the standard drugs, after testing all available antituberculotics, the treatment should be expanded to include at least two effective substances. Combinations of different active ingredients are used: the aminoglycosides kapreomycin and kanamycin , the fluoroquinolones ofloxacin , ciprofloxacin and levofloxacin , the thionamides ethionamide , prothionamide and the bacteriostatic substances paraaminosalicylic acid (PAS) and cycloserine .

The treatment of multi-drug resistant tuberculosis means taking several drugs at the same time for a period of at least 21 months. For the first three months, patients receive a mix of five different drugs. In principle, the chances of successful treatment for multi-drug-resistant tuberculosis are lower than with the treatment of uncomplicated tuberculosis, even if the patient is receiving effective therapy.

The use of ofloxazine and levofloxazine is hardly feasible in poorer countries due to the comparatively high product prices. Both active ingredients are patented by the manufacturer. Kapreomycin is only sold by a single manufacturer (Eli Lilly) at a price that enormously limits its use.

Since 2006, in addition to the multi-resistant mycobacteria, the World Health Organization and the American Center for Disease Control have also identified pathogen strains which, in addition to being multi-resistant to more than two of the conventional tuberculostatics, have resistance to at least three of the six reserve antibiotics. They were called extensive or extremely drug resistant tuberculosis , or XDR-TB for short . An outbreak of 53 cases of XDR tuberculosis was discovered in South Africa in the second half of 2006, of which 52 patients have already died.

The two newer nitromidazole derivatives Delamanid and Pretomanid can be used in combination with other antituberculotics for the oral treatment of multidrug- resistant tuberculosis if there are no other treatment options.

Therapy of complex tuberculosis

In the event of additional complications, such as obstruction of part of the airway through an involved lymph node, the treatment should be extended to a total of nine to twelve months. Miliary tuberculosis or tuberculous meningitis ( meningitis ) require an initial quadruple therapy, even in childhood, for more than three months and an extension of the total treatment duration to nine to twelve months. In addition, the patients should be treated for at least six weeks with prednisolone or, in the case of meningitis, with dexamethasone in descending doses.

The treatment of tuberculosis in simultaneously HIV-infected patients poses a particular therapeutic challenge. In particular, the standard drug rifampicin must not be administered at the same time as certain active ingredients that are used to treat HIV infection due to significant interactions. Therefore, appropriately experienced specialists must either switch to HIV therapy or tuberculostatic therapy.

Prevention

Since there is currently no effective vaccination against tuberculosis, the most important preventive measure is to detect infected people as early as possible and to treat them both quickly and effectively. Because of the low number of cases in Germany, serial examinations in the form of tuberculin tests or X-ray examinations make no sense. The active search for infected people in the form of a surrounding investigation of contact persons of patients with infectious tuberculosis is an indispensable prerequisite for reducing the incidence of the disease. The group of people with an increased risk of tuberculosis who should be actively searched for an infection also includes, for example, people from countries with a high tuberculosis rate, the homeless, drug addicts, prison inmates, but also HIV-positive people.

vaccination

Until 1998 there was an active protective vaccination (live vaccination) with a weakened mycobacteria vaccine strain (BCG) against tuberculosis. When the vaccine was introduced, the Lübeck vaccination accident occurred in Lübeck in 1930 . 208 children were infected with virulent tuberculosis bacteria through incorrect processing of the BCG culture obtained from Paris into a vaccine. 77 of them died. Because of this vaccination accident, we now know a lot about the course of the disease from observing these children. The introduction of vaccination in Germany was delayed until after World War II. The BCG vaccination is no longer recommended by the Standing Vaccination Commission because the limited effectiveness could not outweigh the vaccination complications. In addition, the tuberculin test in vaccinated people is occasionally slightly to moderately positive, even after decades, so that the cut-off (for example in the event of contact with a person suffering from "open" TBC) only occurs when there is a stronger reaction (generally from 15 mm ) is set. The BCG vaccination was also unable to curb the spread of tuberculosis worldwide, although it is one of the most widespread vaccinations. Only the particularly fulminant and feared courses in childhood in the form of tuberculous meningitis or miliary tuberculosis can the BCG vaccination be able to prevent relatively reliably. Various researchers are currently attempting to make genetic modifications to the BCG vaccine strain to increase its effectiveness, so that the vaccine bacteria produce additional antigens through which the immune system can react better to the real mycobacteria.

Chemoprophylaxis and chemoprevention

Since small children under the age of 5 fall ill more often and more quickly than adults after an infection (according to the literature, 20% of infected children with a minimum latency period of around 3 weeks to years or even decades) apply to them after contact with people with tuberculosis Precautionary measures. Even if the tuberculin test is negative, they should be treated prophylactically with antituberculotics (e.g. isoniazid) for two months according to the guidelines of the Swiss Lung League. If after these two months the tuberculin test is still negative, treatment can be stopped. If the tuberculin test has become positive in the meantime, however, active tuberculosis must be ruled out by an X-ray examination of the lungs. In Europe this is done through a breast photograph; In contrast, overseas as in Australia, a computed tomography of the chest organs is recommended, especially for children. Treatment with the antituberculotic drug is then continued for additional months as chemoprevention. If the pathogens at the source of infection are known to be resistant to the antituberculotic, chemoprophylaxis / chemoprevention must of course be carried out with another active ingredient, preferably rifampicin. In the case of multiple resistances, it should even be carried out with two different active substances.

history

With the discovery of the tubercle bacillus in 1882 by Robert Koch (1843–1910), the story of the discovery of effective agents against this dreaded infectious disease began. Both the tuberculin developed by Koch in 1890/91 and treatments with copper and gold preparations were unsuccessful. Robert Behnisch was then able to establish that the thiazole or thiodiazole ring is responsible for the bacteriostatic effect of the sulfothiazoles . In 1940, Bertram Moses Bernheim (1880–1958) determined that salicylic acid stimulates the respiratory tract of tubercle bacteria and thus leads to greater oxygen consumption. Based on this, the Swedish biochemist Jorgen Lehmann (born in 1898) discovered the bacteriostatic effect of p-aminosalicylic acid (PAS). Streptomycin , which was discovered in 1943 and was used to cure the first tuberculosis patient in 1947 , also proved to be another drug against tuberculosis . In 1950, Gerhard Domagk began together with Hans Albert Offe (1912–1993) and Werner Siefken (1903–1968) with the investigation of isonicotinic acid hydrazide (INH). Isonicotinic hydrazide was first used monotherapeutically, then as a two-way combination with PAS and then as a three-way combination with PAS and streptomycin. Another tuberculostatics followed was pyrazinamide , which was synthesized in 1952 by Samuel Kushner and at the same time at Merck (USA). Viomycin was isolated in 1949 and cycloserine in 1955. Rifampicin has been widely used instead of streptomycin since the 1980s . The chemists Raymond George Wilkinson (born 1922) and Robert Gordon Shepherd (born 1915) synthesized ethambutol in 1961 , from which a combination of three or four (e.g. INH, rifampicin and etahmbutol or INH, rifampicin, ethambutol and streptomycin) was possible which enables favorable chances of recovery from tuberculosis. In 1971 the antibiotic capreomycin , which can be used as an antituberculotic, was approved in the USA.

swell

  1. ↑ a b RKI Infectious Diseases A to Z Tuberculosis - Information sheet for doctors of the Robert Koch Institute
  2. ↑ WHO | Emergence of XDR-TB. Retrieved January 22, 2020 .
  3. ↑ D. Biermann: EU approval of Delamanid against multiresistant tuberculosis , Pharmazeutische Zeitung, May 14, 2014.
  4. ↑ A. Mende: US Approval for New Tuberculosis Drug , Pharmazeutische Zeitung, August 15, 2019.
  5. ↑ a b K. Magdorf among others: Tuberculosis. In: Pediatric Guidelines. Munich 2006, ISBN 3-437-22060-8 .
  6. ↑ T. Ulrichs, SHE Kaufmann: Immunology of tuberculosis: consequences for vaccine development . In: The internist. 44 (11), doi: 10.1007 / s00108-003-1057-7
  7. ^ John F. Murray, Dean E. Schraufnagel, Philip C. Hopewell: Treatment of Tuberculosis. A Historical Perspective . In: Annals of the American Thoracic Society . tape 12 , no. December 12 , 2015, ISSN  2329-6933 , p. 1749–1759 , doi : 10.1513 / AnnalsATS.201509-632PS ( atsjournals.org [accessed May 1, 2020]).
  8. ↑ Karl Wurm, AM Walter: Infectious Diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition, ibid. 1961, pp. 9–223, here: p. 55.
  9. ^ Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 223-224 .