The problem of curing patients with respiratory tuberculosis

Antituberculosis drugs are a broad group of synthetic chemotherapeutic drugs that inhibit the growth, reproduction and activity of Mycobacterium tuberculosis.

Tuberculosis is an extremely common, severe infectious disease with a chronic course.

Tuberculosis is caused by special pathogens - mycobacteria (Koch bacilli). They are resistant to most modern antibacterial drugs due to the structural features of their cell wall and metabolism.

There are respiratory tuberculosis (pulmonary tuberculosis - up to 95% of all cases of tuberculosis), as well as extrapulmonary tuberculosis (tuberculosis of the kidneys and urinary tract, abdominal organs, skin, bones, joints, brain and spinal cord, etc.).

Of particular danger is drug-resistant tuberculosis (up to 30% of all tuberculosis cases), which is very difficult to treat and often ends in death.

According to the Center for Medical Statistics of the Ministry of Health of Ukraine, the incidence of tuberculosis is 62-64 cases per 100,000 population, which indicates a fairly wide spread of tuberculosis among Ukrainians.

Treatment of tuberculosis is long and complex. For this purpose, a special group of antibacterial agents is used - anti-tuberculosis drugs.

pharmachologic effect

Anti-tuberculosis drugs have a negative effect on mycobacteria by disrupting the synthesis of the cell wall, DNA, RNA, proteins, and respiratory enzymes of the causative agent of tuberculosis.

Anti-tuberculosis drugs can have both a tuberculocidal effect (kill mycobacteria) and a tuberculostatic effect (slow down the growth and reproduction of tuberculosis pathogens).

Most anti-tuberculosis drugs (with the exception of antibiotics and fluoroquinolones) have a narrow spectrum of antibacterial action - they affect only mycobacterium tuberculosis. Some anti-tuberculosis drugs are also effective against Mycobacterium leprosy, the causative agent of leprosy.

Classification of anti-tuberculosis drugs

Anti-tuberculosis drugs are classified into:

• anti-tuberculosis antibiotics: rifampicin, rifamycin, rifabutin, cycloserine, capreomycin, streptomycin, kanamycin, amikacin, linezolid;
• isonicotinic acid hydrazides: isoniazid, ftivazide;
• thiocarbamide derivatives: prothionamide, ethionamide;
• aminosalicylic acid derivatives: sodium para-aminosalicylate;
• fluoroquinolones: lomefloxacin, ofloxacin, levofloxacin, ciprofloxacin;
• derivatives of different chemical groups: pyrazinamide, ethambutol, terizidone, bedaquiline, pretomanid, delamanid.

In addition, there are combined anti-tuberculosis drugs containing: rifampicin + isoniazid; rifampicin + pyrazinamide + isoniazid; rifampicin + pyrazinamide + ethambutol + isoniazid; rifampicin + ethambutol + isoniazid; sodium para-aminosalicylate + isoniazid; lomefloxacin + pyrazinamide + prothionamide + ethambutol.

Anti-tuberculosis drugs are also classified into:

• First line drugs - main ones: isoniazid, ftivazid, rifampicin, rifamycin, rifabutin, streptomycin, ethambutol, sodium para-aminosalicylate;
• II line drugs - reserve: cycloserine, capreomycin, kanamycin, amikacin, prothionamide, ethionamide, pyrazinamide;
• drugs for the treatment of drug-resistant tuberculosis: lomefloxacin, ofloxacin, levofloxacin, ciprofloxacin, linezolid, bedaquiline, pretomanid, delamanid.

The problem of curing patients with respiratory tuberculosis

IN

Due to the unfavorable epidemic situation regarding tuberculosis, the development and implementation of effective methods for its treatment are of paramount importance in modern phthisiology. What is important in this problem is a comprehensive (both medical and socio-economic) approach to the treatment of tuberculosis, which will significantly reduce the reservoir of tuberculosis infection.

It should be emphasized that tuberculosis is an infectious disease, and socio-economic factors contribute to its development and aggravate the course of the tuberculosis process. Therefore, from the standpoint of the infectious nature of tuberculosis, the main method of treatment is chemotherapy. The therapeutic effect is due to the direct effect of anti-tuberculosis drugs on Mycobacterium tuberculosis (MBT) and their destruction in the patient’s body. The degree of inhibitory effect of chemotherapy drugs depends primarily on the tuberculostatic activity of individual chemotherapy drugs, their dose, as well as on the combinations of anti-tuberculosis drugs used.

As A.G. pointed out. Khomenko (1996), the cure of tuberculosis patients depends on 2 interrelated factors: suppression of the multiplying mycobacterial population with the help of anti-tuberculosis chemotherapy drugs and regression of tuberculosis changes in the affected organs with the development of reparative processes.

Over the course of several decades, significant experience has been accumulated in the use of anti-tuberculosis drugs, which has made it possible to determine the basic principles of treatment of tuberculosis, however, in modern conditions there is a need to constantly improve chemotherapy regimens.
“Chemotherapy regimen” means the choice of a specific combination of chemotherapy drugs, their dosage, method of use in the form of a single daily dose or divided into 2-3 doses, route of administration (orally, intravenously, in the form of aerosols, endobronchial infusions, rectally) and the rhythm of taking chemotherapy drugs ( daily or intermittent). There are several classifications of anti-tuberculosis drugs

.
One of them includes 2 groups of chemotherapy drugs: Group 1
– the most effective anti-tuberculosis drugs (rifampicin, isoniazid);
Group 2
– drugs of average effectiveness (streptomycin, kanamycin, amikacin, florimycin, pyrazinamide, ethambutol, prothionamide, fluoroquinolone group).
According to another classification, all drugs are divided into main (1st row)
- GINK group, rifampicin, rifabutin, streptomycin, pyrazinamide, ethambutol and
reserve drugs (2nd row)
- kanamycin, amikacin, capreomycin, ethionamide, prothionamide, cycloserine, PAS, fluoroquinolone group.
Currently, a group of alternative drugs has been identified (3 series)
- clarithromycin, amoxicillin/clavulanate, clofazimine, rifampentine, thioacetazone.

What determines the effectiveness of treatment?

The clinical effectiveness of anti-tuberculosis drugs is determined by many factors, among which the main ones are: the massiveness of the mycobacterial population itself, the sensitivity or resistance of the MBT in it to the chemotherapy drugs used, the ability of individual individuals to reproduce rapidly; the created concentration of the drug in the blood and the degree of permeability into the lesions; interaction with other drugs; the ability of drugs to influence intracellularly located (non-phagocytosed) MBT; the property of chemotherapy drugs to induce drug resistance of the pathogen, as well as patient tolerance to anti-tuberculosis drugs and their combinations.

The therapeutic effect of anti-tuberculosis drugs is based on their direct bacteriostatic and bactericidal effect on the microbial cell.

It is known that chemotherapy drugs have different effects on microbial cells. Some inhibit the synthesis of bacterial cell walls by destroying peptidoglycan, the lipoprotein fraction, suppressing function and diffusion through the cytoplasmic membrane; others inhibit the synthesis of nucleic acids by disrupting the metabolism of RNA and DNA, selective action on plasmids, mitochondria, inhibition of RNA polymerase, formation of breaks in the DNA chain, inhibition of DNA replication; still others affect the functions of ribosomes, which leads to the destruction of the cytoplasm and granular apparatus.

Thus, isoniazid has a bactericidal effect, especially on young reproducing microbial cells, suppressing the synthesis of myconic acid in the bacterial wall, as well as destroying the cytoplasm and its granular substance consisting of DNA. Isoniazid is capable of destroying more than 90% of MBT after 7 days of use. Rifampicin also has a bactericidal effect by inhibiting the activity of ribosomal RNA polymerase and inhibiting DNA synthesis. Rifampicin, like isoniazid, affects not only rapidly, but also slowly multiplying and even persistent MBT. Pyrazinamide has a bactericidal effect on slowly multiplying MBT, including those located intracellularly in macrophages. The mechanism of action of pyrazinamide has not been fully studied. It has the greatest effect in an acidic environment (pH 5.5) on persistent variants. Streptomycin inhibits ribosomal proteins, suppressing their synthesis. Its effect does not appear immediately, but after several generations of microbial cells. The drug is characterized by a relatively weak bactericidal effect. Ethambutol destroys the microbial cell wall, providing a bactericidal effect only in large doses (24 mg/kg).

The most essential for effective treatment is the bactericidal effect of some anti-tuberculosis drugs, in particular isoniazid and rifampicin, which can quickly kill a large number of actively reproducing MBT.

It should also be borne in mind that chemotherapy drugs have different effects on intracellular and extracellular MBTs.

. Thus, as the process progresses, intensive multiplication of MBT occurs in the human body, their release into the tissues of the affected organs, spread by lymphobronchogenic and hematogenous routes, as a result of which new areas of inflammation appear and caseous necrosis develops. Most mycobacteria during this period are extracellular, and that part of the bacterial population that was phagocytosed by macrophages during the inflammatory reaction, due to intensive intracellular reproduction, causes the destruction of phagocytes and again appears extracellular. Thus, the intracellular localization of MBT at this stage is relatively short-lived. Almost all anti-tuberculosis drugs have a pronounced antibacterial effect on an actively reproducing bacterial population.

As the tuberculosis process subsides, the size of the bacterial population decreases due to the suppression of MBT reproduction. In the context of ongoing chemotherapy and a decrease in the bacterial population in the patient’s body, part of the MBT remains, which are in a state of persistence. Persistent mycobacteria are often detected only microscopically, since they do not grow when inoculated on nutrient media. Such mycobacteria are called “sleeping” or “dormant”, sometimes “killed”. As one of the options for the persistence of mycobacteria, their transformation into L-forms or fine-grained forms is possible. At this stage, when intensive reproduction of the bacterial population is replaced by a state of persistence of the remaining part of it, mycobacteria are located mainly intracellularly (inside phagocytes).

Just a few years ago it was believed that the effectiveness of chemotherapy largely depended on its duration. When the first anti-tuberculosis drugs appeared, the duration of treatment was relatively short (1–3 months). As new chemotherapy drugs became available, the duration of treatment
gradually increased and ranged from 12 to 18 months.

This provision has currently been revised. The method of controlled chemotherapy of shortened duration, tested in many countries, has shown its high efficiency and has made it possible to significantly reduce the duration of treatment (up to 6–9 months) through the use of rational chemotherapy regimens that contribute to the rapid suppression of the mycobacterial population and the cessation of bacterial excretion.

Phases of chemotherapy

Due to the different state of the bacterial population at different stages of the disease during chemotherapy, in recent years it has become customary to divide the entire period of treatment with chemotherapy into 2 phases (stages). It should be pointed out that this division of chemotherapy periods has been used by domestic phthisiatricians for a long time.

The first stage is characterized by intensive, intense chemotherapy; its purpose is to suppress the proliferation of the bacterial population and achieve its quantitative reduction. The second stage of less intensive chemotherapy is the follow-up phase, and its purpose is to influence the remaining bacterial population, mostly located intracellularly in the form of persistent forms of MBT. At this stage, the main task is to prevent the proliferation of remaining mycobacteria.

According to modern concepts, in the first phase of chemotherapy

When the office multiplies rapidly, newly diagnosed bacillary patients are prescribed 4 anti-tuberculosis drugs (isoniazid, rifampicin, pyrazinamide, streptomycin or ethambutol).
Such intensive chemotherapy is carried out for 2 months, and if bacterial excretion persists according to smear microscopy - for 3 months. In the second phase
of chemotherapy in newly diagnosed patients, when the bulk of the mycobacterial population has already been suppressed, 2 drugs (isoniazid and rifampicin) are used daily or every other day for 4 months. For newly diagnosed patients treated irregularly or interrupted treatment, as well as patients with relapse of tuberculosis, it is recommended in the intensive phase to prescribe 5 chemotherapy drugs (isoniazid, rifampicin, pyrazinamide, streptomycin and ethambutol) for 2 months, then 4 chemotherapy drugs are used for another month (cancelled streptomycin). The second phase of chemotherapy for this category of patients is recommended to be carried out with three drugs daily or every other day for the next 5 months.

For patients in whom MBT was not detected during the initial sputum examination, the intensive phase of chemotherapy can also be carried out with 4 drugs (isoniazid, rifampicin, pyrazinamide, ethambutol) for 2 months, after which they can switch to taking two drugs (isoniazid and rifampicin or ethambutol) in within 4 months.

Patients with chronic forms of pulmonary tuberculosis should be treated according to individual chemotherapy regimens, taking into account the resistance of mycobacteria to chemotherapy drugs and with further modification of the chemotherapy regimen in cases of detection of secondary resistance to the drugs used. Most often, such patients, as well as patients in whom MBT multidrug resistance has been identified, are treated with reserve drugs - kanamycin, amikacin, capreomycin, prothionamide (ethionamide), ethambutol, cycloserine, as well as ofloxacin, lomefloxacin, ciprofloxacin.

The effectiveness of chemotherapy is assessed according to several parameters: clinical (reduction or disappearance of symptoms of intoxication and chest complaints); microbiological (reduction of the massiveness of bacterial excretion according to its quantitative assessment); X-ray (reduction of infiltrative-inflammatory changes in the lungs and healing of cavities).

Ensuring regular intake of chemotherapy drugs
When carrying out chemotherapy, an important task is to ensure that the patient regularly takes the prescribed chemotherapy drugs throughout the entire period of treatment. Irregular use of chemotherapy drugs can lead to the development of drug resistance and progression of the process. Methods that ensure the regularity of chemotherapy are closely related to organizational forms of treatment in hospital (sanatorium) and outpatient settings.

When conducting chemotherapy, an important task is to ensure that the patient regularly takes the prescribed chemotherapy drugs throughout the entire treatment period. Irregular use of chemotherapy drugs can lead to the development of drug resistance and progression of the process. Methods that ensure the regularity of chemotherapy are closely related to organizational forms of treatment in hospital (sanatorium) and outpatient settings.

In a hospital setting

The administration of prescribed chemotherapy drugs during both phases is carried out in the presence of medical personnel with precise recording of the doses of medications taken. The dose of medication is understood as the daily dose of each chemotherapy drug included in the combination. Considering the duration of chemotherapy only by the number of calendar days of the month may give an incorrect idea of ​​the number of drugs taken. It often turns out that within 1 or 2 months the number of doses of drugs taken is significantly less than the number of days corresponding to the duration of treatment. This is due to the fact that chemotherapy drugs are often prescribed not immediately, but gradually over several days; If side effects occur, chemotherapy drugs are usually discontinued for some period of time. As a result, within a month the patient may receive not 30 doses, but significantly less. When taking chemotherapy drugs intermittently, the number of doses over the same calendar period is 2 times less than when taking them daily. Therefore, in addition to taking into account the duration of chemotherapy by day, it is necessary to take into account the number of doses of chemotherapy drugs taken by the patient, which is of certain importance when assessing the effectiveness of treatment.

Control over the intake of chemotherapy drugs is facilitated by prescribing the entire daily dose in one dose, as well as with intermittent treatment. One type of controlled chemotherapy is the use of drugs by the parenteral method.

Outpatient

There are several methods. Taking chemotherapy drugs in the presence of medical personnel, which is carried out: a) in anti-tuberculosis dispensaries, b) at the patient’s home. Monitoring the intake of chemotherapy drugs is easier when using the entire daily dose in one dose, as well as with intermittent treatment.

The patient himself takes chemotherapy drugs issued by the dispensary for a certain period, most often for 7 days, with systematic monitoring of the consumption of medications. The cost of chemotherapy must also be taken into account. Thus, if it is impossible to strictly control the intake of rifampicin at home, it is more advisable to switch to ethambutol.

Recently, combined tablet forms

, containing four, three or two of the most active anti-tuberculosis chemotherapy drugs: myrin (isoniazid, rifampicin and ethambutol); Mairin P (isoniazid, rifampicin, ethambutol and pyrazinamide); rifater, Tricox (isoniazid, rifampicin, pyrazinamidrifanag), tibinex (isoniazid and rifampicin), as well as other combination chemotherapy drugs. Their use greatly facilitates chemotherapy monitoring, especially in outpatient settings.

Changing your chemotherapy regimen

The above provisions constitute the basic scheme of programmed chemotherapy.

At the same time, as treatment progresses, some patients have to make changes to the chemotherapy program drawn up after the examination. The need to change medications is caused by a number of reasons:

• the presence of fatal adverse reactions caused by certain drugs,

• detection of primary drug resistance of Mycobacterium tuberculosis to chemotherapy, data about which the doctor usually receives 2–3 months after the start of treatment,

• lack of effect from the therapy, which is most often expressed by continued bacterial excretion and preservation of the cavity, and sometimes by slow resolution of inflammatory changes in the lungs.

There are various possibilities for changing the chemotherapy regimen: changing drugs, changing the method of their administration (intravenously, inhalation, rectally), combining different methods of drug administration, which depends on the specific reason that necessitated modification of the chemotherapy regimen.

At later stages of treatment, especially with delayed regression of the process and bacterial excretion has already stopped, but with a remaining cavity, drugs that stimulate reparative processes are prescribed. Thus, if the effect of chemotherapy is insufficient, it is necessary to choose the optimal treatment method: change the combination of chemotherapy drugs, their doses, change the route of drug administration, additionally use pathogenetic agents and physiotherapeutic methods of treatment. In these cases, it is most advisable to change the chemotherapy regimen no later than 2–3 months after the start of treatment. The later the chemotherapy regimen is changed, the longer the period of treatment with chemotherapy is. It should be taken into account that by the end of the third month there is already data reflecting: a) the results of quantitative examination of sputum by microscopy before the start of treatment and during chemotherapy; b) the results of sputum culture done before the start of treatment, with data on the sensitivity of Mycobacterium tuberculosis to chemotherapy; c) the dynamics of the x-ray picture, in particular, the degree of resorption of inflammatory changes in the lungs and changes in the size of the cavity.

Quantitative assessment of bacterial excretion

in the conditions of modern chemotherapy of pulmonary tuberculosis is one of the methods for determining the effectiveness of treatment measures. A decrease in the size of the vegetative population during chemotherapy is interpreted as a good prognostic sign; long-term stable bacterial excretion or a tendency to increase it are considered as treatment failures.

To quantify the size of the mycobacterial population, bacterioscopic and cultural research methods are used. The effectiveness of these methods is close, but not equivalent. The speed of obtaining information that the bacterioscopic method provides is its undeniable value compared to the cultural method. However, the latter more fully characterizes the microbial population not only from a quantitative, but also a qualitative point of view.

Reasons preventing treatment

Timely correction significantly increases the effectiveness of chemotherapy and promotes faster healing of destructive changes in the lungs. However, not all patients achieve positive treatment results. Therefore, increasing the effectiveness of chemotherapy remains one of the main problems of phthisiology. The literature describes many reasons that prevent the patient from being cured.

Apparently, the most important problem in chemotherapy remains drug resistance of MBT.

, since recently there has been an increase in the frequency of detection of drug-resistant MBT even in newly diagnosed, previously untreated patients with destructive pulmonary tuberculosis.

The phenomenon of drug resistance in MBT has important clinical significance. There is a close relationship between quantitative changes in the bacterial population and changes in a number of biological properties of mycobacteria, one of which is drug resistance. In a large multiplying bacterial population, there is always a small number of drug-resistant mutants, which have no practical significance, but as the bacterial population decreases, the ratio between the number of sensitive and resistant MBT changes. Under these conditions, mainly resistant MBT multiply; this part of the bacterial population increases, reaching a critical proportion, sometimes even exceeding it. Therefore, in clinical practice it is necessary to study the drug sensitivity of mycobacteria and compare the results of this study with the dynamics of the tuberculosis process.

To increase the effectiveness of treatment of patients with multidrug-resistant MTB, it is necessary: ​​firstly, chemotherapy, before receiving the results of a study of sputum or other pathological material, should begin with four or five (for relapses) anti-tuberculosis drugs, taking into account the fact that even if there are mycobacteria in the population that are resistant to 1 –2 drugs, the bacteriostatic effect will be provided by 2 or 3 chemotherapy drugs, to which sensitivity is preserved. Secondly, it is necessary to find accelerated bacteriological methods for detecting drug resistance of MBT, which will make it possible to promptly change the chemotherapy regimen, canceling drugs to which resistance has been identified, and prescribing those to which sensitivity is preserved. Thirdly, the use of reserve drugs in patients whose sputum contains drug-resistant MBT allows for a more rapid cessation of bacterial excretion. Finally, in patients with multidrug resistance, it is necessary to more widely use artificial pneumothorax and surgical treatment methods.

The second, no less significant problem of treatment is the very nature of the process in the lungs

.
We see the complexity of this problem not so much in the prevalence of specific changes in the lungs and the nature of destructive changes, but in a noticeable increase in the frequency of acutely progressive forms of tuberculosis
, of which 33.8% is caseous pneumonia, occurring against the background of severe immunodeficiency with the development of irreversible changes in the lungs.

A set of measures, including intensive chemotherapy using intrapulmonary and lymphotropic administration of chemotherapy drugs, various detoxification agents, including intravascular laser irradiation of blood, plasmapheresis, widespread use of immunostimulants and other methods, made it possible to achieve the cessation of bacterial excretion in 65.4% of patients with caseous pneumonia. However, healing of destructive changes was observed in only 7.7% of patients. Considering the irreversibility of morphological changes in the lungs, patients with caseous pneumonia are subject to surgical treatment.

Have not lost their influence on the effectiveness of chemotherapy and diseases associated with tuberculosis

– diabetes, pathology of the gastrointestinal tract, kidneys, etc. However, it must be emphasized that thanks to the use of modern medications used for these diseases, most patients can undergo full-fledged chemotherapy.

The clinical course and treatment are complicated by nonspecific microflora in the sputum
, which is often a sign of the presence of nonspecific inflammatory processes of the respiratory system. When nonspecific microflora was detected in sputum, intoxication phenomena were observed 3 times more often than in the absence of it. The use of fluoroquinolone drugs in combination with antituberculosis drugs significantly reduces the time of sputum abacillation, especially with massive bacterial excretion.

Side effects of anti-tuberculosis drugs

also limit the possibility of carrying out full-fledged chemotherapy, especially when using standard chemotherapy courses. Chemotherapy drugs, having a toxic, sensitizing effect on the patient’s body, can cause various side effects. They occur especially often in the presence of concomitant diseases of the liver, stomach, kidneys, cardiovascular system, etc. Therefore, when choosing chemotherapy drugs, if possible, you should avoid prescribing drugs that, given the existing condition of the patient’s various organs and systems, are contraindicated or may cause adverse reactions. It should be borne in mind that side effects are more likely to be detected when maximum therapeutic doses are prescribed. The simultaneous use of various pathogenetic agents can prevent or eliminate the side effects of chemotherapy drugs. They are canceled only in cases of complete intolerance or danger of causing severe manifestations of drug complications. However, we were unable to detect a significant increase in the frequency of adverse reactions depending on the increase in the number of chemotherapy drugs. Thus, when using 3 anti-tuberculosis drugs, adverse reactions were observed in 17.5% of patients, 4 drugs – in 18.2%, 5 – in 22.7% of patients. However, the side effects of chemotherapy were 2–3 times more likely to occur in patients with concomitant diseases. For early recognition of adverse reactions, immunological tests with chemotherapy are used. Desensitizing agents, corticosteroid drugs, and extracorporeal treatment methods can eliminate the side effects of chemotherapy drugs in 64% of patients without discontinuing them, and only 36% of patients had to replace the drug that caused the side effect.

Reparative processes and their acceleration

Suppression of the mycobacterial population creates the prerequisites for the development of reparative processes in organs affected by tuberculosis. As a result of the treatment, a different course of the tuberculosis process is noted: regression followed by healing; stabilization of the tuberculosis process without clinical cure with preservation of the cavity, tuberculoma or other changes; temporary subsidence of the inflammatory process followed by exacerbation. If treatment is ineffective, the process can become chronic or lead to progression of the disease, even fatal. Fatal outcomes from tuberculosis are currently most often caused by the development of initially acutely progressive forms of tuberculosis (caseous pneumonia, generalized tuberculosis).

To speed up the healing process, a large arsenal of pathogenetic agents and methods is currently used. Among the most widely used means of pathogenetic therapy

It should be noted the use of corticosteroid drugs, non-hormonal anti-inflammatory drugs, which can be added to chemotherapy during the first phase of treatment, including in its early stages. In recent years, corticosteroids have been combined with immunomodulatory drugs (tactivin, thymalin, levamisole, leukinferon, etc.). The latter can be used independently (in addition to chemotherapy) in the presence of changes in T lymphocytes and a decrease in their function. To stimulate reparative processes during delayed regression of tuberculous changes, tuberculin, BCG vaccine, as well as nonspecific biological agents (pyrogenal, prodigiosan, various tissue preparations) are used. In recent years, physiotherapeutic methods have been widely used: ultrasound, inductothermy, decimeter waves, EHF and various types of laser studies. In acutely progressive forms of tuberculosis, to reduce intoxication, intravenous laser irradiation of blood, plasmapheresis and hemosorption, ozonation, as well as treatment with various antioxidant agents and antikinin drugs are performed. Thus, the pathogenetic agents used for tuberculosis are very numerous, so the doctor is faced with the task of choosing the most reasonable method of treatment.

The problem of treatment is not limited to the above factors. Other factors that reduce the effectiveness of chemotherapy, in particular of an organizational nature, are also significant: the lack of an optimal set of chemotherapy drugs for the entire course of treatment, improper storage conditions, unreasonable breaks in treatment and irregularity in taking chemotherapy drugs, non-compliance with the dosage (per kg of weight), lack of control over taking medications (in hospital, outpatient), lack of doctor-patient cooperation, intervention of healer “medicine”.

Combined drugs -

Mairin (trade name)

Mairin-P (trade name)

(Wyeth-Lederle)

Basics of Tuberculosis Treatment

Treatment of tuberculosis is carried out in special closed or semi-closed medical institutions - tuberculosis dispensaries.

All anti-tuberculosis drugs are prescribed exclusively by a highly specialized doctor - a phthisiatrician.

Treatment of tuberculosis is always complex - it involves taking 3-4 anti-tuberculosis drugs for a fairly long time (according to individual regimens).

The course of treatment for tuberculosis ranges from 6 to 12 months; drug-resistant tuberculosis – up to 18 months.

It is extremely necessary in the treatment of tuberculosis to provide adequate nutrition to the patient - consumption of meat, dairy products, vegetables and fruits, as well as sanatorium-resort treatment in places with a warm maritime climate.

Tuberculosis: first-line therapy and drug resistance

The incidence of tuberculosis in prisons is higher than in the general population, which is associated with overcrowding, inadequate ventilation, poor hygienic conditions, low socio-economic level, poor nutrition and the general health of prisoners [1, 2]. The problem is complicated by late diagnosis and inappropriate treatment [3]. Since 1991, there have been reports of an increase in the incidence of tuberculosis and mortality from this pathology in the republics of the former Soviet Union [4]. In Azerbaijan, data from prisons is not included in the statistics of the Ministry of Health: in 1995, the WHO report registered 1429 cases of tuberculosis (18.8 per 100,000 population) [5], while according to experts, about 700 more patients were among prisoners in Azerbaijani prisons [6].

According to the International Committee of the Red Cross (ICRC), in Azerbaijan, tuberculosis is the most common cause of death among this category of people [6]. In June 1995, in cooperation with the administration of correctional institutions and the Ministry of Justice of Azerbaijan, a program for the treatment of tuberculosis was launched. The program used first-line direct observation therapy short-course strategy (DOTS) [7, 8] in a population of patients with a high prevalence of antibiotic resistance in M. tuberculosis.

Patients and methods

• Patients

The program was conducted at the Central Prison Hospital in Baku, to which patients from correctional institutions in Azerbaijan are sent. The hospital has 450 beds for tuberculosis patients. The ICRC program covered two departments with 160 beds. If a prisoner with suspected tuberculosis was admitted to one of these departments, he was included in the study. The criteria for inclusion of a patient in the program were confirmation of the diagnosis by examining two or three consecutive sputum smears, written consent, and a period of imprisonment exceeding the expected duration of treatment. Patients were included in the study from June 8, 1995 to October 10, 1997. The study of long-term results continued until July 9, 1998.

• Treatment regimens

The treatment regimens were consistent with WHO recommendations for DOTS programs and at the same time depended on previous tuberculosis treatment in each case [8, 9]. According to the WHO classification, cases of the disease were considered primary when the patient had not previously received treatment or the duration of therapy was less than 1 month. These patients were required to undergo an initial phase of treatment consisting of 4 drugs (rifampicin, isoniazid, pyrazinamide and streptomycin) once daily for 2 months, followed by an additional phase of therapy with two drugs (rifampicin and isoniazid) for 4 months. If a high degree of drug resistance was detected, streptomycin was replaced with ethambutol.

If treatment was interrupted no earlier than 1 month and the secretion of mycobacteria in sputum continued, the patient was considered not to respond to therapy. A relapse of the disease is said if the patient, after a complete and effective course of treatment, again begins to detect the pathogen in sputum smears. Those who did not respond to therapy and who developed relapses at the initial stage of therapy were prescribed five drugs for 3 months (rifampicin, isoniazid, pyrazinamide, streptomycin and ethambutol, with streptomycin for 2 months), and then three drugs (rifampicin, isoniazid and ethambutol ) over the next 5 months.

In accordance with WHO recommendations [10], in this study, primary patients whose sputum smears remained positive at the end of the initial phase of therapy were classified as non-responders. In the absence of a response to therapy or the development of a relapse, the duration of the initial stage of therapy was increased by another 1 month. The long-term results of treatment of these patients were assessed separately from those patients who had not previously received anti-tuberculosis therapy (“true primary” cases of the disease) and who were treated for less than 1 month (“pseudo-primary” cases of the disease). Information about previous tuberculosis treatment was confirmed by records in prison registers. Data on treatment outside the correctional facility were not available. Cure was indicated by three consecutive negative sputum smears at the end of treatment.

• Methods

Clinical examinations were performed upon admission to hospital, every 2 weeks during the initial phase of treatment, and once a month during the additional phase of therapy. In addition, the patients received treatment for scabies; The daily diet included a high-calorie milk drink, 150 g of lentils and two eggs. Patients with low body mass index received additional high-calorie cookies.

Sputum samples were collected in the morning for 3 consecutive days before enrollment, at the end of the first stage of therapy, in the middle of the additional stage and at the end of treatment. Smears were stained using the Ziehl-Neelsen method and examined in 300 fields under 1000x magnification. Routine sputum surveillance tests were carried out in laboratories in Antwerp (Belgium).

Until antibiotic susceptibility testing equipment became available in Baku (Azerbaijan), sputum samples were tested in Antwerp (Belgium) and Zurich (Switzerland) [8]. Beginning in October 1996, these studies were carried out in Baku, and control samples were sent to Antwerp and Zurich. In the laboratories of Baku and Antwerp, the proportion method was used to determine sensitivity to antibiotics [11], and in Zurich, a method using the Bactec 460 automatic analyzer was used [12].

Susceptibility to pyrazinamide was determined in only one laboratory, so this study provides data on resistance to isoniazid, rifampicin, streptomycin and ethambutol. Antibiotic resistance data were used only when tests showed that a particular strain was susceptible or resistant to all four drugs. If culture resistance was detected in one laboratory, but not in another, then the culture under study was considered resistant to this antibiotic.

Statistical analysis

Logistic regression was used to create a model of variables predictive of treatment outcome among patients who did not die during the first 2 weeks of treatment and who did not drop out of the study as a result of transfer, release, or retrial. The full model included all indicators that were predictive of treatment failure in univariate analysis. Options (variables) that did not reach a value of 0.2 according to the Wald test were sequentially discarded.

After incorporating data on antibiotic resistance profiles into this model, the number of samples analyzed was reduced from 365 to 104. The paper presents two models—one that included resistance profile data as potential variables, and one that did not. The accuracy of the model was determined using the c2 test. K-statistics were used to compare the results of sputum culture and determination of antibiotic sensitivity obtained in the Baku laboratories and control laboratories. Full statistical analyzes were performed using the STATA software package (StataCorp, College Station, TX, USA, version 5.0).

results

467 men (mean age 29.7 years) had poor nutrition and advanced lung disease. The average body mass index was 18.0±2.2; 38% of patients had cavities in the lungs. In accordance with the WHO classification [9], 235 (50.3%) patients were classified as primary cases, 30 (6.4%) as relapses, and 202 (43.3%) as non-responders. Among the newly diagnosed patients, 64 people had not received any treatment for tuberculosis in the past. These 64 true primary cases were analyzed separately from the 171 pseudoprimary cases.

Data on antibiotic resistance (a full set of tests were performed in 131 patients) indicate that the proportion of patients who relapsed and did not respond to treatment was higher among patients with resistant strains than in the study population as a whole (Table 1). Of the 131 results, 36 came from laboratories in Antwerp or Zurich and 95 results from Baku. In 58 of these 95 cases, a parallel study was also carried out in laboratories in Zurich or Antwerp. Discrepancies between the results obtained in Baku and at least one of the other laboratories were noted in 27 cases out of 224. Data from the laboratory in Baku and control laboratories were in good agreement with each other (k = 0.77). In 21% of patients, M. tuberculosis strains were sensitive to all antibiotics; 23% of patients were infected with multidrug-resistant strains (resistant to both rifampicin and isoniazid). Overall, resistance to various antibiotics was very common (75% of strains were resistant to streptomycin, 55% to isoniazid, 26% to ethambutol, 25% to rifampicin). Monoresistance to ethambutol was not observed. The resistance profile of pseudoprimary cases was much closer to that of patients who relapsed or failed to respond to treatment than to that of true primary cases.

76% of patients completed treatment, 11% died, and 13% did not complete treatment (Table 2). Almost half of all deaths occurred during the first two weeks, and more than 80% of deaths occurred during the initial stage of treatment. In 83% of cases, the inability to complete treatment was due to the transfer of prisoners from prison.

Cure was achieved in 54% of those examined (Table 3), that is, in 71% of those who completed therapy. Cure rates ranged from 26% in patients infected with strains resistant to all 4 antibiotics (including cases of incomplete treatment) to 91% in truly primary patients who completed treatment. In general, cessation of the secretion of mycobacteria in sputum was observed in 42% of patients; this rate differed by approximately threefold between patients infected with non-resistant strains of M. tuberculosis and those infected with strains resistant to three or four antibiotics. The results of sputum testing from the Baku laboratory were in good agreement with the results obtained from the control laboratory in Antwerp (k=0.79).

The first logistic regression model (Table 4), which did not account for resistance as a potential risk factor, showed that bacterial shedding at the end of initial treatment, lung cavities on admission, and treatment compliance less than 98.8% were independently associated with poor therapeutic outcome. effect. An adherence rate of 98.8% was obtained from this distribution: 75% of patients in the study population had an adherence rate greater than 98.8%. Nonresponders, relapsed patients, and pseudoprimary patients were also independently associated with poor treatment response.

The second logistic regression model, which included resistance profile data, found a strong association between infection with a strain of M. tuberculosis that is either multidrug-resistant or resistant to two or three antibiotics and treatment failure. Other factors independently associated with poor response to therapy included pulmonary cavities on admission, edema, body mass index less than 16, bacterial excretion at the end of the initial phase, and non-compliance with treatment.

First-line interactions between lung cavities, patient groups, and resistance profile were analyzed. The interaction between the presence of lung cavities and infection with multidrug-resistant strains was significant (p=0.01).

Discussion

In a population with a high prevalence of antibiotic resistance, first-line therapy resulted in cure in only 54% of patients, despite strict adherence to treatment. This result is inferior to the 85% effectiveness rate recommended by WHO for national tuberculosis treatment programs [9]. The data obtained should serve as a basis for the development of adequate measures due to the limited effectiveness of first-line therapy.

This study had several limitations. The program involved patients of a specific population and some factors in the selection of patients for the study were beyond our control. This could lead to a higher proportion of patients with highly resistant M. tuberculosis strains and treatment failure. However, treatment efficacy in our study was generally low, and the high prevalence of antibiotic resistance that we observed is also found in other studies. In 22 of 73 patients who did not respond to treatment or developed a relapse, multidrug-resistant strains of M. tuberculosis were isolated (in our work, the prevalence of such strains was 30%). Large studies have shown the prevalence of acquired multidrug resistance in patients participating in tuberculosis control programs to be 22.2% in Argentina, 27.3% in Russia, 27.5% in the Republic of Korea and 54.4% in Latvia [ 13].

Although the prevalence of HIV-1 in Azerbaijan is low [14], we cannot assess the possible influence of HIV infection on our results, since appropriate testing was not carried out. The low effectiveness of treatment could be due to inadequate quality of drugs, but the drugs used in the program were obtained from a source in Amsterdam, mentioned by WHO [15] and we have no reason to assume that the quality of the drugs could be reduced.

Implementing a tuberculosis treatment program in a prison setting has its own challenges. Great effort was required to convince staff of the importance of monitoring patients' swallowing of medications. Despite the agreement with the administration, 44 patients who met the inclusion criteria were released early or transferred from prison. Although these patients were provided with information about the importance of pursuing a full course of treatment, the lack of good therapeutic programs in Azerbaijan makes adequate therapy impossible after release. Late detection of TB cases means that a relatively large number of patients had advanced TB at the start of the study and died within the first 2 weeks of treatment. Late detection contributes to tuberculosis infection in prisons.

Detection of the pathogen in sputum at the end of the first phase of treatment was clearly associated with treatment failure in both multivariate models. This interim treatment outcome suggests that more comprehensive recommendations are needed than those currently proposed by WHO [10] - re-registration of these patients as non-responders (if new cases), or extension of the initial stage treatment for another month.

Our data show that the WHO classification has certain limitations. We paid great attention to identifying prior treatment for tuberculosis, but treatment outcomes in pseudoprimary patients were significantly more similar to those of nonresponders than to results in true primary patients. It is unlikely that resistance could arise within one month of treatment; rather, these patients had prior treatment lasting more than 1 month. If our results are confirmed in other studies, especially in patients with a high prevalence of antibiotic resistance, the WHO classification of primary cases will need to be revised to include only those patients who have never previously received any therapy for tuberculosis.

The main question that arises from these data is whether the use of DOTS as first-line therapy is sufficient in this setting. 104 patients completed the full course of treatment under daily observation and nevertheless the pathogen continued to be detected in their sputum (Table 3). The average adherence rate for these patients was 99.2%. Isolation of these patients according to WHO recommendations [16] poses great challenges. Complete resistance data were obtained in 37 of 104 patients. In 27 of them, strains of M. tuberculosis were isolated that were resistant to at least two antibiotics at the time of inclusion in the study. Three patients at enrollment were infected with strains sensitive to all drugs: the fact that these patients did not respond to treatment may be explained by the acquisition of resistant strains of M. tuberculosis during treatment [17]. Data on antibiotic resistance at the end of treatment in those patients who continued to shed bacteria are very limited. Nine of 13 patients who were initially free of resistance to all four antibiotics subsequently developed antibiotic resistance, despite almost perfect adherence to treatment. Some of them developed resistance to three drugs, which suggests exogenous reinfection.

Implementing tuberculosis control programs in prison settings is possible, but is associated with serious organizational, material and medical difficulties. In addition, strict adherence to WHO recommendations may result in relatively low treatment effectiveness if the prevalence of antibiotic resistance is high. There is a risk of transmission from prisoners to the public as they come into contact with families, other prisoners and prison staff. 7% of the patients participating in the study were released from prison during treatment and an additional 3% were transferred to other correctional facilities. Implementers of TB control programs in prisons must take these challenges into account.

DOTS programs contain two main elements: direct observation of drug administration and selection of drugs intended for use. The simplistic interpretation of the lack of effectiveness of DOTS is increasingly untenable as the importance of DOTS increases with second- or third-line therapeutic regimens. Existing recommendations need to be modified to take into account antibiotic resistance. The effect of DOTS as a first-line therapy in settings like ours may simply be to eradicate susceptible strains of M. tuberculosis and persistence of resistant strains. Thus, the short-term success of treatment may be offset by a sharp decrease in the effectiveness of therapy in the long term.

Literature

1. Braun MM, Truman BI, Maguire B. et al. Increasing incidence of tuberculosis in a prison inmate population. JAMA 1989; 261: 393-7. 2. Snider DEJr., Hutton MD Tuberculosis in correctional institutions. JAMA 1989; 261:436-7. 3. Drobniewski F. Tuberculosis in prisons - forgotten plague. Lancet 1995; 345:948-9. 4. WHO. Tuberculosis trends in Central and Eastern Europe and countries of the former USSR. Weekly Epidemiol Rec 1995; 4:21-4. 5. WHO. Global tuberculosis control. Geneva: WHO, 1997: 66. 6. Coninx R, Eshaya-Chauvin B, Reyes H. Tuberculosis in prisons. Lancet 1995; 346:1238-9. 7. WHO. WHO reports on the tuberculosis epidemic, 1995: stop TB at the source. Geneva: WHO, 1995. 8. Coninx R, Pfyffer GE, Mathieu C, et al. Drug resistant tuberculosis in prisons in Azerbaijan: case study. BMJ 1998; 316:1423-5. 9. WHO. Treatment of tuberculosis: guidelines for national programs. Geneva: WHO, 1997. 10. WHO. Managing tuberculosis at district level: a training course. Geneva: WHO, 1994. 11. Canetti G, Fox W, Khomenko A, et al. Advances in techniques of testing mycobacterial drug sensitivity, and the use of sensitivity tests in tuberculosis control programs. Bull WHO 1969; 41: 21-43. 12. Siddiqi SH. Bactec TB system: product and procedure manual. Maryland: Becton Dickinson, 1989. 13. Pablos-Mendez A, Raviglione MC, Laszlo A, et al. Global surveillance for antituberculosis-drug resistance. N Engl J Med 1998; 338:1641-9. 14. European Center for Epidemiological Monitoring of AIDS. HIV/AIDS surveillance in Europe: quarterly report no 52. Saint Maurice, France: ECEMAIDS, 1996: 11. 15. WHO. Tuberculosis control in refugee situations: an inter-agency field manual. Geneva: WHO, 1997. 16. WHO/IUATLD global project on antituberculosis-drug resistance surveillance. Geneva: WHO, 1997: 117. 17. Small PM, Schafer RW, Hopewell PC et al. Exogenous reinfection with multidrug-resistant mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 1993; 328: 1137-44.

Coninx R. Introduction

Features of tuberculosis treatment

In the complex treatment of tuberculosis, it is necessary to combine first and second line anti-tuberculosis drugs. First-line drugs are more active against tuberculosis pathogens, but mycobacteria quickly develop resistance to them. Second-line drugs are less active, but affect bacteria resistant to first-line drugs.

All anti-tuberculosis drugs are quite toxic and cause a large number of side effects.

To prevent or reduce severe side effects of isoniazid (drug-induced hepatitis, seizures, memory impairment, psychosis), it is advisable to use vitamin B6 preparations - pyridoxine.

Rifampicin, rifamycin, rifabutin color all biological fluids of the body (urine, saliva, tears, semen, vaginal secretions) red-orange, but this should not be alarmed, since such an effect does not pose a danger to the life and health of the patient.

How should you be treated for tuberculosis?

How should you be treated for tuberculosis?

You begin treatment for tuberculosis. Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, or Koch's bacillus, named after the scientist who first discovered it. Tuberculosis most often affects the lungs, but can develop in other organs. A patient with tuberculosis can shed Mycobacterium tuberculosis and be infectious to others. This is determined by examining sputum in the laboratory.

Modern medicine has effective treatments for tuberculosis and can cure most patients. To recover from tuberculosis you must:

- undergo a complete course of treatment under the supervision of a TB doctor; treatment of tuberculosis is always long-term – lasts 6 or more months; take all anti-TB drugs prescribed by your doctor and do not take breaks in treatment;

- carry out all examinations prescribed by the doctor - their results allow you to monitor the effectiveness of treatment.

Most anti-TB drugs come in tablet form and are taken orally.

YOU SHOULD ONLY TAKE ANTI-TUBERCULOSIS DRUGS UNDER THE DIRECT SUPERVISION OF A HEALTHCARE PROFESSIONAL

Treatment of tuberculosis consists of two phases:

1. The intensive phase of treatment is carried out, as a rule, in an inpatient tuberculosis dispensary. Depending on the form of the disease, at the beginning of treatment, 5 anti-tuberculosis drugs are prescribed, which must be taken in doses indicated by the doctor and according to the prescribed schedule. The intensive phase of treatment lasts from 2 to 4 months, and its duration depends on the results achieved.

2. The maintenance phase of treatment lasts 4-5 months and is usually carried out on an outpatient basis.

At the same time, you will be under the supervision of a TB doctor who will resolve all issues regarding your treatment and examination.

During the maintenance phase of treatment, it is enough to take 2-3 anti-TB drugs, unless your TB doctor recommends otherwise.

You will be prescribed a specific treatment regimen. The regimen varies according to the regimen and duration of taking anti-tuberculosis drugs. For proper treatment, you need to submit sputum for examination within a strictly prescribed time frame.

Typically these deadlines are as follows:

- provision of three sputum samples before the start of treatment;

- submission of two sputum samples after 2-3 months of treatment;

- provision of two sputum samples after 5 months of treatment;

- giving two sputum samples at the end of treatment - after 6-8 months.

When taking anti-tuberculosis drugs, side effects of the drugs sometimes develop. Some of them are not dangerous and do not require changes in treatment (for example, urine, saliva and tears, in which case contact lenses can be damaged) may turn orange - this is not dangerous and does not require stopping treatment. Others require more active action and changes in treatment. Only your doctor can make a decision in each specific case.

If any adverse reactions occur or your condition worsens during treatment, you should immediately report them to the healthcare professional supervising your treatment.

Deputy Chief Physician for Clinical Expert Work

Sokolova Elena Petrovna

The main misconceptions of tuberculosis patients

1. After starting treatment, the patient’s well-being quickly improves and he believes that he is already healthy and there is no need to continue taking anti-tuberculosis drugs.

Remember! Unauthorized premature cessation or interruption of treatment leads to the development of drug resistance of the tuberculosis pathogen. If treatment is interrupted or treated incorrectly, the disease will return again in an even more severe form, and it will be very difficult, and sometimes impossible, to cure it.

2. You can go to another city to a large hospital or institute, where you will be cured in 1-2 months.

Remember! All over the world, treatment is carried out with the same anti-tuberculosis drugs, and the duration of treatment for a patient with tuberculosis does not depend on the capabilities of the medical institution.

3. Tuberculosis can be cured with folk remedies.

Remember! Not a single folk remedy kills tuberculosis pathogens.

Treatment of tuberculosis is treatment with anti-tuberculosis drugs; there are no other effective drugs.

4. Now there is no time for long-term treatment, and I don’t want anyone to know about the disease. You can buy pills and treat yourself, and then go to a hospital in another city and get cured.

Remember! Without proper and timely treatment under the supervision of a TB doctor, the disease continues to develop. The later proper treatment is started, the less chance of recovery.

Deputy Chief Physician for Clinical Expert Work

Sokolova Elena Petrovna

A patient with open form of tuberculosis in the family

If you isolate Mycobacterium tuberculosis, as your doctor will inform you about, you must remember that you can infect people around you (including your children, relatives, and friends) with tuberculosis.

To avoid this, follow a few simple rules.

1. It is very important that a patient with tuberculosis be provided with a separate room; if this is not possible, then family members should be distributed so that only adults live in the room with the patient.

2. A patient with tuberculosis must have separate bedding, linen, towels, personal hygiene products, and utensils for eating and drinking.

3. It is recommended to pre-soak underwear heavily soiled with phlegm in a 5% chloramine solution or boil for 30 minutes and only then put it in the general wash.

4. To protect others from infection, a patient with tuberculosis should use a special spittoon when collecting sputum. Spitting sputum on the ground, in a handkerchief, sink, etc. is not allowed.

5. Disinfection of the spittoon with sputum:

A) boiling in a 2% soda solution for 15 minutes. from the moment of boiling;

B) complete immersion in a vessel with a lid containing a 5% chloramine solution for 12 hours

6. For children living in such a family, you should buy toys that can be washed daily in a hot 2% soda solution and disinfected in a 5% chloramine solution for 4 hours.

7. The patient’s personal dishes also need to be boiled in a 2% soda solution for 15 minutes or immersed in a 5% chloramine solution for 4 hours.

You will receive more detailed information about the methods, means and modes of disinfection of individual objects in tuberculosis foci from the TB nurse.

Remember! Everyone who is in contact with the patient should be examined by a TB doctor twice a year.

Deputy Chief Physician for Clinical Expert Work

Sokolova Elena Petrovna