Treatment of tuberculosis

The treatment of tuberculosis sets itself certain goals - the elimination of clinical signs of tuberculosis and the persistent healing of tuberculosis changes with the restoration of work capacity and the social status of patients.

Criteria for the effectiveness of treatment of patients with tuberculosis:

• disappearance of clinical and laboratory signs of tuberculous inflammation:
• persistent cessation of bacterial excretion, confirmed by microscopic and bacteriological studies;
• regression of X-ray manifestations of tuberculosis (focal, infiltrative, destructive);
• restoration of functionality and ability to work.

Recently, the notion of "quality of life", which is quite common and has shown practical value in various diseases, is being used to evaluate the effectiveness of tuberculosis treatment.

Treatment of tuberculosis should be carried out in a comprehensive manner against the background of the hygiene regime. The main components of treatment for tuberculosis patients are chemotherapy, surgical treatment, pathogenetic treatment and collapse therapy.

Chemotherapy (etiotropic anti-tuberculosis treatment of tuberculosis) is the main component of tuberculosis treatment. Anti-tuberculosis therapy must necessarily be combined ("polychemotherapy"), i.e. At the same time, several antituberculosis drugs are used for a fairly long time.

Surgical treatment of respiratory tuberculosis is carried out according to indications both in the newly diagnosed and in the chronic forms of tuberculosis patients. These indications are determined depending on the development of complications of tuberculosis, the presence of drug-resistant mycobacteria, intolerance to anti-tuberculosis drugs. Surgical treatment of tuberculosis is an important component of the treatment of chronic forms of tuberculosis that can not be cured by conventional therapeutic treatment.

Pathogenetic treatment of tuberculosis has an anti-inflammatory and antihypoxic effect, prevents the development of toxic-allergic effects of antituberculosis drugs, stimulates reparative processes. The use of pathogenetic agents should correspond to the stages of the course of the tuberculosis process and the phases of etiotropic antituberculous therapy.

The content of treatment is based on standards, which are schemes for the treatment of certain groups of patients, taking into account the form and phase of the tuberculosis process. Within the limits of the standards individualization of medical tactics taking into account the features of the disease dynamics, the drug sensitivity of the pathogen, the pharmacokinetics of the drugs used and their interaction, the tolerability of the drugs and the presence of background and associated diseases are carried out. This principle allows you to combine the standard of treatment of the disease and the individual tactics of treatment of the patient.

Treatment of tuberculosis is carried out under the supervision of a phthisiatrician, who is responsible for the correctness and effectiveness of treatment.

The entire course of treatment of patients with tuberculosis or its individual stages can be performed in a hospital with a 24-hour or only day stay, in a sanatorium, in an outpatient setting. The organizational form of treatment is determined taking into account the severity of the course of the disease, the epidemic danger of the patient, the material and living conditions of his life, the psychological characteristics of the patient, the degree of social adaptation and local conditions.

Regardless of the organizational form, the requirements for the standard of treatment and control of its conduct should be met, as well as continuity between the medical institutions when the organizational form of treatment is changed to another.

The result of treatment is assessed using all the effectiveness criteria and formalized the relevant documentation. Control of the effectiveness of treatment of tuberculosis is exercised by a superior anti-tuberculosis institution.

To assess the effectiveness of each course of chemotherapy requires a quarterly cohort analysis using standard definitions of its results.

For the selection of individual complex chemotherapy, it is necessary to take into account not only the clinical form, the prevalence of tuberculosis, the drug sensitivity of mycobacteria tuberculosis, concomitant diseases, but also the interaction of antituberculous drugs at the microbiological and pharmacokinetic levels.

Anti-TB drugs

Anti-TB drugs are divided into two main groups. The first group includes isoniazid, rifampicin, Etambutol, pyrazinamide, streptomycin. They are called basic, or first-line drugs. These drugs are used mainly for the treatment of patients in whom tuberculosis was detected for the first time, and the pathogen is sensitive to these drugs. The second-line drugs include protionamide, ethionamide, rifabutin, aminosalicylic acid, cycloserine, fluoroquinolones: ofloxacin, lomefloxacin, levofloxacin, kanamycin, capreomycin. Second-line drugs are called reserve drugs. They are used to treat patients with tuberculosis in cases where the causative agent is resistant to first-line drugs or when intolerant of these drugs. Currently, due to weighted tuberculosis. Growth of drug resistance of mycobacterium tuberculosis, both groups of antituberculous drugs should be considered as basic and necessary.

Preparations of the 1 st series

• Isoniazid
• Rifampicin
• Pyrazinamide
• Ethambutol
• Streptomycin

Preparations of the 2 nd series

• Kanamycin (amikacin)
• Ethionamide (protionamide)
• Cycloserine
• Capreomycin
• Aminosalicylic acid
• Fluoroquinolones

Preparations of the 3rd Rada *

• Clarithromycin
• Amoxicillin + clavulanic acid
• Clofazimine
• Linezolid

* Evidence base for use is not available.

[1], [2], [3],

Combined antituberculosis drugs

Combined antituberculous preparations - two-, three-, four- and five-component dosage forms with fixed doses of individual substances. Combined drugs are not inferior in their activity to the constituent components in their separate application. Combined drugs provide more reliable control over the intake of medications, reduce the risk of overdose of individual anti-tuberculosis drugs, are convenient for use in the hospital and, especially, in outpatient settings, as well as for the chemoprophylaxis of tuberculosis. On the other hand, they can limit the selection of individual therapy in connection with intolerance of certain anti-tuberculosis drugs and with the drug resistance of mycobacteria tuberculosis.

Comparability of pharmacokinetic parameters and compliance of doses of combined drugs with anti-tuberculosis, assigned separately. The drugs are used in both acute and in the healing phase. Combined anti-tuberculosis drugs are used mainly in the treatment of newly diagnosed drug-sensitive tuberculosis. Exceptions include lomecomb and prothiocomb, the use of which is possible with a moderate resistance to isoniazid and rifampicin. The presence of Lomefloxacin makes it possible to increase the effectiveness of treatment in the course of progressing tuberculosis, with the addition of non-specific flora. The nature of undesirable phenomena of combined agents is identical to the side effects of individual anti-tuberculosis drugs.

[4], [5], [6],

Chemotherapy for tuberculosis

Chemotherapy for tuberculosis is etiotropic (specific) treatment of tuberculosis, aimed at destroying the mycobacterial population (bactericidal effect) or suppressing its reproduction (bacteriostatic effect). Chemotherapy takes the main place in the treatment of tuberculosis patients.

The main principles of chemotherapy for tuberculosis: the use of scientifically based and authorized in Russia antituberculous drugs, complexity, continuity, adequate duration of therapy and its control. In Russia and abroad, extensive experience in the use of anti-TB drugs has been accumulated, which allowed the development of basic principles of chemotherapy in patients with tuberculosis. Domestic phthisiatricians always used chemotherapy in combination with other methods of treatment.

The evaluation of the effectiveness of chemotherapy has always been carried out from a clinical point of view. The main task was not only a persistent cessation of bacterial excretion, but also the complete elimination of clinical manifestations of the disease and the healing of tuberculosis foci in the affected organ, as well as the maximum restoration of impaired body functions and ability to work. The clinical effectiveness of antituberculosis drugs is influenced by various factors, such as: the number of mycobacterial population, its sensitivity to the drugs used, the concentration of the drug, the degree of penetration of the drug in the lesion and the activity in them, the ability of the drugs to act on extra- and intracellular (phagocytized) mycobacterium tuberculosis . When assessing the effectiveness of chemotherapy, it is necessary to imagine that in the focus of active specific inflammation there are 4 populations of mycobacterium tuberculosis, which differ in localization (extra- or intracellularly located), drug resistance and metabolic activity. Metabolic activity is higher in extracellularly located mycobacterium tuberculosis, lower in intracellular and minimal in persistent forms.

When carrying out chemotherapy, the drug resistance of mycobacteria of tuberculosis is of great importance. In a large and actively multiplying mycobacterial population, there is always a small amount of "wild" mutants resistant to anti-tuberculosis drugs. Mutant bacteria resistant to isoniazid or streptomycin occur at a frequency of 1: 1,000,000, resistant to rifampicin - 1: 100,000,000, resistant to ethambutol - 1: 100,000. Since there are about 100 million Mycobacterium tuberculosis in a cavern with a diameter of 2 cm, there are certainly mutants resistant to anti-TB drugs. With proper chemotherapy, the presence of these mutants does not matter. However, with inadequate regimens of chemotherapy, the use of irrational combinations of anti-TB drugs, and the use of incorrectly calculated doses, favorable conditions for the reproduction of drug-resistant mycobacteria of tuberculosis appear. The main risk factor for the development of drug resistance of mycobacterium tuberculosis is ineffective treatment, especially interrupted and incomplete.

As the tuberculosis inflammation subsides during chemotherapy, the number of mycobacterial populations decreases as a result of the destruction of mycobacterium tuberculosis. Clinically, this is manifested by a decrease in the number of bacteria in the sputum.

With chemotherapy in the patient's body, a portion of the mycobacterium tuberculosis remains. Which are in a state of persistence. Persistent mycobacterium tuberculosis is often detected only when microscopic examination, as when sowing on nutrient media they do not give rise. As one of the variants of the persistence of mycobacterium tuberculosis, their transformation into L-forms, ultrafine and filtering forms is possible. At this stage, when the intensive multiplication of the mycobacterial population is replaced by a state of persistence, the causative agent is often mainly intracellular (inside the phagocytes). Isoniazid, rifampicin, protionamide. Etambutol, cycloserine and fluoroquinolones have approximately the same activity with respect to intra- and extracellularly located mycobacterium tuberculosis. Aminoglycosides and capreomycin have significantly less bacteriostatic activity with respect to intracellular forms. Pyrazinamide with a relatively small bacteriostatic activity enhances the action of isoniazid, rifampicin, ethambutol and other drugs, very well penetrates into cells and has a pronounced activity in the acidic medium that occurs in the focus of caseous lesions. Simultaneous administration of several antituberculous drugs (at least 4) allows to complete the course of treatment before the emergence of drug resistance of mycobacterium tuberculosis or to overcome the resistance of the pathogen to one or two drugs.

In connection with the different state of the mycobacterial population at different stages of the disease, it is scientifically justified to divide the chemotherapy of tuberculosis into two periods or into two phases of treatment. The initial, or intensive, phase of treatment is aimed at suppressing rapid multiplication and active metabolism of the mycobacterial population. The goals of this treatment period are also to reduce the amount of drug-resistant mutants and to prevent the development of secondary drug resistance. For the treatment of tuberculosis in the intensive phase, 5 main anti-tuberculosis drugs are used: isoniazid, rifampicin, pyrazinamide. Etambutol or streptomycin for 2-3 months. Isoniazid, rifampicin and pyrazinamide constitute the core of the combination when exposed to mycobacterium tuberculosis. It should be emphasized that isoniazid and rifampicin equally effectively affect all groups of the mycobacterial population in the focus of tuberculous inflammation. Isoniazid bactericides affect the mycobacterium tuberculosis, sensitive to both drugs, and kills rifampicin-resistant pathogens. Rifampicin also kills mycobacterium tuberculosis, sensitive to these two drugs, and, what is especially important, it has a bactericidal effect on isoniazid-resistant mycobacterium tuberculosis, rifampicin is effective against persistent mycobacteria tuberculosis if they begin to "wake up" and enhance their metabolic activity. In these cases it is better to use rifampicin, not isoniazid. The addition of pyrazinamide, ethambutol and fluoroquinolones to these drugs increases the effect on the pathogen and prevents the formation of secondary drug resistance.

In cases of drug-resistant tuberculosis, the question arises of the use of stand-by antituberculosis drugs, the combination of which and duration of admission are still largely empirical.

In the continuation phase of treatment, the remaining, slowly multiplying mycobacterial population is affected. The metabolic activity of mycobacterium tuberculosis in such a population is low, the causative agent is mainly intracellularly in the form of persistent forms. At this stage, the main tasks are prevention of active reproduction of the remaining bacteria, as well as stimulation of reparative processes in the lungs. Treatment should be performed over a long period of time to neutralize the mycobacterial population, which, due to its low metabolic activity, is not amenable to destruction with the help of antituberculous drugs.

It is important that during the entire period of treatment the patient regularly take anti-tuberculosis drugs. Methods to ensure regularity of medication intake are closely related to organizational forms of treatment in inpatient, sanatorium and outpatient settings, where the patient must take prescribed medications only in the presence of medical personnel.

When using anti-tuberculosis drugs, it should be borne in mind that the effectiveness of a given agent also depends on the dose and mode of administration. The daily dose of antituberculous drugs is administered at a time, and only in case of side effects it can be divided into a maximum of 2 doses. In such a situation, the intervals between receptions should be minimal if possible. From the point of view of the effectiveness of the influence on the causative agent of tuberculosis, this mode of taking antituberculous drugs is considered optimal. However, quite often there are problems associated with possible side effects of anti-tuberculosis drugs. In these cases, changes in the mode of taking medications are inevitable. You can use a daily fractional introduction of a daily dose of the drug or intermittent reception of a full dose (3 times a week), you can increase the interval between taking different drugs, change the way the drug is administered.

In addition to daily chemotherapy, there is a technique for intermittent use of drugs. Intermittent, or intermittent, medication reduces the likelihood of adverse reactions. This method is based on the aftereffect of chemotherapy drugs, which have a bacteriostatic effect on the mycobacterium tuberculosis not only in conditions of their high concentration in the blood serum, but also after excretion from the body for 2 days or more. For intermittent use, almost all anti-tuberculosis drugs are suitable: isoniazid, rifampicin, streptomycin, kanamycin, amikacin, ethambutol, pyrazinamide. They have sufficient effectiveness, if they are applied 3 times a week. With intermittent chemotherapy, the dose of drugs should be higher than with daily administration.

It should be noted that individual anti-tuberculosis drugs can be administered not only inward or intramuscularly, but also intravenously by drip or jetting. Applied intrabronchial infusion, inhalation of aerosols, as well as rectal administration (enema, suppository).

To evaluate the effectiveness of chemotherapy, a quarterly cohort analysis is used (observe a group of patients with the same duration of treatment). This approach allows us to evaluate the results of standard chemotherapy regimens both for monitoring the regularity of taking antituberculous drugs and for identifying patients who need individual correction of treatment tactics.

[7], [8], [9], [10], [11],

Modes of chemotherapy for tuberculosis

The regime of chemotherapy for tuberculosis, i.e. The choice of the optimal combination of antituberculous drugs, their doses, routes of administration, the rhythm of application and the duration of the course of treatment, is determined taking into account:

• the nature of the regional drug sensitivity of mycobacterium tuberculosis to antituberculosis drugs;
• epidemiological danger (infectiousness) of the patient;
• the nature of the disease (a newly diagnosed case, relapse, chronic course);
• prevalence and severity of the process;
• drug resistance of mycobacterium tuberculosis;
• dynamics of clinical and functional indicators;
• dynamics of bacterial excretion;
• involution of local changes in the lungs (resorption of infiltration and closure of caverns).

The chemotherapy regimen can be standard or individual. Standard chemotherapy regimen is performed by combining the most effective anti-TB drugs. This choice is due to the fact that the definition of drug sensitivity of mycobacterium tuberculosis takes 2.5-3 months. After receiving information about the drug sensitivity of the pathogen, the therapy is adjusted and individual treatment is prescribed.

Taking into account the need for different approaches to chemotherapy for different patients, patients are divided into groups according to the regimens of chemotherapy.

Choosing a chemotherapy regimen, you need:

• to determine the indications for the use of antituberculosis drugs and the appropriate regimen of chemotherapy;
• choose a rational organizational form of chemotherapy (treatment in outpatient, inpatient or sanatorium settings) for each patient or individual groups of patients;
• to determine the most appropriate regimen of chemotherapy under specific conditions, the most effective in this form of the process, with some tolerance of antituberculous drugs, and also with specific sensitivity of mycobacterium tuberculosis;
• ensure controlled admission to patients of the prescribed combination of anti-TB drugs throughout the treatment period, both in hospitals and sanatoria, and on an outpatient basis;
• organize dispensary observation of the patient during treatment, periodically examine it to monitor the effectiveness of treatment and evaluate its results;
• choose rational methods of examining the patient and determine the optimal time for their application.

These and other questions related to chemotherapy, the doctor decides individually for each patient. In those cases where the therapeutic effect is insufficient, the examination should help to establish the cause of failure and choose other therapeutic tactics; change the method of chemotherapy or its organizational forms, prescribe additional medicines, and use other methods of treatment, for example, collapse therapy, surgical treatment, etc. The choice of treatment tactics is determined on the one hand by the characteristics of the tuberculosis process and its dynamics, on the other hand, which the doctor has.

Mode I of chemotherapy

The first chemotherapy regimen is prescribed for patients whose lung tuberculosis was diagnosed for the first time, and sputum microscopic data indicate bacterial release. This regimen is also prescribed for patients with advanced forms of pulmonary tuberculosis, in which bacterial excretion is not established. Mode I chemotherapy is effective only in regions where the level of primary MDR of mycobacterium tuberculosis does not exceed 5%, as well as in patients with complete preservation of the sensitivity of the pathogen to the main anti-tuberculosis drugs.

Intensive phase of treatment involves the appointment of four drugs from the main anti-tuberculosis drugs (isoniazid, rifampicin, pyrazinamide, Etambutol or streptomycin) for 2-3 months (before obtaining the data of indirect microbiological determination of the drug sensitivity of the pathogen by the absolute concentration method). During this period, the patient must take a minimum of 60 doses of prescribed anti-TB drugs. Thus, the duration of this phase of treatment is determined by the number of necessary doses of the drug. This calculation of the duration of treatment is used for all regimens of chemotherapy.

The use of streptomycin in place of ethambutol should be based on data on the prevalence of drug resistance of mycobacterium tuberculosis to this drug and isoniazid in a particular region. In cases of primary resistance to isoniazid and streptomycin, etambutol is used as the 4th drug, as it effectively affects isoniazid-resistant and streptomycin-resistant mycobacterium tuberculosis.

Indication for the transition to the continuation phase of therapy is the cessation of bacterial release and positive clinical and radiological dynamics of the process in the lungs. With the preservation of the sensitivity of mycobacteria tuberculosis to drugs, treatment is continued for 4 months (120 doses) with isoniazid and rifampicin. Drugs are taken daily or in an intermittent mode. An alternative regimen in the continuation phase of treatment is the use of isoniazid and ethambutol for 6 months. The total duration of the main course of treatment is 6-7 months.

When the drug resistance of mycobacteria of tuberculosis is detected, but with the termination of bacterial release by the end of the initial phase of treatment at 2 months, a transition to the continuation phase of chemotherapy is possible, but with mandatory correction and lengthening of its terms. With the initial drug resistance of the causative agent to isoniazid and / or streptomycin, treatment in the continuation phase is performed with rifampicin, pyrazinamide and ethambutol for 6 months either with rifampicin and ethambutol for 8 months. The total duration of treatment is 8-10 months.

With initial resistance to rifampicin and / or streptomycin, in the continuation phase of treatment, isoniazid, pyrazinamide and Etambutol are used for 8 months or isoniazid and ethambutol for 10 months. In this case, the total duration of treatment is 10-12 months.

With continued bacterial isolation and the absence of positive clinical and radiological dynamics of the process in the lungs, the intensive phase of treatment with the standard chemotherapy regimen should be continued for another month (30 doses) until the data on the drug resistance of the pathogen are obtained.

When detecting the drug resistance of mycobacteria tuberculosis, chemotherapy is corrected. Perhaps a combination of the main drugs, to which the sensitivity of the pathogen remained, and the reserve preparations. However, the combination should consist of five drugs, of which at least two must be reserved. In the chemotherapy regimen, only 1 reserve drug should never be added because of the risk of drug resistance formation in the pathogen.

After correction of chemotherapy, the intensive phase of treatment with a new combination of anti-TB drugs begins again and lasts for 2-3 months until new data on the drug sensitivity of the pathogen are obtained. Further tactics of treatment and the transition to the continuation phase of chemotherapy, as well as its duration are determined by the effectiveness of the intensive phase and the data of a re-examination of the drug sensitivity of mycobacterium tuberculosis.

If the MDR pathogen is identified with isoniazid and rifampicin, the patient is prescribed IV chemotherapy regimen.

Mode IIa of chemotherapy

Mode IIa of chemotherapy is prescribed for patients with relapses of pulmonary tuberculosis and patients who received inadequate chemotherapy for more than 1 month (improper combination of drugs and insufficient doses), with a low risk of drug resistance in mycobacteria tuberculosis. The chemotherapy regimen is effective only in regions where the level of primary MDR of mycobacterium tuberculosis does not exceed 5%, or in patients with complete preservation of the sensitivity of the pathogen to the main antituberculosis drugs.

This regime provides for the appointment in the intensive phase of treatment for 2 months of five major anti-tuberculosis drugs: isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin and within 1 month of four drugs: isoniazid, rifampicin, pyrazinamide and ethambutol. During this period the patient should receive 90 doses of prescribed medications. In the intensive phase, the use of streptomycin is limited to 2 months (60 doses). The intensive phase of therapy can be continued with preservation of bacterial release and with negative clinical and radiological dynamics of the disease, until the data on drug sensitivity of mycobacterium tuberculosis are obtained.

The indication for the transition to the continuation phase of treatment is the cessation of bacterial release and the positive clinical-x-ray dynamics of a specific process. With the preservation of the sensitivity of mycobacteria tuberculosis treatment is continued for 5 months (150 doses) with three drugs: isoniazid, rifampicin, ethambutol. Drugs can be taken daily or intermittently.

If by the end of the intensive phase of treatment bacterioversion continues and the drug resistance of the causative agent to aminoglycosides, isoniazid or rifampicin is found, they change the chemotherapy regimen. Leave the main drugs, to which the sensitivity of mycobacteria of tuberculosis has been preserved, and at least two reserve chemotherapy drugs are added to the scheme, which leads to an extension of the intensive phase for another 2-3 months. The total duration of treatment is 8-9 months.

When detecting MDR mycobacterium tuberculosis for isoniazid and rifampicin, the patient is prescribed IV chemotherapy regimen.

IIb chemotherapy regimen

The IIb chemotherapy regimen is used in patients with a high risk of developing drug resistance in the pathogen. This group includes patients who have epidemiological (regional level of primary MDR of mycobacterium tuberculosis exceeding 5%), anamnestic (contact with well-known clinics for patients with TB mycobacterium with MDR), social (persons released from penitentiary facilities) and clinical ( patients with ineffective treatment in accordance with regimens I, Ila, III chemotherapy, with inadequate treatment at previous stages, with interruptions in treatment, with prevalence, both newly diagnosed and recurrent forms of pulmonary tuberculosis) indications for the appointment of this regimen.

Treatment of this group of patients in accordance with regimens I and IIa of chemotherapy is significantly complicated by the so-called phenomenon of induction of increasing polyvalent drug resistance of mycobacterium tuberculosis. This phenomenon is manifested in patients with the initial MDR of the pathogen. In these cases, treatment of patients in accordance with I and IIa chemotherapy regimens by the end of the 2-3rd month induces the formation of drug resistance in mycobacteria tuberculosis not only to pyrazinamide, ethambutol and aminoglycosides, but also to protionamide (eti-onimide) and in some cases to other reserve preparations.

In such patients, a standard chemotherapy regimen is used during the intensive phase of treatment for 2-3 months until the data on the drug resistance of mycobacterium tuberculosis are obtained. The scheme includes isoniazid, rifampicin, pyrazinamide. Etambutol, kanamycin (amikacin), fluoroquinolone or protionamide.

In the study in vitro of the combined action of fluoroquinolones (ciprofloxacin, lomefloxacin, ofloxacin, levofloxacin) and line drugs: rifampicin, isoniazid, pyrazinamide and ethambutol installed additive effect. When analyzing different treatment regimens for patients with newly diagnosed tuberculosis and patients with relapses, it was found that combined chemotherapy with the main anti-tuberculosis drugs in combination with fluoroquinolones is more effective than ethambutol. Moreover, in addition to high bactericidal activity against mycobacteria tuberculosis and optimal pharmacokinetics providing high concentrations of phytoquinolones in lung tissues and fluids and in cells of the phagocytic system, the absence of hepatotoxicity and low incidence of side effects are very important. The IIb chemotherapy regimen is currently the main standard regimen for the treatment of patients with pulmonary tuberculosis with the isolation of mycobacterium tuberculosis before receiving data on the drug susceptibility study.

This choice is due to the fact. That for a modern epidemic situation accumulation in antitubercular dispensaries of patients with chronic forms of pulmonary tuberculosis, which are permanent allocators of mycobacteria of tuberculosis, resistant to many anti-tuberculosis drugs, is characteristic. Such patients, being a reservoir of infection, infect healthy individuals with already drug-resistant strains of the pathogen. Therefore, chemotherapy regimens I and IIa are not always effective, firstly, because of the high risk of primary infection with drug resistant strains of mycobacterium tuberculosis and, secondly, because of the high risk of secondary drug resistance of the causative agent in patients with pulmonary tuberculosis when the regimens are inadequate.

Thus, in modern epidemiological conditions with a significant level of primary and secondary drug resistance of mycobacterium tuberculosis, the IIb chemotherapy regimen should be the main one in the treatment of destructive pulmonary tuberculosis with bacterial excretion both in patients with a newly diagnosed process and in patients with relapses of the disease, and fluoroquinolones should take a worthy place in the group of basic anti-TB drugs.

It should be noted that for patients with newly diagnosed tuberculosis and for patients with relapses of the disease, an intensive and largely determining success of chemotherapy is the intensive phase of treatment that is carried out in the hospital.

The proposed set of anti-TB drugs in the IIb chemotherapy regimen. As a rule, provides a bactericidal effect, as rifampicin, isoniazid and Etambutol suppress the multiplication of sensitive mycobacteria tuberculosis, pyrazinamide affects the bacteria found in the areas of casein, and the drug from the group of fluoroquinolones provides an effect in the presence of drug resistance to isoniazid or rifampicin. In MDR, the bactericidal effect is provided by a drug from the group of fluoroquinolones, pyrazinamide and ethambutol. These funds also hamper the development of resistance to other anti-tuberculosis drugs.

After receiving data on the drug sensitivity of mycobacterium tuberculosis, the chemotherapy is adjusted and the further tactics and duration of treatment are determined using pathogenetic methods, collapse therapy and surgical interventions.

When detecting MDR mycobacterium tuberculosis for isoniazid and rifampicin, the patient is prescribed IV chemotherapy regimen.

Regimen III chemotherapy

Mode III of chemotherapy is prescribed to patients with newly diagnosed small forms of pulmonary tuberculosis in the absence of bacterial excretion. Basically, these are patients with focal, limited infiltrative tuberculosis and tuberculosis.

During 2 months of an intensive phase of chemotherapy, 4 anti-tuberculosis drugs are used: isoniazid, rifampicin, pyrazinamide and ethambutol. Introduction to the regimen of chemotherapy with the 4th drug ethambutol is due to the high initial resistance of mycobacteria tuberculosis to streptomycin. The intensive phase of chemotherapy lasts 2 months (60 doses). If information is received on the presence of bacterial excretion. And there is still no drug susceptibility data, treatment is continued even if the duration of the intensive phase exceeds 2 months (60 doses).

In the absence of positive clinical and radiological dynamics of the process in the lungs, the intensive phase of treatment with a standard chemotherapy regimen should be prolonged for another month (30 doses). The further tactics of treatment is determined by the dynamics of the process in the lungs and by the data of a microbiological study.

The indication for the transition to the continuation phase of treatment is a pronounced positive clinical and X-ray dynamics of the disease. For 4 months (120 doses), chemotherapy with isoniazid and rifampicin, using both daily medication and intermittent regimen. Another option is the use of isoniazid and ethambutol for 6 months.

This group of patients is also referred to patients who have been shown to have limited changes in mild, doubtful activity. In the absence of clinical and radiological dynamics after the end of the intensive phase of treatment, the process is regarded as inactive and the treatment is discontinued. With positive X-ray dynamics, the process is regarded as active, and the patients are transferred to the continuation phase of treatment. The total duration of the course is 6-8 months.

With the emergence of unrecoverable adverse reactions of a toxic character to isoniazid or rifampicin, but with the preservation of the sensitivity of mycobacteria tuberculosis to them, it is possible to replace drugs. To replace a drug it is possible only on its or his analogue, instead of on other reserve antituberculous preparation. So. Isoniazid can be replaced with phenazide, ftyvazid or metazide, and rifampicin-rifabutin. In the case of the appearance of unremovable allergic reactions, substitution for analogs is not indicated, and preparations of this group are excluded from the chemotherapy regimen. In this case, isoniazid or rifampicin is replaced by two reserve drugs.

It should be noted that when using chemotherapy regimens I, IIa, IIb and III in patients with pulmonary tuberculosis, the use of combined antituberculous drugs is justified. The optimal combination of the main anti-tuberculosis drugs in one tablet allows for strictly controlled chemotherapy, which is a priority in the treatment of patients with tuberculosis.

The above standard chemotherapy regimens for the treatment of newly diagnosed patients and patients with relapses of pulmonary tuberculosis, fixed in Order No. 109 of the Ministry of Health of the Russian Federation of March 21, 2003, are, in the current epidemiological conditions, more of a historical interest and need revision.

It is advisable to select only two standard chemotherapy regimens for the treatment of newly diagnosed patients and patients with relapses of pulmonary tuberculosis. The first chemotherapy regimen should be used to treat patients with a low risk of developing drug resistance in the pathogen. This group includes newly diagnosed patients who do not secrete mycobacterium tuberculosis, with limited processes in the lungs, without destructing pulmonary tissue, from regions where the level of primary MDR does not exceed 5%. In these cases, in an intensive phase of treatment, a combination of anti-tuberculosis drugs should include isoniazid, rifampicin, pyrazinamide, and ethambutol.

The second chemotherapy regimen should be used to treat patients with a high risk of developing drug resistance in the pathogen. This group includes newly diagnosed patients and patients with recurrence of pulmonary tuberculosis, which secrete mycobacterium tuberculosis, from regions where the level of primary MDR exceeds 5%. This regimen is also used in patients who have had proven contact with patients who release drug-resistant mycobacterium tuberculosis, as well as in patients with interruptions in treatment for more than 1 month. In these cases, in an intensive phase of treatment, a combination of anti-tuberculosis drugs should include isoniazid. Rifampicin, pyrazinamide, ethambutol, kanamycin (amikacin), a drug from the group of fluoroquinolones or protionamide.

Mode IV chemotherapy

The IV chemotherapy regimen is designed for patients with pulmonary tuberculosis, which secrete mycobacterium tuberculosis with MDR. The overwhelming majority of such patients are patients with caseous pneumonia, fibro-cavernous, chronic disseminated and infiltrative pulmonary tuberculosis, with the presence of destructive changes. A relatively small proportion are patients with cirrhotic tuberculosis.

According to WHO definition, tuberculosis pathogens resistant to at least isoniazid and rifampicin are classified as Mycobacterium tuberculosis with MDR. However, this classification is purely epidemiological in nature and in clinical settings its use is not justified, since the doctor at the bedside of the patient must know the specific resistance of the pathogen to the anti-tuberculosis drugs. From the clinical standpoint, the classification of V.Yu. Mishina, according to which patients with pulmonary tuberculosis, secreting Mycobacterium tuberculosis with MDR, are divided into two groups:

• patients with MDR of Mycobacterium tuberculosis to the main anti-tuberculosis drugs:
• patients with MDR of Mycobacterium tuberculosis to a combination of basic and reserve anti-TB drugs.

Patients belonging to the 1st group have a more favorable prognosis, because they can use combinations of reserve antituberculosis drugs in accordance with the IV chemotherapy regimen. Patients belonging to the 2nd group have an unfavorable prognosis, and their treatment causes certain difficulties, since they do not have a full set of reserve anti-tuberculosis drugs.

Before the start of chemotherapy, it is necessary to clarify the drug sensitivity of mycobacterium tuberculosis, as well as to examine the patient before starting treatment. In this regard, it is desirable to use accelerated methods of bacteriological investigation and determination of drug sensitivity.

Treatment is carried out in accordance with the individual regime of chemotherapy. Patients are treated in specialized anti-tuberculosis institutions, where centralized quality control of microbiological studies is carried out and there is a necessary set of reserve anti-tuberculosis drugs.

Intensive phase of treatment according to the IV chemotherapy regimen is 6 months. During which appoint combinations of at least five antituberculous drugs. At the same time, a combination of reserve and basic drugs is possible, if the sensitivity of the pathogen remains to them.

There are different variants of IV chemotherapy regimen in patients with pulmonary tuberculosis, which secrete mycobacterium tuberculosis with MDR.

The intensive phase should continue until positive clinical and radiological dynamics and at least two negative results of microscopy and sputum culture. During this period, artificial pneumothorax and surgical intervention are important components of the complex treatment of pulmonary tuberculosis caused by mycobacteria of tuberculosis with MDR. However, the course of chemotherapy should be carried out in full.

Indications for the transition to the continuation phase of treatment are the cessation of bacterial release, positive clinical and radiological dynamics of a specific process in the lungs and the stabilization of the course of the disease. The combination of antituberculosis drugs should include at least three reserve or major drugs that retain the sensitivity of the pathogen. The duration of treatment should be at least 12 months

However, one can not agree with that. That the results of chemotherapy, even with the correct method of treatment, depend only on the sensitivity of the pathogen to anti-tuberculosis drugs. In the chronic tuberculosis process with the development of fibrotic changes in the pulmonary tissue, blood and lymph circulation in the affected area is disrupted, which leads to a significant slowdown in the diffusion of drugs. In this situation, even isoniazid, which has a bactericidal action and penetrates well into the tissue, is located in the wall and contents of the fibrous cavity at lower concentrations in comparison with blood serum. Morphological studies of the lungs in patients treated with long-term antituberculosis drugs for a long time also confirm the data on the slow healing of extensive caseous foci. In connection with this, in the treatment of such patients it is necessary to raise the question of the use of surgical methods. It is important to emphasize that surgical intervention must be carried out before the development of complications that may interfere with the surgical treatment. The role of antituberculous drugs in the treatment of patients with these forms of tuberculosis is overestimated. Thus, with the development of a chronic destructive process with the release of mycobacteria with MDR. If it is not possible to achieve stabilization of the disease and stop the bacterial release with the help of anti-tuberculosis drugs, surgical intervention is necessary. To operate it is necessary when the process is limited, since the operation can be economical, and the subsequent chemotherapy will preserve health. With a favorable course of events, cure can be achieved with a small anatomical defect.

The total duration of treatment of patients is determined by the initial nature and prevalence of the specific process in the lungs, the nature of the MDR of the pathogen, the rates and timing of resolution of pathological foci, the closure of caverns in the lungs, the cessation of bacterial release and the disappearance of clinical manifestations of the disease. As well as the possibility of using collapse and surgical treatment. Because of the danger of insufficient effectiveness of treatment with a combination of reserve antituberculous drugs and the possible development of tuberculosis relapse caused by mycobacteria with MDR. Chemotherapy is carried out at least 12-18 months. It is very important to provide long-term treatment of such patients with reserve anti-tuberculosis drugs.

Identification of a light pathogens with MDR in patients with MDR to a combination of basic and reserve drugs puts the doctor in an extremely difficult position in terms of the possibilities of chemotherapy. In this case, the chemotherapy regimen is forced, and the treatment regimen may include reserve drugs that retain sensitivity, and some basic ones, such as pyrazinamide and Etambutol. Drug resistance to these drugs and aminosalicylic acid develops rather slowly, at the same time they to some extent prevent its development to other anti-tuberculosis drugs. In this case, the combination of pyrazinamide, ethambutol, a drug from the group of fluoroquinolones and capreomycin shows activity against strains with MDR, but, unfortunately, is inferior in effectiveness to a combination consisting of isoniazid, rifampicin and pyrazinamide with respect to the susceptible pathogen.

Forced regimens of chemotherapy are especially necessary when preparing patients for surgical interventions and in the postoperative period. Currently, the following regimens of chemotherapy are the most effective:

• a regime that includes a combination of the main anti-tuberculosis drugs: isoniazid, rifampicin, pyrazinamide and ethambutol for the treatment of newly diagnosed lung tuberculosis caused by mycobacteria that are sensitive to these drugs;
• a regime that includes a combination of essential antituberculosis drugs in combination with fluoroquinolones and kanamycin (capreomycin) for the treatment of patients with newly diagnosed tuberculosis and patients with relapses of pulmonary tuberculosis caused by mycobacteria with MDR.

With regard to the chemotherapy regimen used to treat patients with pulmonary tuberculosis caused by mycobacteria with MDR, which includes combinations of reserve antituberculosis drugs, there is no consensus. In most cases, this chemotherapy regimen and the timing of its use are empirical.

Surgical methods of treatment of tuberculosis

In the economically prosperous countries of Europe, North America, Australia, Japan, as the prevalence of tuberculosis declines, the need for surgeries and their number have declined significantly.

Against the background of high morbidity, surgical treatment of tuberculosis continues to be a necessary and common method. Every year more than 10 thousand patients are operated.

Indications for operation

In patients with pulmonary tuberculosis, surgery is usually indicated in the following cases:

• insufficient effectiveness of chemotherapy, especially with multiple drug resistance of mycobacterium tuberculosis;
• irreversible morphological changes in the lungs, bronchi, pleura, lymph nodes caused by the tuberculosis process;
• complications and consequences of tuberculosis that threaten life, have clinical manifestations or can lead to undesirable consequences.

Surgical treatment is most often used for tuberculosis and fibro-cavernous tuberculosis, less often for cirrhosis of the lung, tubercular empyema of the pleura, caseous necrotic lesions of lymph nodes, caseous pneumonia.

Surgical treatment is recommended for complications and consequences of the tuberculosis process;

• pulmonary hemorrhage;
• spontaneous pneumothorax and pyopneumothorax;
• nodulobronchial fistula;
• cicatricial stenosis of the main or lobar bronchus;
• bronchiectasis with suppuration;
• bronchitis (bronchus stone);
• pneumofibrosis with hemoptysis;
• bronchial pleurisy or pericarditis with impaired respiratory and circulatory functions.

Absolute majority of operations for tuberculosis are performed in a planned manner. However, it is sometimes necessary to eliminate the immediate threat to the life of the patient, and indications for surgery may be urgent and even urgent.

Possible indications for urgent operations:

• progression of the tuberculosis process against intensive chemotherapy;
• repeated pulmonary hemorrhage. Possible indications for emergency operations:
• profuse pulmonary hemorrhage;
• intense pneumothorax.

In newly diagnosed patients under conditions of combined chemotherapy, indications for planned lung resection and timing for surgery are determined individually. Usually, treatment is continued until chemotherapy provides a positive dynamics of the process. Termination of positive dynamics is the basis for discussing the question of surgical intervention.

In the majority of patients with a limited duration of tuberculosis, after 4-6 months of treatment there is no laboratory-determined bacterial release, but a stable radiologic pattern of pathological changes may be the basis for a small resection of the lung. Totally among the newly diagnosed patients with active tuberculosis, indications for surgery occur in about 12-15%. With tuberculosis, timely resection of the lung prevents the progression of the tuberculosis process, shortens the duration of treatment, allows the patient to be completely rehabilitated in the clinical, labor and social terms. In some cases, the operation prevents frequent errors in the differential diagnosis of tuberculosis and peripheral lung cancer.

In patients with fibrous-cavernous tuberculosis, curing with a conservative method is an exception, not a rule. Unfortunately, among this contingent there are often contraindications to surgical treatment. Usually, only 15% of such patients manage to operate.

With cirrhotic tuberculosis and lung disruption as a result of caseous pneumonia, the assessment of not only indications but also contraindications to surgical treatment is also important in the problem of medical tactics.

In cases of multiple drug resistance of mycobacterium tuberculosis, resection of the lung, if feasible, is an alternative to prolonged chemotherapy with second-line drugs or complements such therapy if it is ineffective.

Contraindications to surgery

In most cases, contraindications to surgical treatment of patients with pulmonary tuberculosis are due to the prevalence of the process. Frequent contraindications to surgery are also poor general condition of patients, old age, dysfunction of breathing, blood circulation, liver and kidneys. To assess these violations requires a multidisciplinary approach to the patient.

It should be borne in mind that in many patients after the removal of the main focus of the infection and the source of intoxication functional indicators improve and even normalize. Most often it happens with caseous pneumonia, pulmonary hemorrhage. Chronic pleural empyema with a wide bronchopleural fistula.

[12], [13], [14], [15]

Preparing for an operation

During the preparation of the patient for surgery, it is necessary to maximally improve his general condition, stop or reduce the release of mycobacterium tuberculosis, reduce intoxication, limit the process, suppress the nonspecific flora. With all surgical interventions for tuberculosis in pre-operative and postoperative periods, combined chemotherapy is performed. Apply also pathogenetic, desensitizing and immune therapy, treatment of concomitant diseases. Under special indications, hemosorption, plasmapheresis, parenteral nutrition is carried out. After the operation, a number of patients should be referred to a sanatorium. It is expedient to carry out the operation in the phase of remission, which is determined by clinical, laboratory and roentgenological data. In this case, it must be taken into account that too long preparation of the patient for the operation is often harmful. It can lead to an increase in the drug resistance of mycobacteria tuberculosis and to another outbreak of the tuberculosis process. Clinical experience also shows that in cases of prolonged waiting for surgery, patients often refuse the proposed surgical intervention.

Types of operations for pulmonary tuberculosis

With pulmonary tuberculosis, pleura, intrathoracic lymph nodes, bronchi, the following surgical interventions are used:

• resection of the lungs, pneumonectomy:
• thoracoplasty:
• extra-pleural filling;
• operations on the cavity (drainage, cavernotomy, cavernoplasty);
• videothoracoscopic sanation of the pleural cavity;
• pleurrectomy, lung decortication;
• thoracostomy;
• operations on the bronchi (occlusion, resection and plastic, reampling stump);
• removal of the intrathoracic lymph nodes;
• destruction of pleural joints for correction of artificial pneumothorax.

Separately, one should mention the endoscopic removal of granulations or bronchiolitis with bronchoscopy and the X-ray endovascular occlusion of bronchial arteries with pulmonary hemorrhage. Operations on the nerves and major lung vessels as independent intervention do not currently produce.

All operations on the chest wall, lungs, pleura, intrathoracic lymph nodes and bronchi are performed under anesthesia with intubation of the trachea or bronchi and artificial ventilation of the lungs.

Lung resection, pneumonectomy

Lung resection can be an operation of different volumes. Patients with tuberculosis often use so-called small or economical resections. In such operations, a portion of the lobe is removed (segmentectomy, wedge-shaped, marginal, planar resection). Even more economical is precision ("high-precision") resection when conglomerate foci, tuberculoma or cavern is removed with a very small layer of lung tissue. The technical implementation of most small resections of the lungs is greatly facilitated by the use of staplers and the imposition of a mechanical seam with brackets of tantalum. Precision resection is performed with a point electrocoagulation or neodymium laser. On the relatively large vascular and bronchial branches impose ligatures.

The removal of one lobe of the lung (lobectomy) or two lobes (bilobectomy) is usually performed with cavernous or fibrous-cavernous tuberculosis with one or more caverns in one lobe of the lung. Lobectomy is also performed with caseous pneumonia, large tuberculosis with large foci in one lobe, with cirrhosis of the lobe, cicatrical stenosis of the lobar or segmental bronchus. If the remaining part of the lung is not sufficient to fill the entire pleural cavity, an additional pneumoperitoneum is applied to raise the diaphragm. Sometimes, to reduce the volume of the corresponding half of the chest, the posterior segments of three or four ribs are resected.

Resection of the lungs, especially small ones, is possible on both sides. In this case, consecutive operations with a time interval (3-5 weeks) and one-step interventions are distinguished. Small resections of the lungs are tolerated well, and they are highly effective. The vast majority of operated patients are cured of tuberculosis.

Pneumonectomy is mainly performed with a widespread unilateral lesion - a polycavernous process in one lung, fibrous-cavernous tuberculosis with bronchogenic colonization, a giant cavern, caseous pneumonia, cicatricial stenosis of the main bronchus. With extensive damage to the lung, complicated by the empyema of the pleural cavity, pleuropneumonectomy is shown, i.e. Removal of the lung with a purulent pleural sac. Pneumonectomy is often the only possible, absolutely shown and effective operation.

Thoracoplasty

The operation consists in resection of the ribs on the side of the affected lung. As a result, the volume of the corresponding half of the thorax decreases and the elastic tension of the lung tissue decreases. Respiratory excursions of the lungs become limited due to the violation of the integrity of the ribs and the function of the respiratory muscles. Then, from the left edge periosteum, fixed bone regenerates are formed. In the collapsed lung, the absorption of toxic products decreases, conditions are created for the fall of the cavity and the development of fibrosis. Thus, thoracoplasty, along with a mechanical effect, causes certain biological changes that contribute to repair in tuberculosis.

Cavern after thoracoplasty is rarely closed by the formation of a scar or a dense encapsulated caseous focus. More often it turns into a narrow slit with an epithelial inner wall. In many cases, the cavern only falls down, but remains lined inside with a granulation tissue with foci of caseous necrosis. Naturally, the preservation of such a cavity can be a cause of aggravation of the process and its progression through various terms after the operation.

Thoracoplasty is produced, as a rule. In cases of contraindications to resection of the lung. Operate in the phase of stabilization of the tuberculosis process at small and medium sizes of the cavity, if the expressed fibrosis did not develop in the pulmonary tissue and wall of the cavity. Urgent indication for thoracoplasty may be bleeding from the cavity. In patients with residual pleural cavity with chronic pleural empyema with bronchial pleural fistula, thoracoplasty in combination with muscular plasty (thoracomioplasty) often serves as an indispensable effective operation.

Thoracoplasty is well tolerated by people of young and middle age. At the age of more than 55-60 years of age, the testimony to it is limited. More often one-stage thoracoplasty is used with resection of the posterior segments of the upper 5-7 ribs. Ribs are removed one or two below the location of the lower edge of the cavity (anteroposterior radiograph). With large upper-lobe caverns, the upper 2-3 ribs should be removed almost completely. After the operation, a pressure bandage is applied for 1.5-2 months.

Complication after thoracoplasty can be atelectasis of the lung on the side of the operation. For its prevention, it is necessary to control the expectoration of sputum and, if necessary, sanitize the bronchial tree with fibrobronchoscopy.

Collapse of the lung can also be provided by the operation of extrapleural pneumolysis. Maintenance of the extrapleural cavity is provided by periodic air blowing or by the insertion of a filling material, for example a silicone seal.

Operations on the cavern

For drainage into the cavity, a catheter is inserted by piercing the chest wall. Through the catheter, a permanent aspiration of the contents of the cavity is established by means of a special suction system. Periodically, drugs are introduced into the cavity. With the use of a thin drainage catheter (micro-irrigator), a prolonged sanation of the cavity with a local application of medications is possible.

In favorable cases, patients notice marked clinical improvement. The content of the cavern gradually becomes more liquid, transparent and acquires a serous character, mycobacterium tuberculosis in the contents of the cavern disappears. The cavity decreases in size. However, cavern healing usually does not occur. In this regard, drainage is often used as an auxiliary method before another operation - resection, thoracoplasty or cavernoplasty.

Autopsy and open cavernous treatment (cavernotomy) is used for large and giant cavities with rigid walls, when other operations are contraindicated - usually because of the high prevalence of the process or the poor functional state of the patient. Before the operation, it is necessary to accurately determine the location of the cavity in computed tomography. After the operation for 4-5 weeks, open local treatment with a tamponade with chemotherapy. The cavity is treated with a low-frequency ultrasound or laser. The walls of the cavern are gradually cleared, bacterial isolation stops, intoxication decreases. At the second stage of surgical treatment, the cavity is closed with thoracoplasty, muscle plasty or a combination of these methods - thoracomioplasty.

With a good sanitation of a single cavern and the absence of mycobacteria tuberculosis, a one-stage operation is possible in its contents - a cavernotomy with a cavernoplasty. For this, the cavern is opened, its walls are scraped and treated with antiseptics, the mouths of the draining bronchi are sutured and then the cavity is in the lung. It is also possible to close the cavity with a muscle flap on the leg (cavernomyoplasty). Sometimes cavernoplasty is also possible with two closely located caverns. During the operation they are connected to each other in a single cavity. One-time cavernoplasty is a clinically effective operation, which patients are well tolerated.

Videotoracoscopic sanitation of the pleural cavity

The essence of the operation consists in the mechanical removal of pus, caseous masses, and fibrin overlays from the pleural cavity. Clusters of pathological contents are eliminated, the cavity is washed with solutions of anti-tuberculosis preparations of intiseptics. Such a sanation, as a rule, is the continuation of the diagnostic videotorakoscopy. After examining the pleural cavity with an optical thoracoscope connected to the monitor, a place is chosen for the second thoracoport. Through it, an aspirator, tongs and other instruments for sanitation are injected into the pleural cavity. After the termination of manipulations through thoracophores, 2 drainages are introduced into the pleural cavity for permanent aspiration.

Plevrrectomy, decortication of the lungs

With tuberculosis, this operation is performed in patients with chronic pleural empyema, pyopneumotorax, chronic exudative pleurisy. The operation consists in removing the entire sack with pus, caseous masses, fibrin. The thickness of the walls of this bag, formed by the parietal pleura and the overlays on the visceral pleura, can exceed 2-3 cm. The operation is sometimes called "empyemectomy", emphasizing its radical nature with empyema of the pleura. In a number of patients with empyema and simultaneous lesion of the lung, removal of the empyema sac is combined with lung resection. In some cases, along with a purulent pleural sac, one must also remove the lung (pleuropneumoniactomy).

After removing the bag empyema and fibrous shell from the lung it spreads and fills the corresponding half of the chest cavity. The respiratory function of the lung gradually improves. Unlike thoracoplasty, pleurectomy with lung decortication is a restorative operation.

Thoracostomy

The essence of the operation is the resection of segments of 2-3 ribs with the opening of the empyema cavity. The edges of the skin are sewn to the deep layers of the wound. In the chest wall a "window" is formed. It allows for open treatment of pleural empyema by washing and tamponade of the cavity, processing it with low-frequency ultrasound, and laser irradiation. Earlier thoracostomy with tuberculosis empyema was widely used as the first stage before thoracoplasty. At present, the indications for Thoracostomy are narrowed.

Surgery on the bronchi

Stitching and crossing the bronchus of the affected lobe of the lung lead to its obstructive atelectasis. As a result, conditions are created for reparative processes in the cavity region, and the closing of the bronchus lumen helps to stop bacterial excretion. However, the clinical effectiveness of operations aimed at creating obturation atelectasis is often low due to bronchial recanalization. In this regard, they are rarely used, on special indications. Resection of the bronchus with superposition of bronchial anastomosis is much more important. It is indicated for patients with post-tuberculous stenosis of the main bronchus, bronchodilator, bronchodular fistula. Excision of the affected segment of the bronchus and restoration of bronchial patency can save a number of patients all the lungs or part of it.

Removal of lymph nodes

With chronically current primary tuberculosis, the caseo-necrotic lymph nodes in the root of the lung and mediastinum are often a source of intoxication and spread of tuberculosis infection. Sometimes, concurrent tuberculosis lesions of the bronchi are noted, breakout of caseous masses into the lumen of the bronchus with bronchodular fistula, the formation of bronchiolitis in the bronchus. The size of the affected nodes, their topography, the degree of calcification and possible complications vary widely. Surgical removal of caseous-necrotic lymph nodes is a highly effective operation. The number of complications is minimal, the immediate and long-term results are good. If bilateral intervention is necessary, one can operate either sequentially or simultaneously.

Complications after surgery

Emergency operations for complications of pulmonary tuberculosis are rarely used in clinical practice. However, they are important, since they can be the only way to save a patient's life. In cases of pulmonary hemorrhage, along with resection of the lung, pneumonectomy or collapsotherapy intervention, X-ray endovascular surgery is very effective. It consists in catheterization of the bronchial artery, bronchial arteriography and subsequent therapeutic occlusion of the artery with special materials that are injected through the catheter.

If there is an intense pneumothorax, an immediate measure should be aspiration drainage of the pleural cavity. It eliminates the immediate threat of death. Then, in cases of rupture of the cavern or pulmonary bulls, the question of the expediency of an operation on the lung is decided.

After small resections of the lungs, the lethality is now below 1%, the number of cured TB is 93-95%. After a lobectomy the lethality is 2-3%, after pneumonectomy - 7-8%. The period of postoperative rehabilitation with a smooth course varies from 2-3 weeks (after small resections) to 2-3 months (after pneumonectomy). Functional results after small resections and lobectomy, as a rule, are good. The ability to work is restored within 2-3 months. After pneumonectomy, functional results in young and middle-aged people are usually quite satisfactory. In elderly people, they are worse, physical activity for them should be limited.

In patients with multiple drug resistance of mycobacterium tuberculosis to chemotherapy, infectious and other postoperative complications are usually caused not by the fact of drug resistance itself, but by many other reasons. The long-term course of the disease, the widespread and complicated destructive process, the weakened immunity, the complexity of the operation, the poor tolerance of the drugs are of major importance. To improve the outcomes of treatment of patients with pulmonary tuberculosis, it is important to use the possibilities of surgery and, at appropriate indications, to operate patients in a timely manner. In this regard, with insufficient effectiveness of conservative treatment and complicated flow, it is advisable to advise patients with pulmonary tuberculosis with a thoracic surgeon.

[16], [17], [18], [19], [20]

Treatment of extrapulmonary tuberculosis

Treatment of extrapulmonary tuberculosis has the following objectives:

• elimination of the local specific process and its complications;
• restoration of the function of the affected organ;
• elimination of the risk of development of the predicted consequences of the disease.

The solution of these problems is not always possible without timely and adequate surgical treatment. Despite the individual (for each location of extrapulmonary tuberculosis) methods of surgical interventions, it is possible to single out general principles and types of operations.

Depending on the purpose, diagnostic, therapeutic or therapeutic-diagnostic operations (manipulations) are distinguished.

The objectives of the diagnostic operation (manipulation):

• clarification of the structure and nature of pathological education;
• obtaining material for research (bacteriological, cytological, histological, biochemical);
• clarification of the degree of prevalence of the pathological process, the relationship of the affected organs;
• visual inspection of the affected organ.

Diagnostic interventions include puncture and biopsy of abscesses, pathological foci, organs and tissues, abscessography and fistulography, endoscopic procedures (arthroscopy, laparoscopy, cystoscopy), diagnostic curettage and other interventions.

Therapeutic interventions are used to achieve a certain clinical effect. Distinguish radical, reconstructive, reconstructive and auxiliary operations.

Radical operations are interventions, during which all pathological tissues of the affected organ are completely removed. The methods of radical operations are necroctomy (removal of pathological tissues), resection (removal of the affected part of the organ within healthy tissues), extirpation (removal of the entire organ), and their combination with the removal of abscesses and fistulas.

To achieve the best anatomical and functional results, radical surgery, as a rule, is supplemented by reconstructive and reconstructive interventions. In such cases, a radical operation is the main stage of combined intervention.

Restorative operation - restoration of the anatomical structure of the destroyed or resected part of the organ by plastic replacement with a similar (or similar in structure) tissue or artificial material.

Reconstructive surgery is used for severe organ damage, while lost (destroyed or removed) anatomical structures are restored by artificially moving organs or their fragments, tissues in an unnatural position. One of the variants of reconstructive operations is endoprosthetics (replacement of the affected part or the whole organ with an artificial prosthesis).

Auxiliary operations are used to influence any component of the pathological process in addition to radical, reconstructive and reconstructive operations or as an independent method of treatment. Most of the auxiliary operations: abscessotomy (abscessectomy) and fistulotomy (fistuloectomy) - are aimed at eliminating complications or consequences of the disease. They are carried out with the impossibility of applying radical intervention, to correct deformations and the size of the organ (segment). Apply mobilizing and stabilizing operations (for example, instrumental fixation), interventions aimed at improving the blood supply of the affected organ (revascularization), and other types of operations.

Optimum operations with active tuberculosis should simultaneously solve several problems (complete removal of pathological tissues, restoration of anatomic integrity and organ functions), therefore, operations performed are often combined, for example, radical reconstructive, radically reconstructive and corrective operations (with tuberculous spondylitis performing radical reconstructions spine, including vertebra resection, spinal canal decompression, anterior spondylodesis, posterior instrument th fixation).

Treatment-diagnostic operations include elements of the listed interventions.

Operational accesses and the means used:

• a traditional (open) method with access through a cutaneous incision providing a sufficient view;
• microsurgical method with the use of special equipment and instruments (for microsurgical interventions include laser operations performed with tuberculosis of the organ of vision);
• endoscopic method with the use of special optical devices (arthroscopy, laparoscopy, cytoscopy).

Variants of endoscopic operations are interventions performed with video-assistant surgery. The operation is performed from the closed (percutaneous) access by special manipulators, the process of performing the intervention is controlled by a monitor.

Sometimes a method is used to replace tissue defects and injured organs. The most widely performed plastic interventions for tuberculosis of bones and joints, organs of the urinary system. Use plastic materials of biological origin (grafts) or synthetic implants (implants). The possibility of using biological tissues of animal origin in extrapulmonary tuberculosis surgery is studied experimentally. However, significant legal, ethical, immunological and epidemiological limitations of their use do not allow us to hope for the introduction of this method into clinical practice in the coming years.

Plastic material for transplantation is obtained from the patient's own tissues (autograft) or from the donor (allograft). To replace defects in bone tissue and joints, grafts of cortical and spongy bone, bone-cartilaginous, perichondrial grafts are used. Distinguish free and not free bone plastic. The feeding leg is formed either only by vessels, or by tissues (vessels, periosteum, muscles). Revascularization is a special variant of transplant nutrition (an artificially created feeding leg).

When interventions on the genitourinary system, plastic surgery is performed using local tissues or by moving fragments of the hollow organs of the gastrointestinal tract (stomach, small and large intestine).

A particular type of implantation, used for osteoarticular lesions, is the complete replacement of the affected organ (segment) with an artificial prosthesis.

Rapid development of medical technologies in recent decades significantly expands the surgical treatment of extrapulmonary tuberculosis, its complications and consequences. The main clinical forms of extrapulmonary tuberculosis and indications for surgical intervention are determined. Indications for surgery are defined as absolute in the case when the method of choice for this form of extrapulmonary tuberculosis or its complication is surgery. Individual indications: the question of the operation depends on the specific clinical manifestations of the disease in a particular patient. Further development of science can expand (or reduce) indications for surgical interventions in extrapulmonary forms of tuberculosis.

Pathogenetic therapy of tuberculosis

The term "pathogenetic treatment of tuberculosis" means the use of nonspecific means of action on the body. Targets of their action are separate elements of the pathogenesis of tuberculosis, mechanisms. The defining features of the course of the disease and its outcome. Rational application of pathogenetic means is possible only when taking into account the mechanisms of pathogenesis and the influence of endogenous and exogenous factors on them.

The long experience of using antibacterial drugs in tuberculosis shows that for the clinical and "social" cure of the patient it is not enough to achieve sterilization of the focus and eliminate specific morphological changes in it. Healing of the focus leads to sclerosing, which captures a larger area than the initial tuberculosis lesion. Therefore, the role of pathogenetic agents, not only potentiating the action of anti-tuberculosis antibacterial agents, but also allowing to control imperfect reparative processes, is great. The effectiveness of etiotropic treatment determines the state of the body's defenses, the activity of which increases as a result of pathogenetic treatment.

The arsenal of means of nonspecific pathogenetic action, which phthisiologists currently have, is extensive. To limit the inflammatory reaction, glucocorticoids are used. Anti-inflammatory drugs and heparin sodium, to prevent the appearance of fibrotic changes - glucocorticoids, hyaluronidase, pyrogen, penicillamine. Adverse reactions of antibiotics are prevented or eliminated with the help of antihistamines, pyridoxine, glutamic acid, pyracetam and other drugs. Widely used immunomodulators and immunocorrectors. Often against the background of protracted anti-tuberculosis chemotherapy, the patient receives simultaneously several pathogenetic and symptomatic agents. This increases the drug load on the adaptive capabilities of the body.

The main attention is paid to the pathogenetic means of polyvalent action, which can simultaneously prevent or eliminate a number of pathophysiological disorders caused by common mechanisms.

Differences in types of pulmonary tuberculosis

Not all patients need pathogenetic treatment. In 20% of patients with newly diagnosed lung tuberculosis, it is possible to achieve clinical cure with minimal residual changes in pulmonary tissue during routine chemotherapy. However, many patients are shown individual pathogenetic therapy that takes into account the clinical manifestations and features of the course of the disease (both before treatment and at various stages of antibacterial treatment).

Due to technical difficulties, multilateral laboratory control is not always possible, therefore, general changes in patients of certain groups with clearly defined clinical manifestations of the disease (both at the time of detection of the disease and at various stages of its course against the background of therapy) are of particular importance.

There are two types of tuberculosis that differ in the clinical and biochemical aspects of pathogenesis.

The first type of flow is characterized by acute (subacute) onset of the disease, expressed manifestations of tuberculous intoxication, bacterioscopic detection of mycobacterium tuberculosis, a picture of the destruction of lung tissue on a survey radiograph. In the lungs, exudative tissue reactions predominate. The infiltrative process proceeds according to the type of recompression (infiltrates in the interlobar slot), the lobite with the formation of foci of caseous necrosis.

The second type of flow: mild manifestations (or lack of symptoms), torpid current, the absence of intoxication. The productive tissue reactions in the pulmonary tissue prevail, by the time of detection of pathogens of tuberculosis in these individuals, pathological changes in the lungs are delimited, around the separate foci of caseous necrosis are formed connective tissue membranes and foci of fibrosis. As a rule, mycobacterium tuberculosis in such patients is detected only by seeding. Destruction of pulmonary tissue is diagnosed only with a targeted tomography study.

Differences in the types of pulmonary tuberculosis are due to the interaction of anti-inflammatory and pro-inflammatory hormones. To anti-inflammatory hormones include glucocorticoids (have antihistamine effect, reduce the permeability of capillary walls and cell membranes, reduce the proliferation of fibroblasts, inhibit the interaction of antibodies with antigens). Promotes the development of inflammation mineralocorticoids and growth hormone pituitary (STH). The pro-inflammatory effect of these compounds is different: mineralocorticoids cause mobilization of endogenous histamine, promote the maturation of granules, degeneration of mucopolysaccharides and the basic substance of connective tissue; STH exerts an antinecrotic effect, stimulates exudation and an increase in the number of fibroblasts. The interaction of various hormones in the norm is balanced. Violations of this balance contribute to the occurrence of allergic reactions or anergy.

[21], [22], [23], [24]

Consecutive application of means of nonspecific pathogenetic action

Nonspecific pathogenetic agents on the background of antibacterial therapy are applied taking into account the tolerability of drugs and the resistance of mycobacteria to tuberculosis. The use of pathogenetic agents depends on the stages of the course of the tuberculosis process and the phases of etiotropic antituberculous chemotherapy. In the intensive phase of treatment, pathogenetic therapy has an anti-inflammatory and antihypoxic effect, prevents the development of adverse toxic-allergic effects of antituberculous drugs. In the second phase of antituberculous therapy, pathogenetic agents are used to stimulate reparative processes.

[25], [26], [27], [28], [29], [30],

Glucocorticoids

Glucocorticoids used in the treatment of tuberculosis have the following properties:

• anti-inflammatory effect (ability to reduce exudation and migration of cells from vessels);
• the effect of desensitization (immunosuppressive and antihistamine property);
• suppression of collagen biosynthesis.

Pharmacokinetics

The most active natural glucocorticoid - 17-hydroxy-corticosterone (hydrocortisone, cortisol) is currently used as a substitute therapy. In clinical practice, synthetic glucocorticoids with minimal mineralocorticoid activity are used.

In natural conditions, glucocorticoids are secreted in the human body periodically, episodes of increased secretion occur 8-12 times a day, the maximum hormone release - in the morning hours, in the evening and at night, the secretion of the hormone decreases (the concentration of cortisol in the blood, depending on the time of the day, can differ by 10 times ). For each individual, the circadian rhythm of the secretion is stable, it must be taken into account when performing glucocorticoid therapy.

Synthetic glucocorticoids undergo inactivation in the liver more slowly than cortisol, and have a longer period of action. Prednisylone and methyl-prednisolone - medium-duration glucocorticoids (T _1/2 from the plasma for about 200 min), triamcinolone (T _1/2 over 200 min) and dexamethasone (T _1/2 over 300 min) are long-acting drugs. Dexamethasone is not used for permanent treatment because of a circadian rhythm disturbance in the fluctuations in the concentration of glucocorticoids in the blood.

Synthetic glucocorticoids bind to albumin (about 60%), 40% of hormones circulate in the blood in a free form. With the deficiency of albumin, the amount of unbound biologically active molecules of glucocorticoids increases and side effects develop. Some medicines (eg, indomethacin) displace glucocorticoids from the complex with proteins and enhance their action.

The main synthetic glucocorticoids

Prednisolone (prednadien-1.4-triol-11β, 17α, 21-dione-3,20 or δ'-dehydrohydrocortisone) is the standard drug in pharmacodynamic therapy, doses of glucocorticoids are often indicated in terms of prednisolone. The ratio of glucocorticoid activity to mineralocorticoid activity is 300: 1.

Methylprednisolone (6-α-methylprednisolone) has less (in comparison with prednisolone) ability to stimulate appetite, is devoid of mineralocorticoid activity. 4 mg of methylprednisolone - a dose equivalent to 5 mg of prednisolone.

Triamtsanololon (9α-fluoro-16α-hydroxyprednisolone) promotes the excretion of sodium and increases diuresis, stimulates appetite a little, with application of the possible development of myopathies, hirsutism and skin rashes. The dose equivalent to 5 mg of prednisolone is 4 mg.

Dexamethasone (9α-fluoro-16α-methylprednisolone) does not have mineralocorticoid activity ("pure" glucocorticoid), inhibits pituitary function, adversely affects calcium metabolism, significantly increases appetite, and has a psychostimulating effect. The dose equivalent to 5 mg of prednisolone is 0.75 mg. As a long-acting drug, dexamethasone is not suitable for permanent reception.

Indications for use

Prednisolone is prescribed to patients with the first type of tuberculosis at the very beginning of treatment (immediately after the appointment of adequate etiotropic therapy). Patients with a second type of disease course, glucocorticoids are included in integrated therapy at 1.3-2 months from the start of treatment, since during this period the activity of mineralocorticoids increases in patients.

Glucocorticoids accelerate the formation of collagen and stimulate the formation of fibrosis as a result of the activation of the collagenase inhibitor. Since collagenase is the only enzyme that cleaves mature collagen, the use of prednisolone promotes the formation of less common but more coarse and persistent fibrous changes.

Stimulation of the formation of foci of fibrosis under the influence of prednisolone, along with a large number of contraindications to its use, justifies the limitation of its use. Prednisolone is prescribed for massive inflammatory changes in pulmonary tissue and severe allergic reactions.

Contraindications

Concomitant diseases (diabetes mellitus, hypertension II-III stages, peptic ulcer and duodenal ulcer, ulcerative colitis, mental illness), chronic alcoholism, the presence of scarring wounds.

[31],

Method of use

The dose of glucocorticoids for pathogenetic treatment of tuberculosis is (in terms of prednisolone) 15 mg per day for persons weighing less than 65 kg and 20 mg for persons weighing more than 65 kg. This dose is received for 4 weeks: at 9.00 - 10 mg (2 tablets), at 14.00 - 5 mg (1 tablet) at a dose of 15 mg per day: at 9.00 - 10 mg (2 tablets), at 10.00 - 10 mg (2 tablets) at a dose of 20 mg per day. Take the drug after 16 hours is not recommended.

During the main course of treatment with glucocorticoids, the attending physician should measure blood pressure at least twice a week, carefully monitor the general condition of the patient (pay attention to the occurrence of anxiety, worsening of sleep). During the period of treatment, moderate leukocytosis may appear in the blood, shifting the leukocyte formula to the left. After the abolition of glucocorticoids, the changed clinical and laboratory parameters are normalized.

Glucocorticoids are canceled gradually, starting with the 6th week of their intake, the daily dose is reduced by 5 mg (in terms of prednisolone) during each subsequent week until the complete elimination of glucocorticoids. In the process of reducing the dose of the drug should carefully monitor the overall condition of the patient.

When there is a decrease in the dose of glucocorticoids arthralgia, weakness, decreased appetite, the course of treatment is prolonged for 1-2 weeks. During which the patient receives 2.5 mg of prednisolone per day.

Throughout the period of glucocorticoids, patients should receive preparations containing potassium (potassium and magnesium asparaginate), ascorbic acid in standard doses. Given the catabolic effect of glucocorticoids, during the period of their cancellation and within 7 days after discontinuation of the drug, it is advisable to prescribe antihistamines in standard doses.

Hyaluronidase

Indications for use

Hyaluronidase is used at the beginning of treatment in patients with a second type of pulmonary tuberculosis. In patients with the first type of disease, hyaluronidase is prescribed in the second period 2-3 weeks after the end of the course of treatment with prednisone, provided the continued release of mycobacterium tuberculosis. In the third period, the drug is used in patients with the first and second types of disease course to reduce the severity of residual changes in the pulmonary tissue.

Contraindications

Adverse allergic reactions to antibacterial drugs, repeated bleeding. The drug can not be used during the reconvalescence period after surgery, during the recovery period after fractures of the bones.

[32],

Method of application

Hyaluronidase is administered intramuscularly at a dose of 64 units a day. 15 injections per course. With the continued allocation of mycobacterium tuberculosis treatment is repeated. The interval between the two courses is 1 month.

Pyrogenal

Pyrogenal is prescribed in the second period (2-4 months from the start of therapy) for patients with the first type of disease course. In time this coincides with the end of the course of treatment with prednisolone. It is advisable to observe an interval of 2-3 weeks between the end of the course of treatment with prednisolone and the beginning of treatment with pyrogenal.

Indications for pyrogenal use

Preservation of cavities on the background of fibrotic changes in the pulmonary tissue and areas of caseous necrosis, the tendency to form tuberculosis.

Contraindications

Fever, pronounced adverse allergic effects of antibacterial drugs, repeated pulmonary hemorrhage.

In the third period (4 months or more from the start of treatment), pyrogenal is used in the complex therapy of patients with the first and second types of disease course in the presence of residual cavities.

[33], [34]

Application Scheme

Pyrogenal is administered intramuscularly at a dose of 50 MTD (minimal pyrogenic doses) every other day, with a gradual increase in the dose by 50-100 MTD, the maximum single dose reaches 1800-2000 MTD, the course dose is 19,000-20,000 MTD.

The reaction to the administration of pyrogenal appears after 2 hours (or later) after application of the drug and is expressed in worsening of general health, headaches, arthralgia, subfebrile temperature. The next day these phenomena pass, there are changes in the leukocyte formula (leukocytosis to 10 thousand, shift of the leukocyte formula to the left), an increase in ESR to 15-20 mm / h. In some patients, with the described changes, there is no clinical symptomatology.

If severe reactions (fever, rise in body temperature to 38 ^on C) pirogenal continue administered at a dose that caused this response. With more pronounced (maximum) reactions to the administration of pyrogenal (convulsions, nausea, vomiting, an increase in body temperature to 40 ° C, a sharp increase in the number of leukocytes to 35,000-40,000, a pronounced shift of the leukocyte formula to the left), pyrogenal is discontinued. Usually, all the side effects disappear in a day, the condition of the patients is normalized.

It should be noted that in the absence of any adverse reactions in response to the administration of pyrogenal, the effect of treatment is minimal.

With positive radiological dynamics, one more course of pyrogenal treatment is carried out after a three-week break.

[35], [36], [37],

Antioxidants

Hyaluronidase and pyrogenal are not recommended for use alone to limit the formation of fibrotic changes or to affect the formed fibrous structures. When treating patients with pulmonary tuberculosis, it is necessary to use nonspecific pathogenetic agents that have different effects: anti-inflammatory, antiallergic, antitoxic, antifibrotic and stimulating reparative processes.

Such effects are possessed by antioxidants regulating LPO processes in biological membranes - the fundamental molecular mechanism of the development of many pathological processes.

Peroxide oxidation of lipids - the formation of an excess of free radicals (highly reactive molecules carrying an unpaired electron). Combining with molecular oxygen, free radicals form new free radicals - peroxide radicals. They interact with a constituent of the biological membrane - an unsaturated fatty acid molecule with the formation of highly toxic hydroperoxides and free radicals. The chain process can be interrupted only by interaction with the antioxidant (an antioxidant radical is formed which is incapable of continuation of the chain). Interest in the problem of LPO is due to the fact that the intensification of this process is accompanied by an intensification of the inflammatory reaction and the formation of fibrotic changes, the development of toxic reactions from the cardiovascular system, liver, pancreas and other organs. LPO products suppress repair processes.

The impact on LPO processes with the help of antioxidants opens up additional opportunities in the treatment of tuberculosis patients. The activity of LPO detected during tuberculosis and the inadequacy of antioxidant protection in both types of disease course (decrease in the blood of the main antioxidant of the human body - α-tocopherol) explain the expediency of using the phthisiatric clinic of antioxidants in complex treatment of patients.

Currently, two antioxidants are used: vitamin E and sodium thiosulfate. These drugs are able to influence the fundamental mechanisms of LPO, which under stress conditions contribute to the development of pathological conditions.

Antioxidants are advisable to use at the initial stage of treatment for the first type of disease course, and for the second type - 2-3 months after the start of treatment.

Indications for use

Vitamin E is an important structural component of membrane lipids, preventing accumulation of peroxides by interaction with free radicals, which results in the formation of an antioxidant radical. Sodium thiosulfate does not have antiradical activity, but it is considered to be an antioxidant, since it inhibits the accumulation of peroxides, reducing the oxidation rate of unsaturated fatty acids. The antioxidant effect of sodium thiosulfate is somewhat less than the effect of vitamin E, but the drug has a broad spectrum of pharmacological activity and a pronounced antiallergic effect.

Vitamin E interferes with the formation of foci of fibrosis. This property is necessary for the treatment of the second type of tuberculosis.

The given data allow to define the differentiated indications for the application of vitamin E and sodium thiosulfate in the complex treatment of patients with pulmonary tuberculosis.

Sodium thiosulfate is indicated for the prevention and elimination of side effects of antituberculous preparations of an allergic nature. The use of sodium thiosulfate is the method of choice for infiltrative tuberculosis with predominantly exudative tissue reactions and fibro-cavernous tuberculosis.

Vitamin E is used to prevent and eliminate side effects of toxic antibiotics in the treatment of patients with infiltrative tuberculosis (both with productive and exudative tissue reactions). The drug is prescribed to prevent the formation of respiratory failure or correction of respiratory failure of grade III in patients with fibrous-cavernous pulmonary tuberculosis.

[38], [39], [40], [41], [42], [43],

Stimulating therapy

Biogenic stimulators (plasmin, aloe extract) are prescribed for chronic, torpidly occurring forms (focal, infiltrative, disseminated, fibro-cavernous) and patients with a newly diagnosed process after 2-3 months of chemotherapy. 1 ml subcutaneously every day or every other day.

Pyrogenic stimulants (bacterial polysaccharides) promote the resorption of infiltrative changes and foci, a decrease in the size of caverns and their subsequent closure. Prodigiozan - 1-2 ml intramuscularly once a week (5-6 injections).

Pyrogenal - starting with a dose of 20-25 MTD intramuscularly every other day with a gradual increase of 25-50 MTD. The last dose is 1000 MTD (individual dose selection due to different tolerability).

Bone marrow preparations

Myelopid is a preparation of a peptide nature, obtained by cultivation of cellular elements of bone marrow of pigs or calves. It restores the indices of the B- and T-links of the immune system, stimulates the production of antibodies. Form release: lyophilized powder in 10 ml vials (3 mg of the drug). Introduction subcutaneously for 3-6 mg daily or every other day, a course of 3-5 injections.

Thymic hormones are polypeptides from the thymus gland of cattle, normalize the level and enhance the differentiation of T cells, their functional activity.

Timalin (thymus extract), form of release: in a vial, for injections of 5-10 mg. Intramuscular injection of 5-20 mg per day for 7-10 days. Repeated course can be done after 1-6 months

Tactivine (thymus extract), form of release: in 0.01% solution in a vial of 1 ml. Introduction subcutaneously in the upper third of the shoulder 1 time per day (at night) from the calculation of 40 mcg / m ² body surface (1-2 mcg / kg) for 5-14 days.

Tystimulin is 1 mg / kg daily for 14 days, then 2 times a week for 12 weeks.

Timoptin - form of release: in bottles of 100 μg of the drug. Introduction subcutaneously, course 4-5 injections with 4-day intervals.

[44], [45], [46], [47], [48], [49], [50], [51], [52], [53]

Immunotherapy in the treatment of tuberculosis

One of the components of the comprehensive treatment of respiratory tuberculosis is the correction of secondary immunodeficiency states. The results of a meta-analysis so far do not allow to classify immunotherapy facilities as having high level of evidence. In patients with active forms of tuberculosis, a violation of the majority of indicators of cellular and humoral immunity is revealed. In particular, the following changes:

• ratio of populations and subpopulations of lymphocytes;
• phagocytic activity of blood cells;
• the content of IgA, IgM, IgG, IgE;
• the content of cytokines.

There are various classifications of immunomodulators. In accordance with the classification proposed by PM Haitov and B.V. Pinegin (1996, 2002), distinguish:

• preparations of microbial origin - BCG vaccine, tuberculin, pyrogenal, prodigiozan, ribomunil, sodium nucleate,
• preparations of endogenous origin, including thymic (thymus extract, imunophane, etc.);
• preparations of bone-marrow origin (myelopid);
• cytokines: leukocyte human interferon, IL-1β, IL-2, molragostim;
• synthetic and semisynthetic (levamisole, glutoxim, polyoxidonium, lycopide).

The classification proposed by M.M. Averbakhom (1980), involves the allocation of immunomodulators specific for tuberculosis inflammation (tuberculin, BCG vaccine), and non-specific drugs (levamisole, thymus preparations, sodium nucleate, methyluracil, etc.).

In the practice of phthisiology, the use of modern immunomodulating agents such as human leukocyte interferon, polyoxidonium, lycopide, glutoxim, interleukin-2 human recombinant is the most common in recent times. At the same time, nonspecific immunomodulating agents, which have been used for a long time in phthisiology: levamisole, sodium nucleate, methyluracil, thymus preparations and others, have not lost their meaning, as well as such specific immunotherapy facilities for tuberculosis patients as tuberculin and BCG vaccine.

Tuberculinotherapy

Currently, tuberculin therapy uses purified tuberculin in standard dilution (allergen tubercle purified liquid in standard dilution).

The mechanism of action of tuberculin therapy:

• decreased excitability of the nervous system;
• increased lymphatic circulation;
• expansion of capillaries in the affected area;
• increased permeability of histohematological barriers:
• increased phagocytic function of the reticuloendothelial system;
• intensification of reactive processes in tuberculosis foci;
• activation of proteolytic systems.

It is also believed that the therapeutic effect of tuberculin is based on the "antigen-antibody" reaction. Some authors note the desensitizing effect of tuberculin. A more pronounced effect of tuberculin therapy in patients with pulmonary tuberculosis with high sensitization and reduced overall reactivity of the body. Tuberculinotherapy is prescribed to enhance reparative reactions with delayed involution of specific changes in the lungs.

The method of electrophoresis of tuberculin

The initial dose of injected tuberculin is 5 TE PPD-L, and at each session it increases by 5 TE. The dose of injected tuberculin is set individually for each patient, by the end of the course it is as much as 100 TE.

Electrophoresis tuberculin is carried out using electrodes used for galvanization, tuberculin in the required dose is applied to previously moistened with warm distilled water gaskets and injected from the positive pole. The patient in the lying position electrodes tightly placed on the chest, respectively, the projection of the affected area of the lung. The current is determined by focusing on the sensations of the patient (light tingling on the skin under the electrodes), but it should not be above 10 mA. The duration of tissue electrophoresis is 20 minutes. An average of 20 sessions. It is recommended to perform tuberculin therapy with an intermittent method (sessions 3 times a week every other day). The question of the course dose of tuberculin and the number of electrophoresis sessions is decided individually, depending on the form of the tuberculosis process in the lungs, the clinical and radiological and laboratory studies, the purpose of tuberculin therapy, and also specify in the process of tuberculin therapy, taking into account the patient's tolerability, the dynamics of x-ray tomographic and laboratory data research. Even with a good tolerability of treatment it is desirable to conduct a control x-ray examination in the middle of the course (at a dose of tuberculin 40-50 TE). When there is a general, local or combined reaction in a patient to tuberculin, the subsequent administration is performed in the same dose. If necessary, the course of tuberculin therapy can be repeated with a break of 1-1.5 months.

The course of tuberculin therapy is recommended to be carried out in all cases against the background of adequate chemotherapy, within a period of 2 weeks or more from the moment of its onset. An indispensable condition is the patient's tolerance of the chemotherapy used. It is desirable to prescribe tuberculin therapy for patients on inpatient treatment in an anti-tuberculosis facility (specialist department) to ensure better control of patients' tolerability of treatment. However, this requirement is not mandatory, given the good tolerability of procedures by patients.

Indications for prescription

• clinical;
• active forms of pulmonary tuberculosis with a tendency to become drained and formed by tuberculosis, with delayed involution of the cavities of decay;
• predominantly productive type of inflammatory reaction;
• immunological;
• medium and high tigers of antibodies to the causative agent of tuberculosis (IgG) in ELISA ,. If they have a high level of sensitivity to tuberculin.

Form release: a solution of purified tuberculin in ampoules of 5 ml. Containing 2 TE PPD-L in 0.1 ml. BCG therapy

Mechanism of action

• stimulates the body's reactivity:
• activates reparative processes.

Method of vaccine therapy

The method of vaccine therapy consists in the introduction of the vaccine in subthreshold doses, which have a pronounced therapeutic effect and at the same time are completely safe for patients. The therapeutic dose of BCG is determined by the results of a Mantoux test with 2 TE. The magnitude of the vaccine dose is inversely related to the severity of the response to tuberculin. If the patient has an infiltrate from 1 to 15 mm in diameter, the treatment starts with a more concentrated BCG suspension: 0.1 ml of the third consecutive 10-fold dilution of the vaccine. With an infiltrate of 16-21 mm, 0.1 ml of the fourth consecutive 10-fold dilution of the vaccine is administered. If the infiltration is more than 21 mm. Then 0.1 ml of the fifth consecutive 10-fold dilution of the vaccine is administered. After establishing the initial dose of the vaccine, the appropriate dilution of the BCG vaccine is administered strictly intradermally at the border of the middle and upper third of the outer surface of the shoulder in successively increasing doses according to the following scheme:

1. 0.000001 mg (0.1 ml of the fifth 10-fold dilution of the vaccine);
2. 0.00001 mg (0.1 ml of the fourth 10-fold dilution of the vaccine);
3. 0.0001 mg (0.1 ml of the third 10-fold dilution of the vaccine);
4. 0.001 mg (0.1 ml of the second 10-fold dilution of the vaccine):
5. 0.01 mg (0.1 ml of the first 10-fold dilution of the vaccine).

Each subsequent injection is done 3-4 weeks after the reaction fading away at the site of the previous one. As a rule, to obtain the optimal effect, it is sufficient to make 3 injections. The number of injections is set individually for each patient.

Indications for prescription

• clinical:
  • active forms of pulmonary tuberculosis with the presence of infiltration and destruction of the lung tissue;
  • predominantly exudative type of inflammatory reaction.
• immunological:
  • low and medium titers of antibodies to the causative agent of tuberculosis (IgG) in ELISA, regardless of their correlation with the level of sensitivity to tuberculin.

Form release: vaccine for tuberculosis (BCG) dry for intradermal administration - ampoules containing 0.5 mg (10 doses) or 1.0 mg (20 doses) of the preparation complete with a solvent - 0.9% solution of sodium chloride.

Interleukin-2 human recombinant

The structural and functional analogue of endogenous IL-2 is isolated from the cells of non-pathogenic baker's yeast Saccharomyces cerevisiae. in the genetic apparatus of which the human IL-2 gene is inserted. The immunotropic effects of human IL-2 recombinant (rhyikoleukin) include the reduction of endogenous IL-2 synthesis by activated CD4 ⁺ and CD8 ⁺ cells.

Mechanism of action

• compensates for the deficiency of endogenous IL-2;
• affects the target cells: NK cells, T-helpers, cytotoxic T-lymphocytes, B-lymphocytes, monocytes, being a factor in the activation of proliferation and differentiation;
• regulates Th1 / Th2-balance;
• Abolishes immunological tolerance, protects activated T cells from premature death;
• performs interaction and regulation of the mechanisms of congenital and acquired immunity;
• stimulates the realization of a dependent and antigen independent immune response, affects the cellular and humoral units of immunity.

Indications for prescription

• clinical:
  • destructive pulmonary tuberculosis with prevalence of exudative inflammation (including caused by drug-resistant strains of mycobacterium tuberculosis);
  • fibro-cavernous tuberculosis of the lungs in the phase of an uncontrollable progression of the process with massive bacterial release against the background of ongoing polychemotherapy;
• immunological:
  • insufficiency of the cellular immune system (lymphocyte count ≤18%, RBTL with PHA ≤50%, RBTL for PPD-L <3%, production of induced PHA IL-2 <10.0 U / ml);
  • with a decrease in lymphocyte count ≤1200 cells / ml. Of mature T-lymphocytes ≤55%. The CD4 / CD8 index ≤1.5, the PBT for PHA ≤50%, the RBT for PPD ≤ 3%, and the PHA-induced IL-2 production ≤5 U / ml in patients with fibrous cavernous tuberculosis during the preparation for the operation.

Schemes of application:

• with progressing, acute progressive forms of pulmonary tuberculosis (infiltrative, disseminated, caseous pneumonia): intravenous drip administration every other day three times (in 500 ml of 0.9% solution of sodium chloride, the stabilizer of the infusion medium is serum human albumin 10% - 10 ml). The rate of administration is 10-14 drops per minute. Single dose 500 000 ME; the course dose of 1500 000 ME.
• with progressive fibrous-cavernous pulmonary tuberculosis: a standard schedule (exchange dose of 3 million ME) - 1 million ME in 48 hours three times; prolonged scheme (the course dose of 7 million ME) - the first week of 1 million ME in 48 hours three times, then 1 million ME 2 times a week for 2 weeks.

Form release: ampoules from neutral glass containing 0.25 mg (250,000 IU), 0.5 mg (500,000 IU), 1 mg (1,000,000 IU) of a freeze dried preparation.

Human interleukin-1 beta is recombinant

The drug was obtained by genetic engineering from E. Colli. Human interleukin-1β is a recombinant (betaleukin) polypeptide with a molecular weight of 18 kDa.

Mechanism of action

• increases the functional activity of neutrophilic granulocytes;
• induces differentiation of T-lymphocyte progenitors;
• enhances IL-2-dependent cell proliferation;
• increases antibody formation.

Indications for prescription

• clinical:
  • the first detected pulmonary tuberculosis of limited length with prevalence of a productive type of tissue reaction (with and without destruction);
  • preservation of the average size of productive foci in the pulmonary tissue and "residual" cavities for 4-5 months of treatment, regardless of the initial form of pulmonary tuberculosis;
• immunological:
  • the number of lymphocytes ≤18%; RBTL on PPD-L <3% or ≥5%. With the PHA-induced production of IL-2 within the norm (≥10.0 U / ml).

Mode of application

Apply in a dose of 5 ng / kg, dissolve in 500.0 ml of 0.9% sodium chloride solution. Enter intravenously drip for 3 hours, daily, the course - 5 procedures.

Form release: ampoules (bottles) of neutral glass containing 0.001 mg (1000 ng), 0.0005 mg (500 ng), 0.00005 mg (50 ng) of the lyophilized preparation.

Polyoxidonium

Polyoxidonium-copolymer of N-hydroxy-1,4-ethylene-piperazine and (N-carboxyethyl) -1,4-ethylene-piperazinium bromide is a high molecular weight physiologically active compound with pronounced immunotropic properties.

Mechanism of action

• immunomodulator, restores and activates the functions of the three most important subpopulations of phagocytes: mobile tissue macrophages, circulating blood phagocytes, sedentary phagocytes of the reticuloendothelial tissue;
• detoxicant: the ability of functional groups of polyoxidonium to interact with highly reactive compounds;
• antioxidant;
• membrane stabilizer.

It has pronounced detoxification properties, does not cause allergic reactions, is well tolerated by patients, is well combined with antibiotics, antihistamines and corticosteroids; the drug is used for various infectious and non-infectious pathologies. Normalization of the immune status in patients with tuberculosis with the use of polyoxidonium is manifested by the rapid excretion of the CIC, stimulation of the previously lost functional activity of cells of the macrophage link. Polyoxidonium activates both oxygen-dependent and oxygen-dependent mechanisms of bactericidal phagocytes. The target cells for polyoxidonium are primarily monocytes / macrophages, neutrophils and NK cells.

The inclusion of polyoxidonium in the complex therapy of patients with pulmonary tuberculosis has a pronounced clinical effect, manifested by the elimination of intoxication in shorter periods, the acceleration of the processes of resorption of infiltrative changes and the closing of the destruction of the pulmonary tissue. As a result of immunotherapy with polyoxidonium, an increase in the absorptivity of monocytes, an increase in the relative content of CD3 ⁺ lymphocytes, a decrease in the initially increased functional activity of neutrophils estimated in chemiluminescent tests are noted . By the nature of the effect on the immune system, polyoxidonium is a true immunomodulator: it increases the lowered and reduces the increased indices of the functional activity of neutrophils, without affecting the unchanged immunological indices.

Indications for use in patients with respiratory tuberculosis

• clinical:
  • active tuberculosis of the lungs with the presence of general intoxication of the body, infiltration, destruction of the lung tissue, progressive and acute progressive forms of pulmonary tuberculosis.

Indications for endobronchial administration of polyoxidonium:

• bronchial tuberculosis, destructive forms of pulmonary tuberculosis;
• immunological:
  • high serum IgA level (400 mg / dl and above), high level of spontaneous luminol-dependent chemiluminescence (L3XL) (30 mV / min), low level of spontaneous LZXL (1.5 mV / min and lower), low relative lymphocyte content in peripheral blood (20% and below).

Mode of application

Intramuscular and endobronchial (ultrasonic inhalation) administration of polyoxidonium at 6 mg twice a week - 10 injections for 5 weeks.

Form release: ampoules of neutral glass, containing 0.006 g of polyoxidonium.

Interferon leukocyte human

It is a complex of natural interferons-α and other cytokines of the first phase of the immune response (IL-1, IL-6, IL-8 and IL-12, TNF-α, macrophage and leukocyte migration inhibition factors) in their natural ratio, immunomodulating, anti-inflammatory and detoxifying effect.

Mechanism of action

• normalization of phagocytic function and activity of B-lymphocytes;
• stimulating effect on T-cell immunity with preferential activation of T-helper type 1: activation of lymphocytes is manifested by stimulation of T-lymphocyte differentiation, normalization of CD4 ⁺ / CD8 ⁺ ratio , stimulation of lymphoid infiltration of inflammatory foci;
• activation of all parameters of phagocytosis: killing function, number of phagocytic cells and their activity;
• normalization of hematological parameters (elimination of leukocytosis, leukopenia, normalization of the number of platelets, lymphocytes, neutrophils, erythrocytes).

Inclusion of the drug in the complex therapy of tuberculosis patients helps to accelerate the regression of symptoms of intoxication, as well as to improve the tolerability of anti-tuberculosis drugs.

Indications for prescription

• clinical:
  • the newly diagnosed forms of active pulmonary tuberculosis are limited and common; predominantly exudative type of inflammatory reaction.
• immunological:
  • stimulating effect of leukinferon on the phagocytic activity of polymorphonuclear leukocytes in an in vitro test , in a clinical blood test - changes in the leukocyte formula.

Mode of application

Intramuscular, endobronchial injection (ultrasonic inhalation), as well as a combination of routes of administration. Single dose 10 000 ME; course dose of 100,000-160000 ME. Perhaps intrapleural, endolymphatic, and endobronchial (with endoscopic examination) drug administration. The minimum course of treatment is 3-4 weeks, but longer courses (3-6 months or more) are desirable until stable remission is achieved.

Form release: ampoules of neutral glass, containing 10 thousand ME by interferon-α.

Lycopid

Likopid (glucosaminylmuramyl dipeptide) is a drug of the muramylpeptide series, which has immunotropic activity. By chemical structure, this is N-acetyl-lglucosaminyl-N-acetylmuramyl-L-alanyl-D-isoglutamine. The drug has a multi-faceted effect on the human immune system, stimulating the development of both cellular and humoral immune response, stimulates leukopoiesis, has anti-infection and antitumor activity. Likopid - a synthetic analogue of the cell wall component of all bacteria, which has pronounced immunomodulatory properties.

Mechanism of action

The main point of application of lycopene in the body are cells of the monocyte-macrophage system, activating which the lycopide raises:

• activity of lysosomal enzymes:
• formation of reactive oxygen species;
• absorption and killing of microbes;
• cytotoxic properties with respect to virus-infected and tumor cells;
• the expression of HLA-DR antigens;
• synthesis of cytokines: IL-1 ,. TNF, colony-stimulating factor, IFN-γ.

The immunological effect of the inclusion of lycopene in the complex therapy of tuberculosis patients is manifested by an increase in the total number of T-lymphocytes. Increased absorption and bactericidal functions of phagocytes. The clinical effect of lycopid immunotherapy in patients with pulmonary tuberculosis is characterized by an acceleration of the processes of elimination of general intoxication, resorption of infiltrative changes and closure of destruction of the lung tissue, as well as cessation of bacterial release in shorter periods.

Indications for prescription

• clinical:
  • the newly diagnosed and chronic forms of pulmonary tuberculosis, including widespread infiltrative tuberculosis, caseous pneumonia, the progression of chronic forms of tuberculosis;
  • forms of pulmonary tuberculosis with intoxication, the prevalence of destruction, destruction of the lung tissue, massive bacterial release;
  • with delayed clinical and radiologic regression of tuberculosis changes in the lungs;
  • when tuberculosis is combined with inflammatory nonspecific respiratory diseases;
• immunological:
  • decrease in the absorption and bactericidal functions of phagocytes; decrease in the number and functional activity of T-lymphocytes and their subpopulations;
  • imbalance of helpers and cytotoxic lymphocytes with normal T cell content.

Mode of application

• with limited forms of tuberculosis of respiratory organs proceeding with scant bacterial excretion, without destruction or with a small cavity of decay in the pulmonary tissue and delayed regression of the lesion - 1-2 courses of 1 tablet (10 mg) on an empty stomach for 10 consecutive days. Breaks between courses for 2 weeks;
• with extensive, widespread forms of tuberculosis of the respiratory system - 1 tablet (10 mg) in the morning on an empty stomach for 10 consecutive days in two courses;
• with chronic forms of tuberculosis - 3 courses of 10 mg in the morning on an empty stomach for 10 consecutive days with 2-week breaks.

Form release: tablets of 10 pieces in a blister in two dosages - 1 mg and 10 mg.

Glutoxime

Glutoxim - bis- (gamma-L-glutamyl) -L-cysteine-bis-glycine-disodium salt - refers to a subgroup of low-molecular immunomodulators. The drug belongs to a new class of drugs - thiopoietins, which modulate the intracellular processes of thiol metabolism, promote the initiation of the cytokine system, activate phagocytosis and increase the activity of tissue macrophages. Being a structural analogue of oxidized glutathione, glutoxim has high bioavailability. A number of investigators have demonstrated the high efficiency of glutoxim as a means of preventing and treating secondary immunodeficient conditions associated with radiation, chemical and infectious factors, acute and chronic viral hepatitis B and C, and with postoperative complications.

Under the experimental conditions, it was confirmed that the positive effect of glutoxim on the functional activity of peritoneal macrophages is significant in the mechanism of the therapeutic action of glutoxim: stimulation of their absorbing and digesting capacity, as well as the production of superoxide radicals, is found.

Mechanism of action

• affects the oxidation-reduction metabolism of the cell;
• stimulates endogenous production of cytokines and homoepoietic factors, including IL-1, IL-4, IL-6, IL-8, IL-10, TNF, IFN, erythropoietin;
• reproduces the effects of IL-2 through the expression of its receptors;
• has a differentiated effect on normal (stimulation of proliferation and differentiation) and transformed (induction of apoptosis) cells;
• produces a systemic cytoprotective effect.

Clinical efficacy of glutoxim in patients with pulmonary tuberculosis is manifested by a reduction in the timing of elimination of intoxication, normalization of the parameters of the clinical blood test (restores the level of neutrophils, monocytes and lymphocytes in the peripheral blood) and sputum smear in patients with bacterial discharges. The inclusion of glutoxim in the complex treatment of tuberculosis allows for a more pronounced resolution of infiltrative changes in the pulmonary tissue, perifocal and pericavital infiltration, a decrease in the size of the foci, and a partial regression of caseous-pneumonic foci.

Mode of application

In the complex therapy of tuberculosis, glutoxim is used daily at a daily dose of 60 mg (30 mg 2 times a day) intravenously or intramuscularly for 2 months. After the transition of a specific inflammation to the productive phase is prescribed intramuscularly 1-2 times a day 3 times a week at a daily dose of 10-20 mg for 1-2 months.

Form release: injection for 1% and 0.5% (1 ml ampoules and 2 ml).

Derinath

Derinat (sodium salt of a 2-helix highly purified depolymerized native deoxyribonucleic acid of low molecular weight) has antioxidant and membrane-stabilizing properties, detoxifying action.

Immunotropic effect is manifested:

• an increase in the number of lymphocytes (T-lymphocytes: an increase in the number and percentage of mature lymphocytes, CD4 ⁺, CD8 ⁺, CD25 ⁺ T cells, an increase in the number of NK cells);
• restoration of bactericidal activity of leukocytes;
• influence on humoral factors (complement activation, decrease or increase in CEC, increase in the number of total and activated B-lymphocytes):
• influence on phagocytosis (increase in adhesion, increase in the number and activity of neutrophils and macrophages).

The use of derinata in the complex therapy of pulmonary tuberculosis increases the immunoregulatory index (Th1 / Th2), reduces the negative impact of the anti-TB drugs used, and improves the overall clinical state of patients.

Mode of application

As part of complex therapy, Derinat is used intramuscularly (from 5 to 10 injections per course). The first 5 injections are performed daily, the next 5 injections - after 48 hours.

Form release: injection for 1.5% (ampoules of 5 ml).

[54], [55], [56],

Tyloron

Tyloron (dihydrochloride-2,7-bis [2 (diethylamino) -ethoxy] -fluorene-9-OH-dihydrochloride) is an oral low-molecular synthetic inducer of endogenous IFN-γ, has a direct antiviral effect.

Mechanism of action

• restores the ratio of T-helpers / T-suppressors;
• increases the activity of natural killers;
• normalizes the humoral immune response;
• regulates pro and contra inflammatory cytokines.

Clinical effect in patients with pulmonary tuberculosis manifests itself more quickly elimination of clinical manifestations, more frequent cessation of bacterial release, more frequent closure of destruction of lung tissue.

Mode of application

In the first 2 days to 0.25 g, then to 0.125 g every other day, for a course of 20 tablets.

Form release: tablets of 0.125 grams and 0.06 grams, coated with a shell.

Levamisole

Levamisole is a synthetic immunomodulator.

Mechanism of action

• accelerates the differentiation and maturation of T-lymphocytes;
• stimulates the function of mature T-lymphocytes;
• increases the activity of natural killers, macrophages, T-suppressors;
• stimulates interferon formation, activates lymphocytes;
• selectively stimulates cellular immunity (imitation of the action of the thymus hormone);
• stimulates the function of lymphocytes irrespective of their role in the immune response:
• increases the production of lymphocytes by lymphocytes (a factor inhibiting the migration of lymphocytes, and a factor that activates macrophages);
• affects the functional state of macrophages - increases their antigen-presenting function and phagocytic activity of mononuclear phagocytes;
• restores disturbances of cellular immunity and interaction of T- and B-lymphocytes; not so much changes the level of T- or B-lymphocytes, how much reduces the number of inactive lymphocytes;
• inhibits the formation of immune complexes and antibodies.

Does not increase immunological responses above normal levels.

Mode of application

Inside for 100 mg or 150 mg per day once 3 times a week for 8 weeks.

Product: 1 tablet (150 mg) per package.

Methyluracil

Methyluracil is a synthetic (chemically pure) substance that has a predominant effect on nonspecific defense factors.

Mechanism of action

• accelerates the processes of cellular regeneration;
• stimulates cellular and humoral defense factors;
• has immunostimulating and anti-inflammatory action:
• is a stimulator of leukopoiesis;
• has anabolic and anti-catabolic activity.

Dosing and Administration

Adults 0.5 g 4 times a day during and after meals.

Product: tablets of 500 mg.

[57], [58], [59], [60]

Physical methods of treatment of tuberculosis

Despite the main importance and obvious effectiveness of modern regimens of chemotherapy, physical methods are still widely used in phthisiopulmonology and remain an important reserve for increasing the effectiveness of treatment of tuberculosis. Physical factors as a component of pathogenetic influence are not alternative with respect to drug therapy, they do not replace it, but supplement and potentiate the possibilities of antibacterial agents.

Adequate clinical situation the use of physiotherapeutic factors stimulates the processes of repair of pulmonary tissue, accelerates the regress of tubercular inflammation, which is manifested by a reduction in the timing of closure of the destruction cavities and the cessation of bacterial release, and determines not only the clinical but also the economic effectiveness of the method due to a reduction in the duration of the inpatient stage of treatment. At the same time, it should be emphasized that unqualified use of physical factors in complex therapy of patients can be dangerous, for example, the appointment of stimulating methods before surgery or in case of ineffective chemotherapy.

The purpose of physiotherapy must be preceded by a detailed analysis of the nature of the course of a specific process. In this case, you should consider:

• clinical form of the process;
• type of tissue reaction (exudative, proliferative);
• localization and length of the process;
• age and adaptability of the patient;
• presence and severity of concomitant pathology.

Indications for the use of physical factors against the background of standardized chemotherapy are all clinical forms of newly diagnosed active tuberculosis of respiratory organs, but their purpose is most appropriate.

• at the widespread (more than 1 segment) or accompanied by clinical displays forms after the beginning of adequate chemotherapy and reduction of symptoms of intoxication;
• with delayed regression of specific inflammation;
• with the preservation of destructive changes in the lungs;
• with concomitant broncho-obstructive syndrome, the presence of "blocked" caverns.

Contraindications for the use of all physical methods

General contraindications:

• hypertensive disease II-III stages, with frequent crises;
• ischemic disease of III-IV functional classes, life-threatening rhythm disturbances;
• the presence of malignant and benign neoplasms (uterine myoma, prostate adenoma, mastopathy, endometriosis, lipomatosis, neurofibromatosis);
• decompensated disorders of circulatory, respiratory, blood coagulation, other basic life support systems;
• pregnancy;
• individual intolerance to the factor.

Contraindications caused by the tuberculosis process:

• progression of a specific inflammation in the form of fever, an increase in intoxication syndrome, an increase in infiltrative changes and the appearance of new cavities of destruction;
• inadequate antibiotic therapy due to intolerance to chemotherapy or multidrug resistance of the mycobacterial population;
• hemoptysis or pulmonary hemorrhage.

In addition, for each of the physical factors, there are specific limitations to the application, the data of which are given in the description of the method.

Characteristics of the main physical factors of treatment

All the physical factors used in the complex of therapeutic effects in tuberculosis, according to the nature of the therapeutic effect, can be divided into three groups with a certain degree of conventionality.

The first group includes physical factors, which are predominantly anti-inflammatory. Including tuberculostatic, and hyposensitizing effects. The methods of treatment based on them also contribute to increasing the concentration of antibacterial drugs in the inflammatory focus, activation of local protective tissue reactions. The main representatives of this group include: exposure to electromagnetic radiation of the ultrahigh-frequency range (UHF-therapy). Extremely high-frequency (millimeter) range (EHF-therapy), as well as combined physical and medicamentous effects - inhalation therapy, electrophoresis. They are prescribed in the initial stage of pulmonary tuberculosis with predominantly exudative-necrotic type of inflammation.

The second group of factors include ultrasound, laser and magnetotherapy, which contribute to resorption of the tuberculosis process, increasing the ability of tissues to regenerate and repair, accelerating cicatrization and fistula healing. This group of factors is used for 2-3 months from the beginning of high-grade chemotherapy. During this period, the specific process in the pulmonary parenchyma undergoes reverse development. There is a resorption of infiltrative changes, scarring of the cavities of destruction, fibrosis of the foci. The application of physical factors of the 2nd group allows to accelerate these processes. In addition, the multicomponent clinical effects of laser and magneto-laser therapy appear to be distinct and in many ways unique biostimulating and adaptogenic action. Promoting stabilization of homeostasis and activation of the natural protective mechanisms of the patient's body. Physiotherapeutic methods of the 2nd group are most effective in the period of the change of exudative-necrotic type of inflammatory tissue reaction to proliferative.

The third group of physical factors helps to minimize residual tuberculosis changes and the full functional restoration of damaged pulmonary tissue in conditions of gradual attenuation of the activity of the productive phase of a specific inflammation. The main tasks at the final stage are prevention of excessive formation of fibrous tissue, resorption of adhesions and scars, increased activity of the metabolism, improvement of microcirculation and trophic tissue of the lung tissue. The most significant representative of this group is the exposure to ultra-high frequency electromagnetic fields - microwave therapy.

[61], [62], [63], [64], [65], [66], [67], [68], [69],

Methods of extracorporal hemocorrection in tuberculosis

Extracorporeal hemocorrection is based on removal of toxic substances from the bloodstream or by perfusion of blood through various adsorbents (hemosorption), or by removing them together with a part of the plasma (plasmapheresis). During hemosorption, medium- and high-molecular toxic metabolites are predominantly removed, while in plasmapheresis, in addition to the plasma part, evacuation of low-molecular toxic products and some electrochemically inert compounds that are not capable of adsorbing on hemosorbents is additionally provided. This serves as a prerequisite for the combined use of these methods of extracorporeal blood processing. At the same time, correction of factors aggravating the course of the main process in the lung or pleural cavity and reducing the effectiveness of its treatment is achieved: the syndrome of endogenous intoxication, toxic-allergic reactions to anti-tuberculosis and other medications, violations of liver function, renal failure, and also improve the clinical course of concomitant diseases (bronchial asthma, diabetes mellitus).

Indications

The use of extracorporeal hemocorrection methods in patients with respiratory tuberculosis is indicated if the complex treatment of the tuberculosis process is inadequate or impossible to perform this treatment, due to the following factors (with their unsatisfactory correction by traditional methods):

• a syndrome of endogenous intoxication due to the presence of a specific process in the lungs or a specific suppuration in the pleural cavity, the presence of pulmonary or pleural pathology associated with tuberculosis of nontuberculous etiology, acute purulent pathology of other organs:
• toxic and allergic reactions to anti-tuberculosis and other medications, food and household allergies that make it difficult to treat the main process;
• violations of the liver function of various genesis (medicamental toxic-allergic hepatitis, the consequences of infectious hepatitis, etc.), resistant to hepatotropic therapy;
• renal failure (acute and chronic), due to the presence of a combination of tuberculosis of the lungs and kidneys, prolonged tubercular intoxication, toxic effects of anti-TB drugs and other causes;
• concomitant diseases, frequent in patients with tuberculosis of respiratory organs and aggravating the course of a specific process, bronchial asthma and diabetes mellitus (especially in its complicated course with the development of polyneuropathy, retinopathy, angiopathy, etc.).

Contraindications

Contraindications to the operation of extracorporal hemocorrection coincide with the general contraindications to the use of large doses of heparin. In addition, the expressed arterial hypo- or hypertension, the agonal state of the patient, is a contraindication to hemoperfusion.

[70], [71]

Technology of the method

When using extracorporeal hemocorrection methods in a planned manner, the preparation of patients with respiratory tuberculosis for hemoperfusion should be aimed at preventing and eliminating the initial hypovolemia, changes in the rheological properties of the blood, correcting water-electrolyte disorders, protein deficiency, anemia and other homeostatic changes in the absence of a causal relationship of these disorders with the factor that was the reason for the application of these methods of blood processing.

Hemosorption in patients with respiratory tuberculosis should be carried out according to a standard scheme ensuring maximum clinical effect and minimizing the risk of complications during the procedure. The extracorporeal circuit should include one sorption column. Hemocarperfusion should be performed by the veno-venous method under conditions of temporary hemodilution. Heparinization total, from the calculation of 250 units / kg body weight. The blood flow velocity should not exceed 70-80 ml / min, while the duration of the procedure should be sufficient for blood perfusion in a volume ranging from 1 to 1.5 times the volume of circulating blood.

The technique of conducting plasmapheresis is determined by the equipment at the disposal of the operator. With a hardware centrifugal (gravitational) plasmapheresis, blood is centrifuged to remove plasma from the bloodstream either in special containers of the "Hemakon" type (intermittent plasmapheresis) in a refrigerated centrifuge, or in various continuous-flow separators (continuous plasmapheresis). Vascular access is performed by catheterization of one peripheral or central vein. Heparinization is general, at a rate of 200 U / kg body weight.

Filtration plasmapheresis using plasma filters (plasma filtering) is carried out with the help of a pump block of PF-0.5, FC-3.5, any other roller pumps or special blood fractions of foreign firms (Fresenius, Gambro, Baxter, etc.). Blood perfusion should be carried out by the veno-venous method against a background of temporary hemodilution. Heparinization total, up to 300 units / kg. Domestic membrane plasma filters PFM (SPb, JSC "Optics") allow one-needle, unpreserved membrane plasmapheresis under the action of gravity alone, using a special system of highways. When carrying out a hardware centrifugal plasmapheresis or plasma filtration in patients with tuberculosis of respiratory organs, up to 1 liter of plasma is evacuated in a single session, replenishment of which is performed with 0.9% sodium chloride solution, rheopolyglucose, and in some cases with native plasma.

The need for repeated extracorporeal operations and the duration of intervals between them should be determined strictly for each patient, taking into account the clinical effectiveness of previous hemosorption or plasmapheresis and the dynamics of laboratory parameters, the duration of maintaining a positive clinical effect, the tactics of further complex treatment (continued conservative therapy or preparation for surgery). It should also take into account the limited possibilities of frequent plasmapheresis with the exfusion of a significant amount of plasma in patients with tuberculosis with severe initial dysproteneemia. If the effectiveness of one of the extracorporeal hemocorrection methods used is insufficient, a combined scheme of hemosorption and plasmapheresis is recommended. In this case, hemosorption and plasmapheresis (in any variant of the method) alternate for 3-4 weeks. Intervals between procedures are 4-6 days.

Complications

The most common complications of extracorporeal hemocorrection are pyrogenic reactions (chills, muscle pains and spasms, hyperthermia) and hemodynamic disorders (collapoid reactions). With the development of complications of this kind, an extracorporeal operation should be discontinued and, according to the indications, appropriate symptomatic therapy should be performed: administration of antihistamines, tri-peridine, in some cases 30-60 mg of prednisolone, intravenous infusion of plasma-substituting solutions,

Of the technical complications should be isolated thrombosis of the extracorporeal circuit and its depressurization. In the event of such situations, blood perfusion should be stopped immediately and the extracorporeal operation should be completed, as its continuation in such conditions is fraught with the development of thrombosis, thromboembolism or air embolism in the pulmonary arterial system. The maximum standardization of the procedure, careful preparation of the extracorporeal contour, monitor monitoring, literacy of medical personnel can dramatically reduce the likelihood of complications and their number.

[72], [73], [74], [75], [76], [77]

Results of using the method

The use of extracorporal hemocorrection methods in patients with respiratory tuberculosis allows to correct most of the disturbed parameters of homeostasis. Observe the positive dynamics of indicators reflecting the state of the myocardium and central hemodynamics, liver and kidneys; reduced ventilation disorders (mainly associated with obstructive changes); improves microcirculation in the lungs: reduces the toxicity of blood serum; corrected hypokalemia, the parameters of peroxide homeostasis, shifts in the acid-base state and gas composition of the blood. In addition, there is an immunomodulating effect on the factors of cellular and humoral immunity, the metabolic activity of phagocytic cells (Neutrophils and monocytes), as well as the bacteriostatic activity of the blood in relation to the mycobacteria of tuberculosis, increases.

The use of hemosorption and plasmapheresis methods creates a favorable background for the main course of anti-tuberculosis chemotherapy in the phthisiotherapy clinic, provides the possibility of treatment using surgical methods, extends the boundaries of operability. Positive clinical effect can be obtained in more than 90% of observations, and a stable correction of various factors that aggravated the course of the main process and made it difficult to treat it - in 75%.