Treatment of tuberculosis

Treatment of tuberculosis has certain goals - elimination of clinical signs of tuberculosis and persistent healing of tuberculous changes with restoration of the ability to work and 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 radiological manifestations of tuberculosis (focal, infiltrative, destructive);
• restoration of functional capabilities and work capacity.

Recently, attempts have been made to use the concept of “quality of life” to assess the effectiveness of tuberculosis treatment. This concept is quite common and has shown practical value in various diseases.

Treatment of tuberculosis must be carried out comprehensively against the background of a hygienic dietary regime. The main components of treatment of patients with tuberculosis 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. several anti-tuberculosis drugs are used simultaneously for a sufficiently long period of time.

Surgical treatment of tuberculosis of the respiratory organs is carried out according to indications both in newly diagnosed patients and in patients suffering from chronic forms of tuberculosis. These indications are determined depending on the development of complications of tuberculosis, the presence of drug-resistant mycobacteria, and intolerance to anti-tuberculosis drugs. Surgical treatment of tuberculosis is the most important component of therapy for chronic forms of tuberculosis that are not amenable to conventional therapeutic treatment.

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

The content of treatment is based on standards, which are treatment regimens for certain groups of patients, taking into account the form and phase of the tuberculosis process. Within the standards, individualization of treatment tactics is carried out, taking into account the characteristics of the dynamics of the disease, drug sensitivity of the pathogen, pharmacokinetics of the drugs used and their interaction, drug tolerance and the presence of background and concomitant diseases. This principle allows combining the standard of treatment of the disease and individual tactics of treating the patient.

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

The entire course of treatment for tuberculosis patients or its individual stages can be carried out in a hospital with a 24-hour or daytime stay only, in a sanatorium, in an outpatient setting. The organizational form of treatment is determined taking into account the severity of the disease, the epidemic risk 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 over its implementation, as well as continuity between medical institutions when changing the organizational form of treatment to another, must be met.

The treatment result is assessed using all the criteria of effectiveness and the corresponding documentation is prepared. The effectiveness of tuberculosis treatment is monitored by the superior anti-tuberculosis institution.

Quarterly cohort analysis using standard outcome definitions is needed to assess the effectiveness of each course of chemotherapy.

To select individual complex chemotherapy, it is necessary to take into account not only the clinical form, prevalence of tuberculosis, drug sensitivity of mycobacterium tuberculosis, concomitant diseases, but also the features of the interaction of anti-tuberculosis drugs at the microbiological and pharmacokinetic levels.

Anti-tuberculosis drugs

Anti-tuberculosis drugs are divided into two main groups. The first group includes isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin. They are called essential or first-line drugs. These drugs are used mainly to treat patients who have been diagnosed with tuberculosis for the first time and the pathogen is sensitive to these drugs. Second-line drugs include prothionamide, 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 pathogen is resistant to first-line drugs or if these drugs are intolerant. Currently, due to the worsening of tuberculosis. Given the growth of drug resistance in Mycobacterium tuberculosis, both groups of anti-tuberculosis drugs should be considered essential and necessary.

First-line drugs

• Isoniazid
• Rifampicin
• Pyrazinamide
• Ethambutol
• Streptomycin

2nd line drugs

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

3rd rad drugs*

• Clarithromycin
• Amoxicillin + clavulanic acid
• Clofazimine
• Linezolid

* There is no evidence base for use.

[ 1 ], [ 2 ], [ 3 ]

Combination anti-tuberculosis drugs

Combined anti-tuberculosis drugs are two-, three-, four- and five-component dosage forms with fixed doses of individual substances. Combined drugs are not inferior in their activity to their components when used separately. Combined drugs provide more reliable control over drug intake, reduce the risk of overdose of individual anti-tuberculosis drugs, are convenient for use in hospitals and, especially, in outpatient settings, as well as for chemoprophylaxis of tuberculosis. On the other hand, they can limit the possibilities of selecting individual therapy due to intolerance to individual anti-tuberculosis drugs and drug resistance of Mycobacterium tuberculosis.

Comparability of pharmacokinetic parameters and dose compliance of combination drugs with anti-tuberculosis drugs prescribed separately have been proven. The drugs are used both in the acute process and in the follow-up phase. Combined anti-tuberculosis drugs are used mainly in the treatment of newly diagnosed drug-sensitive tuberculosis. The exceptions are lomecomb and prothiocomb, which can be used in case of moderate resistance to isoniazid and rifampicin. The presence of lomefloxacin allows to increase the effectiveness of treatment in the progressive course of tuberculosis, with the addition of non-specific flora. The nature of the adverse effects of combination drugs is identical to the side effects of individual anti-tuberculosis drugs.

[ 4 ], [ 5 ], [ 6 ]

Chemotherapy for tuberculosis

Tuberculosis chemotherapy is an etiotropic (specific) treatment of tuberculosis aimed at destroying the mycobacterial population (bactericidal effect) or suppressing its reproduction (bacteriostatic effect). Chemotherapy occupies a major place in the treatment of patients with tuberculosis.

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

The effectiveness of chemotherapy has always been assessed from a clinical perspective. The main objective was not only the 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 working capacity. The clinical effectiveness of anti-tuberculosis drugs is influenced by various factors, such as: the number of mycobacterial populations, their sensitivity to the drugs used, the concentration of the drug, the degree of penetration of the drug into the affected areas and activity in them, the ability of drugs to act on extra- and intracellular (phagocytized) mycobacteria of 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 mycobacteria of tuberculosis, which differ in localization (extra- or intracellularly located), drug resistance and metabolic activity. Metabolic activity is higher in extracellular tuberculosis mycobacteria, lower in intracellular ones, and minimal in persistent forms.

When conducting chemotherapy, the drug resistance of mycobacteria tuberculosis is of great importance. In a large and actively multiplying mycobacterial population, there is always a small number of "wild" mutants resistant to anti-tuberculosis drugs. Mutant bacteria resistant to isoniazid or streptomycin occur with a frequency of 1:1,000,000, resistant to rifampicin - 1:100,000,000, resistant to ethambutol - 1:100,000. Since a cavity with a diameter of 2 cm contains about 100 million mycobacteria tuberculosis, there are certainly mutants resistant to anti-tuberculosis drugs. If chemotherapy is carried out correctly, the presence of these mutants is of no importance. However, with inadequate chemotherapy regimens, the use of irrational combinations of anti-tuberculosis drugs, and the use of incorrectly calculated doses, favorable conditions for the reproduction of drug-resistant mycobacteria tuberculosis arise. The main risk factor for the development of drug resistance in mycobacteria tuberculosis is ineffective treatment, especially interrupted and unfinished.

As tuberculosis inflammation subsides during chemotherapy, the mycobacterial population decreases due to the destruction of tuberculosis mycobacteria. Clinically, this is manifested by a decrease in the number of bacteria in sputum.

During chemotherapy, some of the tuberculosis mycobacteria remain in the patient's body. They are in a state of persistence. Persistent tuberculosis mycobacteria are often detected only by microscopic examination, since they do not grow when sown on nutrient media. One of the variants of tuberculosis mycobacteria persistence is their transformation into L-forms, ultra-small and filterable forms. At this stage, when intensive reproduction of the mycobacterial population is replaced by a state of persistence, the pathogen is often mainly intracellular (inside phagocytes). Isoniazid, rifampicin, protionamide. Ethambutol, cycloserine and fluoroquinolones have approximately the same activity against intra- and extracellular tuberculosis mycobacteria. Aminoglycosides and capreomycin have significantly lower bacteriostatic activity against intracellular forms. Pyrazinamide, with relatively low bacteriostatic activity, enhances the action of isoniazid, rifampicin, ethambutol and other drugs, penetrates cells very well and has pronounced activity in an acidic environment, which occurs in the focus of caseous lesions. Simultaneous administration of several anti-tuberculosis drugs (at least 4) allows you to complete the course of treatment before the appearance of drug resistance of mycobacterium tuberculosis or to overcome the resistance of the pathogen to one or two drugs.

Due to the different state of the mycobacterial population at different stages of the disease, it is scientifically justified to divide tuberculosis chemotherapy into two periods or two treatment phases. The initial, or intensive, treatment phase is aimed at suppressing the rapid reproduction and active metabolism of the mycobacterial population. The goals of this treatment period are also to reduce the number of drug-resistant mutants and 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. Ethambutol or streptomycin for 2-3 months. Isoniazid, rifampicin and pyrazinamide form the core of the combination when acting on mycobacteria tuberculosis. It should be emphasized that isoniazid and rifampicin are equally effective against all groups of the mycobacterial population located in the focus of tuberculosis inflammation. Isoniazid has a bactericidal effect on tuberculosis mycobacteria sensitive to both drugs and kills pathogens resistant to rifampicin. Rifampicin also kills tuberculosis mycobacteria sensitive to both of these drugs and, most importantly, has a bactericidal effect on isoniazid-resistant tuberculosis mycobacteria; rifampicin is effective against persistent tuberculosis mycobacteria if they begin to "wake up" and increase their metabolic activity. In these cases, it is better to use rifampicin rather than isoniazid. The addition of pyrazinamide, ethambutol and fluoroquinolones to these drugs enhances the effect on the pathogen and prevents the formation of secondary drug resistance.

In cases of drug-resistant tuberculosis, the question arises about the use of reserve anti-tuberculosis drugs, the combination of which and the duration of administration are still mainly empirical.

In the continuation phase of treatment, the remaining, slowly multiplying mycobacterial population is affected. The metabolic activity of tuberculosis mycobacteria in such a population is low, the pathogen is mainly intracellular in the form of persistent forms. At this stage, the main tasks are to prevent active reproduction of the remaining bacteria, as well as to stimulate reparative processes in the lungs. Treatment must be carried out over a long period of time to neutralize the mycobacterial population, which, due to its low metabolic activity, is difficult to destroy with anti-tuberculosis drugs.

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

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

In addition to daily administration of chemotherapy drugs, there is a method of intermittent use of drugs. Intermittent or intermittent administration of drugs reduces the likelihood of adverse reactions. This method is based on the aftereffect of chemotherapy drugs, which have a bacteriostatic effect on mycobacteria 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. Almost all anti-tuberculosis drugs are suitable for intermittent use: isoniazid, rifampicin, streptomycin, kanamycin, amikacin, ethambutol, pyrazinamide. They are sufficiently effective if used 3 times a week. With intermittent chemotherapy, the dose of drugs should be higher than with their daily administration.

It should be noted that individual anti-tuberculosis drugs can be administered not only orally or intramuscularly, but also intravenously by drip or jet. Intrabronchial infusions, aerosol inhalations, and rectal administration (enemas, suppositories) are used.

Quarterly cohort analysis is used to assess the effectiveness of chemotherapy (a group of patients with the same duration of treatment is observed). This approach allows us to evaluate the results of standard chemotherapy regimens both to control the regularity of taking anti-tuberculosis drugs and to identify patients who require individual correction of treatment tactics.

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

Tuberculosis Chemotherapy Regimens

The regimen for tuberculosis chemotherapy, i.e. the choice of the optimal combination of anti-tuberculosis drugs, their doses, routes of administration, rhythm of use and duration of treatment, is determined taking into account:

• the nature of regional drug sensitivity of Mycobacterium tuberculosis to anti-tuberculosis drugs;
• epidemiological danger (infectivity) of the patient;
• the nature of the disease (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 cavities).

The chemotherapy regimen can be standard or individual. The standard chemotherapy regimen is carried out using a combination of the most effective anti-tuberculosis drugs. This choice is due to the fact that determining the drug sensitivity of mycobacteria 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 chemotherapy regimens.

When choosing a chemotherapy regimen, it is necessary:

• determine the indications for the use of anti-tuberculosis drugs and the appropriate chemotherapy regimen;
• select a rational organizational form of chemotherapy (treatment in outpatient, inpatient or sanatorium conditions) for each patient or individual groups of patients;
• to determine the most appropriate chemotherapy regimen in specific conditions, the most effective for a given form of the process, with a particular tolerance of anti-tuberculosis drugs, as well as with a specific sensitivity of mycobacterium tuberculosis to them;
• ensure controlled administration of the prescribed combination of anti-tuberculosis drugs to patients throughout the entire period of treatment both in hospitals and sanatoriums, and in outpatient settings;
• organize dispensary observation of the patient during the treatment process, periodically examine him in order to monitor the effectiveness of the treatment and evaluate its results;
• select rational methods of examining the patient and determine the optimal timing of their use.

These and other issues related to chemotherapy are decided by the doctor individually for each patient. In cases where the therapeutic effect is insufficient, the examination should help to establish the cause of failure and choose another treatment strategy; change the chemotherapy method or its organizational forms, prescribe additional medications, and use other treatment methods, such as 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, and on the other hand, by the capabilities of the doctor.

Regime I chemotherapy

Chemotherapy regimen I is prescribed to patients in whom pulmonary tuberculosis has been diagnosed for the first time, and the data of microscopic examination of sputum indicate bacterial excretion. This regimen is also prescribed to patients with widespread forms of pulmonary tuberculosis in whom bacterial excretion has not been established. Chemotherapy regimen I is effective only in regions where the level of primary MDR mycobacterium tuberculosis does not exceed 5%, as well as in patients with complete preservation of the pathogen's sensitivity to the main anti-tuberculosis drugs.

The intensive phase of treatment involves the administration of four drugs from the main anti-tuberculosis agents (isoniazid, rifampicin, pyrazinamide, ethambutol or streptomycin) for 2-3 months (until the data of indirect microbiological determination of the drug susceptibility of the pathogen by the absolute concentration method are obtained). During this period, the patient must take at least 60 doses of the prescribed anti-tuberculosis drugs. Thus, the duration of this phase of treatment is determined by the number of necessary doses of the drug. Such calculation of the duration of treatment is used for all chemotherapy regimens.

The use of streptomycin instead of ethambutol should be based on data on the prevalence of drug resistance of Mycobacterium tuberculosis to this drug and isoniazid in a specific region. In cases of primary resistance to isoniazid and streptomycin, Ethambutol is used as the 4th drug, since in this regimen it effectively affects Mycobacterium tuberculosis resistant to isoniazid and streptomycin.

Indications for the transition to the continuation phase of therapy are the cessation of bacterial excretion and positive clinical and radiological dynamics of the process in the lungs. If the sensitivity of mycobacteria to drugs is maintained, treatment is continued for 4 months (120 doses) with isoniazid and rifampicin. The drugs are taken daily or intermittently. 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.

If drug resistance of mycobacterium tuberculosis is detected, but bacterial excretion ceases by the end of the initial treatment phase after 2 months, a transition to the continuation phase of chemotherapy is possible, but with mandatory correction and extension of its duration. In case of initial drug resistance of the pathogen to isoniazid and/or streptomycin, treatment in the continuation phase is carried out with rifampicin, pyrazinamide and ethambutol for 6 months or rifampicin and ethambutol for 8 months. The total duration of treatment in this case is 8-10 months.

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

If bacterial excretion continues and there is no positive clinical and radiological dynamics of the process in the lungs, the intensive phase of treatment with a standard chemotherapy regimen should be continued for another 1 month (30 doses) until data on the drug resistance of the pathogen is obtained.

If drug resistance of tuberculosis mycobacteria is detected, chemotherapy is adjusted. A combination of primary drugs, to which the pathogen has retained its sensitivity, and reserve drugs is possible. However, the combination should consist of five drugs, of which at least two should be reserve drugs. Only one reserve drug should never be added to the chemotherapy regimen due to the risk of developing drug resistance in the pathogen.

After correction of chemotherapy, the intensive phase of treatment with a new combination of anti-tuberculosis drugs is started again and continues for 2-3 months until new data on the drug sensitivity of the pathogen are obtained. Further treatment tactics 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 repeated study of the drug sensitivity of mycobacterium tuberculosis.

If the pathogen is found to be MDR to isoniazid and rifampicin, the patient is prescribed an IV chemotherapy regimen.

Chemotherapy regimen IIa

Chemotherapy regimen IIa is prescribed to patients with relapses of pulmonary tuberculosis and patients who have received inadequate chemotherapy for more than 1 month (incorrect combination of drugs and insufficient doses), with a low risk of developing drug resistance in Mycobacterium tuberculosis. Chemotherapy regimen Pa is effective only in regions where the level of primary MDR Mycobacterium tuberculosis does not exceed 5%, or in patients with complete preservation of the sensitivity of the pathogen to the main anti-tuberculosis drugs.

This regimen involves the administration of five main anti-tuberculosis drugs in the intensive phase of treatment for 2 months: isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin, and four drugs for 1 month: isoniazid, rifampicin, pyrazinamide and ethambutol. During this period, the patient must receive 90 doses of the prescribed drugs. In the intensive phase, the use of streptomycin is limited to 2 months (60 doses). The intensive phase of therapy can be continued if bacterial excretion persists and the clinical and radiological dynamics of the disease are negative, until data on the drug sensitivity of Mycobacterium tuberculosis are obtained.

The indication for transition to the continuation phase of treatment is the cessation of bacterial excretion and positive clinical and radiological dynamics of the specific process. If the sensitivity of mycobacteria tuberculosis is maintained, treatment is continued for 5 months (150 doses) with three drugs: isoniazid, rifampicin, ethambutol. The drugs can be taken daily or intermittently.

If by the end of the intensive treatment phase the excretion of bacteria continues and drug resistance of the pathogen to aminoglycosides, isoniazid or rifampicin is detected, changes are made to the chemotherapy regimen. The main drugs to which the tuberculosis mycobacteria have retained their sensitivity are left, and at least two reserve chemotherapy drugs are additionally introduced into the regimen, which leads to an extension of the intensive phase by another 2-3 months. The total duration of treatment is 8-9 months.

If MDR mycobacterium tuberculosis to isoniazid and rifampicin is detected, the patient is prescribed an IV chemotherapy regimen.

Regime IIb chemotherapy

Regimen IIb of chemotherapy 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 Mycobacterium tuberculosis exceeding 5%), anamnestic (contact with patients known to the dispensary excreting MDR Mycobacterium tuberculosis), social (persons released from penitentiary institutions) and clinical (patients with ineffective treatment in accordance with regimens I, Ila, III of chemotherapy, with inadequate treatment at previous stages, with interruptions in treatment, with widespread, both newly diagnosed and recurrent forms of pulmonary tuberculosis) indications for prescribing this regimen.

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

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

In vitro studies of the combined action of fluoroquinolones (ciprofloxacin, lomefloxacin, ofloxacin, levofloxacin) and first-line drugs: rifampicin, isoniazid, pyrazinamide and ethambutol revealed an additive effect. Analysis of various treatment regimens for patients with newly diagnosed tuberculosis and patients with relapses of the disease showed that combined chemotherapy with the main anti-tuberculosis drugs in combination with fluoroquinolones is more effective than ethambutol. In addition to high bactericidal activity against Mycobacterium tuberculosis and optimal pharmacokinetics, providing high concentrations of fluoroquinolones 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. Regimen IIb chemotherapy is currently the main standard treatment regimen for patients with pulmonary tuberculosis with the isolation of Mycobacterium tuberculosis until data from a study of the drug susceptibility of the pathogen are obtained.

This choice is due to the fact that the current epidemic situation is characterized by the accumulation of patients with chronic forms of pulmonary tuberculosis in anti-tuberculosis dispensaries, who are constant excretors of Mycobacterium tuberculosis resistant to many anti-tuberculosis drugs. Such patients, being a reservoir of infection, infect healthy individuals with already drug-resistant strains of the pathogen. Consequently, chemotherapy regimens I and IIa are not always effective, firstly, due to the high risk of primary infection with drug-resistant strains of Mycobacterium tuberculosis and, secondly, due to the high risk of developing secondary drug resistance of the pathogen in patients with pulmonary tuberculosis if the indicated regimens are inappropriate.

Thus, in modern epidemiological conditions with a significant level of primary and secondary drug resistance of Mycobacterium tuberculosis, regimen IIb of chemotherapy 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-tuberculosis drugs.

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

The proposed set of anti-tuberculosis drugs in the IIb chemotherapy regimen usually provides a bactericidal effect, since rifampicin, isoniazid and ethambutol suppress the reproduction of tuberculosis mycobacteria sensitive to them, pyrazinamide affects bacteria located in caseous areas, and a drug from the fluoroquinolone group 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 fluoroquinolone group, pyrazinamide and ethambutol. These drugs also inhibit the development of resistance to other anti-tuberculosis drugs.

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

If MDR mycobacterium tuberculosis to isoniazid and rifampicin is detected, the patient is prescribed an IV chemotherapy regimen.

Regime III chemotherapy

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

During the 2-month intensive phase of chemotherapy, 4 anti-tuberculosis drugs are used: isoniazid, rifampicin, pyrazinamide and ethambutol. The introduction of the 4th drug ethambutol into the chemotherapy regimen is due to the high initial resistance of mycobacterium tuberculosis to streptomycin. The intensive phase of chemotherapy lasts 2 months (60 doses). If information is received about the presence of bacterial excretion, but there is no data on the drug sensitivity of the pathogen, 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 extended for another 1 month (30 doses). Further treatment tactics are determined by the dynamics of the process in the lungs and microbiological research data.

The indication for transition to the continuation phase of treatment is a pronounced positive clinical and radiological dynamics of the disease. Chemotherapy with isoniazid and rifampicin is administered for 4 months (120 doses), using both daily and intermittent administration of the drugs. Another option is the use of isoniazid and ethambutol for 6 months.

This group of patients also includes patients who have limited changes in the lungs of questionable activity. In the absence of clinical and radiological dynamics after the end of the intensive phase of treatment, the process is assessed as inactive and treatment is stopped. With positive radiological dynamics, the process is assessed as active, and patients are transferred to the continuation phase of treatment. The total duration of the course is 6-8 months.

If unavoidable toxic side effects to isoniazid or rifampicin occur, but the tuberculosis mycobacteria remain sensitive to them, the drugs can be replaced. The drug can only be replaced with its analogue, and not with another reserve anti-tuberculosis drug. Thus, isoniazid can be replaced with phenazid, ftivazid or metazid, and rifampicin with rifabutin. If unavoidable allergic reactions occur, replacement with analogues is not indicated, and drugs of this group are excluded from the chemotherapy regimen. In this case, isoniazid or rifampicin are replaced with two reserve drugs.

It should be noted that when conducting chemotherapy regimens I, IIa, IIb and III in patients with pulmonary tuberculosis, it is justified to use combined anti-tuberculosis drugs. An 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, established in the order of the Russian Ministry of Health No. 109 of March 21, 2003, in the current epidemiological conditions, are more of historical interest and require revision.

It is advisable to single out 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 excrete mycobacteria tuberculosis, with limited processes in the lungs, without destruction of lung tissue, from regions where the level of primary MDR does not exceed 5%. In these cases, in the intensive phase of treatment, the 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 relapses of pulmonary tuberculosis, excreting mycobacteria 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 excreting drug-resistant mycobacteria tuberculosis, as well as in patients with treatment interruptions of more than 1 month. In these cases, in the intensive phase of treatment, the combination of anti-tuberculosis drugs should include isoniazid, rifampicin, pyrazinamide, ethambutol, kanamycin (amikacin), a drug from the fluoroquinolone group, or prothionamide.

IV chemotherapy regimen

IV chemotherapy regimen is intended for patients with pulmonary tuberculosis, releasing MDR mycobacteria tuberculosis. 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 the WHO definition, MDR mycobacteria tuberculosis include tuberculosis pathogens that are resistant to at least isoniazid and rifampicin. However, this classification is purely epidemiological in nature and its use in clinical settings is not justified, since the doctor at the patient's bedside must know the specific resistance of the pathogen to anti-tuberculosis drugs. From a clinical standpoint, the most justified classification is that of V. Yu. Mishin, according to which patients with pulmonary tuberculosis, excreting MDR mycobacteria tuberculosis, are divided into two groups:

• patients with MDR mycobacterium tuberculosis to the main anti-tuberculosis drugs:
• patients with MDR mycobacterium tuberculosis to a combination of primary and reserve anti-tuberculosis drugs.

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

Before starting chemotherapy, it is necessary to determine the drug sensitivity of tuberculosis mycobacteria, and also to examine the patient before starting treatment. In this regard, it is advisable to use accelerated methods of bacteriological examination and determination of drug sensitivity.

Treatment is carried out in accordance with an individual chemotherapy regimen. 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.

The intensive phase of treatment according to the IV chemotherapy regimen is 6 months, during which combinations of at least five anti-tuberculosis drugs are prescribed. In this case, a combination of reserve and primary drugs is possible if the pathogen remains sensitive to them.

There are various options for IV chemotherapy regimens in patients with pulmonary tuberculosis secreting MDR Mycobacterium tuberculosis.

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 MDR mycobacteria tuberculosis. However, the course of chemotherapy should be carried out in full.

Indications for transition to the continuation phase of treatment are cessation of bacterial excretion, positive clinical and radiological dynamics of the specific process in the lungs and stabilization of the course of the disease. The combination of anti-tuberculosis drugs should include at least three reserve or main drugs to which the pathogen remains sensitive. The duration of treatment should be at least 12 months.

However, it cannot be agreed that the results of chemotherapy, even with the correct treatment method, depend only on the sensitivity of the pathogen to anti-tuberculosis drugs. In the chronic tuberculosis process with the development of fibrous changes in the lung tissue, blood and lymph circulation in the affected area is disrupted, which leads to a significant slowdown in the diffusion of drugs. In such a situation, even isoniazid, which has a bactericidal effect and penetrates well into tissues, is in the wall and contents of the fibrous cavity in lower concentrations compared to blood serum. Morphological studies of the lungs in patients who have been treated for a long time with reserve anti-tuberculosis drugs also confirm data on the slow healing of extensive caseous foci. In this regard, when treating such patients, it is necessary to raise the issue of using surgical methods. It is important to emphasize that surgery must be performed before complications develop that may interfere with surgical treatment. The role of anti-tuberculosis drugs in the treatment of patients with such forms of tuberculosis is overestimated. Thus, in the development of a chronic destructive process with the release of mycobacteria with MDR, if it is not possible to stabilize the disease and stop the release of bacteria using anti-tuberculosis drugs, surgical intervention is necessary. Surgery is necessary when the process is limited, since surgery can be economical, and subsequent chemotherapy will help maintain health. With favorable developments, a cure can be achieved in the presence of 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 pathogen, the rate and timing of resorption of pathological foci, closure of cavities in the lungs, cessation of bacterial excretion and disappearance of clinical manifestations of the disease. as well as the possibility of using collapse therapy and surgical treatment. Due to the risk of insufficient effectiveness of treatment with a combination of reserve anti-tuberculosis drugs and the possible development of relapses of tuberculosis caused by mycobacteria with MDR, chemotherapy is carried out for at least 12-18 months. In this case, it is very important to ensure long-term treatment of such patients with reserve anti-tuberculosis drugs.

The detection of a pathogen with MDR to a combination of primary and reserve drugs in patients with pulmonary tuberculosis 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 to which sensitivity is preserved, and some primary drugs, such as pyrazinamide and ethambutol. Drug resistance to these drugs and aminosalicylic acid develops quite slowly, while they to some extent prevent its development to other anti-tuberculosis drugs. At the same time, a combination of pyrazinamide, ethambutol, a drug from the fluoroquinolone group and capreomycin is active against MDR strains, but, unfortunately, is inferior in effectiveness to a combination consisting of isoniazid, rifampicin and pyrazinamide against a sensitive pathogen.

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

• a regimen that includes a combination of the main anti-tuberculosis drugs: isoniazid, rifampicin, pyrazinamide and ethambutol for the treatment of newly diagnosed pulmonary tuberculosis caused by mycobacteria sensitive to these drugs;
• a regimen that includes a combination of essential anti-tuberculosis 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 MDR mycobacteria.

There is no consensus on the chemotherapy regimen used to treat patients with pulmonary tuberculosis caused by MDR mycobacteria, including combinations of reserve anti-tuberculosis drugs. In most cases, this chemotherapy regimen and the timing of its use are empirical.

Surgical methods of treatment of tuberculosis

In economically prosperous countries of Europe, North America, Australia, and Japan, as the prevalence of tuberculosis has decreased, the need for operations and their number have decreased significantly.

Against the background of high morbidity, surgical treatment of tuberculosis continues to be a necessary and widespread method. More than 10 thousand patients are operated on annually.

Indications for surgery

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

• insufficient effectiveness of chemotherapy, especially in cases of multidrug 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 are life-threatening, have clinical manifestations or can lead to undesirable consequences.

Surgical treatment is most often used for tuberculoma and fibro-cavernous tuberculosis, less often for pulmonary cirrhosis, tuberculous empyema of the pleura, caseous-necrotic lesions of the lymph nodes, and 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;
• broncholitis (bronchus stone);
• pneumofibrosis with hemoptysis;
• armor pleurisy or pericarditis with impaired respiratory and circulatory functions.

The vast majority of tuberculosis surgeries are performed on a planned basis. However, sometimes it is necessary to eliminate an immediate threat to the patient's life, and the indications for surgery may be urgent or even emergency.

Possible indications for emergency surgery:

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

In newly diagnosed patients, under conditions of combined chemotherapy, indications for planned lung resection and the choice of time for surgery are determined individually. Usually, treatment is continued until chemotherapy provides positive dynamics of the process. The cessation of positive dynamics serves as a basis for discussing the issue of surgical intervention.

Most patients with limited-extent tuberculosis lesions do not have laboratory detectable bacterial excretion after 4-6 months of treatment, but a stable radiographic picture of pathological changes may be the basis for minor lung resection. In total, among newly diagnosed patients with active tuberculosis, indications for surgery occur in approximately 12-15%. In case of tuberculoma, timely lung resection prevents the progression of the tuberculosis process, shortens the treatment period, and allows for complete rehabilitation of the patient in clinical, labor, and social terms. In some cases, surgery prevents frequent errors in the differential diagnosis of tuberculoma and peripheral lung cancer.

In patients with fibrous-cavernous tuberculosis, conservative treatment is an exception, not a rule. Unfortunately, among this contingent, there are very often contraindications to surgical treatment. Usually, only 15% of such patients can be operated on.

In cirrhotic tuberculosis and lung destruction as a result of caseous pneumonia, the problem of treatment tactics is also important in assessing not so much the indications as the contraindications to surgical treatment.

In cases of multidrug-resistant Mycobacterium tuberculosis, lung resection, if feasible, is an alternative to long-term 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, respiratory, circulatory, liver and kidney dysfunction. A multidisciplinary approach to the patient is necessary to assess these disorders.

It should be borne in mind that in many patients, after removal of the main source of infection and intoxication, functional indicators improve and even normalize. This most often occurs with caseous pneumonia, pulmonary hemorrhage, chronic empyema of the pleura with a wide bronchopleural fistula.

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

Preparing for surgery

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 non-specific flora. In all surgical interventions for tuberculosis, combined chemotherapy is performed in the preoperative and postoperative periods. Pathogenetic, desensitizing and immune therapy, treatment of concomitant diseases are also used. According to special indications, hemosorption, plasmapheresis, parenteral nutrition are performed. After surgery, a number of patients should be sent to a sanatorium. It is advisable to perform the operation in the remission phase, which is determined by clinical, laboratory and radiological data. It is necessary to take into account that too long preparation of the patient for surgery is often harmful. It can lead to an increase in drug resistance of Mycobacterium tuberculosis and to another outbreak of the tuberculosis process. Clinical experience also shows that in cases of long waiting times for surgery, patients often refuse the proposed surgical intervention.

Types of operations for pulmonary tuberculosis

For tuberculosis of the lungs, pleura, intrathoracic lymph nodes, and bronchi, the following surgical interventions are used:

• lung resection, pneumonectomy:
• thoracoplasty:
• extrapleural filling;
• cavernous operations (drainage, cavernotomy, cavernoplasty);
• video-assisted thoracoscopic sanitation of the pleural cavity;
• pleurectomy, lung decortication;
• thoracostomy;
• operations on the bronchi (occlusion, resection and plastic surgery, reamputation of the stump);
• removal of intrathoracic lymph nodes;
• destruction of pleural adhesions to correct artificial pneumothorax.

Separately, it is necessary to mention endoscopic removal of granulations or broncholith during bronchoscopy and X-ray endovascular occlusion of bronchial arteries during pulmonary hemorrhage. Operations on nerves and main vessels of the lung as independent interventions are not performed at present.

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 varying volume. In patients with tuberculosis, so-called small or economical resections are most often used. In such operations, part of a lung lobe is removed (segmentectomy, wedge, marginal, planar resection). Even more economical is precision ("high-precision") resection when a conglomerate of foci, tuberculoma or cavity is removed with a very small layer of lung tissue. The technical implementation of most small lung resections is significantly facilitated by the use of suturing devices and the application of a mechanical suture with tantalum staples. Precision resection is performed using point electrocoagulation or a neodymium laser. Ligatures are applied to relatively large vascular and bronchial branches.

Removal of one lobe of the lung (lobectomy) or two lobes (bilobectomy) is usually performed in cases of cavernous or fibro-cavernous tuberculosis with one or more cavities in one lobe of the lung. Lobectomy is also performed in cases of caseous pneumonia, large tuberculomas with large foci in one lobe, cirrhosis of a lung lobe, cicatricial stenosis of a lobar or segmental bronchus. If the remaining part of the lung is insufficient to fill the entire pleural cavity, pneumoperitoneum is additionally applied to lift the diaphragm. Sometimes, to reduce the volume of the corresponding half of the chest, the posterior sections of three or four ribs are resected.

Lung resections, especially small ones, are possible on both sides. In this case, a distinction is made between sequential operations with a time interval (3-5 weeks) and one-stage interventions. Small lung resections are well tolerated by patients, and they are highly effective. The vast majority of patients who undergo surgery are cured of tuberculosis.

Pneumonectomy is performed mainly in cases of widespread unilateral lesions - polycavernous process in one lung, fibro-cavernous tuberculosis with bronchogenic seeding, giant cavern, caseous pneumonia, cicatricial stenosis of the main bronchus. In cases of extensive lung lesions complicated by empyema of the pleural cavity, pleuropneumonectomy is indicated, i.e. removal of the lung with a purulent pleural sac. Pneumonectomy is often the only possible, absolutely indicated and effective operation.

Thoracoplasty

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

The cavern after thoracoplasty rarely closes by forming a scar or a dense encapsulated caseous focus. More often, it turns into a narrow gap with an epithelialized inner wall. In many cases, the cavern only collapses, but remains lined from the inside with granulation tissue with foci of caseous necrosis. Naturally, the preservation of such a cavern can be the cause of an exacerbation of the process and its progression at various times after the operation.

Thoracoplasty is usually performed in cases of contraindications to lung resection. The operation is performed in the phase of stabilization of the tuberculosis process with small and medium-sized caverns, if pronounced fibrosis has not developed in the lung tissue and the cavern wall. An urgent indication for thoracoplasty may be bleeding from the cavern. In patients with a residual pleural cavity in chronic empyema of the pleura with a bronchopleural fistula, thoracoplasty in combination with muscle plastic surgery (thoracomioplasty) often serves as an indispensable effective operation.

Thoracoplasty is well tolerated by young and middle-aged people. Indications for it are limited in people over 55-60 years of age. Single-stage thoracoplasty with resection of the posterior sections of the upper 5-7 ribs is most often used. The ribs are removed one or two below the location of the lower edge of the cavity (according to the anteroposterior radiograph). In case of large upper lobe cavities, the upper 2-3 ribs should be removed almost completely. After the operation, a pressure bandage is applied for 1.5-2 months.

A pulmonary atelectasis on the side of the operation may be a complication after thoracoplasty. To prevent it, it is necessary to control the expectoration of sputum and, if necessary, sanitize the bronchial tree during fibrobronchoscopy.

Lung collapse can also be achieved by extrapleural pneumolysis. Maintenance of the extrapleural cavity is achieved by periodic inflation of air or by introducing a filling material, such as a silicone filling.

Cavern operations

For drainage, a catheter is inserted into the cavern by puncturing the chest wall. Through the catheter, constant aspiration of the cavern contents is established using a special suction system. Medicinal substances are periodically injected into the cavern. When using a thin drainage catheter (microirrigator), a fairly long-term sanitization of the cavern by local application of medicinal preparations is possible.

In favorable cases, patients experience significant clinical improvement. The contents of the cavern gradually become more liquid, transparent and acquire a serous character, mycobacteria of tuberculosis in the contents of the cavern disappear. The cavity decreases in size. However, healing of the cavern usually does not occur. In this regard, drainage is often used as an auxiliary method before another operation - resection, thoracoplasty or cavernoplasty.

Opening and treatment of the cavern (cavernotomy) is used for large and giant cavities with rigid walls, when other surgeries are contraindicated - usually due to the widespread nature of the process or the poor functional state of the patient. Before the operation, it is necessary to accurately determine the location of the cavern using computed tomography. After the operation, open local treatment with tamponade with chemotherapy is carried out for 4-5 weeks. The cavity is treated with low-frequency ultrasound or laser. The walls of the cavern are gradually cleaned, bacterial excretion stops, and intoxication is reduced. At the second stage of surgical treatment, the cavity is closed by thoracoplasty, muscle plastic surgery, or a combination of these methods - thoracomioplasty.

With good sanitation of a single cavern and the absence of tuberculosis mycobacteria in its contents, a one-stage operation is possible - cavernotomy with 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 in the lung. It is also possible to close the cavern with a muscle flap on a leg (cavernomyoplasty). Sometimes cavernoplasty is possible with two closely located caverns. During the operation, they are connected to each other into a single cavity. One-stage cavernoplasty is a clinically effective operation that patients tolerate well.

Video-assisted thoracoscopic sanitation of the pleural cavity

The essence of the operation is the mechanical removal of pus, caseous masses, and fibrin deposits from the pleural cavity. Accumulations of pathological contents are eliminated, and the cavity is washed with solutions of anti-tuberculosis intiseptic drugs. Such sanitation, as a rule, is a continuation of diagnostic videothoracoscopy. After examining the pleural cavity with an optical thoracoscope connected to a monitor, a place is chosen for the second thoracoport. An aspirator, forceps, and other instruments for sanitation are inserted into the pleural cavity through it. After the manipulations are completed, 2 drains are inserted into the pleural cavity through the thoracoports for constant aspiration.

Pleurectomy, lung decortication

In tuberculosis, such an operation is performed in patients with chronic pleural empyema, pyopneumothorax, chronic exudative pleurisy. The operation involves removing the entire sac with pus, caseous masses, and fibrin. The thickness of the walls of this sac, formed by the parietal pleura and deposits on the visceral pleura, can exceed 2-3 cm. The operation is sometimes called "empyemactomy", emphasizing its radical nature in case of pleural empyema. In a number of patients with empyema and simultaneous lung damage, removal of the empyema sac is combined with lung resection. In some cases, the entire lung must be removed along with the purulent pleural sac (pleuropneumonectomy).

After the empyema sac and fibrous shell are removed from the lung, it straightens out 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 2-3 rib segments with the opening of the empyema cavity. The edges of the skin are sutured to the deep layers of the wound. A "window" is formed in the chest wall. It allows for open treatment of pleural empyema by washing and tamponade of the cavity, treating it with low-frequency ultrasound, and laser irradiation. Previously, thoracostomy for tuberculous empyema was widely used as the first stage before thoracoplasty. Currently, the indications for thoracostomy have been narrowed.

Bronchial surgery

Stitching and crossing the bronchus of the affected lung lobe leads to its obstructive atelectasis. As a result, conditions are created for reparative processes in the cavity area, and closure of the bronchial lumen helps to stop bacterial excretion. However, the clinical effectiveness of operations aimed at creating obstructive atelectasis is often low due to recanalization of the bronchus. In this regard, they are rarely used, according to special indications. Much more important is resection of the bronchus with the imposition of a bronchial anastomosis. It is indicated for patients with post-tuberculous stenosis of the main bronchus, broncholith, bronchonodular fistula. Excision of the affected section of the bronchus and restoration of bronchial patency allow preserving the entire lung or part of it in some patients.

Removal of lymph nodes

In chronic primary tuberculosis, caseous-necrotic lymph nodes in the root of the lung and mediastinum are often a source of intoxication and spread of tuberculosis infection. Sometimes, simultaneous tuberculous bronchial lesions, breakthrough of caseous masses into the lumen of the bronchus with a broncho-nodular fistula, and formation of a stone in the bronchus - broncholith - are observed. The size of the affected nodes, their topography, 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, and the immediate and long-term results are good. If bilateral intervention is necessary, the operations can be performed either sequentially or simultaneously.

Complications after surgery

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

In the event of tension pneumothorax, the immediate measure should be aspiration drainage of the pleural cavity. It eliminates the immediate threat of death. Then, in cases of rupture of the cavity or pulmonary bullae, the question of the advisability of surgery on the lung is decided.

After minor lung resections, the mortality rate is currently below 1%, the number of people cured of tuberculosis reaches 93-95%. After lobectomy, the mortality rate is 2-3%, after pneumonectomy - 7-8%. The period of postoperative rehabilitation with an uncomplicated course varies from 2-3 weeks (after minor resections) to 2-3 months (after pneumonectomy). Functional results after minor resections and lobectomy are usually good. Working capacity 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 chemotherapeutic agents, infectious and other postoperative complications are usually caused not by the fact of drug resistance itself, but by many other reasons. The main ones are the long course of the disease, widespread and complicated destructive process, weakened immunity, complexity of the operation, poor tolerance of drugs. To improve the treatment outcomes of patients with pulmonary tuberculosis, it is important to use the possibilities of surgery and, if indicated, operate on patients in a timely manner. In this regard, if conservative treatment is ineffective and the course is complicated, it is advisable to consult patients with pulmonary tuberculosis with a thoracic surgeon.

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

Treatment of extrapulmonary tuberculosis

Treatment of extrapulmonary tuberculosis has the following goals:

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

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

Depending on the purpose, a distinction is made between diagnostic, therapeutic or therapeutic-diagnostic operations (manipulations).

Goals of diagnostic surgery (manipulation):

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

Diagnostic interventions include punctures and biopsies 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. There are radical, restorative, reconstructive and auxiliary operations.

Radical operations are interventions during which all pathological tissues of the affected organ are completely removed. Methods of radical operations are necrectomy (removal of pathological tissues), resection (removal of the affected part of the organ within healthy tissues), extirpation (removal of the entire organ), as well as their combinations with removal of abscesses and fistulas.

To achieve the best anatomical and functional results, radical surgeries are usually supplemented with restorative and reconstructive interventions. In such cases, radical surgery is the main stage of the combined intervention.

Reconstructive surgery is the restoration of the anatomical structure of a destroyed or resected part of an organ by plastic replacement with similar (or similar in structure) tissue or artificial material.

Reconstructive surgeries are used for severe organ damage, whereby lost (destroyed or removed) anatomical structures are restored by artificially moving organs or their fragments, tissues into an unnatural position. One of the options for reconstructive surgeries is endoprosthetics (replacing the damaged part or the entire organ with an artificial prosthesis).

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

Optimal operations for active tuberculosis should simultaneously solve several problems (complete removal of pathological tissue, restoration of anatomical integrity and functions of the organ), therefore the operations performed are often of a combined nature, for example, radical restorative, radical reconstructive and corrective operations (in case of tuberculous spondylitis, radical reconstructions of the spine are performed, including resection of the vertebrae, decompression of the spinal canal, anterior spondylodesis, posterior instrumental fixation).

Therapeutic and diagnostic operations include elements of the listed interventions.

Operational accesses and tools used:

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

Endoscopic surgery options - interventions performed with video support (video-assistant surgery). The surgery is performed from a closed (percutaneous) access using special manipulators, the process of performing the intervention is controlled using a monitor.

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

The plastic material for transplantation is obtained from the patient's own tissues (autograft) or from a donor (allograft). Cortical and spongy bone grafts, osteochondral grafts, and perichondrial grafts are used to replace bone tissue and joint defects. A distinction is made between free and non-free bone grafting. The feeding stalk is formed either only by vessels or by tissues (vessels, periosteum, muscles). Revascularization is a special type of transplant feeding (artificially created feeding stalk).

In interventions on the genitourinary system, plastic surgeries are performed using local tissues or by moving fragments of hollow organs of the gastrointestinal tract (stomach, small and large intestines).

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

Rapid development of medical technologies in recent decades has significantly expanded surgical treatment of extrapulmonary tuberculosis, its complications and consequences. The main clinical forms of extrapulmonary tuberculosis and indications for surgical intervention have been determined. Indications for surgery are defined as absolute in the case when the method of choice for a given form of extrapulmonary tuberculosis or its complication is surgery. Individual indications: the question of performing surgery depends on the characteristics of the 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 non-specific means of action on the body. The targets of their action are individual elements of the pathogenesis of tuberculosis, mechanisms that determine the characteristics of the course of the disease and its outcome. Rational use of pathogenetic agents is possible only if the mechanisms of pathogenesis and the influence of endogenous and exogenous factors on them are taken into account.

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

The arsenal of non-specific pathogenetic agents currently available to phthisiologists is extensive. To limit the inflammatory reaction, glucocorticoids, anti-inflammatory drugs and sodium heparin are used; to prevent the development of fibrous changes, glucocorticoids, hyaluronidase, pyrogenal and penicillamine are used. Side effects of antibiotics are prevented or eliminated using antihistamines, pyridoxine, glutamic acid, piracetam and other drugs. Immunomodulators and immunocorrectors are widely used. Often, against the background of long-term anti-tuberculosis chemotherapy, the patient receives several pathogenetic and symptomatic agents simultaneously. This increases the drug load on the body's adaptive capabilities.

The main attention is paid to pathogenetic agents with polyvalent action, capable of simultaneously preventing or eliminating a number of pathophysiological disorders caused by common mechanisms.

Differences in the types of pulmonary tuberculosis

Not all patients require pathogenetic treatment. In 20% of patients with newly diagnosed pulmonary tuberculosis, clinical cure with minimal residual changes in the lung tissue can be achieved during standard chemotherapy. However, many patients require individual pathogenetic therapy, taking into account the clinical manifestations and characteristics of the course of the disease (both before treatment and at various stages of antibacterial treatment).

Due to technical difficulties, it is not always possible to conduct comprehensive laboratory monitoring, therefore general changes in patients of individual 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 during therapy) are of particular importance.

There are two types of tuberculosis progression, differing in the clinical and biochemical aspects of pathogenesis.

The first type of the course is characterized by an acute (subacute) onset of the disease, pronounced manifestations of tuberculosis intoxication, bacterioscopic detection of mycobacteria tuberculosis, a picture of destruction of lung tissue on a survey radiograph. Exudative tissue reactions predominate in the lungs, the infiltrative process occurs as periscissuritis (infiltrates in the interlobar fissure), lobitis with the formation of foci of caseous necrosis.

The second type of course: mild manifestations (or absence of symptoms), torpid course, absence of intoxication phenomena. Productive tissue reactions in the lung tissue predominate; by the time the tuberculosis pathogens are detected in these individuals, pathological changes in the lungs are limited, connective tissue membranes and fibrosis foci are formed around individual foci of caseous necrosis. As a rule, tuberculosis mycobacteria in such patients are detected only by the sowing method. Destruction of the lung tissue is diagnosed only by targeted tomographic examination.

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

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

Consistent use of non-specific pathogenetic agents

Non-specific pathogenetic agents against the background of antibacterial therapy are used taking into account the tolerance of patients to drugs and the resistance of tuberculosis mycobacteria to them. The use of pathogenetic agents depends on the stages of the tuberculosis process and the phases of etiotropic anti-tuberculosis chemotherapy. In the intensive phase of treatment, pathogenetic therapy has an anti-inflammatory and antihypoxic effect, prevents the development of side toxic-allergic effects of anti-tuberculosis drugs. In the second phase of anti-tuberculosis therapy, pathogenetic agents are used to stimulate reparative processes.

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

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);
• desensitization effect (immunosuppressant and antihistamine properties);
• suppression of collagen biosynthesis.

Pharmacokinetics

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

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

Synthetic glucocorticoids are inactivated in the liver more slowly than cortisol and have a longer period of action. Prednisolone and methylprednisolone are medium-acting glucocorticoids (T _1/2 from plasma is about 200 min), triamcinolone (T _1/2 is more than 200 min) and dexamethasone (T _1/2 is more than 300 min) are long-acting drugs. Dexamethasone is not used for continuous treatment due to the disruption of the circadian rhythm of 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 albumin deficiency, the number of unbound biologically active glucocorticoid molecules increases and side effects develop. Some drugs (for example, indomethacin) displace glucocorticoids from the complex with proteins and enhance their effect.

Main synthetic glucocorticoids

Prednisolone (pregnadiene-1,4-triol-11β,17α,21-dione-3,20 or δ'-dehydrohydrocortisone) is a standard drug in pharmacodynamic therapy, glucocorticoid doses are often indicated in terms of prednisolone. The ratio of glucocorticoid activity to mineralocorticoid activity is 300:1.

Methylprednisolone (6-α-methylprednisolone) has a lower (compared to prednisolone) ability to stimulate appetite, lacks mineralocorticoid activity. 4 mg of methylprednisolone is a dose equivalent to 5 mg of prednisolone.

Triamzanolone (9α-fluoro-16α-oxyprednisolone) promotes sodium excretion and increases diuresis, slightly stimulates appetite, and may cause myopathy, hirsutism, and skin rashes when used. The dose equivalent to 5 mg of prednisolone is 4 mg.

Dexamethasone (9α-fluoro-16α-methylprednisolone) has no mineralocorticoid activity ("pure" glucocorticoid), inhibits pituitary function, has a negative effect on 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 continuous use.

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). For patients with the second type of the disease, glucocorticoids are included in the complex therapy regimens 1.3-2 months after the start of treatment, since during this period the activity of mineralocorticoids increases in patients.

Glucocorticoids accelerate collagen formation and stimulate fibrosis formation by activating collagenase inhibitor. Since collagenase is the only enzyme that breaks down mature collagen, prednisolone use promotes the formation of less widespread but more severe and persistent fibrotic changes.

Stimulation of fibrosis foci formation 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 lung tissue and severe allergic reactions.

Contraindications

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

[ 30 ]

Method of use

The dose of glucocorticoids in the pathogenetic treatment of tuberculosis is (in terms of prednisolone) 15 mg per day for individuals weighing less than 65 kg and 20 mg for individuals weighing more than 65 kg. Patients receive this dose 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 14.00 - 10 mg (2 tablets) at a dose of 20 mg per day. It is not recommended to take the drug after 16:00.

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

Glucocorticoids are discontinued gradually, starting from the 6th week of their administration, the daily dose is reduced by 5 mg (in terms of prednisolone) during each subsequent week until complete discontinuation of glucocorticoids. In the process of reducing the dose of the drug, it is necessary to carefully monitor the general condition of the patient.

If arthralgia, weakness, or loss of appetite occur during the reduction of the glucocorticoid dose, the course of treatment is extended by 1-2 weeks, during which the patient receives 2.5 mg of prednisolone per day.

Throughout the entire period of glucocorticoid use, patients should receive preparations containing potassium (potassium and magnesium aspartate), ascorbic acid in standard doses. Given the catabolic effect of glucocorticoids, during their withdrawal and for 7 days after the drug withdrawal, it is advisable to prescribe antihistamines in standard doses.

Hyaluronidase

Indications for use

Hyaluronidase is used at the beginning of treatment in patients with the 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 prednisolone, provided that the isolation of mycobacterium tuberculosis continues. In the third period, the drug is used in patients with the first and second types of disease to reduce the severity of residual changes in the lung tissue.

Contraindications

Side effects: allergic reactions to antibacterial drugs, repeated bleeding. The drug should not be used during the recovery period after surgery, during the recovery period after bone fractures.

[ 31 ]

Method of application

Hyaluronidase is administered intramuscularly at a dose of 64 U every other day. 15 injections per course. If tuberculosis mycobacteria continue to be isolated, the course of treatment is repeated. The interval between two courses is 1 month.

Pyrogenal

Pyrogenal is prescribed in the second period (2-4 months after the start of therapy) of treatment of patients with the first type of disease. This coincides with the end of the prednisolone course of treatment. It is advisable to maintain an interval of 2-3 weeks between the end of the prednisolone course of treatment and the start of pyrogenal treatment.

Indications for the use of pyrogenal

Preservation of cavities against the background of fibrous changes in the lung tissue and areas of caseous necrosis, a tendency to form tuberculomas.

Contraindications

Fever, severe allergic side effects of antibacterial drugs, repeated pulmonary hemorrhages.

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 the disease in the presence of residual cavities.

[ 32 ], [ 33 ]

Application scheme

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

The reaction to the introduction of pyrogenal appears 2 hours (or later) after the use of the drug and is expressed in deterioration of general health, headaches, arthralgia, subfebrile temperature. On the following day, these phenomena pass, changes in the leukocyte formula appear (leukocytosis up to 10 thousand, shift in the leukocyte formula to the left), an increase in ESR to 15-20 mm / h. In some patients, despite the described changes, clinical symptoms are absent.

If severe reactions develop (chills, increase in body temperature to 38 ^° C), pyrogenal is continued to be administered in the dose that caused this reaction. In case of more severe (maximum) reactions to the administration of pyrogenal (convulsions, nausea, vomiting, increase in body temperature to 40 °C, a sharp increase in the number of leukocytes to 35,000-40,000, a pronounced shift in the leukocyte formula to the left), the administration of pyrogenal is stopped. Usually, all side effects disappear within 24 hours, the condition of the patients normalizes.

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

If the radiographic dynamics are positive, another course of treatment with pyrogenal is carried out after a three-week break.

[ 34 ], [ 35 ], [ 36 ]

Antioxidants

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

Antioxidants have such effects, regulating lipid peroxidation processes in biological membranes - a fundamental molecular mechanism for the development of many pathological processes.

Lipid peroxidation is the formation of excess free radicals (highly reactive molecules carrying an unpaired electron). By combining with molecular oxygen, free radicals form new free radicals - peroxide radicals. They interact with a component of the biological membrane - a molecule of unsaturated fatty acid to form highly toxic hydroperoxides and free radicals. The chain process can be interrupted only by interaction with an antioxidant (in this case, an antioxidant radical is formed that is incapable of continuing the chain). Interest in the problem of lipid peroxidation is due to the fact that the intensification of this process is accompanied by an increase in the inflammatory reaction and the formation of fibrous changes, the development of toxic reactions from the cardiovascular system, liver, pancreas and other organs. LPO products suppress reparation processes.

The impact on LPO processes with the help of antioxidants opens up additional possibilities in the treatment of patients with tuberculosis. The LPO activity revealed in tuberculosis and the insufficiency of antioxidant protection in both types of the disease (a decrease in the blood of the main antioxidant of the human body - α-tocopherol) explain the expediency of using antioxidants in the complex treatment of patients in a phthisiology clinic.

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

It is advisable to use antioxidants at the initial stage of treatment for the first type of the disease, 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 the accumulation of peroxides by interacting with free radicals, resulting in the formation of an antioxidant radical. Sodium thiosulfate does not have antiradical activity, but it is classified as an antioxidant, since it inhibits the accumulation of peroxides, reducing the intensity of oxidation of unsaturated fatty acids. The antioxidant effect of sodium thiosulfate is somewhat less than that of vitamin E, but the drug has a wide range of pharmacological activity and a pronounced antiallergic effect.

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

The presented data allow us to determine differentiated indications for the use 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 allergic side effects of anti-tuberculosis drugs. The use of sodium thiosulfate is the method of choice for infiltrative tuberculosis with predominantly exudative tissue reactions and fibrous-cavernous tuberculosis.

Vitamin E is used to prevent and eliminate the 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 development of respiratory failure or to correct stage III respiratory failure in patients with fibrous-cavernous pulmonary tuberculosis.

[ 37 ], [ 38 ], [ 39 ], [ 40 ], [ 41 ], [ 42 ]

Stimulating therapy

Biogenic stimulants (plasmol, aloe extract) are prescribed for chronic torpid forms (focal, infiltrative, disseminated, fibrous-cavernous) and for patients with a newly diagnosed process after 2-3 months of chemotherapy. 1 ml subcutaneously daily or every other day.

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

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

Bone marrow preparations

Myelopid is a peptide preparation obtained by culturing cellular elements of pig or calf bone marrow. Restores the B- and T-links of the immune system, stimulates antibody production. Release form: lyophilized powder in 10 ml vials (3 mg of the preparation). Subcutaneous administration of 3-6 mg daily or every other day, a course of 3-5 injections.

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

Thymalin (thymus extract), release form: in a vial, for injections of 5-10 mg. Intramuscular administration of 5-20 mg per day for 7-10 days. A repeated course can be carried out after 1-6 months

Taktivin (thymus extract), release form: in a 0.01% solution in a 1 ml vial. Subcutaneous administration into the upper third of the shoulder once a day (at night) at the rate of 40 mcg/m2 ^of body surface (1-2 mcg/kg) for 5-14 days.

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

Timoptin - release form: in vials of 100 mcg of the drug. Subcutaneous administration, a course of 4-5 injections with 4-day breaks.

[ 43 ], [ 44 ], [ 45 ], [ 46 ], [ 47 ], [ 48 ], [ 49 ], [ 50 ], [ 51 ], [ 52 ]

Immunotherapy in the treatment of tuberculosis

One of the components of the complex treatment of tuberculosis of the respiratory organs is the correction of secondary immunodeficiency states. The results of meta-analysis do not yet allow us to classify immunotherapy agents as having a high level of evidence. In patients with active forms of tuberculosis, violations of most indicators of cellular and humoral immunity are detected. In particular, the following are changed:

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

There are various classifications of immunomodulators. According to the classification proposed by RM Khaitov and BV Pinegin (1996, 2002), the following are distinguished:

• preparations of microbial origin - BCG vaccine, tuberculin, pyrogenal, prodigiosan, ribomunil, sodium nucleinate,
• drugs of endogenous origin, including thymus (thymus extract, immunofan, etc.);
• bone marrow derived drugs (myelopid);
• cytokines: human leukocyte interferon, IL-1β, IL-2, molgramostim;
• synthetic and semi-synthetic (levamisole, glutoxim, polyoxidonium, licopid).

The classification proposed by M.M. Averbakh (1980) suggests the allocation of immunomodulators specific for tuberculous inflammation (tuberculin, BCG vaccine) and non-specific agents (levamisole, thymus preparations, sodium nucleinate, methyluracil, etc.).

In the practice of phthisiology, the most common use of such modern immunomodulatory agents as human leukocyte interferon, polyoxidonium, likopid, glutoxim, recombinant human interleukin-2 has recently been. At the same time, non-specific immunomodulatory agents, which have been used in phthisiology for a long time, have not lost their significance: levamisole, sodium nucleinate, methyluracil, thymus preparations and others, as well as such agents of specific immunotherapy for tuberculosis patients as tuberculin and BCG vaccine.

Tuberculin therapy

Currently, purified tuberculin in standard dilution (purified liquid tuberculosis allergen in standard dilution) is used for tuberculin therapy.

Mechanism of action of tuberculin therapy:

• decrease in excitability of the nervous system;
• increased lymph circulation;
• dilation of capillaries in the affected area;
• increasing the permeability of histohematic barriers:
• increasing the 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. Tuberculin therapy has a more pronounced effect in patients with pulmonary tuberculosis with high sensitization and reduced overall reactivity of the body. Tuberculin therapy is prescribed to enhance reparative reactions with slow involution of specific changes in the lungs.

Tuberculin electrophoresis technique

The initial dose of administered tuberculin is 5 TE PPD-L, and it is increased by 5 TE at each session. The dose of administered tuberculin is determined individually for each patient, by the end of the course it is a maximum of 100 TE.

Electrophoresis of tuberculin is carried out using electrodes used for galvanization, tuberculin in the required dose is applied to pads pre-moistened with warm distilled water and administered from the positive pole. The electrodes are tightly applied to the patient's chest in a lying position, corresponding to the projection of the affected area of the lung. The current strength is determined based on the patient's sensations (slight tingling on the skin under the electrodes), but it should not be higher than 10 mA. The duration of a tissue electrophoresis session is 20 minutes. On average, 20 sessions are carried out. It is recommended to carry out tuberculin therapy using 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, clinical, radiological and laboratory research data, the purpose of prescribing tuberculin therapy, and is also clarified in the course of tuberculin therapy taking into account the patient's tolerance of the procedures, the dynamics of the X-ray tomographic and laboratory research data. Even with good tolerance of treatment, it is advisable to conduct a control X-ray examination in the middle of the course (at a dose of tuberculin of 40-50 TE). If a general, local or combined reaction to tuberculin appears in the patient, its subsequent administration is carried out in the previous dose. If necessary, the course of tuberculin therapy can be repeated with a break of 1-1.5 months.

A course of tuberculin therapy is recommended in all cases against the background of adequate chemotherapy, within 2 weeks or more from the moment of its start. An indispensable condition is the patient's tolerance of the chemotherapy agents used. It is advisable to prescribe tuberculin therapy to patients undergoing inpatient treatment in an anti-tuberculosis institution (specialized department) to ensure better control of the patient's tolerance of the treatment. However, this requirement is not mandatory, given the good tolerance of the procedures by patients.

Indications for use

• clinical;
• active forms of pulmonary tuberculosis with a tendency to encapsulation and the formation of tuberculomas, with slow involution of decay cavities;
• predominantly productive type of inflammatory reaction;
• immunological;
• medium and high levels of antibodies to the tuberculosis pathogen (IgG) in ELISA, if they correspond to a high level of sensitivity to tuberculin.

Release form: purified tuberculin solution in 5 ml ampoules containing 2 TE PPD-L in 0.1 ml. BCG therapy

Mechanism of action

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

Vaccine therapy technique

The vaccine therapy method involves administering the vaccine in subthreshold doses that have a pronounced therapeutic effect and are completely safe for patients. The therapeutic dose of BCG is determined based on the results of the Mantoux test with 2 TE. The vaccine dose is inversely related to the severity of the reaction to tuberculin. If the patient has an infiltrate from 1 to 15 mm in diameter, treatment begins 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 infiltrate is more than 21 mm, 0.1 ml of the fifth consecutive 10-fold dilution of the vaccine is administered. After establishing the initial dose of the vaccine, the corresponding 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 made 3-4 weeks after the reaction at the site of the previous one has faded. As a rule, 3 injections are sufficient to obtain the optimal effect. The number of injections is determined individually for each patient.

Indications for use

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

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

Interleukin-2 human recombinant

Structural and functional analogue of endogenous IL-2, isolated from cells of non-pathogenic baker's yeast Saccharomyces cerevisiae, into whose genetic apparatus the human IL-2 gene is integrated. The spectrum of immunotropic effects of recombinant human IL-2 (rocoleukin) includes restoration of endogenous IL-2 synthesis by activated CD4 ⁺ - and CD8 ⁺ -cells.

Mechanism of action

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

Indications for use

• Clinical:
  • destructive pulmonary tuberculosis with a predominance of exudative inflammation (including that caused by drug-resistant strains of Mycobacterium tuberculosis);
  • fibrous-cavernous tuberculosis of the lungs in the phase of intractable progression of the process with massive bacterial excretion against the background of ongoing polychemotherapy;
• immunological:
  • insufficiency of the cellular component of immunity (lymphocyte count ≤18%, RBTL with FGA ≤50%, RBTL on PPD-L <3%, production of FGA-induced IL-2 <10.0 U/ml);
  • with a decrease in the lymphocyte content ≤1200 cells/ml, mature T-lymphocytes ≤55%, CD4/CD8 index ≤1.5, RBTL on FGA ≤50%, RBTL on PPD ≤3% and FGA-induced IL-2 production ≤5 U/ml in patients with fibrocavernous tuberculosis during the period of preparation for surgery.

Application schemes:

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

Release form: ampoules made of neutral glass containing 0.25 mg (250,000 IU), 0.5 mg (500,000 IU), 1 mg (1,000,000 IU) of lyophilized drug.

Interleukin-1 β human recombinant

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

Mechanism of action

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

Indications for use

• Clinical:
  • newly diagnosed pulmonary tuberculosis of limited extent with a predominance of the productive type of tissue reaction (with or without destruction);
  • preservation of the average size of productive foci in lung tissue and “residual” cavities for 4-5 months of treatment, regardless of the initial form of pulmonary tuberculosis;
• immunological:
  • lymphocyte count ≤18%; RBTL on PPD-L <3% or ≥5%. with PHA-induced IL-2 production within normal limits (≥10.0 U/ml).

Directions for use

It is used in a dose of 5 ng/kg, dissolved in 500.0 ml of 0.9% sodium chloride solution. It is administered intravenously by drip for 3 hours, daily, the course is 5 procedures.

Release form: ampoules (vials) made of neutral glass, containing 0.001 mg (1000 ng), 0.0005 mg (500 ng), 0.00005 mg (50 ng) of the lyophilized drug.

Polyoxidonium

Polyoxidonium is a copolymer of N-oxy-1,4-ethylenepiperazine and (N-carboxyethyl)-1,4-ethylenepiperazinium bromide - a high-molecular physiologically active compound with pronounced immunotropic properties.

Mechanism of action

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

It has pronounced detoxifying properties, does not cause allergic reactions, is well tolerated by patients, combines well 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 when using polyoxidonium is manifested by the rapid elimination of circulating immune complexes, stimulation of previously lost functional activity of macrophage cells. Polyoxidonium activates both oxygen-dependent and oxygen-independent mechanisms of bactericidal action of phagocytes. The target cells for polyoxidonium are primarily monocytes/macrophages, neutrophils and NK cells.

Inclusion of polyoxidonium in the complex therapy of patients with pulmonary tuberculosis has a pronounced clinical effect, manifested by the elimination of intoxication in a shorter time, acceleration of the processes of resorption of infiltrative changes and closure of the destruction of lung tissue. As a result of immunotherapy with polyoxidonium, an increase in the absorption capacity of monocytes, an increase in the relative content of CD3 ⁺ lymphocytes, a decrease in the initially increased functional activity of neutrophils, assessed in chemiluminescent tests, are noted. By the nature of the effect on the immune system, polyoxidonium is a true immunomodulator: it increases reduced and reduces increased indicators of the functional activity of neutrophils, without affecting unchanged immunological indicators.

Indications for use in patients with tuberculosis of the respiratory organs

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

Indications for endobronchial administration of polyoxidonium:

• tuberculosis of the bronchi, destructive forms of pulmonary tuberculosis;
• immunological:
  • high serum IgA levels (400 mg/dL and above), high spontaneous luminol-dependent chemiluminescence (L3CL) levels (30 mV/min), low spontaneous luminol-dependent chemiluminescence (1.5 mV/min and below), low relative lymphocyte count in peripheral blood (20% and below).

Directions for use

Intramuscular and endobronchial (ultrasonic inhalation) administration of polyoxidonium at 6 mg 2 times a week - 10 injections for 5 weeks.

Release form: ampoules made of neutral glass containing 0.006 g of polyoxidonium.

Human leukocyte interferon

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, factors inhibiting the migration of macrophages and leukocytes) in their natural ratio, has an immunomodulatory, anti-inflammatory and detoxifying effect.

Mechanism of action

• normalization of phagocytic function and activity of B-lymphocytes;
• stimulating effect on T-cell immunity with predominant activation of type 1 T-helpers: activation of lymphocytes is manifested by stimulation of T-lymphocyte differentiation, normalization of the CD4 ⁺ / CD8 ⁺ ratio, stimulation of lymphoid infiltration of inflammatory foci;
• activation of all parameters of phagocytosis: killing function, the 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 patients with tuberculosis helps to accelerate the regression of intoxication symptoms, as well as improve the tolerability of anti-tuberculosis drugs.

Indications for use

• Clinical:
  • newly identified forms of active pulmonary tuberculosis - limited and widespread; 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.

Directions for use

Intramuscular, endobronchial administration (ultrasonic inhalations), as well as a combination of administration routes. Single dose 10,000 IU; course dose 100,000-160,000 IU. Intrapleural, endolymphatic, and endobronchial (during endoscopic examination) administration of the drug is possible. The minimum course of treatment is 3-4 weeks, however, longer courses (3-6 months or more) are desirable until stable remission is achieved.

Release form: ampoules made of neutral glass containing 10 thousand IU of interferon-α.

Lycopid

Likopid (glucosaminylmuramyl dipeptide) is a drug of the muramyl peptide series with immunotropic activity. According to its chemical structure, it is N-acetylglucosaminyl-N-acetylmuramyl-L-alanyl-D-isoglutamine. The drug has a multifaceted effect on the human immune system, stimulating the development of both cellular and humoral immune responses, stimulates leukopoiesis, and has anti-infectious and antitumor activity. Likopid is a synthetic analogue of a component of the cell wall of all bacteria, which has pronounced immunomodulatory properties.

Mechanism of action

The main point of application of licopid in the body are the cells of the monocyte-macrophage system, activating which licopid increases:

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

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

Indications for use

• Clinical:
  • newly diagnosed and chronic forms of pulmonary tuberculosis, including widespread infiltrative tuberculosis, caseous pneumonia, progression of chronic forms of tuberculosis;
  • forms of pulmonary tuberculosis with intoxication, widespread lesion volume, destruction of lung tissue, massive bacterial excretion;
  • in case of delayed clinical and radiological regression of tuberculous changes in the lungs;
  • in combination with tuberculosis and inflammatory non-specific diseases of the respiratory organs;
• immunological:
  • decrease in the absorptive and bactericidal functions of phagocytes; decrease in the number and functional activity of T-lymphocytes and their subpopulations;
  • imbalance of helper and cytotoxic lymphocytes with normal T-cell levels.

Directions for use

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

Release form: 10 tablets in a blister in two dosages - 1 mg and 10 mg.

Glutoxim

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

Under experimental conditions, it was confirmed that the mechanism of the therapeutic action of glutoxim is significantly influenced by its positive effect on the functional activity of peritoneal macrophages: stimulation of their absorption and digestion capacity, as well as the production of superoxide radicals, was detected.

Mechanism of action

• affects the cellular oxidation-reduction metabolism;
• stimulates endogenous production of cytokines and homopoietic 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.

The clinical effectiveness of glutoxim in patients with pulmonary tuberculosis is manifested by a reduction in the time of elimination of intoxication, normalization of clinical blood test parameters (restores the level of neutrophils, monocytes and lymphocytes in the peripheral blood), as well as negativization of sputum in patients excreting bacteria. The inclusion of glutoxim in the complex treatment of tuberculosis allows for a more pronounced resorption of infiltrative changes in the lung tissue, perifocal and pericavitary infiltration, a decrease in the size of foci, and partial regression of caseous-pneumonic foci.

Directions for use

As part of complex therapy for 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 specific inflammation to the productive phase, it is prescribed intramuscularly 1-2 times a day 3 times a week at a daily dose of 10-20 mg for 1-2 months.

Release form: injection solution 1% and 0.5% (ampoules 1 ml and 2 ml).

Derinat

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

The 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 the bactericidal activity of leukocytes;
• impact on humoral factors (complement activation, decrease or increase in CIC, increase in the number of total and activated B-lymphocytes):
• impact on phagocytosis (increased adhesion, increased number and activity of neutrophils and macrophages).

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

Directions for use

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

Release form: injection solution 1.5% (5 ml ampoules).

[ 53 ], [ 54 ]

Tilorone

Tilorone (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 T-helper/T-suppressor ratio;
• increases the activity of natural killers;
• normalizes the humoral immune response;
• regulates pro- and counter-inflammatory cytokines.

The clinical effect in patients with pulmonary tuberculosis is manifested by a more rapid elimination of clinical manifestations, a more frequent cessation of bacterial excretion, and a more frequent closure of lung tissue destruction.

Directions for use

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

Release form: film-coated tablets of 0.125 g and 0.06 g.

Levamisole

Levamisole is a synthetic immunomodulator.

Mechanism of action

• accelerates differentiation and maturation of T-lymphocytes;
• stimulates the functions of mature T-lymphocytes;
• increases the activity of natural killers, macrophages, T-suppressors;
• stimulates interferon production, activates lymphocytes;
• selectively stimulates cellular immunity (imitation of the action of the thymus hormone);
• stimulates the function of lymphocytes regardless of their role in the immune response:
• increases the production of lymphokines by lymphocytes (a factor that inhibits lymphocyte migration and a factor that activates macrophages);
• affects the functional state of macrophages - increases their antigen-presenting function and the phagocytic activity of mononuclear phagocytes;
• restores cellular immunity disorders and interactions between T and B lymphocytes; it does not so much change the level of T or B lymphocytes as it reduces the number of inactive lymphocytes;
• inhibits the formation of immune complexes and antibodies.

Does not increase immunological reactions above normal levels.

Directions for use

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

Release form: 1 tablet (150 mg) per package.

Methyluracil

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

Mechanism of action

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

Method of administration and dosage

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

Release form: tablets of 500 mg.

[ 55 ], [ 56 ], [ 57 ], [ 58 ]

Physical methods of treating tuberculosis

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

Adequate use of physiotherapeutic factors in the clinical situation stimulates the processes of lung tissue reparation, accelerates the regression of tuberculous inflammation, which is manifested by a reduction in the time of closure of destruction cavities and cessation of bacterial excretion and determines not only the clinical but also the economic efficiency 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 the complex therapy of patients can be dangerous, for example, the appointment of stimulating methods before surgery or in case of ineffective chemotherapy.

The appointment of physiotherapy should be preceded by a detailed analysis of the nature of the specific process. In this case, the following should be taken into account:

• clinical form of the process;
• type of tissue reaction (exudative, proliferative);
• localization and duration of the process;
• age and adaptive capacity of the patient;
• the 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 the respiratory organs, but their use is most appropriate.

• in widespread (more than 1 segment) or clinically manifested forms after the start of adequate chemotherapy and reduction of intoxication symptoms;
• with delayed regression of specific inflammation;
• while destructive changes in the lungs persist;
• with concomitant broncho-obstructive syndrome, the presence of “blocked” caverns.

Contraindications for the use of all physical methods

General contraindications:

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

Contraindications due to the tuberculosis process:

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

In addition, each of the physical factors has specific limitations for use, information about which is provided in the description of the method.

Characteristics of the main physical factors of treatment

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

The first group includes physical factors that have predominantly anti-inflammatory, including tuberculostatic, and hyposensitizing effects. Treatment methods based on them also contribute to an increase in the concentration of antibacterial drugs in the inflammation focus, activation of local protective tissue reactions. The main representatives of this group include: exposure to electromagnetic radiation of the ultra-high-frequency range (UHF therapy), extremely high-frequency (millimeter) range (UHF therapy), as well as combined physical and medicinal effects - inhalation therapy, electrophoresis. They are prescribed in the initial stage of pulmonary tuberculosis with a predominantly exudative-necrotic type of inflammation.

The second group of factors includes ultrasound, laser and magnetic therapy, which promote the resorption of the tuberculosis process, increase the ability of tissues to regenerate and repair, accelerate the cicatrization of caverns and the healing of fistulas. This group of factors is used for 2-3 months from the beginning of full-fledged chemotherapy. During this period, the specific process in the lung parenchyma undergoes reverse development. Resorption of infiltrative changes, cicatrization of destruction cavities, and fibrotization of foci occur. The use of physical factors of the 2nd group allows accelerating these processes. In addition, the multicomponent clinical effects of laser and magnetic-laser therapy are manifested by a distinct and largely unique biostimulating and adaptogenic effect, promoting the stabilization of homeostasis and activation of the natural defense mechanisms of the patient's body. Physiotherapeutic methods of the 2nd group are most effective during the period of change from the exudative-necrotic type of inflammatory tissue reaction to the proliferative one.

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

[ 59 ], [ 60 ], [ 61 ], [ 62 ], [ 63 ], [ 64 ], [ 65 ], [ 66 ], [ 67 ]

Methods of extracorporeal hemocorrection in tuberculosis

Extracorporeal hemocorrection is based on the removal of toxic substances from the bloodstream either by perfusion of blood through various adsorbents (hemosorption) or by removing them together with part of the plasma (plasmapheresis). Hemosorption mainly removes medium- and high-molecular toxic metabolites, while plasmapheresis, together with part of the plasma, additionally ensures the evacuation of low-molecular toxic products and some electrochemically inert compounds that are not capable of being adsorbed on hemosorbents. This is a prerequisite for the combined use of these methods of extracorporeal blood treatment. In this case, they achieve correction of factors aggravating the course of the main process in the lungs or pleural cavity and reducing the effectiveness of its treatment: endogenous intoxication syndrome, toxic-allergic reactions to anti-tuberculosis and other drugs, liver dysfunction, 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 tuberculosis of the respiratory organs is indicated when the complex treatment of the tuberculosis process is insufficiently effective or when it is impossible to carry out this treatment, due to the following factors (if they are not corrected satisfactorily using traditional methods):

• endogenous intoxication syndrome caused by the presence of a specific process in the lungs or a specific suppurative process in the pleural cavity, the presence of pulmonary or pleural pathology of non-tuberculous etiology concomitant with tuberculosis, acute purulent pathology of other organs:
• toxic-allergic reactions to anti-tuberculosis and other medications, food and household allergies that complicate the treatment of the underlying process;
• liver dysfunction of various origins (drug-induced toxic-allergic hepatitis, consequences of infectious hepatitis, etc.), resistant to hepatotropic therapy;
• renal failure (acute and chronic) caused by the presence of combined tuberculosis lesions of the lungs and kidneys, prolonged tuberculosis intoxication, toxic effects of anti-tuberculosis drugs and other causes;
• concomitant diseases that are often found in patients with tuberculosis of the respiratory organs and aggravate the course of the specific process are bronchial asthma and diabetes mellitus (especially in its complicated course with the development of polyneuropathy, retinopathy, angiopathy, etc.).

Contraindications

Contraindications to extracorporeal hemocorrection operations coincide with general contraindications to the use of large doses of heparin. In addition, contraindications to hemoperfusion include severe arterial hypo- or hypertension, and the patient's agonal state.

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Technology of the method

When using extracorporeal methods of hemocorrection on a planned basis, the preparation of patients with tuberculosis of the respiratory organs for hemoperfusion should be aimed at preventing and eliminating initial hypovolemia, changes in the rheological properties of the blood, correcting water-electrolyte disturbances, protein deficiency, anemia and other shifts in homeostasis in the absence of a cause-and-effect relationship between the said disturbances and the factor that was the reason for using these methods of blood processing.

Hemosorption in patients with respiratory tuberculosis should be performed according to a standard scheme that ensures maximum clinical effect and minimizes the risk of complications during the procedure. The extracorporeal circuit should include one sorption column. Hemocarboperfusion should be performed using the venovenous method under temporary hemodilution conditions. General heparinization at a rate of 250 U/kg of body weight. The blood flow rate should not exceed 70-80 ml/min, while the duration of the procedure should be sufficient for blood perfusion in a volume of 1 to 1.5 circulating blood volumes.

The plasmapheresis technique is determined by the equipment at the operator's disposal. In hardware centrifugal (gravitational) plasmapheresis, to remove plasma from the bloodstream, the blood is centrifuged either in special containers such as "Gemakon" (intermittent plasmapheresis) in a refrigerated centrifuge, or in various separators of continuous flow action (continuous plasmapheresis). Vascular access is achieved by catheterization of one peripheral or central vein. General heparinization is calculated at 200 U/kg of body weight.

Filtration plasmapheresis using plasma filters (plasma filtration) is carried out using a pump unit of the PF-0.5, FK-3.5 devices, any other roller pumps or special blood fractionators of foreign companies (Fresenius, Gambro. Baxter, etc.). Blood perfusion should be carried out using the venovenous method against the background of temporary hemodilution. General heparinization, up to 300 U/kg. Domestic membrane plasma filters PFM (St. Petersburg, AO Optika) allow for single-needle non-device membrane plasmapheresis under the action of gravity alone using a special system of lines. When performing hardware centrifugal plasmapheresis or plasma filtration in patients with tuberculosis of the respiratory organs, up to 1 liter of plasma is evacuated in one session, which is replenished with a 0.9% sodium chloride solution, rheopolyglucin, and in some cases, native plasma.

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

Complications

The most common complications of extracorporeal hemocorrection operations are pyrogenic reactions (chills, muscle pain and spasms, hyperthermia) and hemodynamic disorders (collapse reactions). If complications of this kind develop, the extracorporeal operation should be stopped and, according to indications, appropriate symptomatic therapy should be administered: administration of antihistamines, trimepidine, in some cases 30-60 mg of prednisolone, intravenous infusion of plasma-substituting solutions, etc.

Among technical complications, extracorporeal circuit thrombosis and its depressurization should be singled out. If such situations arise, blood perfusion should be immediately stopped and the extracorporeal operation should be completed, since its continuation in such conditions is fraught with the development of thrombosis, thromboembolism or air embolism in the pulmonary artery system. Maximum standardization of the technique, careful preparation of the extracorporeal circuit, monitoring control, and literacy of medical personnel can dramatically reduce the likelihood of complications and their number.

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Results of using the method

The use of extracorporeal hemocorrection methods in patients with respiratory tuberculosis allows correcting most of the disturbed homeostasis parameters. Positive dynamics of the parameters reflecting the state of the myocardium and central hemodynamics, liver and kidneys are observed; ventilation disorders are reduced (mainly associated with obstructive changes); microcirculation in the lungs is improved: serum toxicity is reduced; hypokalemia, peroxide homeostasis parameters, shifts in acid-base balance and blood gas composition are corrected. In addition, an immunomodulatory effect is manifested in relation to factors of cellular and humoral immunity, the metabolic activity of phagocytic cells (neutrophils and monocytes) increases, as well as the bacteriostatic activity of the blood in relation to tuberculosis mycobacteria.

The use of hemosorption and plasmapheresis methods creates a favorable background for the main course of anti-tuberculosis chemotherapy in a phthisiotherapeutic clinic, provides the possibility of treatment using surgical methods, and expands the boundaries of operability. A positive clinical effect can be achieved in more than 90% of observations, and a stable correction of various factors that aggravated the course of the main process and complicated its treatment - in 75%.