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The bactericidal therapy in patients with tuberculosis

the Ministry of Healthcare of the Russian Federation
the Russian Society of Phthisiatricians
In: 'The Problems of Tuberculosis and Pulmonary Disease', the monthly science & practical journal (Est. May 1923)
Issue No. 3 (2004), p. 21-26
UDC 616.24-002.5-085.281
the bactericidal therapy in patients with tuberculosis
V.A. Krasnov, I.G. Ursov
The Scientific Research Institute for Tuberculosis of the Ministry of Healthcare of the Russian Federation, State Medical Academy (Novosibirsk)

The appearance of patients with rapidly progressing forms of tuberculosis, the increasing virulence and therapeutic resistance of the causative agent, as well as certain maintenance and logistical concerns of the anti-tuberculosis institutions have all contributed to the substantially decreased efficacy of treatment. In application of the ubiquitously used bacteriostatic therapy the frequency of closure of decay cavities in patients with primarily detected pulmonary tuberculosis during 1-2 years of monitoring has decreased up to 50%. There is one patient removed from the registries due to death per 1-2 patients cured from tuberculosis. There is a long-pending call for revision of current treatment protocols in the primarily and secondarily detected pulmonary tuberculosis in the decay phase. First of all, this concerns changes towards a vigorous aethiotropic therapy with preservation of the principles of the domestic tradition to safeguard the patient’s interests, namely: employing the hygiene-dietetic regimen both in the hospital and in at the sanatorium, additional application of the short-term reversible collapse techniques and early surgical interventions where indicated

The method of intermittent bactericidal chemotherapy had been developed and used successfully for several decades at Novosibirsk Scientific Research Institute for Tuberculosis of the Ministry of Healthcare of the Russian federation and the Chair of Tuberculosis of the Medical Staff  Development Faculty of the Novosibirsk State Medical Academy directed by Prof. Dr. I.G. Ursov, MD, PhD, the Correspondent Member of the Russian Academy of Medical Sciences.

The peculiar features of the tuberculosis causative agent, which should be taken into account at a clinical setting. The mycobacteria of tuberculosis, unlike other bacteria, contain substantial amounts of lipids in their cellular membrane and cytoplasm, which determines their resistance to acids, alkali and alcohol, as well as enables them to penetrate alveolar and other types of macrophages easily. The intracellular persistence of the microbe shields it from the antibodies and immune cells, with protection provided by the external membrane of the macrophage, as well as the membrane of the phagosome hosting the bacterium. Thus, in the treatment of limited processes without bacterial excretion (foci, infiltrative nidi) the anti-tubercular medications have to additionally surmount 2-3 membrane barriers, which lead to loss of therapeutic quantities and their low concentrations in the sites of contact with the microbe. It should be instantly noted that insufficient partial oxygen pressure and acidic PH in the cytoplasm of the macrophage hinder the metabolic processes of mycobacteria, rendering the division retarded. The above circumstance provides an explanation to the relatively small mycobacteria populations in focal processes without decay, that is, tens, hundreds, thousands of bacteria. 
Another important therapy-related peculiarity of mycobacteria is their aerobic metabolism and requirements of high quantities of oxygen to maintain their active vital activity. As a cavity of decay appears in the lung, the relatively small population of mycobacteria increases several million times in 2-3 weeks, the presentation and prognosis of the disease being respectively aggravated. The fresh decay cavity in the lung serves as an ideal incubator for the mycobacteria. It provides all conditions for the unobstructed reproduction and growth of the causative agent: the excess of oxygen coming from the draining bronchi with the air, the optimal temperature of 37-38 C and the abundance of nutrients (proteins, phospholipids, etc).   The decay cavity has neutral or weakly alkaline pH, mycobacteria are found extracellularly and freely vegetate upon the internal surface, dividing once in 15-24 hrs (once in 20 hrs according to radioactive tracing).

The distinctive features of mycobacteria in the host organism. The resistance of M. tuberculosis to antitubercular drugs is a result of spontaneous mutations, occurring with a definite frequency in the process of bacterial reproduction. Mutations, resulting in resistance M. tuberculosis to rifampicin occur with the frequency of 10-10 per cellular division and result in formation of resistance in 1 of 100 mln of susceptible mycobacteria in drug-free media. The frequency of mutations required for the formation of resistance to isoniazid is from 10-7 to 10-9, which results in appearance of 1-100 resistive bacteria per 1 mln susceptible ones.
The multiple drug resistance, also caused by spontaneously occurring mutations, is a rarer event, since mutations resulting in resistance to various classes drugs are not genetically linked. Thus there is not a dedicated gene, the mutations in which would be accompanied by multiple drug resistance. For example, the probability of spontaneous mutation resulting in the development of the resistance of one mycobacterial cell to isoniazid and rifampicin is consequence of individual mutations to each of the respective drugs and is subsequently defined as 10-6 x 10-8 = 10-14 (1 in 1014).

Taken the common assumption that a closed focus of 2.5 cm in diameter contains up to 100 mycobacteria, the likelihood of presence of even one bacterium, resistant to izoniazid does not exceed 10-2. The fresh decay cavity 2.5 cm in diameter will number up to 100 mln of tubercular mycobacteria, of which 100-10 000 mycobacterial units will be resistant to izoniazid and one unit will be resistant to rifampicin. Therefore to achieve the full suppression of all 100 units in the focus of 2.5 cm in diameter, a combination of two drugs is sufficient, for example izoniazid and pyrozinamide. Quite a different situation is typical in open foci. There always is a 100 per cent probability of drug resistance of mycobacteria to antitubercular drugs applied. Therefore in such cases chemotherapy should include not less than 3 drugs.

The notion of primary (wild) drug resistance of mycobacteria encompasses causative agent with the varying degree of resistance, more frequently with mild to moderate resistance surmountable in delivery of maximal attainable concentrations of 3-4 drugs to bacterial habitat. For example in the presence of mycobacterial resistance to 1mcg/ml of izoniazid (which is considered a high degree of resistance) the creation of drug concentration above that level allows of obtaining of favourable therapeutic result. The most frequently found resistance of mycobacteria to 5 mcg/ml of streptomycin is surmounted by the administration of the latter as 1g intramuscularly. In moderate to high degree of mycobacteria resistance to 1-2 drugs the bactericidal effect is achieved in simultaneous delivery of all 3-4 drugs to causative agent in maximal concentrations, which should be accounted for in various venues of drug delivery to the patient organism. Thus, the maximal concentration of drugs in the focus of information will be achieved if the patient first takes tablets/capsules of rifampicin, pyrozinamide or ethambutol orally, then in 1 hr streptomycin is injected intramuscularly and in 30 more minutes izoniazid is administered in an intravenous drip. An alteration of the above order of drug administration is totally unacceptable since that may substantially attenuate the bactericidal effect. The premature impact certain drugs upon the inflammatory focus can cause a portion of metabolically active bacteria to convert into the persistence mode. The drugs which have arrived to the inflammation focus later may not exert their eliminative action upon persisting bacteria. The conversion of mycobacteria into persistence mode impedes the achievement of the desired bactericidal effect.

It is important for the clinician to know that the populations of the mycobacteria in a focus or infiltrate and to a greater degree in a decay cavity are far from being uniform. At every given moment there are dividing microbial cells with the highest metabolic rates, there are also cells with high medium and low metabolic rates respectively, as well as resting persistent mycobacteria. In order to meet its reproductive objective, every mycobacterium upon division into daughter cells must follow the cycle of excitation and augmentation of metabolism in order to accumulate enough energy for at least one generation. The process of division itself does not occur instantly; it rather tends to take some time, but is always performed at the peak of metabolism. It is in this period that the microbial cell receives the greatest quantity of required nutrients from without, therefore becoming most vulnerable to antimetabolites (antibiotics and chemotherapeutic agents). In other words, the bactericidal effect as a rule can be obtained within 5-6 hrs prior to the division the mycobacterium and in 5-6 hrs after the division thereof. The close to the moment of partition of the microbial cell, the shorter is the time required for the cell to receive a little dose of the drug.

Thus, the efficacy of chemotherapy for tuberculosis depends on the constantly changing intensity of metabolism in the microbial cell between the two divisions – from the highest one, to very low one, down to the state of dormancy when 3,4 and 5 are not being received and administration of the above becomes harmful for the patient (toxicity), as well as for the public (misapplication of substantial funds and therapeutic agents).
Being strongly pronounced antimetabolites, the antibiotics and other antitubercular agents, when penetrating into mycobacteria, integrate themselves into enzymatic systems and impede or substantially disrupt metabolism. The destructive potential of the aforementioned agents depends on the intensity of metabolic reactions and the overall biologic activity of the microbe as well as the dose of therapeutic substances, penetrating from interstitial fluid into microbial cytoplasm and the exposure to the antimetabolite. When getting into the mycobacterium, small quantities of therapeutic agents, especially if its metabolism is on a low level, are only capable of converting the cell into the state of dormancy or persistence, and the microbe is spared. It conversion of mycobacteria into the state of dormancy by creating small but consistent drug concentrations that is the chief objective of bacteriostatic therapy. In such schedules the predominant part of persisting mycobacteria population is preserved and only a small quantity of the most metabolically active cells is exterminated. Under such circumstances the achievement of favourable effect, based on restoration of the immunity as the result of many months of hospitalization and the subsequent sanifying activity of immunocompetent cells, as well as defensive mechanisms in their entirety, is quite a remote and currently undefined perspective.

The objectives and the principles of bactericidal therapy. The objective of the bactericidal technique is the as rapid and complete destruction of mycobacterial population as possible via creating conditions for enhancing metabolism in the dormant microbial cells,in order to destroy the activated portion of the bacteria at the peak of their metabolism. Several compulsory conditions are required to meet such an objective:
  • delivery of chemotherapeutic agents to the mycobacteria in the highest (bactericidal) concentration without exceeding the permitted daily dose, authorized by the Pharmacological Committee;
  •  the definite sequence of delivery of aetiotropic agents into the organism in different routes of administration; 
  • utilization of only such drugs, that possess bactericidal properties;
  • the performance of bactericidal procedures 2 times a week from the first days of treatment.
The practical experience has demonstrated that a combination of 3 chemotherapeutic drugs is usually sufficient. Under such protocols, curable and non-curable reactions within the first 3-4 months of therapy are found in approximately 20% of patients, that is, no correction of treatment as such is required. In addition of the 4th drug the frequency of adverse events increase up to 40-45%, which introduces difficulties into continuation of therapy. Thus, in administration of multimodality chemotherapy special caution should be applied, using it only when necessary.

When commencing treatment, the physician has to be absolutely positive that bactericidal effect will occur already at the first administration of anti-tubercular drugs, that is, the majority of metabolically active microbial cells will receive the lethal dose of aetiotropic agents and will perish (the issue is the decay cavities, which are main object of the attention of the tuberculosis specialist). With that in mind, it is important to view the peculiarities of pharmacokinetics and pharmacodynamics of the bactericidal agents.

Antibiotics and chemotherapeutic agents, suitable for bactericidal therapy.
3.1. isoniazid is by right considered the most active anti-tuberculosis medication, being the constituent of virtually all protocols for the treatment of tuberculosis. Its minimal bactericidal concentration is 3-3.5 mcg/ml or 3-3.5 mcg/g. The Pharmacopoeia allows to use a maximal daily dose of isoniazid of 15 mg per 1 kg of body weight, that is, in a patient with body weight of 60 kg the dose will be 0.9 g, in body weight of 70 kg – 1.05 g. For 30 years already isoniazid had been administered by intravenous drip at 12-14 mg/kg of body weight at the Novosibirsk Scientific Research Institute for Tuberculosis; the frequency of adverse events does not exceed 3-3.5% (in a regimen 2 times a week). In order to achieve a bactericidal effect it is compulsory to administer isoniazid intravenously. In that case at the drip rate of 60 drops/min in 1 hour the achieved concentration in the lung exceeds the minimal bactericidal level 2-4 times.

A substantial disadvantage of the currently applied protocols of bacteriostatic therapy, including those suggested by foreign authors is the obliteration of the fact established back in the 50-ies, namely the rapid inactivation of isoniazid by the liver in each other patient, when administered orally (the phenomenon of rapid acetylators).

The rapid (strong) acetylator of isoniazid is the patient that, when administered the drug orally at 12-14 mg/kg of body weight, demonstrates serum concentrations of less than 2 mcg/ml, measured in 1 hour from administration. This property, being genetically determined, is found in almost every other Caucasian. It cannot be surmounted by increasing doses of isoniazid. However, in the past, when isoniazid was used in combination with para-aminosalicylic acid (PASA), acetylated by the liver in a likewise fashion, a substantial portion of isoniazid was preserved against the substantial volumes of PASA; in other words, inactivation of isoniazid was prevented in such way. That is probably why the efficacy of therapy began to decline in the 80-ies, when PASA was taken out of production in Russia. Following the foreign authors, the domestic phthisiatricians began to ignore the strong inactivation of isoniazid by every other patient, that is, deliberately left such patients with unsatisfactory results of chemotherapy.

The massive losses of isoniazid en route to the lungs of rapid inactivators can be overpassed by triple administration routes: intravenous, rectal and topical.

As was indicated above, the intravenous drip administration of isoniazid at 12-14 mg/1 kg of body weight in 150-200 ml of sterile normal saline at 60 drops/min is the most suitable. When the dose of isoniazid has to be decreased by 1/3 in persons over 75 years of age, the creation of high pulmonary concentrations of isoniazid will require the 1/3 faster flow of the therapeutic solution, up to 80 drops/min, respectively.

In oral administration of isoniazid, especially in the scanty doses, recommended by foreign standards (300 mg/day), the losses of the drug occur due to poor absorption in the gastro-intestinal tract in inflammatory and atrophic conditions, as well as due to the already mentioned drug acetylation in the liver, in 30% binding of isoniazid with plasma proteins and when surmounting other barriers in pulmonary tissues. That is why the concentration of this very most active anti-tubercular drug appears to be far from bactericidal levels when in contact with mycobacteria (especially in the decay cavities). That is why oral administration of isoniazid should be strongly rejected when planning mandatory bactericidal therapy.

3.2. Streptomycin is one of the best antibiotics for the therapy of pulmonary tuberculosis with decay cavities. In 1 hr after intramuscular administration there is already bactericidal concentration in the lung, causing impaired protein formation in mycobacteria, as well as destruction of cytoplasmatic membranes, causing cell death. Serum proteins bind less than 10% of the drug. Up to 95% of the drug is not metabolized and is excreted by the kidneys intact. In the acid environment of the macrophage streptomycin is not active against mycobacteria, but its antimicrobial activity is significantly enhanced in weakly alkaline or neutral pH (blood, cavern), therefore it should be applied in haematogenous and cavitary processes. Adverse events in intramuscular administration 2 times a week occur in 15-20% of patients, in intravenous administration – in 3-3.5% of cases. Unfortunately, the intravenous formulation of streptomycin is not produced in Russia effective 1980. 

3.3. Kanamycin is similar to streptomycin in its origin. It is manufactured in two dosage forms – for intravenous and intramuscular administration. After intravenous administration of kanamycin its bactericidal concentration in a pulmonary cavern is 3-4 times higher than the minimal bactericidal dose. That is why in metabolically active mycobacteria the drug profoundly damages the protein-forming function and destroys cellular membranes, which leads to annihilation of the microbe. It is very effective in intravenous administration in treatment of haematogenous and cavitary processes. In the acid environment of the macrophage the drug exerts no antimicrobial properties, since, like streptomycin, it is highly active in neutral and alkaline environments. The adverse events in treatment with administration 2 times a week occur infrequently – in 3-5% of patients.  

3.4. Viomycin is an antibiotic of the aminoglycoside family, as well as streptomycin and kanamycin. It is bactericidalwhen administered intramuscularly at the dose of 1 g. It is not active against mycobacteria in an acid medium; in weakly alkaline and neutral media its antimicrobial activity is not inferior to that of streptomycin. It can replace the latter in issues of intolerability.  

3.5. Rifampicin is an antibiotic of the rifamycine group, whose bactericidal action is achieved via inhibition of RNA synthesis. It is manufactured in capsules of 150 mg for oral administration or vials of 150 mg for intravenous or intramuscular administration. The average adult daily dose is 450-600 mg. In oral administration the fat-soluble drug is absorbed via intestinal villi into the lymphatic capillaries and carried by the flow of lymph through the major thoracic duct into the superior caval vein, right cardiac chambers and pulmonary circulation. Therefore, to achieve high pulmonary concentrations of the drug, it is not imperative to use the intravenous route. It should, however, be taken into consideration that the maximal level of the drug in the lung is achieved in 2-2.5 hours after oral intake, when in intravenous administration the same target level are attained immediately upon completion of the infusion.

In intravenous administration rifampicin in vials is dissolved in 150-200 ml of sterile 5% dextrose and infused at 60 drops/min immediately upon completion of the isoniazid/kanamycin infusion through the same cannula into the cubital vein. The drug is mostly excreted with bile; only 10-15% is excreted in urine. It has a peculiar disadvantage of repeated absorption of its metabolites in the small intestine, which can occur in several repeated cycles. That is why it is important to provide interruptions between treatments of at least 2-3 days to allow the rifampicin to be removed from the lung, causing no inhibition of mycobacteria and no restriction of the onset and development of their metabolism.

Adverse events are infrequent in intravenous route, whereas in oral administration they are found in 13-14% of patients. These are mostly toxic reactions (nausea, loss of appetite, tenderness in the right subcostal area, slight enlargement of the liver), which are reversed by lowering the dose from 600 to 450 mg. In rare occasions of allergic reactions the therapy by rifampicin should be immediately discontinued and resumed not until 1.5 – 2 years later.
3.6. Pyrazinamide is bactericidal in usual doses of 1.5-2 g/day in regards to the intracellular mycobacteria, that is, very active in the acidic medium, but inactive in blood and cavernous substrate. The drug is manufactured as tablets. It may cause fever, porphyria, interstitial nephritis, disuria, hepatitis, anorexia, dyspepsia, arthralgia, myalgia, formation of thrombi, allergic reactions. Adverse events in the standard administration of 2 times a week are found in 9-10% of patients and call for attention. It is more advisable to include pyrazinamide into the protocol of bactericida therapy at the second stage – after liquidation of decay cavities, that is, usually at the 3d-4th nonth of theapy. In that case the average daily dose of 1.5 – 2 g of the drug replaces rifampicin and is administered orally 1.5 – 2 hrs before the intravenous infusion of isoniazid. Due to the similar hepatotoxic action the concomitant administration of isoniazid, rifampicin and pyrazinamide should be avoided. Pyrazinamide is excreted by kidneys mostly as metabolites. The risk of toxicity is substantially reduced in intermittent therapy.
3.7. PASA – exerts a pronounced bactericidal effect in intravenous administration of 400 – 450 ml of the 3% solution, which is important in pharmacological resistance of mycobacteria to isoniazid and streptomycin. The practical experience has demonstrated that as salycilate, the drug possesses a number of useful properties: prevents the formation of rough fibrous tissue, improves rheological properties of blood, reduces inflammation and oedema, enhances penetration of chemotherapeutic agents into infiltrated tissues, etc.   
The discontinuation of PASA production in Russia in mid-80-ies should be viewed as a strategic error, especially given the recent massive emergence of mycobacterial strains, resistant to major anti-tubercular agents.

This method of bactericidal therapy is indicated mostly in patients with focal, infiltrative and disseminated pulmonary tuberculosis in the stage of decay (85% of all primarily registered patients). The patients primarily diagnosed with fibrous cavernous tuberculosis, decaying tuberculoma and caseous pneumonia should be viewed as candidates for tuberculosis-related surgery, since their chances for cure without surgery are dubious. Such subjects should be immediately provided with consultation by a surgeon. In patients with fibrous cavernous tuberculosis and pulmonary tuberculoma the course of 3-4 months of bactericidal therapy should be viewed as a modality of intensive preparation for surgery. In caseous pneumonia the aforemationed course should continue until conversion to the fibrous caseous form, which will require 6-9 months of therapy. The patients, who have had an early surgical intervention, should be treated with the bactericidal method for another 3-4 months and then they should be sent to a sanatorium.

The very principle of early (on the 3-4th month) surgical intervention has become possible only because of advances made since the development of the bactericidal method. The rapid involution of inflammatory changes also allowed for markedly shortened duration of the artificial pneumothorax (down to 2-3 months) and pneumoperitoneum (down to 4 months). When indicated, both these methods of short-term reversible collapse allow accelerating elimination of decay cavities and bacterial secretion already on the 1st-2nd month of treatment. As already mentioned, the presentation of the disease is dramatically changed by the early appearance of a decay cavity, since the latter is the source of explosive (millions of times) increase in the population of bacilli in the body. The bigger and the more numerous the cavities, and the larger the population of Mycobacterium tuberculosis, the higher the virulence and aggressiveness of the microbe, the more mutant bacteria are present, and hence the higher the probability of polyresistance of pathogens to known aetiotropic agents.

That is why hygiene and dietetic regime, bactericidal therapy and the use of therapeutic collapse and surgical cure of the cavity should all be considered as primary modalities in provision of fast and reliable cure of the patient.

The imposition of pneumoperitoneum at the beginning of treatment of patients with caseous pneumonia should be a mandatory measure to prevent bronchogenic insemination into the healthier lower portions of the lungs. It must be maintained until surgery.

Indications to bactericidal therapy. Bactericidal therapy is indicated in patients with:
  • newly diagnosed pulmonary tuberculosis in the phase of infiltration and decay, especially if accompanied by extensive colonization, casefication, and multiple areas of destruction, when it is required to ensure prolonged intensive treatment (for 7-12 months) in the most effective way, without changing the drugs;
  • exacerbations and relapses of pulmonary tuberculosis;
  • newly diagnosed pulmonary tuberculosis in exacerbation of concomitant diseases of the gastrointestinal tract, when patients cannot tolerate anti-tuberculosis drugs taken orally;
  •  primary resistance of mycobacteria to chemotherapy;
  • rapid acetylation of isoniazid;
  • lack of compliance;
  • necessity of accelerated preparation for surgery;
  • limited specific pulmonary processes (for accelerated conversion to the outpatient phase).
Contraindications to bactericidal therapy.
Bactericidal therapy is contraindicated in patients with:
  • severe decompensated comorbidities (diabetes, cardiopulmonary failure of 3d stage, recent myocardial infarction, asthma, schizophrenia, epilepsy, etc.);
  • general contraindications to intravenous therapy.
The benefits and features of the bactericidal method. Organization and implementation.
The vigorous intermittent mode aethiotropic therapy 2 times a week since the first days of treatment significantly improves the tolerability of anti-tubercular drugs, prevents pharmacological overloads of the patient’s organism and allows to:
  • achieve the destruction of dividing and metabolically active microbial cells in each procedure and eradication of Mycobacteria, reversing from dormancy in the days between treatments;
  • accelerate the relief of inflammation and initiation of reparatory processes; promote abacillation and elimination of cavities;
  • dramatically increase the occurrence of complete clinical well-being, with the following clinical cure; 
  • when indicated, use additional methods for cavital processes early (the 2-3-month pneumothorax,the 4-month pneumoperitoneum and surgical interventions);
  • relieve patients from the burdensome and not always attainable many months of hospital stay, as well as provide early conversion to outpatient follow-up care and employment management;
  • overcome the problems of drug intolerance and rehabilitation, associated with daily chemotherapy while 10-12 months in the hospital;
  •  solve the problem of primary (wild) resistance of mycobacteria to anti-tubercular drugs, which has currently become one of the most important reasons for ineffectiveness of etiotropic treatment;
  •  reduce the costs of treatment significantly;
  •  to provide highly effective outpatient treatment for patients with limited processes without prior hospitalization (where indicated).
Bactericidal therapy is aimed at the destruction of the causative agent and its elimination from the patient’s body. Its sanitizing effect on tubercular foci may provide for a biological cure, that is, full prevention of tuberculosis recurrence.

The leading role of isoniazid in the bactericidal effect should be emphasized, since isoniazid appears to be the most biologically active anti-tubercular drug. The goal of the physician is to provide the shortest path for isoniazid to be delivered to the mycobacteria with minimal losses and creation of high concentrations without exceeding the daily doses, permitted by the Pharmacopoeia. The simultaneous delivery of two more bactericidal drugs to foci and cavities can destroy isoniazid-resistant mycobacteria as well.

Thus, compared with existing daily oral chemotherapy, the bactericidal method appears to provide an improved treatment capacity for patients with tuberculosis. The transition to this method is undeniably justified on the entire territory of Russia, as demonstrated by its tolerability and cost-effectiveness. The most conservative estimate is that 200-250 thousand patients may benefit from this method annually. On the average, each of them will require 55-60 treatments. These specific data can be used to calculate the pharmacologic and other logistic requirements of anti-tuberculosis institutions in the country, as well as the healthcare industry orders to launch the production of isoniazid in vials, intravenous streptomycin, sterile PASA powder for ex temporae preparation of intravenous solutions and sufficient amounts of kanamycin and rifampicin for the same purposes.

Overcoming any organizational difficulties in the way of widespread dissemination and implementation of the bactericidal method in the next few years will pay off dramatically by saving lives and healing tens or hundreds of thousands of patients in short terms.

Under existing conditions the Tuberculosis Science cannot offer cost-effective and efficient ways to overcome the deep crisis of routine chemotherapy, other than the twice a week methods of bactericidal therapy, developed and successfully tested for over 30 years by Western-Siberian scientists.