Theoretical basis for chemotherapy of tuberculosis.
According to the theoretical model for tuberculosis to infection four different populations of MBT are known to exist in the lesions of human tuberculosis.
- Population of MBT which actively grow because of high oxygen content and neutral pH in the liquefied caseous material that covers the cavity wall. This population is also responsible for the sputum smear positivity and therefore the infectiousness of tuberculosis. These MBT are particularly vulnerable to isoniazid, and to a lesser extent, to rifampicin, streptomycin and ethambutol.
- Population of MBT which exists in an acidic pH and are located mainly intracelluarly. These MBT, are thought to grow very slowly. Pyrazinamide, which is active in an acidic environment, is particularly effective in killing this population.
- Population of MBT located in solid caseous areas. This population either remains dormant or multiplies slowly or intermittently. They are killed most efficiently by rifampicin.
- Population of MBT which is completely dormant is also thought to exist.
Antitubercular chemotherapy aims are:
- preventing the selection of drug resistant mutants;
- achieving very early sputum conversion;
- assuring complete cure;
All these objectives are achieved by simultaneously administering several drugs to which the organism is susceptible. Killing of the organisms does not occur immediately after initiation of antituberculosis treatment. As the risk of selection of resistant mutants lasts as long as the bacterial population is not significantly reduced, antituberculosis treatment has to remain till such time. This knowledge forms the rationale for administering a combination of several bactericidal drugs in the initial intensive phase of antituberculosis treatment. The slowly/intermittently multiplying MBT being relatively limited in number seldom contain resistant mutants. However, as their multiplication is slow or intermittent, most of the drugs have lesser effect on them than on the rapidly multiplying MBT. These organisms have a tendency to persist in lesions despite chemotherapy and are often the cause of relapses. To kill these MBT and sterilize the lesions, antituberculosis treatment needs to be administered for a prolonged period. These objective is achieved by administering the continuation (maintenance) phase of antituberculosis treatment. This will ensure complete cure without relapse.
The chemotherapy course according to the recommendations Ministry of Health of the Russian Federation consists of two phases with different tasks:
- Phase of intensive chemotherapy;
- The phase of continuation (maintenance) of chemotherapy
1. Phase of intensive chemotherapy is directed on elimination of clinical displays of the disease;
- 1.1. Maximal effect on MBT population, with the purpose of the discontinuance of MBT expectoration and prevention of drug resistance development;
- 1.2. Reduction of infiltrative and destructive changes in organs. The phase of intensive therapy can be as a part of preparation to surgical operation.
2. The phase of continuation of chemo therapy is directed on:
- 2.1. suppression of MBT population in a host;
- 2.2. further reduction of inflammative changes and involution of tubercular process;
- 2.3. Restoration of functional abilities of the patient.
Regime of chemotherapy consists of:
- selected combination of antituberculosis drugs;
- duration of their intake;
- periods and contents of control examinations;
- organizational forms of treatment regimen which are defined depending on groups, to which the tuberculosis patient is regarded.
First (I) regime of chemotherapy is prescribed for the first time revealed MBT positive patient and / or with widespread or complicated defeats of various organs.
Second A (II a) regime of chemotherapy is prescribed at a repeated course of chemotherapy after treatment interruption or relapse at low risk of MBT drug resistance.
Second (II b) regime of chemotherapy is applied to patients with high risk of MBT drug resistance before obtaining results of microbiological examination. Indications for these patients are:
- the patients, who do not have effect from chemotherapy or they have aggravation or progressing of tuberculosis process during chemotherapy;
- The patients who were not receiving earlier antitubeculosis drugs, but who have weighty bases for the suspicion of drug resistance based on anamnesis and / or clinical data.
Third (III) regime of chemotherapy is applied for the first time revealed patient without MBT discharge, with limited and not complicated forms of tuberculosis.
Fourth (IV) regime of chemotherapy is applied for the patient with discharge of MBT simultaneously resistant to rifampicin and isoniazid.
In a phase of intensive therapy 4 basic drugs are used: Isoniazid (H), Rifampicin (R) Pyrazinamide (Z), Ethambutol (E) – (2 H R Z E). The intensive phase is continued for 2 months. In this period the patient should take 60 dozes of the combination from 4 basic drugs. In case of the complete dozes missing the duration of intensive therapy phase is increased up to administration of 60 dozes. After 2 months from the beginning of an intensive phase of therapy the question about transition to the second phase of treatment is solved by a commission on the basis of the clinical-radiographic and microbiological data. At occurrence of MBT discharge (microscopically revealed) and / or in case of unfavorable clinical-radiographic signs of the process after 2 months of treatment it is necessary to determine MBT drug resistance and to make appropriate correction of chemotherapy. In waiting of microbiological results, the course of treatment should be not changed within 1 month. If MBT drug sensitivity is not possible to determine such patient must refer to specialized antituberculous clinic. Regimes of further treatment define in view of MBT drug sensitivity. For favorable clinical-radiographic changes and microscopically proved MBT absence in sputum, treatment of tuberculosis conduct according second phase stage of treatment – the phase of continuation. In the phase of therapy continuation 2 basic preparations are used – isoniazid and rifampicin daily, during 4 months (4HR) or in intermittent mode 3 times in one week (4H3R3). Other regime in the phase of continuation there can be administration of isoniazid and ethambutol during 6 months (6HE).
Organization of chemotherapy of tuberculosis patients.
The treatment of tuberculosis patients should be carried out under the supervisison doctor – phthisiatrist, which provides correctness and efficiency of treatment. In process of chemotherapy it is very important that the medical personnel should directly control drug treatment. The constant cooperation of the patient with medical personnel is necessary, formation of the responsible attitude of the adult patient and parents of the child to treatment. All courses of treatment or its separate phases can be carried out in inpatient with 24 four hours stay duration or only day time duration, in sanatoriums, in out-patient conditions. The organizational form of treatment is determined by the disease burden, epidemic danger of the patient, living and household conditions, psychological features of the patient, degree of social adaptation and local conditions. Irrespective of the organizational form of treatment the standard of treatment and control of its realization should be observed, and also continuity between medical establishments at moving of the patient from one organizational form of treatment to another. The result of treatment is estimated with use of all criteria of efficiency and registration of the appropriate paper work. The control of efficiency of treatment is carried out by specialized antituberculous establishment.
The standard definitions of treatment outcome.
For estimation of efficiency of the each phase of the treatment, the analysis with use standard definitions of treatment outcome are applied with the period of not less once per three months.
- Effective course of chemotherapy, confirmed by clinical, microbiological and radiographic methods.
The patient, discharged MBT prior to the beginning of treatment, completely has passed a treatment course and at his favorable clinical and radiographic changes, the absence MBT discharge is confirmed by inoculation and by sputumм microscopy not less than twice (on 5-th month and at the end of the chemotherapy course. - Effective course of chemotherapy, confirmed by clinical and radiographic signs.
The patient with initially absent MBT discharge has completed course of chemotherapy and has achieved favorable clinical and radiographic changes. - Inefficient course of chemotherapy.
The patient still discharge MBT or he began to discharge MBT on 5-th month of treatment and later. The patient with initially absent MBT discharge has unfavorable clinical and radiographic signs. - Pre-term discontinuance of chemotherapy.
The patient has interrupted treatment after 2 months and more. - Death.
The patient died during the chemotherapy course from unknown reasons. - The patient has been discharged from supervision.
The patient has left from – under supervision medical institution carrying out chemotherapy other administrative territory or department) and the result of chemotherapy is unknown.
Probable multiple drug resistance (MDR).
If previous treatment suggests resistance to isoniazid, rifampicin and streptomycin, treatment is very difficult. The reserve drugs are weaker and have many side-effects. If possible refer the patient to a specialist centre. The specialist will start with 4 or 5 drugs. He will use drugs the patient has not had before, or drugs already used but to which the patient’s bacilli are probably sensitive. When the sputum has become negative he will stop 1 or 2 of the weaker or toxic drugs. He will continue treatment for at least 18 months.
This treatment can be successful, but it needs very skilful supervision and encouragement of the patient to tolerate the unpleasant side-effects of the drugs.
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