1. Antituberculous treatment.
Lecture № 9.

2. Plan of the lecture: Common principles of antituberculous treatment.
Aims and principles of antituberculous chemotherapy in accordance to the WHO-recommendations (DOTS).
Methods of antituberculous treatment.
DOTS-strategy by treatment of TB-patients.

3. Recovery of nearly all TB-patients
must be a result of antituberculous chemotherapy in all medical institutions.

4. Recovery from clinical positions
is a stable healing of tuberculous changes by the development of reparative processes and disappearance of all clinical symptoms. Some anatomic changes may stay as morphological outcome of TB process.

5. Recovery from bacteriological positions
is a stable disappearance of elimination of MBT by findings of sputum microscopy, and confirmation of this fact by sputum culture.

6. Types of favorable outcome of TB-process:
healing without any morphological changes,
scars – line-like and star-like,
focal changes (caseous foci may occur),
fibrosis of lung tissue,
metatuberculous changes (bronchiectasis, cirrhosis of lung tissue, sanitated cavities) may be followed by clinical symptoms.

7. Main principles of antituberculous treatment (Chomenko A.G.):
treatment must be started in time (at the early phase of disease),
treatment must be long and continuous,
complex of methods of antituberculous treatment must be used,
combination of antituberculous medicines must be used,
treatment must be observed,
course of treatment must be without intervals,
treatment must be individual.

8. Methods of antituberculous treatment:
chemotherapy (etiotropic treatment),
pathogenetic treatment,
surgical treatment,
collapsotherapy (artificial pneumothorax and pneumoperitoneum),
hygienic and dietary regimen.

9. Targets of antituberculous treatment:
To cure the patient of TB.
To prevent death from active TB or it’s late affects.
To prevent TB relapse.
To decrease TB transmission to others.

10. Pathogenetic methods of treatment:
corticosteroids (hydrocortisone, prednisolone, dexametasone etc.),
Immune response modifiers (tuberculin, BCG, levamizole etc.),
antioxidants,
anabolic steroids,
modifiers of reticulo-endothelial system,
modifiers of energetic metabolism,
vitamins,
physical therapeutic methods
etc.

11. Principles of chemotherapy in accordance to American Thoracic Society (ATS):
combination of antituberculous drugs is necessary,
course of treatment must be long (6 month at least),
antituberculous medicines must be taken regularly (continuously).

12. The essential antituberculous drugs:
Isoniasid (isonicotinic acid hydrazide – INH) – (H),
Rifampicin – (R),
Pyrazinamide (Z),
Ethambutol (E),
Streptomycin (S).

13. Antituberculous medicines of the second line (reserved):
Ethionamide,
Prothionamide,
Cycloserine,
Kanamycin,
Amycacin,
Capreomycin,
PASA,
Ofloxacin,
Ciprofloxacin.

14. Essential anti-TB drugs Recommended dose (mg/kg)
(abbreviation)
Mode of action
Potency
Recommended dose (mg/kg)
Daily
Intermittent 3×/wk
isoniasid (H)
rifampicin (R)
pyrazinamide (Z)
streptomycin (S)
ethambutol (E)
thioacethazone (T)
bactericidal
bacteriostatic
high
low 5 10 25 15 3 35 30
not applicable

15. Modes of action of anti-TB drugs:
Consider a population of TB bacilli in a TB patient. This population of bacilli consists of the following groups:
metabolically active, continuously growing bacilli inside cavities,
bacilli inside cells, e.g. macrophages,
semidormant bacilli (persisters) which undergo occasional spurts of metabolism,
dormant bacilli which fade away and die on their own.

16. Anti-TB drug treatment
is so long because it is difficult to kill the semi-dormant TB bacilli.

17. Bactericidal drugs
Isoniasid kills 90% of the total population of bacilli during the first few days of treatment. Is the most effective against the metabolically active, continuously growing bacilli.
Rifampicin can kill the semidormant bacilli which isoniasid can not.
Pyrazinamide kills bacilli in an acid environment inside cells, e.g. macrophages.

18. Sterilising action
This means killing all the bacilli. The persisters are hardest to kill. The aim of killing all the bacilli is to prevent relapse. Rifampicin is the most effective sterilising drug. It’s effectiveness makes short course chemotherapy possible. Pyrazinamide is also a good sterilising drug, since it kills the bacilli protected inside cells.

19. Preventing drug resistance
Consider a population of TB bacilli never previously exposed to anti-TB drugs. There will be a few naturally-occurring drug-resistant mutant bacilli. Faced with antituberculous drugs, these drug-resistant mutant bacilli will grow and replace the drug-sensitive bacilli under the following circumstances:
inadequate anti-TB drug combinations,
anti-TB drug treatment not properly applied.
Isoniasid and rifampicin are most effective in preventing resistance to other drugs. Streptomycin and ethambutol are slightly less effective.

20. Standardised TB treatment regimens:
The World Health Organization (WHO) and the International Union against Tuberculosis and Lung Diseases (IUATLD) recommend standardised TB treatment regimens.
Treatment regimens have an initial (intensive) phase and a continuation phase.

21. New cases: Initial phase (2 month)
During the initial phase, there is a rapid killing of TB bacilli. Infectious patient become non-infectious within about 2 weeks. Symptoms improve. The vast majority of patients with sputum smear-positive TB become sputum smear-negative within 2 month. DOT is essential in the initial phase to ensure that the patient takes every single dose. This protects rifampicin against the development of drug resistance. The risk of drug resistance is higher during the early stages of anti-tuberculous drug treatment when there are more TB bacilli.

22. Continuation phase (4-6 month)
Fewer drugs are necessary, but for a long time, in the continuation phase. The drugs eliminate the remaining TB bacilli. Killing the persisters prevents relapse after completion of treatment. DOT is the ideal when the patient receives rifampicin in the continuation phase. The risk of drug-resistance is less during the continuation phase when there are fewer bacilli.

23. Retreatment cases
The initial phase lasts 3 month, with directly observed therapy. The continuation phase lasts 5 month, with a close supervision.

24. Standard code for treatment regimens
There is a standard code of treatment regimens. Each antituberculous drug has an abbreviation. A regimen consists of 2 phases. The number before a phase is the duration of this phase in month. A number in subscript after a letter is the number of doses of that drug per week. If there is no number in subscript after a letter, than treatment with that drug a daily. An alternative drug appears as a letter in brackets.

25. Examples (I) 2HRZE(S)/4H3R3
The initial phase is 2 HRZE(S). The duration of the phase is 2 month. Drug treatment is daily (no subscript number after the letter), with isoniasid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E). Streptomycin (S) is alternation of ethambutol (E).

26. Examples (II) 2HRZE(S)/4H3R3
The continuation phase is 4H3R3. The duration is 4 month, with isoniasid and rifampicin 3 times a week (subscript number 3 after the letter).

27. Alternative treatment regimens for each treatment category (I)
TB treatment category
TB patients
Alternative TB treatment regimens
Initial phase
Continuation phase I
New cases:
smear-positive PTB,
severe forms of PTB and extrapulmonary TB,
spreaded smear-positive PTB.
2 HRZE(S)
4HR
4H3R3
6HE

28. Alternative treatment regimens for each treatment category (II)
TB treatment category
TB patients
Alternative TB treatment regimens
Initial phase
Continuation phase II
Sputum smear positive:
relapse,
treatment failure,
return after default.
2HRZES/
1HRZE
5H3R3E3

29. Alternative treatment regimens for each treatment category (III)
TB treatment category
TB patients
Alternative TB treatment regimens
Initial phase
Continuation phase
III
New cases:
limited smear negative pulmonary TB,
non severe forms of extrapulmonary TB.
2HRZ
4HR
4H3R3
6HE

30. Alternative treatment regimens for each treatment category (IV)
TB treatment category
TB patients
Alternative TB treatment regimens
Initial phase
Continuation phase IV
Chronic patients (still sputum positive after supervised retreatment).
Not applicable
(refer to special center if second-line drugs available).

31. Treatment outcomes in sputum smear-positive patients (I):
Cure – patient who is smear negative at the completion of treatment.
Treatment completed – patient who has completed treatment but in whom control smear results are not available.
Treatment failure – patient who remains or becomes again smear-positive at 5 month or later after started treatment.

32. Treatment outcomes in sputum smear-positive patients (II):
Died – patient who dies for any reason during the course of chemotherapy.
Defaulted (treatment interrupted) – patient whose treatment has been interrupted for more than 2 consecutive month before the end of course of treatment.
Transferred out – patient who has been transferred to another treatment centre and whose treatment results are not known.

33. Thank you
for attention!