1. Treatment of tuberculosis.
Lecture № 5.
The Department of Phthisiology.
KSMA.
Fydorova S.V.

2. The first antituberculosis drug was streptomycin
Streptomycin was made by Waksman in 1943.
In 1944 it was used in practice.
Wide using of streptomycin for the treatment of TB patients in USSR has begun since 1946.

3. Anti-tuberculosis chemotherapy aims
To prevent the selection of drug resistant mutants
To eliminate MBT in sputum
To assure complete cure

4. Anti-tuberculosis chemotherapy aims
Prevent the selection of drug resistant mutants
Eliminate MBT in sputum
Assure complete cure

5. In 1947 only 1 strain of MBT among 89000 was resistant to streptomycin (S).
But after 15 weeks of treatment the rate of resistance increased in 242,5 times (1 strain among 367).
At the end of 1940 para-amino-salicylic-acid (PAS) and thioacetazone (T) were made.

6. In 1950 using of combination of S and PAS allows to decrease the temp of drug resistance developing.
Finishing treatment exactly after clinical symptoms disappear usually causes relapses.
After treatment course during month relapses appear in rare cases.

7. In 1967 rifampicin (R) was made, it allowed to decrease the duration of treatment to 6 month without increasing of relapses’ rate.

8. Methods of treatment Chemotherapy
Pathogenic therapy (hormonal treatment, tuberculin therapy etc)
Collapse therapy and surgical intervention
Sanitary-hygienic regime and therapeutic nutrition
Treatment of concomitant diseases

9. Chemotherapy
Is the method of etiotropic treatment of TB with the help of the chemical agents
Chemotherapy is directed to one agent with the purpose of suppressing the MBT reproduction (bacteriostatic action) or eliminating MBT in the host (bactericidal effect)

10. Classification of TB cases:
New case
Relapse
Treatment after failure
Treatment after default
Failure of treatment
Transfer in
Chronic case
Other

11. New case
A patient who has never had treatment for TB or who has taken antituberculosis drugs for less than 1 month.

12. Relapse
A patient previously treated for TB who has been declared treated or treatment completed, and is diagnosed bacteriologically positive (smear or culture) TB.
Sometimes bacteriologically negative cases should be proved by specialist.

13. Treatment after failure
A patient who is started on re-treatment course after having failed previous treatment.

14. Treatment after default
A patient who returns to treatment, positive bacteriology, following interruption of treatment for 2 month or more.

15. Failure of treatment
A patient who stays or becomes smear-positive again at 5-th month or later during treatment.

16. Transfer in
A patient who has been transferred from another district (TB register) to continue treatment.

17. Other
All cases that do not belong to the above definitions. This group includes chronic cases, a patient who is smear-positive at the end of re-treatment course.

18. What determines case definition?
Site of TB disease
Result of sputum smear
Severity of TB disease
History of previous treatment

19. Definition of TB cases:
Bacteriology
Site of
disease
new
case
smear
positive
pulmonary no
chronic
case
smear
negative
TB cases
yes
extra
pulmonary
failure
relapse
Severity of disease
Previous treatment
return after
default

20. Classification of antituberculous drugs
I line:
H - isoniazid
R - rifampicin
Z - pyrazinamide
E - ethambutol
S - streptomycin
II line:
K – kanamycin
Amk – amykacin
Cap – capreomycin
FQ – ftorquinolons (Cfx, Ofx, Lfx, Mfx)
Eth – ethionamide
Cs – cycloserin
PASA – para-amino-salicylic acid
T - thioacetazone

21. Theoretical basis for standard chemotherapy
Four different populations of MBT:
I - extracellular population of MBT, which is actively multiply in liquefied caseous mass, that covers the cavity wall, because of high oxygen content and neutral pH
II - intracellular population of MBT, which exists in acidic pH
III - semi-dormant population of MBT, which is located in solid caseous focus and multiplies slowly and intermittently
IV - population of dormant (completely inactive) MBT

22. Theoretical basis for standard chemotherapy
I – acute pathway of MBT, source of MBT in sputum is contagious to the surrounding. Predominates in active TB patients. Is sensitive to H, S, R.
II – phagocytosis is the main protect reaction of human body against tuberculosis. Predominats after primary TB infection, is sensitive to Z, R.
III – may reverse to the I and II population, so it is potentially dangerous, presents in infected persons. Is killed most efficiently by R during multiplying.

23. Mode of action R – sterilizative (I, II, III populations)
H, S – bactericidal (I population)
Z – bactericidal (II population)
E – prevention of drug resistance

24. Anti-tuberculosis chemotherapy aims
Prevent the selection of drug resistant mutants
Eliminate MBT in sputum
Assure complete cure

25. Isoniasid Isoniazid (isonicotinic acid hydrazide;
C8H7N3O, MW: 137.1) is one of the
most powerful drugs against TB.
It is a white crystalline powder freely soluble in water. Solutions can be sterilized by autoclaving.
Bactericidal activity to the rapidly multiplying bacilli.

26. Isoniazid (H)
Is derivative of izonicotinic acid. Drugs of this group include methazid (20 mg/kg), ftivazid (30-40 mg/kg), saluzid
Mechanism of action: H rapidly penetrates into actively multiplying MBT, it is a very powerful (bactericidal) drug

27. Isoniazid (H) Administration and standard doses:
Daily: 300 mg (children 5 mg/kg) in a single dose
Intermittant: 15 mg/kg (max 750 mg daily) plus pyridoxine (Vit B6) mg with each dose
Miliary or meningeal tuberculosis 5-10 mg/kg
Chemoprophylaxis: 5 mg/kg
Intravenously: mg (adults) mg (children)

28. Isoniazid (H) Adverse reactions:
Periferal neuropathy – tingling and numbness of the hands and feet
It can be treated by giving mg pyridoxine daily or it can be prevented by giving mg pyridoxine daily from the beginning of treatment with H

29. Streptomycin
As isoniasid, but activity of isoniasid is stronger in 5 times than streptomycin.
Streptomycin (O-2-deoxy-2-methylamino- α-L-glucopyranosyl-(1-2)-O-5-deoxy- 3-C-formyl-α-lyxofuranosyl- (1-4)-N,N-diamidino-D-streptamine; C21H39N7O12; MW: 581.6).
It is a white-whitish crystalline powder, highly hygroscopic and soluble in water that must be stored in airtight containers.

30. Streptomycin (S)
Is antibiotic of wide spectrum action, produced by Streptomyces griseus. It is a member of the aminoglycoside-aminocyclitol group of antibiotics and is bactericidal against wide variety of gram-negative and gram-positive bacteria.
Mechanism of action: S acts by inhibiting bacterial protein synthesis.

31. Streptomycin (S) Administration and dose: Adults:
At the age below 40 years:
- Weight under 50 kg – 0,75 g in single dose
- Over 50 kg – 1,0 g
At the age of years: 0,75 g
Above 60 years: 0,5 g
Children: 10 mg/kg (max 0,75 g)

32. Streptomycin (S) Adverse reactions: Cutaneous hypersensitivity
Quincke’s edema
Eosinophilia
Hemolytic anemia, agranulocytosis, thrombocytopenia
Vestibular and auditory toxity (ototoxity)
Renal failure
Anaphylaxis
S should be not prescribed during pregnancy!

33. Pyrazinamide
Pyrazinamide (pyrazinoic acid amide, C5H5N3O; MW: 123.1) is a white crystalline powder, soluble in water.
Bactericidal activity to the intracellular bacilli, the drug is active only in acid environment.

34. Pyrazinamide (Z) Is a synthetic pyrazin, analogue of nicotinamide
Mechanism of action: the exact mechanism of action of Z is not known. It is transported or diffused across the MBT cell wall. Z is particularly active against the semi-dormant extracellular and intracellular populations of MBT in acidic environment in the inflammated tissure. Z is also active against organisms inside the macrophages

35. Pyrazinamide (Z) Administration and dose: Adults:
- 1,5-2,0 g daily (25-30 mg/kg)

36. Pyrazinamide (Z) Adverse reactions: Hepatotoxity
Arthralgia caused by hyperuricemia

37. Rifampicin
Rifampicin, often spelled rifampin, (5,6,9,17,19,21-Hexahydroxy-23- methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]-2,7-(epoxypen tadeca[1,11,13]trienimino)-naphtho[2,1-b]furan-1,11(2H)-dione21-acetate; C43H58N4O12; MW 822.9) is a red-brown crystalline powder poorly soluble in water;
It is dissolved in methyl alcohol and can be stored at room temperature protected from light.
Is the most potent sterilizing drug available (to the 1-st, 2-nd, 3-rd populations).

38. Rifampicin (R)
Is a semi-synthetic derivative of rifamycin B produced by Amycolatopsis mediterranei
Mechanism of action: bactericidal. R is active against both extracellular and intracellular organisms, and paticulary has a rapid action against slow growing bacilli, in the caseous material, where pH is neutral but oxyganation is poor

39. Rifampicin (R) Administration and dose:
Daily, depending of body weight
- 55 kg and more: max dose 600 mg
- Up to 55 kg: 450 mg (max 10 mg/kg)
- Children: 10 mg/kg (max 450 mg)
Intermittent: 450 mg three times weekly

40. Rifampicin (R) Adverse reactions:
Gastrointestinal toxic effect (nausea, anorexia, mild abdominal pain)
Hemolytic anemia and acute renal failure, thrombocytopenia, leucopenia
Cutaneous reaction (redness, itchiness of skin, rash)
Hepatitis
«Influenza» like syndrome (headache, fever, bone pain)
Respiratory and shock syndrome (shortness of breath, rales in lungs, fall of blood pressure, collapse)
Anaphylactic shock

41. Ethambutol
Ethambutol (N,N’- ethylenebis(2-aminobutan-1- ol) dihydrochloride; C10H24N2O2,2HCl; MW: 277.2)
is a white crystalline powder soluble in water and alcohol that must be stored preserved from air.
Is used in combination with other antituberculosis drugs to prevent the emergence of drug resistance.
But in high concentrations (daily dose more than 25 mg/kg) may cause bactericidal activity.

42. Ethambutol (E) Is a synthetic agent, which is only active against MBT.
Mechanism of action: E rapidly penetrates into MBT where it acts by interfering with the synthesis of the outer envelop of the MBT wall

43. Ethambutol (E) Administration and dose: Adults:
- Daily: 25 mg/kg (20-30 mg/kg)
- Intermittent: 35 mg/kg (30-40 mg/kg)
Children:

44. Ethambutol (E) Adverse reactions:
Progressive loss of vision (optic neuritis)
Hepatotoxity
Arthralgia – the level of uric acid is increased
Anaphylactic reactions
Bronchospasm

45. The chemotherapy course consists of two phases with different tasks
Phase of intensive chemotherapy
Phase of continuation of chemotherapy

46. Aims of intensive phase
To provide maximal effect to MBT population with the purpose to stop MBT excretion and prevent drug resistance development (usually the I and II populations are killed, but the III population stays numerous)
To reduce infiltrative and destructive changes

47. Aims of continuited phase
Suppression of MBT population in a host
Reducing of the inflammatory changes and involution of tubercular process
Restoration of the functional abilities of the patient

48. Standard regimes of chemotherapy
I category – 2HRZE(S)/4H3R3
2HRZE(S)/4HR
II category – 2HRZES/1HRZE/5H3R3E3
2HRZES/1HRZE/5HRE
III category – 2HRZ/4H3R3
2HRZ/4HR

49. Fixed-dose combination tablets

50. Monitoring of chemotherapy
Effect of treatment should be confirmed by
clinical methods
microbiological methods
- I category – 0, 2(3), 5, 6 month
- II category – 0, 3(4), 5, 8 month
- III category – 0, 2 month
X-ray methods

51. Developing of drug resistance
¤ - drug-susceptible MBT  - drug-resistante MBT
¤ ¤ ¤ ¤ ¤ ¤
¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤
¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤
¤ ¤ ¤ ¤ ¤  ¤  ¤ ¤ ¤ ¤
¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤
¤ ¤ ¤ ¤ ¤ ¤ ¤ ¤
¤ ¤ ¤ ¤ ¤
   
      
       
     
 

52. Developing of drug resistance

54. Treatment outcomes Cure Treatment completed Treatment failure Died
Default
Transfer out

55. Cure
Patient who was sputum smear-negative at the starting treatment, but who is sputum smear-negative at the last month of treatment and at least one previous occasion.

56. Treatment completed
Patient who has completed treatment, and outcome is treatment success.

57. Treatment failure
A patient who stays or becomes smear-positive again at 5-th month or later during treatment.

58. Died
A patient who dies for any reason during the course of treatment.

59. Default
Patient whose treatment was interrupted for two consecutive month or more.

60. Transfer out
Patient who has been transferred to another reporting and recording unit for whom the treatment outcome is not known.

61. Thank you
for attention!