1. TREATMENT of TB in ADULTSby
Dr. Irfhan Ali Hyder Ali

2. LEARNING OBJECTIVES
To update on treatment regimes & modalities for PTB & EPTB
To present evidence-based updates to best suit TB management in Malaysia
To emphasise on the importance of proper treatment

3. INTRODUCTION
Important to provide a standardised TB regimen for all TB cases
This section will cover all aspects of treatment:
Pulmonary TB (PTB)
New cases
Relapse cases
Extrapulmonary TB (EPTB)
Standard regimes & duration

4. AIM OF TREATMENT Cure & reduce transmission
Risk of developing TB is determined:
infectiousness of index case
smear positive PTB; PTB with cavities; laryngeal TB
nature & duration of contact
immune status of contact

5. EDUCATION Nature of disease
Necessity of strict adherence with prolonged treatment
Risks of defaulting treatment
Side effects of medication
Risks of transmission & need for respiratory hygiene as well as cough/sneeze etiquette

6. PULMONARY TUBERCULOSIS (PTB) IN ADULTS

7. NEW CASES
6-month regimen consisting of 2 months of EHRZ (2EHRZ) followed by 4 months of HR (4HR) is recommended for newly-diagnosed PTB.

8. RECOMMENDED ANTITB DRUGS
RECOMMENDED DOSES
Daily
3X a week
Dose (range) in mg/kg
body weight
Maximum in mg
Isoniazid (H)
5 (4 - 6)
300
10 (8 - 12)
900
Rifampicin (R)
600
Pyrazinamide (Z)
25 ( )
2000
35 (30 – 40)*
3000*
Ethambutol (E)
15 ( )
1600
30 (25 – 35)*
2400*
Streptomycin (S)
15 ( )
1000
15 (12 – 18)*
1500*

9. NEW CASES (cont.)
Pyridoxine mg daily needs to be added if isoniazid is prescribed.
*Daily treatment is the preferred regimen.
Adopted from WHO. Treatment of Tuberculosis Guidelines (4th Ed.), 2010

10. IMPORTANT POINTS Rifampicin
should be used for the whole duration of treatment.
NS difference in effectiveness & safety between rifampicin & other antibiotics in the rifamycin group.
whenever possible, rifampicin dosage should not be lower than recommended dosage ( mg/kg).
Pyrazinamide beyond 2 months during the intensive phase does not confer further advantage if the organism is fully susceptible.
Recurrence rate is low for both ethambutol-based regimen & for streptomycin-based regimen.

11. TREATMENT OF NEW CASES

12. PREVIOUSLY TREATED TB
New cases who have taken treatment for more than one month & are currently smear or culture positive again (i.e. failure, relapse or return after default)

13. DEFINITION Previously treated
Patient previously treated for TB including relapse, failure & default cases .
Relapse
A patient whose most recent treatment outcome was “cured” or “treatment completed”, & who is subsequently diagnosed with bacteriologically positive TB by sputum smear microscopy or culture.
Treatment after failure
A patient who has received Category I treatment for TB & in whom treatment has failed.
Treatment after default
A patient who returns to treatment, bacteriologically positive by sputum smear microscopy or culture, following interruption of treatment for 2 or more consecutive months.

14. PREVIOUSLY TREATED TB
Recommend: retreatment regimen containing first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR-TB in these patients or if such data is not available.
Drug sensitivity test (DST) must be done for patients. When results become available, drug regimen should be adjusted appropriately.
*This is WHO statement, no retrievable evidence
available.

15. TO START OR NOT? Interruption in intensive phase:
If ≥14 days, to restart from beginning i.e. Day 1.
If <14 days, to continue form last dose.

16. TO START OR NOT? Interruption in maintenance phase:
If interruption occurs after patient receives 80% of total planned doses, treatment may be stopped if sputum AFB smear was negative at initial presentation. If sputum AFB smear was positive, treatment should be continued to achieve total number of doses.
If total doses <80% & interruption lapse is ≥2 months, restart treatment from beginning.
If total doses is <80% & interruption lapse is <2 months, continue treatment from date it stops to complete full course.

17. TREATMENT OF PREVIOUSLY TREATED TB

18. OPTIMAL DURATION
Patients with sputum positive PTB should receive antiTB drugs for a minimum duration of 6 months.
Regimens with shorter duration of rifampicin are associated with higher risk of failure, relapse & acquired drug resistance.
Even in patients with non-cavitary disease & confirmed sputum culture, conversion at 2 months fares poorer with a 4-month regimen compared to 6-month regimen.

19. OPTIMAL DURATION

20. MAINTENANCE PHASE
In new patients with PTB, WHO recommends daily dosing throughout the course of antiTB treatment.
However, a daily intensive phase followed by thrice weekly maintenance phase is an option provided that each dose is directly observed & patient has improved clinically.
A maintenance phase with twice weekly dosing is not recommended.

21. MAINTENANCE PHASE
There is no difference in treatment failure, relapse & acquired drug resistance rates between daily & different intermittent dosing regimens in the maintenance phase.1, 2, 3
1Menzies D et al., PLoS Med, 2009
2Mwandumba HC et al., Cochrane, 2001
3Chang KC et al., Thorax, 2011

22. MAINTENANCE PHASE

23. FIXED-DOSE COMBINATION (FDC) IN MALAYSIA
Forecox-Trac Film Coated Tab: isoniazid, rifampicin, ethambutol & pyrazinamide
Rimactazid 300 Sugar Coated Tab: isoniazid, & rifampicin
Rimcure 3-FDC Film Coated Tab: isoniazid, rifampicin & pyrazinamide
Akurit-Z Tab: isoniazid, rifampin (rifampicin) & pyrazinamide
Akurit Tab: isoniazid & rifampin (rifampicin)
Akurit-Z Kid Dispersible Tab: isoniazid, rifampin (rifampicin) & pyrazinamide
Akurit-4: ethambutol, isoniazid, rifampin (rifampicin) & pyrazinamide

24. FDC IN MOH
4-Drug combination: isoniazid 75 mg, rifampicin 150 mg, pyrazinamide 400 mg & ethambutol 275 mg tablet
3-Drug combination: isoniazid 75 mg, rifampicin 150 mg & pyrazinamide 400 mg tablet

25. RECOMMENDED DOSES 30 - 37 kg body weight: 2 tablets daily
More than 70 kg body weight: 5 tablets daily

26. EFFECTIVENESS
FDCs compared to separate-drug regimens significantly reduce risk of non-compliance by 17% & consequently improve effectiveness of therapy.1
In term of bioavailability, FDCs are proven to be bioequivalent to separate-drugs formulations at the same dose levels.2
1Bangalore S et al., Am J Med, 2007
2Agrawal S et al., Int J Pharm, 2002

27. OTHER ADVANTAGES
Smaller number of tablets to be ingested may also encourage patient adherence.
Prescription errors are likely to be less frequent for FDCs due to easy adjustment of dosage according to patient weight.

28. FDC

29. DIRECTLY OBSERVED THERAPY (DOT)
Direct observation of drug ingestion of the DOTS component should not be the sole emphasis in TB control programmes.
It should not be a blanket approach; instead it should be a process of negotiation & support, incorporating patients’ characteristics & choices.

30. DIRECTLY OBSERVED THERAPY (DOT)
Enhanced DOTS involving intensive contact tracing & treating the contacts with TB can reduce incidence of TB within a community (p=0.04).1
1Cavalcante SC et al., Int J Tuberc & Lung Dis. 2010

31. DOT

32. EXTRAPULMONARY TUBERCULOSIS (EPTB) IN ADULTS

33. DURATION OF EPTB TREATMENT - NICE RECOMMENDATION1
• Meningeal TB – 2 months S/EHRZ+10HR*
• Peripheral lymph node TB – should normally be stopped after 6 months
• Bone & joint TB – 6 months
• Pericardial TB – 6 months
1National Collaborating Centre for Chronic Conditions and the Centre for Clinical Practice. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. 2011

34. DURATION OF EPTB TREATMENT - WHO RECOMMENDATION1
Regimen should contain 6 months of rifampicin: 2HRZE/4HR*
Duration of treatment for TB meningitis is months &, bone & joint TB is 9 months
1World Health Organization. Treatment of tuberculosis Guidelines. Fourth ed. 2010

35. MILIARY & DISSEMINATED TB
There is no retrievable evidence on optimal duration of treatment for disseminated TB & miliary TB.
There should be low threshold to suspect TB meningitis in these groups of patients & treatment duration should be prolonged between 9 to 12 months.

36. OPTIMAL DURATION OF EPTB TREATMENT

37. CORTICOSTEROIDS IN EPTB
Corticosteroid therapy may benefit patients with some forms of EPTB. However literature on corticosteroids in various form of EPTB is scant.

38. CORTICOSTEROIDS IN EPTB TREATMENT

39. TB MENINGITIS Severity Regime Grade I disease
Week 1: IV dexamethasone sodium phosphate 0.3 mg/kg/day
Week 2: 0.2 mg/kg/day
Week 3: Oral dexamethasone 0.1 mg/kg/day
Week 4: Oral dexamethasone a total of 3 mg/day, decreasing by 1 mg each week
Grade II & III disease
Week 1: IV dexamethasone sodium phosphate 0.4 mg/kg/day
Week 2: 0.3 mg/kg/day
Week 3: 0.2 mg/kg/day
Week 4: 0.1 mg/kg/day, then oral dexamethasone for 4 weeks, decreasing by 1 mg each week
Prasad K et al., Cochrane, 2008

40. TB PERICARDITIS

41. SURGERY IN PTB
Diagnosis & obtaining tissue for culture & drug sensitivity
Management of TB complications
Treatment of the disease itself where drug therapy alone may be deemed insufficient to achieve cure

42. SURGERY IN PTB
While the advancement in surgical techniques including video-assisted thoracoscopy surgery/thoracotomy has reduced the surgical mortality & morbidity, surgery for PTB is still associated with significant complications due to the presence of adhesions & scarring.

43. MAIN CHANGES IN CPG TB 2012 Evidence-based
Treatment after interruption explained in more detail
Treatment regimes (maintenance) changed to daily or 3X a week
FDCs mentioned
DOTS covered in more detail & done to suit Malaysian context
Duration of treatment for EPTB more concise
Use of steroids recommended for TB meningitis & pericarditis

44. TAKE HOME MESSAGES Adhere to standard regime
Use correct doses & adequate duration
Ensure compliance
Treatment needs to be individualised
Consult a doctor/physician with experience in TB management when in doubt

45. THANK YOU