DETAILS OF TB MENINGITIS ANTI TUBERCULOUS DRUGS AKT ATT DETAILS OF ANTI TUBERCULOUS DRUGS

1. DR ANKIT GAJJAR
MD, IDCCM, IFCCM, EDIC
CONSULTANT INTENSIVIST
TBM & ATT

2. Pathogenesis
• Primary infection or late reactivation TB
• Severe inflammatory response
- Basal exudates
- Tuberculous vasculitis
- Hydrocephalus

3. Presentation
• Common in elderly, alcoholism, malnutrition,
malignancy, HIV etc
• Subacute presentation
• Fever, headache, stiff neck, vomiting
• Altered sensorium, personality changes, coma
• CN palsies
• Atypical presentation
• Prior history of Pulmonary TB is uncommon

4. Presentation
• STAGES
STAGE 1 – Alert & Oriented
STAGE 2 – Conscious but confuse, GCS - 11-15
STAGE 3 – Coma, Seizure, CN palsies, GCS < 10

5. Complication
• Hydrocephalus
• Hyponatremia
• Vision loss

6. Diagnosis
• History & examination
• Should be evaluate for TB in other parts of body
• CSF analysis
- AFB Smear
- R & M
- AFB C/S – 50%
- Gene Xpert
- ADA
• HIV is must

7. Diagnosis
• RADIOLOGICAL
- Hydrocephalus
- Periventricular infarct
- Basilar exudates
- Tuberculoma

8. Treatment
• ATT drugs + Steroids
• Empiric treatment
• Intensive phase – 4 drugs for 2 months
- HRZ
- Streptomycin > Ethambutol > Levofloxacin
• Continuation phase - 2 drugs for 7-10 months
- HR

9. Treatment
• Steroid
• Dexamethasone
- 0.3-0.4 mg/kg – 2 weeks
- 0.2 mg/kg – 1 week
- 0.1 mg/kg – 1 week
- 4 mg / day – oral 1 week
- Taper 1 mg /week
- Total - 8 weeks
• Prednisone
- 0.5 mg/kg – 4 weeks
- Tapered over next 4 weeks

10. Drug resistant TB
• Drug resistant TB - ≥ 1 drug
• Mono resistant TB – single drug
INH – RZE + FQ’s
R – same as MDR TB
• Poly resistant TB - > 1 drug. INH / Rifampicin
• MDR TB – INH + Rifampicin ± other agent
• Pre XDR TB – INH + Rifampicin + FQ’s
• XDR TB – Pre XDR TB + Bedaquiline/Linezolid
• TDR TB – All drugs

11. MDR TB
• Longer regimen – 5-7 months + 16 months
• Step 1 – Levoflox / Moxiflox
• Step 2 – Linezolid + Bedaquiline
• Step 3 – Clofazimine + Cycloserine
• Step 4 – Amikacin / Streptomycin
• Step 5 – Pyrazinamide + Ethambutol
• Step 6 – Ethionamide / Carbapenem / High dose INH
• Not indicated – Amoxicilin, Kanamycin

12. MDR TB
• Shorter course
• Intensive phase – 7 drugs & 4-6 months
- High dose INH + Ethambutol + Pyrazinamide +
Moxiflox + Amikacin + Clofazimine
• Continuation phase – 4 drugs & 5 months
- Ethambutol + Pyrazinamide + Moxiflox + Clofazimine

13. XDR TB
• Intensive phase – 5-6 months with 5 drugs
• Pyrazinamide
• Ethambutol
• Bedaquiline
• Linezolid
• Clofazimine
• Cycloserine
• Ethionamide
• Meropenem / imipenem
• Continuation phase – 16-24 months

14. Outcome
• 50-60% mortality
• CN palsy, gait disturbance, blindness,
deafness, dementia, learning disabilities

15. Drug selection
• Sensitivity
• Prior history
• Cost
• Availability
• Toxicity
• Oral vs iv

16. Pregnancy
• Longer duration
• No use of Pyrazinamide, Aminoglycosides,
Ethionamide

17. Drugs used in Tuberculosis
1st line drugs
high efficacy, low toxicity
• Isoniazid (INH)
• Rifampin (R)
• Pyrazinamide (Z)
• Ethambutol (E)
• Streptomycin (S)
2nd line drugs
Low efficacy, high toxicity or both
• Ethionamide
• Clofazimine
• Cycloserine
• Amikacin/ Capreomycin/
Kanamycin
• Fluoroquinolones

18. DRUG NAME MOA CSF MAJOR ADR DOSE PREGNANCY
ISONIAZID Bactericidal Yes Peripheral
neuritis
Hepatitis
5 mg/kg (max 300
mg)
Yes
RIFAMPICIN Bactericidal Yes Hepatitis
Dermatological
10 mg/kg (max 600
mg)
Yes
PYRAZINAMIDE Bactericidal Yes Hepatitis
Hyperuricemia
40-55 kg – 1000 mg
55-75 kg – 1500 mg
76-90 kg – 2000 mg
No
ETHAMBUTOL Bacteriostatic Poor Optic neuritis
Hyperuricemia
40-55 kg -800 mg
56-75 kg – 1200 mg
76-90 kg – 1600 mg
Yes

19. DRUG NAME MOA CSF MAJOR ADR DOSE PREGNANCY
AMIKACIN /
STREPTOMYCIN
Bactericidal Mild -
moderate
Nephrotoxic,
Ototoxic,
electrolyte
15 mg/kg
(max 1000
mg)
Avoid
BEDAQUILINE Poor QT prolongation,
GI toxicity
400 mg/day
for 2 weeks
f/b 200 mg 3
times/week
for 24 weeks
Can be use
FQ’s
MOXIFLOX
LEVOFLOX
Bactericidal Good QT prolongation,
CNS toxicity
M – 400 - 800
mg/day
L - 750-1000
mg/day
Potential choice
when no
alternatives
CLOFAZIMINE Bactericidal No data QT prolongation,
photosensitivity
100-200
mg/day
Avoid
ETHIONAMIDE Bacteriostatic Excellent GI toxicity,
Neurotoxicity,
Hypothyroidism
500 mg/day
to 1 gm/da
(OD/BD)
Potential choice
when no
alternatives

20. DRUG NAME MOA CSF MAJOR ADR DOSE PREGNANCY
CYCLOSERINE Bactericidal Good CNS – Psychiatric +
Seizure
Peripheral neuropathy
250 mg BD to
500 mg BD
When no
alternative
available
LINEZOLID Bacteriostatic Good Myelosuppression
Neuropathy
600 mg 0D Avoid
BEDAQUILINE Bacteriostatic Low QT prolongation,
Hepatitis
400 mg OD for
2 weeks
200 mg TDS for
24 weeks
Avoid

21. ISONIAZID
- Essential component of all anti TB regimen
(except intolerance to H or resistance)
- It is tuberculocidal , kills fast multiplying organism &
inhibit slow acting organism
- It is the cheapest AT
- Atypical mycobacteria are not inhibited by INH
- Not active against any other micro-orgs.
-

22. ISONIAZID
- Mechanism of Action :
- Inhibit synthesis of mycolic acid ( unique fatty acid
component of mycobacterial cell wall )
- If INH is given alone, after 2-3 months an apparently
resistant infection emerges .
- Combination therapy with INH has good resistance
preventing action .
- There is no cross resistance .

23. ISONIAZID
Pharmacokinetics :
- Completely absorbed orally , penetrate all bod tissues,
tubercular cavities , placenta & meninges .
- Metabolized in liver by acetylation & metabolites are
excreted in urine
Dose – 4-6 mg/ kg for >50 kg – 300 mg daily
- 600 mg bi-weekly

24. ISONIAZID
ADRs -
Well tolerated drug
1. Peripheral neuritis & other neurological manifestations
parasthesia, numbness & mental disorientation (due to
interference with utilization of pyridoxine & ↑ excretion
in urine )
Due to this Pyridoxine given prophylactically
- 10 mg/day which prevents neurotoxicities
(INH neurotoxicity treated with Pyridoxine-100 mg/ day )
2. Hepatitis – more common in older patients & alcoholics
3. Rashes , fever , acne & arthralgia .

25. RIFAMPICIN
- Bactericidal to M. Tuberculosis & others
- Efficacy is same as INH & better than others
- Best action on slowly or intermittently dividing bacilli
- Also act on many atypical mycobacteria
- Have good resistance preventing action

26. RIFAMPICIN
PKT –
- Well absorbed orally
- Better to take in an empty stomach
- widely distributed in the body , penetrate cavities ,
placenta & meninges .
- Metabolized in liver
- Excreted mainly in bile & some in urine
- Dose – 10 mg/kg (max 600 mg)

27. RIFAMPICIN
ADR’s
1. Hepatitis – mainly in pts having preexisting liver
disease & is dose related- Jaundice req. stoppage
of drug - REVERSIBLE
2. Respiratory syndrome –breathlessness
3. Cutaneous syndrome – flushing , pruritis & rashes (
face & scalp ), redness & watering of eyes.
4. Flue syndrome – Nausea , vomiting, abdominal
cramps
( Urine & secretions may become red – which are harmless & Pt should be
told about this effect)

28. RIFAMPICIN
Rifampicin is microsomal enzyme inducer
-↑ several CYP 450 isoezymes
-↑ its own metabolism as well as of others
e.g.-Oral contraceptive Digoxin
Warfarin Theophylline
Steroids Metoprolol
Sulphonyl urea Fluconazole & Ketoconazole

29. PYRAZINAMAIDE
- Weak tuberculocidal more active in acidic
medium
- More lethal to intracellular bacilli & to those
at sites showing an inflammatory response
(Therefore effective in first two months of therapy where inflammatory changes
are present)
- Inhibit the call wall synthesis
PKT :
- Absorbed orally, widely distributed ,Good
penetration in CSF.
- Metabolized in liver & excreted in urine.
- t½ -6-10 hrs

30. PYRAZINAMAIDE
ADRs :
- Hepatotoxic -dose related
- Arthralgia , hyperuricaemia, flushing , rashes ,
fever & anaemia
- Loss of diabetic control
Dose – 20-30 mg /kg daily
40-55 kg – 1000 mg
56-75 kg – 1500 mg
76-90 kg - 2000 mg

31. ETHAMBUTOL
- Tuberculostatic , clinically active as
Streptomycin
- Fast multiplying bact.s are more sensitive
- Also act against atypical mycobacteria
- If added in triple regimen (RHZ) it is found
to hasten the rate of sputum conversion &
to prevent development of resist.
- Resistance develop slowly
- No cross resistance

32. ETHAMBUTOL
- 3/4th of an oral dose of is absorbed
- Distributed widely but penetrates in meninges
incompletely, more when inflamed
- ½ metabolized , excreted in urine
- Caution is required in pts of renal disease

33. ETHAMBUTOL
- ADR
- Loss of visual acquity / color vision due to optic neuritis,
which is most impt. dose & duration dependent toxicity.
(children can not report this complaint easily therefore not given below 6 yrs of age)
Early recognition –reversible
- Neurological changes
- Hyper uricaemia is due to interference with urate excretion
Dose – 10-20 mg /kg daily
40-55 kg – 800 mg
56-75 kg – 1200 mg
76-90 kg - 1600 mg

34. AMINOGLYCOSIDES
- Amikacin, Streptomycin
- Amikacin is preffered
- It is protein synthesis inhibitor
- It is tuberculocidal , but less effective than INH /
Rifampicin
- Acts on extracellular bacilli only ( poor penetration in
the cells )
- It penetrates tubercular cavities but does not cross BBB
- Resistance when used alone
- ADR – Ototoxicity & Nephrotoxicity
- Dose- 15 ( 12-18 ) mg/kg, >50 mg- 1000mg

35. FQ’s
• Moxiflox, Levoflox, Oflox, Ciproflox
• Bactericidal
• Use for Drug resistance TB
• More effective than Ethambutol
• Resistance if used alone
Moxi – 400 mg
Levo – 1000 mg
Oflox – 800 mg

36. CLOFAZIMINE
• Bactericidal
• ADR
• QT prolongation
• Photosensisitivity
DOSE – 100-200 mg/day

37. ETHIONAMIDE
- Tuberculostatic , having moderate efficacy
- Acts both on extra as well as intracellular bacteria
- Resistance develop readily & some cross
resistance to TZN
- Absorbed orally, distributed all over including CSF
- Dose – start with 250 mg/day, slowly escalate 750
mg/day

38. ETHIONAMIDE
ADR
Anorexia
Nausea & vomiting,
Hypothyroidism
Hepatitis ,
Peripheral / Optic neuritis
Behavioural changes
Pyridoxine – 100 mg/day reduce Neurological
effects

39. CYCLOSERINE
- ↓ Bacterial cell wall synthesis
- Resistance develop slowly, no cross resist
- CNS toxicity is high , neuropsychiatry symptoms
- sleepiness, headache
- tremor, slurred speech
- psychosis, depression
- convulsions
Dose – 250 mg BD increase to 750 mg/day
Pyridoxine 100 mg/day
helpful

40. LINEZOLID
• Bacteriostatic
• DOSE – 600 mg/day
• TOXICITY
• Peripheral neuropathy
• Bone marrow suppression
• Risk of serotonin syndrome (SSRI, TCA, FOOD)

41. MONITORING
• HEPATOTOXICITY
- Isoniazid, Rifampicin, Pyrazinamide, Ethionamide,
Moxifloxacin
- Monthly LFT in high risk pts
• Vision
- Ethambutol, Clofazimine
• Renal & Electrolytes
- Aminoglycosides

42. MONITORING
• QT INTERVAL
- FQ’s, Clofazimine
• Neurological
• Peripheral Neuropathy
- Isoniazid, Ethionmide, Cycloserine, Linezolid
• Psychiatric
- Cycloserine, Ethionamide
• Seizure
- Cycloserine, Carbapenem, FQ’s, INH