2. BASIS OF PHARMACOTHERAPY
ANTI-TUBERCULAR THERAPY
PYRIDOXINE SUPPLEMENTATION
MONITORING AND FOLLOW-UP
PARADOXICAL UPGRADING REACTIONS
3. DETERMINANTS FOR CHOICE OF
DRUGS
Bacillary and metabolic subpopulation (extra-cellular/ intra-
cellular, slow/ rapidly growing, metabolically active/
stationary)
Bacillary load
Drug resistant strains
Lag period of bacterial population
Pharmacokinetic profile
Pathological factors
4. Isoniazid (INH) and rifampicin (RMP) kill the fast-growing bacilli
Pyrazinamide (PZA) acts against intracellular organisms in acidic medium
Extracellular slow growing bacilli are best killed by RMP.
EVERY CASE OF TUBERCULOSIS MUST BE TREATED AT LEAST WITH
THESE DRUGS.
5. Ethambutol is recommended as fourth drug in intensive phase and as a
third drug in the continuation phase due to high INH resistance (around
13%) in new cases.
WHY DAILY THERAPY?
Longer duration of rifampicin treatment, Daily therapy early in the
treatment, and Regimens that included a greater number of drugs- Lower
relapse, failure, and acquired drug resistance rates
6. BIPHASIC TREATMENT
INTENSIVE
Early and rapid killing of Mtb
Prevents deterioration and death
Reduces infectivity
Sputum conversion in 80-90%
Pyrazinimide- has sterilizing effect;
reduces duration to 6 months
Ethambutol- useful if initial drug
resistance to INH is high.
CONTINUATION
Eliminates most residual bacilli
Reduces failures and relapses
Small number of bacilli left- Fewer
drugs needed
In resistance- More drugs needed
7. Dividing time of TB bacilli is about 21 hours
Drugs administered to achieve peak concentration all at one time to hit
bacilli hard
Drug concentration is poor in caseum and sequestrated tissue- Should be
removed surgically wherever feasible
9. CASE DEFINITION- ‘NEW CASES’
Has never had treatment for TB (or)
Has taken anti-TB drugs for less than one month
10. CASE DEFINITION- ‘PREVIOUSLY
TREATED’
Recurrent case
Previously declared as successfully treated (cured/treatment completed)
and is subsequently found to be microbiologically confirmed TB case
Treatment After Failure Case
Previously been treated for TB and whose treatment failed at the end of
their most recent course of treatment.
11. CASE DEFINITION- ‘PREVIOUSLY
TREATED’
Treatment After Lost to Follow Up Case
Previously treated for TB for 1 month or more and was declared lost to follow up in their
most recent course of treatment and subsequently found microbiologically confirmed TB
case
Other Previously Treated Case
Those who have previously been treated for TB but without outcome after their most
recent course of treatment is unknown or undocumented
15. FIXED DOSE COMBINATIONS (FDC)
Safety
Simplified treatment
No errors in missing one or more of the combination drugs
Reduced risk of emergence of drug-resistant strains
Programmatic view point- Simplify drug supply management, shipping
and distribution
16. FIXED DOSE COMBINATIONS (FDC)
TWO TYPES
3 Drugs FDC DT (H 50, R 75, Z150) (10:15:30) for children, +
non-DT Ethambutol (E 100)
4 drugs FDC Adult (H 75, R 150, Z 400, E 275)
17.
18. ADJUNCT- STEROIDS
INTERACTION
BETWEEN THE
MICROBIAL
FACTORS AND
HOST
IMMUNOLOGICA
L FACTORS IN
LUNG, LYMPH
NODES,
INTRACRANIAL
LESIONS
INTERLEU
KIN 2
AND
INTERFER
ON
GAMMA
PARADOXI
CAL
WORSENIN
G OF
SYMPTOM
S
MAJORITY
RECOVER WITH
CONTINUATION
OF THERAPY
SEVERE
LIFE
THREATE
ING
MANIFEST
ATIONS
AND
SEQUELAE
INFLAMM
ATION
CAN BE
SUPPRESS
ED BY
STEROIDS
19. ADJUNCT- STEROIDS
DEFINITE INDICATIONS
TB Meningitis, Pericarditis, Addison disease, Miliary TB with
alveolo-capillary block and TB uveitis
MAY BE USED IN
Endobronchial tuberculosis, Bronchial compression, Mediastinal
compression syndrome, Pleurisy with severe distress, Laryngeal TB,
TB IRIS
Evidence in other forms of intracranial TB like tuberculomas is unclear
20. ADJUNCT- STEROIDS
Predinsolone 1-2 mg/kg/day (or)
Dexamethasone 0.6 mg/kg/day (or)
Equivalent steroid is used
For 4 weeks and then tapered over next 4 weeks
21. PYRIDOXINE SUPPLEMENTATION
WHY?
Isoniazid interferes competitively with pyridoxine metabolism by inhibiting formation of
active form of vitamin- causing peripheral neuropathy.
Initially recommended for
HIV, alcohol abuse, malnutrition, diabetics, Renal/liver failure, MDR treatment
Was NOT routinely recommended for children; children on continuation phase of
Intermittent DOT regime were getting Pyridoxine on drug holidays.
22. PYRIDOXINE SUPPLEMENTATION
CURRENT RECOMMENDATION:
Pyridoxine 10mg per day
JUSTIFICATION FOR RECOMMENDATION:
Increased INH dose to 10-15 mg/kg for treatment and prophylaxis and it can potentially
increase the dose related adverse effects.
High prevalence of malnutrition in children with TB.
Difficult to diagnose peripheral neuropathy in young children (if unrecognised, may result
in severe & prolonged morbidity)
25. CLINICAL FOLLOW-UP
FREQUENCY OF VISITS:
Initial visit within 2 weeks of starting therapy (to check dose/ combination/ tolerance)-
where possible
Every month during treatment
Every 6 months for 2 years (after completion of treatment)
26. CLINICAL FOLLOW-UP
Improvement in clinical symptoms
Physical examination
Side effects of medications
Treatment of Co-morbid conditions
Adherence to therapy
27. CLINICAL FOLLOW-UP
Improvement in clinical symptoms:
Cough, fever, appetite or other clinical symptoms
Classified as no improvement, partial improvement or improved
after asking parents/attendants
Mostly amelioration of symptoms by the end of 4 weeks of therapy
28. CLINICAL FOLLOW-UP
Physical examination:
Individualised relevant examination
Respiratory rate, heart rate, temperature (if fever), blood pressure if needed
Chest indrawing, recording of lymph node size, anemia
Abdomen for organomegaly/distenstion,
Chest examination for breath sound, crepitations, evidence of pleural effusion,
Cardiovascular system if pericardial TB,
Central nervous system if CNS TB
As no improvement, partial improvement or improvement
29. CLINICAL FOLLOW-UP
Weight recording- nearest to 0.1 kg
Causes of poor weight gain: poor intake, vomiting, side effect of medications, wrong
diagnosis, comorbid conditions, concomitant infections such as diarrhea/ pneumonia or
poor response to treatment
If assessment suggests no clinical deterioration, family will be counselled for increasing
food intake
34. SIDE EFFECTS OF MEDICATIONS-
MANAGEMENT
What to do if symptoms of adverse effects occur?
❖ Dose of drugs should be checked
❖ All other causes of symptoms should be excluded
❖ Seriousness of adverse effects should be estimated
❖ Adverse effects should be registered
❖ Drugs may need to be stopped and should eventually be reintroduced gradually when
symptoms disappear
❖ Development of drug resistance should be avoided
35. SIDE EFFECTS OF MEDICATIONS-
ATT INDUCED LIVER INJURY
Definition:
Presence of at least rise of >5 times the upper limit of normal levels of ALT and /or AST,
even when has no symptoms or rise in ALT (and/or)
AST >3 times with nausea, vomiting, diarrhoea or rise in level of serum total bilirubin
above 1.5 mg/dl.
Usually within weeks to months (60% in the first 3 months)
36. SIDE EFFECTS OF MEDICATIONS-
ATT INDUCED LIVER INJURY
Indian setting- high prevalence of hepatotropic infections like Hepatitis A in paediatric
age group
Clinical features: nausea, vomiting, anorexia, pain abdomen, jaundice, unexplained
fatigue, new onset hepatomegaly and bleeding manifestation.
Risk factors: malnutrition, hypoalbuminemia, associated HIV, Hepatitis B, Hepatitis C
infection, extensive TB disease, increases with age, slow acetylators of INH, Presence of
HLA-DQB1*0201, gene polymorphisms at loci of genes coding for cytochrome P450 2E1
and for glutathione-S-transferase.
37. ATT INDUCED LIVER INJURY-
MANAGEMENT
Asymptomatic increases in serum liver transaminases:
To continue ATT,
To monitor for symptoms (anorexia, malaise, vomiting, or
jaundice)
To repeat liver enzymes after a week.
38. ATT INDUCED LIVER INJURY-
MANAGEMENT
If injury fulfils criteria
Stop all hepatotoxic ATT drugs - R, H, Z immediately
Symptomatic treatment should be given.
Look for other causes of hepatitis- viral markers in all cases (A, E).
Consider starting alternative drugs if seriously ill: Ethambutol, Streptomycin, &
Levofloxacin.
Reintroduce primary drugs once symptoms subsided & liver enzymes < 2ULN. The
drugs (in full dose) are to be added every 3-days, with regular LFT monitoring.
39. A new drug is re-instituted only if the ALT is less than twice the upper
limit of normal.
In case the patient is sick, drowsy or have any abnormal bleeds, the case
should be referred to an in-patient facility.
For deciding the final duration of therapy; do not take into account the
days when full complement of treatment was not given.
40. CLINICAL FOLLOW-UP
TREATMENT OF CO-MORBID
CONDITIONS
HIV, SAM should be monitored during each visit.
Decongestive measure and anti-convulsants are often prescribed in neurological TB and
should be monitored at followup.
Any co morbidities If respiratory difficulty and assessed to have pneumothorax, collapse
etc- pediatric consultation.
If subacute intestinal obstruction- gastroenterology/ surgical opinion.
41. CLINICAL FOLLOW-UP
ADHERENCE TO THERAPY
Use Pill count, Social support, family based DOT and Treatment supervisor
as needed
In case the patient has interrupted treatment:
Interruption upto 4 weeks- Resuming the therapy
Interruption for over 4 weeks- Investigated for acquisition of DRTB
42. MONITORING AND FOLLOW-UP
LAB INVESTIGATIONS
Microbiological: At end of IP and end of treatment
(Bacterial negativity- sputum, GA etc with smear and culture; repeat
CBNAAT for any acquisition of Rif Resistance if follow-up smear is
positive)
MGIT culture: should be performed if child is not responding even after 4
weeks of therapy.
43. MONITORING AND FOLLOW-UP
LAB INVESTIGATIONS
Liver function test: No routine LFT testing for patients on first line drugs.
Follow up Chest radiographs should be performed only at end of therapy; or, earlier if
assessed to be clinically non improvement or has any complication or deterioration.
Other imaging (Ultrasound of abdomen, echo-cardiography, CT/MRI scan of affected
organ system) at completion of treatment or assessed to be unresponsive or deterioration
while on treatment.
44. PARADOXICAL UPGRADING
REACTIONS
Enlargement of old lesions or unexpected appearance of new lesions during apparently
adequate ATT
Usually occurs 3–12 weeks after beginning of therapy; (frequently after treatment for 6- 7
weeks) & lasts for ∼2 months.
Self-limiting; resolves without serious sequelae.
Usually regresses without a change of initial drug regimen
May occur post treatment (as late as two years) in cases of lymph node TB
46. PARADOXICAL UPGRADING
REACTIONS
TYPES
1. Increase in size of mediastinal lymph nodes or areas of pulmonary infiltration in
pediatric patients with primary TB
2. Appearance of new lung infiltrates in patients with extrapulmonary TB
3. Development of TB pleural effusion
4. Increase in size of effusion/appearance of effusion on the contra lateral side
5. Appearance of new lymph nodes/ enlargement of original nodes
6. Increase in size or number of tuberculoma/ infarctions / hydrocephalus on treatment of
intracranial TB
48. PARADOXICAL UPGRADING
REACTIONS
Difficult to distinguish a paradoxical reaction from a true drug resistance
and it is always a diagnosis of exclusion
Absence of any systemic symptoms is a useful indicator for Paradoxical
upgrading reactions
49. CLINICAL OR RADIOLOGICAL
DETERIORATION DURING FOLLOW-
UP
i. Incorrect diagnosis (particularly if clinically diagnosed case of TB)
ii. Lack of adherence to therapy
iii. Incorrect drugs or dosages
iv. Not retaining drugs- children often may vomit out drugs due to the bad taste or due to
forceful medication
v. Secondary infection or a comorbidity
vi. Drug resistance
vii. Paradoxical upgrading reactions
50. CLINICAL OR RADIOLOGICAL
DETERIORATION DURING FOLLOW-
UP
Radiological deterioration alone without clinical symptoms should be reviewed with
skilled radiologists.
Often the difference in phase of respiration, rotation, difference in radiological factors
may affect the assessment of follow-up images.
51. CLINICAL OR RADIOLOGICAL
DETERIORATION DURING FOLLOW-
UP
The further steps of investigations are decided based on clinical clues for
the above conditions
History of contact with a proven case of MDR or prolonged or irregular
therapy in a case with in household or peer groups of the child is a good
clue for investigating for DRTB
Drug Susceptibility Testing or Line Probe Assay or CBNAAT needed as
confirmatory test for Drug Resistant TB
