Management of Tuberculosis
In Special Situations
DR. MD. MAHABUB MORSHED
IMO, MEDICINE UNIT-IX
DHAKA MEDICAL COLLEGE HOSPITAL
Tuberculosis-Global
1/3rd of the world population infected(over 2 billion)
10% gets the disease
8.6 million new cases each year
1.3 million deaths each year
2nd leading cause of death from an infectious disease
Tuberculosis-Bangladesh
Ranks 6th amongst 22 highest TB burden countries
10th amongst 27 high MDR-TB burden countries
Prevalence 434/100,000 per year
Incidence 225/100,000 per year
Death rate 45/100,000 per year
MDR-TB incidence- new 1.4%
retreatment 28.5%
HIV associated TB incidence less than 1%
references: 1. National Guidelines and operational manual for Tuberculosis control (5 th edition)
Tuberculosis- Treatment
New case
Smear positive pulmonary TB
Smear negative pulmonary TB
Extra-pulmonary TB
Associated HIV/AIDS
Initial intensive phase- 2RHEZ
Continuation phase- 6RH or 6HE
Re-treatment
Sputum smear-positive PTB with H/O treatment of 1 month/more
Relapse
Treatment failure
Loss to F/up
Others
Initial intensive phase- 2RHEZ+S, 1RHEZ
Continuation phase- 5RHE
Ref.-NTP. National Guidelines & Operational Manual For Tuberculosis Control. 5th edition, 2013
Case scenario
A 55 years old diabetic, hypertensive man, known case of PTB
on anti-tubercular therapy presented with unconsciousness for
1day, H/O convulsion once. Investigations reveals RBS-
32m.mol/L, S.Na-156m.mol/L. On 5th day of admission he
developed DVT in left lower limb. What will be the management
plan of this patient?
Re-evaluation of anti TB
Good control of DM
Drug interactions
Special situations
TB & DM
TB & renal impairment
Liver disease
Pregnancy
Infant of TB mother & breast feeding
Women on OCP
Epilepsy
Hypertension
HIV
Drug interaction
TB & DM
DM increases the risk of TB 2.5 to 3 times
TB increases the risk of DM by 2 times.
Treatment is same as in non-diabetic.
Baseline liver & renal function should be assessed &
monitored carefully.
TB & DM
INH aggravate PN in diabetic patients -
to prevent- Pyridoxine 40mg/day &
to treat - Pyridoxine 100 mg/day.
Glycemic status should be checked within 2 wks of starting
anti-TB drugs.
Should achieve optimum glycemic targets , fasting
<6mmol/L , HbA1c <7%.
TB & DM
Insulin should be given in following situations-
- Severe TB e.g. disseminated/ miliary TB, TB meningitis
-Lean & thin patient
-Associated nephropathy/hepatitis
-Uncontrolled DM/new DM patients with HbA1c>7%
TB & DM
OAD can be given in following situations-
- Obese patients with good appetite
- No contraindication of OAD
- Good glycemic control with OAD(HbA1c<7%)
TB & DM
Duration should be extended beyond 6 months upto 9
months more in following situations-
-Poor clinical response
- Bilateral extensive cavitary lesion/parenchyma involvement
-Delayed sputum conversion
-Delayed radiological improvement
-Poor glycemic control during treatment
TB & DM
Patient should be followed up every 2-4 weeks in the
initial phase & then 2 monthly in continuation
phase.
Renal Impairment- CKD
Acquired immunodeficiency state- High risk of TB
50% tuberculin –ve
Three categories
-CKD
- Dialysis
- Transplant
Creatinine clearance is a better indicator than serum
creatinine
Safest regimen- 2HRZ/4HR
Grades Of Renal Impairment In CKD
Stage 1 CKD: Normal CC with structural abnormality
Stage 2 CKD: CC 60-90ml/ min
Stage 3 CKD: CC 30-60ml/ min
Stage 4 CKD: CC 15-30ml/ min
Stage 5 CKD: CC <15ml/ min with or without dialysis
Renal Impairment
Rifampicin:
Safe, active metabolite excreted in bile
Inactive metabolite(10%) in urine
Use normal dose in all stages
INH:
Safe, metabolized in liver
Add pyridoxine to avoid P.N.
Use normal dose in all stages
Renal Impairment
Pyrazinamide
Metabolized in liver
Delayed elimination of drug & metabolites in CKD 4 & 5
Needs dose interval adjustment
CKD 1-3 <50 kg: 1.5 gm daily
>50 kg: 2gm daily
CKD 4-5 25-30 mg/kg 3x/week
Renal Impairment
Ethambutol
Nephrotoxic, Renal excretion- 80% unchanged
Ocular toxicity- dose dependent
Serum monitoring required- should be <1.0 µg/ml
CKD 1-3 15mg/kg daily
CKD 4-5 15-25 mg/kg 3x/week
max 2.5 gm
Renal Impairment
Aminoglycosides- Streptomycin
Nephrotoxic, renal excretion-80% unchanged
Reduced clearance in elderly
Needs dose interval adjustment in all stages
12-15 mg/kg- 2 or 3 times/week
Monitor serum levels, ensure trough levels (at 24hrs) of
<2µgm/ml
New recommendations- avoid Aminoglycosides
Use Moxifloxacin- 400mg daily CKD 1-3
Renal Impairment
Prothionamide:
Safe, Billiary excretion
Thiacetazone, PAS, Cycloserine:
Should be avoided
Partially excreted by kidneys
Dose chart of ATT in CKD
BTS Guidelines 2010
DRUG Stage 1-3 CKD Stage 4-5 CKD+ Transplant
INH 300mg daily 300mg daily 300mg daily
Or 15mg/kg max
900mg 3x/week
Rifampicin <50kg: 450mg daily <50kg: 450mg daily <50kg: 450mg daily
>50kg: 600mg daily >50kg: 600mg daily >50kg: 600mg daily
Pyrazinamide* <50kg: 1.5g daily 25-30mg/kg three <50kg: 1.5g daily
>50kg: 2g daily times weekly >50kg: 2g daily
Ethambutol** 15mg/kg daily 15-25mg/kg three 15mg/kg daily
times weekly
Max 2.5gm
Moxifloxacin 400mg daily Not suitable or 400mg daily
3x/weekly regimen
+Also applies to dialysis * Check uric acid & monitor for gout ** Check baseline color vision & visual acuity and
warn patients to report in red/green discrimination or visual acuity. Check peak & trough
ATT in Hemodialysis
Immediately after HD- To avoid premature removal
4-6 hrs before HD- To reduce toxicity
R & H standard daily dose
PZA- Standard dose- 3 x weekly
Ethambutol- Standard dose- 3 x weekly
Avoid streptomycin
ATT in Renal Transplant
Active TB should be treated before transplantation
After transplant- Standard dosage & duration of HRZE
May need modification until normal renal function
Ethambutol can be replaced with Moxifloxacin
Rifampicin- Hepatic enzyme inducer- risk of graft rejection
Dose adjustment for cyclosporine, Tacrolimus
Mycofenolate
Double the dose of steroids
Chemoprophylaxis in Renal Transplant
Ideal candidate for Chemoprophylaxis who have>1 of the
following conditions-
MT> 5 mm
IGRA- positive(if MT <5)
H/O inadequately treated TB
H/O contact with active TB patient
Chemoprophylaxis should be provided before
transplantation or immediate post-transplant period
IGRA: Interferon Gamma Release Assay
Chemoprophylaxis
INH 6 months
RH 3 months
R 4-6 months
RZ 2 months
protective efficiency 60-65% with 6H
50% with 3RH
Long term use of INH not recommended
Tuberculosis- Liver Disease
14 folds increase in CLD
Hepatotoxicity -most common adverse effect
Mortality rate 6-12%
Tuberculosis- Liver Disease
Treatment of TB in Liver disease:
It may occur in 3 clinical settings-
A. With pre-existing liver disease
B. Drug induced hepatitis
C. Viral hepatitis during treatment
Tuberculosis- Liver Disease
With pre-existing liver disease :
Advanced/unstable liver disease:
LFT should be done at the starting of the treatment
serum ALT>3times
serum billirubin>2times Withhold standard anti TB & give
clinically icteric alternative regimen
Chronic hepatitis, resolved acute hepatitis, current excessive
alcohol consumption:
Usual TB regimen(2HRZE/4HR)
Tuberculosis- Liver Disease
Possible alternate regimens include-
a. Two hepatotoxic drugs: 9HRE or 2 SHRE/6HR or 6-9 RZE
b. One hepatotoxic drug: 2SHE/10HE
c. No hepatotoxic drugs: 18-24 SEQ
Tuberculosis- Liver Disease
Drug induced hepatitis(DIH)
DIH –
increase in AST or ALT>3times with symptoms
or >5times without symptoms
Asymptomatic increase ALT & AST in 20% of patients
which resolve spontaneously.
Tuberculosis- Liver Disease
Clinical Hepatitis in Persons Taking Isoniazid and Rifampicin*
Drug No of studies Patients Clinical hepatitis%
INH 6 38,257 0.6
INH + other drugs but not RIF 10 2,053 1.6
RIF + other drugs but not INH 5 1,264 1.1
INH + RIF 19 6,155 2.7
Increase with age, underlying liver disease, alcohol, postpartum
women#
*Source: Steele MA, Burk, Des Prez RM. Toxic hepatitis with Isoniazid and Rifampicin: a meta-analysis. Chest 1991;99:465-471
# Franks et al Public Health Rep 1989;104 151-55
Tuberculosis- Liver Disease
British Study:
Clinical hepatitis: 0.3% with INH(6 months)
1.4% with Rifampicin(6 months)
1.25% with PZA(2 months)
Hepatitis rate per patient PZA 3 times > Rifampicin
Hepatitis rate per patient PZA 5 times > INH
Tuberculosis- Liver Disease
Management protocol:
If caused by anti-TB drugs, all drugs should be stopped
Overwhelming TB
Unsafe to stop TB treatment
A non-hepatotoxic regimen consisting of SEQ should be started
Tuberculosis- Liver Disease
When anti-TB stopped wait for LFT & clinical symptoms to
resolve before reintroducing the anti-TB drugs
Once drug induced hepatitis has resolved, the drugs are
reintroduced one at a time
If symptoms recur or LFT become abnormal as the drugs
are reintroduced, the last drug added should be stopped
Tuberculosis- Liver Disease
Start with rifampicin
Next isoniazid (after 3-7 days)
Who tolerate the reintroduction of rifampicin & INH, it is
advisable to avoid PZA
Tuberculosis- Liver Disease
Alternate option:
When hepatitis & jaundice occurs-
During the intensive phase with HRZE: 2HRSE/4HR
During the continuation phase: 4HR
(once hepatitis has resolved )
Tuberculosis- Liver Disease
Viral hepatitis:
Defer TB treatment till acute hepatitis resolved
Necessary to treat during acute hepatitis
No Yes
Acute hepatitis S+E±Q for 3 months
resolved hepatitis fully Hepatitis not
Restart anti-TB resolved fully resolved
treatment continuation phase S+E for another
H+R for 6 months 9 months
Pregnancy
H, R, PZA, E: Safe, no evidence of teratogenecity
Add pyridoxine with INH to avoid small risk of CNS
damage in infants
Streptomycin: contraindicated.
Re-treatment regimen:3(HRZE)/5(HR)E
2nd line anti-tubercular drugs : Teratogenic.
Ref.-NTP. National Guidelines & Operational Manual For Tuberculosis Control. 5th edition, 2013
Infants of TB mothers & Breast Feeding
Mothers must continue A.T.T. during feeding
Child should not be separated
Mother should cover her mouth during cough particularly
if smear +ve
INH prophylaxis: 5mg/kg 6 months or at least 3 months
ahead of the time the mother is consider non-infectious
Do not give BCG while on INH
Ref.-NTP. National Guidelines & Operational Manual For Tuberculosis Control. 5 th edition, 2013
Women on OCP
Rifampicin: Hepatic enzyme inducer
OCP may become ineffective
Extra/alternative protection required
Higher dosage
Ref.-NTP. National Guidelines & Operational Manual For Tuberculosis Control. 5th edition, 2013
Epilepsy & anti-TB drugs
INH associated with increased risk of seizures.
Quinolones -should be avoided
Epilepsy & anti-TB drugs
Serious interactions between
Rifampicin and carbamazepine
Rifampicin and phenytoin
Rifampicin and sodium valproate.
Hypertension
Rifampicin reduces drugs level( beta blocker ,
calcium channel blocker & ACEi)
No interaction with diuretics
Should monitor drug levels & adjust the dose
accordingly
HIV- Infected or AIDS
Standrad regimen- usually good response
Drug reactions more common
Thiacetazone should be avoided
Prolonged treatment
Patients on anti-retroviral therapy- high risk of interaction
with rifampicin
Drug interaction
Rifampicin:
Enzyme inducer
Decrease blood level of many drugs e.g. antihypertensive,
analgesics, anti-fungals, OCP, anti-retroviral agents, anti-
epileptics, warfarin.
Drug interaction
Isoniazid:
Enzyme inhibitor
In slow acetylator increase blood level of many drugs e.g.
antacids, carbamazepine, OCP, paracetamol, Phenytoin,
theophylline, warfarin.
Drug interaction
Ethambutol & Pyrazinamide:
With thiazide diuretics elevate S. urate level
PZA may interact with allopurinol & probenecid as PZA
inhibit the urate clearance
Drug interaction
Streptomycin:
Increased risk of oto or nephro toxicity with other oto or
nephrotoxic drugs
Should be aware to use loop diuretics, anaesthetics or
conventional neuromuscular drugs
Should be avoided in neuromuscular junctional disorder.
e.g. Myasthenia gravis
Treatment of scenario
Anti- TB should continue upto 9 months
Strict control of blood sugar level using insulin
Warfarin for DVT- drug interaction should kept in mind
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