ANTI- TUBERCULAR DRUGS

Dr. Nidhi Malhotra

 Tuberculosis

• Primarily caused by Mycobacterium tuberculosis (MTB)

• Chronic granulomatous disease
• Lungs most commonly effected: Pulmonary Tuberculosis (PTB)
• Occurs by Inhalation of infected droplet nuclei
• Ending the TB epidemic by 2030 is among the health targets of
the Sustainable Development Goals
 PATHOGENIC MYCOBACTERIAL SLOW AND
RAPID GROWERS (RUNYON CLASSIFICATION)

SLOW Runyon I: Mycobacterium kansasii

GROWERS Photochromogens Mycobacterium marinum

Runyon II: Mycobacterium scrofulaceum

Scotochromogens Mycobacterium szulgai
Mycobacterium gordonae

Runyon III: Mycobacterium avium complex

Nonchromogens Mycobacterium haemophilum
Mycobacterium xenopi

RAPID Runyon IV Mycobacterium fortuitum complex

GROWERS Mycobacterium smegmatis group
Mycobacterium abscessus
 Tuberculosis
• Symptomatology:
 Low grade fever in the evening
 Night sweats
 Malaise, fatigue
 Weight loss
 Blood streaked sputum and cough etc.

• Miliary TB: massive dissemination of tubercle bacilli

throghout the body
 Challenges in treating TB
– Intracellular nature of MTB (in phagocytes)
• Drugs and antibiotics can’t reach this location
• Hence, drugs with better penetration are needed

– Rapid development of drug resistance

• Thus, combination therapy is required
• Thus, all regimens uses multiple drugs

– Prolonged duration of therapy

• Because the response to treatment is slow

– Risk of ADRs to drugs is very high

• Thus, monitoring of treatment is required
 Classification Of ATT Drugs

• First Line Essential Drugs:

• Core components of ATT regimen
– Isoniazid (H)
– Rifampicin (R)
– Pyrazinamide (Z)
– Ethambutol (E)

• First Line Supplemental Drugs:

• Reserved drugs, to be used in special settings
– Streptomycin, Rifabutin and Rifapentine
 Classification Of ATT Drugs

• Second Line Drugs:

– Fluoroquinolones ( Ciprofloxacin, Ofloxacin, Levofloxacin,
Moxifloxacin)
– Amikacin, Capreomycin
– Ethionamide, PAS, Cycloserine, Thiacetazone

• New Drugs
– LINEZOLID
– Clarithromycin
– Azithromycin
– BEDAQUILINE
– DELAMANID
Alternative grouping of antitubercular drugs
Group I First line oral anti-TB Isoniazid (INH), Rifampin, Pyrazinamide,
drugs Ethambutol
Group II Injectable anti-TB drugs Streptomycin, Kanamycin, Amikacin,
Capreomycin
Group III Fluoroquinolones Ofloxacin, Levofloxacin, Moxifloxacin,
Ciprofloxacin
Group IV Second line oral anti-TB Ethionamide, Prothionamide,
drugs Cycloserine, Terizidone,
Para-aminosalicylic acid,
Rifabutin,Rifapentine
Group V Drugs with unclear Bedaquiline,coamoxiclav,Thiacetazone,
efficacy Clarithromycin, Clofazimine,
Linezolid,Amoxicillin/clavulanate,
Imipenem/cilastatin

Adopted from: Treatment of Tuberculosis Guidelines; WHO, Fourth edition (2010) and Revised National Tuberculosis
Control Programme (RNTCP), DOTS-Plus Guidelines 2010
 ISONIAZID (INH / H)
• Isonicotinic Acid Hydrazide : very potent synthetic agent;
• Structural resemblance to Pyridoxine
• Bactericidal to actively growing MTB, dormant ones are only inhibited

MECHANISM
The activated form of isoniazid - which blocks mycolic acid synthesis and kills
the cell.
 PHARMACOKINETICS
Absorption
• Rapid and complete; rate can be slowed with food
• Peak Plasma Time: 1-2 hr

Distribution
• All body tissues and fluids including CSF; crosses placenta; enters breast milk
• Protein Bound: 10-15%

Metabolism
• Hepatic - Metabolized by acetylation ( fast, intermediate and slow acetylators)

Elimination
• Half-life elimination: fast acetylators: 30-100 min; slow acetylators: 2-5 hr;
may be prolonged with hepatic or severe renal impairment
• Excretion: Urine (75-95%); feces
Mechanism of resistance:

• Resistance can emerge rapidly if the drug is used alone.

• Resistance can occur due to either

1. High-level resistance is associated with deletion in the katG
gene that codes for a catalase peroxidase involved in the
bioactivation of INH.

2. Low-level resistance occurs via deletions in the inhA gene

that is involved in mycolic acid synthesis
 Adverse Drug Reactions

Major ADRs
• Peripheral Neuropathy: common with slow acetylators
– Prevented by prophylactic use of Vitamin B6 (10-40mg/day)

• Hepatotoxicity: common with fast acetylators, with underlying

liver disease, alcoholics and patients aged 50-65 years

Others
• Allergic reactions
• Xerostomia
• Convulsions and drug induced SLE
 Isoniazid Overdose
• Minimum toxic dose: 1.5 g
• Clinical triad of
Seizures refractory to treatment with phenytoin
and barbiturates
Metabolic acidosis with an anion gap that is
resistant to treatment with sodium bicarbonate
Coma

Antidote : replenishment of pyridoxal 5′-phosphate

DRUG INTERACTIONS:

• INH can increase CBZ concentrations and cause CBZ toxicity. This
interaction occurs more often with INH doses at >/=200 mg/day

• INH and ethionamide may cause a temporary increase in serum

concentrations of INH.  

• Aluminum salts, decrease the absorption of INH by a reducing gastric

emptying. Administration of INH 1 hour before antacids is recommended.

• INH may inhibit valproic acid hepatic metabolism. Elevated valproic acid
concentrations and hepatotoxicity.

• INH is known to inhibit the hepatic metabolism of drugs that undergo

oxidation including warfarin at the dose of 600mg/d
 RIFAMPICIN

• Rifampin is a semisynthetic derivative of rifamycin, an antibiotic

produced by Streptomyces mediterranei.

• It is active against gram positive and gram negative cocci, some

enteric bacteria, mycobacteria and chlamydia.

• Active against M. leprae, Staph. aureus, N. meningitidis, H.

influenzae, Brucella, Legionella

• Bactericidal for both extra and intra-cellular MTB

• Good sterilizing activity

 RIFAMPICIN
Mechanism

• Rifampin binds to the β subunit of bacterial DNA–dependent RNA

polymerase and thereby inhibits RNA synthesis.

• Mammalian DNA–dependent RNA polymerase doesn’t bind to Rifampicin

Resistance Development
• Resistance results from any one of several possible point mutations in repoB,
the gene for the β subunit of RNA polymerase.

• Hence, to be used in combination with other drugs to prevent development of

resistance
 Pharmacokinetics
Absorption
• PO well absorbed; food may delay absorption
• Peak plasma time: 2-4 hr

Distribution
• Highly lipophilic; crosses blood-brain barrier well, with or without
inflammation
• Protein bound: 80%

Metabolism
• Metabolized by liver; undergoes enterohepatic recirculation

Elimination
• Half-life: 3-4 hr (prolonged in hepatic impairment); in end-stage renal disease,
1.8-11 hr
• Excretion: Feces (60-65%) and urine (~30%) as unchanged drug
Contraindications
• Hypersensitivity to rifamycins
• Concomitant administration of live bacterial vaccines
• Contraindicated in patients receiving ritonavir-boosted
saquinavir, because of increased risk of severe hepatocellular
toxicity

Precautions
• May decrease the effectiveness of oral contraceptive pills (OCPs)
• Discontinue therapy if patient develops any signs of
hepatocellular damage, including hyperbilirubinemia
• Use with caution in patients with history of alcoholism and
patients receiving additional medications that may cause
hepatotoxicity
• Rifampin has enzyme-inducing properties that can enhance
metabolism of endogenous substrates, including adrenal
hormones, thyroid hormones, and vitamin D

ADRS:
• Hepatitis: Dose dependent and reversible, risk increased when
given with INH or in other liver pathologies
• Flu like syndrome
• Red-orange color to urine
Drug Interactions:
• Drugs that induce hepatic microsomal enzymes, particularly those
drugs that increase CYP2C9 or CYP2C19 metabolism, can
accelerate phenytoin clearance, reduce the plasma concentrations
and also possibly the efficacy of phenobarbital.

• Reduce the plasma concentrations and possibly the efficacy of

chloramphenicol, dosages may need to be adjusted while the
patient is receiving rifampin.

• Reduce the plasma concentrations and possibly the efficacy of

oral sulfonylureas. Oral sulfonylurea dosages may need to be
adjusted while the patient is receiving rifampin.

• OCPs failure
 Therapeutic Uses

• Treatment of TB
• Prophylaxis of meningococcal disease and H.
influenzae meningitis
• Combined with a β-lactam antibiotic or vancomycin
rifampin may be useful for therapy in selected cases
of staphylococcal endocarditis or osteomyelitis
• In the treatment of brucellosis, 900 mg a day
rifampin can be combined with doxycycline for 6
weeks
 PYRAZINAMIDE
• Synthetic Pyrazine analogue of Nicotinamide
• Initially, its use been reduced due to hepatotoxicity
• Reintroduced with low dose, and to be used in combination
• Mechanism of Action
– Pyrazinamide's exact mechanism of action is not known.

– Susceptible strains  release pyrazinamidase, which converts PZA to

pyrazinoic acid (POA).  
– POA decreases the pH below that which retards the growth of M.
tuberculosis and inhibiting the fatty acid synthesis .
– Studies indicate that PZA is most effective in the initial stages of
treatment, which may be the result of diminished organism
populations in macrophages early in therapy.
 Pyrazinamide
– Thus, highly effective on intracellular mycobacteria

Resistance-:
– A mutation in gene pcn A that encodes pyrazinamidase
enzyme is responsible for drug resistance which can be
minimized by using drug combination therapy
 Pharmacokinetics
• Absorption: well absorbed
• Distribution: widely into body tissues and fluids including liver,
lung, and CSF
• Relative diffusion from blood into CSF: adequate with or
without inflammation
• CSF: blood level ratio: inflamed meninges: 100%
• Protein binding: 50%
• Metabolism: hepatic
• Half-life elimination: 9-10 hr
• Time to peak, serum concentration: within 2 hr
• Excretion: urine (4% as unchanged drug)
 Adverse Effects
• Hepatotoxicity: in about 15% PZA recipients, but less with reduced doses
• Hyperuricemia and related gouty arthritis
• Others include: Nausea, vomiting, anorexia, drug fever, malaise
• Avoided in pregnancy

Interactions
• PZA can increase serum uric acid levels and precipitate gout attacks; the
dosages of antigout agents, including allopurinol, colchicine, probenecid , and
sulfinpyrazone may need to be adjusted.

• PZA is associated with dose-related hepatoxicity. Daily use of ethanol while

receiving pyrazinamide increases the risk of drug-induced hepatitis.
– Liver-function tests should be conducted prior to and every 2—4 weeks
during treatment in patients who consume ethanol routinely while receiving
pyrazinamide therapy.
 ETHAMBUTOL
• Semi-synthetic tuberculostatic drug
• Active against M. tuberculosis, M. kansasii, M. avium-
intracellulare

Mechanism of action
• Ethambutol inhibits mycobacterial arabinosyl transferases.
Arabinosyl transferases are involved in the polymerization
reaction of arabinoglycan, an essential component of the
mycobacterial cell wall.

• Resistance to ethambutol is due to mutations resulting in

overexpression of Emb gene (that encodes the arabinosyl
transferase enzyme) products or within the emb B structural gene.
 Pharmacokinetics
Absorption
• Bioavailability: ~80%
• Peak Plasma Time: 2-4 hr
Distribution
• Widely throughout body; concentrated in kidneys, lungs, saliva, and red
blood cells
• CSF: blood level ratio: 0% (normal meninges); 25% (inflamed
meninges)
• Protein binding: 10-40%
Metabolism
• Hepatic (20%) to inactive metabolite
Elimination
• Half-life elimination: 2.5-3.6 hr; 7-15 hr (end-stage renal disease)
• Excretion: ~50% urine; ~50% feces as unchanged drug.
 ADRS
• Acute gout or hyperuricemia: decreases renal excretion of urates
• Optic neuritis; symptoms may include decreased acuity, color blindness
or visual defects (usually reversible with discontinuation)
• Peripheral neuritis
• Rash

Contraindications
• Optic neuritis: Drug not to be given in children less than 5yrs of age
• Hypersensitivity

Monitoring Parameters
• Ophthalmologic exam
• Platelet count
• Serum creatinine/BUN
• Serum uric acid
 Drug Interactions
• Aluminum hydroxide can reduce the rate or extent of ethambutol
absorption. At least 4 hours should elapse between doses of
aluminum hydroxide-containing antacids and ethambutol.

• Ethambutol may interfere with the development of an immune

response following Bacillus Calmette-Guerin vaccine, BCG. The
vaccine is a live vaccine and is sensitive to commonly used
antituberculosis agents (e.g., isoniazid, ethambutol, rifampin)
 STREPTOMYCIN

• Streptomycin was isolated from a strain of Streptomyces griseus

• First drug to exhibit an effective anti-tubercular activity

• Poor penetration, so effective against only extracellular MTB

• Also active against M. kansasii and M. avium-intracellulare

• Unlike other first line drugs, administred IM

 Streptomycin
Mechanism of action:
Irreversibly inhibits bacterial protein synthesis. Protein synthesis is
inhibited in at least three ways:

1. Interference with the initiation complex of peptide formation

2. Misreading of mRNA, which causes incorporation of incorrect
aminoacids into the peptide, resulting in a nonfunctional or toxic
protein
3. Breakup of polysomes into nonfunctional monosomes

Mechanism of Resistance:
• Spontaneous resistance is related to a point mutation of the genes
(rpsl or rrs) that encodes for ribosomal proteins and ribosomal t-
RNA respectively
 Pharmacokinetics
• Absorption: IM: well absorbed; not absorbed from gut

• Distribution: To extracellular fluid including serum, abscesses, ascitic,

pericardial, pleural, synovial, lymphatic, & peritoneal fluids; crosses
placenta; small amounts enter breast milk

• Protein Bound: 34%

• Half-life elimination: newborns: 4-10 hr; adults: 2-4.7 hr, prolonged

with renal impairment

• Peak Plasma Time: within 1 hr

• Excretion: urine (90% as unchanged drug); feces, saliva, sweat, & tears
(<1%)
Adverse Effects
• Neurotoxicity,
• Ototoxicity (auditory, vestibular),
• Nephrotoxicity.

Monitoring Parameters
• Audiometry
• Serum creatinine/BUN

Drug Interactions
• Streptomycin may interfere with the development of an immune response
following administration of BCG vaccine.
•  Loop diuretics may cause volume depletion and allow for the concentration of
aminoglycosides within the nephron; concurrent therapy has been considered a
risk-factor for aminoglycoside-induced nephrotoxicity.
 Anti-TB drugs have the following three actions-:

1. Early bactericidal activity

2. Sterilizing activity
3. Ability to prevent emergence of drug resistance
DRUGS EARLY STERLIZING PREVENTION OF
BACTERICIDAL ACTIVITY EMERGENCE OF
DRUG
RESISTANCE
Isoniazid ++++ ++ ++++
Rifampicin +++ ++++ +++
Streptomycin +++ - ++
Pyrazinamide ++ +++ +
Ethambutol + - ++
 RIFABUTIN
Structural analogue of Rifampicin

Similarities with Rifampicin:

• Common mechanism of action
• Common spectrum of activity
• Common molecular basis of development of resistance

Differences from Rifampicin:

• Less potent cyt P450 enzyme inducer
• Better activity than Rifampicin against MAC infections (300 mg/day)
• Also active against Rifampicin resistant strains eg: M. leprae
• Longer t1/2 of 45 hrs
 RIFABUTIN
Mechanism of Action
Inhibits DNA-dependent RNA polymerase

Pharmacokinetics
Absorption: readily, 53%
Distribution: body tissues including the lungs, liver, spleen, eyes, & kidneys
• Vd: 9.32 L/kg
• Protein Bound: 85%
• Half-Life, 45 hr (range: 16-69 hr)
• Peak Plasma Time: 2-4 hr

Metabolism: hepatic CYP3A4 to active and inactive metabolites

Excretion
• Urine: 10% as unchanged drug, 53% as metabolites
• Feces: 10% as unchanged drug, 30% as metabolites
Prophylaxis
• Indicated for prevention of disseminated Mycobacterium
avium complex (MAC) disease in patients with advanced HIV
infection: 300 mg PO qDay
• Patients with N/V diathesis: 150 mg PO BID with food

Active TB (off-label)
• 5 mg/kg PO qD or 2-3x/week + other antitubercular agents, no
more than 300 mg/dose
 ADRs
• Skin rashes, GI intolerance
• Neutropenia, Hepatits
• Red-orange discoloration of urine

Drug Interactions
• Enzyme induction causes failure of many drugs
• Fluconazole increases Rifabutin plasma concentration
resulting in pseudojaundice and polymyalgia
syndrome
 RIFAPENTINE
• Longer acting (t1/2 13-15 hrs) analogue of Rifampicin

• Mechanism of action
• Cross resistance
• Enzyme induction
• Toxic profile Similar to Rifampicin
• Clinical use

• 600 mg OD/BD

• Drug interactions: Rifampicin > Rifapentine > Rifabutin

 SECOND LINE DRUGS
Fluoroquinolones

• Ciprofloxacin, Levofloxacin, Gatifloxacin and Moxifloxacin (esp. MDR strains)

• They are also active against atypical mycobacteria.

• Moxifloxacin is the most active against M tuberculosis

• Good penetration in cells, convenient dosage schedule and good tolerability

• Can be substituted in drug combinations if first line drugs are C/I

Mechanism of action:
• They inhibit bacterial DNA synthesis by inhibiting bacterial topoisomerase II
(DNA Gyrase) and topoisomerase IV.
 Pharmacokinetics
Rapidly absorbed orally- but food delays absorption,

BA: C- 60-80%, L- 100%, G- 96%

PPB: C- 20-35%, L- 15%, G- 20%
Half life: C- 3-5hrs, L-8hrs, G- 8hrs

High tissue penetration: lungs, sputum, muscle, prostate but low in CSF
Excreted primarily in urine, urinary and biliary concentrations are 10-50 times
more than plasma

Recommended Dosage

 Ciprofloxacin 750mg BD,PO or 500mg TDS,PO

 Ofloxacin 400mg BD,PO
 Levofloxacin 500mg OD.PO
 Moxifloxacin 400mg OD. PO
 Para amino salicylic acid
Mechanism of action
Aminosalicylic acid is a folate synthesis antagonist that is active almost
exclusively against mycobacterium tuberculosis.
It is structurally similar to p-amino benzoic acid(PABA) and the sulfonamides.
Pharmacokinetics
Absorption
• T max is about 6 h
Distribution
• About 50% to 60% is protein bound.
Elimination
• 80% is excreted in the urine with at least 50% excreted in acetylated form.
• The t 1/2 of free aminosalicylic acid is 26.4 min.
Dose: 4g 3 times daily, children < 15yrs: 200-300mg/kg daily in 2-4 divided
doses.

Adverse Reactions
GIT
• Nausea; vomiting; diarrhea; abdominal pain.
Metabolic
• Goiter with or without myxedema.
Miscellaneous
• Hypersensitivity (eg, fever, skin eruptions, leukopenia, thrombocytopenia,
hemolytic anemia, jaundice, hepatitis, encephalopathy, Loffler syndrome,
vasculitis).
Hepatic Function- Use with caution.
CHF- Use with caution because of high sodium content (55 mg of sodium per
500 mg tablet).
Crystalluria- Maintain urine at neutral or alkaline pH to avoid crystalluria.
 ETHIONAMIDE
• Rarely used due to intense gastric irritation and neurological toxicity at
recommended dose of 1gm/day

• Also it is hepatotoxic

• So, daily dose of 500-750 mg is used

Mechanism of Action:
• Ethionamide, like pyrazinamide, is a nicotinic acid derivative related to
isoniazid. It is thought that ethionamide undergoes intracellular modification
and acts in a similar fashion to isoniazid
• Interferes with mycolic acid synthesis
 CYCLOSERINE
• Cycloserine is an antibiotic produced by streptomyces orchidaceus.
• Tuberculostatic to MTB, also effective against E.coli, Staph. aureus,
Enterococcus, Nocardia, Chlamydia

Mechanism of action :
• It inhibits mycobacterial cell wall synthesis
• Cycloserine used exclusively to treat tuberculosis caused by mycobacterium
tuberculosis resistant to first line agents

• Readily absorbed after oral administration, and excreted through kidneys

• Hence, used for Renal tuberculosis
• Also used for treatment of MDR-TB
• 500mg BD orally
 ADR
• Peripheral neuropathy
• Dizziness
• Tremors
• Psychotic behavioral changes

• Vitamin B6 100mg/day can reduce neurological toxicity

 THIOACETAZONE
Mechanism of action: Bacteriostatic- inhibits cyclopropanaton of cell wall
mycolic acids.

Uses: It continues to be used as a convenient low cost drug to prevent emergence

of isoniazid resistance, streptomycin & ethambutol.

Dose:150mg OD in adults;2.5mg/kg in children; it is frequently combine with

isoniazid

T1/2: 12 hrs

ADR: hepatitis, exfoliative dermatitis, SJS, bone marrow depression rarely

Common: Abdominal discomfort, loose motions, rashes, mild anemia, anorexia.
 AMIKACIN
• Aminoglycoside, with significant ototoxicity and nephrotoxicity
• Hence, second choice for MDR-TB after streptomycin

• Also, useful in disseminated MAC in AIDS patients

• MTB strains resistant to streptomycin are sensitive to amikacin

• Recommended dosage: 15mg/Kg/day IM/IV for 5 days a week x 2 months

and then 1g/day thrice weekly for another 4 months
 CAPREOMYCIN
• Tuberculocidal polypeptide antibiotic

• Effective against MTB, M. kansasii & M. avium

• Poorly absorbed from GIT, hence given IM (1 gm/day)

• Important drug for MDR-TB

• Ototoxicity and Nephrotoxicity are the major adverse effects

 Clofazimine

• Clofazimine is a fat-soluble riminophenazine dye.

• Possible Mechanism of Action:
 membrane disruption
 inhibition of mycobacterial phospholipase A2
 inhibition of microbial K+ transport
 generation of hydrogen peroxide
 interference with the bacterial electron transport chain
 efflux pump inhibition
• Antibacterial activity + anti-inflammatory effects
• Bacterial Resistance: mutation in the gene encoding a transcription
repressor for efflux pump MmpL; this is associated with cross resistance to
bedaquiline
PHARMACOKINETICS:
• Absorption: oral bioavailability is 45%–60%; it is increased 2-fold by high-fat
meals and decreased 30% by antacids
• tmax is 5.3– 7.8 h. After prolonged repeated dosing, the t1/2 is about 70 days.
• Distribution : into of skin and body
• Metabolism: liver in four steps: hydrolytic dehalogenation, hydrolytic
deamination, glucuronidation, and hydroxylation.
Adverse Effects:
• Abdominal pain
• crystal deposition in intestinal mucosa, liver, spleen, and abdominal lymph
nodes
• Body secretion discoloration, eye discoloration, and skin discoloration
(Reddish black)
Drug Interactions
• Anti-inflammatory effects may be inhibited by dapsone.
Newer Anti-tubercular Drugs
 LINEZOLID

• Effective against both drug sensitive and resistant MTB

• Part of multi-drug regimen used for MDR-TB

• Serious dose-dependent adverse effects on prolonged use are:

– Bone marrow suppression - reversible
– Peripheral neuropathy – irreversible

• Given orally or IV as 600mg OD

• Considered as drug of last resort to treat MDR-TB

 BEDAQUILINE
• Diarylquinoline anti-tuberculosis drug
• First new medicine to fight TB in more than forty years
• Effective against both dividing and non-dividing bacteria (↑sterilizing act.)
• Specifically approved to treat multi-drug-resistant tuberculosis

• Mechanism of action : Inhibits the proton pump for ATP synthase

• Drug was shown to be effective in reducing the time to TB-free sputum

cultures

• Drug Interactions
 Should not be co-administered with inducers or inhibitors of cyt P450
ADVERSE EVENTS OF BEDAQUILINE
1. AST and/or ALT elevations
2. Amylase and/or lipase elevation
3. Musculoskeletal system abnormalities- myalgia
4. Cardiac rhythm disturbances
– QT interval monitoring: An ECG should be obtained before initiation of
treatment and daily for the first 2 weeks, then every 2 weeks for 3
months and then monthly.
– ECGs should be done at least weekly throughout the BDQ course if
other QT prolonging drugs like FQ (Mfx, gatifloxacin [Gfx]), Cfz or
macrolide antibacterial drugs (erythromycin, clarithromycin,
azithromycin) are included in the regimen.
– If the QTc interval is> 500ms (confirmed by repeat ECG), DISCONTINUE
BDQ

5. Gastrointestinal system disorders

 Bedaquiline: Dosage
• Week 0–2: BDQ 400 mg (4 tablets of 100 mg) daily (7
days per week) + OBR

• Week 3–24: BDQ 200 mg (2 tablets of 100 mg) 3 times

per week (with at least 48 hours between doses) for a
total dose of 600 mg per week + OBR

• Week 25 (start of month 7) to end of treatment:

Continue other second-line anti-TB drugs only as per
RNTCP recommendations .

OBR: Optimized Background Regimen

 Pretomanid
• Approved by FDA on August 14, 2019 ( by NGO TB Alliance)
• Treatment for XDR-TB or MDR-TB who are treatment-
intolerant or non-responsive (collectively “highly drug-resistant
TB”)
• It is approved as part of a three-drug, 6-month, all-oral
regimen: Bedaquiline, Pretomanid & Linezolid –BPaL
regimen
• ADR: hepatotoxicity, myelosuppression, peripheral and optic
neuropathy.
 Delamanid(DLM)
• First approved drug in the class of nitro-dihydro-
imidazo-oxazoles for the treatment of MDR-TB
• Bactericidal with Half-life of 36 hours
• Achieve culture conversion in 6 to 13 days
(protective role in preventing the emergence of
additional drug resistance.)
 Delamanid: Dosage
• Week 0–24: Delamanid 100 mg (two tablets of
50 mg) orally twice a day + OBR
• Week 25 (start of month 7) to end of treatment:
Continue other second-line anti-TB drugs only as
per RNTCP recommendations.
• Drug-Drug Interactions: (minimal)
– FQs and Cfz may potentially increase the risk of cardiotoxicity
– Some antiretroviral medications can cause modest QT
prolongation, especially ritonavir-containing regimens

OBR: Optimized Background Regimen

 Adverse events of Delamanid
1. MC: nausea, vomiting, and dizziness
2. QTc interval prolongation:
• ECGs obtained before initiation of treatment and
monthly during treatment with Dlm
• Treatment should not be started or should be
discontinued if a QTc > 500 ms
• Some of the medicines as the fluoroquinolones, can
cause QTc interval prolongation. If possible, avoid the
use of QT prolonging drugs with Dlm.
Treatment of tuberculosis
(a) Rapidly growing with high bacillary load as in the wall of a
cavitary lesion where oxygen tension is high and pH is neutral.
These bacilli are highly susceptible to H and to a lesser extent to
R, E and S.
(b) Slow growing located intracellularly (inside macrophages) and at
inflamed sites where pH is low. They are particularly vulnerable to
Z, while H, R and E are less active, and S is inactive.
(c) Spurters found mostly within caseous material where oxygen
tension is low but pH is neutral: the bacilli grow intermittently
with occasional spurts of active metabolism. R is most active on
this subpopulation.
(d) Dormant some bacilli remain totally inactive for prolonged
periods. No antitubercular drug is significantly active against
them.
 Case definitions
• Presumptive pulmonary TB refer to a person with
any of the symptoms or signs suggestive of TB
including
1. cough > 2 week
2. fever >2 week
3. significant weight loss
4. hemoptysis
5. any abnormality in chest radiograph.
 Case definitions
• Presumptive DR-TB: refers to following
patients in order of their risk:
1. TB patients found positive on any follow-up sputum smear
examination during treatment with first line ATD including
treatment failures
2. Paediatric TB non-responders
3. TB patients who are contacts of DR-TB
4. Previously treated TB patients
5. New TB patients with HIV coinfection
6. All notified new TB patients
 CLASSIFICATION OF DR-TB
• Mono-resistance TB (MR): A TB patient, whose biological specimen is
resistant to one first-line ATD only
• Poly-Drug Resistance TB (PDR): A TB patient, whose biological specimen
is resistant to more than one first-line ATD, other than both H and R.
• Rifampicin Resistance (RR): A TB patient, whose biological specimen is
resistant to R, detected using phenotypic or genotypic methods, with or
without resistance to other ATD. It includes any resistance to R, in the
form of mono-resistance, poly-resistance, MDR or XDR
• Multi Drug Resistance (MDR) : A TB patient, whose biological specimen
is resistant to both H and R with or without resistance to other first line
ATD. MDR- TB patients may also have additional resistance to any/all FQ
OR any/all SLI anti-TB drug.
• Extensive Drug Resistance (XDR): A MDR TB patient, whose biological
specimen is additionally resistant to a FQ (Ofx, Lfx, or Mfx) AND a
second-line injectable ATD (Km, Am or Cm).
 Goals of antitubercular chemotherapy

(a) Kill dividing bacilli Drugs with early bactericidal

action rapidly reduce bacillary load in the patient and
achieve quick sputum negativity so that the patient is
non-contagious to the community: transmission of TB
is interrupted. This also affords quick symptom relief.
(b) Kill persisting bacilli To effect cure and prevent
relapse. This depends on sterilizing capacity of the
drug.
(c) Prevent emergence of resistance So that the bacilli
remain susceptible to the drugs
 Diagnostic PROCEDURES
 From 2012,serological tests for diagnosis of TB have been banned by
WHO as well as Govt. of India.
 Molecular Diagnosis: CBNAAT, LPA
• DR-diagnostic tech.: 1st --CBNAAT/LPA 2nd --Liquid culture
isolation
• Time Advantage:
– Solid LJ media- 12 weeks
– Liquid Culture (MGIT)- 6weeks
– LPA up to 72 hours
– CBNAAT - 2 hours
• ISSUES: -High inter and intra reader variation: 10-15%
-Underreading: culture +ve cases remain undiagnosed -
Overreading: 50%pts diagnosed as TB by X-ray alone might not be TB
CBNAAT: Cartridge Based Nucleic Acid Amplification Test; LPA: Line Probe Assay
 DR-TB Diagnostic Algorithm
Presumptive All
TB diagnosed
TB
patients
Key/Vulnerable • Non responders
CBNA to
populations
• Paediatric age AT treatment
group • DR-TB contacts
• People living with • Previously
HIV treated TB
• EPTB site RR
For discordance
on LPA for RR-TB
RS • TB-HIV co-
– repeat CBNAAT TB infection
TB at LPA lab • New TB patients
$

SL - FL-
LPA** LPA*

FQ and SLI FQ and/or SLI H Sensitive

Sensitive H Resistant
Resistance
 TREATMENT OF TUBERCULOSIS
CATEGORY and TYPE of Drug Regimen Total duration
patient
Category I: All new patients Intensive Phase: 6 months
2(H 3R3Z3E3Phase
Intensive ), plus (IP):
New (untreated) smear 2(HRZE), plus
positive pulmonary TB Continuation Phase:
New (untreated) smear 4(H 3R3)
negative pulmonary TB Continuation Phase (CP):
All new cases of extra- 4(HR)
pulmonary TB
Category II: All previously Intensive Phase: 8 months
treated patients 2(H3R3Z3E3S3) + 1(H3R3Z3E3),
plus
Intensive Phase:
Treatment Failure
Relapse 2(HRZE), plus Phase:
Continuation
Default 5(H3R3E3) 6 months
Continuation Phase:
4(HR)

CP in both new and previously treated cases may be extended by 3-6 months
in certain form of TB: CNS TB, Skeletal TB, Disseminated TB
 Follow up evaluation in ds-tb patients
1. Clinical follow-up (new addition):
– Should be at least monthly
– Can be in clinical facility/patient’s house
– To observe improvement of chest symptoms, weight-gain & control
comorbidities (HIV)
– To monitor any adverse reaction to ATD
2. Laboratory investigation:
– Sputum smear examination at the end of IP and at the end of
treatment
– MO may consider repeat sputum smear in CP (New addition), if required
– DST should be done if any follow up sputum comes positive
– At the completion of t/t, sputum smear and culture done for every patient
– CXR – to be offered whenever required and available.
3. Long-term follow-up (new addition): After completion of treatment, the
patient should be followed up at the end of 6, 12, 18 and 24 months
(clinical + sputum)
(no provision of long-term follow-up in the previous guidelines)
 Treatment for DR-TB
• Pre-treatment evaluation required
• All DR-TB cases offered HIV counselling and testing (If HIV status is not
known/or result is negative >6mnths)
• All DR-TB cases undergo baseline HBsAg
• All DR-TB cases undergo LC with DST by LPA at baseline for FQs and SLIs

MDR-TB: Resistant to H+R± other first line ATD + to any/all FQ OR any/all

SLI
• IP- 6 drugs X 6 months
• CP- 4 drugs X 18 months
XDR-TB: MDR+ any/all FQ AND any/all SLI
• IP- 7 drugs X 6 months
• CP- 6 drugs X 18 months
 Treatment Drug resistant TB
Type of TB cases Intensive Phase Continuation Phase Total duration
(IP) (CP)

Isoniazide (6-9) LfxREZ 6-9 months

(mono/poly-res)

Shorter MDR (4-6) Mfx(high (5) Mfx(high 9-11 months

regimen (R res + H dose)Km/Am dose) Cfz Z E
sensitive/unknown Eto Cfz Z
or MDR TB) H(high dose) E

All oral longer MDR 18-20 Bdq(6) Lfx Lzd Cfz Cs 18-20 months
regimen (RR or
MDR-TB)

XDR-TB (6-12) (18) Mfx(high dose) 24-30 months

Mfx(high dose)Cm Eto Cs Lzd Cfz E
Eto Cs Z Lzd Cfz
E
Follow up evaluation in dR-tb patients
• After initiation of Rx from the DR-TB Centre, MO
District/Nodal-DR TB center conduct clinical and lab
investigations in follow up
 At monthly intervals during the IP
 At 3-monthly intervals during the CP until the end of
treatment
• Assess clinical, microbiologic, and radiologic response to
treatment
• Measure weight
• Assess possible adverse drug reactions (ADR)
• Encourage the patient to continue treatment
• Verify treatment card
 Revised TB Control Programme
(RNTCP)
• Launched in 1993
• GOALS: achieve universal access of quality of TB
diagnosis and treatment of all TB patients in the
community.
• OBJECTIVES:
1. 90% notification rate for all cases
2. 90% success rate for all new and 85% for re-
treatment cases
3. To significantly improve outcome DRTB cases
4. To decreased morbidity/mortality for HIV + TB
cases
5. To improve TB care in the private sectors

National Tuberculosis Elimination Program (NTEP)

NATIONAL STRATEGIC PLAN FOR
TUBERCULOSIS ELIMINATION
2017–2025
•VISION: TB-Free India with zero deaths, disease and poverty
due to tuberculosis

•GOAL: To achieve a rapid decline in burden of TB, morbidity

and mortality while working towards elimination of TB in
India by 2025.

•TARGET: “Detect – Treat – Prevent – Build”

(DTPB)
 TB notification
• Govt. of India declared Tuberculosis a
notifiable disease on 7th May 2012
• All public and private health providers shall
notify TB cases diagnosed and/or treated by
them to the nodal officers for TB notification.
 Nikshay 2.0
• Nikshay is an online portal for Patient
Management workflow and autoupdation of
patient status
• Nikshay was launched in 2012 and since then,
many improvements
• Nikshay Version 2: launched in September 2018
• It provides: unified interface for public and private
sector health care providers
• Mobile friendly website with mobile app
 Nikshay Poshan Yojana

• Launched by Govt.
of India in March
2018
• Main aim to
provide incentives
(Rs 500/month for
the duration of
treatment) for
nutritional support
to TB patients.
 99 DOTS
A low-cost approach for monitoring and improving
TB medication adherence

• ADVANTAGE
 Instead of traveling to a center for every dose, patients can
provide evidence of dosing from their home
 It improves the efficiency of care providers
 Adherent patients can proceed with less supervision, while
limited program resources are focused on cases that need the
most attention
• Using 99DOTS, each anti-TB blister pack is wrapped in a custom envelope,
which includes hidden phone numbers that are visible only when doses are
dispensed.
• After taking daily medication, patients make a free call to the hidden phone
number, yielding high confidence that the dose was “in-hand” and has been
taken.
 Chemoprophylaxis
• Indicated to household members and other contacts
• Also to the neonate of tubercular mother

• INH 300gm/day (5mg/Kg/day for children) for 6-12 months; OR

• INH (5mg/Kg/day) + R(10mg/Kg/day) for 6 months
 Tuberculosis in pregnant women

• Treatment of TB should not be withheld or

delayed because of pregnancy
• 2 HRE + 7HR (total 9 months)

• Add pyridoxine 10–25 mg/day when on INH

 Management of ADRs
• Minor side effects are to be managed symptomatically without altering medication;
e.g
 nausea, anorexia— give the drugs with small meals
 Drowsiness— give drugs before bed time
 flu syndrome due to intermittent dosing of R—change to daily dosing of R
 T/t of Z induced arthralgia- analgesic-NSAIDs
 T/t of peripheral neuritis due to H- pyridoxine

• If more severe reactions like skin rashes, itching develop,

 all drugs should be stopped promptly
 After resolution of the reaction, the drugs are to be reintroduced one at a time by
challenging with small doses and increasing every 3 days
 When the offendng drug is identified, it should be stopped and the regimen
reconstituted
 However, never reintroduce R in case of haemolysis, thrombocytopenia or renal
failure
 Discontinue Ethambutol at the first sign of optic neuritis
 Role of corticosteroids

(a) In seriously ill patients (miliary or severe pulmonary TB)

to buy time for drugs to act
(b) When hypersensitivity reactions occur to antitubercular
drugs
(c) In meningeal/renal/pericardial TB or pleural effusion—to
reduce exudation, prevent its organisation and strictures,
etc
(d) In AIDS patients with severe manifestations of
tuberculosis
C/I: Intestinal T.B (silent perforation can occur)
 Drugs for MAC in AIDS patients
INTENSIVE PHASE

1. Clarithromycin (500mg BD,PO) or Azithromycin (500mg OD,PO)

2. Ethambutol 1000mg (15mg/Kg/day)
3. Rifabutin 300mg/day OD,PO
±
Ciprofloxacin 500mg twice daily or
Levofloxacin 500mg once daily or
Moxifloxacin 400mg once daily

MAINTENANCE PHASE

• Clarithromycin/Azithromycin
• Ethambutol/Rifabutin/one fluoroquinolone
 TAKE HOME MESSAGE

• Introd. of CBNAAT/ Gene-Expert •  Non declaration of TB

• Cat 2 patient (R/D/F) are ALL now Cat 1 punishable
Both new+previously treated cases T/t • Nikshay
duration is 6 month(2+4) with no extension
• Nikshay Poshan Yojna
of IP
• All MDR-TB get access highest-ranked • Nikshay Aushadhi
med.+ fully oral regimen • 99 DOTS
• All MDR-TB: LC+DST(FQ,SLI) • RT-MERM
• FDC with 5 adult wb & 6 pediatric wb • Mobile TB vans for ACF
• Long term Follow up (6,12,18 & 24 month)
• Incentives: Private doctor-Rs.1000,
Patient-Rs.750
TH Y
AN O
K U