Pharmacotherap

y of M.
Tuberculosis
- Dr. Hitesha Trivedi
• Tuberculosis is an infectious disease primarily caused by mycobacterial
tuberculosis.
• The disease primarily affects the lungs but it may affect the intestine,
meninges, bones, joints, lymph nodes, skin, or other body tissues.
• It is mainly transmitted by droplet infection from sputum-positive
patients with pulmonary tuberculosis.
• The incubation period is generally 3 to 6 weeks and may vary
depending upon closeness of contact, dose of infection, immunity of
recipient, etc.
• Patients present with clinical features such as fever, Night sweats,
weight loss, cough for more than 2 weeks, and longer with
expectoration, hemoptysis, weakness, fatigue, breathlessness, etc.
Investigations
• Radiological Investigations:-
1. HRCT
2. Chest x-ray mainly shows nodules, masses, or lesions which suggest
colonies of bacteria.
• Microbiological Investigations:-
1. ZN stain (Sputum smear)
2. CBNAAT – detects Rifampicin resistance
3. Line Probe Assay – detects Isoniazid, Rifampicin, Fluoroquinolones,
2nd line injectable drug resistance
4. Culture
 Antitubercular Drugs

First line drugs Second line drugs

Isoniazid
Rifampin
Pyrazinamide Other oral drugs Newer/
Fluroquinolones repurposed
Ethambutol Ethionamide
Levofloxacin drugs
Prothionamide
Moxifloxacin Bedaquiline
Cycloserine
Terizidone Delamanid
PAS Pretomanid
Rifapentine Linezolid
Clofazimine
Imipenem/
Injectable drugs Cilastatin
Amikacin Meropenem
Streptomycin
Definitions
1. Monoresistance: resistance to one first-line anti-TB drug only
except Rifampicin.
2. Polydrug resistance: resistance to more than one first line anti-TB
drug, other than both isoniazid and rifampicin.
3. Multidrug resistance: resistance to at least both isoniazid and
rifampicin.
4. Extensive drug resistance: resistance to any fluoroquinolone and at
least one of three second line injectable drugs in addition to
multidrug resistance.
1st line antitubercular drugs
1. Isoniazid:
• It is primarily a tuberculocidal drug. It Is an important drug for the chemotherapy of
drug-susceptible TB and in some cases of drug-resistant TB.
• Fast multiplying bacteria are rapidly killed but quiescent ones are only inhibited.
• Isoniazid enters bacilli by passive diffusion & it acts on extracellular as well on
intracellular bacilli.
• Primary mechanism of INH is the inhibition of the synthesis of mycolic acids which are a
unique fatty acid component of the mycobacterial cell wall.
• INH enters sensitive mycobacteria which convert it into the reactive metabolite by
catalase peroxidase enzyme, which forms an adduct with NAD that inhibits InhA and
KasA, which are the genes in function of mycolic acid synthesis .
• The reactive INH metabolite forms adduct with NADP as well which
inhibits mycobacterial DHFRase resulting in interruption of DNA
synthesis.
• The most common mechanism which confers high level INH
resistance is by mutation of the catalase peroxidase gene (KatG) so
that bacteria do not generate the reactive metabolite of INH. This
type of resistance can not overcome.
• Another type of resistance can be caused by inhA gene mutation. This
resistance can be overcome by increase in dose of INH.
• Resistance based on efflux of INH from bacterial cell is also possible.
• INH has good resistance preventing action when combined with other
anti TB drugs.
• INH is completely absorbed orally and penetrates all body tissues &
tubercular cavity. It is metabolized in liver, most important pathway
being N-acetylation by NAT2.
• The rate of INH acetylation shows genetic variation. There are either fast
acetylators and slow acetylators.
• Isoniazid induced peripheral neuritis is more common in slow acetylators.
• A hepatotoxic metabolite is produce by CYP2E1 from acetylhydrazine.
• Adverse effects : - Peripheral neuritis and a variety of neurological manifestations
like paresthesia, numbness, mental disturbance, rarely convulsions are most
important dose dependent side effects.
- These side effects are due to disturbance in production of the active
coenzyme pyridoxal phosphate from pyridoxine and its increase in excretion in
urine.
-Hepatitis = drug must be stopped
- lethargy, rashes, mild anemia, arthralgia
• Interactions: Aluminum hydroxide inhibits its absorption & INH inhibits
metabolism of phenytoin, theophylline, warfarin.
2. Rifamycin: (Rifampin, Rifapentine, and Rifabutin)
• They are bactericidal, macrocyclic antibiotics important in the treatment of
most mycobacterial diseases.
• Rifampin enters bacilli and binds to the β subunit of DNA-dependent RNA
polymerase (rpoB) to form a stable drug-enzyme complex and inhibits chain
formation in RNA synthesis.
• Rifampin inhibits the growth of most gram-positive bacteria as well as many
gram-negative microorganisms including M. tuberculosis, & Mycobacterium
leprae.
• Rifampin resistance is mainly due to alteration in gene rpoB .
• Rifamycin monoresistance occurs at higher rates when rifamycins are dosed
intermittently, especially among patients with HIV, or when companion drugs
are underdosed and are not present at high enough concentrations
• Food decreases the rifampin maximal plasma concentration by one-third. So it
is better to take Rifampin on an empty stomach.
• These are metabolized by microsomal β-esterases and cholinesterases. But
the major pathway is CYP3A. Due to autoinduction, clearance of all three
rifamycins increases with repeated administration.
• The drug is eliminated via feces, with urine being a minor elimination
pathway.
• A parenteral form of rifampin is also available.
• Rifapentine is not currently used for the treatment of TB disease.
• Rifampin is also useful for the prophylaxis of meningococcal disease and H.
influenzae meningitis. To prevent meningococcal disease, adults may be
treated with 600 mg twice daily for 2 days or 600 mg once daily for 4 days.
• Combined with a second antibacterial, rifampin may be useful for therapy in
selected cases of staphylococcal endocarditis or osteomyelitis, especially for
infections associated with prosthetic materials.
• They frequently cause harmless red-orange discoloration of skin, urine,
feces, saliva, tears, and contact lenses.
• Hepatitis is a major adverse effect, generally occurs in patients with
preexisting liver disease, and is dose-related. Jaundice requires
discontinuation of the drug, after which it is reversible.
• Other minor reactions are –
Cutaneous: Flushing, pruritus + rash, redness, and watering eyes.
Flu-like symptoms: Chills, fever, headache, malaise, and bone pain.
Abdominal cramps, nausea, vomiting, diarrhea, etc.
• Rifampin is a potent inducer of cytochrome P450 (CYP) and phase 2
metabolizing enzymes.
• As a result, its administration often results in higher clearance for
concurrently administered medicines can lead to treatment failure.
3. Pyrazinamide :-
• It is bactericidal but weaker than INH and more active in acidic
medium.
• It is more lethal to intracellularly located bacilli and to those at sites
showing inflammatory response.
• It has no other use than tuberculosis. And they are highly effective
during first 2 months of therapy.
• It is also having sterilizing effect.
• The mechanism of action is not well known but it is also converted
into active metabolite pyrazinoic acid by enzyme pyrazinamidase
encoded by pncA gene. This metabolites get accumulated and inhibits
mycolic acid synthesis.
• Resistance to pyrazinamide is mostly due to mutation in the pncA
gene.
• It is absorbed orally. It has good penetration in CSF because of which
it is useful in meningeal TB.
• Most common side effect is Hepatotoxicity. So it is contraindicated in
patient with liver disease.
• Hyperuricemia is common and is due to inhibition of uric acid
secretion.
• Other side effects are abdominal distress, arthralgia, flushing, rashes,
fever, etc.
• Repeated blood sugar monitoring is needed in diabetics.
4. Ethambutol:
• It is selectively tuberculostatic and is active against MAC as well as
some other types of bacteria. Fast-multiplying bacteria are more
susceptible.
• It mainly acts via inhibition of arabinosyl transferases, by interfering
with mycolic acid incorporation in mycobacterial cell wall.
• No cross-resistance with any other antitubercular drug has been
noted.
• It is absorbed orally,
The second line drugs
• Fluroquinolones:-
- Fluroquinolones like ofloxacin, levofloxacin, ciprofloxacin &
moxifloxacin are relatively new potent oral bactericidal drugs for TB.
- Moxifloxacin is the most active against M. tuberculosis f/b
levofloxacin, ofloxacin, ciprofloxacin.
- The FQs penetrate cells and kill mycobacteria lodged inside
macrophages as well.
- The primary indication of FQs is for the treatment of drug resistance
tuberculosis and it is the key component of all regimens for MDR-TB.
- Resistance is mainly seen due to mutation in DNA gyrase gene.
• Aminoglycosides:- (Injectables)
- It is recommended in the treatment of MDR-TB & XDR-TB when patient does not respond to
oral agents.
- The recommended daily dose is 1 g per day for 60 to 120 days, followed by
1 g two or three times a week.
- Most common side effects are irreversible hearing loss and vestibular
damage.

• Cycloserine:-
- It inhibits bacterial cell wall synthesis by inactivating the enzymes which
racemize L- alanine and link two D- alanine.
- It is basically tuberculostatic and no cross resistance with other anti
tubercular drugs occurs.
- Oral absorption is good and its concentration is in CSF is equal to that of
plasma.
- Most common side effects are, sleepiness, headache, tremors, slurring of speech, altered
behavior.
• Ethionamide:-
- It acts on both extra and intra bacilli. Chemically it resembles isoniazid
and also it get converted into active metabolites which interfere with
mycolic acid cell wall.
- It is absorbed orally, and distributed all over and cross into CSF.
- Its tolerability is poor with side effects like anorexia, nausea, vomiting,
salivation, metallic taste, epigastric discomfort, belching, hepatitis,
peripheral neuritis, behavioral changes, rashes, impotence, goiter, etc.
- It is mainly reserved for drug resistance tuberculosis.
• Bedaquiline:-
- It is a diarylquinoline antimycobacterial drug indicated as part of
combination therapy in adults (≥ 18 years) with pulmonary multi-drug
resistant tuberculosis only.
- It inhibits mycobacterial ATP synthetase, thereby limiting energy production
within mycobacterial cell.
- It is taken 400 mg once daily for 2 weeks followed by 200 mg 3 times per
week for 22 weeks with food.
- It is given in combination with 4 other susceptible antitubercular drugs .
- It is well absorbed orally and fatty food improves its absorption. It is highly
plasma bound and extensively distributed in tissues. Metabolism occurs in
liver, mainly by CYP3A4. excretion occurs mainly by faces.
- It is contraindicated in children and pregnant women.
- The background anti TB drugs should be continued after stopping
BDQ for the total 24 months treatment of MDR-TB. This is to ensure
that any surviving bacilli are not exposed to BDQ alone which persists
in the body for > 5 months after stopping the drug.
- Most common side effects are nausea, arthralgia, QT prolongation,
hepatitis, etc.
• Delamanid:-
- It is a new agent approved for the treatment of XDR- Tb.
- It is a prodrug, its active metabolites inhibits mycolic acid production.
- It is currently dispensed in 50mg tablets, and it is taken at dose of 100
mg twice daily with food.
- Side effects are headache, insomnia, QT prolongation.
• Pretomanid:-
- Newer agent approved for the treatment of XDR- Tb.
- Under aerobic condition it inhibits mycolic acid and protein synthesis.
- It is metabolized by CYP3A, coadministration of rifampin can reduce
pretomanid exposure.
- It is administered at 200mg/day along with food.
• PAS :-
- It acts mainly by inhibition of folate synthase.
- It is not active against other bacteria. It is only used in the treatment of
resistant TB.
- It is tuberculostatic and one of the least active drug, does not add to the
efficacy of more active drugs that are given with it.
- Absorbed orally and distributed all over except CSF.
- Patient acceptability is poor because of anorexia, nausea, epigastric
pain. And other side effects are rashes, fever, rashes, goiter,
hypokalemia.
Treatment of drug sensitive TB
Intensive Phase (2 months) Continuation Phase (4 months)
1. Isoniazid (H) 1. Isoniazid (H)
2. Rifampicin (R) 2. Rifampicin (R)
3. Pyrazinamide (Z) 3. Ethambutol (E)
4. Ethambutol (E)
+ Pyridoxine 100mg/day
MDR-Tb RNTCP Regime
Intensive Phase (6-9 months) Continuation Phase (18months)
1. Kanamycin 1. Levofloxacin
2. Levofloxacin 2. Ethionamide
3. Ethionamide 3. Cycloserine
4. Cycloserine 4. Ethambutol
5. Pyrazinamide
6. Ethambutol
+ Pyridoxine 100mg/day
Shorter oral Bedaquiline-containing MDR/RR-TB
regimen
• Shorter oral Bedaquiline-containing MDR/RR-TB regimen is recommended for
those MDR/ RR-TB patients in whom resistance to the component drugs has been
excluded or those who have not been previously treated for more than one month
with second-line drugs used in shorter oral Bedaquiline-containing MDR/RR-TB
regimen.
• A shorter oral Bedaquiline-containing MDR/RR-TB regimen of 9–11 months
duration is recommended.
• The regimen consists of an initial phase of 4 months that may be extended up to 6
months and a continuation phase of 5 months, giving a total duration of 9–11
months. Bdq is used for a duration of 6 months.
Intensive Phase (4-6 months) Continuation Phase (5months)
1. Bedaquiline (6months) 1. Levofloxacin
2. Levofloxacin 2. Clofazimine
3. Clofazimine 3. Pyrazinamide
4. Isoniazid (high dose) 4. Ethambutol
5. Pyrazinamide
6. Ethambutol
7. Ethionamide
+ Pyridoxine 100mg/day
Isoniazid (H) mono/poly DR-TB regimen
(6 or 9) Lfx R E Z

• Total duration of H mono/poly DR-TB regimen is of 6 months. It can

be extended directly to 9 months in certain conditions. In patients with
extensive disease; uncontrolled comorbidity; extra- pulmonary TB; if
smear at the end of month 4 is found positive and when regimen is
modified, the treatment may be directly extended to 9 months.
* Reference Park’s Textbook of preventive and social medicine 27th edition
Longer oral M/XDR-TB regimen
(18-20) Lfx Bdq (6 month or longer) Lzd# Cfz Cs
• The dose of Lzd will be tapered to 300 mg after the initial 6–8 months
of treatment
• Bdq will be given for 6 months & extended beyond 6 months as an
exception
• Pyridoxine to be given to all DR-TB patients as per weight band
• For Pre-XDR-TB and XDR-TB patients the duration of longer oral
XDR-TB regimen would be for 20 months with appropriate
modifications
THANK YOU