2. Mycobacterial disease
Tuberculosis Leprosy Atypical Mycobacterium
Caused by M. tuberculosis
Caused by M. Leprae Caused by M. avium complex
(MAC)
Tuberculosis (TB):-chronic granulomatous infectious disease caused by M.
tuberculosis, an acid-fast bacillus (AFB)
Spread through inhalation of droplet containing bacilli
Characteristics of Mycobacterium tuberculosis (TB):-
Tubercular bacilli grow slowly, dividing only once in 1-2 days (hence drugs
which acts most against growing cells are relatively ineffective
Lipid rich mycolic cell wall is impermeable to many drugs
Infection it consists of excessive fibrous tissue which tend to block blood vessels
supplying the necrotic area
3. • Tubercular bacilli →are intracellular pathogen reside in macrophages hence
inaccessible to drug which penetrate these cells poorly
• A single drug should never be used in tuberculosis as this leads to the rapid
development of drug resistant tubercle bacilli. This can be prevented by drug
combination therapy
• Classification:-
Anti-Tubercular drugs
First-line drugs
(standard drugs)
Isoniazid (H)
Rifampicin (R)
Pyrazinamide (Z)
Ethambutol (E)
Streptomycin (S)
Second-line drugs
(Reserve drugs)
Others
Ciprofloxacin,
Levofloxacin,
Moxifloxacin,
Ofloxacin,
Clarithromycin,
Rifabutin,
Rifapentine
Para-Aminosalicylic acid
Thiacetazone,
Cycloserine,
Ethionamide,
Kanamycin,
Capreomycin,
Amikacin
4. First-line antitubercular drugs (standard drugs):-
Cheap
More effective
Routinely used
Less toxic
Isoniazid [Isonicotinic Acid Hydrazide (INH)]:-
• Highly effective and the most widely used first line antitubercular agent.
• Orally effective, cheapest →Tuberculocidal activity.
• Active against both intracellular and extracellular bacilli.
• Also used for chemoprophylaxis of tuberculosis
MOA:- Isoniazid inhibits the biosynthesis of mycolic acids, which are essential
constituents of the mycobacterial cell wall
5. • Pharmacokinetics:-
• Absorption:- from Gut
• Distribution:- well all over the body, tubercular cavities and body fluids like CSF
• crosses placental barrier.
• Metabolism:- live by acetylation by N-acetyl transferase
• Rate of acetylation- under genetic control(genetic variation) resulting in either rapid or
slow acetylators
• Fast acetylators:- Present in 30-40% of Indian due to high acetyl transferase activity
(t1/2-1hr.)
• Resulted → Hepatotoxicity
• Slow Acetylators:-Due to slow acetyl transferase activity (t1/2-3hr.)
• Resulted → Peripheral neuritis (Rx-Vit-B6-10mg/day)
• Excretion:- urine.
Isoniazid
(Prodrug)
Inside mycobacteria
Converted to
Active form
Inhibits the synthesis of
mycolic acid (Component of
mycobacterial cell wall)
Death of bacteria
(Tuberculocidal)
6. • Uses:-
• First-line drug for the treatment of TB.
• Chemoprophylaxis of TB.
• Adverse effects:-
1. Hepatotoxicity:- The risk of hepatic damage is more
In chronic alcoholics, older people, Rapid acetylators.
It is reversible on discontinuation of the drug
Patients receiving INH should be monitored for symptoms like anorexia, nausea,
vomiting, jaundice, etc.
2. Peripheral neuritis:- Dose-related toxicity.
Isoniazid is structurally similar to pyridoxine; hence, isoniazid competitively
interferes with utilization of pyridoxine.
It also promotes the excretion of pyridoxine.
Pyridoxine 10 mg/day is routinely given along with INH
7. • Pyridoxine 10 mg/day is routinely given along with INH to reduce the risk of
peripheral neuritis.
• It is also used for the treatment of INH induced peripheral neuritis.
3. Other side effects- Fever, skin rashes, arthralgia, anaemia, GI disturbances,
psychosis and rarely convulsions.
Interaction:-
Isoniazid ×
• Rifampin (Rifampicin):-
• Rifampicin is a semisynthetic derivative of Rifamycin-B
• First-line antitubercular drug (Tuberculocidal)
• “Sterilizing agent”-Effective against on all types of bacillary subpopulations
(Intracellular + Extracellular + Dormant bacilli)
Phenytoin,
Carbamazepine
Warfarin
INH inhibits the metabolism of those drugs
leading to ↑Cp →result in Toxicity
8. • MOA:- Rifampicin binds to bacterial DNA-dependent RNA polymerase and
inhibits RNA synthesis.
• Anti-microbial spectrum- It has bactericidal effect against mycobacteria, N.
meningitidis, H. influenzae, S. aureus, E. coli, Pseudomonas, etc.
• Pharmacokinetics:-
• Absorption- administered orally & rapidly absorbed from the GI tract
• But food→ ↓ absorption
• Distribution:- widely throughout the body including CSF
• Metabolism:- in liver (Potent Enzyme Inducer)
• Excretion:-
• Via Bile→ active deacetylated form & undergoes enterohepatic recycling
• Via Urine→ The rest of the drug
9. • USES:-
1. Tuberculosis: Treatment (Rifampicin +Isoniazide and other antitubercular
drugs)
Chemoprophylaxis of tuberculosis
2. Leprosy:- with other antileprotic drugs
3. Prophylaxis of meningococcal and H. influenzae meningitis: Rifampicin
reaches high concentration in the nasopharynx and eradicates the carrier state in
case of meningococcal and H. influenzae infections.
4. Staphylococcal infections:- Rifampicin +β-lactam antibiotics may be useful in
such as endocarditis, osteomyelitis, etc.
5. Brucellosis:- Rifampicin +doxycycline
Adverse effects:-
Hepatitis –more common in alcoholics and elderly patients
Flu-like syndrome with fever, chills, headache, muscle and joint pain
GI disturbances such as nausea, vomiting and abdominal discomfort
10. • Skin rashes, itching and flushing
• Harmlessly stains various body fluids such as urine, tears, saliva, sweat, sputum,
etc. (orange red)
• Drug interaction:-
• Rifampicin ×
• It also induces its own metabolism
Pyrazinamide is a synthetic analogue of nicotinamide
It is active in acidic pH—effective against intracellular bacilli (has sterilizing
activity)
Oral contraceptives
Oral anticoagulants,
Oral antidiabetic drugs,
HIV protease inhibitors and non-nucleoside
reverse transcriptase inhibitors (NNRTIs)
Therapeutic failure
↓Cp of those drugs
Pyrazinamide
11. • It has tuberculocidal activity.
• MOA:-Inhibits mycobacterial mycolic acid biosynthesis but by a different
mechanism.
• Pharmacokinetics:-
• Absorption:-well from GI tract after oral administration
• Distribution:- widely throughout the body including the CSF.
• Metabolism:- liver
• Excretion- in urine
• Side effects:-
• Hepatotoxicity:- dose-dependent
• Hyperurecemia- due to inhibition of excretion of UA from kidney
• Other side effects include- Arthralgia, Flushing, Fever
12. Ethambutol
First-line antitubercular drug
It is a bacteriostatic drug
Effective against-Both Intracellular & Extracellular bacilli
MOA:- Inhibits incorporation of mycolic acid into bacterial cell wall by
inhibiting arabinosyl transferase
Pharmacokinetics:-
Absorption:- well absorbed (80%) after oral administration
Distribution:- widely in the body including CSF & cross BBB in meningitis
Metabolism:- in liver
Excretion:-in urine.
• USES:- with other anti-Tb drugs prevent development of resistance.
• SE:- Optic neuritis-↓visual acuity and color-vision defects (red–green)
13. • # Periodic eye examination is necessary when the patient is on ethambutol
• Side effect can be→ reversible upon discontinuation of treatment early following
onset of symptoms.
• Avoided in children→ below 6 years of age because they may not be able to
report the disturbances in the vision, and it is also difficult to test visual acuity in
children.
• Hyperuricaemia→ ↓clearance of urates.
• Other side effects→ are nausea, vomiting, abdominal pain, skin rashes, itching
and joint pain.
• Aminoglycoside antibiotic with tuberculocidal
• Effective against only extracellular bacilli →due to poor penetration
• Not effective orally-(Administered-I.M.)
• Effective against-M.Kansasii & M.Avium intracellulare
Streptomycin
14. • Lower margin of safety due to ototoxicity, Nephrotoxicity but not Hepatotoxicity
• Due to lower margin of safety → reserve as first line drug in life threatening Tb
or if any 1st line drug is contraindicated
•Second-line Antitubercular Agents:-
• They are less effective, more costly and more toxic than the first-line drugs; hence,
they are reserve drugs for tuberculosis.
• Use in case of resistance to 1st line agents
• Effective against-Atypical strain of mycobacterium
• Para-aminosalicylic Acid (PAS):-
• Structural Analogue of PABA similar to sulphonamides
• MOA:-Ccompetitively inhibits folate synthetase enzyme and produces
tuberculostatic effect (Least potent)
• USE:-Reserve drug for the management of MDR-tuberculosis
• SE:-Anorexia, Nausea, Epigastric pain, skin rashes, fever, hepatitis
15. • Ethionamide:-
• It is structurally similar to INH but is less efficacious (Tuberculostatic drug)
• Cross resistance between INH & ethionamide occurs
• MOA:-It inhibits synthesis of mycolic acids
• SE:-Nausea, vomiting and epigastric pain.
• Other side effects are hepatitis, headache, blurred vision and paraesthesia
• Cycloserine:-
• It is a second-line antitubercular drug with Tuberculostatic activity.
• It inhibits bacterial cell wall synthesis.
• Uses:-treatment of renal tuberculosis (As significantly excreted through kidney)
• SE:-headache, tremor, psychosis and convulsions, peripheral neuropathy
(prevented by Vit-B6)
• Kanamycin→ for streptomycin resistant mycobacterial tuberculosis but
availability of least toxic drugs like Amikacin has made it absolute
16. • Amikacin-used for streptomycin resistant or MDR-TB(chance of developing
resistance is less)
• Also effective for Atypical mycobacterium
• No cross resistance→ between streptomycin & Amikacin
• Capreomycin:- Tuberculocidal effective against MDR-TB & Atypical
mycobacterium
• Poorly absorbed from GIT→ administered I.M.
• SE:- nephrotoxicity and ototoxicity similar to aminoglycosides
• Other Antitubercular Agents:
• Fluoroquinolones:- Ciprofloxacin, moxifloxacin and levofloxacin
• Bactericidal agents → given orally
• USE:-
• TB in HIV infected pt.→ as combined regimen
• MDR-TB & MAC:- Due to better tolerability & good penetration
17. • Macrolides:-
• Azithromycin and clarithromycin—given orally.
• Treatment of MAC- along with ethambutol & rifabutin
• In TB with HIV infected pt.→ Azithromycin(doesn’t interact with drugs used to
treat HIV)
• Rifamycins: Rifapentine and rifabutin—bactericidal agents, given orally
• Rifabutin:- It is a derivative of rifampicin with longer duration & less interaction
profile
• USES:-
• Treatment of tuberculosis in HIV- with patients on protease inhibitors (PIs) as
rifabutin is a less potent enzyme inducer.
• MAC infection:- in combination with clarithromycin and ethambutol.
• Rifapentine-analogue of rifampin
18. Treatment of Tuberculosis:-
WHO recommends the use of multi-drug therapy (MDT) for all cases of tuberculosis
Objective:-
To make the patient non-infectious as early as possible by using 3 to 4 bactericidal
drugs
To prevent the development of drug-resistant bacilli
To prevent relapse
To reduce the total duration of effective therapy
Short-course chemotherapy:-
There are several short-course regimens of 6–9-months duration, which are
convenient, highly effective and less toxic.
All regimens have two phases—
Intensive phase:- 2–3 months followed by
Continuation phase:- 4–6 months
20. WHO-recommended Treatment Regimens:-
Directly observed treatment short course’ (DOTS) protocol
RNTCP-Revised National Tuberculosis Control Programme (RNTCP) was launched in India in
1997
Category Intensive phase Continuous phase Duration Comment
I
New Patient
2 HRZE Daily 4 HR Daily 6 OPTIMAL
2 HRZE Daily 4 H3R3 6 Acceptable if DOT ensured
2 H3R3Z3E3 4 H3R3 6 Acceptable if DOT ensured , and no
HIV or its risk
II
Previously
treated patients
pending DST
result
2 HRZES Daily
+
1 HRZE daily
5 HRE Daily 8 For patient with low/medium risk of
MDR-TB (failure, default)
Empirical
(standardized)
MDR- regimen
Empirical
(standardized)
18-24 or till
DST result
For patient with high risk of MDR-
TB (failure, 2nd default, contact of
MDR TB)
21.
22. Multidrug resistant (MDR)-TB:-
When bacilli is resistant to Isoniazide, rifampicin, with or without resistant to
other drug.
Common cause:-
Irregular consumption
frequent interruption in taking treatment,
Irrational treatment for TB are the most common cause
Treatment:-
Intensive phase (6-9 month) – 6 drugs use
• Kanamycin, levofloxacin, ethionamide, pyrazinamide, Ethambutol, cycloserine
Continuation phase:-(18 month)- 4 drugs
• Levofloxacin, ethionamide, ethambutol, cycloserine
23. Extensively drug resistant TB(XDR-TB):-
Subset of MDR-TB
Bacilli is resistant to isoniazide, rifampicin & fluroquinolones + any 1 of -2nd
line injectable drugs like (kanamycin, capreomycin or amikacin)
TB Treatment in HIV Patients:-
Generally, TB treatment is the same for HIV-infected as for non-HIV-infected TB
patients.
Short-course chemotherapy must be started, once TB is diagnosed.
Rifabutin→ Preferred over rifampicin in HIV (No interaction with protease
inhibitors which is Anti-retroviral drug )
24. • Women on OC pills:-
• Rifampicin × OCP (↑ metabolism, leading to ↓ efficiency )
• In pregnancy:- Contraindicated streptomycin
• 2HRE daily+7HR daily × 9 month (IND)
• In renal failure:- HRZ safely given as they excreted by entero-hepatic
circulation.
• Dose of Streptomycin, ethambutol should be adjusted according to the
creatinine level.
• MAC (Mycobacterium Avium complex):-
• Infection in immunocompromised pt. by M.avium + M.intracellulare
(opportunistic pathogen)
• Intensive phase of 2–6 months
• Maintenance phase for at least 12 months
25. • Intensive phase:-
1. Clarithromycin 500 mg BD or Azithromycin 500 mg OD
2. Ethambutol 1000 mg (15 mg/kg) per day
3. Rilabutin 300 mg per day
+
with any one
Ciprofloxacin 500 mg BD /Levofloxacin 500 mg OD/ Moxifloxacin 400 mg OD
Maintenance phase:-
1. Clarithromycin/Azithromycin
2. Ethambutol/Rifabutin/One fluoroquinolone
Regimen for treatment of MAC infection
26. Role of Glucocorticoids in Tuberculosis
• Glucocorticoids relative contraindicated→ especially intestinal Tb (cause
perforation)
• USE:- Certain situations with effective antitubercular therapy
Tuberculosis of serous membranes (pleura, pericardium, meninges, etc.)
Tuberculosis of the eye, larynx
Severe pulmonary TB-seriously ill pt.
To treat hypersensitivity reactions to antitubercular drugs
• Drug- Prednisolone is the preferred agent,
• Exception- Meningitis (dexamethasone is preferred →lacks mineralocorticoid
activity)
27. Question paper discussion
1. Comment on the following combinations:- (3M)
• Pyridoxine(Vit-B6) with isoniazid
2.Discuss the rational for use of:- (4M)
• Triple drug therapy for pulmonary tuberculosis
3.Discuss the Pharmcological basis for the use of :- (4M)
• Multidrug treatment in tuberculosis
4. Write uses & Adverse effects of :- (2.5M)
• Rifampicin
5. Discuss the following in detail: - Anti tubercular drug (4M)
6. Discuss drug treatment of :- Paucibacillary leprosy (4M)
28. • Leprosy→ chronic infectious stigmatized disease caused by Mycobacterium
leprae, which is an acid-fast bacillus
• Types:-
1. Paucibacillary leprosy (PBL):- less than 5 skin lesions
The patient has few bacilli but negative skin smear at all sites
It’s 3 types-
A.TT(Tuberculoid Type):- large flat skin lesion which is painless,
Hypopigmentation & Hairless
B.BT (Borderline tuberculoid):-
C.IT(Intermediate Type):-
2.Multibacillary Leprosy:- More than 5 skin lesions with Positive skin smear at all
sites.Patient has more lepra bacilli in skin lesions hence multibacillary.
Anti-leprotic drugs
29. • Types:-
• BB:-Boarderline
• BL-Boarderline Lepromatous
• LL-Lepromatous Leprosy:-loss of Cell medicated immunity with stuffy nose.
Drugs used for the treatment of leprosy:-
1. Dapsone (Diamino-diphenylsulfone, DDS),
2. Clofazimine
3. Anti-tubercular drugs-Rifampicin, ethionamide,
4. Others Antibiotics:-ofloxacin, Minocycline and clarithromycin
Dapsone:-
Leprostatic, a sulfone, is the oldest, cheapest and most widely used agent for the
treatment of leprosy
Chemical structure & mechanism of Action→ similar to Sulfonamides
30. • MOA:-Lepra bacilli utilize PABA→ synthesis of folic acid for growth and
multiplication.
• Dapsone is structurally similar to PABA
• competitively inhibits folate synthetase enzyme
& prevents the formation of
tetrahydrofolic acid (THFA)→leprostatic drug
Pharmacokinetics:-
Absorption-Completely absorbed after oral administration
Distribution-Widely distributed, retained in skin, muscle, liver & kidney
Metabolism-by liver(Acetylation)
Excretion-Enterohepatic circulation (T1/2-24hr.)
(Leprostatic effect)
31. • USES:-
Leprosy:- Treatment of Multibacillary leprosy & Paucibacillary leprosy along
with other drugs
In chloroquine resistant malaria→ Dapsone+ Pyrimethamine
DOC-Dermatitis herpetiformis
In Pneumocystosis jiroveci infection in AIDS
Side effect:-
GIT irritation, Fever, Skin rash,
Haemolytic anaemia in G-6-PD deficiency,
Methemoglobinemia,
Agranulocytosis,
Hepatitis, Peripheral neuropathy
Lepra Reaction/Sulfone syndrome:-These are immunologically mediated
reactions that occur during the course of the disease.
32. • The exact cause of such reactions is not clear and is usually precipitated by
infection, trauma, mental stress, etc.
• Types:-
• Type-1 lepra reaction (reversal reaction):-
• Delayed type of hypersensitivity reaction →seen in patient with tuberculoid
leprosy(TT)
• Occur after the initiation of therapy
• Nerves are frequently affected
• There are signs of inflammation in the existing skin lesions—they become red,
warm and swollen
• Rx-Clofazimine & Prednisolone
• Type-2 Lepra reaction [erythema nodosum leprosum (ENL)]:-
• Type-III hypersensitivity reaction (due to release of antigen from the dying lepra
bacilli)→ seen in patient with lepromatous leprosy
33. • There is erythema nodosum—red, painful, tender cutaneous and subcutaneous
nodules with fever
• Nerves may be affected.
• The type-2 reaction may be due to release of antigen from the dying lepra bacilli.
Rx-
• Thalidomide, (Except-pregnancy), Aspirin, clofazimine, chloroquine, prednisolone.
• Clofazimine:-
• It’s a dye with leprostatic as well as anti-inflammatory action
• MOA:-Clofazimine binds to mycobacterial DNA to inhibit its template function
• Well absorbed by oral route(fatty meal→↑absorption)
• It accumulates in tissues—t/2 is 70 days
• USE:-Multidrug therapy of multibacillary-along with other drugs
• Treatment of type-2 lepra reaction-due to anti-inflammatory action
34. • Use in chronic skin ulcer (Buruli ulcer cause by M. ulcerans)
• Side effect:-
• Skin- reddish–black discolouration of the skin on exposed parts.
• It can cause pigmentation of the conjunctiva and Cornea, discolouration of the
hair, tears, sweat, urine, etc.
• Nausea, vomiting, diarrhoea, and abdominal pain are its other side effects.
• Rifampicin:-
• most effective and rapidly acting bactericidal drug for lepra bacilli; it kills most of
the bacilli
• Prevent development of resistance to dapsone
• Ethionamide-it has significant antileprotic action but cause hepatotoxicity
• Other antibiotics:-
• Ofloxacin:-alternative to rifampicin(dose-400mg OD)
35. • Clarithromycin-only macrolide with significant anti-leprotic action
• Minocycline:- Due to high lipophilicity this tetracycline is effective (M. leprae)
• Treatment According to WHO:-
• Objective:-WHO recommends the use of MDT for all leprosy cases
1. To make the patient noncontagious as early as possible by killing the dividing
bacilli.
2. To prevent the development of drug-resistant bacilli.
3. To prevent relapse.
4. To shorten the duration of effective therapy
Treatment Schedules of Leprosy:-
All drugs are administered orally
36. Drug Dose Frequency Comment
Rifampicin 600mg Once monthly Supervised
Dapsone 100mg One daily Self-administered
Clofazimine 300mg Once monthly Supervised
Clofazimine 50mg Once daily Self-administered
1. For multibacillary leprosy (LL, BL and BB):-
1-Year
Followed up for a period of
3–5 years
# If Clofazimine is unacceptable, the alternative drug
→Ethionamide 250 mg daily, unsupervised.
2. For paucibacillary leprosy (TT, BT and I):-
Drug Dose Frequency Comment
Rifampicin 600mg Once monthly Supervised
Dapsone 100mg One daily Self-administered
6-Month
Followed up for a period of 1–2 years
