You can find out detailed chemotherapy of TB and Leprosy

1. MYCOBACTERIAL
INFECTIONS (TB &
LEPROSY)
By:
Kavya M
Assistant Professor
Dept. of Pharmacology
KLE College of Pharmacy, Bengaluru

2.  The main mycobacterial infections in humans are
Tuberculosis & leprosy
 Both are typically chronic infections
 Caused by Mycobacterium tuberculosis & M. leprae
respectively

3.  TB most imp communicable disease in the world
 1/3 rd of world’s population is infected with M.tuberculosis
 Some are at high risk for TB include HIV-infected patients,
Immigrants from countries, Homeless, Health care
professionals, persons taking immunosuppressive agents

4.  Concepts in the treatment of TB:-
• Mycobacteria are slow growing intracellular organisms
• They remain dormant but viable & capable of causing
disease
• Required to administer multidrug in a combination
• For extended periods
• To achieve effective therapy & to prevent emergence of
resistance

5.  3 basic considerations in TB treatment :-
 Regimen must contain multiple drugs to which the organism
is susceptible
 Drugs must be taken regularly
 Drug therapy must continue for a sufficient time

6.  Classification of Anti-TB drugs:-
First line drugs:
Isoniazid ( H)
Rifampicin (R)
Ethambutol (E)
Pyrazinamide ( Z)
Streptomycin ( S) now reserved drug in first line
• These drugs are superior in efficacy
• Possess an acceptable degree of toxicity
• Most of the patients with TB can be used routinely & treated
successfully

7. Second line drugs:
Thiacetazone (Tzn)
Para aminosalicylic acid
(PAS)
Ethionamide ( Etm)
Kanamycin (Kmc)
Cycloserine (Cys)
Amikacin (Am)
Capreomycin (Cpr)
Newer Second Line drugs:
Ciprofloxacin
Ofloxacin
Levofloxacin
Clarithromycin
Azithromycin
Rifabutin
• More toxic & less effective
• Indicated only when M. tuberculosis organisms are resistant
to 1st line agents
• Used only in special circumstances

8. MYCOBACTERIAL CELL WALL
Baron S (ed.) Medical Microbiology. 4th edition. Chapter 33

9.  First line drugs:-
 Isoniazid:- most active drug for the treatment of TB & is the
cheapest drug
MOA:
 Inhibit synthesis of mycolic acid ( unique fatty acid
component of mycobacterial cell wall)
 INH enters the bacilli by passive diffusion
 It must be activated to become toxic to bacilli
 Activated by Kat G (Catalase - peroxidase, a mycobacterial
enzyme)

10.  INH to Isonicotinoyl radical
 Which subsequently inter-acts with mycobacterial NAD &
NADP to produce dozen of adducts
 One of these, a nicotinoyl NAD isomer which ↓ the activity
of enoyl acyl carrier protein reductase (Inh A) & β-
ketoacyl carrier protein synthase ( Kas A)
 Inhibition of these enzymes↓ the synthesis of mycolic acid
 An essential component of the mycobacterial cell wall &
causes cell death

11. SPECTRUM OF ACTIVITY:-
 Bactericidal for rapidly dividing organisms
 Bacteriostatic for bacilli in stationary phase
 Effective against both intracellular (within macrophage) &
extracellular
 Equally active in acidic & alkaline medium
 Atypical mycobacteria (MAC, M. kansasii) are not inhibited
by INH

12. MOR:-
 Mutations in catalase-peroxidase (Kat-G) enzyme
 Missense mutation related to inhA gene
 P.K.s:-
 A:- well absorbed, food impairs absorption (particularly
carbohydrates & Al containing antacids)
 D:- well diffused into all body fluids, cells & caseous material
also in CSF. Readily penetrates host cells & effective against
bacilli growing intracellularly
 M:- acetylation & hydrolysis
 E:- Glomerular filtration

13. ADES:-
• Related to dose & duration of therapy
• Hepatitis, peripheral neuropathy
• Burning sensation, pricking or numbness in the limbs-
burning feet is v common complaint
• Peripheral neuropathy is probably due to a deficiency of
pyridoxine (Vit.B6)
• Because INH treatment increases urinary excretion of the
vitamin
• Therefore Vit.B6 (small dose, 6mg/day) administration
prevent development of toxic changes in the nerves
• Otherwise it will antagonizes INH action

14. • Other ADEs optic neuritis, convulsions, rashes & fever
 DIs:-
 High INH plasma levels inhibit phenytoin metabolism &
increases its toxicity

15.  Rifampicin:- it is a semisynthetic macrocyclic antibiotic
 Obtained from Streptomyces mediterranei
 it is bactericidal for both intracellular & extracellular
organisms
 MOA: blocks transcription by interacting with β-subunit of
bacterial but not human DNA-dependent RNA polymerase
 Thereby inhibits RNA synthesis by suppressing the initiation step
 MOR: point mutation or deletion in rpoB gene codes for β-subunit
of RNA polymerase, thereby prevents binding of RNA polymerase

17. ANTIMICROBIAL SPECTRUM:-
 Bactericidal for both intra & extracellular org.
 Also for Mycobacteria M. kansasii
 Effective against many gram +ve & gram-ve org.
 Also used as Anti-leprotic drug
 Rifabutin, analogue of Rifampicin active against MAC but
less active against tuberculosis

18. o P.K.s:-
 A: Well absorbed orally
 D: widely distributed in the body , penetrate cavities ,
caseous mass, placenta & meninges
 M: Metabolized in liver (hepatic mixed function oxidase)
 E: Excreted mainly in bile & some in urine
 t½- 2-5 hrs
 Urine & feces as well as other secretions have an orange-
red colour; patient should be forewarned

19. ADVERSE EFFECTS:-
 GI disturbances & nervous system symptoms (Nausea,
Vomiting, Head ache, Dizziness & Fatigue)
 Hepatitis (increased if it is combined with INH)
 Hypersensitivity reactions pruritis, cutaneous vasculitis,
thrombocytopenia
o DIs:
 It is a CYP450 inducer, therefore high dose requirements is
necessary with the drugs which undergoes metabolism by
this enzyme

20.  Pyrazinamide:- analogue of Nicotinamide
 Synthetic, orally effective, bactericidal, anti-TB agent used in
combination of INH & R
 Bactericidal to dividing, only intracellular (acidic
environment) bacteria
 MOA:- exact mechanism is not known
 It appears to target the mycobacterial fattyacid synthase
(FAS)
 Which involves in mycolic acid biosynthesis
 Prior activation into Pyrazinoic acid is necessary by
pyrazinamidase (Mycobacterial enzyme)

21.  MOR:
• Mutation in the gene that encodes for pyrazinamidase
 P.K.s:-
• Well absorbed from GIT
• Widely distributed
• In liver
• Renal glomerular filtration
 ADEs:- hepatotoxicity, hyperuricemia, acute gouty arthritis
• Nausea, vomiting, anorexia, drug fever, malaise
• CI in prenacy

22.  Ethambutol:- water soluble drug
 Acts by inhibiting “Arabinosyl transferase” enzyme which
involved in cell wall biosynthesis (bacteriostatic)
 M. tuberculosis, M. kansasii & most strains of MAC sensitive
to Ethambutol
 Active against intra & extracellular organisms
 MOR:- point mutation in the gene that codes for Arabinosyl
transferase enzyme

23.  P.K.s:-
• Well absorbed, widely distributed in all body fluids including
CSF
• Excreted through urine
 ADEs:- not hepatotoxic, optic neuritis & red-green
discrimination (dose related effect)
• Mild GI intolerance, allergic reaction, fever, dizziness &
mental confusion
• Hyperuricemia, gouty arthritis

24.  Streptomycin:- bactericidal but inactive against intracellular
organisms
 MOA: inhibits protein synthesis (initiation complex)
 MOR: point mutation with gene that encodes for ribosomal
proteins & binding sites
 ADEs: not hepatotoxic but causes ototoxicity,
nephrotoxicity
 CI in pregnancy

25. DRUG ACTION HEPATOTOXI
C
BACTERIA
INHIBITED
H Cidal Yes Both
R Cidal Yes Both
Z Cidal Yes Intracellular
E Static No Both
S Cidal No Extracellular

26. MOA OF 1ST LINE DRUGS
Mycolic Acid
Arabinogalactan
Peptidoglycan
Cell membrane
R
I
B
O
S
O
M
e
Protein
Isoniazid
-
Pyrazinamide
- Mitochondria
(ATP)
- Rifampin
-
Ethambutol
-
Streptomycin
- Cytoplasm

27.  SECOND LINE DRUGS:-
 PAS: structural analogue of PABA
 Therefore interferes with incorporation of PABA into folic acid
except CSF
 Readily absorbed from GIT & widely distributed
 Undergoes metabolism through acetylation (SLE)
 Crystal urea, poor compliance due to GI intolerance & lupus
like reaction

28.  Ethionamide: derivative of Isonicotinic acid & is chemically
related to INH
 Bacteriostatic
 Exact MOA is not known but it is believed to be involve inhibition
of oxygen-dependent mycolic acid synthesis
 Mutation of inhA gene involved in mycolic acid synthesis offers
resistance
 Well absorbed, distributed including CSF
 GI disturbances, nausea, vomiting, intense gastric irritation
 Neurological effects like confusion, psychosis, peripheral
neuropathy (Vit B6), seizures
 Rare ADEs: Gynaecomastia, impotence, postural hypotension

29.  Cycloserine: competitively inhibit D-alanine racemase & D-
alanine ligase
 Used in MDR-TB also in renal tuberculosis (because most of
the drug is excreted unchanged in urine)
 Readily absorbed orally & distributes throughout the body
also CSF
 Rifabutin: as effective as R in drug-susceptible TB & used
in latent TB infection either alone or in combination
 ADEs: GI intolerance, rash, neutropenia, polymyalgia
syndrome
 yellowish-tan discoluration of skin (pseudo jaundice)
 Hepatitis, ornge-red discolouration of body fluids

30.  Capreomycin: injectable polypeptide obtained from
S.capreolus
 Act by inhibiting protein synthesis
 Bacteriostatic against M.tuberculosis
 Reserved for MDR-TB
 Carefully monitored to prevent nephrotoxicity & ototoxicity
 Macrolides: limited activity against M.tuberculosis
 Clofazimine: primarily used against M. leprae & MAC

31.  Thioacetazone: active against many starins of
M.tuberculosis
 But not marketed in U.S.
 Because of its low cost, used as 1st line agent in East-Africa
(in combination with INH)
 ADEs: GI intolerance, rashes
 Ototoxicity (specially when co-administered with
Streptomycin)
 Bone marrow suppression (CI in HIV patients)
 Life threatening hypersensitivity reactions such as hepatitis,
transient marrow aplastic syndrome, neutropenia &
thrombocytopenia

32.  Quinolones: ciprofloxacin, levofloxacin, ofloxacin
 These Qs have activity against M.tuberculosis & MAC
 They inhibit 90% of strains of susceptible tubercula bacilli at
conc. Less than 2 μg/ml
 MOA: act by inhibiting bacterial DNA-gyrase
 MOR: spontaneous mutations in gene that changes DNA
gyrase or reduced permeability
 Therefore, these Qs are imp recent additions to therapeutic
agents used in TB specially MDR strains
 Kanamycin, Amikacin are injectable AGs used in MDR TB

33.  Treatment of Tuberculosis:-
o Goals of anti-tubercular chemotherapy
 Kill dividing bacilli: Patient is non-contagious :
transmission of TB is interrupted.
 Kill persisting bacilli: To effect cure and prevent relapse.
 Prevent emergence of resistance: so that the bacilli
remain susceptible to the drugs.

34.  To treat massive infections at least 3 drugs & a single drug
is sufficient for prophylaxis
 H & R are most efficacious drugs ,their
combination is synergistic, therefore duration of therapy is
shortened from>12 months to 9 months

35. Directly observed treatment, Short course regimen
(DOTS)-
• Regimen of 6-9 months treatment
• In 1997 WHO framed clear cut guidelines for different
category of TB treatment .
• All regimen have initial intensive phase 2-3 months to
rapidly kill the TB bacilli & bring sputum conversion & afford
symptomatic relief
• Followed by continuation phase last for 4-6 months for
elementary remaining bacilli

36.  1st Initial phase: 2 months consisting of 3 drugs used
concomitantly [(H+R+Z)+E]
 2nd Continuation phase: 4 months consisting of 2 drugs
[H+R]
 Treatment of TB divided into 4 categories (1997
guidelines) according to:
 Site of disease (pulmonary or extrapulmonary) and its
severity
 Sputum smear positivity/ negativity: positive cases are
infectious and high mortality
 History of previous treatment: risk of drug resistance is more
in irregularly treated patients

37.  Category I: New case of sputum smear positive or severe
pulmonary TB, or severe forms of extrapulmonary TB
 Category II: Defaulted, irregularly treated and relapse cases
 Category III: New sputum smear negative pulmonary TB and
less severe forms of extrapulmonary TB
 Category IV: Chronic cases who remained or again became
sputum smear positive after receiving fully supervised
category II treatment

38.  New guideline with revised categorization of patients brought
out in 2010.
 According to these, category III has been merged with
category I and patients of TB are now classified only as “New
cases” or “Previously treated” patients
 Drug resistant including MDR-TB

40.  MDR-TB (Multi Drug Resistant-TB):- defined as resistance
to both H and R, and may be any number of other (1st line)
drug(s).
 Its treatment requires complex multiple 2nd line drug
regimens which are more expensive and toxic.
 In India MDR-TB accounts for 2.8% of all new TB cases and
12-17% of retreatment cases.
 As per the WHO India has the highest number of MDR-TB
cases in South- East Asia.

41.  RNTCP initiated DOTS-Plus programme and it is revised in
2010, to treat MDR-TB cases
 Treatment regimen is as follows:
 6 drugs intensive phase for 6-9 months
 4 drugs continuation phase of 18 months

42.  XDR-TB (Extensively drug-resistant TB):- these are MDR-
TB cases that are also resistant to FQs as well as one of the
injectable 2nd line drugs and may be any number of other
drugs.
 Therefore, the bacilli are resistant to at least 4 most effective
cidal drugs (H,R,FQs and one of Km/Am/Cm)
 In case XDR-TB to prevent further amplification of resistance
the MDR regimen must be immediately stopped
 Drugs with unclear efficacy like thiacetazone, clarithromycin,
clofazimine, linezolid, amoxicillin, imipenem can be given

43. ANTI-LEPROTIC DRUGS

44.  Leprosy caused by M. leprae, chronic, curable infectious
disease mainly causing skin lesion and nerve damage
 Drugs: Dapsone (Sulfone), Clofazimine (Phenazine
derivative), Rifampin, Ethionamide (Anti-TB drugs),
Ofloxacin, Moxifloxacin, Minocycline, Clarithromycin (other
antibiotics)
 Dapsone (DDS: diamino diphenyl sulfone):
 It is chemically related to sulphonamides (same MOA)
 Inhibits incorporation of PABA into folic acid by folate
synthase
 Also used in the treatment of malaria in combination with
pyrimethamine

45.  It is leprostatic at very low conc. But effective at higher
concentration
 MOR: mutation to folate synthase
 However peak serum conc. Of dapsone after 100mg/day dose
exceeds MIC for M.leprae by nearly 500 times, it continues to be
active against low to moderately resistant bacilli
 P.Ks:
 A: completely absorbed after oral administration
 D: widely distributed (CSF penetration is poor), concentrated in
skin, muscle, liver and kidney, t1/2 >24 hrs
 M: acetylation also glucuronidation, sulfate conjugation
 E: in bile

46.  ADEs:
 Mild haemolytic anaemia (more with G6PD deficient patients)
 Gastric intolerance: nausea, anorexia
 Methaemoglobinaemia, headache, drug fever
 Allergic rashes, hypermelanosis, phototoxicity
 Sulfone syndrome: it is the reaction which develops 4-6 weeks
after starting dapsone treatment
 Characterised by fever, malaise, lymph node enlargement,
desquamation of skin, jaundice, anaemia
 Generally seen in malnourished patients
 Treatment: stopping dapsone and instituting corticosteroid
therapy along with supportive measures

47.  Clofazimine: it is a dye with leprostatic and ant-inflammatory
properties
 MOA: Interference with template function of DNA in M.leprae
 Alteration of memb. Str. And its transport function
 Disruption of mitochondrial electron transport chain
 It is orally active, accumulates in macrophage and get deposited
in tissues like subcutaneous fat
 Its entry in CSF is poor
 T1/2 is 70 days
 Used as a component in MDT of leprosy
 ADEs: reddish-black discolouration of skin, dryness and itching,
nausea, anorexia, weight loss
 CI in early pregnancy, liver & kidney damage patients

48.  Rifampin: most potent cidal drug for M.leprae
 Renders patients noncontagious
 99.9% of M.leprae are killed in 3-7 days by 600mg/day dose
 Suggested to use in MDT
 Ofloxacin: many FQs are highly active against M.leprae
 Used as a component of MDT
 99.9% of M.leprae are killed by 22 daily doses (400mg/day)
of ofloxacin monotherapy
 Minocycline: because of its lipophilicity penetrates into
M.leprae
 A dose of 100mg/day produces peak blood levels that
exceed MIC against M.leprae by 10-20 times

49.  Treatment of leprosy:-
 Leprosy is a granulomatous infection caused by M.leprae
 Primarily affecting skin, mucous memb., nerves
 In India the National Leprosy Control Programme was
launched in 1955
 But in 1982, it was changed to National Leprosy Eradication
Programme (NLEP)
 India introduced MDT for leprosy and achieved elimination
of leprosy as a public health problem in 2005

50.  There 2 main types of leprosy:-
 For operational purpose WHO divides leprosy into:

51.  Multidrug therapy (MDT) of leprosy:-
 Advantages of MDT:
 Effective in cases with primary dapsone resistance
 Prevents emergence of dapsone resistance
 Affords quick symptom relief and renders MBL cases
noncontagious within few days
 Reduces total duration of therapy

53. THANK YOU