Anti TB Drugs 2

By

Prof Saadia Shahzad Alam

Pakistan: annual incidence of TB =259/100,000 adds about 420,000 new

cases annually (Pak Population 2021= 231.4 million ),Mortality 20/100,
 Selection of Chemotherapeutic
Regimen
• First line Drugs: INH(H), rifampicin(R),streptomycin(S), pyrazinamide(Z) are the four
bactericidal ATT preferred for initial intensive therapy.
• For short course therapy (6m(2+4)-9m(2+7) unable to take(Z)(H+R w/w/o E/S)
• Delay the development of acquired resistance and prolong effective therapy
• Eliminate persisters
• Shorten the course of therapy
• Reduce Adverse Drug Reactions
• Fixed Dose Combinations(FDC) like Myrin P Used
• Reduction in number of pills to be used
• Improvement in drug compliance
• Convenience in Mass treatment of population
Initial intensive phase(2m) most tubercle bacilli are killed patient becomes non infectious
(4m)Continuation or sterilizing phase necessary to eliminate persisters and reduce failure.
 Tuberculosis

Drugs given half an hour before breakfast.

DOT (Direct Observation of Therapy)of every dose of treatment in the
initial intensive phase of therapy and at least first dose of the week in
the continuation phase of treatment
Pyrazinamide(Z)
• Related to thiosemicarbazones and nicotinamide, effective in M.tuberculosis
resistant to INH but ineffective against bovine and atypical forms of tubercle
bacillus.
• Bactericidal,effective against tubercle bacillus within macrophages(Intracellular
effect)
• Good meningeal penetration
• In combination with streptomycin,INH,rifampicin, pyrazinamide exerts a potent
sterilizing effect on the tuberculous lesions in the first 2 months of therapy. MOA:
Pro drug converted to pyrazinoic acid inhibits bacterial synthesis of mycolic acid
Pyrazinamide(Z)
Absorption,fate,excretion
• Rapidly absorbed from GIT.
• Peak level in 1-3 hrs and can be detected in plasma upto 15hrs.
• Widely distributed in body and CSF
• Deaminated in liver
• Degradation products and free drug excreted in urine
Pyrazinamide(Z) Adverse reactions
• 1. Metallic taste and sulphurous eructations
• Anorexia,nausea ,vomiting
• Malaise,arthralgia,mild skin rashes
• Rarely photosensitivity resulting in bright red brown discoloration of
exposed parts of the body
• Severe hepatotoxicity can occur at any time during treatment and is
not dose related. Therefore drug is contraindicated in presence of
hepatic insufficiency
Ethambutol(E)
• Ethambutol is a dextrorotatory isomer of 2,2 ethylenediamine-di-L-butanol. The
levorotatoryform is inactive against mycobacteria but is equally toxic.
• Effective orally against mycobacteria resistant to INH,streptomycin and
ethionamide and many atypical mycobacteria
• Bacteriostatic
• Primary resistance to ethambutol not reported
• When used in combination,bacterial resistance to other drugs is greatly delayed
Ethambutol (E) MOA
• Acts mainly against rapidly multiplying organisms in walls of cavities.
• Inhibits the synthesis of bacterial cell wall arabinosyl transferase. embCABoperon.
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
products or within the embBstructural gene
Absorption.fate,excretion
• Nearly 70% absorbed after oral administration.
• Penetrates into erythrocytes which act as depot from which drug is released into
circulation.
• Does not persist in other tissues and body fluids
• CSF level is only 50% of plasma level
• 50% of oral dose excreted unchanged in urine.15% excreted in two
metabolites.Accumulates in poor renal function
Ethambutol(E) Adverse Reactions
• Retrobulbar Optic neuritis on prolonged therapy. The early symptoms are blurring
and haziness
• Progressive decrease in visual acuity
• Contraction of visual fields
• Central scotomas
• Poor colour discrimination, particularly loss of ability to see green.
• Symptoms disappear when drug is discontinued15mg/kg/day.
• Should be avoided under 8 years because of difficulty in identifying early reduction
in visual acuity
• Test for visual acuity before and after treatment
• Nausea,anorexia,confusion,headache and allergic reactions
Learning Objectives
• To understand why , when Second line and 3rd line T.B Drugs are
administered
• To state the response indicators for chemotherapy
• To outline the treatment of MDR and XDR TB
• To state the categorization of TB patients and their treatment as per
the National Tuberculosis Program of Pakistan ,Community Based TB
Care (DOTS)
Second line Drugs
• Majority of these are less effective and more toxic than the first drugs. Need to be given daily.
Streptomycin(S).Aminoglycoside
• It is not absorbed orally and administered intramuscularly. Injection is painful
• It is bactericidal
• Does not penetrate macrophages and caseous material
• Concentration in CSF is poor
• Much more toxic than INH and rifampicin.
• Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are the most common
adverse effects and may be permanent
• Streptomycin is Nephrotoxic should be given with caution in elderly0.75g daily.
• Avoid in patients with known renal insufficiency.
• Kanamycin and amikacin ,bactericidal and active against mycobacteria resistant
streptomycin,INH and cycloserine
• Capreomycin obtained from streptomycin
carpreolus,polypeptide,soluble in water .
• Bactericidal
• In vitro activity half of streptomycin but effective against
mycobacteria resistant to standard agents.
• Resistance to it occurs slowly
• MOA, pharmacokinetics and adverse reactions are similar to
streptomycin,including nephrotoxicity
Fluoroquinolones
• Ciprofloxacin, ofloxacin, levofloxacin,moxifloxacin are active against
M.tuberculosis even those resistant to other drugs
• Oral or I.V bactericidal
• Readily penetrate macrophages
• Levofloxacin,moxifloxacin and ofloxacin have long elimination half
lives given once daily
• Used for M.tuberculosis and Mycobacterium avium complex. Non
tuberculous mycobacterial infections resistant to first line drugs.
Ethionamide
• Structurally related to INH with same mechanism of action
• Effective against tubercle bacilli resistant to other drigs and effective
against atypical mycobacteria. Cross resistance to pyrazinamide
• Absorption ,fate and excretion
• Absorbed fairly rapidly from gut but a GI irritant
• Widespread distribution
• Metabolized by liver in to several metabolites
• Only 1% excreted in active form in urine
Ethionamide Adverse reactions

• 30% cases drug withdrawal due to toxicity.

• Allergic reactions
• Skin reactions and alopecia
• Purpura and anaphylactoid shock
• GI disturbances anorexia,nausea vomiting diarrhea
• To minimize single dose after evening meal orat bed time
• Neurological disturbances similar to INH
• Toxic hepatitis
Second line Drugs
• Cycloserine: Inhibits peptidoglycan synthesis, effective against TB
resistant to INH Rifampicin and atypical mycobacteria.Orally
absorbed.Widely distributed ,renal excretion
• ADR: Psycho-neuro-toxicity
• Thioacetazone: Used as companion to INH,Bacteriostatic, widely
diffused in tissues, crosses placental barrier.Excreted in urine
• ADR: A,N,V Fever,rashes,Stevens Johnsons,blood dyscrasias,liver and
kidney damage.Fatal skin reaction in AIDS patients
• Para aminosalicylic acid:
• Folate antagonist.useful in MDR T.B
Rifapentine
• Semi synthetic rifamycin antibiotic like rifampicin and longer
acting,metabolized to active metabolite 25 decacetyl rifapentine.
• Enzyme inducer.
• Given in continuous phase.Given in dose of 600mg once or twice
weekly
• Rifabutin :Non tuberculous mycobacterial infection
Third line Drugs
• Macrolides: Azithromycin and clarithromycin
• Used to treat atypical mycobacterial infections and relapse cases
• Clofazimine: Antileprosy drug given in combination in MDR-T.B
• Linezolid: Used in combination with other drugs for MDR/XDR(300-
600mg O.D).Bacteriostatic, achieves adequate intracellular
concentration.Toxicity is dose related anemia.neuropathies,
myelosuppression
Newer Drugs
• Bedaquiline: New compound is diaryl quinolone.
• Inhibits mycobacterial ATP synthase , so no energy for tuberculous bacilli
• Bactericidal against sensitive and MDR tuberculous bacilli, also acts on dormant bacilli
• Nausea.anorexia.hepatic damage and arthralgia.
• QT prolongation.
• Metabolized by CYP3A4.long t1/2. in plasma even after 5 months
• Accumulates in tissues
• Always administered with more than 3 drugs in MDR T.B (Resistance seen)

• Delaminid: Nitro-dihydroimidazo-oxazole.Mycolic acid synthesis inhibitor,

• Generates nitric oxide and kills intracellular tuberculous bacilli.
• Metabolized by CYP3A4
• Given as add on therapy for MDR pulmonary T.B.
MDR Tuberculosis Management
• MDR is resistance of M.tuberculosis to INH and rifampicin with or
without resistance to other drugs.
• Treatment of MDR is complex needs elaborate evaluation and drug
sensitivity testing.
• 6-9 months of intensive therapy with six
drugs(kanamycin+levofloxacin+ethionamide+pyrazinamideZ+Ethambu
tol+cycloserine)
• followed by 18 months of continuation phase with 4
drugs(levofloxacin+Ethionamide+Ethambutol+cycloserine).
• Capreomycin ,PAS ,or the flouroquinolones can be added
Extensively drug resistant TB(XDR-
T.B)
• Defined as resistance to at least INH and Rifampicin (MDR) plus
resistance to one of the floroquinolones and any one of the second
line injectables (amikacin,kanamycin,capreomycin) . Treatment is
difficult.
• 6-12 months of intensive phase with 7 drugs (capreomycin, PAS,
moxifloxacin, high dose INH,clofazimine, linezolid, amoxicillin
+clavulinic acid)
• 18 months continuation phase with 6 drugs
(PAS, moxifloxacin, high dose INH,clofazimine, linezolid, amoxicillin
+clavulinic acid)
Other forms of T.B
• Extrapulmonary forms of T.B like meningitis, skeletal TB, pericarditis
and acute military TB require continuation phase extended by 3-6
months.
• 3-4 drugs for 18-24 months with glucocorticoids to overcome severe
toxemia, prevent bronchial stenosis, prevent fibrosis,hypersensitivity
to drugs.
• T.B of the genitourinary tract,bones,joints larynx responds well ocular
T.B topical and systemic glucocorticoids maybe required in addition to
systemic chemotherapy.