First-line agents

 Isoniazid(INH)
 Rifampicin
 Pyrazinamide
 Ethambutol
 Streptomycin
 Isoniazid(INH)
 Most active drug for tuberculosis
 MOA:
 Inhibits synthesis of mycolic acid
 Prodrug-activated by KatG,
mycobacterial catalase-peroxidase.
 Activated form, forms covalent
complex with AcpM & KasA.
 Resistance to INH
 Mutation from overexpression of
inhA(low resistance).
 Mutation or deletion of katG
gene(high resistance)
 Overexpression of ahpc
 Mutation in KasA.
 PK:
 Clinical uses:
 Adverse Reactions:
 Immunological reactions
 Direct toxicity:
 Hepatitis
 Peripheral neuropathy
 Pyridoxine deficiency
 Anemia, tinitis, GI discomfort.
 RIFAMPICIN
 Antimicrobial activity:
 Binds to ß-subunit of bacterial DNA
dependent RNA polymerase &
inhibits RNA synthesis.
 Bacteriocidal for mycobacteria.
 It will kill intracellular organisms &
those sequestered in abscesses &
lung cavities.
 Resistance:
 Mutation in rpoB, the gene for ß-
subunit of RNA polymerase.
 Mutations--Result in reduced binding
of rifampin to RNA polymerase.
 PK:
 Absobed after oral adm.
 Excerted –through liver into bile.
 Distributed widely in body tissue &
fluids.
 Highly protein bound, adequate CSF
conc. –meningeal inflammation.
 RIFAMPICIN
 Clinical uses:
 Mycobacterial infections- 600mg orally.
 Atypical Mycobacterial infect.& in leprosy.
 Prophylaxis ( only in pts with INH-
resistance).
 OTHERS:
 Meningococcal carriers.
 Prophylaxis--H.influenzae type B
 Staphylococcal carriage.
 Staph. Infect. As osteomyelitis, prostatic
valve endocarditis.
 RIFAMPICIN
 Harmless orange color to urine, sweat, tears,
contact lenses.
 Rashes, thrombocytopenia & nephritis.
 Choleststic jaundice, light chain proteinuria.
 Flu-like syndrome, fever, chills, myalgia, anemia,
thrombocytopenia, acute tubular necrosis.
 Strongly induces most cytochrome P450
isoforms.(inc. elimination of methadone,
anticoagulants, cyclosporine, anticonvulsants, PI,
NNRTI, contraceptives).
 Lower serum level of the above drugs.
 Ethambutol
 MOA:
 Inhibits mycobacterial arabinosyl
transferase.(coded by embCAB operon)
 Responsible for polymerisation reaction of
arabinoglycan--- component of mycobacterial cell
wall.
 Resistance: mutation of emb gene.
 S/E:
 Hypersensitivity
 Loss of visual acuity– red-green color blindness.
 CI; in children -- red-green color blindness.
 Pyrazinamide
 Related to nicotinamide.
 MOA:
 Taken up by macrophages & active against mycobacteria
residing in the acidic environment of lysosomes.
 Converted to pyrazinoic acid ( active form of drug) by
mycobacterial pyrazinamidase—enceded by pncA
 Resistance:
 Impaired uptake.
 mutation of pncA.
 S/E
 Hepatotoxic
 Nausea, vomiting, drug fever.
 Hyperurecemia--- gouty arthritis.
 Streptomycin
 MOA:
 Penetrates into the cell poorly & is active against
extracellular tubercle bacilli.
 Crosses b/b barrier & active therappeutic conc. in

inflammed meningies.
 Clinical uses:

 Inj. indicated for life threatening form of TB e.g

meningitis, disseminated diseases, inf. Resistant to

other drugs,
 S/E;

 Ototoxic & nephrotoxic.

 Vertigo & hearing loss--- may be permanent

( red by therapy no more than 6 months).

TREATMENT OF MDR-
TUBERCULOSIS
DR.SAMIA
TB IN SPUTUM
 First-line agents
 Isoniazid(INH)
 Rifampicin
 Pyrazinamide
 Ethambutol
 Streptomycin
 Second-line drugs
 In case of
 resistance to first-line
 failure of clinical response to
conventional therapy
 Serious treatment limiting adverse
drug reactions
 Expert guidance is available to deal
with toxic effects.
 Drug resistant tuberculosis is transmitted in the
same way as regular TB.
 Primary resistance:
 occurs in persons who are infected with a
resistant strain of TB.
 Secondary resistance:
 inadequate treatment, not taking the prescribed
regimen appropriately, or using low quality
medication.
 Multi-drug resistant TB (MDR-TB) is defined as
resistance to the two most effective first line TB
drugs: rifampicin and isoniazid.
 Extensively drug-resistant TB (XDR-TB) is also
resistant to three or more of the six classes of
second-line drugs.
 ALTERNATIVE
SECOND-LINE DRUGS
 Ethionamide
 Capreomycin
 Cycloserine
 Aminosalicylic acid
 Kanamycin & Amikacin
 Fluoroquinolones
 Linezolides
 Rifabutin
 Rifapentine
 Ethionamide
 Chemically related to INH.
 Blocks synthesis of mycolic acids.
 Available in oral form
 S/E:
 gastric irritation ( 1g/d)
 neurological symptoms( Rx-
pyridoxine)
 hepatotoxicity
 Resistance- single agent.
 Capreomycin
 Protein synthesis inhibitor
 1g-i/m- MDR strains
 Inj. treatment for MDR-TB
 Resistance- due to rrs mutation.
 S/E:
 nephrotoxic
 Ototoxic- tinnitus, deafness,
vestibular disturbance.
 Inj. site- local pain, sterile
abscesses.
 Cycloserine

 Inhibitor of cell wall synthesis.

 Cleared – renaly (dose is red. to ½ if
creatinine clearance is less than
50ml/min).
 S/E:
 Peripheral neuropathy.
 CNS dysfunction-Psychosis,
depression.
 Aminosalicylic acid
 Folate synthesis antagonist.
 Structurally similar to PABA &
sulfonamides.
 Widely distributed in fluids & body tissue
except CSF.
 S/E:
 Peptic ulcers, hemorrhages(give with
meals)
 Hypersensitivity reactions- fever, joint
pain, skin rashes, hepatosplenomegaly,
hepatitis, adenopathy, granulocytopenia,
 Kanamycin & Amikacin
 Inc. used due to MDR.
 For streptomycin resistant or MDR.
 Combination with two or three drugs.
 MOA: Protein synthesis inhibitor by
binding to specific 30S-subunit
ribosomal protein.
 S/E: ototoxic & nephrotoxic.
 Fluoroquinolones
 Ciprofloxacin, levofloxacin,
gatifloxacin, moxifloxacin.
 For resistant strains against first-line
drugs.
 Resistance:
 Mutations in gyrase A subunit ( if
used as single agent)
 Linezolides
 Achieves good intracellular conc.
 In combination with other second-line
drugs.
 MOA: inhibit protein synthesis by
preventing formation of ribosome complex
that initiate protein synthesis.
 S/E:
 Bone marrow suppression
 Irreversible peripheral & optic neuropathy.
 Drug of last resort.
 Rifabutin
 Derived from rifamycin.
 Resistance:
 rpo B mutation.
 Less potent inducer(P450 enzymes)
is indicated in place of rifampin for
HIV-infected patients.
 Rifapentine
 Analog of rifampin
 Both M tuberculosis & M avium.
 Potent inducer of P450 enzymes.
 Cross-resistance b/w rifampin &
rifapentine is complete.
 Should not be used in HIV-infected
pts –high relapse rate with rifampin-
resistant organisms.
 Rifapentine is & microbiological
active metabolite (25-
desacetylrifapentine has elimination
½ life of 13 hrs.
 Once weekly in rifampin-susceptible

strains during continuation phase.

( after first two months therapy).