First-line agentsFirst-line agents Isoniazid(INH)Isoniazid(INH) RifampicinRifampicin PyrazinamidePyrazinamide EthambutolEthambutol StreptomycinStreptomycin

Isoniazid(INH)Isoniazid(INH) Most active drug for tuberculosisMost active drug for tuberculosis MOA:MOA: Inhibits synthesis of mycolic acidInhibits synthesis of mycolic acid Prodrug-activated by KatG, Prodrug-activated by KatG,

mycobacterial catalase-peroxidase.mycobacterial catalase-peroxidase. Activated form, forms covalent Activated form, forms covalent

complex with AcpM & KasA.complex with AcpM & KasA.

Resistance to INHResistance to INH Mutation from overexpression of Mutation from overexpression of

inhA(low resistance).inhA(low resistance). Mutation or deletion of katG Mutation or deletion of katG

gene(high resistance)gene(high resistance) Overexpression of ahpcOverexpression of ahpc Mutation in KasA.Mutation in KasA. PK:PK: Clinical uses:Clinical uses:

Adverse Reactions:Adverse Reactions: Immunological reactionsImmunological reactions Direct toxicity:Direct toxicity: HepatitisHepatitis Peripheral neuropathyPeripheral neuropathy Pyridoxine deficiencyPyridoxine deficiency Anemia, tinitis, GI discomfort.Anemia, tinitis, GI discomfort.

RIFAMPICINRIFAMPICIN Antimicrobial activity:Antimicrobial activity: Binds to Binds to ß-subunit of bacterial DNA ß-subunit of bacterial DNA

dependent RNA polymerase & dependent RNA polymerase & inhibits RNA synthesis.inhibits RNA synthesis.

Bacteriocidal for mycobacteria.Bacteriocidal for mycobacteria. It will kill intracellular organisms & It will kill intracellular organisms &

those sequestered in abscesses & those sequestered in abscesses & lung cavities. lung cavities.

Resistance:Resistance: Mutation in rpoB, the gene for ß-Mutation in rpoB, the gene for ß-

subunit of RNA polymerase.subunit of RNA polymerase. Mutations--Result in reduced binding Mutations--Result in reduced binding

of rifampin to RNA polymerase.of rifampin to RNA polymerase. PK:PK: Absobed after oral adm.Absobed after oral adm. Excerted –through liver into bile.Excerted –through liver into bile. Distributed widely in body tissue & Distributed widely in body tissue &

fluids.fluids. Highly protein bound, adequate CSF Highly protein bound, adequate CSF

conc. –meningeal inflammation.conc. –meningeal inflammation.

RIFAMPICINRIFAMPICIN Clinical uses:Clinical uses: Mycobacterial infections- 600mg orally.Mycobacterial infections- 600mg orally. Atypical Mycobacterial infect.& in leprosy.Atypical Mycobacterial infect.& in leprosy. Prophylaxis ( only in pts with INH-Prophylaxis ( only in pts with INH-

resistance).resistance). OTHERS:OTHERS: Meningococcal carriers.Meningococcal carriers. Prophylaxis--H.influenzae type BProphylaxis--H.influenzae type B Staphylococcal carriage.Staphylococcal carriage. Staph. Infect. As osteomyelitis, prostatic Staph. Infect. As osteomyelitis, prostatic

valve endocarditis.valve endocarditis.

RIFAMPICINRIFAMPICIN Harmless orange color to urine, sweat, tears, Harmless orange color to urine, sweat, tears,

contact lenses.contact lenses. Rashes, thrombocytopenia & nephritis.Rashes, thrombocytopenia & nephritis. Choleststic jaundice, light chain proteinuria.Choleststic jaundice, light chain proteinuria. Flu-like syndrome, fever, chills, myalgia, anemia, Flu-like syndrome, fever, chills, myalgia, anemia,

thrombocytopenia, acute tubular necrosis.thrombocytopenia, acute tubular necrosis. Strongly induces most cytochrome P450 isoforms.Strongly induces most cytochrome P450 isoforms.

(inc. elimination of methadone, anticoagulants, (inc. elimination of methadone, anticoagulants, cyclosporine, anticonvulsants, PI, NNRTI, cyclosporine, anticonvulsants, PI, NNRTI, contraceptives).contraceptives).

Lower serum level of the above drugs.Lower serum level of the above drugs.

EthambutolEthambutol

MOA:MOA: Inhibits mycobacterial arabinosyl transferase.Inhibits mycobacterial arabinosyl transferase.

(coded by embCAB operon) (coded by embCAB operon) Responsible for polymerisation reaction of Responsible for polymerisation reaction of

arabinoglycan--- component of mycobacterial cell arabinoglycan--- component of mycobacterial cell wallwall. .

Resistance:Resistance: mutation of emb gene. mutation of emb gene. S/E:S/E: HypersensitivityHypersensitivity Loss of visual acuity– red-green color blindness.Loss of visual acuity– red-green color blindness. CI; in children -- red-green color blindness.CI; in children -- red-green color blindness.

PyrazinamidePyrazinamide Related to nicotinamide.Related to nicotinamide. MOA:MOA: Taken up by macrophages & active against mycobacteria Taken up by macrophages & active against mycobacteria

residing in the acidic environment of lysosomes.residing in the acidic environment of lysosomes. Converted to pyrazinoic acid ( active form of drug) by Converted to pyrazinoic acid ( active form of drug) by

mycobacterial pyrazinamidase—enceded by mycobacterial pyrazinamidase—enceded by pncApncA Resistance:Resistance: Impaired uptakeImpaired uptake.. mutation of mutation of pncA.pncA. S/ES/E HepatotoxicHepatotoxic Nausea, vomiting, drug fever.Nausea, vomiting, drug fever. Hyperurecemia--- gouty arthritis.Hyperurecemia--- gouty arthritis.

StreptomycinStreptomycin MOA:MOA: Penetrates into the cell poorly & is active against Penetrates into the cell poorly & is active against

extracellular tubercle bacilli.extracellular tubercle bacilli. Crosses b/b barrier & active therappeutic conc. in Crosses b/b barrier & active therappeutic conc. in

inflammed meningies. inflammed meningies. Clinical uses:Clinical uses: Inj. indicated for life threatening form of TB e.g Inj. indicated for life threatening form of TB e.g

meningitis, disseminated diseases, inf. Resistant to meningitis, disseminated diseases, inf. Resistant to other drugs,other drugs,

S/E;S/E; Ototoxic & nephrotoxic.Ototoxic & nephrotoxic. Vertigo & hearing loss--- may be permanentVertigo & hearing loss--- may be permanent( red by therapy no more than 6 months).( red by therapy no more than 6 months).

TREATMENT OF MDR-TREATMENT OF MDR-TUBERCULOSISTUBERCULOSIS

DR.SAMIADR.SAMIA

TB IN SPUTUMTB IN SPUTUM

First-line agentsFirst-line agents Isoniazid(INH)Isoniazid(INH) RifampicinRifampicin PyrazinamidePyrazinamide EthambutolEthambutol StreptomycinStreptomycin

Second-line drugsSecond-line drugs In case of In case of resistance to first-lineresistance to first-line failure of clinical response to failure of clinical response to

conventional therapyconventional therapy Serious treatment limiting adverse Serious treatment limiting adverse

drug reactionsdrug reactions Expert guidance is available to deal Expert guidance is available to deal

with toxic effects.with toxic effects.

Drug resistant tuberculosis is transmitted in the Drug resistant tuberculosis is transmitted in the same way as regular TB. same way as regular TB.

Primary resistance: Primary resistance: occurs in persons who are infected with a occurs in persons who are infected with a

resistant strain of TB. resistant strain of TB. Secondary resistance:Secondary resistance: inadequate treatment, not taking the prescribed inadequate treatment, not taking the prescribed

regimen appropriately, or using low quality regimen appropriately, or using low quality medication.medication.

Multi-drug resistant TBMulti-drug resistant TB ( (MDR-TBMDR-TB) is defined as ) is defined as resistance to the two most effective first line TB resistance to the two most effective first line TB drugs: drugs: rifampicinrifampicin and and isoniazidisoniazid..

Extensively drug-resistant TBExtensively drug-resistant TB ( (XDR-TBXDR-TB) is also ) is also resistant to three or more of the six classes of resistant to three or more of the six classes of second-line drugs.second-line drugs.

ALTERNATIVEALTERNATIVESECOND-LINE DRUGSSECOND-LINE DRUGS

EthionamideEthionamide CapreomycinCapreomycin CycloserineCycloserine Aminosalicylic acidAminosalicylic acid Kanamycin & AmikacinKanamycin & Amikacin FluoroquinolonesFluoroquinolones LinezolidesLinezolides RifabutinRifabutin RifapentineRifapentine

EthionamideEthionamide Chemically related to INH.Chemically related to INH. Blocks synthesis of mycolic acids.Blocks synthesis of mycolic acids. Available in oral formAvailable in oral form S/E:S/E: gastric irritation ( 1g/d)gastric irritation ( 1g/d) neurological symptoms( Rx-neurological symptoms( Rx-

pyridoxine)pyridoxine) hepatotoxicityhepatotoxicity ResistanceResistance- single agent.- single agent.

CapreomycinCapreomycin Protein synthesis inhibitorProtein synthesis inhibitor 1g-i/m- MDR strains1g-i/m- MDR strains Inj. treatment for MDR-TBInj. treatment for MDR-TB Resistance- Resistance- due to rrs mutation.due to rrs mutation. S/E:S/E: nephrotoxicnephrotoxic Ototoxic- tinnitus, deafness, Ototoxic- tinnitus, deafness,

vestibular disturbance. vestibular disturbance. Inj. site- local pain, sterile abscesses.Inj. site- local pain, sterile abscesses.

CycloserineCycloserine

Inhibitor of cell wall synthesis.Inhibitor of cell wall synthesis. Cleared – renaly (dose is red. to ½ if Cleared – renaly (dose is red. to ½ if

creatinine clearance is less than creatinine clearance is less than 50ml/min).50ml/min).

S/E:S/E: Peripheral neuropathy.Peripheral neuropathy. CNS dysfunction-Psychosis, CNS dysfunction-Psychosis,

depression.depression.

Aminosalicylic acidAminosalicylic acid Folate synthesis antagonist.Folate synthesis antagonist. Structurally similar to PABA & Structurally similar to PABA &

sulfonamides.sulfonamides. Widely distributed in fluids & body tissue Widely distributed in fluids & body tissue

except CSF.except CSF. S/E: S/E: Peptic ulcers, hemorrhages(give with Peptic ulcers, hemorrhages(give with

meals)meals) Hypersensitivity reactions- fever, joint Hypersensitivity reactions- fever, joint

pain, skin rashes, hepatosplenomegaly, pain, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, granulocytopenia, hepatitis, adenopathy, granulocytopenia,

Kanamycin & AmikacinKanamycin & Amikacin Inc. used due to MDR.Inc. used due to MDR. For streptomycin resistant or MDR.For streptomycin resistant or MDR. Combination with two or three drugs.Combination with two or three drugs. MOA:MOA: Protein synthesis inhibitor by Protein synthesis inhibitor by

binding to specific 30S-subunit binding to specific 30S-subunit ribosomal protein.ribosomal protein.

S/ES/E: ototoxic & nephrotoxic.: ototoxic & nephrotoxic.

FluoroquinolonesFluoroquinolones

Ciprofloxacin, levofloxacin, Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin.gatifloxacin, moxifloxacin.

For resistant strains against first-line For resistant strains against first-line drugs.drugs.

Resistance:Resistance: Mutations in gyrase A subunit ( if Mutations in gyrase A subunit ( if

used as single agent)used as single agent)

LinezolidesLinezolides Achieves good intracellular conc. Achieves good intracellular conc. In combination with other second-line In combination with other second-line

drugs.drugs. MOA:MOA: inhibit protein synthesis by inhibit protein synthesis by

preventing formation of ribosome complex preventing formation of ribosome complex that initiate protein synthesis.that initiate protein synthesis.

S/E:S/E: Bone marrow suppressionBone marrow suppression Irreversible peripheral & optic neuropathy.Irreversible peripheral & optic neuropathy. Drug of last resort.Drug of last resort.

RifabutinRifabutin

Derived from rifamycin.Derived from rifamycin. Resistance:Resistance: rpo Brpo B mutation. mutation. Less potent inducer(P450 enzymes) Less potent inducer(P450 enzymes)

is indicated in place of rifampin for is indicated in place of rifampin for HIV-infected patients.HIV-infected patients.

RifapentineRifapentine

Analog of rifampinAnalog of rifampin Both Both M tuberculosisM tuberculosis & & M aviumM avium.. Potent inducer of P450 enzymes.Potent inducer of P450 enzymes. Cross-resistance b/w rifampin & Cross-resistance b/w rifampin &

rifapentine is complete.rifapentine is complete. Should not be used in HIV-infected Should not be used in HIV-infected

pts –high relapse rate with rifampin-pts –high relapse rate with rifampin-resistant organisms.resistant organisms.

Rifapentine is & microbiological Rifapentine is & microbiological active metabolite (25-active metabolite (25-desacetylrifapentine has elimination desacetylrifapentine has elimination ½ life of 13 hrs.½ life of 13 hrs.

Once weekly in rifampin-susceptible Once weekly in rifampin-susceptible strains during continuation phase.strains during continuation phase.

( after first two months therapy).( after first two months therapy).