1.
First-line agents <ul><li>Isoniazid(INH) </li></ul><ul><li>Rifampicin </li></ul><ul><li>Pyrazinamide </li></ul><ul><li>Ethambutol </li></ul><ul><li>Streptomycin </li></ul>

2.
Isoniazid(INH) <ul><li>Most active drug for tuberculosis </li></ul><ul><li>MOA: </li></ul><ul><li>Inhibits synthesis of mycolic acid </li></ul><ul><li>Prodrug-activated by KatG, mycobacterial catalase-peroxidase. </li></ul><ul><li>Activated form, forms covalent complex with AcpM & KasA. </li></ul>

3.
Resistance to INH <ul><li>Mutation from overexpression of inhA(low resistance). </li></ul><ul><li>Mutation or deletion of katG gene(high resistance) </li></ul><ul><li>Overexpression of ahpc </li></ul><ul><li>Mutation in KasA. </li></ul><ul><li>PK: </li></ul><ul><li>Clinical uses: </li></ul>

4.
<ul><li>Adverse Reactions: </li></ul><ul><li>Immunological reactions </li></ul><ul><li>Direct toxicity: </li></ul><ul><li>Hepatitis </li></ul><ul><li>Peripheral neuropathy </li></ul><ul><li>Pyridoxine deficiency </li></ul><ul><li>Anemia, tinitis, GI discomfort. </li></ul>

5.
RIFAMPICIN <ul><li>Antimicrobial activity: </li></ul><ul><li>Binds to ß-subunit of bacterial DNA dependent RNA polymerase & inhibits RNA synthesis. </li></ul><ul><li>Bacteriocidal for mycobacteria. </li></ul><ul><li>It will kill intracellular organisms & those sequestered in abscesses & lung cavities. </li></ul>

6.
<ul><li>Resistance: </li></ul><ul><li>Mutation in rpoB, the gene for ß-subunit of RNA polymerase. </li></ul><ul><li>Mutations--Result in reduced binding of rifampin to RNA polymerase. </li></ul><ul><li>PK: </li></ul><ul><li>Absobed after oral adm. </li></ul><ul><li>Excerted –through liver into bile. </li></ul><ul><li>Distributed widely in body tissue & fluids. </li></ul><ul><li>Highly protein bound, adequate CSF conc. –meningeal inflammation. </li></ul>

7.
RIFAMPICIN <ul><li>Clinical uses: </li></ul><ul><li>Mycobacterial infections- 600mg orally. </li></ul><ul><li>Atypical Mycobacterial infect.& in leprosy. </li></ul><ul><li>Prophylaxis ( only in pts with INH-resistance). </li></ul><ul><li>OTHERS: </li></ul><ul><li>Meningococcal carriers. </li></ul><ul><li>Prophylaxis--H.influenzae type B </li></ul><ul><li>Staphylococcal carriage. </li></ul><ul><li>Staph. Infect. As osteomyelitis, prostatic valve endocarditis. </li></ul>

8.
RIFAMPICIN <ul><li>Harmless orange color to urine, sweat, tears, contact lenses. </li></ul><ul><li>Rashes, thrombocytopenia & nephritis. </li></ul><ul><li>Choleststic jaundice, light chain proteinuria. </li></ul><ul><li>Flu-like syndrome, fever, chills, myalgia, anemia, thrombocytopenia, acute tubular necrosis. </li></ul><ul><li>Strongly induces most cytochrome P450 isoforms.(inc. elimination of methadone, anticoagulants, cyclosporine, anticonvulsants, PI, NNRTI, contraceptives). </li></ul><ul><li>Lower serum level of the above drugs. </li></ul>

9.
Ethambutol <ul><li>MOA: </li></ul><ul><li>Inhibits mycobacterial arabinosyl transferase.(coded by embCAB operon) </li></ul><ul><li>Responsible for polymerisation reaction of arabinoglycan--- component of mycobacterial cell wall . </li></ul><ul><li>Resistance: mutation of emb gene. </li></ul><ul><li>S/E: </li></ul><ul><li>Hypersensitivity </li></ul><ul><li>Loss of visual acuity– red-green color blindness. </li></ul><ul><li>CI; in children -- red-green color blindness. </li></ul>

10.
Pyrazinamide <ul><li>Related to nicotinamide. </li></ul><ul><li>MOA: </li></ul><ul><li>Taken up by macrophages & active against mycobacteria residing in the acidic environment of lysosomes. </li></ul><ul><li>Converted to pyrazinoic acid ( active form of drug) by mycobacterial pyrazinamidase—enceded by pncA </li></ul><ul><li>Resistance: </li></ul><ul><li>Impaired uptake . </li></ul><ul><li>mutation of pncA. </li></ul><ul><li>S/E </li></ul><ul><li>Hepatotoxic </li></ul><ul><li>Nausea, vomiting, drug fever. </li></ul><ul><li>Hyperurecemia--- gouty arthritis. </li></ul>

11.
Streptomycin <ul><li>MOA: </li></ul><ul><li>Penetrates into the cell poorly & is active against extracellular tubercle bacilli. </li></ul><ul><li>Crosses b/b barrier & active therappeutic conc. in inflammed meningies. </li></ul><ul><li>Clinical uses: </li></ul><ul><li>Inj. indicated for life threatening form of TB e.g meningitis, disseminated diseases, inf. Resistant to other drugs, </li></ul><ul><li>S/E; </li></ul><ul><li>Ototoxic & nephrotoxic. </li></ul><ul><li>Vertigo & hearing loss--- may be permanent </li></ul><ul><li>( red by therapy no more than 6 months). </li></ul>

12.
TREATMENT OF MDR-TUBERCULOSIS DR.SAMIA

13.
TB IN SPUTUM

14.
First-line agents <ul><li>Isoniazid(INH) </li></ul><ul><li>Rifampicin </li></ul><ul><li>Pyrazinamide </li></ul><ul><li>Ethambutol </li></ul><ul><li>Streptomycin </li></ul>

15.
Second-line drugs <ul><li>In case of </li></ul><ul><li>resistance to first-line </li></ul><ul><li>failure of clinical response to conventional therapy </li></ul><ul><li>Serious treatment limiting adverse drug reactions </li></ul><ul><li>Expert guidance is available to deal with toxic effects. </li></ul>

16.
<ul><li>Drug resistant tuberculosis is transmitted in the same way as regular TB. </li></ul><ul><li>Primary resistance: </li></ul><ul><li>occurs in persons who are infected with a resistant strain of TB. </li></ul><ul><li>Secondary resistance: </li></ul><ul><li>inadequate treatment, not taking the prescribed regimen appropriately, or using low quality medication. </li></ul><ul><li>Multi-drug resistant TB ( MDR-TB ) is defined as resistance to the two most effective first line TB drugs: rifampicin and isoniazid . </li></ul><ul><li>Extensively drug-resistant TB ( XDR-TB ) is also resistant to three or more of the six classes of second-line drugs. </li></ul>

17.
ALTERNATIVE SECOND-LINE DRUGS <ul><li>Ethionamide </li></ul><ul><li>Capreomycin </li></ul><ul><li>Cycloserine </li></ul><ul><li>Aminosalicylic acid </li></ul><ul><li>Kanamycin & Amikacin </li></ul><ul><li>Fluoroquinolones </li></ul><ul><li>Linezolides </li></ul><ul><li>Rifabutin </li></ul><ul><li>Rifapentine </li></ul>

18.
Ethionamide <ul><li>Chemically related to INH. </li></ul><ul><li>Blocks synthesis of mycolic acids. </li></ul><ul><li>Available in oral form </li></ul><ul><li>S/E: </li></ul><ul><li>gastric irritation ( 1g/d) </li></ul><ul><li>neurological symptoms( Rx-pyridoxine) </li></ul><ul><li>hepatotoxicity </li></ul><ul><li>Resistance - single agent. </li></ul>

19.
Capreomycin <ul><li>Protein synthesis inhibitor </li></ul><ul><li>1g-i/m- MDR strains </li></ul><ul><li>Inj. treatment for MDR-TB </li></ul><ul><li>Resistance- due to rrs mutation. </li></ul><ul><li>S/E: </li></ul><ul><li>nephrotoxic </li></ul><ul><li>Ototoxic- tinnitus, deafness, vestibular disturbance. </li></ul><ul><li>Inj. site- local pain, sterile abscesses. </li></ul>

20.
Cycloserine <ul><li>Inhibitor of cell wall synthesis. </li></ul><ul><li>Cleared – renaly (dose is red. to ½ if creatinine clearance is less than 50ml/min). </li></ul><ul><li>S/E: </li></ul><ul><li>Peripheral neuropathy. </li></ul><ul><li>CNS dysfunction-Psychosis, depression. </li></ul>

21.
Aminosalicylic acid <ul><li>Folate synthesis antagonist. </li></ul><ul><li>Structurally similar to PABA & sulfonamides. </li></ul><ul><li>Widely distributed in fluids & body tissue except CSF. </li></ul><ul><li>S/E: </li></ul><ul><li>Peptic ulcers, hemorrhages(give with meals) </li></ul><ul><li>Hypersensitivity reactions- fever, joint pain, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, granulocytopenia, </li></ul>

22.
Kanamycin & Amikacin <ul><li>Inc. used due to MDR. </li></ul><ul><li>For streptomycin resistant or MDR. </li></ul><ul><li>Combination with two or three drugs. </li></ul><ul><li>MOA: Protein synthesis inhibitor by binding to specific 30S-subunit ribosomal protein. </li></ul><ul><li>S/E : ototoxic & nephrotoxic. </li></ul>

23.
Fluoroquinolones <ul><li>Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin. </li></ul><ul><li>For resistant strains against first-line drugs. </li></ul><ul><li>Resistance: </li></ul><ul><li>Mutations in gyrase A subunit ( if used as single agent) </li></ul>

24.
Linezolides <ul><li>Achieves good intracellular conc. </li></ul><ul><li>In combination with other second-line drugs. </li></ul><ul><li>MOA: inhibit protein synthesis by preventing formation of ribosome complex that initiate protein synthesis. </li></ul><ul><li>S/E: </li></ul><ul><li>Bone marrow suppression </li></ul><ul><li>Irreversible peripheral & optic neuropathy. </li></ul><ul><li>Drug of last resort. </li></ul>

25.
Rifabutin <ul><li>Derived from rifamycin. </li></ul><ul><li>Resistance: </li></ul><ul><li>rpo B mutation. </li></ul><ul><li>Less potent inducer(P450 enzymes) is indicated in place of rifampin for HIV-infected patients. </li></ul>

26.
Rifapentine <ul><li>Analog of rifampin </li></ul><ul><li>Both M tuberculosis & M avium . </li></ul><ul><li>Potent inducer of P450 enzymes. </li></ul><ul><li>Cross-resistance b/w rifampin & rifapentine is complete. </li></ul><ul><li>Should not be used in HIV-infected pts –high relapse rate with rifampin-resistant organisms. </li></ul>

27.
<ul><li>Rifapentine is & microbiological active metabolite (25-desacetylrifapentine has elimination ½ life of 13 hrs. </li></ul><ul><li>Once weekly in rifampin-susceptible strains during continuation phase. </li></ul><ul><li>( after first two months therapy). </li></ul>