The drug that acts by inhibiting bacterial RNA polymerase is
Answer: b) RifampicinANTI TUBERCULAR DRUGSFirst line DrugsEssential: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E),Supplementary: Streptomycin (S), Rifabutin, RifapentineSecond Line DrugsOld Drugs: Thiacetazone, Paraaminosalicylic acid, Ethionamide , Cycloserine, Kanamycin,Amikacin, Capreomycin, Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxacin, LinezolidAll first line Anti tubercular drugs are bactericidal except Ethambutol which is static.* Isoniazid: bacteriostatic against resting & bactericidal against rapidly multiplying organisms,o Effective against intracellular & extracellular organisms.o Resistance occurs d/t mutation in Kat G (gene for catalase peroxidase) or INH-A* Rifampicin: excreted in feces- safe in renal failure. Bactericidal against dormant organisms.o Effective against intracellular & extracellular organisms.* Ethambutol: inhibits the synthesis of arabinogalactan (cell wall component), d/t inhibition of arabinosyl transferase.* Pyrazinamide: active against intracellular bacteria only & in acidic media.* Streptomycin: active against extracellular bacteria only, given IM, contraindicated in pregnancyDrugMechanisms of Action and ResistanceAdverse effectsIsoniazidInhibit mycolic acid synthesisHigh level resistance - mutation in gene coding for Catalase peroxidaseHepatitis, Peripheral neuritis (always given in combination with pyridoxine), Hemolysis in G6PD deficiency, SLE in, slow acetylators, cheese reactionRifampicinInhibits DNA dependent RNA polymeraseResistance due to mutation in repo B geneProteinuria, Hepatitis, Flu-like syndrome,Red orange urine, Thrombocytopenia.Potent microsomal enzyme inducer;Contraindicated in patients on ARTEthambutolInhibits synthesis of arabinogalactan (cell wall component)Dose dependent retro bulbar neuritis, |.visual acuity and Red-green blindnessPyrazinamideAction similar to that of INHResistance due to mutation in the gene which encodes for enzyme generation in the active metabolite.Polyarthralgia, myalgia, Hepatitis & RashHyperuricemia, phototoxicity,| porphyrin synthesis, non gouty arthritis (40%)StreptomycinProtein synthesis inhibitorDeafness, Vestibular dysfunction &Nephrotoxicity.ISONIAZID* Isoniazid: prodrug that is activated by KatG, the mycobacterial catalase-peroxidase.* The target of the isoniazid derivative is enoyl-ACP reductase of fatty acid synthase II.* Fast acetylators: (30-40% of Indians) tl/2 of INH: 1 hr.* Slow acetylators: (60-70% of Indians tl/2 of INH: 3 hrs.* Isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis.* Fast multiplying organisms are rapidly killed, but quiescent ones are only inhibited.* It acts on extracellular as well as on intracellular TB (bacilli present within macrophages); is equally active in acidic and alkalinemedium.* Isoniazid penetrates well into caseous material and persists in therapeutic concentrations.* Main excretory products in humans result from acetylation (acetylisoniazid) and hydrolysis (isonicotinic acid).* Hepatitis is d/t the metabolite acetylhydrazine.* Isoniazid induced peripheral neuritis - more common in slow acetylators.* Mental abnormalities may appear, including euphoria, transient memory impairment, loss of self- control, and psychosis.* Approximately 1 in 106tubercle bacilli will be genetically resistant to isoniazid.* INH neurotoxicity is treated by pyridoxine-100 mg/day.* The other congener of hydrazine- iproniazid is found to be a mood elevator.RIFAMPICIN* Acts best on slowly or intermittently (spurters) dividing ones, as well as on many atypical mycobacteria.* Both extra- and intracellular organisms are affected.* It has good sterilizing and resistance preventing actions.Rifampicin toxicity* Major adverse effecto Hepatitis, a, is dose-related and is reversible on discontinuation,o 'Respiratory syndrome': breathlessness associated with shock and collapse,o Purpura, haemolysis, shock and renal failure.* Minor reactions: not requiring drug withdrawal and more common with intermittent regimenso 'Cutaneous syndrome': flushing, pruritus + rash (especially on face and scalp), redness and watering of eyes.o 'Flu syndrome': with chills, fever, headache, malaise and bone pain,o 'Abdominal syndrome': nausea, vomiting, abdominal cramps with or without diarrhoea,o Orange discolouration of soft contact lenses.Other uses of rifampin* Leprosy* Prophylaxis of Meningococcal and H. influenzae meningitis and carrier state.* Second/third choice drug for MRSA, diphtheroids and Legionella infections.* Combination of doxycycline and rifampin is the first line therapy of brucellosis.DERIVATIVES OF RIFAMPICINRIFABUTIN: (Ansamycin)* Similar in action to rifampicin and shows cross resistance to rifampicin.* Mild inducer of cytochrome P-450 unlike rifampicin & rifapentin. Causes pseudojaundice.* Indicated in the treatment of tuberculosis in HIV patients on anti retroviral therapy due to less toxicity.* Rarely, it can cause anterior uveitis, hepatitis, Clostridium difficile-associated diarrhea, diffuse polymyalgia syndrome, yellow skin discoloration (Pseudo-jaundice) and pancytopenia. Unlike rifampicinRifabutin (as compared to rifampicin) is* Less effective against TB* More effective against MAC* Longer acting, ti/2 (45 hours)* Less potential to induce microsomal enzymes* Donot require dose adjustment in liver diseaseRIFAPENTIN:* Similar in action to rifampicin and shows cross resistance to rifampicin.* Potent Inducer of cytochrome P-450. Can cause light chain proteinuria.* Metabolized to 25-desacetyl rifapentin.* Should not be used in HIV individuals as it leads to drug resistance & more prone for toxicity.RIFAXIMIN: indicated for traveler's diarrhea (E.coli) & hepatic encephalopathy.OTHER DRUGS* Thiacetazone: tuberculostatic drug. Major adverse effects include hepatitis, bone marrow suppression and Steven Johnson syndrome (not used in HIV positive patients).* Para amino salicylic acid (PAS): bacteriostatic. It can cause kidney, liver and thyroid dysfunction.* Cycloserine is a cell wall synthesis inhibiting drug and can cause neuropsychiatric adverse effects.* Kanamycin, capreomycin and amikacin are injectable aminoglycosides, used in MDR tuberculosis.* Ethionamide: tuberculostatic can cause hepatitis, optic neuritis and impotence. Also used in leprosy.o Ethionamide also inhibit mycolic acid biosynthesis with consequent impairment of cell-wall synthesis.o Resistance can develop rapidly in vivo when ethionamide is used as a single-agent treatment, including low-level cross-resistance to isoniazid.* Fluoroquinolones: ciprofloxacin, ofloxacin, moxifloxacin& sparfloxacin. Effective against MAC in AIDS patients.* Newer macrolides like azithromycin and clarithromycin are effective against non-tubercular atypical mycobacteria.* Bedaquiline is an inhibitor of mycobacterial ATP synthase. It is indicated as a part of MDT in adults with pulmonary MDR-TB. It can cause QT prolongation.MULTI DRUG RESISTANT TUBERCULOSIS (MDR-TB)* Resistance to both Isoniazid & Rifampicin and may be any number of other anti-TB drugs.* Treatment is mainly based on culture sensitivity.* Usually fluoroquinolones are added.* For H resistance: RZE is given for 12 months.* For H+R resistance: ZE + S/ Kanamycin/Amikacin/ Capreomycin + cipro/Ofloxacin + Ethionamide.EXTENSIVELY DRUG RESISTANT TUBERCULOSIS (XDR-TB)* Resistance to four most effective drugs: H, R, a fluoroquinolone, one of Kanamycin/Amikacin/ Capreomycin and may be any number of other anti-TB drugs* Virtually untreatable: high mortality, particularly among HIV positive patients.
Cephalosporins
Rifampicin
Macrolides
Aminoglycosides
Anti Microbial