Anti-Mycobacterial Agents PDF

Anti-Mycobacterial Agents Thomas A. Panavelil, Ph.D., M.S., M.B.A.  Mycobacteria: Mycobacteria are aerobic, acid fast bacilli or rods. Mycobacteria is an obligate aerobe (highly oxygenated areas get infected). Mycobacteria are termed acid fast because o...

Anti-Mycobacterial Agents Thomas A. Panavelil, Ph.D., M.S., M.B.A.  Mycobacteria: Mycobacteria are aerobic, acid fast bacilli or rods. Mycobacteria is an obligate aerobe (highly oxygenated areas get infected). Mycobacteria are termed acid fast because of their ability to retain carbolfuchsin stain despite of washing with ethanol-hydrochloric acid mixture. The cell walls of mycobacteria have a high lipid content (60%) that makes mycobacteria acid fast. The long-chain fatty acid (C70 to C90) mycolic acid contributes to mycobacteria’s acid fastness. Mycobacterium tuberculosis can be grown in specialized media (Lowenstein-Jensen) with malachite green (prevents other bacteria growing), but M. leprae cannot be grown in bacteriologic media.  Mycobacteria Tuberculosis: M. tuberculosis Leprosy: M. leprae Disseminated infections by Atypical Mycobacteria: M. avium, M. avium-intracellulare, M. ulcerans, rapidly growing mycobacteria- M. marinum, M. abscessus, M. haemophilum, M. xenopi, many more….. Immune Both supprescal susceptible  Tuberculosis The transformation from MDR tuberculosis (multidrug resistant tuberculosis resistant to isoniazid and rifampin) to XDR tuberculosis (extensive drug resistance with resistance to SLDs) has been a fortresses major challenge of this decade. When MDR usually results from misuse of first line agents, XDR results from misuse of second line agents. Therapy for infections by M. tub, M. leprae and M avium-intracellulare are complicated due to limited information about mechanisms, drug resistance, the intracellular location of infection and the advancement of the disease. Multidrug-Resistant TB (MDR TB): Multidrug-resistant TB (MDR TB) is TB that is resistant to at least two of the best anti-TB drugs, isoniazid and rifampicin. These drugs are considered first-line drugs and are used to treat all persons with TB disease. Extensively Drug-resistant TB (XDR TB): Extensively drug-resistant TB (XDR TB) is a relatively rare type of MDR TB. XDR TB is defined as TB that is resistant to isoniazid and rifampin, plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin). Because XDR TB is resistant to first-line and second-line drugs, patients are left with treatment options that are much less effective. Source: http://www.cdc.gov/tb/topic/drtb/default.htm Patentsmustbe compliantfor 6months DOT (Direct Observation Therapy) Drugs given directly to patients and watching them swallow the medications. This ensures adherence. dueto significantadverseeffects patientsstruggleto becompliant This is a preferred core management strategy for all patients with tuberculosis.  DRUGS First-line Drugs (FLDs) essential and supplemental (RIPE) Isoniazid (INH) exclusive TB to (Rifapentine, RPT and Rifabutin, RFB in patients Rifampin (Rifadin, Rimactane) knowttt taking retroviral drugs) Ethambutol (Myambutol) contraindication Pyrazinamide (PZA) Second-line Drugs (SLDs): Amikacin, Ciprofloxacin (Cipro) and other fluoroquinolones, Ethionamide (Trecator- SC), p-Aminosalicylic acid, Capreomycin (Capastat), Streptomycin, Cycloserine (Seromycin), PAS, Viomycin, Thiacetazone, Kanamycin, Clofazimine, Clarithromycin, Rifabutin (Mycobutin), Rifapentine (Priftin), Quinolones etc. (Streptomycin (SM) is now considered a second-line drug because of the increasing prevalence of resistance in many parts of the world. The requirement for parenteral administration and nephrotoxicity are additional drawbacks to SM. There are other parts of the world Streptomycin is still considered a first line drug.).  Tuberculosis FLDs & SLDs (Ref: Katzung) First-line agents Isoniazid 300 mg/d Willnot Rifampin 600 mg/d Osagequizon Pyrazinamide 25 mg/kg/d Ethambutol 15–25 mg/kg/d Second-line agents Amikacin 15 mg/kg/d Aminosalicylic acid 8–12 g/d usedindevelopingCountries Bedaquiline 400 mg/d Capreomycin 15 mg/kg/d Clofazimine 200 mg/d Cycloserine 500–1000 mg/d, divided Cell wallinhibitor Ethionamide 500–750 mg/d Levofloxacin 500–750 mg/d Linezolid 600 mg/d Moxifloxacin 400 mg/d Rifabutin2 300 mg/d Rifapentine3 600 mg once weekly Streptomycin 15 mg/kg/d  Isoniazid (INH, Nydrazid): Isoniazid is the best antituberculous drug available. This drug is included in all regimens unless the organism is resistant. Very narrow spectrum drug for tuberculosis. Mechanism: Isoniazid is the hydrazide of isonicotinic acid. It is water-soluble and penetrates the cell wall. The mechanism of action of inhibition of synthesis of enzymes needed for mycolic acid synthesis is mediated via oxygen dependent pathways such as catalase-peroxidase reaction. It is bacteriostatic. Isoniazid is a structural congener of pyridoxine. Clinical uses: In combination therapy in most drug regimens. Isoniazid also is used in the prophylaxis of skin test converters. Used in contacts of active disease patients. Route: Oral and intramuscular forms available. Oral, absorbed well intracellularly, inactivated in liver, half-life varies with patients. It also reaches therapeutic levels in CSF and Caseous (Cheese like) granulomas. Suspected Cancerbut for causedby TB Isoniazid Adverse effects: Hepatotoxicity with elevation of aminotransferases and Neurotoxicity (peripheral neuropathy only 1-2 per 1000 patients). Pyridoxine alleviates these effects. Hepatotoxicity increases with age. Clinical hepatitis seen only in 1-6 per 1000 patients. Rarely it causes anemia, acne, lupus-like syndrome (less than 1% with symptoms but 20% develop DNA antibodies), hemolysis in G-6-P-DH deficient patients, optic atrophy etc. Liver enzymes are monitored in high-risk patients. verytoxic hemolysis pPB o  Rifampin (RIF, Rimactane, Rifadin) Rifampin is a fat soluble macrocyclic antibiotic. It is the second most important antituberculosis agent. The efficacy of this drug is comparable to that of isoniazid. Mechanism: Rifampin is bactericidal. Rifampin blocks bacterial RNA synthesis by binding to DNA dependent RNA polymerase in Mycobacteria (prevents elongation). Resistance develops by point mutations on this enzyme (rpoB gene on beta subunit) thus altering drug sensitivity, if used alone. Clinical Uses: Tuberculosis and leprosy in combination regimen. In tuberculosis, it is also used as prophylactic drug in area INH intolerant patients. (In meningococcal and Staphylococcal carrier states this drug is used). Kinetics: Orally, distributed well including CNS. RIF is partially metabolized in the liver. Rifampin turns urine, sputum, saliva and body fluids to a red-orange color and this can be Iron an easy test on patient’s compliance to therapy. Free drugore and metabolites eliminated in the feces (orange color) Adverse: Well tolerated. GI upset is very common adverse effect. Elderly and alcoholic _edevelop hepatitis. Rifampin may increase isoniazid-associated hepatitis. patients tend to Proteinuria and impaired antibody response are other adverse effects. Rare skin rashes (cutaneous reaction in up to 6% patients), thrombocytopenia, liver dysfunction, flu-like syndromes etc. Induces liver drug metabolizing enzymes and eliminates many drugs. seamstresses In HIV infections, rifampin (used in atypical mycobacteria disseminated infections) cannot be 00 and used along with protease inhibitors (Rifampin makes PIs sub-therapeutic in concentration PIS make rifampin levels to increase Hepatotoxicity & GI toxicity).  Rifamycins (First line agents in patients taking retroviral drugs) usewhenon Protease inhibitors Rifapentine, RPT (Priftin): Mechanism is similar to rifampin. Rifapentine is a second-line agent for the treatment of tuberculosis used once weekly. Rifapentine is a similar in microbiological activity to rifampin, but has a longer half- life. It is also contraindicated with the protease inhibitors due to drug interactions. Rifabutin, RFB (Mycobutin): Mostly used in patients who e cannot be given rifampin due to interactions and intolerance. It is a semisynthetic rifamycin derivative active against some strains of women rifampin resistant M. tuberculosis. It is also more active against MAI and other non-tuberculosis mycobacteria. It is very useful in prophylaxis of disseminated MAI infection. Whether it is more valuable than rifampin as antituberculous agent is being evaluated. Mechanism, adverse effects and resistance are similar to rifampin. lessoften due tolonghalflife maybegiven  Ethambutol (EMB) Mechanism: A derivative of ethylene diamine and is water-soluble. It is bacteriostatic. Mechanism not clear. It blocks arabino-galactin (arabinose + galactose), a component of mycobacterial cell wall. Kinetics: Oral, distributed well including CNS. Eliminated unchanged in urine. Clinical uses: Tuberculosis, as combination regimen. Adverse: Visual disturbance (eg. Green blindness), t retinal damage (retrobulbar optic neuritis), headache, e confusion, peripheral neuritis. she  Pyrazinamide (PZA) narrow spectrajustTB Pyrazinamide is a derivative of nicotinic acid. It is bactericidal. Pyrazinamidases (an enzyme) in M. tub converts this drug to an active form, pyrazinoic acid. Mechanism: Similar to isoniazid, narrow spectrum specific for tuberculosis. Inhibit fatty acid synthetase Clinical Usage: As a combination drug against M. tub in short (6-month) treatment regimens. shorttreatment Kinetics: Orally well absorbed, distributed well including CNS. Eliminated unchanged in urine as well as the metabolite pyrazinoic acid. Adverse: Hepatic dysfunction most prominent. Polyarthralgia (joint pain), Hyperuricemia (high uric acid), myalgia, photosensitivity etc. are other complications. most toxic of FLO RIPE  Combinations Rifamate: RIF + INH Rifater: RIF + INH + PZA  Alternate drugs in cases resistant to first line agents Streptomycin (IM route only, now only available from Pfizer or X-gen directly) Used in drug combinations, for the treatment including tuberculosis meningitis and organ tuberculosis. Limits usefulness due to resistance. Aminoglycosides See aminoglycosides for further details. Parenteral, Ototoxic Thiacetazone: Also known as amithiozone, widely used in the world. Not available in the US. Structurally related to isoniazid, bacteriostatic. WHO warns HIV infected patients not to use this drug due to severe GI upset and fatal skin reactions. Amikacin & Kanamycin: Used in strains caused by streptomycin- and multidrug- resistant mycobacterial infections. Fluoroquinolones: Ciprofloxacin, Levofloxacin: Active against M. tub resistant to first-line agents. Ethionamide: A congener of INH with no cross-resistance. GI irritation (very common) and neurologic effects are common. Para-amino salicylic acid (PAS, Paser): Used rarely due to resistance and severe GI problems. Available as granules in 4g packets Capreomycin (Capastat): Protein synthesis inhibitor with significant nephrotoxicity and useful as injectable agent in drug resistant tuberculosis. Cycloserine: Cycloserine is almost exclusively used to treat tuberculosis caused by M. tuberculosis caused by first-line agents. Cycloserine is a D-alanine analogue that inhibits incorporation of D-alanine into Isomer peptidoglycan synthesis. The drug is widely distributed in tissues. Cycloserine is known to cause restlessness, headache and other CNS disorders. SimilartoVance  M. Leprae (Hansen’s disease) drugs 9bandAmadilos Prevalent drugs are Sulfones (Dapsone, Acedapsone) and Clofazimine (Lamprene). Totlike begrown Sulfones Dapsone (Test bummer: Application of this drug in AIDS patients is PJP, not MAC) inmate origind – (Diaminodiphenyl sulfone) is the most effective drug against M. leprae. – Mechanism: Inhibition of bacterial folic acid synthesis. Resistance can emerge if used in low doses in lepromatous leprosy. ers – Kinetics: Enterohepatic cycling, and is eliminated in the urine as acetylated metabolite. – Adverse: GI, fever, skin rash, methemoglobinemia – Hemolysis is G-6-PDH deficiency. Acedapsone: It is a repository (storage) form of dapsone that provides inhibitory concentration for several months. (Remember, dapsone is an alternative drug for Pneumocystis carinii (jirovecii) pneumonia in AIDS patients). Clofazimine: Mechanism involves DNA binding. Alternate drug for leprosy. Causes skin discoloration. CasepatientonHivdrug Dapsome used topreventPSP notformyco  Atypical mycobacterial infections (M. avium, M. avium-intracellulare, M. ulcerans, rapidly growing mycobacteria- M. marinum, M. abscessus, M. haemophilum, M. xenopi etc.) Major Antimycobacterial used: Ethambutol, Rifampin (Rifabutin alternative) etc. Other antibiotics: Erythromycin, Amikacin, AzithromycinIE for Clarithromycin, Ciprofloxacin etc. M. avium complex (MAC, MAI) causes disseminated infections in AIDS patients. Antimycobacterial agents are used along with other antibiotics.  Notquized Atypical Mycobacterial Drugs knowwhenAtypicalshappenand howtotreat Species Clinical Features Treatment Options Amikacin, clarithromycin, ethambutol, isoniazid, M kansasii Resembles tuberculosis moxifloxacin, rifampin, streptomycin, trimethoprim-sulfamethoxazole Amikacin, clarithromycin, ethambutol, doxycycline, M marinum Granulomatous cutaneous disease levofloxacin, minocycline, rifampin, trimethoprim- sulfamethoxazole Amikacin, erythromycin (or other macrolide), M scrofulaceum Cervical adenitis in children rifampin, streptomycin (Surgical excision is often curative and the treatment of choice.) Pulmonary disease in patients with chronic lung disease; Amikacin, azithromycin, clarithromycin, M avium complex (MAC) disseminated infection in AIDS ethambutol, moxifloxacin, rifabutin Amikacin, doxycycline, imipenem, linezolid, M chelonae Abscess, sinus tract, ulcer; bone, joint, tendon infection macrolides, tobramycin Amikacin, cefoxitin, ciprofloxacin, doxycycline, M fortuitum Abscess, sinus tract, ulcer; bone, joint, tendon infection imipenem, minocycline, moxifloxacin, ofloxacin, trimethoprim-sulfamethoxazole Clarithromycin, isoniazid, streptomycin, rifampin, M ulcerans Skin ulcers minocycline, moxifloxacin (Surgical excision may be effective.) Focus on Cellwallsynthesisinhibitors Antifungels Serious gram Carbopatens AmpB flocytosine Cephlasporine know name pergenerton CNS3rd levelCeph Bglucaninhibitors ends infungins Ceftriaxone ghonohnen fertenafirs pencil.ve colstridiumperinges shyphilis Vanco knowit polymixins Bactracins Antivirals Herpose A classes Influenza HPV Hep B DrugsforB DNA RTI HPEproventobecued combotherapy Pol In prot In