PM 716 Pharmacology I Anti-TB Slides PDF

PM 716 Pharmacology I Chapter 47 Antimycobacterials RMRocco, PhD PM716 C47 AntiTB 1  Tuberculosis Death Rate Per Year Per 100 000 People in 1939 Chile 253 Japan 209 France 118 England 64 US 50...

PM 716 Pharmacology I Chapter 47 Antimycobacterials RMRocco, PhD PM716 C47 AntiTB 1  Tuberculosis Death Rate Per Year Per 100 000 People in 1939 Chile 253 Japan 209 France 118 England 64 US 50 PM716 C47 AntiTB 2  Mycobacterium tuberculosis At the start of the 20th century, the leading cause of death among children under the age of 10 years. Major source of M. tuberculosis, raw milk. In attempt to eradicate the disease among children, US government in 1925 institutes national requirement that all milk must be pasteurized. PM716 C47 AntiTB 3 Mycobacterium tuberculosis 1882 R. Koch discovers stain for TB Aerobic bacteria “acid- fast” rods 1940 TB was a leading cause of death (> 20 million/year worldwide) Penicillin ineffective against TB PM716 C47 AntiTB 4  M. tuberculosis Diagnosis Positive PPD (tuberculin) skin test at 48 h Purified Protein Derivative of cell wall glycolipids highly enriched in M. tuberculosis. Positive sputum stain for acid-fast bacillus Organism cell wall contains 60% long chain fatty acids called mycolic acids. Auramine O fluorescence and Kinyoun dyes stain with some selectivity. Clinical signs, symptoms and chest films. PM716 C47 AntiTB 5  M. tuberculosis Typical patient presentation: cough for several weeks recent weight loss night sweats, subjective feeling of fatigue emigrant from country with endemic TB chest films with atypical infiltrates PM716 C47 AntiTB 6 Chapter 47 Antimycobacterial Drugs PM716 C47 AntiTB 7 © The McGraw-Hill Companies, Inc,  Isoniazid Structure similar to pyridoxine Active against intra and extracellular organisms. Isoniazid inhibits mycolic acid synthesis in mycobacterial cell walls. A prodrug that is converted into a drug by bacterial enzyme. Main action is to inhibit mycolic acid production. PM716 C47 AntiTB 8  Isoniazid Use of a single agent leads to resistance. Lesions often contain 1 mutant resistant organism per 106 total organisms. The probability of an organism developing two different mutations to two different drugs (with different mechanisms of action) is 1 in 106 (a x 106) = 1 x 1012 Two different drugs always combined to prevent resistance. PM716 C47 AntiTB 9  Isoniazid Dosing is based on rapid vs slow acetylators (pharmacogenomics). Drug administered along with pyridoxine (PYD). Most common ADR is drug induced hepatitis. Many patients develop elevated AST which does not lead to hepatitis. PM716 C47 AntiTB 10  Isoniazid 10-20% patients develop peripheral neuropathy (PN) (dose dependent). PN caused by pyridoxine deficiency, because isoniazide promotes excretion of pyridoxine. Reason pyridoxine is given with isoniazid. PM716 C47 AntiTB 11  Rifampin Semisynthetic produced by Streptomyces mediterranei. Resistant mutants found at 1 x 106. Never used alone. Drug inhibits RNA synthesis through inhibition of a bacterial DNA-dependent RNA polymerase. PM716 C47 AntiTB 12  Rifampin ADR includes yellow urine, sweat, tears, contact lenses permanently stained. PM716 C47 AntiTB 13  Ethambutol Synthetic that inhibits mycobacterial arabinosyl transferase required for cell wall synthesis. Most common ADR is red-green color blindness. Not indicated for children too young to permit assessment of color blindness. PM716 C47 AntiTB 14  Pyrazinamide Mycobacterium convert the prodrug pyrazinamide into pyrazinoic acid, the active drug. Drug inhibits cell wall synthesis and/or function in an unknown way. May induce acute gouty arthritis. PM716 C47 AntiTB 15 The Search for New Antibiotics Albert Schatz Selman Waksman (1920 - 2005) (1888-1973) PM716 C47 AntiTB 16 Streptomyces Gram Pos anaerobic soil bacterium Resemble fungi but are true prokaryotes Give soil its smell Mycobacterium carried by cows. Mycobacterium added to soil causes death of the TB organism. PM716 C47 AntiTB 17 Albert Schatz (1920-2005) A. Schatz discharged from the army in 1943 and starts graduate work at Rutgers U., in New Jersey under S. Waksman. October 19, 1943 Schatz isolates Streptomycin from Actinomyces. PM716 C47 AntiTB 18 Streptomycin Jones, D., Metzger, H. J., Schatz, A., Waksman, S. Control of gram- negative bacteria in experimental animas by streptomycin. Science 100(2588): 103-105 (1944) August 4 PM716 C47 AntiTB 19 Streptomyces October 19, 1943 Schatz isolates “antibiotic” that inhibits TB Schatz names compound “streptomycin”. Waksman coins word “antibiotic” Schatz-Waksman US Patent 2, 449, 866 assigned to Rutgers University. PM716 C47 AntiTB 20  Streptomycin Schatz, A., Waksman, S. A. Effect of streptomycin upon Mycobacterium tuberculosis and related organisms. Proc. Soc. Exp. Biol. Med. 67:244-248 (1944) PM716 C47 AntiTB 21 Streptomycin Mechanism of action against M. tuberculosis. PM716 C47 AntiTB 22  Streptomycin Corwin and Feldman at the Mayo Clinic inject streptomycin into a human being for the first time, November 20, 1944. A 21 year old with advanced TB. After 5 months of injections, patient becomes free of TB. For the first time in history a patient is cured of TB In the US alone death rate from TB falls from 50/100 000 in 1939 to 7/100 000 in 1947. PM716 C47 AntiTB 23 Randomized Clinical Trial (RCT) Medical Research Council Streptomycin in Tuberculosis Trials Committee Streptomycin treatment for pulmonary tuberculosis. British Medical Journal 2:769-783 (1948) One of the first double blind clinical trials of a drug with the use of randomization for placebo vs drug selection. PM716 C47 AntiTB 24  Streptomycin Waksman becomes international hero and never talks about Schatz except as “a graduate student who helped.” Schatz earns his PhD, leaves Rutgers in 1946 for teaching position at Brooklyn College at $4 950/year. The royalty on Schatz-Waksman Patent assigned to Rutgers U.---$200 000/month (1940’s dollars). (New car $900; Apt Rent $40/month; One year at Harvard $420). PM716 C47 AntiTB 25  Streptomycin On March 10, 1950 Schatz files suit against Waksman because Waksman had made a separate private deal with Merck which earned him up to $350 000 to date. Schatz sues for recognition to be named co- discover and wins. PM716 C47 AntiTB 26 S. Waxsman, Nobel Prize, 1952 PM716 C47 AntiTB 27 PM716 C47 AntiTB 28  Antibiotics from Streptomyces 1999 World Market for antibiotics about $23 billion dollars. About 200 different antibiotics available. About 8100 different antibiotics discovered and described as of 1999. Over 50% have been found in Streptomycetes species of bacteria. PM716 C47 AntiTB 29  Second-Line Drugs to Treat TB Used only when (a) resistance to first-line drugs (b) first-line drugs fail (c) first-line ADRs limits compliance PM716 C47 AntiTB 30  Second-Line Drugs Ethionamide: similar to isoniazide, inhibits mycolic acid synthesis Capreomycin: im, protein synthesis inhibitor Cycloserine: cell wall synthesis inhibitor, see Chap 43 Aminosalicylic acid (PAS): folate synthesis inhibitor. PM716 C47 AntiTB 31  Second-Line Drugs Kanamycin & Amikacin: aminoglycosides, Chap 45 Fluoroquinolones: Chap 46 Linezolid: Chap 44 Rifabutin: similar to rifampin Rifapentine: analog of rifampin Bedaquiline: inhibits ATP synthesis (first new mechanism since 1971) PM716 C47 AntiTB 32  Leprosy Hansen’s Disease Causative bacterium (Mycobacterium leprae) has never been grown in vitro, only in mouse footpads. Dapsone & other sulfones: related to sulfa drugs, inhibits folate synthesis. PM716 C47 AntiTB 33  Dapsone The world’s first drug used to treat leprosy. Discovered in the early 1940’s. Derived from the sulfonamides, dapsone inhibits folic acid synthesis, stops DNA Often used in combination with rifampin to prevent resistance. Drug retained in skin which makes if effective for treating skin lesions. PM716 C47 AntiTB 34  Dapsone t1/2 = 1-2 days, perfect for once daily dosing. G6PD deficient patients can develop red cell hemolysis Rifampin, given in combination with dapsone Clofazimine is a dye with an unknown mechanism of action, t1/2 2 months, ADR, stains skin. PM716 C47 AntiTB 35  Leprosy Rifampin: see op cit Clofazimine: phenazine dye. PM716 C47 AntiTB 36  Preparations Available Drugs for TB: 12 with all different names (sorry) Drugs for Leprosy: 3, clofazimine, dapsone, rifampin PM716 C47 AntiTB 37  Case Study 45-year old male, 2 month history fatigue, weight loss, fever, night sweats and productive cough. Chest film shows right apical infiltrate. Placed on TB isolation. Patient has positive bacilli in sputum and is HIV positive. PM716 C47 AntiTB 38  Case Study Four drugs in combination is required. Rifampin, isoniazid, pyrazinamide, ethambutol. Anti-retroviral (HIV) drugs can cause serious drug-drug interactions with Anti-TB drugs and this needs to be examined before starting drug therapy for TB. PM716 C47 AntiTB 39