USMLE Step 1 Review Pages 288-291 First Aid, 5th Edition Monday, March 20th, 2006 By Dip Jadav Review of Definitions Bactericidal – a substance that kills organisms directly; severe, life- threatening, or complicated infections require treatment with bactericidal drugs. Bacteriostatic – a substance that stops further growth of an organism; mild, uncomplicated infections may be treated with bacteriostatic drugs. Aminoglycosides – Gentamycin, Neomycin, Amikacin, Tobramycin, Streptomycin Mechanism of Action Bactericidal. Two main capabilities. Inhibit the formation of the initiation complex, thus depleting the available ribosomal pool and leading to decreased protein synthesis. Cause misreading (and subsequent mistranslation) of mRNA, leading to faulty or truncated proteins. Aminoglycoside entry to the cytoplasm is through oxygen- dependent active transport. Anaerobic bacteria are resistant through inability to take up the drug. Facultative anaerobes can be relatively resistant if they are in an anaerobic environment. Aminoglycosides – Gentamycin, Neomycin, Amikacin, Tobramycin, Streptomycin Clinical Use Severe gram-negative rod infections. Synergistic with β-lactam antibiotics. They have different mechanisms of action, and it has been noted that their efficacy is greater when used together than would be expected if used. Neomycin has been used orally to sterilize the bowel prior to surgery. This, however, does carry the risk of the development of antibiotic-associated colitis. Aminoglycosides – Gentamycin, Neomycin, Amikacin, Tobramycin, Streptomycin Toxicity Nephrotoxicity, especially when used with cephalosporins due to their inherent nephrotoxicity. Ototoxicity, especially when used with loop diuretics due to their inherent ototoxicity. Tetracyclines – Tetracycline, Doxycycline, Demeclocycline, Minocycline Mechanism of Action Bacteriostatic. Bind reversibly to the 30S subunit of ribosomes and reduce the affinity of the aminoacyl-tRNA for the mRNA-ribosome complex, preventing elongation of the protein being synthesized. Tetracyclines – Tetracycline, Doxycycline, Demeclocycline, Minocycline Clinical Use Active against a broad spectrum of bacteria that are aerobic, anaerobic, gram-positive, and gram-negative and protozoa. VACUUM your BedRoom Tonight. Tetracyclines – Tetracycline, Doxycycline, Demeclocycline, Minocycline Toxicity GI distress. Tetracyclines are irritative. They cause epigastric burning, abdominal distress, nausea, and vomiting. Discoloration of teeth and inhibition of bone growth. Deposition of tetracyclines into teeth and bones may result from chelation of the calcium in these tissues. They may retard skeletal development in the fetus and permanently discolor tooth enamel. This can follow administration to children less than 8 years old or to pregnancy or nursing women, since tetracyclines can cross the placenta and into breastmilk. Macrolides – Erythromycin, Azithromycin, Clarithromycin Mechanism of Action Bacteriostatic. Inhibit protein synthesis by blocking translocation (the movement of the elongated peptide from the A site to the P site). Macrolides – Erythromycin, Azithromycin, Clarithromycin Clinical Use An alternative in the treatment of URIs in patients who are allergic to penicillin. STDs. Macrolides – Erythromycin, Azithromycin, Clarithromycin Toxicity GI discomfort due to ability to act as an agonist at motilin receptors, increasing gut motility. Chloramphenicol Mechanism of Action Bacteriostatic. Binds to the 50S subunit and inhibits the peptidyltransferase enzyme. This prevents the addition of new amino acids onto the growing peptide chain. Chloramphenicol Clinical Use Meningitis. In general, due to its toxicities, use chlomaphenicol only in life-threatening infections when other drugs of choice cannot be used or when it is clearly superior. Chloramphenicol Toxicity Gray baby syndrome – abdominal distention, vomiting, pallor, cyanosis, and circulatory collapse. It arises because the immature liver of the newborn or premature infant cannot conjugate chloramphenicol. Clindamycin Mechanism of Action Bacteriostatic. Block peptide bond formation at the 50S ribosomal subunit. Specifically, they may inhibit binding of aminoacyl- tRNA or Inhibit the translocation reaction once the aminoacyl-tRNA is bound. Clindamycin Clinical Use Highly effective against anaerobic bacteria, such as Clostridia and Bacteriodes. Clindamycin Toxicity While highly efficacious against anaerobic infections, Clostridia are often more resistant than other anaerobes. The inability to eradicate C. dificile may contribute to the development of antibiotic-associated pseudomembranous colitis. Sulfonamides – Sulfamethoxazole (SMX), Sulfisoxazole, Triple Sulfas Mechanism of Action Bacteriostatic. Sulfonamides are structurally related to PABA (para- aminobenzoic acid). They compete with PABA for the active site of the bacterial enzyme dihydropteroate synthetase. Dihydropteroate synthetase catalyzes the synthesis of dihydropteroic acid, an intermediate in the pathway to the synthesis of tetrahydrofolate (THF). THF acts as a coenzyme, which transports one- carbon units from one molecule to another. Needed in the synthesis of molecules such as Thymine, Purines, and f-Met-tRNA. Sulfonamides – Sulfamethoxazole (SMX), Sulfisoxazole, Triple Sulfas Clinical Use Wide variety of uses. Triple sulfas or SMX for simple UTI. Sulfonamides – Sulfamethoxazole (SMX), Sulfisoxazole, Triple Sulfas Toxicity Hypersensitivity reactions – rashes, eosinophilia, fever. Hemolysis. Blood cells use reduced glutathione to inactivate peroxides and oxygen radicals. Sulfonamides deplete the pool of reduced glutathione. In normal cells, the pool is replenished though NADPH generated when Glc-6-P is converted to 6-phosphogluconate by the dehydrogenase. Cells deficient in the enzyme are susceptible to peroxide and radical-induced hemolysis. Kernictus Bilirubin will be displaced by sulfonamides from its serum protein binding sites. The free bilirubin can then pass the blood-brain barrier of newborns and become deposited in the basal ganglia or subthalamic nuclei of the brain. Trimethoprim Mechanism of Action Bacteriostatic. Inhibits DHFR. Trimethoprim Clinical Use Extremely broad antibacterial spectrum, covering most gram-positive and gram- negative organisms. Often used in conjunction with Sulfonamides for synergistic effect. Trimethoprim Toxicity Can result in megaloblastic anemia, leucopenia, and granulocytopenia. Can be reversed by administering folinic acid (leucovorin, citrovorum). Folinic acid bypasses the trimethoprim block in the cells of the bone marrow by conversion to the one- carbon cofactor 5-methyltetrahydrofolate. Fluoroquinolones Mechanism of Action Bactericidal. Inhibits DNA topoisomerase II, which is involved in the unwinding of DNA to allow it wrap around histones for condensation. Fluoroquinolones Clinical Use The fluorine group increases activity against gram-positive organisms while other structural changes facilitate entry into gram- negative organisms. Anaerobes usually resistant. Main use is against gram-negative rods of the urinary and gastrointestinal tracts, such as Pseudomonas. Fluoroquinolones Toxicity Many. Metronidazole Mechanism of Action Bactericidal. Forms toxic metabolites. The lipid solubility of the compound allows it to diffuse easily into microorganisms. In the cell, the 5’-NO2 group is reduced by the pyruvate:ferredoxin oxidoreductase system. During this reduction reaction, short-lived, highly reactive intermediates are formed that disrupt the organism’s DNA, causing strand breaks, helix destabilization, and unwinding. Metronidazole Clinical Use Antiprotozoal – Giardia, Entamoeba, Trichomonas. Antibacterial – Bacteriodes, Clostridia. Part of triple therapy for the treatment of H. pylori. Metronidazole Toxicity Present. Polymyxins – Polymyxin B, Polymyxin E Mechanism of Action Bind to cell membranes of bacteria and disrupt their osmotic properties. Polymyxins – Polymyxin B, Polymyxin E Clinical Use Resistant gram-negative infections. Especially useful against enteric, aerobic gram-negative bacilli, such as E. coli, Klebsiella, and Pseudomonas. Polymyxins – Polymyxin B, Polymyxin E Toxicity Neurotoxicity includes paresthesias, dizziness, and ataxia. Antituberculosis Drugs First Line Drugs Combine the greatest level of efficacy with an acceptable degree of toxicity. Rifampin Ethambutol Streptomycin Pyrazinamide Isoniazid (INH) Antituberculosis Drugs Second Line Drugs Reserved for use when the bacilli exhibit or are expected to enhibit multiple resistance to the first line drugs or when one or more first line drugs are contraindicated. Cycloserine Many others Isoniazid (INH) Mechanism of Action Highly selective for mycobacteria. Inhibits synthesis of mycolic acids, which are unique constituents of mycobacterial cell walls. Isoniazid (INH) Clinical Use Tuberculosis. Only agent used alone for prophylaxis against tuberculosis. Isoniazid (INH) Toxicity Neurotoxicity. Results from the hydrazine portion of isoniazid interacting with pyridoxalphosphate, inactivating the coenzyme. PLP is a cofactor of many enzymatic reactions in the body as it is the active form of Vitamin B6. The neurotoxicity can be prevented or treated with pyridoxine (B6) administration. Rifampin Mechanism of Action Inhibits DNA-dependent RNA polymerase, thus preventing RNA synthesis. Clinical Use Tuberculosis. Others; usage against tuberculosis most common by far. Toxicity Yes, of course. Resistance Mechanisms for Various Antibiotics Mechanisms used by bacteria against antibiotics. Nonsurgical Antimicrobial Prophylaxis What we use when a patient is at risk of developing or contracting a certain condition. Done!
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