Pharmacology 2 - Antibacterial Protein Synthesis PDF

Pharmacology 2 Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogramins, & Linezolid Introduction Introduction The drugs -inhibit bacterial protein synthesis by binding to and interfering with ribosomes. -Most are bacteriostatic, but a few are bactericidal against certain organis...

Pharmacology 2 Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogramins, & Linezolid Introduction Introduction The drugs -inhibit bacterial protein synthesis by binding to and interfering with ribosomes. -Most are bacteriostatic, but a few are bactericidal against certain organisms. Tetracycline and macrolide resistance is common. INHIBITORS OF MICROBIAL PROTEIN SYNTHESIS Drugs that inhibit protein synthesis vary considerably in terms of chemical structures and their spectrum of antimicrobial activity. MECHANISMS OF ACTION Most of the antibiotics reviewed in this chapter are bacteriostatic inhibitors of protein synthesis acting at the ribosomal level the binding sites for these antibiotics are on the 50S ribosomal subunit. Chloramphenicol inhibits transpeptidation (catalyzed by peptidyl transferase) by blocking the binding of the aminoacyl moiety of the charged (tRNA) acceptor site on (mRNA) complex CHLORAMPHENICOL A. Classification and Pharmacokinetics has a simple and distinctive structure, and no other antimicrobials have been discovered in this chemical class. effective orally as well as parenterally and is widely distributed, readily crossing the placental and blood-brain barriers. undergoes enterohepatic cycling, and a small fraction of the dose is excreted in the urine unchanged. Most drug is inactivated by a hepatic glucuronosyltransferase CHLORAMPHENICOL B. Antimicrobial Activity has a wide spectrum of antimicrobial activity and is usually bacteriostatic. Some strains of Haemophilus influenzae, Neisseria meningitidis, and Bacteroides are highly susceptible, and for these organisms chloramphenicol may be bactericidal. It is not active against Chlamydia species. Resistance to chloramphenicol, which is plasmid-mediated, occurs through the formation of acetyltransferases that inactivate the drug. CHLORAMPHENICOL C. Clinical Uses Because of its toxicity, chloramphenicol has very few uses as a systemic drug. It is a backup drug for severe infections caused by Salmonella species and for the treatment of pneumococcal and meningococcal meningitis in beta-lactam-sensitive persons. sometimes used for rickettsial diseases and for infections caused by anaerobes such as Bacteroides fragilis. is commonly used as a topical antimicrobial agent CHLORAMPHENICOL D. Toxicity 1.Gastrointestinal disturbances—These conditions may occur from direct irritation and from superinfections, especially candidiasis. 2. Bone marrow—Inhibition of red cell maturation leads to a decrease in circulating erythrocytes. This action is dose-dependent and reversible 3. Gray baby syndrome—This syndrome occurs in infants and is characterized by decreased red blood cells, cyanosis, and cardiovascular collapse 4. Drug interactions—Chloramphenicol inhibits hepatic drug metabolizing enzymes, thus increasing the elimination half-lives of drugs including phenytoin, tolbutamide and warfarin. TETRACYCLINES TETRACYCLINES -Free tetracyclines are crystalline amphoteric substances of low solubility. - are available as hydrochlorides, which are more soluble. - Such solutions are acidic and fairly stable. - Tetracyclines chelate divalent metal ions, which can interfere with their absorption and activity. - Tigecycline is a glycylcycline and a semisynthetic derivative of minocycline. TETRACYCLINES A. Classification Drugs in this class are broad-spectrum bacteriostatic antibiotics that have only minor differences in their activities against specific organisms. TETRACYCLINES B. Pharmacokinetics Oral absorption, may be impaired by foods and multivalent cations (calcium, iron, aluminum). Tetracyclines may -cross the placental barrier. All the tetracyclines undergo enterohepatic cycling. Doxycycline is excreted mainly in feces; the other drugs are eliminated primarily in the urine. The half-lives of doxycycline and minocycline are longer than those of other tetracyclines. Tigecycline, formulated only for IV use, is eliminated in the bile and has a half-life of 30–36 h TETRACYCLINES C. Antibacterial Activity Tetracyclines are broad-spectrum antibiotics with activity against gram- positive and gram-negative bacteria -resistance to most tetracyclines is widespread. Resistance mechanisms includes: the development of mechanisms (efflux pumps) for active extrusion of tetracyclines and the formation of ribosomal protection proteins that interfere with tetracycline binding. These mechanisms do not confer resistance to tigecycline in most organisms, with the exception of the multidrug efflux pumps of Proteus and Pseudomonas species. TETRACYCLINES D. Clinical Uses 1. Primary uses—Tetracyclines are recommended in the treat ment of infections caused by Mycoplasma pneumoniae (in adults), chlamydiae, rickettsiae, vibrios, and some spirochetes. Doxycycline is currently an alternative to macrolides in the initial treatment of community-acquired pneumonia. 2. Secondary uses—Tetracyclines are alternative drugs in the treatment of syphilis. -also used in the treatment of respiratory infections caused by susceptible organisms, for prophylaxis against infection in chronic bronchitis, treatment of leptospirosis, and treatment of acne. TETRACYCLINES D. Clinical Uses 3. Selective uses —Specific tetracyclines are used in the treatment of gastrointestinal ulcers caused by Helicobacter pylori (tetracycline), — in Lyme disease (doxycycline), and — in the meningococcal carrier state (minocycline). Doxycycline is also used for the prevention of malaria and in the treatment of amebiasis Demeclocycline inhibits the renal actions of antidiuretic hormone (ADH) and is used in the management of patients with ADH-secreting tumors TETRACYCLINES D. Clinical Uses 4. Tigecycline—Unique features of this glycylcycline derivative of minocycline include a broad spectrum of action that includes organ isms resistant to standard tetracyclines. The antimicrobial activity of tigecycline includes gram-positive cocci resistant to methicillin (MRSA strains) and vancomycin (VRE strains), beta-lactamase–producing gram-negative bacteria, anaerobes, chlamydiae, and mycobacteria. The drug is formulated only for intravenous use. TETRACYCLINES E. Toxicity 1. Gastrointestinal disturbances—Effects on the gastrointestinal system range from mild nausea and diarrhea to severe, possibly life- threatening enterocolitis 2. Bony structures and teeth—Fetal exposure to tetracyclines may lead to tooth enamel dysplasia and irregularities in bone growth. 3. Hepatic toxicity—High doses of tetracyclines, especially in pregnant patients and those with preexisting hepatic disease, may impair liver function and lead to hepatic necrosis. TETRACYCLINES E. Toxicity 4. Renal toxicity—One form of renal tubular acidosis, Fanconi’s syndrome, has been attributed to the use of outdated tetracyclines. -tetracyclines may exacerbate preexisting renal dysfunction. 5. Photosensitivity—demeclocycline, may cause enhanced skin sensitivity to ultraviolet light. 6. Vestibular toxicity—reversible dizziness and vertigo have been reported with doxycycline and minocycline MACROLIDES MACROLIDES A. Classification and Pharmacokinetics The macrolide antibiotics (erythromycin, azithromycin, and clarithromycin) are large cyclic lactone ring structures with attached sugars. The drugs have good oral bioavailability, but azithromycin absorption is impeded by food. Macrolides distribute to most body tissues, but azithromycin is unique in that the levels achieved in tissues and in phagocytes The elimination of erythromycin (via biliary excretion) and clarithromycin is fairly rapid (half-lives of 2 and 6 h, respectively). Azithromycin is eliminated slowly (half-life 2–4 d) MACROLIDES B. Antibacterial Activity Erythromycin has activity against many species of Campylobacter, Chlamydia, Mycoplasma, Legionella, gram-positive cocci, and some gram-negative organisms. The spectra of activity of azithromycin and clarithromycin are similar but include greater activity against species of Chlamydia, Mycobacterium avium complex, and Toxoplasma. MACROLIDES B. Antibacterial Activity Erythromycin has activity against many species of Campylobacter, Chlamydia, Mycoplasma, Legionella, gram-positive cocci, and some gram-negative organisms. The spectra of activity of azithromycin and clarithromycin are similar but include greater activity against species of Chlamydia, Mycobacterium avium complex, and Toxoplasma. MACROLIDES C. Clinical Uses Azithromycin has a similar spectrum of activity but is more active against H influenzae, Moraxella catarrhalis, and Neisseria. Because of its long half-life, a single dose of azithromycin is effective in the treatment of urogenital infections caused by C trachomatis, and a 4-d course of treatment has been effective in community- acquired pneumonia. Clarithromycin has almost the same spectrum of antimicrobial activity and clinical uses as erythromycin. The drug is also used for prophylaxis against and treatment of M avium complex and as a component of drug regimens for ulcers caused by H pylori. MACROLIDES C. Clinical Uses Fidaxomicin is a narrow-spectrum macrolide antibiotic that inhibits protein synthesis and is selectively active against gram-positive aerobes and anaerobes. Given orally, systemic absorption is minimal. Fidaxomicin has proved to be as effective as vancomycin for the treatment of C difficile colitis, possibly with lower relapse rate. MACROLIDES D. Toxicity Adverse effects, especially with erythromycin, include gastrointestinal irritation (common) via stimulation of motolin receptors, skin rashes, and eosinophilia. A hypersensitivity-based acute cholestatic hepatitis may occur with erythromycin estolate. Hepatitis is rare in children, erythromycin estolate in the pregnant patient. Erythromycin inhibits several forms of hepatic cytochrome P450 and can increase the plasma levels of many drugs, including anticoagulants, carbamazepine, cisapride, digoxin, and theophylline. TELITHROMYCIN Telithromycin is a ketolide structurally related to macrolides. The drug has the same mechanism of action as erythromycin and a similar spectrum of antimicrobial activity. However, some macrolide-resistant strains are susceptible to telithromycin. used in community-acquired pneumonia including infections caused by multidrug-resistant organisms. given orally once daily and is eliminated in the bile and the urine. The adverse effects of telithromycin include hepatic dysfunction and prolongation of the QTc interval. CLINDAMYCIN A. Classification and Pharmacokinetics inhibits bacterial protein synthesis via a mechanism similar to that of the macrolides, although it is not chemically related. Mechanisms of resistance include methylation of the binding site on the 50S ribosomal subunit and enzymatic inactivation. Gram-negative aerobes are intrinsically resistant. Cross-resistance between clindamycin and macrolides is common. Good tissue penetration occurs after oral absorption. Clindamycin undergoes hepatic metabolism, and both intact drug and metabolites are eliminated by biliary and renal excretion. CLINDAMYCIN B. Clinical Use and Toxicity The main use of clindamycin is in the treatment of severe infec tions caused by certain anaerobes such as Bacteroides. Clindamycin has been used as a backup drug against gram-positive cocci (it is active against community-acquired strains of methicillin- resistant S aureus) and is recommended for prophylaxis of endocarditis in valvular disease patients who are allergic to penicillin. The drug is also active against Pneumocystis jirovecii and is used in combina tion with pyrimethamine for AIDS-related toxoplasmosis. The toxicity of clindamycin includes gastrointestinal irritation, skin rashes, neutropenia, hepatic dysfunction, and possible superinfections such as C difficile pseudomembranous colitis. STREPTOGRAMINS Quinupristin-dalfopristin, a combination of 2 streptogramins, is bactericidal and has a duration of antibacterial activity longer than the half-lives of the 2 compounds (post antibiotic effects). Antibacterial activity includes penicillin-resistant pneumococci, methicillin-resistant (MRSA) and vancomycin-resistant staphylococci (VRSA), and resistant E faecium; Administered intravenously, the combination product may cause pain and an arthralgia-myalgia syndrome. Streptogramins are potent inhibitors of CYP3A4 and increase plasma levels of many drugs, including astemizole, cisapride, cyclosporine, diazepam, non nucleoside reverse transcriptase inhibitors, and warfarin. LINEZOLID The first of a novel class of antibiotics (oxazolidinones), linezolid is active against drug-resistant gram-positive cocci, including strains resistant to penicillins (eg, MRSA, PRSP) and vancomycin (eg, VRE). The drug is also active against L monocytogenes and corynebacteria. Linezolid binds to a unique site located on the 23S ribosomal RNA of the 50S ribosomal subunit, and there is currently no cross-resistance with other protein synthesis inhibitors. LINEZOLID Resistance (rare to date) involves a decreased affinity of linezolid for its binding site. Linezolid is available in both oral and parenteral formulations and should be reserved for treatment of infections caused by multidrug resistant gram-positive bacteria. The drug is metabolized by the liver and has an elimination half-life of 4– 6 h. Thrombocytopenia and neutropenia occur, most commonly in immunosuppressed patients. Linezolid has been implicated in the serotonin syndrome when used in patients taking selective serotonin reuptake inhibitors (SSRIs)