Pharmacology 2 Overview

Pharmacology 2 Overview

• Topics covered include Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogramins, and Linezolid.

Introduction to Drug Action

• Drugs inhibit bacterial protein synthesis by binding to and interfering with ribosomes.
• Most drugs are bacteriostatic, but some are bactericidal against specific organisms.
• Tetracycline and macrolide resistance is common.

Inhibitors of Microbial Protein Synthesis

• Drugs that inhibit protein synthesis vary in chemical structures and antimicrobial activity.
• Chloramphenicol (broad spectrum).
• Macrolides (moderate spectrum).
• Ketolide (moderate spectrum).
• Lincosamides (moderate spectrum).
• Tetracyclines (broad spectrum).
• Streptogramins (broad spectrum).
• Linezolid (moderate spectrum).

Mechanisms of Action

• Most antibiotics reviewed inhibit protein synthesis at the ribosomal level.
• Binding sites for these antibiotics are on the 50S ribosomal subunit.
• Chloramphenicol inhibits transpeptidation by blocking the binding of the aminoacyl moiety of the charged tRNA acceptor site on the mRNA complex.

Chloramphenicol

• Simple and distinctive chemical structure.
• Effective orally and parenterally, crossing placental and blood-brain barriers.
• Undergoes enterohepatic cycling.
• Inactivated by hepatic glucuronosyltransferase.
• Primarily bacteriostatic, but can be bactericidal against some organisms.
• Not effective against Chlamydia species.
• Resistance is plasmid-mediated, occurring through acetyltransferases.
• Limited clinical use due to toxicity.
• Backup drug for severe Salmonella, pneumococcal, and meningococcal infections (in beta-lactam-sensitive patients).
• Sometimes used for rickettsial diseases and infections caused by anaerobes (e.g., Bacteroides fragilis).
• Commonly used as a topical antimicrobial agent.
• Toxicity includes gastrointestinal disturbances, bone marrow suppression, and gray baby syndrome.
• Drug interactions increase elimination half-lives of certain drugs (e.g., phenytoin, tolbutamide, warfarin).

Tetracyclines

• Broad-spectrum bacteriostatic antibiotics with minor differences in activity against specific organisms.
• Free tetracyclines are crystalline amphoteric substances of low solubility.
• Available as hydrochlorides, which are more soluble.
• Tetracycline solutions are acidic and fairly stable
• Tetracyclines chelate divalent metal ions – interfering with absorption and activity.
• Tigecycline is a glycylcycline and a semisynthetic derivative of minocycline.
• Oral absorption may be impaired by food and multivalent cations (calcium, iron, aluminum)
• Tetracyclines may cross the placental barrier
• Tetracyclines undergo enterohepatic cycling.
• Doxycycline is excreted primarily in feces, other tetracyclines in urine.
• Doxycycline and minocycline have longer half-lives than other tetracyclines.
• Tigecycline is formulated for IV use and has a half-life of 30-36h.
• Resistance to most tetracyclines is widespread – mechanisms include efflux pumps and ribosomal protection proteins.
• Resistance does not affect Tigecycline in most organisms
• Primary uses: infections caused by Mycoplasma pneumoniae, Chlamydiae, Rickettsiae, Vibrios, and some spirochetes.
• Secondary uses: treatment of syphilis, respiratory infections caused by susceptible organisms treatment of leptospirosis, and treatment of acne.
• selective uses: treatment of gastrointestinal ulcers caused by helicobacter pylori (tetracycline); Lyme disease (doxycycline); meningococcal carrier state (minocycline); prevention of malaria; treatment of amebiasis
• Tigecycline is for intravenous use and has broad spectrum.
• Toxicity includes gastrointestinal disturbances, bony structure and tooth effects, hepatic toxicity.
• Renal toxicity - one form of renal tubular acidosis (fanconi's syndrome) has been attributed to the use of outdated tetracyclines; Photosensitivity (demeclocycline), Vestibular toxicity (reversible dizziness and vertigo reported)

Macrolides

• Large cyclic lactone ring structures with attached sugars.

• Good oral bioavailability.

• Azithromycin absorption is impeded by food.

• Distribute to most body tissues, but azithromycin concentrates in phagocytes.

• Erythromycin (half-life 2 hours).

• Clarithromycin (half-life 6 hours).

• Azithromycin (half-life 2-4 days).

• Antibacterial activity against Campylobacter, Chlamydia, Mycoplasma, Legionella, gram-positive cocci, and some gram-negative organisms.

• Azithromycin and clarithromycin have greater activity against species of Chlamydia, Mycobacterium avium complex, and Toxoplasma.

• Azithromycin has a similar spectrum of activity, but is more active against H. influenzae, Moraxella catarrhalis, and Neisseria.

• Clinical uses: treatment of urogenital infections; community-acquired pneumonia; prophylaxis against and treatment of M avium complex; component of drug regimens for ulcers caused by H. pylori.

• Fidaxomicin (narrow-spectrum macrolide, inhibits protein synthesis). -Active against Gram positive anaerobes

• Systemic absorption is minimal

• Effective in treatment of C. difficile colitis (possibly lower relapse rate)

• Toxicity includes gastrointestinal irritation, skin rashes, eosinophilia (especially with erythromycin).

• Hypersensitivity-based acute cholestatic hepatitis (with erythromycin estolate).

• Erythromycin inhibits hepatic cytochrome P450, potentially increasing levels of other drugs (anticoagulants, carbamazepine, cisapride, digoxin, and theophylline).

• Toxicity includes gastrointestinal disturbances, bony structure effects, and hepatic toxicity.

Telithromycin (Ketolide)

• Structurally related to macrolides, similar spectrum of activity as erythromycin
• Active against some macrolide-resistant strains.
• Used in community-acquired pneumonia, including infections from multidrug resistant organisms.
• Elimination in bile and urine.
• Adverse effects include hepatic dysfunction, QTc prolongation.

Clindamycin

• Inhibits bacterial protein synthesis via a mechanism similar to macrolides, but not chemically related

• Cross-resistance between clindamycin and macrolides is common

• Mechanisms of resistance include methylation of the 50S ribosome subunit binding site; enzymatic inactivation

• Gram-negative aerobes are intrinsically resistant.

• Good tissue penetration after oral absorption

• Metabolites are eliminated via biliary and renal excretion.

• Clinical uses: severe infections caused by anaerobes; gram-positive cocci; prophylaxis of endocarditis.

• Combination with pyrimethamine for AIDS-related toxoplasmosis.

• Toxicity includes gastrointestinal irritation, skin rashes, neutropenia and possible superinfections (e.g., C. difficile colitis).

Streptogramins

• Combination of two streptogramins (quinupristin-dalfopristin)
• Bactericidal activity with longer duration (post-antibiotic effects).
• Active against pneumococci, MRSA, VRSA & E. Faecium.
• Administered intravenously.
• Potential for pain and arthralgia-myalgia syndrome. -Potent inhibitors of CYP3A4 increasing plasma levels of many drugs (e.g., astemizole, cisapride, cyclosporine, diazepam, non nucleoside reverse transcriptase inhibitors (NNRTI), and warfarin)

Linezolid

• Novel class of antibiotics (oxazolidinones)
• Active against drug-resistant gram-positive cocci (MRSA, PRSP, VRE).
• Active against L. monocytogenes and corynebacteria.
• Binds to unique site on 23S ribosomal RNA of 50S subunit.
• No cross-resistance with other protein synthesis inhibitors.
• Available as oral and parenteral forms
• Eliminated by the liver (4-6 hour half life)
• Toxicity includes thrombocytopenia and neutropenia
• Possible serotonin syndrome when given with SSRIs