Protein Synthesis Inhibitors

Macrolides/Ketolides

• Examples: Erythromycin, Roxithromycin, Azithromycin, Clarithromycin, Telithromycin

Macrocyclic

• Example: Fidaxomicin

Lincosamides

• Example: Clindamycin

Oxazolidinones

• Examples: Linezolid, Tedizolid

Others

• Examples: Chloramphenicol, Quinupristin/Dalfopristin

Macrolides and Ketolides

• Structure: Macrocyclic lactone with one or more deoxy sugars attached.

• Erythromycin:

  • First clinical application.

  • First-line drug and alternative to penicillin in patients with β-lactam allergies.

• Clarithromycin, Roxithromycin, Azithromycin:

  • Similar to erythromycin but with improved features.

  • Clarithromycin is a methylated form of erythromycin.

  • Azithromycin has a larger lactone ring.

• Telithromycin:

  • Semisynthetic derivative of erythromycin.

  • First "ketolide" antimicrobial agent.

Mechanism of Action

• Macrolides and ketolides bind irreversibly to the 50S subunit of the bacterial ribosome.

• Inhibition: Inhibits translocation steps of protein synthesis and may interfere with transpeptidation.

• Bacteriostatic vs. Bactericidal: Generally bacteriostatic, but can be bactericidal at higher doses.

• Binding Site: Identical or close to clindamycin and chloramphenicol binding sites.

Antibacterial Spectrum

• Erythromycin:

  • Effective against many organisms similar to penicillin G.

  • Alternative for patients with penicillin allergy.

• Clarithromycin:

  • Activity similar to erythromycin.

  • Effective against Haemophilus influenzae.

  • Greater activity against intracellular pathogens like Chlamydia, Legionella, Moraxella, Ureaplasma, and Helicobacter pylori.

• Roxithromycin:

  • Long-acting, acid-stable, semisynthetic derivative of erythromycin.

  • N-oxime side chain on the lactone ring.

  • Antibacterial and antimalarial activities.

  • Concentrates in polymorphonuclear leukocytes and macrophages.

  • Exhibits intracellular bactericidal activity.

  • Enhances adhesive and chemotactic functions of cells.

  • Potent activity against Gardnerella vaginalis, Moraxella catarrhalis, Haemophilus ducreyi, etc.

• Azithromycin:

  • Less active than erythromycin against streptococci and staphylococci.

  • More active against respiratory pathogens like H. influenzae and Moraxella catarrhalis.

  • Extensive use has led to increased Streptococcus pneumoniae resistance.

• Telithromycin:

  • Antimicrobial spectrum similar to azithromycin.

  • Structural modification neutralizes common macrolide resistance mechanisms.

Clinical Uses

• Corynebacterium diphtheriae: Erythromycin or penicillin to eliminate carrier state.

• Chlamydial Infections: Azithromycin or doxycycline.

• Gram (+) Cocci: Streptococcus pyogenes, Streptococcus pneumoniae.

• Gram (+) Bacilli: Corynebacterium diphtheriae.

• Gram (-) Cocci: Moraxella catarrhalis, Neisseria gonorrhoeae.

• Gram (-) Rods: Bordetella pertussis, Campylobacter jejuni, Haemophilus influenzae, Legionella pneumophila.

• Anaerobic Organisms: Various.

• Spirochetes: Treponema pallidum.

• Mycoplasma: Mycoplasma pneumoniae, Ureaplasma urealyticum.

• Chlamydia: Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis.

• Other: Mycobacterium avium complex.

• Legionnaires Disease (Legionellosis): Fluoroquinolones or azithromycin.

• Mycoplasma Pneumonia: Azithromycin or doxycycline.

• Mycobacterium Avium Complex: Clarithromycin (with rifampin and ethambutol), or azithromycin as an alternative. Azithromycin can be used for prophylaxis in AIDS patients.

Resistance

• Mechanisms:

  1. Inability of organism to take up the antibiotic.

  2. Efflux pumps.

  3. Decreased affinity of 50S ribosomal subunit due to methylation of adenine in 23S rRNA (gram-positive organisms).

  4. Plasmid-associated erythromycin esterases (gram-negative organisms like Enterobacteriaceae).

• Erythromycin: Limited use due to increasing resistance.

• Cross-Resistance: Clarithromycin and azithromycin share cross-resistance with erythromycin.

• Telithromycin: May be effective against macrolide-resistant organisms.

Pharmacokinetics

• Erythromycin Base: Destroyed by gastric acid; requires enteric-coated or esterified forms for oral absorption.

• Acid-Stable Macrolides: Clarithromycin, roxithromycin, azithromycin, and telithromycin are acid-stable and well-absorbed.

• Food Effect:

  • Decreases absorption of erythromycin, azithromycin, and roxithromycin.

  • Increases absorption of clarithromycin.

• IV Formulations: Erythromycin and azithromycin are available in IV formulations.

• Distribution: Erythromycin distributes well to all body fluids except CSF and accumulates in prostatic fluid and macrophages.

• Hepatic Concentration: Macrolides concentrate in the liver; azithromycin and roxithromycin accumulate in neutrophils, macrophages, and fibroblasts.

• Volume of Distribution: Azithromycin has the largest volume of distribution among macrolides.

• Metabolism: Macrolides are extensively metabolized by the liver and can interfere with CYP450-metabolized drugs (e.g., theophylline, statins, antiepileptics).

• Excretion:

  • Azithromycin and erythromycin are primarily excreted in bile as active drugs.

  • Roxithromycin has partial renal excretion with enterohepatic recycling.

  • Clarithromycin is metabolized in the liver, with active drug and metabolites excreted mainly in urine (dose adjustments needed in renal impairment).

• CNS Penetration: Azithromycin and Erythromycin do not penetrate the CNS.

• Bile Excretion: Azithromycin and erythromycin and their metabolites.

• Urine Excretion: Clarithromycin appears in urine.

Drug Interactions (Inhibition of Cytochrome P450 System)

• Erythromycin, Clarithromycin, Telithromycin

• Can increase serum concentrations of:

  • Afluzosin

  • Atorvastatin

  • Carbamazepine

  • Protease inhibitors

  • Sildenafil

  • Simvastatin

  • Valproate

  • Warfarin

Adverse Effects

• Gastric Distress and Motility:

  • Most common adverse effect (especially with erythromycin).

  • May lead to poor patient compliance.

  • Other macrolides are better tolerated.

  • High doses of erythromycin can cause smooth muscle contractions, useful for gastroparesis or postoperative ileus.

• Cholestatic Jaundice:

  • Most common with the estolate form of erythromycin.

  • Reported with other formulations and agents in the class.

• Ototoxicity:

  • Transient deafness associated with erythromycin (especially at high dosages).

  • Azithromycin associated with irreversible sensorineural hearing loss.

• QTc Prolongation:

  • Macrolides and ketolides may prolong the QTc interval.

  • Use with caution in patients with proarrhythmic conditions or concomitant use of proarrhythmic agents.

• Contraindications:

  • Caution in patients with hepatic dysfunction (erythromycin, telithromycin, or azithromycin), as these drugs accumulate in the liver.

  • Severe hepatotoxicity with telithromycin has limited its use.

• Drug Interactions:

  • Erythromycin, telithromycin, roxithromycin, and clarithromycin inhibit hepatic metabolism of several drugs.

  • Interaction with digoxin (antibiotic eliminates intestinal flora that inactivates digoxin).

Macrolide Comparison

Fidaxomicin

• Class: Macrocyclic antibiotic, structurally related to macrolides.

• Mechanism of Action: Inhibits bacterial transcription by targeting the sigma subunit of RNA polymerase, leading to protein synthesis termination and cell death.

• Spectrum: Narrow spectrum, active only against gram-positive aerobes and anaerobes.

• Use: Primarily for Clostridium difficile infections.

• Resistance: No documented cross-resistance with other antibiotic classes.

• Pharmacokinetics: Minimal systemic absorption, remains in the gastrointestinal tract.

• Adverse Effects: Nausea, vomiting, abdominal pain, rare cases of anemia and neutropenia. Hypersensitivity reactions reported.

• Caution: Advised in patients with macrolide allergies.

Chloramphenicol

• Use: Restricted to life-threatening infections due to toxicity.

Mechanism of Action

• Binds reversibly to the bacterial 50S ribosomal subunit.

• Inhibits protein synthesis at the peptidyl transferase reaction.

• Inhibits protein and ATP synthesis in mammalian mitochondrial ribosomes at high concentrations, causing bone marrow toxicity.

Antibacterial Spectrum

• Active against many microorganisms:

  • Chlamydiae

  • Rickettsiae

  • Spirochetes

  • Anaerobes

• Bacteriostatic vs. Bactericidal: Primarily bacteriostatic, but may be bactericidal depending on dose and organism.

Resistance

• Mechanisms:

  • Enzymes that inactivate chloramphenicol.

  • Decreased ability to penetrate the organism.

  • Ribosomal binding site alterations.

Pharmacokinetics

• Administration: Intravenously.

• Distribution: Widely distributed throughout the body, including therapeutic concentrations in the CSF.

• Metabolism: Primarily hepatic metabolism to inactive glucuronide.

• Excretion: Via renal tubule in urine.

• Dose Adjustments: Needed in patients with liver dysfunction or cirrhosis.

• Breast Milk: Secreted into breast milk; avoid in breastfeeding mothers.

Adverse Effects

• Anemias:

  • Dose-related anemia.

  • Hemolytic anemia (in patients with glucose-6-phosphate dehydrogenase deficiency).

  • Aplastic anemia (independent of dose, may occur after therapy).

• Gray Baby Syndrome:

  • Neonates have low capacity to glucuronidate the antibiotic and underdeveloped renal function.

  • Drug accumulation interferes with mitochondrial ribosome function.

  • Causes poor feeding, depressed breathing, cardiovascular collapse, cyanosis, and death.

  • Adults receiving very high doses may also exhibit this toxicity.

• Drug Interactions:

  • Inhibits some hepatic mixed-function oxidases.

  • Prevents metabolism of drugs such as warfarin and phenytoin, potentiating their effects.

Clindamycin

• Mechanism of Action: Similar to macrolides.

• Spectrum:

  • Gram-positive bacteria (including MRSA and streptococcus).

  • Anaerobes.

• Resistance: Similar to erythromycin, with cross-resistance.

• C. difficile: Resistant to clindamycin.

• Administration: IV and oral forms (oral use limited by GI intolerance).

• Distribution: Well into body fluids, poor CSF penetration.

• Metabolism: Extensive hepatic metabolism.

• Excretion: Bile and urine.

• Urinary Tract Infections: Low urinary excretion limits use.

• Accumulation: May occur in severe renal or hepatic impairment.

• Adverse Effects:

  • Skin rash and diarrhea.

  • Pseudomembranous colitis due to C. difficile overgrowth.

• C. difficile Infections: Treated with oral metronidazole or vancomycin.

• Topical Use: Acne treatment caused by Propionibacterium acnes.

Pharmacokinetics

• Brain Penetration: Adequate levels are not achieved in the brain

• Excretion: Metabolites of clindamycin are excreted in the bile and urine.

Quinupristin/Dalfopristin

• Composition: Mixture of two streptogramins (30:70 ratio).

• Use: Reserved for severe infections caused by vancomycin-resistant Enterococcus faecium (VRE) when other options are unavailable.

Mechanism of Action

• Each component binds to a separate site on the 50S bacterial ribosome.

• Dalfopristin: Disrupts elongation by interfering with the addition of new amino acids.

• Quinupristin: Prevents elongation and causes release of incomplete peptide chains.

• Synergistic Effect: Interrupt protein synthesis.

• Activity: Bactericidal against most susceptible organisms, long PAE.

Antibacterial Spectrum

• Primarily active against gram-positive cocci, including those resistant to other antibiotics.

• Use: Treatment of E. faecium infections (including VRE strains), bacteriostatic.

• Not Effective: Against E. faecalis.

Resistance

• Mechanisms:

  • Enzymatic resistance (methylation of 23S rRNA hindering quinupristin binding).

  • Enzymatic modifications reducing bactericidal activity to bacteriostatic.

  • Plasmid-associated acetyltransferase inactivating dalfopristin.

  • Active efflux pumps lowering intracellular antibiotic levels.

Pharmacokinetics

• Administration: Intravenously.

• CSF Penetration: Does not achieve therapeutic concentrations in CSF.

• Metabolism: Hepatic metabolism.

• Excretion: Mainly in feces.

Adverse Effects

• Venous Irritation: Common when administered through a peripheral line.

• Hyperbilirubinemia: Occurs in about 25% of patients (competition for excretion).

• Arthralgia and Myalgia: Reported with higher doses.

• Drug Interactions: Inhibits cytochrome P450 CYP3A4 isoenzyme, leading to toxicities with concomitant drugs metabolized by this pathway.

Oxazolidinones (Linezolid and Tedizolid)

• Development: Synthetic oxazolidinones for combating gram-positive organisms, including resistant isolates (MRSA, VRE, penicillin-resistant streptococci).

Mechanism of Action

• Bind to the bacterial 23S ribosomal RNA of the 50S subunit.

• Inhibit formation of the 70S initiation complex and translation of bacterial proteins.

Antibacterial Spectrum

• Targets: Gram-positive bacteria (staphylococci, streptococci, enterococci, Corynebacterium, Listeria).

• Activity: Moderate activity against Mycobacterium tuberculosis.

• Use: Mainly for drug-resistant gram-positive infections.

• Activity: Generally bacteriostatic, but linezolid is bactericidal against streptococci.

• Linezolid: Alternative to daptomycin for VRE infections.

• Use: Due to bacteriostatic nature, not first-line options for MRSA bacteremia.

Resistance

• Mechanism: Reduced binding at the target site.

• Resistance Reported: S. aureus and Enterococcus sp.

• Cross-Resistance: Does not occur with other protein synthesis inhibitors.

Pharmacokinetics

• Bioavailability: High oral bioavailability, IV formulations available.

• Distribution: Widely throughout the body.

• Linezolid Metabolism: Oxidation to inactive metabolites, full pathway not completely understood.

• Linezolid Excretion: Via both renal and nonrenal routes.

• Tedizolid Metabolism: By sulfation, primarily eliminated via the liver.

• Tedizolid Excretion: Mainly excreted in the feces.

• Dose Adjustments: No dose adjustments needed for renal or hepatic dysfunction.

Adverse Effects

• Common: Gastrointestinal upset, nausea, diarrhea, headache, and rash.

• Thrombocytopenia: May occur, especially with use beyond 10 days.

• Monoamine Oxidase Inhibition: Risk of serotonin syndrome when combined with tyramine-rich foods, SSRIs, or MAO inhibitors.

• Neuropathy: Prolonged use (>28 days) linked to irreversible peripheral neuropathy and optic neuritis, potentially causing blindness.