PCOL

• Protein Synthesis Inhibitors


  Selectively inhibit bacterial protein synthesis
• Protein synthesis in microorganisms is not identical to mammalian cells
• Bacteria

  • 70S ribosomes
  • Mammalians: 80S ribosomes
• Basis for selective toxicity


  Differences in ribosomal subunits, chemical composition, and functional specificities of component nucleic acids and proteins between microorganisms and mammalian cells
• Mechanism of action

  • Bacteriostatic
  • Bactericidal - Oxazolidinones and Pleuromutilins
• Bacterial Protein Synthesis Inhibitors

  • Broad spectrum: Chloramphenicol
  • Moderate spectrum: Macrolides
  • Narrow spectrum: Ketolides, Lincosamides
• Chloramphenicol


  • Simple and distinctive structure
  • Effective orally as well as parenterally
  • Inhibits microbial protein synthesis and is bacteriostatic against most susceptible organisms
  • Binds reversibly to the 50S subunit of the bacterial ribosome and inhibits peptide bond formation
• Chloramphenicol


  • Broad spectrum: active against both aerobic and anaerobic gram-positive and gram-negative organisms
  • Bacteriostatic
  • Bactericidal - strains of H. influenzae, N. meningitidis, and some strains of Bacteroides
  • Not active against Chlamydia species
  • Resistance is plasmid-mediated: formation of chloramphenicol acetyltransferases
• Clinical Uses of Chloramphenicol

  • Rickettsial infections: typhus and Rocky Mountain spotted fever
  • Alternative to a β-lactam antibiotic for treatment of bacterial meningitis occurring in patients who have major hypersensitivity reactions to penicillin
• Chloramphenicol Pharmacokinetics


  • IV formulation: chloramphenicol succinate (prodrug) -> hydrolyzed to yield free chloramphenicol
  • Widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid
  • Concentration in the brain tissue may be equal to that in serum
  • Penetrates cell membranes readily; readily cross the placental and blood-brain barriers
  • Inactived by: (1) conjugation with glucuronic acid or (2) reduction to inactive aryl amines
  • Excretion: Active chloramphenicol + inactive degradation products are eliminated in the urine. A small amount of active drug is excreted into bile and feces
• Chloramphenicol Toxicity


  • Gastrointestinal disturbances: Nausea, vomiting, diarrhea
  • Oral or vaginal candidiasis due to alteration of normal microbial flora
  • Bone marrow: Inhibition of red cell maturation (dose-dependent and reversible), Aplastic anemia rare idiosyncratic reaction (usually irreversible and may be fatal)
  • Gray baby syndrome: Lacks effective glucuronic acid conjugation mechanism for the degradation and detoxification, Vomiting, flaccidity, hypothermia, gray color, shock, and vascular collapse
• Chloramphenicol Drug Interactions


  Inhibits hepatic drug-metabolizing enzymes, Increasing the elimination half-lives of drugs like Phenytoin, Tolbutamide, Chlorpropamide, Warfarin
• Tetracyclines


  • Broad-spectrum, Bacteriostatic
  • Bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex and prevents addition of amino acids to the growing peptide
• Tetracycline Pharmacokinetics


  • Absorption: 60–70% for tetracycline and demeclocycline, 95–100% for doxycycline and minocycline, Tigecycline and eravacycline = intravenously
  • Absorption impaired by multivalent cations, dairy products, antacids, and alkaline pH
  • Wide tissue distribution except CSF, Cross the placental barrier and excreted in breast milk
  • Excreted mainly in bile and urine, except Doxycycline and tigecycline (eliminated by nonrenal mechanisms)
  • Short-acting – tetracycline (oral), Intermediate-acting – demeclocycline (oral), Long-acting (oral and IV)– doxycycline and minocycline, Long half-lives: Tigecycline (IV), Eravacycline (IV), Omadacycline (oral and IV)
• Tetracycline Antibacterial Activity


  • Active against gram-positive and gram-negative bacteria, certain anaerobes, rickettsiae, chlamydiae, and mycoplasmas
• Tetracycline Resistance Mechanisms


  • Impaired influx or increased efflux by an active transport protein pump
  • Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome
  • Enzymatic inactivation
• Tetracycline Clinical Uses


  • Primary uses: Mycoplasma pneumoniae (in adults), Chlamydiae, Rickettsiae, Borrelia sp., Vibrios, some spirochetes, Anaplasma phagocytophilum, Ehrlichia sp
  • Secondary uses: Community-acquired pneumonia (CAP), Syphilis, Chronic bronchitis, Leptospirosis, Acne
  • Selective uses: Gastrointestinal ulcers caused by H. pylori (tetracycline), Lyme disease (doxycycline), Meningococcal carrier state (minocycline), Malaria prophylaxis and treat ameobiasis (doxycycline), ADH-secreting tumors (demeclocycline), CONS, MRSA, VRE, Streptococci, enterococci, gram-positive rods, Enterobacteriaceae, Acinetobacter sp, anaerobes, rickettsiae, Chlamydia sp, L. pneumophila, and rapidly growing mycobacteria (tigecycline, eravacycline, omadacycline)
• Tetracycline Toxicity


  • Gastrointestinal disturbances: Nausea, vomiting, diarrhea, esophageal ulceration, life-threatening enterocolitis, candidiasis (oral and vaginal), bacterial superinfections S. aureus or C. difficile
  • Bony structures and teeth: Fetal exposure causes tooth enamel dysplasia and irregularities in bone growth, Younger children enamel dysplasia and crown deformation (permanent teeth)
  • Hepatic toxicity: high doses, pregnant patients, preexisting hepatic disease
  • Renal toxicity: Fanconi syndrome - outdated tetracyclines, Nephrotoxicity = tetracycline + diuretic, exacerbate preexisting renal dysfunction
  • Photosensitivity: Tetracyclines especially demeclocycline, enhanced skin sensitivity to ultraviolet light
  • Vestibular toxicity: Doxycycline and minocycline, Dose-dependent reversible dizziness and vertigo
• Macrolides


  • Macrocyclic lactone ring with attached sugars
  • Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA
  • Prolong the electrocardiographic QT interval due to an effect on potassium channels: torsades de pointes arrhythmia
• Macrolide Pharmacokinetics


  • Good oral bioavailability, Azithromycin absorption impeded by food
  • Distribute to most body tissues, Azithromycin: tissues and phagocytes > plasma
  • Primarily hepatic metabolism
  • Erythromycin (oral and IV) half-life: 2 hours, Clarithromycin (oral) half-life: 6 hours, Azithromycin (oral and IV) half-life 2 to 4 days
• Erythromycin Antibacterial Activity

  • Gram-positive organisms: pneumococci, streptococci, staphylococci, and corynebacteria. Mycoplasma pneumoniae, L pneumophila, Chlamydia trachomatis, Chlamydophila psittaci, Chlamydophila pneumoniae, H pylori, Listeria monocytogenes, and certain mycobacteria
  • Gram-negative organisms: Neisseria sp, Bordetella pertussis, Bartonella henselae, Bartonella quintana, some Rickettsia species, Treponema pallidum, and Campylobacter species
• Erythromycin Resistance Mechanisms


  • Reduced permeability of the cell membrane or active efflux
  • Production (by Enterobacteriaceae) of esterases that hydrolyze macrolides
  • Modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase
• Clarithromycin (oral) half-life

  6 hours
• Azithromycin (oral and IV) half-life

  2 to 4 days
• Gram-positive organisms affected by Erythromycin


  • pneumococci
  • streptococci
  • staphylococci
  • corynebacteria
  • Mycoplasma pneumoniae
  • L pneumophila
  • Chlamydia trachomatis
  • Chlamydophila psittaci
  • Chlamydophila pneumoniae
  • H pylori
  • Listeria monocytogenes
  • Mycobacterium kansasii
  • Mycobacterium scrofulaceum
• Gram-negative organisms affected by Erythromycin


  • Neisseria sp
  • Bordetella pertussis
  • Bartonella henselae
  • Bartonella quintana
  • Rickettsia species
  • Treponema pallidum
  • Campylobacter species
• Cross-resistance occurs between erythromycin and the other macrolides
• Erythromycin absorption


  Food interferes with absorption
• Erythromycin excretion


  Excreted mainly in the bile (only 5% in the urine), adjustment for renal failure not necessary
• Erythromycin distribution


  Absorbed drug is distributed widely except to the brain and cerebrospinal fluid
• Erythromycin tissue distribution


  Taken up by polymorphonuclear leukocytes and macrophages
• Erythromycin placental transfer


  Traverses the placenta and reaches the fetus
• Erythromycin clinical uses


  • Corynebacterial and chlamydial infections, M pneumoniae, and L pneumophila, useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci and streptococci
• Erythromycin adverse reactions


  • Anorexia
  • Nausea
  • Vomiting
  • Diarrhea
  • Acute cholestatic hepatitis
• Erythromycin drug interactions


  • Theophylline
  • Warfarin
  • Cyclosporine
  • Methylprednisolone
  • Digoxin
• Clarithromycin


  • More active against Mycobacterium avium complex; also has activity against M leprae, T gondii, and H influenzae
• Clarithromycin metabolism


  Metabolized in the liver and is partially eliminated in the urine
• Clarithromycin metabolite


  14-hydroxyclarithromycin (major metabolite) with antibacterial activity and eliminated in the urine
• Clarithromycin dosage adjustment


  Dosage reduction is recommended for patients with creatinine clearances less than 30 mL/min
• Clarithromycin adverse reactions


  Lower incidence of gastrointestinal intolerance