Lecture 12 - Antibiotics II - Drugs that Inhibit Protein Synthesis

‭Vancomycin‬ ‭MOA‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ I‭ nhibits cell wall synthesis by binding with pre-cursor molecules needed for synthesis‬ ‭Not a beta-lactam‬ ‭Does not interact with PBPs‬ ‭Bactericidal‬ ‭Indications‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭ ram (+) infections only‬ G ‭Methicillin-Resistant‬‭S. Aureus‬‭(‭M ‬ RSA‬‭)‬ ‭C. diff‬‭: Severe cases‬ ‭Alternative to PCN (allergy)‬ ‭Pharmacokinetics/Dynamics‬ ‭●‬ ‭Poor GI absorption if given orally‬ ‭○‬ ‭Can be given orally for‬‭C. diff‬‭infection‬ ‭●‬ ‭Can cross the placenta and CSF‬ ‭●‬ ‭Renal or fecal excretion‬ ‭○‬ ‭Renal impairment → decrease dose‬ ‭Adverse Effects‬ ‭●‬ ‭Nephrotoxicity‬ ‭○‬ ‭Dose-related‬ ‭○‬ ‭Monitor serum creatinine (clearance)‬ ‭●‬ ‭Thrombophlebitis‬ ‭●‬ ‭Potential ototoxicity with some drugs‬ ‭○‬ ‭Rare and reversible‬ ‭●‬ ‭Patients should be monitored if on nephrotoxic or ototoxic drugs‬ ‭●‬ ‭Hypersensitivity reactions‬ ‭○‬ ‭“Red Man Syndrome”‬ ‭○‬ ‭3-47% affected‬ ‭Red Man Syndrome‬ ‭●‬ ‭Caused by rapid IV infusion (< 1 hour) of initial dose‬ ‭●‬ ‭Stimulates histamine release‬ ‭●‬ ‭Effects:‬ ‭○‬ ‭Flushing‬ ‭○‬ ‭Rash‬ ‭○‬ ‭Burning, pruritus‬ ‭‬ ○ ‭○‬ ‭○‬ ‭○‬ ‭ rticaria‬ U ‭Tachycardia‬ ‭Angioedema (rare)‬ ‭Hypotension‬ ‭Nursing Action‬ ‭●‬ ‭Depends on protocol‬ ‭○‬ ‭Slow infusion; contact provider‬ ‭○‬ ‭Stop infusion; contact provider‬ ‭●‬ ‭Monitor:‬ ‭○‬ ‭IV site‬ ‭○‬ ‭Infusion rate‬ ‭○‬ ‭S/S of hypersensitivity‬ ‭○‬ ‭BP, vital signs‬ ‭○‬ ‭Kidney function (I/O, creatinine)‬ ‭○‬ ‭Hearing, ringing in ears, balance, dizziness‬ ‭●‬ ‭Evidence of an adverse effect:‬ ‭○‬ ‭S/S of nephrotoxicity (cloudy/pink urine)‬ ‭○‬ ‭S/S of superinfection (ex. Cramping, diarrhea)‬ ‭○‬ ‭S/S of disturbed auditory perceptions‬ ‭●‬ ‭Evaluate for therapeutic effects‬ ‭Telavancin‬ ‭●‬ ‭Synthetic derivative of vancomycin‬ ‭MOA‬ ‭ ‬ I‭ nhibits wall synthesis by binding with membrane and disrupts membrane function‬ ● ‭●‬ ‭Bactericidal‬ ‭Indications‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭ ram (+) infections only‬ G ‭MRSA‬ ‭Streptococcus‬ ‭Enterococcus‬ ‭Should be reserved for vancomycin-resistant infections‬ ‭Alternative to linezolid or daptomycin‬ ‭Pharmacokinetics/Dynamics‬ ‭‬ G ● ‭ iven parenterally‬ ‭●‬ ‭90% protein binding‬ ‭ ‬ ‭Lower dosage for patients with lower protein levels‬ ○ ‭○‬ ‭Determines amount of free drug‬ ‭○‬ ‭Competition for binding‬ ‭ ‬ ‭Renal excretion‬ ● ‭Adverse Effects‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭ aste disturbance, N/V‬ T ‭Nephrotoxicity‬ ‭Red Man Syndrome‬ ‭Prolonged QT interval‬ ‭Aztreonam‬ ‭●‬ ‭Prototype: Monobactam‬ ‭MOA‬ ‭ ‬ I‭ nhibits bacterial cell wall synthesis‬ ● ‭●‬ ‭Highly resistant to beta-lactamases‬ ‭○‬ ‭Has a beta-lactam ring but not used with a second ring‬ ‭●‬ ‭Bactericidal‬ ‭Indications‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭ arrow-spectrum; gram (-) aerobic bacteria‬ N ‭Neisseria‬ ‭H. influenzae‬ ‭P. aeruginosa‬ ‭E. coli, Klebsiella, Proteus, Serratia, Salmonella, Shigella‬ ‭Pharmacokinetics/Dynamics‬ ‭‬ G ● ‭ iven parenterally‬ ‭●‬ ‭Widely distributed, can reach therapeutic concentrations in the CSF‬ ‭●‬ ‭Renal excretion‬ ‭Adverse Effects‬ ‭●‬ ‭Pain, thrombophlebitis‬ ‭Bacteriostatic Inhibitors of Protein Synthesis‬ ‭‬ T ● ‭ etracyclines‬ ‭●‬ ‭Macrolides‬ ‭●‬ ‭Clindamycin‬ ‭Tetracyclines‬ ‭General Characteristics‬ ‭●‬ ‭Broad-spectrum‬ ‭●‬ ‭Similar actions but differ in pharmacokinetic properties‬ ‭○‬ ‭Absorption, distribution, metabolism, excretion‬ ‭Examples‬ ‭●‬ ‭Tetra‬‭cycline‬ ‭●‬ ‭Demeclo‬‭cycline‬ ‭●‬ ‭Mino‬‭cycline‬ ‭●‬ ‭Doxy‬‭cycline‬ ‭MOA‬ ‭●‬ I‭ nhibit protein synthesis by binding to the bacterial 30s ribosome and preventing the‬ ‭binding of tRNA to the mRNA-ribosome complex‬ ‭Selective Toxicity‬ ‭●‬ ‭Tetracycline enters bacteria via active transport‬ ‭●‬ ‭Mammalian cells do not have this transport system‬ ‭●‬ ‭Humans have different ribosomal complex‬ ‭Mechanisms of Resistance‬ ‭●‬ ‭Produce proteins that protect ribosomes‬ ‭●‬ ‭Develop mechanisms to actively transport drug out of cytoplasm‬ ‭Indications‬ ‭●‬ ‭Acne: Topical form is used commonly‬ ‭○‬ ‭Tx with tetracycline‬ ‭●‬ ‭Helicobacter pylori‬ ‭●‬ ‭Rickettsial diseases (ex. Rock Mountain Spotted Fever)‬ ‭○‬ ‭Tx with doxycycline‬ ‭●‬ ‭Lyme disease (‬‭B. burgdorferi‬‭)‬ ‭●‬ ‭Chlamydia trachomatis‬ ‭●‬ ‭Mycoplasma pneumoniae‬ ‭ harmacokinetics‬ P ‭Duration of Action‬ ‭●‬ ‭Short, intermediate, long-acting‬ ‭●‬ ‭Determined by lipid-solubility of the drug‬ ‭○‬ ‭More lipid-soluble → longer duration‬ ‭Absorption‬ ‭●‬ ‭Variable impact of food on absorption‬ ‭●‬ ‭Forms non-soluble chelates with certain metal ions‬ ‭○‬ ‭Calcium, iron, magnesium, zinc, aluminum‬ ‭●‬ ‭Chelate formation decreases absorption‬ ‭●‬ ‭Avoid taking with:‬ ‭○‬ ‭Calcium supplements‬ ‭○‬ ‭Milk/dairy products‬ ‭○‬ ‭Magnesium-containing laxatives‬ ‭○‬ ‭Antacids‬ ‭○‬ ‭Iron supplements‬ ‭Hepatic and Renal Elimination‬ ‭●‬ ‭Short/intermediate: Renal elimination‬ ‭●‬ ‭Long-acting: Hepatic elimination‬ ‭Adverse Effects‬ ‭●‬ ‭Gi irritation‬ ‭●‬ ‭Bones/teeth discoloration‬ ‭●‬ ‭Superinfections‬ ‭●‬ ‭Hepatotoxicity‬ ‭●‬ ‭Renal toxicity‬ ‭●‬ ‭Photosensitivity (ex. sunburn)‬ ‭Administration Considerations‬ ‭●‬ ‭Drug/food interactions‬ ‭●‬ ‭Monitor liver and kidney function‬ ‭●‬ ‭Avoid in pregnancy/breastfeeding‬ ‭●‬ ‭Not safe in children under 8 years old‬ ‭○‬ ‭Binding to calcium‬ ‭○‬ ‭Enamel still forming‬ ‭●‬ ‭Photosensitivity‬ ‭○‬ ‭Avoid the sun‬ ‭●‬ ‭Can interfere with digoxin‬ ‭Macrolides‬ ‭‬ B ● ‭ road-spectrum‬ ‭●‬ ‭Bacteriostatic‬ ‭‬ L ● ‭ arge chemical structure‬ ‭●‬ ‭Prototype: Erythromycin‬ ‭○‬ ‭Clarithromycin, azithromycin‬ ‭MOA‬ ‭ ‬ I‭ nhibit protein synthesis by binding to the bacterial 50s ribosome‬ ● ‭●‬ ‭Prevents additional amino acids being added to the peptide chain‬ ‭Indications‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭ ost gram-positive; some gram-negative‬ M ‭Patients with PCN allergy‬ ‭Whooping cough (‬‭Bordetella pertussis)‬ ‭Diphtheria (‬‭Corynebacterium diphtheria‬‭)‬ ‭Prophylactic tx of newborns: Eye ointment‬ ‭Pharmacokinetics‬ ‭‬ A ● ‭ bsorption variable‬ ‭●‬ ‭Wide distribution, but CSF penetration poor‬ ‭●‬ ‭Primarily eliminated by CYP3A4 of P450 system‬ ‭Resistance‬ ‭‬ P ● ‭ roduction of a pump that exports the drug‬ ‭●‬ ‭Ability to modify ribosomes so that macrolides are unable to bind and disrupt protein‬ ‭synthesis‬ ‭Adverse Effects‬ ‭GI Side-Effects‬ ‭●‬ ‭Most common‬ ‭●‬ ‭Epigastric pain, N/V, diarrhea‬ ‭●‬ ‭Reduce by taking with meals (only if necessary)‬ ‭Cardiotoxicity: QT Prolongation‬ ‭●‬ ‭QT Wave: Depolarization/repolarization of ventricles‬ ‭●‬ ‭Increased risk when using macrolides with drugs that inhibit CYP3A4 enzymes‬ ‭●‬ ‭Risk for sudden cardiac death ↑ 5x when erythromycin combines w/ a CYP3A4 inhibitor‬ ‭Clindamycin‬ ‭Indications‬ ‭●‬ ‭Limited‬ ‭‬ A ● ‭ naerobic infections outside the CNS‬ ‭●‬ ‭Severe‬‭Group A Streptococcus‬ ‭●‬ ‭Alternative to PCN‬ ‭Dynamics/Kinetics‬ ‭●‬ ‭Given orally, IM, IV‬ ‭●‬ ‭Hepatic metabolism/renal excretion‬ ‭Adverse Effects‬ ‭●‬ ‭Common: Diarrhea, hypersensitivity rash‬ ‭●‬ ‭Most concerning:‬‭C.‬‭difficile‬‭-associated‬‭diarrhea (CDAD)‬