Antibiotics III: Protein Synthesis Inhibitors Flashcards
How do Protein Synthesis Inhibitors work?
work by binding to ribosome & interfering with protein synthesis
mammalian cells have 80S ribosome (60S & 40S subunits)
bacteria have 70S ribosome (50S & 30S subunits)
diff. therefore we can target the 50S for ex & it won’t affect our cells
What do the Protein Synthesis Inhibitors include?
- Macrolides
- Tetracyclines
- Aminoglycosides
- Lincomycin
- Oxazolidinones
- Streptogramins & Chloramphenicol
What is the process of Protein Synthesis?
ADD!
What are examples of Macrolides?
- Erythromycin, Azithromycin – IV or PO
- Clarithromycin – PO (CYP3A4 Inhibitor & substrate)
What is the target of Macrolides?
- Azithromycin – prolongs QT, CYP3A4 substrate, very long half life ~ 70 hours (*benefit b/c can dose it for 3 days at a high dose instead of needing it for a week – t1/2 allows it to stick around for a while)
- Ezithromycin – CYP3A4 substrate & inhibitor
- Binds to 50S subunit & prevents translocation (movement of ribosome along mRNA)
What are the features of Macrolides?
- Bacteriostatic, time dependent
- Distribution – extensive into tissue, poor CSF penetration
What is the Spectrum of Activity for Macrolides?
- Variable gram + (good listeria), some gram -, some anaerobes, good atypical coverage
What are examples of Tetracyclines?
- Tetracycline, doxycycline, minocycline – PO
- Doxycycline – 1st line for lime disease (after a tick bite & for treatment)
What is the target of Tetracyclines?
- Binds to the 30S subunit & interferes with the attachment of tRNA to mRNA-ribosome complex
What are the features of Tetracyclines?
- Bacteriostatic, time dependent
- Divalent cations (Ca2+, Mg2+) bind to tetracyclines in gut & prevent absorption (avoid milk or Ca2+, Mg2+ supplements)
- Doxycycline does NOT have to be adjusted in renal impairment
- Good tissue & body fluid distribution but NOT CSF
What is the Spectrum of Activity for Tetracyclines?
- Variable gram + (sometimes will cover MRSA, covers listeria), moderation gram -, some anaerobes, good atypical coverage
What are examples of Aminoglycosides?
- Gentamicin, tobramycin, amikacin – IV/IM, topical (in eye & ear drops, ~ IV in hospital)
- Great drugs; v. effective, but v. toxic
What is the target of Aminoglycosides?
- Binds to 30S ribosomal subunit & causes mRNA to be incorrectly read
What are the features of Aminoglycosides?
- Concentration dependent killing (more imp. Is how highly that peak is above the MIC)
- Bacteriocidal
- Post-antibiotic effect – allows for high dose once daily administration (even when antibiotic is away, it still inhibits the regrowth of a bacterium for a period of time)
- Adjust dose for renal impairment
- distribution - mostly into ECF, low tissue concentrations, poor CSF penetration (therefore don’t cross BBB v. well)
What is the Spectrum of Activity for Aminoglycosides?
NARROW
* Aerobic gram – coverage incl. pseudomonas aeruginosa
What are the adverse effects of Aminoglycosides?
- NEPHROTOXICITY – taken up by the cells in the proximal tubule & can cause an acute tubular necrosis
o Risk factors incl: large total dose, prolonged duration of therapy, high trough concentrations, CKD, elderly, dehydration - NEUROTOXICITY – may cause issues with hearing & balance-usually irreversible
- OTHER – numbness, twitching, tingling skin, convulsions (monitor & ask about this)
What is the monitoring for Aminoglycosides?
- Drug levels, usually trough levels (initially weight based dosing – Ideal Body Weight) – want to see v. minimal levels of aminoglycosides after 24 hrs
What are examples of Lincomycin?
- Clindamycin – IV or PO
What is the target of Lincomycin?
- Reversibly binds to the 50S subunit & prevents peptide bond formation (prevents peptide being added & the chain becoming longer)
What are the features of Lincomycin?
- Bacteriostatic
- Hepatic clearance
- Distribution: Tissues & body fluids, NOT CSF
What is the Spectrum of Activity for Lincomycin?
- Good gram + coverage (incl. MRSA), no gram – coverage, good anaerobic coverage but NOT clostridium difficile
- therefore good gram + & anaerobic but rest not (no gram -)
What are the adverse effects of Lincomycin?
- c. difficile associated colitis (severe diarrhea that can be fatal), esophagitis
What are examples of Oxazolidinones?
- Linezolid IV or PO
What is the target of Oxazolidinones?
- Binds to the 23S ribosomal RNA of the 50S subunit
- It prevents the formation of the initiation complex that is required for translation (prevents everything from really starting)
What are the features of Oxazolidinones?
- Bacteriostatic (enterococcus & staph)
- Bacteriocidal (strep)
- Time dependent
- Dose not adjusted in renal impairment
What is the Spectrum of Activity for Oxazolidinones?
- Gram + incl. MRSA & vancomycin resistant enterococci (VRE)
What are the adverse effects of Oxazolidinones?
- Hematologic (BIG CONCERN) & neurotoxicity (generally avoid treatment duration longer than 2 weeks – b/c almost everyone gets hematological toxicity)
- Distribution – good tissue penetration, CSF penetration
What are examples of Streptogramins & Chloramphenicol?
- Streptogramins – quinupristin/dalfopristin
- Chloramphenicol
What is the target of Streptogramins & Chloramphenicol?
- Streptogramins – quinupristin/dalfopristin
o *individually bacteriostatic, combo is bacteriocidal
o Bind to diff. sites of the 50S subunit (dalfopristin inhibits peptidyl transfer as well as increases quinupristin binding; quinupristin prevents chain elongation) - Chloramphenicol
o Binds to 50S subunit & inhibits formation of peptid bond
o Rare use due to SE’s: gray baby syndrome (swollen stomach, low BP), & hematologic toxicity – don’t use it unless you absolutely have to)
What are the Resistance Mechanisms?
- Porin mutations – decrease entry into gram – bacteria (b/c porins will change)
- Efflux pumps – increased removal
- Altered targets or increased # of targets (ex: PBPs)
- Antibiotic degradation
o Ex’s: break open the beta lactam ring through hydrolysis rendering the antibiotic inactive (4 mem. Ring that’s under a lot of stress)
Penicillinases
Extended spectrum betalactamases (ESBLs)
Carbapenemases
