Protein Synthesis Inhibitors

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  1. tetracycline, doxycycline, minocycline
    • 30S inhibitor - tetracyclines
    • action: reversible binding to 30S subunit on bacterial ribosome, block aminoacyl tRNA from entering ribosome
    • spectrum: VERY broad: superinfections; generally more active against G+, bacteriostatic
    • resistance: decreased intracellular levels (decrease influx, inc. efflux), enzymatic inactivation of drug, expression of proteins that protect ribosomes from drug
    • pharmacokinetics: oral admin (30-100% absorption), decreased by divalent and trivalent cations (dairy products, antacids, iron supplements) w/ exceptions (doxy and mino can be given with dairy), decreased when gastric pH is elevated
    • Wide distribution - liver, spleen, bone marrow, skin, tears, bone, dentine, enamel (in inactive form), good CNS penetration (doxy and mino for CSF), crosses placenta
    • Excretion: through kidneys, some enterohepatic cycling, resorption in small intestines; exception - doxy eliminated as inactive chelate in feces w/ no impact on normal flora, mino passed in feces
    • use: acne, drug of choice in treatment of Ricksettial diseases (chlamydia, myco pneumoniae, Y pestis, Borrelia
    • Adverse effects: GI irritation and superinfections (including pseudomembranous colitis), photosensitivity, hepatotoxicity, renal toxicity, vestibular disturbances, discoloration of teeth - fetal and childhood risks (therefore, should not be givent to pregnant women or children under 8)
    • drug interactions: MANY
    • - antagonizes cidal antibiotics (penicillins)
    • - increase other drug levels by altering hepatic / intestinal CYP3A4 metabolism (flibanserin, lomitapide)
    • - digoxin - increase levels via changes in intestinal flora, reduced metabolism
    • - tretinoin and acitretin - increase intracranial pressure, unclear how
  2. Tigecycline
    • minocycline derivative
    • give IV
    • mechanism: similar to tetracyclines, but binds with higher affinity to 30S ribosome
    • effective against strains that are tet-resistant, some MRSA, treat skin, intra-abdominal infections
  3. Gentamicin
    • aminoglycoside - bind irreversibly to 30S ribosomal subunit and inhibit protein synthesis at several levels
    • bactericidal
    • concentration-dependent killing with significant PAE
    • spectrum: extended spectrum, primarily G- aerobic bacilli, combination therapy with penicillin or vancomycin acts synergistically on S auerus and S epidermidis
    • resistance: mutant bacterial ribosome, decreased uptake or efflux, enzymatic inactivation of the drug
    • pharmacokinetics
    • -absorption: highly polar; poor GI absorption - IM or IV admin
    • -distribution: not well distributed to most cells, eye or CNS, high concentrations only in inner ear and renal cortex = toxicities
    • adverse effects: ototoxicity (tinnitus and largely irreversible loss of hearing), vestibular toxicity, renal toxicity
    • use: severe G- infections
  4. spectinomycin
    • structurally related to aminoglycosides - binds 30S subunit
    • bacteriostatic
    • Extended spectrum: Mostly G- but many G+
    • use: antibiotic-resistant gonorrhea, MRSA, enterococci
    • few adverse effects but resistance develops rapidly
  5. azithromycin, clarithromycin, erythromycin
    • macrolide - bind reversibly to 50S subunit
    • competitively inhibit ribosome binding of streptogramins, clindamyin, and chloramphenicol = antagonism
    • bacteriostatic (generally) - dosing and pH considerations
    • narrow spectrum (broader than pens), greater accumulation in G+ bacteria, clarithro and azithro are more effective than erythro against anaerobes
    • resistance: rapid and cross-resistant; efflux pump, methylase modifies the bacterial ribosome making drug unable to bind (MLS-type B resistance (macrolide, lincosamide, streptogramin)), hydrolysis by esterases in Enterobacteriaceae
    • pharmacokinetics
    • - administration: oral because acid stable (erythromycin not acid stable, given as salt)
    • - distribution: poor penetration of CNS, WIDE erythromycin penetrates into abcesses
    • use: alternative to penicillins, esp in allergic patients, respiratory infections from atypical microbes, common bacterial infections (acne), but resistance develops rapidly
    • adverse effects: GI disturbances, hepatotoxicity - allergic type of reversible cholestatic hepatitis with erytheomycin estolate
    • Interactions - inhibit CYP3A4, potentiates other drugs (azithromycin is structurally unique, no interaction with CYP 450 system)
  6. telithromycin
    • ketolid
    • structural derivative of erythromycin - inc. acid stability, inc affinity for bacterial 50S ribosome, reduced induction of bacterial resistance
    • mechanism: binds 50S ribosome at 2 sites, bacteriostatic (cidal against susceptible S. pneumoniae)
    • pharmacokinetics: oral, well absorbed with food
    • use: community acquired RTI's (pneumonia), acute bacterial sinusitis, chronic bronchitis
    • adverse effects: commonly GI, less commonly visual effects (blurred vision, difficulty focusing), rarely liver damage/failure, exacerbates disease symptoms in myasthenia gravis
    • drug interaction: increase levels of other CYP3A4 substrates
  7. chloramphenicol
    • bacteriostatic
    • binds reversibly to 50S ribosome - near binding of clindamycin and macrolides
    • Broad spectrum, inhibits most anaerobic bacteria, inhibits most G- bacilli
    • resistance: huge problem, due to acetyltransferases, modify drug
    • pharmacokinetics: oral, topical, or parenteral, wide distribution (CNS, crosses placenta), complete absorption, metabolized by liver
    • use: few, restricted toxicity, severe infections unresonsive to tetracyclines or cephalosporins
    • adverse effects: many, hematological (aplastic anemia), hypersensitivity, gray baby syndrome - can't metabolize drug; vomiting, cyanosis, ashen color, hypothermic, 40% death within 2 days
    • drug interactions: inhibits hepatic cytochrome P450 enzymes; prolongs the half-life of drugs that are metabolized by CYPs

  8. Synercid (Quinupristin/dalfopristin 30:70)
    • streptogramin
    • mechanism: binds to 50S ribosome at same site as macrolides; dalfopristin binds nearby, enhances quinupristin binding = synergism
    • activity: individually bacteriostatic, combined = bactericidal
    • use: MRSA, serious / life-threatening vancomycin-resistant G+ infections (VREF, VRSA, S. pneumoniae
    • adverse effects: pain, phlebitis at IV site, deregulation of levels of drugs that are metabolized by CYPs
    • resistance:to quinupristin - erm-encoded methylases (50S rib), vgb-encoded lactonases (drug)
    • - to dalfopristin - vat or sat-encoded acetyltransferases (drug), vga-vgb-encoded ATP binding efflux proteins to transport the drug out of the cell
  9. Linezolid
    • mechanism: binds novel site in 23S ribosomal RNA of the 50S ribosomal subunit
    • characteristics: no cross-resistance with other protein synthesis inhibitors, bacteriostatic (cidal vs streptococci), oral admin (100% bioavailability),
    • use: serious infections (MRSA, VREf, multidrug-resistant S. pneumoniae)
  10. clindamycin
    • lincosamide
    • action: binds 50S subunit of bacterial ribosomes
    • MLS-typeB resistance
    • narrow spectrum - most G+ are susceptible, better than macrolides against anaerobes, NOT aerobic G-, STATIC
    • resistance: slow / stepwise, due to ribosomal methylase that modifies target, clindamycin does not induce methylase expression in microbes
    • pharmacokinetics: oral or parenteral, wide distribution (bone - active form), metabolized in liver
    • use: drug of choice for RTI caused by anaerobes, abcesses, severe GroupA strep infections, MRSA, skin and soft tissue infections, osteomyelitis
    • adverse effects: diarrhea, pseudomembranous colitis (C diff), skin rash, Stevens-Johnson syndrome, anaphylaxis
  11. mupirocin
    • topical use only, useful for treating impetigo caused by MRSA or Group A strep
    • mechanism: inhibits isoleucyl tRNA synthetase
    • rapid metabolized to inactive form
    • resistance = rare
    • static at [low], cidal at [high]
Card Set:
Protein Synthesis Inhibitors
2016-08-24 21:30:19
MOHD4 antibiotics

MOHD4 lecture 14b
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