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Lecture 4
Protein Synthesis Inhibitors
| Question | Answer |
|---|---|
| Overview | inhibit bacterial protein synthesis by binding to and interfering with bacterial ribosomes; resistance to tetracycline and macrocodes common |
| Tetracyclines chemistry | four fused rings; substitutions on rings affect individual pharmacokinetics and antimicrobial activity; broad spectrum and bacteriostatic; chelate divalent metal ions |
| Tetracyclines Preparations Brands/Generics | demeclyocycline = declomycin; doxycycline=vibramycin, doryx; minocycline=minocin; tigecycline=tygacil |
| Tetracyclines MOA | passive diffusion and energy-dependent transport protein system |
| Tetracyclines MOA | tetracyclines concentrate inside susceptible organisms |
| Tetracyclines MOA | reversibly bind to bacterial ribosome 30S subunit |
| Tetracyclines MOA | stops addition of amino acids to growing peptide inhibiting protein synthesis |
| Tetracyclines Resistance methods | impaired influx or increased efflux; ribosome protection interfering with tetracycline binding; enzymatic inactivation |
| Tetracyclines Resistance: most common method is___ | efflux pump |
| Tetracyclines Resistance: resistance is not ____ | universal. tetracycline resistant strains possibly susceptible to doxycycline, minocycline, tigecycline. **poor substrates for efflux pumps** |
| Tetracyclines Absorption: impaired by** | multivalent cations, dairy products, antacids, alkaline pH |
| Tetracyclines Absorption: tetracycline and democycline administered on ____ | empty stomach |
| Tetracyclines Absorption: doxycycline and minocycline not affected by ____ | food. chelation less problematic with doxy and mini compared to tetra but doses should be separated by at least 2 hours from these products |
| Tetracyclines Distribution | bind to tissues undergoing calcification or to tumors with high calcium content |
| Tetracyclines Distribution | minocycline and doxycycline achieve therapeutic levels in CSF (due to lipid solubility) |
| Tetracyclines Distribution | all cross placenta and excreted in breast milk |
| Tetracyclines Elimination short acting** | t1/2 6-8 hours (tetracycline/sumycin) |
| Tetracyclines Elimination intermediate acting | t1/2 12 hours (demeclocycline/declomycin) |
| Tetracyclines Elimination long acting ** | t1/2 16-18 hours (doxy/vibra, mino/mino). *doxy 100mg PO BID* |
| Tetracyclines Elimination tigecycline/tigacil | t1/2 36 hours |
| Tetracyclines Antibacterial Spectrum: active against | gram positive and negative, protozoa, spirochetes, mycobacteria, atypical species, commonly used in acne and chlamydia infections |
| Tetracyclines Clinical Uses | drug of choice in infections caused by rickettsieae and borrelia sp (Rocky Mountain spotted fever, Lyme disease) |
| Tetracyclines Clinical Uses | used in combo to treat helicobacter pylori; effective in chlamydial infections |
| Tetracyclines Clinical Uses | doxycycline alternative agent for primary and secondary syphilis in penicillin allergic patients |
| Tetracyclines Clinical Uses | minocycline able to eradicate meningococcal carrier state but due to AE and resistance, not preferred drug |
| Tetracyclines Adverse Effects: avoid tetracyclines in ___and children less than ___of age | pregnancy, 8 years. |
| Tetracyclines Adverse Effects: most AE due to ____of drug or alteration of _____ | toxicity, microbial flora |
| Tetracyclines Adverse Effects: GI effects | nausea, vomiting, diarrhea, esophagitis |
| Tetracyclines Adverse Effects: should be taken on an ____stomach | empty |
| Tetracyclines Adverse Effects: effects on calcified tissues | readily bound to calcium deposited in newly formed bone or teeth; causes discoloration, enamel dysplasia of teeth; deposited in bone-may cause deformity or stunting of growth |
| Tetracyclines Adverse Effects: phytotoxicity | most frequently seen with tetracycline and demeclocycline but possible with all; sensitivity to sunlight or UV light |
| Tetracyclines Adverse Effects: hepatoxicity | may impair hepatic function |
| Tetracyclines Adverse Effects: vestibular dysfunction | dizziness, vertigo, tinnitus particularly with minocycline |
| Tetracyclines Adverse Effects: contraindications | do not use in pregnant or breast feeding women; do not use in children less than 8 years old |
| Macrolides | characterized by macrocyclic lactone ring; erythromycin was prototype, clarithromycin and azithromycin |
| Macrolides MOA | irreversibly bind to site on 50S subunit of bacterial ribosome --> inhibit translocation steps of protein synthesis; binding site same or close to those for clindamycin and chloramphenicol |
| erythromycin: available as | base, ethylsuccinate, lactobionate, stearate |
| erythromycin: base form destroyed by ____; enteric coating necessary | stomach acid |
| erythromycin: food interferes with ___ | absorption |
| erythromycin: stearate and ethylsuccinate formulations are more acid ___ and absorption is improved | resistant |
| erythromycin antibacterial spectrum: effective against many same organisms as ___. alternative for patients with ___allergy | Pen G, penicillin |
| clarithromycin (Biaxin): improved acid stability and oral absorption compared to erythromycin. lower incidence of _____intolerance and dosing less frequent compared with erythromycin. regular release preparations typically dosed ___ | GI. BID |
| clarithromycin Antibacterial spectrum | similar to erythromycin; haemophilus influenzae; greater activity against intracellular pathogens (chlamydia, legionella, mortadella, ureaplasma species, h pylori) |
| azithromycin (Zithromax) | less active than erythromycin against streptococci and staphylococci; more active against respiratory pathogens; highly active against chlamydia sp; t1/2 3 days, slowly released from tissues, once daily dosing |
| Z-pack ** | 250mg tablets; take 2 tablets PO on day 1(500mg) then take one tablet PO daily on days 2-5(250mg) |
| Macrolide Resistance: due to | inability of organism to take up antibiotic; presence of efflux pumps; decreased affinity for 50S ribosomal subunit for antibiotic; enzymes in gram negative organisms that hydrolyze macrolides |
| Macrolide Absorption | erythromycin base destroyed by gastric acid; EC tablets or esterified forms of antibiotic |
| Macrolide Adverse Effects | GI disturbances; jaundice; ototoxicity; QT prolongation |
| Macrolide Adverse Effects: GI effects | most common; sometimes used for treating gastroparesis (therapeutic adverse effect) |
| Clindamycin (cleocin) MOA | similar to macrocodes; interferes with translocation reactions; binding site for clindamycin on 50S subunit identical to erythromycin |
| Clindamycin Spectrum Activity/Resistance | resistance similar to erythromycin with cross resistance: receptor site mutations, receptor modifications by a constitutively expressed methyl's, enzymatic inactivation |
| Clindamycin Pharmacokinetics: distributed well into body fluids but poor in ___. penetrates well into ___ | CSF, abscesses |
| Clindamycin indications | gram positive (MRSA, streptococcus, anaerobic bacteria); skin and soft tissue infections; TSS, necrotizing fasciitis, prophylaxis of endocarditis, c difficile resistant |
| Clindamycin adverse effects | diarrhea, nausea, skin rashes, impaired liver function and neutropenia, risk factor for diarrhea and colitis due to C difficile (watery diarrhea, abdominal pain, fever, loss of appetite, weight loss, treat with metronidazole or vancomycin PO) |
| Chloramphenicol MOA | broad spectrum antibiotic; restricted to life threatening infections |
| Chloramphenicol MOA | reversibly binds to bacterial 50S ribosomal subunit and inhibits protein synthesis at peptide transferase reaction; high levels may block mitochondrial protein synthesis --> bone marrow toxicity |
| Chloramphenicol antibacterial spectrum | primarily bacteriostatic; bactericidal depending on dose and organism; broad spectrum (active against aerobic/anaerobic gram positive and negative) |
| Chloramphenicol Adverse Effects ** anemia | dose-related anemia; hemolytic anemia; aplastic anemia=dependent of dose and can occur after drug has been discontinued (tends to be irreversible, boxed warning added to label) |
| Chloramphenicol Adverse Effects ** gray baby syndrome | infants have low ability to glucuronidate Chloramphenicol to degrade and detoxify Chloramphenicol; drug accumulates; causes poor feeding, depressed breathing, cyanosis, death; should be used with caution and dose limited in infants |
| Oxazolidinones examples | linezolid (Zyvox) and tedizolid (sivextro) |
| Oxazolidinones spectrum of activity | active against gram positive, primarily bacteriostatic, bactericidal against streptococci, active against mycobacterium tuberculosis, used to treat infections caused by drug resistant gram positive |
| Oxazolidinones MOA | inhibits protein synthesis; prevents formation of ribosome complex that initiates protein synthesis |
| Oxazolidinones MOA** | binds to bacterial 23S ribosomal RNA of the 50S subunit blocking formation of 70S initial complex and translation of bacterial proteins |
| Oxazolidinones Adverse Effects | GI effects=nausea and diarrhea; hematologic=reversible, thrombocytopenia, anemia, neutropenia) |
| Tedizolid/Sivextro | highly active against gram positive; PO and IV; advantages over linezolid (increased potency against staph; longer t1/2-12 hours-once daily dosing) |
| Aminogylcosides: list AGNTS | amikacin, gentamicin, neomycin, streptomycin, tobramycin |
| Aminogylcosides: overview | bactericidal inhibition of protein synthesis; commonly used in combo with other agents for drug-resistant organisms; aerobic gram negative bacilli; use limited due to toxicity |
| Aminogylcosides MOA | irreversibly inhibit protein synthesis; passive diffusion through porin channels across outer membrane; then actively transported across cell membrane into cytoplasm |
| Aminogylcosides MOA | transport may be enhanced by cell wall active drugs (penicillin); once inside cell bind to 30S ribosomal subunit |
| Aminogylcosides MOA: protein synthesis inhibited by___. effect is irreversible and causes cell death | interference with initiation complex of peptide formation; misreading mRNA; breakup of polysomes into nonfunctional monosomes |
| Aminogylcosides pharmacokinetics | long post-antibiotic effect (PAE) and poor absorption from intact GIT |
| Aminogylcosides pharmacokinetics | almost all given parenterally (except neomycin=topical); administered IV as 30-60 min infusions; IM injections |
| Aminogylcosides Distribution | do not enter cells readily; CNS concentrations poor; cross placental barrier |
| Aminogylcosides Antibacterial Spectrum | aerobic gram-negative bacilli; combined with beta-lactam antibiotics to treat enterococcus faecalis; enterococcus faecium infective endocarditis |
| Aminogylcosides Adverse Effects | ototoxicity and nephrotoxicity, neuromuscular paralysis |
| Aminogylcosides Adverse Effects: likely to cause auditory damage | neomycin, kanamycin, amikacin |
| Aminogylcosides Adverse Effects: most vestibulotoxic | streptomycin, gentamicin |
| Aminogylcosides Adverse Effects: most nephrotoxic | neomycin, tobramycin, gentamicin |
| Miscellaneous Antimicrobial Agents | mupirocin and nitrofurantoin |
| mupirocin | bactroban; available as ointment, cream; protein synthesis inhibitor; active against gram positive cocci |
| mupirocin indications | treatment of impetigo and other minor skin infections; not recommended over large areas; nasal ointment eliminates MRSA |
| mupirocin adverse effects | pruritus, skin rash, burning |
| Urinary Antiseptics: UTI typically treated with fluoroquinolones or SMZ/TMP. increasing ____ | resistance |
| Urinary Antiseptics | oral drugs, high concentrations in urine, lower UTI, nitrofurantoin, methenamine |
| nitrofurantoin | inhibits DNA and RNA synthesis; bactericidal for many gram positive and gram negative; susceptible organisms include (e coli, klebsiella sp, enterococcus sp, staphylococcus sp) |
| nitrofurantoin: renal function | contraindicated in renal insufficiency |
| nitrofurantoin: macrodantin dosed ____ | 100mg QID |
| nitrofurantoin: Macrobid is long acting formulation and ___dosing. two forms=macrocrystalline and nitrofurantoin monohydrate | BID |
| nitrofurantoin Adverse effects | nausea, vomiting, diarrhea; neuropathies, pulmonary toxicities possible with prolonged use or in renal impairment; hemolytic anemia in patients with G6PD deficiency |
Created by:
bluedolphin7
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