Protein Synthesis Inhibitors Flashcards
Bacterial Protein Synthesis sites of action:
Aminoglycosides
Gentamicin
Neomycin
Amikacin
Tobramycin
Streptomycin
Aminoglycosides
block:
static? cidal?
require_for transport:
effect on intracellular organisms:
Block initiation of protein synthesis • Primarily bind 30S • Misreading of genetic code • Bacteria cannot divide, produce cellular proteins • Cell death (bactericidal)
Require O2 for transport into cells therefore Not effective against anaerobes
Do not effect eukaryotic cells (different ribosomes) • Not transferred into eukaryotic cells • Not effective intracellular organisms (Rickettsia/Chlamydia)
Aminoglycosides:
often added to:
endocarditis:
newborn mening:
CF patients:
Often added to β-lactams • Synergistic effects • Combination more effective than sum of effects
Vancomycin/gentamycin for endocarditis
Ampicillin/gentamycin for newborn meningitis
Pip/Tazo + tobramycin for CF patients (pseudomonas)
Most common mechanism resistance Aminoglycosides:
“Aminoglycoside modifying enzymes” • Bacteria acquire enzymes that modify drug structure • Modified structure binds poorly to ribosomes • Phosphorylation (mediated by aminoglycoside kinases) • Adenylation/acetylation (mediated by transferases)
4 Aminoglycosides Adverse Effects:
Ototoxicity • Toxic to 8th cranial nerve • Hearing loss, balance problems (falls) • Mechanism not clear
Nephrotoxicity • Acute tubular necrosis • 5-10% of drug taken up by proximal tubular cells • Serum Cr will rise
Neuromuscular blockade • Rare side effect • Can block/limit release of ACh at neuromuscular junctions • Usually occurs when levels are high or pre-existing neuromuscular disease
Pregnancy class D • Reports of renal and ototoxicity in fetus
3 Macrolides
Azithromycin , Clarithromycin, Erythromycin
Macrolides mechanism of action:
50S ribosomal subunit
tRNA binds “A site” • Ribosome RNA catalyzes peptide bonds (peptidyl transferase) • Ribosome advances along mRNA • tRNA moves to “P site”
Macrolides bind to P site: • Block tRNA movement to P site (translocation) • Promote tRNA dissociation • May also block peptidyl transferase
Macrolides
coverage:
intracellular pathogens?
Covers many gram (+) cocci, especially strep
Some gram (-) coverage
Concentrated inside macrophages, other cells • Effective against intracellular pathogens • Chlamydia (obligate), Legionella (facultative)
common uses for Macrolides Azithromycin:
Clarithromycin:
Erythromycin:
Community acquired pneumonia • Azithromycin covers Strep, H. flu, Atypicals • Good for penicillin allergic patients
Chlamydia infection • Azithromycin (safe in pregnancy) • Often co-administered with Ceftriaxone (gonorrhea)
Erythromycin • Binds to motilin receptors in GI tract • Stimulates smooth muscle contraction • Can be used in GI motility disorders
Clarithromycin • Part of triple therapy for H. pylori
Macrolides Resistance mechanism:
• Resistance mechanism • 23S rRNA = component of 50S ribosome • Location of macrolide binding • Methylation of this site → resistance
5 Macrolides Adverse Effects
Nausea, diarrhea, abdominal pain (motility) • Erythromycin worst offender
Prolonged QT on EKG • Erythromycin also worst offender
Acute cholestatic hepatitis • ↑AST/ALT/Alk Phos/Bilirubin • Case reports in patients on Azithromycin • Contraindicated with history of cholestatic jaundice or hepatic dysfunction
Rash • Maculopapular allergic reaction
P450 Enzyme Inhibitors • Will raise serum levels of P450 metabolized drugs • Theophylline, Warfarin
4 Tetracyclines:
Tetracycline, doxycycline, demeclocycline, minocycline
Tetracyclines mechanism of action:
• Transported into bacterial cells • Binds 30S ribosome • Prevents attachment of tRNA
Demeclocycline • Not used as an antibiotic • ADH antagonist • Given in SIADH • Causes nephrogenic DI to reverse SIADH
Tetracyclines • Absorption impaired by:
Absorption impaired by minerals and antacids • Calcium, magnesium (antacids) • Iron • Dairy including milk • These substances are cations that chelate the drug •
Cannot be taken with antacids or milk!
Tetracyclines Resistance
Different from many other antibiotics: • No alteration of drug by bacteria!
Decreasing influx or increasing efflux from cells • Plasmid-encoded transport pumps
2 Tetracyclines Adverse Effects
what about in kids?
pregnancy?
GI distress (common) • Epigastric pain, nausea, vomiting and anorexia
Photosensitivity • Red rash or blisters in sun exposed areas
Discoloration of teeth • Brown-yellow discoloration of teeth • Children under the age of eight (does not occur in adults)
Inhibition of bone growth in children • Deposit in bones • Chelate with calcium
Contraindicated in pregnancy • Cross placenta • Can accumulate in fetal bone and teeth
Chloramphenicol MOA:
Inhibits peptidyl transferase • 50S ribosomal subunit • tRNA binds “A site” • Ribosome RNA catalyzes peptide bonds (peptidyl transferase) • Ribosome advances along mRNA • Moves tRNA to “P site” • Chloramphenicol blocks peptidyl transferase
Chloramphenicol
rarely used in:
used in:
• Rarely used in developed world, TOXICITY,
Broad coverage of gram (+), gram (-), atypicals • Can be used in pregnancy instead of doxycycline • Rickettsia (RMSF), Ehrlichia • Only in 1st/2nd trimester • 3 rd trimester risk of gray baby syndrome • Can be used for meningitis (developing world) • Covers Neisseria • Less effective than alternative drugs
Chloramphenicol Adverse effects
Anemia • Bone marrow suppression
Aplastic anemia • Idiosyncratic • Irreversible → often fatal
Gray baby syndrome • Babies lack liver UDP-glucuronyl transferase • Required for metabolism/excretion of drug • Skin turns ashen, gray • Hypotension • Often fatal
Clindamycin MOA:
50S ribosome • 23S rRNA component • Prevents translocation • Same as macrolides • Resistance mechanism • 23S rRNA = component of 50S ribosome • Location of macrolide binding • Methylation of this site → resistance • Same as macrolides
Clindamycin coverage:
Covers some gram (+) • Staph, viridans strep, Strep pyogenes, and S. pneumoniae
Covers many anaerobes* • Clostridium perfringens • Mouth anaerobes: Fusobacterium, Prevotella, Peptostreptococcus
anaerobes above the diaphragm
Main use of Clindamycin
cover anaerobes “above the diaphragm” • Aspiration pneumonia • Lung abscesses • Oral infections (mouth anaerobes)
Lots of resistance to clindamycin in B. fragilis • Anaerobic infections “below the diaphragm” • Metronidazole
Clindamycin Adverse Events
Classic cause of C. difficile infection • Up to 10% of patients • Pseudomembranous colitis • C . difficile overgrowth • Massive, watery diarrhea
Antibiotic-associated diarrhea • Milder than C. diff infection • Changes in GI flora • Less absorption of solutes → osmotic diarrhea • Stops when drug discontinued
Linezolid MOA & main use
Binds to 50S Ribosome • Blocks initiation of DNA synthesis • Main use: Vancomycin-resistant enterococcus (VRE) • Epidemics in hospitals • Usually occurs in patients with prior antibiotic treatment
Linezolid is a weak: therefore:
Weak monoamine oxidase (MAO) inhibitor • Can cause serotonin syndrome • High risk when given with SSRIs • Fever, confusion, agitation, hyperreflexia
Streptogramins quinupristin/dalfopristin MOA & uses:
Block protein synthesis 50S ribosome • Used together for sequential protein synthesis block • Synercid (quinupristin/dalfopristin)
Used for vancomycin resistant bacteria • VRSA • VRE
Bacteriostatic vs. Bactericidal
