Protein Synthesis Inhibitors

Question 1

Bacterial Protein Synthesis sites of action:

Answer 1

Question 2

Aminoglycosides

Answer 2

Gentamicin

Neomycin

Amikacin

Tobramycin

Streptomycin

Question 3

Aminoglycosides

block:

static? cidal?

require_for transport:

effect on intracellular organisms:

Answer 3

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)

Question 4

Aminoglycosides:

often added to:

endocarditis:

newborn mening:

CF patients:

Answer 4

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)

Question 5

Most common mechanism resistance Aminoglycosides:

Answer 5

“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)

Question 6

4 Aminoglycosides Adverse Effects:

Answer 6

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

Question 7

3 Macrolides

Answer 7

Azithromycin , Clarithromycin, Erythromycin

Question 8

Macrolides mechanism of action:

Answer 8

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

Question 9

Macrolides

coverage:

intracellular pathogens?

Answer 9

Covers many gram (+) cocci, especially strep

Some gram (-) coverage

Concentrated inside macrophages, other cells • Effective against intracellular pathogens • Chlamydia (obligate), Legionella (facultative)

Question 10

common uses for Macrolides Azithromycin:

Clarithromycin:

Erythromycin:

Answer 10

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

Question 11

Macrolides Resistance mechanism:

Answer 11

• Resistance mechanism • 23S rRNA = component of 50S ribosome • Location of macrolide binding • Methylation of this site → resistance

Question 12

5 Macrolides Adverse Effects

Answer 12

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

Question 13

4 Tetracyclines:

Answer 13

Tetracycline, doxycycline, demeclocycline, minocycline

Question 14

Tetracyclines mechanism of action:

Answer 14

• 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

Question 15

Tetracyclines • Absorption impaired by:

Answer 15

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!

Question 16

Tetracyclines Resistance

Answer 16

Different from many other antibiotics: • No alteration of drug by bacteria!

Decreasing influx or increasing efflux from cells • Plasmid-encoded transport pumps

Question 17

2 Tetracyclines Adverse Effects

what about in kids?

pregnancy?

Answer 17

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

Question 18

Chloramphenicol MOA:

Answer 18

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

Question 19

Chloramphenicol

rarely used in:

used in:

Answer 19

• 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

Question 20

Chloramphenicol Adverse effects

Answer 20

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

Question 21

Clindamycin MOA:

Answer 21

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

Question 22

Clindamycin coverage:

Answer 22

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

Question 23

Main use of Clindamycin

Answer 23

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

Question 24

Clindamycin Adverse Events

Answer 24

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

Question 25

Linezolid MOA & main use

Answer 25

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

Question 26

Linezolid is a weak: therefore:

Answer 26

Weak monoamine oxidase (MAO) inhibitor • Can cause serotonin syndrome • High risk when given with SSRIs • Fever, confusion, agitation, hyperreflexia

Question 27

Streptogramins quinupristin/dalfopristin MOA & uses:

Answer 27

Block protein synthesis 50S ribosome • Used together for sequential protein synthesis block • Synercid (quinupristin/dalfopristin)

Used for vancomycin resistant bacteria • VRSA • VRE

Question 28

Bacteriostatic vs. Bactericidal

Answer 28