Antibacterial Agents III - Inhibitors of protein synthesis 2

Question 1

aminoglycosides: mechanism of action

Answer 1

binds to 30S ribosomal subunit and inhibits protein synthesis

• bacteriostatic at [low] and bacteriocidal at [high]
• not effective against anaerobic organisms

Question 2

aminoglycosides: pharmacokinetics

Answer 2

1. IV or IM (rapid and complete absorption) - not oral!
2. limited to ECF
3. crosses CNS only if meninges are inflamed
   - selectively accumulates in the renal cortex and inner ear
4. not metabolized
5. excreted renally
   - dosage adjustment required if impaired renal function to avoid drug accumulation and toxicity
   - –once daily dosing: concentration-dependent killing and a post-abx effect

**subject to great interindividual variation

Question 3

aminoglycosides: Spectrum of activity and Major clinical uses

Answer 3

• **declining use due to toxicity
  1. g- enteric organisms
• -p. aeruginosa!
• -E. coli
• -presurgery bowel sterilization (po neomycin) and wound infection (topical neomycin)
  2. m. tyberculosis (streptomycin)
  3. enterococci (genatmycin + a PCN or vanc)

Question 4

aminoglycosides: side effects and significant DDIs

Answer 4

VERY TOXIC

1. vestibular and auditory ototoxicity (CN 8 damage - often irreversible)
   - –dependent on dose-Cp and duration of therapy
   - -most likely to occur in patients with impaired renal function
2. nephrotoxicity (usually reversible)
3. neuromuscular blockade: muscular paralysis and apnea
   - ——————————————–
   - synergy with B-lactams
   - irreversible binding of aminoglycosides to certain PCNs can result in inactivation of the aminoglycosides

Question 5

Chloramphenicol: mechanism of action

Answer 5

• bacteriostatic (bacteriocidal against some bacteriodes, H. influenzae, N. meningitidis)
• inhibit shost mito protein synthesis in human bon e marrow (diminished selective toxicity)
• binds to the 50S ribosomal subunit, inhibits protein synthesis (block of peptidyl transferase)
• think Cl: wide spectrum, but toxic

Question 6

Chloramphenicol: Pharmacokinetics

Answer 6

1. Oral or IV (rapid and complete in GI tract)
   - –widely distributed, included CNS and CSF
2. metabolized and completely inactivated in the liver (by glucuronidation)
   - –thus toxic in fetus and neonate immature liver
3. metabolites excreted in the urine
   - –also excreted in breast milk

Question 7

Chloramphenicol: Spectrum of activity and Major clinical uses

Answer 7

• Broad spectrum agent, but potential toxicity (only use w/ severe infections when less hazardous drugs are ineffective or pt is allergic
• bacterial meningitis or rickettsial infections
• bacteriodes (brain abscess, intraabdominal sepsis)

Question 8

Chloramphenicol: side effects and significant DDIs

Answer 8

1. Bone marrow depression
   - –dose related (reversible)
   - –aplastic anemia (can appear wks/mos after tx is stopped - usually fatal)
2. Gray baby syndrome
   - –immature hepatic fn + inefficient renal fn –> toxic accumulations
   - –V, abnl respiration, cyanosis –> vasomotor collapse
3. GI probs

DDI: Inhibits metabolism of phenytoin, oral anticoagulants, and 1st generation oral hypoglycemic agents

Question 9

Linezolid: Mechanism of action

Answer 9

First member of oxazolidinone class of abx

• bacteriostatic
• binds to 50S subunit and inhibits protein synthesis (diff site than other inhibitors –> cross-resistance)

Question 10

Linezolid: pharmacokinetics

Answer 10

1. Oral (F=100%!) or IV
2. metabolized partially in the liver
3. metabolites and unchanged drug excreted in urine

Question 11

Linezolid: Spectrum of activity and major clinical uses:

Answer 11

Should be held in reserve for life-threatening infections.

gram + cocci (including VRE, MRSA and PNE)

Question 12

Linezolid: side effects and DDI

Answer 12

1. bone marrow suppression (all 3 lines)
2. mild HA
3. mild GI irritation: N/D

Important DDI: Reversibly and non-selectively inhibits MAO. A hypertensive response may occur with administration of sympathomimetic agents or foods high in tyramine or serotonin syndrome if given with SSRIs

Question 13

Quinupristin/Dalfopristin: mechanism of action

Answer 13

inhibits 50S ribosomal subunit (inhibits peptide elongation, leading to early termination of protein synthesis)
-30:70 ratio

Question 14

Quinupristin/Dalfopristin: pharmacokinetics

Answer 14

• IV only

- biotransformtion primarily via hepatic conjugation rxns with subsequent elimination via the feces

Question 15

Quinupristin/Dalfopristin: spectrum of activity and major clinical uses

Answer 15

• **Should be held in reserve for life-threatening infections.
  1. complicated skin infections with GAS and s. aureus
  2. life threatening bacteremia with VRE

Question 16

Quinupristin/Dalfopristin: side effects and significant DDIs

Answer 16

Common effects include infusion site irritation, arthalgia/myalgia, nausea, diarrhea, skin rashes

Important drug interaction: Inhibits cytochrome 3A4 and may lead to increased plasma levels of 3A4 substrates such as: benzodiazepines cisapride, calcium channel blockers, carbamazepine, cyclosporine, HMG CoA reductase inhibitors, and HIV protease inhibitors