Protein synthesis inhibitors - Aminoglycosides Flashcards
1
Q
Streptomycin
A
Bacteriocidal
First generation
Target:
- Aerobic Gram - eneteric bacteria
- Pseudomonas, Acinetobacter, Enterobacter
- Yersinia Pestis
- Mycobacteria
- NOT effective against anaerobes (need O2 for uptake)
- Synergistic w/ Beta-lactams or Vanc for TX of endocarditis caused by enterococci, strep, staph, and TB
Indications:
- Enterococcal infections
- second line TB tx
Mechanism:
- irreversible inhibitors of protein synthesis
- concentration-dependent killing (faster)
- blocks initiation of protein synthesis
- blocks further translation and elicits premature termination
- incorporation of incorrect AA
- alter memb function leading to increased permeability and leakage of intracellular contents (less protein synthesis)
Route of Administration:
- Generally IV or IM
- poorly absorbed PO
Absorption:
- IV or IM
- poor PO absorption (<1%) except in GI disease, ulcers
- enter cells via passive diffusion through porins (outer membrane of Gram - )
- O2 dependent transport across cell membrane
- coupled to proton pump, electrochem gradient drives process
- inhibited by divalent cations, low pH, and anaerobic conditions
- increased uptake facilitated by cell wall inhibitors (PCN, Vanc)
Distribution:
- low binding to serum proteins
- polar, cationic compounds, do not enter cells/tissues easily
- do not enter CNS or eye
- may enter CNS if inflammation present or after intrathecal/IV injection
Metabolism and Excretion:
- via urine (glomerular filtration)
- dosing monitored in renal impairment
Toxicities:
- can be very common
- Ototoxicity (10-25%)
- irreversible
- mechanism = accumulation of drug in inner ear/cochlea = hair cell death via binding phospholipids, Ca, oxidative stress?)
- can occur w/ renal impairment, prolonged use and concurrent use w/ loop diuretics
- vestibular damage (vertigo, ataxia, disequilibrium)
- auditory damage (tinnitus, high-freq HL)
- nephrotoxicity (10-25%)
- increased serum drug concentrations
- accumulation in proximal tubule
- binds to phospholipids
- reversible damage, proximal tubule cells regenerate
- not really Streptomycin
- Neuromuscular toxicity
- interferes w/ Ca signaling (high doses); fail to release Ach, respiratory distress
Drug Interactions: -
Pt considerations:
- careful dosing in renal impairment
Resistance:
- enzymatic inactivation (major)
- acetylation, P, adenylation
- impaired uptake
- porin gene mutation
- mutation of proteins required for gradient
- anaerobic conditions
- mutation of ribosomal protein (less common)
- specific for streptomycin (limits usage)
Notes:
- Strong postantibiotic effect (hours) in absence of detectable drug
2
Q
Amikacin
A
Bacteriocidal
Target:
- Aerobic Gram - eneteric bacteria
- Pseudomonas, Acinetobacter, Enterobacter
- Yersinia Pestis
- Mycobacteria
- NOT effective against anaerobes (need O2 for uptake)
- Synergistic w/ Beta-lactams or Vanc for TX of endocarditis caused by enterococci, strep, staph, and TB
- can be used in some organisms resistant to gentamicin (nosocomial)
Indications:
- Enterococcal infections, second line TX
Mechanism:
- irreversible inhibitors of protein synthesis
- concentration-dependent killing (faster)
- blocks initiation of protein synthesis
- blocks further translation and elicits premature termination
- incorporation of incorrect AA
- alter memb function leading to increased permeability and leakage of intracellular contents (less protein synthesis)
Route of Administration:
- Generally IV or IM
- poorly absorbed PO
Absorption:
- IV or IM
- poor PO absorption (<1%) except in GI disease, ulcers
- enter cells via passive diffusion through porins (outer membrane of Gram - )
- O2 dependent transport across cell membrane
- coupled to proton pump, electrochem gradient drives process
- inhibited by divalent cations, low pH, and anaerobic conditions
- increased uptake facilitated by cell wall inhibitors (PCN, Vanc)
Distribution:
- low binding to serum proteins
- polar, cationic compounds, do not enter cells/tissues easily
- do not enter CNS or eye
- may enter CNS if inflammation present or after intrathecal/IV injection
Metabolism and Excretion:
- via urine (glomerular filtration)
- dosing monitored in renal impairment
Toxicities:
- can be very common
- Ototoxicity (10-25%)
- irreversible
- mechanism = accumulation of drug in inner ear/cochlea = hair cell death via binding phospholipids, Ca, oxidative stress?)
- can occur w/ renal impairment, prolonged use and concurrent use w/ loop diuretics
- vestibular damage (vertigo, ataxia, disequilibrium)
- auditory damage (tinnitus, high-freq HL)
- nephrotoxicity (10-25%)
- increased serum drug concentrations
- accumulation in proximal tubule
- binds to phospholipids
- reversible damage, proximal tubule cells regenerate
Neuromuscular toxicity
- interferes w/ Ca signaling (high doses); fail to release Ach, respiratory distress
Drug Interactions: -
Pt considerations:
- careful dosing in renal impairment
Resistance:
- Amakcain designed to be resistant to metabolic degradation so no inactivation
- impaired uptake
- porin gene mutation
- mutation of proteins required for gradient
- anaerobic conditions
- mutation of ribosomal protein (less common)
Notes:
- Strong postantibiotic effect (hours) in absence of detectable drug
- Semi-synthetic derivative of Kanamycin, less resistance, broad activity, save for severe cases
3
Q
Gentamicin
A
Bacteriocidal
Target:
- Gram - (bacilli) and Gram + (aerobic)
- NOT effective against anaerobes (need O2 for uptake)
- Synergistic w/ Beta-lactams or Vanc for TX of endocarditis caused by enterococci, strep, staph, and TB
Indications:
- for severe infections (sepsis, pneumo)
Mechanism:
- irreversible inhibitors of protein synthesis
- concentration-dependent killing (faster)
- blocks initiation of protein synthesis
- blocks further translation and elicits premature termination
- incorporation of incorrect AA
- alter memb function leading to increased permeability and leakage of intracellular contents (less protein synthesis)
Route of Administration:
- Generally IV or IM
- poorly absorbed PO
Absorption:
- IV or IM
- poor PO absorption (<1%) except in GI disease, ulcers
- enter cells via passive diffusion through porins (outer membrane of Gram - )
- O2 dependent transport across cell membrane
- coupled to proton pump, electrochem gradient drives process
- inhibited by divalent cations, low pH, and anaerobic conditions
- increased uptake facilitated by cell wall inhibitors (PCN, Vanc)
Distribution:
- low binding to serum proteins
- polar, cationic compounds, do not enter cells/tissues easily
- do not enter CNS or eye
- may enter CNS if inflammation present or after intrathecal/IV injection
Metabolism and Excretion:
- via urine (glomerular filtration)
- dosing monitored in renal impairment
Toxicities:
- can be very common
- Ototoxicity (10-25%)
- irreversible
- mechanism = accumulation of drug in inner ear/cochlea = hair cell death via binding phospholipids, Ca, oxidative stress?)
- can occur w/ renal impairment, prolonged use and concurrent use w/ loop diuretics
- vestibular damage (vertigo, ataxia, disequilibrium)
- auditory damage (tinnitus, high-freq HL)
- nephrotoxicity (10-25%)
- increased serum drug concentrations
- accumulation in proximal tubule
- binds to phospholipids
- reversible damage, proximal tubule cells regenerate
Neuromuscular toxicity
- interferes w/ Ca signaling (high doses); fail to release Ach, respiratory distress
Drug Interactions: -
Pt considerations:
- careful dosing in renal impairment
Resistance:
- enzymatic inactivation (major)
- acetylation, P, adenylation
- impaired uptake
- porin gene mutation
- mutation of proteins required for gradient
- anaerobic conditions
- mutation of ribosomal protein (less common)
- Gentamicin resistance = cross resistance to other aminoglycosides
Notes:
- Strong postantibiotic effect (hours) in absence of detectable drug
- similar to tobramycin (inhaled)
4
Q
Neomycin
A
Bacteriocidal
- similar to kanamycin
- active against Gram + and Gram - aerobes
- poorly absorced from gut (used as bowel sterilant)
- used topically
