Aminoglycosides Flashcards
Explain the mechanisms of action of the aminoglycosides
Aminoglycosides irreversibly bind to the 30S ribosomal subunit (some to 50S subunits), which results in a disruption in the initiation of protein synthesis, a measurable decrease in protein synthesis, and misreading of messenger RNA.
Describe the concept of synergy between cell wall active agents and aminoglycosides.
Aminoglycosides can’t penetrate cells. Cell wall active agents “hold the door open”
Synergy has been demonstrated for:
- Enterococcus - with ampicillin, penicillin or vancomycin (gent or strep)
- S. aureus, viridans streptococci- with b-lactams or vancomycin (gent)
- P. aeruginosa and other gram-negatives
Explain the pharmacokinetics and pharmacodynamics of the aminoglycosides and apply this information to dosing strategies: absorption
Poor bioavailability
Intravenous infusion is the preferred route of administration.
Tobramycin is often given via inhalation (10-20% systemic absorption)
Explain the pharmacokinetics and pharmacodynamics of the aminoglycosides and apply this information to dosing strategies: distribution
- Volume of distribution that approximates extracellular space, low protein binding (~10%).
- Minimal penetration into the CSF (more with inflamed meninges), bronchial secretions, bile (30% of serum), vitreous humor (40%).
- Pleural, pericardial, ascetic, and synovial fluids ~50% of serum; high concentrations in urine.
Explain the pharmacokinetics and pharmacodynamics of the aminoglycosides and apply this information to dosing strategies: elimination
- Rapidly excreted, primarily by glomerular filtration. Reabsorption into the proximal tubule may lead to accumulation in the renal cortex which is responsible for nephrotoxicity. High urinary concentrations.
- 30 – 40% removed by hemodialysis
Compare traditional vs extended‐interval aminoglycoside dosing strategies.
Traditional - multiple small doses per day
Extended-interval - one big dose. Fewer complications, easier on nursing staff, cheaper, extended post-antibiotic effect, less of a chance for bacteria to develop adaptive resistance, conc.-dependent killing, more efficacious
Explain the mechanisms of resistance of the aminoglycosides
A. Synthesis of aminoglycoside-modifying enzymes
Plasmid-mediated resistance factor that enables the resistant bacteria to covalently modify the aminoglycoside, to keep it from entering the cell or binding to ribosomes. Amikacin is resistant to many enzymes.
B. Alteration in aminoglycoside uptake
1. Chromosomal mutations that influence any part of the binding and/or electrochemical gradient that facilitates aminoglycoside uptake leads to
decreased penetration of aminoglycoside inside the bacteria.
C. Alteration in ribosomal binding sites (rare)
Clinical uses for gentamicin
Gram-negative infections:
- Used in combination with beta-lactams to treat Pseudomonas aeruginosa and other highly resistant gram negative bacilli
- Often used for sepsis, especially from a urinary source; may be used for bloodstream, intraabdominal and skin and soft tissue infections. Given low pulmonary penetration, consider giving high-dose.
- Rarely used as monotherapy (only for urinary tract infections)
Gram-positive infections:
- Used in combination with beta-lactams (ampicillin or nafcillin) or vancomycin for severe gram-positive infections (e.g., enterococcal or staphylococcal endocarditis)
Clinical uses for streptomicin
Gram-positive infections:
Used in combination with beta-lactams (ampicillin or nafcillin) or vancomycin for severe gram-positive infections (e.g., enterococcal or staphylococcal endocarditis)
Mycobacterial infections (amikacin or streptomycin) 1. Used in combination with multiple antimycobacterial agents
Clinical uses for amikacin
Gram-negative infections:
- Used in combination with beta-lactams to treat Pseudomonas aeruginosa and other highly resistant gram negative bacilli
- Often used for sepsis, especially from a urinary source; may be used for bloodstream, intraabdominal and skin and soft tissue infections. Given low pulmonary penetration, consider giving high-dose.
- Rarely used as monotherapy (only for urinary tract infections)
Mycobacterial infections (amikacin or streptomycin) 1. Used in combination with multiple antimycobacterial agents
Clinical uses for tobramicin
Gram-negative infections:
- Used in combination with beta-lactams to treat Pseudomonas aeruginosa and other highly resistant gram negative bacilli
- Often used for sepsis, especially from a urinary source; may be used for bloodstream, intraabdominal and skin and soft tissue infections. Given low pulmonary penetration, consider giving high-dose.
- Rarely used as monotherapy (only for urinary tract infections)
static or cidal?
Bacteriocidal