Aminoglycosides

Question 1

Explain the mechanisms of action of the aminoglycosides

Answer 1

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.

Question 2

Describe the concept of synergy between cell wall active agents and aminoglycosides.

Answer 2

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

Question 3

Explain the pharmacokinetics and pharmacodynamics of the aminoglycosides and apply this information to dosing strategies: absorption

Answer 3

Poor bioavailability
Intravenous infusion is the preferred route of administration.
Tobramycin is often given via inhalation (10-20% systemic absorption)

Question 4

Explain the pharmacokinetics and pharmacodynamics of the aminoglycosides and apply this information to dosing strategies: distribution

Answer 4

1. Volume of distribution that approximates extracellular space, low protein binding (~10%).
2. Minimal penetration into the CSF (more with inflamed meninges), bronchial secretions, bile (30% of serum), vitreous humor (40%).
3. Pleural, pericardial, ascetic, and synovial fluids ~50% of serum; high concentrations in urine.

Question 5

Explain the pharmacokinetics and pharmacodynamics of the aminoglycosides and apply this information to dosing strategies: elimination

Answer 5

1. 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.
2. 30 – 40% removed by hemodialysis

Question 6

Compare traditional vs extended‐interval aminoglycoside dosing strategies.

Answer 6

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

Question 7

Explain the mechanisms of resistance of the aminoglycosides

Answer 7

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)

Question 8

Clinical uses for gentamicin

Answer 8

Gram-negative infections:

1. Used in combination with beta-lactams to treat Pseudomonas aeruginosa and other highly resistant gram negative bacilli
2. 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.
3. Rarely used as monotherapy (only for urinary tract infections)

Gram-positive infections:

1. Used in combination with beta-lactams (ampicillin or nafcillin) or vancomycin for severe gram-positive infections (e.g., enterococcal or staphylococcal endocarditis)

Question 9

Clinical uses for streptomicin

Answer 9

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

Question 10

Clinical uses for amikacin

Answer 10

Gram-negative infections:

1. Used in combination with beta-lactams to treat Pseudomonas aeruginosa and other highly resistant gram negative bacilli
2. 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.
3. Rarely used as monotherapy (only for urinary tract infections)

Mycobacterial infections (amikacin or streptomycin)
1. Used in combination with multiple antimycobacterial agents

Question 11

Clinical uses for tobramicin

Answer 11

Gram-negative infections:

1. Used in combination with beta-lactams to treat Pseudomonas aeruginosa and other highly resistant gram negative bacilli
2. 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.
3. Rarely used as monotherapy (only for urinary tract infections)

Question 12

static or cidal?

Answer 12

Bacteriocidal