Aminoglycosides Flashcards
What is the mechanism of action of aminoglycosides?
- Multifactorial, but ultimately involves the inhibition of protein synthesis.
- Irreversibly bind to the 30S ribosomal subunit, resulting in a disruption in the initiation of protein synthesis, a measurable decrease in protein synthesis, and misreading of messenger RNA (bactericidal in activity because it binds irreversibly; concentration dependent manner).
- For gram-negative bacteria, the aminoglycosides must first bind to and diffuse through the outer membrane through porin proteins. Polycationic aminoglycosides bind to negatively charged residues in polar heads of phospholipids (no energy required).
- Once in the periplasmic space, the aminoglycosides must then be transported across the cytoplasmic membrane energy dependent, required oxygen, and is rate-limiting. The transfer across the cytoplasmic membrane can be impaired by hyperosmolarity, divalent cations, low pH, and anaerobiosis (all impair the membrane potential that drives transport) reduced antibacterial activity. They then the aminoglycosides bind to polysomes and inhibit the synthesis of proteins.
What are the aminoglycosides?
tobramycin, gentamicin, amikacin, streptomycin, plazomicin (new)
What is the mechansims by which bacteria become resistant to aminoglycosides?
- Alteration in aminoglycoside uptake from chromosomal mutations.
- Synthesis of aminoglycoside-modifying enzymes: most common; enzymatically modify the structure of the aminoglycoside by acetylation, phosphorylation, or adenylation. Cross resistance in gentamicin and tobramycin, not amikacin or plazomicin because they’re semisynthetic.
- Alteration in ribosomal binding sites: rarely occurs with gentamicin, tobramycin, and amikacin because they bind multiple sites on 30S and 50S ribosomal subunits. May be in streptomycin because it only binds to single site on 30S ribosomal subunit.
Spectrum of activity of aminogylcosides
- Concentration-dependent bactericidal activity against aerobic gram-negative bacteria (peak:MIC ratio of 10:1 is optimal).
- Gram-positive aerobes: NEVER used ALONE, always used in LOW DOSES with cell-wall active agents to provide synergy – primarily gentamicin; enterococcus spp. Most strains of staphylococcus aureus and coagulase negative staphylococci.
- Gram-negative aerobes: gentamicin, tobramycin, amikacin, and plazomicin (A,P>T>G, NOT streptomycin) are very active against gram-negative aerobes; amikacin, gentamicin, and tobramycin are often used with cell-wall active agents to provide synergy, HIGHER doses are used – pseudomonas aeruginosa. Plazomicin has activity against some ESBL, AmpC, and KPC producing bacteria.
- Anaerobes: INACTIVE
- Mycobacteria: streptomycin active against these.
- Post-antibiotic affect (PAE): aminoglycosides display a PAE for most gram-negative bacteria as well as S aureus.
- Synergy: between the aminoglycosides and beta-lactams and vancomycin – enterococcus (with ampicillin, penicillin or vanc), S aureus (with beta-lactams or vanc), pseudomonas aeruginosa (with beta-lactams).
Aminoglycosides absorption
very poorly absorbed from GI tract, for systemic infections, give IV or IM. Well absorbed after IM administration – absorption may be decreased in patients with hypotension and should NOT be used in critically ill patients.
Aminoglycosides are what type of compound?
- These are very polar compounds that are polycationic, highly soluble in water (distribute primarily into extracellular fluid compartment, renally eliminated), and incapable of crossing lipid-containing cellular membranes (poor oral absorption, poor penetration through meninges, poor lung penetration).
Aminoglycoside distribution
Distributed primarily in extracellular fluid compartment. Distributed poorly into CSF, sputum, and adipose tissue. Ideal body weight should be used for dosing. Physiologic space that accounts for aminoglycoside distribution is susceptible to volume-related changes, these volume differences must be taken into account when calculating an aminoglycoside dose because they are concentration-dependent bactericidal agents: Vdnormal = 0.25 L/kg; Vddehydration = 0.15-0.20 L/kg; Vdedema = 0.30-0.35 L/kg.
Aminoglycoside elimination
Eliminated unchanged by kidney via glomerular filtration; dose adjustments needed in renal insufficiency; removed by hemodialysis.
Describe patient characteristics that may alter the volume of distribution and clearance of the aminoglycosides, as well as how these alterations may influence dosing of the aminoglycosides.
- Interpatient variability exists in the PK parameters of volume of distribution and clearance, influencing dosing of the aminoglycosides.
Serum concentration monitoring in aminoglycosides
- Serum concentration monitoring is necessary in ALL patients because of interpatient variability in PK parameters and the narrow therapeutic index of the aminoglycosides.
When should peak and trough concentrations of aminoglycosides be obtained?
- Peak concentrations should be obtained 30 minutes after a 30-minute infusion for standard/traditional dosing, and 60 minutes after a 60 minute infusion for once-daily/extended interval dosing. Trough concentrations should be obtained anytime within 30 min prior to next dose.
Standard/traditional aminoglycoside dosing
- Standard/traditional dosing: smaller doses administered with the dosing interval dictated by the patient’s renal function; subsequent doses based on peak and trough serum concentrations obtained at steady state.
It is imperative to achieve therapeutic aminoglycoside concentrations within how many hours in patients with sepsis?
24 hours in patients with gram-negative sepsis.
What is the target peak and trough for gentamicin and tobramycin in standard/traditional dosing?
- Gram negative infections:
- moderate infections (UTIs): peak = 4-6, trough = 0.5-1.5
- Moderate-severe infections (soft-tissue infections, bacteremia): peak = 6-8, trough = 1-1.5
- Severe infections (pneumonia, burn wound, life-threatening infections): peak = 8-10, trough = <2
- Gram-positive synergy: gentamicin only – peak = 3-5, trough =1
What is the target peak and trough for gentamicin and tobramycin in extended interval dosing?
- Larger doses are administered q24hrs to obtain high peak concentrations and undetectable trough concentrations: gent/tobra = 5-7 mg/kg as a single daily dose (CrCl has to be >40-40 ml/min, normal Vd, and only if treating – urosepsis, intraabdominal infection, skin/soft tissue infections (gram-negative infections only).
- If CrCl <40-50 ml/min: prolong dosing interval to q36-48hrs
- Subsequent doses are based on serum concentrations obtained at 2 and 10 hours after the end of infusion of the 1st dose OR using the Hartford dosing nomogram with a serum concentration drawn 8-12 hours after 1st dose.
- Once daily dosing gent/tobra: peak = 13-20, trough = <0.5
What are the clinical uses of aminoglycosides?
- RARELY used ALONE (except plazomicin).
- Amikacin, gentamicin, and tobramycin are used for the treatment of serious infections due to gram-negative aerobic bacteria (including pseudomonas aeruginosa).
- Plazomicin used in complicated UTIs due to MDR gram-negative bacteria.
- Gentamicin or streptomycin used with cell wall active agents (ampicillin, vancomycin_ for serious infections due to enterococci, viridans streptococci, or staphylococci.
What are the major AEs that may occur with aminoglycosides?
- Nephrotoxicity (reversible): risk factors include prolonged high trough concentrations, prolonged therapy, presence of underlying renal insufficiency, advanced age, hypovolemia and concomitant used of vancomycin, amphotericin B, cisplatin, CT contrast.
- Ototoxicity (irreversible): auditory and vestibular. Risk factors include prolonged trough concentrations, prolonged therapy, presence of renal insufficiency, advanced age, and concomitant use of vancomycin and loop diuretics.
