Erdman - aminoglycosides Flashcards
CHEMISTRY
The aminoglycosides are very ___ compounds that are ___ , highly soluble in water (distribute primarily into extracellular fluid compartment;
___ eliminated, and incapable of crossing lipid-containing cellular membranes
- poor ___ absorption; poor penetration through ___ , poor ___ penetration
- polar
- polycationic
- renally
- oral
- CSF
- lung
MECHANISM OF ACTION
Aminoglycosides irreversibly bind to the ___ ribosomal subunit
- disruption in the initiation of protein synthesis
- a measurable decrease in protein synthesis
- misreading of messenger RNA
Aminoglycoside antibiotics are rapidly ___ in a ___ -
dependent manner against Gram ___ aerobes, and only display bacteriostatic activity against Enterococcus spp
- 30S
- bacteriocidal, concentration
- negative
MECHANISMS OF RESISTANCE
- Alteration in aminoglycoside ___
- Synthesis of aminoglycoside-modifying enzymes (acetylation, phosphorylation, or adenylation)
- Alteration in ___ binding sites (rare)
uptake
ribosomal
SPECTRUM OF ACTIVITY
The aminoglycosides demonstrate concentration-dependent bactericidal activity against ___ Gram ___ bacteria, where the Peak:MIC ratio correlates best with clinical efficacy
Gram ___ aerobes: (NEVER USED ALONE, always used in ___ DOSES with cell-wall active agents to provide synergy) – primarily ___
aerobic, negative
positive, LOW, gentamicin
SOA
Gram-negative aerobes: gentamicin, tobramycin, amikacin and plazomicin (A,P>T>G; NOT ___ ) are very active
- often used with cell-wall active agents
to provide synergy; ___ DOSES ARE USED
- ___
- streptomycin
- HIGHER
- Pseudomonas aeruginosa
T or F: aminoglycosides are active against anaerobes
FALSE
aerobes only
Streptomycin covers ___
Mycobacteria
Also, Amikacin is active against most strains
T of F: PAE occurs for most Gram-negative bacteria, as well as S. aureus
TRUE
The PAE exists for a finite period of time;
usually 2 to 4 hours against Gram-negative bacteria
Synergy
Synergy exists between the aminoglycosides and cell-wall active agents, such as the ___ and ___
- Thought to be due to enhanced uptake of aminoglycoside into bacteria whose cell walls have been damaged by cell wall synthesis inhibitors
- B-lactams, vancomycin
Aminoglycosides are highly ___ ___, which accounts for their lack of absorption after ___ administration, their pattern of distribution throughout the body, and their elimination in the urine as unchanged drug
- Interpatient ___ exists in the pharmacokinetic parameters of ___ of distribution and ___
These volume differences must be taken into account when calculating an aminoglycoside dose because the aminoglycosides are concentration-dependent bactericidal agents
Vd normal = 0.25 L/kg
Vd dehydrated = 0.15-0.2 L/kg
Vd edema = 0.3-0.35 L/kg
Vd neonates = > 0.5 L/kg
- polar, cations
- oral
- variability
- V, Cl
Absorption
- must be administered __ or __
- ___ should not be used in critically ill patients
- Intermittent intravenous infusion is the preferred route of administration, with doses infused over 30 to 60 minutes
- IV, IM
IM
Distribution
Aminoglycosides are distributed primarily in the ___ fluid compartment
(ascites, pericardial, peritoneal, pleural, and synovial fluids as well as into the urinary tract)
- distribute poorly into ___ , ocular tissue, bile, sputum, and ___ tissue
- ___ weight should be used when dosing
- extracellular
- CSF, adipose
- IBW
Elimination
- unchanged in kidney
- Decreases in renal function directly
influence the elimination of the aminoglycosides, causing a ___ of the half-life - Hemodialysis removes 30 to 50% of aminoglycoside present in the bloodstream, requiring supplemental dosing. Peritoneal dialysis removes 25% of serum concentrations over 48 to 72 hours
- prolongation
Serum concentration monitoring – Gentamicin, tobramycin and amikacin
T or F: serum concentration monitoring is necessary in ALL patients
TRUE
- Because of interpatient variability in pharmacokinetic parameters and the narrow therapeutic index of the aminoglycosides
It is imperative to achieve “therapeutic” aminoglycoside concentrations within ___ hours in patients with Gram-negative sepsis, as studies have demonstrated increased mortality with subtherapeutic levels in these patients
24 hrs
Dosing of aminoglycosides (G,T,A)
factors to consider
volume status, renal function, age, gender, weight, infection being treated, severity of infection, etc
Dosing of aminoglycosides (G,T,A)
Standard or Traditional Dosing – ___ doses (1 to 2.5 mg/kg/dose) are administered with the dosing interval dictated by the patient’s ___ function; subsequent doses are based on peak and trough serum concentrations obtained at steady state
- smaller
- renal
Once-Daily (or Extended Interval) Aminoglycoside Dosing
Gent/Tobra: __ - __ mg/kg as a single daily dose (use IBW or ADW)
Amikacin: __ - __ mg/kg as a single daily dose (use IBW or ADW)
Some institutions employ this dosing method in patients with renal insufficiency (CrCl < 40-50 ml/min), but prolong the dosing interval to every ___ or every ___ hours (AKA Extended Interval Dosing)
Subsequent doses are based on serum concentrations obtained at __ and ___ hours after the end of infusion of the first dose OR using the ___ dosing nomogram with a serum concentration drawn 8 to 12 hours after the first dose
5-7
15-25
36, 48
2, 10, Hartford
Actual peak and trough concentrations are rarely obtained with once daily/extended interval aminoglycoside dosing. In these rare instances, the
desired target concentrations are
- G, T: peak: __ - __ , trough: < __
- A: peak: __ - __ , trough: < __
- 13-20, 0.5
40-50, 4
Plazomicin Dosing and Monitoring
Dose = 15 mg/kg IV (using IBW or ADW) every 24 hours for patients with CrCl ≥ 60
dosage adjustments required in ___ insufficiency
renal
CLINICAL USES
- aminoglycosides are RARELY USED ALONE (except ___ )
plazomicin
CLINICAL USES
___ , ___ , and ___ are used for the treatment of serious infections due to Gram-negative aerobic bacteria (including ___ ) such as bacteremia, bone and joint infections, skin and soft tissue infections, respiratory tract infections, intraabdominal infections, and complicated
urinary tract infections.
___ or ___ may be used with appropriate cell wall active agents (ampicillin, vancomycin, etc) for the treatment of serious infections (endocarditis) due to ___ , ___ , or ___ (EVS)
- Amikacin, gentamicin, and tobramycin
- P. aeruginosa
- Gentamicin or streptomycin
- enterococci, viridans streptococci, or staphylococci
ADVERSE EFFECTS
___ risk factors:
- prolonged high ___ concentrations
- prolonged therapy > 2 weeks
- underlying renal insufficiency
- advanced age
- hypovolemia
- use of concomitant nephrotoxins (vancomycin, amphotericin B, cisplatin, CT contrast, etc.)
Nephrotoxicity
trough
ADVERSE EFFECTS
___ - auditory and vestibular
- damage is ___
risk factors:
- prolonged high ___ concentrations
- prolonged therapy > 2 weeks
- underlying renal insufficiency
- advanced age
- concomitant use of ototoxins ( ___ , ___ diuretics)
- ototoxicity
- irreversible
- trough
- vancomycin, loop
