Lecture 14 - Optimising Antimicrobial Therapy Flashcards
What is volume of distribution? (V)
apparent volume that a drug distributes into, based on dose amount and serum concentration?
What is clearance? (CL)
volume of blood cleared of drug per unit time (L/h)
main routes = renal excretion and hepatic metabolism
What is the elimination rate constant? (k)
rate of decline of concentration
k (/h) = CL (L/h)/V(L)
What is the elimination half life?
time for the concentration to fall to half
T1/2 (h) = -Ln (0.5) / k
T1/2 (h) = 0.693 / k
What is concentration at time 0?
C0 = dose (mg) / V (L)
What does concentration any time after the dose depend on?
dose, volume of distribution, elimination rate constant and the time after the dose
How many half lives does it take to reach steady state?
5 half lives to ~97% steady state
What does the accumulation factor account for?
all previous drug doses and changes the equation from a single dose, to a steady state dose
What is gentamicin used for?
gram negative sepsis
community or healthcare acquired, urinary tract, neutropenic, unknown source
Spectrum of gentamicin?
relatively narrow spectrum
gives less risk of C difficile overgrowth
How is gentamicin sometimes used?
synergistically (low dose) with penicillins or vancomycin against gram positive organisms
What is amikacin used for?
neutropenic sepsis, multi resistant mycobacterial infections
What is tobramycin used for?
exacerbations in patients with cystic fibrosis (pseudomonas aeruginosa)
Aminoglycoside absorption?
highly polar, water soluble
low oral bioavailability, administered IV (or topically in ear/eye drops)
Where do aminoglycosides distribute into?
extracellular fluid (0.2-0.4L/kg)
What increases V of aminoglycosides?
oedema, ascites, burns, malnutrition
What decreases V of aminoglycosides?
dehydration
How are aminoglycosides elminated?
90-100% renal excretion via glomerular filtration
What do clearance and dose requirements of aminoglycosides depend on?
renal function
What is the concentration dependent kill rate of aminoglycosides?
higher peaks produce a faster kill, more effective against bacteria
need high peaks and low troughs
What is the energy dependent uptake into bacteria of aminoglycosides?
reduced after exposure of antibiotic, this gives temporary resistance
What is the post antibiotic effect of aminoglycosides?
prolonged suppression of bacterial growth even when antibiotic concentrations fall below detection limit
What is nephrotoxicity?
acute tubular necrosis
uptake into proximal renal tubule causes damage, leading to renal impairment
What is acute tubular necrosis lower with?
a single large dose than multiple daily doses
What is ototoxicity?
damage to outer/inner hair cells in ear
Vestibulotoxicity?
dizziness, vertigo, oscillopsia, nystagmus associated with gentamicin and tobramycin
Cochleotoxicity?
hearing loss, tinnitus - associated with amikacin
What is toxicity generally related to?
exposure
duration of therapy, cumulative area under the curve (AUC)
rare genetic predisposition to cochleotoxicity
Ototoxicity symptoms?
sudden onset of dizziness with nausea and vomiting
Vestibular toxicity?
gentamicin
linked to duration of therapy
rare if therapy is <6 days
Auditory toxicity?
amikacin
linked to genetic background and age
Monitoring patients on aminoglycoside?
question patient about dizziness and balance problems
STOP if the patient raises concerns
What is the ideal aminoglycoside concentration-time profile?
high peak (Cmax) and low trough (Cmin)
What is the target peak concentration of gentamicin?
> 12mg/L
3-5mg/L in synergistic use
What is the target trough concentration of gentamicin?
<0.5mg/L in sepsis
<1mg/L for synergistic use
How do we measure concentrations in sepsis?
measure a mid-dose concentration and plot on a nomogram - in some cases we would measure two concentrations
How do we measure concentrations in endocarditis?
we would usually measure peak and trough concentrations
