Lecture 14 - Optimising Antimicrobial Therapy

Question 1

What is volume of distribution? (V)

Answer 1

apparent volume that a drug distributes into, based on dose amount and serum concentration?

Question 2

What is clearance? (CL)

Answer 2

volume of blood cleared of drug per unit time (L/h)

main routes = renal excretion and hepatic metabolism

Question 3

What is the elimination rate constant? (k)

Answer 3

rate of decline of concentration

k (/h) = CL (L/h)/V(L)

Question 4

What is the elimination half life?

Answer 4

time for the concentration to fall to half

T1/2 (h) = -Ln (0.5) / k
T1/2 (h) = 0.693 / k

Question 5

What is concentration at time 0?

Answer 5

C0 = dose (mg) / V (L)

Question 6

What does concentration any time after the dose depend on?

Answer 6

dose, volume of distribution, elimination rate constant and the time after the dose

Question 7

How many half lives does it take to reach steady state?

Answer 7

5 half lives to ~97% steady state

Question 8

What does the accumulation factor account for?

Answer 8

all previous drug doses and changes the equation from a single dose, to a steady state dose

Question 9

What is gentamicin used for?

Answer 9

gram negative sepsis

community or healthcare acquired, urinary tract, neutropenic, unknown source

Question 10

Spectrum of gentamicin?

Answer 10

relatively narrow spectrum

gives less risk of C difficile overgrowth

Question 11

How is gentamicin sometimes used?

Answer 11

synergistically (low dose) with penicillins or vancomycin against gram positive organisms

Question 12

What is amikacin used for?

Answer 12

neutropenic sepsis, multi resistant mycobacterial infections

Question 13

What is tobramycin used for?

Answer 13

exacerbations in patients with cystic fibrosis (pseudomonas aeruginosa)

Question 14

Aminoglycoside absorption?

Answer 14

highly polar, water soluble

low oral bioavailability, administered IV (or topically in ear/eye drops)

Question 15

Where do aminoglycosides distribute into?

Answer 15

extracellular fluid (0.2-0.4L/kg)

Question 16

What increases V of aminoglycosides?

Answer 16

oedema, ascites, burns, malnutrition

Question 17

What decreases V of aminoglycosides?

Answer 17

dehydration

Question 18

How are aminoglycosides elminated?

Answer 18

90-100% renal excretion via glomerular filtration

Question 19

What do clearance and dose requirements of aminoglycosides depend on?

Answer 19

renal function

Question 20

What is the concentration dependent kill rate of aminoglycosides?

Answer 20

higher peaks produce a faster kill, more effective against bacteria

need high peaks and low troughs

Question 21

What is the energy dependent uptake into bacteria of aminoglycosides?

Answer 21

reduced after exposure of antibiotic, this gives temporary resistance

Question 22

What is the post antibiotic effect of aminoglycosides?

Answer 22

prolonged suppression of bacterial growth even when antibiotic concentrations fall below detection limit

Question 23

What is nephrotoxicity?

Answer 23

acute tubular necrosis

uptake into proximal renal tubule causes damage, leading to renal impairment

Question 24

What is acute tubular necrosis lower with?

Answer 24

a single large dose than multiple daily doses

Question 25

What is ototoxicity?

Answer 25

damage to outer/inner hair cells in ear

Question 26

Vestibulotoxicity?

Answer 26

dizziness, vertigo, oscillopsia, nystagmus associated with gentamicin and tobramycin

Question 27

Cochleotoxicity?

Answer 27

hearing loss, tinnitus - associated with amikacin

Question 28

What is toxicity generally related to?

Answer 28

exposure

duration of therapy, cumulative area under the curve (AUC)

rare genetic predisposition to cochleotoxicity

Question 29

Ototoxicity symptoms?

Answer 29

sudden onset of dizziness with nausea and vomiting

Question 30

Vestibular toxicity?

Answer 30

gentamicin

linked to duration of therapy

rare if therapy is <6 days

Question 31

Auditory toxicity?

Answer 31

amikacin

linked to genetic background and age

Question 32

Monitoring patients on aminoglycoside?

Answer 32

question patient about dizziness and balance problems

STOP if the patient raises concerns

Question 33

What is the ideal aminoglycoside concentration-time profile?

Answer 33

high peak (Cmax) and low trough (Cmin)

Question 34

What is the target peak concentration of gentamicin?

Answer 34

> 12mg/L

3-5mg/L in synergistic use

Question 35

What is the target trough concentration of gentamicin?

Answer 35

<0.5mg/L in sepsis

<1mg/L for synergistic use

Question 36

How do we measure concentrations in sepsis?

Answer 36

measure a mid-dose concentration and plot on a nomogram - in some cases we would measure two concentrations

Question 37

How do we measure concentrations in endocarditis?

Answer 37

we would usually measure peak and trough concentrations