Lecture 19 - Optimising Antibiotic Therapy (2) Flashcards
What are the 3 general pharmacokinetic-pharmacodynamic relationships of antibiotics?
response related to ratio of max concentration to the minimum inhibitory conc
time above MIC is important, where the concentrations are above that min value
area under concentration time curve relative to the MIC is the determine of the clinical efficacy
What is the ideal aminoglycoside concentration-time profile?
high peak and low trough
optimise Cmax/MIC ratio
What do beta lactams exhibit?
time dependent killing
What is the best determinant of beta lactam efficacy?
percentage of dosage interval that unbound (free) conc remain above the MIC (% f T>MIC)
What is the usual target to optimise bacterial killing for penicillins?
> 40 - 60% f T>MIC
What might critically ill patients need?
100% fT>MIC or 100%fT>4xMIC
so higher doses are often used
What are glycopeptide antibiotics?
vanomycin and teicoplanin
What are glycopeptide antibiotics used for?
active against gram positives
used in patients with a penicillin allergy or MRSA
What is MRSA?
methicillin resistant stap aureus
What is the accepted PK/PD target for vancomycin?
AUC24/MIC ratio
What are glycopeptides traditionally regarded as?
time dependent
What is the target for vancomycin?
AUC24/MIC ratio >400
What is AUC24?
the daily AUC
How to calculate AUC24?
AUC24 = daily dose (mg)/clearance (L/h)
AUC24 = Cssaverage x 24h
What is red man/neck syndrome?
a sign of vancomycin toxicity
How many patients suffer from red man syndrome?
4-47% of patients
varying severity, soon after the start or end of a infusion
What is red man sydrome related to?
the infusion rate
What is red man syndrome caused by?
histamine release following degranulation of mast cells and basophils
Symptoms of red man syndrome?
erythematous rash spreads across face, neck and upper torso with burning and severe pruritus
What else may patients with red man syndrome be?
dizzy, agitated, experience headache, chills, fever, paraesthesia, chest pain, dyspnoea
How do you reduce the risk of red neck syndrome?
doses are administered by infusion at a rate not greater than 500mg/h
What is nephrotoxicity with vancomycin?
mechanism is unclear
oxidative stress, renal tubular ischaemia, acute tubulointerstitial damage
what is nephrotoxicity associated with?
high trough concentrations and long duration of therapy
How to reduce risk of nephrotoxicity?
low = dose <15mg/L medium = >15mg/L high = >20mg/L
low = <7 days medium = >7 days high = >14 days
what can nephrotoxicity potentiate?
aminoglycoside toxicity
What are other less common side effects of vancomycin?
IgA mediated bullous dermatosis
neutropenia, especially with long term use
thrombocytopenia
Anaphylaxis associated with vancomycin?
rare, associated with release of IgE
What is efficacy best related to? (IDSA)
AUC24/MIC ratio
target is >400mg.h/L, assuming an MIC of <1mg/L
What are troughs not?
optimal surrogates for AUC24
What should be aimed for with vancomycin?
AUC of 400-600mg.h/L and steady state concentration during continuous infusion of 20-25mg/L
What are trough concentrations currently used for?
routine monitoring of vancomycin given by intermittent infusion
When is oral administration of vancomycin given?
ONLY to treat C difficile infections in the gut, no systemic absorption
How is vancomycin given?
IV for systemic infections
What are the two IV modes of administration of vancomycin?
continuous infusion
intermittent infusion
What is a continuous infusion?
mainly used in critically ill patients
Css average target 20-25mg/L
AUC24 target 480-600mg.h/L
What is an intermittent infusion?
easier to manage in general medical and surgical wards
trough target 10-20mg/L (previously 15-20mg/L)
AUC = 400-600mg h/L (assuming MIC <1mg/L)
In clinical practice what do we start treatment with?
A loading infusion
this is a large dose to get the concentrations up, and then they decline as soon as this stops
What happens at the end of the loading infusion?
we would start the maintenance continuous infusion
What do we start intermittent infusions with?
a loading infusion to achieve therapeutic concentrations quickly
When do we start the next intermittent infusion?
at the end of the dosage interval
As a clinical pharmacist what might you need to do?
recommend a loading and maintenance dosage regimen (continuous or intermittent)
check if a prescribed dosage regimen is appropriate for a patient
interpret measured vancomycin concentrations and recommend dose adjustment
Target peak concentration of vancomycin?
do not have one
What does a typical loading dose of 25mg/kg achieve peaks of?
25-30mg/L
Cpeak (mg/L) = ?
dose (mg) / volume of distribution (L)
or
Two approaches to administer by continuous infusion?
the daily dose is prescribed with the instruction to administer by continuous infusion over 24h
the daily dose is split into two and prescribed with the instruction to administer as two 12h infusions
AUC24 (mg.h/L) = ?
daily dose (mg) / CL(L/h)
Aminoglycosides efficacy?
peak:MIC ratio, aim for high peak low trough
Aminoglycoside use?
gram negative sepsis and synergistic use
Aminoglycoside administration?
short IV infusion (30-60 minutes) or IV bolus
Penicillin efficacy?
% time free concentrations >MIC (40-60% fT>MIC)
Penicillins use?
wide therapeutic range, ideal profile is flat
Vancomycin administration?
loading infusion then intermittent IV infusion over 1-4h or continuous infusion
