Lecture 19 - Optimising Antibiotic Therapy (2) Flashcards by Phoebe Roper

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

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What is the ideal aminoglycoside concentration-time profile?

high peak and low trough

optimise Cmax/MIC ratio

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What do beta lactams exhibit?

time dependent killing

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What is the best determinant of beta lactam efficacy?

percentage of dosage interval that unbound (free) conc remain above the MIC (% f T>MIC)

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What is the usual target to optimise bacterial killing for penicillins?

> 40 - 60% f T>MIC

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What might critically ill patients need?

100% fT>MIC or 100%fT>4xMIC

so higher doses are often used

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What are glycopeptide antibiotics?

vanomycin and teicoplanin

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What are glycopeptide antibiotics used for?

active against gram positives

used in patients with a penicillin allergy or MRSA

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What is MRSA?

methicillin resistant stap aureus

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What is the accepted PK/PD target for vancomycin?

AUC24/MIC ratio

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What are glycopeptides traditionally regarded as?

time dependent

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What is the target for vancomycin?

AUC24/MIC ratio >400

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What is AUC24?

the daily AUC

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How to calculate AUC24?

AUC24 = daily dose (mg)/clearance (L/h)

AUC24 = Cssaverage x 24h

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What is red man/neck syndrome?

a sign of vancomycin toxicity

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How many patients suffer from red man syndrome?

4-47% of patients

varying severity, soon after the start or end of a infusion

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What is red man sydrome related to?

the infusion rate

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What is red man syndrome caused by?

histamine release following degranulation of mast cells and basophils

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Symptoms of red man syndrome?

erythematous rash spreads across face, neck and upper torso with burning and severe pruritus

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What else may patients with red man syndrome be?

dizzy, agitated, experience headache, chills, fever, paraesthesia, chest pain, dyspnoea

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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