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Aminoglycoside Pharmacokinetics/Pharmacodynamics

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Aminoglycoside Dosing: Pharmacokinetic Model RationaleYazan Kherallah

ObjectivesUnderstand the rationale supporting the pharmacokinetic dosing modelDiscuss and interpret pharmacokinetic concepts that affect aminoglycoside dosingVolume of distributionHalf-life / Elimination rateUtilize pharmacokinetics to properly dose aminoglycosides

Pharmacokinetics (PK) vs. Pharmacodynamics (PD)Definitions:PK: The process by which a drug is absorbed, distributed, metabolized, and eliminated by the body PD: The study of the action or effects of drugs on living organisms In other terms:PK: what the body does to the drugPD: how the drug acts on the bodyOne must understand the PD of a drug before using PK to design a dosing regimen

Aminoglycoside PD

- Bactericidal- Bind to 50S subunit to inhibit DNA synthesis

Concentration dependent killing

Literature SupportMultiple studies have demonstrated the relationship of PK/PD for aminoglycosidesPlasma levels and outcomeSepsisPneumoniaPeak:MIC ratioAltered Vd in the critically illGoalsProvide efficacious dosingMinimize drug toxicity

Association of Serum Levels and OutcomeInitial doses of 2 mg/kg gentamicin or tobramycin (8 mg/kg amikacin) given to septic patients (n=89)In combination with a -lactamTherapeutic initial peaksGent/tobra: > 5 mcg/mlAmikacin: > 20 mcg/mlOutcome = MortalityTherapeutic: 2.4% (1/41)Subtherapeutic: 20.9% (9/43)J Infect Dis 1984;149(3):443-8

Association of Serum Levels and OutcomeInitial doses of 2 mg/kg gentamicin or tobramycin (8 mg/kg amikacin) given to pneumonia patients (n=37)In combination with a -lactamTherapeutic initial peaksGent/tobra: > 7 mcg/mlAmikacin: > 28 mcg/mlOutcome = Successful OutcomesTherapeutic: 78% (14/18)Subtherapeutic: 32% (6/19)Multivariate analysisMost important predictor of positive outcomeAm J Med 1984;77:657-662

Importance of Peak:MIC RatioInitial doses of 2 mg/kg gentamicin or tobramycin (8 mg/kg amikacin) given to sepsis patients (n=236)In combination with a -lactam188/236 patients had favorable response to antibioticsMost important factors for favorable response (univariate analysis)Favorable underlying prognosis (p=0.0001; R=0.36)Maximal peak:MIC ratio > 10 (p=0.0005; R=0.21)J Infect Dis 1987;155(1):93-9

Importance of Peak:MIC RatioTable of Peak:MIC ratios and relative odds of favorable responseMax Peak:MIC (mcg/ml)Relative Odds95% Confidence Interval< 21.002-

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