Amikacin target achievement in adult cystic fibrosis patients utilizing Monte Carlo simulation

Abstract

Aim: Pseudomonas aeruginosa (PsA) is a common pathogen in cystic fibrosis (CF). Management of an acute pulmonary exacerbation (APE) caused by PsA is dual anti-pseudomonal antibiotics, a beta-lactam plus aminoglycoside. Aminoglycoside dosing in CF differs from the general population due to altered pharmacokinetics. The primary objective of this study was to utilize pharmacokinetic data from adult CF patients that received amikacin to determine the probability of target attainment for APEs caused by PsA.

Methods: This was a single-center, non-randomized, retrospective cohort study of patients >18 years with CF that received intravenous amikacin between January 2010 and July 2016. Amikacin dose, frequency, and serum concentrations were used to calculate pharmacokinetic parameters assuming a one-compartment model. Monte Carlo simulation was conducted with MIC values from CF patients with a PsA positive sputum culture between January 2014 and September 2016 to predict concentration-time profiles for different doses of amikacin.

Results: This study included pharmacokinetic parameters for 14 amikacin courses administered to six unique patients. The average empiric dose of amikacin was 24.3 ± 14.6 mg/kg, achieving a peak:MIC ratio ≥8 at a rate of 37% (median 5.87; IQR 3.05-10.96). A dose of 45 mg/kg/day was needed to achieve target peak:MIC ratios 90% of the time for a PsA MIC of 8 mg/L.

Conclusion: Our data suggests it may not be clinically feasible to utilize amikacin for PsA isolates with a MIC of 16 mg/L. Current guideline dosing recommendations of amikacin 30-35 mg/kg/day are only adequate for PsA with a MIC ≤4 mg/L.

Keywords: P. aeruginosa; aminoglycoside; multi-drug resistant Pseudomonas; pharmacokinetic-pharmacodynamics.