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.

What is the recommended amikacin dosing for cystic fibrosis patients with acute pulmonary exacerbations?

“…With the average weight (57.2 ± 13.3 kg) of patients involved in the study of Nolt et al, the predicted amikacin dose falls within a range between 21 and 34 mg/kg/day, which is more than 10 mg/kg lower than the dose recommended by the authors.…”

“…Nolt et al have recently reassessed dosing recommendations for acute pulmonary exacerbation (APE) in adult cystic fibrosis (CF) patients. Using a Monte Carlo simulation based on a retrospective analysis of six patients, they recommend a dose 1.5 times higher than that of the CF Foundation guidelines (30 mg/kg/day) .…”

“…We advise taking Nolt et al dosing recommendations with caution. First, the small sample size (n = 6) likely led to errors of approximation.…”

“…Second, Nolt et al conducted a Monte Carlo simulation based on PK parameters that were calculated using equations assuming a one‐compartment model. However, no proper modeling was performed.…”

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis

“…Lung infections in patients with CF are common and frequently caused by Pseudomonas aeruginosa leading to progressive lung damage due to chronic lung inflammation and fibrosis resulting in high morbidity and mortality . Furthermore, the emergence and spread of multidrug‐resistant P. aeruginosa infections are of great concern given the limited number of therapeutic options effective against these bacterial strains . To date, there is no consensus on the optimal antibiotic protocol for P. aeruginosa infection in patients with CF​​​​​, but intravenous administration of beta‐lactams plus aminoglycosides such as tobramycin or amikacin is the cornerstone of treatment of CF pulmonary exacerbations due to this bacteria …”