Amikacin Initial Dose in Critically Ill Patients: a Nonparametric Approach To Optimize A Priori Pharmacokinetic/Pharmacodynamic Target Attainments in Individual Patients

Abstract

Amikacin is commonly used for probabilistic antimicrobial therapy in critically ill patients with sepsis. Its narrow therapeutic margin makes it challenging to determine the right individual dose that ensures the highest efficacy target attainment rate (TAR) in this setting. This study aims to develop a new initial dosing approach for amikacin by optimizing the a priori TAR in this population. A population pharmacokinetic model was built with a learning data set from critically ill patients who received amikacin. It was then used to design an initial dosing approach maximizing a priori TAR for a target ratio of ≥8 for the peak concentration to the MIC (Cmax/MIC) or of ≥75 for the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC0–24/MIC). In the 166 patients included, 53% had amikacin Cmax of ≥64 mg/liter with a median dose of 23.4 mg/kg. A two-compartment model with creatinine clearance and body surface area as covariates best described the data and showed good predictive performance. Our dosing approach was successful in optimizing TAR for Cmax/MIC, with a rate of 92.9% versus 67.9% using a 30-mg/kg regimen, based on an external subset of data and assuming a MIC of 8 mg/liter. Mean optimal doses were higher (3.5 ± 0.5 g) than with the 30-mg/kg regimen (2.1 ± 0.3 g). Suggested doses varied with the MIC, the target index, and desired TAR threshold. A dosing algorithm based on the method is proposed for a large range of patient covariates. Clinical studies are necessary to confirm efficacy and safety of this optimized dosing approach.

Population Pharmacokinetic Study of the Suitability of Standard Dosing Regimens of Amikacin in Critically Ill Patients with Open-Abdomen and Negative-Pressure Wound Therapy

“…For a ratio of the AUC from 0 to 24 h (AUC 0 -24 )/MIC of Ն75, the observed target attainment rate was less than 70% for most pathogens in patients with normal renal function, and patients with ARC were particularly at risk for never reaching the desirable PK/PD targets. Those results corroborate recent findings (26), suggesting that further studies are needed to better assess the safety of increased dosing regimens and/or dosage intervals of aminoglycosides in patients with ARC. Moreover, our results also corroborate the observation that achieving adequate peak concentrations and low trough concentrations at 24 h is not possible in a large proportion of patients.…”

“…On the one hand, we chose a C min target of Ͻ2.5 mg/liter, in accordance with French recommendations (9). As previously noticed by Boidin et al, the evidence supporting this recommendation is limited, and several safety thresholds have been previously described (26). In our opinion, the achievement of optimal PK/PD targets of efficacy with the first dose of amikacin remains of paramount importance, whereas the risk of accumulation can be managed by subsequent drug monitoring.…”

“…As serum creatinine is no longer an accurate estimator of renal function and as the Cockcroft-Gault equation cannot be used in patients under CRRT, two predefined subgroups were assessed independently: patients who received continuous renal replacement therapy (CRRT) and those who did not (non-CRRT). In patients not treated by CRRT, CL CR was estimated according to the Cockcroft-Gault equation (26). Renal failure was defined by a CL CR of Ͻ60 ml/min/1.73 m 2 .…”

“…Studied efficacy targets were a C max /MIC ratio of Ն8 and AUC 0 -24 /MIC of Ն75 (26,34). Monte Carlo simulations (n ϭ 10,000) were employed to determine the fractional target attainment (FTA) for the PK/PD targets for various MIC values (0.5 to 8.0 mg/liter) and various renal function levels (need for RRT, renal failure, normal renal function, and ARC).…”

“…We aimed to assess the adequacy of dosing in terms of the worst-case scenario as the type of pathogen and MIC data are often not initially available to the clinician prescribing an empirical (i.e., probabilistic) antimicrobial regimen. Supratherapeutic exposure was defined by a trough concentration (C min ) of Ն2.5 mg/liter, in accordance with French recommendations and previously published studies (9,26,33).…”