Impact of augmented renal clearance on the pharmacokinetics of linezolid: Advantages of continuous infusion from a pharmacokinetic/pharmacodynamic perspective

Abstract

The aim of this study was to assess the influence of renal function, in particular the presence of augmented renal clearance (ARC), on the pharmacokinetics of linezolid in critically ill patients. The effect of continuous infusion on the probability of therapeutic success from a pharmacokinetic/pharmacodynamic (PK/PD) perspective was also evaluated. Methods: Seventeen patients received linezolid (600 mg every 12 h) as a 30-min infusion and 26 as a continuous infusion (50 mg/h). The PK parameters were calculated and the probability of PK/PD target attainment (PTA) was estimated by Monte Carlo simulation (MCS) for different doses administered by intermittent (600 mg every 12 h or 600 mg every 8 h) or continuous infusion (50 mg/h or 75 mg/h). Results: In patients without ARC, the standard dose was adequate to attain the PK/PD target. However, linezolid clearance was significantly higher in ARC patients, leading to sub-therapeutic concentrations. Continuous infusion (50 mg/h) provided concentrations !2 mg/l in 70% of the ARC patients. MCS revealed that concentrations !2 mg/l would be reached in >90% of patients receiving 75 mg/h. Conclusions: ARC increases linezolid clearance and leads to a high risk of underexposure with the standard dose. Continuous infusion increases the PTA, but an infusion rate of 75 mg/h should be considered to ensure concentrations !2 mg/ml.

Pharmacokinetic of linezolid dose adjustment for creatinine clearance in critically ill patients: a multicenter, prospective, open-label, observational study

“…This was different from the previous studies on Caucasian patients, for the upper limits of the concentrations were not included in their PK/PD indexes. The patients with ARC were common in the ICU, a 24 h continuous infusion of a daily dose of 1200 mg or 1800 mg LNZ was recommended in a previous study [16]. In our study, 900 mg q12h could also achieve a similar clinical response.…”

“…The standard dose ensured a relatively high probability of treatment success in patients with MIC ≤ 1 mg/L [16,31]. However, in patients with normal or residual renal function, the standard dose was insu cient, and 900 mg q8h provided a higher probability of treatment success without compromising the safety [16]. In the present study, 1800 mg/day (600 mg q8h) or 1200 mg/day continuous infusion resulted in C min within MIC of 10 mg/L.…”

“…For dose optimization, the population pharmacokinetic (PK) approach had been used to simulate the dosing regimens in Caucasian patients with acute respiratory distress syndrome (ARDS) [14], renal impairment [15], augmented renal clearance (ARC) [16], or on continuous renal replacement therapy (CRRT) [17]. Based on a population PK model of LNZ in healthy Chinese volunteers, Yang et al simulated different dosing regimens for a range of MICs [18].…”

Augmented Renal Clearance and How to Augment Antibiotic Dosing

“…However, renal impairment and renal replacement therapy appear to be risk factors for this drug-related thrombocytopenia [ 58 , 59 ], suggesting that this concern may not be applicable to patients with ARC. Of note, a recent study observed that linezolid clearance was still exceptionally elevated in those with ARC and the investigators concluded that a continuous confusion at 75 mg/h would be necessary to remain at concentrations of 2 mg/L or above [ 60 ]. Thus, even for drugs with non-renal elimination pathways, dosing adjustments may still need to be made.…”

Some Suggestions from PK/PD Principles to Contain Resistance in the Clinical Setting—Focus on ICU Patients and Gram-Negative Strains

“…ARC seems to have no effects on meropenem 2g × 3 even for CrCl values of up to 250 mL/min, according to a study by Tamatsukuri et al [ 95 ]. For linezolid, continuous infusion seems to allow higher probability of reaching an optimal PK/PD target than intermittent infusion [ 96 ].…”