Association between Extended Meropenem Regimen and Achievement of Aggressive PK/PD in Patients Receiving Continuous Renal Replacement Therapy for Septic AKI

Abstract

Aggressive pharmacokinetic (PK)/pharmacodynamic (PD) targets have shown better microbiological eradication rates and a lower propensity to develop resistant strains than conservative targets. We investigated whether meropenem blood levels, including aggressive PK/PD, were acceptable in terms of efficacy and safety using a meropenem regimen of 1 g infusion every 8 h over 3 h in patients undergoing continuous renal replacement therapy (CRRT) for septic acute kidney injury (AKI). Aggressive PK/PD targets were defined as the percentage of time that the free concentration (%fT) > 4 × minimal inhibitory concentration (MIC), the toxicity threshold was defined as a trough concentration >45 mg/L, and the percentage of achievement at each MIC was evaluated. The 100% fT > 4 × MIC for a pathogen with an MIC of 0.5 mg/L was 89%, and that for a pathogen with an MIC of 2 mg/L was 56%. The mean steady-state trough concentration of meropenem was 11.9 ± 9.0 mg/L and the maximum steady-state trough concentration was 29.2 mg/L. Simulations using Bayesian estimation showed the probability of achieving 100% fT > 4 × MIC for up to an MIC of 2 mg/L for the administered administration via continuous infusion at 3 g/24 h. We found that an aggressive PK/PD could be achieved up to an MIC of 0.5 mg/L with a meropenem regimen of 1 g infused every 8 h over 3 h for patients receiving CRRT for septic AKI. In addition, the risk of reaching the toxicity range with this regimen is low. In addition, if the MIC was 1-2 mg/L, the simulation results indicated that aggressive PK/PD can be achieved by continuous infusion at 3 g/24 h without increasing the daily dose.

Keywords: acute kidney injury; continuous renal replacement therapy; critically ill patients; meropenem; pharmacokinetics/pharmacodynamics analysis; therapeutic drug monitoring.

Figure 1

Correlation between eGFR and meropenem clearance. □: QF of 2000 mL/h (n = 5), ×: QF of 1000 mL/h (n = 4). (a) Plot correlation between eGFR (mL/min) and total clearance of MEPM (L/h), (b) Plot correlation between eGFR (mL/min) and MEPM clearance of CVVH (L/h). Abbreviations: MEPM, meropenem; QF, quantity of filtration flow rate; eGFR, estimated glomerular filtration rate; CVVH, continuous venovenous filtration.

Figure 2

(a) Predictions obtained by Bayesian estimation versus observations of all measured meropenem plasma concentrations. Black line: line of identity. (b) The difference between the predictions obtained by Bayesian estimation and the observations of all measured meropenem plasma concentrations. Dotted lines indicate mean and ± 2 SD. Abbreviations: RMSE, root mean squared error; MAPE, mean absolute percentage error; SD, standard deviation.

Figure 3

Percentage of patients achieving target PK/PD in each MIC. Abbreviations: MEPM, meropenem; MIC, minimal inhibitory concentration; PK, pharmacokinetic; PD, pharmacodynamic.

Figure 4

Percentage of cases achieving target PK/PD at each MIC when simulations using Bayesian estimation with 3 g infused over 24 h. Abbreviations: MEPM, meropenem; MIC, minimal inhibitory concentration; PK, pharmacokinetic; PD, pharmacodynamic.

Figure 5

PTA versus MIC profiles for various simulated MEPM dosing regimens based on the PK/PD targets of 100% fT > 4 × MIC. Dashed horizontal lines represent a PTA of 90%. Abbreviations: MEPM, meropenem; PTA, probability of target attainment; MIC, minimal inhibitory concentration; PK, pharmacokinetics; PD, pharmacodynamics.