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Association between Extended Meropenem Regimen and Achievement of Aggressive PK/PD in Patients Receiving Continuous
Shinya Chihara1,2, Tomoyuki Ishigo3, Satoshi Kazuma1
1Department of Intensive Care Medicine, Sapporo Medical University, School of Medicine, Sapporo 060-8543, Japan.
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.
Insights
Aggressive pharmacokinetic/pharmacodynamic (PK/PD) targets for meropenem are effective in patients with septic acute kidney injury on continuous renal replacement therapy (CRRT). This regimen achieves therapeutic goals with a low risk of toxicity.
Area of Science:
- Pharmacology
- Nephrology
- Infectious Diseases
Background:
- Aggressive pharmacokinetic/pharmacodynamic (PK/PD) targets improve outcomes and reduce resistance compared to conservative targets.
- Meropenem dosing requires optimization in patients with septic acute kidney injury (AKI) undergoing continuous renal replacement therapy (CRRT).
Purpose of the Study:
- To evaluate the efficacy and safety of an aggressive meropenem regimen (1 g infusion every 8 h over 3 h) in patients with septic AKI on CRRT.
- To determine meropenem blood levels and assess achievement of PK/PD targets.
Main Methods:
- PK/PD targets defined as %fT > 4 × MIC; toxicity threshold at trough concentration >45 mg/L.
- Meropenem regimen: 1 g infusion every 8 h over 3 h in patients on CRRT.
- Bayesian estimation used for simulations to predict PK/PD target achievement.
Main Results:
- The 100% fT > 4 × MIC was 89% for MIC 0.5 mg/L and 56% for MIC 2 mg/L.
- Mean steady-state trough concentration was 11.9 ± 9.0 mg/L; maximum was 29.2 mg/L.
- Aggressive PK/PD targets achievable up to MIC 0.5 mg/L; continuous infusion (3 g/24 h) may achieve targets up to MIC 2 mg/L.
Conclusions:
- The meropenem regimen of 1 g every 8 h over 3 h is associated with a low toxicity risk in CRRT patients with septic AKI.
- Aggressive PK/PD targets are achievable for MICs up to 0.5 mg/L.
- Continuous infusion meropenem (3 g/24 h) may be necessary to achieve aggressive PK/PD targets for higher MICs (1-2 mg/L).
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