Ensuring Sufficient Trough Plasma Concentrations for Broad-Spectrum Beta-Lactam Antibiotics in Children With Malignancies: Beware of Augmented Renal Clearance!

Introduction: Broad-spectrum beta-lactams are commonly prescribed for empirical or selective treatment of bacterial infections in children with malignancies. In the immunocompromised, appropriate concentration exposure is crucial to ensure antimicrobial efficacy. Augmented renal clearance (ARC) is increasingly recognized in this population, and raises concern for unmet concentration targets. We conducted a retrospective evaluation of meropenem and piperacillin exposure in our hospital's pediatric hematology-oncology patients.Materials and Methods: We compared trough levels of meropenem and piperacillin in a cohort of unselected pediatric hematology-oncology patients stratified based on their estimated renal function as decreased, normal or with ARC, and on their neutrophil count.Results: Thirty-two children provided a total of 51 meropenem and 76 piperacillin samples. On standard intermittent intravenous regimen, 67% of all trough plasma concentrations were below targeted concentrations. In neutropenic children with bacterial infection, all meropenem and 60% of piperacillin levels were below target. Nearly two-thirds of total samples came from children with ARC. In these patients, antimicrobial exposure was insufficient in 85% of cases (compared to 36% in the decreased or normal renal function groups), despite a dosage sometimes exceeding the maximum recommended daily dose. Under continuous infusion of piperacillin, only 8% of plasma levels were insufficient.Discussion: Intermittent administration of meropenem and piperacillin often fails to ensure sufficient concentration exposure in children treated for malignancies, even at maximal recommended daily dosage. This can in part be attributed to ARC. We recommend thorough assessment of renal function, resolute dosage adjustment, continuous infusion whenever possible and systematic therapeutic drug monitoring.

Population Pharmacokinetics of Meropenem in Critically Ill Korean Patients and Effects of Extracorporeal Membrane Oxygenation

Limited studies have investigated population pharmacokinetic (PK) models and optimal dosage regimens of meropenem for critically ill adult patients using the probability of target attainment, including patients receiving extracorporeal membrane oxygenation (ECMO). A population PK analysis was conducted using non-linear mixed-effect modeling. Monte Carlo simulation was used to determine for how long the free drug concentration was above the minimum inhibitory concentration (MIC) at steady state conditions in patients with various degrees of renal function. Meropenem PK in critically ill patients was described using a two-compartment model, in which glomerular filtration rate was identified as a covariate for clearance. ECMO did not affect meropenem PK. The simulation results showed that the current meropenem dosing regimen would be sufficient for attaining 40%fT>MIC for Pseudomonas aeruginosa at MIC ≤ 4 mg/L. Prolonged infusion over 3 h or a high-dosage regimen of 2 g/8 h was needed for MIC > 2 mg/L or in patients with augmented renal clearance, for a target of 100%fT>MIC or 100%fT>4XMIC. Our study suggests that clinicians should consider prolonged infusion or a high-dosage regimen of meropenem, particularly when treating critically ill patients with augmented renal clearance or those infected with pathogens with decreased in vitro susceptibility, regardless of ECMO support.

Augmented Renal Clearance: What Have We Known and What Will We Do?

Augmented renal clearance (ARC) is a phenomenon of increased renal function in patients with risk factors. Sub-therapeutic drug concentrations and antibacterial exposure in ARC patients are the main reasons for clinical treatment failure. Decades of increased research have focused on these phenomena, but there are still some existing disputes and unresolved issues. This article reviews information on some important aspects of what we have known and provides suggestion on what we will do regarding ARC. In this article, we review the current research progress and its limitations, including clinical identification, special patients, risk factors, metabolism, animal models and clinical treatments, and provide some promising directions for further research in this area.

Prediction of Insufficient Beta-Lactam Concentrations in Extracorporeal Membranous Oxygenation Patients

Background: The aim of this study was to identify predictors of insufficient beta-lactam concentrations in patients undergoing extracorporeal membrane oxygenation (ECMO). Methods: Retrospective analysis of all patients receiving ECMO support and treated with ceftazidime or cefepime (CEF), piperacillin/tazobactam (TZP), or meropenem (MEM). Trough drug concentrations (Cmin) were measured before the subsequent dose, according to the decision of the attending physician. Insufficient drug concentrations were identified if Cmin was below the clinical breakpoint of Pseudomonas aeruginosa. Results: A total of 222 Cmin (CEF, n = 41; TZP, n = 85; MEM, n = 96) from 110 patients were included; insufficient concentrations were observed in 26 (12%) antibiotic assessments; 21 (81%) of those occurred during MEM therapy. Insufficient Cmin were associated with a shorter time from initiation of antibiotics to measurement, a lower single dose of antibiotic, a higher creatinine clearance (CrCL), lower sequential organ failure assessment (SOFA) scores, and less use of continuous renal replacement therapy (CRRT) when compared to others. Conclusions: Insufficient broad-spectrum beta-lactam concentrations were observed in 12% of drug measurement during ECMO therapy. Higher than recommended drug regimens could be considered in the very early phase of therapy and in those patients with augmented renal clearance and with less severe organ dysfunction.

Population Pharmacokinetic Modeling and Dose Optimization of Vancomycin in Chinese Patients with Augmented Renal Clearance

Patients with augmented renal clearance (ARC) have been described as having low vancomycin concentration. However, the pharmacokinetic model that best describes vancomycin in patients with ARC has not been clarified. The purpose of this study is to determine the pharmacokinetic of vancomycin in Chinese adults and the recommend dosage for patients with different renal function, including patients with ARC. We retrospectively collected 424 vancomycin serum concentrations from 209 Chinese patients and performed a population pharmacokinetic model using NONMEM 7.4.4. The final model indicated that the clearance rate of vancomycin increased together with the creatinine clearance, and exhibited a nearly saturated curve at higher creatinine clearance. The estimated clearance of vancomycin was between 3.46 and 5.58 L/h in patients with ARC, with 5.58 being the maximum theoretical value. The central volume of distribution increased by more than three times in patients admitted to Intensive Care Unit. Monte Carlo simulations were conducted to explore the probability of reaching the target therapeutic range (24-h area under the curve: 400–650 mg·h/L, trough concentration: 10–20 mg/L) when various dose regimens were administered. The simulations indicated that dose should increase together with the creatinine clearance until 180 mL/min. These findings may contribute to improving the efficacy and safety of vancomycin in patients with ARC.

Augmented Renal Clearance, Muscle Catabolism and Urinary Nitrogen Loss: Implications for Nutritional Support in Critically Ill Trauma Patients

The main objective of this pilot study was to determine the association between augmented renal clearance (ARC), urinary nitrogen loss and muscle wasting in critically ill trauma patients. We conducted a retrospective analysis of a local database in 162 critically ill trauma patients without chronic renal dysfunction. Nutritional-related parameters and 24 h urinary biochemical analyses were prospectively collected and averaged over the first ten days after admission. Augmented renal clearance was defined by a mean creatinine clearance (CLCR) > 130 mL/min/1.73 m2. The main outcome was the cumulated nitrogen balance at day 10. The secondary outcome was the variation of muscle psoas cross-sectional area (ΔCSA) calculated in the subgroup of patients who underwent at least two abdominal CT scans during the ICU length of stay. Overall, there was a significant correlation between mean CLCR and mean urinary nitrogen loss (normalized coefficient: 0.47 ± 0.07, p < 0.0001). ARC was associated with a significantly higher urinary nitrogen loss (17 ± 5 vs. 14 ± 4 g/day, p < 0.0001) and a lower nitrogen balance (−6 ± 5 vs. −4 ± 5 g/day, p = 0.0002), without difference regarding the mean protein intake (0.7 ± 0.2 vs. 0.7 ± 0.3 g/kg/day, p = 0.260). In the subgroup of patients who underwent a second abdominal CT scan (N = 47), both ΔCSA and %ΔCSA were higher in ARC patients (−33 [−41; −25] vs. −15 [−29; −5] mm2/day, p = 0.010 and −3 [−3; −2] vs. −1 [−3; −1] %/day, p = 0.008). Critically ill trauma patients with ARC are thus characterized by a lower nitrogen balance and increased muscle loss over the 10 first days after ICU admission. The interest of an increased protein intake (>1.5 g/kg/day) in such patients remains a matter of controversy and must be confirmed by further randomized trials.