UNASSIGNED: To optimise the dosing regimen of meropenem for treating Pseudomonas aeruginosa (PA) infections in critically ill patients with augmented renal clearance (ARC) using pharmacokinetic/pharmacodynamic (PK/PD) principles and Monte Carlo simulation (MCS).
UNASSIGNED: This research involves an MCS based on PK data from patients with ARC and a minimum inhibitory concentration (MIC) distribution of PA. This study simplifies the methods section, focusing on the critical aspects of simulation and target values for effective treatment.
UNASSIGNED: The study highlights key findings and emphasises that tailored dosing based on bacterial MIC values is essential for patients with ARC. It also notes that empirical treatment in patients with ARC should consider the MIC distribution, with 2 g every (q) 6 h administered to achieve the PK/PD target, while 3 g q 6 h is effective in inhibiting resistance.
UNASSIGNED: Tailored dosing based on bacterial MIC values is crucial for patients with ARC. Prolonged infusion time alone does not enhance efficacy. Empirical treatment in patients with ARC should consider MIC distribution; a dosage of 2 g q 6 h achieves the PK/PD target, while 3 g q 6 h (≥12 g daily) inhibits resistance.

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Background: The optimal ampicillin-sulbactam dosing regimen for carbapenem-susceptible Acinetobacter baumannii isolates in critically ill trauma patients has not been clearly defined. One strategy to provide the adequate sulbactam dose includes high-dose continuous infusion. Case(s) Description: We present three cases of critically ill trauma patients with augmented renal clearance treated with high-dose ampicillin-sulbactam through an intravenous continuous infusion for ventilator-associated pneumonia. All A. baumannii isolates were susceptible to sulbactam with low minimum inhibitory concentrations. All achieved clinical cure at the end of therapy and no recurrent pneumonia was noted. No clinically substantial adverse effect attributable to ampicillin-sulbactam therapy occurred. Discussion: There is limited evidence to endorse high-dose, continuous infusion ampicillin-sulbactam for treatment of infections caused by carbapenem-susceptible A. baumannii. This report presents three critically ill trauma patients with augmented renal clearance that achieved positive clinical outcomes with higher doses of ampicillin-sulbactam administered through a continuous infusion.

BACKGROUND: Augmented renal clearance (ARC) is prevalent in trauma populations. Identification is underrecognized by calculated creatinine clearance or estimated glomerular filtration rate equations. Predictive scores may assist with ARC identification. The goal of this study was to evaluate validity of the ARCTIC score and ARC Predictor to predict ARC in critically ill trauma patients.
METHODS: This single center, retrospective study was performed at an academic level 1 trauma center. Critically ill adult trauma patients undergoing 24-h urine-collection were included. Patients with serum creatinine >1.5 mg/dL, kidney replacement therapy, suspected rhabdomyolysis, chronic kidney disease, or inaccurate urine collection were excluded. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for ARCTIC Score and ARC Predictor were calculated. Receiver operating characteristic curves were created for ARCTIC score and ARC Predictor models.
RESULTS: One-hundred and twenty-two patients with ARC and 78 patients without ARC were included. The ARCTIC score sensitivity, specificity, PPV, and NPV were 89%, 54%, 75%, and 75%, respectively. The ARC Predictor demonstrated sensitivity, specificity, PPV, and NPV of 77%, 88%, 91%, and 71%, respectively. Regression analyses revealed both ARCTIC score ≥6 and ARC Predictor threshold >0.5 as significant risk factors for ARC in presence of traumatic brain injury, obesity, injury severity score, and negative nitrogen balance (ARCTIC ≥6: odds ratio 8.59 [95% confidence interval 3.90-18.92], P < 0.001; ARC Predictor >0.5: odds ratio 20.07 [95% confidence interval 8.53-47.19], P < 0.001).
CONCLUSIONS: These findings corroborate validity of two pragmatic prediction tools to identify patients at high risk of ARC. Future studies evaluating correlations between ARCTIC score, ARC Predictor, and clinical outcomes are warranted.

Augmented renal clearance (ARC), defined as a creatinine clearance (CrCl) > 130 mL/min/1.73 m2, is observed in 30-65% of critically ill patients. When following standard dosage guidelines, patients with ARC often experience subtherapeutic vancomycin levels, resulting in treatment failure due to accelerated drug elimination. This review aims to explore ARC\'s impact on vancomycin pharmacokinetics and pharmacodynamics (PK/PD) indices in ARC patients, seeking to identify an accurate dose adjustment method for this patient population. In September 2023, a comprehensive literature search was conducted on the MEDLINE and EMBASE databases to include all available studies providing information on the impact of ARC on vancomycin therapy in critically ill adults. Articles that studied the pediatric population and those with insufficient PK data were excluded. A total of 21 articles met the inclusion criteria. The findings revealed a positive correlation between CrCl and vancomycin clearance, indicating low serum concentrations. Therefore, upward dosing adjustments are necessary to improve treatment success. Younger age consistently emerged as a major contributor to ARC and vancomycin PK/PD alterations. This study summarizes the PK/PD alterations, current dosage recommendations and proposes preliminary recommendations on possible dosing approaches to decrease the risk of subtherapeutic exposure in this patient population.

Cefotaxime administration is recommended in doses of 3-12 g/day in adults with a Glomerular Filtration Rate (GFR) > 5 mL/min. This study aimed to assess the impact of renal function and obesity on cefotaxime concentrations in intensive care unit (ICU) patients. A retrospective cohort study was conducted on consecutive ICU patients receiving continuous cefotaxime infusion between 2020 and 2022 [IRBN992021/CHUSTE]. Doses were not constant; consequently, a concentration-to-dose ratio (C/D) was considered. Statistical analysis was performed to assess the relationship between cefotaxime concentrations, renal function, and obesity. A total of 70 patients, median age 61 years, were included, with no significant difference in cefotaxime concentrations between obese and non-obese patients. However, concentrations varied significantly by GFR, with underdosing prevalent in patients with normal to increased renal function and overdosing in those with severely impaired renal function. Adjustment of cefotaxime dosing according to GFR was associated with improved target attainment. Cefotaxime dosing in critically ill patients should consider renal function, with higher initial doses required in patients with normal to increased GFR and lower doses in those with severely impaired renal function. Therapeutic drug monitoring may aid in optimising dosing regimens. Prospective studies are warranted to validate these findings and inform clinical practice.

Meropenem is an ultrabroad-spectrum antimicrobial agent that is often recommended for the treatment of bacterial meningitis (BM) in children. However, a subtherapeutic phenomenon occurred in BM children complicated with augmented renal clearance (ARC) at the recommended dose of meropenem. To support its pharmacokinetics, a sensitive, fast and robust ultra-liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to measure meropenem concentrations in serum and cerebrospinal fluid (CSF). The method involved protein precipitation, and samples were diluted with a large proportion of water to eliminate solvent effects. The separation of samples was performed on a Waters Acquity™ BEH C18 column (2.1 × 50 mm i.d., 1.7 μm) with a gradient profile. The mobile phases were formic acid-water (1:1000, v/v) and acetonitrile. The linear range was good, with a concentration range of 0.100-100 μg/mL for serum and 0.0400-20.0 μg/mL for CSF. The intra-day and inter-day precisions were less than 8.0%, and the intra-day and inter-day accuracies varied -6.6% from 6.5% for the both serum and CSF. The selectivity, carry-over, dilution integrity, matrix effect, recovery and stability were validated according to international guidelines. The developed UPLC-MS/MS method successfully determined the meropenem concentrations in the serum and CSF of children with BM complicated with ARC. The results indicated that under the recommended dosing regimen (40 mg/kg every 8 h), the time to reach the effective treatment target of 50%T > MIC was only approximately 3 h and lower CSF concentrations of meropenem were observed in children with BM with ARC.

Background: Augmented renal clearance (ARC) is a phenomenon observed in critically ill patients, leading to supraphysiologic drug clearance and concern for suboptimal antibiotic concentrations. The purpose of this study was to compare the clinical outcomes of our institutional protocolized antibiotic dosing regimen in critically ill patients with bacteremia and ARC compared with critically ill patients without ARC. Patients and Methods: We performed a retrospective study comparing the efficacy of an institutional protocolized antibiotic dosing regimen in critically ill patients with bacteremia and ARC compared with critically ill patients without ARC. The primary end point was in-hospital mortality. Secondary outcomes were intensive care unit (ICU) mortality, days requiring mechanical ventilation, ICU length of stay (LOS), hospital LOS, development of drug resistance to index antibiotic agent, and documented clearance of blood cultures within 72 hours. Results: There were 75 patients included in this study. Twenty percent of patients in the ARC group died in the hospital versus 31% in the non-ARC group (p = 0.26). The results for the ARC group versus the non-ARC group for the secondary outcomes of ICU mortality (20% vs. 26%; p = 0.56), ICU LOS (14.7 days vs. 7 days; p = 0.07), hospital LOS (28.3 days vs. 21.6 days; p = 0.03), days requiring mechanical ventilation (14 days vs. 12 days; p = 0.49), duration of antibiotic therapy (7.5 days vs. 9.0 days; p = 0.39), documented clearance of blood cultures within 72 hours (41% vs. 33%; p = 0.56), and the development of drug resistance to the index antibiotic agent (0% vs. 0%; p > 0.99) were also calculated. Conclusions: Among critically ill patients with bacteremia and ARC, there was no difference in in-hospital mortality compared with critically ill patients without ARC. There was a difference in hospital LOS, with a shorter duration of stay for the non-ARC group. There was no development of multi-drug-resistant organisms in either group.

BACKGROUND: Several studies report lack of meropenem pharmacokinetic/pharmacodynamic (PK/PD) target attainment (TA) and risk of therapeutic failure with intermittent bolus infusions in intensive care unit (ICU) patients. The aim of this study was to describe meropenem TA in an ICU population and the clinical response in the first 72 h after therapy initiation.
METHODS: A prospective observational study of ICU patients ≥18 years was conducted from 2014 to 2017. Patients with normal renal clearance (NRC) and augmented renal clearance (ARC) and patients on continuous renal replacement therapy (CRRT) were included. Meropenem was administered as intermittent bolus infusions, mainly at a dose of 1 g q6h. Peak, mid, and trough levels were sampled at 24, 48, and 72 h after therapy initiation. TA was defined as 100% T > 4× MIC or trough concentration above 4× MIC. Meropenem PK was estimated using traditional calculation methods and population pharmacokinetic modeling (P-metrics®). Clinical response was evaluated by change in C-reactive protein (CRP), Sequential Organ Failure Assessment (SOFA) score, leukocyte count, and defervescence.
RESULTS: Eighty-seven patients were included, with a median Simplified Acute Physiology (SAPS) II score 37 and 90 days mortality rate of 32%. Median TA was 100% for all groups except for the ARC group with 45.5%. Median CRP fell from 175 (interquartile range [IQR], 88-257) to 70 (IQR, 30-114) (p < .001) in the total population. A reduction in SOFA score was observed only in the non-CRRT groups (p < .001).
CONCLUSIONS: Intermittent meropenem bolus infusion q6h gives satisfactory TA in an ICU population with variable renal function and CRRT modality, except for ARC patients. No consistent relationship between TA and clinical endpoints were observed.

Augmented renal clearance or glomerular hyperfiltration (GHF) can significantly affect the clinical outcomes of renally eliminated drugs by promoting subtherapeutic drug exposure. The aggression suffered in patients who suffer severe trauma is a predisposition to manifest GHF and the identification of these patients remains a clinical challenge. The main objective of this study was to describe the prevalence of GHF in a cohort of critically ill trauma patients.
Prospective observational study of a cohort of adult patients admitted after suffering severe trauma or polytrauma in the Anesthesiology ICU of the University Hospital of Albacete (Spain). Creatinine clearance (ClCr) was calculated in a 4-h urine collection sample at 24, 72 and 168 h after admission applying the formula; CrCl: [Diuresis in ml (urine/4 h) × Creatinine in urine (mg/dl)] ÷ [240 (minutes) × Creatinine in plasma (mg/dl)]. A CrCl above 130 mL/min was considered GHF. The analyses were performed with the statistical software R version 4.0.4.
85 patients were included. The median age of the patients was 51 years (IQR 26), 78.82% male. 68 patients were male (78.82%). 75.29% of the patients were polytraumatized. 61 patients (71.76%) presented GHF at some point in the CrCl determination. At 24 h of admission, 56.34% of the patients presented GHF with a mean CrCl of 195.8 ml/min, 61.11% of the patients presented it at 72 h with a mean CrCl of /min and 56.52% presented GHF at 168 h of admission with a mean CrCl of 207 ml/min. A significant positive relationship (p = 0.07) was found between GHF manifested at 72 h and at 168 h. We observed a statistically significant relationship between this phenomenon with younger ages, lower ISS scores and lower plasma creatinines.
GHF are a common condition in critically ill patients admitted for severe trauma. We recommend the use of CrCl to assess renal function and make dosage adjustments. Studies are required to understand the clinical impact of these phenomena on drug elimination and to be able to establish the ideal dosage in those cases.