Search Results (42)

Background/Objectives: Sepsis is a life-threatening condition associated with high mortality. Optimal dosing strategies for β-lactam antibiotics in sepsis remain controversial, particularly in patients with renal impairment. Cefepime (CFPM) is widely used as empiric therapy; however, its appropriate initial dosing in critically ill patients is unclear. This study aimed to evaluate whether high-dose CFPM administration during the first 48 h improves survival in patients with sepsis, irrespective of renal function. Methods: This single-center, retrospective, observational study included adult intensive care unit (ICU) patients with sepsis who received CFPM as initial therapy between January 2017 and December 2024. Patients were categorized into High-dose (12 g within 48 h; 2 g every 8 h) and Low-dose (<12 g/48 h) groups. The primary outcome was ICU survival. To address confounding, inverse probability of treatment weighting (IPTW) based on serum creatinine was applied, with sensitivity analyses using 1% trimmed and stabilized IPTW. Results: Of 122 eligible patients, 84 were analyzed (High-dose: n = 27; Low-dose: n = 57). After IPTW adjustment, high-dose CFPM was significantly associated with improved ICU survival (odds ratio [OR] 5.43, 95% confidence interval [CI] 1.60–18.39, p = 0.0066). This association remained consistent in the 1% trimmed IPTW analysis (OR 4.07, 95% CI 1.19–13.97, p = 0.0256). Stabilized IPTW yielded a similar effect estimate, though without statistical significance (OR 5.43, 95% CI 0.72–41.16, p = 0.1017). Overall, results were consistent in direction and magnitude across models. Conclusions: High-dose CFPM administration during the initial 48 h was associated with improved ICU survival in patients with sepsis, independent of renal function. Full article

Background: Meropenem (MEM) is frequently prescribed for the empirical management of severe infections in the pediatric intensive care unit (PICU). Critically ill children exhibit substantial pharmacokinetic (PK) variability, and current dosing strategies remain inadequately evaluated, particularly in neonates, infants, and those with altered renal function. Methods: This study employed a dual modeling approach integrating population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) methodologies. Clinical data from two PICUs were utilized for PopPK model development and PBPK model evaluation. Both models were rigorously assessed using goodness-of-fit plots and prediction-based metrics. Monte Carlo simulations were subsequently conducted to calculate the probability of target attainment (PTA) for multiple dosing regimens across MICs of 0.25–16 mg/L. The pharmacodynamic target (PDT) was defined as maintaining unbound plasma concentrations above the MIC for 100% of the dosing interval (100% ƒT _{> MIC}), and dosing regimens were considered acceptable if the PTA exceeded 90% for efficacy while avoiding potential toxicity (Css ≥ 50 mg/L). Results: A total of 202 MEM plasma concentrations from 101 pediatric patients were analyzed. Marked inter-individual variability in MEM pharmacokinetics and pharmacodynamics was observed. Augmented renal clearance (ARC) was frequently identified in PICU patients. We simultaneously developed a two-compartment population pharmacokinetic model incorporating body weight and estimated glomerular filtration rate, and a whole-body physiologically based pharmacokinetic model scaled from adults with adjustments for transporter ontogeny and renal function. The PopPK model, by incorporating interindividual variability on clearance and volume of distribution, captured a wider range of drug exposures and demonstrated superior predictive performance, particularly in subgroups with high eGFR. The PBPK model showed higher precision in the low eGFR subgroup but slightly lower overall predictive accuracy. Both models identified ARC as a key driver of subtherapeutic exposure. Standard regimens were insufficient for preterm neonates when the MIC was ≥4 mg/L, and even the maximum label-recommended dose failed to achieve the pharmacodynamic target for infants older than 1 month when the MIC was ≥2 mg/L. Conclusions: Both PBPK and PopPK frameworks reliably predicted MEM pharmacokinetics in critically ill pediatric patients, with complementary strengths across renal function strata. Model-informed simulations highlighted the inadequacy of standard dosing under conditions of ARC or elevated MIC, supporting individualized, precision-guided dosing strategies based on age, eGFR, and pathogen MIC. Full article

Sepsis-associated acute kidney injury (SA-AKI) often requires renal replacement therapy (RRT), which markedly alters antimicrobial pharmacokinetics (PK) and pharmacodynamics (PD). Novel β-lactam/β-lactamase inhibitor (BL/BLI) combinations broaden options against multidrug-resistant Gram-negative bacteria, but dosing during RRT remains uncertain. This review summarizes PK/PD features, extracorporeal clearance, and practical dosing considerations about ceftolozane–tazobactam, ceftazidime–avibactam, aztreonam–avibactam, cefiderocol, meropenem–vaborbactam, imipenem–relebactam, and newer agents including sulbactam–durlobactam, cefepime–enmetazobactam, and cefepime–taniborbactam. Pharmacokinetic data, RRT impact, PK/PD targets, pediatric aspects, and clinical outcomes were extracted from experimental models, case reports, and clinical studies. Drug exposure varies with RRT modality, effluent flow, membrane properties, and patient-specific factors such as augmented renal clearance, hypoalbuminemia, and fluid overload. Standard renal-adjusted dosing often yields subtherapeutic concentrations in critically ill patients. Pediatric data remain scarce and largely limited to case reports. Optimal BL/BLI use in septic patients with SA-AKI on RRT requires individualized dosing that accounts for PK/PD variability and dialysis settings. Full-dose initiation during the first 24–48 h, followed by careful adjustment, appears prudent. Therapeutic drug monitoring should be used when available, and institution-specific protocols should be integrated into stewardship programs to improve efficacy and minimize resistance. Full article

Background/Objectives: The pharmacokinetics of vancomycin (VCM) in patients with febrile neutropenia (FN) are highly variable due to coexisting conditions such as systemic inflammatory response syndrome and augmented renal clearance. Upon hematopoietic recovery, VCM clearance (CLvcm) is expected to normalize, which contributes to intra-individual variability. This study aimed to investigate the factors contributing to intra-individual variability in CLvcm among pediatric patients with FN. Methods: This retrospective, single-center study analyzed 33 pediatric patients (48 FN episodes) who met the inclusion criteria. CLvcm was estimated using Bayesian estimation based on the pediatric population pharmacokinetic model developed by Le et al., and standardized with allometrically scaled body weight. The change (Δ) in each clinical laboratory parameter or CLvcm was calculated as the difference between the values at the current and previous TDM within the same episode. Results: A total of 155 VCM TDM data points were analyzed. Intra-individual comparisons revealed that CLvcm decreased significantly in patients recovering from FN to a non-FN state (n = 18, p = 0.0285). Further analysis of intra-individual variability revealed that Δ CLvcm correlated significantly with Δ hemoglobin, Δ C-reactive protein, and Δ maximum daily body temperature, with the strongest correlation observed for Δ maximum daily body temperature (rs = 0.325, p = 0.001). Multivariate analysis confirmed Δ maximum daily body temperature as a significant factor influencing Δ CLvcm (B = 0.376, 95% CI: 0.074 to 0.678, p = 0.015). Conclusions: Maximum daily body temperature was identified as a factor influencing intra-individual variability in CLvcm in pediatric FN patients, particularly during the recovery process from FN to a non-FN state. The finding suggests that dose adjustment based on maximum daily body temperature may allow safe and effective VCM therapy in FN patients. Full article

Objectives: We aimed to develop a population pharmacokinetic (PopPK) model and evaluate dosing regimens for different renal clearances and continuous renal replacement therapy (CRRT) settings. Methods: Data were collected from four studies in intensive care unit (ICU) adult patients receiving 400–600 mg of ceftaroline every 8–12 h in a one-hour infusion. The PopPK model was developed according to non-linear mixed effects modeling implemented in Monolix 2024R1. To investigate dosing recommendations, Monte Carlo simulations and probability of target attainment (PTA) analysis were performed in Simulx 2024R1. Results: We collected 296 plasma concentrations from 29 non-CRRT patients and 24 pre-filter (systemic), 23 post-filter, and 23 effluent concentrations from four CRRT patients using WebPlotDigitizer (Version 4.7). A five-compartment model, with the first-order elimination from the central compartment and additional elimination with the effluent during CRRT, best described the ceftaroline concentrations. Creatinine clearance (Cl_Cr) was identified as a covariate on the clearance of elimination (Cl) and CRRT modality on the central and peripheral compartments’ volumes and intercompartmental clearance. The results of dosage simulations for different CRRT modalities and Cl_Cr, S. pneumoniae (MIC = 0.25 mg/L) and methicillin-resistant S. aureus (MRSA) (MIC = 1 mg/L) infections, and assumed 100%ƒT_>MIC target, revealed that registered ceftaroline dosages are sufficient to achieve assumed PTA, except MRSA infection in patients with augmented renal clearance (ARC). Conclusions: Our successfully developed model allows flexible PK simulations of ceftaroline, including real-time changes in settings and even temporary or permanent cessation of CRRT. However, the results of our study warrant clinical validation and should be used with caution primarily due to the limited CRRT patient number included in the analysis. Full article

Vancomycin is an antimicrobial agent that exhibits high efficacy against Gram-positive bacteria. The importance of therapeutic drug monitoring (TDM) for vancomycin has been substantiated in specific patient cohorts, underscoring the significance of determining vancomycin plasma levels. This study presents the development and validation of a simple, reproducible, and practical approach for quantifying vancomycin levels in human plasma samples through high-performance liquid chromatography (HPLC). Deproteinization of plasma samples (0.3 mL) was achieved using 10% perchloric acid. The chromatographic separation was achieved using a C18 column. The mobile phase, consisting of phosphate buffer and acetonitrile (90:10, v/v), was run at a flow rate of 1 mL/min. Ultraviolet detection was conducted at a wavelength of 192 nm and the method was linear in the range of 4.5–80 mg/L (r² > 0.99). Inter- and intra-day assay precision and accuracy were determined to be within the acceptable range. The run time was noted to be 10 min. This method was evaluated using different greenness tools, which indicated that the method is environmentally friendly. Our method was effectively applied to analyze vancomycin concentrations in critically ill patients. Thus, our approach has the potential for practical implementation in routine TDM procedures. Full article

Background/Objectives: Meropenem is a broad-spectrum antibiotic essential for treating resistant Gram-negative infections in pediatric patients. Current dosing recommendations may not consistently achieve optimal pharmacokinetic (PK) targets, especially in critically ill children. Methods: We conducted a retrospective cohort study at IRCCS Istituto Giannina Gaslini, analyzing 97 plasma levels from 86 pediatric patients (<18 years) hospitalized between January 2020 and December 2023 in the neonatal and pediatric intensive care unit. Patients receiving meropenem for proven or suspected infections were included. Demographic, clinical, and PK parameters were assessed, with a focus on trough concentrations (C_trough). Results: The median age was 25 months, with neonates representing 15.5% of cases. The median C_trough was 2.8 mg/L and was significantly higher in neonates (8.9 mg/L) compared to older patients (2.2 mg/L, p < 0.001). Only 27.8% of patients achieved the target C_trough of >8 mg/L, with estimated glomerular filtration rate (eGFR) being the primary factor influencing these levels. Patients with C_trough > 8 mg/L had a significantly lower eGFR (61 mL/min/1.73 m²) compared to those below this threshold (131 mL/min/1.73 m², p = 0.001). Conclusions: The current meropenem dosing regimen may not reliably meet PK targets in critically ill pediatric patients, particularly those with augmented renal clearance or when treating pathogens with increased meropenem MIC. Our findings suggest that increased dosages and prolonged infusion times may be necessary to optimize therapeutic efficacy against resistant Gram-negative bacteria in this vulnerable population. Further studies are needed to refine dosing strategies and improve patient outcomes. Full article

Background: Gentamicin (GM) is extensively used as an antibiotic for the treatment of infections caused by Gram-negative bacteria. Oxidative stress and proinflammatory cytokines are implicated in GM-induced renal damage. Chrysin (CH), also known as 5,7-dihydroxyflavone, has been used in traditional medicine to treat various kidney disorders. The aim of this study was to investigate the antioxidant, anti-apoptotic, and anti-inflammatory effects of CH against nephrotoxicity induced by GM. Methods: Male rats were separated into four equal groups: a negative control group (NC), a CH-treated group (100 mg/kg/day per os), a group treated with GM (100 mg/kg/day IM), and a group treated with both GM and CH (100 mg/kg/day), for 10 days. Blood and urine renal markers were investigated. Results: GM caused increases in the serum creatinine and urea levels and decreases in creatinine clearance, urine flow, and urine volume in the GM-treated rats. Moreover, there were increases in the levels of IL-1β, TNF-α, IL-18, and MDA in the renal tissues, with an augmented expression of NF-κB/KIM-1, as well as decreases in antioxidant marker (GSH, GPx, CAT, and SOD) activities and decreased expressions of the anti-inflammatory transcription factors Nrf2 and AKT. The simultaneous treatment with CH in the GM-treated group protected renal tissues against the nephrotoxicity induced by GM, as demonstrated by the normalization of renal markers and improvement in histopathological damage. Conclusions: This study reveals that CH may attenuate GM-induced renal toxicity in rats. Full article

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. Full article

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. Full article

Ceftobiprole is a fifth-generation cephalosporin used for different Gram-positive bacterial infections. A population pharmacokinetic analysis was conducted in real-life clinical patients to assess the adequacy of current dosages. Population pharmacokinetics was conducted using non-linear mixed effect modeling. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) of free trough or steady-state concentration over MIC (fC_trough/MIC or fC_ss/MIC) ≥ 1 or ≥4 associated with both the standard and intensified dosing regimens adjusted for renal function. Cumulative fraction of response (CFR) against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were also calculated. A total of 132 patients with 503 concentrations were included. Most of them (107/132, 81.1%) had hospital- or community-acquired pneumonia, endocarditis, and bacteremia. A three-compartment model adequately fitted ceftobiprole concentration-time data. Estimated glomerular filtration rate significantly affected drug clearance. Monte Carlo simulations showed that the optimal target of fC_trough/MIC or fC_ss/MIC ≥ 4 is achieved only with the use of the standard dosages administered by continuous infusion (CI) against MRSA infections in patients with preserved renal function. Intensified dosages administered by CI are needed in patients with impaired renal function and/or augmented renal clearance against MRSA and in patients with preserved renal functions against MRSE. Full article

(1) Objectives: To describe the attainment of optimal pharmacokinetic/pharmacodynamic (PK/PD) targets in orthotopic liver transplant (OLT) recipients treated with continuous infusion (CI) beta-lactams optimized using a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program during the early post-surgical period. (2) Methods: OLT recipients admitted to the post-transplant intensive care unit over the period of July 2021–September 2023, receiving empirical or targeted therapy with CI meropenem, piperacillin-tazobactam, meropenem-vaborbactam, or ceftazidime-avibactam optimized using a real-time TDM-guided ECPA program, were retrospectively retrieved. Steady-state beta-lactam (BL) and/or beta-lactamase inhibitor (BLI) plasma concentrations (C_ss) were measured, and the C_ss/MIC ratio was selected as the best PK/PD target for beta-lactam efficacy. The PK/PD target of meropenem was defined as being optimal when attaining a fC_ss/MIC ratio > 4. The joint PK/PD target of the BL/BLI combinations (namely piperacillin-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam) was defined as being optimal when the fC_ss/MIC ratio > 4 of the BL and the fC_ss/target concentration (C_T) ratio > 1 of tazobactam or avibactam, or the fAUC/C_T ratio > 24 of vaborbactam were simultaneously attained. Multivariate logistic regression analysis was performed for testing potential variables that were associated with a failure in attaining early (i.e., at first TDM assessment) optimal PK/PD targets. (3) Results: Overall, 77 critically ill OLT recipients (median age, 57 years; male, 63.6%; median MELD score at transplantation, 17 points) receiving a total of 100 beta-lactam treatment courses, were included. Beta-lactam therapy was targeted in 43% of cases. Beta-lactam dosing adjustments were provided in 76 out of 100 first TDM assessments (76.0%; 69.0% decreases and 7.0% increases), and overall, in 134 out of 245 total ECPAs (54.7%). Optimal PK/PD target was attained early in 88% of treatment courses, and throughout beta-lactam therapy in 89% of cases. Augmented renal clearance (ARC; OR 7.64; 95%CI 1.32–44.13) and MIC values above the EUCAST clinical breakpoint (OR 91.55; 95%CI 7.12–1177.12) emerged as independent predictors of failure in attaining early optimal beta-lactam PK/PD targets. (4) Conclusion: A real-time TDM-guided ECPA program allowed for the attainment of optimal beta-lactam PK/PD targets in approximately 90% of critically ill OLT recipients treated with CI beta-lactams during the early post-transplant period. OLT recipients having ARC or being affected by pathogens with MIC values above the EUCAST clinical breakpoint were at high risk for failure in attaining early optimal beta-lactam PK/PD targets. Larger prospective studies are warranted for confirming our findings. Full article

Children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are prone to developing acute kidney injury (AKI). Markers of kidney damage: kidney injury molecule (KIM)-1, interleukin (IL)-18, and neutrophil gelatinase-associated lipocalin (NGAL) may ease early diagnosis of AKI. The aim of this study was to assess serum concentrations of KIM-1, IL-18, and NGAL in children undergoing HSCT in relation to classical markers of kidney function (creatinine, cystatin C, estimated glomerular filtration rate (eGFR)) and to analyze their usefulness as predictors of kidney damage with the use of artificial intelligence tools. Serum concentrations of KIM-1, IL-18, NGAL, and cystatin C were assessed by ELISA in 27 children undergoing HSCT before transplantation and up to 4 weeks after the procedure. The data was used to build a Random Forest Classifier (RFC) model of renal injury prediction. The RFC model established on the basis of 3 input variables, KIM-1, IL-18, and NGAL concentrations in the serum of children before HSCT, was able to effectively assess the rate of patients with hyperfiltration, a surrogate marker of kidney injury 4 weeks after the procedure. With the use of the RFC model, serum KIM-1, IL-18, and NGAL may serve as markers of incipient renal dysfunction in children after HSCT. Full article

Bloodstream infections (BSI) from coagulase-negative-staphylococci (CoNS) are among the most frequent healthcare-related infections. Their treatment involves the use of vancomycin, a molecule whose optimal pharmacokinetic/pharmacodynamic (PK/PD) target for efficacy and safety is an area-under-curve/minimum inhibitory concentration (AUC/MIC) ratio ≥ 400 with AUC < 600. BSIs from CoNS in pediatric and neonatal intensive care unit that occurred at the Gaslini Institute over five years were evaluated to investigate the efficacy of vancomycin therapy in terms of achieving the desired PK/PD target and determining whether any variables interfere with the achievement of this target. AUC/MIC ≥ 400 with AUC < 600 at 48 and 72 h after therapy initiation was achieved in only 21% of the neonatal population and 25% of the pediatric population. In the pediatric population, an inverse correlation emerged between estimated glomerular filtration rate (eGFR) and achieved AUC levels. Median eGFR at 72 h was significantly higher (expression of hyperfiltration) in events with AUC < 400, compared with those with AUC ≥ 400 (p < 0.001). A cut-off value of eGFR in the first 72 h has been identified (145 mL/min/1.73 m²), beyond which it is extremely unlikely to achieve an AUC ≥ 400, and therefore a higher dose or a different antibiotic should be chosen. Full article

Augmented Renal Clearance (ARC) refers to the increased renal clearance of circulating solute in critically ill patients. In this study, the analytical research method of transcriptomics combined with metabolomics was used to study the pathogenesis of ARC at the transcriptional and metabolic levels. In transcriptomics, 534 samples from 5 datasets in the Gene Expression Omnibus database were analyzed and 834 differential genes associated with ARC were obtained. In metabolomics, we used Ultra-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry to determine the non-targeted metabolites of 102 samples after matching propensity scores, and obtained 45 differential metabolites associated with ARC. The results of the combined analysis showed that purine metabolism, arginine biosynthesis, and arachidonic acid metabolism were changed in patients with ARC. We speculate that the occurrence of ARC may be related to the alteration of renal blood perfusion by LTB4R, ARG1, ALOX5, arginine and prostaglandins E2 through inflammatory response, as well as the effects of CA4, PFKFB2, PFKFB3, PRKACB, NMDAR, glutamate and cAMP on renal capillary wall permeability. Full article