Luigi Brunetti

Cefazolin serves as the antibiotic choice for surgical prophylaxis to prevent surgical site infection, yet consensus on dosing guidelines for patients with obesity is not well defined. To quantify cefazolin exposure in plasma and subcutaneous adipose tissue during abdominal surgery, and to build a popPK model comparing standard anthropometrics, calculated body-composition metrics, and directly measured body-composition values as predictors of interindividual variability. A single center prospective study was conducted at Robert Wood Johnson Barnabas University Hospital, NJ, USA. Institutional standard for dosing was 2 g < 120 kg, or 3 g of cefazolin for subjects ≥ 120 kg for 101 adult subjects. Serial blood samples and subcutaneous adipose tissue samples were collected for the assessment of cefazolin concentration. All subjects received body composition assessments. Cefazolin concentrations in plasma remained within the therapeutic range in all stratification groups, yet subcutaneous adipose tissue concentrations failed to meet therapeutic cut offs, with 2- to 8.5-fold decrease in target attainment in subjects with increasing body fat percentages and BMI. A three-compartment biophase model best characterized our data and served as our base popPK model. Stepwise covariate modeling of measured body composition metrics outperformed both calculated body composition metrics and standard anthropomorphic values. The results support the claim that existing weight-based dosing methods fall short at the site of action, while simultaneously providing a proof of concept for the first in-human body composition informed popPK model. Measured body composition metrics can enhance characterization of cefazolin prophylactic exposure for subjects with obesity receiving abdominal surgery.

Objective: To compare the efficacy and safety of ceftriaxone (CRO) 1 g intravenously (IV) daily to higher doses for treating non-central nervous system (CNS) infections in adults. Data Sources: PubMed, Embase, Scopus, and Web of Science were used. A search was run from database inception to August 8, 2023 and rerun May 12, 2025. Search terms were CRO, Rocephin, pneumonia, intra-abdominal infections, appendicitis, typhlitis, pyelonephritis, bacteremia, and sepsis. Study Selection and Data Extraction: Articles included had to compare CRO 1 g IV daily to higher dosing for the outcomes of interest: clinical cure (CC), hospital length of stay (LOS), mortality, and toxicity. Randomized controlled trials (RCTs) or observational studies were included. Studies including pediatric, pregnant, and outpatient administration were excluded. Clinical cure was evaluated using a Mantel-Haenszel random-effects model with Peto odds ratios (pORs), and 95% confidence intervals (CIs) were calculated. Heterogeneity was identified using Cochrane I ² statistic. Data Synthesis: Eight studies (5145 patients) were included. No statistically significant difference was found for CC (pOR 0.958; 95% CI [0.525-1.749]; I ² = 60.23; P = .888); LOS (Std difference in means, 0.052; 95% CI [−0.418, 0.523]; I ² = 96.047; P = .828); or mortality (pOR 0.932; 95% CI [0.789-1.100]; I ² = 0.000; P = .405). Relevance to Patient Care and Clinical Practice: Ceftriaxone dosing ranges from 1 to 2 g IV daily for treating non-CNS infections. Optimal dosing remains controversial, as RCTs have used different doses. This meta-analysis showed no difference between high and low CRO dosing for efficacy and safety. Because infection type and pharmacokinetic factors were not accounted for, findings may not be applicable to certain high-risk infections or situations where CRO pharmacokinetics are altered, such as hypoalbuminemia. Prospective studies can compare regimens and confirm findings. Conclusions: Ceftriaxone doses greater than 1 g IV daily did not improve CC, LOS, or mortality.

Background: Levetiracetam (LEV) is an antiepileptic drug (AED) used to treat a variety of seizures in adult and pediatric populations. It is an ideal AED due to its favorable pharmacokinetic (PK) and pharmacodynamic profile and lack of interactions with other AEDs.Methods: This retrospective cohort study was designed to identify covariates that affect LEV clearance and volume of distribution and to generate a population PK model. Adults with a seizure history receiving LEV during hospital admission with a minimum of one serum LEV concentration available were included in the study. Population PK modeling and covariate testing was performed with MONOLIX Suite 2020R1 (Lixoft, France).Results: A total of 162 serum concentrations were collected from 143 patients. Age, sex, body weight descriptors, serum creatinine, creatinine clearance (CrCL), serum albumin, liver enzymes, and total bilirubin were evaluated. Body surface area (BSA) was a significant covariate for the apparent volume of distribution (V/F). The exclusion of BSA as a covariate of V/F increased the objective function value (OFV) 5.6. CrCL was a significant covariate of apparent plasma clearance (CL/F). The exclusion of CrCL increased the OFV by 18.16 and significantly increased the root square error (RSE) % of the between‐subject variabilities of the parameters.Conclusion: LEV clearance is an effective predictor of serum concentration. CrCL was a significant covariate influencing LEV clearance, and BSA was found to influence the volume of distribution. Further studies are needed to determine the effect of body weight descriptors on LEV clearance and, ultimately, outcomes.

Background/Objectives: Gabapentin has variable pharmacokinetics (PK), which contributes to difficulty in dosing and increased risk of adverse events. The objective of this study was to leverage gabapentin concentrations from therapeutic drug monitoring (TDM) to develop a population PK (popPK) model and characterize significant covariates that impact gabapentin PK. Methods: Data were retrospectively collected from 82 hospitalized adult patients with TDM gabapentin concentrations. Renal function indicators (i.e., estimated glomerular filtration rate, creatinine clearance, acute kidney injury), body weight parameters (i.e., actual body weight, ideal body weight, adjusted body weight, lean body weight, body mass index, obesity status), fasting plasma glucose levels, and diagnosis of type 2 diabetes were tested as potential covariates. A popPK model was developed in MONOLIX (2020R1, Lixoft, France). Results: A one-compartment model best described gabapentin PK with first-order absorption, dose-dependent bioavailability, first-order elimination, and no lag time. Population parameter estimates for the volume of distribution (V_d), and clearance (Cl) were 44.61 L, and 5.73 L/h, respectively. Serum creatinine was a significant covariate on Cl. Conclusions: The popPK model highlights the importance of renal function in the interindividual variability of gabapentin PK and suggests that diabetes and body weight parameters have no impact on gabapentin PK. Moreover, our study supports the utility of leveraging data obtained from clinical TDM for popPK model development.

Background: Pathophysiological changes associated with obesity might impact various drug pharmacokinetics (PK) parameters. The liver and kidneys are the primary organs involved in drug clearance, and the function of hepatic and renal transporters is critical to efficient drug elimination (or reabsorption). Considering the impact of an increased BMI on the drug’s PK is crucial in directing dosing decisions. Given the critical role of transporters in drug biodisposition, this study investigated how overweight and obesity affect the gene expression of renal and hepatic drug transporters. Methods: Human liver and kidney samples were collected post-mortem from 32 to 28 individuals, respectively, which were divided into the control group (lean subjects; 18.5 ≤ BMI < 25 kg/m²) and the study group (overweight/obese subjects; BMI ≥ 25 kg/m²). Real-time quantitative PCR was performed for the analysis of 84 drug transporters. Results: Our results show significant changes in the expression of genes involved in human transporters, both renal and hepatic. In liver tissue, we found that ABCC4 was up-regulated in overweight/obese subjects. In kidney tissue, up-regulation was only observed for ABCC10, while the other differentially expressed genes were down-regulated: ABCA1, ABCC3, and SLC15A1. Conclusions: The observed alterations may be reflected by the differences in drug PK between lean and obese populations. However, these findings need further evaluation through the proteomic and functional study of these transporters in this patient population.

Background: There are many reported pharmacist‐led transitions of care (TOC) programs to address medication‐related problems (MRP) at discharge from the acute care setting. Most have identified time and labor resources as significant limitations. This study aims to assess the effectiveness of a medication risk score (MRS)‐driven clinical decision support system (CDSS) in identifying actionable MRPs and improving medication safety in the acute care discharge TOC setting. Methods: A cross‐sectional analysis was conducted in a cohort of 481 subjects discharged from the acute care setting. The MRS‐CDSS was utilized to identify MRPs and provide recommendations for risk reduction. The distribution of MRPs, recommendations, and their associations with MRS severity were analyzed. Additionally, the potential reduction in MRS per subject and its correlation with MRS severity were examined. Results: The median MRS reduction per subject was 2 points, while high/severe‐risk patients showed a median potential reduction of 7 points. Among the identified MRPs ( n = 691), drug interaction, drug use without indication, and adverse drug reaction accounted for 89.7% of all MRPs. The top three recommendations, discontinue medication, change the time of administration, and start alternative therapy, represented 94.1% of all recommendations. Stratified analysis by MRS category revealed a significant increase in adverse drug reaction MRPs and recommendations to discontinue medications with higher MRS severity. The results were consistent with previous outpatient studies, supporting the MRS‐CDSS's ability to enhance medication safety. Conclusion: This study demonstrates that the MRS‐CDSS effectively identifies actionable MRPs and has the potential to substantially reduce overall pharmacotherapy regimen risk when applied during acute care discharge TOC. The findings support implementable recommendations directed at patient safety and the allocation of health care resources to high‐risk patients for maximum benefit.

Background: Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction–associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19. Methods: First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients’ livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15 ^ile−/−) to determine the effects of FGF15 deficiency on improving the metabolic effects. Results: SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15 ^ile−/− mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis. Conclusions: FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.

Linezolid (LZD) has a longstanding reported association with the onset of serotonin toxicity (ST), secondary to drug–drug interactions with serotoninergic agents. There have been no conclusive data supporting the incidence or contributing risk factors to date. The study evaluated the incidence of ST in patients treated with LZD and serotonergic agents concomitantly versus LZD alone. The secondary objectives included a comparison of ST incidence in patients treated with one serotonergic agent + LZD versus two or more serotonergic agents + LZD. The studies used for this meta-analysis were retrieved from PubMed, Scopus, and Google Scholar. All studies including a comparison between LZD alone and LZD + a serotonergic agent published between 1 January 2000 and 1 October 2023 and meeting the quality standards were considered for inclusion. Fourteen studies were identified, with five meeting all inclusion and exclusion criteria with no significant heterogeneity. For the analysis of LZD monotherapy vs. SA combination therapy, four studies with 6025 patients total were analyzed and yielded an odds ratio of 1.78 (CI [1.04, 3.02]; I² = 49%; GRADE certainty: low). Four studies and 2501 patients were included in the analysis of one versus more than one SA with an odds ratio of 5.18 (CI [1.05, 25.49]; I² = 44.87; GRADE certainty: moderate). The Newcastle–Ottawa score, visual inspection of the funnel plot, and Egger’s statistic were used to evaluate quality and heterogeneity. The Peto method was used to calculate the summary odds ratios. All analyses were performed using Comprehensive Meta-Analysis version 3.0 and R, while GRADE was used to evaluate the quality of the final recommendation. The number of concomitant serotonergic agents may play a role in the development of serotonin toxicity in patients prescribed linezolid. In patients requiring linezolid therapy and serotonergic agents, risk versus benefit analysis should pay attention to the number of interacting drugs.

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and the resulting Coronavirus disease 2019 emerged in late 2019 and is responsible for significant morbidity and mortality worldwide. A hallmark of severe COVID‐19 is exaggerated systemic inflammation, regarded as a “cytokine storm,” which contributes to the damage of various organs, primarily the lungs. The inflammation associated with some viral illnesses is known to alter the expression of drug‐metabolizing enzymes and transporters. These alterations can lead to modifications in drug exposure and the processing of various endogenous compounds. Here, we provide evidence to support changes in the mitochondrial ribonucleic acid expression of a subset of drug transporters (84 transporters) in the liver, kidneys, and lungs and metabolizing enzymes (84 enzymes) in the liver in a humanized angiotensin‐converting enzyme 2 receptor mouse model. Specifically, three drug transporters (Abca3, Slc7a8, Tap1) and the pro‐inflammatory cytokine IL‐6 were upregulated in the lungs of SARS‐CoV‐2 infected mice. We also found significant downregulation of drug transporters responsible for the movement of xenobiotics in the liver and kidney. Additionally, expression of cytochrome P‐450 2f2 which is known to metabolize some pulmonary toxicants, was significantly decreased in the liver of infected mice. The significance of these findings requires further exploration. Our results suggest that further research should emphasize altered drug disposition when investigating therapeutic compounds, whether re‐purposed or new chemical entities, in other animal models and ultimately in individuals infected with SARS‐CoV‐2. Moreover, the influence and impact of these changes on the processing of endogenous compounds also require further investigation.