BACKGROUND: Intravenous fosfomycin (IVFOF) is gaining interest in severe infections. Its use may be limited by adverse events (AEs). Little experience exists on IVFOF therapeutic drug monitoring (TDM) in real-life setting.
METHODS: Retrospective study of patients receiving IVFOF for > 48 h at Policlinico Hospital (Milan, Italy) from 01/01/2019 to 01/01/2023. AEs associated to IVFOF graded CTCAE ≥ II were considered. Demographic and clinical risk factors for IVFOF-related AEs were analysed with simple and multivariable regression models. The determination of IVFOF TDM was made by a rapid ultraperformance liquid chromatography mass spectrometry method (LC-MS/MS) on plasma samples. The performance of TDM (trough levels (Cmin) in intermittent infusion, steady state levels (Css) in continuous infusion) in predicting AEs ≤ 5 days after its assessment was evaluated.
RESULTS: Two hundred and twenty-four patients were included. At IVFOF initiation, 81/224 (36.2%) patients were in ICU and 35/224 (15.7%) had septic shock. The most frequent infection site was the low respiratory tract (124/224, 55.4%). Ninety-five patients (42.4%) experienced ≥ 1AEs, with median time of 4.0 (2.0-7.0) days from IVFOF initiation. Hypernatremia was the most frequent AE (53/224, 23.7%). Therapy discontinuation due to AEs occurred in 38/224 (17.0%). ICU setting, low respiratory tract infections and septic shock resulted associated with AEs (RRadjusted 1.59 (95%CI:1.09-2.31), 1.46 (95%CI:1.03-2.07) and 1.73 (95%CI:1.27-2.37), respectively), while IVFOF daily dose did not. Of the 68 patients undergone IVFOF TDM, TDM values predicted overall AEs and hypernatremia with AUROC of 0.65 (95%CI:0.44-0.86) and 0.91 (95%CI:0.79-1.0) respectively for Cmin, 0.67 (95%CI:0.39-0.95) and 0.76 (95%CI:0.52-1.0) respectively for Css.
CONCLUSIONS: We provided real world data on the use of IVFOF-based regimens and associated AEs. IVFOF TDM deserves further research as it may represent a valid tool to predict AEs.
CONCLUSIONS: Real world data on intravenous fosfomycin for severe bacterial infections. AEs occurred in over 40% (therapy discontinuation in 17%) and were related to baseline clinical severity but not to fosfomycin dose. TDM showed promising results in predicting AEs.

OBJECTIVE: Ceftobiprole is a recent 5th generation parenteral cephalosporin with antibacterial activity against a large range Gram+ and Gram- bacteria. Therapeutic drug monitoring (TDM) is an essential tool for maintaining plasma concentrations of antibiotics above the MIC by the end of the dosing interval, thus preventing the resistant strain diffusion. TDM is already recommended for other cephalosporins, and it is a reasonable tool contributing to the safety and efficacy of these drugs. During the treatment of patients in real-life, a number of pharmacokinetic (PK) changes not normally seen in healthy volunteers can occur which can impair the pharmacokinetic/pharmacodynamic target attainment. We aimed to develop simple and rapid HPLC-UV method for determination of ceftobiprole in human serum to implement TDM in clinical practice and support PKs and pharmacokinetic/pharmacodynamic (PK/PD) studies.
METHODS: Samples preparation of calibration standards, QC, and anonymous patients serum samples was performed by protein precipitation by adding 0.01 ml of sulphosalicylic acid at 30 % to 0.1 ml of each sample. Then samples were vortexed and the centrifuged at 12,000 rpm for 10 min at 4 °C. Fifty microlitres of clear supernatant were diluted 1:1 with mobile phase and transferred into HPLC autosampler held at 8 °C. Chromatographic separation was carried out in a gradient mode at 35 °C on an ultra-Biphenyl column using a Thermo Scientific chromatographic system with a Diode array. Data management was performed with Chromeleon 7.4 software.
RESULTS: The HPLC-UV method proved to be linear over wide concentration ranges (0.5-50.0 mg/L) and was accurate and reproducible in the absence of matrix effects, allowing for robust, specific, and rapid quantification of ceftobiprole from a low amount of serum (0.1 mL). The mean steady state Ctrough and Cend values measured in the anonymous patients\' samples were 6.26 ± 3.81 mg/L and 22.56 ± 15.69 mg/L, respectively.
CONCLUSIONS: We report a broadened simple and fast HPLC with UV detection method for quantification of ceftobiprole in human serum to implement ceftobiprole TDM as clinical routine, and support future (PK/PD) studies in special patients\' population.

OBJECTIVE: Use of infliximab (IFX) has improved outcomes in children with inflammatory bowel disease (IBD). However, a proportion of patients does not respond to IFX or loses response over time. Population pharmacokinetic (PopPK) modelling is a promising approach for IFX dose optimization, but with the increasing number of PopPK models in literature, model evaluation is essential. The aims of this study are: (i) to validate the predictive performance of existing IFX PopPK models using a cohort of children with IBD; and (ii) to perform a Bayesian estimation of the most suitable model to predict the next IFX concentrations.
METHODS: PubMed was searched for IFX PopPK models in children. Selected models were rebuilt and analysed using R. Model performance was assessed through goodness-of-fit-plots, residuals against time, prediction error and prediction-corrected visual predictive checks. The validation cohort consisted of 73 children with IBD who were treated with IFX in our centre between 2017 and 2023 (340 IFX measurements).
RESULTS: We identified 9 PopPK models. Model bias for individual predicted values ranged from -9.29% to 8.01% compared to bias for population predicted values. The model by Vande Casteele et al. demonstrated superior performance (individual predicted bias 2.13, population predicted bias -6.11); upon Bayesian estimation, it predicted induction trough levels with median error of 12.95% but had a median error of -69% predicting maintenance concentrations.
CONCLUSIONS: The model by Vande Casteele et al. displayed superior performance in initial evaluations but had a high error in estimating next IFX levels and can only be used in practice to predict induction levels.

UNASSIGNED: Anti-tumor necrosis factor (TNF) monoclonal antibodies, especially infliximab (IFX) and adalimumab (ADA), are considered the first-line treatment for active Crohn\'s disease (CD). However, the predictive role of therapeutic drug monitoring (TDM) of serum anti-TNF in monitoring the treatment of inflammatory bowel disease (IBD) remains controversial.
UNASSIGNED: To explore the correlation between serum anti-TNF levels and early endoscopic response in active CD using a TDM-based nomogram.
UNASSIGNED: Cross-sectional study.
UNASSIGNED: The simplified endoscopic activity score for CD (SES-CD), Crohn\'s disease activity index (CDAI), laboratory parameters, and the serum trough levels of IFX and ADA were assessed.
UNASSIGNED: The trough levels of IFX or ADA were significantly higher in patients with endoscopic response compared to non-responders in the development cohort (p < 0.001). The IFX and ADA levels showed a weak but significantly negative correlation with SES-CD (p < 0.001), CDAI (p < 0.001), and C-reactive protein (CRP) (p < 0.001) at week 14 post-IFX therapy in the development cohort. Furthermore, the receiver operating characteristic curve revealed that an optimal level of IFX (4.80 μg/mL) and ADA (8.80 μg/mL) exhibited the best performance in predicting endoscopic response. Concomitantly, we developed a novel nomogram prediction model based on the results of multivariate logistic regression analysis, which consisted of CRP, albumin (Alb), and anti-TNF trough levels at week 14. The nomogram showed significant discrimination and calibration for both IFX and ADA in the development cohort and performed well in the external validation cohort.
UNASSIGNED: This study demonstrates a robust association between serum concentrations of IFX, ADA, Alb, and CRP and primary endoscopic response in active CD patients. Importantly, the TDM- and laboratory marker-based nomogram may be used to evaluate the primary endoscopic response to anti-TNF therapy, especially for optimizing treatment strategies and switching therapy in CD patients.
Therapeutic drug monitoring-based nomogram predicts primary endoscopic response in Crohn’s disease The present study established a therapeutic drug monitoring-based nomogram, which exhibits an exceptional predictive value, remarkable accuracy, and discrimination. This algorithmic nomogram holds the potential to enhance clinicians’ comprehension of the underlying mechanisms contributing to individual patients’ failure in achieving expected efficacy. Such approach is crucial for optimizing therapy options and facilitating biologic switching in refractory Crohn’s disease.

BACKGROUND: Current treatments for chronic hepatitis B management include orally administered nucleos(t)ide analogues, such as tenofovir (TDF), which is an acyclic adenine nucleotide analogue used both in HBV and human immune deficiency virus (HIV). The course of HBV infection is mainly dependent on viral factors, such as HBV genotypes, immunological features and host genetic variables, but a few data are available in the context of HBV, in particular for polymorphisms of genes encoding proteins involved in drug metabolism and elimination. Consequently, the aim of this study was to evaluate the potential impact of genetic variants on TDF plasma and urine concentrations in patients with HBV, considering the role of HBV genotypes.
METHODS: A retrospective cohort study at the Infectious Disease Unit of Amedeo di Savoia Hospital, Torino, Italy, was performed. Pharmacokinetic analyses were performed through liquidi chromatography, whereas pharmacogenetic analyses through real-time PCR.
RESULTS: Sixty - eight patients were analyzed: ABCC4 4976 C>T genetic variant showed an impact on urine TDF drug concentrations (p = 0.014). In addition, SLC22A6 453 AA was retained in the final regression multivariate model considering factors predicting plasma concentrations, while ABCC4 4976 TC/CC was the only predictor of urine concentrations in the univariate model.
CONCLUSIONS: In conclusion, this is the first study showing a potential impact of genetic variants on TDF plasma and urine concentrations in the HBV context, but further studies in different and larger cohorts of patients are required.

The phytocomplex of Cannabis is made up of approximately 500 substances: terpeno-phenols metabolites, including Δ-9-tetrahydrocannabinol and cannabidiol, exhibit pharmacological activity. Medical Cannabis has several pharmacological potential applications, in particular in the management of chronic and neuropathic pain. In the literature, a few data are available concerning cannabis pharmacokinetics, efficacy and safety. Thus, aim of the present study was the evaluation of cannabinoid pharmacokinetics in a cohort of patients, with chronic and neuropathic pain, treated with inhaled medical cannabis and decoction, as a galenic preparation. In this study, 67 patients were enrolled. Dried flower tops with different THC and CBD concentrations were used: Bedrocan® medical cannabis with THC level standardized at 19% and with a CBD level below 1%, Bediol® medical cannabis with THC and CBD level standardized at similar concentration of 6.5% and 8%, respectively. Cannabis was administered as a decoction in 47 patients and inhaled in 11 patients. The blood withdrawn was obtained before the new dose administration at the steady state and metabolites plasma concentrations were measured with an UHPLC-MS/MS method. Statistically significant differences were found in cannabinoids plasma exposure between inhaled and oral administration of medical cannabis, between male and female and cigarette smokers. For the first time, differences in cannabinoid metabolites exposures between different galenic formulations were suggested in patients. Therapeutic drug monitoring could be useful to allow for dose adjustment, but further studies in larger cohorts of patients are required in order to confirm these data.

Measuring biological drugs\' trough concentrations and the concentrations of anti-drug antibodies is a valuable practice for treatment optimization. ELISA techniques are the gold standard for biological drug concentration quantification, but new techniques such as chemiluminescence immunoassays present some advantages. The aim of this unicentric prospective observational study is to compare the infliximab, adalimumab, vedolizumab and ustekinumab trough levels and anti-adalimumab and anti-infliximab antibodies concentrations obtained when using a chemiluminescent instrument (i-TRACK®, Theradiag, Croissy-Beaubourg, France) and an ELISA instrument (TRITURUS®, Griffols, Barcelona, Spain). Linear regression, Pearson or Spearman tests, Bland-Altman plots and the Cohen kappa test were applied for every sample. The correlation was excellent for both assays in the measurement of all drug concentrations. In general, values were lower when measured using i-TRACK than when using TRITURUS, especially when the values were high. Both techniques proved valuable in clinical practice for monitoring adalimumab and infliximab drug concentration. However, the results were modest for ustekinumab and vedolizumab, so caution is recommended and further research is needed. The limited number of anti-drug antibody-positive samples precluded a comparison between the techniques.

Over the years, vedolizumab (VDZ) has emerged as a more effective target therapy for inflammatory bowel disease. The aim of this work was to analyze a cohort of inflammatory bowel disease patients, evaluating the association between VDZ serum concentrations at 6 months from starting therapy and their clinical and biochemical indexes within one year of treatment, correlating drug levels with response and clinical remission. Forty patients treated with VDZ were enrolled. Drug concentrations were quantified through ELISA methods. VDZ levels correlated with hemoglobin levels at twelve months of therapy (p = 0.03) and with clinical remission at twelve months of therapy (p = 0.03); patients who reached clinical remission showed higher VDZ concentrations. A VDZ cut-off value of 43.1 μg/mL was suggested, predicting clinical remission at twelve months of therapy. A statistically significant association between VDZ levels at T6 and calprotectin <250 μg/g at T12 was found (p = 0.04). Furthermore, the optimal threshold value of VDZ levels at T6 associated with calprotectin <250 μg/g at T12 was identified: through levels higher than 45.2 µg/mL, we were able to predict remission one year after therapy. In the final regression multivariate model, no factor was retained as a predictor of clinical remission at one year of treatment. In conclusion, this is the first pilot study reporting a possible VDZ serum cut-off value able to predict not only the clinical remission at twelve months of therapy but also the calprotectin level, which is very important, as it is a surrogate marker of mucosal healing.

OBJECTIVE: Ante-mortem diagnosis of Johne\'s disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is normally achieved through faecal culture, PCR, or serological tests, but agreement as to which samples are positive for Johne\'s disease is often poor and sensitivities are low, particularly in early-stage infections. The potential solution: Mycobacterial cells contain very complex characteristic mixtures of mycolic acid derivatives that elicit antibodies during infection; this has been used to detect infections in humans. Here, we explore its application in providing an assay differentiating infected from vaccinated animals (DIVA assay) for Johne\'s disease in cattle.
METHODS: Antibody responses to different classes of mycolic acid derivatives were measured using ELISA for serum from cattle positive for MAP by both faecal PCR and commercial serum ELISA, or just by PCR, and from animals from herds with no history of Johne\'s disease, bovine tuberculosis reactors, BCG-vaccinated, BCG-vaccinated and M. bovis-infected, and Gudair-vaccinated animals.
RESULTS: The best-performing antigens, ZAM295 and ST123-the latter a molecule present in the cells of MAP but not of Mycobacterium bovis-achieved a sensitivity of 75% and 62.5%, respectively, for serum from animals positive by both faecal PCR and a commercial MAP serum ELISA, at a specificity of 94% compared to 80 no-history negatives. Combining the results of separate assays with two antigens (ST123 and JRRR121) increased the sensitivity/specificity to 75/97.5%. At the same cut-offs, animals vaccinated with Gudair or BCG vaccines and bTB reactors showed a similar specificity. The specificity in BCG-vaccinated but M. bovis-infected animals dropped to 85%. Combining the results of two antigens gave a sensitivity/specificity of 37.5/97.5% for the full set of 80 PCR-positive samples, detecting 30 positives compared 16 for IDEXX.
CONCLUSIONS: Serum ELISA using synthetic lipids distinguishes effectively between MAP-negative cattle samples and those positive by both PCR and a commercial MAP serodiagnostic, without interference by Gudair or BCG vaccination. It identified almost twice as many PCR positives as the commercial serodiagnostic, offering the possibility of earlier detection of infection.

BACKGROUND: Acute intestinal obstruction (AIO) is a syndrome defined by the cessation of intestinal transit caused by an obstacle or paralysis of intestinal peristalsis. It is a diagnostic and therapeutic emergency. The multi-bar CT scan has revolutionized the management of this pathology, as it allows the surgeon to answer different questions. The aim of our study was to describe the CT aspects of AIO, to determine the etiologies and to show the place of CT in the management of AIO.
METHODS: This was a retrospective descriptive study conducted over 5 years (January 2010 to December 2015) on 81 patient files collected in the imaging departments of the CHU Aristide Le Dantec and the Hôpital Principal. The files retained were those whose diagnosis was established from the clinic, imaging and/or not from surgery.
RESULTS: Mechanical occlusions represented 94.4% (76 cases) and functional occlusions 5.6% (05 cases). They were of the small bowel type in 70% of cases and colonic in 30%. The elementary lesions found were: transitional zone (36 patients), feces sign (28 patients), beak sign (06 patients), whirlpool sign (11 patients), signs of severity (36 patients). Seventy-two patients received surgery and 04 patients received medical treatment. The preoperative diagnosis was confirmed by surgery in 68 patients. Surgery corrected the diagnosis in 04 cases. Signs of severity were confirmed at surgery in all our patients.
CONCLUSIONS: The CT scan has a major role in the therapeutic choice of AIO. It should be requested in first intention before an occlusive syndrome.
BACKGROUND: L\'occlusion intestinale aiguë (OIA) est un syndrome défini par l\'arrêt du transit intestinal provoqué par un obstacle ou par une paralysie du péristaltisme intestinal. Il s\'agit d\'une urgence diagnostique et thérapeutique. Le scanner multibarrette a révolutionné la prise en charge de cette pathologie, car permettant de répondre aux différentes questions du chirurgien.Le but de notre étude était de décrire les aspects scanographiques des OIA, de déterminer les étiologies et de montrer la place de la TDM dans la prise en charge des OIA.
UNASSIGNED: Il s\'agissait d\'une étude rétrospective descriptive réalisée sur 05ans (Janvier 2010 à décembre 2015) portant sur 81 dossiers de patients colligés dans les services d\'imagerie du CHU Aristide Le Dantec et de l\'hôpital Principal. Les dossiers retenus sont ceux dont le diagnostic était établi à partir de la clinique, de l\'imagerie et/ou non de la chirurgie.
UNASSIGNED: Les occlusions mécaniques représentaient 94,4% (76 cas) et fonctionnelles 5.6% (05 cas).Elles étaient de type grêle dans 70% des cas et colique dans 30%.Les lésions élémentaires mises en évidence étaient : zone transitionnelle (36 patients), signe du fèces (28 patients), signe du bec (06 patients), signe du tourbillon (11 patients), signes de gravité (36 patients). Soixante-douze patients ont bénéficié d\'une chirurgie et 04 patients d\'un traitement médical. Le diagnostic préopératoire était confirmé par la chirurgie chez 68 patients. La chirurgie a redressé le diagnostic dans 04 cas. Les signes de gravité étaient confirmés à la chirurgie chez tous nos patients.
CONCLUSIONS: La TDM occupe une place prépondérante dans le choix thérapeutique des OIA. Elle doit être demandée en première intention devant un syndrome occlusif.