Background:Ceftriaxone is a first-line beta-lactam antibiotic used in diverse clinical settings. Owing to pharmacokinetic alterations, ceftriaxone therapeutic drug monitoring is currently recommended for patients in the intensive care unit. Ultrafiltration is typically used to measure unbound ceftriaxone concentrations, as it is less costly and time-consuming compared with equilibrium dialysis. However, the reference method, equilibrium dialysis, has not been compared with equilibrium dialysis for ceftriaxone to measure the unbound ceftriaxone concentrations. Therefore, unbound ceftriaxone fractions measured by ultrafiltration versus equilibrium dialysis were compared in patients in the intensive care unit.Methods:Total and unbound ceftriaxone plasma fractions were measured by ultrafiltration (9500g at 37 degrees C for 30 minutes) and equilibrium dialysis (12 kDa, 37 degrees C for 4 hours) in 32 plasma samples from 28 patients who were critically ill collected during a previous prospective pharmacokinetic study. Passing-Bablok regression and Bland-Altman analyses were performed to evaluate the agreements between both methods.Results:The median (range) total ceftriaxone plasma concentration was 108.6 (5.2-233) mg/L. The median unbound concentration measured by equilibrium dialysis and ultrafiltration was 14.5 (0.7-52.9) and 23.3 (0.9-79.2) mg/L, respectively, showing a significant difference. Passing-Bablok regression analysis revealed significant proportional and systematic bias. This result was confirmed by Bland-Altman analysis, with a mean relative bias of 43.3% and wide agreement limits (-21% to 108%).Conclusions:Ultrafiltration substantially overestimates the unbound ceftriaxone fraction compared with equilibrium dialysis at 37 degrees C. It is important to report methodological details and consider this information when interpreting unbound fractions of ceftriaxone and other drugs. These findings may impact the therapeutic drug monitoring of ceftriaxone.

INTRODUCTION:β-Lactams are the most widely used antibiotics in children. Their optimal dosing is essential to maximize their efficacy, while minimizing the risk for toxicity and the further emergence of antimicrobial resistance. However, most β-lactams were developed and licensed long before regulatory changes mandated pharmacokinetic studies in children. As a result, pediatric dosing practices are poorly harmonized and off-label use remains common today. AREAS COVERED:β-Lactam pharmacokinetics and dose optimization strategies in pediatrics, including fixed dose regimens, therapeutic drug monitoring, and model-informed precision dosing are reviewed. EXPERT OPINION/COMMENTARY:Standard pediatric doses can result in subtherapeutic exposure and non-target attainment for specific patient subpopulations (neonates, critically ill children, e.g.). Such patients could benefit greatly from more individualized approaches to dose optimization, beyond a relatively simple dose adaptation based on weight, age, or renal function. In this context, Therapeutic Drug Monitoring (TDM) and Model-Informed Precision Dosing (MIPD) emerge as particularly promising avenues. Obstacles to their implementation include the lack of strong evidence of clinical benefit due to the paucity of randomized clinical trials, of standardized assays for monitoring concentrations, or of adequate markers for renal function. The development of precision medicine tools is urgently needed to individualize therapy in vulnerable pediatric subpopulations.

Purpose We present the case of a 67-year-old woman with severely reduced renal clearance suffering from ceftazidime-induced encephalopathy. Subsequently, we search the literature to review and describe the neurotoxicity of ceftazidime. Methods A search string was developed to search PubMed for relevant cases from which relevant information was extracted. Using the collected data a ROC analysis was performed in R to determine a neurotoxicity threshold. Results Our patient suffered from progressive loss of consciousness and myoclonic seizures, with improvements noted a few days after discontinuation of treatment. The dose was not appropriately reduced to take into account her reduced renal function. The highest ceftazidime concentration recorded was 234.9 mg/mL. Using the Naranjo score we found a probable relationship between our patient’s encephalopathy and ceftazidime administration. In the literature we found a total of 32 similar cases, most of which also had some form of renal impairment. Using our collected data and ceftazidime concentrations provided in the literature, a ROC analysis provided a neurotoxicity threshold of 78 mg/L for ceftazidime neurotoxicity. Conclusion Ceftazidime-related neurotoxicity is a known issue, especially in patients with severe renal impairment. Yet no concrete toxicity threshold has been reported so far. We propose the first toxicity threshold for ceftazidime of 78 mg/L. Future prospective studies are needed to validate and optimize the neurotoxicity threshold as upper limit for ceftazidime therapeutic drug monitoring.

With increasing numbers of cancer cases, the use of antineoplastic agents is expected to rise. This will be accompanied by an increase in occupational exposure, which can cause unwanted health effects in workers. Our aim was to give an overview of genotoxic and epigenetic effects after occupational exposure to antineoplastic agents and to assess the concentration−effect relation. Four databases were searched for papers investigating genotoxic and/or epigenetic effects of occupational exposure to antineoplastic agents. Out of the 245 retrieved papers, 62 were included in this review. In this systematic literature review, we confirmed that exposure of healthcare workers to antineoplastic agents can lead to genotoxic damage. However, we observed a lack of data on exposure as well as genotoxic and epigenetic effects in workers other than healthcare workers. Furthermore, gaps in the current knowledge regarding the potential epigenetic effects caused by antineoplastic drug exposure and regarding the link between internal antineoplastic drug concentration and genotoxic and epigenetic effects after occupational exposure to antineoplastic agents were identified, offering a first step for future research.

Introduction It is important to monitor unintended exposure to antineoplastic drugs (ANDs) and potential effects occurring after exposure. Our aims were to develop a method sensitive enough to measure trace levels of ANDs in urine, evaluate environmental contamination and occupational exposure to ANDs. Finally, we aimed to study the link between exposure and genotoxic/epigenetic effects. Materials and Methods UPLC-UniSpray-MS/MS was used for quantification of ANDs in urine (n=83), while UPLC-ESI-MS/MS was used for analysis of wipe samples (n=62) collected in 6 different departments from a university hospital. Novum simplified liquid cartridges were used for extraction of urine samples, liquid extraction was used for wipe samples. The link between exposure and effects was studied through a systematic review. Results and Conclusions A method for urine analysis was fully developed and validated with LLOQs of 0.05 ng/mL, 0.3 ng/mL and 0.7 ng/mL for cyclophosphamide, ifosfamide and paclitaxel, respectively. All wipe samples and 17 urine samples had quantifiable concentrations of at least one compound. Concentrations in urine ranged from <LOQ-15.80ng/mL and in wipes from <LOQ- 208.85 ng/cm2. The highest levels were observed in the oncology department. Despite the numerous guidelines, healthcare workers are thus still exposed to ANDs, therefore, actions should be taken to limit the presence of ANDs in the work environment. In the systematic review, we confirmed the possibility of genotoxic damage after occupational exposure to ANDs. However, we revealed a lack of data on biomonitoring, epigenetic effects, exposure-effect link. Therefore, in the next phase, we will generate valuable information on the concentration-effect link. Ethical approval 'Conseil d'Ethique et de Déontologie de l'Université de Tlemcen' (15/12/2016). Funding Industrieel Onderzoeksfonds KU Leuven Program: C3 project: (C32/15/029) Occupational dermal exposure to cytostatics (3M170331). The Research Foundation – Flanders (1SD2322N). The authors declare no conflict of interest.

During recent years, we are moving away from the 'one exposure, one disease'-approach in occupational settings and towards a more comprehensive approach, taking into account the totality of exposures during a life course by using an exposome approach. Taking an exposome approach however is accompanied by many challenges, one of which, for example, relates to the collection of biological samples. Methods used for sample collection in occupational exposome studies should ideally be minimally invasive, while at the same time sensitive, and enable meaningful repeated sampling in a large population and over a longer time period. This might be hampered in specific situations e.g., people working in remote areas, during pandemics or with flexible work hours. In these situations, using self-sampling techniques might offer a solution. Therefore, our aim was to identify existing self-sampling techniques and to evaluate the applicability of these techniques in an occupational exposome context by conducting a literature review. We here present an overview of current self-sampling methodologies used to characterize the internal exposome. In addition, the use of different biological matrices was evaluated and subdivided based on their level of invasiveness and applicability in an occupational exposome context. In conclusion, this review and the overview of self-sampling techniques presented herein can serve as a guide in the design of future (occupational) exposome studies while circumventing sample collection challenges associated with exposome studies.

BACKGROUND:Many guidelines and safety measures led to a decrease in exposure to antineoplastic agents. Since healthcare workers are often exposed to lower concentrations than patients, a sensitive method is needed to quantify occupational exposure.OBJECTIVE:The aim of this study was to develop and validate a sensitive method for simultaneous detection and quantification of cyclophosphamide, ifosfamide and paclitaxel in urine by use of UPLC-MS/MS with a UniSpray ionisation source.METHODS:Compounds were extracted from urine using Novum simplified liquid extraction cartridges, separated on a C18 column, ionised by a UniSpray ionisation source and detected with MS/MS. In the second part of the study, a field study was performed to assess occupational exposure to antineoplastic agents.RESULTS:Eighty-three samples from healthcare workers were analysed and resulted in seventeen samples containing quantifiable concentrations of at least one compound. In conclusion, a sensitive method for simultaneous detection and quantification of cyclophosphamide (LLOQ 0.05 ng/mL), ifosfamide (LLOQ 0.3 ng/mL) and paclitaxel (LLOQ 0.7 ng/mL) was developed and validated.