Beta-lactam antibiotics (βLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and ...pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients.
A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only "optional" recommendations.
After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding βLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of βLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement.
The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering βLA in critically ill patients.
The increasing burden of invasive fungal infections results in growing challenges to antifungal (AF) therapeutic drug monitoring (TDM). This review aims to provide an overview of recent advances in ...AF TDM.
We conducted a PubMed search for articles during 2016-2020 using "TDM" or "pharmacokinetics" or "drug-drug-interaction" with "antifungal," consolidated for each AF. Selection was limited to English language articles with human data on drug exposure.
More than 1000 articles matched the search terms. We selected 566 publications. The latest findings tend to confirm previous observations in real-life clinical settings. The pharmacokinetic variability related to special populations is not specific but must be considered. AF benefit-to-risk ratio, drug-drug interaction (DDI) profiles, and minimal inhibitory concentrations for pathogens must be known to manage at-risk situations and patients. Itraconazole has replaced ketoconazole in healthy volunteers DDI studies. Physiologically based pharmacokinetic modeling is widely used to assess metabolic azole DDI. AF prophylactic use was studied more for Aspergillus spp. and Mucorales in oncohematology and solid organ transplantation than for Candida (already studied). Emergence of central nervous system infection and severe infections in immunocompetent individuals both merit special attention. TDM is more challenging for azoles than amphotericin B and echinocandins. Fewer TDM requirements exist for fluconazole and isavuconazole (ISZ); however, ISZ is frequently used in clinical situations in which TDM is recommended. Voriconazole remains the most challenging of the AF, with toxicity limiting high-dose treatments. Moreover, alternative treatments (posaconazole tablets, ISZ) are now available.
TDM seems to be crucial for curative and/or long-term maintenance treatment in highly variable patients. TDM poses fewer cost issues than the drugs themselves or subsequent treatment issues. The integration of clinical pharmacology into multidisciplinary management is now increasingly seen as a part of patient care.
A new liquid chromatography assay with isocratic elution and tandem mass spectrometry detection (LC–MS/MS) using an electrospray ionization interface in the multiple reaction monitoring mode was ...developed and validated for ertapenem determination in microdialysate samples. Linearity was demonstrated between 10
ng
mL
−1 (lower limit of quantification, LLoQ) and 160
ng
mL
−1. The precision (CV%) and accuracy (bias%) in microdialysates at the LLoQ were respectively 2.2% and 17.3% within-day and 10.6% and 2.7% between-days. Ertapenem was stable for 1 month at −20
°C and −80
°C but unstable at +4
°C. This new LC–MS/MS assay is simple, rapid and more sensitive than previously described assays.
Endocrine-disrupting chemicals (EDC) are compounds that alter functions of the endocrine system due to their ability to mimic or antagonize endogenous hormones, or that alter their synthesis and ...metabolism, causing adverse health effects. Human biomonitoring (HBM) is a reliable method to assess human exposure to chemicals through measurement in human body fluids and tissues. It identifies new sources of exposure and determines their distribution, thereby enabling detection of the most exposed populations. Blood and urine are commonly used for HBM of EDC, but their interest is limited for compounds presenting short half-lives. Hair appears as an interesting alternative insofar as it provides a large exposure window. For the present study, we evaluated the relevance of hair in determining EDC exposure. With this in mind, we undertook a literature review focusing on the bioanalytical aspects and performances of methods developed to determine EDC in hair. The literature review was performed through methodical bibliographical research. Relevant articles were identified using two scientific databases: PubMed and Web of Science, with search equations built from a combination of keywords, MeSH terms and Boolean operators. The search strategy identified 2949 articles. After duplicates were removed, and following title, abstract, and full-text screenings, only 31 were included for qualitative synthesis. Hair collection was mainly performed in the back of the head and preparation involved two processes: cutting into small pieces or grounding to powder. The off-line LC-MS/MS method remains the main technique used to assess EDC through hair. Differences regarding the validation of analytical methods and interpretation of HBM results were highlighted, suggesting a need for international harmonisation to obtain reliable and comparable results. External contamination of hair was identified as a main limitation in the interpretation of results, highlighting the need to better understand EDC transfers through hair and to develop relevant hair decontamination processes.
Display omitted
•Review of analytical methods for the assessment of EDCs through hair.•Work especially focused on extraction processes and analytical performance.•Discussion about the relevance of hair matrix as a biomarker of exposure to EDCs.
N-ethylhexedrone (NEH) is a new cathinone derivative with, currently, low toxicocokinetic, and toxicocodynamic knowledge. We present 3 documented clinical cases of NEH intoxication with plasma, and ...urine concentrations. A thorough search for metabolites was performed. The 3 patients were admitted to the emergency department, and 2 out of the 3 were hospitalized for an extended period. While recovering from the drug effects, 12 to 24 hours after nasal intake of New Psychoactive Substance (NPS), the patients described the following disorders: anxiety, feelings of persecution, asthenia, anhedonia, abulia, psychomotor slowing, and loss of consciousness. NEH was identified in all samples by liquid chromatography-high resolution mass spectrometry (LC-HRMS), and quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS). Quantitative analysis showed decreasing concentrations over time: for case 1, from 97.2 (Day 1, D1) to 0.7 (Day 7, D7) µg/L for plasma, and from 724 (D1) to 0.5 (D7) µg/L for urine. NEH concentration of 7.9 µg/L was found in the plasma collected at admission for case 2. For case 3: concentrations ranging from 49 (D1) to 1.8 (D7) µg/L in plasma, and from 327.3 (Day 5, D5) to 116.8 (D7) µg/L in urine were found. NEH was no longer detected in the urine sample at Day 10. Elimination half-life was estimated at 19, and 28 hours in patients 1 and 3, respectively. Four metabolites were identified in blood and urine: reduced NEH, dealkyl-NEH, reduced dealkyl-NEH, and hydroxy-NEH. The cases presented highlight the long detectable lifetime of NEH. Characterization of the metabolites will allow better identification of the consumption of this drug. Serious adverse events can be observed after NEH consumption, as 2 out of 3 patients required intubation and ventilation. A syndrome of inappropriate antidiuretic hormone secretion (SIADH) was also diagnosed. Two out of the three cases are notable because of the number of samples collected and because NEH was the only drug of abuse detected.
Abstract
Background
Crushing or dissolving bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) tablets is not recommended because there are no data supporting this practice.
Methods
A ...crossover, randomized trial in healthy adults (NCT04244448) investigated the bioavailability of two off-label uses of BIC/TAF/FTC (50/200/25 mg), dissolved in water or crushed in apple compote, compared with the solid tablet. Pharmacokinetic (PK) parameters were estimated from sequential intensive plasma antiretroviral concentrations over a 72 h period post dose. Bioequivalence was met if the 90% CIs of the geometric least-squares means ratios comparing BIC/TAF/FTC exposures (AUC and Cmax) from the experimental phases were within 80%–125% of the reference.
Results
Eighteen subjects participated in each of the three phases. Dissolved tablet Cmax geometric mean ratio (90% CI) for BIC/TAF/FTC was 105% (93–119)/97% (87–108)/96% (74–124), respectively. Dissolved tablet AUC geometric mean ratio (90% CI) for BIC/TAF/FTC was 111% (100–122)/100% (94 to 105)/99% (81 to 120), respectively. Crushed tablet Cmax geometric mean ratio (90%) CI for BIC/TAF/FTC was 110% (97 to 124)/70% (63–78)/66% (51–85), respectively. Crushed tablet AUC geometric mean ratio (90%) CI for BIC/TAF/FTC was 107% (96–118)/86% (82–91)/84% (69–103), respectively.
Conclusions
Crushing BIC/TAF/FTC tablets may lead to suboptimal emtricitabine and tenofovir alafenamide drug exposures. Dissolving BIC/TAF/FTC in water may be acceptable if the tablet cannot be swallowed whole.
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