The novel dysprosium borate DyB
5
O
8
(OH)
2
was synthesized in a Walker‐type multianvil apparatus at a pressure of 2.5 GPa and a temperature of 673 K. Single‐crystal diffraction data provided the ...basis for the structure solution and refinement. The compound crystallizes in the acentric monoclinic space group
C
2 (no. 5) with the lattice parameters
a
= 7.9288(5),
b
= 4.4009(3),
c
= 9.3409(8) Å, and a monoclinic angle of 113.76(1)°. Generally, DyB
5
O
8
(OH)
2
is comprised of a layer‐like structure consisting of corner sharing BO
4
5–
tetrahedra forming dreier and sechser rings, and eightfold coordinated dysprosium cations. Further characterizations were performed by IR and luminescence spectroscopy as well as high‐temperature X‐ray diffraction.
Meropenem is one of the most frequently used antibiotics to treat life-threatening infections in critically ill patients. This study aimed to develop a meropenem dosing algorithm for the treatment of ...Gram-negative infections based on intensive care unit (ICU)-specific resistance data. Antimicrobial susceptibility testing of Gram-negative bacteria obtained from critically ill patients was carried out from 2016 to 2020 at a tertiary care hospital. Based on the observed MIC distribution, stochastic simulations (
= 1,000) of an evaluated pharmacokinetic meropenem model, and a defined pharmacokinetic/pharmacodynamic target (100%
while minimum concentrations were <44.5 mg/L), dosing recommendations for patients with varying renal function were derived. Pathogen-specific MIC distributions were used to calculate the cumulative fraction of response (CFR), and the overall MIC distribution was used to calculate the local pathogen-independent mean fraction of response (LPIFR) for the investigated dosing regimens. A CFR/LPIFR of >90% was considered adequate. The observed MIC distribution significantly differed from the EUCAST database. Based on the 6,520 MIC values included, a three-level dosing algorithm was developed. If the pathogen causing the infection is unknown (level 1), known (level 2), known to be neither Pseudomonas aeruginosa nor Acinetobacter baumannii, or classified as susceptible (level 3), a continuous infusion of 1.5 g daily reached sufficient target attainment independent of renal function. In all other cases, dosing needs to be adjusted based on renal function. ICU-specific susceptibility data should be assessed regularly and integrated into dosing decisions. The presented workflow may serve as a blueprint for other antimicrobial settings.
Objective
Infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can lead to severe pneumonia, but also thrombotic complications and non‐pulmonary organ failure. Recent studies ...suggest intravascular neutrophil activation and subsequent immune cell–triggered immunothrombosis as a central pathomechanism linking the heterogenous clinical picture of coronavirus disease 2019 (COVID‐19). We sought to study whether immunothrombosis is a pathognomonic factor in COVID‐19 or a general feature of (viral) pneumonia, as well as to better understand its upstream regulation.
Approach and results
By comparing histopathological specimens of SARS‐CoV‐2 with influenza‐affected lungs, we show that vascular neutrophil recruitment, NETosis, and subsequent immunothrombosis are typical features of severe COVID‐19, but less prominent in influenza pneumonia. Activated neutrophils were typically found in physical association with monocytes. To explore this further, we combined clinical data of COVID‐19 cases with comprehensive immune cell phenotyping and bronchoalveolar lavage fluid scRNA‐seq data. We show that a HLADRlow CD9low monocyte population expands in severe COVID‐19, which releases neutrophil chemokines in the lungs, and might in turn explain neutrophil expansion and pulmonary recruitment in the late stages of severe COVID‐19.
Conclusions
Our data underline an innate immune cell axis causing vascular inflammation and immunothrombosis in severe SARS‐CoV‐2 infection.
The altered pharmacokinetics of renally cleared drugs such as meropenem in critically ill patients receiving continuous renal replacement therapy (CRRT) might impact target attainment. Model-informed ...precision dosing (MIPD) is applied to individualize meropenem dosing. However, most population pharmacokinetic (PopPK) models developed to date have not yet been evaluated for MIPD. Eight PopPK models based on adult CRRT patients were identified in a systematic literature research and encoded in NONMEM 7.4. A data set of 73 CRRT patients from two different study centers was used to evaluate the predictive performance of the models using simulation and prediction-based diagnostics for i)
dosing based on patient characteristics only and ii) Bayesian dosing by including the first measured trough concentration. Median prediction error (MPE) for accuracy within |20%| (95% confidence intervals including zero) and median absolute prediction error (MAPE) for precision ≤ 30% were considered clinically acceptable. For
dosing, most models (
= 5) showed accuracy and precision MPE within |20%| and MAPE <35%. The integration of the first measured meropenem concentration improved the predictive performance of all models (median MAPE decreased from 35.4 to 25.0%; median MPE decreased from 21.8 to 4.6%). The best predictive performance for intermittent infusion was observed for the O'Jeanson model, including residual diuresis as covariate (
and Bayesian dosing MPE within |2%|, MAPE <30%). Our study revealed the O'Jeanson model as the best-predicting model for intermittent infusion. However, most of the selected PopPK models are suitable for MIPD in CRRT patients when one therapeutic drug monitoring sample is available.
We describe a young patient who ingested 18 g (240 times the daily therapeutic dose) of venlafaxine in a suicide attempt. She developed severe cardiomyopathy in a takotsubo distribution causing ...cardiogenic shock and multi-organ dysfunction syndrome (MODS). She was successfully treated with intravenous lipid emulsion (ILE), extracorporeal life support (ECLS) and CytoSorb®. This is remarkable as, to the best of the authors’ knowledge, this is the highest amount of venlafaxine intake seen in the literature with a nonfatal outcome.
BACKGROUND.Cytomegalovirus (CMV)-infection remains a major cause of morbidity and mortality after lung transplantation. Treatment with currently available drugs poses treatment difficulties in some ...patients due to drug resistance or intolerability.
METHODS.We report a series of 4 lung transplant recipients with CMV-infection and treatment failure upon standard care due to antiviral drug resistance and treatment-limiting side effects. As rescue therapy letermovir recently approved for the prophylaxis of CMV-infection in patients after hematopoietic stem cell transplantation was initiated. Patients received 480 mg/day for a follow up of 36.1 ± 12.9 weeks. Efficacy and tolerability were assessed retrospectively.
RESULTS.Mild nausea, vomiting, and diarrhea were the only side effects of letermovir reported by a single patient. A small adjustment of the tacrolimus dose was mandatory upon treatment initiation with letermovir. CMV viral load could be decreased and cleared subsequently in all patients. CMV clearance was observed after 17.7 ± 12.6 weeks despite lack of CMV-immunity.
CONCLUSIONS.CMV-infection and -disease were successfully managed with letermovir. Letermovir was well tolerated and effective in treating CMV-infections in lung transplant recipients failing on currently available antiviral agents.
The concentration-time profile of linezolid varies considerably in critically ill patients. Question of interest is, if the site of infection influences linezolid serum concentrations.
68 critically ...ill patients, treated with linezolid, were included. The concentration-time-profile for linezolid was determined using maximum a-posteriori predictions. A trough concentration (Cmin) between 2 and 10 mg/L was defined as the target. A generalized linear model (GLM) was established to evaluate potential covariates.
The indications for linezolid therapy were in descending order: peritonitis (38.2%), pneumonia (25.0%), infectious acute respiratory distress syndrome (ARDS) (19.1%), and other non-pulmonary infection (17.7%). 27.2 and 7.9% of Cmin were subtherapeutic and toxic, respectively. In the GLM, ARDS (mean: −2.1 mg/L, CI: −3.0 to −1.2 mg/L) and pneumonia (mean: −2.2 mg/L, CI: −2.8 to −1.6 mg/L) were significant (p < 0.001) determinants of Cmin. Patients with ARDS (mean: 2.3 mg/L, 51.2% subtherapeutic, 0.0% toxic) and pneumonia (mean: 3.5 mg/L, 41.5% subtherapeutic, 7.7% toxic) had significantly (p < 0.001) lower Cmin than those with peritonitis (mean: 5.5 mg/L, 14.4% subtherapeutic, 9.3% toxic) and other non-pulmonary infection (mean: 5.2 mg/L, 3.3% subtherapeutic, 16.5% toxic).
Linezolid serum concentrations are reduced in patients with pulmonary infections. Future studies should investigate if other linezolid thresholds are needed in those patients due to linezolid pooling in patients´ lung.
Figure: Subtherapeutic, therapeutic and toxic linezolid trough concentrations in different patient populations. Note: Red, green and black plots represent the percentage of subtherapeutic, therapeutic and toxic linezolid through concentrations, respectively. ARDS: acute respiratory distress syndrome, vv-ECMO: venovenous extracorporeal membrane oxygenation. Display omitted
•Despite routine TDM, 35% of linezolid trough concentrations were outside the target (27% subtherapeutic, 8% toxic).•Patients with ARDS and pneumonia had lower linezolid trough concentrations than those with non-pulmonary infections.•51% of linezolid trough concentrations in patients with ARDS were subtherapeutic.•Therapeutic linezolid concentrations in the lung might be achieved by its pooling.
Abstract
The novel potassium nickel borate nitrate K
7
NiB
18
O
24
(OH)
9
(NO
3
)
6
·(H
3
BO
3
) was obtained from a simple hydrothermal synthesis in a stainless-steel autoclave at
T
= 513 K ...starting with nickel dichloride hexahydrate, and boric and nitric acid with the pH adjusted to 8 by KOH. Single-crystal X-ray diffraction data provided the basis for the structure analysis and refinement. The compound crystallizes in the trigonal space group
R
3̅ (no. 148) with the lattice parameters
a
= 1222.29(8) and
c
= 5478.4(4) pm. Generally, K
7
NiB
18
O
24
(OH)
9
(NO
3
)
6
·(H
3
BO
3
) is comprised of nitrate layers and complex nickel borate layers surrounded by boric acid, nitrate anions, and potassium cations.
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