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Human monocytes are a heterogeneous cell population, which can be divided into a classical (CD14++CD16−), a non-classical (CD14+CD16+) and an intermediate (CD14++CD16+) subset. We hypothesized that low-grade inflammation may differentially affect monocyte subsets. We used a human lipopolysaccharide (LPS) infusion model to mimic low-grade inflammation to identify, which monocyte subsets are preferentially activated under these conditions. Monocyte subsets were identified by staining for CD14 and CD16, activation status of monocytes was analyzed by staining for CD11b and a novel in situ mRNA hybridization approach to detect IL-6 and IL-8 specific mRNA at the single-cell level by flow cytometry. After LPS challenge, cell numbers of monocyte subsets dropped after 2 h with cell numbers recovering after 6 h. Distribution of monocyte subsets was skewed dramatically towards the intermediate subset after 24 h. Furthermore, intermediate monocytes displayed the largest increase of CD11b expression after 2 h. Finally, IL-6 and IL-8 mRNA levels increased in intermediate and non-classical monocytes after 6 h whereas these mRNA levels in classical monocytes changed only marginally. In conclusion, our data indicates that the main responding subset of monocytes to standardized low-grade inflammation induced by LPS in humans is the CD14++CD16+ intermediate subset followed by the CD14+CD16+ non-classical monocyte subset. Circulating classical monocytes showed comparably less reaction to LPS challenge in vivo .

Objective: For meropenem 40%T > MIC is associated with optimal killing of P. aeruginosa and E. coli . However, it is unknown how the distribution of %T > MIC through a treatment day impacts the antimicrobial effect in vitro . Therefore, we investigated the in vitro antibiotic activity of meropenem, precisely if 40%T > MIC is achieved in one single long period (single dose), 2 × 20% periods (dosing-bid), or 3 × 13.3% (dosing t.i.d.) thereby keeping the overall period of T > MIC constant. Material/Methods: Time kill curves (TKC) with P. aeruginosa -ATCC-27853 and E. coli -ATCC-25922 and five clinical isolates each were implemented over 24 h in CAMHB with concentrations from 0.25×MIC-32×MIC. Periods over and under MIC were simulated by centrifugation steps (discarding supernatant and refilling with fresh CAMHB). Double and triple dosing involved further addition and removal of antibiotic. Complementary growth controls (GC) with and without centrifugation steps were done and the emergence of phenotypical resistance was evaluated (repeated MIC-testing after antibiotic administration). Results: No impact of centrifugation on bacterial growth was seen. TKC with P. aeruginosa showed the best killing in the triple dosage, followed by the double and single dose. In multiple regimens at least a concentration of 4×MIC was needed to achieve a recommended 2-3 log10 killing. Likewise, a reduction of E. coli was best within the three short periods. Contrary to the TKCs with P. aeruginosa we could observe that after the inoculum reached a certain CFU/mL (≥10^8), no further addition of antibiotic could achieve bacterial killing (identified as the inoculum effect). For P. aeruginosa isolates resistance appeared within all regimens, the most pronounced was found in the 40%T > MIC experiments indicating that a single long period might accelerate the emergence of resistance. Contrary, for E. coli no emergence of resistance was found. Conclusion/Outlook: We could show that not solely the %T > MIC is decisive for an efficient bacterial eradication in vitro , but also the distribution of the selected %T > MIC. Thus, dividing the 40%T > MIC in three short periods requested lowers antibiotic concentrations to achieve efficient bacterial killing and reduces the emergence of resistance in P. aeruginosa isolates. The distribution of the %T > MIC did impact the bacterial eradication of susceptible pathogens in vitro and might play an even bigger role in infections with intermediate or resistant pathogens.

Background: To date, no oral antiviral drug has proven to be beneficial in hospitalized patients with COVID-19. Methods: In this randomized, controlled, open-label, platform trial, we randomly assigned patients ≥18 years hospitalized with COVID-19 pneumonia to receive either camostat mesylate (CM) (considered standard-of-care) or lopinavir/ritonavir (LPV/RTV). The primary endpoint was time to sustained clinical improvement (≥48 h) of at least one point on the 7-category WHO scale. Secondary endpoints included length of stay (LOS), need for mechanical ventilation (MV) or death, and 29-day mortality. Results: 201 patients were included in the study (101 CM and 100 LPV/RTV) between 20 April 2020 and 14 May 2021. Mean age was 58.7 years, and 67% were male. The median time from symptom onset to randomization was 7 days (IQR 5–9). Patients in the CM group had a significantly shorter time to sustained clinical improvement (HR = 0.67, 95%-CI 0.49–0.90; 9 vs. 11 days, p = 0.008) and demonstrated less progression to MV or death [6/101 (5.9%) vs. 15/100 (15%), p = 0.036] and a shorter LOS (12 vs. 14 days, p = 0.023). A statistically nonsignificant trend toward a lower 29-day mortality in the CM group than the LPV/RTV group [2/101 (2%) vs. 7/100 (7%), p = 0.089] was observed. Conclusion: In patients hospitalized for COVID-19, the use of CM was associated with shorter time to clinical improvement, reduced need for MV or death, and shorter LOS than the use of LPV/RTV. Furthermore, research is needed to confirm the efficacy of CM in larger placebo-controlled trials. Systematic Review Registration : [ https://clinicaltrials.gov/ct2/show/NCT04351724 , https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001302-30/AT ], identifier [NCT04351724, EUDRACT-NR: 2020–001302-30].

Background: Elimination of a drug during renal replacement therapy is not only dependent on flow rates, molecular size and protein binding, but is often influenced by difficult to predict drug membrane interactions. In vitro models allow for extensive profiling of drug clearance using a wide array of hemofilters and flow rates. We present a bovine blood based in vitro pharmacokinetic model for intermittent renal replacement therapy. Methods: Four different drugs were analyzed: gentamicin, doripenem, vancomicin and teicoplanin. The investigated drug was added to a bovine blood reservoir connected to a hemodialysis circuit. In total seven hemofilter models were analyzed using commonly employed flow rates. Pre-filter, post-filter and dialysate samples were drawn, plasmaseparated and analyzed using turbidimetric assays or HPLC. Protein binding of doripenem and vancomycin was measured in bovine plasma and compared to previously published values for human plasma. Results: Clearance values were heavily impacted by choice of membrane material and surface as well as by dialysis parameters such as blood flow rate. Gentamicin clearance ranged from a minimum of 90.12 ml/min in a Baxter CAHP-170 diacetate hemofilter up to a maximum of 187.90 ml/min in a Fresenius medical company Fx80 polysulfone model (blood flow rate 400 ml/min, dialysate flow rate 800 ml/min). Clearance of Gentamicin vs Vancomicin over the F80s hemofilter model using the same flow rates was 137.62 mL vs 103.25 ml/min. Doripenem clearance with the Fx80 was 141.25 ml/min. Conclusion: Clearance values corresponded very well to previously published data from clinical pharmacokinetic trials. In conjunction with in silico pharmacometric models. This model will allow precise dosing recommendations without the need of large scale clinical trials.

Purpose The transversus abdominis plane (TAP) block is a regional anesthetic technique used for pain control following abdominal surgical procedures. While a minimum of systemic side effects is usually expected after local anesthesia, it is unknown to which extent systemic absorption and redistribution to the abdominal wall contributes to the effects of anesthetics. The aim of this study was to determine concentration–time profiles of ropivacaine after the injection of 150 mg of ropivacaine into the lateral abdominal wall in various compartments. Methods The microdialysis technique was used to measure ropivacaine in plasma as well as at abdominal wall sites cranial from the injection site (below the 12th rip) and caudal from the injection site (cranial from the iliac crest) and in the skeletal muscle tissue of the contra lateral thigh of eight healthy volunteers. Results The mean exposure to ropivacaine measured as the area under the concentration–time curve was significantly higher at the two abdominal sites (240.9 ± 409.1  and 86.18 ± 133.50 μg h/mL, respectively) than in plasma (5.1 ± 1.0 μg h/mL) or in peripheral tissue (1.1 ± 1.2 μg h/mL). While the high mean concentrations of ropivacaine measured at the abdominal wall sites support the topical concept of the TAP block, the observed variability was striking. Conclusions While the systemic pharmacokinetics was comparable between subjects, the local distribution of ropivacaine was highly variable after TAP block.

Lipopolysaccharide (LPS) stimulation of human whole blood ex vivo has been widely used to investigate human innate immune responses. However, there are uncertainties regarding the reproducibility and reliability of this assay. In this prospective, single-center study, cytokine responses (interleukin 8, interferon-α, interferon-γ, interleukin 10, interleukin 1-β, interleukin 6, and tumor necrosis factor-α) to ex vivo whole blood LPS stimulation were assessed in 12 healthy volunteers. Cytokine levels were measured at 0, 2, and 4 h using a multiplex immunoassay (Luminex ). Stimulation was repeated after six weeks. We examined reproducibility across technical and biological replicates at baseline and between repeated experiments after 6 weeks based on the area under the curve (AUC) of the individual cytokines using Pearson's correlation coefficient and the mean coefficient of variation. The lowest mean coefficients of variation were observed for the technical replicates (5.4 to 9.2%), followed by the biological replicates (8.1 to 24.8%), and the repeated experiments after 6 weeks (17 to 31.2%). Between the baseline and 6-week AUCs, the following Pearson correlation coefficients R were observed: interleukin 10, 0.97; interferon-α, 0.84; interleukin 1-β, 0.83; interleukin 8, 0.79; interleukin 6, 0.73; interferon-γ, 0.73; and tumor necrosis factor-α, 0.63. The level of agreement between the baseline and week-6 cytokine response to ex vivo LPS stimulation was high across the seven cytokines analyzed. While interleukin 10 exhibited the lowest level of variability over time, tumor necrosis factor-α showed the highest variability in repeated experiments, which should be considered in the design and interpretation of future studies.

For treatment of peritoneal dialysis-related peritonitis, intraperitoneal administration of antibiotics remains the preferable route. For home-based therapy, patients are commonly supplied with peritoneal dialysis fluids already containing antimicrobial agents. The present study set out to investigate the compatibility of fosfomycin with different peritoneal dialysis fluids, namely, Extraneal ® , Nutrineal ® , Physioneal ® 1.36% and Physioneal ® 2.27%, under varying storage conditions. The peritoneal dialysis fluid bags including 4 g fosfomycin were stored over 14 days at refrigeration temperature (6°C) and room temperature (25°C) and over 24 h at body temperature (37°C). Drug concentrations over time were determined by using high-performance liquid chromatography coupled to a mass spectrometer. In addition, drug activity was assessed by a disk diffusion method, diluent stability by visual inspection and drug adsorption by comparison of the measured and calculated concentrations. Blank peritoneal dialysis fluids and deionized water were used as comparator solutions. Fosfomycin was stable in all peritoneal dialysis fluids and at each storage condition investigated over the whole study period. The remaining drug concentrations ranged between 94% and 104% of the respective initial concentrations. No significant drug adsorption was observed for any peritoneal dialysis fluid at any storage condition. No relevant reduction of antimicrobial activity was observed. Fosfomycin is compatible with Extraneal ® , Nutrineal ® and Physioneal ® for up to two weeks at refrigeration or room temperature and may be used for home-based therapy. No dose adjustment is needed due to adsorption or degradation.

There were no significant differences in the area under the curve of unmetabolized (R)-[11C]verapamil in plasma between the elderly and young group, both for baseline scans and scans after ABCB1 inhibition. [...]tariquidar plasma concentrations at the time of the PET scan were not significantly different between the two groups.

Objective: Although major impairment of activity at lower pH values has been reported for fluoroquinolones, acidification is a widely recommended practice for the prophylaxis and treatment of uncomplicated urinary tract infections (UTIs). Until now, there is little evidence for the influence of pH on the activity on other antimicrobial classes in urine. Methods: Bacterial growth curves of Staphylococcus aureus (ATCC 29213), Klebsiella oxytoca (ATCC 700324), Proteus mirabilis (ATCC 14153), Escherichia coli (ATCC 25922) and Enterococcus faecalis (ATCC 29212) were performed in Mueller-Hinton broth and in pooled human urine with a pH of between 5.0 and 8.0. Bacterial killing of trimethoprim, fosfomycin, amikacin, colistin and ertapenem against the five strains (where appropriate) was determined consecutively at concentrations equal to the MIC. Results: While no difference in the bacterial growth of E. coli, S. aureus, P. mirabilis and K. oxytoca was observed at different pH values, bacterial growth of E. faecalis was significantly reduced at low pH. Acidification to pH 5 impaired the antimicrobial activity of all investigated antibiotics, i.e. the net effect of bacterial growth and killing resulted in increased colony-forming units/ml at the end of the experiment. Conclusion: The present in vitro findings indicate that acidification of urine during the treatment of UTIs should be carefully considered. While growth curves of one strain supports the concept of therapeutic or prophylactic acidification during UTIs, the most common pathogen, E. coli, was not affected by low pH. Independent of the investigated strain or antibiotic, pH values below 6 lead to a reduction of antimicrobial activity.

Cation-dependent inhibition of antimicrobial activity was reported for polymyxin antibiotics. Ca 2+ and Mg 2+ concentrations recommended by the Clinical and Laboratory Standards Institute (CLSI) for the supplementation of Müller–Hinton broth (MHB) are markedly lower than interstitial space fluid (ISF) concentrations in vivo. Hence, it was speculated that the antimicrobial activity of colistin might be overestimated if tested using conventional cation-adjusted MHB. The antimicrobial activity of colistin against n  = 100 clinical isolates of Pseudomonas aeruginosa , Acinetobacter baumannii , Klebsiella pneumoniae and Escherichia coli ( n  = 25 each) was evaluated by broth microdilution and, for selected isolates, by time–kill curves, in MHB without cations (MHB ONLY ), MHB supplemented with 25 mg/L Ca 2+ and 12.5 mg/L Mg 2+ according to CLSI recommendations (MHB CLSI ), and in MHB adjusted to 50 mg/L Ca 2+ and 20 mg/L Mg 2+ simulating ISF concentrations (MHB ISF ). The minimum inhibitory concentration (MIC) values of colistin against the vast majority of isolates of both P. aeruginosa and A. baumannii increased significantly with higher cation concentrations. The susceptibility of K. pneumoniae isolates to colistin did not show significant changes between cation-supplemented media, while the MICs of E. coli decreased with ascending cation concentrations. These findings were confirmed in time–kill studies, where colistin killing against P. aeruginosa 1514 and A. baumannii 1485 declined with increasing cation concentrations. Contrarily, the killing of selected concentrations of colistin against K. pneumoniae 15 and E. coli 16 was enhanced in the presence of increasing cation concentrations. The present data suggest that the clinical antimicrobial activity of colistin might be misestimated in vitro if tested in conventional growth media.