Fluid management for sepsis-induced hypotension in patients with advanced chronic kidney disease: a secondary analysis of the CLOVERS trial.

BACKGROUND: Early fluid management in patients with advanced chronic kidney disease (CKD) and sepsis-induced hypotension is challenging with limited evidence to support treatment recommendations. We aimed to compare an early restrictive versus liberal fluid management for sepsis-induced hypotension in patients with advanced CKD. METHODS: This post-hoc analysis included patients with advanced CKD (eGFR of less than 30 mL/min/1.73 m2 or history of end-stage renal disease on chronic dialysis) from the crystalloid liberal or vasopressor early resuscitation in sepsis (CLOVERS) trial. The primary endpoint was death from any cause before discharge home by day 90. RESULTS: Of 1563 participants enrolled in the CLOVERS trial, 196 participants had advanced CKD (45% on chronic dialysis), with 92 participants randomly assigned to the restrictive treatment group and 104 assigned to the liberal fluid group. Death from any cause before discharge home by day 90 occurred significantly less often in the restrictive fluid group compared with the liberal fluid group (20 [21.7%] vs. 41 [39.4%], HR 0.5, 95% CI 0.29-0.85). Participants in the restrictive fluid group had more vasopressor-free days (19.7 ± 10.4 days vs. 15.4 ± 12.6 days; mean difference 4.3 days, 95% CI, 1.0-7.5) and ventilator-free days by day 28 (21.0 ± 11.8 vs. 16.5 ± 13.6 days; mean difference 4.5 days, 95% CI, 0.9-8.1). CONCLUSIONS: In patients with advanced CKD and sepsis-induced hypotension, an early restrictive fluid strategy, prioritizing vasopressor use, was associated with a lower risk of death from any cause before discharge home by day 90 as compared with an early liberal fluid strategy. TRIAL REGISTRATION: NCT03434028 (2018-02-09), BioLINCC 14149.

Pharmacokinetic/pharmacodynamic model-based optimization of temocillin dosing strategies for the treatment of systemic infections.

BACKGROUND: Temocillin is increasingly considered as an alternative to carbapenems. However, there is no consensus on optimal dosing strategies and limited data on temocillin efficacy in systemic infections. OBJECTIVES: We compared temocillin dosing strategies using pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation based on plasma exposure and in vitro time-kill data. METHODS: Temocillin effects on four Escherichia coli strains were evaluated using static time-kill experiments and the hollow-fibre infection model, in which unbound plasma concentrations following intermittent and continuous infusion regimens of 4 and 6 g daily were replicated over 72 h. A PK/PD model was developed to describe the time-kill data. The PK/PD model was coupled to a population PK model of temocillin in critically ill patients to predict bacterial killing and resistance development following various dosing regimens. RESULTS: Amplification of resistant subpopulations was observed within 24 h for all strains. The PK/PD model described the observed bacterial kill kinetics and resistance development from both experimental systems well. Simulations indicated dose-dependent bacterial killing within and beyond the currently used daily dose range, and a superiority of continuous compared with intermittent infusions. However, regrowth of resistant subpopulations was frequently observed. For two strains, bacteriostasis over 72 h was predicted only with doses that are higher than those currently licensed. CONCLUSIONS: Continuous infusions and 6 g daily doses of temocillin kill E. coli more effectively than 4 g daily doses and intermittent infusions, and may increase efficacy in the treatment of systemic infections. However, higher daily doses may be required to suppress resistance development.

Prevalence and clinical implications of bloodstream infections in intensive care patients with or without burn injury: a retrospective cohort study.

PURPOSE: Severe burn injuries are often accompanied by infections and associated with high morbidity and mortality. This study aimed to compare the prevalence and clinical impact of bacteremia between patients receiving intensive care with and without burns. METHODS: This single-center retrospective cohort study at the University Hospital Vienna, Austria, analyzed blood cultures from intensive care unit (ICU) patients with and without burns (2012-2022) to assess the prevalence of bacteremia, the associated pathogen distribution and the 60-day all-cause mortality. RESULTS: In 1170 ICU patients, 303 with burns and 867 without, the prevalence of bacteremia was similar among patients with at least one blood culture (31/157 [19.7%] versus 44/213 [20.7%], OR [95%CI] = 0.95 [0.57-1.57]). Burn patients exhibited a significantly higher frequency of microbiological sampling (51.5% versus 24.5%, p < 0.001), resulting in a higher overall prevalence of bacteremia (10.2% versus 5.1%, p = 0.002). 16.2% of all identified pathogens were multidrug-resistant (MDR). The 60-day all-cause mortality was higher in patients with MDR pathogens than in patients without bacteremia (41.7% versus 10.6%, p = 0.026). CONCLUSION: Bacteremia prevalence was similar in burn and non-burn patients, with high rates of multidrug-resistant Gram-negative pathogens. The 60-day all-cause mortality was significantly higher in patients with MDR pathogens than in patients without bacteremia.

Association of prediabetes with clinical outcomes in patients with chronic coronary syndrome: a post hoc analysis of the ISCHEMIA and ISCHEMIA-CKD trials.

BACKGROUND: There is conflicting evidence whether prediabetes is associated with adverse clinical outcomes in patients with chronic coronary syndrome. We aimed to assess the effect of prediabetes in patients with chronic coronary syndrome on clinical outcomes. METHODS: This is a secondary analysis of data from the ISCHEMIA and ISCHEMIA-CKD trials, including patients with chronic coronary syndrome determined by coronary computed tomography angiography or exercise-stress testing. Participants were assigned to the normoglycemia group (HbA1c < 5.7% [< 39 mmol/mol]), prediabetes group (HbA1c 5.7-6.4% [40-47 mmol/mol]), or diabetes group (HbA1c ≥ 6.5% [≥ 48 mmol/mol]). The primary end point of this study was all-cause mortality. Secondary endpoints included major adverse cardiovascular events and composites thereof. RESULTS: Overall, the primary endpoint all-cause mortality occurred in 330 (8.4%) of 3910 patients over a median follow-up time of 3.1 years (IQR 2.1-4.1). The primary endpoint all-cause mortality occurred in 37 (5.2%) of 716 patients in the normoglycemia group, in 63 (6.9%) of 911 in the prediabetes group, and in 230 (10.1%) of 2283 in the diabetes group. In the covariate-adjusted Cox model analysis, the estimated adjusted HR (aHR) in the prediabetes group as compared with the normoglycemia group was 1.45 (95%CI, 0.95-2.20). The aHR in the diabetes group as compared with the normoglycemia group was 1.84 (95%CI, 1.29-2.65). Prediabetes, compared with normoglycemia, was associated with an increased risk of stroke (aHR, 3.44, 95%CI, 1.15-10.25). Subgroup analyses suggested an increased risk of all-cause death associated with prediabetes in males and patients under 65 years. CONCLUSIONS: In patients with chronic coronary syndrome, diabetes but not prediabetes was associated with significantly increased risk of all-cause death within a median follow-up period of 3.1 years. Trial Registration NCT01471522, BioLINCC ID 13936.

Challenges in assessing the immunization status of adults in Germany-lessons from a population-based VACCELERATE survey on polio vaccination.

PURPOSE: Considering the re-emergence of poliomyelitis (PM) in non-endemic regions, it becomes apparent that vaccine preventable diseases can rapidly develop epi- or even pandemic potential. Evaluation of the current vaccination status is required to inform patients, health care providers and policy makers about vaccination gaps. METHODS: Between October 28 2022 and November 23 2022, 5,989 adults from the VACCELEREATE Volunteer Registry completed an electronic case report form on their previous PM vaccine doses including number, types/-valencies and the time of administration based on their vaccination records. A uni-/multivariable regression analysis was performed to assess associations in participant characteristics and immunization status. RESULTS: Among German volunteers (n = 5,449), complete PM immunization schedule was found in 1,981 (36%) participants. Uncertain immunization, due to unknown previous PM vaccination (n = 313, 6%), number of doses (n = 497, 9%), types/-valencies (n = 1,233, 23%) or incoherent immunization schedule (n = 149, 3%) was found in 40% (n = 2,192). Out of 1,276 (23%) participants who reported an incomplete immunization schedule, 62 (1%) never received any PM vaccine. A total of 5,074 (93%) volunteers reported having been vaccinated at least once and 2,087 (38%) indicated that they received vaccination within the last ten years. Female sex, younger age, as well as availability of first vaccination record were characteristics significantly associated with complete immunization (p < 0.001). CONCLUSION: Full PM immunization schedule was low and status frequently classified as uncertain due to lack of details on administered doses. There is an obviousneed for improved recording to enable long-term access to detailed vaccination history in the absence of a centralized immunization register.

St. John's wort extract with a high hyperforin content does not induce P-glycoprotein activity at the human blood-brain barrier.

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [11C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.

Effects of lung inflammation and injury on pulmonary tissue penetration of meropenem and vancomycin in a model of unilateral lung injury.

OBJECTIVE: The timing and dosing of antimicrobial therapy are key in the treatment of pneumonia in critically ill patients. It is uncertain whether the presence of lung inflammation and injury affects tissue penetration of intravenously administered antimicrobial drugs. The effects of lung inflammation and injury on tissue penetration of two antimicrobial drugs commonly used for pneumonia were determined in an established model of unilateral lung injury. METHODS: Unilateral lung injury was induced in the left lung of 13 healthy pigs through cyclic rinsing; the right healthy lung served as control. Infusions of meropenem and vancomycin were administered and concentrations of these drugs in lung tissue, blood, and epithelial lining fluid (ELF) were compared over a period of 6 h. RESULTS: Median vancomycin lung tissue concentrations and penetration ratio were higher in inflamed and injured lungs compared with uninflamed and uninjured lungs (AUC0-6h: P = 0.003 and AUCdialysate/AUCplasma ratio: P = 0.003), resulting in higher AUC0-24/MIC. Median meropenem lung tissue concentrations and penetration ratio in inflamed and injured lungs did not differ from that in uninflamed and uninjured lungs (AUC0-6: P = 0.094 and AUCdialysate/AUCplasma ratio: P = 0.173). The penetration ratio for both vancomycin and meropenem into ELF was similar in injured and uninjured lungs. CONCLUSION: Vancomycin penetration into lung tissue is enhanced by acute inflammation and injury, a phenomenon barely evident with meropenem. Therefore, inflammation in lung tissue influences the penetration into interstitial lung tissue, depending on the chosen antimicrobial drug. Measurement of ELF levels alone might not identify the impact of inflammation and injury.

Distribution of Bevacizumab into the Cerebrospinal Fluid of Children and Adolescents with Recurrent Brain Tumors.

BACKGROUND: To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF). OBJECTIVE: This study assessed the penetration of bevacizumab, as part of a metronomic antiangiogenic treatment regimen, into the CSF of children, adolescents, and young adults with recurrent brain tumors. PATIENTS AND METHODS: Serum and CSF concentrations, malignant cells, and vascular endothelial growth factor A (VEGF-A) were analyzed in 12 patients (5-27 years) following 10 mg/kg bevacizumab intravenous biweekly administration (EudraCT number 2009-013024-23). A population pharmacokinetic model including body weight, albumin, and tumor type as influential factors was extended to quantify the CSF penetration of bevacizumab. RESULTS: Apart from in serum (minimum concentration/maximum concentration [Cmin/Cmax] 77.0-305/267-612 mg/L, median 144/417 mg/L), bevacizumab could be quantified in the CSF (0.01-2.26 mg/L, median 0.35 mg/L). The CSF/serum ratio was 0.16 and highly variable between patients. Malignant cells could be detected in CSF before initiation of treatment in five of 12 patients; after treatment, the CSF was cleared in all patients. VEGF-A was detected in three patients before treatment (mean ± SD: 20 ± 11 pg/mL), and was still measurable in one of these patients despite treatment (16 pg/mL). CONCLUSIONS: This pharmacokinetic pilot study indicated penetration of bevacizumab into the CSF in a population of children, adolescents, and young adults with recurrent brain tumors.

First-in-human study of alpibectir (BVL-GSK098), a novel potent anti-TB drug.

BACKGROUND: The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. OBJECTIVES: A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). METHODS: Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts. RESULTS: No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean Tmax range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean Tmax 3.87 h), a lower Cmax (-17.7%) and increased AUC0-t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both Cmax and AUC0-tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0-tau) compared with Cmax (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. CONCLUSIONS: Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food.

Liposomal Bupivacaine for Peripheral Nerve Blockade: A Randomized, Controlled, Crossover, Triple-blinded Pharmacodynamic Study in Volunteers.

BACKGROUND: Little is known about the pharmacodynamic characteristics of liposomal bupivacaine. Hypothesizing that they would not identify pharmacodynamic differences from plain bupivacaine during the initial period after administration, but would find better long-term pharmacodynamic characteristics, the authors designed a randomized, controlled, triple-blinded, single-center study in volunteers. METHODS: Volunteers aged 18 to 55 yr (body mass index, 18 to 35 kg/m2) received two ulnar nerve blocks under ultrasound guidance. Using a crossover design with a washout phase of 36 days or more, one block was performed with liposomal and one with plain bupivacaine. Which came first was determined by randomization. Sensory data were collected by pinprick testing and motor data by thumb adduction, either way in comparison with the contralateral arm. Endpoints included success, time to onset, and duration of blockade. Residual efficacy was assessed by the volunteers keeping a diary. Statistical analysis included Wilcoxon signed-rank and exact McNemar's tests, as well as a generalized estimation equation model. RESULTS: Successful sensory blockade was noted in 8 of 25 volunteers (32%) after liposomal and in 25 of 25 (100%) after plain bupivacaine (P < 0.0001). Significant differences emerged for time to onset, defined as 0% response to pinpricking in four of five hypothenar supply areas (P < 0.0001), and for time from onset to 80% or 20% in one of five areas (P < 0.001; P < 0.001). Carryover effects due to the randomized sequencing were unlikely (estimate, -0.6286; sequence effect, 0.8772; P = 0.474). Self-assessment greater than 3.5 days did reveal, for liposomal bupivacaine only, intermittent but unpredictable episodes of residual sensory blockade. CONCLUSIONS: The results show that liposomal bupivacaine is not a suitable "sole" drug for intraoperative regional anesthesia. Findings of its limited long-term efficacy add to existing evidence that a moderate effect, at best, should be expected on postoperative pain therapy.

A national evaluation analysis and expert interview study of real-world data sources for research and healthcare decision-making.

Real-world data (RWD) can provide intel (real-world evidence, RWE) for research and development, as well as policy and regulatory decision-making along the full spectrum of health care. Despite calls from global regulators for international collaborations to integrate RWE into regulatory decision-making and to bridge knowledge gaps, some challenges remain. In this work, we performed an evaluation of Austrian RWD sources using a multilateral query approach, crosschecked against previously published RWD criteria and conducted direct interviews with representative RWD source samples. This article provides an overview of 73 out of 104 RWD sources in a national legislative setting where major attempts are made to enable secondary use of RWD (e.g. law on the organisation of research, "Forschungsorganisationsgesetz"). We were able to detect omnipresent challenges associated with data silos, variable standardisation efforts and governance issues. Our findings suggest a strong need for a national health data strategy and data governance framework, which should inform researchers, as well as policy- and decision-makers, to improve RWD-based research in the healthcare sector to ultimately support actual regulatory decision-making and provide strategic information for governmental health data policies.

Advancing 6-bromo-7-[11C]methylpurine to clinical use: improved regioselective radiosynthesis, non-clinical toxicity data and human dosimetry estimates.

BACKGROUND: 6-Bromo-7-[11C]methylpurine ([11C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [11C]BMP afforded a mixture of 7- and 9-[11C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [11C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data. RESULTS: [11C]BMP was synthesised by regioselective N7-methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [11C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [11C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [11C]methyl iodide, with a radiochemical purity > 99% and a molar activity at end of synthesis of 197 ± 130 GBq/µmol (n = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [11C]BMP will deliver an effective dose in the typical range of 11C-labelled radiotracers. CONCLUSIONS: [11C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [11C]BMP will be safe and well tolerated in humans.

Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions.

BACKGROUND: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited. MATERIALS AND METHODS: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus. RESULTS: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ±â€Š1.68 mg/L (mean ±â€ŠSD) and 106 ±â€Š32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ±â€Š0.03, 0.94 ±â€Š0.46 and 27.1 ±â€Š17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ±â€Š32.1, 1.68 ±â€Š0.72, 22.6 ±â€Š11.0 and 650 ±â€Š426 mg·h/L, respectively. CONCLUSION: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L.

Integrative model-based comparison of target site-specific antimicrobial effects: A case study with ceftaroline and lefamulin.

OBJECTIVE: Predictions of antimicrobial effects typically rely on plasma-based pharmacokinetic-pharmacodynamic (PK-PD) targets, ignoring target-site concentrations and potential differences in tissue penetration between antibiotics. In this study, we applied PK-PD modelling to compare target site-specific effects of antibiotics by integrating clinical microdialysis data, in vitro time-kill curves, and antimicrobial susceptibility distributions. As a case study, we compared the effect of lefamulin and ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) at soft-tissue concentrations. METHODS: A population PK model describing lefamulin concentrations in plasma, subcutaneous adipose and muscle tissue was developed. For ceftaroline, a similar previously reported PK model was adopted. In vitro time-kill experiments were performed with six MRSA isolates and a PD model was developed to describe bacterial growth and antimicrobial effects. The clinical PK and in vitro PD models were linked to compare antimicrobial effects of ceftaroline and lefamulin at the different target sites. RESULTS: Considering minimum inhibitory concentration (MIC) distributions and standard dosages, ceftaroline showed superior anti-MRSA effects compared to lefamulin both at plasma and soft-tissue concentrations. Looking at the individual antibiotics, lefamulin effects were highest at soft-tissue concentrations, while ceftaroline effects were highest at plasma concentrations, emphasising the importance of considering target-site PK-PD in antibiotic treatment optimisation. CONCLUSION: Given standard dosing regimens, ceftaroline appeared more effective than lefamulin against MRSA at soft-tissue concentrations. The PK-PD model-based approach applied in this study could be used to compare or explore the potential of antibiotics for specific indications or in populations with unique target-site PK.

Immunogenicity and safety of COVID-19 booster vaccination: A population-based clinical trial to identify the best vaccination strategy.

BACKGROUND: Various SARS-CoV-2 variants of concerns (VOCs) characterized by higher transmissibility and immune evasion have emerged. Despite reduced vaccine efficacy against VOCs, currently available vaccines provide protection. Population-based evidence on the humoral immune response after booster vaccination is crucial to guide future vaccination strategies and in preparation for imminent COVID-19 waves. METHODS: This multicenter, population-based cohort study included 4697 individuals ≥18 years of age who received a booster vaccination. Antibody levels against SARS-CoV-2 receptor binding domain (RBD) and neutralizing antibodies against wild-type (WT) virus and Omicron variants were assessed at baseline (day of booster vaccination) and after four weeks. Safety was evaluated daily within the first week using a participant-completed electronic diary. Antibody levels were compared across different vaccination strategies, taking into account individual host factors. RESULTS: Our main model including 3838 participants revealed that individuals who received a booster with mRNA-1273 compared to BNT162b2 vaccine had a significantly higher increase (95 %CI) in anti-RBD-antibody levels (37,707 BAU/mL [34,575-40,839] vs. 27,176 BAU/mL [26,265-28,087]), and of neutralization levels against WT (1,681 [1490-1872] vs. 1141 [1004-1278] and Omicron variant (422 [369-474] vs. 329 [284-374]). Neutralizing antibody titres highly correlated with anti-RBD antibodies, with neutralizing capacity 4.4 fold higher against WT compared to Omicron. No differences in safety were found between the two booster vaccines. CONCLUSION: Our study underlines the superiority of a booster vaccination with mRNA-1273, independent of the primary vaccination and therefore provides guidance on the vaccination strategy.

Pulmonary surfactant impacts in vitro activity of selected antifungal drugs against Candida krusei and Candida albicans.

PURPOSE: This study investigates how surfactants affect the in-vitro anti-infective efficacy of micafungin, caspofungin, anidulafungin, and amphotericin B in treating pulmonary mycoses. METHODS: MIC values for antifungal agents were determined against Candida krusei (now Pichia kudriavzevii) ATCC 6258, Candida albicans ATCC 90028, and 18 clinical isolates using the broth microdilution method in RPMI medium, following EUCAST recommendations. MIC assays included testing with and without Curosurf® surfactant at 1 mg/mL for C. krusei ATCC 6258 and all C. krusei isolates. Subsequent Time-kill studies in Sabouraud broth involved testing both C. albicans ATCC 90028 and C. krusei ATCC 6258 strains at concentrations equal their respective MIC values, with and without surfactant, using all four antifungals. CFU/mL were assessed at multiple time points up to 24 h. TKCs with different surfactant concentrations for C. krusei ATCC 6258 and mini-TKCs at various concentrations relative to the MIC of C. krusei isolates and the reference strain were conducted with micafungin, anidulafungin, and caspofungin. RESULTS: MIC results showed that 1 µg/mL surfactant reduced killing of micafungin and anidulafungin against C. krusei, while caspofungin was unaffected. Amphotericin B's MIC decreased by half. TKCs demonstrated significant effects of surfactant on micafungin and anidulafungin against C. krusei, with complete abolition of anidulafungin's activity against C. albicans. CONCLUSION: This in-vitro study highlights the concentration-dependent inhibitory effect of surfactant on antifungal activity against C. krusei and, to some extent, C. albicans, necessitating further clinical validation for invasive lung mycoses treatment.

Interspecies variability in protein binding of antibiotics basis for translational PK/PD studies-a case study using cefazolin.

For antimicrobial agents in particular, plasma protein binding (PPB) plays a pivotal role in deciphering key properties of drug candidates. Animal models are generally used in the preclinical development of new drugs to predict their effects in humans using translational pharmacokinetics/pharmacodynamics (PK/PD). Thus, we compared the protein binding (PB) of cefazolin as well as bacterial growth under various conditions in vitro. The PB extent of cefazolin was studied in human, bovine, and rat plasmas at different antibiotic concentrations in buffer and media containing 20-70% plasma or pure plasma using ultrafiltration (UF) and equilibrium dialysis (ED). Moreover, bacterial growth and time-kill assays were performed in Mueller Hinton Broth (MHB) containing various plasma percentages. The pattern for cefazolin binding to plasma proteins was found to be similar for both UF and ED. There was a significant decrease in cefazolin binding to bovine plasma compared to human plasma, whereas the pattern in rat plasma was more consistent with that in human plasma. Our growth curve analysis revealed considerable growth inhibition of Escherichia coli at 70% bovine or rat plasma compared with 70% human plasma or pure MHB. As expected, our experiments with cefazolin at low concentrations showed that E. coli grew slightly better in 20% human and rat plasma compared to MHB, most probably due to cefazolin binding to proteins in the plasma. Based on the example of cefazolin, our study highlights the interspecies differences of PB with potential impact on PK/PD. These findings should be considered before preclinical PK/PD data can be extrapolated to human patients.