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The interpretation of ‘susceptible (S)’ or ‘resistant (R)’ results of antimicrobial susceptibility testing is easily understood, but the interpretation of the ‘intermediate (I)’ category can be confusing. This review critically discusses how this categorization (clinical breakpoints) comes into being with the emphasis on the use of pharmacokinetics and pharmacodynamic data. It discusses the differences between the ‘I’ according to the CLSI and the EUCAST. This review also discusses the recent EUCAST change of the ‘I’ definition, and the impact of this change from laboratory and clinical points of view.

Background High protein binding (PB) of antibiotics has an impact on their antimicrobial activity. It has been questioned whether in vitro PB determination can capture the dynamic and concentration-dependent PB of highly bound antibiotics. Objectives This clinical study compared in vitro ultrafiltration (UF) and in vivo IV microdialysis (MD) methods to determine ceftriaxone PB. Methods Six healthy male volunteers received a single IV 2 g dose of ceftriaxone. Unbound ceftriaxone plasma concentrations were measured with MD and venous plasma sampling with subsequent UF. Pharmacokinetic parameters were determined using non-compartmental pharmacokinetic analysis. Non-linear mixed-effects modelling was used to quantify the PB. The PTA was estimated. Results The Cmax of ceftriaxone total plasma concentration (297.42 ± 21.0 mg/L) was approximately 5.5-fold higher than for free concentrations obtained with UF (52.83 ± 5.07 mg/L), and only 3.5-fold higher than for free concentrations obtained with MD (81.37 ± 26.93 mg/L). Non-linear, saturable PB binding was confirmed for both UF and MD. Significantly different dissociation constants (Kd) for the albumin/ceftriaxone complex were quantified: in UF it was 23.7 mg/L (95% CI 21.3–26.2) versus 15.9 mg/L (95% CI 13.6–18.6) in MD. Moreover, the estimated number of binding sites (95% CI) per albumin molecule was 0.916 (0.86–0.97) in UF versus 0.548 in MD (0.51–0.59). The PTA obtained with MD was at most 27% higher than with UF. Conclusions In vitro UF versus in vivo intravasal MD revealed significantly different PB, especially during the distribution phase. The method of PB determination could have an impact on the breakpoint determination and dose optimisation of antibiotics.

BackgroundAn understanding vaccine-dependent effects on protective and sustained humoral immune response is crucial to planning future vaccination strategies against coronavirus disease 2019 (COVID-19).MethodsIn this multicenter, population-based, cohort study including 4601 individuals after primary vaccination against COVID-19 ≥ 4 months earlier we compared factors associated with residual antibody levels against severe acute respiratory syndrome coronavirus-2 receptor-binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1).ResultsOur main model including 3787 individuals (2 × BNT162b2, n = 2271; 2 × mRNA-1273, n = 251; 2 × ChAdOx1, n = 1265), predicted significantly lower levels of anti-RBD antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 binding antibody units per milliliter [BAU/mL]) compared with those vaccinated with BNT162b2 (1179.5 BAU/mL) or mRNA-1273 (2098.2 BAU/mL). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (−21.5; 95% confidence interval [CI], −24.7 to −18.3) and no significant association for mRNA-1273 (−4.0; 95% CI, −20.0 to 12.1) or ChAdOx1 (1.7; 95% CI, .2 to 3.1). The predicted decrease over time since full immunization was highest in mRNA-1273 (−23.4; 95% CI, −31.4 to −15.4) compared with BNT162b2 (−5.9; 95% CI, −7 to −4.8).ConclusionsOur study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of individualized vaccine selection, especially in elderly individuals.

The effects of the human endotoxin challenge on tissue pharmacokinetics are unknown. In the present study, we aimed to assess the effect of the endotoxin challenge on interstitial fluid pharmacokinetics of tedizolid in healthy volunteers using intramuscular microdialysis. Eight healthy male subjects were treated with 200 mg of tedizolid phosphate for 6 days. On Day 6, an intravenous bolus of lipopolysaccharide (LPS) (2 ng/kg body weight) was administered. LPS infusion did not affect plasma pharmacokinetics of tedizolid. In contrast, following LPS infusion, median muscle tissue fAUC (0.83 [0.75-1.15] vs. 1.14 [1.11-1.43] mg × h/L, P = .0078) and muscle tissue fC

Background: Microdialysis sampling after drug microdosing may provide tissue pharmacokinetic data early in clinical drug development. However, low administered doses and small sample volumes pose an analytical challenge, particularly for highly protein-bound drugs. Materials & methods: Carbon-14 [14C]diclofenac was used as a model drug to assess the technical and analytical feasibility of in vivo microdialysis after microdose administration in an in vitro setup. Results: [14C]diclofenac dialysate concentrations were accurately quantified with accelerator MS. [14C]diclofenac dialysate recoveries were similar in the presence and absence of therapeutic diclofenac concentrations but were considerably decreased when albumin was added to the immersion solution, suggesting high protein binding. Conclusion: These results demonstrate the feasibility of combining microdosing and microdialysis to assess tissue pharmacokinetics.

Purpose Clinical research relies on data from patients and volunteers, yet the target sample size is often not achieved. Here, we assessed the perception of clinical research among clinical trial participants to improve the recruitment process for future studies. Methods We conducted a single-center descriptive and exploratory study of 300 current or former participants in various phase I–III clinical trials. Questionnaires were either distributed to current clinical trial participants or emailed to former subjects. Results Subjects strongly agreed or agreed that contributing to improving medical care (> 81%), contributing to scientific research (> 79%), and trusting their treating physicians (> 77%) were motives for study participation. Among healthy volunteers, financial motives positively correlated with the number of clinical trials they had participated in (p p Conclusion Altruistic motives and trust in treating physicians were predominant motives for clinical trial participation. Older patients expected to receive the best available treatment during participation. Healthy volunteers who reported financial motives had participated in more clinical trials. Consistent with great trust in medical staff and government research institutions, little concern was expressed about the misuse of personal data during the trial.

Rabbits are frequently used for the examination of the pharmacokinetics and effectiveness of antibiotic substances. However, antibiotics vary substantially in protein binding affecting the concentration of the antimicrobially effective unbound drug. We hypothesized that the binding properties of vancomycin, meropenem and ceftriaxone might vary between human and rabbit plasma. In an in-vitro study we observed dose dependent variability in protein binding of antibiotics between species. Thus, in-vitro-pre-studies are required to guarantee for translational conditions.

Several studies investigated diclofenac tissue concentrations using microdialysis (MD). However, thorough evaluations of the optimal MD set-up for diclofenac are unavailable. Thus, this in vitro MD study aimed to compare different set-ups to improve quantitative recovery of diclofenac. In forward and reverse in vitro MD experiments with diclofenac at two concentrations (1 and 100 ng/ml), the perfusion solutions physiological saline 0.9% (PS) and human albumin 1% (HSA) were compared using tissue probes (10-mm membrane) and customized intravenous (iv) probes (30-mm membrane). Using PS, the mean relative recovery of diclofenac at 1 ng/ml was 1.6% ± 0.04% and 3.12% ± 0.00% with the tissue probe and the iv probe, respectively. The respective mean relative recovery for diclofenac at 100 ng/ml was 0.02% ± 0.01% and 0.21% ± 0.11%. Using HSA, the mean relative recovery was 314% ± 25% (tissue probe) and 1064% ± 97% (iv probe) for diclofenac at 1 ng/ml and 444% ± 91% and 1415% ± 217% for diclofenac at 100 ng/ml. In reverse dialysis using PS, the mean relative loss of diclofenac was 99.2% ± 0.5% (tissue probe) and 95.8% ± 1.7% (iv probe). Using HSA, the mean relative loss was -4.4% ± 7.2% and 0.2% ± 7.5%, respectively. PS and HSA were not suitable perfusion solutions for quantification of absolute diclofenac concentrations. Despite methodological challenges, HSA may be used for comparative experiments or bioequivalence studies.

Pathogen-focused, randomized, controlled trials (PF-RCT) are important in the fight against carbapenem-resistant (CR) Gram-negative infections. Some recently approved antibiotics and older generic antibiotics with activity against CR Gram-negative bacteria were investigated in PF-RCTs in a variety of infections. We searched Pubmed, Cochrane database and international clinical trial databases for PF-RCTs for the period between 2005 and 2020 and compared the study designs, patient populations, infection types, pathogens, and Day-28 all-cause mortality (ACM). PF-RCTs are particularly challenging to quantitatively assess and compare due to the heterogeneity in infection types, pathogens, CR mechanism, inclusion/exclusion criteria, and endpoints. Data interpretation is further complicated by lack of formal statistical analysis plans and/or non-inferiority design, and limited power across most PF-RCTs. The studies with new antibiotics (i.e. plazomicin, meropenem/vaborbactam, cefiderocol) ranked lower regarding feasibility, with relatively small sample sizes (analyzed: 37–118) versus the comparative effectiveness studies of older generic drugs (analyzed: 94–406). ACM ranged between 11.8% and 40% for CR Enterobacterales, 17.7% and 57.4% for CR Acinetobacter spp., and 20.0% and 30.8% for CR Pseudomonas aeruginosa. The information gathered must be considered carefully alongside the study limitations and caution should be exercised when making direct comparisons across trials. PLAIN LANGUAGE SUMMARY New antibiotics to treat multidrug-resistant Gram-negative bacterial infections are needed because antimicrobial resistance has become a global threat. In recent years, several pathogen-focused, randomized, controlled clinical trials were conducted to test new antibiotics or combinations of older generic antibiotics in the fight against resistant bacteria. However, these trials were exceptionally challenging and most of them enrolled relatively few patients. These studies were highly heterogeneous in terms of species, antibiotics, infection site, mechanism of resistance, endpoints and patient factors. In these trials, all-cause mortality at Day 28 or Day 30 were numerically lower with the new antibiotics in infections caused by carbapenem-resistant (CR) Enterobacterales. However, in the trials which investigated CR Acinetobacter spp. infections, there was no reduction in all-cause mortality at Day 28 or Day 30 with combinations of older generic antibiotics compared with colistin monotherapy. Limited information was available for CR Pseudomonas aeruginosa. More pathogen-focused, randomized, controlled clinical trials with more feasible design and higher patient numbers are needed to demonstrate clinical benefit in drug-resistant infections.

Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron emission tomography (PET) imaging-based pharmacokinetic (PK) analysis to assess the effect of different drugs, which may cause transporter-mediated DDIs, on the tissue distribution and excretion of [ 18 F]ciprofloxacin as a radiolabeled model antimicrobial drug.

Background Patients with cancer are at high risk for severe courses of COVID-19. Based on (pre-)clinical data suggesting a potential protective effect due to the immunomodulating properties of azithromycin, we have initiated a prospective randomized trial. Methods This randomized, single-center, single-blinded, placebo-controlled phase 2 trial included adult patients with cancer undergoing systemic treatment. Patients were 1:1 randomized to oral azithromycin (1500 mg once weekly for 8 weeks) or placebo. The primary endpoint was the cumulative number of SARS-CoV-2 infections 12 weeks after treatment initiation. Results In total, 523 patients were screened, 68 patients were randomized, and 63 patients received at least one dose of the study drug. Due to low acceptance and a lack of SARS-CoV-2 infections in the study cohort, the study was prematurely closed. With no reported grade III–IV possibly treatment-related adverse events, azithromycin was generally well tolerated. Overall survival (OS) rates after 12 months were 83.5% and 70.3% in the azithromycin and placebo group, respectively (p = 0.37). Non-SARS-CoV-2 infections occurred in 4/32 (12.5%) in the azithromycin and 3/31 (9.7%) in the placebo group (p = 1). No emergence of azithromycin-resistant S. aureus strains could be observed. According to treatment group, longitudinal alterations in systemic inflammatory parameters were detected for neutrophil/lymphocyte and leukocyte/lymphocyte ratios. Conclusion Although efficacy could not be assessed due to premature closure and low incidence of SARS-CoV-2 infections, azithromycin was associated with a favorable side effect profile in patients with cancer. As other prophylactic treatments are limited, SARS-CoV-2 vaccination remains a high priority in oncological patients. ClinicalTrials.gov registration number and date (dd/mm/yyyy): NCT04369365, 30/04/2020.

Legislations incentivising orphan drug development and scientific advances have made orphan drugs pharma’s high-end favourite for the past two decades. Currently, around 50% of new marketing authorizations are for orphan drugs. For third-party healthcare payers (“payers”) the rise of orphan drugs presents new challenges, including a high degree of uncertainty around clinical benefits and harms, a moderate effect size (for many orphan drugs), and a high price tag. The association of high clinical uncertainty and moderate effect sizes is not surprising in small target populations but in combination with high prices creates the risk of allocative and technical inefficiencies for payers. We here discuss and illustrate these risks. A combination of policies is needed for mitigation of allocative inefficiency: while there may be a rationale for higher prices for orphan than non-orphan drugs, a focus of pricing and reimbursement negotiations should include considerations of product profitability and of the consequences of orphan drug costs on the distribution inequality of medication costs for individual insured persons, coupled to knowledge generation from reimbursement contracts covering high-price orphan drugs that would benefit the wider patient community. Performance-based managed entry agreements could help to de-risk the economic consequences of clinical uncertainty and to mitigate technical inefficiency.

Background and objectives: A quantitative evaluation of the PK of meropenem, a broad-spectrum ��-lactam antibiotic, in plasma and interstitial space fluid (ISF) of subcutaneous adipose tissue of obese patients is lacking as of date. The objective of this study was the characterisation of meropenem population pharmacokinetics in plasma and ISF in obese and non-obese patients for identification of adequate dosing regimens via Monte-Carlo simulations. Methods: We obtained plasma and microdialysate concentrations after administration of meropenem 1000 mg to 15 obese and 15 non-obese surgery patients from a prospective clinical trial. After characterizing plasma- and microdialysis-derived ISF pharmacokinetics via population pharmacokinetic analysis, we simulated thrice-daily (TID) meropenem short-term (0.5 h), prolonged (3.0 h), and continuous infusions. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) analysis based on time unbound concentrations exceeded minimum inhibitory concentrations (MIC) on treatment day 1 (%fT > MIC) and the sum of PTA weighted by relative frequency of MIC values for infections by pathogens commonly treated with meropenem. To avoid interstitial tissue fluid concentrations below MIC for the entire dosing interval during continuous infusions, a more conservative PK/PD index was selected (%fT > 4 �� MIC). Results: Adjusted body weight (ABW) and calculated creatinine clearance (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.5-81.5 kg/m2) explained a considerable proportion of the between-patient pharmacokinetic variability (15.1-31.0% relative reduction). The ISF:plasma ratio of %fT > MIC was relatively similar for MIC ��� 2 mg/L but decreased for MIC = 8 mg/L over ABW = 60-120 kg (0.50-0.20). Steady-state concentrations were 2.68 times (95% confidence interval [CI] = 2.11-3.37) higher in plasma than in ISF, supporting PK/PD targets related to four times the MIC during continuous infusions to avoid suspected ISF concentrations constantly below the MIC. A 3000 mg/24 h continuous infusion was sufficient at MIC = 2 mg/L for patients with CLCRCG_ABW ��� 100 mL/min and ABW < 90 kg, whereas 2000 mg TID prolonged infusions were adequate for those with CLCRCG_ABW ��� 100 mL/min and ABW > 90 kg. For MIC = 2 mg/L and %fT> MIC = 95, PTA was adequate in patients over the entire investigated range of body mass and renal function using a 6000 mg continuous infusion. A prolonged infusion of meropenem 2000 mg TID was sufficient for MIC ��� 8 mg/L and all investigated ABW and CLCRCG_ABW when employing the PK/PD target %fT > MIC = 40. Short-term infusions of 1000 mg TID were sufficient for CLCRCG_ABW ��� 130 mL/min and distributions of MIC values for Escherichia coli, Citrobacter freundii, and Klebsiella pneumoniae but not for Pseudomonas aeruginosa. Conclusions: This analysis indicated a need for higher doses (��� 2000 mg) and prolonged infusions (��� 3 h) for obese and non-obese patients at MIC ��� 2 mg/L. Higher PTA was achieved with prolonged infusions in obese patients and with continuous infusions in non-obese patients.

BACKGROUND The pan-European VACCELERATE network aims to implement the first transnational harmonized and sustainable vaccine trial Volunteer Registry, being a single entry point for potential volunteers of large-scale vaccine trials across Europe. This work exhibits a set of harmonized vaccine trial–related educational and promotional tools for the general public, designed and disseminated by the pan-European VACCELERATE network. OBJECTIVE This study primarily aimed to design and develop a standard toolkit to increase positive attitudes and access to trustworthy information for better access and increased recruitment to vaccine trials for the public. More specifically, the produced tools are focused on inclusiveness and equity, and are targeting different population groups, including underserved ones, as potential volunteers for the VACCELERATE Volunteer Registry (older individuals, migrants, children, and adolescents). The promotional and educational material is aligned with the main objectives of the Volunteer Registry to increase public literacy and awareness regarding vaccine-related clinical research or trials and trial participation, including informed consent and legal issues, side effects, and frequently asked questions regarding vaccine trial design. METHODS Tools were developed per the aims and principles of the VACCELERATE project, focusing on trial inclusiveness and equity, and are adjusted to local country-wise requirements to improve public health communication. The produced tools are selected based on the cognitive theory, inclusiveness, and equity of differently aged and underrepresented groups, and standardized material from several official trustworthy sources (eg, COVID-19 Vaccines Global Access; the European Centre for Disease Prevention and Control; the European Patients’ Academy on Therapeutic Innovation; Gavi, the Vaccine Alliance; and the World Health Organization). A team of multidisciplinary specialists (infectious diseases, vaccine research, medicine, and education) edited and reviewed the subtitles and scripts of the educational videos, extended brochures, interactive cards, and puzzles. Graphic designers selected the color palette, audio settings, and dubbing for the video story-tales and implemented QR codes. RESULTS This study presents the first set of harmonized promotional and educational materials and tools (ie, educational cards, educational and promotional videos, extended brochures, flyers, posters, and puzzles) for vaccine clinical research (eg, COVID-19 vaccines). These tools inform the public about possible benefits and disadvantages of trial participation and build confidence among participants about the safety and efficacy of COVID-19 vaccines and the health care system. This material has been translated into several languages and is intended to be freely and easily accessible to facilitate dissemination among VACCELERATE network participant countries and the European and global scientific, industrial, and public community. CONCLUSIONS The produced material could help fill knowledge gaps of health care personnel, providing the appropriate future patient education for vaccine trials, and tackling vaccine hesitancy and parents’ concerns for potential participation of children in vaccine trials.

Exhaustive pharmacokinetic (PK) studies in paediatric patients are unavailable for most antibiotics and feasibility of PK studies is limited by challenges, such as low blood volume and venipuncture-related pain. Microdialysis (MD) represents a promising method to overcome these obstacles. The aim of this proof-of-concept study was to develop and validate modified MD catheters that can be used to obtain concentration-time profiles of antibiotics in paediatric patients.Following extensive in vitro MD experiments, a prospective open-labelled study in ten healthy adult volunteers (HVs) was conducted. Subjects received a single intravenous dose of 1000 mg vancomycin, then plasma and intravascular microdialysate were sampled over 24 h. In vivo MD probe calibration was conducted using the retrodialysis technique. Plasma protein binding was measured using ultrafiltration. Confirmation of the measurements was performed using a Bland-Altman plot, relevant PK parameters were calculated, and a pharmacometric model was established.No safety issues were encountered. The concentration-time curves of microdialysate and plasma measurements showed good alignment. The Bland-Altman plot yielded a mean bias of 0.19 mg/L and 95% limits of agreement of - 9.34 to 9.71 mg/L. A two-compartment model best described plasma PK, model-based estimates for recovery of the MD probes being in high agreement with the observed values. Quantified estimates of fraction unbound were comparable between plasma and microdialysate (p = 0.56).An innovative MD catheter that can be inserted into small intravenous lines was successfully developed and applied in HV. This proof-of-concept study is encouraging and opens the way to further experiments leading towards future use of MD in paediatric patients.

Drugs for the treatment of respiratory diseases are commonly administered by oral inhalation. Yet surprisingly little is known about the pulmonary pharmacokinetics of inhaled molecules. Nuclear medicine imaging techniques (i.e. planar gamma scintigraphy, single-photon emission computed tomography [SPECT] and positron emission tomography [PET]) enable the noninvasive dynamic measurement of the lung concentrations of radiolabeled drugs or drug formulations. This review discusses the potential of nuclear medicine imaging techniques in inhalation biopharmaceutical research.(i) Planar gamma scintigraphy studies with radiolabeled inhalation formulations to assess initial pulmonary drug deposition; (ii) imaging studies with radiolabeled drugs to assess their intrapulmonary pharmacokinetics; (iii) receptor occupancy studies to quantify the pharmacodynamic effect of inhaled drugs.Imaging techniques hold potential to bridge the knowledge gap between animal models and humans with respect to the pulmonary disposition of inhaled drugs. However, beyond the mere assessment of the initial lung deposition of inhaled formulations with planar gamma scintigraphy, imaging techniques have rarely been employed in pulmonary drug development. This may be related to several technical challenges encountered with such studies. Considering the wealth of information that can be obtained with imaging studies their use in inhalation biopharmaceutics should be further investigated.

Ceftaroline, approved to treat skin infections and pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA), has been considered for the treatment of central nervous system (CNS) infections. A population pharmacokinetic (popPK) model was developed to describe ceftaroline soft tissue and cerebrospinal fluid (CSF) distributions and investigate the probability of target attainment (PTA) of the percentage of the dosing interval that the unbound drug concentration exceeded the MIC (%fT(>MIC)) to treat MRSA infections. Healthy subjects’ plasma and microdialysate concentrations from muscle and subcutaneous tissue following 600 mg every 12 h (q12h) and q8h and neurosurgical patients’ plasma and CSF concentrations following single 600-mg dosing were used. Plasma concentrations were described by a two-compartment model, and tissue concentrations were incorporated as three independent compartments linked to the central compartment by bidirectional transport (clearance in [CL(in)] and CL(out)). Apparent volumes were fixed to physiological interstitial values. Healthy status and body weight were identified as covariates for the volume of the central compartment, and creatinine clearance was identified for clearance. The CSF glucose concentration (GLUC) was inversely correlated with CL(in,CSF). Simulations showed a PTA of >90% in plasma and soft tissues for both regimens assuming an MIC of 1 mg/L and a %fT(>MIC) of 28.8%. Using the same target, patients with inflamed meninges (0.5

Impaired response to COVID-19 vaccination is of particular concern in immunosuppressed patients. To determine the best vaccination strategy for this vulnerable group we performed a single center, 1:1 randomized blinded clinical trial. Patients who failed to seroconvert upon two mRNA vaccinations (BNT162b2 or mRNA-1273) are randomized to receive either a third dose of the same mRNA or the vector vaccine ChAdOx1 nCoV-19. Primary endpoint is the difference in SARS-CoV-2 spike antibody seroconversion rate between vector and mRNA vaccinated patients four weeks after the third dose. Secondary outcomes include cellular immune responses. Seroconversion rates at week four are significantly higher in the mRNA (homologous vaccination, 15/24, 63%) as compared to the vector vaccine group (heterologous vaccination, 4/22, 18%). SARS-CoV-2-specific T-cell responses are reduced but could be increased after a third dose of either vector or mRNA vaccine. In a multivariable logistic regression analysis, patient age and vaccine type are associated with seroconversion. No serious adverse event is attributed to COVID-19 booster vaccination. Efficacy and safety data underline the importance of a booster vaccination and support the use of a homologous mRNA booster vaccination in immunosuppressed patients.Trial registration: EudraCT No.: 2021-002693-10.

Background Inadequate antibiotic exposure in cerebral infections might have detrimental effects on clinical outcome. Commonly, antibiotic concentrations within the CSF were used to estimate cerebral target levels. However, the actual pharmacological active unbound drug concentration beyond the blood–brain barrier is unknown. Objectives To compare meropenem concentrations in blood, CSF and cerebral microdialysate of neurointensive care patients. Patients and methods In 12 patients suffering subarachnoid haemorrhage, 2000 mg of meropenem was administered every 8 h due to an extracerebral infection. Meropenem concentrations were determined in blood, CSF and cerebral microdialysate at steady state (n = 11) and following single-dose administration (n = 5). Results At steady state, the free AUC0–8 was 233.2 ± 42.7 mg·h/L in plasma, 7.8 ± 1.9 mg·h/L in CSF and 26.6 ± 14.0 mg·h/L in brain tissue. The brain tissue penetration ratio (AUCbrain/AUCplasma) was 0.11 ± 0.06, which was more than 3 times higher than in CSF (0.03 ± 0.01), resulting in an AUCCSF/AUCbrain ratio of 0.41 ± 0.16 at steady state. After single-dose administration similar proportions were achieved (AUCbrain/AUCplasma = 0.09 ± 0.08; AUCCSF/AUCplasma = 0.02 ± 0.00). Brain tissue concentrations correlated well with CSF concentrations (R = 0.74, P Conclusions Meropenem achieves sufficient bactericidal concentrations for the most common bacterial strains of cerebral infections in both plasma and brain tissue, even in non-inflamed brain tissue. CSF concentrations would highly underestimate the target site activity of meropenem beyond the blood–brain barrier.

To investigate immunogenicity and safety of BNT162b2 booster vaccination with and without a tetravalent influenza vaccine.A prospective, open-label cohort study on immunogenicity and safety of COVID-19 booster vaccination with or without a tetravalent influenza vaccine was performed. 838 health care workers were included in the following study arms: BNT162b2 booster-only, influenza-vaccine-only or combination of both. Levels of antibodies against SARS-CoV-2 spike receptor binding domain (RBD), and haemagglutinine inhibition (HAI) tested for four different influenza strains (A(H1N1)pdm09, A(H3N2), B/Victoria, B/Yamagata) were measured at time of vaccination and four weeks later.After four weeks, median [IQR] anti-RBD antibody levels and relative change from baseline were higher in individuals who received BNTb162b2 booster vaccination only (absolute: 16,600 [10,980-24,360] vs. 12,630 [8,198-18,750] BAU/mL (p0·0001); relative increase: 49% [23·6-95·3] vs. 40% [21·9-80·6](p = 0·048); booster-only n=521 vs. combination-arm n=229 respectively). Results were confirmed after matching for sex, age, BMI, baseline antibody levels and vaccine compound received for primary immunization (absolute: 13,930 [10,610 - 22,760] vs. 12,520 [8,710 - 17,940]; p = 0·031); relative increase: 55·7% [27·8-98·5] vs. 42·2% [22·9-74·5]; p = 0·045). Adverse events were almost identical in the booster-only and the combination-arm, but numerically lower in the influenza arm (525/536[97·9] % vs.235/240 [97·9%] vs. 26/33 [78·8 %]).While no safety concerns occurred, our study provides evidence on reduced immunogenicity of a BNT162b2 booster vaccination in combination with a tetravalent influenza vaccine. Further studies investigating new influenza variants as well as potential differences vaccine effectiveness are needed.

Objectives The efficacy and quality of generic antibacterial drug formulations are often questioned by both healthcare specialists and patients. Therefore, the present study investigated the interchangeability of generic drugs with their originators by comparing bioequivalence parameters and stability data of generic cefepime, linezolid and piperacillin/tazobactam with their respective originator drugs. Methods In this open-label, randomized, crossover bioequivalence study, three groups of 12 healthy volunteers each received a single intravenous infusion of either 2 g of cefepime or 4.5 g of piperacillin/tazobactam and two generic formulations, or 600 mg of linezolid and one generic formulation. Plasma sampling was performed, with a 5 day washout period between study days. Stability was tested by storing reconstituted generic and originator products according to their own storage specifications and those of the comparator products. All concentrations were measured by LC-MS. Results Similar ratios of generic/originator (90% CI) Cmax were observed for Cefepime-MIP/Maxipime [93.7 (88.4–99.4)], Cefepime Sandoz/Maxipime [95.9 (89.1–103.2)], Linezolid Kabi/Zyvoxid [104.5 (91.1–119.9)], Piperacillin Kabi/Tazobac [95.9 (90.4–101.7)], Piperacillin Aurobindo/Tazobac [99.7 (84.9–104.7)], Tazobactam Kabi/Tazobac [93.4 (87.4–99.8)] and Tazobactam Aurobindo/Tazobac [97.4 (89.7–105.8)]. Accordingly, similar ratios of AUC0–t were observed for Cefepime-MIP/Maxipime [91.1 (87.6–94.8)], Cefepime Sandoz/Maxipime [97.9 (92.5–103.5)], Linezolid Kabi/Zyvoxid [99.7 (93.3–106.6)], Piperacillin Kabi/Tazobac [92.2 (88.3–96.3)], Piperacillin Aurobindo/Tazobac [99.9 (97.0–102.8)], Tazobactam Kabi/Tazobac [91.4 (86.4–96.7)] and Tazobactam Aurobindo/Tazobac [98.8 (94.3–103.6)]. Stable and similar concentrations were measured for all contiguous substances, regardless of storage conditions. Conclusions Compared with their respective originator drugs, generic cefepime, linezolid and piperacillin/tazobactam met the predetermined bioequivalence criteria. All formulations were stable under the storage conditions of their respective comparators.

Objectives To investigate ceftolozane/tazobactam pharmacokinetics (PK) in plasma and interstitial space fluid (ISF) of muscle and subcutaneous tissue and establish a population PK model. Methods Eight healthy volunteers received four IV doses of 1000/500 mg ceftolozane/tazobactam q8h in a prospective, open-labelled PK study. ISF concentration–time profiles were determined via in vivo microdialysis up to 8 h post-dose and efficacy of unbound ceftolozane and tazobactam was estimated using the time above MIC (%ƒT>MIC) and time above threshold concentration (%T>CT), respectively. A population PK model was established by merging derived plasma and soft tissue PK data. Results Ceftolozane reached %ƒT>MIC values of 100% in plasma, muscle and subcutaneous ISF for Enterobacteriaceae and 87%, 89% and 87%, respectively, for Pseudomonas aeruginosa. Tazobactam %T>CT was 21%, 22% and 21% in plasma, muscle and subcutaneous ISF, respectively. Plasma protein binding was 6.3% for ceftolozane and 8.0% for tazobactam. Multiple-dose ceftolozane AUC0–8 ISF/plasma ratios were 0.92 ± 0.17 in muscle and 0.88 ± 0.18 in subcutis, and tazobactam ratios were 0.89 ± 0.25 in muscle and 0.87 ± 0.21 in subcutis, suggesting substantial soft tissue penetration. Conclusions Tazobactam %T>CT values were distinctly below proposed target values, indicating that tazobactam might be underdosed in the investigated drug combination. However, ISF/unbound plasma ratios of ceftolozane and tazobactam support their use in soft tissue infections. A plasma and soft tissue PK model adds important information on the PK profile of ceftolozane/tazobactam. Further investigations in patients suffering from wound infections are needed to confirm these findings.

Purpose AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations. Methods This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77–196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks. Results The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was −7.2% (95% CI [−10.4 to −3.9], P Conclusions Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development. Trial registration EudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.

Introduction: Increasing resistance of gram-negative bacteria poses a serious threat to global health. Thus, efficacious and safe antibiotics against resistant pathogens are urgently needed. Cefiderocol, a siderophore cephalosporin, addresses this unmet need.Areas covered: For this article, we screened all preclinical and clinical studies on cefiderocol published by January 2021 on PubMed. Also, regulatory documents, recent conference contributions, and selected data of antibiotic competitors are reviewed. We provide a comprehensive overview of the mode of action, in vitro and in vivo activity, pharmacokinetics/pharmacodynamics, and human pharmacokinetics. Last, we discuss the efficacy and safety data from the pivotal trials.Expert opinion: Cefiderocol was in vitro potent against virtually all gram-negative pathogens and resistance was rare. The target site pharmacokinetics (i.e. urinary and lung penetration) have been well described in humans and important PK/PD targets were reached. In the clinical trials, cefiderocol was non-inferior to carbapenems in the treatment of complicated urinary tract infections and nosocomial pneumonia. Against carbapenem-resistant gram-negative pathogens, cefiderocol was similar to the best available therapy, which was mainly based on the backbone agent colistin. Overall, a substantial body of evidence supports the clinical use of cefiderocol in patients with gram-negative infections and limited treatment options.

Background: Meropenem is a second-line agent for the treatment of peritoneal dialysis-associated peritonitis (PD peritonitis), while information on pharmacokinetics (PK) of intraperitoneal (i.p.) meropenem is limited in this patient group. The objective of the present evaluation was to assess a pharmacokinetic rationale for the selection of meropenem doses in automated PD (APD) patients based on population PK modelling. Methods: Data were available from a PK study in six patients undergoing APD who received a single 500 mg dose of meropenem intravenous or i.p. A population PK model was developed for plasma and dialysate concentrations ( n = 360) using Monolix. Monte Carlo simulations were carried out to assess the probability of achieving meropenem concentrations above minimum inhibitory concentrations (MICs) of 2 and 8 mg/L, representing susceptible and less susceptible pathogens respectively, for at least 40% of the dosing interval ( T >MIC ≥ 40%). Results: A two-compartment model for each plasma and dialysate concentrations with one transit compartment for the transfer from plasma to dialysate fluid described the data well. An i.p. dose of 250 and 750 mg, for an MIC of 2 and 8 mg/L respectively, was sufficient to attain the pharmacokinetic/pharmacodynamic target ( T >MIC ≥ 40%) in more than 90% patients in plasma and dialysate. Additionally, the model predicted that no relevant meropenem accumulation in plasma and/or peritoneal fluid would occur with prolonged treatment. Conclusion: Our results suggest that an i.p. dose of 750 mg daily is optimal for pathogens with an MIC 2–8 mg/L in APD patients.

Background: Antibiotic eye drops are frequently used in clinical practice. Due to the anatomical connection via the nasolacrimal duct, it seems possible that they have an influence on the nasal/pharyngeal microbiome. This was investigated by using two different commonly used antibiotic eye drops. Methods: 20 subjects were randomized to four groups of five subjects receiving eye drops containing gentamicin, ciprofloxacin, or, as controls, unpreserved povidone or benzalkonium chloride-preserved povidone. Nasal and pharyngeal swabs were performed before and after the instillation period. Swabs were analyzed by Illumina next-generation sequencing (NGS)-based 16S rRNA analysis. Bacterial culture was performed on solid media, and bacterial isolates were identified to the species level by MALDI-TOF MS. Species-dependent antimicrobial susceptibility testing was performed using single isolates and pools of isolates. Results: Bacterial richness in the nose increased numerically from 163 ± 30 to 243 ± 100 OTUs (gentamicin) and from 114 ± 17 to 144 ± 45 OTUs (ciprofloxacin). Phylogenetic diversity index (pd) of different bacterial strains in the nasal microbiome increased from 12.4 ± 1.0 to 16.9 ± 5.6 pd (gentamicin) and from 10.2 ± 1.4 to 11.8 ± 3.1 pd (ciprofloxacin). Unpreserved povidone eye drops resulted in minimal changes in bacterial counts. Preservative-containing povidone eye drops resulted in no change. A minor increase (1–2-fold) in the minimal inhibitory concentration (MIC) was observed in single streptococcal isolates. Conclusions: Antibiotic eye drops could affect the nasal microbiome. After an instillation period of seven days, an increase in the diversity and richness of bacterial strains in the nasal microbiome was observed.

COVID-19-associated pulmonary aspergillosis (CAPA) is a life-threatening fungal infection that mainly affects critically ill patients. The aim of this study was to assess the incidence and clinical outcomes of putative CAPA in critically ill COVID-19 patients. This retrospective observational cohort study included 181 cases from 5 ICUs at Vienna General Hospital between January 2020 and April 2022. Patients were diagnosed with putative CAPA according to the AspICU classification, which included a positive Aspergillus culture in a bronchoalveolar lavage sample, compatible signs and symptoms, and abnormal medical imaging. The primary outcome was adjusted 60-day all-cause mortality from ICU admission in patients with vs. without putative CAPA. Secondary outcomes included time from ICU admission to CAPA diagnosis and pathogen prevalence and distribution. Putative CAPA was identified in 35 (19.3%) of 181 COVID-19 patients. The mean time to diagnosis was 9 days. Death at 60 days occurred in 18 of 35 (51.4%) patients with CAPA and in 43 of 146 (29.5%) patients without CAPA (adjusted HR (95%CI) = 2.15 (1.20–3.86, p = 0.002). The most frequently isolated Aspergillus species was Aspergillus fumigatus. The prevalence of putative pulmonary aspergillosis in critically ill COVID-19 patients was high and was associated with significantly higher mortality.

Spider silk has fascinated mankind for millennia, but it is only in recent decades that scientific research has begun to unravel all its characteristics and applications. The uniqueness of spider silk resides in its versatility, in which a combination of high strength and extensibility results in extraordinary toughness, superior to almost all natural and man-made fibers. Dragline silk consists of proteins with highly repetitive amino acid sequences, which have been correlated with specific secondary structures responsible for its physical properties. The native fiber also shows high cytocompatibility coupled with low immunogenicity, making it a promising natural biomaterial for numerous biomedical applications. Recently, novel technologies have enabled new insights into the material and biomedical properties of silk. Due to the increasing interest in spider silk, as well as the desire to produce synthetic alternatives, we present an update on the current knowledge of silk fibers produced by the spider genus Trichonephila.

Understanding vaccine-dependent effects on protective and sustained humoral immune response are crucial to plan further vaccination strategies against COVID-19. Population-based data comparing different vaccination strategies are lacking.This multicenter, population-based cohort study included 4,601 individuals ≥18 years of age after primary vaccination against COVID-19 at least four months ago (full immunization). We compared factors associated with residual antibody levels against SARS-CoV-2 receptor binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 [ChAdOx1]).Our main model including 3,787 individuals (2xBNT162b2 n = 2,271, 2xmRNA-1273 n = 251, 2xChAdOx1 n = 1,265) predicted significantly lower levels of anti-RBD-antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 BAU/ml) compared to those vaccinated with BNT162b2 (1179.5 BAU/ml) or mRNA-1273 (2098.2 BAU/ml). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (-21.5 [95%CI -24.7 to -18.3]) and no significant association for mRNA-1273 (-4.0 [95%CI -20.0 to 12.1]) or ChAdOx1 (1.7 [95%CI 0.2 to 3.1]). The predicted decrease over time since full immunization was highest in mRNA-1273 (-23.4 [95%CI -31.4 to -15.4]) compared to BNT162b2 -5.9 [95%CI -7 to -4.8]). Higher antibody levels were observed for individuals with systemic adverse events upon vaccination and current smoking (BNT162b2), for days between first and second vaccination (BNT162b2 and ChAdOx1) and for absence of comorbidities (all).Our study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of an individualized vaccine selection, especially in elderly individuals.

BACKGROUND: In patients with atopic dermatitis (AD), Staphylococcus aureus frequently colonizes lesions and is hypothesized to be linked to disease severity and progression. Treatments that reduce S. aureus colonization without significantly affecting the skin commensal microbiota are needed.METHODS AND FINDINGS: In this study, we tested ATx201 (niclosamide), a small molecule, on its efficacy to reduce S. aureus and propensity to evolve resistance in vitro. Various cutaneous formulations were then tested in a superficial skin infection model. Finally, a Phase 2 randomized, double-blind and placebo-controlled trial was performed to investigate the impact of ATx201 OINTMENT 2% on S. aureus colonization and skin microbiome composition in patients with mild-to-severe AD (EudraCT:2016-003501-33). ATx201 has a narrow minimal inhibitory concentration distribution (.125-.5 μg/ml) consistent with its mode of action - targeting the proton motive force effectively stopping cell growth. In murine models, ATx201 can effectively treat superficial skin infections of methicillin-resistant S. aureus. In a Phase 2 trial in patients with mild-to-severe AD (N = 36), twice-daily treatment with ATx201 OINTMENT 2% effectively reduces S. aureus colonization in quantitative colony forming unit (CFU) analysis (primary endpoint: 94.4% active vs. 38.9% vehicle success rate, p = .0016) and increases the Shannon diversity of the skin microbiome at day 7 significantly compared to vehicle.CONCLUSION: These results suggest that ATx201 could become a new treatment modality as a decolonizing agent.

Development of new antibacterial agents is necessary as drug-resistant bacteria are a threat to global health. In Europe, the European Medicines Agency has been guiding this development process for more than two decades. We investigated preclinical and clinical pre-approval studies to illuminate the current authorization process with emphasis on pharmacokinetic/pharmacodynamic approaches and clinical phases. All centrally authorized systemic antibacterial and antimycobacterial drugs within the European Union were included without any time restriction. Additionally, US Food and Drug Administration-approved antibiotics of the previous 3 years, which were not yet approved by the European Medicines Agency, were included. We focused on preclinical pharmacokinetic/pharmacodynamic studies and phase II and phase III clinical trials. Furthermore, we looked at the recommended dosing regimens and approved indications. In this review, we designed tree diagrams as a new means of illustrating the development process of antibiotics to relate pharmacokinetic/pharmacodynamic phase II and III studies to approved indications. We included 23 (European Medicines Agency, 18; US Food and Drug Administration, 5) antimicrobial agents. Tetracyclines, carbapenems, and cephalosporins were the leading classes. The recommended dosing intervals were significantly shorter in time- vs exposure-dependent drugs (median 8 vs 12, p = 0.006). The majority of approved indications (i.e., acute bacterial skin and soft-tissue infection, community-acquired pneumonia, complicated intra-abdominal infection, complicated urinary tract infection, and complicated skin and soft-tissue infection) used non-inferiority trials. Phase II and III clinical trials investigating community-acquired pneumonia involved the fewest patients. Some promising drugs were marketed in recent years; the individual steps to their authorizations are illuminated. We confirmed the relevance of preclinical pharmacokinetic/pharmacodynamic studies in dosing optimization and decision making in antimicrobial drug development. Non-inferiority clinical trials predominated.

Background The broad antibacterial spectrum of piperacillin/tazobactam makes the combination suitable for the treatment of nosocomial bacterial central nervous system (CNS) infections. As limited data are available regarding piperacillin CNS exposure in patients without or with low-grade inflammation, a clinical study was conducted (1) to quantify CNS exposure of piperacillin by cerebral microdialysis and (2) to evaluate different dosing regimens in order to improve probability of target attainment (PTA) in brain. Methods Ten acute hemorrhagic stroke patients (subarachnoid hemorrhage, n = 6; intracerebral hemorrhage, n = 4) undergoing multimodality neuromonitoring received 4 g piperacillin/0.5 g tazobactam every 8 h by 30-min infusions for the management of healthcare-associated pneumonia. Cerebral microdialysis was performed as part of the clinical neuromonitoring routine, and brain interstitial fluid samples were retrospectively analyzed for piperacillin concentrations after the first and after multiple doses for at least 5 days and quantified by high-performance liquid chromatography. Population pharmacokinetic modeling and Monte Carlo simulations with various doses and types of infusions were performed to predict exposure. A T>MIC of 50% was selected as pharmacokinetic/pharmacodynamic target parameter. Results Median peak concentrations of unbound piperacillin in brain interstitial space fluid were 1.16 (range 0.08–3.59) and 2.78 (range 0.47–7.53) mg/L after the first dose and multiple doses, respectively. A one-compartment model with a transit compartment and a lag time (for the first dose) between systemic and brain exposure was appropriate to describe the brain concentrations. Bootstrap median estimates of the parameters were: transfer rate from plasma to brain (0.32 h−1), transfer rate from brain to plasma (7.31 h−1), and lag time [2.70 h (coefficient of variation 19.7%)]. The simulations suggested that PTA would exceed 90% for minimum inhibitory concentrations (MICs) up to 0.5 mg/L and 1 mg/L at a dose of 12–16 and 24 g/day, respectively, regardless of type of infusion. For higher MICs, PTA dropped significantly. Conclusion Limited CNS exposure of piperacillin might be an obstacle in treating patients without general meningeal inflammation except for infections with highly susceptible pathogens. Brain exposure of piperacillin did not improve significantly with a prolongation of infusions. Electronic supplementary material The online version of this article (10.1007/s12028-020-00947-x) contains supplementary material, which is available to authorized users.

Purpose Voriconazole is a therapeutically challenging antifungal drug associated with high interindividual pharmacokinetic variability. As a prerequisite to performing clinical trials using the minimally-invasive sampling technique microdialysis, a comprehensive in vitro microdialysis characterization of voriconazole (VRC) and its potentially toxic N-oxide metabolite (NO) was performed. Methods The feasibility of simultaneous microdialysis of VRC and NO was explored in vitro by investigating the relative recovery (RR) of both compounds in the absence and presence of the other. The dependency of RR on compound combination, concentration, microdialysis catheter and study day was evaluated and quantified by linear mixed-effects modeling. Results Median RR of VRC and NO during individual microdialysis were high (87.6% and 91.1%). During simultaneous microdialysis of VRC and NO, median RR did not change (87.9% and 91.1%). The linear mixed-effects model confirmed the absence of significant differences between RR of VRC and NO during individual and simultaneous microdialysis as well as between the two compounds (p > 0.05). No concentration dependency of RR was found (p = 0.284). The study day was the main source of variability (46.3%) while the microdialysis catheter only had a minor effect (4.33%). VRC retrodialysis proved feasible as catheter calibration for both compounds. Conclusion These in vitro microdialysis results encourage the application of microdialysis in clinical trials to assess target-site concentrations of VRC and NO. This can support the generation of a coherent understanding of VRC pharmacokinetics and its sources of variability. Ultimately, a better understanding of human VRC pharmacokinetics might contribute to the development of personalized dosing strategies.

Convalescent plasma is a suggested treatment for Coronavirus disease 2019 (Covid-19), but its efficacy is uncertain. We aimed to evaluate whether the use of convalescent plasma is associated with improved clinical outcomes in patients with Covid-19.In this systematic review and meta-analysis, we searched randomized controlled trials investigating the use of convalescent plasma in patients with Covid-19 in Medline, Embase, Web of Science, Cochrane Library, and medRxiv from inception to October 17th, 2021. Two reviewers independently extracted the data. The primary efficacy outcome was all-cause mortality. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. This study was registered with PROSPERO, CRD42021284861. Of the 8874 studies identified in the initial search, sixteen trials comprising 16 317 patients with Covid-19 were included. In the overall population, the all-cause mortality was 23.8% (2025 of 8524) with convalescent plasma and 24.4% (1903 of 7769) with standard of care (risk ratio (RR) 0.97, 95% CI 0.90-1.04) (high-certainty evidence). All-cause mortality did not differ in the subgroups of noncritically ill (21.7% [1288 of 5929] vs. 22.4% [1320 of 5882]) and critically ill (36.9% [518 of 1404] vs. 36.4% [455 of 1247]) patients with Covid-19. The use of convalescent plasma in patients who tested negative for anti-SARS-CoV-2 antibodies at baseline was not associated with significantly improved survival (RR 0.94, 95% CI 0.87-1.02). In the overall study population, initiation of mechanical ventilation (RR 0.97, 95% CI 0.88-1.07), time to clinical improvement (HR 1.09, 95% CI 0.91-1.30), and time to discharge (HR 0.95, 95% CI 0.89-1.02) were similar between the two groups. In patients with Covid-19, treatment with convalescent plasma, as compared with control, was not associated with lower all-cause mortality or improved disease progression, irrespective of disease severity and baseline antibody status.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42021284861).

Concerns have been expressed about the interchangeability of innovator and generic antifungals in their activity and chemical stability.The activity of two different antimycotics was tested, each with one originator and two generics. For voriconazole, the originator VFENDMIC results showed no significant difference in activity of generic and innovator antimycotic in all settings, which was also confirmed by TKC. Stability testing revealed no differences between originator and generic drugs.The present study demonstrates the interchangeability of generic and originator antimycotic in-vitro, potentially leading to broader public acceptance for generic antimycotics.

Background and objective: Tigecycline, a broad-spectrum glycylcycline antibiotic, is approved for use at a fixed dose irrespective of body weight. However, its pharmacokinetics may be altered in obesity, which would impact on the antibiotic's effectiveness. The objective of this study was to investigate the plasma and subcutaneous tissue concentrations of tigecycline in obese patients compared with those in a non-obese control group. Methods: Fifteen obese patients (one class II and 14 class III) undergoing bariatric surgery and 15 non-obese patients undergoing intra-abdominal surgery (mainly tumour resection) received a single dose of 50 or 100 mg tigecycline as an intravenous short infusion. Tigecycline concentrations were measured up to 8 h after dosing in plasma (total concentration), in ultrafiltrate of plasma (free concentration), and in microdialysate from subcutaneous tissue, respectively. Results: In obese patients, total peak plasma concentration (1.31 ± 0.50 vs 2.27 ± 1.40 mg/L) and the area under the concentration-time curve from 0 to 8 h (AUC8h,plasma: 2.15 ± 0.42 vs 2.74 ± 0.73 h⋅mg/L), as normalized to a 100 mg dose, were significantly lower compared with those of non-obese patients. No significant differences were observed regarding the free plasma concentration, as determined by ultrafiltration, or the corresponding AUC8h (fAUC8h,plasma). Concentrations in interstitial fluid (ISF) of subcutaneous tissue were lower than the free plasma concentrations in both groups, and they were lower in obese compared to non-obese patients: the AUC8h in ISF (AUC8h,ISF) was 0.51 ± 0.22 h⋅mg/L in obese and 0.79 ± 0.23 h⋅mg/L in non-obese patients, resulting in a relative tissue drug exposure (AUC8h,ISF/fAUC8h,plasma) of 0.38 ± 0.19 and 0.63 ± 0.24, respectively. Conclusion: Following a single dose of tigecycline, concentrations in the ISF of subcutaneous adipose tissue are decreased in heavily obese subjects, calling for an increased loading dose. Eu clinical trials registration number: EudraCT No. 2012-004383-22.

Pharmacokinetics (PK) is the discipline investigating the absorption, distribution, metabolization and elimination of a drug in the body [...]