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Central nervous system (CNS) infections cause substantial morbidity and mortality worldwide, with mounting concern about new and emerging neurologic infections. Stratifying etiologies based on initial clinical and laboratory data would facilitate etiology-based treatment rather than relying on empirical treatment. Here, we report the epidemiology and clinical outcomes of patients with CNS infections from a prospective surveillance study that took place between 2013 and 2016 in Singapore. Using multiple correspondence analysis and random forest, we analyzed the link between clinical presentation, laboratory results, outcome and etiology. Of 199 patients, etiology was identified as infectious in 110 (55.3%, 95%-CI 48.3–62.0), immune-mediated in 10 (5.0%, 95%-CI 2.8–9.0), and unknown in 79 patients (39.7%, 95%-CI 33.2–46.6). The initial presenting clinical features were associated with the prognosis at 2 weeks, while laboratory-related parameters were related to the etiology of CNS disease. The parameters measured were helpful to stratify etiologies in broad categories, but were not able to discriminate completely between all the etiologies. Our results suggest that while prognosis of CNS is clearly related to the initial clinical presentation, pinpointing etiology remains challenging. Bio-computational methods which identify patterns in complex datasets may help to supplement CNS infection diagnostic and prognostic decisions. [ABSTRACT FROM AUTHOR]

Background: Studies have suggested the reduced effectiveness of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections with high vancomycin minimum inhibitory concentrations. Alternative agents such as daptomycin may be considered. We conducted a randomized controlled study comparing daptomycin against vancomycin in the treatment of MRSA bloodstream infections with high vancomycin minimum inhibitory concentrations.Methods: Patients were randomized to receive vancomycin or daptomycin for a minimum of 14 days. The primary end point was the rate of all-cause mortality at day 60.Results: A total of 14 patients were randomized in this study, with 7 patients in each treatment arm. The study was terminated early due to slow patient accrual. At day 60, there was one death in the vancomycin arm and none in the daptomycin arm. The median time to microbiological clearance was 4 days in both arms (IQR 3-5 days in the vancomycin arm and 3-7 days in daptomycin arm). Only one patient in the vancomycin arm had recurrence of bacteremia. Rates of adverse events were similar in both arms. There was one case of musculoskeletal toxicity and one case of drug-related nephrotoxicity - both events occurred in the daptomycin arm. None of the patients in either treatment arm required cessation of study treatment or addition of a second anti-MRSA agent because of worsening infection.Conclusion: Based on the limited number of patients evaluated in this study, it remains unclear if alternative, more expensive agents such as daptomycin are superior to vancomycin in the treatment of high vancomycin minimum inhibitory concentration MRSA bloodstream infections. More studies are urgently needed but investigators may wish to consider employing novel, alternative trial methodologies to ensure a greater chance of success.Trial Registration: ClinicalTrials.gov, NCT01975662 . Registered on 5 November 2013. [ABSTRACT FROM AUTHOR]

Background: Insufficient vaccine doses and the lack of therapeutic agents for yellow fever put global health at risk, should this virus emerge from sub-Saharan Africa and South America.Methods: In phase 1a of this clinical trial, we assessed the safety, side-effect profile, and pharmacokinetics of TY014, a fully human IgG1 anti-yellow fever virus monoclonal antibody. In a double-blind, phase 1b clinical trial, we assessed the efficacy of TY014, as compared with placebo, in abrogating viremia related to the administration of live yellow fever vaccine (YF17D-204; Stamaril). The primary safety outcomes were adverse events reported 1 hour after the infusion and throughout the trial. The primary efficacy outcome was the dose of TY014 at which 100% of the participants tested negative for viremia within 48 hours after infusion.Results: A total of 27 healthy participants were enrolled in phase 1a, and 10 participants in phase 1b. During phase 1a, TY014 dose escalation to a maximum of 20 mg per kilogram of body weight occurred in 22 participants. During phases 1a and 1b, adverse events within 1 hour after infusion occurred in 1 of 27 participants who received TY014 and in none of the 10 participants who received placebo. At least one adverse event occurred during the trial in 22 participants who received TY014 and in 8 who received placebo. The mean half-life of TY014 was approximately 12.8 days. At 48 hours after the infusion, none of the 5 participants who received the starting dose of TY014 of 2 mg per kilogram had detectable YF17D-204 viremia; these participants remained aviremic throughout the trial. Viremia was observed at 48 hours after the infusion in 2 of 5 participants who received placebo and at 72 hours in 2 more placebo recipients. Symptoms associated with yellow fever vaccine were less frequent in the TY014 group than in the placebo group.Conclusions: This phase 1 trial of TY014 did not identify worrisome safety signals and suggested potential clinical benefit, which requires further assessment in a phase 2 trial. (Funded by Tysana; ClinicalTrials.gov number, NCT03776786.). [ABSTRACT FROM AUTHOR]

Antibiotic-associated diarrhea (AAD) affects a significant proportion of patients receiving antibiotics. We sought to understand if differences in the gut microbiome would influence the development of AAD. We administered a 3-day course of amoxicillin-clavulanate to 30 healthy adult volunteers, and analyzed their stool microbiome, using 16S rRNA gene sequencing, at baseline and up to 4 weeks post antibiotic administration. Lower levels of gut Ruminococcaceae were significantly and consistently observed from baseline until day 7 in participants who developed AAD. Overall, participants who developed AAD experienced a greater decrease in microbial diversity. The probability of AAD could be predicted based on qPCR-derived levels of Faecalibacterium prausnitzii at baseline. Our findings suggest that a lack of gut Ruminococcaceae influences development of AAD. Quantification of F. prausnitzii in stool prior to antibiotic administration may help identify patients at risk of AAD, and aid clinicians in devising individualized treatment regimens to minimize such adverse effects., Competing Interests: Eric J Alm is co-founder of Finch Therapeutics, a microbiome-based therapeutics company. All other authors have no conflicts of interests to declare., (© 2021 The Author(s).)

Background: Human Rabies infection continues to be potentially fatal despite the availability of post-exposure prophylaxis with rabies vaccine. The PIKA Rabies vaccine adjuvant is a TLR3 agonist and has been shown to be safe and immunogenic in clinical phase I studies., Methods: We conducted a phase II, open label, randomized study in healthy adults to assess the safety and immunogenicity of the PIKA rabies vaccine under an accelerated regimen. 126 subjects were randomized into two groups: control vaccine classic regimen ("control-classic") and PIKA vaccine accelerated regimen ("PIKA-accelerated"). Subjects were followed up for safety and rabies virus neutralizing antibodies (RVNA)., Results: Both the control and PIKA vaccines were generally well tolerated. 57.6% of subjects in the PIKA vaccine group, compared with 43.8% of subjects in the control-classic group, achieved the target RVNA titer of ≥0.5 IU/mL by Day 7. All subjects achieved the target RVNA titer by Day 14. The RVNA geometric mean titer at Day 7 was 0.60 IU/ml in the PIKA vaccine group and 0.39 IU/ml in the control-classic group. At Day 14, the RVNA geometric mean titer was 18.25 IU/ml in the PIKA-accelerated group and 19.24 IU/ml in the control-classic group. The median time taken to reach the target RVNA titer level of ≥0.5 IU/mL was 7.0 days (95% CI: 7.0-42.0 days) in the PIKA-accelerated group and 14.0 days (95% CI: 7.0-42.0 days) in the control-classic group., Conclusion: The accelerated regimen using the investigational PIKA Rabies vaccine was well-tolerated and demonstrated non-inferior immunogenicity compared to the classic regimen using the commercially available vaccine in healthy adults. Clinical trial registry: The study was registered with clinicaltrials.gov (NCT02956421)., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Rabies is a fatal disease where post-exposure prophylaxis (PEP) is crucial in preventing infection. However, deaths even after appropriate PEP, have been reported. The PIKA Rabies vaccine adjuvant is a TLR3 agonist that activates B and T cells leading to a robust immune response., Methods: We conducted a phase I, open label, randomized study in healthy adults to assess the safety and immunogenicity of the PIKA Rabies vaccine and an accelerated vaccine regimen. Thirty-seven subjects were randomized into 3 groups: control vaccine classic regimen, PIKA vaccine classic regimen and PIKA vaccine accelerated regimen. Subjects were followed up for safety, rabies virus neutralizing antibodies (RVNA) and T cell responses., Results: Both the control and PIKA Rabies vaccine were well tolerated. All adverse events (AEs) were mild and self-limiting. Seventy-five percent of subjects in the PIKA accelerated regimen achieved a RVNA titer ⩾0.5IU/mL on day 7, compared to 53.9% in the PIKA classic regimen (p=0.411) and 16.7% in control vaccine classic regimen (p=0.012). The PIKA rabies vaccine elicited multi-specific rabies CD4 mediated T cell response already detectable ex vivo at day 7 after vaccination and that was maintained at day 42., Conclusion: The investigational PIKA rabies vaccine was well tolerated and more immunogenic than the commercially available vaccine in healthy adults. Clinical trial registry: The study was registered with clinicaltrials.gov NCT02657161., (Copyright © 2017 Elsevier Ltd. All rights reserved.)