Novel antifungal agents in clinical trials

Invasive fungal diseases due to resistant yeasts and molds are an important and increasing public health threat, likely due to a growing population of immunosuppressed hosts, increases in antifungal resistance, and improvements in laboratory diagnostics. The significant morbidity and mortality associated with these pathogens bespeaks the urgent need for novel safe and effective therapeutics. This review highlights promising investigational antifungal agents in clinical phases of development: fosmanogepix, ibrexafungerp, rezafungin, encochleated amphotericin B, oteseconazole (VT-1161), VT-1598, PC945, and olorofim. We discuss three first-in-class members of three novel antifungal classes, as well as new agents within existing antifungal classes with improved safety and tolerability profiles due to enhanced pharmacokinetic and pharmacodynamic properties.

Immunogenic Properties of MVs Containing Structural Hantaviral Proteins: An Original Study

Hemorrhagic fever with renal syndrome (HFRS) is an emerging infectious disease that remains a global public health threat. The highest incidence rate is among zoonotic disease cases in Russia. Most cases of HFRS are reported in the Volga region of Russia, which commonly identifies the Puumala virus (PUUV) as a pathogen. HFRS management is especially challenging due to the lack of specific treatments and vaccines. This study aims to develop new approaches for HFRS prevention. Our goal is to test the efficacy of microvesicles (MVs) as PUUV nucleocapsid (N) and glycoproteins (Gn/Gc) delivery vehicles. Our findings show that MVs could deliver the PUUV N and Gn/Gc proteins in vitro. We have also demonstrated that MVs loaded with PUUV proteins could elicit a specific humoral and cellular immune response in vivo. These data suggest that an MV-based vaccine could control HFRS.

Evolution of Enterococcus faecium to A Combination of Daptomycin and Fosfomycin Reveals Distinct and Diverse Adaptive Strategies

Infections caused by vancomycin-resistant Enterococcus faecium (VREfm) are an important public health threat. VREfm have become increasingly resistant to the front-line antibiotic, daptomycin (DAP). As such, the use of DAP combination therapies (like fosfomycin [FOS]), has received increased attention. Antibiotic combinations could extend the efficacy of current available antibiotics and potentially delay the onset of further resistance. We investigated the potential for E. faecium HOU503, a clinical VREfm isolate that is DAP and FOS susceptible, to develop resistance to a DAP-FOS combination. Of particular interest was whether the genetic drivers for DAP-FOS resistance might be epistatic and, thus, potentially decrease the efficacy of a combinatorial approach in either inhibiting VREfm or in delaying the onset of resistance. We show that resistance to DAP-FOS could be achieved by independent mutations to proteins responsible for cell wall synthesis for FOS and in altering membrane dynamics for DAP. However, we did not observe genetic drivers that exhibited substantial cross-drug epistasis that could undermine DAP-FOS combination. Of interest was that FOS resistance in HOU503 was largely mediated by changes in phosphoenolpyruvate (PEP) flux as a result of mutations in pyruvate kinase (pyk). Increasing PEP flux could be a readily accessible mechanism for FOS resistance in many pathogens. Importantly, we show that HOU503 were able to develop DAP resistance through a variety of biochemical mechanisms and were able to employ different adaptive strategies. Finally, we showed that the addition of FOS can prolong the efficacy of DAP, significantly extending the timeline to resistance in vitro.

Interferon-γ-Inducible Protein 10 (IP-10) Kinetics after Antiretroviral Treatment Initiation in Ethiopian Adults with HIV

To reach the goal of elimination of HIV as public health threat, access to antiretroviral treatment (ART) has to be further scaled up. To ensure viral suppression in individuals receiving ART, novel and robust systems for treatment monitoring are required.

A Peer Educational Tool to Promote Antimicrobial Stewardship on a University Campus

Antibiotic resistance is a major public health threat. Patient education on the appropriate use of antibiotics is a key component in combating antimicrobial resistance. The purpose of this study was to analyze the utility of an origami fortune teller as a novel peer educational tool in promoting antimicrobial stewardship on a university campus. An origami fortune teller, with various case scenarios to demonstrate key antibiotic principles, was developed and used by peer educators to educate students attending a university wellness fair. The case studies included: antibiotic indications; differentiation between viral vs. bacterial infection; proper use of antibiotics; non-pharmacologic measures to combat infection; and antibiotic resistance. Students were asked to take an assessment pre and post working with the tool. One hundred and forty-three students received education using the novel tool. A significant improvement in the assessment score was observed after education was completed using the novel tool (69.5 vs. 96.6 p ≤ 0.05).

Genomic analysis of early SARS-CoV-2 breakthrough infections from the state of Kerala suggest a preponderance of variants of concern

The SARS-CoV-2 Variant of Concern, Delta (B.1.617.2) was first reported in December 2020 in India and has spread colossally throughout the globe. Owing to factors like increased transmissibility, immune escape, and virulence, the delta variant has been considered as a potential public health threat apart from other variants of concern like alpha, beta and gamma. Kerala was one of the first states in India to enroll in the systematic genomic surveillance. In the present report, vaccine breakthrough infections were followed up in 147 patients including 55 healthcare workers who had been vaccinated with ChAdOx1 nCoV- 19/BBV152 across eleven districts from the state of Kerala. The timeline of samples analysed were from April 2021 till June 2021. Severity of the infections reported in the enrolled patients found to be mildly symptomatic, majorly with only 0.7% (n=1) of the cohort to be asymptomatic. Genomic analysis of the samples revealed the Delta variant (B.1.617.2) to constitute about 81.6% (n=120) in the studied cohort. This was followed by the Kappa variant B.1.617.1 (8.35%, n=9), AY.1 (0.6%, n= 1), AY.12 (0.6%, n= 1), AY.4 (1.2%, n= 2), AY.9 (1.2%, n= 2) and Eta variant, B.1.525 (0.6%, n= 1). 11 samples were not assigned any lineage. Evidence from this study suggests the preponderance of the Delta variant in the samples analysed.

Main protease mutants of SARS-CoV-2 variants remain susceptible to PF-07321332

The COVID-19 pandemic continues to be a public health threat. Multiple mutations in the spike protein of emerging variants of SARS-CoV-2 appear to impact on the effectiveness of available vaccines. Specific antiviral agents are keenly anticipated but their efficacy may also be compromised in emerging variants. One of the most attractive coronaviral drug targets is the main protease (Mpro). A promising Mpro inhibitor of clinical relevance is the peptidomimetic PF-07321332. We expressed Mpro of five SARS-CoV-2 lineages (C.37 Lambda, B.1.1.318, B.1.2, B.1.351 Beta, P.2 Zeta), each of which carries a strongly prevalent missense mutation (G15S, T21I, L89F, K90R, L205V). Enzyme kinetics showed that these Mpro variants are similarly catalytically competent as the wildtype. We show that PF-07321332 has similar potency against the variants as against the wildtype. Our in vitro data suggest that the efficacy of specific Mpro inhibitors such as PF-07321332 is not compromised in current COVID-19 variants.

Prior fluid and electrolyte imbalance is associated with COVID-19 mortality

Background The COVID-19 pandemic represents a major public health threat. Risk of death from the infection is associated with age and pre-existing comorbidities such as diabetes, dementia, cancer, and impairment of immunological, hepatic or renal function. It remains incompletely understood why some patients survive the disease, while others do not. As such, we sought to identify novel prognostic factors for COVID-19 mortality. Methods We performed an unbiased, observational retrospective analysis of real world data. Our multivariable and univariable analyses make use of U.S. electronic health records from 122,250 COVID-19 patients in the early stages of the pandemic. Results Here we show that a priori diagnoses of fluid, pH and electrolyte imbalance during the year preceding the infection are associated with an increased risk of death independently of age and prior renal comorbidities. Conclusions We propose that future interventional studies should investigate whether the risk of death can be alleviated by diligent and personalized management of the fluid and electrolyte balance of at-risk individuals during and before COVID-19.

Mapping the human genetic architecture of COVID-19: an update

The Coronavirus Disease 2019 (COVID-19) pandemic continues to pose a major public health threat especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity we formed the COVID19 Host Genetics Initiative. Here we present GWAS meta-analysis of up to 125,584 cases and over 2.5 million controls across 60 studies from 25 countries, adding 10 new genome-wide significant loci to the 13 we previously identified1. Genes in novel loci include SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.