The safety and efficacy of adenoviruses (AdVs) for oral administration are readily apparent, underscored by the prolonged use of oral AdV-4 and -7 vaccines in the U.S. military. Hence, these viruses seem to be the perfect framework for the development of oral replicating vector vaccines. Yet, the study of these vaccines is constrained by the poor replication of human adenoviruses in laboratory animal hosts. The natural host setting for mouse adenovirus type 1 (MAV-1) facilitates the study of infection under replicating conditions. microbiota assessment A MAV-1 vector expressing influenza hemagglutinin (HA) was used for oral vaccination of mice to assess the conferred protection against subsequent intranasal influenza challenge. This vaccine, administered orally just once, induced influenza-specific and neutralizing antibodies, fully safeguarding mice from clinical signs of infection and viral replication, akin to the protective effect of traditional inactivated vaccines. Public health mandates new vaccine types that are easier to administer, thereby gaining broader acceptance, to counter the perennial threat of pandemics and the annual influenza vaccination necessity, especially concerning emerging agents such as SARS-CoV-2. In a relevant animal model, we have found that the use of replicative oral adenovirus vaccine vectors can make vaccination against major respiratory diseases more accessible, more widely accepted, and consequently, more effective. Over the coming years, these outcomes might be pivotal in the ongoing struggle against seasonal and emerging respiratory illnesses, including the likes of COVID-19.

In the human gut, Klebsiella pneumoniae acts as both a colonizer and an opportunistic pathogen, heavily influencing the global burden of antimicrobial resistance. Virulent bacteriophages show strong prospects for removing bacterial populations and providing medical treatments. In contrast to other phage types, the majority of isolated anti-Kp phages demonstrate exceptional specificity towards specific capsular subtypes (anti-K phages), considerably restricting the prospect of phage therapy in the face of the extensive variability in the Kp capsule. An original approach for isolating anti-Kp phages (anti-Kd phages) is presented, using capsule-deficient Kp mutants as hosts. Anti-Kd phages infect non-encapsulated mutants of multiple genetic sublineages and various O-types, showcasing a broad host range. Furthermore, anti-Kd phages exhibit a reduced rate of in vitro resistance development, and their combined use with anti-K phages enhances killing efficacy. Within the confines of a mouse gut colonized by a capsulated Kp strain, anti-Kd phages exhibit the capacity for replication, which suggests the presence of un-encapsulated Kp subpopulations. A novel strategy presented here offers a promising approach to overcoming the Kp capsule host restriction, suggesting therapeutic possibilities. Ecologically adaptable and opportunistic, Klebsiella pneumoniae (Kp) is a bacterium responsible for hospital-acquired infections and a major contributor to the global burden of antimicrobial resistance. In the recent decades, virulent phages have shown limited improvement as an alternative or complement to antibiotics in addressing Kp infections. An isolation strategy for anti-Klebsiella phages, showcasing potential, addresses the constraint of limited host range in anti-K phages. non-alcoholic steatohepatitis Anti-Kd phages might exhibit activity within infection locations where capsule expression is either intermittent or suppressed, or synergistically with anti-K phages, which frequently induce the loss of the capsule in escaping mutant strains.

A challenging treatment for Enterococcus faecium arises from its growing resistance to most clinically available antibiotics. Daptomycin (DAP) is the first-line treatment; however, high doses (12 mg/kg body weight per day) were insufficient to eradicate some of the vancomycin-resistant strains. Although the combination of DAP and ceftaroline (CPT) might improve the binding of -lactams to their target penicillin-binding proteins (PBPs), a simulated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic (PK/PD) model found that DAP-CPT did not achieve the desired therapeutic outcome against a DAP-nonsusceptible (DNS) vancomycin-resistant Enterococcus faecium (VRE) isolate. check details For combating infections with substantial bacterial loads and antibiotic resistance, phage-antibiotic combinations (PACs) have been suggested as a potential strategy. To achieve maximal bactericidal effect from PAC, alongside the prevention/reversal of phage and antibiotic resistance, we employed an SEV PK/PD model with the DNS isolate R497. Using a modified checkerboard minimal inhibitory concentration (MIC) method and 24-hour time-kill assays, phage-antibiotic synergy (PAS) was scrutinized. In subsequent evaluations, 96-hour SEV PK/PD models were used to analyze the impact of human-simulated antibiotic doses of DAP and CPT, combined with phages NV-497 and NV-503-01, on R497. The phage cocktail NV-497-NV-503-01, when used in combination with the DAP-CPT PAC, displayed synergistic bactericidal activity, yielding a dramatic decrease in bacterial viability down to 3 log10 CFU/g, a significant reduction from the initial 577 log10 CFU/g, with statistical significance (P < 0.0001). This combination further displayed the resensitization of isolated cells to DAP. Post-SEV phage resistance evaluation demonstrated that PACs incorporating DAP-CPT prevented phage resistance. In a high-inoculum ex vivo SEV PK/PD model, our results reveal novel bactericidal and synergistic activity of PAC against a DNS E. faecium isolate. This is coupled with subsequent DAP resensitization and prevention of phage resistance. Within a high-inoculum simulated endocardial vegetation ex vivo PK/PD model utilizing a daptomycin-nonsusceptible E. faecium isolate, our study indicates a pronounced advantage for the combination of standard-of-care antibiotics with a phage cocktail when compared to antibiotic monotherapy. Significant morbidity and mortality are observed in patients with *E. faecium*-associated hospital-acquired infections. Daptomycin, the standard initial treatment for vancomycin-resistant Enterococcus faecium (VRE), has, in published reports, not been successful in eradicating some VRE isolates, even at the highest administered doses. The inclusion of a -lactam with daptomycin may yield a synergistic action, however, earlier laboratory findings show that combining daptomycin and ceftaroline failed to clear a VRE isolate. Proposed as a secondary treatment for severe, high-density bacterial infections, phage therapy alongside antibiotics faces a challenge in designing and executing comparative clinical trials for endocarditis, underscoring the immediate need for such rigorous analysis.

For global tuberculosis control, the administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important consideration. Long-acting injectable (LAI) drug formulations might offer a method of condensing and simplifying treatment protocols for this specific application. Rifapentine and rifabutin exhibit antitubercular activity and suitable physicochemical properties for long-acting injectable formulations, yet limited data hinders the determination of optimal exposure profiles for efficacy within tuberculosis treatment regimens. To establish the link between drug exposure and effectiveness of rifapentine and rifabutin, this study aimed to produce data supporting the development of LAI formulations for TPT. By utilizing a validated paucibacillary mouse model of TPT coupled with dynamic oral dosing of both drugs, we examined and evaluated the relationship between exposure and activity to aid in establishing optimal posology for future LAI formulations. This work highlighted multiple exposure patterns of rifapentine and rifabutin that mirror those observed with LAI formulations. These patterns, if replicated by LAI formulations, hold promise for efficacy in TPT regimens. Therefore, these patterns serve as experimentally identified targets for the development of new LAI formulations of these drugs. This novel methodology explores the relationship between exposure and response, ultimately guiding the investment decision for developing LAI formulations, which have value beyond the treatment of latent tuberculosis infection.

While repeated respiratory syncytial virus (RSV) infections are possible, severe illness is not a common consequence for most individuals. Regrettably, infants, young children, the elderly, and immunocompromised individuals are susceptible to severe RSV illnesses. RSV infection, according to a recent study, prompted cellular growth, resulting in in vitro bronchial wall thickening. Determining if viral actions on lung airways reflect the patterns of epithelial-mesenchymal transition (EMT) is yet to be established. Using three in vitro lung models—the A549 cell line, primary normal human bronchial epithelial cells, and pseudostratified airway epithelium—we report that RSV does not induce epithelial-mesenchymal transition. In the RSV-infected airway epithelium, an increase in cell surface area and perimeter was noted, a distinct characteristic when compared to the cell elongation characteristic of the potent EMT inducer, transforming growth factor-1 (TGF-1), indicative of cell mobility. A comprehensive transcriptomic analysis across the entire genome demonstrated distinct regulatory effects of RSV and TGF-1 on gene expression, implying that RSV's impact on the transcriptome differs significantly from epithelial-mesenchymal transition (EMT). Heightened airway epithelial layers, a result of RSV-induced cytoskeletal inflammation, are unevenly increased, reminiscent of non-canonical bronchial wall thickening. Epithelial cell morphology is transformed by RSV infection, a process contingent on the regulation of actin polymerization by the actin-protein 2/3 complex. Hence, it is sensible to inquire into the relationship between RSV-induced changes in cell shape and their possible involvement in EMT.