Search Results (592)

Background: Therapeutic drug monitoring (TDM) is essential for ensuring safe, effective, and individualized anti-infective therapy, particularly in patients with complex clinical needs. Variability in pharmacokinetics, challenges in drug administration, and high-dose regimens can compromise adherence and increase the risk of therapeutic failure or resistance. Swallowing difficulties, a common barrier to oral therapy, often necessitate alternative administration routes or customized formulations. However, interventions such as pharmaceutical compounding or manipulation of solid dosage forms may significantly alter drug bioavailability and pharmacokinetic profiles, making TDM indispensable for guiding dose adjustments and maintaining therapeutic targets. Objectives: This review not only emphasizes the clinical relevance of TDM but also addresses practical strategies that enable therapy when standard formulations are unsuitable or unavailable, while minimizing risks that could compromise treatment efficacy and safety. Special focus is given to anti-infective agents, such as antibiotics, antivirals, and antifungals, illustrating how TDM, combined with tailored pharmaceutical approaches, supports precision dosing and informed decision-making. Conclusions: Through clinical examples and pharmacokinetic considerations, we demonstrated that TDM is a cornerstone of personalized medicine, improving outcomes, and reducing adverse effects in anti-infective treatment. Full article

Inflammasomes are signaling complexes of the innate immune system that are assembled in distinct sentinel cell types to coordinate inflammation. As demonstrated by the emergence of viral antagonists and evasion mechanisms, inflammasomes are critical to contain viral infections. As virions are entirely composed of host cell-derived molecules, infection is either recognized by molecules or modifications exposed in unusual compartments, or by activities and host cell damage indicative of virus replication. Rather than enumerating all viruses that activate inflammasomes, this review classifies common pathways or signatures that activate antiviral inflammasomes. We define a set of minimal criteria that we think is critical to prove virus-triggered inflammasome assembly. We further discuss the consequences of virus-induced inflammasome assembly and define relevant open questions in the field. Full article

Comparative transcriptomics offers a powerful approach to elucidate host–virus interactions across related pathogens, yet systematic evaluations across species-matched cellular systems remain limited. We performed a cross-species RNA sequencing analysis of respective species’ cells infected with three alphaherpesviruses—herpes simplex virus 1 (HSV-1), bovine alphaherpesvirus 1 (BHV-1), and equid alphaherpesvirus 1 (EHV-1)—to dissect conserved and virus-specific transcriptional responses. We show that certain orthologous genes and orthologous pathways are differentially regulated upon infection among the three species like pathways related to translation rRNA processing and TNF-alpha signalling. We find that the earliest sampled timepoint of infection, 2 h post infection (hpi), shows the most commonly enriched pathways among the three species compared to later timepoints. At 6 h and 9 h post infection, BHV-1- and EHV-1 infections have more in common with each other in terms of enriched pathways than with HSV-1 infections. Moreover, we provide a comprehensive analysis of temporal viral gene expression for all three herpesviruses. Together, these findings provide a comparative framework for understanding alphaherpevirus–host interactions and reveal both conserved core responses and species-specific transcriptional signatures. This work establishes a foundation for identifying broadly acting antiviral targets as well as virus-specific vulnerabilities that may inform host-directed therapies and cross-species disease management. Full article

Host–virus relationships regulate every phase of viral infection and critically influence course of illness and the effectiveness of treatment. Viruses utilize host receptors, intracellular trafficking routes, metabolic programs, and immunological signaling networks to introduce infection, while host cells use innate and adaptive immune responses that both limit viral replication and, in certain situations, cause tissue damage. Given the fast viral evolution and drug resistance linked to virus-directed therapy, there is growing proof that these host-dependent mechanisms are appealing and underutilized targets for antiviral treatment. Recent developments in single-cell technology, proteomics, and functional genomics have made it possible to systematically identify host dependency and restriction factors shared by different viral families, exposing common molecular vulnerabilities that might be targeted therapeutically. This review integrates current knowledge of virus–host interplay via a translational lens, highlighting processes that directly guide the formation of host-directed antivirals and immune-regulating treatments. We emphasize host processes involved in viral entry, replication, and immune signaling that have shown therapeutic significance, while illustrating the difficulties of balancing antiviral effectiveness with immunopathology. By framing host–virus interactions through a therapeutic lens, this review attempts to offer a targeted and translationally relevant viewpoint for next-generation antiviral research. Full article

Bovine gammaherpesvirus 4 (BoGHV-4) is an opportunistic uterine pathogen whose reactivation is associated with postpartum inflammation and bacterial lipopolysaccharide (LPS). Platelet-rich plasma (PRP) is a regenerative biotherapeutic capable of modulating inflammatory responses, although its effects may vary depending on BoGHV4 genotype. In this study, primary bovine endometrial cells (BECs) were cultured in medium containing 10% PRP instead of fetal bovine serum, infected with two genetically divergent BoGHV-4 isolates (07-435, genotype 3; 10-154, genotype 2), and subsequently stimulated with bacterial lipopolysaccharide (LPS, 100 ng/mL). Expression of the viral immediate-early gene IE-2 and host immune genes (TLR4, TNF-α, CXCL8, and IFN-γ) were quantified by RT-qPCR from 4 to 48 h after stimulation. Isolate 07-435 induced a sustained activation of IE-2 and gradual cytokine upregulation, while isolate 10-154 elicited an early but transient inflammatory response followed by gene downregulation. PRP did not modify the strain-specific patterns of viral and inflammatory gene expression but established a common inflammatory baseline, whereas the magnitude and temporal profile of the response continued to be dictated by the viral genotype. These findings indicate that BoGHV-4 genotypic diversity remained the main determinant of response intensity and duration, supporting PRP as a context-dependent rather than a universal antiviral modulator. Full article

Background/Objectives: Antimicrobial resistance (AMR) in ocular infections has become a serious concern with major implications for vision preservation. Bacterial AMR contributed to 4.71 million deaths worldwide in 2021, and ophthalmology mirrors these trends with multidrug resistance rates as high as 66% documented in some regions and persistently high methicillin resistance among common ocular pathogens. Across regions and care settings, traditional empiric therapies are losing effectiveness against an expanding range of pathogens, resulting in slower recovery, more complications, and, in many cases, permanent vision loss. This review aims to synthesize recent clinical, microbiologic, and pharmacologic evidence on ocular AMR, focusing on recent studies to capture current resistance patterns, therapeutic challenges, and evolving management strategies. Methods: Most included papers were published between 2020 and 2025, with additional foundational studies referenced where appropriate. Reports and systematic reviews addressing bacterial, viral, fungal, and parasitic ocular pathogens were evaluated to characterize current resistance mechanisms and management strategies across ocular pathogens. Results: The eye’s anatomic and physiologic barriers limit drug penetration, often promoting resistance and reducing therapeutic efficacy. Resistance mechanisms vary by pathogens; Pseudomonas keratitis is driven mainly by efflux pumps and biofilm formation, while CMV retinitis’ mutations in UL97 and UL54 are linked with clinical failure, and in MRSA associated Staphylococcus keratitis, the presence of mecA necessitates vancomycin-based therapy across bacterial, viral, fungal, and parasitic infections, with mechanisms such as β-lactamase production, efflux pump overexpression, target-site mutation, and biofilm formation contributing to poor response to standard therapy. MDR Pseudomonas keratitis remains the leading cause of rapidly progressive corneal infection with high risk of perforation and vision loss, while resistant CMV retinitis continues to threaten sight in immunocompromised patients despite antiviral advances. MDR organisms are recalcitrant to treatment and may lead to longer treatment courses and potentially worse outcomes and are discussed in detail within the manuscript. Conclusions: Ocular AMR represents an urgent and expanding clinical challenge. This review centers on the two most encountered multidrug-resistant organisms and their corresponding ocular sites, Pseudomonas aeruginosa (anterior segment) and CMV (posterior segment), while contextualizing them within the broader spectrum of resistant bacterial, viral, fungal, and parasitic pathogens. Despite growing awareness of AMR in ophthalmology, comprehensive surveillance data and longitudinal epidemiologic studies remain limited, making it difficult to track evolving resistance trends or guide region-specific therapy. Preserving vision in the AMR era will require faster diagnostics, improved ocular drug-delivery systems, and pathogen-specific therapies. Full article

Orthoebolaviruses (OEV) are highly pathogenic viruses responsible for the Ebola virus disease (EVD). To establish a successful infection, OEV hijacks the host cell machinery, which in turn responds to infection by activating cellular antiviral pathways. These processes are regulated via post-translational modifications (PTMs) of both cellular and viral proteins. The most common PTMs include phosphorylation, ubiquitination, acetylation, methylation, and glycosylation. These modifications regulate stability, activity, and interactions between proteins that control the immune response, cell metabolism, and cell death, among others. PTMs are critical during the viral replication cycle as they can be either proviral, facilitating adequate virus replication inside the infected cell, or antiviral, most commonly hindering essential viral processes such as viral genome transcription or replication. Here, we review the different roles of PTMs known to occur during OEV infection in both viral and cellular proteins. Understanding how OEV modulates the fate of host cell proteins through specific PTMs can provide a basis for the development of novel therapeutic strategies. Full article

The potyvirus helper component proteinase (HcPro) is a multifunctional protein, with one of its most documented functions being host antiviral RNA silencing suppression. This study shows that the HcPro of potato virus Y (PVY), an important member of the potyvirus group, prevents the replication of a related competing secondary virus. This phenomenon, referred to as superinfection exclusion (SIE), is common in bacterial, human, and plant virus infections. We also report that HcPro’s induction of SIE is strain-specific and that this specificity is provided by the first four amino acid residues of the protein. Consistent with the mechanism of SIE, the study found that HcPro does not exclude a resident virus. Additionally, HcPro’s induction of SIE was observed to function independently of its ability to suppress antiviral RNA silencing. HcPro’s induction of SIE is relevant given the prevalence of multiple PVY strains that routinely co-infect the same cell and that may lead to recombination and emergence of new and more virulent strains. Furthermore, cross-protection or systemic acquired resistance (SAR) that is employed in plant virus disease management occurs when SIE moves from the cellular level and spreads systemically, emphasizing the importance of studying SIE. Full article

Toxoplasma gondii is the most common infectious cause of posterior uveitis in immunocompetent adults. While the parasite is typically acquired through ingestion of undercooked meat or contaminated food and water, unpasteurized goat milk has been identified as a less frequent but plausible source of infection. Coinfections in ocular toxoplasmosis are rare, and the role of Epstein–Barr virus (EBV) in these coinfections remains poorly understood. We report the case of a 70-year-old immunocompetent male presenting with severe, refractory panuveitis in the left eye. Initial serologic testing confirmed acquired Toxoplasma gondii infection, and treatment was initiated with systemic antimicrobials and corticosteroids. Intraocular inflammation persisted despite sequential therapy with trimethoprim–sulfamethoxazole, clindamycin, and azithromycin, eventually requiring pars plana vitrectomy with intravitreal clindamycin and dexamethasone due to non-clearing vitreous hemorrhage. Vitreous PCR testing revealed intraocular concurrent detection of EBV DNA, prompting combined antimicrobial and antiviral therapy. Epidemiological history revealed recent consumption of unpasteurized goat milk, suggesting a potential oral transmission route for Toxoplasma gondii. Although visual acuity improved following surgical intervention and targeted therapy, it remained markedly compromised due to the severity of the disease. This case illustrates the diagnostic value of multiplex PCR in refractory uveitis, enabling the detection of Toxoplasma gondii and the concurrent detection of EBV DNA in an immunocompetent patient. It highlights the importance of early molecular testing and detailed epidemiological assessment, including atypical transmission routes such as unpasteurized goat milk. Full article

Background/Objectives: The prevalence of Hepatitis C Virus (HCV) among men who have sex with men (MSM) is not negligible; however, data from Italy—especially regarding MSM who are not infected with Human Immunodeficiency Virus (HIV)—are limited. We report data from an HCV screening programme targeted at MSM in Rome, starting in 2019 in two hospital settings and in four urban community-based (CB) settings run by non-governmental organizations (NGOs). Methods: Adult MSM (>18 years old) who presented for HIV or sexually transmitted infection testing, or who attended CB activities, were invited to undergo a free-of-charge rapid HCV antibody test (OraQuick HCV^®), after providing informed consent. For all participants, demographic, clinical and behavioural data were collected using an anonymous questionnaire for all participants. Free confirmatory standard serology tests were offered for those found reactive at a rapid HCV test. Individuals with confirmed chronic HCV infection were referred through a dedicated “fast track” pathway for further clinical and laboratory assessment and direct-acting antiviral agents (DAAs) treatment according to the national treatment guidelines. Results: Between July 2019 and July 2023, 2714 MSM agreed to be screened for HCV infection. The median age was 36 years (interquartile range, IQR = 29–46), 91.0% were Italians, 58.0% enrolled in the two clinical centres and 10.7% reported living with HIV (people living with HIV, PLWH). Overall, 9 (0.33%) MSM tested reactive for HCV-specific antibodies using a rapid test. Eight MSM were retested and seven were confirmed to have chronic HCV infection (HCV viremia range: 8 × 10³–23 × 10⁶ IU/mL). The prevalence of confirmed cases was 0.26% (7/2714; 95%CI: 0.10–0.53) and was higher in PLWH compared to those not reporting HIV infection (1.04% vs. 0.17, p = 0.03). Four of seven confirmed HCV cases attended the STI clinic. All confirmed HCV cases reported high-risk behaviours for HCV infection and/or history of sexual transmitted infection (STI). Bening a PLWH (OR = 6.30) and current/former IDU (O = 17.02) resulted in being significantly associated with HCV infection. Other risk factors such as fisting, groupsex, chemsex and condomless anal intercourse were more common in the HCV case (OR > 2), but lacked statistical significance, likely due to small sample size. All seven individuals were linked to care, clinically assessed and started on DAAs treatment, achieving sustained viral response (SVR) in all cases. Conclusions: These data suggest the feasibility and potential effectiveness of a preventive programme targeting MSM living in Rome, combining HCV screening, case finding and prompt linkage to care. HCV prevalence in the screened population was lower than anticipated, although it is significantly higher in PLWH and in those with high-risk behaviours. Considering this condition of low prevalence of HCV infection among MSM in Italy, a targeted screening in PLWH and in individuals with high-risk behaviours may be more effective to achieve HCV eradication than universal screening in MSM. Full article

This study aimed to unravel the genomic uniqueness of Streptomyces chrestomyceticus ADP4 using whole-genome sequence analysis, with a focus on identifying strain-specific genes/proteins associated with a novel therapeutic source. The genome of the strain ADP4 was sequenced and assembled to a total size of 9.64 MB. A total of 8378 coding regions were identified. Strain ADP4 was found to be clustered into a clade of the species S. chrestomyceticus. Fifty-one biosynthetic gene clusters were predicted in the genome of the strain ADP4, and three of them were common to all the strains of S. chrestomyceticus. A comparative metabolic profile of S. chrestomyceticus revealed a unique metabolic protein, supporting strain-level variations. Comparative genome analysis led to the identification of the genomic sequences that were specific to the strain ADP4. These strain-specific unique sequences of ADP4 were identified across the available data, underscoring their distinct genetic identity. Among these eight functionally uncharacterized hypothetical proteins (HPs), only two could be assigned with functional attributes, wherein one of them, HP2, was ascertained to be a peptide with possible antiviral activity, underscoring its potential as a novel drug candidate for aantiviraltherapy. The structural validation and peptide–protein molecular docking have evidently demonstrated anantiviralctivity of HP2 against significant human viral pathogens, for example, HIV, SARS-CoV2, HCV, ZIKV, JEV, and DENV. Full article

Background: In the post-pandemic era, respiratory viruses continue to cause substantial morbidity and mortality among hospitalized adults. SARS-CoV-2 and influenza remain the most common pathogens, while RSV and rhinovirus have re-emerged as relevant causes of severe illness. This study compared the characteristics and outcomes of virus-specific infections detected by multiplex real-time PCR over two consecutive seasons. Methods: This retrospective cohort study was conducted at a 1010-bed tertiary-care hospital in Türkiye between June 2022 and June 2024. Adults hospitalized with at least one respiratory virus detected by MRT-PCR were included. Demographic, clinical, and laboratory data were analyzed. Pathogen-specific comparisons were limited to monoinfections, and predictors of in-hospital mortality were identified using multivariable logistic regression. Results: Among 518 admissions, influenza (33.6%) and SARS-CoV-2 (29.3%) were the predominant pathogens, followed by rhinovirus (11.2%), RSV (6.6%), and other respiratory viruses (19.6%). Overall in-hospital mortality was 26.6%. Mortality differed across virus groups in unadjusted analyses, being highest in SARS-CoV-2 and RSV and lowest in rhinovirus. Non-survivors were older, more comorbid, more often immunosuppressed, and more likely to require oxygen therapy or ICU care at sampling. In multivariable analysis, independent predictors of mortality were ICU location at sampling (aOR 5.52), oxygen requirement (aOR 3.39), immunosuppression (aOR 3.67), older age (per 10-year increase: aOR 1.25), and secondary bacterial infection (aOR 7.00). Viral etiology, including SARS-CoV-2, was not independently associated with mortality after adjustment. Conclusions: Among hospitalized adults, mortality was driven primarily by host-related factors and secondary bacterial infection rather than by viral etiology. These findings highlight the need for strengthened adult immunization programs, reliable respiratory virus surveillance, the prevention of bacterial superinfection, and the development of and equitable access to effective vaccines and antiviral therapies to reduce severe outcomes in high-risk adults. Full article

Pangenotypic direct-acting antivirals (pDAAs) have transformed hepatitis C virus (HCV) treatment. In Italy, sofosbuvir/velpatasvir (SOF/VEL) and glecaprevir/pibrentasvir (GLE/PIB) are available. While both show similar efficacy, differences in patient profiles and potential drug–drug interactions (DDIs) may influence treatment choice. This study examined factors affecting pDAA selection and potential prescribing gaps. Using administrative databases (2018–2023) covering 3.7 million citizens, HCV patients were divided into SOF/VEL and GLE/PIB cohorts and compared by demographic, clinical, and therapeutic data. Among 5565 patients, 2837 (51%) received SOF/VEL and 2728 (49%) received GLE/PIB. SOF/VEL patients were older (60.8 vs. 57.6 years, p < 0.001) and had more comorbidities: diabetes (24% vs. 17%), mental disorders (22% vs. 14%), cancer (14% vs. 9%), and cardiovascular disease (31% vs. 22%). Hospitalization rates were higher (19% vs. 13%), as were exemption codes for chronic hepatitis (58% vs. 50%) and hypertension (32% vs. 23%). Polypharmacy was more common with SOF/VEL; 25% used ≥10 non-pDAA drugs (vs. 17%), and mean medications per patient were higher (6.3 ± 5.6 vs. 4.9 ± 5.2). SOF/VEL was often used for older, frailer patients, likely due to a more favourable DDI profile. These prescribing trends highlight the importance of tailoring pDAA choice to patient comorbidity profiles, ensuring appropriate and individualized HCV treatment. Full article

Astragalus species are characterized by rich active compounds, mainly polysaccharides, saponins, and polyphenols, with various important bioactivities, such as antioxidant, antitumor, anti-diabetes, antiviral, etc. In this study, the chemical profiles of ethanol, ethyl acetate, and dichloromethane extracts from different parts (leaves, flowers, and roots) of two endemic Astragalus species growing in Türkiye, i.e., A. strictispinus and A. macrocephalus subsp. finitimus were determined, along with their antioxidant, anti-enzymatic, and antibacterial properties. According to the results, naringenin and apigenin were identified as two common phenolic compounds of both Astragalus species, while only ethanol extracts of the roots and leaves and ethyl acetate extracts of flowers of A. strictispinis exhibited a low level of antioxidant activity (5–16%). Moreover, AChE and BChE inhibitory activities were higher in the ethyl acetate extract of A. macrocephalus subsp. finitimus leaves, while all leaf extracts of the analyzed Astragalus species, except dichloromethane extract of A. strictispinus, exhibited antibacterial activity against S. aureus. In conclusion, this study provides detailed information that may serve as the scientific basis for the use of Astragalus species as sources of bioactive compounds with multiple functions in the nutraceutical, cosmetic, and pharmaceutical industries. Full article

Lancehead pitvipers, Bothrops snakes, or, popularly, “jararacas”, are common and broadly distributed in the Americas, especially in Brazil, where they are responsible for causing a high number of snakebite accidents. Their venoms are able to induce local and systemic effects, such as hemorrhaging, acute kidney failure, and shock, that can be fatal. Among the compounds of the venom are phospholipases A₂ (PLA₂s), which are abundant in some Bothrops species. PLA₂s can perform different activities during envenoming, such as neurotoxicity, myotoxicity, and cytotoxicity, among others, through the hydrolysis of the ester bond at the sn-2 position of phospholipids, producing free fatty acids and lysophospholipids. Although different PLA₂s can be classified into different PLA₂ groups and subgroups, according to structure, function, size, localization and Ca²⁺ dependence, they converge to be available in biotechnological and therapeutic applications, such as antiviral and antitumor, among others, being relevant molecules to be deeply studied. Here, we provide the state of the art of PLA₂s, found in snake venoms, focusing on Bothrops venoms, as well as their potential applications, beyond their inhibitors, that also receive attention due their importance in PLA₂ studies and diverse applications. Full article