Infectious Diseases and Therapy

IntroductionPublic and regulatory scrutiny of immunization safety has intensified in recent years. The COVID-19 pandemic has been instrumental in this. The accelerated timeline of COVID-19 vaccine development combined with the amplification of resultant side effects have proven corrosive to confidence. Unsurprisingly, COVID-19 vaccine uptake has declined year-on-year. This conflicts with the threat that infection still presents: predictors and prognoses of post-acute complications remain uncertain. Restoring public trust in these technologies will require meaningful progress in the availability and accessibility of clinical safety and pharmacovigilance data. MethodsExpanding upon recent comparisons of COVID-19 vaccine reactogenicity, we present a post-hoc safety analysis of adintrevimab, an intramuscular (IM) anti-SARS-CoV-2 spike recombinant investigational monoclonal antibody (mAb) for the pre-exposure and post-exposure prophylaxis of COVID-19, as assessed by the multi-center, double-blind, Phase 2/3 randomized placebo-controlled EVADE study (NCT04859517). Exploratory endpoints included the incidence of [≥]1 systemic symptoms within 7 days of study drug administration as well as symptom number, duration and severity. Safety reporting encompassed solicited and unsolicited treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), vital signs, and clinical laboratory assessments. ResultsEVADE study participants (n=2582) were randomized between April 2021 - January 2022. Baseline characteristics were balanced across treatment groups. Within the 7 day post-dose period, 25/1241 (2.0%) of adintrevimab recipients and 12/1242 (1.0%) of placebo recipients reported at least one systematic TEAE. Multiple systemic TEAEs were less prevalent, with 0.3% and 0.1% reporting two systemic TEAEs, and 0.1% and 0.1% reporting three TEAEs in adintrevimab and placebo groups, respectively. The majority of TEAEs reported were mild to moderate in severity, primarily involving headache (0.4% adintrevimab, 0.8% placebo), fatigue (adintrevimab 0.4%, placebo 0.2%), and nausea/vomiting (adintrevimab 0.4%, placebo 0.1%). For those participants who experienced any TEAEs in the 7 day post-dose period, mean (+/-standard deviation) number of systemic symptoms was 1.2 (0.5) for adintrevimab and 1.3 (0.6) for placebo with symptoms consistently resolving within 3 days. ConclusionsIncreased expectations for pharmaceutical safety data generation are to be welcomed, offering patients the information they need to appropriately weigh the benefits and risks of any novel therapeutic. These analysis results support the high tolerability of IM-administered adintrevimab, with reactogenicity data broadly comparable to placebo. While the co-administration of vaccines and monoclonal antibodies limit direct comparisons between historical safety reports, findings such as these demonstrate the potential clinical value of controlled head-to-head studies such as the anticipated LIBERTY trial.

PurposePatients with common variable immunodeficiency (CVID) frequently exhibit impaired antibody responses to vaccination, yet the dynamics of humoral and cellular immunity following mRNA immunisation remain incompletely defined. This study aimed to characterise the temporal evolution of anti-SARS-CoV-2 antibody and T cell responses across successive vaccine doses in a well-characterised CVID cohort, and to identify key determinants of vaccine responsiveness in this population. MethodsWe performed a longitudinal and cross-sectional analysis of serum and peripheral blood mononuclear cell (PBMC) samples collected from 88 CVID patients after two, three, or four doses of mRNA vaccine (Moderna/mRNA-1273 or Pfizer-BioNTech/BNT162b2). Anti-receptor-binding domain (RBD) IgG titers were quantified in relation to vaccine dose, time since last vaccination, and clinical characteristics. Vaccine-specific CD4+ and CD8+ T cell responses were assessed ex vivo using an activation-induced marker (AIM) assay by flow cytometry. ResultsThe proportion of patients with detectable anti-RBD IgG increased from 35% after two doses to more than 80% after four doses. Boosting-dependent increases in IgG titers were observed exclusively in samples collected more than three months after the last dose, and antibody levels correlated positively with time since vaccination, consistent with delayed but progressive humoral kinetics that stabilised after the third dose. In contrast, spike-specific CD4+ and CD8+ T cell responses were rapidly induced and remained stable across all timepoints. ConclusionVaccine-induced immunity in CVID is characterised by delayed humoral responses alongside preserved cellular immunity. Early post-vaccination serology may systematically underestimate vaccine responsiveness, and booster vaccination supports stabilisation of antibody responses in this population.

A multiplex diagnostic test is evaluated for self-reported long COVID associated persistent symptoms and a poor recovery from a SARS-CoV-2 infection. A mass-standardised concentration of total antibodies (AC), high-quality (HQ) antibodies and percentage of HQ antibodies (HQ%) is assessed against a spectrum of spike proteins to the SARS-CoV-2 variants: Wuhan, , {delta}, and the Omicron variants BA.1, BA.2, BA.2.12.1, BA.2.75, BA.5, CH.1.1, BQ.1.1 and XBB.1.5 in three cohorts. A cohort of control patients (n = 46) recovered (CC) and a cohort of self-declared long COVID patients (n = 113) (LCC). A nested Receiver Operating Characteristic (ROC) analysis, performed for the variant with lowest HQ concentration in the spectrum, produced an area under the curve and AUC = 0.61 (0.53-0.70) for the CC vs LCC cohorts. For the LCC cohort, the cut-off thresholds for AC = 0.8 mg/L, HQ = 1.5 mg/L and HQ% of 34% were determined, leading to a 71% sensitivity and 66% specificity derived by the Youden metric. The cohorts may be fully classified based on ROC and outlier analysis to give an incidence of persistent virus 62% (95% CI 52% - 71%), hyperimmune 12% (95% CI 7% - 20%) and unclassified, 26% (95% CI 18% - 35%). The overall diagnostic accuracy for both the hyper and hypo immune is 69%. All clinical interventions can now be tailored for the heterogenous long COVID patient cohort.

Objectives: Influenza is a widespread acute respiratory illness posing a major public health challenge for both the National Health Service (NHS) and society, particularly among older adults. This study aimed to assess the cost-effectiveness of high-dose quadrivalent vaccine (HD-QIV) versus adjuvanted quadrivalent vaccine (aQIV) in older adults in Spain. Methods: Public health and economic benefits were evaluated using a decision-tree model considering influenza cases, GP and ED visits, hospitalizations, and influenza-related mortality. Deterministic and probabilistic sensitivity analyses addressed epidemiological and economic uncertainties. Results: From a societal perspective, HD-QIV prevented 54,039 influenza cases, 7,733 GP consultations, 1,585 ED visits, 27,398 episodes of hospitalization due to cardiorespiratory events over a single influenza season and 1,203 deaths compared to aQIV when vaccinating adults [≥]65 years old in Spain, resulting in 14,316 LYs and 12,440 QALYs gained over a lifetime horizon. The reduction in health outcomes outweighed the increase in vaccination costs, translating to a reduction in total costs with HD-QIV compared to aQIV. Therefore, vaccinating older adults in Spain with HD-QIV instead of aQIV was a dominant strategy when evaluating hospitalizations due to respiratory and cardiovascular events. HD-QIV remained dominant from a NHS perspective. Sensitivity analyses confirmed the robustness of the model. Conclusions: This analysis showed that vaccinating older adults in Spain with HD-QIV instead of aQIV would reduce influenza cases, GP and ED visits, hospitalizations, deaths, and associated costs, and thus it should be the strategy of choice in a situation of budgetary constraints from either a societal or an NHS perspective.

Objective. To evaluate the effectiveness of a bundle of interventions involving a clinical pharmacologist aimed at changing surgeons approach to perioperative antibiotic prophylaxis (PAP) in an oncourology department. Materials and Methods. A single-center retrospective observational study was conducted. Data from 226 patients who underwent prostatectomy or nephrectomy in the oncourology department of Regional Clinical Hospital No. 2 (Krasnodar, Russia) between 2023 and 2025 were analyzed. Periods before (n=125) and after (n=101) the implementation of an Antimicrobial Stewardship (AMS) strategy bundle with active participation of a clinical pharmacologist (pre-authorization, audit with feedback, education, handshake stewardship) were compared. The primary endpoint was the proportion of surgeries performed in compliance with the PAP protocol. Secondary endpoints included the incidence of infectious complications, antibiotic consumption (DDD/100 bed-days), direct costs of antibacterial drugs, dynamics of the microbial landscape, and the Drug Resistance Index (DRI). Results. After AMS implementation, the proportion of surgeries performed in accordance with the PAP protocol increased from 0% to 47.7% for prostatectomies and to 55.6% for nephrectomies. The mean duration of antibiotic use decreased from 7 to 2 days (p<0.001). Antibiotic consumption decreased by 31.2%, and costs were reduced by a factor of 4.3. The proportion of ESKAPE organisms in the microbial profile decreased from 26.3% to 16.4%. There was no statistically significant increase in the frequency of infectious complications (2.4% vs. 3.0%; p=1.000) or mortality (0% in both groups). Conclusions. AMS implementation integrating a clinical pharmacologist into the oncourology department workflow significantly improved adherence to clinical guidelines, reduced irrational antibiotic use and financial costs without compromising patient safety. This approach can serve as a model for optimizing PAP in other surgical departments. Keywords: antibiotic prophylaxis, antimicrobial stewardship, drug resistance, clinical pharmacologist, cost-benefit analysis, oncourology

Nasopharyngeal (NP) swabs remain the dominant gold standard for respiratory infection diagnostics. While there has been increased use of alternative sample types since the COVID-19 pandemic, guidance on their use for detecting respiratory viruses is not yet definitive, especially for children. In this systematic review and meta-analysis, we aimed to compare the diagnostic accuracy and tolerability of multiple respiratory specimen types for detecting respiratory viruses in pediatric populations. Searches were conducted on July 17, 2025 in MEDLINE, Embase, Web of Science, and Scopus, with screening and data extraction performed in Covidence. English-language primary research articles published since 2000 comparing respiratory virus detection rates in children, using nucleic acid amplification tests between paired respiratory specimens, were included. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies criteria. We calculated pooled sensitivities and specificities of index specimens: nasopharyngeal aspirates (NPA), mid-turbinate swabs (MT), anterior nasal swabs (ANS), oropharyngeal swabs (OP), and bronchoalveolar lavage fluid (BAL), as compared to the reference, NP swabs, using random-effects modeling, firstly without discrimination by virus. Index specimens were then grouped by sample collection site as nasal, oral, and lower respiratory tract (LRT) specimens for virus-specific analyses. Overall performance and statistical validity were evaluated by hierarchical summary receiver operating characteristic (HSROC) analysis. Data regarding sampling tolerability was also assessed. We screened 2,448 studies and identified 36 publications (total N participants = 10,687) that reported diagnostic test accuracy using paired index-reference data in children. Of these, 18 (total N participants = 4,310) used NP specimens as the reference and were included in the diagnostic test accuracy analysis. Virus-agnostic pooled sensitivity estimates indicated that MT (0.92%) performed most similarly to NP, though sensitivities of ANS (0.79%) and OP (0.70%) were also moderately high for detection of any respiratory virus. BAL sensitivity was the lowest (0.37%). All sample types demonstrated high specificity (0.98%-0.99%). Group estimates and HSROC statistics found that nasal specimens, when grouped, had the highest sensitivity and accuracy for all examined viruses, including for influenza (92%) and RSV (90%). By comparison, oral and LRT specimens performed less well, with more variability, though both showed moderately high sensitivities for RSV (78%, 76%, respectively) and influenza (82%, 80%, respectively), and LRT samples showed high sensitivity for HMPV (82%). Analysis of sample tolerability found that NP swabs consistently ranked as the least comfortable and least preferred, while nasal swabs and saliva both performed well. Datasets for LRT and oral specimens were sparser than for nasal, and this contributed to greater variability, underscoring the need for further diagnostic accuracy studies on alternatives to NP sampling. These data support the viability of nasal and oral alternatives to NP swabs and affirm their application in pediatric care, particularly in outpatient settings. Such alternatives could greatly improve sampling tolerability and increase global access, including in resource-limited settings, to accurate diagnostic methods for respiratory infections.

Background: Digital antimicrobial stewardship (AMS) interventions, such as clinical decision support systems, audit and feedback platforms, and electronic prescribing tools, have been increasingly adopted to improve antibiotic use. However, the effectiveness of these interventions across healthcare settings remains uncertain, and the certainty of the evidence has not been comprehensively evaluated. The objective of this study was to provide a comprehensive understanding of the role of digital interventions in optimizing antimicrobial use and improving clinical outcomes within a broad spectrum of healthcare settings. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials evaluating digital AMS interventions that followed PRISMA 2020 guidelines and registered in PROSPERO CRD420251178854 and funded by the Wellcome Trust CAMO Net programme. Searches were performed across major databases. Primary outcomes included the appropriateness of antibiotic prescriptions and the antibiotic prescription rate. Secondary outcomes included 30 day mortality, 30 day hospital readmission, and length of hospital stay (LOS). Random effects models were used to pool effect sizes. Risk of bias was assessed RoB 2, and certainty of evidence was rated using GRADE. A Summary of Findings table was prepared to present effect estimates, sample sizes, and evidence certainty. Results: Eleven RCTs met the inclusion criteria, and nine were included in the quantitative synthesis. Digital AMS interventions did not show a significant effect on appropriateness of antibiotic prescribing (RR 0.99, 95%CI 0.93 to 1.05; very low certainty). There was no reduction in antibiotic prescription (RR 0.98, 95%CI 0.88 to 1.09), with substantial statistical heterogeneity and very low certainty. Across clinical outcomes, digital AMS showed no effect on 30 day mortality (RR 0.91, 95%CI 0.77 to 1.09; very low certainty) or 30 day readmission (RR 0.95, 95%CI 0.79 to 1.14; very low certainty). For LOS, results were inconsistent across studies, and the pooled effect showed no clinically meaningful change (MD 0.17 days, 95%CI 0.01 to 0.35; very low certainty). Most trials had some concerns of bias due to deviations from intended interventions. Conclusion: Meta-analyses of digital AMS RCTs showed a lack of evidence with a high level of certainty on antibiotic prescribing or clinical outcomes due to high heterogeneity in interventions and study designs, as well as RCTs' limitations (no adoption/fidelity metrics).

Use of fungal mycelia, which has antiviral properties, constitutes a novel strategy for addressing existing and newly emerging viral diseases. We evaluated safety and feasibility of fungal mycelia (Fomitopsis officinalis and Trametes versicolor, FoTv) for treatment of COVID-19 and assessed its antiviral effects and potential to reduce symptoms. In a randomized, double-blind, placebo-controlled, dual site (UCSD/UCLA medical centers) clinical trial we examined non-hospitalized patients who contracted mild-to-moderate COVID-19 [&le;] 96 hours, and experienced symptom onset [&le;] nine days, before enrollment. FoTv was safe, well-tolerated, and feasible for COVID-19 treatment. Minor differences in biochemical markers were observed between groups (26 FoTv, 24 Placebo). FoTv significantly reduced the number and severity of symptoms, particularly sore throat/cough, and in vitro SARS-CoV-2 (pseudovirus) cellular infection. In conclusion, FoTv was safe and reduced COVID-19 symptoms and cellular viral infection. Future studies should investigate therapeutic benefits of fungal mycelia for SARS-CoV-2 and other viruses. Clinicaltrials.gov registration:NCT04667247.

BackgroundAn upsurge in Streptococcus pyogenes infections 2022-2023 highlighted potential benefits of point-of-care tests (POCT) to support clinical pathways, prevent outbreaks, and optimise antibiotic use. ObjectivesWe conducted a pilot research study in a west London paediatric emergency department (ED) to determine whether a molecular POCT had potential to alter management in children who were also having a conventional throat swab taken for culture. MethodsChildren <16 years presenting to ED who had a throat swab requested by a clinician were invited to have a second swab taken for research purposes only. Clinical management was unaffected by the research swab result, which was processed using a molecular POCT that was not approved for use in the host NHS Trust. ResultsPrevalence of streptococcal infection was low during the study (May 2023-June 2025); swab positivity in symptomatic children was 12.8% (6/47). Overall, 38/49 (77.6%) participants who had throat swabs received antibiotics. Of those children recommended to receive antibiotics, 29/38 (76.3%) had a negative POCT. Mean time to reporting of positive throat swab culture results was 3.67 days (range 3-5 days) leading to occasional delay in treatment, although POCT identified positive results within minutes. ConclusionAntibiotic use was frequent and could be avoided or stopped by use of a rule out POCT in over three-quarters of children in the ED, if suspicion of S. pyogenes is the main driver for prescribing. POCT were easy to process and produced immediate results compared with culture, in theory enabling timely decision-making and avoiding treatment delay.

Background Plasma gelsolin (pGSN) is a non-immunosuppressive anti-inflammatory immunomodulator with demonstrated efficacy in animal models of acute lung injury. Its potential role in moderate-to-severe acute respiratory distress syndrome (ARDS) is currently under investigation. Methods We conducted a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of recombinant human pGSN (rhu-pGSN) following intravenous (IV) administration to healthy volunteers. Thirty-two participants were assigned to 4 sequentially ascending dose cohorts (6, 12, 18, 24 mg/kg of body weight) to receive five IV infusions of rhu-pGSN or saline placebo. Each cohort includes 8 subjects randomized 3:1 with rhu-pGSN or placebo. Doses were administered at 0 hours, 12 hours, 36 hours, 60 hours, and 84 hours. The primary outcome is the incidence and severity of clinical and laboratory AEs regardless of causality. Secondary outcomes include the pharmacokinetics of IV rhu-pGSN and the presence of anti-rhu-pGSN antibodies at Day 28. Results Overall, 10 subjects (41.7%) who received rhu-pGSN reported a total of 13 adverse events (AEs), and 1 subject (12.5%) who received placebo reported an AE. All AEs were mild or moderate. AEs in system organ classes that were reported by 2 or more subjects in either arm were skin and subcutaneous tissue disorders (12.5% rhu-pGSN; 0% placebo), gastrointestinal disorders (8.3% rhu-pGSN; 0% placebo), and nervous system disorders (12.5% rhu-pGSN; 12.5% placebo). No AEs by preferred term were reported by more than 1 subject in either arm. Three subjects (12.5%) experienced an AE assessed as related to study drug. No serious AEs occurred, and no AEs led to study discontinuation, dose interruption/reduction, or death. There were no apparent between-treatment differences in laboratory abnormalities, vital signs, or electrocardiogram findings. Conclusions Overall, in this study, IV rhu-pGSN (up to 24 mg/kg daily) appeared safe and well tolerated compared to placebo. The median half-life of rhu-pGSN exceeded 14 h across all dosing regimens, supporting once daily IV dosing in healthy subjects. Trial registration This study was registered with ClinicalTrials.gov on 2023-03-29 under the registration identifier NCT05789745.

Background: Long COVID presents with one or multiple symptoms or diagnosable conditions after SARS-CoV-2 infection. To study whether use of the antiviral remdesivir in persons hospitalized with acute COVID-19 is associated with reduced Long COVID, we created a computational phenotype for Long COVID. Methods: In electronic health records (EHR) from a multistate healthcare system (US), hospital admissions from 5/1/20 - 9/30/22 were reviewed. The study group was hospitalized with acute COVID-19 and the control group was hospitalized for other reasons without prior SARS-CoV-2 infection. The populations were balanced with overlap weights based on a high-dimensional propensity score of pre-specified variables and the top 100 comorbidities differing between the groups. Hazard ratios (HR) were calculated for the combined primary outcome: U09.9 (Post-Covid Conditions) or any incident secondary outcome from 90 to 365 days after admission. Secondary outcomes included 27 individual incident diagnoses, corrected for multiplicity with Holm-Bonferroni. Results: Admissions included 45,540 with, and 409,186 without COVID-19 during the study period, evaluable for the primary outcome. After weighting, standardized difference was < 0.01 for all measured confounders including demographic and clinical features. In the COVID+ and non-COVID groups 38.0% and 29.3% met the combined primary outcome, respectively. Weighted HR (95%CI) for the primary outcome was 1.37 (1.35, 1.40), p < 0.0001. All secondary outcomes were associated with the COVID+ group, when adjusted for multiplicity. Incident diagnoses with strong associations (HR > 2) included thromboembolism, hair loss, diabetes mellitus, obesity, and hypoxia. Anosmia/dysgeusia was associated with COVID, but wide confidence intervals reflected few charted diagnoses. Conclusions: Manifestations of Long COVID at population scale are detectable as part of routine symptoms and clinical diagnoses in the EHR after admissions for COVID-19, compared with all other hospital admissions. This a prior computational phenotype for Long COVID will be used to assess whether remdesivir use is associated with decreased Long COVID.

Circulating stem and progenitor cells (SPCs), including mesenchymal stromal cells (MSCs) and hematopoietic stem/progenitor cells (HSPCs), are mobilised after tissue injury but their temporal behaviour after hemorrhagic shock (HS) and relationship to cytokine milieus and outcome remain unclear. In a prospective observational cohort at JPN Apex Trauma Centre, AIIMS, New Delhi we studied 100 participants: 50 trauma patients with hemorrhagic shock and traumatic brain injury (HS index group), 25 trauma patients without HS, and 25 minor-injury controls. Peripheral blood was collected at admission (day 0) for all groups and additionally at days 3, 7 and 14 for the HS group. PBMCs were phenotyped by flow cytometry (HSPC markers: CD45, CD123, CD38, CD34; MSC markers: CD105, CD73, CD90) and serum SDF-1, VEGF-A, EGF, GRO- and GRO-{beta}, GM-CSF and G-CSF were measured by ELISA; group and time effects were evaluated with mixed-effects models and correlations by Spearman tests (two-tailed p<0.05). At admission, trauma patients without HS had significantly higher MSC and HSPC-like populations versus controls (p<0.0001). In the HS cohort SPC percentages rose modestly at day 0-3 then declined sharply by days 7-14 (time effect p<0.0001); non-survivors exhibited significantly higher early SPC and cytokine levels that persisted until death while survivors showed an early rise followed by decline (outcome and time interaction p<0.0001). All cytokines were up-regulated in trauma groups, peaked at day 0-3 in HS patients, and correlated positively with SPC counts (notably SDF-1, VEGF-A, G-CSF, Gro- and GM-CSF; Spearman p<0.05); higher early SPC and cytokine signatures associated with greater organ dysfunction (higher SOFA) and with timing of sepsis. These findings indicate that trauma provokes an early SPC and cytokine response that in HS is followed by later decline, and that persistent early elevation predicts worse outcomes, suggesting serial SPC and cytokine profiling may have prognostic value and identify an early therapeutic window for regenerative or immunomodulatory interventions.

Introduction: Synthetic oligopeptides provide a rapid and cost-efficient approach to developing antibodies and diagnostics for emerging viral variants. Methods: This study computationally and experimentally characterized a synthetic peptide analog of the SARS-CoV-2 spike subdomain 2 major disulfide loop (SD2MDL), designated S621 (CPVAIHADQLTPTWRVYSTC). Binding affinity was computationally estimated using the Heuristic Affinity Prediction Tool for Immune Complexes (HAPTIC), while experimental validation was performed using enzyme-linked immunosorbent assay (ELISA) with rabbit-derived antipeptide antibodies. Clinical diagnostic accuracy testing was done using plasma samples from RT-PCR-confirmed COVID-19 patients and pre-COVID-19 controls. Results: S621 demonstrated nanomolar binding affinity (Kdapp = 1.14 nM) and high avidity (3.67 nM), closely matching HAPTIC predictions (3.54 nM). Diagnostic evaluation yielded a sensitivity of 89.92% and specificity of 27.79%, corresponding to an overall accuracy of 71.79%. Discussion: These findings demonstrate that a single synthetic peptide derived from a conserved spike subdomain can function as a high-affinity surrogate for full-length antigens, supporting its potential application in rapid peptide-based immunodiagnostics.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition associated with pediatric SARS-CoV-2 infection. While COVID-19 vaccines prevent infection and reduce severity, less conclusive evidence exists regarding their role in preventing MIS-C during breakthrough infections. This systematic review assessed the impact of SARS-CoV-2 vaccination on MIS-C risk during breakthrough infection. Cross-sectional studies, surveillance studies, and cohort studies were included. Of the 944 studies identified, 6 were included. A significant protective effect was seen in patients who received two doses of SARS-CoV-2 vaccination after exclusion of a biased sample (d= 0.71 [95% CI 0.07 to 1.35; p=0.03]). A trend towards a protective effect was seen after one dose of vaccination, but this effect was not statistically significant. Current literature supports a protective effect of two doses of SARS-CoV-2 vaccination against development of MIS-C in breakthrough COVID-19. The evidence supports clinician advocacy for continued vaccination of children against SARS-CoV-2.

BackgroundShigella flexneri 2a (SF2a) and 6 (SF6) are two of the most common S. flexneri serotypes. They have distant O-specific polysaccharide (O-SP) structures. Previous studies showed no cross-reactivity or cross-protection between the two serotypes in a guinea pig model of infection. However, partial cross-reactivity and cross-protection were reported in humans immunized with a SF2a lattice-type conjugate vaccine candidate comprising the chemically detoxified lipopolysaccharide (LPS) attached to recombinant Pseudomonas aeruginosa Exoprotein A (rEPA). ObjectivesThis study aimed at deciphering the possible cross-reactivity with heterologous SF6 strains of antibodies induced in humans by SF2a-TT15, a sun-type SF2a conjugate vaccine candidate featuring a non-O-acetylated synthetic oligosaccharide (OS) as surrogate of the detoxified LPS. Special focus was on the impact of the O-SP non-stoichiometric O-acetylation on cross-reactivity. MethodsSerum IgG antibody titers to LPSs from SF6 strains harboring different degrees of O-SP O-acetylation, and from Escherichia coli O147 (EC147) which shares an identical but non-O-acetylated O-SP with SF6, were measured by ELISA in 63 serum samples of volunteers receiving 2 {micro}g and 10 {micro}g OS doses of SF2a-TT15 or placebo in the frame of a phase I clinical study. Antibody in-lymphocyte-supernatants (ALS), avidity, and serum bactericidal activity (SBA) were measured in a subset of volunteers. ResultsSF2a-TT15 induced cross-reacting IgG antibodies to all SF6 LPSs and EC147 LPS. A [&ge;]4-fold rise in anti-SF6 IgG titers was more frequent with the 10 {micro}g dose than with 2 {micro}g (50% vs 22%, p=0.045). Cross-reactivity rate was higher with the low O-acetylated SF6 O-SP than with the high O-acetylated one (50% versus 21%, p<0.05). Anti-SF6 responses correlated with homologous anti-SF2a LPS responses. Similar cross-reactivity was detected in ALS samples at day 7 after vaccination. Cross-reacting antibodies were partially functional against the heterologous SF6 parental strains, as shown by bactericidal activity and increased avidity. ConclusionsSF2a-TT15 induces stronger SF6 cross-reactive IgG responses than the previously tested detoxified O-acetylated SF2a LPS-rEPA conjugate. While both serotypes are included in most multivalent Shigella vaccine candidates, cross-reactivity and cross-protection between SF2a and SF6 could enhance the immunogenicity and efficacy of a Shigella multivalent vaccine candidate, particularly in infants in low- and middle-income countries, the primary target population for a Shigella vaccine.

Objectives: Optimising parenteral antimicrobial use is central to antimicrobial resistance (AMR) control, yet its appropriateness is difficult to assess. We aimed to develop a quantitative indicator to evaluate the appropriateness of parenteral antimicrobial therapy in hospitalised patients with bloodstream infections. Methods: We developed the Susceptibility-Spectrum Discrepancy Index (S2DI), reflecting the discrepancy between antimicrobial susceptibility of blood culture isolates and the spectrum width of prescribed agents. Using a database from 67 National Hospital Organization hospitals in Japan, we identified patients with Staphylococcus aureus or Escherichia coli bacteraemia from 2017 to 2023. An expert panel of 10 infectious disease physicians independently ranked antimicrobial susceptibility (A) and spectrum width of commonly used agents (B). S2DI was defined as B minus A on day 7 after treatment initiation, with values closer to zero indicating more appropriate therapy. S2DI was calculated for individual cases, aggregated at the hospital level, and analysed using linear mixed-effects models with hospital-level random effects. Results: A total of 4,505 S. aureus and 9,563 E. coli bacteraemia cases were included. Median S2DI was 1 (IQR 0-1) for S. aureus and 2 (IQR 0-3) for E. coli. For both pathogens, later calendar years were significantly associated with more favourable S2DI, suggesting gradual improvement in antimicrobial use. In E. coli bacteraemia, female sex and younger age were also associated with more appropriate therapy. Conclusions: Although variation across hospitals persists, appropriateness of parenteral antimicrobial use has improved over time. S2DI is a simple metric that may support optimisation of antimicrobial use.

APC148 is a novel metallo-beta-lactamase inhibitor with broad activity against Ambler class B enzymes including NDM, VIM and IMP. It is being developed for patients with serious infections caused by multidrug-resistant Gram-negative bacteria. APC148 is combined with the broad-spectrum beta-lactam antibiotic meropenem and the serine-beta-lactamase inhibitor avibactam, which targets Ambler class A, C, and some class D (OXA-48-like) enzymes. In combination with meropenem and avibactam, APC148 demonstrated superior in vitro activity against a global, multidrug resistant collection of Enterobacterales, showing its promising activity against beta-lactamase producing pathogens. In this randomized, placebo-controlled, first-in-human study, the safety, tolerability and pharmacokinetics of APC148 were evaluated in healthy adults. Single doses ranging from 50 mg to 760 mg APC148 were administered intravenously over 3 h to 46 participants across six dose groups. APC148 was well tolerated at all dose levels. All adverse events were of mild intensity, and no serious adverse events or adverse events leading to study- or treatment discontinuation occurred. The pharmacokinetics of APC148 were dose-proportional with low plasma clearance, low to moderate volume of distribution and a mean plasma half-life of 2.6 h. APC148 is well tolerated in humans at therapeutically relevant doses and represents a promising candidate in the fight against antibiotic-resistant bacteria. (This study has been registered at ClinicalTrials.gov under registration number NCT06360640).

BackgroundTransfer of Streptococcus agalactiae, or Group B Streptococcus (GBS) from parent to newborn during delivery can produce life-threatening infections in neonates. Probiotics could potentially prevent GBS colonization in pregnant individuals. We conducted a systematic review and meta-analysis to evaluate the effectiveness of probiotic administration in treating Group B Streptococcus colonization. MethodsMEDLINE, ClinicalTrials.gov, PROSPERO, and the Cochrane, Wild Card, Central Register of Controlled Trials were searched from the July 2015 of each database until July 2025 that completed a randomized controlled trial which compared Probiotic versus control. We utilized the Cochrane Risk of Bias 2.0 (RoB 2) tool to assess bias in the systematic review. Results14 randomized controlled clinical trials met our inclusion criteria. The trials used oral probiotic administration compared to either a placebo or a control group. A meta-analysis showed that probiotic administration produced a statistically significant decrease in the rate of GBS colonization in pregnant individuals. The individual studies ranged from four showing great effectiveness, while the other 10 studies showed a range of effectiveness, from partially effective to no effectiveness in preventing GBS colonization. ConclusionOverall, probiotics were effective in lowering infection rates of GBS, but individual studies showed great variability. Probiotics show promise in decreasing GBS colonization in pregnant people, but more studies need to be performed in order to use them effectively and decrease antibiotic usage.

BackgroundBenchmarking has been used to target clinically unwarranted variation in antimicrobial prescribing in UK primary care. However, variation in antibiotic prescribing between general practices may be partly explained by differences in case-mix. We aimed to quantify how much variation in antibiotic prescribing for common infections was attributable to differences in prescribing between practices after accounting for case mix. MethodsWe used the UK Clinical Practice Research Datalink (CPRD) Aurum database to identify GP consultations for 11 common infections. Three-way variance decomposition quantified the proportions of total variance attributable to patient case-mix, between practice variation, and residual unexplained variance using variables recorded in electronic medical records, across three models (no, minimal (age/sex), and full case mix adjustment). For lower respiratory tract infection (LRTI) and sore throat, external data to impute illness severity were used to estimate the potential effect of unmeasured infection severity. FindingsWe identified 3,820,806 consultations in 2019. There was clear variability in antibiotic prescribing across practices for most conditions. In fully adjusted models, between practice variation explained 5.8-32.6% of total variance, exceeding variation attributed to case-mix in 9 out of 11 infections. Compared to no adjustment, full case-mix adjustment reduced between-practice differences, lowering their contribution to total explained variation by more than 20% in 6 of 11 infections and by 10-20% in 4 others. Minimal age-sex adjustment had little impact, with changes below 5% in 8 of 11 infections. Imputing infection severity in addition to full case-mix adjustment further reduced contribution of between-practice variance to the total variance (by 25.9% for LRTI and 8.5% for sore throat). InterpretationDifferences in practice-level prescribing, beyond patient case-mix, call for targeted interventions and highlight the value of providing feedback at the practice level. Comprehensive case-mix adjustment, including imputed infection severity, improves the assessment of prescribing variation and supports fairer performance comparisons. FundingWellcome Trust; NIHR RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched MEDLINE for articles published between 1 January 2005 and 31 July 2025, using a combination of key terms including "antibiotic" (or "antimicrobial" or "antibacterial"), "prescribing" (or "prescription" or "use" or "utilisation" or "utilization"), "primary health care" (or "primary care" or "general practice" or "general practitioner" or "GP"), and "United Kingdom" (or "UK" or "England"). We focused on studies using patient-level data to compare antibiotic prescribing between general practices (GP practices). Most studies assessed overall prescribing or focused on a small subset of infections. Only a few examined condition-specific measures across a broader range of infections. We found no studies that decomposed variance into that caused by patient case-mix versus practice performance adjusting for case-mix across a wide range of infections. Added value of this studyUsing individual-level data from 3.8 million consultations for eleven common infections in the UK Clinical Practice Research Datalink (CPRD) Aurum, we applied three-way variance decomposition to quantify the proportions of total variance attributable to patient case-mix, between-practice differences after adjusting for case-mix, and residual variation under three adjustment strategies (non, age-sex only, and full case-mix adjustment). There was clear variability in antibiotic prescribing across practices for most conditions. The total variance attributable to between-practice differences exceeded that attributed to case-mix in 9 out of 11 infections according, according to the fully adjusted case-mix models. Fully adjusting for case-mix based on routinely collected data substantially reduced between-practice differences, lowering their contribution to explained variance (the sum of the patient case-mix variance and between-practice variance) by more than 20% in 6 of 11 infections and by 10-20% in 4 others, whereas minimal age-sex adjustment had little impact. Between-practice differences were reduced further incorporating external information to simulate unmeasured infection severity. Implications of all the available evidenceDifferences in practice-level prescribing, beyond patient case-mix, call for targeted interventions and highlight the value of providing feedback at the practice level. Full case-mix adjustment substantially reduces the risk of overstating between-practice differences, performing far better than adjusting for age/sex alone. Condition-specific indicators with sufficient case-mix adjustment may be more effective benchmarks of practice performance than aggregated total antibiotic use levels as general practitioners (GPs) are more likely to respond positively to comparisons they perceive as fair. In particular, acute otitis media and upper respiratory tract infection, conditions with substantial variability in antibiotic prescribing across GP practices and the highest variance attributable to adjusted between-practice differences (12.6% and 10.3%, respectively), are promising candidates for fair prescribing indicators.

Abstract Introduction: Streptococcus is the second genus involved in bone and joint infections (BJIs) after Staphylococcus. Streptococcus agalactiae is the predominant Streptococcus species implicated in BJIs. However, unlike Staphylococcus-related BJIs, data on S. agalactiae infections remain scarce. Methods: We conducted a retrospective cohort study from the West Region cohort of the CRIOAc registry among six university hospitals including all microbiologically confirmed streptococcal BJI in adults between 2014 and 2023. Results: 1454 patients were included, with a median age of 67 years and 65% male. S. agalactiae was the predominant streptococcal species involved 423/1454(29%). The most prevalent comorbidities identified were obesity (378/1454;26%) and diabetes mellitus (343/1454;24%). Prosthetic joint infections (PJIs) were the most common (653/1454;45%), although diabetic foot osteitis was less prevalent overall, it was significantly more associated with S. agalactiae infections (48/423;11% versus 70/1031;7%, p=0.05). S. agalactiae BJIs were more frequently lower-limb infections and chronic infections (240/423;57% versus 502/1031;49%, p=0.04). Half of the cohort had a polymicrobial infection and were slightly more frequent with S. agalactiae BJIs (235/423;56% versus 498/1031;48%, p=0.1). These results were consistent with a sensitivity analysis excluding diabetic foot related osteitis. Logistic regression analysis identified arteriopathy (OR: 4.16; IC95:1.64-11.24, p=0.003), and obesity (OR: 2.57; IC95: 1.41-4.78, p=0.002) as specific risk factors for S. agalactiae BJIs. Conclusion: S. agalactiae emerges as a prominent and distinct pathogen in complex streptococcal BJIs, with specific risk factors such as arteriopathy, obesity and diabetes mellitus, and more chronic infections.