Journal of Infection

The Variant of Concern (VOC)-202012/01 (also known as B.1.1.7) is a rapidly growing lineage of SARS-CoV-2. In January 2021, VOC-202012/01 constituted about 80% of SARS-CoV-2 genomes sequenced in England and was present in 27 out of 29 countries that reported at least 50 viral genomes. As this strain will likely spread globally towards fixation, it is important to monitor its molecular evolution. Based on GISAID data we systematically estimated growth rates of mutations acquired by the VOC lineage to find that L18F substitution in viral spike protein has initiated a substrain characterized by replicative advantage of 1.70 [95% CI: 1.56-1.96] in relation to the remaining VOC-202012/01 substrains. The L18F mutation is of significance because when recently analyzed in the context of the South African strain 501Y.V2 it has been found to compromise binding of neutralizing antibodies. We additionally indicate three mutations that were acquired by VOC-202012/01 in the receptor binding motif of spike, specifically E484K, F490S, and S494P, that may also give rise to escape mutants. Such mutants may hinder efficiency of existing vaccines and expand in response to the increasing after-infection or vaccine-induced seroprevalence.

BackgroundSince June 2022, there has been a rise in the number of ceftriaxone resistant Neisseria gonorrhoeae cases detected in England (n = 15), of which one third were extensively-drug resistant (XDR). We describe the demographic and clinical details of the recent cases and investigate the phenotypic and molecular characteristics of the isolates. For a comprehensive overview, we also reviewed 16 ceftriaxone-resistant cases previously identified in England since December 2015 and performed a global genomic comparison of all publicly available ceftriaxone-resistant N. gonorrhoeae strains with mosaic penA alleles. MethodsAll N. gonorrhoeaeisolates resistant to ceftriaxone (MIC >0.125 mg/L) were whole-genome sequenced and compared with 142 global sequences of ceftriaxone-resistant N. gonorrhoeae. Demographic, behavioural, and clinical data were collected, including treatment and outcomes. ResultsAll cases were heterosexuals, and most infections were associated with travel to or from the Asia-Pacific region. However, some had not travelled outside England within the previous few months. There were no ceftriaxone genital treatment failures, but 3/5 pharyngeal infections and the only rectal infection failed treatment. The isolates represented 13 different multi-locus sequence types (MLSTs), and most had the mosaic penA-60.001 allele. The global genomes clustered into eight major phylogroups, with regional associations. All XDR isolates belonged to the same phylogroup, represented by MLST 16406. ConclusionCeftriaxone resistance in N. gonorrhoeae continues to be associated with the penA-60.001 allele within multiple genetic backgrounds and with widespread dissemination in the Asia-Pacific region. Heightened surveillance activities have been initiated to detect further cases with the aim of interrupting further transmission.

ObjectivesEnterovirus (EV) and parechovirus (PeV) meningitis are significant causes of illness in febrile infants. The clinical significance of detecting EV/PeV in the CSF, particularly in the absence of pleocytosis and neurological symptoms, remains uncertain in this age group. We aimed to characterise the relationship between clinical features, systemic neuroinflammatory and immune responses, and CSF pleocytosis in infants with EV/PeV meningitis. MethodsProspective multicentre observational cohort study of febrile infants <90 days old undergoing CSF testing for infection. Infants were recruited as part of the Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study from 35 Paediatric Emergency Research in the UK and Ireland (PERUKI) sites from 6th July 2022 to 31st August 2023 (NCT05259683). Plasma proteomic profiling of 724 inflammation and neurology-related proteins was performed using Olink technology and compared with clinical and laboratory data. Results603 febrile infants were included, with 21/603 (3{middle dot}5%) PeV, and 173/197 (28.7%) EV meningitis cases. Lymphopenia was significantly more common in infants without pleocytosis, 62/101 (63.9%), than those with pleocytosis 7/54 (16.7%). No significant differences in clinical symptoms or timing of presentation were observed with differing CSF WBC counts. Proteomic analysis (n=131) revealed that infants without pleocytosis exhibited elevated inflammatory cytokine responses and enrichment of pathways related to apoptosis and CNS involvement. In contrast, those with pleocytosis showed muted cytokine responses. ConclusionsThe absence of CSF pleocytosis in EV and PeV meningitis may result from systemic lymphocyte depletion, potentially mediated by cytokine-driven apoptosis. Our findings do not support the hypothesis that the lack of pleocytosis is primarily attributable to early presentation or to incidental detection of viral RNA due to viremia in infants.

BackgroundWe have successfully used whole-genome sequencing to provide additional information for transmission pathways in infectious spread. We report and interpret genomic sequencing results in clinical context from a large outbreak of COVID-19 with 46 cases across staff and patients in a community hospital in the UK. MethodsFollowing multiple symptomatic cases within a two-week period, all staff and patients were screened by RT-PCR and staff subsequently had serology tests. ResultsThirty staff (25%) and 16 patients (62%) tested positive for COVID-19. Genomic sequencing data showed significant overlap of viral haplotypes in staff who had overlapping shift patterns. Patient haplotypes were more distinct from each other but had overlap with staff haplotypes. ConclusionsThis study includes clinical and genomic epidemiological detail that demonstrates the value of a combined approach. Viral genetic sequencing has identified that staff transmission of COVID-19 was important in this community hospital outbreak. Key pointsO_LIDetailed analysis of a large community hospital outbreak in older adults and staff with concurrent clinical and genomic data, including working patterns. C_LIO_LIStaff transmission was important in this community hospital outbreak. C_LIO_LIWe found plausible associations between staff and patient cases. C_LI

Control of SARS-CoV-2 transmission is complicated by the emergence of variants, especially those containing mutations in the spike protein. By enhancing infectivity and evading immunity, infection with these variants might result in more severe clinical outcomes as well as being more resistant to vaccines developed on the basis of the original prototypic virus variant. One such example is the alpha variant (B.1.1.7), which has been detected in more than 100 countries and rapidly become the dominant strain in the UK in late 2020 and early 2021. There is an urgent need to develop appropriate surveillance programmes to rapidly monitor the spread of variants and to better understand the role of variants in disease outcomes and immune evasion. The nucleotide sequencing method, the gold standard of variant detection, is unsuitable as a fast-response surveillance tool by frontline diagnostic services which require detection methods with short turnaround times. We developed a screening protocol based of sequential allele-specific qPCR for detection of the N501Y mutation and H69/V70 deletion present in the alpha/B.1.1.7 variant. We tested this protocol in previously confirmed positive samples from the Pathology Dept, University Hospital Coventry and Warwickshire during the second wave period in the UK (December 2020-March 2021). In these samples variant identity was confirmed by NGS sequencing via COG-UK. Our results identified increased incidence of variants containing both N501Y and {Delta}69/70 HV mutations, especially in patients admitted during January and early February 2021. This approach, which yields results within 3 hours, can be used as an initial rapid screening step with NGS as confirmatory follow-up. We also report that the increased prevalence of alpha/B.1.1.7 variant in admitted patients since mid-January 2021, a period that characterised peaked mortality rates, was associated with a sharp 2.5-fold rise in the mean circulating IL-6 level and to a lesser extent Troponin-T. More detailed biomarker analysis of a small cohort of patients (n=83), where variant status and clinical outcomes were available, demonstrated that deceased patients infected with the alpha/B.1.1.7 variant had significantly higher levels of inflammation and cell injury markers, especially IL-6 and LDH, compared to deceased patients infected with a non-alpha/B.1.1.7 variant, pointing towards a more severe inflammatory disease phenotype. In contrast, both groups survivors most biomarker exhibited levels below the group average, with distinct patterns of modified z-scores present.

We analyzed over 40 years of bacteriological surveillance data to reveal a 4-fold increase in Group A streptococcal (GAS) meningitis in 2022 compared to the annual average of 1982-2021 (n=5/year). Already 10 GAS meningitis cases occurred in 2023 (until March 13th). Molecular typing revealed that 25 out-of-29 (86%) isolates received in 2022 and 2023 were emm1.0 (Figure 1). WGS analysis of 19 emm1.0 isolates (2019 until 20th December 2022) demonstrated that 15 out-of-19 (79%) isolates belonged to the toxicogenic M1UK lineage. Based on these observations, we urge clinicians to be vigilant regarding clinical sign of meningitis with invasive GAS infections, since this disease manifestation appears to have a higher than expected occurrence due to clonal replacement by the recently-emerged M1UK variant. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/23286423v3_fig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@12ea749org.highwire.dtl.DTLVardef@1e8c4e6org.highwire.dtl.DTLVardef@d6dd1forg.highwire.dtl.DTLVardef@4f26dc_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Number of received S. pyogenes CSF isolates with proportion of emm1.0, 2013-2023 (until March 13th). C_FIG

BackgroundThe epidemiology of suspected pediatric meningoencephalitis has shifted in the era of conjugate vaccines and multiplex PCR diagnostics, with viral pathogens now predominating over bacterial causes. Updated epidemiologic data are essential to adapt diagnostic and therapeutic algorithms to current clinical practice. MethodsThis retrospective single-center study included children and adolescents <18 years who underwent lumbar puncture with cerebrospinal fluid multiplex PCR for suspected central nervous system infection at a tertiary-care pediatric hospital in Germany between 2016 and 2024. Clinical, laboratory, and outcome data were extracted from electronic medical records. Cerebrospinal fluid was analyzed using the BioFire(R) FilmArray(R) Meningitis/Encephalitis Panel. Statistical analyses included descriptive statistics, nonparametric group comparisons, receiver operating characteristic analyses. ResultsAmong 1,198 included children, definite bacterial meningitis was diagnosed in 13 (1.1%), definite viral meningitis in 80 (6.7%), aseptic meningitis of unknown etiology in 131 (11.0%), confirmed/probable encephalitis in 53 (4.4%), and possible encephalitis in 34 (2.8%). Bacterial meningitis accounted for 5.8% of all meningitis cases. A causative pathogen was identified in all bacterial meningitis cases, most commonly Streptococcus pneumoniae (n = 7). Enterovirus (n = 52) and parechovirus (n = 9) predominated in viral meningitis, whereas an infectious etiology was identified in only 13 of 53 confirmed/probable encephalitis cases. The Bacterial Meningitis Score showed a sensitivity of 80.0% and a specificity of 57.6%. The recently published UK-ChiMES-pre- and post-lumbar puncture scores demonstrated sensitivities of 84.6% and 76.9% and specificities of 86.3% and 92.7%, respectively. DiscussionBacterial meningitis was rare in this contemporary cohort, while viral and etiologically unresolved infections predominated despite routine multiplex PCR diagnostics. Clinical prediction scores supported risk stratification, with the UK-ChiMES-pre-lumbar puncture score showing the most favorable balance between sensitivity and specificity and potential to guide diagnostic decisions and antiinfective therapy.

BackgroundWhy particular individuals are more at risk of a given infectious disease than others has been a topic of interest for scientists, clinicians, and polymaths for millennia. Complex webs of factors-sociodemographic, clinical, genetic, environmental-intersect, rendering causality difficult to decipher. We aimed to demonstrate the ability of Mendelian Randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of infectious diseases, using Epstein Barr Virus (EBV) as a model pathogen. MethodsWe mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8,422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal. ResultsOur GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed educational attainment, number of sexual partners, and smoking as causal risk factors for EBV serostatus. ConclusionsOur study demonstrates the power of MR to decipher complex webs of putative risk factors and determine which are causal for the acquisition of an infectious disease. The factors identified for EBV will be important for vaccine deployment. Key messagesO_LIThe risk of infectious disease acquisition is dependent on many interacting sociodemographic, lifestyle, clinical, genetic, environmental, and national and international health governance factors. C_LIO_LITraditional epidemiological studies of these risk factors are often hindered by issues of confounding and therefore whether a given putative risk factor is causally associated with infection acquisition is difficult to decipher. C_LIO_LIUsing Epstein Barr Virus (EBV) as a model pathogen, we demonstrate the power of Mendelian randomization to understand if putative risk factors are causal, while controlling for confounding. C_LIO_LIBetter understanding of infectious disease risk factors using Mendelian randomization can inform vaccine strategies and deployment e.g. by identifying priority populations for vaccination. C_LI

The Omicron variant is characterised by more than 50 distinct mutations, the majority of which are located in the spike protein. The implications of these mutations for disease transmission, tissue tropism and diagnostic testing are still to be determined. We evaluated the relative performance of saliva and mid-turbinate swabs as RT-PCR samples for the Delta and Omicron variants. The positive percent agreement (PPA) of saliva swabs and mid-turbinate swabs to a composite standard was 71% (95% CI: 53-84%) and 100% (95% CI: 89-100%), respectively, for the Delta variant. However, for the Omicron variant saliva and mid-turbinate swabs had a 100% (95% CI: 90-100%) and 86% (95% CI: 71-94%) PPA, respectively. This finding supports ex-vivo data of altered tissue tropism from other labs for the Omicron variant. Reassessment of the diagnostic testing standard-of-care may be required as the Omicron variant become the dominant variant worldwide.

BackgroundRecurrent sore throat affects a small minority of adults but can cause substantial morbidity. Evidence to guide tonsillectomy eligibility in adults is limited, and current criteria are extrapolated from paediatric populations. We aimed to describe the epidemiology, management, and prognosis of adult sore throat in UK primary care. MethodsUsing CPRD Aurum (2010-2020 adults with a first coded episode of sore throat or tonsillitis were identified and matched to controls. Episode frequency, antibiotic use, ENT referral, and tonsillectomy were analysed. Predictors of recurrent episodes ([&ge;]3 in 365 days), referral, and tonsillectomy were assessed using time-to-event, multinomial logistic, and multilevel mixed-effects regression models. FindingsOf 4.45 million adults, 1.70 million (38.3%) had [&ge;]1 episode; most (61.5%) had only one, but 4.1% experienced [&ge;]3 within 1 year. Recurrent episodes were more common in younger females and those from more deprived areas. Only 21,869 patients (0.5% of the exposed cohort) underwent tonsillectomy, and just 25.7% of these met Paradise criteria at any time; conversely, only 13.9% of those meeting criteria underwent surgery. Patients who had a tonsillectomy tended to be younger, female, and from less deprived areas. Pre-tonsillectomy episode rates were unexpectedly low, but the data indicated that individuals with high baseline burden continue to experience elevated episode rates over several years. ConclusionsRecurrent sore throat is uncommon, but those affected face substantial disease burden. Current tonsillectomy patterns are poorly aligned with disease burden and show inequities by deprivation. Earlier identification of adults likely to develop recurrent episodes, and more timely surgical intervention, may improve patient outcomes and the cost-effectiveness of tonsillectomy.

Since the emergence of SARS-CoV-2, global monitoring of the virus using whole genome sequencing has identified mutations occurring across the viral genome. Whilst the majority have little impact on the virus, they are used effectively to monitor the movement of the virus globally and to inform locally on transmission chains. In late 2020, a variant of SARS-CoV-2 (B.1.1.7 - VOC 202012/01) was identified in the UK with a distinct constellation of mutations, including in the spike gene that increased transmissibility. A deletion in spike also affected one of the screening qPCR tests being used in the UK outside of Wales, causing a failure to detect the target. This quickly became a surrogate marker for the variant to allow rapid monitoring of the virus as it seeded into new regions of the UK. A screening study using this assay as a proxy marker, was undertaken to understand the prevalence of the variant in Wales. Secondary analysis of a screening qPCR that didnt target the S gene and also included an endogenous control, was also performed to understand viral load excretion in those infected with the variant compared to other circulating lineages. Using a combination of analytical methods based on the Ct values of two gene targets normalised against the endogenous control, there was a difference in the excreted viral load. Those with the variant excreting more virus than those not infected with the variant. Supporting not only increased infectivity but offering a plausible reason why increased transmission was associated with this particular variant. Whilst there are limitations in this study, the method using Ct as a proxy for viral load can be used at the population level to determine differences in viral excretion kinetics associated with different variants.

BackgroundAs of March 2021, three SARS-CoV-2 variants of concern (VOC) have been identified (B.1.1.7, B.1.351 and P.1) and been detected in over 111 countries. Despite their widespread circulation, little is known about their transmission characteristics. There is a need to understand current evidence on VOCs before practice and policy decisions can be made. This study aimed to map the evidence related to the transmission characteristics of three VOCs. MethodsA rapid scoping review approach was used. Seven databases were searched on February 21, 2021 for terms related to VOCs, transmission, public health and health systems. A grey literature search was conducted on February 26, 2021. Title/abstracts were screened independently by one reviewer, while full texts were screened in duplicate. Data were extracted using a standardized form which was co-developed with infectious disease experts. A second data extractor verified the results. Studies were included if they reported on at least one of the VOCs and transmissibility. Animal studies and modeling studies were excluded. The final report was reviewed by content experts. ResultsOf the 1796 articles and 67 grey literature sources retrieved, 16 papers and 7 grey sources were included. Included studies used a wide range of designs and methods. The majority (n=20) reported on B.1.1.7. Risk of transmission, reported in 15 studies, was 45-71% higher for B.1.1.7 compared to non-VOCs, while R0 was 75-78% higher and the reported Rt ranged from 1.1-2.8. There was insufficient evidence on the transmission risk of B.1.35.1 and P.1. Twelve studies discussed the mechanism of transmission of VOCs. Evidence suggests an increase in viral load among VOCs based on cycle threshold values, and possible immune evasion due to increased ACE2 binding capacity of VOCs. However, findings should be interpreted with caution due to the variability in study designs and methods. ConclusionVOCs appear to be more transmissible than non-VOCs, however the mechanism of transmission is unclear. With majority of studies focusing on the B.1.1.7 VOC, more research is needed to build upon these preliminary findings. It is recommended that decision-makers continue to monitor VOCs and emerging evidence on this topic to inform public health policy.

The appearance of the SARS-CoV-2 lineage B.1.1.7 in the UK in late 2020, associated with faster transmission, sparked the need to find effective ways to monitor its spread. The set of mutations that characterise this lineage include a deletion in position 69 and 70 of the spike protein, which is known to be associated with Spike Gene Target Failure (SGTF) in a commonly used three gene diagnostic qPCR assay. The lower cost and faster turnaround times compared to whole genome sequencing make the use of qPCR for monitoring of the variant spread an attractive proposition. However, there are several potential issues with this approach. Here we use 826 SARS-CoV-2 samples collected in a hospital setting as part of the Hospital Onset COVID Infection (HOCI) study where qPCR was used for viral detection, followed by whole genome sequencing (WGS), to identify the factors to consider when using SGTF to infer lineage B.1.1.7 prevalence in a hospital setting, with potential implications for locations where this variant has recently been introduced.

BackgroundDespite extensive vaccine efforts, central nervous system (CNS) infections remain a significant cause of morbidity and mortality in the African meningitis belt. This is increasingly complicated by the rising antimicrobial resistance (AMR) in pathogens not covered by the vaccine. We mapped pathogen-specific AMR profiles and diagnostic gaps in CNS bacterial pathogens to inform precision microbiological-based interventions for improved surveillance and empiric therapy in Nigeria. MethodsWe conducted a retrospective analysis of a three year national AMR surveillance data, focusing on CNS bacterial pathogens. Data from 25 sentinel laboratories were extracted, analysed and interpreted per CLSI/GLASS standards. AMR profiles and diagnostic gaps were assessed using descriptive statistics and Chi-square tests for demographic and temporal comparisons. ResultsAmong all 84,548 valid cultures from over 26,000 patients, culture positivity rate was higher in females (35.1%) and older adults (>65 years, 40.0%, p < 0.001). CSF specimens were underrepresented, while species-level ambiguity was high for CNS-associated infections. Staphylococcus aureus, Escherichia coli and Klebsiella species were the dominant isolates, while Pseudomonas aeruginosa and Acinetobacter species showed persistent low-level presence. Alarmingly, Streptococcus pneumoniae showed rising penicillin resistance, reaching 100% by 2018. Other pathogens, including Klebsiella species, E. coli, and Pseudomonas aeruginosa showed high AMR across multiple drug classes. Gap analysis scored all CNS associated bacterial pathogens at maximum clinical risk (5/5), with major deficits in detection and the laboratory capacity. A precision-targeted recommendation map tailored microbiological interventions, such as neonatal AST protocol for E. coli and ICU infection registries for Pseudomonas species. ConclusionSpecies-level identification gaps and high AMR in CNS infections bacterial pathogens demand targeted microbiological-led diagnostics to include expanded CSF testing and AST-guided empiric therapy in resource-limited settings. HighlightsO_LIFirst national AMR gap analysis for CNS pathogens across 84,000 cultures in Nigeria C_LIO_LILinks resistance trends with diagnostic gaps for tailored stewardship interventions C_LIO_LIIntroduces scalable microbiology-driven precision surveillance for LMIC settings C_LIO_LIInforms treatment protocols, lab policies and strategies for high-risk CNS infections C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=149 HEIGHT=200 SRC="FIGDIR/small/25333494v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@4c442borg.highwire.dtl.DTLVardef@10f9471org.highwire.dtl.DTLVardef@1da9edaorg.highwire.dtl.DTLVardef@1f30ea7_HPS_FORMAT_FIGEXP M_FIG C_FIG

Urogenital infections caused by Neisseria meningitidis (Nm) are increasing globally, yet the prevalence, antimicrobial resistance profiles, and transmission dynamics of Nm in men who have sex with men (MSM) remain poorly defined. We conducted an oropharyngeal carriage study in 174 MSM attending a London sexual health clinic in 2023, prior to the implementation of 4CMenB vaccination and doxycycline post-exposure prophylaxis (doxyPEP). Nm was detected in 21.26% of participants, with carriage significantly associated with throat gonorrhoea, consistent with frequent co-colonisation. Whole-genome sequencing identified diverse lineages, including hyperinvasive clonal complexes (CC)11 and CC4821, and revealed widespread tetracycline resistance: 43% of isolates carried either a conjugative tet(M) plasmid or chromosomal tet(B) efflux locus. These findings indicate that MSM represent an important reservoir of tetracycline-resistant Nm, with the potential amplification of this phenotype following doxyPEP implementation, underscoring the need for genomic surveillance of Neisseria species in sexual networks.

Andexanet alfa was recommended by the National Institute for Health and Clinical Excellence (NICE) as an option in the management of major gastrointestinal bleeding in patients taking apixaban or rivaroxaban in May 2021. To assess the uptake of andexanet alfa, we analysed pharmacy stock control data from NHS Trusts in England using the openly available Secondary Care Medicines Dataset. Between May 2021 and July 2024, 14,092 vials of andexanet alfa were issued in NHS Trusts in England. There was wide variation in uptake across NHS Trusts, which likely reflects variation in local protocols. This study is the first analysis of adoption of a new treatment using the OpenPrescribing Hospitals platform, which is expected to provide a generalisable framework for similar analyses in the future.

Linezolid is an alternative to vancomycin for treating Gram-positive central nervous system (CNS) healthcare-associated infections. The recommended dosing regimen remains debated. PK-Pop-LCR is a prospective population pharmacokinetic-pharmacodynamic multicenter study which included brain injured patients with an external ventricular drainage receiving linezolid at different dosing regimens. The cerebrospinal fluid (CSF) penetration of linezolid was investigated and a population pharmacokinetic model developed using plasma and CSF data. Monte Carlo simulations were conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) in CSF against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), for different dosing regimens. The plasma pharmacodynamic target, AUC/MIC > 100, was used in CSF. Over 25 patients included, blind adjudication confirmed 14 cases of CNS infections. The mean AUCCSF/fAUCplasma ratio was close to 80% with no difference between patients with and without CNS infection, despite higher CSF cytokines levels in CNS-infected patients. The recommended dose of 1200 mg/24h allowed to reach PTAs [&ge;] 90% only for MICs [&le;] 0.5 mg/L, and CFR of 3.2% and 40% for MRSA and MRSE, respectively. 2 700 mg/24h would allow to achieve PTA > 90% for MIC up to 1 mg/L and CFR of 90% for MRSE but none of dosing regimens tested was appropriate for MRSA infections. We confirmed the extensive CSF distribution of linezolid. Higher doses than those recommended should be considered to treat CNS infection in critically brain injured patients. However, pharmacodynamic target for CNS infections should be further investigated to confirm these findings. FundingsFrench Ministry of Health.

Bordetella pertussis continues to circulate globally despite wide-spread vaccination, with an emergent international epidemic in 2024. The resurgence of disease is confounded by the emergence of pertactin-deficient, macrolide-resistant B. pertussis (MRBP) strains in Asia and Europe, which are under-recognised using traditional diagnostic and surveillance methods. This study addressed these gaps by applying a probe-capture hybridisation technique, which enables targeted culture-independent sequencing of genomes (tNGS) directly from respiratory specimens. Seven co-circulating lineages of B. pertussis were identified in Australia, including two associated with MRBP. Eight epidemiologically unrelated and geographically dispersed cases of MRBP in Australia with a A2037G mutation in all three copies of 23S rRNA were documented, three of which were confirmed by phenotypic testing and sequencing of corresponding isolates. The estimated rate of MRBP among B. pertussis PCR positive cases was 4.4%. This study demonstrated the value of tNGS based on target enrichment and probe capture sets designed for respiratory pathogens for public health laboratory surveillance of pertussis. This approach can improve the resolution and completeness of B. pertussis surveillance given the increasing diversity and vaccine evasion capability of this pathogen.

Abstract Objectives: Following the COVID-19 pandemic, multiple countries reported a surge in invasive group A streptococcus (iGAS) infections. Posited explanations include reduced population immunity, increased respiratory virus co-infection, and emergence of hypervirulent GAS clones. To assess the relative contribution of these factors, we analyzed the epidemiology and genomics of 3,408 iGAS infections in Scotland. Methods: National surveillance data from 2014-2024 were analyzed to characterize iGAS incidence. Hybrid whole genome sequencing was used to comprehensively genetically characterize 404 emm1 isolates collected from invasive and tonsillitis infections. Results: iGAS incidence markedly increased in late 2022 and early 2023, disproportionately affecting children and older adults. This surge was not associated with a proportional increase in bacteremia but did coincide with increased influenza and respiratory syncytial virus infections. Genomic analyses found that emm1 post-pandemic isolates were not genetically distinct from pre-pandemic isolates in genome-wide polymorphisms, accessory genes including virulence and antimicrobial resistance determinants, mobile genetic elements, or chromosomal structural variants. Conclusions: The post-pandemic iGAS surge in Scotland was not associated with emergence of a novel hypervirulent emm1 clone. Instead, the epidemiologic and population genomic findings are consistent with increased host susceptibility following reduced pathogen exposure during the pandemic and increased respiratory virus co-infection as predominant contributing factors.

BackgroundThroughout the SARS-CoV-2 pandemic, several vaccines have been rolled out and distinct variants with different severity and immune profiles emerged in England. Using data from enhanced surveillance of COVID-19 in vaccine eligible individuals we investigated the antibody response following SARS-CoV-2 infection according to vaccination status and variant. MethodsPCR-positive eligible individuals were identified from community PCR testing data in England between February 2021 and April 2022 and contacted by nurses to complete questionnaires at recruitment and 21 days post recruitment. Individuals were sent self-sampling kits and self-sampled nasal/oropharyngeal swabs were taken day 1, day 3 and day 7 post-recruitment as well as acute (day 1), convalescent (follow-up) serum and oral fluid samples. Regression analyses were used to investigate how N antibody seroconversion differs by vaccine status, and to investigate how N and S antibody levels differ by vaccine status overall and stratified by variants. Interval-censored analyses and regression analyses were used to investigate the effect of acute S antibody levels on the duration of positivity, the cycle threshold values, the self-reported symptom severity and the number of symptoms reported. ResultsA total of 1,497 PCR positive individuals were included. A total of 369 (24.7%) individuals were unvaccinated, 359 (24.0%) participants were infected with Alpha, 762 (50.9%) with Delta and 376 (25.2%) with Omicron. The median age of participants was 49 years old (IQR 39-57). Convalescent anti-N antibody levels were lower in vaccinated individuals and convalescent anti-S antibody levels were higher in vaccinated individuals and increased with the number of doses received. Acute anti-S antibody level increased with the number of doses received. Higher acute anti-S antibody levels were associated with a shorter duration of positivity (overall and for the Delta variant). Higher acute anti-S antibody levels were also associated with higher Ct values (overall and for the Alpha and Delta variants). There was no association between the acute anti-S antibody level and self-reported symptom severity. Individuals with higher acute anti-S antibody level were less likely to report six or more symptoms (overall and for Delta variant). ConclusionUnderstanding the characteristics of the antibody response, its dynamics over time and the immunity it confers is important to inform future vaccination strategies and policies. Our findings suggest that vaccination is associated with high acute anti-S antibody level but reduced convalescent anti-N antibody level. High anti-S antibody level is associated with reduced duration of infection, reduced infectiousness and may also be associated with reduced symptoms severity and number of symptoms.