A hypervirulent
(hvKp) pathotype is undergoing global dissemination. In contrast to the usual health care-associated epidemiology of classical
(cKp) infections, hvKp causes tissue-invasive infections ...in otherwise healthy individuals from the community, often involving multiple sites. An accurate test to identify hvKp strains is needed for improved patient care and epidemiologic studies. To fill this knowledge gap, clinical criteria or random blood isolates from North American and United Kingdom strain collections were used to assemble hvKp-rich (
= 85) and cKp-rich (
= 90) strain cohorts, respectively. The isolates were then assessed for multiple candidate biomarkers hypothesized to accurately differentiate the two cohorts. The genes
,
,
, plasmid-borne
gene (
), and
all demonstrated >0.95 diagnostic accuracy for identifying strains in the hvKp-rich cohort. Next, to validate this epidemiological analysis, all strains were assessed experimentally in a murine sepsis model.
,
,
,
, and
were all associated with a hazard ratio of >25 for severe illness or death, additionally supporting their utility for identifying hvKp strains. Quantitative siderophore production of ≥30 μg/ml also strongly predicted strains as members of the hvKp-rich cohort (accuracy, 0.96) and exhibited a hazard ratio of 31.7 for severe illness or death. The string test, a widely used marker for hvKp strains, performed less well, achieving an accuracy of only 0.90. Last, using the most accurate biomarkers to define hvKp, prevalence studies were performed on two Western strain collections. These data strongly support the utility of several laboratory markers for identifying hvKp strains with a high degree of accuracy.
We investigated determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike IgG responses in healthcare workers (HCWs) following one or two doses of Pfizer–BioNTech or ...Oxford–AstraZeneca vaccines.
HCWs participating in regular SARS-CoV-2 PCR and antibody testing were invited for serological testing prior to first and second vaccination, and 4 weeks post-vaccination if receiving a 12-week dosing interval. Quantitative post-vaccination anti-spike antibody responses were measured using the Abbott SARS-CoV-2 IgG II Quant assay (detection threshold: ≥50 AU/mL). We used multivariable logistic regression to identify predictors of seropositivity and generalized additive models to track antibody responses over time.
3570/3610 HCWs (98.9%) were seropositive >14 days post first vaccination and prior to second vaccination: 2706/2720 (99.5%) were seropositive after the Pfizer–BioNTech and 864/890 (97.1%) following the Oxford–AstraZeneca vaccines. Previously infected and younger HCWs were more likely to test seropositive post first vaccination, with no evidence of differences by sex or ethnicity. All 470 HCWs tested >14 days after the second vaccination were seropositive. Quantitative antibody responses were higher after previous infection: median (IQR) >21 days post first Pfizer–BioNTech 14 604 (7644–22 291) AU/mL versus 1028 (564–1985) AU/mL without prior infection (p < 0.001). Oxford–AstraZeneca vaccine recipients had lower readings post first dose than Pfizer–BioNTech recipients, with and without previous infection, 10 095 (5354–17 096) and 435 (203–962) AU/mL respectively (both p < 0.001 versus Pfizer–BioNTech). Antibody responses >21 days post second Pfizer vaccination in those not previously infected, 10 058 (6408–15 582) AU/mL, were similar to those after prior infection followed by one vaccine dose.
SARS-CoV-2 vaccination leads to detectable anti-spike antibodies in nearly all adult HCWs. Whether differences in response impact vaccine efficacy needs further study.
Summary Background The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the ...implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility. Methods Regional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998–2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses. Findings National fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations <0·59). Regionally, C difficile decline was driven by elimination of fluoroquinolone-resistant isolates (approximately 67% of Oxfordshire infections in September, 2006, falling to approximately 3% in February, 2013; annual incidence rate ratio 0·52, 95% CI 0·48–0·56 vs fluoroquinolone-susceptible isolates: 1·02, 0·97–1·08). C difficile infections caused by fluoroquinolone-resistant isolates declined in four distinct genotypes (p<0·01). The regions of phylogenies containing fluoroquinolone-resistant isolates were short-branched and geographically structured, consistent with selection and rapid transmission. The importance of fluoroquinolone restriction over infection control was shown by significant declines in inferred secondary (transmitted) cases caused by fluoroquinolone-resistant isolates with or without hospital contact (p<0·0001) versus no change in either group of cases caused by fluoroquinolone-susceptible isolates (p>0·2). Interpretation Restricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes. Funding UK Clinical Research Collaboration (Medical Research Council, Wellcome Trust, National Institute for Health Research); NIHR Oxford Biomedical Research Centre; NIHR Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (Oxford University in partnership with Public Health England PHE), and on Modelling Methodology (Imperial College, London in partnership with PHE); and the Health Innovation Challenge Fund.
The mcr-1-associated plasmid in the study by Liu and colleagues, pHNSHP45, is an approximate 64 kb IncI plasmid with substantial sequence homology (>=80% sequence identity over >=80% of the query) to ...only four other plasmid sequences in GenBank (Accession numbers:
•Paediatric respiratory virus seasonality in Oxfordshire was altered by the SARS-CoV-2 pandemic.•Detection of all pathogens was suppressed during the first national lockdown.•SARS-CoV-2 incidence ...reflects the national pandemic infection curves.•Rhinovirus and adenovirus rates increased when schools reopened Sept-Dec 2020.•An inter-seasonal rise in RSV was seen in July 2021, influenza remained supressed.
Objective To describe the impact of the SARS-CoV-2 pandemic on the incidence of paediatric viral respiratory tract infection in Oxfordshire, UK.
Methods Data on paediatric Emergency Department (ED) attendances (0–15 years inclusive), respiratory virus testing, vital signs and mortality at Oxford University Hospitals were summarised using descriptive statistics.
Results Between 1-March-2016 and 30-July-2021, 155,056 ED attendances occurred and 7,195 respiratory virus PCRs were performed. Detection of all pathogens was suppressed during the first national lockdown. Rhinovirus and adenovirus rates increased when schools reopened September-December 2020, then fell, before rising in March-May 2021. The usual winter RSV peak did not occur in 2020/21, with an inter-seasonal rise (32/1,000 attendances in 0–3 yr olds) in July 2021. Influenza remained suppressed throughout. A higher paediatric early warning score (PEWS) was seen for attendees with adenovirus during the pandemic compared to pre-pandemic (p = 0.04, Mann-Witney U test), no other differences in PEWS were seen.
Conclusions SARS-CoV-2 caused major changes in the incidence of paediatric respiratory viral infection in Oxfordshire, with implications for clinical service demand, testing strategies, timing of palivizumab RSV prophylaxis, and highlighting the need to understand which public health interventions are most effective for preventing respiratory virus infections.
Plasmids are extra-chromosomal genetic elements ubiquitous in bacteria, and commonly transmissible between host cells. Their genomes include variable repertoires of 'accessory genes,' such as ...antibiotic resistance genes, as well as 'backbone' loci which are largely conserved within plasmid families, and often involved in key plasmid-specific functions (e.g., replication, stable inheritance, mobility). Classifying plasmids into different types according to their phylogenetic relatedness provides insight into the epidemiology of plasmid-mediated antibiotic resistance. Current typing schemes exploit backbone loci associated with replication (replicon typing), or plasmid mobility (MOB typing). Conventional PCR-based methods for plasmid typing remain widely used. With the emergence of whole-genome sequencing (WGS), large datasets can be analyzed using
plasmid typing methods. However, short reads from popular high-throughput sequencers can be challenging to assemble, so complete plasmid sequences may not be accurately reconstructed. Therefore, localizing resistance genes to specific plasmids may be difficult, limiting epidemiological insight. Long-read sequencing will become increasingly popular as costs decline, especially when resolving accurate plasmid structures is the primary goal. This review discusses the application of plasmid classification in WGS-based studies of antibiotic resistance epidemiology; novel
plasmid analysis tools are highlighted. Due to the diverse and plastic nature of plasmid genomes, current typing schemes do not classify all plasmids, and identifying conserved, phylogenetically concordant genes for subtyping and phylogenetics is challenging. Analyzing plasmids as nodes in a network that represents gene-sharing relationships between plasmids provides a complementary way to assess plasmid diversity, and allows inferences about horizontal gene transfer to be made.
Summary Background Weekend hospital admission is associated with increased mortality, but the contributions of varying illness severity and admission time to this weekend effect remain unexplored. ...Methods We analysed unselected emergency admissions to four Oxford University National Health Service hospitals in the UK from Jan 1, 2006, to Dec 31, 2014. The primary outcome was death within 30 days of admission (in or out of hospital), analysed using Cox models measuring time from admission. The primary exposure was day of the week of admission. We adjusted for multiple confounders including demographics, comorbidities, and admission characteristics, incorporating non-linearity and interactions. Models then considered the effect of adjusting for 15 common haematology and biochemistry test results or proxies for hospital workload. Findings 257 596 individuals underwent 503 938 emergency admissions. 18 313 (4·7%) patients admitted as weekday energency admissions and 6070 (5·1%) patients admitted as weekend emergency admissions died within 30 days (p<0·0001). 9347 individuals underwent 9707 emergency admissions on public holidays. 559 (5·8%) died within 30 days (p<0·0001 vs weekday). 15 routine haematology and biochemistry test results were highly prognostic for mortality. In 271 465 (53·9%) admissions with complete data, adjustment for test results explained 33% (95% CI 21 to 70) of the excess mortality associated with emergency admission on Saturdays compared with Wednesdays, 52% (lower 95% CI 34) on Sundays, and 87% (lower 95% CI 45) on public holidays after adjustment for standard patient characteristics. Excess mortality was predominantly restricted to admissions between 1100 h and 1500 h (pinteraction =0·04). No hospital workload measure was independently associated with mortality (all p values >0·06). Interpretation Adjustment for routine test results substantially reduced excess mortality associated with emergency admission at weekends and public holidays. Adjustment for patient-level factors not available in our study might further reduce the residual excess mortality, particularly as this clustered around midday at weekends. Hospital workload was not associated with mortality. Together, these findings suggest that the weekend effect arises from patient-level differences at admission rather than reduced hospital staffing or services. Funding NIHR Oxford Biomedical Research Centre.
Pathogen genome sequencing can reveal details of transmission histories and is a powerful tool in the fight against infectious disease. In particular, within-host pathogen genomic variants identified ...through heterozygous nucleotide base calls are a potential source of information to identify linked cases and infer direction and time of transmission. However, using such data effectively to model disease transmission presents a number of challenges, including differentiating genuine variants from those observed due to sequencing error, as well as the specification of a realistic model for within-host pathogen population dynamics. Here we propose a new Bayesian approach to transmission inference, BadTrIP (BAyesian epiDemiological TRansmission Inference from Polymorphisms), that explicitly models evolution of pathogen populations in an outbreak, transmission (including transmission bottlenecks), and sequencing error. BadTrIP enables the inference of host-to-host transmission from pathogen sequencing data and epidemiological data. By assuming that genomic variants are unlinked, our method does not require the computationally intensive and unreliable reconstruction of individual haplotypes. Using simulations we show that BadTrIP is robust in most scenarios and can accurately infer transmission events by efficiently combining information from genetic and epidemiological sources; thanks to its realistic model of pathogen evolution and the inclusion of epidemiological data, BadTrIP is also more accurate than existing approaches. BadTrIP is distributed as an open source package (https://bitbucket.org/nicofmay/badtrip) for the phylogenetic software BEAST2. We apply our method to reconstruct transmission history at the early stages of the 2014 Ebola outbreak, showcasing the power of within-host genomic variants to reconstruct transmission events.
Abstract
Background
Natural and vaccine-induced immunity will play a key role in controlling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. SARS-CoV-2 variants have the ...potential to evade natural and vaccine-induced immunity.
Methods
In a longitudinal cohort study of healthcare workers (HCWs) in Oxfordshire, United Kingdom, we investigated the protection from symptomatic and asymptomatic polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection conferred by vaccination (Pfizer-BioNTech BNT162b2, Oxford-AstraZeneca ChAdOx1 nCOV-19) and prior infection (determined using anti-spike antibody status), using Poisson regression adjusted for age, sex, temporal changes in incidence and role. We estimated protection conferred after 1 versus 2 vaccinations and from infections with the B.1.1.7 variant identified using whole genome sequencing.
Results
In total, 13 109 HCWs participated; 8285 received the Pfizer-BioNTech vaccine (1407 two doses), and 2738 the Oxford-AstraZeneca vaccine (49 two doses). Compared to unvaccinated seronegative HCWs, natural immunity and 2 vaccination doses provided similar protection against symptomatic infection: no HCW vaccinated twice had symptomatic infection, and incidence was 98% lower in seropositive HCWs (adjusted incidence rate ratio 0.02 95% confidence interval {CI} < .01–.18). Two vaccine doses or seropositivity reduced the incidence of any PCR-positive result with or without symptoms by 90% (0.10 95% CI .02–.38) and 85% (0.15 95% CI .08–.26), respectively. Single-dose vaccination reduced the incidence of symptomatic infection by 67% (0.33 95% CI .21–.52) and any PCR-positive result by 64% (0.36 95% CI .26–.50). There was no evidence of differences in immunity induced by natural infection and vaccination for infections with S-gene target failure and B.1.1.7.
Conclusions
Natural infection resulting in detectable anti-spike antibodies and 2 vaccine doses both provide robust protection against SARS-CoV-2 infection, including against the B.1.1.7 variant.
Natural infection resulting in detectable anti-spike antibodies and two vaccine doses both provided ≥85% protection against symptomatic and asymptomatic SARS-CoV-2 infection in healthcare workers, including against the B.1.1.7 variant. Single dose vaccination reduced symptomatic infection by 67%.
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