Genome entropy and network centrality contrast exploration and exploitation in evolution of foodborne pathogens.

Modelling evolution of foodborne pathogens is crucial for mitigation and prevention of outbreaks. We apply network-theoretic and information-theoretic methods to trace evolutionary pathways ofSalmonellaTyphimurium in New South Wales, Australia, by studying whole genome sequencing surveillance data over a five-year period which included several outbreaks. The study derives both undirected and directed genotype networks based on genetic proximity, and relates the network's structural property (centrality) to its functional property (prevalence). The centrality-prevalence space derived for the undirected network reveals a salient exploration-exploitation distinction across the pathogens, further quantified by the normalised Shannon entropy and the Fisher information of the corresponding shell genome. This distinction is also analysed by tracing the probability density along evolutionary paths in the centrality-prevalence space. We quantify the evolutionary pathways, and show that pathogens exploring the evolutionary search-space during the considered period begin to exploit their environment (their prevalence increases resulting in outbreaks), but eventually encounter a bottleneck formed by epidemic containment measures.

Identifying factors associated with intravenous fluid administration in patients with sepsis presenting to the emergency department: a retrospective cohort study.

BACKGROUND: Appropriate and timely administration of intravenous fluids to patients with sepsis-induced hypotension is one of the mainstays of sepsis management in the emergency department (ED), however, fluid resuscitation remains an ongoing challenge in ED. Our study has been undertaken with two specific aims: firstly, for patients with sepsis, to identify factors associated with receiving intravenous fluids while in the ED; and, secondly to identify determinants associated with the actual time to fluid administration. METHODS: We conducted a retrospective multicentre cohort study of adult ED presentations between October 2018 and May 2019 in four metropolitan hospitals in Western Sydney, Australia. Patients meeting pre-specified criteria for sepsis and septic shock and treated with antibiotics within the first 24 h of presentation were included. Multivariable models were used to identify factors associated with fluid administration in sepsis. RESULTS: Four thousand one hundred forty-six patients met the inclusion criteria, among these 2,300 (55.5%) patients with sepsis received intravenous fluids in ED. The median time to fluid administration from the time of diagnosis of sepsis was 1.6 h (Interquartile Range (IQR) 0.5 to 3.8), and the median volume of fluids administered was 1,100 mL (IQR 750 to 2058). Factors associated with patients receiving fluids were younger age (Odds Ratio (OR) 1.05, 95% Confidence Interval (CI (1.03 to 1.07), p < 0.001); lower systolic blood pressure (OR 1.11, 95% CI (1.08 to 1.13), p < 0.001); presenting to smaller hospital (OR 1.48, 95% CI (1.25 to 1.75, p < 0.001) and a Clinical Rapid Response alert activated (OR 1.64, 95% CI (1.28 to 2.11), p < 0.001). Patients with Triage Category 1 received fluids 101.22 min earlier (95% CI (59.3 to131.2), p < 0.001) and those with Category 2 received fluids 43.58 min earlier (95% CI (9.6 to 63.1), p < 0.001) compared to patients with Triage Category 3-5. Other factors associated with receiving fluids earlier included septic shock (-49.37 min (95% CI (-86.4 to -12.4), p < 0.001)); each mmol/L increase in serum lactate levels (-9.0 min, 95% CI (-15.7 to -2.3), p < 0.001) and presenting to smaller hospitals (-74.61 min, 95% CI (-94.0 to -55.3), p < 0.001). CONCLUSIONS: Younger age, greater severity of sepsis, and presenting to a smaller hospital increased the probability of receiving fluids and receiving it earlier. Recognition of these factors may assist in effective implementation of sepsis management guidelines which should translate into better patient outcomes. Future studies are needed to identify other associated factors that we have not explored.

Comparison of clinical characteristics and outcomes of patients with sepsis identified by the Sepsis-3 criteria by blood and urine culture results: A multicentre retrospective cohort study.

Background and Aims: Blood and urine are the most common culture testing for sepsis patients. This study aimed to compare clinical characteristics and outcomes of sepsis patients by blood and urine culture positivity and to identify factors associated with positive cultures. Methods: This retrospective study included patients aged ≥16 years with sepsis identified by the Sepsis-3 criteria presenting to the emergency department at four hospitals between 2017 and 2019 in Australia. Patient clinical outcomes were in-hospital mortality, intensive care unit (ICU) admission, hospital length of stay, and representation following discharge. Four culture groups were defined based on the positivity of blood cultures (BC) and urine cultures (UC) ordered within 24 h of triage. Results: Of 4109 patient encounters with sepsis, 2730 (66%) were nonbacteremic, urine culture-negative (BC-UC-); 767 (19%) nonbacteremic, urine culture-positive (BC-UC+); 359 (9%) bacteremic, urine culture-negative (BC+UC-); and 253 (6%) bacteremic, urine culture-positive (BC+UC+). Compared with BC-UC- patients, BC+UC- patients had the highest risk of ICU admission (adjusted odds ratio [AOR] 95% CI: 1.60 [1.18-2.18]) while BC-UC+ patients had lowest risk (adjusted odds ratio [AOR]: 0.56 [0.41-0.76]). BC+UC- patients had the highest risk of 3-day representation (AOR: 1.51 [1.02-2.25]) and second longest hospital stay (adjusted relative risk 1.17 [1.03-1.34]). Antibiotic administration before sample collection for culture was associated with lower odds of positive blood or urine culture results (AOR: 0.38, p < 0.0001). Conclusions: Enhanced clinical care should be beneficial for nongenitourinary sepsis patients (BC+UC-) who had the highest comparative risk of adverse clinical outcomes. Every effort needs to be made to collect relevant culture samples before antibiotic administration, to follow up on culture results, and tailor treatment accordingly.

Association between timing and adequacy of antibiotics and adverse outcomes in patients with sepsis and septic shock: A multicentre retrospective cohort study.

OBJECTIVES: To investigate the association between the timing and adequacy of antibiotics administered to patients presenting with culture-positive sepsis and septic shock to the ED and in-hospital mortality and/or intensive care unit (ICU) admission. METHODS: Multicentre retrospective cohort study of ED presentations at four metropolitan hospitals in Sydney, Australia between January 2017 and November 2019. Encounters for patients aged ≥16 years meeting specified criteria for sepsis or septic shock with antibiotic administration within the first 6 h of presentation were included. RESULTS: Of 7611 encounters included in the study, 2328 (31%) were culture positive, and 2228 (29%) met the criteria for septic shock. In culture-positive sepsis encounters, partial or inadequate antibiotic coverage was associated with higher risk of death or ICU admission (adjusted odds ratio [AOR] 1.50, 95% confidence interval [CI] 1.04-2.06 and 1.95, 95% CI 1.28-2.99, respectively). This effect was not significant in septic shock encounters (AOR 1.10, 95% CI 0.64-1.88) with partial coverage and (AOR 1.63, 95% CI 0.81-3.3) inadequate coverage. Time to antibiotics was not significantly associated with the risk of mortality/ICU admission. This inference remained the same when analysis was restricted to cases with adequate antibiotic coverage. CONCLUSIONS: In a large multicentre sample of patients with culture-positive sepsis, inadequacy of antibiotics was associated with higher risk of in-hospital mortality or ICU admission.

Pangenome Analysis of a Salmonella Enteritidis Population Links a Major Outbreak to a Gifsy-1-Like Prophage Containing Anti-Inflammatory Gene gogB.

A major outbreak of the globally significant Salmonella Enteritidis foodborne pathogen was identified within a large clinical data set by a program of routine WGS of clinical presentations of salmonellosis in New South Wales, Australia. Pangenome analysis helped to quantify and isolate prophage content within the accessory partition of the pangenome. A prophage similar to Gifsy-1 (henceforth GF-1L) was found to occur in all isolates of the outbreak core SNP cluster, and in three other isolates. Further analysis revealed that the GF-1L prophage carried the gogB virulence factor. These observations suggest that GF-1L may be an important marker of virulence for S. Enteritidis population screening and, that anti-inflammatory, gogB-mediated virulence currently associated with Salmonella Typhimurium may also be displayed by S. Enteritidis. IMPORTANCE We examined 5 years of genomic and epidemiological data for the significant global foodborne pathogen, Salmonella enterica. Although Salmonella enterica subspecies enterica serovar Enteritidis (S. Enteritidis) is the leading cause of salmonellosis in the USA and Europe, prior to 2018 it was not endemic in the southern states of Australia. However, in 2018 a large outbreak led to the endemicity of S. Enteritidis in New South Wales, Australia, and a unique opportunity to study this phenomenon. Using pangenome analysis we uncovered that this clone contained a Gifsy-1-like prophage harboring the known virulence factor gogB. The prophage reported has not previously been described in S. Enteritidis isolates.

A laboratory framework for ongoing optimization of amplification-based genomic surveillance programs.

IMPORTANCE: This study provides a laboratory framework to ensure ongoing relevance and performance of amplification-based whole genome sequencing to strengthen public health surveillance during extended outbreaks or pandemics. The framework integrates regular reviews of the performance of a genomic surveillance system and highlights the importance of ongoing monitoring and the identification and implementation of improvements to whole genome sequencing methods to enhance public health responses to pathogen outbreaks.

Advancing pathogen genomics in resource-limited settings.

Genomic sequencing has emerged as a powerful tool to enhance early pathogen detection and characterization with implications for public health and clinical decision making. Although widely available in developed countries, the application of pathogen genomics among low-resource, high-disease burden settings remains at an early stage. In these contexts, tailored approaches for integrating pathogen genomics within infectious disease control programs will be essential to optimize cost efficiency and public health impact. We propose a framework for embedding pathogen genomics within national surveillance plans across a spectrum of surveillance and laboratory capacities. We adopt a public health approach to genomics and examine its application to high-priority diseases relevant in resource-limited settings. For each grouping, we assess the value proposition for genomics to inform public health and clinical decision-making, alongside its contribution toward research and development of novel diagnostics, therapeutics, and vaccines.

Guiding the design of SARS-CoV-2 genomic surveillance by estimating the resolution of outbreak detection.

Genomic surveillance of SARS-CoV-2 has been essential to inform public health response to outbreaks. The high incidence of infection has resulted in a smaller proportion of cases undergoing whole genome sequencing due to finite resources. We present a framework for estimating the impact of reduced depths of genomic surveillance on the resolution of outbreaks, based on a clustering approach using pairwise genetic and temporal distances. We apply the framework to simulated outbreak data to show that outbreaks are detected less frequently when fewer cases are subjected to whole genome sequencing. The impact of sequencing fewer cases depends on the size of the outbreaks, and on the genetic and temporal similarity of the index cases of the outbreaks. We also apply the framework to an outbreak of the SARS-CoV-2 Delta variant in New South Wales, Australia. We find that the detection of clusters in the outbreak would have been delayed if fewer cases had been sequenced. Existing recommendations for genomic surveillance estimate the minimum number of cases to sequence in order to detect and monitor new virus variants, assuming representative sampling of cases. Our method instead measures the resolution of clustering, which is important for genomic epidemiology, and accommodates sampling biases.

Association between intravenous fluid resuscitation and outcome among patients with suspected infection and sepsis: A retrospective cohort study.

OBJECTIVE: To investigate the association between timing and volume of intravenous fluids administered to ED patients with suspected infection and all-cause in-hospital mortality. METHODS: Retrospective cohort study of ED presentations at four metropolitan hospitals in Sydney, Australia, between October 2018 and May 2019. Patients over 16 years of age with suspected infection who received intravenous fluids within 24 h of presentation were included. RESULTS: During the study period, 7533 patients with suspected infection received intravenous fluids. Of these, 1996 (26.5%) and 231 (3.1%) had suspected sepsis and septic shock, respectively. Each 1000 mL increase in intravenous fluids administered was associated with a reduction in risk of in-hospital mortality (adjusted odds ratio [AOR] 0.87, 95% confidence interval [CI] 0.76-0.99). This association was stronger in patients with septic shock (AOR 0.66, 95% CI 0.49-0.89), and those admitted to intensive care unit (ICU) (AOR 0.74, 95% CI 0.56-0.96). Patients with suspected sepsis and septic shock who received a total volume of >3600 mL had lower in-hospital mortality (AOR 0.44, 95% CI 0.22-0.91; AOR 0.16, 95% CI 0.05-0.57) compared to those administered <3600 mL within the first 24 h of presenting to the ED. There was no association between the time of initiation of fluids and in-hospital mortality among survivors and non-survivors (2.3 vs 2.5 h, P = 0.50). CONCLUSION: We observed a reduction in risk of in-hospital mortality for each 1000 mL increase in intravenous fluids administered in patients with septic shock or admitted to ICU suggesting illness severity to be a likely effect modifier.