The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) present clinical criteria for the classification of patients with sepsis. We investigated incidence and long-term outcomes of patients diagnosed with these classifications, which are currently unknown.

The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition.

Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.

Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.

The Third International Consensus Definitions Task Force defined sepsis as "life-threatening organ dysfunction due to a dysregulated host response to infection." The performance of clinical criteria for this sepsis definition is unknown.

Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains.

Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain.

In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.

Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established.

The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.

Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.

In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes.

To define the terms "sepsis" and "organ failure" in a precise manner.

Kuehn B.

Clinicians are being urged to monitor patients after platelet transfusion for signs of bacterial infection after 2 separate US outbreaks linked to these blood products led to serious illnesses and deaths.

Abstract Purpose Pre-clinical animal studies precede the majority of clinical trials. While the clinical sepsis definitions and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May, 2017. The conference goal was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the “Minimum Quality Threshold in Pre-Clinical Sepsis Studies” (MQTiPSS), to enhance translational value of these models. Methods 31 experts from 13 countries participated and were divided into 6 thematic Working Groups (WG): (1) Study Design, (2) Humane modeling, (3) Infection types, (4) Organ failure/dysfunction, (5) Fluid resuscitation and (6) Antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002–2013). Results Overall, the participants reached consensus on 29 points; 20 at “recommendation” (R) and 9 at “consideration” (C) strength. This Executive Summary provides a synopsis of the MQTiPSS consensus (Tables 1–3). Conclusions We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as “best practices” that should be implemented for animal sepsis models. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.

Kidson, Kristen M.; Henderson, William R.; Hutcheon, Jennifer A.

Objectives: Case fatality in pregnancy-associated severe sepsis or septic shock appears reduced compared with nonpregnant women with severe sepsis or septic shock. It remains unclear if this difference is due to pregnancy or better baseline health status, among others. Our study compared adverse outcomes of pregnancy-associated severe sepsis or septic shock with nonpregnant women with severe sepsis or septic shock while controlling for age and chronic comorbidities. Design: Retrospective cohort study. Setting: Nationwide Inpatient Sample, a stratified sample of 20% acute care hospital admissions in the United States. Each entry includes patient and hospital characteristics as well as International Classification of Diseases, 9th revision, Clinical Modification, diagnoses and procedures. Subjects: Women of childbearing age (15–44 yr) with severe sepsis or septic shock–related hospitalizations during 1998–2012 identified using International Classification of Diseases, 9th revision, Clinical Modification, codes. Outcomes: Case fatality, hospital length of stay, length of stay until death, number of organ failures, rates of mechanical ventilation, and hemodialysis were compared in women according to pregnancy status, controlling for age, and chronic comorbidities. Measurements and Main Results: We identified 5,968 pregnancy-associated severe sepsis or septic shock and 85,240 nonpregnant women with severe sepsis or septic shock hospitalizations. Crude case fatality of pregnancy-associated severe sepsis or septic shock (9.6%) was lower than nonpregnant women with severe sepsis or septic shock (16.8%). The rate ratio for case fatality adjusted for socioeconomic status and race was 0.57 (95% CI, 0.52–0.62) while sequential adjustments for age and chronic comorbidities did not eliminate the association (rate ratio, 0.62 [95% CI, 0.57–0.68]) and 0.63 [95% CI, 0.57–0.68], respectively). Pregnancy-associated severe sepsis or septic shock was associated with shorter hospital length of stay (–0.83 d [95% CI, –1.32 to –0.34 d]), longer length of stay until death (2.61 d; [95% CI, 1.28–3.94 d]), and fewer organ failures (rate ratio, 0.95 [95% CI, 0.94–0.97]). Conclusions: Case fatality and adverse outcomes are reduced in women with pregnancy-associated severe sepsis or septic shock compared with nonpregnant women with severe sepsis or septic shock, and this is not explained by differences in age or chronic comorbidities alone. A less severe presentation of sepsis or protective effect of pregnancy may account for the difference observed with pregnancy-associated severe sepsis or septic shock. This work was performed at University of British Columbia. Ethics: This study was exempt from review by the University of British Columbia/British Columbia Children’s and Women’s Hospital Research Ethic Board as it used deidentified, publicly available data. Dr. Kidson was involved in the study concept, design, analysis, and interpretation of data, drafting the article, and critical review of the article. Dr. Henderson was responsible for study design, interpretation of data, and critical review of the article. Dr. Hutcheon was responsible for study design, data acquisition, analysis and interpretation of data, and critical review of the article. All authors approved the final version submitted for publication. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: kmsokalski@alumni.ubc.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Irving, Sharon Y.; Daly, Bridget; Verger, Judy; Typpo, Katri V.; Brown, Ann-Marie; Hanlon, Alexandra; Weiss, Scott L.; Fitzgerald, Julie C.; Nadkarni, Vinay M.; Thomas, Neal J.; Srinivasan, Vijay; for the Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Netw

Objectives: The impact of nutrition status on outcomes in pediatric severe sepsis is unclear. We studied the association of nutrition status (expressed as body mass index z score) with outcomes in pediatric severe sepsis. Design: Secondary analysis of the Sepsis Prevalence, Outcomes, and Therapies study. Patient characteristics, ICU interventions, and outcomes were compared across nutrition status categories (expressed as age- and sex-adjusted body mass index z scores using World Health Organization standards). Multivariable regression models were developed to determine adjusted differences in all-cause ICU mortality and ICU length of stay by nutrition status. Setting: One-hundred twenty-eight PICUs across 26 countries. Patients: Children less than 18 years with severe sepsis enrolled in the Sepsis Prevalence, Outcomes, and Therapies study (n = 567). Interventions: None. Measurements and Main Results: Nutrition status data were available for 417 patients. Severe undernutrition was seen in Europe (25%), Asia (20%), South Africa (17%), and South America (10%), with severe overnutrition seen in Australia/New Zealand (17%) and North America (14%). Severe undernutrition was independently associated with all-cause ICU mortality (adjusted odds ratio, 3.0; 95% CI, 1.2–7.7; p = 0.02), whereas severe overnutrition in survivors was independently associated with longer ICU length of stay (1.6 d; p = 0.01). Conclusions: There is considerable variation in nutrition status for children with severe sepsis treated across this selected network of PICUs from different geographic regions. Severe undernutrition was independently associated with higher all-cause ICU mortality in children with severe sepsis. Severe overnutrition was independently associated with greater ICU length of stay in childhood survivors of severe sepsis. Members of the Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators are listed in Appendix 1. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the Endowed Chair, Department of Anesthesia and Critical Care, University of Pennsylvania Perelman School of Medicine, and the Center for Pediatric Clinical Effectiveness at the Children’s Hospital of Philadelphia. Dr. Weiss is also supported by National Institute of General Medical Sciences K23GM110496. Financial support for data collection in all U.K. centers was provided by the U.K. National Institute of Health (NIHR) Clinical Research Network and in Southampton by the Southampton NIHR Wellcome Trust Clinical Research Facility. None of the funders participated in the design and conduct of study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the article. Dr. Daly received funding from the Biostatistics Consulting Unit at the University of Pennsylvania School of Nursing. Dr. Typpo’s institution received funding from the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases, and Baxter. Dr. Brown received funding from Akron Children’s Hospital Foundation for a different research project, but none related to this project. Dr. Hanlon’s institution received funding from the Children’s Hospital of Philadelphia (CHOP). Dr. Weiss’s institution received funding from Center for Pediatric Clinical Effectiveness at CHOP and National Institute of General Medical Sciences K23GM110496; he received funding from ThemoFisher Scientific (honoraria for lectures unrelated to current topic), Medscape via an unrestricted grant from Roche, and Bristol-Myers Squibb Company (Member of Advisory Panel); and he received support for article research from the NIH. Dr. Fitzgerald’s institution received funding from CHOP Center for Pediatric Clinical Effectiveness. Dr. Thomas received funding from Therabron, CareFusion, and Gene Fluidics. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: srinivasan@email.chop.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Background The emergence and spread of antibiotic resistant micro-organisms is a global concern, which is largely attributable to inaccurate prescribing of antibiotics to patients presenting with non-bacterial infections. The use of ‘omics’ technologies for discovery of novel infection related biomarkers combined with novel treatment algorithms offers possibilities for rapidly distinguishing between bacterial and viral infections. This distinction can be particularly important for patients suffering from lower respiratory tract infections (LRTI) and/or sepsis as they represent a significant burden to healthcare systems. Here we present the study details of the TAILORED-Treatment study, an observational, prospective, multi-centre study aiming to generate a multi-parametric model, combining host and pathogen data, for distinguishing between bacterial and viral aetiologies in children and adults with LRTI and/or sepsis. Methods A total number of 1200 paediatric and adult patients aged 1 month and older with LRTI and/or sepsis or a non-infectious disease are recruited from Emergency Departments and hospital wards of seven Dutch and Israeli medical centres. A panel of three experienced physicians adjudicate a reference standard diagnosis for all patients (i.e., bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. Nasal swabs and blood samples are collected for multi-omics investigations including host RNA and protein biomarkers, nasal microbiota profiling, host genomic profiling and bacterial proteomics. Simplified data is entered into a custom-built database in order to develop a multi-parametric model and diagnostic tools for differentiating between bacterial and viral infections. The predictions from the model will be compared with the consensus diagnosis in order to determine its accuracy. Discussion The TAILORED-Treatment study will provide new insights into the interplay between the host and micro-organisms. New host- or pathogen-related biomarkers will be used to generate a multi-parametric model for distinguishing between bacterial and viral infections. This model will be helpful to better guide antimicrobial therapy for patients with LRTI and sepsis. This study has the potential to improve patient care, reduce unnecessary antibiotic prescribing and will contribute positively to institutional, national and international healthcare economics. Trial Registration NCT02025699. Registration Date: January, 1, 2014.

Lisa K. Torres

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 3, Page 298-300, August 1, 2018.

Jennifer A. Muszynski

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 3, Page 361-369, August 1, 2018.

Abstract Background MALDI-TOF mass spectrometry (MS) on whole cells enables the detection of different cell types and cell activation. Here, we wondered whether this approach would be useful to investigate the host response in sepsis. Methods Peripheral blood mononuclear cells (PBMCs) from patients with severe sepsis and healthy donors were analyzed with MALDI-TOF MS. PBMCs from healthy donors were also stimulated with lipopolysaccharide, peptidoglycan, CpG oligonucleotides, polyinosinic polycytidylic acid, and with heat-inactivated bacteria. Averaged spectra of PBMCs stimulated in vitro by different agonists were generated from the database using the Biotyper software and matching scores between each spectrum from patients and averaged spectra from the database were calculated. Results We show that the MALDI-TOF MS signature of PBMCs from septic patients was specific, compared with healthy controls. As the fingerprints observed in patients may be related to PBMC activation, PBMCs from healthy controls were stimulated with cytokines, soluble Pathogen-Associated Molecular Patterns (PAMPs) and heat-killed bacteria, and we created a database of reference spectra. The MALDI-TOF MS profiles of PBMCs from septic patients were then compared with the database. No differences were found between patients with documented infection (n = 6) and those without bacteriological documentation (n = 6). The spectra of PBMCs from septic patients matched with those of interferon-γ- and interleukin-10-stimulated PBMCs, confirming that sepsis is characterized by both inflammatory and immunoregulatory features. Interestingly, the spectra of PBMCs from septic patients without documented infection matched with the reference spectrum of PBMCs stimulated by CpG oligonucleotides, suggesting a bacterial etiology in these patients. Conclusions Despite the limits of this preliminary study, these results indicate that the monitoring of functional status of PBMCs in peripheral blood by whole cell MALDI-TOF MS could provide unique opportunities to assess disease progression or resolution in clinical settings.

Abstract Background Severe falciparum malaria can be compounded by bacterial sepsis, necessitating antibiotics in addition to anti-malarial treatment. The objective of this analysis was to develop a prognostic model to identify patients admitted with severe malaria at higher risk of developing bacterial sepsis. Methods A retrospective data analysis using trial data from the South East Asian Quinine Artesunate Malaria Trial. Variables correlating with development of clinically defined sepsis were identified by univariable analysis, and subsequently included into a multivariable logistic regression model. Internal validation was performed by bootstrapping. Discrimination and goodness-of-fit were assessed using the area under the curve (AUC) and a calibration plot, respectively. Results Of the 1187 adults with severe malaria, 86 (7.3%) developed clinical sepsis during admission. Predictors for developing sepsis were: female sex, high blood urea nitrogen, high plasma anion gap, respiratory distress, shock on admission, high parasitaemia, coma and jaundice. The AUC of the model was 0.789, signifying modest differentiation for identifying patients developing sepsis. The model was well-calibrated (Hosmer–Lemeshow Chi squared = 1.02). The 25th percentile of the distribution of risk scores among those who developed sepsis could identify a high-risk group with a sensitivity and specificity of 70.0 and 69.4%, respectively. Conclusions The proposed model identifies patients with severe malaria at risk of developing clinical sepsis, potentially benefiting from antibiotic treatment in addition to anti-malarials. The model will need further evaluation with more strictly defined bacterial sepsis as outcome measure.

Abstract Background Maternal vaginal colonization with antibiotic resistant organisms is a growing concern in countries with high antibiotic resistance rates. Methods A low vaginal swab was collected from mothers on admission, on discharge and a peri-rectal swab was collected from the neonates born to these mothers on discharge. Routine microbiological methods were used to identify the colonization rates for Escherichia coli, Klebsiella spp. and Streptococcus agalactiae. Results The pre-delivery colonization rate among the 250 participants for total Enterobacteriaceae was 18.8%. The colonization rates for Klebsiella spp., E. coli and S. agalactiae were, 12.4, 5.6 and 14.8% respectively. Two Klebsiella spp. and two E. coli isolates were confirmed to be exentend spectrum β lactamase (ESBL) producers with the commonest resistant determinant being blaCTX-M. Post-delivery swabs were collected from 130 participants and the colonization rates were 41.5% for Enterobacteriaceae, 25.4% for Klebsiella spp., 10.8% for E. coli, and 10.8% for S. agalacteiae. Three Klebsiella isolates and one E. coli isolate were confirmed to be ESBL producers with the commonest resistant determinant being blaCTX-M. Considering the 130 participants with both samples, there was a significant increase in the colonization with any Enterobacteriaceae and Klebsiella spp. (p 

Paoli, Carly J.; Reynolds, Mark A.; Sinha, Meenal; Gitlin, Matthew; Crouser, Elliott

Objectives: To characterize the current burden, outcomes, and costs of managing sepsis patients in U.S. hospitals. Design: A retrospective observational study was conducted using the Premier Healthcare Database, which represents ~20% of U.S. inpatient discharges among private and academic hospitals. Hospital costs were obtained from billing records per the cost accounting method used by each hospital. Descriptive statistics were performed on patient demographics, characteristics, and clinical and economic outcomes for the index hospitalization and 30-day readmissions. Setting: Sepsis patient hospitalizations, including inpatient, general ward, and ICU (intermediate and/or step-down). Patients: Adults over 18 years old with a hospital discharge diagnosis code of sepsis from January 1, 2010, to September 30, 2016. Interventions: None. This was a retrospective observational study of deidentified data. Measurements and Main Results: The final study cohort consisted of 2,566,689 sepsis cases, representing patients with a mean age of 65 years (50.8% female). Overall mortality was 12.5% but varied greatly by severity (5.6%, 14.9%, and 34.2%) for sepsis without organ dysfunction, severe sepsis, and septic shock, respectively. Costs followed a similar pattern increasing by severity level: $16,324, $24,638, and $38,298 and varied widely by sepsis present at admission ($18,023) and not present at admission ($51,022). Conclusions: The highest burden of incidence and total costs occurred in the lowest severity sepsis cohort population. Sepsis cases not diagnosed until after admission, and those with increasing severity had a higher economic burden and mortality on a case-by-case basis. Methods to improve early identification of sepsis may provide opportunities for reducing the severity and economic burden of sepsis in the United States. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. This research was conducted at Premier, Inc. Supported, in part, by Beckman Coulter, Inc. Drs. Paoli and Dr. Reynolds are both employees of and hold stock in Beckman Coulter, Inc./Danaher Corp. (parent company of Beckman Coulter). Dr. Sinha is an employee of Premier, Inc., which received funding to conduct the research project. Dr. Gitlin is an employee of BluePath Solutions, which received funding to conduct the research project, and his institution received funding from Danaher Corp., Diagnostics & Life Science Platforms. Drs. Sinha’s and Crouser’s institutions received funding from Beckman Coulter, Inc. Dr. Crouser has received support from Beckman Coulter, Inc. as a scientific consultant and as principal investigator of a clinical trial investigating a novel sepsis biomarker, and his institution also received funding from the National Institutes of Health and Foundation for Sarcoidosis Research Address requests for reprints to: Carly J. Paoli, PharmD, MPH, Global Health Economics & Reimbursement, Danaher Corp., Diagnostics & Life Science Platforms | Beckman Coulter, 250 S. Kraemer Blvd, Brea, CA 92822. E-mail: cjworden@beckman.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Vinci RJ, Melendez E.

Sepsis has been recognized by the United Nations World Health Assembly as a global threat to the health of children and adults. The World Health Organization has established as a priority the identification of strategies for prevention, early diagnosis, and treatment of sepsis.

Evans IR, Phillips GS, Alpern ER, et al.

This cohort study determines the risk-adjusted association between completing a 1-hour pediatric sepsis bundle and individual bundle elements with in-hospital mortality following statewide mandated care for pediatric sepsis in New York.

Li P, Zhou Y, Goodwin A, et al.

AbstractPericytes are vascular mural cells and are embedded in the basement membrane of the microvasculature. Recent studies suggest a role for pericytes in LPS-induced microvascular dysfunction and mortality, but the mechanisms of pericyte loss in sepsis are largely unknown. By using cecal ligation and puncture (CLP)-induced murine model of sepsis, we observed that CLP led to lung and renal pericyte loss and reduced lung pericyte density and pericyte/endothelial cell (EC) coverage. Up-regulated Friend leukemia virus integration 1 (Fli-1) mRNA and protein levels were found in lung pericytes from CLP mice in vivo and in LPS-stimulated lung pericytes in vitro. Knockout of Fli-1 in Foxd1-derived pericytes prevented CLP-induced pericyte loss, vascular leak and improved survival. Disrupted Fli-1 expression by siRNA inhibited LPS-induced inflammatory cytokines and chemokines in cultured lung pericytes. Furthermore, CLP-induced pericyte pyroptosis was mitigated in pericyte Fli-1 knockout mice. Our findings suggest that Fli-1 is a potential therapeutic target in sepsis.

Stefan Hagel, Katrin Ludewig, Mathias W. Pletz, Janina Frosinski, Anne Moeser, Martin Wolkewitz, Petra Gastmeier, Stephan Harbarth, Frank M. Brunkhorst, Miriam Kesselmeier, André Scherag

To evaluate whether a hospital-wide infection control programme (ICP) is effective at reducing the burden of healthcare-associated infections (HAIs) and associated severe sepsis/septic shock or death (severe HAIs).

Hatfield, Kelly M.; Dantes, Raymund B.; Baggs, James; Sapiano, Mathew R. P.; Fiore, Anthony E.; Jernigan, John A.; Epstein, Lauren

Objectives: To assess the variability in short-term sepsis mortality by hospital among Centers for Medicare and Medicaid Services beneficiaries in the United States during 2013–2014. Design: A retrospective cohort design. Setting: Hospitalizations from 3,068 acute care hospitals that participated in the Centers for Medicare and Medicaid Services inpatient prospective payment system in 2013 and 2014. Patients: Medicare fee-for-service beneficiaries greater than or equal to 65 years old who had an inpatient hospitalization coded with present at admission severe sepsis or septic shock. Interventions: None. Measurements and Main Results: Individual level mortality was assessed as death at or within 7 days of hospital discharge and aggregated to calculate hospital-level mortality rates. We used a logistic hierarchal linear model to calculate mortality risk-adjusted for patient characteristics. We quantified variability among hospitals using the median odds ratio and calculated risk-standardized mortality rates for each hospital. The overall crude mortality rate was 34.7%. We found significant variability in mortality by hospital (p < 0.001). The middle 50% of hospitals had similar risk-standardized mortality rates (32.7–36.9%), whereas the decile of hospitals with the highest risk-standardized mortality rates had a median mortality rate of 40.7%, compared with a median of 29.2% for hospitals in the decile with the lowest risk-standardized mortality rates. The median odds ratio (1.29) was lower than the adjusted odds ratios for several measures of patient comorbidities and severity of illness, including present at admission organ dysfunction, no identified source of infection, and age. Conclusions: In a large study of present at admission sepsis among Medicare beneficiaries, we showed that mortality was most strongly associated with underlying comorbidities and measures of illness on arrival. However, after adjusting for patient characteristics, mortality also modestly depended on where a patient with sepsis received care, suggesting that efforts to improve sepsis outcomes in lower performing hospitals could impact sepsis survival. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the salary funds at the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Drs. Hatfield, Baggs, Sapiano, Fiore, Jernigan, and Epstein disclosed government work. Dr. Dantes disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: UYL3@cdc.gov Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Nubwa Medugu, Kenneth Iregbu, Pui-Ying Iroh Tam, Stephen Obaro

by Nubwa Medugu, Kenneth Iregbu, Pui-Ying Iroh Tam, Stephen Obaro Background Group B Streptococcus (GBS) causes invasive infections in neonates and has been implicated as a cause of prelabour rupture of membranes, preterm delivery and stillbirths. The success of phase II trials of polyvalent polysaccharide GBS vaccines indicates that these infections are potentially preventable. Nigeria is the most populous country in Africa with one of the highest birth rates, one of the highest neonatal sepsis incidence rates and one of the highest mortality rates in the world. Therefore, before the possible introduction of preventive strategies such as intrapartum antibiotic prophylaxis or GBS vaccine into Nigeria, it is vital that there is accurate data on the aetiology of neonatal sepsis and on the incidence of GBS neonatal sepsis in particular. The objective of this study was to determine the incidence and aetiology of neonatal sepsis in Nigeria with a focus on GBS sepsis and also to assess the potential impact of a GBS vaccine. Methods A literature search was conducted on the databases of African journals online, PubMed and Google Scholar for works conducted between 1987 to 2017. Case reports, reviews, and studies not stating specific culture methods or specific bacteria isolated were excluded. Data extracted included; incidence of neonatal sepsis, method of blood culture, blood volume, sample size, bacterial agents isolated and history of antibiotic use. PRISMA guidelines were followed and modified Down’s and Black criteria used to evaluate the quality of studies. Results A total of 5,114 studies were reviewed for neonatal sepsis out of which 24 consisting of a total of 2,280 cases were selected for final review. Nine studies met criteria for assessment of hospital based incidence of neonatal sepsis representing 31,305 hospital births. The incidence of neonatal sepsis was 18.2/1000 livebirths with range from 7-55/1000 livebirths while the GBS incidence was 0.06/1000 livebirths with range from 0-2/1000 live births. We discovered various limitations such as identification techniques that could result in underestimation of the true incidence of GBS sepsis. Pathogens such as Klebsiella pneumoniae and Staphylococcus aureus were more commonly isolated than GBS. Implications of key findings The hospital based incidence of neonatal sepsis was high at 18.2/1000 live births while that due to GBS was 0.06/1000 live births. The burden of neonatal sepsis, including that attributable to GBS is substantial and could be reduced by preventive strategies such as intrapartum antibiotic prophylaxis or GBS vaccine. There is however very sparse meaningful data currently. Well planned prospective studies with larger sample sizes, more advanced isolation and identification techniques and those following up invasive disease cases for possible short and long term sequelae are needed—not only prior to possible introduction of the vaccine to determine the baseline epidemiology, but also thereafter to monitor its impact on the population. Strategies need to be developed to also reduce the morbidity and mortality attributable to other bacteria that have an incidence even greater than that of GBS.

Abiodun D. Ogunniyi, Zlatko Kopecki, Elizabeth E. Hickey, Manouchehr Khazandi, Emma Peel, Katherine Belov, Alexandra Boileau, Sanjay Garg, Henrietta Venter, Wei Yee Chan, Peter B. Hill, Stephen W. Page, Allison J. Cowin, Darren J. Trott

by Abiodun D. Ogunniyi, Zlatko Kopecki, Elizabeth E. Hickey, Manouchehr Khazandi, Emma Peel, Katherine Belov, Alexandra Boileau, Sanjay Garg, Henrietta Venter, Wei Yee Chan, Peter B. Hill, Stephen W. Page, Allison J. Cowin, Darren J. Trott There are very few articles in the literature describing continuous models of bacterial infections that mimic disease pathogenesis in humans and animals without using separate cohorts of animals at each stage of disease. In this work, we developed bioluminescent mouse models of partial-thickness scald wound infection and sepsis that mimic disease pathogenesis in humans and animals using a recombinant luciferase-expressing Staphylococcus aureus strain (Xen29). Two days post-scald wound infection, mice were treated twice daily with a 2% topical mupirocin ointment for 7 days. For sepsis experiments, mice were treated intraperitoneally with 6 mg/kg daptomycin 2 h and 6 h post-infection and time to moribund monitored for 72 h. Consistent bacterial burden data were obtained from individual mice by regular photon intensity quantification on a Xenogen IVIS Lumina XRMS Series III biophotonic imaging system, with concomitant significant reduction in photon intensities in drug-treated mice. Post-mortem histopathological examination of wounds and bacterial counts in blood correlated closely with disease severity and total flux obtained from Xen29. The bioluminescent murine models provide a refinement to existing techniques of multiple bacterial enumeration during disease pathogenesis and promote animal usage reduction. The models also provide an efficient and information-rich platform for preclinical efficacy evaluation of new drug classes for treating acute and chronic human and animal bacterial infections.

Katherine Crawford

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 2, Page 280-282, July 15, 2018.