Abstract Introduction Staphylococcus aureus frequently causes infections in outpatient and hospital settings and can present as a highly variable entity. Typical manifestations are endocarditis, osteoarticular infections or infection of implanted prostheses, intravascular devices or foreign bodies. A thorough diagnostic evaluation with early focus identification is mandatory to improve patient outcome. Case report We report a case of a 68-year old patient with a history of double allogeneic stem cell transplant for acute myeloid leukemia who developed a S. aureus bacteremia with dissemination, severe sepsis and lethal outcome due to nasal handkerchief packing after nose bleeding. Conclusion A thorough medical examination with further diagnostic work-up is most important in S. aureus blood stream infection to identify and eradicate the portal(s) of entry, to rule out endocarditis, to search for spinal abscesses, osteomyelitis or spondylodiscitis. Adherence to management guides for clinicians must be of major importance to achieve optimal quality of clinical care, and thus improve patient outcome.

Johnson J, Johnston B, Porter S, et al.

AbstractBackgroundThe distinguishing characteristics of extraintestinal pathogenic Escherichia coli (ExPEC) strains are incompletely defined.MethodsWe characterized 292 diverse-source human E. coli isolates (116 fecal, 27 cystitis, 30 pyelonephritis, 93 blood) for phylogenetic group, sequence type complex (STc), and 49 putative ExPEC-associated virulence genes. We then assessed these traits and ecological source as predictors of illness severity in a murine sepsis model.ResultsThe study isolates exhibited a broad range of virulence in mice. Most of the studied bacterial characteristics corresponded significantly with experimental virulence, as did ecological source and established molecular definitions of ExPEC and uropathogenic E. coli (UPEC). Multivariable modeling identified similar bacterial traits as independent predictors of illness severity both overall and among the fecal and clinical isolates separately: fyuA (yersiniabactin receptor), kpsM K1 (K1 capsule), and kpsM II (group 2 capsules). Molecular UPEC status predicted virulence independently only among fecal isolates. Neither ecological source (e.g., clinical vs. fecal) nor molecular ExPEC status added predictive power to these traits, which accounted collectively for up to 49% of observed virulence variation.ConclusionsAmong human-source E. coli isolates, specific accessory traits and phylogenetic/clonal backgrounds predict experimental virulence in a murine sepsis model better than does ecological source.

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.

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.

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.

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.

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.

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.

Abstract To describe the characteristics of adult invasive H. influenzae disease, 34 patients diagnosed at a single tertiary center between 2004 and 2017 were analyzed in a retrospective case series study. The annual estimated incidence was 0.1 cases/100.000 inhabitants. Dominant source of infection was pneumonia accompanied by sepsis (62%) and caused by nontypeable strains (74%) with low ampicillin resistance (14%). Survival (94%) and complication rates were high (35%). Main empirical treatments were ceftriaxone or levofloxacine.

Abstract Background Sepsis-like illness with suspected meningitis or encephalitis is a common reason for using empiric antimicrobial therapy in infants and children. However, in cases of viral meningitis not covered by these antimicrobials, this management is ineffective and due to side effects potentially harmful. Methods A retrospective analysis of cerebrospinal fluid (CSF) multiplex PCRs (Biofire FilmArray®) in children with clinical suspicion of meningitis, encephalitis or sepsis-like illness was performed over the period of 1 year. Subsequently, a subgroup of children (age of 8–84 days of life) diagnosed with viral meningitis (enterovirus, HHV-6, human parechovirus) was compared to an age-matched control group. Results During the study period, the multiplex PCR panel was performed on 187 individual CSF samples that met the inclusion criteria. About half of the patients (92/187) were less than 1 year of age. In 27 cases (14.4%), the PCR yielded a positive result with the majority (12/27) being indicative of an enteroviral infection. In the age group of 8–84 days of life, 36.4% of the patients had a positive result. When the patients with a PCR positive for a viral agent were compared to an age-matched group of patients, no differences were observed regarding symptoms and laboratory parameters. However, the duration of antimicrobial therapy could be significantly reduced through the use of multiplex PCR. Conclusion The use of on-site diagnostic multiplex PCR was able to reduce the use of antimicrobials in selected cases. This test can guide clinical decisions earlier during the course of medical care compared to standard diagnostics.

Jérôme Allyn, Cyril Ferdynus, Hugo Lo Pinto, Bruno Bouchet, Romain Persichini, David Vandroux, Berenice Puech, Nicolas Allou

by Jérôme Allyn, Cyril Ferdynus, Hugo Lo Pinto, Bruno Bouchet, Romain Persichini, David Vandroux, Berenice Puech, Nicolas Allou Background Treatment by venoarterial extracorporeal membrane oxygenation (VA-ECMO) is widely used today, even though it is associated with high risks of complications and death. While studies have focused on the relationship between some of these complications and the risk of death, the relationship between different complications has never been specifically examined, despite the fact that the occurrence of one complication is known to favor the occurrence of others. Our objective was to describe the relationship between complications in patients undergoing VA-ECMO in intensive care unit (ICU) and to identify, if possible, patterns of patients according to complications. Methods and findings As part of a retrospective cohort study, we conducted a multiple correspondence analysis followed by a hierarchical ascendant classification in order to identify patterns of patients according to main complications (sepsis, thromboembolic event, major transfusion, major bleeding, renal replacement therapy) and in-ICU death. Our cohort of 145 patients presented an in-ICU mortality rate of 50.3%. Morbidity was high, with 36.5% of patients presenting three or more of the five complications studied. Multiple correspondence analysis revealed a cumulative inertia of 76.9% for the first three dimensions. Complications were clustered together and clustered close to death, prompting the identification of four patterns of patients according to complications, including one with no complications. Conclusions Our study, based on a large cohort of patients undergoing VA-ECMO in ICU and presenting a mortality rate comparable to that reported in the literature, identified numerous and often interrelated complications. Multiple correspondence analysis and hierarchical ascendant classification yielded clusters of patients and highlighted specific links between some of the complications studied. Further research should be conducted in this area.

The original version of this article unfortunately contained mistakes.

Lisa K. Torres

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

Ibrahim, H., Askar, B., Hulme, S., Neilson, P., Barrow, P., Foster, N.

We studied the effect of two S. Typhimurium (host adapted) strains (14028 and 4/74) and three S. Choleraesuis (non-host adapted) strains (A50, A45 and B195) in human monocytes between 2-24h post-infection (pi); to investigate whether difference in the immune response may explain the much higher prevalence of sepsis in individuals infected with S. Choleraesuis.Both serovars significantly increased production of cytokines associated with acute sepsis (TNF-α, IL-β and IL-6) but temporal differences occurred between these serovars and between different S. Choleraesuis strains. Generally, all S. Choleraesuis strains induced significantly greater production of inflammatory cytokines compared to S. Typhimurium strains (P

Schaltz-Buchholzer F, Biering-Sørensen S, Lund N, et al.

AbstractObjectiveTo examine effects of early Bacille Calmette-Guérin (BCG) vaccination on the risk, cause and severity of infant hospitalizations. DesignAnalysis of three trials randomizing low-weight neonates to early-BCG(intervention) versus no-BCG(usual practice in low-weight neonates, control), with hospitalizations as secondary outcome. MethodsHospitalization data was collected at the pediatric ward of the National Hospital. Effects of BCG on hospitalization risk were assessed in Cox-models providing overall and major disease-group incidence rate ratios(IRRs). Severity was assessed by in-hospital case-fatality rates and compared by group as cohort study risk ratios(RRs). ResultsAmong 6,583 infants (3,297 BCG; 3,286 controls), there were 908 infant hospitalizations (450 BCG; 458 controls) and 135 in-hospital deaths (56 BCG; 79 controls). The neonatal(28days), 6-week and infant(1year) BCG versus control hospitalization IRRs were 0.97(95% CI 0.72-1.31), 0.95(0.73-1.24) and 0.96(0.84-1.10). Corresponding BCG versus control case-fatality RRs were 0.58(0.35-0.94), 0.56(0.35-0.90) and 0.72(0.53-0.99). BCG tended to reduce neonatal and infant sepsis hospitalization rates, IRRs being 0.75(0.50-1.13) and 0.78(0.55-1.11), and reduced in-hospital neonatal sepsis mortality, RR=0.46(0.22-0.98). There were no confirmed tuberculosis hospitalizations.ConclusionBCG did not affect hospitalization rates but reduced in-hospital mortality significantly, primarily by preventing fatal cases of sepsis. The observed beneficial effects of BCG on in-hospital mortality were entirely non-specific.

Pu, Hong; Doig, Gordon S.; Heighes, Philippa T.; Allingstrup, Matilde J.

Objectives: To identify, appraise, and synthesize current evidence to determine whether early enteral nutrition alters patient outcomes from major burn injury. Data Sources: Medline, Embase, and the China National Knowledge Infrastructure were searched. The close out date was May 1, 2018. Study Selection: Early enteral nutrition was defined as a standard formula commenced within 24 hours of injury or admission to ICU or burn unit. Comparators included any form of nutrition support “except” early enteral nutrition. Only randomized controlled trials reporting patient-centered outcomes were eligible for inclusion. Data Extraction: The primary outcome was mortality. Gastrointestinal hemorrhage, sepsis, pneumonia, renal failure, and hospital stay were evaluated as secondary outcomes. Data Synthesis: Nine-hundred fifty-eight full-text articles were retrieved and screened. Seven randomized controlled trials enrolling 527 participants with major burn injury were included. Compared with all other types of nutrition support, early enteral nutrition significantly reduced mortality (odds ratio, 0.36; 95% CI, 0.18–0.72; p = 0.003; I2 = 0%). Early enteral nutrition also significantly reduced gastrointestinal hemorrhage (odds ratio, 0.21; 95% CI, 0.09–0.51; p = 0.0005; I2 = 0%), sepsis (odds ratio, 0.23; 95% CI, 0.11–0.48; p < 0.0001; I2 = 0%), pneumonia (odds ratio, 0.41; 95% CI, 0.21–0.81; p = 0.01; I2 = 63%), renal failure (odds ratio, 0.27; 95% CI, 0.09–0.82; p = 0.02; I2 = 32%), and duration of hospital stay (–15.31 d; 95% CI, –20.43 to –10.20; p < 0.00001; I2 = 0%). Conclusions: The improvements in clinical outcomes demonstrated in this meta-analysis are consistent with the physiologic rationale cited to support clinical recommendations for early enteral nutrition made by major clinical practice guidelines: gut integrity is preserved leading to fewer gastrointestinal hemorrhages, less infectious complications, a reduction in consequent organ failures, and a reduction in the onset of sepsis. The cumulative benefit of these effects improves patient survival and reduces hospital length of stay. 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). Dr. Pu’s Visiting Fellowship with the University of Sydney’s Northern Clinical School Intensive Care Research Unit was enabled by a grant from the National Leading Clinical Specialty Foundation for the Department of Critical Care Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, People’s Republic of China. Dr. Allingstrup reported receiving academic research grants from Fresenius Kabi Deutschland GmbH, Medinor A/S Denmark, and COSMED Srl, Rome, Italy and speakers honoraria from Fresenius Kabi A/S Denmark, Baxter Healthcare A/S Denmark and Nutricia A/S Denmark. Dr. Doig reported receiving academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd and speakers honoraria from Fresenius Kabi Deutschland GmbH, Baxter Healthcare Australia, Pty Ltd, Nestle Healthcare, Vevy, Switzerland, and Nutricia Pharmaceutical (Wuxi) Ltd. China (lecture fees). Dr. Heighes has not disclosed any potential conflicts of interest. For information regarding this article, E-mail: gdoig@med.usyd.edu.au Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Jennifer A. Muszynski

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

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).

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.

Kievlan, Daniel R.; Zhang, Li A.; Chang, Chung-Chou H.; Angus, Derek C.; Seymour, Christopher W.

Objectives: Among patients with suspected infection, a single measurement of the quick Sepsis-related Organ Failure Assessment has good predictive validity for sepsis, yet the increase in validity from repeated measurements is unknown. We sought to determine the incremental predictive validity for sepsis of repeated quick Sepsis-related Organ Failure Assessment measurements over 48 hours compared with the initial measurement. Design: Retrospective cohort study. Setting: Twelve hospitals in southwestern Pennsylvania in 2012. Patients: All adult medical and surgical encounters in the emergency department, hospital ward, postanesthesia care unit, and ICU. Interventions: None. Measurements and Main Results: Among 1.3 million adult encounters, we identified those with a first episode of suspected infection. Using the maximum quick Sepsis-related Organ Failure Assessment score in each 6-hour epoch from onset of suspected infection until 48 hours later, we characterized repeated quick Sepsis-related Organ Failure Assessment with: 1) summary measures (e.g., mean over 48 hr), 2) crude trajectory groups, and 3) group-based trajectory modeling. We measured the predictive validity of repeated quick Sepsis-related Organ Failure Assessment using incremental changes in the area under the receiver operating characteristic curve for in-hospital mortality beyond that of baseline risk (age, sex, race/ethnicity, and comorbidity). Of 37,591 encounters with suspected infection, 1,769 (4.7%) died before discharge. Both the mean quick Sepsis-related Organ Failure Assessment at 48 hours (area under the receiver operating characteristic, 0.86 [95% CI, 0.85–0.86]) and crude trajectory groups (area under the receiver operating characteristic, 0.83 [95% CI, 0.83–0.83]) improved predictive validity compared with initial quick Sepsis-related Organ Failure Assessment (area under the receiver operating characteristic, 0.79 [95% CI, 0.78–0.80]) (p < 0.001 for both). Group-based trajectory modeling found five trajectories (quick Sepsis-related Organ Failure Assessment always low, increasing, decreasing, moderate, and always high) with greater predictive validity than the initial measurement (area under the receiver operating characteristic, 0.85 [95% CI, 0.84–0.85]; p < 0.001). Conclusions: Repeated measurements of quick Sepsis-related Organ Failure Assessment improve predictive validity for sepsis using in-hospital mortality compared with a single measurement of quick Sepsis-related Organ Failure Assessment at the time a clinician suspects infection. This work was performed at the University of Pittsburgh School of Medicine. Drs. Kievlan, Angus, and Seymour contributed to study concept and design; Drs. Kievlan and Seymour contributed to acquisition of data; Drs. Kievlan, Zhang, Chang, Angus, and Seymour contributed to analysis and interpretation of data; Dr. Kievlan contributed to first drafting of the article; Drs. Kievlan, Zhang, Chang, Angus, and Seymour contributed to critical revision of the article for important intellectual content; Drs. Kievlan, Chang, and Seymour contributed to statistical analysis; Drs. Kievlan and Seymour contributed to sdministrative, technical, and material support; Dr. Seymour contributed to study supervision: Drs. Kievlan and Seymour contributed to data access and responsibility and they had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. 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 National Institutes of Health, T32HL007820 (to Dr. Kievlan) and R35GM119519 (to Drs. Chang, Angus, and Seymour). Dr. Kievlan’s institution received funding from National Heart, Lung, and Blood Institute, and he disclosed that Drs. Chang, Angus, and Seymour received support from the National Institute of General Medical Services. Drs. Kievlan, Zhang, Chang, and Seymour received support for article research from the National Institutes of Health (NIH). Drs. Zhang’s and Seymour’s institutions received funding from the NIH. Dr. Seymour received funding from Beckman Coulter. For information regarding this article, E-mail: daniel.kievlan@gmail.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Lubkin, David T.; Bishawi, Muath; Barbas, Andrew S.; Brennan, Todd V.; Kirk, Allan D.

Objectives: Extracellular mitochondrial DNA and N-formyl peptides released following tissue damage may contribute to systemic inflammation through stimulation of the innate immune system. In this review, we evaluate existing in vivo human data regarding a role for mitochondrial DNA and N-formyl peptides in producing systemic inflammation in trauma and critical illness, investigate the utility of these molecules in risk prediction and clinical decision support, and provide suggestions for standardization of future research. Data Sources: PubMed, Embase (1971–2017). Study Selection: Studies measuring extracellular mitochondrial DNA and/or N-formyl peptides in acutely ill patients. Data Extraction: Fifty-four studies were analyzed. Data extracted included article characteristics, methods, results, and performance in clinical prediction. Data Synthesis: The most common patient types investigated were trauma (19 studies) and sepsis (eight). In studies comparing patient mitochondrial DNA or N-formyl peptide levels to healthy controls, 38 (90.5%) reported significantly elevated mitochondrial DNA levels in patients at first reported time point, as did the one study making this comparison for N-formyl peptides. Nine studies (81.8%) reported significantly elevated plasma/serum mitochondrial DNA levels in at least one time point in patients who developed inflammatory complications of their primary pathology compared with patients without inflammatory complications. For the ability of mitochondrial DNA to predict complications or outcomes, the area under the curve was 0.7 or greater in 84.6% of receiver operating characteristic curves, and 92.9% of odds, adjusted odds, risk, and hazard ratios were statistically significant. Conclusions: Extracellular mitochondrial DNA levels are elevated early in patients’ hospital courses in many acute illnesses and are higher in patients who develop inflammatory complications. Elevated mitochondrial DNA levels may be clinically useful in risk prediction and clinical decision support systems. Further research is needed to determine the role of extracellular N-formyl peptides in systemic inflammation and their possible clinical utility. 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 grant HT9404-13-1-0032 (to Dr. Kirk) from the Department of Defense. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Allan.Kirk@Duke.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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.

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.

Carter, G. P., Ussher, J. E., Goncalves Da Silva, A., Baines, S. L., Heffernan, H., Riley, T. V., Broadbent, R., van der Linden, A., Lee, J., Monk, I. R., Stinear, T. P., Howden, B. P., Williamson, D. A.

Coagulase-negative staphylococci (CoNS) such as Staphylococcus capitis, are major causes of bloodstream infections in neonatal intensive care units (NICUs). Recently a distinct clone of S. capitis (designated S. capitis NRCS-A) has emerged as an important pathogen in NICUs internationally. Here, 122 S. capitis isolates from New Zealand (NZ) underwent whole genome sequencing (WGS), and these data were supplemented with publicly available S. capitis sequence reads. Phylogenetic and comparative genomic analyses were performed, as were phenotypic assessments of antimicrobial resistance, biofilm formation and plasmid segregational stability on representative isolates. A distinct lineage of S. capitis was identified in NZ, associated with neonates and the NICU environment. Isolates from this lineage produced increased levels of biofilm, displayed higher levels of tolerance to chlorhexidine, and were multidrug-resistant. Although similar to globally circulating NICU-associated S. capitis at a core genome level, NZ NICU S. capitis isolates carried a novel, stably maintained multidrug-resistant plasmid that was not present in non-NICU isolates. Neonatal blood culture isolates were indistinguishable to environmental S. capitis isolates found on fomites such as stethoscopes and neonatal incubators, but were generally distinct from those isolates carried by NICU staff. This work implicates the NICU environment as a potential reservoir for neonatal sepsis caused by S. capitis, and highlights the capacity of genomics-based tracking and surveillance to inform future hospital infection control practices aimed at containing the spread of this important neonatal pathogen.

Abstract Introduction Gut permeability is increased in critically ill patients, and associated with the development of the systemic inflammatory response syndrome and multiple organ dysfunction syndrome (MODS). The pathogenetic link(s) and potential therapies are an area of intense research over the last decades. Methods We thoroughly reviewed the literature on gut-origin sepsis and MODS in critically ill patients, with emphasis on the implicated pathophysiological mechanisms and therapeutic interventions. Findings Intestinal barrier failure leading to systemic bacterial translocation associated with MODS was the predominant pathophysiological theory for several years. However, clinical studies with critically ill patients failed to provide the evidence of systemic spread of gut-derived bacteria and/or their products as a cause of MODS. Newer experimental data highlight the role of the mesenteric lymph as a carrier of gut-derived danger-associated molecular patterns (DAMPs) to the lung and the systemic circulation. These substances are recognized by pattern recognition receptor-bearing cells in diverse tissues and promote proinflammatory pathways and the development MODS. Therefore, the gut becomes a pivotal proinflammatory organ, driving the systemic inflammatory response through DAMPs release in mesenteric lymph, without the need for systemic bacterial translocation. Conclusions There is an emerging need for application of sensitive non-invasive and easily measured biomarkers of early intestinal injury (e.g., citrulline, intestinal fatty acid protein, and zonulin) in our everyday clinical practice, guiding the early pharmacological intervention in critically ill patients to restore or prevent intestinal injury and improve their outcomes.

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 Staphylococcus aureus bacteraemia (SAB) causes considerable morbidity and mortality in children. Despite this, its epidemiology and risk factors are poorly understood, with minimal paediatric clinical trial data available to guide clinicians in management. We conducted a pilot study to characterise SAB and validate a severity classification for use in future clinical trials. Methods Patients with SAB were prospectively identified at Princess Margaret Hospital for Children (Perth, Western Australia) from May 2011 to December 2013. Retrospective data were collected from clinical and laboratory records. Cases were classified based on a priori defined criteria as simple (single or contiguous, peripheral site focus) or complex (multi-site, deep tissue, no focus or sepsis) and tested against risk factors and markers of severity of infection. Results There were 49 cases of SAB (median age 7.7 years), with classification as simple (n = 30, 61%) and complex (n = 19, 39%) respectively. There were no deaths or relapses in our cohort. Only 10% of isolates were methicillin resistant S. aureus (MRSA), and none of these were healthcare-associated. Age, gender, Indigenous status, MRSA and healthcare-associated infections were not predictive of complex infection. Pre-existing malignancy was a risk factor for complex infection (p = 0.02). Complex infections were associated with a higher median maximum C reactive protein (216 mg/L vs 50 mg/L, p = 

Hui Jiang, Yang Huai, Hui Chen, Timothy M. Uyeki, Maoyi Chen, Xuhua Guan, Shali Liu, Youxing Peng, Hui Yang, Jun Luo, Jiandong Zheng, Jigui Huang, Zhibin Peng, Nijuan Xiang, Yuzhi Zhang, John D. Klena, Dale J. Hu, Jeanette J. Rainey, Xixiang Huo, Lin Xiao, Xuesen Xing, Faxian Zhan, Hongjie Yu, Jay K. Varma

by Hui Jiang, Yang Huai, Hui Chen, Timothy M. Uyeki, Maoyi Chen, Xuhua Guan, Shali Liu, Youxing Peng, Hui Yang, Jun Luo, Jiandong Zheng, Jigui Huang, Zhibin Peng, Nijuan Xiang, Yuzhi Zhang, John D. Klena, Dale J. Hu, Jeanette J. Rainey, Xixiang Huo, Lin Xiao, Xuesen Xing, Faxian Zhan, Hongjie Yu, Jay K. Varma Background Streptococcus pneumoniae (Sp) is a leading cause of bacterial pneumonia, meningitis, and sepsis and a major source of morbidity and mortality worldwide. Invasive pneumococcal disease (IPD) is defined as isolation of Sp from a normally sterile site, including blood or cerebrospinal fluid. The aim of this study is to describe outcomes as well as clinical and epidemiological characteristics of hospitalized IPD case patients in central China. Methods We conducted surveillance for IPD among children and adults from April 5, 2010 to September 30, 2012, in four major hospitals in Jingzhou City, Hubei Province. We collected demographic, clinical, and outcome data for all enrolled hospitalized patients with severe acute respiratory infection (SARI) or meningitis, and collected blood, urine, and cerebrospinal fluid (CSF) for laboratory testing for Sp infections. Collected data were entered into Epidata software and imported into SPSS for analysis. Results We enrolled 22,375 patients, including 22,202 (99%) with SARI and 173 (1%) with meningitis. One hundred and eighteen (118, 3%) with either SARI or meningitis were Sp positive, 32 (0.8%) from blood/CSF culture, and 87 (5%) from urine antigen testing. Of those 118 patients, 57% were aged ≥65 years and nearly 100% received antibiotics during hospitalization. None were previously vaccinated with 7-valent pneumococcal conjugate vaccine (PCV 7), 23-valent pneumococcal polysaccharide vaccine, or seasonal influenza vaccine. The main serotypes identified were 14, 12, 3, 1, 19F, 4, 5, 9V, 15 and 18C, corresponding to serotype coverage rates of 42%, 63%, and 77% for PCV7, PCV10, and PCV13, respectively. Conclusions Further work is needed to expand access to pneumococcal vaccination in China, both among children and potentially among the elderly, and inappropriate use of antibiotics is a widespread and serious problem in China.

Norris, M. H., Somprasong, N., Schweizer, H. P., Tuanyok, A.

Burkholderia pseudomallei causes the severe disease melioidosis. The bacterium subverts the host immune system, replicates inside cells, and host mortality primarily results from sepsis related complications. Lipopolysaccharide (LPS) is a major virulence factor and mediator of sepsis that many pathogens capable of intracellular growth modify to reduce their immunological "foot print". The binding strength of B. pseudomallei LPS for human LPS binding protein (hLBP) was measured using surface plasmon resonance. The structures of lipid A isolated from B. pseudomallei under different temperatures were analyzed by MALDI-TOF and the gene expression of two lipid A remodeling genes, lpxO and pagL, were investigated. The LPS were characterized in their ability to trigger TNF-α release and activate caspase-11 triggered pyroptosis by introduction of LPS into the cytosol. Lipid A from long-term chronic isolates was isolated and characterized by MALDI-TOF and also by ability to trigger caspase-11 mediated cell death. Lipid A from B. pseudomallei 1026b lpxO and pagL mutants was characterized by positive and negative mode MALDI-TOF to ultimately identify their role in lipid A structural modifications. Replication of lpxO and pagL mutants and their complements within macrophages showed that lipid A remodeling can effect growth in host-cells and activation of caspase-11 mediated cytotoxicity.

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 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 

Chauzy, A., Lamarche, I., Adier, C., Couet, W., Marchand, S.

The purpose of this study was to investigate aztreonam (ATM) and avibactam (AVI) distribution in intraperitoneal fluid and muscle interstitial fluid by microdialysis in rats, with or without peritonitis, and to compare the unbound concentrations in tissue with the unbound concentrations in blood. Microdialysis probes were inserted into the jugular vein, hind leg muscle and peritoneal cavity of control rats (n = 5) and rats with intra-abdominal sepsis (n = 9) induced by cecal ligation and punctures. ATM and AVI probe recoveries in each media were determined for both molecules in each rat by retrodialysis by drug. ATM-AVI combination was administered as an intravenous (IV) bolus at a dose of 100-25 mg⋅kg-1. Microdialysis samples were collected over 120 min, and ATM-AVI concentrations were determined by LC-MS/MS. Non-compartmental pharmacokinetic analysis was conducted and non-parametric test were used for statistical comparisons between groups (infected versus control) and medium. ATM and AVI distribution in intraperitoneal fluid and muscle was rapid and complete both in control rats and in rats with peritonitis and concentration profiles in blood, intraperitoneal fluid and muscle were virtually superimposed, in control and infected animals, both for ATM and AVI. No statistically significant difference was observed between unbound tissue extracellular fluid (ECF) and systemic areas under the curve for both molecules in control and infected animals. In the present study, intraperitoneal infection induced by cecal ligation and puncture had no apparent effect on ATM and AVI pharmacokinetics in rats.

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.

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.

Zhao, Zhiling; Han, Songyun; Yao, Gaiqi; Li, Shuangling; Li, Wenxiong; Zhao, Yangyu; Qiao, Jie; Zhang, Jianxin; Lu, Junli; Tao, Liyuan; Han, Yue

Objectives: To identify the key points for improving severe maternal morbidity by analyzing pregnancy-related ICU admissions in Beijing. Design: This was a retrospective, multicenter cohort study. Setting: Three ICUs in tertiary hospitals in Beijing. Patients: A total of 491 severe maternal cases in any trimester of pregnancy or within 42 days of delivery were reviewed between January 1, 2008, and December 31, 2016. Interventions: None. Measurements and Main Results: Among 491 obstetric ICU admissions (median Sequential Organ Failure Assessment score, 2) out of 87,850 hospital deliveries (a frequency of 5.6 admissions per 1,000 deliveries), the leading diagnoses were postpartum hemorrhage (170; 34.62%), hypertensive disorders of pregnancy (156; 31.77%), and cardio-cerebrovascular diseases (78; 15.9%). Comparing 2008–2011 to 2012–2016, the rates of maternal mortality (2.5% vs 1.9%; p = 0.991) and fetal loss (8.5% vs 8.6%; p = 0.977) did not decrease significantly, whereas the rates of ICU admission (3.05% vs 7.85%; p trends < 0.001) and postpartum hemorrhage (23% vs 38.5%; p = 0.002) increased. Hypertensive disorder (150/156; 96.2% transferred to the ICU postpartum, 24/28 women with fetal loss transferred from lower-level hospitals) was an independent maternal factor associated with fetal loss, and infections were the leading cause of maternal death (6/10) in the ICU. Conclusions: Our study highlights the increasing rate of intensive care admissions for postpartum hemorrhage. Improving prenatal care quality for pregnancy-induced hypertension and sepsis at lower-level hospitals may improve maternal and fetal outcomes. Specifically, providing more effective regional cooperation before transfer and shifting patients who require continuous surveillance but not necessarily intensive care to a transitional ward in a tertiary hospital would provide more ICU beds for more prenatal intensive care for the most complex medical conditions. 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. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: yaogaiqi@sina.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Katherine Crawford

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

Jou-Valencia, Daniela; Molema, Grietje; Popa, Eliane; Aslan, Adnan; van Dijk, Fransien; Mencke, Rik; Hillebrands, Jan-Luuk; Heeringa, Peter; Hoenderop, Joost G.; Zijlstra, Jan G.; van Meurs, Matijs; Moser, Jill

Objectives: To determine the applicability of recombinant Klotho to prevent inflammation and organ injury in sepsis in man and mice. Design: Prospective, clinical laboratory study using “warm” human postmortem sepsis-acute kidney injury biopsies. Laboratory study using a mouse model of endotoxemia. Setting: Research laboratory at a university teaching hospital. Subjects: Adult patients who died of sepsis in the ICU and control patients undergoing total nephrectomy secondary to renal cancer; male C57BL/6 and Klotho haploinsufficient mice. Interventions: Lipopolysaccharide (0.05 mg/kg) injection and kill after 4, 8, and 24 hours. Mice received recombinant Klotho (0.05 mg/kg) 30 minutes prior to lipopolysaccharide (1 mg/kg) injection. Mice treated with saline were included as controls. Measurements and Main Results: Quantitative reverse transcription polymerase chain reaction and immunohistochemical staining were used to quantify Klotho messenger RNA and protein expression in the kidney of sepsis-acute kidney injury patients and the kidney and brain of mice. The messenger RNA and protein expression of damage markers, inflammatory cytokine, chemokines, and endothelial adhesion molecules were also determined in mice. Renal neutrophil influx was quantified. We found significantly lower renal Klotho messenger RNA and protein levels in sepsis-acute kidney injury biopsies than in control subjects. These findings were recapitulated in the kidney and brain of lipopolysaccharide-challenged mice. Decreased Klotho expression paralleled an increase in kidney damage markers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Administration of recombinant Klotho prior to lipopolysaccharide injection attenuated organ damage, inflammation and endothelial activation in the kidney and brain of mice. Furthermore, less neutrophils infiltrated into the kidneys of recombinant Klotho mice compared with lipopolysaccharide only treated mice. Conclusions: Renal Klotho expression in human sepsis-acute kidney injury and in mouse models of sepsis was significantly decreased and correlated with renal damage. Recombinant Klotho intervention diminished organ damage, inflammation, and endothelial activation in the kidney and brain of lipopolysaccharide-challenged mice. Systemic Klotho replacement may potentially be an organ-protective therapy for septic patients to halt acute, inflammatory organ injury. 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. 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 Department of Critical Care Research Foundation, University Medical Center Groningen. Dr. van Meurs was supported by a Kolff grant of the Dutch Kidney Foundation (13OKJ35). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: j.moser@umcg.nl Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Kubra Aykac , Eda Karadag Oncel , Sevgen Tanir Basaranoglu , Alpaslan Alp , Ali Bulent Cengiz , Mehmet Ceyhan , Ates Kara

Abstract Background Knowledge of infections leading sepsis is needed to develop comprehensive infection prevention and sepsis early recognition and treatment strategies.The aim of this study was to investigate the etiology of sepsis and evaluate the proportion of respiratory viral pathogens in infants under two years of age with possible sepsis. Methods The prospective study was performed in two years. Multiplex RT‐PCR was performed to detect viral pathogens. All patients who were included in this study had sepsis symptoms as defined by the Surviving Sepsis Campaign. Results We compared 90 patients with sepsis into three groups as patients (n=33) had only viral positivity in nasopharyngeal swab and patients (17) had proven bacterial infection with or without viral infection and patients (40) without pathogen detection. Human rhinovirus (16.7%) and influenza (7.8%) were the most commonly seen viruses. Cough was more common in viral infection group than other groups (p=0.02) and median thrombocyte count was lower in bacterial infection group than the others (p=0.01). Patients had bacterial sepsis had the longest duration of hospitalization than the other groups (p=0.04). In winter and spring patients with sepsis mostly had viral infection however in summer and autumn patients were mostly that we could not prove an infection agents (p=0.02). Conclusions Our results suggest that respiratory tract viruses may play an important role in patients with sepsis and they should be kept in mind especially in winter and spring seasons. With an overall viral respiratory viruses as a single pathogen detection rate of 36.6% in sepsis etiology. This article is protected by copyright. All rights reserved.

Sakusic, Amra; Gajic, Ognjen; Singh, Tarun D.; O’Horo, John C.; Jenkins, Gregory; Wilson, Gregory A.; Petersen, Ronald; Fryer, John D.; Kashyap, Rahul; Rabinstein, Alejandro A.

Objectives: Persistent cognitive impairment after critical illness is an important healthcare problem forecasted to worsen in the near future. However, the epidemiology is insufficiently explored. We aimed to determine potentially modifiable risk factors during ICU hospitalization that play a significant role in developing persistent cognitive impairment. Design: An observational case-control study. Settings: Mayo Clinic ICUs between July 1, 2004, and November 20, 2015. Patients: We conducted a study nested in a large cohort of 98,227 adult critically ill patients. Using previously validated computable phenotypes for dementia and cognitive impairment, we determined the onset of cognitive impairment relative to ICU hospitalization and associated risk factors. The primary endpoint of the study was new and persistent cognitive impairment documented between 3 and 24 months after ICU discharge. Interventions: Unadjusted and adjusted analyses were performed to identify potentially modifiable risk factors during ICU hospitalization. Measurements and Main Results: Among 21,923 unique patients identified as cognitively impaired (22% of the entire ICU cohort), 2,428 (2.5%) developed incident new and persistent cognitive dysfunction after the index ICU admission. Compared with age- and sex-matched ICU controls (2,401 pairs), cases had higher chronic illness burden (Charlson Comorbidity Index, 6.2 vs 5.1; p < 0.01), and were more likely to have multiple ICU stays (22% vs 14%; p < 0.01). After adjustment for baseline differences, new and persistent cognitive dysfunction was associated with higher frequency of acute brain failure in the ICU, a higher exposure to severe hypotension, hypoxemia, hyperthermia, fluctuations in serum glucose, and treatment with quinolones or vancomycin. Association with sepsis observed in univariate analysis did not persist after adjustment. Conclusions: Cognitive dysfunction is highly prevalent in ICU patients. Incident new and persistent cognitive impairment is less common but important, potentially preventable problem after critical illness. Chronic comorbidities and number of ICU stays increase the risk of post-ICU cognitive dysfunction irrespective of age. Modifiable ICU exposures were identified as potential targets for future prevention trials. 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). This publication was made possible, supported, in part, by funding from The Mayo Critical Care Research Committee and grants from the National Institute on Aging (U01 AG006786, P50 AG016574, and R01 AG034676). Drs. Sakusic, Gajic, O`Horo, and Singh, Mr. Jenkins, Mr. Wilson, and Drs. Petersen and Fryer have made substantial contribution to conception and design, acquisition of data, analysis and interpretation. Dr. O’Horo received support for article research from the National Institutes of Health. Drs. O’Horo and Jenkins disclosed work for hire. Dr. Rabinstein takes full responsibility for the data, the analysis and interpretation, and the conduct of research. All the authors have provided the final approval of the version to be published. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: rabinstein.alejandro@mayo.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Christian Brun-Buisson

Meta-analyses of accuracy of the qSOFA to predict hospital mortality of patients with suspected infection show suboptimal performance of this abridged score. However, a score composed of only 3 clinical variables, such as the qSOFA or CRB can hardly be very accurate, but can serve as a warning integrated into clinical decision making, to help triaging patients in the ED. qSOFA does not help identifying infection. More complete, generic severity scores are nevertheless of major interest for stratification or analyses of epidemiolgical studies and clinical trials in septic patients.

Abstract Background Human parechovirus type 3 (HPeV-3) is known to cause cold-like symptoms, diarrhea, or severe infections such as sepsis in infants and children. In adults, HPeV-3 infection is rarely diagnosed because the symptoms are generally mild and self-limiting; however, this infection has been linked to epidemic myalgia, regardless of the presence of underlying diseases, immunosuppression, or sex. Case presentation We describe an adult case of severe systemic myalgia and orchiodynia after infection with HPeV-3, which was transmitted from the child of the patient. Interleukin-6 (IL-6) level was found to be elevated in the patient’s serum. Conclusion Severe myalgia associated with HPeV-3 infection is potentially caused by an elevated serum level of IL-6.

Abstract Background Septic cardiomyopathy represents cardiac impairment in sepsis and is a part of systemic involvement in sepsis. Cytokine storm is responsible for septic shock and for myocardial dysfunction of potentially reversible septic cardiomyopathy. Several case reports and case series demonstrated successful removal of circulating cytokines by combined blood purification techniques. In this way, septic shock and survival of septic patients improved. However, the evidences for reversal of myocardial dysfunction are rare. Case presentation We present a patient with a history of chemotherapy for coat cell lymphoma, splenectomy and autologous bone marrow transplantation, who suffered severe pneumococcal sepsis, septic shock and septic cardiomyopathy, resistant to pharmacological therapy. Combined blood purification techniques 36 h after the start of treatment successfully decreased Interleukin-6 level, lactacidosis, the need for vasopressors to maintain normotension, improved systolic function of the left ventricle and clinical outcome. Conclusions Our case suggests that combined blood purification techniques initiated even 36 h after the start of treatment successfully removed inflammatory cytokines, reversed circulatory failure and improved left ventricular systolic function in pneumococcal sepsis.

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 Fungal bloodstream infections (BSI) may be serious and are associated with drastic rise in mortality and health care costs. Candida spp. are the predominant etiological agent of fungal sepsis. The prompt and species-level identification of Candida may influence patient outcome and survival. The aim of this study was to develop and evaluate the CanTub-simplex PCR assay coupled with Tm calling and subsequent high resolution melting (HRM) analysis to barcode seven clinically relevant Candida species. Methods Efficiency, coefficient of correlation and the limit of reliable detection were estimated on purified Candida EDTA-whole blood (WB) reference panels seeded with Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida krusei, Candida guilliermondii, Candida dubliniensis cells in a 6-log range. Discriminatory power was measured on EDTA-WB clinical panels on three different PCR platforms; LightCycler®96, LightCycler® Nano, LightCycler® 2.0. Inter- and intra assay consistencies were also calculated. Results The limit of reliable detection proved to be 0.2–2 genomic equivalent and the method was reliable on broad concentration ranges (106–10 CFU) providing distinctive melting peaks and characteristic HRM curves. The diagnostic accuracy of the discrimination proved to be the best on Roche LightCycler®2.0 platform. Repeatability was tested and proved to be % C.V.: 0.14 ± 0.06 on reference- and % C.V.: 0.14 ± 0.02 on clinical-plates accounting for a very high accuracy. Reproducibility was % C.V.: 0.11 between reference- and % C.V.: 0.12between clinical-panels which is highly acceptable. Conclusion Our assay demonstrates recent advances on Tm calling and HRM analysis for the molecular identification of relevant Candida species. This unique, simplex PCR assay may be capable to outperform conventional phenotypic methods by reducing time and providing accurate and reliable results directly from blood (2 h) or from whole blood culture bottles (12–24 h).

Nicolas Allou, Aurélien Soubeyrand, Nicolas Traversier, Romain Persichini, Caroline Brulliard, Dorothée Valance, Olivier Martinet, Sandrine Picot, Olivier Belmonte and Jérôme Allyn

Abstract. Gram-negative bacilli Vibrio spp., Aeromonas spp., and Shewanella spp. are a major cause of severe waterborne infection. The aim of this study was to assess the clinical and microbiological characteristics and prognosis of patients hospitalized in Reunion Island for a waterborne infection. This retrospective study was conducted in the two university hospitals of Reunion Island between January 2010 and March 2017. Patients diagnosed with a Vibrio, Aeromonas, or Shewanella infection were evaluated. Over the study period, 112 aquatic strains were isolated at Reunion Island: Aeromonas spp. were found in 91 patients (81.3%), Shewanella spp. in 13 patients (11.6%), and Vibrio spp. in eight patients (7.2%). The in-hospital mortality rate was 11.6%. The main sites of infection were skin and soft tissue (44.6%) and the abdomen (19.6%). Infections were polymicrobial in 70 cases (62.5%). The most commonly prescribed empiric antibiotic regimen was amoxicillin–clavulanate (34.8%). Eighty-four percent of the aquatic strains were resistant to amoxicillin–clavulanate and more than > 95% were susceptible to third or fourth generation cephalosporins and fluoroquinolones. After multivariate analysis, the only independent risk factor of in-hospital mortality was the presence of sepsis (P < 0.0001). In Reunion Island, the most commonly isolated aquatic microorganisms were Aeromonas spp. Sepsis caused by aquatic microorganisms was frequent (> 50%) and associated with higher in-hospital mortality. This study suggests that empiric antibiotic regimens in patients with sepsis or septic shock caused by suspected aquatic microorganisms (tropical climate, skin lesion exposed to seawater…) should include broad-spectrum antibiotics (third or fourth generation cephalosporins).

F. Wu, Y. Ye, X. Zhou

We read with interest the meta-analysis by Maitra et al. who found that quick Sequential (sepsis-related) Organ Failure Assessment (qSOFA) seemed to be a poorly sensitive predictive marker for in-hospital mortality in hospitalized patients with suspected infection [1]. Though the review sounds comprehensive and scientific, we have some different views to address.