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.…

Seilesh Kadambari, Heli Harvala, Peter Simmonds, Andrew J Pollard, Manish Sadarangani

Human parechovirus infections are the second most common cause of viral meningitis in children. These infections are most frequently seen in infants younger than 90 days. Clinical manifestations include encephalitis, meningitis, myocarditis, and sepsis, which can lead to serious neurodevelopmental sequelae in young infants. Molecular techniques, including PCR assays, are the preferred diagnostic methods and have contributed to an increase in reported cases, along with an increasing awareness of the causal role of human parechovirus in infant diseases.

Judith A Gilbert

Sepsis affects 27–30 million people worldwide every year, resulting in 6–9 million deaths annually. The condition occurs when the body has an extreme immune response to an infection, causing widespread inflammation. Without early diagnosis and treatment, sepsis can lead to tissue damage, organ failure, and death. The Surviving Sepsis Campaign (SSC) was formed in collaboration between the Society of Critical Care Medicine and the European Society of Intensive Care Medicine in 2002. The aim of SSC is to reduce mortality from sepsis globally, and their first evidence-based clinical practice guidelines were published in 2004, with updates every four years thereafter.

Talha Khan Burki

A new analysis of data from 133 hospital trusts in England has revealed sharp increases in the number of admissions for sepsis and recorded deaths. Brian Jarman, former president of the British Medical Association and head of the Dr Foster Unit at Imperial College London, UK, examined National Health Service (NHS) mortality data from the past few years. In the year to April, 2015, there were 55 171 hospital admissions for sepsis and 11 527 deaths. Records for 2016–17 showed 77 996 admissions and 15 851 deaths, an increase of 41% and 38%, respectively.

Paul E Marik

Glucocorticoids have been used as adjunctive therapy in patients with sepsis and septic shock for more than four decades. The rationale for the use of glucocorticoids is that this class of drugs downregulates the proinflammatory response and limits the anti-inflammatory response while preserving innate immunity. Between 1976 and 2017, 22 randomised placebo-controlled trials have been published evaluating the benefit of glucocorticoids in patients with community-acquired pneumonia, sepsis, and septic shock.

Ranzani, Otavio T.; Shankar-Hari, Manu; Harrison, David A.; Rabello, Lígia S.; Salluh, Jorge I. F.; Rowan, Kathryn M.; Soares, Marcio

Objectives: To test whether differences in both general and sepsis-specific patient characteristics explain the observed differences in sepsis mortality between countries, using two national critical care (ICU) databases. Design: Cohort study. Setting: We analyzed 62 and 164 ICUs in Brazil and England, respectively. Patients: Twenty-two–thousand four-hundred twenty-six adult ICU admissions from January 2013 to December 2013. Interventions: None. Measurements and Main Results: After harmonizing relevant variables, we merged the first ICU episode of adult medical admissions from Brazil (ORganizational CHaractEeriSTics in cRitical cAre study) and England (Intensive Care National Audit & Research Centre Case Mix Programme). Sepsis-3 definition was used, and the primary outcome was hospital mortality. We used multilevel logistic regression models to evaluate the impact of country (Brazil vs England) on mortality, after adjustment for general (age, sex, comorbidities, functional status, admission source, time to admission) and sepsis-specific (site of infection, organ dysfunction type and number) patient characteristics. Of medical ICU admissions, 13.2% (4,505/34,150) in Brazil and 30.7% (17,921/58,316) in England met the sepsis definition. The Brazil cohort was older, had greater prevalence of severe comorbidities and dependency compared with England. Respiratory was the most common infection site in both countries. The most common organ dysfunction was cardiovascular in Brazil (41.2%) and respiratory in England (85.8%). Crude hospital mortality was similar (Brazil 41.4% vs England 39.3%; odds ratio, 1.12 [0.98–1.30]). After adjusting for general patient characteristics, there was an important change in the point-estimate of the odds ratio (0.88 [0.75–1.02]). However, after adjusting for sepsis-specific patient characteristics, the direction of effect reversed again with Brazil having higher risk-adjusted mortality (odds ratio, 1.22 [1.05–1.43]). Conclusions: Patients with sepsis admitted to ICUs in Brazil and England have important differences in general and sepsis-specific characteristics, from source of admission to organ dysfunctions. We show that comparing crude mortality from sepsis patients admitted to the ICU between countries, as currently performed, is not reliable and that the adjustment for both general and sepsis-specific patient characteristics is essential for valid international comparisons of mortality amongst sepsis patients admitted to critical care units. Drs. Rowan and Soares are senior authors. † In memoriam. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health. Drs. Ranzani and Shankar-Hari are equal contributors. Dr. Ranzani did data analyses. Drs. Ranzani and Shankar-Hari wrote the first draft of the article. Drs. Harrison, Rabello, Salluh, Rowan, and Soares led data collection. Dr. Rabello died during the peer-review process of this article. All authors unanimously agreed on her fundamental contribution for this study. All authors conceptualized and designed the study, interpreted data, and critically revised the article. 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 original ORganizational CHaractEeriSTics in cRitical cAre study was supported by the National Council for Scientific and Technological Development (Grant number 304240/2014-1), Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro and by departmental funds from the D’Or Institute for Research and Education. The Case Mix Programme is a subscription-based, national quality assessment program. The current study was funded internally by Intensive Care National Audit & Research Centre. The funding sources had no role in the design, conduct or analyses of the study. Dr. Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (NIHR-CS-2016-16-011). Dr. Soares disclosed that he is founder and equity shareholder at Epimed Solutions. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: otavioranzani@usp.br Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Sims, Charles R.; Warner, Matthew A.; Stelfox, Henry Thomas; Hyder, Joseph A.

Objectives: We examined recommendations within critical care guidelines to describe the pairing patterns for strength of recommendation and quality of evidence. We further identified recommendations where the reported strength of recommendation was strong while the reported quality of evidence was not high/moderate and then assessed whether such pairings were within five paradigmatic situations offered by Grading of Recommendations Assessment, Development and Evaluation methodology to justify such pairings. Data Sources and Extraction: We identified all clinical critical care guidelines published online from 2011 to 2017 by the Society of Critical Care Medicine along with individual guidelines published by Surviving Sepsis Campaign, Kidney Disease Improving Global Outcomes, American Society for Parenteral and Enteral Nutrition, and the Infectious Disease Society of America/American Thoracic Society. Data Synthesis: In all, 15 documents specifying 681 eligible recommendations demonstrated variation in strength of recommendation (strong n = 215 [31.6%], weak n = 345 [50.7%], none n = 121 [17.8%]) and in quality of evidence (high n = 41 [6.0%], moderate n = 151 [22.2%], low/very low n = 298 [43.8%], and Expert Consensus/none n = 191 [28.1%]). Strength of recommendation and quality of evidence were positively correlated (ρ = 0.66; p < 0.0001). Of 215 strong recommendations, 69 (32.1%) were discordantly paired with evidence other than high/moderate. Twenty-two of 69 (31.9%) involved Strong/Expert Consensus recommendations, a category discouraged by Grading of Recommendations Assessment, Development and Evaluation methodology. Forty-seven of 69 recommendations (68.1%) were comprised of Strong/Low or Strong/Very Low variation requiring justification within five paradigmatic scenarios. Among distribution in the five paradigmatic scenarios of Strong/Low and Strong/Very Low recommendations, the most common paradigmatic scenario was life threatening situation (n = 20/47; 42.6%). Four Strong/Low or Strong/Very Low recommendations (4/47; 8.5%) were outside Grading of Recommendations Assessment, Development and Evaluation methodology. Conclusions: Among a large, diverse assembly of critical care guideline recommendations using Grading of Recommendations Assessment, Development and Evaluation methodology, the strength of evidence of a recommendation was generally associated with the quality of evidence. However, strong recommendations were not infrequently made in the absence of high/moderate quality of evidence. To improve clarity and uptake, future guideline statements may specify why such pairings were made, avoid such pairings when outside of Grading of Recommendations Assessment, Development and Evaluation criteria, and consider separate language for Expert Consensus recommendations (good practice statements). 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 (httpm://journals.lww.com/ccmjournal). This work was performed without extramural funding. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sims.charles@mayo.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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.…

Barash, J. R., Castles, J. B., Arnon, S. S.

Infant botulism is an infectious intestinal toxemia that results from colonization of the infant large bowel by Clostridium botulinum (or rarely, by neurotoxigenic C. baratii or C. butyricum), with subsequent intraintestinal production and absorption of botulinum neurotoxin that then produces flaccid paralysis. The disease is often initially misdiagnosed as suspected sepsis or meningitis, diagnoses that require prompt empiric antimicrobial therapy. Antibiotics may also be needed to treat infectious complications of infant botulism, such as pneumonia or urinary tract infection. Clinical evidence suggests (see included case report) that broad-spectrum antibiotics that are eliminated by biliary excretion may cause progression of the patient’s paralysis by lysing C. botulinum vegetative cells in the large bowel lumen and thereby increasing the amount of botulinum neurotoxin available for absorption. The purpose of this antimicrobial susceptibility study was to identify an antimicrobial agent with little or no activity against C. botulinum that could be used to treat infant botulism patients initially diagnosed with suspected sepsis or meningitis, or who acquired secondary infections, without lysing C. botulinum. Testing of 12 antimicrobial agents indicated that almost all California infant botulism patient isolates are susceptible to most clinically utilized antibiotics and are also susceptible to newer antibiotics not previously tested against large numbers of C. botulinum patient isolates. No antibiotic with little or no activity against C. botulinum was identified. These findings reinforce the importance of promptly treating infant botulism patients with Human Botulism Immune Globulin (BIG-IV; BabyBIG®).…

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.

Ba, B., Gaudin, K., Desire, A., Phoeung, T., Langlois, M.-H., Behl, C. R., Unowsky, J., Patel, I. H., Malick, A. W., Gomes, M., White, N., Kauss, T.

Neonatal sepsis is a major cause of infant mortality in developing countries because of delayed injectable treatment, making it urgent to develop non-injectable formulations that can reduce treatment delays in resource limited settings. Ceftriaxone, available only for injection, needs absorption enhancers to achieve adequate bioavailability via non-parenteral administration. This article presents all available ceftriaxone human and animal non-parenteral absorption data, including unpublished work carried out by F. Hoffmann-La Roche (Roche) in the 1980s and new rabbit pre-clinical data and discusses the importance of these data for the development of non-injectable formulations for non-invasive treatment. The combined results indicate that rectal absorption of ceftriaxone is feasible and likely to lead to a bioavailable formulation that can reduce treatment delays in neonatal sepsis. A bile salt, Chenodeoxycholate sodium salt (Na-CDC) used as an absorption enhancer at a 125 mg dose together with a 500 mg dose of ceftriaxone, provided 24% rectal absorption of ceftriaxone and Cmax of 21 µg/ml with good tolerance in human subjects. The rabbit model developed can also be used to screen for bioavailability of other formulations before human assessment.…

Julio Collazos, Belén de la Fuente, Alicia García, Helena Gómez, C. Menéndez, Héctor Enríquez, Paula Sánchez, María Alonso, Ian López-Cruz, Manuel Martín-Regidor, Ana Martínez-Alonso, José Guerra, Arturo Artero, Marino Blanes, Javier de la Fuente, Víctor Asensi

by Julio Collazos, Belén de la Fuente, Alicia García, Helena Gómez, C. Menéndez, Héctor Enríquez, Paula Sánchez, María Alonso, Ian López-Cruz, Manuel Martín-Regidor, Ana Martínez-Alonso, José Guerra, Arturo Artero, Marino Blanes, Javier de la Fuente, Víctor Asensi Background Cellulitis is a frequent cause of hospital admission of adult patients. Increasing prevalence of multiresistant microorganisms, comorbidities, predisposing factors and medical and surgical therapies might affect cellulitis response and recurrence rate. Methods Prospective and observational study of 606 adult patients with cellulitis admitted to several Spanish hospitals. Comorbidities, microbiological, clinical, diagnostic, treatment (surgical and antibiotic) data were analyzed according to the cellulitis response. Good response implied cure. Poor response implied failure to cure or initial cure but relapse within 30 days of hospital discharge. Results Mean age was 63.3 years and 51.8% were men. Poor responses were significantly associated with age, previous episodes of cellulitis, prior wounds and skin lesions, venous insufficiency, lymphedema, immunosuppression and lower limbs involvement. No differences in ESR or CRP blood levels, leukocyte counts, pus or blood cultures positivity or microbiological or imaging aspects were observed in those with good or poor responses. Regarding antimicrobials, no differences in previous exposition before hospital admission, treatment with single or more than one antibiotic, antibiotic switch, days on antimicrobials or surgical treatment were observed regarding good or poor cellulitis response. Prior episodes of cellulitis (P = 0.0001), venous insufficiency (P = 0.004), immunosuppression (P = 0.03), and development of sepsis (P = 0.05) were associated with poor treatment responses, and non-surgical trauma (P = 0.015) with good responses, in the multivariate analysis. Conclusions Prior episodes of cellulitis, non-surgical trauma, venous insufficiency, sepsis and immunosuppression were independently associated with treatment response to cellulitis, but not the causative microorganism, the number of antimicrobials administered or its duration.…

Joseph A. Hippensteel

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 8, Page 981-983, October 15, 2018. …

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.…

Viriya Hantrakun, Ranjani Somayaji, Prapit Teparrukkul, Chaiyaporn Boonsri, Kristina Rudd, Nicholas P. J. Day, T. Eoin West, Direk Limmathurotsakul

by Viriya Hantrakun, Ranjani Somayaji, Prapit Teparrukkul, Chaiyaporn Boonsri, Kristina Rudd, Nicholas P. J. Day, T. Eoin West, Direk Limmathurotsakul Infection and sepsis are leading causes of death worldwide but the epidemiology and outcomes are not well understood in resource-limited settings. We conducted a four-year prospective observational study from March 2013 to February 2017 to examine the clinical epidemiology and outcomes of adults admitted with community-acquired infection in a resource-limited tertiary-care hospital in Ubon Ratchathani province, Northeast Thailand. Hospitalized patients with infection and accompanying systemic manifestations of infection within 24 hours of admission were enrolled. Subjects were classified as having sepsis if they had a modified sequential organ failure assessment (SOFA) score ≥2 at enrollment. This study was registered with ClinicalTrials.gov, number NCT02217592. A total of 4,989 patients were analyzed. Of the cohort, 2,659 (53%) were male and the median age was 57 years (range 18–101). Of these, 1,173 (24%) patients presented primarily to the study hospital, 3,524 (71%) were transferred from 25 district hospitals or 8 smaller hospitals in the province, and 292 (6%) were transferred from one of 30 hospitals in other provinces. Three thousand seven hundred and sixteen (74%) patients were classified as having sepsis. Patients with sepsis had an older age distribution and a greater prevalence of comorbidities compared to patients without sepsis. Twenty eight-day mortality was 21% (765/3,716) in sepsis and 4% (54/1,273) in non-sepsis patients (p

Lindell, Robert B.; Nishisaki, Akira; Weiss, Scott L.; Balamuth, Fran; Traynor, Danielle M.; Chilutti, Marianne R.; Grundmeier, Robert W.; Fitzgerald, Julie C.

Objectives: To compare the performance of three methods of identifying children with severe sepsis and septic shock from the Virtual Pediatric Systems database to prospective screening using consensus criteria. Design: Observational cohort study. Setting: Single-center PICU. Patients: Children admitted to the PICU in the period between March 1, 2012, and March 31, 2014. Interventions: None. Measurements and Main Results: During the study period, all PICU patients were prospectively screened daily for sepsis, and those meeting consensus criteria for severe sepsis or septic shock on manual chart review were entered into the sepsis registry. Of 7,459 patients admitted to the PICU during the study period, 401 met consensus criteria for severe sepsis or septic shock (reference standard cohort). Within Virtual Pediatric Systems, patients identified using “Martin” (n = 970; κ = 0.43; positive predictive value = 34%; F1 = 0.48) and “Angus” International Classification of Diseases, 9th Edition, Clinical Modification codes (n = 1387; κ = 0.28; positive predictive value = 22%; F1 = 0.34) showed limited agreement with the reference standard cohort. By comparison, explicit International Classification of Diseases, 9th Edition, Clinical Modification codes for severe sepsis (995.92) and septic shock (785.52) identified a smaller, more accurate cohort of children (n = 515; κ = 0.61; positive predictive value = 57%; F1 = 0.64). PICU mortality was 8% in the reference standard cohort and the cohort identified by explicit codes; age, illness severity scores, and resource utilization did not differ between groups. Analysis of discrepancies between the reference standard and Virtual Pediatric Systems explicit codes revealed that prospective screening missed 66 patients with severe sepsis or septic shock. After including these patients in the reference standard cohort as an exploratory analysis, agreement between the cohort of patients identified by Virtual Pediatric Systems explicit codes and the reference standard cohort improved (κ = 0.73; positive predictive value = 70%; F1 = 0.75). Conclusions: Children with severe sepsis and septic shock are best identified in the Virtual Pediatric Systems database using explicit diagnosis codes for severe sepsis and septic shock. The accuracy of these codes and level of clinical detail available in the Virtual Pediatric Systems database allow for sophisticated epidemiologic studies of pediatric severe sepsis and septic shock in this large, multicenter database. 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, and Division of Emergency Medicine, The Children’s Hospital of Philadelphia, and the University of Pennsylvania Perelman School of Medicine. Dr. Nishisaki’s institution received funding from Agency for Healthcare Research and Quality R18 HS022464-01 and R18 HS024511-01 and the National Institute of Child Health and Human Development (NICHD) 1R21HD089151-01A, and he received support for article research from the National Institutes of Health. Dr. Weiss’ institution received funding from National Institute of General Medical Sciences K23GM110496, and he received funding from Bristol-Myers Squibb Company (consultant) and Medscape (honorarium for lecture). Dr. Balamuth is also supported by NICHD K23-HD082368. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Robert B. Lindell, MD, Department of Anesthesiology and Critical Care Medicine, University of Pennsylvania Perelman School of Medicine, Children’s Hospital of Philadelphia, 34th St. & Civic Center Blvd., Philadelphia, PA 19104. E-mail: LindellR@email.chop.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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.…

Vincent, Jean-Louis; Mongkolpun, Wasineenart

Purpose of review Sepsis is a common condition in critically ill patients and associated with high morbidity and mortality. Sepsis is the result of infection by many potential pathogens, including Gram-negative bacteria. There are no specific antisepsis therapies and management relies largely on infection control and organ support, including hemodynamic stabilization. We discuss these key aspects and briefly mention potential immunomodulatory strategies. Recent findings New aspects of sepsis management include the realization that early treatment is important and that fluids and vasopressor agents should be administered simultaneously to insure rapid restoration of an adequate perfusion pressure to limit development and worsening of organ dysfunction. New immunomodulatory therapies, both suppressive and stimulatory, are being tested. Summary Early diagnosis enabling rapid treatment can optimize outcomes. The multiple components of adequate sepsis management necessitate a team approach. Correspondence to Jean-Louis Vincent, Department of Intensive Care, Erasme University Hospital, Route De Lennik 808, 1070 Brussels, Belgium. Tel: +32 2 555 3380; fax: +32 2 555 4555; e-mail: jlvincent@intensive.org Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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

Abstract Background Urinary tract infections (UTIs) are one of the most frequent diseases encountered by humans worldwide. The presence of multidrug-resistant (MDR) uropathogenic Escherichia coli (UPEC) harboring several virulence factors, is a major risk factor for inpatients. We sought to investigate the rate of antibiotic resistance and virulence-associated genes among the UPECs isolated from an Iranian symptomatic population. Methods A total of 126 isolates from inpatients with UTI from different wards were identified as UPEC using the conventional microbiological tests. After identification of UPECs, all the isolates were subjected to antimicrobial susceptibility test and polymerase chain reaction (PCR) to identify the presence of 9 putative virulence genes and their association with the clinical outcomes or antimicrobial resistance. Results The data showed that the highest and the lowest resistance rates were observed against ampicillin (88.9%), and imipenem (0.8%), respectively. However, the frequency of resistance to ciprofloxacin was found to be 55.6%. High prevalence of MDR (77.8%) and extended-spectrum β-lactamase (ESBL) (54.8%) were substantial. PCR results revealed the frequency of virulence genes ranged from 0 to 99.2%. Among 9 evaluated genes, the frequency of 4 genes (fimH, sfa, iutA, and PAI marker) was > 50% among all the screened isolates. The iutA, pap GII, and hlyA genes were more detected in the urosepsis isolates with significantly different frequencies. The different combinations of virulence genes were characterized as urovirulence patterns. The isolates recovered from pyelonephritis, cystitis, and urosepsis cases revealed 27, 22, and 6 virulence patterns, respectively. A significant difference was determined between ESBL production with pap GII, iutA, and PAI marker genes. Conclusions Our study highlighted the MDR UPEC with high heterogeneity of urovirulence genes. Considering the high rate of ciprofloxacin resistance, alternative drugs and monitoring of the susceptibility profile for UPECs are recommended.…

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).

Lankadeva, Yugeesh R.; Kosaka, Junko; Iguchi, Naoya; Evans, Roger G.; Booth, Lindsea C.; Bellomo, Rinaldo; May, Clive N

Objectives: To examine the effects of fluid bolus therapy on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, PO2, renal function, and fluid balance in experimental early septic acute kidney injury. Design: Interventional study. Setting: Research institute. Subjects: Adult Merino ewes. Interventions: Implantation of flow probes on the pulmonary and renal arteries and laser Doppler oxygen-sensing probes in the renal cortex, medulla, and within a bladder catheter in sheep. Infusion of Escherichia coli to induce septic acute kidney injury (n = 8). After 24, 25, and 26 hours of sepsis, fluid bolus therapy (500 mL of Hartmann’s solution over 15 min) was administered. Measurements and Main Results: In conscious sheep, infusion of Escherichia coli decreased creatinine clearance and increased plasma creatinine, renal blood flow (+46% ± 6%) and cortical perfusion (+25% ± 4%), but medullary perfusion (–48% ± 5%), medullary PO2 (–56% ± 4%), and urinary PO2 (–54% ± 3%) decreased (p < 0.01). The first fluid bolus therapy increased blood pressure (+6% ± 1%), central venous pressure (+245% ± 65%), cardiac output (+11% ± 2%), medullary PO2 (+280% ± 90%), urinary PO2 (+164% ± 80%), and creatinine clearance (+120% ± 65%) at 30 minutes. The following two boluses had no beneficial effects on creatinine clearance. The improvement in medullary oxygenation dissipated following the third fluid bolus therapy. Study animals retained 69% of the total volume and 80% of sodium infused. Throughout the study, urinary PO2 correlated significantly with medullary PO2. Conclusions: In early experimental septic acute kidney injury, fluid bolus therapy transiently improved renal function and medullary PO2, as also reflected by increased urinary PO2. These initial effects of fluid bolus therapy dissipated within 4 hours, despite two additional fluid boluses, and resulted in significant volume retention. 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 a grant from the National Health and Medical Research Council of Australia (APP1050672), and by funding from the Victorian Government Operational Infrastructure Support Grant. Dr. Lankadeva was supported by Postdoctoral Fellowships by the National Heart Foundation of Australia (100869; 101853). Dr. Booth received other support from the National Health and Medical Research Council of Australia early career fellowship and the Australian Academy of Technology and Engineering travel fellowship. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: clive.may@florey.edu.au Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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.…

Toliver-Kinsky, T., Cui, W., Törö, G., Lee, S.-J., Shatalin, K., Nudler, E., Szabo, C.

The biological mediator hydrogen sulfide (H2S) is produced by bacteria and has been shown to be cytoprotective against oxidative stress and to increase the sensitivity of various bacteria to a range of antibiotic drugs. Here we evaluated whether bacterial H2S provides resistance against the immune response, using two bacterial species that are common sources of nosocomial infections, Escherichia coli and Staphylococcus aureus. Elevations in H2S increased the resistance of both species to immune-mediated killing. Clearance of infections with wild type and genetically H2S-deficient E. coli and S. aureus was compared in vitro and in mouse models of abdominal sepsis and burn wound infection. Also, inhibitors of H2S-producing enzymes were used to assess bacterial killing by leukocytes. We found that inhibition of bacterial H2S production can increase susceptibility of both bacterial species to rapid killing by immune cells and can improve bacterial clearance after severe burn, an injury that increases susceptibility to opportunistic infections. These findings support the role of H2S as a bacterial defense mechanism against the host response and implicate bacterial H2S inhibition as a potential therapeutic intervention in the prevention or treatment of infections.…

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.…

Lu, Chunmei; Liu, Qing; Yuan, Hao; Wang, Laishuan

Objectives: We aimed to implement our Smart Use of Antibiotics Program to ensure the proper use of antimicrobials, improve patient care and outcomes, and reduce the risks of adverse effects and antimicrobial resistance. Design: We compared the time periods before (baseline) and after (intervention) the implementation of an antibiotic protocol by performing surveillance and assessments of all antibiotic use during a 29-month interrupted period. Setting: Level 3–4 neonatal ICU in one referral center. Patients: All 13,540 infants who received antibiotics during their hospital stay from 2015 to 2017. Interventions: Prospective audit of targeted antibiotic stewardship program. Measurements and Main Results: The primary outcome was the change in total antibiotic days of therapy per 1,000 patient-days between the baseline and intervention periods. The secondary outcomes included readmissions for infection, late-onset sepsis (length of stay), necrotizing enterocolitis, or death in infants at 32 weeks of gestation or younger and the prevalence of multidrug-resistant organism colonization. No differences in safety outcomes were observed between the intervention and baseline periods. Following the implementation of our Smart Use of Antibiotics Program, the total quantity of antibiotics in the intervention phase was significantly decreased from 543 days of therapy per 1,000 patient-days to 380 days of therapy/1,000 patient-days compared with that of baseline (p = 0.0001), which occurred in parallel with a reduction in length of stay from 11.4% during the baseline period to 6.5% during the intervention period (p = 0.01). A reduced multidrug-resistant organism rate was also observed following Smart Use of Antibiotics Program implementation (1.4% vs 1.0%; p = 0.02). The overall readmission rate did not differ between the two periods (1.2% vs 1.1%; p = 0.16). Conclusions: Smart Use of Antibiotics Program implementation was effective in reducing antibiotic exposure without affecting quality of care. Antibiotic stewardship programs are attainable through tailoring to special stewardship targets even in a developing country. Dr. Lu disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: laishuanwang@yahoo.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Chung, Kuei-Pin; Chen, Guan-Yuan; Chuang, Tzu-Yi; Huang, Yen-Tsung; Chang, Hou-Tai; Chen, Yen-Fu; Liu, Wei-Lun; Chen, Yi-Jung; Hsu, Chia-Lin; Huang, Miao-Tzu; Kuo, Ching-Hua; Yu, Chong-Jen

Objectives: Recent metabolomic studies of sepsis showed that increased circulatory acylcarnitines were associated with worse survival. However, it is unknown whether plasma carnitine and acylcarnitines can reflect the severity of sepsis, and the role of specific acylcarnitines in prognostic assessment need further confirmation. This study aimed to clarify these questions. Design: Prospective multicenter cohort studies with derivation and validation cohort design. Setting: ICUs at two medical centers and three regional hospitals in Taiwan. Patients: Patients with sepsis and acute organ dysfunction were enrolled. Recruitment of the derivation (n = 90) and validation cohorts (n = 120) occurred from October 2010 through March 2012 and January 2013 through November 2014, respectively. Interventions: Plasma samples were collected immediately after admission, and the levels of carnitine and acylcarnitines were measured by ultra-high performance liquid chromatography-mass spectrometry. Measurements and Main Results: In the derivation cohort, increased plasma levels of short- and medium-chain acylcarnitines were significantly associated with hepatobiliary dysfunction, renal dysfunction, thrombocytopenia, and hyperlactatemia. However, acetylcarnitine is the only acylcarnitine significantly correlating with various plasma cytokine concentrations and also associated with blood culture positivity and 28-day mortality risk. The association between plasma acetylcarnitine and multiple organ dysfunction severity, blood culture positivity, and 28-day mortality, was confirmed in the validation cohort. Patients with high plasma acetylcarnitine (≥ 6,000 ng/mL) had significantly increased 28-day mortality compared with those with plasma acetylcarnitine less than 6,000 ng/mL (52.6% vs 13.9%; hazard ratio, 5.293; 95% CI, 2.340–11.975; p < 0.001 by Cox proportional hazard model). Conclusions: We confirm that plasma acetylcarnitine can reflect the severity of organ dysfunction, inflammation, and infection in sepsis and can serve as a prognostic biomarker for mortality prediction. 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 Science Council (No. 100-2321-B-002-019), Excellent Translational Medicine Research Projects of National Taiwan University College of Medicine and National Taiwan University Hospital (No. 102C101-42), National Taiwan University Hospital (No. 105-S-3080), and Taoyuan General Hospital, Department of Health and Welfare (PTH10326, North 101–15). Drs. G.-Y. Chen and M.-T. Huang disclosed government work. Dr. M.-T. Huang received support for article research from the National Science Council, Taiwan. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: kuoch@ntu.edu.tw; jefferycjyu@ntu.edu.tw Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Yuuki Bamba, Hiroshi Moro, Nobumasa Aoki, Takeshi Koizumi, Yasuyoshi Ohshima, Satoshi Watanabe, Takuro Sakagami, Toshiyuki Koya, Toshinori Takada, Toshiaki Kikuchi

by Yuuki Bamba, Hiroshi Moro, Nobumasa Aoki, Takeshi Koizumi, Yasuyoshi Ohshima, Satoshi Watanabe, Takuro Sakagami, Toshiyuki Koya, Toshinori Takada, Toshiaki Kikuchi Background Presepsin is a widely recognized biomarker for sepsis. However, little is known about the usefulness of presepsin in invasive fungal infection. The aim of this study was to determine the plasma levels of presepsin in fungal bloodstream infections and to investigate whether it reflects the disease severity, similar to its utility in bacterial infections. Methods We prospectively measured presepsin in plasma samples from participants with fungemia from April 2016 to December 2017. The associations of C-reactive protein, procalcitonin, and presepsin concentrations with the severity of fungemia were statistically analyzed. In vitro assay was performed by incubating Escherichia coli, Candida albicans, and lipopolysaccharide to whole blood cells collected from healthy subjects; after 3 h, the presepsin concentration was measured in the supernatant and was compared among the bacteria, fungi, and LPS groups. Results Presepsin was increased in 11 patients with fungal bloodstream infections. Serial measurement of presepsin levels demonstrated a prompt decrease in 7 patients in whom treatment was effective, but no decrease or further increase in the patients with poor improvement. Additionally, presepsin concentrations were significantly correlated with the Sequential Organ Failure Assessment score (r = 0.89, p < 0.001). In vitro assay with co-incubation of C. albicans and human whole blood cells indicated that the viable cells of C. albicans caused an increase in presepsin, as seen with E. coli. Conclusions Plasma presepsin levels increased in patients with fungal bloodstream infection, with positive association with the disease severity. Presepsin could be a useful biomarker of sepsis secondary to fungal infections.…

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 = 

James, K. L., Mogen, A. B., Brandwein, J. N., Orsini, S. S., Ridder, M. J., Markiewicz, M. A., Bose, J. L., Rice, K. C.

Staphylococcus aureus nitric oxide synthase (saNOS) is a major contributor to virulence, stress resistance, and physiology, yet the specific mechanism(s) by which saNOS intersects with other known regulatory circuits are largely unknown. The SrrAB two-component system, which modulates gene expression in response to the reduced state of respiratory menaquinones, is a positive regulator of nos expression. Several SrrAB-regulated genes were also previously-shown to be induced in an aerobically-respiring nos mutant, suggesting potential interplay between saNOS and SrrAB. Therefore, a combination of genetic, molecular and physiological approaches was employed to characterize a nos srrAB mutant, which had significant reductions in maximum specific growth rate and oxygen consumption when cultured in conditions promoting aerobic respiration. The nos srrAB mutant secreted elevated lactate levels, correlating with increased transcription of lactate dehydrogenases. Expression of nitrate and nitrite reductase genes were also significantly enhanced in the nos srrAB double mutant, and its aerobic growth defect could be partially rescued with supplementation with nitrate, nitrite, or ammonia. Furthermore, elevated ornithine and citrulline levels and highly upregulated expression of arginine deiminase genes were observed in the double mutant. These data suggest that dual deficiency in saNOS and SrrAB limits S. aureus to fermentative metabolism, with a reliance on nitrate assimilation and the urea cycle to help fuel energy production. The nos, srrAB, and nos srrAB mutants showed comparable defects in endothelial intracellular survival, whereas srrAB and nos srrAB mutants were highly attenuated during murine sepsis, suggesting that SrrAB-mediated metabolic versatility is dominant in vivo.…

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.…

Walley, Keith R.; Boyd, John H.; Kong, HyeJin Julia; Russell, James A.

Objectives: Low low-density lipoprotein levels are associated with increased mortality in sepsis. Whether low low-density lipoprotein levels contribute causally to adverse sepsis outcome is unknown. Design: Retrospective analysis of two sepsis patient cohorts using a Mendelian Randomization strategy. Setting: Sepsis patients enrolled into clinical research cohorts at tertiary care teaching hospitals. Patients: The first cohort included 200 sepsis patients enrolled in an observational study in a hospital Emergency Department. The second cohort included genotyped patients enrolled in the Vasopressin and Septic Shock Trial. Interventions: Retrospective analysis of these patient datasets. In 632 patients enrolled in Vasopressin and Septic Shock Trial, Proprotein Convertase Subtilisin/Kexin type 9, and 3-Hydroxy-3-Methylglutaryl-CoA Reductase single nucleotide polymorphisms known to be associated with low-density lipoprotein levels were genotyped, and a genetic score related to low-density lipoprotein levels was calculated. Measurements and Main Results: In the first cohort, we replicated the finding that low low-density lipoprotein levels are associated with increased 28-day mortality. In genotyped patients in the Vasopressin and Septic Shock Trial trial, we found that the 3-Hydroxy-3-Methylglutaryl-CoA Reductase genetic score, known to be directly related to low low-density lipoprotein levels, was not associated with increased mortality. Surprisingly the Proprotein Convertase Subtilisin/Kexin type 9 genetic score, known to be directly related to low low-density lipoprotein levels, was associated with decreased (not increased) mortality. Conclusions: Both 3-Hydroxy-3-Methylglutaryl-CoA Reductase and Proprotein Convertase Subtilisin/Kexin type 9 genetic scores should have been associated with increased mortality if low low-density lipoprotein levels contributed causally to sepsis mortality. But this was not the case, and the opposite was observed for the Proprotein Convertase Subtilisin/Kexin type 9 genetic score. This suggests that low-density lipoprotein levels, per se, do not contribute causally to adverse sepsis outcomes. The Proprotein Convertase Subtilisin/Kexin type 9 genetic score finding raises the possibility that increased low-density lipoprotein clearance (the effect of these Proprotein Convertase Subtilisin/Kexin type 9 genotypes) may contribute to improved sepsis outcomes. 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 Canadian Institutes of Health Research FDN 154311. Dr. Walley is supported by the Canadian Institutes of Health Research (CIHR) FDN 154311. Dr. Boyd disclosed he is a Co-Founder of Cyon Therapeutics, a biotech company aiming to develop Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors for sepsis. Ms. Kong’s institution received funding from CIHR. Dr. Russell received funding from Asahi Kasei Pharma America (developing thrombomodulin in sepsis), consulting fees from Cubist Pharmaceuticals (now owned by Merck, formerly Trius Pharmaceuticals, developing antibiotics), Ferring Pharmaceuticals (which manufactures vasopressin and is developing selepressin), Grifols (which sells albumin), MedImmune (regarding sepsis), Leading Biosciences (developing a sepsis therapeutic), La Jolla Pharmaceuticals (developing a sepsis therapeutic), CytoVale (developing a sepsis diagnostic), Asahi Kesai (developing a sepsis therapeutic), Sirius Genomics (now closed, formerly involved in pharmacogenomics research in sepsis), and received grant support from Sirius Genomics and Ferring Pharmaceuticals that was provided to and administered by University of British Columbia (UBC). Drs. Walley, Boyd, and Russell report being inventors on patents owned by the UBC that are related to PCSK9 inhibitor(s) and sepsis and related to the use of vasopressin in septic shock. For information regarding this article, E-mail: Keith.Walley@hli.ubc.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.