Invasive Bacterial Infections Research Articles

Hydroxyurea in sickle cell disease and invasive bacterial infections: a case-control study.

Hydroxyurea decreases painful events among children with sickle cell disease but could increase the risk of infections in treated patients through leucopenia. We performed a case-control study, comparing hydroxyurea treatment for sickle cell disease in cases with an invasive bacterial infection and in controls without infection. No difference was found.

Post-COVID-19 pandemic increased incidence of invasive bacterial infections: potential links with altered herd trained immunity.

There has been a global increase in the incidence of various infectious diseases observed since the end of the COVID-19 pandemic. It could be hypothesized that this increase results from two independent phenomena. One is related to impaired immunity of long Covid patients. The second, the major, is associated with the long-term isolation of many people during the global pandemic lockdown resulting in an extreme reduction of contact with natural environmental human microbiota. This, in turn, led to a silencing state of the body's defense systems, including a decline of the pre-pandemic trained immunity (innate memory) that persists only for weeks to months after exposure. This decrease in trained immunity may be especially important for morbidity of infectious diseases without currently available vaccines, such as invasive Group A Streptococcus pyogenes (GAS) infections, primarily streptococcal toxic shock syndrome (STSS). This review discusses the data that support the important role of trained macrophages in host defense and demonstrates the potential clinical implications of β-glucan, the major inducer of trained macrophages, for prophylactic and therapeutic use in a case of impaired personal innate immunity. Altogether, it might be speculated that trained innate immunity within an entire population can lead to the development of Herd Trained Immunity, the novel coined the medical term. HTI can supplement classical antigen-specific herd immunity (memory B and T cells) and plays a key role in preventing various infectious diseases, including invasive GAS infections. Unfortunately, the global HTI has been overthrown during the COVID-19 pandemic but it should be restored shortly.

Neuropeptide Y affects B-cell activation functions

Introduction: Sympathetic nerves secrete neurotransmitters in response to pathogenic organisms in various immunological contexts. Most studies have focused on norepinephrine (NE) which has shown numerous immunomodulatory effects involving pro- and anti-inflammatory responses. However, sympathetic neurons contain also varicosities where neuropeptides, mainly neuropeptide Y (NPY), are stored. NPY play roles in various physiological processes, including regulating metabolism, vascular function, and immune function but little is known on its action during bacterial respiratory infection. The regulation of its secretion and its impact on the immune system during infection remains unclear. We investigated the role of NPY in B-cell responses during bacterial infection. Methods: Naïve B-cells isolated from mice splenocytes (2M/2F) were stimulated with IL-4 and LPS, along with NE or NPY. After 96 hours, cells were stained and analyzed by flow cytometry and transcripts were isolated for quantitative real-time PCR. Media was collected until immunoglobulin analysis. To investigate NPY role during infection, we used a mice model of bacterial lung infection. Mice were intranasally exposed twice with streptococcus pneumoniae (serotype 19F on day 0: 104 CFU and on day 9: 108 CFU); experiments took place 16 hours later. Control animals were infused with vehicle only. Results: Apart from beta2-adrenergic receptor, isolated B-cells were found to express alpha2- and beta1-adrenergic receptor transcripts. In vitro stimulation of B-cell with IL-4 and LPS (T-cell independent activation) downregulated beta-adrenergic and upregulated alpha2-adrenergic, as well as NPY receptors (Npy1r, Npy2r, Npy4r, Npy5r). Unlike NE, NPY has shown to affect B-cell proliferation and drastically increases IgG positive-cells during stimulation. However, neither NE nor NPY seem to regulate IgG release in this condition. In vivo experiments indicate that NPY level increased in the lung in response to streptococcal challenge, contrasting with the unchanged levels of NE. Conclusion: Our findings contribute to our understanding of how sympathetic neurotransmitters regulates B-cell expansion, memory, and antibody production during infection. Furthermore, our research gives new insights into the function(s) and antimicrobial capacity of neuropeptide Y. These findings allow for the development of new and more effective therapeutic strategies for invasive bacterial infections. 1R21AI159221, UCOP TRDRP T32KT4708. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Improving Guideline-Concordant Care for Febrile Infants Through a Quality Improvement Initiative.

We aimed to examine the impact of a quality improvement (QI) collaborative on adherence to specific recommendations within the American Academy of Pediatrics' Clinical Practice Guideline (CPG) for well-appearing febrile infants aged 8 to 60 days. Concurrent with CPG release in August 2021, we initiated a QI collaborative involving 103 general and children's hospitals across the United States and Canada. We developed a multifaceted intervention bundle to improve adherence to CPG recommendations for 4 primary measures and 4 secondary measures, while tracking 5 balancing measures. Primary measures focused on guideline recommendations where deimplementation strategies were indicated. We analyzed data using statistical process control (SPC) with baseline and project enrollment from November 2020 to October 2021 and the intervention from November 2021 to October 2022. Within the final analysis, there were 17 708 infants included. SPC demonstrated improvement across primary and secondary measures. Specifically, the primary measures of appropriately not obtaining cerebrospinal fluid in qualifying infants and appropriately not administering antibiotics had the highest adherence at the end of the collaborative (92.4% and 90.0% respectively). Secondary measures on parent engagement for emergency department discharge of infants 22 to 28 days and oral antibiotics for infants 29 to 60 days with positive urinalyses demonstrated the greatest changes with collaborative-wide improvements of 16.0% and 20.4% respectively. Balancing measures showed no change in missed invasive bacterial infections. A QI collaborative with a multifaceted intervention bundle was associated with improvements in adherence to several recommendations from the AAP CPG for febrile infants.

Leukopenia, neutropenia, and procalcitonin levels in young febrile infants with invasive bacterial infections.

Serum procalcitonin (PCT) is a highly accurate biomarker for stratifying the risk of invasive bacterial infections (IBIs) in febrile infants ≤60 days old. However, PCT is unavailable in some settings. We explored the association of leukopenia and neutropenia with IBIs in non-critically ill febrile infants ≤60 days old, with and without PCT. We conducted a secondary analysis of a prospective observational cohort consisting of 7407 non-critically ill infants ≤60 days old with temperatures ≥38°C. We focused on the risk of IBIs in patients with leukopenia (white blood cell [WBC] count <5000 cells/μL) or neutropenia (absolute neutrophil count [ANC] <1000 cells/μL), categorized to extremes of lower values, and the impact of PCT on these associations. Multiple logistic regression was used to identify independent predictors of IBIs. Final analysis included 6865 infants with complete data; 45% (3098) had PCT data available. Of the 6865, a total of 111 (1.6%) had bacteremia without bacterial meningitis, 18 (0.3%) had bacterial meningitis without bacteremia, and 19 (0.3%) had both bacteremia and bacterial meningitis. IBI was present in four of 20 (20%) infants with WBC counts ≤2500 cells/μL and four of 311 (1.3%) with ANC <1000 cells/μL. In multivariable logistic regression analysis not including PCT, a WBC count <2500 cells/μL was significantly associated with IBI (OR 13.48, 95% CI 2.92-45.35). However, no patients with leukopenia or neutropenia and PCT ≤0.5 ng/mL had IBIs. Leukopenia ≤2500 cells/μL in febrile infants ≤60 days old is associated with IBIs. However, in the presence of normal PCT levels, no patients with leukopenia had IBIs. While this suggests leukopenia ≤2500 cells/μL is a risk factor for IBIs in non-critically ill young febrile infants only when PCT is unavailable or elevated, the overall low frequency of leukopenia in this cohort warrants caution in interpretation, with future validation required.

Beyond the β-amino alcohols framework: identification of novel β-hydroxy pyridinium salt-decorated pterostilbene derivatives as bacterial virulence factor inhibitors.

Bacterial virulence factors are involved in various biological processes and mediate persistent bacterial infections. Focusing on virulence factors of phytopathogenic bacteria is an attractive strategy and crucial direction in pesticide discovery to prevent invasive and persistent bacterial infection. Hence, discovery and development of novel agrochemicals with high activity, low-risk, and potent anti-virulence is urgently needed to control plant bacterial diseases. A series of novel β-hydroxy pyridinium cation decorated pterostilbene derivatives were prepared and their antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) were systematacially assessed. Among these pterostilbene derivatives, compound 4S exhibited the best antibacterial activity against Xoo in vitro, with an EC50 value of 0.28 μg mL-1. A series of biochemical assays including scanning electron microscopy, crystal violet staining, and analyses of biofilm formation, swimming motility, and related virulence factor gene expression levels demonstrated that compound 4S could function as a new anti-virulence factor inhibitor by interfering with the bacterial infection process. Furthermore, the pot experiments provided convinced evidence that compound 4S had the high control efficacy (curative activity:71.4%, protective activity: 72.6%), and could be used to effectively manage rice bacterial leaf blight in vivo. Compounds 4S is an attractive virulence factor inhibitor with potential for application in treating plant bacterial diseases by suppressing production of several virulence factors. This article is protected by copyright. All rights reserved.

The Prospect of Biomimetic Immune Cell Membrane-Coated Nanomedicines for Treatment of Serious Bacterial Infections and Sepsis.

Invasive bacterial infections and sepsis are persistent global health concerns, complicated further by the escalating threat of antibiotic resistance. Over the past 40 years, collaborative endeavors to improve the diagnosis and critical care of septic patients have improved outcomes, yet grappling with the intricate immune dysfunction underlying the septic condition remains a formidable challenge. Anti-inflammatory interventions that exhibited promise in murine models failed to manifest consistent survival benefits in clinical studies through recent decades. Novel therapeutic approaches that target bacterial virulence factors, for example with monoclonal antibodies, aim to thwart pathogen-driven damage and restore an advantage to the immune system. A pioneering technology addressing this challenge is biomimetic nanoparticles-a therapeutic platform featuring nanoscale particles enveloped in natural cell membranes. Borne from the quest for a durable drug delivery system, the original red blood cell-coated nanoparticles showcased a broad capacity to absorb bacterial and environmental toxins from serum. Tailoring the membrane coating to immune cell sources imparts unique characteristics to the nanoparticles suitable for broader application in infectious disease. Their capacity to bind both inflammatory signals and virulence factors assembles the most promising sepsis therapies into a singular, pathogen-agnostic therapeutic. This review explores the ongoing work on immune cell-coated nanoparticle therapeutics for infection and sepsis. SIGNIFICANCE STATEMENT: Invasive bacterial infections and sepsis are a major global health problem made worse by expanding antibiotic resistance, meaning better treatment options are urgently needed. Biomimetic cell-membrane-coated nanoparticles are an innovative therapeutic platform that deploys a multifaceted mechanism to action to neutralize microbial virulence factors, capture endotoxins, and bind excessive host proinflammatory cytokines, seeking to reduce host tissue injury, aid in microbial clearance, and improve patient outcomes.

Real-World Dalbavancin Use for Serious Gram-Positive Infections: Comparing Outcomes Between People Who Use and Do Not Use Drugs.

Dalbavancin has been used off-label to treat invasive bacterial infections in vulnerable populations like people who use drugs (PWUD) because of its broad gram-positive coverage and unique pharmacological properties. This retrospective, multisite study examined clinical outcomes at 90 days in PWUD versus non-PWUD after secondary treatment with dalbavancin for bacteremia, endocarditis, osteomyelitis, septic arthritis, and epidural abscesses. Patients at 3 teaching hospitals who received dalbavancin for an invasive infection between March 2016 and May 2022 were included. Characteristics of PWUD and non-PWUD, infection highlights, hospital stay and treatment, and outcomes were compared using χ2 for categorical variables, t test for continuous variables, and nonparametric tests where appropriate. There were a total of 176 patients; 78 were PWUD and 98 were non-PWUD. PWUD were more likely to have a patient-directed discharge (26.9% vs 3.1%; P < .001) and be lost to follow-up (20.5% vs 7.14%; P < .01). Assuming loss to follow-up did not achieve clinical cure, 73.1% of PWUD and 74.5% of non-PWUD achieved clinical cure at 90 days (P = .08). Dalbavancin was an effective treatment option for invasive gram-positive infections in our patient population. Despite higher rates of patient-directed discharge and loss to follow-up, PWUD had similar rates of clinical cure at 90 days compared to non-PWUD.

An all-inclusive model for predicting invasive bacterial infection in febrile infants age 7-60 days.

Invasive bacterial infections (IBIs) in febrile infants are rare but potentially devastating. We aimed to derive and validate a predictive model for IBI among febrile infants age 7-60 days. Data were abstracted retrospectively from electronic records of 37 emergency departments (EDs) for infants with a measured temperature >=100.4 F who underwent an ED evaluation with blood and urine cultures. Models to predict IBI were developed and validated respectively using a random 80/20 dataset split, including 10-fold cross-validation. We used precision recall curves as the classification metric. Of 4411 eligible infants with a mean age of 37 days, 29% had characteristics that would likely have excluded them from existing risk stratification protocols. There were 196 patients with IBI (4.4%), including 43 (1.0%) with bacterial meningitis. Analytic approaches varied in performance characteristics (precision recall range 0.04-0.29, area under the curve range 0.5-0.84), with the XGBoost model demonstrating the best performance (0.29, 0.84). The five most important variables were serum white blood count, maximum temperature, absolute neutrophil count, absolute band count, and age in days. A machine learning model (XGBoost) demonstrated the best performance in predicting a rare outcome among febrile infants, including those excluded from existing algorithms. Several models for the risk stratification of febrile infants have been developed. There is a need for a preferred comprehensive model free from limitations and algorithm exclusions that accurately predicts IBIs. This is the first study to derive an all-inclusive predictive model for febrile infants aged 7-60 days in a community ED sample with IBI as a primary outcome. This machine learning model demonstrates potential for clinical utility in predicting IBI.

Performance of Febrile Infant Algorithms by Duration of Fever.

To analyze the performance of commonly used blood tests in febrile infants ≤90 days of age to identify patients at low risk for invasive bacterial infection (bacterial pathogen in blood or cerebrospinal fluid) by duration of fever. We conducted a secondary analysis of a prospective single-center registry that includes all consecutive infants ≤90 days of age with fever without a source evaluated at 1 pediatric emergency department between 2008 and 2021. We defined 3 groups based on caregiver-reported hours of fever (<2, 2-12, and ≥12) and analyzed the performance of the biomarkers and Pediatric Emergency Care Applied Research Network, American Academy of Pediatrics, and Step-by-Step clinical decision rules. We included 2411 infants; 76 (3.0%) were diagnosed with an invasive bacterial infection. The median duration of fever was 4 (interquartile range, 2-12) hours, with 633 (26.3%) patients with fever of <2 hours. The area under the curve was significantly lower in patients with <2 hours for absolute neutrophil count (0.562 vs 0.609 and 0.728) and C-reactive protein (0.568 vs 0.760 and 0.812), but not for procalcitonin (0.749 vs 0.780 and 0.773). Among well-appearing infants older than 21 days and negative urine dipstick with <2 hours of fever, procalcitonin ≥0.14 ng/mL showed a better sensitivity (100% with specificity 53.8%) than that of the combination of biomarkers of Step-by-Step (50.0% and 82.2%), and of the American Academy of Pediatrics and Pediatric Emergency Care Applied Research Network rules (83.3% and 58.3%), respectively. The performance of blood biomarkers, except for procalcitonin, in febrile young infants is lower in fever of very short duration, decreasing the accuracy of the clinical decision rules.

Predictors of Invasive Bacterial Infection in Febrile Infants Aged 2 to 6 Months in the Emergency Department

Our goal was to identify predictors of invasive bacterial infection (ie, bacteremia and bacterial meningitis) in febrile infants aged 2 to 6 months. In our multicenter retrospective cohort, older age and lower temperature identified infants at low risk for invasive bacterial infection who could safely avoid routine testing.

Evaluation of Pediatric Invasive Bacterial Infections After the COVID-19 Pandemic

Evaluation of Pediatric Invasive Bacterial Infections After the COVID-19 Pandemic

Diagnostic test accuracy of procalcitonin and C-reactive protein for predicting invasive and serious bacterial infections in young febrile infants: a systematic review and meta-analysis

Febrile infants presenting in the first 90 days of life are at higher risk of invasive and serious bacterial infections than older children. Modern clinical practice guidelines, mostly using procalcitonin as a diagnostic biomarker, can identify infants who are at low risk and therefore suitable for tailored management. C-reactive protein, by comparison, is widely available, but whether C-reactive protein and procalcitonin have similar diagnostic accuracy is unclear. We aimed to compare the test accuracy of procalcitonin and C-reactive protein in the prediction of invasive or serious bacterial infections in febrile infants. For this systematic review and meta-analysis, we searched MEDLINE, EMBASE, Web of Science, and The Cochrane Library for diagnostic test accuracy studies up to June 19, 2023, using MeSH terms "procalcitonin", and "bacterial infection" or "fever" and keywords "invasive bacterial infection*" and "serious bacterial infection*", without language or date restrictions. Studies were selected by independent authors against eligibility criteria. Eligible studies included participants aged 90 days or younger presenting to hospital with a fever (≥38°C) or history of fever within the preceding 48 h. The primary index test was procalcitonin, and the secondary index test was C-reactive protein. Test kits had to be commercially available, and test samples had to be collected upon presentation to hospital. Invasive bacterial infection was defined as the presence of a bacterial pathogen in blood or cerebrospinal fluid, as detected by culture or quantitative PCR; authors' definitions of serious bacterial infection were used. Data were extracted from selected studies, and the detection of invasive or serious bacterial infections was analysed with two models for each biomarker. Diagnostic accuracy was determined against internationally recognised cutoff values (0·5 ng/mL for procalcitonin, 20 mg/L for C-reactive protein) and pooled to calculate partial area under the curve (pAUC) values for each biomarker. Optimum cutoff values were identified for each biomarker. This study is registered with PROSPERO, CRD42022293284. Of 734 studies derived from the literature search, 14 studies (n=7755) were included in the meta-analysis. For the detection of invasive bacterial infections, pAUC values were greater for procalcitonin (0·72, 95% CI 0·56-0·79) than C-reactive protein (0·28, 0·17-0·61; p=0·016). Optimal cutoffs for detecting invasive bacterial infections were 0·49 ng/mL for procalcitonin and 13·12 mg/L for C-reactive protein. For the detection of serious bacterial infections, procalcitonin and C-reactive protein had similar pAUC values (0·55, 0·44-0·69 vs 0·54, 0·40-0·61; p=0·92). For serious bacterial infections, the optimal cutoffs for procalcitonin and C-reactive protein were 0·17 ng/mL and 16·18 mg/L, respectively. Heterogeneity was low for studies investigating the test accuracy of procalcitonin in detecting invasive bacterial infection (I2=23·5%), high for studies investigating procalcitonin for serious bacterial infection (I2=75·5%), and moderate for studies investigating C-reactive protein for invasive bacterial infection (I2=49·5%) and serious bacterial infection (I2=28·3%). The absence of a single definition of serious bacterial infection across studies was the greatest source of interstudy variability and potential bias. Within a large cohort of febrile infants, a procalcitonin cutoff of 0·5 ng/mL had a superior pAUC value to a C-reactive protein cutoff of 20 mg/L for identifying invasive bacterial infections. In settings without access to procalcitonin, C-reactive protein should therefore be used cautiously for the identification of invasive bacterial infections, and a cutoff value below 20 mg/L should be considered. C-reactive protein and procalcitonin showed similar test accuracy for the identification of serious bacterial infection with internationally recognised cutoff values. This might reflect the challenges involved in confirming serious bacterial infection and the absence of a universally accepted definition of serious bacterial infection. None.

NAD+ prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages.

Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD+ treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1β and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-β/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.

NAD+ prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages

Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD+ treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1β and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-β/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.

Management of well-appearing febrile young infants aged ≤90 days

Abstract The evaluation and management of young infants presenting with fever remains an area of significant practice variation. While most well-appearing febrile young infants have a viral illness, identifying those at risk for invasive bacterial infections, specifically bacteremia and bacterial meningitis, is critical. This statement considers infants aged ≤90 days who present with a rectal temperature ≥38.0°C but appear well otherwise. Applying recent risk-stratification criteria to guide management and incorporating diagnostic testing with procalcitonin are advised. Management decisions for infants meeting low-risk criteria should reflect the probability of disease, consider the balance of risks and potential harm, and include parents/caregivers in shared decision-making when options exist. Optimal management may also be influenced by pragmatic considerations, such as access to diagnostic investigations, observation units, tertiary care, and follow-up. Special considerations such as temperature measurement, risk for invasive herpes simplex infection, and post-immunization fever are also discussed.

Performance of Febrile Infant Decision Tools on Hypothermic Infants Evaluated for Infection.

Given the lack of evidence-based guidelines for hypothermic infants, providers may be inclined to use febrile infant decision-making tools to guide management decisions. Our objective was to assess the diagnostic performance of febrile infant decision tools for identifying hypothermic infants at low risk of bacterial infection. We conducted a secondary analysis of a retrospective cohort study of hypothermic (≤36.0 C) infants ≤90 days of age presenting to the emergency department or inpatient unit among 9 participating sites between September 1, 2016 and May 5, 2021. Well-appearing infants evaluated for bacterial infections via laboratory testing were included. Infants with complex chronic conditions or premature birth were excluded. Performance characteristics for detecting serious bacterial infection (SBI; urinary tract infection, bacteremia, bacterial meningitis) and invasive bacterial infection (IBI; bacteremia, bacterial meningitis) were calculated for each tool. Overall, 314 infants met the general inclusion criteria, including 14 cases of SBI (4.5%) and 7 cases of IBI (2.2%). The median age was 5 days, and 68.1% of the infants (214/314) underwent a full sepsis evaluation. The Philadelphia, Boston, IBI Score, and American Academy of Pediatrics Clinical Practice Guideline did not misclassify any SBI or IBI as low risk; however, they had low specificity and positive predictive value. Rochester and Pediatric Emergency Care Applied Research Network tools misclassified infants with bacterial infections. Several febrile infant decision tools were highly sensitive, minimizing missed SBIs and IBIs in hypothermic infants. However, the low specificity of these decision tools may lead to unnecessary testing, antimicrobial exposure, and hospitalization.

A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection

Mast cells localize to mucosal tissues and contribute to innate immune defense against infection. How mast cells sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other related enterobacteria, here we show that mast cells can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and mast cells colocalize in the mouse gut during acute Salmonella infection. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure lipopolysaccharide, causes a modest induction of cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human mast cells triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to drive the full-blown mast cell response. Supernatants from S.Tm-infected mast cells boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that mast cells can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.

Conundrums in the Management of Febrile Infants under Three Months of Age and Future Research.

Febrile infants under three months of age pose a diagnostic challenge to clinicians. Unlike in older children, the rates of invasive bacterial infections (IBIs), such as bacteraemia or meningitis, are high. This greater risk of IBI combined with the practical challenges of assessing young infants results in a cautious approach with many febrile infants receiving parenteral antibiotics "just in case". However, there is a range of validated tailored care guidelines that support targeted investigation and management of febrile infants, with a cohort identified as lower risk suitable for fewer invasive procedures and observation without parenteral antibiotics. This manuscript outlines five common conundrums related to the safe application of tailored-care guidelines for the assessment and management of febrile infants under three months of age. It also explores future research which aims to further refine the management of febrile infants.

Contaminant Organism Growth in Febrile Infants at Low Risk for Invasive Bacterial Infection

In this multicenter, cross-sectional, secondary analysis of 4042 low-risk febrile infants, nearly 10% had a contaminated culture obtained during their evaluation (4.9% of blood cultures, 5.0% of urine cultures, and 1.8% of cerebrospinal fluid cultures). Our findings have important implications for improving sterile technique and reducing unnecessary cultures.