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There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-\"Low\" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-\"Medium\" Watch), 18.0% (n = 566) started a carbapenem (Group 4-\"High\" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. ClinicalTrials.gov, (NCT03721302).

Background The high rates of culture-positive sepsis, sepsis-related mortality, and multidrug resistance in neonates admitted to special care newborn units in district hospitals (DH) in India necessitate urgent actions to prevent infections in these settings. Immediate kangaroo mother care (iKMC), initiated before stabilization within the first few hours of life, has been shown to reduce neonatal mortality among low birth weight (LBW) neonates admitted to tertiary care hospitals. However, the effect of iKMC on sepsis and sepsis-related mortality, particularly in DH, remains unclear. This study aims to evaluate whether iKMC can lower the incidence of mortality or culture-positive sepsis in LBW neonates admitted to neonatal units in district hospitals. Methods This stepped-wedge cluster randomized trial will be conducted in ten district hospitals in Chhattisgarh, India, over 42 months. All neonates weighing between 1000 and 1799 g at birth and admitted to the participating hospitals, in whom KMC can be initiated within 12 h of life, will be eligible for inclusion. During the pre-intervention period (control), routine KMC will be practiced at the sites as is. Following a baseline period of 6 months, iKMC will be implemented sequentially in ten steps across the ten study sites at intervals of 3 months. The intervention includes initiating continuous skin-to-skin contact with the mother or relatives within 12 h of life, continuing KMC until discharge or weight 2.5 kg, and providing breastfeeding support. The primary outcome is the incidence of all-cause neonatal mortality and/or culture-positive sepsis until 28 days of life. Relative risks with 95% confidence intervals will be reported and analyzed using a generalized linear mixed model. An intention-to-treat analysis will be conducted. Discussion The PRISM (Protective Role of Immediate KMC in neonatal Sepsis and Mortality) trial will sequentially implement iKMC for LBW neonates in ten district hospitals with a relatively high burden of sepsis in India. If proven effective in reducing the risks of sepsis or neonatal mortality, the trial will provide necessary evidence for its safety and efficacy, as well as the impetus for implementing and upscaling the intervention in district hospitals across India and other low- and middle-income countries. Trial registration Clinical Trial Registry of India, CTRI/2024/09/074269. Registered on 24/09/2024, https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MTE0MzY3&Enc=&userName=immediate%20kangaroo%20mother%20care .

Hemophagocytic lymphohistocytosis (HLH) is characterized by fulminant cytokine storm leading to multiple organ dysfunction and high mortality. HLH is classified into familial (fHLH) and into secondary (sHLH). fHLH is rare and it is due to mutations of genes encoding for perforin or excretory granules of natural killer (NK) cells of CD8-lymphocytes. sHLH is also known as macrophage activation syndrome (MAS). Macrophage activation syndrome (MAS) in adults is poorly studied. Main features are fever, hepatosplenomegaly, hepatobiliary dysfunction (HBD), coagulopathy, cytopenia of two to three cell lineages, increased triglycerides and hemophagocytosis in the bone marrow. sHLH/MAS complicates hematologic malignancies, autoimmune disorders and infections mainly of viral origin. Pathogenesis is poorly understood and it is associated with increased activation of macrophages and NK cells. An autocrine loop of interleukin (IL)-1β over-secretion leads to cytokine storm of IL-6, IL-18, ferritin, and interferon-gamma; soluble CD163 is highly increased from macrophages. The true incidence of sHLH/MAS among patients with sepsis has only been studied in the cohort of the Hellenic Sepsis Study Group. Patients meeting the Sepsis-3 criteria and who had positive HSscore or co-presence of HBD and disseminated intravascular coagulation (DIC) were classified as patients with macrophage activation-like syndrome (MALS). The frequency of MALS ranged between 3 and 4% and it was an independent entity associated with early mortality after 10 days. Ferritin was proposed as a diagnostic and surrogate biomarker. Concentrations >4,420 ng/ml were associated with diagnosis of MALS with 97.1% specificity and 98% negative predictive value. Increased ferritin was also associated with increased IL-6, IL-18, IFNγ, and sCD163 and by decreased IL-10/TNFα ratio. A drop of ferritin by 15% the first 48 h was a surrogate finding of favorable outcome. There are 10 on-going trials in adults with sHLH; two for the development of biomarkers and eight for management. Only one of them is focusing in sepsis. The acronym of the trial is PROVIDE (ClinicalTrials.gov NCT03332225) and it is a double-blind randomized clinical trial aiming to deliver to patients with septic shock treatment targeting their precise immune state. Patients diagnosed with MALS are receiving randomized treatment with placebo or the IL-1β blocker anakinra.

Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment. We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned [1:1] using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932. Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI −4·6 to 4·8) in the intention-to-treat analysis (5 [0·6%] of 866 neonates in the procalcitonin group vs 4 [0·5%] of 844 neonates in the standard group) and 0·1% (−5·2 to 5·3) in the per-protocol analysis (5 [0·7%] of 745 neonates in the procalcitonin group vs 4 [0·6%] of 663 neonates in the standard group). Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death. The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.

PurposeSepsis is a heterogeneous syndrome and identification of sub-phenotypes is essential. This study used trajectories of vital signs to develop and validate sub-phenotypes and investigated the interaction of sub-phenotypes with treatment using randomized controlled trial data.MethodsAll patients with suspected infection admitted to four academic hospitals in Emory Healthcare between 2014–2017 (training cohort) and 2018–2019 (validation cohort) were included. Group-based trajectory modeling was applied to vital signs from the first 8 h of hospitalization to develop and validate vitals trajectory sub-phenotypes. The associations between sub-phenotypes and outcomes were evaluated in patients with sepsis. The interaction between sub-phenotype and treatment with balanced crystalloids versus saline was tested in a secondary analysis of SMART (Isotonic Solutions and Major Adverse Renal Events Trial).ResultsThere were 12,473 patients with suspected infection in training and 8256 patients in validation cohorts, and 4 vitals trajectory sub-phenotypes were found. Group A (N = 3483, 28%) were hyperthermic, tachycardic, tachypneic, and hypotensive. Group B (N = 1578, 13%) were hyperthermic, tachycardic, tachypneic (not as pronounced as Group A) and hypertensive. Groups C (N = 4044, 32%) and D (N = 3368, 27%) had lower temperatures, heart rates, and respiratory rates, with Group C normotensive and Group D hypotensive. In the 6,919 patients with sepsis, Groups A and B were younger while Groups C and D were older. Group A had the lowest prevalence of congestive heart failure, hypertension, diabetes mellitus, and chronic kidney disease, while Group B had the highest prevalence. Groups A and D had the highest vasopressor use (p < 0.001 for all analyses above). In logistic regression, 30-day mortality was significantly higher in Groups A and D (p < 0.001 and p = 0.03, respectively). In the SMART trial, sub-phenotype significantly modified treatment effect (p = 0.03). Group D had significantly lower odds of mortality with balanced crystalloids compared to saline (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.23–0.67, p < 0.001).ConclusionSepsis sub-phenotypes based on vital sign trajectory were consistent across cohorts, had distinct outcomes, and different responses to treatment with balanced crystalloids versus saline.

Introduction Neonatal sepsis is a leading cause of infant mortality worldwide with non-specific and varied presentation. We aimed to catalogue the current definitions of neonatal sepsis in published randomised controlled trials (RCTs). Method A systematic search of the Embase and Cochrane databases was performed for RCTs which explicitly stated a definition for neonatal sepsis. Definitions were sub-divided into five primary criteria for infection (culture, laboratory findings, clinical signs, radiological evidence and risk factors) and stratified by qualifiers (early/late-onset and likelihood of sepsis). Results Of 668 papers screened, 80 RCTs were included and 128 individual definitions identified. The single most common definition was neonatal sepsis defined by blood culture alone ( n  = 35), followed by culture and clinical signs ( n  = 29), and then laboratory tests/clinical signs ( n  = 25). Blood culture featured in 83 definitions, laboratory testing featured in 48 definitions while clinical signs and radiology featured in 80 and 8 definitions, respectively. Discussion A diverse range of definitions of neonatal sepsis are used and based on microbiological culture, laboratory tests and clinical signs in contrast to adult and paediatric sepsis which use organ dysfunction. An international consensus-based definition of neonatal sepsis could allow meta-analysis and translate results to improve outcomes.

IntroductionNewborns are at risk for early-onset sepsis (EOS). In the Netherlands, EOS affects less than 0.2% of newborns, but approximately 5% are treated with empirical antibiotics. These numbers form an example of overtreatment in countries using risk-factor based guidelines for administrating antibiotics. An alternative to these guidelines is the EOS calculator, a tool that calculates an individual EOS risk and provides management recommendation. However, validation outside the North-American setting is limited, especially for safety outcomes. We aim to investigate whether EOS calculator use can safely reduce antibiotic exposure in newborns with suspected EOS compared with the Dutch guideline.Methods and analysisThis protocol describes a cluster randomised controlled trial assessing whether EOS calculator use is non-inferior regarding safety, and superior regarding limiting overtreatment, compared with the Dutch guideline. We will include newborns born at ≥34 weeks’ gestation, with at least one risk factor consistent with EOS within 24 hours after birth. After 1:1 randomisation, the 10 participating Dutch hospitals will use either the Dutch guideline or the EOS calculator as standard of care for all newborns at risk for EOS. In total, 1830 newborns will be recruited. The coprimary non-inferiority outcome will be the presence of at least one of four predefined safety criteria. The coprimary superiority outcome will be the proportion of participants starting antibiotic therapy for suspected and, or proven EOS within 24 hours after birth. Secondary outcomes will be the total duration of antibiotic therapy, the percentage of antibiotic therapy started between 24 and 72 hours after birth, and parent-reported quality of life. Analyses will be performed both as intention to treat and per protocol.Ethics and disseminationThis trial has been approved by the Medical Ethics Committee of the Amsterdam UMC (NL78203.018.21). Results will be presented in peer-reviewed journals and at international conferences.Trial registration numberNCT05274776.

Background Clinical implications of metagenomics next-generation sequencing (mNGS) in sepsis have not been fully evaluated. This study aimed to determine the diagnostic, therapeutic, and prognostic impacts of mNGS in sepsis. Methods This multicenter prospective study was conducted at 19 sites in China from 2020 to 2021, and 859 adult patients hospitalized with sepsis were enrolled. The advantages, challenges, knowledge gaps and privacy risks of mNGS were carefully introduced to all participants, and participants chose on their own to either receive conventional microbiological test (CMT) alone (conventional-test-only group, n  = 394) or receive mNGS test along with CMT (combined test group, n  = 465). For prognostic analysis, the primary endpoint was 28-day mortality. Secondary endpoints included 7-day mortality and average per-day hospital cost. Inverse probability of treatment weighting was used to balance covariates between groups. Concurrent CMT and mNGS results from patients in the combined test group were used for diagnostic analyses. Therapeutic impact of mNGS was evaluated based on subsequent antibiotic adjustment. Results Compared with composite reference standard, the positive percent agreement of mNGS among infected site samples was significantly higher than that of CMT (92.0% [95% CI, 88.7 to 94.5] vs. 51.1% [95% CI, 45.9 to 56.2], p  < 0.001), while the negative percent agreement of mNGS was inferior to that of CMT (39.6% [95% CI, 29.5 to 50.4] vs. 69.2% [95% CI, 58.7 to 78.5], p  < 0.001). The mNGS test identified causal microbes in 344 (74.0%) patients, and concomitant antibiotic changes occurred in 136 patients (29.2%). Death by day 7 occurred in 24 of 465 (5.2%) patients in the combined test group and in 34 of 394 (8.6%) patients in the conventional-test-only group (hazard ratio, 0.44 [95% CI, 0.26 to 0.77], p  = 0.004). However, no significant difference in 28-day mortality was observed between two study groups (hazard ratio, 0.82 [0.56 to 1.20], p  = 0.300). Conclusions The mNGS test of infected site samples exhibited 40% higher pathogen detection rate than CMT in patients with sepsis, which led to improved etiological diagnosis and tailored antibiotic therapy. Additional use of mNGS halved the risk of early death in 7 days, but did not improve 28-day survival in patients with sepsis. Trial registration chictr.org.cn Identifier: ChiCTR2000031113. Registered 22 March 2020.

Background Early-life antibiotic exposure is disproportionately high compared to the burden of culture-proven early-onset sepsis (CP-EOS). We assessed the contribution of culture-negative cases to the overall antibiotic exposure in the first postnatal week. Methods We conducted a retrospective analysis across eleven countries in Europe, North America, and Australia. All late-preterm and term infants born between 2014 and 2018 who received intravenous antibiotics during the first postnatal week were classified as culture-negative cases treated for ≥5 days (CN ≥ 5d), culture-negative cases treated for <5 days (CN < 5d), or CP-EOS cases. Results Out of 757,979 infants, 21,703 (2.9%) received intravenous antibiotics. The number of infants classified as CN ≥ 5d, CN < 5d, and CP-EOS was 7996 (37%), 13,330 (61%), and 375 (1.7%). The incidence of CN ≥ 5d, CN < 5d, and CP-EOS was 10.6 (95% CI 10.3–10.8), 17.6 (95% CI 17.3–17.9), and 0.49 (95% CI 0.44–0.54) cases per 1000 livebirths. The median (IQR) number of antibiotic days administered for CN ≥ 5d, CN < 5d, and CP-EOS was 77 (77–78), 53 (52–53), and 5 (5-5) per 1000 livebirths. Conclusions CN ≥ 5d substantially contributed to the overall antibiotic exposure, and was 21-fold more frequent than CP-EOS. Antimicrobial stewardship programs should focus on shortening antibiotic treatment for culture-negative cases. Impact In a study of 757,979 infants born in high-income countries, we report a presumed culture-negative early-onset sepsis incidence of 10.6/1000 livebirths with an associated antibiotic exposure of 77 antibiotic days per 1000 livebirths. This study sheds light on the major contribution of presumed culture-negative early-onset sepsis to early-life antibiotic exposure. Given the diagnostic uncertainty surrounding culture-negative early-onset sepsis, the low mortality rate, and the disproportionate antibiotic exposure associated with this condition, our study emphasizes the importance of targeting culture-negative early-onset sepsis in antimicrobial stewardship programs.

Sepsis is a heterogeneous syndrome and phenotypes have been proposed using clinical data. Less is known about the contribution of protein biomarkers to clinical sepsis phenotypes and their importance for treatment effects in randomized trials of resuscitation. The objective is to use both clinical and biomarker data in the Protocol-Based Care for Early Septic Shock (ProCESS) randomized trial to determine sepsis phenotypes and to test for heterogeneity of treatment effect by phenotype comparing usual care to protocolized early, goal-directed therapy(EGDT). In this secondary analysis of a subset of patients with biomarker sampling in the ProCESS trial (n = 543), we identified sepsis phenotypes prior to randomization using latent class analysis of 20 clinical and biomarker variables. Logistic regression was used to test for interaction between phenotype and treatment arm for 60-day inpatient mortality. Among 543 patients with severe sepsis or septic shock in the ProCESS trial, a 2-class model best fit the data (p = 0.01). Phenotype 1 (n = 66, 12%) had increased IL-6, ICAM, and total bilirubin and decreased platelets compared to phenotype 2 (n = 477, 88%, p < 0.01 for all). Phenotype 1 had greater 60-day inpatient mortality compared to Phenotype 2 (41% vs 16%; p < 0.01). Treatment with EGDT was associated with worse 60-day inpatient mortality compared to usual care (58% vs. 23%) in Phenotype 1 only (p-value for interaction = 0.05). The 60-day inpatient mortality was similar comparing EGDT to usual care in Phenotype 2 (16% vs. 17%). We identified 2 sepsis phenotypes using latent class analysis of clinical and protein biomarker data at randomization in the ProCESS trial. Phenotype 1 had increased inflammation, organ dysfunction and worse clinical outcomes compared to phenotype 2. Response to EGDT versus usual care differed by phenotype.