Whole Genome Sequencing of Invasive Neonatal Escherichia coli from Uppsala County, Sweden.

BACKGROUND: This study sought to investigate associations between a virulence factors and phylogeny in all neonatal E. coli bloodstream infections from patients admitted to the neonatal intensive care unit at Uppsala University Hospital between 2005 to 2020. METHODS: A total of 37 E. coli isolates from 32 neonates were whole genome sequenced and analysed for virulence factors related to extraintestinal E. coli, patient-related data were collected retrospectively in the medical records. RESULTS: E. coli isolates that belong to phylogroup B2 were associated with mortality (OR 26, p < 0.001), extreme prematurity with delivery before gestational week 28 (OR 9, p < 0.05) and shock (OR 9, p < 0.05) compared with isolates of non-B2 group. Female neonates were more often infected by isolates of phylogroup B2 E. coli compared with male neonates (OR 7, p = 0.05). The identification of the genotoxin determinant clb coding for colibactin exhibited strong associations with mortality (OR 67, p < 0.005), gestational age (OR 18, p < 0.005), and shock (OR 26, p < 0.005). DISCUSSION: The study highlighted the correlation between neonatal E. coli bacteraemia caused by phylogroup B2 and the role of colibactin. Moreover, it emphasised sex-based differences in bloodstream infections among the bacterial population of E. coli.

The impact of butyrate on group B Streptococcus-induced intestinal barrier disruption.

Group B Streptococcus (Streptococcus agalactiae; GBS) is a leading cause of neonatal sepsis worldwide. As a pathobiont of the intestinal tract, it is capable of translocating across barriers leading to invasive disease. Neonatal susceptibility to invasive disease stems from immature intestinal barriers. GBS intestinal colonization induces major transcriptomic changes in the intestinal epithelium related to barrier function. Butyrate, a microbial metabolite produced by fermentation of dietary fiber, bolsters intestinal barrier function against enteric pathogens, and these effects can be transferred in utero via the placenta to the developing fetus. Our aim was to determine if butyrate mitigates GBS disruption of intestinal barriers. We used human intestinal epithelial cell (IEC) lines to evaluate the impact of butyrate on GBS-induced cell death and GBS adhesion and invasion. IECs and human fetal tissue-derived enteroids were used to evaluate monolayer permeability. We evaluated the impact of maternal butyrate treatment (mButyrate) using our established mouse model of neonatal GBS intestinal colonization and late-onset sepsis. We found that butyrate reduces GBS-induced cell death, GBS invasion, monolayer permeability, and translocation in vitro. In mice, mButyrate decreases GBS intestinal burden in offspring. Our results demonstrate the importance of bacterial metabolites, such as butyrate, in their potential to bolster epithelial barrier function and mitigate neonatal sepsis risk.IMPORTANCEGroup B Streptococcus (GBS) is a leading cause of neonatal morbidity and mortality. It is a commensal of the intestines that can translocate across barriers leading to sepsis in vulnerable newborns. With the rise in antibiotic-resistant strains and no licensed vaccine, there is an urgent need for preventative strategies. Butyrate, a short-chain fatty acid metabolized in the gut, enhances barrier function against pathogens. Importantly, butyrate is transferred in utero, conferring these benefits to infants. Here, we demonstrate that butyrate reduces GBS colonization and epithelial invasion. These effects were not microbiome-driven, suggesting butyrate directly impacts epithelial barrier function. Our results highlight the potential impact of maternal dietary metabolites, like butyrate, as a strategy to mitigate neonatal sepsis risk.

Early-Onset Infection Caused by Escherichia coli Sequence Type 1193 in Late Preterm and Full-Term Neonates.

Using whole-genome sequencing, we characterized Escherichia coli strains causing early-onset sepsis (EOS) in 32 neonatal cases from a 2019-2021 prospective multicenter study in France and compared them to E. coli strains collected from vaginal swab specimens from women in third-trimester gestation. We observed no major differences in phylogenetic groups or virulence profiles between the 2 collections. However, sequence type (ST) analysis showed the presence of 6/32 (19%) ST1193 strains causing EOS, the same frequency as in the highly virulent clonal group ST95. Three ST1193 strains caused meningitis, and 3 harbored extended-spectrum ß-lactamase. No ST1193 strains were isolated from vaginal swab specimens. Emerging ST1193 appears to be highly prevalent, virulent, and antimicrobial resistant in neonates. However, the physiopathology of EOS caused by ST1193 has not yet been elucidated. Clinicians should be aware of the possible presence of E. coli ST1193 in prenatal and neonatal contexts and provide appropriate monitoring and treatment.

Gentamicin concentration and acute kidney injury in term neonates treated for neonatal sepsis with gentamicin and ampicillin-cloxacillin combination.

Gentamicin is widely used to treat neonatal infections caused by both Gram-negative and Gram-positive bacteria, and the WHO recommends its use while monitoring serum creatinine and gentamicin concentrations to avoid drug-induced nephrotoxicity and ototoxicity. Yet in some resource-limited settings, the drug is used without monitoring. A population pharmacokinetics study involving term neonates with neonatal infection admitted to a neonatal unit. Participants were started on intravenous gentamicin 5 mg/kg once a day in combination with ampicilin-cloxacillin. Blood samples for serum gentamicin concentration were taken at 0.25, 0.5, 1, 2, 3, 5, 6, 8, 10, 12, 14, 16, 18, 20, 23, and 24 hours after the initial dose, each participant contributing two samples to the 24 hour sampling schedule. An additional sample for trough concentration was taken from each participant just before the third gentamicin dose while serum creatinine concentration was measured before and after treatment. Twenty-four participants were enrolled into the study and included in the final analysis. Mean (SD) peak and trough serum gentamicin concentrations were 16.66 (0.64) µg/mL and 3.28 (0.70) µg/mL, respectively. Gentamicin clearance (CL) was 0.40 mL min-1 kg-1 and volume of distribution (VD) was 0.31 L kg-1. Mean (SD) serum creatinine level after treatment was 209.7 (70.4) µmol/L compared to 103.3 (23.6) µmol/L before treatment [mean difference (106.4 ± 67.1; 95% confidence interval (CI): 78.1; 134.7 µmol/L; t (23) = 7.77; P < 0.001]. All participants fulfilled the Kidney Disease Improving Global Outcomes (KDIGO) criteria for acute kidney injury after treatment. Treatment of neonatal infection with antimicrobial regimen containing gentamicin, without renal function and gentamicin concentration monitoring, carries a significant risk for drug-induced acute kidney injury.

Trends in C-Reactive Protein Use in Early-onset Sepsis Evaluations and Associated Antibiotic Use.

OBJECTIVE: To determine the prevalence of C-reactive protein (CRP) use in early-onset sepsis (EOS) evaluations in neonatal intensive care units (NICUs) across the US over time and to determine the association between CRP use and antibiotic use. STUDY DESIGN: A retrospective cohort study of NICUs contributing data to Premier Healthcare Database from 2009 through 2021. EOS evaluation was defined as a blood culture charge ≤ 3 days after birth. CRP use for each NICU was calculated as the proportion of infants with a CRP test obtained ≤ 3 days after birth among those undergoing an EOS evaluation and categorized as, low (<25%); medium-low (25 to < 50%), medium-high (50 to < 75%), and high (≥75%). Outcomes included antibiotic use and mortality ≤ 7 days after birth. RESULTS: Among 572 NICUs, CRP use varied widely and was associated with time. The proportion of NICUs with high CRP use decreased from 2009 to 2021 (24.7% vs 17.4%, P < .001), and those with low CRP use increased (47.9% vs 64.8%, P < .001). Compared with low-use NICUs, high-use NICUs more frequently continued antibiotics > 3 days (10% vs 25%, P < .001). This association persisted in multivariable-adjusted regression analyses (adjusted risk ratio 1.95, 95%CI 1.54, 2.48). Risk of mortality was not different in high-use NICUs (adjusted risk difference -0.02%, 95%CI -0.04%, 0.0008%). CONCLUSIONS: CRP use in EOS evaluations varied widely across NICUs. High CRP use was associated with prolonged antibiotic therapy but not mortality ≤ 7 days after birth. Reducing routine CRP use in EOS evaluations may be a target for neonatal antibiotic stewardship efforts.

High prevalence of multidrug-resistant Enterobacterales carrying extended-spectrum beta-lactamase and AmpC genes isolated from neonatal sepsis in Ahvaz, Iran.

OBJECTIVES: In the recent years, multidrug resistant (MDR) neonatal septicemia-causing Enterobacterales has been dramatically increased due to the extended-spectrum beta-lactamases (ESBLs) and AmpC enzymes. This study aimed to assess the antibiotic resistance pattern, prevalence of ESBLs/AmpC beta-lactamase genes, and Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC-PCR) fingerprints in Enterobacterales isolated from neonatal sepsis. RESULTS: In total, 59 Enterobacterales isolates including 41 (69.5%) Enterobacter species, 15 (25.4%) Klebsiella pneumoniae and 3 (5.1%) Escherichia coli were isolated respectively. Resistance to ceftazidime and cefotaxime was seen in all of isolates. Furthermore, all of them were multidrug-resistant (resistant to three different antibiotic categories). The phenotypic tests showed that 100% of isolates were ESBL-positive. Moreover, AmpC production was observed in 84.7% (n = 50/59) of isolates. Among 59 ESBL-positive isolates, the highest percentage belonged to blaCTX-M-15 gene (66.1%) followed by blaCTX-M (45.8%), blaCTX-M-14 (30.5%), blaSHV (28.8%), and blaTEM (13.6%). The frequency of blaDHA, blaEBC, blaMOX and blaCIT genes were 24%, 24%, 4%, and 2% respectively. ERIC-PCR analysis revealed that Enterobacterales isolates were genetically diverse. The remarkable prevalence of MDR Enterobacterales isolates carrying ESBL and AmpC beta-lactamase genes emphasizes that efficient surveillance measures are essential to avoid the more expansion of drug resistance amongst isolates.

Metabolic trade-offs in Neonatal sepsis triggered by TLR4 and TLR1/2 ligands result in unique dysfunctions in neural breathing circuits.

Neonatal sepsis remains one of the leading causes of mortality in newborns. Several brainstem-regulated physiological processes undergo disruption during neonatal sepsis. Mechanistic knowledge gaps exist at the interplay between metabolism and immune activation to brainstem neural circuits and pertinent physiological functions in neonates. To delineate this association, we induced systemic inflammation either by TLR4 (LPS) or TLR1/2 (PAM3CSK4) ligand administration in postnatal day 5 mice (PD5). Our findings show that LPS and PAM3CSK4 evoke substantial changes in respiration and metabolism. Physiological trade-offs led to hypometabolic-hypothermic responses due to LPS, but not PAM3CSK4, whereas to both TLR ligands blunted respiratory chemoreflexes. Neuroinflammatory pathways modulation in brainstem showed more robust effects in LPS than PAM3CSK4. Brainstem neurons, microglia, and astrocyte gene expression analyses showed unique responses to TLR ligands. PAM3CSK4 did not significantly modulate gene expression changes in GLAST-1 positive brainstem astrocytes. PD5 pups receiving PAM3CSK4 failed to maintain a prolonged metabolic state repression, which correlated to enhanced gasping latency and impaired autoresuscitation during anoxic chemoreflex challenges. In contrast, LPS administered pups showed no significant changes in anoxic chemoreflex. Electrophysiological studies from brainstem slices prepared from pups exposed to either TLR4 or PAM3CSK4 showed compromised transmission between preBötzinger complex and Hypoglossal as an exclusive response to the TLR1/2 ligand. Spatial gene expression analysis demonstrated a region-specific modulation of PAM3CSK4 within the raphe nucleus relative to other anatomical sites evaluated. Our findings suggest that metabolic changes due to inflammation might be a crucial tolerance mechanism for neonatal sepsis preserving neural control of breathing.

Water birth: a systematic review and meta-analysis of maternal and neonatal outcomes.

OBJECTIVE: This systematic review and meta-analysis aimed to conduct a thorough and contemporary assessment of maternal and neonatal outcomes associated with water birth in comparison with land-based birth. DATA SOURCES: We conducted a comprehensive search of PubMed, EMBASE, CINAHL, and gray literature sources, from inception to February 28, 2023. STUDY ELIGIBILITY CRITERIA: We included randomized and nonrandomized studies that assessed maternal and neonatal outcomes in patients who delivered either conventionally or while submerged in water. METHODS: Pooled unadjusted odds ratios with 95% confidence intervals were calculated using a random-effects model (restricted maximum likelihood method). We assessed the 95% prediction intervals to estimate the likely range of future study results. To evaluate the robustness of the results, we calculated fragility indices. Maternal infection was designated as the primary outcome, whereas postpartum hemorrhage, perineal lacerations, obstetrical anal sphincter injury, umbilical cord avulsion, low Apgar scores, neonatal aspiration requiring resuscitation, neonatal infection, neonatal mortality within 30 days of birth, and neonatal intensive care unit admission were considered secondary outcomes. RESULTS: Of the 20,642 articles identified, 52 were included in the meta-analyses. Based on data from observational studies, water birth was not associated with increased probability of maternal infection compared with land birth (10 articles, 113,395 pregnancies; odds ratio, 0.93; 95% confidence interval, 0.76-1.14). Patients undergoing water birth had decreased odds of postpartum hemorrhage (21 articles, 149,732 pregnancies; odds ratio, 0.80; 95% confidence interval, 0.68-0.94). Neonates delivered while submerged in water had increased odds of cord avulsion (10 articles, 91,504 pregnancies; odds ratio, 1.75; 95% confidence interval, 1.38-2.24) and decreased odds of low Apgar scores (21 articles, 165,917 pregnancies; odds ratio, 0.69; 95% confidence interval, 0.58-0.82), neonatal infection (15 articles, 53,635 pregnancies; odds ratio, 0.64; 95% confidence interval, 0.42-0.97), neonatal aspiration requiring resuscitation (19 articles, 181,001 pregnancies; odds ratio, 0.60; 95% confidence interval, 0.43-0.84), and neonatal intensive care unit admission (30 articles, 287,698 pregnancies; odds ratio, 0.56; 95% confidence interval, 0.45-0.70). CONCLUSION: When compared with land birth, water birth does not appear to increase the risk of most maternal and neonatal complications. Like any other delivery method, water birth has its unique considerations and potential risks, which health care providers and expectant parents should evaluate thoroughly. However, with proper precautions in place, water birth can be a reasonable choice for mothers and newborns, in facilities equipped to conduct water births safely.

Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment.

Clinical chorioamnionitis, the most common infection-related diagnosis in labor and delivery units, is an antecedent of puerperal infection and neonatal sepsis. The condition is suspected when intrapartum fever is associated with two other maternal and fetal signs of local or systemic inflammation (eg, maternal tachycardia, uterine tenderness, maternal leukocytosis, malodorous vaginal discharge or amniotic fluid, and fetal tachycardia). Clinical chorioamnionitis is a syndrome caused by intraamniotic infection, sterile intraamniotic inflammation (inflammation without bacteria), or systemic maternal inflammation induced by epidural analgesia. In cases of uncertainty, a definitive diagnosis can be made by analyzing amniotic fluid with methods to detect bacteria (Gram stain, culture, or microbial nucleic acid) and inflammation (white blood cell count, glucose concentration, interleukin-6, interleukin-8, matrix metalloproteinase-8). The most common microorganisms are Ureaplasma species, and polymicrobial infections occur in 70% of cases. The fetal attack rate is low, and the rate of positive neonatal blood cultures ranges between 0.2% and 4%. Intrapartum antibiotic administration is the standard treatment to reduce neonatal sepsis. Treatment with ampicillin and gentamicin have been recommended by professional societies, although other antibiotic regimens, eg, cephalosporins, have been used. Given the importance of Ureaplasma species as a cause of intraamniotic infection, consideration needs to be given to the administration of antimicrobial agents effective against these microorganisms such as azithromycin or clarithromycin. We have used the combination of ceftriaxone, clarithromycin, and metronidazole, which has been shown to eradicate intraamniotic infection with microbiologic studies. Routine testing of neonates born to affected mothers for genital mycoplasmas could improve the detection of neonatal sepsis. Clinical chorioamnionitis is associated with decreased uterine activity, failure to progress in labor, and postpartum hemorrhage; however, clinical chorioamnionitis by itself is not an indication for cesarean delivery. Oxytocin is often administered for labor augmentation, and it is prudent to have uterotonic agents at hand to manage postpartum hemorrhage. Infants born to mothers with clinical chorioamnionitis near term are at risk for early-onset neonatal sepsis and for long-term disability such as cerebral palsy. A frontier is the noninvasive assessment of amniotic fluid to diagnose intraamniotic inflammation with a transcervical amniotic fluid collector and a rapid bedside test for IL-8 for patients with ruptured membranes. This approach promises to improve diagnostic accuracy and to provide a basis for antimicrobial administration.

Comparison of the accuracy of hematological parameters in the diagnosis of neonatal sepsis: a network meta-analysis.

BACKGROUND: Currently, there are hundreds of hematological parameters used for rapid diagnosis of neonatal sepsis, but there is no network meta-analysis to compare the diagnostic efficacy of these parameters. METHODS: We searched for literature on the diagnostic neonatal sepsis and selected 20 of the most common parameters to compare their diagnostic efficacy. We used Bayesian network meta-analysis, Frequentist network meta-analysis, and individual traditional diagnostic meta-analysis to analyze the data and verify the stability of the results. Based on the above analysis, we ranked the diagnostic efficacy of 20 parameters and searched for the optimal indicator. We also conducted subgroup analysis based on different designs. GRADE was used to evaluate the quality of evidence. RESULTS: 311 articles were included in the analysis, of which 206 articles were included in the network meta-analysis. Bayesian models fond the top three of the advantage index were P-SEP, SAA, and CD64. In Individual model, P-SEP, SAA, and CD64 had the best sensitivity; ABC, SAA, and P-SEP had the best specificity. Frequentist model showed that CD64, P-SEP, and IL-10 ranked in the top three for sensitivity, while P-SEP, ABC, and I/M in specificity. Overall, P-SEP, SAA, CD64, and PCT have good sensitivity and specificity among all the three methods. The results of subgroup analysis were consistent with the overall analysis. All evidence was mostly of moderate or low quality. CONCLUSIONS: P-SEP, SAA, CD64, and PCT have good diagnostic efficacy for neonatal sepsis. However, further studies are required to confirm these findings.

Maternal Streptococcus agalactiae colonization in Europe: data from the multi-center DEVANI study.

INTRODUCTION: Despite national guidelines and use of intrapartum antibiotic prophylaxis (IAP), Streptococcus agalactiae (group B streptococci (GBS)) is still a leading cause of morbidity and mortality in newborns in Europe and the United States. The European DEVANI (Design of a Vaccine Against Neonatal Infections) program assessed the neonatal GBS infection burden in Europe, the clinical characteristics of colonized women and microbiological data of GBS strains in colonized women and their infants with early-onset disease (EOD). METHODS: Overall, 1083 pregnant women with a GBS-positive culture result from eight European countries were included in the study. Clinical obstetrical information was collected by a standardized questionnaire. GBS strains were characterized by serological and molecular methods. RESULTS: Among GBS carriers included in this study after testing positive for GBS by vaginal or recto-vaginal sampling, 13.4% had at least one additional obstetrical risk factor for EOD. The five most common capsular types (i.e., Ia, Ib, II, III and V) comprised ~ 93% of GBS carried. Of the colonized women, 77.8% received any IAP, and in 49.5% the IAP was considered appropriate. In our cohort, nine neonates presented with GBS early-onset disease (EOD) with significant regional heterogeneity. CONCLUSIONS: Screening methods and IAP rates need to be harmonized across Europe in order to reduce the rates of EOD. The epidemiological data from eight different European countries provides important information for the development of a successful GBS vaccine.

Loop-mediated isothermal amplification (LAMP) assay for early on-site detection of Group B Streptococcus infection in neonatal sepsis blood sample.

BACKGROUND: Neonatal sepsis, often attributed to Group B Streptococcus (GBS) infection, poses a critical health risk to infants, demanding rapid and accurate diagnostic approaches. Existing diagnostic approaches are dependent on traditional culture methods, a process that requires substantial time and has the potential to delay crucial therapeutic assessments. METHODS: This study introduces an innovative Loop-Mediated Isothermal Amplification (LAMP) assay for the early on-site detection of GBS infection from neonatal sepsis blood samples. To develop a LAMP assay, the primers are designed for the selective targeting of a highly conserved segment within the cfb gene encoding the CAMP factor in Streptococcus agalactiae ensuring high specificity. RESULTS: Rigorous optimization of reaction conditions, including temperature and incubation time, enhances the efficiency of the LAMP assay, enabling rapid and reliable GBS detection within a short timeframe. The diagnostic efficacy of the LAMP assay was evaluated using spiked blood samples by eliminating the DNA extraction step. The simplified colorimetric LAMP assay has the capability to detect S. agalactiae in a neonatal blood sample containing 2 CFU/mL during sepsis. Additionally, the LAMP assay effectively detected S. agalactiae in both the standard and spiked blood samples, with no detectable interference with blood. CONCLUSION: This optimised LAMP assay emerges as a promising tool for early GBS detection, offering a rapid and accurate on-site solution that has the potential to inform timely interventions and improve outcomes in neonatal sepsis cases.

How can we reduce neonatal sepsis after universal group B streptococcus screening?

BACKGROUND: Group B Streptococcus (GBS) infection remains a leading cause of newborn morbidity and mortality. The study aimed to determine the adherence rate to the universal screening policy a decade after its introduction. Secondly, whether the timing of antibiotics given in GBS carriers reduces the incidence of neonatal sepsis. METHODS: Delivery records at Hong Kong Baptist Hospital in 2022 were examined to retrieve antenatal and intrapartum details regarding maternal GBS carrier status, previous maternal GBS carrier status, antibiotic treatment, timing of treatment, neonatal condition at birth and whether the neonate had sepsis. Univariate statistics was used to assess the relationship between maternal GBS carrier and neonatal sepsis overall. Incidence of neonatal sepsis was stratified according to mode of delivery and timing of antibiotic. RESULTS: The adherence rate to the universal GBS screening policy was 97%. The risk of neonatal sepsis was 5.45 (95% CI 3.05 to 9.75) times higher in women who were GBS screened positive when compared to non-GBS carriers (p < 0.001). Amongst term neonates from GBS carriers delivered by Caesarean section, the risk of neonatal sepsis significantly decreased by 70% after antenatal antibiotic treatment (p = 0.041) whereas in term neonates delivered vaginally, the risk of neonatal sepsis decreased by 71% (p = 0.022) if intrapartum antibiotic prophylaxis was given 4 or more hours. CONCLUSION: Giving antenatal antibiotic treatment before Caesarean section or intrapartum antibiotic prophylaxis for 4 or more hours before vaginal delivery may decrease the risk of neonatal sepsis in term neonates delivered from GBS carriers.

Early onset neonatal sepsis and its associatited factors: a cross sectional study.

BACKGROUND: Sepsis is the 3rd leading cause of neonatal mortality in Ethiopia contributing to 16% of neonatal death. In a hospital study, neonatal sepsis was the leading diagnosis at admission and the second leading cause of neonatal death at the neonatal intensive care unit. Among other factors repeated vaginal examination during labor is known to contribute to sepsis in low-income settings. However, there is limited evidence in the Ethiopian setting. OBJECTIVE: The objective of this study was to examine the association between early-onset neonatal sepsis and repeated vaginal examinations. METHODS: The study was conducted at Gandhi Memorial Hospital, a public maternity and newborn care hospital. We followed 672 mother-newborn pairs by phone until 7 days of age to detect clinical sepsis. Data were analyzed using SPSS version 20 software. Adjusted odds ratio risk (AOR) with a corresponding 95% confidence interval (CI) was used to show the strength of associations and variables with p-value < 0.05 were considered to be statistically significant. RESULTS: The incidence of early-onset neonatal sepsis was found to be 20.83% (95% CI 17.60, 24.00). Having a frequent vaginal examination (four or more times) during labor and delivery, prolonged rupture of membranes, induced labor and gestational age < 37 weeks were strongly associated with the development of early-onset neonatal sepsis, (AOR 2. 69;95 CI: 1.08, 6.70) AOR 5.12(95% CI 1.31, 20.00), AOR of 5.24 (95% CI 1.72, AOR4.34 (95% CI 1.20, 15.68), 16.00), respectively. CONCLUSION: Frequent digital vaginal examination prolonged rupture of membranes, induced labor and gestational age < 37 weeks significantly increases the risk of early onset neonatal sepsis. We also recommend further study using neonatal blood culture to better diagnose early onset neonatal sepsis objectively.

Risk factors of multidrug-resistant organisms neonatal sepsis in Surabaya tertiary referral hospital: a single-center study.

BACKGROUND: Bacterial organisms causing neonatal sepsis have developed increased resistance to commonly used antibiotics. Antimicrobial resistance is a major global health problem. The spread of Multidrug-Resistant Organisms (MDROs) is associated with higher morbidity and mortality rates. This study aimed to determine the risk factors for developing MDRO neonatal sepsis in the Neonatal Intensive Care Unit (NICU), dr. Ramelan Navy Central Hospital, in 2020-2022. METHODS: A cross-sectional study was performed on 113 eligible neonates. Patients whose blood cultures were positive for bacterial growth and diagnosed with sepsis were selected as the study sample. Univariate and multivariate analysis with multiple logistic regression were performed to find the associated risk factors for developing multidrug-resistant organism neonatal sepsis. A p-value of < 0.05 was considered significant. RESULTS: Multidrug-resistant organisms were the predominant aetiology of neonatal sepsis (91/113, 80.5%). The significant risk factors for developing MDRO neonatal sepsis were lower birth weight (OR: 1.607, 95% CI: 1.003 - 2.576, p-value: 0.049), history of premature rupture of the membrane (ProM) ≥ 18 (OR: 3.333, 95% CI: 2.047 - 5.428, p-value < 0.001), meconium-stained amniotic fluid (OR: 2.37, 95% CI: 1.512 - 3.717, p-value < 0.001), longer hospital stays (OR: 5.067, 95% CI: 2.912 - 8.815, p-value < 0.001), lower Apgar scores (OR: 2.25, 95% CI: 1.442 - 3.512, p-value < 0.001), and the use of respiratory support devices, such as invasive ventilation (OR: 2.687, 95% CI: 1.514 - 4.771, p-value < 0.001), and non-invasive ventilation (OR: 2, 95% CI: 1.097 - 3.645, p-value: 0.024). CONCLUSIONS: Our study determined various risk factors for multidrug-resistance organism neonatal sepsis and underscored the need to improve infection control practices to reduce the existing burden of drug-resistant sepsis. Low-birth-weight, a maternal history of premature rupture of the membrane lasting more than 18 hours, meconium-stained amniotic fluid, longer hospital stays, a low Apgar score, and the use of ventilators were the risk factors for developing drug-resistant neonatal sepsis.

Impact of neonatal sepsis on neurocognitive outcomes: a systematic review and meta-analysis.

INTRODUCTION: Sepsis is associated with neurocognitive impairment among preterm neonates but less is known about term neonates with sepsis. This systematic review and meta-analysis aims to provide an update of neurocognitive outcomes including cognitive delay, visual impairment, auditory impairment, and cerebral palsy, among neonates with sepsis. METHODS: We performed a systematic review of PubMed, Embase, CENTRAL and Web of Science for eligible studies published between January 2011 and March 2023. We included case-control, cohort studies and cross-sectional studies. Case reports and articles not in English language were excluded. Using the adjusted estimates, we performed random effects model meta-analysis to evaluate the risk of developing neurocognitive impairment among neonates with sepsis. RESULTS: Of 7,909 studies, 24 studies (n = 121,645) were included. Majority of studies were conducted in the United States (n = 7, 29.2%), and all studies were performed among neonates. 17 (70.8%) studies provided follow-up till 30 months. Sepsis was associated with increased risk of cognitive delay [adjusted odds ratio, aOR 1.14 (95% CI: 1.01-1.28)], visual impairment [aOR 2.57 (95%CI: 1.14- 5.82)], hearing impairment [aOR 1.70 (95% CI: 1.02-2.81)] and cerebral palsy [aOR 2.48 (95% CI: 1.03-5.99)]. CONCLUSION: Neonates surviving sepsis are at a higher risk of poorer neurodevelopment. Current evidence is limited by significant heterogeneity across studies, lack of data related to long-term neurodevelopmental outcomes and term infants.

New and old lessons from a devastating case of neonatal E coli meningitis.

BACKGROUND: Neonatal Escherichia coli (E coli) meningitis results in significant morbidity and mortality. We present a case of a premature infant with extensive central nervous system (CNS) injury from recurrent E coli infection and the non-traditional methods necessary to identify and clear the infection. CASE PRESENTATION: The infant was transferred to our institution's pediatric intensive care unit (PICU) after recurrence of E coli CNS infection requiring neurosurgical intervention. He had been treated for early onset sepsis (EOS) with ampicillin and gentamicin for 10 days followed by rapid development of ampicillin-resistant E coli septic shock and meningitis after discontinuation of antibiotics. Sterility of the CNS was not confirmed at the end of 21 days of cefepime therapy and was subsequently followed by recurrent ampicillin-resistant E coli septic shock and CNS infection. Despite 6 weeks of appropriate therapy with sterility of CSF by traditional methods, he suffered from intractable seizures with worsening hydrocephalus. Transferred to our institution, he underwent endoscopic 3rd ventriculostomy with cyst fenestration revealing purulent fluid and significant pleocytosis. An additional 3 weeks of systemic and intraventricular antibiotics with cefepime and tobramycin were given but a significant CNS neutrophil-predominant pleocytosis persisted (average of ∼ 21,000 cells/mm3). Repeated gram stains, cultures, polymerase chain reaction (PCR) testing, and metagenomic next generation sequencing (NGS) testing of CSF were negative for pathogens but acridine orange stain (AO) revealed numerous intact rod-shaped bacteria. After the addition of ciprofloxacin, sterility and resolution of CSF pleocytosis was finally achieved. CONCLUSION: Neonatal E coli meningitis is a well-known entity but unlike other bacterial infections, it has not proven amenable to shorter, more narrow-spectrum antibiotic courses or limiting invasive procedures such as lumbar punctures. Further, microbiologic techniques to determine CSF sterility suffer from poorly understood limitations leading to premature discontinuation of antibiotics risking further neurologic damage in vulnerable hosts.

Associations between maternal bacteremia during the peripartum period and early-onset neonatal sepsis: a retrospective cohort study.

INTRODUCTION: Early-onset neonatal sepsis (EONS) significantly impacts neonatal morbidity and mortality, with maternal bacteremia during the peripartum period being a potential risk factor. This study aims to explore the association between peripartum maternal bacteremia and EONS. METHODS: A retrospective cohort study at the Women's Wellness and Research Center in Doha, Qatar (2015-2019) compared women with and without bacteremia, based on blood cultures taken from up to seven days before to 48 h after delivery, examining the association with EONS. RESULTS: Among the 536 maternal blood cultures analyzed, 102 (19.0%) were positive. The most prevalent organisms were Group B streptococcus (GBS) (39.2%), followed by Escherichia coli (14.7%) and anaerobes (10.8%). Neonates from bacteremic mothers had lower birth weights (2913 ± 86 g vs. 3140 ± 745 g; MD 227.63 g; 95% CI 61.72 - 393.55; p = 0.007), required more resuscitation (27.5% vs. 13.2%; OR 2.48; 95% CI 1.48 - 4.17; p < 0.001), and received antibiotics for ≥ 7 days more frequently (41.2% vs. 16.6%; OR 3.51; 95% CI 2.20 - 5.62; p < 0.001) compared to those from non-bacteremic mothers. Maternal Gram-positive (GP) organisms were more commonly isolated in term gestation (67.9%) compared to Gram-negative (GN) (22.2%) and anaerobic bacteremias (9.9%). During intrapartum, GP bacteremia was predominant (67.1%) vs. GN (21.4%) and Anaerobes (11.4%), with GN bacteremia being more common in postpartum samples. Culture-proven EONS occurred in 0.75% of the cohort, affecting 3.9% of infants from bacteremic mothers vs. none in controls (OR 2.34; 95% CI 1.27 - 4.31; p < 0.001). Culture-negative EONS appeared in 14.7% of infants from bacteremic mothers vs. 7.8% in controls (OR 2.02; 95% CI, 1.05 - 3.88; p = 0.03). Among 40 cases of maternal GBS bacteremia, culture-proven GBS EONS occurred in 3 neonates (7.5%), all from mothers with negative GBS screening, compared to none in the control group. A strong association was found between EONS and maternal bacteremia due to any organism (aOR 2.34; 95% CI, 1.24 - 4.41; p = 0.009), GP bacteremia (aOR 3.66; 95% CI, 1.82 - 7.34; p < 0.001), or GBS (aOR 5.74; 95% CI, 2.57 - 12.81; p < 0.001). Bacteremia due to GN and Anaerobic organisms were not associated with EONS. Chorioamnionitis and antepartum fever were independent predictors for EONS associated with significant bacterial isolates. CONCLUSION: This study underscores the significant impact of maternal GP bacteremia, particularly from GBS, on EONS. The strong association highlights the need for vigilant monitoring and interventions in pregnancies complicated by bacteremia to reduce adverse neonatal outcomes.

Exploration of programmed cell death-associated characteristics and immune infiltration in neonatal sepsis: new insights from bioinformatics analysis and machine learning.

BACKGROUND: Neonatal sepsis, a perilous medical situation, is typified by the malfunction of organs and serves as the primary reason for neonatal mortality. Nevertheless, the mechanisms underlying newborn sepsis remain ambiguous. Programmed cell death (PCD) has a connection with numerous infectious illnesses and holds a significant function in newborn sepsis, potentially serving as a marker for diagnosing the condition. METHODS: From the GEO public repository, we selected two groups, which we referred to as the training and validation sets, for our analysis of neonatal sepsis. We obtained PCD-related genes from 12 different patterns, including databases and published literature. We first obtained differential expressed genes (DEGs) for neonatal sepsis and controls. Three advanced machine learning techniques, namely LASSO, SVM-RFE, and RF, were employed to identify potential genes connected to PCD. To further validate the results, PPI networks were constructed, artificial neural networks and consensus clustering were used. Subsequently, a neonatal sepsis diagnostic prediction model was developed and evaluated. We conducted an analysis of immune cell infiltration to examine immune cell dysregulation in neonatal sepsis, and we established a ceRNA network based on the identified marker genes. RESULTS: Within the context of neonatal sepsis, a total of 49 genes exhibited an intersection between the differentially expressed genes (DEGs) and those associated with programmed cell death (PCD). Utilizing three distinct machine learning techniques, six genes were identified as common to both DEGs and PCD-associated genes. A diagnostic model was subsequently constructed by integrating differential expression profiles, and subsequently validated by conducting artificial neural networks and consensus clustering. Receiver operating characteristic (ROC) curves were employed to assess the diagnostic merit of the model, which yielded promising results. The immune infiltration analysis revealed notable disparities in patients diagnosed with neonatal sepsis. Furthermore, based on the identified marker genes, the ceRNA network revealed an intricate regulatory interplay. CONCLUSION: In our investigation, we methodically identified six marker genes (AP3B2, STAT3, TSPO, S100A9, GNS, and CX3CR1). An effective diagnostic prediction model emerged from an exhaustive analysis within the training group (AUC 0.930, 95%CI 0.887-0.965) and the validation group (AUC 0.977, 95%CI 0.935-1.000).

Improving possible serious bacterial infection (PSBI) management in young infants when referral is not feasible: lessons from embedded implementation research in Ethiopia and Kenya.

BACKGROUND: Sepsis is a leading cause of neonatal mortality, despite the availability of effective treatment of possible serious bacterial illness (PSBI), including when referral to a hospital is not feasible. Gaps in access and delivery worsened during COVID-19. We conducted embedded implementation research in Ethiopia and Kenya aimed at mitigating the impact of COVID-19 and addressing various implementation challenges to improve PSBI management. METHODS: The implementation research projects were implemented at the subnational level in Ethiopia and Kenya between November 2020-June 2022 (Ethiopia) and December 2020-August 2022 (Kenya). Guided by the implementation research frameworks, both projects conducted mixed formative quantitative and exploratory research from April to May 2021, followed by summative evaluations conducted between June and July 2022. Frameworks encompassed Consolidated Framework for Implementation Research (CFIR), Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM), as well as health systems framework that incorporates cascades of care and World Health Organization Health Systems Building Blocks. Results were synthesized across the projects through document review and sharing cross-project measures and strategies through a project community of practice. RESULTS: Despite differences in settings across the projects, cross-cutting facilitators included community health worker program and support, and existence of guidelines for PSBI management at primary care levels. Barriers included community attitudes towards seeking care for sick newborns, COVID-19 risks and fear, and lack of health care worker competence. Country-specific contextual barriers included supply chain issues, civil conflict (Ethiopia), and labor strikes (Kenya). Strategies chosen to mitigate barriers and support implementation and sustainability in both settings included leveraging community health workers to address resistance to care-seeking, health workers' training, COVID-19 infection prevention measures, stakeholder engagement, and advocacy to integrate PSBI management into existing programs, policies, and training. Other strategies addressing emerging project-specific barriers, included improving follow-up through a community health desk and PSBI mobile app (Kenya) and supply chain strengthening (Ethiopia). Both projects improved PSBI management coverage, increased adoption and uptake, and informed national policy changes supporting potential for sustainability. CONCLUSIONS: Pragmatic embedded implementation research effectively supports the identification of barriers and mapping to strategies designed to increase effective coverage of PSBI management when referral is not feasible during the COVID-19 pandemic. Despite differences in context, cross-cutting strategies identified could inform broader scale-up in the region, including during future health system shocks.