Effect of oropharyngeal colostrum therapy on neonatal sepsis in preterm neonates: A systematic review and meta-analysis.

Various studies have shown that oropharyngeal colostrum application (OPCA) is beneficial to preterm neonates. We performed a systematic review and meta-analysis to assess whether OPCA reduces the incidence of culture-proven neonatal sepsis in preterm neonates. Randomized controlled trials comparing OPCA with placebo or standard care in preterm neonates were included. Medline, Embase, Web of Science, Cumulated Index to Nursing and Allied Health Literature, Scopus, and CENTRAL were searched for studies published up to June 15, 2023. We used the Cochrane Risk of Bias tool, version 2, for risk of bias assessment, the random-effects model (RevMan 5.4) for meta-analysis, and Gradepro software for assessing the certainty of evidence. Twenty-one studies involving 2393 participants were included in this meta-analysis. Four studies had a low risk of bias, whereas seven had a high risk. Oropharyngeal colostrum significantly reduced the incidence of culture-proven sepsis (18 studies, 1990 neonates, risk ratio [RR]: 0.78, 95% confidence interval [95% CI]: 0.65, 0.94), mortality (18 studies, 2117 neonates, RR: 0.73, 95% CI: 0.59, 0.90), necrotizing enterocolitis (NEC) (17 studies, 1692 neonates, RR: 0.59, 95% CI: 0.43, 0.82), feeding intolerance episodes (four studies, 445 neonates, RR: 0.59, 95% CI: 0.38, 0.92), and the time to full enteral feeding (19 studies, 2142 neonates, mean difference: -2 to 21 days, 95% CI: -3.44, -0.99 days). There was no reduction in intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, ventilator-associated pneumonia, neurodevelopmental abnormalities, hospital stay duration, time to full oral feeding, weight at discharge, pneumonia, and duration of antibiotic therapy. The certainty of the evidence was high for the outcomes of culture-positive sepsis and mortality, moderate for NEC, low for time to full enteral feeding, and very low for feeding intolerance. OPCA reduces culture-positive sepsis and mortality (high certainty), NEC (moderate certainty), and time to full enteral feeding (low certainty) in preterm neonates. However, scarcity of data from extremely premature infants limits the generalizability of these results to this population.

Identification and Validation of Signature Genes and Their Correlations with Infiltrated Immune Cells in Neonatal Sepsis.

Background and Objective: There is increasing demand to identify accurate and reliable molecular biomarkers for early diagnosis of neonatal sepsis. We aimed to identify and verify signature genes in neonatal sepsis through comprehensive bioinformatics analysis. Methods: A Gene Expression Omnibus data set was used to identify differentially expressed genes (DEGs) in patients with neonatal sepsis and healthy controls by functional and disease enrichment analysis. Gene set enrichment analysis, screening of DEGs using 2 machine algorithms, analysis of receiver operating characteristic curves, and correlation analysis with infiltrating immune cells was performed. Results: We identified 433 DEGs: 144 downregulated and 289 upregulated. Gene Ontology analysis identified DEGs for T cell activation, positive regulation of cytokine production, secretory granule cavity, cytoplasmic vesicle cavity, immune receptor activity, and antioxidant activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified DEGs for hematopoietic cell lineage, cytokine-cytokine receptor interaction, and coronavirus disease (COVID-19). Disease Ontology analysis identified DEGs for hematopoietic system diseases, skin system diseases, and bacterial infectious diseases. We also gained understanding of the enrichment of various functions and pathways by gene set enrichment analysis. In the neonatal sepsis group, Gene Ontology analysis results were significant for coagulation, endocytosis, white cell migration, myeloid leukocyte-mediated immunity, and phagocytosis; KEGG analysis results were significant for chemokine signaling pathway, complement and coagulation cascade, leukocyte migration across endothelium, regulation of actin cytoskeleton, and toll-like receptor signaling pathway. We screened 2 signature DEGs (GSN and SEMA4B) using the least absolute shrinkage and selection operator and support vector machine recursive feature elimination algorithms and verified their diagnostic accuracy by receiver operating characteristic curves. We correlated GSN and SEMA4B expression levels with the infiltration levels of 22 types of immune cell. Conclusion: GSN and SEMA4B expression accurately predicted early-stage neonatal sepsis, which is beneficial for early clinical diagnosis and treatment.

MiRNAs as biomarkers for diagnosis of neonatal sepsis: a systematic review and meta-analysis.

BACKGROUND: The relationship between circulating miRNAs and neonatal sepsis and the mechanism of action are still unclear at this time. Therefore, the potential diagnostic role of miRNAs in neonatal sepsis (NS) was studied through meta-analysis. METHOD: Web of Science, Cochrane Library, PubMed, and Embase are retrieved, supplemented by manual search, and the search was conducted to find related studies without time limit until May 2022.The quality of the literature was assessed via QUADAS criteria and meta-analyzed via Stata 11.0 software, including the assessment of specificity, sensitivity, likelihood ratio and diagnostic odds ratio. Then, sensitivity analysis and heterogeneity testing were conducted, and finally, the summary receiver operating characteristics (SROC) curve was drawn. RESULT: This study included 14 articles, including 20 miRNAs and 1597 newborns(control group: 727 and case group: 870). Among them, one article was of low quality, three articles were of high quality, and the rest were of medium quality. According to the results of random effects model analysis, the pooled specificity and sensitivity of miRNA for the diagnosis of NS were 0.83 (95%CI: 0.79-0.87) and 0.76 (95%CI: 0.72-0.80), respectively. And negative likelihood ratio, positive likelihood ratio, and diagnostic odds ratio were 0.29 (95%CI: 0.24-0.34), 4.51 (95%CI: 3.52-5.78), and 15.81 (95%CI: 10.71-23.35), respectively. The area under the SROC curve was 0.86, and there was no evidence publication bias detected in the funnel plot. CONCLUSION: Circulating miRNAs may be very useful in the development of early diagnostic strategies for neonatal sepsis.

Atuação da psicologia em unidade neonatal no contexto da pandemia da covid-19 / The work of psychology in a neonatal unit in the covid-19 pandemic / Actuación de la psicología en una unidad neonatal en el contexto de la pandemia de la covid-19

A pandemia de covid-19 provocou intensas mudanças no contexto do cuidado neonatal, exigindo dos profissionais de saúde a reformulação de práticas e o desenvolvimento de novas estratégias para a manutenção da atenção integral e humanizada ao recém-nascido. O objetivo deste artigo é relatar a atuação da Psicologia nas Unidades Neonatais de um hospital público de Fortaleza (CE), Brasil, durante o período de distanciamento físico da pandemia de covid-19. Trata-se de estudo descritivo, do tipo relato de experiência, que ocorreu no período de março a agosto de 2020. No contexto pandêmico, o serviço de Psicologia desenvolveu novas condutas assistenciais para atender às demandas emergentes do momento, como: atendimento remoto; registro e envio on-line de imagens do recém-nascido a seus familiares; visitas virtuais; e reprodução de mensagens de áudio da família para o neonato. Apesar dos desafios encontrados, as ações contribuíram para a manutenção do cuidado centrado no recém-nascido e sua família, o que demonstra a potencialidade do fazer psicológico.(AU)

The COVID-19 pandemic brought intense changes to neonatal care and required health professionals to reformulate practices and develop new strategies to ensure comprehensive and humanized care for newborn. This study aims to report the experience of the Psychology Service in the Neonatal Units of a public hospital in Fortaleza, in the state of Ceará, Brazil, during the social distancing period of the COVID-19 pandemic. This descriptive experience report study was conducted from March to August 2020. During the pandemic, the Psychology Service developed new care practices to meet the emerging demands of that moment, such as remote care, recordings and online submission of newborns' pictures and video images for their family, virtual tours, and reproduction of family audio messages for the newborns. Despite the challenges, the actions contributed to the maintenance of a care that is centered on the newborns and their families, which shows the potential of psychological practices.(AU)

La pandemia de la COVID-19 ha traído cambios intensos en el contexto de la atención neonatal, que requieren de los profesionales de la salud una reformulación de sus prácticas y el desarrollo de nuevas estrategias para asegurar una atención integral y humanizada al recién nacido. El objetivo de este artículo es reportar la experiencia del Servicio de Psicología en las Unidades Neonatales de un hospital público de Fortaleza, en Ceará, Brasil, durante el periodo de distanciamiento físico en la pandemia de la COVID-19. Se trata de un estudio descriptivo, un reporte de experiencia, que se llevó a cabo de marzo a agosto de 2020. En el contexto pandémico, el servicio de Psicología desarrolló nuevas conductas asistenciales para atender a las demandas emergentes del momento, tales como: atención remota; grabación y envío em línea de imágenes del recién nacido; visitas virtuales; y reproducción de mensajes de audio de la familia para el recién nacido. A pesar de los desafíos encontrados, las acciones contribuyeron al mantenimiento de la atención centrada en el recién nacido y su familia, lo que demuestra el potencial de la práctica psicológica.(AU)

Attenuating the virulence of the resistant superbug Staphylococcus aureus bacteria isolated from neonatal sepsis by ascorbic acid, dexamethasone, and sodium bicarbonate.

BACKGROUND: Infections affecting neonates caused by Staphylococcus aureus are widespread in healthcare facilities; hence, novel strategies are needed to fight this pathogen. In this study, we aimed to investigate the effectiveness of the FDA-approved medications ascorbic acid, dexamethasone, and sodium bicarbonate to reduce the virulence of the resistant Staphylococcus aureus bacteria that causes neonatal sepsis and seek out suitable alternatives to the problem of multi-drug resistance. METHODS: Tested drugs were assessed phenotypically and genotypically for their effects on virulence factors and virulence-encoding genes in Staphylococcus aureus. Furthermore, drugs were tested in vivo for their ability to reduce Staphylococcus aureus pathogenesis. RESULTS: Sub-inhibitory concentrations (1/8 MIC) of ascorbic acid, dexamethasone, and sodium bicarbonate reduced the production of Staphylococcus aureus virulence factors, including biofilm formation, staphyloxanthin, proteases, and hemolysin production, as well as resistance to oxidative stress. At the molecular level, qRT-PCR was used to assess the relative expression levels of crtM, sigB, sarA, agrA, hla, fnbA, and icaA genes regulating virulence factors production and showed a significant reduction in the relative expression levels of all the tested genes. CONCLUSIONS: The current findings reveal that ascorbic acid, dexamethasone, and sodium bicarbonate have strong anti-virulence effects against Staphylococcus aureus. Thus, suggesting that they might be used as adjuvants to treat infections caused by Staphylococcus aureus in combination with conventional antimicrobials or as alternative therapies.

Assessment of flomoxef combined with amikacin in a hollow-fibre infection model for the treatment of neonatal sepsis in low- and middle-income healthcare settings.

BACKGROUND: Annual mortality from neonatal sepsis is an estimated 430 000-680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum ß-lactam (e.g. ampicillin) and gentamicin as first-line empirical therapy. However, available epidemiological data demonstrate high rates of resistance to both agents. Alternative empirical regimens are needed. Flomoxef and amikacin are two off-patent antibiotics with potential for use in this setting. OBJECTIVES: To assess the pharmacodynamics of flomoxef and amikacin in combination. METHODS: The pharmacodynamic interaction of flomoxef and amikacin was assessed in chequerboard assays and a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment. The combination was further assessed in HFIM experiments mimicking neonatal plasma exposures of clinically relevant doses of both drugs against five Enterobacterales isolates with a range of flomoxef/amikacin MICs. RESULTS: Flomoxef and amikacin in combination were synergistic in bacterial killing in both assays and prevention of emergence of amikacin resistance in the HFIM. In the HFIM assessing neonatal-like drug exposures, the combination killed 3/5 strains to sterility, (including 2/5 that monotherapy with either drug failed to kill) and failed to kill the 2/5 strains with flomoxef MICs of 32 mg/L. CONCLUSIONS: We conclude that the combination of flomoxef and amikacin is synergistic and is a potentially clinically effective regimen for the empirical treatment of neonatal sepsis in LMIC settings and is therefore suitable for further assessment in a clinical trial.

Optimal dose of meropenem for the treatment of neonatal sepsis: Dosing guideline variations and clinical practice deviations.

AIMS: Meropenem is increasingly used to treat neonatal sepsis. There are several guidelines recommending different dosing regimens of meropenem in neonates. Furthermore, deviations from these guidelines regularly occur in daily clinical practice. Therefore, the current study aimed to evaluate the variations of meropenem dosing guidelines and compare the difference between guideline and clinical practice in terms of the probability of target attainment. METHODS: This study is based on a population pharmacokinetic model. After defining the predictive performance of the model, Monte Carlo simulations were used to calculate the probability of target attainment of the currently existing dosing guidelines of meropenem and their use in daily clinical practice. RESULTS: Two guidelines and two labels were included in the Monte Carlo simulations. For 70% fT>MIC (fraction of time when the free meropenem concentration exceeded the minimum inhibitory concentration during the dosing interval), the probability of target attainment of four recommended doses ranged from 59% to 88% (MIC = 2 mg·L-1 ) and from 17% to 47% (MIC = 8 mg·L-1 ). At the clinical practice evaluation, only 20% of patients attained target exposure for the MIC of 8 mg·L-1 with 70% fT>MIC , which was much less than those found in the Food and Drug Administration labels (40%). CONCLUSION: This model-based population pharmacokinetics simulation showed that improper guidelines and/or clinical practice deviations will result in low probability of target attainment for patients infected with resistant bacteria and critically ill patients. It is important to develop and adhere to evidence-based and clinically pragmatic guidelines.

Flomoxef and fosfomycin in combination for the treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance.

BACKGROUND: Neonatal sepsis is a serious bacterial infection of neonates, globally killing up to 680 000 babies annually. It is frequently complicated by antimicrobial resistance, particularly in low- and middle-income country (LMIC) settings with widespread resistance to the WHO's recommended empirical regimen of ampicillin and gentamicin. OBJECTIVES: We assessed the utility of flomoxef and fosfomycin as a potential alternative empirical regimen for neonatal sepsis in these settings. METHODS: We studied the combination in a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment and chequerboard assays. We further assessed the combination using clinically relevant regimens in the HFIM with six Enterobacterales strains with a range of flomoxef/fosfomycin MICs. RESULTS: Pharmacokinetic/pharmacodynamic modelling of the HFIM experimental output, along with data from chequerboard assays, indicated synergy of this regimen in terms of bacterial killing and prevention of emergence of fosfomycin resistance. Flomoxef monotherapy was sufficient to kill 3/3 strains with flomoxef MICs ≤0.5 mg/L to sterility. Three of three strains with flomoxef MICs ≥8 mg/L were not killed by fosfomycin or flomoxef monotherapy; 2/3 of these were killed with the combination of the two agents. CONCLUSIONS: These data suggest that flomoxef/fosfomycin could be an efficacious and synergistic regimen for the empirical treatment of neonatal sepsis in LMIC settings with prevalent antimicrobial resistance. Our HFIM results warrant further assessment of the flomoxef/fosfomycin combination in clinical trials.

The Multi-Component Causes of Late Neonatal Sepsis-Can We Regulate Them?

Elucidating the mechanisms of bacterial translocation is crucial for the prevention and treatment of neonatal sepsis. In the present study, we aimed to evaluate the potential of lactoferrin to inhibit the development of late-onset blood infection in neonates. Our investigation evaluates the role of key stress factors leading to the translocation of intestinal bacteria into the bloodstream and, consequently, the development of life-threatening sepsis. Three stress factors, namely weaning, intraperitoneal administration of Gram-positive cocci and oral intake of Gram-negative rods, were found to act synergistically. We developed a novel model of rat pups sepsis induced by bacterial translocation and observed the inhibition of this process by supplementation of various forms of lactoferrin: iron-depleted (apolactoferrin), iron-saturated (hololactoferrin) and manganese-saturated lactoferrin. Additionally, lactoferrin saturated with manganese significantly increases the Lactobacillus bacterial population, which contributes to the fortification of the intestinal barrier and inhibits the translocation phenomenon. The acquired knowledge can be used to limit the development of sepsis in newborns in hospital neonatal intensive care units.

Association of lower vitamin a levels in neonates and their mothers with increased risk of neonatal late-onset sepsis: A case-control study.

BACKGROUND: In developing countries, neonatal sepsis is one of the major causes of mortality and morbidity. Vitamin A deficiency also affects the immune system severely and is associated with various neonatal infections. We aimed to compare maternal and neonatal vitamin A levels among neonates with and without late-onset sepsis. MATERIAL AND METHODS: 40 eligible infants were entered into this case-control study according to inclusion criteria. The case group included 20 term or near-term infants who had late-onset neonatal sepsis from three to seven days of life. The control group consisted of 20 term or near-term infants who were icteric hospitalized neonates without sepsis. Demographic, clinical and paraclinical features, as well as neonatal and maternal vitamin A levels, were compared between the two groups. RESULTS: The average gestational age of the neonates was 37.1 ± 1.2, ranging from 35 to 39 days. There was a significant difference between the septic and non-septic groups in terms of white blood cell and neutrophil count, C-reactive protein, and neonatal and maternal vitamin A levels. A Spearman correlation analysis showed a significant direct correlation among maternal and neonatal vitamin A levels (correlation coefficient = 0.507; P-value = 0.001). Multivariate regression analysis showed that neonates' vitamin A level had a significant direct association with sepsis (OR: 0.541; P-value=0.017). CONCLUSION: Our findings demonstrated the association of lower vitamin A levels in neonates and their mothers with an increased risk of late-onset sepsis, which emphasizes the importance of the consideration of vitamin A level evaluation and its appropriate neonatal and maternal supplementation.

Zinc Supplementation in Preterm Neonates with Late-Onset Sepsis: Is It Beneficial?

OBJECTIVE: Neonatal sepsis (NS) is a serious neonatal disease. The aim of this study was to detect the role of zinc (Zn) supplementation in preterm neonates with late-onset sepsis (LOS). STUDY DESIGN: A prospective randomized clinical trial study which was done at Tanta University Hospital from August 2016 to March 2018 on 180 preterm neonates with LOS. The studied neonates were divided into two groups: group 1 (90 neonates), which received Zn and antibiotics, and group 2 (90 neonates), which received antibiotics and placebo. In group 1, the neonates received 1.4 mg elemental Zn/kg/d orally for 10 days. Sepsis score, C-reactive protein (CRP), and procalcitonin (PCT) were done for both groups. RESULTS: As regards sepsis score, it showed that before beginning the treatment, there were 85 and 84 neonates who had high probable sepsis (HPS) in intervention and control groups, respectively, and this revealed nonstatistically significant difference (non-SSD) between both groups (p-value is 0.756) and after 10 days of treatment, there were 1 and 4 neonates who had HPS in intervention and control group, respectively, and this revealed SSD between both groups (p-value is 0.045*). As regards CRP and PCT, the results showed that before beginning the treatment, the mean ± standard deviation (SD) of CRP and PCT were 39.4 ± 10.1 mg/L and 5.2 + 1.8 ng/mL, respectively, in intervention group, while it was 39.6 + 9.9 mg/L and 5.1 + 1.9 ng/mL, respectively, in control group and this revealed non-SSD between both groups (p-value is 0.893 and 0.717, respectively) and after 10 days of treatment, the mean ± SD of CRP and PCT were 5.3 ± 1.8 mg/L and 0.39 ± 0.13 ng/mL, respectively, in intervention group and 6.1 + 2 mg/L and 0.61 + 0.22 ng/mL, respectively, in control group and this revealed SSD between both groups (p-value is 0.008* and 0.044*, respectively). CONCLUSION: Zn supplementation in preterm neonates with LOS is beneficial in improving the clinical and laboratory finding. RECOMMENDATION: Zn supplementation for preterm neonates with LOS. KEY POINTS: · NS is a serious neonatal disease.. · Preterm neonates are more liable to infections.. · Zn supplementation in preterm neonates with LOS is beneficial in improving the condition..

Ten Versus 14 Days of Antibiotic Therapy in Culture-Proven Neonatal Sepsis: A Randomized, Controlled Trial.

OBJECTIVES: To compare the efficacy of 10 d versus 14 d of antibiotic therapy in neonates with culture-positive sepsis. METHODS: Neonates with culture-positive sepsis were randomized to either 10-d or 14-d antibiotic therapy. These neonates were followed up to 28 d after discharge for treatment failure. Primary outcome of the study was treatment failure which was defined as readmission to the NICU within 4 wk of discharge with blood culture growing same organism with similar antibiogram or any readmission with signs of sepsis with negative blood culture. RESULTS: A total of 70 neonates were randomized to receive either 10 d (n = 35) or 14 d (n = 35) of antibiotic therapy. Gram-negative infections were encountered in majority of the neonates. Treatment failure occurred in 1 neonate in 10-d group and none in 14-d group. The duration of hospital stay was significantly less in 10-d group as compared to 14-d group (16 d vs. 23 d, p  <  0.01). CONCLUSIONS: Ten days of antibiotics in neonates with culture-positive sepsis, who have achieved clinical and microbiologic remission at day 7, is noninferior to 14 d of therapy. Larger adequately powered trials will address this issue with certainty.

Antimicrobial Susceptibility Profiles Among Neonatal Early-onset Sepsis Pathogens.

BACKGROUND: Empiric administration of ampicillin and gentamicin is recommended for newborns at risk of early-onset sepsis (EOS). There are limited data on antimicrobial susceptibility of all EOS pathogens. METHODS: Retrospective review of antimicrobial susceptibility data from a prospective EOS surveillance study of infants born ≥22 weeks' gestation and cared for in Neonatal Research Network centers April 2015-March 2017. Nonsusceptible was defined as intermediate or resistant on final result. RESULTS: We identified 239 pathogens (235 bacteria, 4 fungi) in 235 EOS cases among 217,480 live-born infants. Antimicrobial susceptibility data were available for 189/239 (79.1%) isolates. Among 81 Gram-positive isolates with ampicillin and gentamicin susceptibility data, all were susceptible in vitro to either ampicillin or gentamicin. Among Gram-negative isolates with ampicillin and gentamicin susceptibility data, 72/94 (76.6%) isolates were nonsusceptible to ampicillin, 8/94 (8.5%) were nonsusceptible to gentamicin, and 7/96 (7.3%) isolates were nonsusceptible to both. Five percent or less of tested Gram-negative isolates were nonsusceptible to each of third or fourth generation cephalosporins, piperacillin-tazobactam, and carbapenems. Overall, we estimated that 8% of EOS cases were caused by isolates nonsusceptible to both ampicillin and gentamicin; these were most likely to occur among preterm, very-low birth weight infants. CONCLUSIONS: The vast majority of contemporary EOS pathogens are susceptible to the combination of ampicillin and gentamicin. Clinicians may consider the addition of broader-spectrum therapy among newborns at highest risk of EOS, but we caution that neither the substitution nor the addition of 1 single antimicrobial agent is likely to provide adequate empiric therapy in all cases.

Flomoxef for neonates: extending options for treatment of neonatal sepsis caused by ESBL-producing Enterobacterales.

BACKGROUND: Neonatal sepsis is a serious and frequently lethal infection, often complicated by antimicrobial resistance (including ESBLs) in low- and middle-income countries (LMICs). Flomoxef is an off-patent oxacephem ß-lactam with stability against non-AmpC ESBLs, with potential for utility in these settings. To date, there has been no published flomoxef neonatal population pharmacokinetic (PopPK) model. OBJECTIVES: To summarize the clinical data available for flomoxef, build a neonatal PopPK model and assess the adequacy of different neonatal flomoxef regimens. METHODS: A systematic literature search returned all available clinical or pharmacokinetic data of flomoxef use in neonates. Pharmacokinetic data were used to construct a PopPK model, with progressive incorporation of covariates into the final model. Monte Carlo simulations were performed using this final model to simulate drug exposures of different flomoxef regimens to calculate PTAs. RESULTS: Individual-level clinical and pharmacokinetic data were extracted for 313 and 146 neonates, respectively, with population clinical data extracted for a further 199 neonates. Clinical and microbiological success rates were 89.71% and 82.8%, respectively, with minimal side effects. The final PopPK model incorporated body weight and postnatal age as covariates. PTA analyses predicted that IV regimens of 20 mg/kg q12h, 20 mg/kg q6-8h and 40 mg/kg q6-8h are adequate for neonates aged 0-7, 7-14 and 14-28 days, respectively. CONCLUSIONS: To the best of our knowledge, this is the first published neonatal PopPK model for flomoxef. Given the high treatment success rates, low toxicity rates and off-patent status, this drug has potential for use in the treatment of neonatal sepsis in ESBL-prevalent LMIC settings.

Sepsis treatment options identified by 10-year study of microbial isolates and antibiotic susceptibility in a level-four neonatal intensive care unit.

AIM: This observational study investigated the microbiology of blood culture-positive sepsis episodes and susceptibility to empiric antibiotics in early-onset sepsis (EOS) and late-onset sepsis (LOS) in a level-four neonatal intensive care unit (NICU) from 2010 to 2019. METHODS: It was based on patient records and data that Oslo University Hospital, Norway, routinely submitted to the Norwegian Neonatal Network database. Clinical data were merged with blood culture results, including antibiotic susceptibility. RESULTS: We studied 5249 infants admitted to the NICU 6321 times and identified 324 positive blood cultures from 287 infants, with 30 EOS and 305 LOS episodes. Frequent causative agents for EOS were group B streptococci (33.3%), Escherichia coli (20.0%) and Staphylococcus aureus (16.7%). All were susceptible to empiric ampicillin and gentamicin. LOS was most frequently caused by coagulase-negative staphylococci (CONS) (73.8%), Staphylococcus aureus (15.7%) and Enterococci (6.9%). CONS, Staphylococcus aureus, Enterococci, Escherichia coli, Klebsiella and Enterobacter represented 91.9% of LOS episodes and were susceptible to vancomycin and cefotaxime (96.1%), vancomycin and gentamicin (97.0%) and cloxacillin and gentamicin (38.1%). CONCLUSION: Empiric treatment with ampicillin and gentamicin was adequate for EOS. Combining vancomycin and gentamicin may be a safer alternative to cefotaxime for LOS, as this reduces exposure to broad-spectrum antibiotics.

Efficacy of empiric antibiotic treatment of late-onset neonatal sepsis caused by Enterobacteriaceae: A systematic review.

Neonatal sepsis is a serious condition, where an adequate empiric antibiotic treatment is crucial. The objective of this systematic review is to assess whether the World Health Organization's recommended treatment regime remains applicable for late-onset neonatal sepsis caused by Enterobacteriaceae, in the time of increased antimicrobial resistance. PubMed was searched for articles from 2009 to 2020. A total of 49 articles were eligible for inclusion. The review was carried out in accordance with PRISMA guidelines. For Klebsiella spp. 100, 68 and 63% of the studies found sensitivity to ampicillin, gentamicin and third-generation cephalosporin in <50% of the isolates. For Escherichia coli, the corresponding values were 88, 50 and 42% respectively, whilst for Enterobacter spp. 100, 70 and 94% of the studies found <50% sensitivity to these antibiotics. Overall, there is low sensitivity to all agents in the WHO's recommended empiric treatment regimes (WHO recommends ampicillin plus gentamicin as first-line treatment and third-generation cephalosporin as second-line treatment). A revised guideline for empiric antibiotic treatment of neonatal sepsis is urgently needed due to the increased threat of antimicrobial resistant Enterobacteriaceae causing neonatal sepsis.

Efficacy of oropharyngeal administration of pasteurized colostrum in very low birthweight newborns in reducing late onset sepsis at a tertiary government hospital in Manila City: A randomized control trial

Background@#Early administration of colostrum is beneficial because of the number of its immunologic components. The problem with very low birthweight (VLBW) patients is the establishment of early, tolerated, and sustained feeding. The study aimed to determine if early initiation of colostrum through oropharyngeal administration within the first hour of life reduces the risk of late-onset sepsis (LOS) among VLBW newborns. @*Methods@#In this single-blinded randomized control trial, 84 VLBW infants with pediatric aging equal to greater than 28 weeks requiring oxygen support were enrolled. They were allocated to receive either pasteurized colostrum via oropharyngeal administration (treatment group) or none (control group). The occurrence of LOS, duration of ventilator use and oxygen support, time to reach full feeds, length of NICU stay, the occurrence of NEC, and mortality were documented. @*Results@#A significantly greater proportion of patients who developed LOS were noted in the control group (n=38 (90.4%)) than in the treatment group (n=30 (71.4%)) (p=0.013). The use of colostrum, had a protective effect for LOS (RR=0.77; 95% CI=0.63-0.94). There were no significant differences in the secondary outcomes. Still, there was a trend towards a lower proportion of mortality (p=0.08), shorter duration of ventilator use (p=0.24) and oxygen support (p=0.17), shorter time to reach full feeds (p=0.30), and shorter NICU stay (p=0.33) in the treatment group. @*Conclusion@#Patients given pasteurized colostrum had significantly less occurrence of LOS. The treatment group had a lower mortality rate, shorter ventilator use and oxygen support duration, faster time to reach full feeds, and shorter NICU stay, but the differences were not statistically significant. Oropharyngeal administration of pasteurized colostrum within the first hour of life reduces the risk of LOS among VLBW infants admitted to the NICU.

Berberine Attenuates Neonatal Sepsis in Mice By Inhibiting FOXA1 and NF-κB Signal Transduction Via the Induction of MiR-132-3p.

Neonatal sepsis (NS) is a severe syndrome in newborns that is induced by infections, and the initiation and development of NS are closely associated with the function of miRs. In the current study, the effects of berberine, which is a functional component in traditional Chinese medicine (TCM), against NS were assessed by focusing on the interaction of berberine with miR-132-3p-mediated signaling. An NS model was induced using cecal slurry (CS) in vivo and LPS in vitro, and berberine treatment was applies. The changes in survival rate, intestinal structure, and systemic inflammation in mice and the viability, apoptosis, and inflammatory response in intestinal cells were measured. At the molecular level, miR-132-3p levels and the activities of the FOXA1 and NF-κB pathways were analyzed. The data showed that berberine increased the survival rates of CS-induced mice. The intestinal injuries induced by CS were also attenuated by berberine, which was associated with inhibition of the production of systemic IL-6, IL-1ß, and TNF-α. At the molecular level, the expression of miR-132-3p was upregulated, suppressing the expression of FOXA1, p-IκBα, and p65 while inducing the expression of IκBα. The effects of berberine on NS-induced impairments were blocked by the injection of the miR-132-3p antagomir, which exacerbated intestinal injuries, induced systemic inflammation, and reactivated the FOXA1 and NF-κB pathways. The findings in the in vivo model were validated with in vitro assays. Collectively, the findings outlined in the current study indicated that berberine had solid protective effects against NS-induced symptoms in newborn mice, and the effects depended on the upregulation of miR-132-3p.

Potential Antibiotics for the Treatment of Neonatal Sepsis Caused by Multidrug-Resistant Bacteria.

Neonatal sepsis causes up to an estimated 680,000 deaths annually worldwide, predominantly in low- and middle-income countries (LMICs). A significant and growing proportion of bacteria causing neonatal sepsis are resistant to multiple antibiotics, including the World Health Organization-recommended empiric neonatal sepsis regimen of ampicillin/gentamicin. The Global Antibiotic Research and Development Partnership is aiming to develop alternative empiric antibiotic regimens that fulfil several criteria: (1) affordable in LMIC settings; (2) activity against neonatal bacterial pathogens, including extended-spectrum ß-lactamase producers, gentamicin-resistant Gram-negative bacteria, and methicillin-resistant Staphylococcus aureus (MRSA); (3) a licence for neonatal use or extensive experience of use in neonates; and (4) minimal toxicities. In this review, we identify five antibiotics that fulfil these criteria: amikacin, tobramycin, fosfomycin, flomoxef, and cefepime. We describe the available characteristics of each in terms of mechanism of action, resistance mechanisms, clinical pharmacokinetics, pharmacodynamics, and toxicity profile. We also identify some knowledge gaps: (1) the neonatal pharmacokinetics of cefepime is reliant on relatively small and limited datasets, and the pharmacokinetics of flomoxef are also reliant on data from a limited demographic range and (2) for all reviewed agents, the pharmacodynamic index and target has not been definitively established for both bactericidal effect and emergence of resistance, with many assumed to have an identical index/target to similar class molecules. These five agents have the potential to be used in novel combination empiric regimens for neonatal sepsis. However, the data gaps need addressing by pharmacokinetic trials and pharmacodynamic characterisation.