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Objective: Catheter-related sepsis (CRS) is a major complication with significant morbidity and mortality. Evidence is lacking regarding the most appropriate antiseptic for skin disinfection before percutaneous central venous catheter (PCVC) insertion in preterm neonates. To inform the feasibility and design of a definitive randomised controlled trial (RCT) of two antiseptic formulations, we conducted the Antiseptic Randomised Controlled Trial for Insertion of Catheters (ARCTIC) feasibility study to assess catheter colonisation, sepsis, and skin morbidity., Design: Feasibility RCT., Setting: Two UK tertiary-level neonatal intensive care units., Patients: Preterm infants born <34 weeks' gestation scheduled to undergo PCVC insertion., Interventions: Skin disinfection with either 2% chlorhexidine gluconate (CHG)-aqueous or 2% CHG-70% isopropyl alcohol (IPA) before PCVC insertion and at removal., Primary Outcome: Proportion in the 2% CHG-70% IPA arm with a colonised catheter at removal., Main Feasibility Outcomes: Rates of: (1) CRS, catheter-associated sepsis (CAS), and CRS/CAS per 1,000 PCVC days; (2) recruitment and retention; (3) data completeness., Safety Outcomes: Daily skin morbidity scores recorded from catheter insertion until 48 hours post-removal., Results: 116 babies were randomised. Primary outcome incidence was 4.1% (95% confidence interval: 0.9% to 11.5%). Overall catheter colonisation rate was 5.2% (5/97); CRS 2.3/1000 catheter days; CAS 14.8/1000 catheter days. Recruitment, retention and data completeness were good. No major antiseptic-related skin injury was reported., Conclusions: A definitive comparative efficacy trial is feasible, but the very low catheter colonisation rate would make a large-scale RCT challenging due to the very large sample size required. ARCTIC provides preliminary reassurance supporting potential safe use of 2% CHG-70% IPA and 2% CHG-aqueous in preterm neonates., Trial Registration Number: ISRCTN82571474., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Neonatal bacterial infections have long been recognized as an important cause of acute morbidity and mortality, but long-term neurodevelopmental consequences have not been comprehensively described and discussed., Objectives: We aimed to summarize evidence on the pathogenesis, diagnosis, and epidemiology of long-term sequelae after neonatal bacterial sepsis and meningitis. We also discuss approaches for future studies to quantify the public health impact of neonatal infection-associated neurodevelopmental impairment., Sources: We identified studies, both research articles and reviews, which provide mechanistic information on the long-term disease, as well as epidemiological studies that describe the frequency of neurodevelopmental impairment in children with and, for comparison, without a history of neonatal bacterial infection. Tools currently used in clinical practice and research settings to assess neurodevelopmental impairment were also reviewed., Content: We first enumerate potential direct and indirect mechanisms that can lead to brain injury following neonatal infections. We then discuss summary data, either frequencies or measures of association, from epidemiological studies. Risk factors that predict long-term outcomes are also described. Finally, we describe clinical approaches for identifying children with neurodevelopmental impairment and provide an overview of common diagnostic tools., Implications: The limited number of studies that describe the long-term consequences of neonatal infections, often undertaken in high-income settings and using variable designs and diagnostic tools, are not sufficient to inform clinical practice and policy prioritization. Multi-country studies with follow-up into adolescence, standardized diagnostic approaches, and local comparator groups are needed, especially in low and middle-income countries where the incidence of neonatal sepsis is high., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: We sought to compare the incidence of early-onset sepsis (EOS) in infants ≥34 weeks' gestation identified >24 hours after birth, in hospitals using the Kaiser Permanente Sepsis Risk Calculator (SRC) with hospitals using the National Institute for Health and Care Excellence (NICE) guidance., Design and Setting: Prospective observational population-wide cohort study involving all 26 hospitals with neonatal units colocated with maternity services across London (10 using SRC, 16 using NICE)., Participants: All live births ≥34 weeks' gestation between September 2020 and August 2021., Outcome Measures: EOS was defined as isolation of a bacterial pathogen in the blood or cerebrospinal fluid (CSF) culture from birth to 7 days of age . We evaluated the incidence of EOS identified by culture obtained >24 hours to 7 days after birth. We also evaluated the rate empiric antibiotics were commenced >24 hours to 7 days after birth, for a duration of ≥5 days, with negative blood or CSF cultures., Results: Of 99 683 live births, 42 952 (43%) were born in SRC hospitals and 56 731 (57%) in NICE hospitals. The overall incidence of EOS (<72 hours) was 0.64/1000 live births. The incidence of EOS identified >24 hours was 2.3/100 000 (n=1) for SRC vs 7.1/100 000 (n=4) for NICE (OR 0.5, 95% CI (0.1 to 2.7)). This corresponded to (1/20) 5% (SRC) vs (4/45) 8.9% (NICE) of EOS cases (χ=0.3, p=0.59). Empiric antibiotics were commenced >24 hours to 7 days after birth in 4.4/1000 (n=187) for SRC vs 2.9/1000 (n=158) for NICE (OR 1.5, 95% CI (1.2 to 1.9)). 3111 (7%) infants received antibiotics in the first 24 hours in SRC hospitals vs 8428 (15%) in NICE hospitals., Conclusion: There was no significant difference in the incidence of EOS identified >24 hours after birth between SRC and NICE hospitals. SRC use was associated with 50% fewer infants receiving antibiotics in the first 24 hours of life., Competing Interests: Competing interests: CB reports grants and personal awards funded by the National Institute for Health Research, personal fees from Chiesi Pharmaceuticals and AbbVie Pharmaceuticals and is deputy chair of the NIHR Health Technology Assessment Prioritisation Committee for hospital-based care. PTH was a member of NICE CG149 guideline committee and deputy chair of NICE CG195 guideline committee. The other authors do not have any conflicts of interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: 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., Methods and Findings: 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., Conclusion: 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., Trial Registration: ClinicalTrials.gov, (NCT03721302)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Members of the funder (MB, NK, SE) participated as authors on the study, reviewed the manuscript, and approved the final manuscript as submitted. All other authors have declared that no competing interests exist., (Copyright: © 2023 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: Potential conflicts of interest. P. T. H. reports research grants to institution for group B streptococcal vaccine study unrelated to this work from Pfizer and Minervax. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Background: Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms., Methods: NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was -10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996)., Findings: Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference -7% [95% CI -15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group)., Interpretation: In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants., Funding: EU Seventh Framework Programme for research, technological development and demonstration., Competing Interests: Declaration of interests PTH is a member of the National Institute for Health and Care Excellence neonatal infection guideline development group. LR is an employee of Therakind. DD obtained a PhD that was funded by Fondazione Penta; the capacity and remit of this PhD was independent and unrelated to involvement with NeoVanc. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Group B Streptococcus (GBS) is a common intestinal colonizer during the neonatal period, but also may cause late-onset sepsis or meningitis in up to 0.5% of otherwise healthy colonized infants after day 3 of life. Transmission routes and risk factors of this late-onset form of invasive GBS disease (iGBS) are not fully understood. Cases of iGBS with recurrence (n=25) and those occurring in parallel in twins/triplets (n=32) from the UK and Ireland (national surveillance study 2014/15) and from Germany and Switzerland (retrospective case collection) were analyzed to unravel shared (in affected multiples) or fixed (in recurrent disease) risk factors for GBS disease. The risk of iGBS among infants from multiple births was high (17%), if one infant had already developed GBS disease. The interval of onset of iGBS between siblings was 4.5 days and in recurrent cases 12.5 days. Disturbances of the individual microbiome, including persistence of infectious foci are suggested e.g. by high usage of perinatal antibiotics in mothers of affected multiples, and by the association of an increased risk of recurrence with a short term of antibiotics [aOR 4.2 (1.3-14.2), P=0.02]. Identical GBS serotypes in both recurrent infections and concurrently infected multiples might indicate a failed microbiome integration of GBS strains that are generally regarded as commensals in healthy infants. The dynamics of recurrent GBS infections or concurrent infections in multiples suggest individual patterns of exposure and fluctuations in host immunity, causing failure of natural niche occupation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Freudenhammer, Karampatsas, Le Doare, Lander, Armann, Acero Moreno, Boyle, Buxmann, Campbell, Chalker, Cunney, Doherty, Davies, Efstratiou, Elling, Endmann, Essers, Hentschel, Jones, Kallsen, Kapatai, Krüger, Ladhani, Lamagni, Lindsay, Meehan, O’Sullivan, Patel, Reynolds, Roll, Schulzke, Smith, Stein, von der Wense, Voss, Wieg, Härtel, Heath and Henneke.)

Background and Objectives: Group B Streptococcus (GBS) is the leading cause of sepsis and meningitis in infants <90 days. In this study, the burden of GBS disease and mortality in young infants in England was assessed., Methods: Using linked hospitalization records from every National Health Service (NHS) hospital from April 1, 1998 to March 31, 2017, we calculated annual GBS incidence in infants aged <90 days and, using regression models, compared their perinatal factors, rates of hospital-recorded disease outcomes, and all-cause infant mortality rates with those of the general infant population., Results: 15 429 infants aged <90 days had a hospital-recorded diagnosis of GBS, giving an average annual incidence of 1.28 per 1000 live births (95% CI 1.26-1.30) with no significant trend over time. GBS-attributable mortality declined significantly from 0.044 (95% CI .029-.065) per 1000 live births in 2001 to 0.014 (95% CI .010-.026) in 2017 (annual percentage change -6.6, 95% CI -9.1 to -4.0). Infants with GBS had higher relative rates of visual impairment (HR 7.0 95% CI 4.1-12.1), cerebral palsy (HR 9.3 95% CI 6.6-13.3), hydrocephalus (HR 17.3 95% CI 13.8-21.6), and necrotizing enterocolitis (HR 18.8 95% CI 16.7-21.2) compared with those without GBS., Conclusions: Annual rates of GBS disease in infants have not changed over 19 years. The reduction in mortality is likely multifactorial and due to widespread implementation of antibiotics in at-risk mothers and babies, as well as advances in managing acutely unwell infants. New methods for prevention, such as maternal vaccination, must be prioritized., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

We used data from 2 global point prevalence surveys of antibiotic prescribing to describe the treatment of sepsis in hospitalized neonates and children. One hundred eighty-five of 824 neonates (22.5%) and 9/786 children (1.1%) received a World Health Organization-recommended first-line treatment; of the remainder, 9/639 neonates (1.4%) and 102/777 children (13.1%) received a World Health Organization-recommended second-line treatment. Reasons for this low adherence to guidance should be explored.

The optimal standard of care for carbapenem-resistant bloodstream infections in children is currently unknown. This systematic review, aiming to define the best available treatments to be compared with new antibiotics in clinical trials, clearly points out the paucity of available data. The simplification and a wider harmonization of study design are a global priority to inform the best strategies to treat these life-threatening infections in children.

Background: Gram-negative antimicrobial resistance (AMR) is of global concern, yet there are few reports from low- and low-middle-income countries, where antimicrobial choices are often limited., Methods: This study offers a systematic review of PubMed, Embase, and World Health Organization (WHO) regional databases of Gram-negative bacteremia in children in low- and low-middle-income countries reporting AMR since 2001., Results: Data included 30 studies comprising 71 326 children, of whom 7056 had positive blood cultures, and Gram-negative organisms were isolated in 4710 (66.8%). In neonates, Klebsiella pneumoniae median resistance to ampicillin was 94% and cephalosporins 84% in Asia; 100% and 50% in Africa. Large regional variations in resistance rates to commonly prescribed antibiotics for Salmonella spp. were identified. Multidrug resistance (resistance to ampicillin, chloramphenicol, and cotrimoxazole) was present in 30% (interquartile range [IQR], 0-59.6) in Asia and 75% (IQR, 30-85.4) in Africa., Conclusions: There is a need for an international pediatric antimicrobial resistance surveillance system that collects local epidemiological data to improve the evidence base for the WHO guidance for childhood Gram-negative bacteremia., (© The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Rates of invasive fungal infection are highest among neonates, especially those of low birthweight. This study aimed to describe the current epidemiology of invasive neonatal fungal infections in a UK neonatal infection surveillance network. From 2004 to 2010 prospective multicentre surveillance was conducted by 14 neonatal units using a web-based database. Clinicians then completed a standardized pro forma for each positive fungal blood and/or cerebrospinal fluid culture. The overall incidence was 2.4/1000 neonatal unit admissions and was highest among babies <1000 g (extreme low birthweight, 18.8/1000). Only five infants (6%) were >1500 g. The majority of infections were caused by Candida albicans (59; 69%) and Candida parapsilosis (17; 20%); 33% of infants had received antifungal prophylaxis. Known risk factors (use of central venous catheter, parenteral nutrition, previous antibiotic use) were common among cases. The attributable case fatality rate was 21% (18/84). Extreme low birthweight infants remain at highest risk of invasive fungal infection and prophylaxis should be particularly considered for this group. The number needing to receive prophylaxis to prevent one case varies significantly among units, hence unit-specific decisions are required. Further research is still needed into the optimal empiric and therapeutic strategies., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)

Background: Each year an estimated four million neonates die, the majority in the first week of life. One of the major causes of death is sepsis. Proving the incidence and aetiology of neonatal sepsis is difficult, particularly in resource poor settings where the majority of the deaths occur., Methods: We conducted a three year observational study of clinically diagnosed early onset (<7 days of age) neonatal sepsis (EONS) in infants born to mothers following antenatal care at the Shoklo Malaria Research Unit clinic in Maela camp for displaced persons on the Thailand-Myanmar border. Episodes of EONS were identified using a clinical case definition. Conventional and molecular microbiological techniques were employed in order to determine underlying aetiology., Results: From April 2009 until April 2012, 187 infants had clinical signs of EONS, giving an incidence rate of 44.8 per 1000 live births (95% CI 38.7-51.5). One blood culture was positive for Escherichia coli, E. coli was detected in the cerebrospinal fluid specimen in this infant, and in an additional two infants, by PCR. Therefore, the incidence of bacteriologically proven EONS was 0.7 per 1000 live births (95% CI 0.1-2.1). No infants enrolled in study died as a direct result of EONS., Conclusion: A low incidence of bacteriologically proven EONS was seen in this study, despite a high incidence of clinically diagnosed EONS. The use of molecular diagnostics and nonspecific markers of infection need to be studied in resource poor settings to improve the diagnosis of EONS and rationalise antibiotic use.

Antibiotic licensing studies remain a problem in neonates. The classical adult clinical syndrome-based licensing studies do not apply to neonates, where sepsis is the most common infection. The main obstacle to conducting neonatal antibiotic trials is a lack of consensus on the definition of neonatal sepsis itself and the selection of appropriate endpoints. This article describes the difficulties of the clinical and laboratory definitions of neonatal sepsis and reviews the varying designs of previous neonatal sepsis trials. The optimal design of future trials of new antibiotics will need to be based on pharmacokinetic/pharmacodynamic parameters, combined with adequately powered clinical studies to determine safety and efficacy.

Background: In industrialized countries, Staphylococcus aureus (SA) is a leading cause of late-onset neonatal sepsis., Methods: Culture-proven episodes were identified prospectively from neonatal units participating in the neonatal infection surveillance network. Demographic, risk factor, and outcome data were collected., Results: Between 2004 and 2009, there were 117 episodes of SA infections (including 8 methicillin-resistant SA) in 116 infants from 13 units. The median gestational age and birth-weight were 27 weeks (90% ≤ 37 weeks, 85% ≤ 32 weeks) and 850 g (90% ≤ 2500 g), respectively. The overall incidence was 0.6 per 1000 live births and 23/1000 in infants <1500 g. Most episodes (94%) occurred more than 48 hours after birth (late onset). There were 7 early-onset episodes (< 48 hours) (median gestational age, 38.5 weeks), all due to methicillin-susceptible SA. At the time of culture, 67 of 95 (71%) infants were receiving respiratory support and 47 of 94 (50%) had a central line in situ. The majority of infants had nonspecific clinical features although evidence of focal infection (skin, soft tissue, bone, joint, or pneumonia) was ultimately seen in 41 of 91 (45%). There were 18 deaths, 4 (all late onset) directly due to methicillin-susceptible SA sepsis (4.4%)., Conclusions: SA is the second most common pathogen causing late-onset neonatal infections in this neonatal network. Infants who weigh < 1500 g in intensive care settings are the most vulnerable group. Clinical signs are not sufficiently distinctive to allow targeted therapy, suggesting that an antistaphylococcal agent should be part of empiric therapy for late-onset sepsis in premature infants.

Background: Late onset neonatal sepsis (LOS) with the mortality of 17 to 27% is still a serious disease. Meropenem is an antibiotic with wide antibacterial coverage. The advantage of it over standard of care could be its wider antibacterial coverage and thus the use of mono-instead of combination therapy., Methods: NeoMero-1, an open label, randomised, comparator controlled, superiority trial aims to compare the efficacy of meropenem with a predefined standard of care (ampicillin + gentamicin or cefotaxime + gentamicin) in the treatment of LOS in neonates and infants aged less than 90 days admitted to a neonatal intensive care unit.A total of 550 subjects will be recruited following a 1:1 randomisation scheme. The trial includes patients with culture confirmed (at least one positive culture from normally sterile site except coagulase negative staphylococci in addition to one clinical or laboratory criterion) or clinical sepsis (at least two laboratory and two clinical criteria suggestive of LOS in subjects with postmenstrual age < 44 weeks or fulfilment of criteria established by the International Pediatric Sepsis Consensus Conference in subjects with postmenstrual age ≥ 44 weeks). Meropenem will be given at a dose of 20 mg/kg q12h or q8h depending on the gestational- and postnatal age. Comparator agents are administered as indicated in British National Formulary for Children. The primary endpoint measured at the test of cure visit (2 days after end of study therapy) is graded to success (all baseline symptoms and laboratory parameters are resolved or improved with no need to continue antibiotics and the baseline microorganisms are eradicated and no new microorganisms are identified and the patient has received allocated treatment for 11 ± 3 days with no modification) or a failure (all remaining cases). Secondary outcome measures include comparison of survival, relapse rates or new infections by Day 28, clinical response at Day 3 and end of therapy, duration of hospitalisation, population pharmacokinetic analysis of meropenem and effect of antibiotics on mucosal colonisation and development of antibacterial resistance.The study will start recruitment in September 2011; the total duration is of 24 months., Trial Registration: EudraCT 2011-001515-31.

Background: Meningococcal polysaccharide (MPLS) vaccines protect against Serogroup C disease, but do not produce an immune response in infants less than two years of age. This limitation can be overcome by linking C polysaccharide to carrier proteins ('conjugating'), to create meningococcal serogroup C conjugate (MCC) vaccines. In the absence of trial data, the immune response to vaccination has been considered to be a reasonable surrogate for vaccine protection., Objectives: To assess the immunogenicity, safety and efficacy of MCC vaccines for preventing meningitis and septicaemia., Search Strategy: We searched the Cochrane Central Register Controlled Trials (CENTRAL) (The Cochrane Library 2005, issue 3); MEDLINE (1966 to September, Week 1 2005); and EMBASE (1990 to June 2005) and references of studies., Selection Criteria: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) in humans comparing MCC vaccines against a control vaccine or none. In the absence of any trials on vaccine efficacy, population-based observational studies about effectiveness were included., Data Collection and Analysis: Two authors independently screened the results of the literature searches, selected eligible studies, extracted the data and evaluated the quality of them., Main Results: The studies showed that MCC vaccine was highly immunogenic in infants after two and three doses, in toddlers after one and two doses and in older age groups after one dose. In general higher titres were generated after MCC than after MPLS vaccines. Immunological hypo-responsiveness seen after repeated doses of MPLS vaccine may be overcome with MCC. Observational studies have documented a significant decline in meningococcal C disease in countries where MCC vaccines have been widely used. The timing of the vaccinations schedules, the specific conjugate used, and the vaccines given concomitantly or combined, may be important., Authors' Conclusions: The MCC vaccine appears to be safe, immunogenic and able to induce immunological memory in all age groups. Observational studies strongly suggest that MCC is clinically effective.

Objectives: To determine the incidence, mortality and risk factors for neonatal late onset gram-negative sepsis and meningitis (LOGNS)., Design: Retrospective case-control study., Setting: Tertiary neonatal unit in London., Patients: Consecutive inborn infants with late onset (>48 h of life) invasive gram-negative infections diagnosed between 1999 and 2005. Controls were healthy infants matched for gestation and time of admission to the neonatal unit., Main Outcome Measures: Clinical and risk factor data., Results: 73 cases of LOGNS were identified of which 48 were inborn and included in the study (incidence 1.85/1000 live births). Enterobacter spp. (28%), Escherichia coli (27%) and Klebsiella spp. (21%) were the most common pathogens. The majority of infants were of very low birthweight (VLBW; 79%), and cases and controls were well matched (median gestation 26 weeks). Overall case death was 27% in cases versus 13.5% in controls (p=0.08). There was no significant difference between cases and controls regarding maternal risk factors. Mechanical ventilation, total parenteral nutrition (TPN) and its duration, presence of a central venous line and its duration, use of specific antibiotics and the occurrence of necrotising enterocolitis at or before the first positive culture were all significantly associated with case status in univariate analysis. In multivariate logistic regression analysis, only duration of TPN at or before first positive blood culture remained independently associated with LOGNS (p<0.001)., Conclusions: LOGNS occurs predominantly in VLBW infants. When the influence of gestational age is accounted for, the only independent risk factor found for late onset gram-negative neonatal infections is the duration of TPN.

Introduction: Neonatal infection is an important cause of morbidity and mortality. Neonatal infection surveillance networks are necessary for defining the epidemiology of infections and monitoring changes over time., Design: Prospective multicentre surveillance using a web-based database., Setting: 12 English neonatal units., Participants: Newborns admitted in 2006-2008, with positive blood, cerebrospinal fluid or urine culture and treated with antibiotics for at least 5 days., Outcome Measure: Incidence, age at infection, pathogens and antibiotic resistance profiles., Results: With the inclusion of coagulase negative Staphylococci (CoNS), the incidence of all neonatal infection was 8/1000 live births and 71/1000 neonatal admissions (2007-2008). The majority of infections occurred in premature (<37 weeks) and low birthweight (<2500 g) infants (82% and 81%, respectively). The incidence of early onset sepsis (EOS; ≤48 h of age) was 0.9/1000 live births and 9/1000 neonatal admissions, and group B Streptococcus (58%) and Escherichia coli (18%) were the most common organisms. The incidence of late onset sepsis (LOS; >48 h of age) was 3/1000 live births and 29/1000 neonatal admissions (7/1000 live births and 61/1000 admissions including CoNS) and the most common organisms were CoNS (54%), Enterobacteriaceae (21%) and Staphylococcus aureus (18%, 11% of which were methicillin resistant S aureus). Fungi accounted for 9% of LOS (72% Candida albicans). The majority of pathogens causing EOS (95%) and LOS (84%) were susceptible to commonly used empiric first line antibiotic combinations of penicillin/gentamicin and flucloxacillin/gentamicin, respectively (excluding CoNS)., Conclusions: The authors have established NeonIN in England and defined the current epidemiology of neonatal infections. These data can be used for benchmarking among units, international comparisons and as a platform for interventional studies.

Background: Meningococcal polysaccharide (MPLS) vaccines protect against Serogroup C disease, but do not produce an immune response in infants less than two years of age. This limitation can be overcome by linking C polysaccharide to carrier proteins ('conjugating'), to create meningococcal serogroup C conjugate (MCC) vaccines. In the absence of trial data, the immune response to vaccination has been considered to be a reasonable surrogate for vaccine protection., Objectives: To assess the immunogenicity, safety and efficacy of MCC vaccines for preventing meningitis and septicaemia., Search Strategy: We searched the Cochrane Central Register Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005); MEDLINE (1966 to September, Week 1 2005); and EMBASE (1990 to June 2005) and references of studies., Selection Criteria: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) in humans comparing MCC vaccines against a control vaccine or none. In the absence of any trials on vaccine efficacy, population-based observational studies about effectiveness were included., Data Collection and Analysis: Two authors independently screened the results of the literature searches, selected eligible studies, extracted the data and evaluated the quality of them., Main Results: The studies showed that MCC vaccine was highly immunogenic in infants after two and three doses, in toddlers after one and two doses and in older age groups after one dose. In general higher titres were generated after MCC than after MPLS vaccines. Immunological hypo-responsiveness seen after repeated doses of MPLS vaccine may be overcome with MCC. Observational studies have documented a significant decline in meningococcal C disease in countries where MCC vaccines have been widely used. The timing of the vaccinations schedules, the specific conjugate used, and the vaccines given concomitantly or combined, may be important., Authors' Conclusions: The MCC vaccine appears to be safe, immunogenic and able to induce immunological memory in all age groups. Observational studies strongly suggest that MCC is clinically effective.

Neonatal infections currently cause about 1.6 million deaths annually in developing countries. Sepsis and meningitis are responsible for most of these deaths. Resistance to commonly used antibiotics is emerging and constitutes an important problem world wide. To reduce global neonatal mortality, strategies of proven efficacy, such as hand washing, barrier nursing, restriction of antibiotic use, and rationalisation of admission to neonatal units, need to be implemented. Different approaches require further research.