Background Intestinal dysbiosis is implicated in the pathogenesis of necrotising enterocolitis and late-onset sepsis in preterm babies. The provision of non-invasive positive pressure ventilation is a common clinical intervention in preterm babies, and may be hypothesised to adversely affect intestinal bacterial growth, through increased aerophagia and induction of a hyperoxic intestinal environment; however this relationship has not been previously well characterised.Methodology In this prospectively recruited cohort study, high-throughput 16S rRNA gene sequencing was combined with contemporaneous clinical data collection, to assess within-subject changes in microbiome development around the time of transitioning from non-invasive positive pressure respiratory support to unsupported spontaneous breathing.Results In a group of 14 preterm infants, bacterial diversity was seen to increase by 0.34 units/week (inverse Simpson index) at the point of transitioning off non-invasive positive pressure respiratory support. Correspondingly, a significant increase in anaerobic genera (Bifidobacteria spp, Veillonella spp), and a non-significant fall in Enterobacteriaceae was also seen at this time.Conclusions Provision of non-invasive positive pressure ventilation is associated with suppression of both diversity accrual and obligate anaerobic growth in the preterm intestine. This has clinical implications in view of the widespread use of non-invasive positive pressure ventilation in preterm neonatal care (and wider adult use), and demonstrates the need for potential strategies (eg, probiotic support; reduced aerophagia) to support the development of a healthy gut microbiome during this time.

Background Intestinal dysbiosis is implicated in the origins of necrotising enterocolitis and late-onset sepsis in preterm babies. However, the effect of modulators of bacterial growth ( e.g. antibiotics) upon the developing microbiome is not well-characterised. In this prospectively-recruited, retrospectively-classified, case–control study, high-throughput 16S rRNA gene sequencing was combined with contemporaneous clinical data collection, to assess the within-subject relationship between antibiotic administration and microbiome development, in comparison to preterm infants with minimal antibiotic exposure. Results During courses of antibiotics, diversity progression fell in comparison to that seen outside periods of antibiotic use (-0.71units/week vs . + 0.63units/week, p < 0.01); Enterobacteriaceae relative abundance progression conversely rose (+ 10.6%/week vs . -8.9%/week, p < 0.01). After antibiotic cessation, diversity progression remained suppressed (+ 0.2units/week, p = 0.02). Conclusions Antibiotic use has an acute and longer-lasting impact on the developing preterm intestinal microbiome. This has clinical implications with regard to the contribution of antibiotic use to evolving dysbiosis, and affects the interpretation of existing microbiome studies where this effect modulator is rarely accounted for.

Proposals for SARS-CoV-2 virus vaccination priorities in the UK and in many other countries are heavily influenced by epidemiological models, which use outcome measures such as deaths or hospitalisation. Limiting the values under consideration to those attributable to the direct effects of infection has the advantage of simplifying the models and the process of decision-making. However, the consequences of the pandemic extend beyond outcomes directly attributable to SARS-CoV-2 infection, and include restrictions on educational and work opportunities, access to services, recreational activities, affiliations and relationships with others, freedom of movement (including escaping abusive relationships), and other determinants of human experience. Capability theory gives emphasis to the freedoms that individuals have to express themselves (in doings and beings). Restrictions on freedoms restrict our capabilities. Capability theory has been used to provide a framework for the evaluation and comparison of international development approaches and in the evaluation of public health policy. There is a clustering of disadvantages associated with this pandemic that adds to pre-existing inequalities. Much of the disadvantage engendered in the SARS-CoV-2 pandemic is left out when public health policy is based on a limited range of metrics. Acknowledging the impact of policy across the range of human freedoms at both a national and international level has the potential to improve policy, facilitate the mitigation of direct and indirect adverse consequences, and improve public confidence and the effectiveness of vaccine deployment strategies.

Mother-to-baby transmission of group B Streptococcus (GBS) is the main cause of early-onset infection. We evaluated whether, in women with clinical risk factors for early neonatal infection, the use of point-of-care rapid intrapartum test to detect maternal GBS colonisation reduces maternal antibiotic exposure compared with usual care, where antibiotics are administered due to those risk factors. We assessed the accuracy of the rapid test in diagnosing maternal GBS colonisation, against the reference standard of selective enrichment culture. We undertook a parallel-group cluster randomised trial, with nested test accuracy study and microbiological sub-study. UK maternity units were randomised to a strategy of rapid test (GeneXpert GBS system, Cepheid) or usual care. Within units assigned to rapid testing, vaginal-rectal swabs were taken from women with risk factors for vertical GBS transmission in established term labour. The trial primary outcome was the proportion of women receiving intrapartum antibiotics to prevent neonatal early-onset GBS infection. The accuracy of the rapid test was compared against the standard of selective enrichment culture in diagnosing maternal GBS colonisation. Antibiotic resistance profiles were determined in paired maternal and infant samples. Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units; 906 mothers (951 babies) were in usual care units. There was no evidence of a difference in the rates of intrapartum antibiotic prophylaxis (relative risk 1.16, 95% CI 0.83 to 1.64) between the rapid test (41%, 297/716) and usual care (36%, 328/906) units. No serious adverse events were reported. The sensitivity and specificity measures of the rapid test were 86% (95% CI 81 to 91%) and 89% (95% CI 85 to 92%), respectively. Babies born to mothers who carried antibiotic-resistant Escherichia coli were more likely to be colonised with antibiotic-resistant strains than those born to mothers with antibiotic-susceptible E. coli. The use of intrapartum rapid test to diagnose maternal GBS colonisation did not reduce the rates of antibiotics administered for preventing neonatal early-onset GBS infection than usual care, although with considerable uncertainty. The accuracy of the rapid test is within acceptable limits. ISRCTN74746075 . Prospectively registered on 16 April 2015

BACKGROUND:Mother-to-baby transmission of group B Streptococcus (Streptococcus agalactiae) is the main cause of early-onset infection. OBJECTIVES:We investigated if intrapartum antibiotic prophylaxis directed by a rapid intrapartum test reduces maternal and neonatal antibiotic use, compared with usual care (i.e. risk factor-directed antibiotics), among women with risk factors for vertical group B Streptococcus transmission, and examined the accuracy and cost-effectiveness of the rapid test. DESIGN:An unblinded cluster randomised controlled trial with a nested test accuracy study, an economic evaluation and a microbiology substudy. SETTING:UK maternity units were randomised to either a strategy of rapid test or usual care. PARTICIPANTS:Vaginal and rectal swabs were taken from women with risk factors for vertical group B Streptococcus transmission in established term labour. The accuracy of the GeneXpert® Dx IV GBS rapid testing system (Cepheid, Maurens-Scopont, France) was compared with the standard of selective enrichment culture in diagnosing maternal group B Streptococcus colonisation. MAIN OUTCOME MEASURES:Primary outcomes were rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection and accuracy estimates of the rapid test. Secondary outcomes were maternal antibiotics for any indication, neonatal antibiotic exposure, maternal antibiotic duration, neonatal group B Streptococcus colonisation, maternal and neonatal antibiotic resistance, neonatal morbidity and mortality, and cost-effectiveness of the strategies. RESULTS:Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units and 906 mothers (951 babies) participated in usual-care units. There were no differences in the rates of intrapartum antibiotic prophylaxis for preventing early-onset group B Streptococcus infection in the rapid test units (41%, 297/716) compared with the usual-care units (36%, 328/906) (risk ratio 1.16, 95% confidence interval 0.83 to 1.64). There were no differences between the groups in intrapartum antibiotic administration for any indication (risk ratio 0.99, 95% confidence interval 0.81 to 1.21). Babies born in the rapid test units were 29% less likely to receive antibiotics (risk ratio 0.71, 95% confidence interval 0.54 to 0.95) than those born in usual-care units. The sensitivity and specificity of the rapid test were 86% (95% confidence interval 81% to 91%) and 89% (95% confidence interval 85% to 92%), respectively. In 14% of women (99/710), the rapid test was invalid or the machine failed to provide a result. In the economic analysis, the rapid test was shown to be both less effective and more costly and, therefore, dominated by usual care. Sensitivity analysis indicated potential lower costs for the rapid test strategy when neonatal costs were included. No serious adverse events were reported. CONCLUSIONS:The Group B Streptococcus 2 (GBS2) trial found no evidence that the rapid test reduces the rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection. The rapid test has the potential to reduce neonatal exposure to antibiotics, but economically is dominated by usual care. The accuracy of the test is within acceptable limits. FUTURE WORK:The role of routine testing for prevention of neonatal infection requires evaluation in a randomised controlled trial. TRIAL REGISTRATION:Current Controlled Trials ISRCTN74746075. FUNDING:This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 12. See the NIHR Journals Library website for further project information.

Infection and infection-related complications are important causes of death and morbidity following preterm birth. Despite this risk, there is limited understanding of the development of the immune system in those born prematurely, and of how this development is influenced by perinatal factors. Here we prospectively and longitudinally follow a cohort of babies born before 32 weeks of gestation. We demonstrate that preterm babies, including those born extremely prematurely (<28 weeks), are capable of rapidly acquiring some adult levels of immune functionality, in which immune maturation occurs independently of the developing heterogeneous microbiome. By contrast, we observe a reduced percentage of CXCL8-producing T cells, but comparable levels of TNF-producing T cells, from babies exposed to in utero or postnatal infection, which precedes an unstable post-natal clinical course. These data show that rapid immune development is possible in preterm babies, but distinct identifiable differences in functionality may predict subsequent infection mediated outcomes.

AbstractNussbaum’s capability theory by drawing attention to multiple determinants of wellbeing provides a rich and relevant evaluative space for framing antibiotic resistance. I consider the implications of antibiotic resistance for child development and adult capabilities. There are common risk factors for childhood growth stunting and the spread of infectious diseases in both antibiotic sensitive and resistant forms. The interaction between infectious diseases, antibiotic resistance and growth stunting illustrates a clustering of disadvantage. The control of antibiotic resistance requires wide-ranging cooperative action. Cooperation is predicated on an expectation of equitable access to effective antibiotics. This expectation is confounded by inequality both in access to antibiotics, and in the risk that available antibiotics will be ineffective. Securing child development (and adult capabilities) requires that inequalities both in access to antibiotics and in risk factors for the dissemination and transmission of antibiotic resistance are addressed. Inequality undermines the cooperative activity that is control of infectious diseases and compounds the threat to the securing of capabilities that arises from antibiotic resistance.

BACKGROUND:Uncertainty remains about the role of probiotics to prevent necrotising enterocolitis (NEC) some of which arises from the variety of probiotic interventions used in different trials, many with no prior evidence of potential efficacy. Mechanistic studies of intestinal barrier function embedded in a large probiotic trial could provide evidence about which properties of probiotics might be important for NEC prevention thus facilitating identification of strains with therapeutic potential.METHODS:Intestinal permeability, stool microbiota, SCFAs and mucosal inflammation were assessed from the second postnatal week in babies enrolled to a randomised controlled trial of B. breve BBG-001 (the PiPS trial). Results were compared by allocation and by stool colonisation with the probiotic.RESULTS:Ninety-four preterm babies were recruited across six nested studies. B. breve BBG-001 content was higher by allocation and colonisation; Enterobacteriaceae and acetic acid levels were higher by colonisation. No measure of intestinal barrier function showed differences. The PiPS trial found no evidence of efficacy to reduce NEC.CONCLUSIONS:That the negative results of the PiPS trial were associated with failure of this probiotic to modify intestinal barrier function supports the possibility that the tests described here have the potential to identify strains to progress to large clinical trials.IMPACT:Uncertainty about the therapeutic role of probiotics to prevent necrotising enterocolitis is in part due to the wide range of bacterial strains with no previous evidence of efficacy used in clinical trials. We hypothesised that mechanistic studies embedded in a probiotic trial would provide evidence about which properties of probiotics might be important for NEC prevention. The finding that the probiotic strain tested, Bifidobacterium breve BBG-001, showed neither effects on intestinal barrier function nor clinical efficacy supports the possibility that these tests have the potential to identify strains to progress to large clinical trials.

There are substantial inequalities associated with antibiotics and the determinants of their effectiveness, including the risk of exposure to antibiotic-resistant microbes, access to relevant treatment advice, diagnostic facilities, risk of life-threatening infectious disease, and access to antibiotics. Current arrangements (social, political, economic) allow inequalities in the distribution of antibiotic benefits and burdens. This article focuses on the justification of relevant inequalities from a contractualist perspective.

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99.5%] of 1098 in the lactoferrin group and 1089 [99.0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0.95 (95% CI 0.86-1.04; p=0.233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49). Copyright (c) 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.

This chapter covers infections in neonates and young children. In this chapter the term ‘young children’ indicates children under two years of age. For information on congenital infections interested readers are referred to Chapter 37. Early neonatal infection is variably defined as infection presenting up to a week after birth, but most infections present in the first seventy-two hours. Microbial invasion of the chorio-amniotic membranes or uterine cavity occur in a significant proportion of pregnancies before rupture of membranes (> 50% with preterm birth before thirty weeks gestation, 10% with term delivery), and in the majority of those with prolonged rupture of membranes (> 24 hours). It is likely that the majority of cases of early sepsis arise through ascending infection of the uterus (through the cervical canal). Ascending infection may be important in the pathogenesis of preterm birth and is more common in infants born preterm. Group B Streptococci (GBS) (Streptococcus agalactiae) and Escherichia coli are the most common agents of early neonatal infection. Infection with Listeria monocytogenes probably arises following ingestion of contaminated food by the mother, blood stream infection, and transplacental spread. Early infection with GBS usually presents with respiratory distress and can be difficult to differentiate from respiratory distress associated with other causes, particularly prematurity. The incidence of GBS blood stream infection in England and Wales has been 0.3–0.45/ 1000 live births over the last five years. Maternal genital herpes simplex infection can spread to the newborn infant and cause a wide range of serious clinical presentations, with skin, systemic, and central nervous system involvement. Maternal infection with Neisseria gonorrhoea or Chlamydia trachomatis can also infect the infant. Either can cause conjunctivitis which can sometimes be of sufficient severity to cause substantial damage to the eyes. Gonococcal conjunctivitis usually presents in the first few days of life. Infection with Chlamydia trachomatis (conjunctivitis or pneumonitis) tends to present later. Traditionally, penicillin and an aminoglycoside have been used to treat infants with suspected early sepsis (to cover GBS and Escherichia coli). Newborn infants are often empirically treated because it can be difficult to differentiate early bacterial sepsis from respiratory distress associated with prematurity, and death may ensue rapidly if the infection is not treated.

An important consideration in pregnancy is the relationship between infection in the mother and the developing foetus. Infections can indirectly impact the foetus through effects on the mother, for example, maternal urinary tract infection is associated with preterm birth, or can infect the foetus. Routes of infection can be ascending from the birth canal through the cervical os, transplacentally, or rarely, contiguously. The effect on the mother is also important: pregnancy is considered an immunosuppressive state and the growing foetus causes significant mechanical and physiological changes. Although the first trimester is the key developmental phase for the growing foetus, during the third trimester the mother is more susceptible to severe respiratory infection and some viral infections such as varicella zoster virus (VZV), due to the mechanical changes produced by the growing foetus. There is a paucity of evidence supporting the safety of drugs in pregnancy. Use of any medicinal drug in pregnancy, including antibiotics, requires good reasons. The optimum choice of antibiotics depends on the trimester of the pregnancy. In general, beta-lactams are safe and tetracyclines should be avoided throughout pregnancy. Nitrofurantoin is safe until after thirty-five weeks gestation and trimethoprim should be avoided in the first trimester but is safe otherwise (perhaps with folic acid supplementation if < 20 weeks). Specific patterns of colonization and infection of the genitourinary tract can be associated with an increased risk of an adverse pregnancy outcome, particularly preterm birth. Sexually transmitted diseases such as gonorrhoea and chlamydia are associated with an increased risk of spontaneous preterm birth, which may extend to infection in the pre-conception period. Bacterial vaginosis is an abnormal pattern of vaginal colonization and is also linked with an increased risk of preterm birth. The US Center for Disease Control recommends screening all pregnant women for chlamydia, gonorrhoea, syphilis, HIV, and hepatitis B, symptomatic women for trichomonas and genital herpes, women considered at high risk of preterm birth for bacterial vaginosis, and women at high risk of blood-borne virus infection for hepatitis C. Treatment is administered to reduce the risk of an adverse pregnancy outcome (syphilis, gonorrhoea, chlamydia, trichomonas, and bacterial vaginosis) or to prevent transmission to the infant (herpes, HIV, hepatitis B, and C).

A great variety of biomedical devices are used in patient care. Almost all hospitalized patients will have a vascular catheter placed to support administration of drugs, fluids, electrolytes, blood products, feeding solutions, or for haemodynamic monitoring. Many will also be exposed to urinary catheters, or tracheal tubes. There is also increasing use of a variety of prosthetic devices. Different biomedical devices have different infection associations. Examples of associations include cardiac pacemakers with Staphylococcus aureus blood-stream infection, contact lenses with amoebic keratitis, tampons with toxic shock, and historically, intra-uterine devices with pelvic actinomycosis. The most common causative organisms associated with device infections are bacteria (less commonly fungi). For many devices coagulase-negative staphylococci are the most frequent cause of infection. It is important to remember that an enormous range of microbes have been reported to cause device-associated infection. Biomedical devices predispose to infection through a wide range of mechanisms. These may include (depending on the device) traversing of anatomical barriers (such as the skin), protected niches for microbial proliferation, inappropriate immune activation, and provision of a surface(s) for biofilm formation. Few devices are completely inert. Most devices elicit an immune response, which depletes local complement levels and reduces oxidative killing by neutrophils, some directly damage tissues, and some release biologically-active products. There is much interest in the molecular mechanisms and physical interactions that underlie the formation of communal microbial structures on biomaterial surfaces. Many difference strategies have been proposed both to prevent, and to destroy microbial biofilms associated with biomedical devices. Complications associated with devices are most likely to be mechanical or infective. It is estimated that up to 25% of patients with a central venous catheter (CVC) will suffer a serious mechanical or infection related complication. Risk factors for infection include host, device, and operator factors. Extremes of age, co-morbidities such as diabetes, active infection at the time of insertion, and loss of relevant anatomical barriers to infection are host risk factors that apply to most devices. Operator risk factors include poor compliance with insertion or post-insertion ‘best practice’.

In a multi-centre randomised controlled trial (RCT), we are assessing whether giving very preterm (i.e., born at < 32 weeks’ gestation) infants prophylactic enteral bovine lactoferrin supplementation (150 mg/kg/day) from shortly after birth until 34 weeks’ post-menstrual age reduces the incidence of late-onset invasive infection (primary outcome), all-cause mortality, bronchopulmonary dysplasia, necrotising enterocolitis, retinopathy of prematurity, and the duration of antibiotic exposure, intensive care, and hospital admission. The trial is recruiting 2,200 participants from 37 neonatal care centres in the UK over 4 years. We will undertake an economic evaluation within the RCT to evaluate cost-effectiveness and provide an estimate of incremental costs for differences in the pre-specified outcomes in primary and subgroup analyses. If a statistically significant and clinically important effect on the primary outcome is detected, we will seek further funding and approval to assess the impact of enteral lactoferrin supplementation on rates of adverse neuro-developmental outcomes in the participating infants when they are 5 years old.

Introduction We describe a case of progressive disseminated histoplasmosis (PDH) and disseminated cytomegalovirus (CMV) with development of haemophagocytic lymphohistiocytosis in a 62-year-old man of Bangladeshi origin living in the UK. Case presentation The patient had a background of ulcerative colitis for which he took prednisolone and azathioprine. He presented with fever, lethargy, cough, weight loss and skin redness, and was initially treated for bacterial cellulitis and investigated for underlying malignancy. He developed multiple progressive erythematous skin lesions, sepsis and colitis requiring management on intensive care. A skin biopsy showed yeasts in the dermis and sub-cutaneous fat, which were confirmed as Histoplasma capsulatum by PCR. Disseminated CMV with evidence of end organ gastrointestinal disease was also diagnosed. Despite anti-viral and anti-fungal treatment, the patient deteriorated with evidence of bone marrow suppression and a diagnosis of haemophagocytic lymphohistiocytosis was made. Conclusion PDH is classically seen in patients with significant immunosuppression, e.g. those with human immunodeficiency virus (HIV) or on anti-TNF therapy; however, we present a case of reactivation of Histoplasma in a non-HIV patient. We consider the importance of contemplating reactivation of endemic mycoses and CMV in critically unwell and deteriorating patients.

Background: Necrotising enterocolitis (NEC) is a significant cause of infant morbidity and mortality, disproportionately affecting those of extreme prematurity and/or very low birth weight. A number of risk factors have been identified, including an association between the use of antibiotics, and the subsequent development of NEC. Aim: This review sought to address whether the choice of antibiotic(s) used to treat infants with suspected late onset sepsis (LOS) influences the risk of developing NEC. Methods: A systematic review was performed across Web of Knowledge, Cochrane Library, Ovid Medline, EMBASE and CINAHL databases, up to February 2018, assessing the primary outcome of NEC occurrence, as extracted directly from the published articles. Studies were included if they were randomised control trials (or featured adequate adjustment for confounders); included clear criteria for defining LOS/NEC; and assessed occurrence of NEC in premature infants treated for LOS with intravenous antibiotics. Studies were excluded if non-original, not exclusively featuring premature infants, or where treatment was given for early-onset sepsis only. Findings: 2291 titles and abstracts were identified, of which one study (81 subjects) was suitable for analysis, following screening against eligibility criteria. This suggested a decreased risk of developing definite NEC following treatment with a vancomycin/aztreonam combination, versus a vancomycin/gentamicin regimen (OR = 0.08, 95%CI = 0.00-1.45). Conclusion: This systematic review identified one study where the occurrence of NEC was reported in the context of comparing different antibiotic regimens for late onset sepsis and highlights that the type of antibiotic used to treat LOS in preteen infants might be a determinant of the risk of developing NEC. Although it is known that different antibiotic combinations impact the enteric microbiome and that antibiotic exposure is a risk factor for NEC, there is a paucity of well-designed studies that look at the relationship between NEC risk and specific antibiotic exposures.

The microbial dysbiosis associated with necrotizing enterocolitis (NEC) in preterm infants suggests that early exposure to probiotics may decrease and antibiotics may increase NEC risk. However, administration of Bifidobacterium breve strain BBG-001 to preterm infants did not affect NEC incidence in a multicenter randomised controlled phase 3 trial (PiPS trial). Using a subset of these subjects we compared the fecal microbiome of probiotic and placebo groups and assessed the impact of early antibiotic treatment. Extracted DNA from 103 fecal samples collected at 36weeks post-menstrual age underwent PCR amplification of a fragment of the 16S rRNA gene. Heatmaps were constructed showing the proportions of sequences from bacterial families present at >1% of the community. Stepwise logistic regression assessed the association between early antibiotic exposure and microbiome group. There was no difference in the microbial richness and diversity of the microbiome of preterm infants following treatment with probiotic or a placebo. Conversely, early antimicrobial exposure was associated with different patterns of colonisation, specifically a relative abundance of Proteobacteria. These findings highlight that the potential influence of probiotics on the microbiome of preterm infants remains unclear whereas the modulatory effect of antibiotic exposure on microbial colonisation requires further research.

OBJECTIVES:The objectives of this study were to characterize ESBL-producing Enterobacteriaceae present in 24 neonatal units (NNUs) in eight networks participating in a multicentre probiotic study and to test the hypothesis that specific strains would cluster within individual units and networks.METHODS:We performed analysis of stool samples for the presence of ESBL-producing Enterobacteriaceae at 2 weeks post-natal age and 36 weeks post-menstrual age. ESBL-producing Enterobacteriaceae were characterized and typed using molecular methods.RESULTS:ESBL-producing Enterobacteriaceae (n = 71) were isolated from 67/1229 (5.5%) infants from whom we received a sample at either sampling time or both sampling times, and from infants in 18 (75%) of the 24 recruiting NNUs. Thirty-three Escherichia coli, 23 Klebsiella spp. and 6 Enterobacter spp. strains were characterized. ESBL-producing E. coli were all distinguishable within individual NNUs by antibiotic resistance genotype, serogroup (O25b), phenotype, phylotype or ST. Ten of the 33 were ST131 and 9 of the 10 ST131 isolates were ciprofloxacin resistant. Seven of the 10 ST131 isolates carried genes encoding CTX-M group 1 enzymes. ST131 isolates were isolated from centres within five of the eight NNU networks. There were clusters of indistinguishable ESBL-producing Klebsiella and Enterobacter isolates associated with specific NNUs.CONCLUSIONS:Strains of E. coli ST131 were distributed across neonatal networks in the south of England. There was no evidence of clustering of clonally related ESBL-producing E. coli strains, by contrast with Klebsiella spp. and Enterobacter spp., which did cluster within units. The possibility that ESBL-producing E. coli strains are spread by vertical transmission requires further investigation.