Microbiotoxicity: antibiotic usage and its unintended harm to the microbiome.

PURPOSE OF REVIEW: Antibiotic use is associated with development of antimicrobial resistance and dysregulation of the microbiome (the overall host microbial community). These changes have in turn been associated with downstream adverse health outcomes. This review analyses recent important publications in a rapidly evolving field, contextualizing the available evidence to assist clinicians weighing the potential risks of antibiotics on a patient's microbiome. RECENT FINDING: Although the majority of microbiome research is observational, we highlight recent interventional studies probing the associations between antibiotic use, microbiome disruption, and ill-health. These studies include germ-free mouse models, antibiotic challenge in healthy human volunteers, and a phase III study of the world's first approved microbiome-based medicine. SUMMARY: The growing body of relevant clinical and experimental evidence for antibiotic-mediated microbiome perturbation is concerning, although further causal evidence is required. Within the limits of this evidence, we propose the novel term 'microbiotoxicity' to describe the unintended harms of antibiotics on a patient's microbiome. We suggest a framework for prescribers to weigh microbiotoxic effects against the intended benefits of antibiotic use.

A systematic review and meta-analysis of the prevalence of human cytomegalovirus shedding in seropositive pregnant women.

The detection of human cytomegalovirus (HCMV) in an individual's bodily fluid by culture techniques or through HCMV DNA detection by polymerase chain reaction, is known as HCMV shedding. Human cytomegalovirus shedding has the potential to transmit HCMV infection, where an individual can become infected with HCMV through contact with the bodily fluid of another individual containing HCMV. Human cytomegalovirus shedding can occur in primary infection and in non-primary infection for individuals with prior infection (HCMV seropositive). Human cytomegalovirus infection causes few or no symptoms in a pregnant woman, but can cause significant harm to her foetus if congenital CMV (cCMV) infection occurs. The association between HCMV shedding in HCMV seropositive pregnant women and the vertical transmission of HCMV to result in cCMV infection is poorly investigated, challenged by a limited understanding of the distribution of HCMV shedding in HCMV seropositive pregnant women. We systematically reviewed the published literature to describe the prevalence of HCMV shedding in HCMV seropositive women during pregnancy up to delivery. This analysis identified nine studies that met our eligibility criteria. In these studies, the prevalence of HCMV shedding in any bodily fluid of HCMV seropositive women during pregnancy and at delivery ranged from 0% to 42.5%. A meta-analysis, performed on six of the nine studies with suitable sample sizes, estimated a pooled prevalence of 21.5% [95% CI 12.7%,30.3%]. To our knowledge, this is the first review to systematically search the literature to summarise the prevalence of HCMV shedding in HCMV seropositive pregnant women. These estimates can help in the development of disease burden models and therapeutic or preventative strategies against cCMV infection in the context of non-primary maternal HCMV infection.

The infant pharyngeal microbiomes: origin, impact and manipulation.

PURPOSE OF REVIEW: There has been an exponential increase in research into infant microbiome evolution, and it appears that pharyngeal microbiota are associated with clinical phenotypes (e.g. infection and asthma). Although broad consensus views are emerging, significant challenges and uncertainties remain. RECENT FINDINGS: Infant pharyngeal microbiome research is limited by low biomass, high temporal diversity and lack of agreed standards for sampling, DNA sequencing and taxonomic reporting. Analysis of amplicon sequence variants and improved cost and availability of whole-genome sequencing are promising options for improving taxonomic resolution of such studies. Infant respiratory microbiomes arise, at least in part, from maternal flora (e.g. the respiratory tract and breastmilk), and are associated with environmental and clinical factors (e.g. mode of feeding and delivery, siblings, daycare attendance, birth season and antibiotic usage). Interventional research to modify the infant pharyngeal microbiota has recently been reported, using dietary supplements. SUMMARY: Further work is needed to improve characterization of the infant pharyngeal microbiomes, including routes of bacterial acquisition, role of environmental factors and associations with disease phenotypes. Methodological standards are desirable to facilitate more reproducible, comparable research. Improved understanding may enable manipulation of infant pharyngeal microbiota to improve clinical outcomes.

The nonpathogenic commensal Neisseria: friends and foes in infectious disease.

PURPOSE OF REVIEW: Nonpathogenic commensal Neisseria are rarely considered in the clinical setting despite evidence that they can cause invasive opportunistic infections. In contrast, they may offer protection against pathogenic Neisseria, and such relationships are being actively explored in experimental studies. RECENT FINDINGS: Recent case reports are presented of invasive infection caused by nonpathogenic Neisseria in patients on novel biologic therapies. On the other hand, Neisseria lactamica, a nonpathogenic commensal, has been shown in human challenge studies to inhibit colonization by Neisseria meningitidis. Experimental mouse models have also explored the inhibitory effects of nonpathogenic Neisseria on Neisseria gonnhoreae infection. Cutting-edge advances in metagenomics and microbiomics are being used to understand the mechanisms underpinning these effects. SUMMARY: Clinicians should have increased awareness of nonpathogenic Neisseria. First, as new immunomodulating therapies become licenced, the interactions that maintain balance between commensals and their human hosts may be altered. Second, these bacteria are showing promise in their capacity to exclude pathogenic Neisseria species from their anatomical niches.

Painful lymphadenopathy due to silicone breast implant rupture following extensive global air travel.

A 25-year-old Caucasian flight attendant with an extensive travel history presented with night sweats, fevers, weight loss and axillary and supraclavicular lymphadenopathy. Apart from surgical breast augmentation, she had no past medical or surgical history. She was anaemic, leucopenic and lymphopenic, and a broad infection screen was negative. Cross-sectional imaging revealed ipsilateral silicone breast implant rupture, with leaking of implant contents into the surrounding tissue. Histological examination of an axillary lymph node core biopsy confirmed the diagnosis of silicone lymphadenopathy. This case illustrates the broad differential for acute painful lymphadenopathy in the context of global travel, and the use of targeted infection testing, early cross-sectional imaging and biopsy to arrive at an unexpected diagnosis.

Abortion legislation: exploring perspectives of general practitioners and obstetrics and gynaecology clinicians.

Abortion legislation remains a contentious topic in the UK, which receives much attention from politicians, clinicians and professional bodies alike. In this study, the perspectives of general practitioners and obstetrics and gynaecology clinicians on the Abortion Act 1967 was explored. To this end, a short electronic questionnaire was distributed to all 211 GP and obstetrics and gynaecology clinicians affiliated with the University of Cambridge School of Clinical Medicine. Of the 100 anonymous responses collected, a significant majority felt that abortion law in Northern Ireland should be changed in line with the rest of the UK. The respondents' votes, however, were either opposed to or divided over any other changes to the Abortion Act, including altering the 24 week time limit, clarifying the legal definition of fetal abnormalities, introducing abortion purely on the woman's request, and modifying the requirement for two clinicians to approve any request for abortion. These perspectives were not entirely aligned with the recommendations of the Royal College of Obstetricians and Gynaecologists and the House of Commons Science and Technology Committee, or with current medical evidence and demographic data.

Cassandra's prophecy: medic or mother? Exploring the relevance of age-related fertility decline to women in medicine.

This commentary presents a response to 'Cassandra's prophecy' from the perspective of a final-year medical student, in an attempt to gauge the particular relevance of age-related fertility decline to female doctors. Women in the UK are increasingly trying to have children at an older age, with a resultant rise in the incidence of age-related fertility decline and obstetric problems. The literature suggests that the trend towards older motherhood is seen particularly among highly educated women, but that such women lack sufficient knowledge about how fertility and obstetric outcomes decline with age. Recent data indicate that female doctors have children significantly later than women in the general population, but are overall no more likely to remain childless. However, there is significant variation between different specialties; for instance, female surgeons have children significantly later and are more likely to be childless by age 35, as compared with both male surgeons and female doctors in other specialties. This commentary explores various explanations for and implications of these data, in the context of recent changes in NHS workforce gender demographics.

Artificial intelligence, machine learning and deep learning: Potential resources for the infection clinician.

BACKGROUND: Artificial intelligence (AI), machine learning and deep learning (including generative AI) are increasingly being investigated in the context of research and management of human infection. OBJECTIVES: We summarise recent and potential future applications of AI and its relevance to clinical infection practice. METHODS: 1617 PubMed results were screened, with priority given to clinical trials, systematic reviews and meta-analyses. This narrative review focusses on studies using prospectively collected real-world data with clinical validation, and on research with translational potential, such as novel drug discovery and microbiome-based interventions. RESULTS: There is some evidence of clinical utility of AI applied to laboratory diagnostics (e.g. digital culture plate reading, malaria diagnosis, antimicrobial resistance profiling), clinical imaging analysis (e.g. pulmonary tuberculosis diagnosis), clinical decision support tools (e.g. sepsis prediction, antimicrobial prescribing) and public health outbreak management (e.g. COVID-19). Most studies to date lack any real-world validation or clinical utility metrics. Significant heterogeneity in study design and reporting limits comparability. Many practical and ethical issues exist, including algorithm transparency and risk of bias. CONCLUSIONS: Interest in and development of AI-based tools for infection research and management are undoubtedly gaining pace, although the real-world clinical utility to date appears much more modest.

Qualitative interview study exploring the perspectives of pregnant women on participating in controlled human infection research in the UK.

INTRODUCTION: Pregnant women have been historically excluded from interventional research. While recent efforts have been made to improve their involvement, there remains a disparity in the evidence base for treatments available to pregnant women compared with the non-pregnant population. A significant barrier to the enrolment of pregnant women within research is risk perception and a poor understanding of decision-making in this population. OBJECTIVE: Assess the risk perception and influences on decision-making in pregnant women, when considering whether to enrol in a hypothetical interventional research study. DESIGN: Semistructured interviews were undertaken, and thematic analysis was undertaken of participant responses. PARTICIPANTS: Twelve pregnant women were enrolled from an antenatal outpatient clinic. RESULTS: Participants were unanimously positive about enrolling in the proposed hypothetical interventional study. Risk perception was influenced by potential risks to their fetus and their previous experiences of healthcare and research. Participants found the uncertainty in quantifying risk for new research interventions challenging. They were motivated to enrol in research by altruism and found less invasive research interventions more tolerable. CONCLUSION: It is vital to understand how pregnant women balance the perceived risks and benefits of interventional research. This may help clinicians and scientists better communicate risk to pregnant women and address the ongoing under-representation of pregnant women in interventional research.

A Questionnaire-based Study Exploring Participant Perspectives in a Perinatal Human Challenge Trial.

BACKGROUND: Pregnant women have historically been excluded from most medical research, including human challenge studies. The proof-of-concept Lactamica 9 human challenge study investigated whether nasal inoculation of pregnant women with commensal bacteria leads to horizontal transmission to the neonate. Given the unique practical and ethical considerations of both human challenge studies and interventional research involving pregnant women and their newborns, we sought to investigate the motivations, concerns and experiences of these volunteers. METHODS: Pre- and post-participation questionnaires were given to all participants in the Lactamica 9 study. These fully anonymized qualitative and Semi-quantitative questionnaires used forced Likert scales, word association and free-text questions. RESULTS: Pre- and post-participation questionnaires were completed by 87.1% (27/31) and 62.5% (15/24) of eligible participants, respectively. Almost all pre-participation respondents agreed with altruistic motivations for participation, and most concerns were related to discomfort from study procedures, with few concerned about the theoretical risks of inoculation to themselves (5/27; 18.5%) or their baby (6/27; 22.2%). Participants most frequently associated the study intervention with the terms "bacteria," "natural," "protective" and "safe." For the post-participation questionnaire, 93.3% (14/15) found all study procedures acceptable, and qualitative feedback was almost entirely positive, with particular emphasis on the research team's flexibility, approachability and friendliness. CONCLUSIONS: The successful completion of the Lactamica 9 study demonstrates that human challenge research in healthy pregnant women can be acceptable and feasible. Participants' initial concerns of potential discomfort were outweighed by predominantly altruistic motivations and perception of the intervention as "natural."

Controlled human infection with Neisseria lactamica in late pregnancy to measure horizontal transmission and microbiome changes in mother-neonate pairs: a single-arm interventional pilot study protocol.

INTRODUCTION: Infant upper respiratory microbiota are derived partly from the maternal respiratory tract, and certain microbiota are associated with altered risk of infections and respiratory disease. Neisseria lactamica is a common pharyngeal commensal in young children and is associated with reduced carriage and invasive disease by Neisseria meningitidis. Nasal inoculation with N. lactamica safely and reproducibly reduces N. meningitidis colonisation in healthy adults. We propose nasal inoculation of pregnant women with N. lactamica, to establish if neonatal pharyngeal colonisation occurs after birth, and to characterise microbiome evolution in mother-infant pairs over 1 month post partum. METHODS AND ANALYSIS: 20 healthy pregnant women will receive nasal inoculation with N. lactamica (wild type strain Y92-1009) at 36-38 weeks gestation. Upper respiratory samples, as well as optional breastmilk, umbilical cord blood and infant venous blood samples, will be collected from mother-infant pairs over 1 month post partum. We will assess safety, N. lactamica colonisation (by targeted PCR) and longitudinal microevolution (by whole genome sequencing), and microbiome evolution (by 16S rRNA gene sequencing). ETHICS AND DISSEMINATION: This study has been approved by the London Central Research Ethics Committee (21/PR/0373). Findings will be published in peer-reviewed open-access journals as soon as possible. TRIAL REGISTRATION NUMBER: NCT04784845.

Effect of colonisation with Neisseria lactamica on cross-reactive anti-meningococcal B-cell responses: a randomised, controlled, human infection trial.

BACKGROUND: Pharyngeal colonisation by the commensal bacterium Neisseria lactamica inhibits colonisation by Neisseria meningitidis and has an inverse epidemiological association with meningococcal disease. The mechanisms that underpin this relationship are unclear, but could involve the induction of cross-reactive immunity. In this study, we aimed to evaluate whether colonisation with N lactamica induces N lactamica-specific B-cell responses that are cross-reactive with N meningitidis. METHODS: In this randomised, placebo-controlled, human infection trial at University Hospital Southampton Clinical Research Facility (Southampton, UK), healthy adults aged 18-45 years were randomly assigned (2:1) to receive intranasal inoculation with either 105 colony-forming units of N lactamica in 1 mL phosphate-buffered saline (PBS) or 1 mL PBS alone. Participants and researchers conducting participant sampling and immunological assays were masked to allocation. The primary endpoint was the frequency of circulating N lactamica-specific plasma cells and memory B cells after N lactamica inoculation (day 7-28) compared with baseline values (day 0), measured using enzyme-linked immunospot assays. The secondary endpoint was to measure the frequency of N meningitidis-specific B cells. In a second study, we measured the effect of duration of N lactamica colonisation on seroconversion by terminating carriage at either 4 days or 14 days with single-dose oral ciprofloxacin. The studies are now closed to participants. The trials are registered with ClinicalTrials.gov, NCT03633474 and NCT03549325. FINDINGS: Of 50 participants assessed for eligibility between Sept 5, 2018, and March 3, 2019, 31 were randomly assigned (n=20 N lactamica, n=11 PBS). Among the 17 participants who were colonised with N lactamica, the median baselines compared with peak post-colonisation N lactamica-specific plasma-cell frequencies (per 105 peripheral blood mononuclear cells) were 0·0 (IQR 0·0-0·0) versus 5·0 (1·5-10·5) for IgA-secreting plasma cells (p<0·0001), and 0·0 (0·0-0·0) versus 3·0 (1·5-9·5) for IgG-secreting plasma cells (p<0·0001). Median N lactamica-specific IgG memory-B-cell frequencies (percentage of total IgG memory B cells) increased from 0·0024% (0·0000-0·0097) at baseline to 0·0384% (0·0275-0·0649) at day 28 (p<0·0001). The frequency of N meningitidis-specific IgA-secreting and IgG-secreting plasma cells and memory B cells also increased signficantly in participants who were colonised with N lactamica. Upper respiratory tract symptoms were reported in ten (50%) of 20 participants who were inoculated with N lactamica and six (55%) of 11 participants who were inoculated with PBS (p>0·99). Three additional adverse events (two in the N lactamica group and one in the PBS group) and no serious adverse events were reported. In the second study, anti-N lactamica and anti-N meningitidis serum IgG titres increased only in participants who were colonised with N lactamica for 14 days. INTERPRETATION: Natural immunity to N meningitidis after colonisation with N lactamica might be due to cross-reactive adaptive responses. Exploitation of this microbial mechanism with a genetically modified live vector could protect against N meningitidis colonisation and disease. FUNDING: Wellcome Trust, Medical Research Council, and NIHR Southampton Biomedical Research Centre.

The politics of human embryo research and the motivation to achieve PGD.

This article reports a historical study of factors influencing the achievement of clinical preimplantation genetic diagnosis (PGD) in 1990, 22 years after its first demonstration in animals. During the 1970s, research on PGD continued in large farm animals, but serious interest in human PGD was not evident until 1986. First, interest in PGD during the 1970s waned with the advent of prenatal testing, which for gynaecologists was clinically more familiar, technically simpler and ethically less challenging than IVF. Indeed, IVF was viewed with widespread suspicion until the first IVF births in 1978. Second, interest in clinical PGD was stimulated by the UK Parliamentary reaction against human embryo research that greeted the Warnock Report in 1984. This hostility led scientists to initiate a pro-research campaign, further galvanized in 1985 by MP Enoch Powell's bid to ban such research. However, while Powell abhorred embryo research, he approved of PGD, a stance that divided the anti-research lobby. Accordingly, the campaigners for research emphasized that it was needed to achieve PGD. Powell demanded evidence of such projects and PGD research increased from 1986. It is concluded that UK political debates on embryo research played a critical role in stimulating the achievement of clinical PGD. Human pregnancies following preimplantation genetic diagnosis (PGD) for embryo sex were announced in 1990, 22 years after the technique was pioneered in animals. PGD in humans required not only technological advances, such as IVF and sensitive diagnostic tests, but also the motivation to develop and apply them. Our historical analysis shows that, although research on PGD continued in large farm animals during the 1970s, and techniques of the required sensitivity were developed on mouse embryo models, interest in clinical PGD was not evident until 1986. Two factors stimulated this sudden change in motivation. First, interest in PGD was depressed during the 1970s by the advent of prenatal diagnostic techniques, which for gynaecologists were clinically, technically and ethically less challenging than IVF. IVF was then regarded with a suspicion that only started to wane in the early 1980s following the first IVF births. Second, the UK Parliamentary reaction against human embryo research that greeted the Warnock Report in 1984 provided a positive stimulus to clinical PGD by prompting scientists to form a pro-research lobby, which was further galvanized in early 1985 by MP Enoch Powell's almost-successful bid to ban human embryo research. We show that while Powell abhorred embryo research, he approved of PGD, a stance that fractured the unity of the anti-research lobby. Accordingly, the pro-research lobby emphasized that embryo research was needed to achieve PGD. Powell demanded evidence of such projects, thereby, we argue, stimulating PGD research from 1986. Our evidence shows that UK political debates about PGD played a critical role in stimulating the achievement of PGD clinically.

Manipulating the infant respiratory microbiomes to improve clinical outcomes: A review of the literature.

BACKGROUND: The association between infant respiratory microbiota and disease (including respiratory tract infections and asthma) is increasingly recognised, although the mechanism remains unclear. Respiratory infections and asthma account for a large proportion of infant morbidity and mortality, so the possibility of preventing disease or modifying clinical outcomes by manipulating microbiome development warrants investigation. OBJECTIVES AND METHODS: We identified studies that investigated the efficacy of live bacteria (probiotics or human challenge) or their substrates to modify respiratory colonisation or clinical outcomes in infants. ELIGIBILITY CRITERIA: Interventional studies involving infants under one year of age, administration of live bacteria or their substrates, and outcome measures including bacterial colonisation, microbiome profile, or respiratory disease phenotypes. RESULTS AND LIMITATIONS: Some bacterial interventions can reduce infant respiratory infections, although none have been shown to reduce asthma incidence. The literature is heterogeneous in design and quality, precluding meaningful meta-analysis. CONCLUSIONS: Upper respiratory tract infant microbiome manipulation may alter outcomes in respiratory tract infection, but further well-conducted research is needed to confirm this. Improved regulation of proprietary bacterial products is essential for further progress.

Excluding Clinically Significant Bacteremia by 24 Hours in Otherwise Well Febrile Children Younger Than 16 Years: A Study of More Than 50,000 Blood Cultures.

BACKGROUND: In febrile children given empiric parenteral antibiotics, guidelines advise provisional reporting of negative blood cultures and antibiotic review after 36 hours incubation for neonates and 48 hours for older children. Following improvements in culture processing and childhood vaccination, we revisited this important clinical topic, assessing time to exclude clinically significant bacteremia in well-appearing febrile children with no comorbidities or features of sepsis. METHODS: We analyzed the results of all 53,276 pediatric blood cultures taken during an 8-year period at a UK hospital. RESULTS: 1308 (2.5%) cultures were positive, of which 333 (25.5%) grew pathogens typically associated with clinically significant bacteremia. The remaining 975 (74.5%) grew organisms associated with contaminated culture, or with opportunistic infection only in children with relevant risk factors. Time to positivity (TTP) from incubation was significantly shorter for the 333 definite pathogens than the 975 contaminating/opportunistic organisms, with 92% of definite pathogens identified by 24 hours incubation. Only 3 of all definite pathogens were identified after 24 hours in children otherwise eligible for discharge at 24 hours. There was no significant difference in TTP for definite pathogens between neonates and older children. Median time from specimen collection to incubation was 3 hours. CONCLUSIONS: Clinically significant bacteremia can be excluded by 24 hours incubation in well-appearing febrile children with no comorbidities or features of sepsis. This is the largest dataset of its kind, and the second to compare neonates and older children. Our findings may inform future guidelines, facilitating earlier antibiotic review and discharge.