Antimicrobial susceptibility profiles of invasive bacterial infections among children from low- and middle-income countries in the Western Pacific Region (WPRO) - a systematic review and meta-analysis.

Background: Antimicrobial resistance increasingly impacts paediatric mortality, particularly in resource-constrained settings. We aimed to evaluate the susceptibility profiles of bacteria causing infections in children from the Western Pacific region. Methods: We conducted a systematic review and meta-analysis of bacteria responsible for common infections in children. We included studies published from January 2011 to December 2023 (PROSPERO CRD42021248722). Pooled susceptibilities were evaluated against empiric antibiotics recommended to treat common clinical syndromes. Findings: Fifty-one papers met inclusion criteria, incorporating 18,330 bacterial isolates. Of available published data, only six countries from the region were represented. Escherichia coli revealed a pooled susceptibility to ampicillin of 17% (95% CI 12-23%, n = 3292), gentamicin 63% (95% CI 59-67%, n = 3956), and third-generation cephalosporins 59% (95% CI 49-69%, n = 3585). Susceptibility of Klebsiella spp. to gentamicin was 71% (95% CI 61-80%, n = 2323), third-generation cephalosporins 35% (95% CI 22-49%, n = 2076), and carbapenems 89% (95% CI 78-97%, n = 2080). Pooled susceptibility of Staphylococcus aureus to flucloxacillin was 72% (95% CI 58-83%, n = 1666), and susceptibility of Streptococcus pneumoniae meningitis isolates to ampicillin was 26% (95% CI 11-44%, n = 375), and 63% (95% CI 40-84%, n = 246) to third-generation cephalosporins. Interpretation: The burden of antimicrobial resistance among bacteria responsible for common infections in children across the Western Pacific region is significant, and the currently recommended World Health Organization antibiotics to treat these infections may be inefficacious. Strategies to improve the availability of high-quality data to understand the burden of antimicrobial resistance in the region are necessary. Funding: The study was supported by an Australian GovernmentNational Health and Medical Research Council Investigator Grant. This research was funded in part by the Wellcome Trust [220211/Z/20/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Understanding hospital antimicrobial prescribing decisions and determinants of uptake of new local antimicrobial prescribing guidelines in Laos.

Background: Antimicrobial use in Laos is among the highest in Southeast Asia. The first Lao comprehensive antimicrobial prescribing guidelines have been available since 2021. This study explored the determinants of antibiotic prescribing decisions and how the new prescribing guidelines were being used. Methods: In August 2022, in-depth interviews were conducted with 16 Lao prescribers from two hospitals. Participants were questioned about their prescribing behaviours, attitudes to guidelines, how they learned about the guidelines and factors influencing their uptake. The interviews were audio-recorded, transcribed, and translated into English. Thematic analysis of the transcripts was conducted. Results: Lao prescribers considered multiple factors before deciding to prescribe antibiotics to their patients. The most common factor was based on the clinical judgement of the prescribers. Lack of certain antibiotics and turnaround times of laboratory results were the main challenges to prescribing antibiotics appropriately. The majority of participants were satisfied with the guidelines, regarding them as comprehensive, simple and convenient. However, most participants admitted that they did not access the guidelines very often. The main reason was that they could remember the treatment recommendations because they treat similar diseases on a daily basis. Improving antibiotic knowledge was the most common recommendation in order to improve the appropriate use of antibiotics. Raising awareness of the guidelines and promoting their use should also be considered. In addition, heads of the wards, and policy and implementation leaders, should support, monitor and feedback their use to encourage all prescribers to follow the guidelines. Conclusions: Several factors contribute to enhancing appropriate antibiotic prescription. Key factors for improving antibiotic prescription include enhancing prescribers' clinical knowledge, ensuring access to essential antibiotics, and updating guidelines regularly. Health leaders must get involved to promote their use.

In Laos, antibiotic use is high compared to other Southeast Asian countries. In 2021, the first guidelines for prescribing antibiotics were introduced in Laos. This study aims to explore what influences doctors' decisions in prescribing antibiotics and how they used the new guidelines. In August 2022, we conducted in-depth interviews with 16 doctors in two Lao hospitals. We asked them how they decided which antibiotics to give, what they thought about the guidelines, how they found the guidelines and what could make them use the guidelines more. We recorded, transcribed, and translated the conversations. Then, we identified common themes and patterns. Before giving antibiotics, doctors in Laos considered many things. The most important thing was their own judgment based on their medical knowledge. Not having some antibiotics and waiting long time for the laboratory results were the main issues that made it challenging for doctors to prescribe antibiotics. Most interviewees liked the guidelines. They found the guidelines easy to understand and useful. Many of them said that they did not use the guidelines a lot. The main reason was that they remembered the treatment recommendations because they treat similar diseases every day. The most common suggestion to use antibiotics better was to learn and understand more about them. Also, leaders of hospital departments and those in charge of making rules should help, keep an eye on the use, and give feedback to make sure everyone who prescribes antibiotics uses the guidelines. To make sure doctors prescribe antibiotics better, they need to know and understand more about infectious diseases, have easy access to essential antibiotics, and regularly update the guidelines with support from the leaders.

Frequency of antimicrobial-resistant bloodstream infections in 111 hospitals in Thailand, 2022.

OBJECTIVES: To evaluate the frequency of antimicrobial-resistant bloodstream infections (AMR BSI) in Thailand. METHODS: We analyzed data from 2022, generated by 111 public hospitals in health regions 1 to 12, using the AutoMated tool for Antimicrobial resistance Surveillance System (AMASS), and submitted to the Ministry of Public Health, Thailand. Multilevel Poisson regression models were used. RESULTS: The most common cause of community-origin AMR BSI was third-generation cephalosporin-resistant Escherichia coli (3GCREC, 65.6%; 5101/7773 patients) and of hospital-origin AMR BSI was carbapenem-resistant Acinetobacter baumannii (CRAB, 51.2%, 4968/9747 patients). The percentage of patients tested for BSI was negatively associated with the frequency of community-origin 3GCREC BSI and hospital-origin CRAB BSI (per 100,000 tested patients). Hospitals in health regions 4 (lower central region) had the highest frequency of community-origin 3GCREC BSI (adjusted incidence rate ratio, 2.06; 95% confidence interval: 1.52-2.97). Health regions were not associated with the frequency of hospital-origin CRAB BSI, and between-hospital variation was high, even adjusting for hospital level and size. CONCLUSION: The high between-hospital variation of hospital-origin CRAB BSI suggests the importance of hospital-specific factors. Our approach and findings highlight health regions and hospitals where actions against AMR infection, including antimicrobial stewardship and infection control, should be prioritized.

Time trends in the epidemiology of food allergy in England: an observational analysis of Clinical Practice Research Datalink data.

BACKGROUND: Estimates for the prevalence of food allergy vary widely, with a paucity of data for adults. The aim of this analysis was to report trends in the incidence and prevalence of food allergy in England, using a national primary care dataset. METHODS: We analysed data from Clinical Practice Research Datalink between 1998 and 2018, with linked data to relevant hospital encounters in England. The main outcomes were incidence and prevalence of food allergy, according to three definitions of food allergy: possible food allergy, probable food allergy, and probable food allergy with adrenaline autoinjectors prescription. We also evaluated the difference in proportion of patients prescribed adrenaline autoinjectors by English Index of Multiple Deprivation (IMD), age, and by previous food anaphylaxis, and explored differences in patient encounters (general practice vs emergency department setting). FINDINGS: 7 627 607 individuals in the dataset were eligible for inclusion, of whom 150 018 (median age 19 years [IQR 4-34]; 82 614 [55·1%] female and 67 404 [44·9%] male) had a possible food allergy. 121 706 met diagnostic criteria for probable food allergy, of whom 38 288 were prescribed adrenaline autoinjectors. Estimated incidence of probable food allergy doubled between 2008 and 2018, from 75·8 individuals per 100 000 person-years (95% CI 73·7-77·9) in 2008 to 159·5 (156·6-162·3) individuals per 100 000 person-years in 2018. Prevalence increased from 0·4% (23 399 of 6 432 383) to 1·1% (82 262 of 7 627 607) over the same period and was highest in children under 5 years (11 951 [4·0%] of 296 406 in 2018) with lower prevalence in school-aged children (from 11 353 [2·4%] of 473 597 in 2018 for children aged 5-9 years to 6896 [1·7%] of 404 525 for those aged 15-19 years) and adults (42 848 [0·7%] of 5 992 454 in 2018). In those with previous food anaphylaxis, only 2321 (58·3%) of 3980 (975 [64·0%] of 1524 children and young people and 1346 [54·8%] of 2456 adults) had a prescription for adrenaline autoinjector. Adrenaline autoinjectors prescription was less common in those resident in more deprived areas (according to IMD). In the analysis of health-care encounters, 488 604 (97·1%) of 503 198 visits recorded for food allergy occurred in primary care, with 115 655 (88·4%) of 130 832 patients managed exclusively in primary care. INTERPRETATION: These estimates indicate an important and increasing burden of food allergy in England. Our findings that most patients with food allergy are managed outside the hospital system, with low rates of adrenaline autoinjector prescription in those with previous anaphylaxis, highlight a need to better support those working in primary care to ensure optimal management of patients with food allergy. FUNDING: UK Food Standards Agency and UK Medical Research Council.

Microbe Profile: Bacteriophage ϕ6: a model for segmented RNA viruses and the evolutionary consequences of viral 'sex'.

Bacteriophage ϕ6 is a segmented dsRNA virus with a lipid envelope, which are unusual traits in bacterial viruses but common in eukaryotic viruses. This uniqueness allowed ϕ6 and its Pseudomonad hosts to serve as a molecular model for RNA genetics, mutation, replication, packaging, and reassortment in both bacterial and eukaryotic viruses. However, an additional uniqueness of ϕ6, created by its high mutation rate, was its use as an experimental system to study key questions such as the evolution of sex (segment reassortment), host-pathogen interactions, mutational load, rates of adaptation, genetic and phenotypic complexity, and game theory.

Management of Refractory Anaphylaxis: An Overview of Current Guidelines.

In this review, we compare different refractory anaphylaxis (RA) management guidelines focusing on cardiovascular involvement and best practice recommendations, discuss postulated pathogenic mechanisms underlining RA and highlight knowledge gaps and research priorities. There is a paucity of data supporting existing management guidelines. Therapeutic recommendations include the need for the timely administration of appropriate doses of aggressive fluid resuscitation and intravenous (IV) adrenaline in RA. The preferred second-line vasopressor (noradrenaline, vasopressin, metaraminol and dopamine) is unknown. Most guidelines recommend IV glucagon for patients on beta-blockers, despite a lack of evidence. The use of methylene blue or extracorporeal life support (ECLS) is also suggested as rescue therapy. Despite recent advances in understanding the pathogenesis of anaphylaxis, the factors that lead to a lack of response to the initial adrenaline and thus RA are unclear. Genetic factors, such as deficiency in platelet activating factor-acetyl hydrolase or hereditary alpha-tryptasaemia, mastocytosis may modulate reaction severity or response to treatment. Further research into the underlying pathophysiology of RA may help define potential new therapeutic approaches and reduce the morbidity and mortality of anaphylaxis.

Evolutionary Invasion Analysis of Modern Epidemics Highlights the Context-Dependence of Virulence Evolution.

Models are often employed to integrate knowledge about epidemics across scales and simulate disease dynamics. While these approaches have played a central role in studying the mechanics underlying epidemics, we lack ways to reliably predict how the relationship between virulence (the harm to hosts caused by an infection) and transmission will evolve in certain virus-host contexts. In this study, we invoke evolutionary invasion analysis-a method used to identify the evolution of uninvadable strategies in dynamical systems-to examine how the virulence-transmission dichotomy can evolve in models of virus infections defined by different natural histories. We reveal peculiar patterns of virulence evolution between epidemics with different disease natural histories (SARS-CoV-2 and hepatitis C virus). We discuss the findings with regards to the public health implications of predicting virus evolution, and in broader theoretical canon involving virulence evolution in host-parasite systems.

Neutralizing antibodies after nebulized phage therapy in cystic fibrosis patients.

BACKGROUND: Cystic fibrosis (CF) patients are prone to recurrent multi-drug-resistant (MDR) bacterial lung infections. Under this scenario, phage therapy has been proposed as a promising tool. However, the limited number of reported cases hampers the understanding of clinical outcomes. Anti-phage immune responses have often been overlooked and only described following invasive routes of administration. METHODS: Three monophage treatments against Staphylococcus aureus and/or Pseudomonas aeruginosa lung infections were conducted in cystic fibrosis patients. In-house phage preparations were nebulized over 10 days with standard-of-care antibiotics. Clinical indicators, bacterial counts, phage and antibiotic susceptibility, phage detection, and immune responses were monitored. FINDINGS: Bacterial load was reduced by 3-6 log in two of the treatments. No adverse events were described. Phages remained in sputum up to 33 days after completion of the treatment. In all cases, phage-neutralizing antibodies were detected in serum from 10 to 42 days post treatment, with this being the first report of anti-phage antibodies after nebulized therapy. CONCLUSIONS: Nebulized phage therapy reduced bacterial load, improving quality of life even without bacterial eradication. The emergence of antibodies emphasizes the importance of long-term monitoring to better understand clinical outcomes. These findings encourage the use of personalized monophage therapies in contrast to ready-to-use cocktails, which might induce undesirable antibody generation. FUNDING: This study was supported by the Spanish Ministry of Science, Innovation and Universities; Generalitat Valenciana; and a crowdfunding in collaboration with the Spanish Cystic Fibrosis Foundation.

Experimental Evolution Studies in Φ6 Cystovirus.

Experimental evolution studies, in which biological populations are evolved in a specific environment over time, can address questions about the nature of spontaneous mutations, responses to selection, and the origins and maintenance of novel traits. Here, we review more than 30 years of experimental evolution studies using the bacteriophage (phage) Φ6 cystovirus. Similar to many lab-studied bacteriophages, Φ6 has a high mutation rate, large population size, fast generation time, and can be genetically engineered or cryogenically frozen, which facilitates its rapid evolution in the laboratory and the subsequent characterization of the effects of its mutations. Moreover, its segmented RNA genome, outer membrane, and capacity for multiple phages to coinfect a single host cell make Φ6 a good non-pathogenic model for investigating the evolution of RNA viruses that infect humans. We describe experiments that used Φ6 to address the fitness effects of spontaneous mutations, the consequences of evolution in the presence of coinfection, the evolution of host ranges, and mechanisms and consequences of the evolution of thermostability. We highlight open areas of inquiry where further experimentation on Φ6 could inform predictions for pathogenic viruses.

Frequency and mortality rate following antimicrobial-resistant bloodstream infections in tertiary-care hospitals compared with secondary-care hospitals.

There are few studies comparing proportion, frequency, mortality and mortality rate following antimicrobial-resistant (AMR) infections between tertiary-care hospitals (TCHs) and secondary-care hospitals (SCHs) in low and middle-income countries (LMICs) to inform intervention strategies. The aim of this study is to demonstrate the utility of an offline tool to generate AMR reports and data for a secondary data analysis. We conducted a secondary-data analysis on a retrospective, multicentre data of hospitalised patients in Thailand. Routinely collected microbiology and hospital admission data of 2012 to 2015, from 15 TCHs and 34 SCHs were analysed using the AMASS v2.0 (www.amass.website). We then compared the burden of AMR bloodstream infections (BSI) between those TCHs and SCHs. Of 19,665 patients with AMR BSI caused by pathogens under evaluation, 10,858 (55.2%) and 8,807 (44.8%) were classified as community-origin and hospital-origin BSI, respectively. The burden of AMR BSI was considerably different between TCHs and SCHs, particularly of hospital-origin AMR BSI. The frequencies of hospital-origin AMR BSI per 100,000 patient-days at risk in TCHs were about twice that in SCHs for most pathogens under evaluation (for carbapenem-resistant Acinetobacter baumannii [CRAB]: 18.6 vs. 7.0, incidence rate ratio 2.77; 95%CI 1.72-4.43, p<0.001; for carbapenem-resistant Pseudomonas aeruginosa [CRPA]: 3.8 vs. 2.0, p = 0.0073; third-generation cephalosporin resistant Escherichia coli [3GCREC]: 12.1 vs. 7.0, p<0.001; third-generation cephalosporin resistant Klebsiella pneumoniae [3GCRKP]: 12.2 vs. 5.4, p<0.001; carbapenem-resistant K. pneumoniae [CRKP]: 1.6 vs. 0.7, p = 0.045; and methicillin-resistant Staphylococcus aureus [MRSA]: 5.1 vs. 2.5, p = 0.0091). All-cause in-hospital mortality (%) following hospital-origin AMR BSI was not significantly different between TCHs and SCHs (all p>0.20). Due to the higher frequencies, all-cause in-hospital mortality rates following hospital-origin AMR BSI per 100,000 patient-days at risk were considerably higher in TCHs for most pathogens (for CRAB: 10.2 vs. 3.6,mortality rate ratio 2.77; 95%CI 1.71 to 4.48, p<0.001; CRPA: 1.6 vs. 0.8; p = 0.020; 3GCREC: 4.0 vs. 2.4, p = 0.009; 3GCRKP, 4.0 vs. 1.8, p<0.001; CRKP: 0.8 vs. 0.3, p = 0.042; and MRSA: 2.3 vs. 1.1, p = 0.023). In conclusion, the burden of AMR infections in some LMICs might differ by hospital type and size. In those countries, activities and resources for antimicrobial stewardship and infection control programs might need to be tailored based on hospital setting. The frequency and in-hospital mortality rate of hospital-origin AMR BSI are important indicators and should be routinely measured to monitor the burden of AMR in every hospital with microbiology laboratories in LMICs.

Exploring the pediatric nasopharyngeal bacterial microbiota with culture-based MALDI-TOF mass spectrometry and targeted metagenomic sequencing.

The nasopharynx is an important reservoir of disease-associated and antimicrobial-resistant bacterial species. This proof-of-concept study assessed the utility of a combined culture, matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), and targeted metagenomic sequencing workflow for the study of the pediatric nasopharyngeal bacterial microbiota. Nasopharyngeal swabs and clinical metadata were collected from Cambodian children during a hospital outpatient visit and then biweekly for 12 weeks. Swabs were cultured on chocolate and blood-gentamicin agar, and all colony morphotypes were identified by MALDI-TOF MS. Metagenomic sequencing was done on a scrape of all colonies from a chocolate agar culture and processed using the mSWEEP pipeline. One hundred one children were enrolled, yielding 620 swabs. MALDI-TOF MS identified 106 bacterial species/40 genera: 20 species accounted for 88.5% (2,190/2,474) of isolates. Colonization by Moraxella catarrhalis (92.1% of children on ≥1 swab), Haemophilus influenzae (87.1%), and Streptococcus pneumoniae (83.2%) was particularly common. In S. pneumoniae-colonized children, a median of two serotypes [inter-quartile range (IQR) 1-2, range 1-4] was detected. For the 21 bacterial species included in the mSWEEP database and identifiable by MALDI-TOF, detection by culture + MALDI-TOF MS and culture + mSWEEP was highly concordant with a median species-level agreement of 96.9% (IQR 86.8%-98.8%). mSWEEP revealed highly dynamic lineage-level colonization patterns for S. pneumoniae which were quite different to those for S. aureus. A combined culture, MALDI-TOF MS, targeted metagenomic sequencing approach for the exploration of the young child nasopharyngeal microbiome was technically feasible, and each component yielded complementary data. IMPORTANCE: The human upper respiratory tract is an important source of disease-causing and antibiotic-resistant bacteria. However, understanding the interactions and stability of these bacterial populations is technically challenging. We used a combination of approaches to determine colonization patterns over a 3-month period in 101 Cambodian children. The combined approach was feasible to implement, and each component gave complementary data to enable a better understanding of the complex patterns of bacterial colonization.

Robustness in population-structure and demographic-inference results derived from the Aedes aegypti genotyping chip and whole-genome sequencing data.

The mosquito Aedes aegypti is the primary vector of many human arboviruses such as dengue, yellow fever, chikungunya, and Zika, which affect millions of people worldwide. Population genetic studies on this mosquito have been important in understanding its invasion pathways and success as a vector of human disease. The Axiom aegypti1 SNP chip was developed from a sample of geographically diverse A. aegypti populations to facilitate genomic studies on this species. We evaluate the utility of the Axiom aegypti1 SNP chip for population genetics and compare it with a low-depth shotgun sequencing approach using mosquitoes from the native (Africa) and invasive ranges (outside Africa). These analyses indicate that results from the SNP chip are highly reproducible and have a higher sensitivity to capture alternative alleles than a low-coverage whole-genome sequencing approach. Although the SNP chip suffers from ascertainment bias, results from population structure, ancestry, demographic, and phylogenetic analyses using the SNP chip were congruent with those derived from low-coverage whole-genome sequencing, and consistent with previous reports on Africa and outside Africa populations using microsatellites. More importantly, we identified a subset of SNPs that can be reliably used to generate merged databases, opening the door to combined analyses. We conclude that the Axiom aegypti1 SNP chip is a convenient, more accurate, low-cost alternative to low-depth whole-genome sequencing for population genetic studies of A. aegypti that do not rely on full allelic frequency spectra. Whole-genome sequencing and SNP chip data can be easily merged, extending the usefulness of both approaches.

Preparing Patients for Oral Immunotherapy (PPOINT): International Delphi consensus for procedural preparation and consent.

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process. OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form. METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was reached using Delphi methodology, and the consent information form was developed. RESULTS: The expert panel reached consensus for 4 themes and 103 statements specific to OIT preparatory procedures, of which 76 statements reached consensus for inclusion specific to the following themes: general considerations for counseling patients about OIT; patient- and family-specific factors that should be addressed before initiating OIT and during OIT; indications for initiating OIT; and potential contraindications and precautions for OIT. The panel reached consensus on 9 OIT consent form themes: benefits, risks, outcomes, alternatives, risk mitigation, difficulties/challenges, discontinuation, office policies, and long-term management. From these themes, 219 statements were proposed, of which 189 reached consensus, and 71 were included on the consent information form. CONCLUSION: We developed consensus recommendations to prepare and counsel patients for safe and effective OIT in clinical practice with evidence-based risk mitigation. Adoption of these recommendations may help standardize clinical care and improve patient outcomes and quality of life.

Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells.

Phage therapy is a therapeutic approach to treat multidrug-resistant (MDR) infections that employs lytic bacteriophages (phages) to eliminate bacteria. Despite the abundant evidence for its success as an antimicrobial in Eastern Europe, there is scarce data regarding its effects on the human host. Here, we aimed to understand how lytic phages interact with cells of the airway epithelium, the tissue site that is colonized by bacterial biofilms in numerous chronic respiratory disorders. Using a panel of Pseudomonas aeruginosa phages and human airway epithelial cells (AECs) derived from a person with cystic fibrosis (CF), we determined that interactions between phages and epithelial cells depend on specific phage properties as well as physiochemical features of the microenvironment. Although poor at internalizing phages, the airway epithelium responds to phage exposure by changing its transcriptional profile and secreting antiviral and proinflammatory cytokines that correlate with specific phage families. Overall, our findings indicate that mammalian responses to phages are heterogenous and could potentially alter the way that respiratory local defenses aid in bacterial clearance during phage therapy. Thus, besides phage receptor specificity in a particular bacterial isolate, the criteria to select lytic phages for therapy should be expanded to include mammalian cell responses.

High-risk Escherichia coli clones that cause neonatal meningitis and association with recrudescent infection.

Neonatal meningitis is a devastating disease associated with high mortality and neurological sequelae. Escherichia coli is the second most common cause of neonatal meningitis in full-term infants (herein NMEC) and the most common cause of meningitis in preterm neonates. Here, we investigated the genomic relatedness of a collection of 58 NMEC isolates spanning 1974-2020 and isolated from seven different geographic regions. We show NMEC are comprised of diverse sequence types (STs), with ST95 (34.5%) and ST1193 (15.5%) the most common. No single virulence gene profile was conserved in all isolates; however, genes encoding fimbrial adhesins, iron acquisition systems, the K1 capsule, and O antigen types O18, O75, and O2 were most prevalent. Antibiotic resistance genes occurred infrequently in our collection. We also monitored the infection dynamics in three patients that suffered recrudescent invasive infection caused by the original infecting isolate despite appropriate antibiotic treatment based on antibiogram profile and resistance genotype. These patients exhibited severe gut dysbiosis. In one patient, the causative NMEC isolate was also detected in the fecal flora at the time of the second infection episode and after treatment. Thus, although antibiotics are the standard of care for NMEC treatment, our data suggest that failure to eliminate the causative NMEC that resides intestinally can lead to the existence of a refractory reservoir that may seed recrudescent infection.

Coverage gaps in empiric antibiotic regimens used to treat serious bacterial infections in neonates and children in Southeast Asia and the Pacific.

Background: High levels of antimicrobial resistance (AMR) are propagating deaths due to neonatal and paediatric infections globally. This is of particular concern in Southeast Asia and the Pacific, where healthcare resources are constrained and access to newer agents to treat multidrug-resistant pathogens is limited. Methods: To assess the coverage provided by commonly prescribed empiric antibiotic regimens for children in low- and middle-income countries in Southeast Asia and the Pacific, we built a weighted incidence syndromic combination antibiogram (WISCA), parameterised using data obtained from a systematic review of published literature incorporating WHO-defined SEARO and WPRO regions in Ovid MEDLINE, EMBASE, Global Health and PubMed. Susceptibility data for bacterial pathogens were extracted to provide coverage estimates for pre-specified antibiotics (aminopenicillins, gentamicin, third-generation cephalosporins and carbapenems), reported at the regional level. Findings: 6648 bacterial isolates from 11 countries across 86 papers were included in the Bayesian WISCA model, which weighted bacterial incidence and antimicrobial susceptibility of relevant isolates. Coverage provided by aminopenicillins in neonatal sepsis/meningitis was 26% (80% credible interval: 16-49) whilst gentamicin coverage was 45% (29-62). Third-generation cephalosporin coverage was only 29% (16-49) in neonatal sepsis/meningitis, 51% (38-64) in paediatric sepsis and 65% (51-77) in paediatric meningitis. Carbapenems were estimated to provide the highest coverage: 81% (65-90) in neonatal sepsis/meningitis, 83% (72-90) in paediatric sepsis and 79% (62-91) in paediatric meningitis. Interpretation: These findings reveal alarmingly high rates of resistance to commonly prescribed empirical therapies for neonatal and paediatric sepsis and meningitis in the Asia-Pacific region. Funding: This research was funded in whole, or in part, by the Wellcome Trust [220211]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. PCMW is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant. NHMRC had no involvement in the design or conduct of the research.

Streptococcus pneumoniae as a colonizing agent of the Nasopharynx - Oropharynx in adults: A systematic review and meta-analysis.

BACKGROUND: Streptococcus pneumoniae (Spn) is a commensal pathogen that usually colonizes the upper respiratory tract of children. Likewise, Spn colonization has been considered a critical factor in the development of pneumococcal invasive disease. However, Spn prevalence in adults remains unclear. This study performs a systematic review and meta-analysis to explore the prevalence of Spn Nasopharynx - Oropharynx Colonization (NOC) in adults. METHODS: A Systematic review of scientific databases was utilized to identify eligible studies that follow strict selection criteria. Subsequently, a meta-analysis was conducted to establish NOC prevalence in adults (≥18 years old). The heterogeneity and sensitivity analyses were assessed using the microorganism identification technique, sample type, and age subgroups. RESULTS: Initial selection includes 69 studies, with 37 selected for the meta-analysis, involving 23,724 individuals. The overall prevalence (95 % CI) of Spn NOC among adults was 6 % (5-9). The subgroup analysis revealed that young adults (YA), 18-64 years old, had a prevalence of 10 %, whereas older adults (OA), ≥65 years old, had a prevalence of 2 %. The identification of Spn NOC may vary depending on the method of diagnosis used. High heterogeneity (I2 > 90 %) was observed but diminished to 70 % when the analysis was restricted to oropharyngeal swabs as an identification method. Furthermore, heterogeneity decreased to 58 % when exclusively employing traditional culture as the identification method. CONCLUSIONS: This study found a low prevalence of Spn NOC in adults. Notably, the prevalence of Spn NOC was higher in younger adults than in older adults. It is essential to highlight a significant heterogeneity among studies, which indicates there is no standardized method of Spn NOC identification.

Updated grading system for systemic allergic reactions: Joint Statement of the World Allergy Organization Anaphylaxis Committee and Allergen Immunotherapy Committee.

There is a lack of consensus over the description and severity assignment of allergic adverse reactions to immunotherapy, although there seems to be a consensus at least in terms of using the World Allergy Organization (WAO) grading systems to describe local adverse events for Sublingual Immunotherapy (SLIT) and Systemic Allergic Reactions (SARs) to Subcutaneous Immunotherapy (SCIT) amongst the major national/regional allergy societies. In this manuscript, we propose a modification of the previous WAO Grading system for SARs, which aligns with the newly-proposed Consortium for Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions in Food Allergy (version 3.0). We hope this can facilitate a unified grading system appropriate to SARs due to allergen immunotherapy, independent of allergen and route of administration, and across clinical and research practice.