Serotype epidemiology and antibiotic resistance of pneumococcal isolates colonizing infants in Botswana (2016-2019).

BACKGROUND: In 2012, Botswana introduced 13-valent pneumococcal conjugate vaccine (PCV-13) to its childhood immunization program in a 3+0 schedule, achieving coverage rates of above 90% by 2014. In other settings, PCV introduction has been followed by an increase in carriage or disease caused by non-vaccine serotypes, including some serotypes with a high prevalence of antibiotic resistance. METHODS: We characterized the serotype epidemiology and antibiotic resistance of pneumococcal isolates cultured from nasopharyngeal samples collected from infants (≤12 months) in southeastern Botswana between 2016 and 2019. Capsular serotyping was performed using the Quellung reaction. E-tests were used to determine minimum inhibitory concentrations for common antibiotics. RESULTS: We cultured 264 pneumococcal isolates from samples collected from 150 infants. At the time of sample collection, 81% of infants had received at least one dose of PCV-13 and 53% had completed the three-dose series. PCV-13 serotypes accounted for 27% of isolates, with the most prevalent vaccine serotypes being 19F (n = 20, 8%), 19A (n = 16, 6%), and 6A (n = 10, 4%). The most frequently identified non-vaccine serotypes were 23B (n = 29, 11%), 21 (n = 12, 5%), and 16F (n = 11, 4%). Only three (1%) pneumococcal isolates were resistant to amoxicillin; however, we observed an increasing prevalence of penicillin resistance using the meningitis breakpoint (2016: 41%, 2019: 71%; Cochran-Armitage test for trend, p = 0.0003) and non-susceptibility to trimethoprim-sulfamethoxazole (2016: 55%, 2019: 79%; p = 0.04). Three (1%) isolates were multi-drug resistant. CONCLUSIONS: PCV-13 serotypes accounted for a substantial proportion of isolates colonizing infants in Botswana during a four-year period starting four years after vaccine introduction. A low prevalence of amoxicillin resistance supports its continued use as the first-line agent for non-meningeal pneumococcal infections. The observed increase in penicillin resistance at the meningitis breakpoint and the low prevalence of resistance to ceftriaxone supports use of third-generation cephalosporins for empirical treatment of suspected bacterial meningitis.

Understanding the influence of the microbiome on childhood infections.

INTRODUCTION: The microbiome is known to have a substantial impact on human health and disease. However, the impacts of the microbiome on immune system development, susceptibility to infectious diseases, and vaccine-elicited immune responses are emerging areas of interest. AREAS COVERED: In this review, we provide an overview of development of the microbiome during childhood. We highlight available data suggesting that the microbiome is critical to maturation of the immune system and modifies susceptibility to a variety of infections during childhood and adolescence, including respiratory tract infections, Clostridioides difficile infection, and sexually transmitted infections. We discuss currently available and investigational therapeutics that have the potential to modify the microbiome to prevent or treat infections among children. Finally, we review the accumulating evidence that the gut microbiome influences vaccine-elicited immune responses among children. EXPERT OPINION: Recent advances in sequencing technologies have led to an explosion of studies associating the human microbiome with the risk and severity of infectious diseases. As our knowledge of the extent to which the microbiome influences childhood infections continues to grow, microbiome-based diagnostics and therapeutics will increasingly be incorporated into clinical practice to improve the prevention, diagnosis, and treatment of infectious diseases among children.

Comprehensive Assessment of the Intrinsic Pancreatic Microbiome.

OBJECTIVE: We sought to comprehensively profile tissue and cyst fluid in patients with benign, precancerous, and cancerous conditions of the pancreas to characterize the intrinsic pancreatic microbiome. SUMMARY BACKGROUND DATA: Small studies in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) have suggested that intra-pancreatic microbial dysbiosis may drive malignant transformation. METHODS: Pancreatic samples were collected at the time of resection from 109 patients. Samples included tumor tissue (control, n=20; IPMN, n=20; PDAC, n=19) and pancreatic cyst fluid (IPMN, n=30; SCA, n=10; MCN, n=10). Assessment of bacterial DNA by quantitative PCR and 16S ribosomal RNA gene sequencing was performed. Downstream analyses determined the relative abundances of individual taxa between groups and compared intergroup diversity. Whole-genome sequencing data from 140 patients with PDAC in the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) were analyzed to validate findings. RESULTS: Sequencing of pancreatic tissue yielded few microbial reads regardless of diagnosis, and analysis of pancreatic tissue showed no difference in the abundance and composition of bacterial taxa between normal pancreas, IPMN, or PDAC groups. Low-grade dysplasia (LGD) and high-grade dysplasia (HGD) IPMN were characterized by low bacterial abundances with no difference in tissue composition and a slight increase in Pseudomonas and Sediminibacterium in HGD cyst fluid. Decontamination analysis using the CPTAC database confirmed a low-biomass, low-diversity intrinsic pancreatic microbiome that did not differ by pathology. CONCLUSIONS: Our analysis of the pancreatic microbiome demonstrated very low intrinsic biomass that is relatively conserved across diverse neoplastic conditions and thus unlikely to drive malignant transformation.

Immunogenicity of Monovalent mRNA-1273 and BNT162b2 Vaccines in Children <5 Years of Age.

BACKGROUND AND OBJECTIVES: The messenger RNA (mRNA)-based coronavirus disease 2019 vaccines approved for use in children <5 years of age have different antigen doses and administration schedules that could affect vaccine immunogenicity and effectiveness. We sought to compare the strength and breadth of serum binding and neutralizing antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicited by monovalent mRNA-based coronavirus disease 2019 vaccines in young children. METHODS: We conducted a prospective cohort study of children 6 months to 4 years of age who completed primary series vaccination with monovalent mRNA-1273 or BNT162b2 vaccines. Serum was collected 1 month after primary vaccine series completion for the measurement of SARS-CoV-2-specific humoral immune responses, including antibody binding responses to Spike proteins from an ancestral strain (D614G) and major variants of SARS-CoV-2 and antibody neutralizing activity against D614G and Omicron subvariants (BA.1, BA.4/5). RESULTS: Of 75 participants, 40 (53%) received mRNA-1273 and 35 (47%) received BNT162b2. Children receiving either primary vaccine series developed robust and broad SARS-CoV-2-specific binding and neutralizing antibodies, including to Omicron subvariants. Children with a previous history of SARS-CoV-2 infection developed significantly higher antibody binding responses and neutralization titers to Omicron subvariants, which is consistent with the occurrence of identified infections during the circulation of Omicron subvariants in the region. CONCLUSIONS: Monovalent mRNA-1273 and BNT162b2 elicited similar antibody responses 1 month after vaccination in young children. In addition, previous infection significantly enhanced the strength of antibody responses to Omicron subvariants. The authors of future studies should evaluate incorporation of these vaccines into the standard childhood immunization schedule.

The effects of antibiotic exposures on the gut resistome during hematopoietic cell transplantation in children.

Antibiotic resistance is a global threat driven primarily by antibiotic use. We evaluated the effects of antibiotic exposures on the gut microbiomes and resistomes of children at high risk of colonization by antibiotic-resistant bacteria. We performed shotgun metagenomic sequencing of 691 serially collected fecal samples from 80 children (<18 years) undergoing hematopoietic cell transplantation. We evaluated the effects of aerobic (cefepime, vancomycin, fluoroquinolones, aminoglycosides, macrolides, and trimethoprim-sulfamethoxazole) and anaerobic (piperacillin-tazobactam, carbapenems, metronidazole, and clindamycin) antibiotic exposures on the diversity and composition of the gut microbiome and resistome. We identified 372 unique antibiotic resistance genes (ARGs); the most frequent ARGs identified encode resistance to tetracyclines (n = 88), beta-lactams (n = 84), and fluoroquinolones (n = 79). Both aerobic and anaerobic antibiotic exposures were associated with a decrease in the number of bacterial species (aerobic, ß = 0.71, 95% CI: 0.64, 0.79; anaerobic, ß = 0.66, 95% CI: 0.53, 0.82) and the number of unique ARGs (aerobic, ß = 0.81, 95% CI: 0.74, 0.90; anaerobic, ß = 0.73, 95% CI: 0.61, 0.88) within the gut metagenome. However, only antibiotic regimens that included anaerobic activity were associated with an increase in acquisition of new ARGs (anaerobic, ß = 1.50; 95% CI: 1.12, 2.01) and an increase in the relative abundance of ARGs in the gut resistome (anaerobic, ß = 1.62; 95% CI: 1.15, 2.27). Specific antibiotic exposures were associated with distinct changes in the number and abundance of ARGs for individual antibiotic classes. Our findings detail the impact of antibiotics on the gut microbiome and resistome and demonstrate that anaerobic antibiotics are particularly likely to promote acquisition and expansion of antibiotic-resistant bacteria.

The Microbiome and Pediatric Transplantation.

The microbial communities that inhabit our bodies have been increasingly linked to host physiology and pathophysiology. This microbiome, through its role in colonization resistance, influences the risk of infections after transplantation, including those caused by multidrug-resistant organisms. In addition, through both direct interactions with the host immune system and via the production of metabolites that impact local and systemic immunity, the microbiome plays an important role in the establishment of immune tolerance after transplantation, and conversely, in the development of graft-versus-host disease and graft rejection. This review offers a comprehensive overview of the evidence for the role of the microbiome in hematopoietic cell and solid organ transplant complications, drivers of microbiome shift during transplantation, and the potential of microbiome-based therapies to improve pediatric transplantation outcomes.

Child Health Needs and the Pediatric Infectious Diseases Workforce: 2020-2040.

Pediatric infectious diseases (PID) physicians prevent and treat childhood infections through clinical care, research, public health, education, antimicrobial stewardship, and infection prevention. This article is part of an American Board of Pediatrics Foundation-sponsored supplement investigating the future of the pediatric subspecialty workforce. The article offers context to findings from a modeling analysis estimating the supply of PID subspecialists in the United States between 2020 and 2040. It provides an overview of children cared for by PID subspecialists, reviews the current state of the PID workforce, and discusses the projected headcount and clinical workforce equivalents of PID subspecialists at the national, census region, and census division levels over this 2-decade period. The article concludes by discussing the education and training, clinical practice, policy, and research implications of the data presented. Adjusting for population growth, the PID workforce is projected to grow more slowly than most other pediatric subspecialties and geographic disparities in access to PID care are expected to worsen. In models considering alternative scenarios, decreases in the number of fellows and time spent in clinical care significantly affect the PID workforce. Notably, model assumptions may not adequately account for potential threats to the PID workforce, including a declining number of fellows entering training and the unknown impact of the COVID-19 pandemic and future emerging infections on workforce attrition. Changes to education and training, clinical care, and policy are needed to ensure the PID workforce can meet the future needs of US children.