Exploratory Pilot Studies to Demonstrate Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics.

Context: Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. One of the most common indications for probiotic treatment is the prevention of antibiotic-associated diarrhea (AAD). Unfortunately, many probiotic products used for AAD are not supported by rigorous independent research, and often results in non-evidence-based usage. Additionally, it is not clear when is the most appropriate time to take a probiotic when on an antibiotic course. Objectives: The primary aim is to determine the ability of BB-12 to impact antibiotic-induced reduction in short chain fatty acid concentration (SCFA), as reflected by the levels of acetate on day 14. Secondarily to determine the ability of BB-12 to impact antibiotic-induced disruption of the gut microbiota with 16S rDNA profiling, with the addition of the time variable of probiotic consumption. Study Design and Interventions: A five group randomized controlled trial, finished in December 2022, we are currently analyzing all the data, but will be finished much prior to NAPCRG. All participants were given a 7-day prescription for amoxicillin-clavulanic acid 875mg taken twice daily. One group received no other interventions. While the other participants were broken into 4 groups. Two groups consumed the yogurt intervention (either yogurt+probiotic or control yogurt) four hours after the antibiotic and two groups consumed the yogurt intervention (either yogurt+probiotic or control yogurt) concomitantly with antibiotics. This timing question is important, as it is unknown if the optimal time for patients to administer probiotics is concurrently with, or after four hours following antibiotic consumption. Setting: Capital Areal Primary Care Practice Based Research Network. Population Studied: 118 participants, ages 18-65 years, generally healthy. Outcome Measures: Change in SCFA among the five groups, microbiome reduced disruption and clinically diagnosed diarrhea. Results: Study is complete and analysis is underway. Should have full results by end of July 2023, much before NAPCRG. .

Efficacy and Safety of BB-12 Supplemented Strawberry Yogurt For Healthy Children on Antibiotics (PLAY ON).

Context: Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. One of the most common indications for probiotic treatment is the prevention of antibiotic-associated diarrhea (AAD). Unfortunately, many probiotic products used for AAD are not supported by rigorous independent research, and often results in non-evidence-based usage. The overarching objective is to move research forward for the most well-studied Bifidobacterium strain. Objectives: The primary aim is to test the efficacy of high dose, BB-12-supplemented yogurt in preventing AAD, compared to yogurt without BB-12, in children receiving antibiotics. Other aims are to further assess the safety of yogurt supplemented with BB-12, and to carry out longitudinal community structure and gene expression analysis of fecal microbiota to evaluate the impact of high dose BB-12 in a pediatric population receiving antibiotics. The microbiota includes hundreds of species, and its disruption is hypothesized to be an important factor in the development of AAD. AIM 1: To test the efficacy of high dose, BB-12-supplemented yogurt in preventing AAD, compared to yogurt without BB-12, in children receiving antibiotics. Hypothesis: Children receiving antibiotics who receive the yogurt with BB-12 will demonstrate less diarrhea than those receiving a control yogurt without BB-12. This is a Phase II trial that requires additional safety evaluation of high dose BB-12. Hypotheses 3: Administration of antibiotics will alter the composition and gene expression profile of the gut microbiota in pediatric patients, and concomitant ingestion of BB-12 in yogurt will mitigate the antibiotic-induced disturbance in the gut microbiota, as identified using 16S rRNA and metatranscriptomic profiling. Study Design and Analysis: We will finish in the June 2023 a Phase II, randomized, doubleblinded controlled trial with allocation concealment. Setting: Capital Areal Primary Care Practice Based Research Network. Population Studied: 270 patients, ages 3-12 years, clinically diagnosed with a respiratory infection requiring 7-10 days of antibiotics. Interventions: The two arms are, BB-12-supplemented yogurt and non-supplemented control yogurt, in a 1:1 randomized allocation. Participants of all ages will be asked to consume the same dose, 100 ml, of product per day. The 100 ml serving of probiotic yogurt will deliver ≥1010 CFU of BB-12. The BB-12 probiotic was not be added.

Triage Discordance in an Academic Pediatric Emergency Department and Disparities by Race, Ethnicity, and Language for Care.

BACKGROUND: Minoritized patients are disproportionately represented in low-acuity emergency department (ED) visits in the United States in part caused by lack of timely access to primary and urgent care. However, there is also the possibility that implicit bias during triage could contribute to disproportionate representation of minority groups in low-acuity ED visits. Triage discordance, defined as when ED resources used are different from initial triage score predictions, can be used as a proxy for triage accuracy. Recent data suggest that discordant triage may be common, although little is known about the interaction with race, ethnicity, and language for care. OBJECTIVES: This study aims to determine the prevalence of discordant triage among moderate- and low-acuity pediatric ED encounters and the interaction with patient race, ethnicity, and language for care. METHODS: We performed a retrospective analysis of pediatric ED encounters from 2019 with Emergency Severity Index (ESI) scores of 3, 4, or 5 at an academic referral hospital. The primary outcome was triage discordance, encompassing overtriage (ESI 3 and 4) and undertriage (ESI 4 and 5). Logistic and multinomial regressions were used to assess discordant triage by race, ethnicity, and language group. RESULTS: Triage discordance occurred in 47% (n = 18,040) of encounters. Black and Hispanic patients had higher likelihood of undertriage for ESI 5 (adjusted odds ratio 1.21, 95% confidence interval [CI] 1.01-1.46 and 1.27, 95% CI 1.07-1.52, respectively), and Black patients were more likely to be overtriaged in ESI 3 (1.18, 95% CI 1.09-1.27). Those with a language other than English for care had higher proportions of overtriage for ESI 3 (1.08, 95% CI 1.04-1.12) and undertriage for ESI 5 (1.23, 95% CI 1.11-1.37). CONCLUSIONS: We found high rates of triage discordance in our pediatric ED, with significant associations with race, ethnicity, and language for care. Future research should evaluate the source of triage discordance and develop quality improvement efforts to improve equitable care.

Trisomy 21 and Coronavirus Disease 2019 in Pediatric Patients.

We present 4 pediatric patients with trisomy 21 (T21) and associated comorbidities who developed coronavirus disease 2019 requiring hospitalization. A review of the literature revealed that comorbidities associated with T21 may predispose patients to severe disease. Children with T21 should be considered high risk and monitored carefully if infected with severe acute respiratory syndrome coronavirus 2.

Inclusion, Diversity, Access, and Equity (IDA&E) Roadmap: Infectious Diseases Society of America's Commitment to the Future.

This article identifies the major elements of the strategic road map for the Infectious Diseases Society of America's (IDSA) Inclusion, Diversity, Access, and Equity (IDA&E) initiative and discusses the long-term goals and the proposed steps needed to achieve these goals.

Location Matters: Geographic Disparities and Impact of Coronavirus Disease 2019.

The coronavirus disease 2019 (COVID-19) pandemic in the United States has revealed major disparities in the access to testing and messaging about the pandemic based on the geographic location of individuals, particularly in communities of color, rural areas, and areas of low income. This geographic disparity, in addition to deeply rooted structural inequities, have posed additional challenges to adequately diagnose and provide care for individuals of all ages living in these settings. We describe the impact that COVID-19 has had on geographically disparate populations in the United States and share our recommendations on what might be done to ameliorate the current situation.

Racial Disparity of Coronavirus Disease 2019 in African American Communities.

The coronavirus disease 2019 (COVID-19) pandemic has unveiled unsettling disparities in the outcome of the disease among African Americans. These disparities are not new but are rooted in structural inequities that must be addressed to adequately care for communities of color. We describe the historical context of these structural inequities, their impact on the progression of COVID-19 in the African American (black) community, and suggest a multifaceted approach to addressing these healthcare disparities. (Of note, terminology from survey data cited for this article varied from blacks, African Americans, or both; for consistency, we use African Americans throughout.).

Novel α-Globin Splice Site Mutation (HBA2: c.96-5C>A) in Combination with Three-Gene Deletion Hb H Disease.

The choice of acceptor splice site during exon-exon splicing by the spliceosome is determined by a variety of factors. We report here a family with a novel acceptor splice site variant within intron 1 of the α-globin gene that provides some in vivo insight into the rules governing RNA splicing in homo sapiens. A 2-year-old female with Hb H disease, was found to have not only three α-globin genes deleted (- -FIL/-α3.7) but also a HBA2: c.96-5C>A variant on her remaining α-globin gene. The HBA2: c.96-5C>A variant was in cis with -α3.7 and mRNA studies indicate that this variant creates a new acceptor splice site which is used in approximately 35.0% of α-globin mRNA transcripts. The reduced levels of normal mRNA transcript predicts a more severe Hb H disease than expected for the three-gene deletion Hb H disease with a phenotype similar to nondeletional Hb H disease. We propose that this variant be called Hb Beach Haven (HBA2: c.96-5C>A).

Pneumococcal Pneumonia Requiring Hospitalization in US Children in the 13-Valent Pneumococcal Conjugate Vaccine Era.

BACKGROUND.: The impact of PCV13 on a number of clinical aspects of pneumococcal pneumonia (PP) in children has not been reported. We compared the serotype distribution, antibiotic susceptibility, and outcomes of children with PP 4 years before and 4 years after the introduction of PCV13. METHODS.: We identified patients ≤18 years with PP at 8 children's hospitals in the United States (2006-2014). Pneumococcal isolates were collected prospectively. Serotyping and antibiotic susceptibility were performed in a central laboratory. Clinical and laboratory data were collected retrospectively. Annual pneumococcal pneumonia hospitalization rates per 100 000 admissions with 95% confidence intervals were calculated. Dichotomous variables were analyzed by χ2 test and continuous variables with Mann-Whitney U test. RESULTS.: A total of 377 patients with PP requiring hospitalization were identified. Hospitalization rates of PP decreased from 53.6 to 23.3 per 100000 admissions post PCV13 (P < .0001). Complicated PP rates also decreased (P < .0001). Need for intensive care, mechanical ventilation, and invasive procedure remained unchanged after the introduction of PCV13. Comorbidities were more common among children with uncomplicated than complicated pneumonia (52.2% vs. 22.5%, P < .001). Overall, PCV13 serotypes 19A, 3, 7F, and 1 caused 80% of PP. Hospitalization rates of PCV13 serotype pneumonia decreased from 47.2 to 15.7 per 100000 admissions post PCV13. In 2014, the most common serotypes were 3, 19A and 35B. CONCLUSIONS.: PP requiring hospitalization significantly decreased in children after PCV13 introduction. Complicated PP rates decreased steadily in 2011-2014. PCV13 serotypes 19A and 3 were still responsible for half of the cases of PP in 2011-2014.

Emergence of Multidrug-Resistant Pneumococcal Serotype 35B among Children in the United States.

Streptococcus pneumoniae serotype 35B is a nonvaccine serotype associated with high rates of penicillin nonsusceptibility. An increase in the proportion of multidrug-resistant (MDR) 35B isolates has recently been reported. The genetic events contributing to the emergence of MDR serotype 35B are unknown. The sequence type (ST) composition of 78 serotype 35B isolates obtained from pediatric patients with invasive pneumococcal disease from 1994 to 2014 and 48 isolates from pediatric patients with otitis media (noninvasive) from 2011 to 2014 was characterized by multilocus sequence typing (MLST). The most common STs were ST558 (69.2%), ST156 (10.3%), and ST452 (3.8%). Two major clonal complexes (CC), CC558 and CC156, were identified by eBURST analysis. Overall, 91% (71/78) of isolates were penicillin nonsusceptible and 16.7% (13/78) were MDR. Among all invasive serotype 35B isolates, MDR isolates increased significantly, from 2.9% (1/35) to 27.9% (12/43) (P = 0.004), after the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced. All CC156 isolates were identified after the introduction of PCV13 (0/35 [0%] before versus 9/43 [20.9%] after; P = 0.003) and were MDR. All CC156 isolates had similar antimicrobial susceptibility patterns; in contrast, high variability in antimicrobial susceptibility was observed among CC558 isolates. The distributions of CC558 and CC156 among invasive and noninvasive isolates were not different. The increased prevalence of MDR serotype 35B after the introduction of PCV13 was directly associated with the emergence of ST156. Genotyping suggests that capsular switching has occurred between MDR vaccine serotypes belonging to ST156 (e.g., 9V, 14, and 19A) and serotype 35B.

Invasive pneumococcal infections in children following transplantation in the pneumococcal conjugate vaccine era.

BACKGROUND: Pediatric recipients of hematopoietic stem cell and solid organ transplants are at increased risk of invasive pneumococcal infections (IPI). Data on IPI in this population are scarce. To our knowledge, this is the first study describing the epidemiology of IPI among pediatric transplant recipients in the pneumococcal conjugate vaccine (PCV) era. METHODS: We identified transplant recipients with IPI at 8 children's hospitals in the U.S. from our surveillance database (2000-2014). Pneumococcal isolates were collected prospectively. Serotyping and antibiotic susceptibility were performed in a central laboratory. Categorical variables were analyzed by Fisher's exact test and continuous variables with nonparametric tests. Indirect cohort study design was used to calculate vaccine effectiveness. RESULTS: We identified 65 episodes of IPI in transplant recipients. Recurrent IPI was observed in 10% of transplant recipients. The IPI crude incidence rate in solid organ transplant recipients was higher than in the general population. Most IPI episodes occurred >6 months after transplantation. Bacteremia and pneumonia were the most common presentations. Meningitis was unusual. No case fatalities were observed. Serotype 19A was the most common serotype (n=10), followed by 6C (n=7). In 2010-2014, 37% of IPI was caused by PCV13 serotypes. Four cases of vaccine breakthrough were identified. Most isolates were susceptible to penicillin and ceftriaxone. Pneumococcal conjugate and polysaccharide immunization rates were low. CONCLUSION: Pediatric transplant recipients remain at increased risk of IPI in the vaccine era. Most cases presented as a late post-transplant infection. The interval between transplantation and IPI may allow adequate time for pneumococcal immunization.

Safety of Bifidobacterium animalis Subsp. Lactis (B. lactis) Strain BB-12-Supplemented Yogurt in Healthy Children.

OBJECTIVES: Probiotics are live microorganisms that may provide health benefits to the individual when consumed in sufficient quantities. For studies conducted on health or disease endpoints on probiotics in the United States, the Food and Administration has required those studies to be conducted as investigational new drugs. This phase I, double-blinded, randomized, controlled safety study represents the first requirement of this pathway. The purpose of the study was to determine the safety of Bifidobacterium animalis subsp. lactis (B lactis) strain BB-12 (BB-12)-supplemented yogurt when consumed by a generally healthy group of children. The secondary aim was to assess the effect of BB-12-supplemented yogurt on the gut microbiota of the children. METHODS: Sixty children ages 1 to 5 years were randomly assigned to consume 4 ounces of either BB-12-supplemented yogurt or nonsupplemented control yogurt daily for 10 days. The primary outcome was to assess safety and tolerability, as determined by the number of reported adverse events. RESULTS: A total of 186 nonserious adverse events were reported, with no significant differences between the control and BB-12 groups. No significant changes due to probiotic treatment were observed in the gut microbiota of the study cohort. CONCLUSIONS: BB-12-supplemented yogurt is safe and well-tolerated when consumed by healthy children. The present study will form the basis for future randomized clinical trials investigating the potential effects of BB-12-supplemented yogurt in different disease states.

Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Meningitis in US Children.

BACKGROUND: The impact of 13-valent pneumococcal conjugate vaccine (PCV13) on pneumococcal meningitis (PM) in US children is unknown. We compared the serotype distribution, antibiotic susceptibility, hospital course, and outcomes of children with PM 3 years before and 3 years after the introduction of PCV13. METHODS: We identified patients ≤ 18 years of age with PM at 8 children's hospitals in the United States. Pneumococcal isolates were collected prospectively. Serotyping and antibiotic susceptibility were performed in a central laboratory. Clinical data were abstracted from medical records. Patients were divided into 3 subgroups: pre-PCV13 (2007-2009), transitional year (2010), and post-PCV13 (2011-2013). Categorical variables were analyzed by the χ(2) test and continuous variables by the Mann--Whitney U test. RESULTS: During the study period, 173 of 1207 episodes (14%) of invasive pneumococcal disease were identified as PM; 76 of 645 (12%) were during 2007-2009 and 69 of 394 (18%) during 2011-2013 (50% increase; P = .03). The proportion of PCV13 serotype cases decreased from 54% in 2007-2009 to 27% in 2011-2013 (P = .001). Non-PCV13 serotype cases represented 73% of the isolates in 2011-2013. Isolates with ceftriaxone minimum inhibitory concentration ≥ 1 µg/mL decreased (13% to 3%) from 2007-2009 to 2011-2013 (P = .03). No significant differences were identified for hospital course or outcome, with the exception that a greater proportion of patients had subdural empyema and hemiparesis in 2011-2013. CONCLUSIONS: After the introduction of PCV13, the number of cases of PM in children remained unchanged compared with 2007-2009, although the proportion of PCV13 serotypes decreased significantly. Serotype 19A continued to be the most common serotype in 2011-2013. Antibiotic resistance decreased significantly. Morbidity and case-fatality rate due to PM remain substantial.

Multicenter surveillance of Streptococcus pneumoniae isolates from middle ear and mastoid cultures in the 13-valent pneumococcal conjugate vaccine era.

BACKGROUND: Streptococcus pneumoniae is a common cause of otitis media (OM) in children; mastoiditis remains an important complication of OM. Limited data are available on the impact of the 13-valent pneumococcal conjugate vaccine (PCV13) on pneumococcal otitis. METHODS: Investigators from 8 children's hospitals in the United States prospectively collected pneumococcal isolates from middle ear or mastoid cultures from children from 2011 to 2013. Serotype and antibiotic susceptibilities were determined and PCV13 doses for children documented. RESULTS: Over the 3-year period, the proportion of isolates included in PCV13 (plus a related serotype) decreased significantly (P = .0006) among the middle ear/mastoid isolates (2011, 50% [74/149]; 2012, 40.5% [47/116]; 2013, 29% [34/118]). The number of serotype 19A isolates in 2013 (n = 12, 10.2% of total) decreased 76% compared with the number of 19A isolates in 2011 (n = 50, 33.6% of total). Of the children from whom serotype 19A was isolated (n = 93), 55% had previously received <3 doses of PCV13. The most common non-PCV13 serotypes for the combined years were 35B (n = 37), 21 (n = 20), 23B (n = 20), 15B (n = 18), 11 (n = 17), 23A (n = 14), 15A (n = 14), and 15C (n = 14). The proportion of isolates with a penicillin minimal inhibitory concentration >2 µg/mL decreased significantly over the 3 years (2011, 22% [35/154]; 2012, 20% [24/118]; 2013, 10% [12/120]; P < .02). CONCLUSIONS: The number of pneumococcal isolates and the percentage of isolates with high-level penicillin resistance from cultures taken from children with OM or mastoiditis for clinical indications have decreased following PCV13 use, largely related to decreases in serotype 19A isolates.

Short-term, daily intake of yogurt containing Bifidobacterium animalis ssp. lactis Bf-6 (LMG 24384) does not affect colonic transit time in women.

The present study investigated the effect of Bifidobacterium animalis ssp. lactis Bf-6 (LMG 24 384) (Bf-6)-supplemented yogurt on colonic transit time (CTT). A triple-blinded, randomised, placebo-controlled, two-period cross-over trial was conducted with sixty-eight women with a self-reported history of straining during bowel movements or hard or lumpy stools in the past 2 years. As per regulatory requirements for probiotic studies, eligible women were generally healthy and not actively constipated at the time of enrolment. Participants consumed both Bf-6 and placebo yogurts for 14 d each in a randomised order, with a 6-week washout period between the treatments. The primary outcome, CTT, was assessed via Sitz marker X-rays. The average CTT was 42·1 h for the active period and 43·3 h for the control period (mean difference 1·2 h, 95 % CI - 4·9, 7·4). Since the statistical tests for the cross-over study implied that the mean CTT for the active and control periods in period 2 were biased, the standard protocol suggests examining the results of only period 1 as a traditional randomised controlled trial. This showed that the mean CTT was 35·2 h for the active period v. 52·9 h for the control period (P= 0·015). Bootstrapping demonstrated that both the mean and median differences remained significant (P= 0·016 and P= 0·045, respectively). Few adverse events were noted, with no differences among the active and control periods. The paired analysis showed no differences between the active and control periods during the cross-over trial. Further trials should be conducted in populations with underlying problems associated with disordered transit to determine the potential value of probiotic supplementation more accurately.

Pediatric invasive pneumococcal disease in the United States in the era of pneumococcal conjugate vaccines.

Invasive infections caused by Streptococcus pneumoniae continue to be a major cause of morbidity and mortality worldwide, especially in children under 5 years of age. In the United States, 90% of invasive pneumococcal infections in children are caused by 13 serotypes of S. pneumoniae. The licensure (in 2000) and subsequent widespread use of a heptavalent pneumococcal conjugate vaccine (PCV7) have had a significant impact on decreasing the incidence of serious invasive pneumococcal disease (IPD) in all age groups, especially in children under 2 years of age. However, the emergence of replacement non-PCV7 serotypes, especially serotype 19A, has resulted in an increase in the incidence of serious and invasive infections. In 2010, a 13-valent PCV was licensed in the United States. However, the impact that this vaccine will have on IPD remains to be seen. The objectives of this review are to discuss the epidemiology of serious and invasive pneumococcal infections in the United States in the PCV era and to review some of the pneumococcal vaccines that are in development.

The current state of pertussis vaccination in pregnancy around the world, with recommendations for improved care: Consensus statements from the Global Pertussis Initiative.

Bordetella pertussis, which causes a respiratory disease known as pertussis ("whooping cough") remains an important global challenge, with the incidence in pertussis cases increasing in recent years. Newborns and infants are at increased risk for severe morbidity and mortality from this bacterium. Vaccination in pregnancy has become an important strategy to both passively transfer immunity as well as prevent infection in pregnant persons, who are a major source of newborn infection, thus attempting to decrease the impact of this serious disease. It is considered safe for the pregnant person, the developing fetus, and the infant, and during the first 3 months of life it has been shown to be highly effective in preventing pertussis. There are a variety of strategies, recommendations, and adherence rates associated with pertussis vaccination in pregnancy around the world. We summarize the 2021 Global Pertussis Initiative Annual Meeting that reviewed the current global status of pertussis vaccination in pregnancy and remaining medical and scientific questions, with a focus on vaccination challenges and strategies for obstetric and gynecologic healthcare providers.

Public health management of pertussis in adults: Practical challenges and future strategies.

A panel of 24 international experts met in July 2022 to discuss challenges associated with pertussis detection, monitoring, and vaccination in adults; conclusions from this meeting are presented. There has been a shift in the epidemiology of pertussis toward older children and adults. This shift has been attributed to the waning of infection- or vaccine-induced immunity, newer detection techniques causing detection bias, and possibly the replacement of whole-cell pertussis with acellular vaccines in high-income countries, which may lead to immunity waning more quickly. The burden of adult pertussis is still likely under-ascertained due to widespread under-recognition by healthcare professionals (HCPs), under-diagnosis, and under-reporting in this age group. Non-standardized testing guidance and varied case definitions have contributed to under-reporting. Key barriers to HCP engagement with the tetanus, diphtheria, and pertussis (Tdap) vaccine include low awareness, lack of time/funding, and lack of motivation due to low prioritization of Tdap.

Understanding the impact of adult pertussis and current approaches to vaccination: A narrative review and expert panel recommendations.

Pertussis has several notable consequences, causing economic burden, increased strain on healthcare facilities, and reductions in quality of life. Recent years have seen a trend toward an increase in pertussis cases affecting older children and adults. To boost immunity, and protect vulnerable populations, an enduring approach to vaccination has been proposed, but gaps remain in the evidence surrounding adult vaccination that are needed to inform such a policy. Gaps include: the true incidence of pertussis and its complications in adults; regional variations in disease recognition and reporting; and incidence of severe disease, hospitalizations, and deaths in older adults. Better data on the efficacy/effectiveness of pertussis vaccination in adults, duration of protection, and factors leading to poor vaccine uptake are needed. Addressing the critical evidence gaps will help highlight important areas of unmet need and justify the importance of adult pertussis vaccination to healthcare professionals, policymakers, and payers.