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Background: Shigella is a leading cause of diarrhea and dysentery in children in low-resource settings, which is frequently treated with antibiotics. The primary goal of a Shigella vaccine would be to reduce mortality and morbidity associated with Shigella diarrhea. However, ancillary benefits could include reducing antibiotic use and antibiotic exposures for bystander pathogens carried at the time of treatment, specifically for fluoroquinolones and macrolides (F/M), which are the recommended drug classes to treat dysentery. The aim of the study was to quantify the reduction in Shigella attributable diarrhea, all diarrhea, and antibiotic use in the first 2 years of life that could be prevented by a Shigella vaccine., Methods and Findings: We used data from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study, a birth cohort study that followed 1,715 children with twice weekly surveillance for enteric infections, illnesses, and antibiotic use for the first 2 years of life from November 2009 to February 2014 at 8 sites. We estimated the impact of 2 one-dose (6 or 9 months) and 3 two-dose (6 and 9 months, 9 and 12 months, and 12 and 15 months) Shigella vaccines on diarrheal episodes, overall antibiotic use, and F/M use. Further, we considered additional protection through indirect and boosting effects. We used Monte Carlo simulations to estimate the absolute and relative reductions in the incidence of diarrhea and antibiotic use comparing each vaccination scenario to no vaccination. We analyzed 9,392 diarrhea episodes and 15,697 antibiotic courses among 1,715 children in the MAL-ED birth cohort study. There were 273.8 diarrhea episodes, 30.6 shigellosis episodes, and 457.6 antibiotic courses per 100 child-years. A Shigella vaccine with a mean vaccine efficacy of 60% against severe disease given at 9 and 12 months prevented 10.6 (95% CI [9.5, 11.5]) Shigella diarrhea episodes of any severity per 100 child-years (relative 34.5% reduction), 3.0 (95% CI [2.5, 3.5]) F/M courses for Shigella treatment per 100 child-years (relative 35.8% reduction), and 5.6 (95% CI [5.0, 6.3]) antibiotic courses of any drug class for Shigella treatment per 100 child-years (relative 34.5% reduction). This translated to a relative 3.8% reduction in all diarrhea, a relative 2.8% reduction in all F/M courses, a relative 3.1% reduction in F/M exposures to bystander pathogens, and a relative 0.9% reduction in all antibiotic courses. These results reflect Shigella incidence and antibiotic use patterns at the 8 MAL-ED sites and may not be generalizable to all low-resource settings., Conclusions: Our simulation results suggest that a Shigella vaccine meeting WHO targets for efficacy could prevent about a third of Shigella diarrhea episodes, antibiotic use to treat shigellosis, and bystander exposures due to shigellosis treatment. However, the reductions in overall diarrhea episodes and antibiotic use are expected to be modest (<5%)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Brennhofer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Clostridium difficile is the leading cause of infectious diarrhea that develops in patients after hospitalization during antibiotic administration. It has also become a big issue in community-acquired diarrhea. The emergence of hypervirulent strains of C. difficile poses a major problem in hospital-associated diarrhea outbreaks and it is difficult to treat. The antimicrobial resistance in C. difficile has worsened due to the inappropriate use of broad-spectrum antibiotics including cephalosporins, clindamycin, tetracycline, and fluoroquinolones together with the emergence of hypervirulent strains., Objective: To estimate the pooled prevalence and antimicrobial resistance pattern of C. difficile derived from hospitalized diarrheal patients, a systematic review and meta-analysis was performed., Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed to review published studies conducted. We searched bibliographic databases from PubMed, Scopus, Google Scholar, and Cochrane Library for studies on the prevalence and antimicrobial susceptibility testing on C. difficile. The weighted pooled prevalence and resistance for each antimicrobial agent was calculated using a random-effects model. A funnel plot and Egger's regression test were used to see publication bias., Results: A total of 15 studies were included. Ten articles for prevalence study and 5 additional studies for antimicrobial susceptibility testing of C. difficile were included. A total of 1967/7852 (25%) C. difficile were isolated from 10 included studies for prevalence study. The overall weighted pooled proportion (WPP) of C. difficile was 30% (95% CI: 10.0-49.0; p<0.001). The analysis showed substantial heterogeneity among studies (Cochran's test = 7038.73, I2 = 99.87%; p<0.001). The weighed pooled antimicrobial resistance (WPR) were: vancomycin 3%(95% CI: 1.0-4.0, p<0.001); metronidazole 5%(95% CI: 3.0-7.0, p<0.001); clindamycin 61%(95% CI: 52.0-69.0, p<0.001); moxifloxacin 42%(95% CI: 29-54, p<0.001); tetracycline 35%(95% CI: 22-49, p<0.001); erythromycin 61%(95% CI: 48-75, p<0.001) and ciprofloxacin 64%(95% CI: 48-80; p< 0.001) using the random effect model., Conclusions: A higher weighted pooled prevalence of C. difficile was observed. It needs a great deal of attention to decrease the prevailing prevalence. The resistance of C. difficile to metronidazole and vancomycin was low compared to other drugs used to treat C. difficile infection. Periodic antimicrobial resistance monitoring is vital for appropriate therapy of C. difficile infection., Competing Interests: The authors have declared that no competing interests exist.

Background: Diarrheal disease (DD)-associated mortality has declined since 1990; however, the incidence of DD has experienced a less-pronounced decrease. Thus, it is important to track progress in managing DD by following loss of healthy years. A disability-adjusted life-year (DALY), which combines data on years-of-life lost (YLL) and years-lived with-disability (YLD), is a metric that can track such a burden., Methods and Findings: Using all 28 years of data in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, we compared DD DALYs among different demographic subsets including sex, age, country, and World Bank (WB) income level. We also evaluated DD DALYs as a function of the socio-demographic index (SDI), a measure of a region's socio-demographic development. On a global level, DD DALYs have decreased by approximately 85.43% from 1990 to 2017. Incidence and prevalence have decreased by 1.53% and 4.45%, respectively. A dramatic decrease in DD DALYs were observed for WB low-income countries, but not for WB high-income constituents. The temporal decrease in DD DALY rates in WB low-income countries was likely driven by a decrease in YLL. Alternatively, temporal increases in both YLL and YLD may have contributed to the apparent lack of progress in WB high-income countries. Regardless of WB income classification, children under the age of five and the elderly were the most vulnerable to DD. In nearly every year from 1990 to 2017, DD DALYs for females were higher than those for males in WB high-income regions, but lower than those for males in WB low-income constituents. The reason for these differences is not known. We also observed that the rate of DD DALYs was highly correlated to SDI regardless of WB income classification., Conclusions: To the best of our knowledge, this is the only temporal study of DD DALYs that encompasses all 28 years of data available from the GBD. Overall, our analyses show that temporal reductions in DD DALYs are not equivalent across regions, sexes and age groups. Therefore, careful attention to local and demography-specific risk factors will be necessary to tailor solutions in region- and demography-specific manners., Competing Interests: The authors have declared that no competing interests exist.

Travelers' diarrhea (TD) is the most prevalent illness encountered by deployed military personnel and has a major impact on military operations, from reduced job performance to lost duty days. Frequently, the etiology of TD is unknown and, with underreporting of cases, it is difficult to accurately assess its impact. An increasing number of ailments include an altered or aberrant gut microbiome. To better understand the relationships between long-term deployments and TD, we studied military personnel during two nine-month deployment cycles in 2015-2016 to Honduras. To collect data on the prevalence of diarrhea and impact on duty, a total of 1173 personnel completed questionnaires at the end of their deployment. 56.7% reported reduced performance and 21.1% reported lost duty days. We conducted a passive surveillance study of all cases of diarrhea reporting to the medical unit with 152 total cases and a similar pattern of etiology. Enteroaggregative E. coli (EAEC, 52/152), enterotoxigenic E. coli (ETEC, 50/152), and enteropathogenic E. coli (EPEC, 35/152) were the most prevalent pathogens detected. An active longitudinal surveillance of 67 subjects also identified diarrheagenic E. coli as the primary etiology (7/16 EPEC, 7/16 EAEC, and 6/16 ETEC). Eleven subjects were recruited into a nested longitudinal substudy to examine gut microbiome changes associated with deployment. A 16S rRNA amplicon survey of fecal samples showed differentially abundant baseline taxa for subjects who contracted TD versus those who did not, as well as detection of taxa positively associated with self-reported gastrointestinal distress. Disrupted microbiota was also qualitatively observable for weeks preceding and following the incidents of TD. These findings illustrate the complex etiology of diarrhea amongst military personnel in deployed settings and its impacts on job performance. Potential factors of resistance or susceptibility can provide a foundation for future clinical trials to evaluate prevention and treatment strategies., Competing Interests: One of the coauthors, Jamie Fraser, is affiliated with the non-profit Henry M. Jackson Foundation. The Henry M. Jackson Foundation only provided Fraser with a salary, and did not have any role in our study design, execution, or manuscript preparation.

Diarrhea is a leading cause of antibiotic consumption among children in low- and middle-income countries. While vaccines may prevent diarrhea infections for which children often receive antibiotics, the contribution of individual enteropathogens to antibiotic use is minimally understood. We used data from the Global Enteric Multicenter Study (GEMS) to estimate pathogen-specific incidence of antibiotic-treated diarrhea among children under five years old residing in six countries of sub-Saharan Africa and South Asia before rotavirus vaccine implementation. GEMS was an age-stratified, individually-matched case-control study. Stool specimens were obtained from children presenting to sentinel health clinics with newly-onset, acute diarrhea (including moderate-to-severe and less-severe diarrhea) as well as matched community controls without diarrhea. We used data from conventional and quantitative molecular diagnostic assays applied to stool specimens to estimate the proportion of antibiotic-treated diarrhea cases attributable to each pathogen. Antibiotics were administered or prescribed to 9,606 of 12,109 moderate-to-severe cases and 1,844 of 3,174 less-severe cases. Across all sites, incidence rates of clinically-attended, antibiotic-treated diarrhea were 12.2 (95% confidence interval: 9.0-17.8), 10.2 (7.4-13.9) and 1.9 (1.3-3.0) episodes per 100 child-years at risk at ages 6 weeks to 11 months, 12-23 months, and 24-59 months, respectively. Based on the recommendation for antibiotic treatment to be reserved for cases with dysentery, we estimated a ratio of 12.6 (8.6-20.8) inappropriately-treated diarrhea cases for each appropriately-treated case. Rotavirus, adenovirus serotypes 40/41, Shigella, sapovirus, Shiga toxin-producing Escherichia coli, and Cryptosporidium were the leading antibiotic-treated diarrhea etiologies. Rotavirus caused 29.2% (24.5-35.2%) of antibiotic-treated cases, including the largest share in both the first and second years of life. Shigella caused 14.9% (11.4-18.9%) of antibiotic-treated cases, and was the leading etiology at ages 24-59 months. Our findings should inform the prioritization of vaccines with the greatest potential to reduce antibiotic exposure among children., Competing Interests: JAL has received grants and consulting fees from Pfizer Inc. and Merck, Sharp, & Dohme unrelated to the submitted work. KLK has received grants from Merck, Sharp & Dohme unrelated to the submitted work. All other authors declare no competing interests exist.

Background: Campylobacter is one of the main causes of gastroenteritis worldwide. Most of the current knowledge about the epidemiology of this food-borne infection concerns two species, C. coli and C. jejuni. Recent studies conducted in developing countries and using novel diagnostic techniques have generated evidence of the increasing burden and importance of other Campylobacter species, i.e. non-C. coli/jejuni. We performed a nested case-control study to compare the prevalence of C. coli/jejuni and other Campylobacter in children with clinical dysentery and severe diarrhea as well as without diarrhea to better understand the clinical importance of infections with Campylobacter species other than C. coli/jejuni., Methodology/principal Findings: Our nested case-control study of 439 stool samples included dysenteric stools, stools collected during severe diarrhea episodes, and asymptomatic stools which were systematically selected to be representative of clinical phenotypes from 9,160 stools collected during a birth cohort study of 201 children followed until two years of age. Other Campylobacter accounted for 76.4% of the 216 Campylobacter detections by qPCR and were more prevalent than C. coli/jejuni across all clinical groups. Other Campylobacter were also more prevalent than C. coli/jejuni across all age groups, with older children bearing a higher burden of other Campylobacter. Biomarkers of intestinal inflammation and injury (methylene blue, fecal occult test, myeloperoxidase or MPO) showed a strong association with dysentery, but mixed results with infection. MPO levels were generally higher among children infected with C. coli/jejuni, but Shigella-infected children suffering from dysentery recorded the highest levels (26,224 ng/mL); the lowest levels (10,625 ng/mL) were among asymptomatic children infected with other Campylobacter. Adjusting for age, sex, and Shigella infection, dysentery was significantly associated with C. coli/jejuni but not with other Campylobacter, whereas severe diarrhea was significantly associated with both C. coli/jejuni and other Campylobacter. Compared to asymptomatic children, children suffering from dysentery had a 14.6 odds of C. coli/jejuni infection (p-value < 0.001, 95% CI 5.5-38.7) but were equally likely to have other Campylobacter infections-odds ratio of 1.3 (0.434, 0.7-2.4). Children suffering from severe diarrhea were more likely than asymptomatic children to test positive for both C. coli/jejuni and other Campylobacter-OR of 2.8 (0.034, 1.1-7.1) and 1.9 (0.018, 1.1-3.1), respectively. Compared to the Campylobacter-free group, the odds of all diarrhea given C. coli/jejuni infection and other Campylobacter infection were 8.8 (<0.001, 3.0-25.7) and 2.4 (0.002, 1.4-4.2), respectively. Eliminating other Campylobacter in this population would eliminate 24.9% of the diarrhea cases, which is almost twice the population attributable fraction of 15.1% due to C. coli/jejuni., Conclusions/significance: Eighty-seven percent of the dysentery and 59.5% of the severe diarrhea samples were positive for Campylobacter, Shigella, or both, emphasizing the importance of targeting these pathogens to limit the impact of dysentery and severe diarrhea in children. Notably, the higher prevalence of other Campylobacter compared to C. coli/jejuni, their increasing burden during early childhood, and their association with severe diarrhea highlight the importance of these non-C. coli/jejuni Campylobacter species and suggest a need to clarify their importance in the etiology of clinical disease across different epidemiological contexts.

Swine dysentery (SD) is a mucohemorrhagic colitis, classically seen in grower/finisher pigs and caused by infection with the anaerobic intestinal spirochete Brachyspira hyodysenteriae. More recently, however, the newly described species Brachyspira hampsonii and Brachyspira suanatina have been identified as causing SD in North America and/or Europe. Furthermore, there have been occasions where strains of B. hyodysenteriae have been recovered from healthy pigs, including in multiplier herds with high health status. This study investigated whether cases of SD in Australia may be caused by the newly described species; how isolates of B. hyodysenteriae recovered from healthy herds compared to isolates from herds with disease; and how contemporary isolates compare to those recovered in previous decades, including in their plasmid gene content and antimicrobial resistance profiles. In total 1103 fecal and colon samples from pigs in 97 Australian herds were collected and tested. Of the agents of SD only B. hyodysenteriae was found, being present in 34 (35.1%) of the herds, including in 14 of 24 (58%) herds that had been considered to be free of SD. Multilocus sequence typing applied to 96 isolates from 30 herds and to 53 Australian isolates dating from the 1980s through the early 2000s showed that they were diverse, distinct from those reported in other countries, and that the 2014/16 isolates generally were different from those from earlier decades. These findings provided evidence for ongoing evolution of B. hyodysenteriae strains in Australia. In seven of the 20 herds where multiple isolates were available, two to four different sequence types (STs) were identified. Isolates with the same STs also were found in some herds with epidemiological links. Analysis of a block of six plasmid virulence-associated genes showed a lack of consistency between their presence or absence and their origin from herds currently with or without disease; however, significantly fewer isolates from the 2000s and from 2014/16 had this block of genes compared to isolates from the 1980s and 1990s. It is speculated that loss of these genes may have been responsible for the occurrence of milder disease occurring in recent years. In addition, fewer isolates from 2014/16 were susceptible to the antimicrobials lincomycin, and to a lesser extent tiamulin, than those from earlier Australian studies. Four distinct multi-drug resistant strains were identified in five herds, posing a threat to disease control., Competing Interests: The authors have declared that no competing interests exist.

Objective: In this study, a novel grey self-memory coupling model was developed to forecast the incidence rates of two notifiable infectious diseases (dysentery and gonorrhea); the effectiveness and applicability of this model was assessed based on its ability to predict the epidemiological trend of infectious diseases in China., Methods: The linear model, the conventional GM(1,1) model and the GM(1,1) model with self-memory principle (SMGM(1,1) model) were used to predict the incidence rates of the two notifiable infectious diseases based on statistical incidence data. Both simulation accuracy and prediction accuracy were assessed to compare the predictive performances of the three models. The best-fit model was applied to predict future incidence rates., Results: Simulation results show that the SMGM(1,1) model can take full advantage of the systematic multi-time historical data and possesses superior predictive performance compared with the linear model and the conventional GM(1,1) model. By applying the novel SMGM(1,1) model, we obtained the possible incidence rates of the two representative notifiable infectious diseases in China., Conclusion: The disadvantages of the conventional grey prediction model, such as sensitivity to initial value, can be overcome by the self-memory principle. The novel grey self-memory coupling model can predict the incidence rates of infectious diseases more accurately than the conventional model, and may provide useful references for making decisions involving infectious disease prevention and control.

Diet has been implicated as a major factor impacting clinical disease expression of swine dysentery and Brachyspira hyodysenteriae colonization. However, the impact of diet on novel pathogenic strongly beta-hemolytic Brachyspira spp. including "B. hampsonii" has yet to be investigated. In recent years, distillers dried grains with solubles (DDGS), a source of insoluble dietary fiber, has been increasingly included in diets of swine. A randomized complete block experiment was used to examine the effect of increased dietary fiber through the feeding of DDGS on the incidence of Brachyspira-associated colitis in pigs. One hundred 4-week-old pigs were divided into five groups based upon inocula (negative control, Brachyspira intermedia, Brachyspira pilosicoli, B. hyodysenteriae or "B. hampsonii") and fed one of two diets containing no (diet 1) or 30% (diet 2) DDGS. The average days to first positive culture and days post inoculation to the onset of clinical dysentery in the B. hyodysenteriae groups was significantly shorter for diet 2 when compared to diet 1 (P = 0.04 and P = 0.0009, respectively). A similar difference in the average days to first positive culture and days post inoculation to the onset of clinical dysentery was found when comparing the "B. hampsonii" groups. In this study, pigs receiving 30% DDGS shed on average one day prior to and developed swine dysentery nearly twice as fast as pigs receiving 0% DDGS. Accordingly, these data suggest a reduction in insoluble fiber through reducing or eliminating DDGS in swine rations should be considered an integral part of any effective disease elimination strategy for swine dysentery.

Outbreaks of mucohemorrhagic diarrhea in pigs caused by Brachyspira hyodysenteriae in the late 2000s indicated the re-emergence of Swine Dysentery (SD) in the U.S. Although the clinical disease was absent in the U.S. since the early 1990s, it continued to cause significant economic losses to other swine rearing countries worldwide. This study aims to fill the gap in knowledge pertaining to the re-emergence and epidemiology of B. hyodysenteriae in the U.S. and its global relationships using a multi-locus sequence typing (MLST) approach. Fifty-nine post re-emergent isolates originating from a variety of sources in the U.S. were characterized by MLST, analyzed for epidemiological relationships (within and between multiple sites of swine systems), and were compared with pre re-emergent isolates from the U.S. Information for an additional 272 global isolates from the MLST database was utilized for international comparisons. Thirteen nucleotide sequence types (STs) including a predominant genotype (ST93) were identified in the post re-emergent U.S. isolates; some of which showed genetic similarity to the pre re-emergent STs thereby suggesting its likely role in the re-emergence of SD. In the U.S., in general, no more than one ST was found on a site; multiple sites of a common system shared a ST; and STs found in the U.S. were distinct from those identified globally. Of the 110 STs characterized from ten countries, only two were found in more than one country. The U.S. and global populations, identified as clonal and heterogeneous based on STs, showed close relatedness based on amino acid types (AATs). One predicted founder type (AAT9) and multiple predicted subgroup founder types identified for both the U.S. and the global population indicate the potential microevolution of this pathogen. This study elucidates the strain diversity and microevolution of B. hyodysenteriae, and highlights the utility of MLST for epidemiological and surveillance studies.

Background: Shigella dysenteriae type 1 (Sd1) is a cause of major dysentery outbreaks, particularly among children and displaced populations in tropical countries. Although outbreaks continue, the characteristics of such outbreaks have rarely been documented. Here, we describe the Sd1 outbreaks occurring between 1993 and 1995 in 11 refugee settlements in Rwanda, Tanzania and Democratic Republic of the Congo (DRC). We also explored the links between the different types of the camps and the magnitude of the outbreaks., Methodology/principal Findings: Number of cases of bloody diarrhea and deaths were collected on a weekly basis in 11 refugee camps, and analyzed retrospectively. Between November 1993 and February 1995, 181,921 cases of bloody diarrhea were reported. Attack rates ranged from 6.3% to 39.1% and case fatality ratios (CFRs) from 1.5% to 9.0% (available for 5 camps). The CFRs were higher in children under age 5. In Tanzania where the response was rapidly deployed, the mean attack rate was lower than in camps in the region of Goma without an immediate response (13.3% versus 32.1% respectively)., Conclusions/significance: This description, and the areas where data is missing, highlight both the importance of collecting data in future epidemics, difficulties in documenting outbreaks occurring in complex emergencies and most importantly, the need to assure that minimal requirements are met.