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Diarrheal disease affects a large proportion of military personnel deployed to developing countries, resulting in decreased job performance and operational readiness. Travelers' diarrhea is self-limiting and generally resolves within 5 days; however, antibiotic treatment significantly reduces symptom severity and duration of illness. Presently, azithromycin is the preferred first-line antibiotic for the treatment of acute watery diarrhea (single dose 500 mg), as well as for febrile diarrhea and dysentery (single dose 1,000 mg). Levofloxacin and ciprofloxacin are also options for acute watery diarrhea (single dose 500 mg and 750 mg, respectively) and febrile diarrhea/dysentery in areas with high rates of Shigella (500 mg once for 3 days [once daily with levofloxacin and twice daily with ciprofloxacin]), but are becoming less effective because of increasing fluoroquinolone resistance, particularly among Campylobacter spp. Another alternate for acute watery diarrhea is rifaximin (200 mg 3 times per day for 3 days); however, it should not be used with invasive illness. Use of loperamide in combination with antibiotic treatment is also beneficial as it has been shown to further reduce gastrointestinal symptoms and duration of illness. Because of regional differences in the predominance of pathogens and resistance levels, choice of antibiotic should take travel destination into consideration.

Enterobacter cloacae is a Gram-negative rod with multidrug-resistant potential due to chromosomally-induced AmpC β-lactamase. We evaluated characteristics, antibiotic utilization, and outcomes associated with battlefield-related E . cloacae infections (2009–2014). Single initial and serial E . cloacae isolates (≥24 hours from initial isolate from any site) associated with a clinical infection were examined. Susceptibility profiles of initial isolates in the serial isolation group were contrasted against last isolate recovered. Characteristics of 112 patients with E . cloacae infections (63 [56%] with single initial isolation; 49 [44%] with serial isolation) were compared to 509 patients with bacterial infections not attributed to E . cloacae . E . cloacae patients sustained more blast trauma (78%) compared to non- E . cloacae infections patients (75%; p<0.001); however, injury severity scores were comparable (median of 34.5 and 33, respectively; p = 0.334). Patients with E . cloacae infections had greater shock indices (median 1.07 vs 0.92; p = 0.005) and required more initial blood products (15 vs. 14 units; p = 0.032) compared to patients with non- E . cloacae infections. Although E . cloacae patients had less intensive care unit admissions (80% vs. 90% with non- E . cloacae infection patients; p = 0.007), they did have more operating room visits (5 vs. 4; p = 0.001), longer duration of antibiotic therapy (43.5 vs. 34 days; p<0.001), and lengthier hospitalizations (57 vs. 44 days; p<0.001). Patients with serial E . cloacae had isolation of infecting isolates sooner than patients with single initial E . cloacae (median of 5 vs. 8 days post-injury; p = 0.046); however, outcomes were not significantly different between the groups. Statistically significant resistance to individual antibiotics did not develop between initial and last isolates in the serial isolation group. Despite current combat care and surgical prophylaxis guidelines recommending upfront provision of AmpC-inducing antibiotics, clinical outcomes did not differ nor did significant antibiotic resistance develop in patients who experienced serial isolation of E . cloacae versus single initial isolation.

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.

Recent reclassification of the Klebsiella genus to include Klebsiella variicola , and its association with bacteremia and mortality, has raised concerns. We examined Klebsiella spp. infections among battlefield trauma patients, including occurrence of invasive K . variicola disease. Klebsiella isolates collected from 51 wounded military personnel (2009–2014) through the Trauma Infectious Disease Outcomes Study were examined using polymerase chain reaction (PCR) and pulsed-field gel electrophoresis. K . variicola isolates were evaluated for hypermucoviscosity phenotype by the string test. Patients were severely injured, largely from blast injuries, and all received antibiotics prior to Klebsiella isolation. Multidrug-resistant Klebsiella isolates were identified in 23 (45%) patients; however, there were no significant differences when patients with and without multidrug-resistant Klebsiella were compared. A total of 237 isolates initially identified as K . pneumoniae were analyzed, with 141 clinical isolates associated with infections (remaining were colonizing isolates collected through surveillance groin swabs). Using PCR sequencing, 221 (93%) isolates were confirmed as K . pneumoniae , 10 (4%) were K . variicola , and 6 (3%) were K . quasipneumoniae . Five K . variicola isolates were associated with infections. Compared to K . pneumoniae , infecting K . variicola isolates were more likely to be from blood (4/5 versus 24/134, p = 0.04), and less likely to be multidrug-resistant (0/5 versus 99/134, p<0.01). No K . variicola isolates demonstrated the hypermucoviscosity phenotype. Although K . variicola isolates were frequently isolated from bloodstream infections, they were less likely to be multidrug-resistant. Further work is needed to facilitate diagnosis of K . variicola and clarify its clinical significance in larger prospective studies.

Functional gastrointestinal disorders (FGDs) are recognized sequelae of infectious gastroenteritis (IGE). Within the active duty military population, a group with known high IGE rates, the population-based incidence, risk factors, and attributable burden of care referable to FGD after IGE are poorly defined. Using electronic medical encounter data (1999-2007) on active duty US military, a matched, case-control study describing the epidemiology and risk determinants of FGD (irritable bowel syndrome (IBS), functional constipation (FC), functional diarrhea (FD), dyspepsia (D)) was conducted. Incidence rates and duration of FGD-related medical care were estimated, and conditional logistic regression was utilized to evaluate FGD risk after IGE. A total of 31,866 cases of FGD identified were distributed as follows: FC 55% (n=17,538), D 21.2% (n=6,750), FD 2.1% (n=674), IBS 28.5% (n=9,091). Previous IGE episodes were distributed as follows: specific bacterial pathogen (n=65, 1.2%), bacterial, with no pathogen specified (n=2155, 38.9%), protozoal (n=38, 0.7%), viral (n=3431, 61.9%). A significant association between IGE and all FGD (odds ratio (OR) 2.64; P<0.001) was seen, with highest risk for FD (OR 6.28, P<0.001) and IBS (OR 3.72, P<0.001), and moderate risk for FC (2.15, P<0.001) and D (OR 2.39, P<0.001). Risk generally increased with temporal proximity to, and bacterial etiology of, exposure. Duration of FGD-related care was prolonged with 22.7% having FGD-associated medical encounters 5 years after diagnosis. FGD are common in this population at high risk for IGE. When considering effective countermeasures and mitigation strategies, attention directed toward prevention as well as the acute and chronic sequelae of these infections is needed.

Experimental human challenge models have played a major role in enhancing our understanding of infectious diseases. Primary outcomes have typically utilized overly simplistic outcomes that fail to entirely account for complex illness syndromes. We sought to characterize clinical outcomes associated with experimental infection with enterotoxigenic Escherichia coli (ETEC) and to develop a disease score. Data were obtained from prior controlled human ETEC infection studies. Correlation and univariate regression across sign and symptom severity was performed. A multiple correspondence analysis was conducted. A 3-parameter disease score with construct validity was developed in an iterative fashion, compared to standard outcome definitions and applied to prior vaccine challenge trials. Data on 264 subjects receiving seven ETEC strains at doses from 1x105 to 1x1010 cfu were used to construct a standardized dataset. The strongest observed correlation was between vomiting and nausea (r = 0.65); however, stool output was poorly correlated with subjective activity-impacting outcomes. Multiple correspondence analyses showed covariability in multiple signs and symptoms, with severity being the strongest factor corresponding across outcomes. The developed disease score performed well compared to standard outcome definitions and differentiated disease in vaccinated and unvaccinated subjects. Frequency and volumetric definitions of diarrhea severity poorly characterize ETEC disease. These data support a disease severity score accounting for stool output and other clinical signs and symptoms. Such a score could serve as the basis for better field trial outcomes and gives an additional outcome measure to help select future vaccines that warrant expanded testing in pivotal pre-licensure trials.

Abstract Background The relationship between postvaccination symptoms and strength of antibody responses is unclear. The goal of this study was to determine whether adverse effects caused by vaccination with the Pfizer/BioNTech BNT162b2 vaccine are associated with the magnitude of vaccine-induced antibody levels. Methods We conducted a single-center, observational cohort study consisting of generally healthy adult participants that were not severely immunocompromised, had no history of coronavirus disease 2019, and were seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein before vaccination. Severity of vaccine-associated symptoms was obtained through participant-completed questionnaires. Testing for immunoglobulin G antibodies against SARS-CoV-2 spike protein and receptor-binding domain was conducted using microsphere-based multiplex immunoassays performed on serum samples collected at monthly visits. Neutralizing antibody titers were determined by microneutralization assays. Results Two hundred six participants were evaluated (69.4% female, median age 41.5 years old). We found no correlation between vaccine-associated symptom severity scores and vaccine-induced antibody titers 1 month after vaccination. We also observed that (1) postvaccination symptoms were inversely correlated with age and weight and more common in women, (2) systemic symptoms were more frequent after the second vaccination, (3) high symptom scores after first vaccination were predictive of high symptom scores after second vaccination, and (4) older age was associated with lower titers. Conclusions Lack of postvaccination symptoms after receipt of the BNT162b2 vaccine does not equate to lack of vaccine-induced antibodies 1 month after vaccination. We found no correlation between BNT162b2-associated symptom severity and vaccine-induced antibody titers 1 month after vaccination. Adverse effects inversely correlated with age and weight, whereas symptom severity after first vaccination was predictive of that after second vaccination.

The human microbiome is comprised of a complex and diverse community of organisms that is subject to dynamic changes over time. As such, cross-sectional studies of the microbiome provide a multitude of information for a specific body site at a particular time, but they fail to account for temporal changes in microbial constituents resulting from various factors. To address this shortcoming, longitudinal research studies of the human microbiome investigate the influence of various factors on the microbiome of individuals within a group or community setting. These studies are vital to address the effects of host and/or environmental factors on microbiome composition as well as the potential contribution of microbiome members during the course of an infection. The relationship between microbial constituents and disease development has been previously explored for skin and soft tissue infections (SSTIs) within congregate military trainees. Accordingly, approximately 25% of the population carries Staphylococcus aureus within their nasal cavity, and these colonized individuals are known to be at increased risk for SSTIs. To examine the evolution of the nasal microbiota of U.S. Army Infantry trainees, individuals were sampled longitudinally from their arrival at Fort Benning, Georgia, until completion of their training 90 days later. These samples were then processed to determine S. aureus colonization status and to profile the nasal microbiota using 16S rRNA gene-based methods. Microbiota stability differed dramatically among the individual trainees; some subjects exhibited great stability, some subjects showed gradual temporal changes and some subjects displayed a dramatic shift in nasal microbiota composition. Further analysis utilizing the available trainee metadata suggests that the major drivers of nasal microbiota stability may be S. aureus colonization status and geographic origin of the trainees. Nasal microbiota evolution within the congregate setting imposed by military training is a complex process that appears to be affected by numerous factors. This finding may indicate that future campaigns to prevent S. aureu s colonization and future SSTIs among high-risk military trainees may require a ‘personalized’ approach.

: Diarrhea is a frequent clinical syndrome affecting international travellers. Bacterial etiologic agents have a long history of emergent antimicrobial resistance against commonly used antibiotics. Current approaches applying first-line antimicrobial therapy are being challenged by increasingly resistant organisms. This review summarizes recent epidemiological and clinical evidence of antibiotic resistance among enteropathogens causing traveller's diarrhea and the subsequent impact on current treatment recommendations. : The PubMed database was systemically searched for articles related to antibiotic susceptibility and diarrheal pathogens. : Antibiotic resistance related to travellers' diarrhea has increased in recent years. Most notably, fluoroquinolone resistance has expanded from the Campylobacter -associated cases well documented in Southeast Asia in the 1990s to widespread occurrence, as well as increases among other common bacterial enteropathogens including, enterotoxigenic and enteroaggregative Escherichia coli , Shigella and non-typhoidal Salmonella . Multidrug resistance among enteropathogenic Enterobacteriacae and Campylobacter species create further challenges with the selection of empiric therapy. Treatment failures requiring early use of alternative agents, as well as delayed recovery comparable to placebo rates emphasize the impact of antimicrobial resistance on effective treatment. : Although there are limitations in the available data, the increasing antibiotic resistance and adverse impact on clinical outcome require continued surveillance and reconsideration of practice guidelines.

International travelers are frequently afflicted by acute infectious diarrhea, commonly referred to as travelers’ diarrhea (TD). Antibiotics are often prescribed as treatment or prophylaxis for TD; however, little is known about the impacts of these regimens on travelers’ gut microbiomes and carriage of antibiotic resistance genes (ARGs). Here, we analyzed two cohorts totaling 153 US and UK servicemembers deployed to Honduras or Kenya. These subjects either experienced TD during deployment and received a single dose of one of three antibiotics [Trial Evaluating Ambulatory Therapy of Travelers’ Diarrhea (TrEAT TD) cohort] or took once-daily rifaximin (RIF), twice-daily RIF, or placebo as prophylaxis to prevent TD [Trial Evaluating Chemoprophylaxis Against Travelers’ Diarrhea (PREVENT TD) cohort]. We applied metagenomic sequencing on 340 longitudinally collected stool samples and whole-genome sequencing on 54 Escherichia coli isolates. We found that gut microbiome taxonomic diversity remained stable across the length of study for most treatment groups, but twice-daily RIF prophylaxis significantly decreased microbiome richness post-travel. Similarly, ARG diversity and abundance were generally stable, with the exception of a significant increase for the twice-daily RIF prophylaxis group. We also did not identify significant differences between the ARG abundance of E. coli isolates from the TrEAT TD cohort collected from different treatment groups or timepoints. Overall, we found no significant worsening of gut microbiome diversity or an increase in ARG abundance following single-dose treatment for TD, underscoring that these can be effective with low risk of impact on the microbiome and resistome, and identified the relative microbiome risks and benefits associated with the three regimens for preventing TD. The travelers’ gut microbiome is potentially assaulted by acute and chronic perturbations (e.g., diarrhea, antibiotic use, and different environments). Prior studies of the impact of travel and travelers’ diarrhea (TD) on the microbiome have not directly compared antibiotic regimens, and studies of different antibiotic regimens have not considered travelers’ microbiomes. This gap is important to be addressed as the use of antibiotics to treat or prevent TD—even in moderate to severe cases or in regions with high infectious disease burden—is controversial based on the concerns for unintended consequences to the gut microbiome and antimicrobial resistance (AMR) emergence. Our study addresses this by evaluating the impact of defined antibiotic regimens (single-dose treatment or daily prophylaxis) on the gut microbiome and resistomes of deployed servicemembers, using samples collected during clinical trials. Our findings indicate that the antibiotic treatment regimens that were studied generally do not lead to adverse effects on the gut microbiome and resistome and identify the relative risks associated with prophylaxis. These results can be used to inform therapeutic guidelines for the prevention and treatment of TD and make progress toward using microbiome information in personalized medical care.