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1.
J Antimicrob Chemother ; 77(10): 2737-2741, 2022 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-35869778

RESUMEN

BACKGROUND: To date, no real-world data are available to describe cefiderocol use in carbapenem-resistant Acinetobacter baumannii (CRAB) meningitis. Furthermore, cefiderocol pharmacokinetic (PK) data to support CNS penetration in human subjects are limited. These gaps pose a significant concern for clinicians who are faced with treating such infections when considering cefiderocol use. OBJECTIVES: To describe cefiderocol CSF and plasma PK and pharmacodynamic (PD) data from two different dosing regimens [2 g IV q6h (regimen 1) and 2 g IV q8h (regimen 2)] during treatment of CRAB meningitis. PATIENTS AND METHODS: A 61-year-old woman with CRAB meningitis was treated with cefiderocol and intraventricular gentamicin. Steady-state plasma and CSF cefiderocol concentrations were evaluated on Day 19 (regimen 1) and Day 24 (regimen 2) during the cefiderocol treatment course. RESULTS: CSF AUC was 146.49 and 118.28 mg·h/L, as determined by the linear-log trapezoidal method for regimens 1 and 2, respectively. Penetration into CSF estimated as the AUCCSF/AUCfree plasma ratio was 68% and 60% for regimens 1 and 2, respectively. Estimated free plasma and CSF concentrations exceeded the MIC of the isolate for 100% of the dosing interval. Microbiological and clinical cure were achieved, and no cefiderocol-associated adverse effects were observed. CONCLUSIONS: Cefiderocol, when given as 2 g q8h and 2 g q6h, attained CSF concentrations that exceeded the organism-specific MIC and the CLSI susceptible breakpoint (≤4 mg/L) for 100% of the dosing interval.


Asunto(s)
Acinetobacter baumannii , Meningitis , Antibacterianos/farmacología , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Cefalosporinas/uso terapéutico , Femenino , Gentamicinas , Humanos , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Cefiderocol
2.
Artículo en Inglés | MEDLINE | ID: mdl-34669040

RESUMEN

The controlled human infection model (CHIM) for enterotoxigenic Escherichia coli (ETEC) has been instrumental in defining ETEC as a causative agent of acute watery diarrhea, providing insights into disease pathogenesis and resistance to illness, and enabling preliminary efficacy evaluations for numerous products including vaccines, immunoprophylactics, and drugs. Over a dozen strains have been evaluated to date, with a spectrum of clinical signs and symptoms that appear to replicate the clinical illness seen with naturally occurring ETEC. Recent advancements in the ETEC CHIM have enhanced the characterization of clinical, immunological, and microbiological outcomes. It is anticipated that omics-based technologies applied to ETEC CHIMs will continue to broaden our understanding of host-pathogen interactions and facilitate the development of primary and secondary prevention strategies.

3.
Clin Trials ; 19(1): 116-118, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34708664

RESUMEN

The use of the controlled human infection model to facilitate product development and to advance understanding of host-pathogen interactions is of increasing interest. While administering a virulent (or infective) organism to a susceptible host necessitates an ongoing evaluation of safety and ethical considerations, a central theme in conducting these studies in a safe and ethical manner that yields actionable data is their conduct in facilities well-suited to address their unique attributes. To that end, we have developed a framework for evaluating potential sites in which to conduct inpatient enteric controlled human infection model to ensure consistency and increase the likelihood of success.


Asunto(s)
Interacciones Huésped-Patógeno , Pacientes Internos , Humanos
4.
Gastroenterology ; 159(1): 96-104, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32165208

RESUMEN

BACKGROUND & AIMS: Biomarkers are needed to identify patients at risk for development of inflammatory bowel diseases. We aimed to identify serum biomarkers of Crohn's disease and ulcerative colitis that can be detected and quantified before diagnosis. METHODS: We obtained serum samples from patients archived before a diagnosis of Crohn's disease (n = 200) or ulcerative colitis (n = 199), as well as from 200 healthy individuals (controls), collected from 1998 through 2013 as part of the US Defense Medical Surveillance System. We measured levels of antibodies against microbes (anti-Saccharomyces cerevisiae IgA or IgG, anti-Escherichiacoli outer membrane porin C, anti-CBir1, anti-flagellin 2, anti-flagellin X, and perinuclear anti-neutrophil cytoplasmic antibodies) and 1129 proteins in each sample. We then used functional principal component analysis to derive the time-varying trajectory for each marker, which then was used in a multivariate model to predict disease status. Predictive performances at different prediagnosis timepoints were evaluated using area under the receiver operating characteristic curves (AUROCs). Biological pathways that were up-regulated in serum from patients with Crohn's disease were identified based on changes in protein abundance at different time periods preceding diagnosis. RESULTS: We identified a panel of 51 protein biomarkers that were predictive of Crohn's disease within 5 years with an AUROC of 0.76 and a diagnosis within 1 year with an AUROC of 0.87. Based on the proteins included in the panel, imminent development of CD was associated with changes in the complement cascade, lysosomes, innate immune response, and glycosaminoglycan metabolism. Serum antibodies and proteins identified patients who received a diagnosis of ulcerative colitis within 5 years with an AUROC of only 0.56 and within 1 year with an AUROC of 0.72. CONCLUSIONS: We identified a panel of serum antibodies and proteins that were predictive of patients who will receive a diagnosis of Crohn's disease within 5 years with high accuracy. By contrast we did not identify biomarkers associated with future diagnosis of ulcerative colitis.


Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/sangre , Anticuerpos Antibacterianos/sangre , Anticuerpos Antifúngicos/sangre , Colitis Ulcerosa/diagnóstico , Enfermedad de Crohn/diagnóstico , Adulto , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Anticuerpos Antibacterianos/inmunología , Anticuerpos Antifúngicos/inmunología , Biomarcadores/sangre , Estudios de Casos y Controles , Colitis Ulcerosa/sangre , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/sangre , Enfermedad de Crohn/inmunología , Escherichia coli/inmunología , Femenino , Voluntarios Sanos , Humanos , Inmunidad Innata , Masculino , Modelos Estadísticos , Valor Predictivo de las Pruebas , Pronóstico , Proteómica , Curva ROC , Saccharomyces cerevisiae/inmunología , Factores de Tiempo , Adulto Joven
5.
Proc Natl Acad Sci U S A ; 115(38): E8968-E8976, 2018 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-30126994

RESUMEN

Enterotoxigenic Escherichia coli (ETEC) is a global diarrheal pathogen that utilizes adhesins and secreted enterotoxins to cause disease in mammalian hosts. Decades of research on virulence factor regulation in ETEC has revealed a variety of environmental factors that influence gene expression, including bile, pH, bicarbonate, osmolarity, and glucose. However, other hallmarks of the intestinal tract, such as low oxygen availability, have not been examined. Further, determining how ETEC integrates these signals in the complex host environment is challenging. To address this, we characterized ETEC's response to the human host using samples from a controlled human infection model. We found ETEC senses environmental oxygen to globally influence virulence factor expression via the oxygen-sensitive transcriptional regulator fumarate and nitrate reduction (FNR) regulator. In vitro anaerobic growth replicates the in vivo virulence factor expression profile, and deletion of fnr in ETEC strain H10407 results in a significant increase in expression of all classical virulence factors, including the colonization factor antigen I (CFA/I) adhesin operon and both heat-stable and heat-labile enterotoxins. These data depict a model of ETEC infection where FNR activity can globally influence virulence gene expression, and therefore proximity to the oxygenated zone bordering intestinal epithelial cells likely influences ETEC virulence gene expression in vivo. Outside of the host, ETEC biofilms are associated with seasonal ETEC epidemics, and we find FNR is a regulator of biofilm production. Together these data suggest FNR-dependent oxygen sensing in ETEC has implications for human infection inside and outside of the host.


Asunto(s)
Escherichia coli Enterotoxigénica/patogenicidad , Infecciones por Escherichia coli/microbiología , Proteínas de Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Interacciones Huésped-Patógeno/genética , Proteínas Hierro-Azufre/genética , Adulto , Biopelículas , Diarrea/epidemiología , Diarrea/microbiología , Diarrea/prevención & control , Células Epiteliales/microbiología , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/prevención & control , Proteínas de Escherichia coli/metabolismo , Vacunas contra Escherichia coli/administración & dosificación , Femenino , Voluntarios Sanos , Humanos , Intestinos/citología , Intestinos/microbiología , Proteínas Hierro-Azufre/metabolismo , Masculino , Persona de Mediana Edad , Virulencia/genética , Factores de Virulencia/genética , Factores de Virulencia/inmunología , Adulto Joven
6.
N Engl J Med ; 376(4): 330-341, 2017 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-25830322

RESUMEN

BACKGROUND: The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD. METHODS: We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed. RESULTS: The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months. CONCLUSIONS: This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV∆G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .).


Asunto(s)
Vacunas contra el Virus del Ébola/inmunología , Ebolavirus/inmunología , Fiebre Hemorrágica Ebola/prevención & control , Adulto , Anticuerpos Antivirales/sangre , Método Doble Ciego , Vacunas contra el Virus del Ébola/administración & dosificación , Vacunas contra el Virus del Ébola/efectos adversos , Ebolavirus/genética , Ebolavirus/aislamiento & purificación , Ensayo de Inmunoadsorción Enzimática , Femenino , Fiebre Hemorrágica Ebola/inmunología , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Seroconversión , Vacunas Atenuadas/inmunología , Virus de la Estomatitis Vesicular Indiana , Proteínas del Envoltorio Viral/aislamiento & purificación , Viremia
7.
Clin Infect Dis ; 66(9): 1435-1441, 2018 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-29145631

RESUMEN

Background: Campylobacter species are a leading cause of diarrheal disease globally with significant morbidity. Primary prevention efforts have yielded limited results. Rifaximin chemoprophylaxis decreases rates of travelers' diarrhea and may be suitable for high-risk persons. We assessed the efficacy of rifaximin in the controlled human infection model for Campylobacter jejuni. Methods: Twenty-eight subjects were admitted to an inpatient facility and randomized to a twice-daily dose of 550 mg rifaximin or placebo. The following day, subjects ingested 1.7 × 105 colony-forming units of C. jejuni strain CG8421. Subjects continued prophylaxis for 3 additional days, were followed for campylobacteriosis for 144 hours, and were subsequently treated with azithromycin and ciprofloxacin. Samples were collected to assess immunologic responses to CG8421. Results: There was no difference (P = 1.0) in the frequency of campylobacteriosis in those receiving rifaximin (86.7%) or placebo (84.6%). Additionally, there were no differences in the clinical signs and symptoms of C. jejuni infection to include abdominal pain/cramps (P = 1.0), nausea (P = 1.0), vomiting (P = .2), or fever (P = 1.0) across study groups. Immune responses to the CG8421 strain were comparable across treatment groups. Conclusions: Rifaximin did not prevent campylobacteriosis in this controlled human infection model. Given the morbidity associated with Campylobacter infection, primary prevention efforts remain a significant need. Clinical Trials Registration: NCT02280044.


Asunto(s)
Antibacterianos/uso terapéutico , Infecciones por Campylobacter/prevención & control , Quimioprevención , Rifaximina/uso terapéutico , Adulto , Antibacterianos/administración & dosificación , Azitromicina/uso terapéutico , Campylobacter jejuni , Ciprofloxacina/uso terapéutico , Diarrea/prevención & control , Método Doble Ciego , Femenino , Voluntarios Sanos , Experimentación Humana , Humanos , Masculino , Rifaximina/administración & dosificación , Adulto Joven
8.
Clin Infect Dis ; 65(12): 2008-2017, 2017 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-29029033

RESUMEN

BACKGROUND: Recommended treatment for travelers' diarrhea includes the combination of an antibiotic, usually a fluoroquinolone or azithromycin, and loperamide for rapid resolution of symptoms. However, adverse events, postdose nausea with high-dose azithromycin, effectiveness of single-dose rifaximin, and emerging resistance to front-line agents are evidence gaps underlying current recommendations. METHODS: A randomized, double-blind trial was conducted in 4 countries (Afghanistan, Djibouti, Kenya, and Honduras) between September 2012 and July 2015. US and UK service members with acute watery diarrhea were randomized and received single-dose azithromycin (500 mg; 106 persons), levofloxacin (500 mg; 111 persons), or rifaximin (1650 mg; 107 persons), in combination with loperamide (labeled dosing). The efficacy outcomes included clinical cure at 24 hours and time to last unformed stool. RESULTS: Clinical cure at 24 hours occurred in 81.4%, 78.3%, and 74.8% of the levofloxacin, azithromycin, and rifaximin arms, respectively. Compared with levofloxacin, azithromycin was not inferior (P = .01). Noninferiority could not be shown with rifaximin (P = .07). At 48 and 72 hours, efficacy among regimens was equivalent (approximately 91% at 48 and 96% at 72 hours). The median time to last unformed stool did not differ between treatment arms (azithromycin, 3.8 hours; levofloxacin, 6.4 hours; rifaximin, 5.6 hours). Treatment failures were uncommon (3.8%, 4.4%, and 1.9% in azithromycin, levofloxacin, and rifaximin arms, respectively) (P = .55). There were no differences between treatment arms with postdose nausea, vomiting, or other adverse events. CONCLUSIONS: Single-dose azithromycin, levofloxacin, and rifaximin with loperamide were comparable for treatment of acute watery diarrhea. CLINICAL TRIAL REGISTRATION: NCT01618591.


Asunto(s)
Antibacterianos/uso terapéutico , Diarrea/tratamiento farmacológico , Levofloxacino/uso terapéutico , Viaje , Enfermedad Aguda/epidemiología , Adulto , Afganistán/epidemiología , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Azitromicina/administración & dosificación , Azitromicina/efectos adversos , Azitromicina/uso terapéutico , Diarrea/microbiología , Djibouti/epidemiología , Método Doble Ciego , Quimioterapia Combinada , Escherichia coli/efectos de los fármacos , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/epidemiología , Femenino , Honduras/epidemiología , Humanos , Kenia/epidemiología , Levofloxacino/administración & dosificación , Levofloxacino/efectos adversos , Loperamida/administración & dosificación , Loperamida/efectos adversos , Loperamida/uso terapéutico , Masculino , Personal Militar/estadística & datos numéricos , Resultado del Tratamiento
9.
Gastroenterology ; 149(6): 1408-14, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26255560

RESUMEN

BACKGROUND & AIMS: Some acute enteric infections are associated with the development of functional gastrointestinal disorders, most commonly irritable bowel syndrome but also other functional and organic gastrointestinal sequelae. Clostridium difficile infection has increased in incidence and severity, however, few studies have evaluated functional disorders after this infection. METHODS: We evaluated the epidemiology and sequelae of C difficile in the US military population by using the US Department of Defense's Armed Forces Health Surveillance Center Defense Medical Ecounter Database. We then performed a retrospective cohort study of 891 active-duty US military personnel who developed C difficile from 1998 to 2010 and 3231 matched subjects who had not been exposed to C difficile. Subjects were identified based on International Classification of Diseases, 9th revision, Clinical Modification codes for C difficile disease. RESULTS: C difficile was associated independently with increased rate ratios (RRs) for incident irritable bowel syndrome (RR, 6.1; 95% confidence interval [CI], 2.9-12.9), gastroesophageal reflux disease (GERD) (RR, 1.9; 95% CI, 1.4-2.6), dyspepsia (RR, 3.3; 95%, 1.4-7.7), and constipation (RR, 2.2; 95% CI, 1.3-3.7). Approximately 14.1% of subjects with C difficile later were identified with one of these functional gastrointestinal disorders (FGDs), compared with 6% of controls. Community- and health care-associated C difficile were associated at similar rates with these sequelae. Patients were at increased risk for FGDs within 3 months of a C difficile episode, with one additional case of FGD developing for every 12 diagnoses of C difficile. CONCLUSIONS: The incidence of community- and health care-associated C difficile has increased in the US military population from 1998 through 2010. As for other gastrointestinal infections, C difficile disease is associated with clinically relevant functional sequelae in this military population.


Asunto(s)
Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium/complicaciones , Infecciones por Clostridium/epidemiología , Enfermedades Gastrointestinales/epidemiología , Adulto , Estudios de Casos y Controles , Infecciones por Clostridium/diagnóstico , Estreñimiento/epidemiología , Dispepsia/epidemiología , Femenino , Reflujo Gastroesofágico/epidemiología , Enfermedades Gastrointestinales/diagnóstico , Humanos , Incidencia , Síndrome del Colon Irritable/epidemiología , Masculino , Persona de Mediana Edad , Personal Militar/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Estados Unidos/epidemiología , Adulto Joven
10.
Dig Dis Sci ; 60(11): 3379-85, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26115751

RESUMEN

BACKGROUND: Previous studies have linked an increase in functional and pathological gastrointestinal (GI) disorders following antecedent infectious gastroenteritis (IGE), yet studies of other chronic GI disorders such as tropical sprue (TS) and intestinal malabsorption (IM) are lacking. This study was performed to evaluate the association between documented IGE and the risk of TS and IM using a matched case-control study. METHODS: The odds of IGE (exposure) among subjects with TS and IM were compared to the odds of exposure in matched controls. Data were obtained from the Defense Medical Surveillance System. Incidence was estimated based on the number of active duty military personnel, and conditional logistic regression models were used to evaluate the relationship between IGE and TS/IM while adjusting for potential confounders. RESULTS: The overall incidence of TS and IM was 0.24 and 1.98 per 100,000 person-years, respectively. After adjusting for important covariates, prior IGE was associated with an increase in the odds of TS (odds ratio (OR) 36.64) and IM (OR 3.93) (p < 0.001). Other covariates demonstrating an increased risk were being of Caucasian race, having greater than high school education, and service in military branches other than the Army. CONCLUSION: Overall, this study demonstrates the first significant estimates that a case of antecedent IGE is associated with an increased risk of TS and IM in an active duty military population. Ultimately, acquisition of TS or IM has the potential to decrease operational efficiency, which may have a significant impact on deployed military missions.


Asunto(s)
Disentería/epidemiología , Síndromes de Malabsorción/epidemiología , Medicina Militar , Esprue Tropical/epidemiología , Adulto , Estudios de Casos y Controles , Disentería/diagnóstico , Femenino , Humanos , Incidencia , Modelos Logísticos , Síndromes de Malabsorción/diagnóstico , Masculino , Personal Militar , Análisis Multivariante , Oportunidad Relativa , Factores de Riesgo , Esprue Tropical/diagnóstico , Factores de Tiempo , Estados Unidos , Adulto Joven
11.
Microorganisms ; 12(2)2024 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-38399692

RESUMEN

BACKGROUND: Enterotoxigenic E. coli (ETEC) is a principal cause of diarrhea in travelers, deployed military personnel, and children living in low to middle-income countries. ETEC expresses a variety of virulence factors including colonization factors (CF) that facilitate adherence to the intestinal mucosa. We assessed the protective efficacy of a tip-localized subunit of CF antigen I (CFA/I), CfaE, delivered intradermally with the mutant E. coli heat-labile enterotoxin, LTR192G, in a controlled human infection model (CHIM). METHODS: Three cohorts of healthy adult subjects were enrolled and given three doses of 25 µg CfaE + 100 ng LTR192G vaccine intradermally at 3-week intervals. Approximately 28 days after the last vaccination, vaccinated and unvaccinated subjects were admitted as inpatients and challenged with approximately 2 × 107 cfu of CFA/I+ ETEC strain H10407 following an overnight fast. Subjects were assessed for moderate-to-severe diarrhea for 5 days post-challenge. RESULTS: A total of 52 volunteers received all three vaccinations; 41 vaccinated and 43 unvaccinated subjects were challenged and assessed for moderate-to-severe diarrhea. Naïve attack rates varied from 45.5% to 64.7% across the cohorts yielding an overall efficacy estimate of 27.8% (95% confidence intervals: -7.5-51.6%). In addition to reducing moderate-severe diarrhea rates, the vaccine significantly reduced loose stool output and overall ETEC disease severity. CONCLUSIONS: This is the first study to demonstrate protection against ETEC challenge after intradermal vaccination with an ETEC adhesin. Further examination of the challenge methodology is necessary to address the variability in naïve attack rate observed among the three cohorts in the present study.

12.
mBio ; 15(1): e0279023, 2024 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-38085102

RESUMEN

IMPORTANCE: 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.


Asunto(s)
Diarrea , Microbioma Gastrointestinal , Humanos , Diarrea/prevención & control , Viaje , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Farmacorresistencia Microbiana
13.
BMC Infect Dis ; 13: 609, 2013 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-24373384

RESUMEN

BACKGROUND: Clostridium difficile associated disease (CDAD) has risen in incidence and the experience in the US military has not been described. METHODS: We evaluated the U.S. military's database and identified CDAD cases and demographic characteristics among affected military personnel from 1998 to 2010. RESULTS: 2,423 cases were identified. CDAD incidence was 13.2 cases (95% CI: 12.7-13.7) per 100 K p-yr and increased over study years. CA-CDAD and HA-CDAD incidence was 5.5 (95% CI: 5.2, 5.9) per 100 K p-y and 1.3 (95% CI: 1.2, 1.4) per 1,000 hospitalizations respectively. Females comprised a larger proportion of CA-CDAD than HA-CDAD (25.5% vs. 19.3%; p < 0.001) cases as did Air Force service (29% vs. 23.4%; p < 0.01). On multivariate analysis female gender, Coast Guard or Air Force service, and a married status was associated with CA-CDAD whereas Male gender and Marine Corps service were associated with HA-CDAD cases. CONCLUSIONS: CDAD has increased among military personnel, with female cases more likely to be community associated. Gender, marital status and branch of service had the strongest association with CDAD subtype. Further work is needed to evaluate the epidemiologic factors that have led to these increased rates in otherwise low-risk populations and associated sequelae.


Asunto(s)
Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium/epidemiología , Personal Militar/estadística & datos numéricos , Adulto , Clostridioides difficile/fisiología , Infecciones por Clostridium/microbiología , Estudios de Cohortes , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/microbiología , Infección Hospitalaria/epidemiología , Infección Hospitalaria/microbiología , Femenino , Humanos , Masculino , Estados Unidos/epidemiología , Adulto Joven
14.
Microorganisms ; 11(11)2023 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-38004700

RESUMEN

INTRODUCTION: Enterotoxigenic E. coli (ETEC) is a leading cause of diarrhea in travelers as well as for children living in low- to middle-income countries. ETEC adhere to intestinal epithelium via colonization factors (CFs). CFA/I, a common CF, is composed of a polymeric stalk and a tip-localized minor adhesive subunit, CfaE. Vaccine delivery by the transcutaneous immunization of dscCfaE was safe but was poorly immunogenic in a phase 1 trial when administered to volunteers with LTR(192G) and mLT. To potentially enhance the immunogenicity of CfaE while still delivering via a cutaneous route, we evaluated the safety and immunogenicity of two CfaE constructs administered intradermally (ID) with or without mLT. METHODS: CfaE was evaluated as a donor strand-complemented construct (dscCfaE) and as a chimeric construct (Chimera) in which dscCfaE replaces the A1 domain of the cholera toxin A subunit and assembles non-covalently with the pentamer of heat-labile toxin B (LTB). Subjects received three ID vaccinations three weeks apart with either dscCfaE (1, 5, and 25 µg) or Chimera (2.6 and 12.9 µg) with and without 0.1 µg of mLT. Subjects were monitored for local and systemic adverse events. Immunogenicity was evaluated by serum and antibody-secreting cell (ASC) responses. RESULTS: The vaccine was well-tolerated with predominantly mild and moderate local vaccine site reactions characterized by erythema, induration and post-inflammatory hyperpigmentation. High rates of serologic and ASC responses were seen across study groups with the most robust responses observed in subjects receiving 25 µg of dscCfaE with 0.1 mcg of LT(R192G). CONCLUSION: Both ETEC adhesin vaccine prototypes were safe and immunogenic when co-administered with mLT by the ID route. The observed immune responses induced with the high dose of dscCfaE and mLT warrant further assessment in a controlled human infection model.

15.
Curr Gastroenterol Rep ; 14(5): 395-405, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22864805

RESUMEN

Campylobacteriosis is a leading cause of acute infectious diarrhea in the developing world, where it causes considerable mortality, and in developed countries, where it accounts for significant healthcare and other costs. Evidence has emerged from basic science, clinical, and epidemiological domains that suggests that Campylobacter infection is not limited to acute illness but is also involved in the development of well-described extraintestinal sequelae, such as the Guillain-Barré syndrome and reactive arthritis, and may also contribute to the pathogenesis of chronic gastrointestinal conditions. This review will focus on the role of Campylobacter infection as a risk factor for the development of chronic gastrointestinal sequelae, such as functional gastrointestinal disorders, with which irritable bowel syndrome has been most frequently associated, inflammatory bowel disease, and celiac disease.


Asunto(s)
Infecciones por Campylobacter/complicaciones , Campylobacter/patogenicidad , Enfermedad Celíaca/etiología , Enfermedades Gastrointestinales/etiología , Enfermedades Inflamatorias del Intestino/etiología , Infecciones por Campylobacter/epidemiología , Costo de Enfermedad , Enfermedades Gastrointestinales/epidemiología , Humanos , Incidencia , Enfermedades Inflamatorias del Intestino/epidemiología
16.
Mil Med ; 177(6): 627-34, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22730836

RESUMEN

The Current Topics in Military Tropical Medicine series provides focused reviews addressing specific questions faced by operational military medical personnel. This issue in the series explores the diagnosis and management of persistent diarrhea in deployed service members.


Asunto(s)
Diarrea/terapia , Enfermedades Gastrointestinales/diagnóstico , Personal Militar , Viaje , Adulto , Algoritmos , Infecciones por Campylobacter/diagnóstico , Infecciones por Campylobacter/terapia , Campylobacter jejuni , Enfermedad Crónica , Diarrea/microbiología , Humanos , Masculino
17.
Sleep Med ; 100: 404-409, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36240601

RESUMEN

BACKGROUND: Acute diarrhea is the most frequent diagnosis among ill travelers. Sleep loss may weaken the body's defense against pathogens and increase susceptibility to infection. The relationship between sleep and infectious diarrhea has not been studied and was assessed utilizing data from a controlled human infection model (CHIM) for enterotoxigenic Escherichia coli (ETEC). METHODS: During a CHIM assessing the efficacy of an immunoprophylactic targeting ETEC against moderate-to-severe diarrhea (MSD) following challenge, we measured sleep via actigraphy over an 8-day inpatient period. We hypothesized better sleep pre-challenge would predict illness symptomatology following challenge. RESULTS: Among 57 participants (aged 34.4 ± 8.1 years, 64% male), there was no relationship between sleep metrics and incidence of MSD. However, longer total sleep time the night preceding ETEC challenge was associated with lower maximum 24 h diarrhea volume (B = -1.80, p = 0.01) and total diarrhea volume (B = -2.45, p = 0.01). CONCLUSIONS: This novel study showed that shorter sleep duration predicted diarrhea severity over the course of an ETEC infection. Future work should experimentally manipulate sleep to further clarify its impact on diarrhea-related outcomes for ETEC and other important enteric pathogens.


Asunto(s)
Escherichia coli Enterotoxigénica , Infecciones por Escherichia coli , Masculino , Humanos , Femenino , Anticuerpos Antibacterianos , Diarrea/prevención & control , Infecciones por Escherichia coli/prevención & control , Sueño
18.
Vaccine ; 39(39): 5548-5556, 2021 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-34419306

RESUMEN

INTRODUCTION: Enterotoxigenic Escherichia coli (ETEC) is a common cause of infectious diarrhoea and a leading cause of morbidity and mortality in children living in resource-limited settings. It is also the leading cause of travellers' diarrhoea among civilian and military travellers. Its dual importance in global public health and travel medicine highlights the need for an effective vaccine. ETEC express colonization factors (CFs) that mediate adherence to the small intestine. An epidemiologically prevalent CF is coli surface antigen 6 (CS6). We assessed the safety and immunogenicity of a CS6-targeted candidate vaccine, CssBA, co-administered intramuscularly with the double-mutant heat-labile enterotoxin, dmLT [LT(R192G/L211A)]. METHODS: This was an open-label trial. Fifty subjects received three intramuscular injections (Days 1, 22 and 43) of CssBA alone (5 µg), dmLT alone (0.1 µg) or CssBA (5, 15, 45 µg) + dmLT (0.1 and 0.5 µg). Subjects were actively monitored for adverse events for 28 days following the third vaccination. Antibody responses (IgG and IgA) were characterized in the serum and from lymphocyte supernatants (ALS) to CS6 and the native ETEC heat labile enterotoxin, LT. RESULTS: Across all dose cohorts, the vaccine was safe and well-tolerated with no vaccine-related severe or serious adverse events. Among vaccine-related adverse events, a majority (98%) were mild with 79% being short-lived vaccine site reactions. Robust antibody responses were induced in a dose-dependent manner with a clear dmLT adjuvant effect. Response rates in subjects receiving 45 µg CssBA and 0.5 µg dmLT ranged from 50 to 100% across assays. CONCLUSION: This is the first study to demonstrate the safety and immunogenicity of CssBA and/or dmLT administered intramuscularly. Co-administration of the two components induced robust immune responses to CS6 and LT, paving the way for future studies to evaluate the efficacy of this vaccine target and development of a multivalent, subunit ETEC vaccine.


Asunto(s)
Toxinas Bacterianas , Escherichia coli Enterotoxigénica , Infecciones por Escherichia coli , Proteínas de Escherichia coli , Vacunas contra Escherichia coli , Anticuerpos Antibacterianos , Niño , Enterotoxinas , Infecciones por Escherichia coli/prevención & control , Proteínas de Escherichia coli/genética , Vacunas contra Escherichia coli/efectos adversos , Calor , Humanos , Vacunas de Subunidad
19.
MSMR ; 27(8): 4-7, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32876465

RESUMEN

Travelers' diarrhea (TD) has historically been common among deployed military personnel and remains a leading infectious disease threat to this population. The risk factors, work performance, and illness associated with TD among British active duty service members exercising at British Army Training Unit Kenya (BATUK) were assessed. Members of the British Army who were finishing a 6-week combined arms training exercise in Nanyuki, Kenya, completed routine public health surveillance questionnaires. Survey data included information on demographics, rank, risk factors, illness characteristics, and impact on work performance. Among 1,227 survey respondents, 21.9% (n=269) reported having diarrhea, with an estimated 824 days of total missed work and 1,215 days of work underperformance. The majority of cases (54.6%) had multiple diarrheal episodes. One quarter (24.9%) of the respondents with TD sought medical care and 19.7% were bedded down because of their illness. There were no statistically significant differences between the TD and no TD groups on the demographic characteristics examined. The strongest risk factor for diarrhea was having a colleague with diarrhea (adjusted odds ratio=51.78; 95% confidence interval: 29.44-91.06). TD had a notable impact on duty status and operational capability. Efforts are needed to improve BATUK's participant education on the importance of diarrheal disease prevention and management.


Asunto(s)
Diarrea/epidemiología , Personal Militar/estadística & datos numéricos , Adulto , Estudios de Casos y Controles , Estudios Transversales , Diarrea/fisiopatología , Femenino , Humanos , Kenia , Masculino , Encuestas y Cuestionarios , Reino Unido/epidemiología , Adulto Joven
20.
Vaccine ; 38(21): 3773-3779, 2020 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-32253098

RESUMEN

BACKGROUND: Trials assessing the safety of novel vaccine candidates are essential in the evaluation and development of candidate vaccines. Immunogenicity and dose-sparing features of vaccination approaches which target skin and associated tissues have garnered increased interest; for enteric vaccines, cutaneous vaccination has been of particular interest. Cutaneous vaccine site reactions are among the most common and visible vaccine related adverse events (AEs) when skin routes are used. Regulatory guidelines governing classification of severity focus on functional impact but are insufficient to characterize a spectrum of skin reaction and allow for comparisons of routes, doses and products with similar local cutaneous AEs. OBJECTIVES: Our group developed a grading scale to evaluate and compare cutaneous vaccine site reactions ahead of early-phase clinical trials of intradermal (ID) and transcutaneous immunization (TCI) with enterotoxigenic E.coli (ETEC) vaccine candidates (adhesin-based vaccine co-administered with LTR192G). We reviewed existing methods for characterizing the appearance and severity of local vaccine site reactions following TCI and ID vaccination and devised a standardized vaccine site appearance grading scale (VSAGS) for use in the clinical development of novel ETEC vaccine candidates which focused on pathophysiologic manifestation of skin findings. RESULTS: Available data from published reports revealed erythematous papules and pruritus were the most common local AEs associated with TCI. Frequency of reactions varied notably across studies as did TCI vaccination methodologies and products. ID vaccination commonly results in erythema and induration at the vaccine site as well as pigmentation changes. There was no published methodology to characterize the spectrum of dermatologic findings. CONCLUSION: ID and TCI vaccination are associated with a largely predictable range of cutaneous AEs. A grading scale focused on the appearance of cutaneous changes was useful in comparing cutaneous AEs. A standardized grading scale will facilitate documentation and comparison of cutaneous AEs.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Vacunas contra Escherichia coli/efectos adversos , Piel/patología , Vacunación/efectos adversos , Administración Cutánea , Ensayos Clínicos como Asunto , Escherichia coli Enterotoxigénica , Humanos , Inmunización , Inyecciones Intradérmicas/efectos adversos
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