Antimotility Agents Research Articles

P-118. Patient Reported Outcomes (PRO) Analysis of the Phase 2 Multi-Center, Prospective, Randomized, Double-Blind Study Assessing Nitazoxanide for the Treatment of Norovirus in Hematopoietic Stem Cell and Solid Organ Transplant Recipients

Abstract Background Norovirus (NoV) results in relapsing, remitting diarrhea in immunocompromised hosts (ICH). No prospective studies of existing therapies including nitazoxanide (NTZ) have included evaluation of patient reported outcomes (PRO) or reported impact on patient quality of life (QOL). Methods We conducted a NIH-sponsored multi-center, prospective, randomized, double-blind study of NTZ for the treatment of NoV in adult HSCT and SOT recipients. Subjects with a positive NoV testing and active GI symptoms were randomly assigned (1:1) to NTZ 500 mg twice daily or placebo (P) for 56 consecutives doses and followed for 6 months. PRO diary assessments based on recognized questionnaires were collected: IBSQOL, EuroQOL, PROMIS Emotional, PROMIS GI, PANAS and PROMIS Physical Function Questionnaires.Figure 1.Patient-Reported Quality of Life by EuroQOL-5 Dimension and Study Day – Nitazoxanide vs Placebo, mITT Population Results 31 subjects (16 NTZ, 15 P) were enrolled (Table 1). Early withdrawal was documented in 5 subjects from each group. Thirty (30) had received solid organ transplants. Most had chronic (> = 14d) symptoms (77%). Based on data collected from PRO diaries, there were no significant between-treatment differences for change in diarrhea or nausea from baseline to day 180 (p=0.590 and 0.271). There was no significant difference in median time to 50% reduction in antimotility agents (NTZ 7d vs placebo 5d, p=0.830). However, the EuroQOL-5 questionnaire responses showed that patients seem to report less problems with anxiety/depression (NTZ 29% vs placebo 38%), mobility (21% vs 50%) and usual activities (29 vs 64%) at the end of study drug with NTZ (Fig. 1). There were significant difference in improvement of reported incontinence events between groups over time, which likely impact perceived QOL and activity level. Importantly, analysis of PROs demonstrates the significant and longstanding impact of NoV on ICH with high rates of anxiety/depression and reduced mobility at 180 days. Conclusion PROs from this study provided significant insight into the expected course of NoV infection in ICH, including persistent but intermittent diarrhea, prolonged anxiety and depression, reduced mobility and reduced usual activity even out to 180 days post monitoring. This study provides data to support the use of PROs as primary endpoints in these studies. Disclosures Ajit Limaye, Professor/MD, Memo: Advisor/Consultant|merck: Advisor/Consultant|merck: Grant/Research Support|moderna: Advisor/Consultant|moderna: site investigator|NobelPharma: DSMB member Steven A. Pergam, MD, MPH, Cidara: Advisor/Consultant|F2G: Advisor/Consultant|Global Life Technologies: Grant/Research Support|Symbio: Advisor/Consultant Michael D. Green, MD, MPH, ADMA: Advisor/Consultant|Bristol Myers Squibb: Advisor/Consultant|ITB-MED: Advisor/Consultant|kamada: Honoraria Lara A. Danziger-Isakov, MD, MPH, Aicuris: clinical research contract, paid to institutio|Ansun BioPharma: clinical research contract, paid to institution|Astellas: Advisor/Consultant|Astellas: clinical research contract, paid to institutio|Merck: clinical research contract, paid to institutio|Pfizer: Grant/Research Support|Takeda: clinical research contract, paid to institutio Michael Ison, MD MS, GlaxoSmithKline: Grant/Research Support|UpToDate: Royalties

P0653 Patients with ileo-anal J-Pouch display altered, higher pouch contractility than controls as measured with motility MRI

Abstract Background After colectomy, many patients with ileo-anal pouch anastomosis develop high bowel frequency and become refractory to antimotility agents despite normal pouch morphology. Recently, it has been shown that Liraglutide but not placebo reduces bowel frequency1. We investigate the potential underlying contractility (hereafter referred to as ‘motility’) of the pouch with motility MRI (which measures regional peristalsis) in this retrospective study. Methods 30 patients with ileoanal pouches (mean age 44 years, 9 female) and 10 controls (mean age 44, 5 male: 5 with non-colonic Crohn’s disease, 5 with ulcerative colitis) underwent standard MR Enterography including motility ‘cine’ imaging. All pouches were delineated by an experienced sub-specalty radiologist (Entrolytics, Motilent, UK). Clinical observations were extracted from medical records by a sub-speciality Gastroenterologist. Motility assessment of the pouch/rectum was performed using GIQuant (Motilent, London, UK) with a bowel wall contour placed at the pouch, to produce a numerical score for pouch/rectum wall motion.We 1) compared pouch against normal rectum, 2) compared pouch motility in the cohort separated by inflammation activity as seen on pouchoscopy, 3) compared frequency against pouch motility and finally 4) against symptoms via clinical assessment from patient notes. Non-parametric statistics were used. Results 1. Mean pouch motility score was 157 (25 to 391) and in controls was 59 (23 to 104). Difference of 98, P = 0.002. 2. Patients with pouchoscopy were dichotomised into normal vs non-normal. Endoscopically normal pouch had motility of 185 vs 119, P = 0.05. 3. Based on Pouch Frequency, when dichotomised into =>10 (bowel movements) and <10 (bowel movements), pouch motility was 205 vs 116, a significant difference of 88 units P = 0.007 and correlation of bowel movements with motility showed positive relationship, Rho = 0.46, p =0.01. 4. Based on Patient Reported Symptoms, dichotomised as ‘symptomatic’ vs ‘coping,’ pouch motility was 183 vs 132 with a non-significant difference of 50 units P = 0.1. Conclusion J-Pouch demonstrates markedly altered physiology with an elevated contractility phenotype, in terms of peristalsis, compared to disease-free controls. Pouch motility was associated with pouch frequency providing supportive mechanistic evidence for the efficacy of Liraglutide1. A weaker association was seen with pouchoscopy and symptoms which may now be followed up in an appropriately powered study.

Angiotensin-Converting Enzyme Inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB) Use are Associated With Increased Readmission After Ileostomy Creation.

High output is a common cause for readmission after new ileostomy creation. The loss of sodium leads to compensatory activation of the renin-angiotensin-aldosterone system (RAAS). Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are first-line therapy for hypertension in the United States. We hypothesized that concurrent use of ACEI/ARB increases the risk of readmission following new ileostomy creation due to the loss of this compensatory mechanism. Patients undergoing ileostomy creation between 2009-2022 at an integrated managed health care system were included in this retrospective study. Primary outcomes were hospital readmission and ED visit within 30-days. Additional variables included ACEI/ARB use, ileostomy type, Charlson Comorbidity Index, additional antihypertensives at discharge (furosemide, hydrochlorothiazide, spironolactone, amlodipine, nifedipine, and diltiazem), and readmission diagnosis. Descriptive and advanced statistical analysis was completed with SPSS. Of 540 patients, 41.9% were readmitted or visited an ED within 30 days. There was no difference in readmission or ED visit based on age, gender, or ileostomy type. Patients discharged with ACEI/ARB (37.4% vs 25.5%, P = .005) and additional antihypertensives (37.2% vs 17.3%, P = .006) were at a higher risk for readmission. Inhibition of RAAS is associated with increased risk for hospital readmission. In patients with hypertension undergoing ileostomy creation, individualized care plans are needed with earlier antimotility agent use or intravenous rehydration plans.

A REVIEW ON CURRENT TRENDS IN Helicobacter pylori MANAGEMENT WITH MEDICINAL PLANTS AND ITS CONSTITUENTS

Helicobacter pylori is a bacterium associated with gastric diseases and disorders of the upper gastrointestinal tract. The gram-negative bacterium Helicobacter pylori is known as a persistent colonizer of the human stomach, and this bacteria is also involved in extra-intestinal diseases. In 1994, the International Agency for Research on Cancer, World Health Organization classified H. pylori as a class 1 carcinogen, the only bacterium given this classification. Besides, the emergence of H. pylori resistance to antibiotics has been a major clinical challenge in the field of gastroenterology, and this concern has been shown an increasing tendency in many regions of the world. To overcome the current circulating difficulties, new potential therapeutic targets were uncovered to find active substances for the treatment of H. pylori infection. Several medicinal plants and their isolated compounds have been reported for their antimicrobial activity against H. pylori. It is demonstrated that they are efficacious against H. pylori strains that are resistant to drugs. The mechanism of action of many of these plant extracts and plant-derived compounds is different from that of conventional antibiotics. Therefore, natural compounds are emerging as a potential source of raw materials with diverse mechanisms of action. Some commonly known mechanisms can be listed as anti-urease activity, anti-adhesive activity, anti-inflammatory and gastroprotective activity, and effects on the oxidative stress process. Recently, new classes of drugs with reasonable antibacterial mechanisms against H. pylori have also been mentioned, including (1) anti-biofilm agents, (2) anti-virulence molecules (anti-VacA, anti-CagA agents, toxin BabA and LPS inhibitors, anti-motility agents, Helicobacter pylori quorum sensing inhibitors), (3) mucolytic agents, and (4) compounds that impact on essential proteins in the physiology of H. pylori such as inosin-5‘monophosphate dehydrogenase and HsrA inhibitors. This review article aims to summarize current prospects, identify possible novel targets, and be considered as a complementary therapy in the eradication treatment against Helicobacter pylori.

Abstract PO3-13-01: ONTARGET: Phase 3 randomized, double-blind, placebo-controlled trial evaluating crofelemer for the prophylaxis of diarrhea in adult patients with solid tumors receiving targeted therapies with or without standard chemotherapy

Abstract Background: Cancer therapy-related diarrhea (CTD) can result in fluid and electrolyte losses, malnutrition, unexpected hospitalization, and poor quality of life (QoL) of patients with cancer. CTD can also limit response to cancer therapy due to treatment interruption, discontinuations, or dose modifications. CTD is a common side effect of targeted therapies (TTx) (e.g., inhibitors of tyrosine kinases, EGFR, CDK4/6, VEGFR) with or without concomitant chemotherapy (ChemoRx) for treating various solid tumors, including breast cancer (BRCA). TTx induce CTD by increasing intracellular cAMP or Ca++ leading to activation of two intestinal Cl- channels, CFTR and CaCC, increasing luminal secretion of Cl- and accompanying loss of Na+ and fluids. For most patients with cancer, CTD management with dietary modifications and antimotility agents is suboptimal. New drugs are needed to prevent or mitigate CTD, a huge unmet medical need. Since the mechanism of CTD is mostly secretory, we hypothesized that crofelemer (CRO) an oral botanical drug purified from the latex of the Croton lechleri tree that modulates both intestinal Cl- ion channels, CFTR and CaCC, may benefit preventing CTD. CRO is negligibly absorbed orally and is FDA-approved for symptomatic relief of noninfectious diarrhea in adults with HIV/AIDS on antiretroviral therapy. In a phase 2 study in 51 women with BRCA receiving THP/TCHP (HALT-D), CRO given daily, compared to standard of care (SOC), for 2 cycles resulted in grade ≥2 diarrhea in significantly fewer subjects (9.0% vs. 33.3%, p=0.0361) in cycle 2 and was 1.8 times more likely to resolve diarrhea (p=0.0425) (Pohlmann et al. 2022; NCT02910219) Methods: ONTARGET (NCT04538625) is a randomized, multicenter, international, double-blind, placebo-controlled pivotal trial evaluating CRO for the prophylaxis of diarrhea in adults with solid tumors receiving 1 of 24 diarrheagenic TTx known to cause any grade diarrhea in ≥50% of patients. This study is designed to show a 40% reduction in loose/watery (LW) stools in patients randomized 1:1 CRO to placebo (1-sided α=0.025) and stratified by tumor type (lung, breast, other) and TTx type (CDK4/6i, TKIs, or other). Eligible patients require a new TTx, ECOG 0-2, lack baseline diarrhea and can complete patient-reported outcome (PRO) diary using a mobile device. Key exclusions include immunotherapy, neratinib or irinotecan (due to required SOC antimotility prophylaxis), colitis/ostomy/abdominal surgery ≤3 months, or antidiarrheal/laxative/antibiotic use ≤7 days. Oral CRO 125 mg or a matching placebo is administered twice daily concomitant with TTx initiation and continued for 12 weeks, with the option to continue blinded treatment through 24 weeks. Rescue antidiarrheal medication is permitted when participants have ≥4 LW stools and can continue thereafter. PRO diaries capture clinical and QoL outcomes. The primary endpoint is the mean weekly number of LW stools over 12 weeks based on PRO diary using the Bristol Stool Form Scale. Key secondary endpoints include time to TTx/ChemoRx dose reduction or discontinuation, time to ≥4 LW stools for 2 consecutive days, fecal incontinence episodes, and time to durable responder status (≤7 LW stools/week). PRO diaries capture: 1) LW stool frequency daily; 2) TTx/ChemoRx dose reduction/discontinuation, use of antimotility drugs, fecal incontinence daily; and 3) CTD’s impact on QoL weekly. Results: Enrollment is complete with 287 patients from 46 sites in 5 countries from 8/2020 through 5/2023. Primary cancer diagnoses were breast (183; 64%), lung (37; 13%), renal (36; 12.5%), liver (12; 4%) and other (19; 6.5%). Most frequent TTx were CDK 4/6 and EGFR inhibitors. To our knowledge this trial evaluating CRO is the first prospective, randomized double blind study for prevention of targeted therapy CTD. Topline results for the study are expected in Q4 2023 and will be reported at the meeting. Funded by Napo Pharmaceuticals (a Jaguar Health Co.) Citation Format: Lee Schwartzberg, Pablo Okhuysen, Eric Roeland, Gregory Vidal, Kathleen Harnden, Richard Zuniga, Snezana Bosnjak, Sreedevi Daggubati, Daliborka Bursac. ONTARGET: Phase 3 randomized, double-blind, placebo-controlled trial evaluating crofelemer for the prophylaxis of diarrhea in adult patients with solid tumors receiving targeted therapies with or without standard chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-01.

Efficacy and Safety of Liraglutide in Patients With an Ileal Pouch-Anal Anastomosis and Chronic High Bowel Frequency: A Placebo-Controlled, Crossover, Proof-of-Concept Study.

After colectomy with ileoanal pouch anastomosis (IPAA), many patients develop high bowel frequency (BF) refractory to antimotility agents, despite normal IPAA morphology. Low circulating levels of glucagon-like protein-1 (GLP-1), a modulator of gastroduodenal motility, have been reported after colectomy. Double-blind crossover study of 8 IPAA patients with refractory high BF treated with daily administration of the GLP-1 receptor agonist liraglutide or placebo. Liraglutide, but not placebo, reduced daily BF by more than 35% ( P < 0.03). Larger randomized controlled studies are warranted to delineate the treatment potential of GLP-1 receptor agonists in IPAA patients suffering from noninflammatory high BF.

Effect of Glucagon-Like Peptide-1 Receptor Agonists on Bowel Preparation for Colonoscopy.

Inadequate bowel preparation can result in decreased diagnostic accuracy and therapeutic safety of colonoscopy for colon cancer screening. The Boston Bowel Preparation Scale (BBPS) has been used to assess the quality of bowel preparation. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are commonly used medications for diabetes mellitus and obesity that are known to delay gastrointestinal motility. We hypothesized that the use of GLP-1RA would be associated with decreased quality of bowel preparation. We performed a retrospective cohort study of patients who underwent screening or surveillance colonoscopy at a large academic medical center between December 2021 and December 2022. We included patients taking any GLP-1RA for diabetes or obesity during colonoscopy defined as our cases, and patients who were prescribed GLP-1RA at one point but not within 3 months of colonoscopy defined as our controls. We excluded patients on any promotility or antimotility agents and those without BBPS recorded on their procedure report. Independent t test assessed statistical differences in the case and control groups to compare the quality of bowel preparation for continuous variables, and the χ 2 test was used for categorical variables. Multivariate linear regression including diabetes as a covariate was also performed for continuous variables, and multivariate logistic regression was performed for categorical variables. A total of 446 patients were included in the study, comprising 265 (59%) cases and 181 controls (41%). There were no statistically significant differences between groups at baseline except for the diagnosis of diabetes ( P = 0.001) with a higher proportion of patients with diabetes in the cases. The mean BBPS was significantly higher in controls (7.0 ± 1.9 vs 7.5 ± 2.4, P = 0.046) when controlling for diabetes. The percentage of patients with a total BBPS score of <5 was significantly higher in cases (15.5% vs 6.6%, P = 0.01). The proportion of patients who required a repeat colonoscopy due to poor bowel preparation was also significantly higher in cases (18.9% vs 11.1%, P = 0.041). The use of GLP-1RA was associated with a statistically significantly lower quality of bowel preparation, with additional clinical significance given a notable difference in the need for a repeat colonoscopy. It will be essential to understand the cumulative effect of medications that may delay gastric emptying on the quality of bowel preparation to better understand the appropriate measures and counseling that need to be taken before undergoing outpatient colonoscopies.

Pharmacological management of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common longstanding condition with a variety of symptoms including constipation, diarrhoea and abdominal cramps or bloating. There are no specific causes of IBS; therefore, symptoms and management are individualised to each patient. Management strategies involve lifestyle advice on diet and exercise, medications and psychological therapies. IBS can be extremely debilitating to patients’ quality of life and is usually diagnosed as a process of elimination of other gastrointestinal conditions that can have similar symptoms, such as inflammatory bowel disease. Medications to manage IBS include laxatives, antispasmodics, antimotility agents and neuromodulators, as IBS is believed to be a disorder of the gut–brain axis.

Racecadotril Versus Loperamide in Acute Radiation Enteritis: A Randomized, Double-Masked, Phase 3, Noninferiority Trial

There is currently no gold standard for the management of acute radiation enteritis. We compared the efficacy and safety of Racecadotril, an anti-hypersecretory drug, versus Loperamide, an anti-motility agent, in acute radiation enteritis. We conducted a randomized, double-masked, non-inferiority trial at a single research institute. Patients receiving curative radiation for pelvic malignancies, who developed grade 2 or 3 diarrhea (as per Common Terminology Criteria for Adverse Events, v 4.0) were included in the study. Patients in the intervention arm received Racecadotril and placebo. Patients in the control arm received Loperamide and placebo. The primary outcome was the resolution of diarrhea, 48 hours after the start of treatment. 162 patients were randomized between 2019 and 2022. On intention-to-treat analysis, 68/81 patients, 84%, (95% CI, 74.1%-91.2%) in the Racecadotril arm and 70/81, 86.4%, (95% CI, 77.0%-93.0%) in the Loperamide arm improved from grade 2 or 3 diarrhea to grade 1 or 0, (P= .66, χ2 test). The difference in proportion was 2.4% (95% CI: -8.5% to 13.4%). Since the upper boundary of the 95% CI crossed our non-inferiority margin of 10% (13.4%) we could not prove the non-inferiority of Racecadotril over Loperamide. Rebound constipation was more in the Loperamide arm compared to Racecadotril (17.3% vs 6.2%; P=.028) CONCLUSIONS: The non-inferiority of Racecadotril to Loperamide in acute radiation enteritis could not be demonstrated. However, Racecadotril can be the preferred drug of choice in acute radiation enteritis because Racecadotril does not affect bowel motility, achieved a high clinical success rate similar to that of Loperamide, and was associated with lesser side effects.

Nutritional management of a malnourished cancer patient with high output ileostomy

High output stoma is a complication that may follow ileostomy formation, with an incidence of 23%. There is no general consensus on the limit of ileostomy production to be defined as high output. However, output of more than 2000 mL/day, can cause fluid and electrolyte imbalance, also malnutrition due to reduced nutrient absorption. Delay in recognition and treatment, especially in cancer patient with high risk of malnutrition, can further deteriorate patient’s nutritional status. A 43-year-old malnourished female with ascending colon cancer underwent tumor resection and ileocolostomy surgery. Starting from the third postoperative day, ileostomy effluent drastically increased to 2700 mL/day, causing severe hyponatremia, hypokalemia, and hypomagnesemia. Risk factors of high output stoma identified were routine prokinetic medication use and unresolved malignancy-related retroperitoneal abscess. Moreover, increment of food intake in the first days after surgery, specifically food high in insoluble fiber, was one of the contributing factors. High output stoma was then resolved by abscess drainage, discontinuation of prokinetic agent, and administration of antimotility agent. Hyponatremia and hypomagnesemia improved with correction, whereas hypokalemia needed longer time to resolve. Enteral nutrition was maintained and increased gradually to prevent further malnutrition. Oral hypotonic fluid intake was limited to 1000 mL/day and isotonic solution consumption was advised. High stoma production due to hypersecretory phase after ileostomy was expected, but thorough management would prevent patient’s deterioration that was caused by the fluid, electrolyte, and nutritional imbalances.

Pharmacological management of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common longstanding condition with a variety of symptoms including constipation, diarrhoea and abdominal cramps or bloating. There are no specific causes of IBS; therefore, symptoms and management are individualised to each patient. Management strategies involve lifestyle advice on diet and exercise, medications and psychological therapies. IBS can be extremely debilitating to patients' quality of life and is usually diagnosed as a process of elimination of other gastrointestinal conditions that can have similar symptoms, such as inflammatory bowel disease. Medications to manage IBS include laxatives, antispasmodics, antimotility agents and neuromodulators, as IBS is believed to be a disorder of the gut–brain axis.

Abstract 570: Dual acting bone defender agents inhibit prostate cancer-mediated bone destruction

Abstract Introduction: Bone metastasis is clinically observed in approximately 90% of patients with advanced prostate cancer (PCa). Metastatic bone destruction is driven by a self-reinforcing process coupling osteoclast (OC)-mediated bone degradation to PCa growth, and where cell movement acts to keep these two cooperating cell types in close proximity and to move them across the bone surface. We sought to create a new class of therapeutics that would be highly effective at inhibiting PCa-mediated bone destruction by targeting both OC function and cell motility. Methods: We synthesized new chemical entities, termed Dual Acting Bone Defender agents (DABDs), that couple the small molecule anti-motility agent, KBU2046, with bisphosphonate (bis), through a chemical linker. Assays for in vitro efficacy included: cell migration and invasion, binding to bone mineral, inhibiting osteoclast (OC)-mediated bone destruction, inhibition of Raf1 phosphorylation and inhibition of protein prenylation. In vivo assays included intra-cardiac (IC) injection of human PCa cells into mice, followed by real time monitoring of tumor growth and bone destruction by IVIS and CT imaging, respectively. Findings: We successfully created a novel route of chemical synthesis allowing us to access and probe unique chemical space, providing for single small molecules with bis functional groups linked to a KBU2046 core through a linker moiety. DABDs retain the cellular and molecular characteristics of KBU2046 and bis. Like KBU2046, they inhibit PCa cell motility and phosphorylation of Raf1 on its activation motif. They also inhibit the motility of breast and lung cancer cells. Like bis, they inhibit OC-mediated bone mineral destruction, prenylation of Ras small GTPase proteins, and chemically bind hydroxyapatite. Administered prior to IC injection, DABDs are so effective that they prolong animal survival and inhibit bone destruction in a dose-dependent manner. In mice with established bone metastasis to the femur, after IC injection, DABDs inhibit the growth of tumors. Doses 3,000 fold higher than that required for efficacy had no clinical or critical organ toxicity. Conclusions: DABDs represent a new multifunctional class of therapeutic agents that inhibit PCa-mediated bone destruction and have a high potential for advancing clinical efficacy in PCa patients with bone metastasis. Citation Format: Fangfang Qiao, Ryan Gordon, Abhinandan Pattanayak, Katelyn O’Neill, Nina Chaika, Weining Chen, Rachel Rhatigan, Raymond Bergan. Dual acting bone defender agents inhibit prostate cancer-mediated bone destruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 570.

Factors affecting dialysis duration in children with Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome.

Predicting disease severity can be informative for management of HUS. Dialysis requirement, volume depletion, elevated white blood cell counts, very young age, and use of antimotility agents are known factors associated with severe HUS. A retrospective cohort analysis was performed to identify factors associated with dialysis duration using electronic medical record and chart review of 76 children ≤ 18years of age at presentation with STEC-HUS identified through billing data from July 2008 to April 2020 at James Whitcomb Riley Hospital for Children, Indiana University, Indiana. Novel findings associated with prolongeddialysis duration were age ≥ 6years old at presentation (p = 0.041) and lack of drop in platelets below 60,000/mm3 anytime during the illness (p = 0.015). In addition, children with NSAID exposure trended longer on dialysis: 15days with vs. 10days without (p = 0.117). Known risk factors for severe disease including elevated peak white blood cell (WBC) count and higher hematocrit at presentation were also associated with longer dialysis duration: children with peak WBC > 20,000/mm3 were on dialysis for 15 vs. 9.5days (p = 0.002) and in children on dialysis ≥ 14days hematocrit at presentation was 29.6% vs. 24.2% (p = 0.03). Children requiring dialysis for 20days or longer were more likely to be on anti-hypertensive medications (p = 0.025) and have chronic kidney disease at 12-month follow up (p = 0.044). Age ≥ 6, elevated WBC count > 20,000/mm3, higher hematocrit at presentation, lack of drop in platelets to < 60,000/mm3, and possibly NSAID exposure during illness are associated with longer dialysis duration in STEC-HUS. A higher resolution version of the Graphical abstract is available as Supplementary information.

Pediatric sigmoid colonic perforation with Campylobacter enterocolitis: a case report and review of the literature

BackgroundCampylobacter-related infectious gastroenteritis is common and usually self-limited. Intestinal perforation is a rare complication of the infectious colitis caused by Campylobacter, and only handful of cases have been reported. This is the first published case report of pediatric Campylobacter intestinal perforation located in the sigmoid colon.Case presentationA 15-year-old previously Taiwanese healthy boy presented with 5 days of fever up to 39.8 °C, with right lower quadrant abdominal pain and watery diarrhea. Although he received antimotility agents and antipyretics at a local clinic to relieve symptoms, he came to the emergency department with signs of shock manifesting as hypothermia to 35.2 °C, tachycardia, and low blood pressure. Laboratory testing demonstrated leukocytosis with left shift and significant elevation of C-reactive protein. Stool and blood cultures were obtained, and he was admitted for fluid challenge and antibiotic treatment. On the second day of admission, he suffered from sudden onset of severe, diffuse abdominal pain. Physical examination revealed muscle guarding, rebounding tenderness, and silent bowel sound. Abdominal X-ray showed subdiaphragmatic free air at standing view. The patient underwent emergent exploratory laparotomy, which revealed sigmoid colon perforation about 0.5 cm. Enterolysis and repair of sigmoid colon were performed. Intraoperative stool specimen nucleic acid amplification testing had turned positive for Campylobacter spp. with negative results for other bacterial pathogens. His symptoms improved and he tolerated food well, and was discharged 15 days after admission.ConclusionsWe present this case because of the rarity of Campylobacter-induced sigmoid colon perforation in the pediatric population. It is important to keep in mind that sigmoid colon perforation can be due to an infectious cause, and one of the culprits can be Campylobacter. Infectious colitis caused by Campylobacter spp. should be managed cautiously and the use of antimotility agents in such conditions should be considered judiciously.

S2001 Chronic Norovirus Infection in a Double Solid Organ Transplant Patient

Introduction: Infectious diarrhea is a common complication in the postoperative course of a solid organ transplant (SOT) recipient. While self-limiting in immunocompetent patients, transplant patients on long-term immunosuppression can have severe, prolonged disease with significant morbidity. We present a case of chronic diarrhea due to recurrent norovirus infection in a double SOT patient to encourage early recognition. Case Description/Methods: A 61-year-old male presented with 35-pound weight loss despite a good appetite and large-volume watery diarrhea intermittently for 2 years. He had a liver-kidney transplant 14 years prior secondary to cryptogenic cirrhosis and renal cell carcinoma. Immunosuppression consisted of prednisone, tacrolimus, and mycophenolate mofetil (MMF). Stool PCR was positive for norovirus and negative for other viruses, bacteria, and parasites. His MMF dose was reduced with no benefit. He was discharged with supportive care with initial improvement in the diarrhea but returned to the hospital 4 other times with worsening diarrhea and weight loss. Infectious workup was persistently positive for norovirus. Bi-directional endoscopy with biopsies revealed colonic mucosa with rare epithelial apoptosis, chronic duodenitis, and increased intraepithelial lymphocytosis in the duodenum and ileum consistent with chronic norovirus (Figure). The full diagnostic workup is detailed in Table 1. He was managed conservatively during each hospitalization with fluids and antimotility agents and recently discharged home with plans to start nitazoxanide outpatient. Discussion: Norovirus infection among SOT patients can lead to severe and symptomatic chronic infection. Patients can develop dehydration, transplant rejection, and malnutrition making them higher risk for hospitalizations and death. It is unclear why some immunocompromised patients recover spontaneously while others demonstrate a protracted course but supportive care is the mainstay of therapy. Limited case series have shown nitazoxanide to be effective in treating SOT patients with chronic norovirus infection. However, nitazoxanide needs to be continued until stool RNA studies become negative. This case highlights the importance of considering chronic norovirus when a SOT patient presents with chronic diarrhea and weight loss. Early initiation of supportive care and nutrition consultation are imperative in reducing morbidity in these patients. Nitazoxanide can be effective in patients that are refractory to supportive therapy.Figure 1.: Duodenal biopsy (A): Focal intraepithelial lymphocytosis and lamina propria plasma cell infiltrates. Terminal ileum biopsies (B,C): Focal intraepithelial lymphocytosis and lamina propria plasma cell infiltrates (B); popcorn-like epithelial apoptosis (C). Table 1. - Diagnostic Workup Test/Procedure Result Creatinine, serum 2.1 mg/dl (baseline 1 mg/dl) Stool PCR -Positive for norovirus-Negative for Clostridium difficile toxins, Salmonella, Shigella, Yersinia, and Campylobacter Osmolality, feces 420 mOsm/kg Fecal fat Abnormal Duodenal biopsy -Mucosa with intraepithelial lymphocytosis, dense plasma cell infiltrates in the lamina propria, and rare apoptotic bodies-Negative for CMV, EBV, HSV Stomach biopsy -Gastric antral and oxyntic gland mucosa with chronic inactive gastritis-Negative for H. pylori Right colon biopsy Rare epithelial apoptosis Left colon biopsy Rare epithelial apoptosis Terminal ileum biopsy Mucosa with intraepithelial lymphocytosis, dense plasma cell infiltrates in lamina propria, and rare apoptotic bodies

Antibacterial, antibiofilm, and antimotility signatures of some natural antimicrobials against Vibrio cholerae.

Vibrio cholerae is an etiological cause of cholera and has been implicated in several epidemics. Exploration of the antimicrobial signatures of culinary spices has become an important industrial tool to suppress the growth of foodborne bacterial pathogens including Vibrio spp. The antibiofilm and antimotility activities of some selected natural antimicrobial agents were then evaluated. All the extracts showed vibriostatic activities with minimum inhibitory concentration (MIC) ranging from 0.1% to 0.4%. Cinnamon and black pepper demonstrated significant biofilm inhibition activity from 94.77% to 99.77% when administered at 100% MIC. Black pepper extract also demonstrated the highest biofilm inhibition activity against the established biofilms of V. cholerae O1 and O139. Cinnamon, calabash nutmeg, and black pepper significantly inhibited swimming and swarming motility by 85.51% to 94.87%. Sub-MICs (50% and 75%) of some extracts were also effective as an antibiofilm and antimotility agent against the tested strains. The findings of our study suggest the potential application of natural antimicrobial agents such as spices in food to inhibit biofilm formation and motility, which consequently mitigate the virulence and persistence of the pathogen in the food supply chain.

High Output Stoma Complicating Nutritional Therapy in Severely Malnourished Patient With Right Ascending Colon Cancer: A Case Report

ObjectivesAscending colon cancer makes up of 27% colorectal cancers, and its incidence has continuously increased. Malnutrition is common in cancer patients, posing as a risk of poor surgical outcome. High output stoma (HOS) is a commonly encountered complication with an incidence of 23%. Not only causes fluid and electrolyte imbalance, it also deteriorates patient's nutritional status, forming a vicious cycle of malnutrition.MethodsA 43-year-old malnourished female with ascending colon cancer presented to the emergency department with signs of bowel obstruction. The patient underwent tumor resection and ileocolostomy surgery. Starting from the third postoperative day, ileostomy effluent drastically increased to 2700 mL/day. Simultaneously, severe hyponatremia, severe hypokalemia, and hypomagnesemia were observed. Intravenous electrolyte correction and antimotility drug were given. It was decided that oral nutrition intake remained to be given. Oral hypotonic fluid intake was limited to 1000 mL/day. Malignancy-related retroperitoneal abscess further complicated patient's condition.ResultsHypersecretory phase was expected in first days after ileostomy surgery. However, HOS, especially with output of more than 2000 mL/day, could cause fluid and electrolyte imbalance. Moreover, HOS could cause malnutrition due to reduced nutrient absorption. Risk factors of HOS identified in this case were prokinetic medication use and unresolved retroperitoneal abscess causing intraabdominal inflammation. Increment of food intake was also observed from prior anorexic period, specifically fruits high in insoluble fiber were consumed. Fruit pulp was found in the stoma effluent, raising concern of reduced bowel absorption capacity. High output stoma was resolved by abscess drainage, discontinuation of prokinetic agent, and administration of antimotility agent. Hyponatremia and hypomagnesemia improved with correction, whereas hypokalemia needed longer time to be resolved. Oral nutrition was maintained and increased gradually to prevent further malnutrition, while stoma production was monitored strictly.ConclusionsThis case report showed that strict evaluation on stoma production and management of HOS in malnourished cancer patients must be done promptly, preventing further deterioration.Funding SourcesNone.

Tratamiento empírico de las diarreas inflamatorias de probable origen infeccioso

Inflammatory diarrhea of infectious origin is defined as diarrhea with feces that may include mucus or blood accompanied by abdominal pain, rectal tenesmus, and fever. It requires a therapeutic approach that is mainly based on proper hydration and diet. It is essential to identify situations which require empirical antibiotic treatment, as it is not indicated in all patients. It is administered when there is severe disease (diarrhea with blood or mucus, more than six bowel movements per day, fever higher than 38.5° C, dehydration/hypovolemia that requires hospitalization, or intense abdominal pain) or certain patient risk factors are present (patients younger than 12 months or older than 50 years; immunosuppressed patients; or patients with significant heart, valvular, or atrial disease). Treatment with antimotility agents is not recommended in inflammatory diarrhea due to risk of perpetuating the infection and leading to more severe cases.

Military and Civilian Sector Practice Patterns for Short-Term Travelers' Diarrhea Self-Treatment in Adults.

ABSTRACT.The Deployment and Travel Medicine Knowledge, Attitude, Practice and Outcomes Study investigates the various clinician and traveler contributions to medical outcomes within the U.S. Military Health System. Travelers’ diarrhea is among the most common travel-related illnesses, making travelers’ diarrhea self-treatment (TDST) important for traveler health. A cohort of 80,214 adult travelers receiving malaria chemoprophylaxis for less than 6 weeks of travel were identified within the U.S. Department of Defense Military Health System Data Repository. Associated prescriptions for TDST medications within 2 weeks of chemoprophylaxis prescriptions were identified. Prescription patterns were compared by service member versus beneficiary status and site of care, military facility versus civilian facility. At military facilities, medical provider demographics were analyzed by clinical specialty and categorized as travel medicine specialists versus nonspecialists. Overall, there was low prescribing of TDST, particularly among civilian providers and military nonspecialists, despite guidelines recommending self-treatment of moderate to severe travelers’ diarrhea. This practice gap was largest among service member travelers, but also existed for beneficiaries. Compared with nonspecialists, military travel medicine specialists were more likely to prescribe a combination of an antibiotic and antimotility agent to beneficiaries, more likely to provide any form of TDST to service members, and more likely to prescribe azithromycin than quinolones when using antibiotics. Our study suggests that enhancing provider knowledge and use of travelers’ diarrhea treatment recommendations combined with improved access to formal travel medicine services may be important to increase the quality of care.

927. Clinical Characteristics and Outcomes of Norovirus Infection in Patients with Hematologic Malignancies: A Retrospective, Single Center Study

BackgroundNorovirus (NV) gastroenteritis has been identified as a cause of significant morbidity among hematopoietic stem cell transplant (HSCT) recipients, often with associated complications. Current guidelines recommend symptomatic relief with antimotility agents, rehydration, and reduction in immune suppression. Nitazoxanide (NTZ) is an anti-parasitic agent but some literature suggests a benefit of nitazoxanide therapy for NV. MethodsWe conducted a single center, retrospective chart review study and evaluated adult patients (age >18 years) who had NV infection and either: 1) underwent stem cell transplantation; or 2) received myeloablative chemotherapy within 4 weeks of NV diagnosis by positive test on gastrointestinal pathogen panel during the time period from January 2015 through March 2020. Results26 patients were reviewed. 14 patients (54%) had a history of HCST prior to infection. Three patients (12%) received both myeloablative chemotherapy and HSCT within four weeks of NV infection. Six patients (46%) had autologous, six (46%) had matched unrelated donor, and one (8%) had haploidentical allogeneic transplants. Nine (69%), three (23%), and one (8%) underwent myeloablative, reduced intensity and non-myeloablative conditioning, respectively. Median duration of diarrhea was 4.5 days (IQR = 2.25-7 days). Three (12%) patients received NTZ or intravenous immune globulin. The 6 month mortality was 42% (11/26), however, none of the deaths were directly attributable to NV infection.ConclusionNV infection led to severe diarrheal disease in our cohort. Overall mortality was high, and a trend toward increased mortality was seen among patients receiving NV-directed therapy; these patients likely received NV-directed therapy due to the severity of their illness. Clinicians must have a high suspicion for this illness and obtain PCR testing for timely diagnosis and management.Table 1. Characteristics of patients with hematologic malignancies and norovirus infection Disclosures All Authors: No reported disclosures