Anti diarrheal medication for the treatment of diarrhea induced by the Ebola virus

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1 Anti diarrheal medication for the treatment of diarrhea induced by the Ebola virus The supportive care regimens used during the Ebola hemorrhagic fever outbreak in Kikwit, Democratic Republic of the Congo and subsequent outbreaks included the alleviation of nausea and vomiting (metoclopramide, promethazine), dyspepsia (aluminum hydroxide, cimetidine, ranitidine, omeprazole), anxiety, agitation, or confusion (diazepam, chlorpromazine), and pain (paracetamol, tramadol, and morphine). In addition to these medications, patients received oral fluid rehydration, nutritional supplementation, and psychosocial support. Despite the majority of patients having diarrhea, there is no mention of anti diarrheal medication use. 1 In a review of filovirus outbreaks, analgesics, antipyretics, and antiemetic s were typically available and administered as needed. Other symptomatic treatments occasionally available included antidiarrheals, sedatives, and antipsychotics to reduce anxiety and agitation. 2 An unknown amount of the 318 patients with reported Ebola virus infection in Yambuku, Zaire in 1976 received unspecified anti diarrheal medications. One patient in the U.K. in 1976 with EBV received diphenoxylate hydrochloride and atropine sulfate for diarrhea. All other cases up through 2011 either did not report using anti diarrheal medication or did not provide information on the clinical management of the patients. In general, non antibiotic anti diarrheal medications are not recommended for diarrhea associated with fever. It is also not recommended for mucous containing diarrhea marked by inflammation, ulceration, or bleeding of the gastrointestinal tract. 3 Other articles make broad statements such as loperamide may cause dangerous prolongation of illness in patients with some forms of bloody or inflammatory diarrhea and, therefore, should be restricted to patients with non bloody stool. A recent review article claims that the anti secretory drug bismuth subsalicylate is a safe alternative in patients with fever and inflammatory diarrhea, but cites an older paper specific to the use of diphenoxylate and atropine during shigellosis to make this claim. 4,5 Additionally, when an open label, parallel comparison study compared loperamide to bismuth subsalicylate in adults with acute, infectious diarrhea, there was a lower number of unformed bowel movements and a longer diarrhea free time period in the loperamide group. 6 Another review article claims, loperamide [should not be considered] in the treatment of a acute diarrhea when an infectious origin may be presumed. 7 However, this paper cites a retrospective casecontrol series specific to loperamide worsening a Clostridium difficile infection and extrapolates the results to any infectious diarrhea. 8 One randomized, controlled trial concluded that loperamide should be considered for the treatment of infectious diarrhea, so long as it is in combination with proper antibiotics for bacillary dysentery. 9 However, based on the findings of case report, if the underlying infectious condition progresses to a severe colitis, loperamide should be discontinued as it is associated with the development of toxic megacolon. 10 A single center, randomized, double blind trial assessed bismuth subsalicylate versus placebo in healthy volunteers inoculated with the Norwalk virus. Reduction in the severity and duration of abdominal cramps and duration of GI symptoms were improved in the treatment group. There was no difference in viral excretion into the stool. 11 Data on the use of anti diarrheal medication for the treatment of infectious diarrhea is mostly limited to bacterial sources. For viral gastroenteritis, short courses of anti diarrheal medications for mild to moderate episodes are used, with weak evidence of benefit and weak evidence of causing harm (e.g., constipation like periods). 12 There are also many trials of acute diarrhea treatment in which the cause

2 of diarrhea is unknown. Presuming some of these unknown causes are viral, there have never been any post hoc analyses performed to suggest inefficacy or harm when a virus was the cause. It is difficult to extrapolate results of the literature search to diarrhea induced by the Ebola virus to diarrhea associated with severe bacterial gastrointestinal infections. The key question is: In the pathophysiology of Ebola virus disease, does diarrhea play a protective role through elimination of the infectious agent? Cytomegalovirus (CMV) infection is known to cause diarrhea and hematochezia. CMV colitis has been treated with valganciclovir in combination with high doses (24 mg/day) of loperamide. 13 In CMV colitis diarrhea refractory to loperamide, multiple case reports exist to support the use of octreotide 50 mcg subcutaneously three times daily. {Teraishi, 2008, Cytomegalovirus colitis after systemic chemotherapy in a patient with recurrent colon cancer: a case report}{nomura, 2005, Severe cytomegalovirus enterocolitis after standard chemotherapy for non Hodgkin's lymphoma}{andrews, 2003, Octreotide treatment of massive hemorrhage due to cytomegalovirus colitis} 13 Despite these successful case reports, there is still concern that concomitant administration of an anti diarrheal agent could obscure the efficacy of antiviral treatment. To further complicate the issue, secondary bacterial infections in patients with Ebola virus disease occurs at an unknown incidence.{fowler, 2014, Caring for Critically Ill Patients with Ebola Virus Disease. Perspectives from West Africa} The concern is legitimate enough for most clinical treatment protocols to include the treatment of such infections. A source of such infections may be gastrointestinal bacterial translocation, a process which may theoretically be augmented by the use of anti motility agents. A leading physician in the field in West Africa during the most current outbreak indicates that current providers are uncomfortable and hesitant to use anti diarrheal medication. He indicates that it should be a clinical trial priority due to the volume of diarrhea and volume loss that occurs. (Robert Fowler, MD, e mail communication, 10/30/14). In the United States, diphenoxylate and atropine has been used to treat Ebola induced diarrhea. Providers were aware that there was no data for its use, but reasoned that since it has not been demonstrated that it is essential to eliminate the pathogen via diarrhea, it was reasonable to administer a few doses in the setting of careful patient monitoring. Subjectively, no benefit was reported, and abdominal distention may have resulted. (Andrew Faust, PharmD, ASHP Connect Ebola Community, 10/31/14). A systematic review of the treatment of diarrhea in adults was performed in One of the questions they sought to answer was What are the effects of treatment of severe diarrhea in resource poor countries? 12 Their review indicated that there are no systematic reviews or randomized controlled trials to evaluate the benefit or harm of treating severe diarrhea with anti motility agents. We performed a PubMed search of studies in the English language through September 2014 using combinations of the terms Ebola; diarrhea or gastroenteritis or colitis or hematochezia; and antidiarrheal or loperamide or bismuth subsalicylate or diphenoxylate and atropine or octreotide or gastroenteritis or colitis. This search did not provide any evidence of trials that have addressed this question before. Therefore, the treatment of Ebola induced diarrhea will have to be based on clinical judgment with full assessment of the benefits and risks of using such therapies. Clinicians should consider the use of loperamide and/or diphenoxylate and atropine for mild to moderate Ebola induced diarrhea and also consider the addition of octreotide for the use of severe, life threatening Ebola

3 induced diarrhea. Very careful monitoring of patients should be performed with discontinuation of therapy should abdominal distention or other suspected adverse events arise. A clinical trial of antidiarrheal medication for the treatment of Ebola induced diarrhea is clinically warranted. References 1. Roddy P, Howard N, Van Kerkhove MD, et al. Clinical manifestations and case management of Ebola haemorrhagic fever caused by a newly identified virus strain, Bundibugyo, Uganda, PLoS One 2012;7:e Clark DV, Jahrling PB, Lawler JV. Clinical management of filovirus infected patients. Viruses 2012;4: DuPont HL. Acute infectious diarrhea in immunocompetent adults. N Engl J Med 2014;370: Barr W, Smith A. Acute diarrhea. Am Fam Physician 2014;89: DuPont HL, Hornick RB. Adverse effect of lomotil therapy in shigellosis. Jama 1973;226: DuPont HL, Flores Sanchez J, Ericsson CD, et al. Comparative efficacy of loperamide hydrochloride and bismuth subsalicylate in the management of acute diarrhea. Am J Med 1990;88:15s 9s. 7. Franceschi F, Scaldaferri F, Riccioni ME, et al. Management of acute dyarrhea: current and future trends. Eur Rev Med Pharmacol Sci 2014;18: Kato H, Iwashima Y, Nakamura M, Nakamura A, Ueda R. Inappropriate use of loperamide worsens Clostridium difficile associated diarrhoea. J Hosp Infect. England2008: Murphy GS, Bodhidatta L, Echeverria P, et al. Ciprofloxacin and loperamide in the treatment of bacillary dysentery. Ann Intern Med 1993;118: Brown JW. Toxic megacolon associated with loperamide therapy. Jama 1979;241: Steinhoff MC, Douglas RG, Jr., Greenberg HB, Callahan DR. Bismuth subsalicylate therapy of viral gastroenteritis. Gastroenterology 1980;78: de Bruyn G. Diarrhoea in adults (acute). Clin Evid (Online) 2008; Bartels MC, Mergenhagen KA. Octreotide for symptomatic treatment of diarrhea due to cytomegalovirus colitis. Ann Pharmacother 2011;45:e4. Author : Ron Kendall, PharmD, PGY 2 ID

4 Reference Population Studied Intervention Outcomes Limitations DuPont et. al. JAMA healthy, adult male inmate volunteers in Jessup, MD Brown. JAMA of a 24 year old female with ulcerative colitis Steinhoff et al. Gastroenterol Graham et al. Gastroenterol DuPont et al. Am J Med Young, healthy volunteers in Rochester, NY Healthy, hospitalized volunteers in Houston, TX Young adults in California and Arizona Volunteers were inoculated with Shigella flexneri and all who developed diarrhea were receive diphenoxylate and atropine or placebo and oxolinic acid or placebo. Patient received 8 days of prednisone and loperamide 12 mg/day Volunteers were inoculated with the Norwalk virus, and were then receive bismuth subsalicylate or placebo Volunteers were inoculated with enterotoxigenic E. coli (ETEC) strain H10407 and were then receive bismuth subsalicylate or placebo Subjects were enrolled if they had Fever was prolonged in patients who received only diphenoxylate and atropine. Shigella was eradicated from the stool in 4 out of 6 men treated with oxolinic acid alone, but only 1 out of 6 men treated with oxolinic acid and diphenoxylate and atropine. Toxic megacolon developed. Statistically significant reduction in severity and duration of abdominal cramps and duration of GI symptoms occurred in the treatment group. Study did not have enough outcomes to support or disprove whether or not bismuth subsalicylate is useful to treat diarrhea induced by ETEC. Loperamide reduced diarrhea significantly more than bismuth Single center. Small sample size. Single case report. Single center. Small sample size. Single center. Small sample size. Small observation period of 48 hours.

5 Murphy et al. Ann Intern Med Andrews et al. Can J Gastroenterol Nomura et al. Scand J Gastroenterol with recent travel to Guadalajara, Mexico Thailand, , patients with dysentery diagnosed by 3 or more stools with blood or mucus with either cramps, nausea, vomiting, or temperature > 38 C for fewer than 60 hours. Exclusion: antimotility agent or antibiotics in previous 7 days, pregnancy, immunosuppression, or lack of follow up for 10 days. acute (less than 72 hours) of non specific diarrhea plus one other symptom of enteric infection. They were be treated with loperamide or bismuth subsalicylate for 48 hours. Patients were receive ciprofloxacin 500 mg PO BID x 3 days plus either placebo or loperamide 4 mg initial dose plus 2 mg after every loose stool (maximum 16 mg per day). CMV colitis diagnosed by histopathology after 5 days of bloody diarrhea treated with octreotide. CMV enterocolitis unresponsive to subsalicylate. Loperamide provided better subjective relief than bismuth subsalicylate. There were only minor adverse effects, none leading to discontinuation of therapy. Median daily stools was fewer in the loperamide group 4.5 vs. 7 (P = 0.03). Subgroup analysis of patients with Shigella or enteroinvase E. coli found patients in the loperamide group had 19 (6 42) hours of diarrhea vs. 42 (21 46) hours in placebo (P = 0.028) and fewer diarrheal stools after treatment 2 (1 5) vs. 6.5 (2 9) (P=0.016). Blood loss stopped almost immediately and no further transfusions were required. Diarrhea rapidly improved over the next 2 days and then ceased. Single center. Due to low patient enrollment, the study was extended in order to enroll enough patients. Single case report. Temporal association, rather than direct cause and effect. Single case report. Temporal association, rather than

6 Kato et al. J Hosp Infect Teraishi et al. J Med Case Report Bartels et al. Ann Pharmacother Japan, 2003, Clostridium difficile (CD) infection diagnosed by stool culture or diarrhea with a positive CD toxin A. All patients were treated with oral vancomycin. ganciclovir and foscarnet was treated with the addition of octreotide 100 mcg IM daily. Compared clinical records of patients with Clostridium difficile associated diarrhea treated with loperamide (6 patients) with 80 control cases without loperamide. CMV colitis was treated with ganciclovir and octreotide 200 mcg/day subcutaneously for 10 days CMV colitis treated with oral valgancyclovir and loperamide 24 mg/day, followed by IV ganciclovir and loperamide 8 mg/day, followed by the addition of octreotide 50 mcg subcutaneously every 8 hours. Duration of diarrhea more than twice a day was 9.0 +/ 0.9 days vs / 3.3 days (P < 0.001) favoring no loperamide. Maximum episodes of diarrhea per day was 9.2 +/ 4.3 episodes vs / 2.8 episodes (P < 0.005) in favor of no loperamide. Duration of disease was / 8.9 days vs / 2.8 days in favor of no loperamide (P < 0.05). Patient gradually improved, with multiple ulcers demonstrating partial healing on 4 week repeat colonoscopy. Diarrhea improved within a few days of starting octreotide. CMV colitis resolved later that month. direct cause and effect. Small sample size. Retrospective design. Single case report. Temporal association, rather than direct cause and effect. Single case report. Temporal association, rather than direct cause and effect.

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