Metronidazole for treatment of norovirus in pediatric transplant recipients

Abstract

Background Norovirus is a common cause of gastroenteritis in both immunocompetent and immunocompromised hosts. In transplant recipients, it can lead to prolonged shedding and chronic diarrhea. Treatment with nitazoxanide, oral immunoglobulin, or mammalian target of rapamycin inhibitors has shown varying degrees of benefit in case reports and case series. Prior studies have shown that the commensal gastrointestinal bacterial flora may influence the pathogenesis of norovirus infection. Metronidazole is often used to modulate gastrointestinal flora and was trialed in our hospital for norovirus in some immunocompromised patients after observing an association with anecdotal improvement. Methods We retrospectively reviewed episodes of norovirus in the stool of 38 patients with a history of solid organ or stem cell transplantation between July 2014 and March 2019. Results There were 85 positive norovirus tests among the 38 patients. In 25 of the 85 positive norovirus tests, nitazoxanide was given, with clinical improvement in 15 of these episodes (60%). Eight positive tests were treated with metronidazole alone, in all cases after a course of nitazoxanide had been used. Improvement was observed for 6 of these episodes (75%). Conclusion Further investigation of the use of metronidazole for norovirus gastroenteritis in transplant recipients is warranted.

A Standardized Antiviral Pipeline for Human Norovirus in Human Intestinal Enteroids Demonstrates No Antiviral Activity of Nitazoxanide

“…For example, it is possible NTZ could exert indirect antiviral activity via immune cells which are lacking in our current model. However, our data are consistent with several observational clinical studies where no differences were reported between NTZ treatment and other or no treatments in chronically infected HuNoV patients (32,34,35). A recent clinical trial (NCT03395405) aimed to assess NTZ treatment for persons chronically infected with HuNoV but failed to enroll its targeted number of patients because of the COVID-19 pandemic; that said, reported outcomes of the 31 randomized patients suggest that NTZ did not improve clinical resolution of symptoms compared to placebo, with no effect on fecal viral load observed.…”

“…In most experiments, the EC50 was close in value to the CC50, demonstrating that inhibition of viral replication was largely attributed to its cytotoxicity. Our data are consistent with recent observational clinical studies reporting NTZ's inefficacy for chronically infected HuNoV patients compared to other or no treatments (32,34,35). Thus, HIEs can serve as a valuable preclinical tool to robustly evaluate antivirals for HuNoV infection.…”

“…The 6 HuNoV-infected but otherwise healthy patients who received NTZ treatment had symptom resolution significantly faster than those who received placebo (n = 7), although the median time to recovery in the placebo recipients was much longer than usual for previously healthy persons. Subsequent case reports and studies have demonstrated inconsistent efficacy of administering NTZ to resolve chronic norovirus-associated diarrhea (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). The reason for this inconsistency remains unclear.…”