Rifaximin alone versus combination with norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis with hepatic encephalopathy: A randomized-controlled trial

Background: Spontaneous bacterial peritonitis (SBP) and hepatic encephalopathy (HE) are the most important events of decompensation in natural history of liver cirrhosis with poor short-term mortality requiring liver transplantation as definitive management. Norfloxacin is recommended for primary as well as secondary prophylaxis of SBP. Rifaximin for secondary prophylaxis of SBP has been evaluated in multiple trials but still not recommended. We compared rifaximin alone vs. combination with norfloxacin for secondary prophylaxis of patients of cirrhosis with SBP and HE. Methods: All patients of cirrhosis with SBP and HE on admission were included in this prospective, open-label, randomized-controlled trial between Jan 2020 and Dec 2020. On discharge, patients were given rifaximin 400 mg TID (Group I) and rifaximin 400 mg TID with norfloxacin 400 mg OD (Group II) as secondary prophylaxis of SBP. The standard medical treatment was continued in both groups.The original sample size was 40 patients in each group;however, due to COVID-19 pandemic and further lockdown, enrollment was limited. Primary outcomes were recurrent SBP and HE at 6-months and 28-day, 90-day and 6-month mortality. Secondary outcomes included number of hospitalizations, episodes of UGI bleed, new AKI episodes and change in CTP and MELD scores over next 6 months. The study was approved by institutional ethics committee. Results: Of 62 patients of cirrhosis with SBP and HE on admission, 25 patients had in-hospital mortality and six were excluded. Finally, 31 patients were included and randomized to Group I (n=15) and Group II (n=16). The HE was grade 2 (10 vs. 12) and grade 3 (5 vs. 4) in Group I and II respectively. All baseline characteristics including CTP and MELD were comparable between two groups (P>0.05). Primary outcomes as recurrent SBP at 6-months (6.7% vs. 6.2%;P=0.9), recurrent HE at 6-months (13.3% vs. 6.2%;P=0.9), 28-day (6.7% vs. 6.2%;P=0.9) and 90-day mortality (6.7% vs. 6.2%;P=0.9), 6-month mortality (26% vs. 31%, P=0.3) were comparable between two groups respectively. Secondary outcomes as number of hospitalizations (33.3% vs. 18.7%, P=0.4), episodes of UGI bleed (0% vs. 12.5%, P=0.4), new AKI episodes (13.3% vs. 0%, P=0.08), ΔCTP (median;-4 vs. -4, P=0.5) and ΔMELD (median;-0.9 vs. -0.8, P=0.7) over next 6-monthswere not significantly different between two groups respectively. Conclusion: Patients of cirrhosis with SBP and HE on admission have dismal prognosis. Rifaximin alone has been shown to have comparable efficacy against its combination with norfloxacin for secondary prophylaxis of SBP with HE. Rifaximin has a dual role in prevention of recurrence of HE as well as SBP.