Background: Bacterial infections remain a significant cause of morbidity and mortality in patients with cirrhosis. Despite, significant improvements in the management of cirrhosis, mortality from infection, particularly secondary infections, remains unchanged. This thesis aimed to investigate if rifaximin, a non-absorbable, broad-spectrum antibiotic reduced bacterial translocation, modulated inflammatory and immune responses, and subsequently prevented secondary infections in patients with cirrhosis.
Method: Rifaximin to reduce infection in decompensated cirrhosis (R-RID) was an investigator-initiated, multicentre, double-blinded, randomised, placebo-controlled trial. Hospitalised patients with cirrhosis on antibiotic treatment for infection were randomised to receive rifaximin (550mg twice daily) or placebo for 6 months, followed by a 6 month follow up phase. An intention-to-treat analysis on 65 participants who completed the study was performed.
Results: 746 patients were screened for study eligibility between January 2017 and May 2018. Common causes of screen failure included concurrent rifaximin use, observed in 22.1% (165/746), and absence of primary infection at admission in 20.0% (149/746) screened for study suitability. 78 participants were randomly assigned in a 1:1 allocation with 65/78 completing participation. 31/65 received rifaximin and 34/65 placebo. Secondary infections occurred in 8/31 (25.8%) on rifaximin and 7/34 (20.6%) on placebo. No statistical differences were observed between treatment groups in the 12-month incidence of secondary infection development, even after adjusting for confounders. Mechanistically rifaximin did not affect levels of bacterial DNA, cytokine concentrations and monocyte phenotype or function at any interval time points.
Conclusions: The work presented in this thesis demonstrated that rifaximin did not prevent secondary infections in patients with cirrhosis. This may be attributed to a lack of effect on mechanistic pathways contributing to bacterial infection development in cirrhosis. This was an underpowered study, with limitations that must be considered during interpretation.