Published online Nov 27, 2023. doi: 10.4254/wjh.v15.i11.1226
Peer-review started: July 8, 2023
First decision: August 15, 2023
Revised: September 5, 2023
Accepted: October 23, 2023
Article in press: October 23, 2023
Published online: November 27, 2023
Rifaximin is frequently administered to critically ill patients with liver disease and hepatic encephalopathy (HE). However, data supporting the use of rifaximin in this population, particularly in combination with broad-spectrum antibiotics, are extremely limited. Due to the overlapping spectrums of antibiotic activity, it was hypothesized that withholding rifaximin during broad-spectrum antibiotic therapy would be safe and reduce healthcare costs. The present study is the first to evaluate the feasibility and safety of rifaximin discontinuation during broad-spectrum antibiotic therapy and represents a highly vulnerable patient population.
The gap in available evidence demonstrates the need to better understand the role of rifaximin in this unique population, as intensive care unit (ICU) hospitalizations for patients with HE are typically characterized by severe disease and increased morbidity and mortality. Therefore, after protocol development the need to assess clinical and safety outcomes was clear. Additionally, given the opportunity to reduce healthcare expenditures with decreased use of rifaximin during ICU admission, costs of therapy were quantified. This proof-of-concept evaluation also provides a foundation for future, larger-scale, well-controlled studies to confirm and expand on the findings.
The present study aimed to evaluate the safety, efficacy, and financial impact of discontinuing rifaximin during broad-spectrum antibiotic use. The efficacy of withholding rifaximin was evaluated using a surrogate marker for short-term cognitive impact, days alive and free of delirium and coma. Multiple, robust safety outcomes were considered including mortality, ICU length of stay, 48-h change in vasopressor requirements, duration of mechanical ventilation, and successful extubation. Cost avoidance was evaluated by comparing rifaximin drug costs during the observation period pre- and post-protocol. The outcomes utilized provided an initial, comprehensive assessment of the pilot protocol that could be replicated in further investigations.
This was a single-center, quasi-experimental study evaluating outcomes pre- and post-implementation of a pharmacist-driven protocol for rifaximin discontinuation in critically ill liver patients being treated in a medical ICU. To address potential sources of bias, multivariable analysis of the primary outcome was performed with characteristics selected based on biological plausibility and univariate screening. Inferential statistics were performed in the usual fashion based on data type and distribution. The study achieved 80% power to detect a 0.65 d difference in the primary outcome.
In this pilot investigation, rifaximin discontinuation during broad-spectrum antibiotic therapy in critically ill patients with liver disease was not associated with more days of delirium or coma [3 (0, 8) vs 2 (0, 9.5); P = 0.93]. Protocol application was associated with a high rate of adherence (91.4%) and resulted in a significant reduction in days of combination therapy [6 (3-9.5), 1 (0-1); P < 0.001] and medication expenditures (estimated per patient cost avoidance $316.00 to $632.00 USD). No signals of harm were detected in any safety endpoint. The results of this study support the safety and feasibility of a protocolized discontinuation of rifaximin during broad-spectrum antibiotic therapy. Due to the limited sample size and retrospective nature of the present study, future evaluations should prioritize larger sample sizes and prospective designs to the greatest extent possible. Many questions remain regarding the optimal use of rifaximin among patients being treated with broad-spectrum antibiotics, including non-critically ill patients and those receiving long courses of therapy.
This was a novel evaluation that provides new insight about the potential safety of discontinuing rifaximin during short-term, broad-spectrum antibiotic therapy in critically ill patients with liver disease which has not yet been investigated in the literature. The safety, efficacy, and cost-saving results of this study warrant confirmation in an investigation with a larger sample size and prospective, well-controlled methods which could lead to broader application of a similar protocol. Finally, this study provides further support that pharmacists may be leveraged to assist with antimicrobial stewardship efforts in specific and dynamic patient populations.
Future research related to this question should focus on: Confirmation of the reported findings; longer-term outcomes of withholding rifaximin therapy, particularly during prolonged courses of broad-spectrum antibiotics; the impact of a similar protocol among non-critically ill patients; and opportunities to optimize protocol application.