Rifaximin discontinuation during broad-spectrum antibiotic treatment in critically ill patients with hepatic encephalopathy

Abstract

Hepatic encephalopathy (HE) is one of the main complications of cirrhosis, characterized by a wide spectrum of neuropsychiatric alterations that lead to an increase in mortality, morbidity and recurrent hospitalizations. Due to the central role in HE pathogenesis of ammonia and other neurotoxins primarily produced by the gut microbiota, the main therapeutic approaches for the treatment of HE are based on the modulation of the gut microbiota. Rifaximin is a non-absorbable broad-spectrum antibiotic, that is effective against ammonia-producing gram-positive, gram-negative, and anaerobic species, approved for the treatment of HE in secondary prophylaxis. The chronic administration of rifaximin in this setting is associated with a lower risk of HE recurrence and mortality, while the role of rifaximin for the treatment of an overt-HE episode in inpatients is still unclear. Limited data exist about the coadministration of rifaximin and broad-spectrum antibiotics commonly used to treat concomitant infections, as patients receiving or recently treated with antibiotics were frequently excluded from clinical trials. In this editorial we comment on the article by Ward et al published in the recent issue of the World Journal of Hepatology. It is a single center, retrospective, quasi-experimental, pharmacist-driven protocol, with the aim to evaluate the feasibility and safety of rifaximin discontinuation in critically ill patients with HE and chronic liver disease receiving broad-spectrum antibiotic therapies in intensive care units. The study revealed no differences between the protocol and control group in terms of primary outcome (days alive and free of delirium and coma to day 14) and secondary outcomes which include: Intensive care mortality, intensive care length of stay, intravenous vasopressor requirement changes and adverse effects rate. Therefore, rifaximin discontinuation during broad-spectrum antibiotic therapy does not appear to negatively impact the clinical status of critically ill liver patients, with a similar safety profile and significant cost savings, as compared to the coadministration of rifaximin and broad-spectrum antibiotics. In agreement with Ward et al, a recently published double-blind, randomized controlled trial provided additional evidence to support the feasibility of withholding rifaximin during broad-spectrum antibiotic therapy in critically ill cirrhotic patients. However, given the limitations of these studies, further multicentric and prospective clinical trials, enrolling a larger sample of non-critically ill patients, are needed to better establish the role of rifaximin in this setting.

Key Words: Hepatic encephalopathy; Rifaximin discontinuation; Broad-spectrum antibiotics; Critically ill patients; Intensive care unit

Core Tip: According to the current international guidelines, rifaximin administration is recommended only for the secondary prophylaxis of recurrent hepatic encephalopathy (HE). The rifaximin role for the treatment of an overt HE episode in inpatients is still unclear. However, in clinical practice, it is common to keep on rifaximin therapy that patients were already on prior to hospitalization during an overt HE episode. The Ward et al study demonstrated for the first time the feasibility and safety of rifaximin discontinuation during broad-spectrum antibiotic therapy, with significant cost saving during hospitalization.

TO THE EDITOR

Hepatic encephalopathy (HE) is one of the main complications of cirrhosis, with a considerable clinical and economic burden due to the reduction in quality of life and the increase in mortality, morbidity and recurrent hospitalizations[1]. HE includes a wide spectrum of neuropsychiatric alterations, from mild behavioral and cognitive alterations to coma[2]. Given its heterogeneous clinical manifestations, many classification systems have been adopted in clinical practice, also useful for prognostic evaluation and therapeutic choices. Among these, the EASL clinical practice guidelines recommend using the West Haven criteria as an accurate tool for grading HE. These criteria differentiate four degrees of clinically manifest HE, with severity progressively increasing from grade 1 to 4, and a fifth grade called minimal HE, which includes patients with abnormal results on established psychometric or neuropsychological tests without clinical manifestations of HE[3]. Because of the poor reliability of the West Haven criteria, especially when grading HE I, in 2014 the International Society for HE and Nitrogen Metabolism consensus introduced a new classification that divides HE into two broad categories: Covert HE (which consists on minimal HE and West Haven grade 1 HE) and overt HE (which includes West Haven grades 2, 3 and 4) (Table 1)[4,5].

Table 1 Grading of hepatic encephalopathy according to West Haven criteria and international society for hepatic encephalopathy and nitrogen metabolism criteria.

West Haven criteria including minimal hepatic encephalopathy	International society for hepatic encephalopathy and nitrogen metabolism	Description
Minimal	Covert	Abnormal results of established psychometric or neuropsychological tests without clinical manifestations
Grade I		Despite oriented in time and space, the patient appears to have some cognitive/behavioral decay. Euphoria, anxiety, shortened attention span, slight mental slowing
Grade II	Overt	Disoriented for time. Lethargy, apathy, inappropriate behavior. Slight personality disorders
Grade III		Disoriented for time and space. Somnolence/semi-stupor. Responsive to stimuli. Bizarre behavior. Aggressive
Grade IV		Coma

Despite the research efforts to investigate the pathogenic mechanisms of HE, its pathophysiology is still not entirely understood. Recent clinical trials have shown the involvement of several pathways, including systemic and neuroinflammation, as well as oxidative stress and cellular senescence. Their dysfunction is sustained by high blood levels of neurotoxins and metabolites, first of all ammonia, but also oxindole, phenols, mercaptans, and short-chain fatty acids[6,7]. However, ammonia remains the central player in the pathogenesis of HE acting simultaneously across different pathways. As a result of liver dysfunction, portosystemic shunts and sarcopenia, typical of patients with liver necrosis, ammonia generated from the bacterial metabolism of urea and proteins in the gut can’t be cleared adequately. This results in a rise of ammonia blood levels that crosses the blood-brain barrier and reaches astrocytes in the central nervous system, where ammonia is metabolized into glutamine through glutamine synthetase[8]. Compared to ammonia, glutamine has an osmotic activity, and excessive amounts change the osmotic gradient and cause intracellular swelling and edema[9]. Moreover, ammonia may bind to the GABA receptor complex on astrocytes, which may trigger the synthesis of neurosteroids, which are GABA agonists[10,11]. At the same time, gut bacterial translocation and superimposed infections aggravate systemic inflammation which acts synergetically with hyperammonemia to induce neuroinflammation, resulting in increased GABAergic tone[12,13]. In this way, the increased GABAergic tone contributes to the neuropathology of HE.

Considering the gut microbiota as the principal responsible for the production and release of ammonia, the main therapeutic approaches for the treatment of HE are based on gut microbiota modulation, especially through the administration of non-absorbable antibiotics that act primarily on the gut. Different broad-spectrum antibiotics were tested for HE treatment, but the high risk of adverse events (e.g. neomycin oto- and nephrotoxicity, metronidazole neurotoxicity) and potential for resistance emergence (e.g. vancomycin-resistant enterococcus) have limited the use of many of them[14,15].

According to the 2022 EASL clinical practice guidelines on the management of hepatic encephalopathy, rifaximin is the only antimicrobial agent recommended for HE treatment as an adjunct to lactulose in secondary prophylaxis following 1 or more additional episodes of overt HE within 6 months of the first one[16]. Rifaximin is an oral non-systemic antibiotic with broad-spectrum antibacterial activity against gram positive, gram negative and anaerobic organisms, characterized by a good safety profile due to its minimal gastrointestinal absorption[17]. Rifaximin elicits its beneficial effect on HE primarily through the modulation of the gut microbiota and the reduction of intestinal permeability, with a subsequent reduction of systemic inflammation[18]. Chronic administration of rifaximin (6 months) has been shown to be associated with an improvement in the quality of life and a lower risk of recurrence of HE, hospitalizations and mortality[19]. Moreover, studies have proven the cost-effectiveness of rifaximin treatment in patients with recurrent HE due to the economic burden related to hospitalizations[20]. While the use of rifaximin in secondary prophylaxis for HE has been widely established, its role in the treatment of an overt HE episode in inpatients is still unclear. The current guidelines don’t recommend the use of rifaximin in this setting, confirming the central role of lactulose[21]. In addition to pharmacological therapy with non-absorbable disaccharides, the identification and correction of precipitating factors plays a central role in the treatment of overt-HE episodes, first of all infections, which can require the administration of broad-spectrum antibiotics. Other historically known precipitants are gastrointestinal bleeding, dehydration, electrolyte disorders and constipation. Furthermore, recent studies have highlighted the role of malnutrition and portosystemic shunts as new precipitants of HE. Their management and correction is fundamental for an effective HE treatment[22]. However, in clinical practice, there is a trend towards the use of rifaximin in inpatients, but it is most likely a continuation of rifaximin that they were already on prior to hospitalization.

While rifaximin targets specific gut microbiota, many broad-spectrum antibiotics also affect similar bacterial populations, but limited data exist on the coadministration of rifaximin and broad-spectrum antibiotics, as patients receiving or recently treated with antibiotics were often excluded from clinical trials. Therefore, it is unclear whether this overlap results in improved patient outcomes or if it leads to redundant therapy without any added benefit.

Considering the existing limitations and uncertainties, recent studies have begun to explore the potential benefits of discontinuing rifaximin during broad-spectrum antibiotic therapy.

These studies aim to evaluate whether the withdrawal of rifaximin may not only simplify treatment regimens but also mitigate any potential risks associated with unnecessary polypharmacy. The Ward et al[23] study is a single-center, quasi-experimental, retrospective, pharmacist-driven protocol that evaluates rifaximin discontinuation in critically ill patients with HE and chronic liver disease receiving broad-spectrum antibiotic therapies in intensive care units. The aim of this study is to define the clinical, safety and financial impact of rifaximin discontinuation in these patients, based on the assumption that the coadministration of rifaximin and broad-spectrum antibiotics may be unnecessary due to the overlap of their spectrum of activity. A total of 64 patients were included in the study and equally divided into two cohorts: The protocol group (32 patients) has rifaximin withheld during broad-spectrum antibiotic treatment, the control group (32 patients) receives both rifaximin and broad-spectrum antibiotics. Broad-spectrum antibiotic regimens were defined as mono- or combined therapies providing gram-positive, gram-negative, and anaerobic coverage.

The results of the study highlighted the absence of differences between the two cohorts in primary outcome (days alive and free of delirium and coma to day 14) also after the adjustment in multivariable analysis and secondary outcomes, including: Days alive and free of delirium to day 14, days alive and free of coma to day 14, intensive care mortality, intensive care length of stay, and intravenous vasopressor requirement changes at 48 hours. In this way, Ward et al[23] demonstrated that rifaximin withheld during broad-spectrum antibiotic therapy was not associated with a clinical and neurological state worsening. Moreover, due to the absence of an increased adverse effects rate in the protocol group, they established the safety of rifaximin discontinuation in this setting. Finally, the financial evaluation showed in the protocol group an estimated cost savings of $316.00 to $632.00 (United States dollars) per patient.

CONCLUSION

Nowadays, limited data are available in the literature regarding the use of rifaximin during broad-spectrum antibiotic therapies for the treatment of overt HE episodes. Therefore, there is a lack of clarity regarding the utility and effectiveness of combination therapy in these patients. Considering the overlap in the spectrum of action of the antibiotic therapies, combination therapy may not be necessary. Recent research has shed new light on this topic, most notably the study by Ward et al[23] is the first in the literature to demonstrate the feasibility and safety of rifaximin discontinuation during broad-spectrum antibiotic therapy with significant cost savings during hospitalization. Its contribution could significantly impact the management of HE, particularly in inpatient settings. Further, the application of this protocol will result in a reduction of healthcare costs, fundamental in this post-pandemic historical period. The implications of this study extend beyond mere cost reduction, they provide crucial insights into the role of rifaximin in treating HE and its interactions with broad-spectrum antibiotics. By demonstrating that discontinuing rifaximin therapy does not lead to a deterioration in the clinical and neurological condition, Ward et al[23] have reinforced the hypothesis that coadministration of rifaximin and broad-spectrum antibiotics may be unnecessary, given their overlapping spectrum of activity. Supporting the findings of Ward et al[23], Kulkarni et al[24] recently conducted a double-blind and randomized controlled trial in patients with overt-HE admitted to the intensive care unit. They showed that overt-HE reversal in patients on broad-spectrum antibiotic therapy was comparable with those on rifaximin combined with broad-spectrum antibiotics, thus confirming the feasibility of rifaximin discontinuation in this setting[24]. However, the Ward et al[23] study has several limitations.

Firstly, the retrospective design and single-center nature of the study, combined with a relatively small patient sample, limit the overall strength and generalizability of the findings, potentially impacting the applicability of the results to a broader clinical context.

Secondly, there is a critical concern regarding the differences in intravenous vasopressor requirements at the time of admission between the two cohorts examined in the study. These discrepancies could potentially distort the findings, as a higher demand for vasopressors is typically associated with a poorer prognosis.

Thirdly, due to intubation and sedation at the admission, many patients were unable to be assigned a baseline West Haven grade. This limitation imposed the need to use multiple surrogate endpoints, as the evaluation of HE using West Haven criteria could not be included as an outcome.

Moreover, as demonstrated by Cordoba et al[25], patients with HE and acute on chronic liver failure (ACLF) have higher short- and long-term mortality than patients with HE alone, therefore patients should be stratified according to the presence of ACLF. This underscores the importance of stratifying patients based on the presence of ACLF, as it could significantly influence treatment decisions and prognostic evaluations.

Given these limitations, it becomes evident that further research is necessary to build upon these findings. Future studies should ideally be prospective and multicenter in design, with a larger patient sample that includes non-critically ill individuals. This approach would enhance the generalizability of the results and provide a more comprehensive understanding of the impact of various factors on patient outcomes. Additionally, incorporating the evaluation of HE using the West Haven criteria as an outcome, in line with EASL guidelines, is imperative to ensure a standardized assessment of HE severity.