Rifaximin: One Molecule to Rule Them All?

Letter to Editor

The antibiotic rifaximin has been prescribed since the mid ‘80s to treat intestinal infections of Gram + and Gram -. Considering its effectiveness and consolidated use, in recent years rifaximin has been administered with or without scientific basis to achieve different therapeutic outcomes. In addition to the approved indications, rifaximin is routinely used for irritable bowel syndrome with diarrhoea symptoms and diverticular disease (SUDD) of various forms [1,2]. In the first case, the FDA released the recommendation to use in 2020, in this setting rifaximin is used as standard therapy to differentially diagnose IBS and other diseases [3]. On the other hand, the application for the treatment of diverticular disease remains highly controversial. The literature spends a great deal on empirically evaluating the beneficial effect on the symptoms associated with intestinal diverticula [4]. However, there is neither evidence nor real-world data sufficient to endorse the success of the therapeutic outcome. Finally, the position paper of the Italian Society of Gastroenterology and Digestive Endoscopy (SIGE), issued in 2022 agrees with the lack of effectiveness of a long term rifaximin use for the treatment of SUDD [5]. It is certainly true that rifaximin, given its physicochemical nature, is unlikely to cause adverse drug reactions, but repeated administration, continuous or cyclical, does not improve the outcomes and exposes patients to clinical risks such as the damage of the intestinal wall [6]. Following the concerning spike of prescriptions delivered in our local area, the Pharmaceutical Department undertook a deep analysis of the current uses of rifaximin by analysing the risks and possible alternatives. The most common dose regimens are presented in Table 1 sorted by indications on label and off label as stated by the Italian Regulatory Agency (AIFA). As regard the off-label use, the table has been filled out after a narrative review of the literature. Nonetheless, the reader must be aware that the recommended dosage and duration can be tailored to the patient's needs. To establish a standard dose regimen for the off label use, we relied on the latest scientific evidence [7,8]. Rifaximin has shown a little but clinically relevant interaction with warfarin resulting in the reduction of the INR levels, this is likely due to the augmented intestinal permeability occurred in patients affected by Small Intestine Bacterial Overgrowth (SIBO) which may increase the oral bioavailability of rifaximin and therefore the induction of the CYP3A4 enzyme [9]. In other conditions, the potential induction on the CYP3A4 enzyme constitutes a mild to low concern for the healthcare team given the very low percentage of absorption of rifaximin [10]. The great effort made to limit the antibiotic resistance spreading all around the world is in contrast with the libertine prescription of rifaximin. In the most recent years, many studies have highlighted that, on the contrary with what has always been believed, the mutation of rpoβ gene has opened to the potential resistance to rifaximin carried by different pathogens such as Clostridium difficile and tuberculosis linked strains [11]. Moreover, recent evidence revealed a relationship between the difficult eradication of Candida spp. in immunodeficient patients treated with long term rifaximin [12]. The development of resistance or cross-resistance with other antibiotics such as rifampicin shadows the strong belief that rifaximin can be safely used with the “try and error” approach. Finally, interviewing GPs and analysing the literature, we realised that the differences between hyperammonemia and hepatic Encephalopathy (EE) is very narrow and it cannot be detected by clinicians. In this letter, it is important to stress the difference in dosage and medical product for the treatment of hyperammonemia vs EE. Low dose rifaximin is administered as the ammonium blood levels increase and to prevent the symptoms related to EE [13]. If the symptoms occur it is recommended to switch to the higher dose formulation prescribed by registered hospital specialists.

  

    
Therapeutic Indication
    
Dose Regimen
  
  

    
ON LABEL
  
  

    
Pre/post-surgery prophylaxis (a) 
    
1000 mg prophylaxis pre-surgery, 
  
  

    
repeat post-surgery if needed
  
  

    
Intestinal Infections (a)
    
200 mg QID
  
  

    
Traveller’s diarrhoea (a) 
    
400 mg/day for 3 days
  
  

    
Hyperammonemia (a)
    
400 mg TID
  
  

    
OFF LABEL
  
  

    
SUDD (b)
    
400 mg BID for 7 days/month for 12 months
  
  

    
(Symptomatic Uncomplicated Diverticular Disease) 
  
  

    
IBS-D (b)
    
1200 mg/day for 14 days
  
  

    
Treatment should be discontinued after 7 days (a)
  

Table 1: Therapeutic Indications of Rifaximin in Europe. Details regarding the dose regimens are retrieved from the SmPC (a), clinical practice and literature (b).