Rifaximin

A Review of its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Potential in Conditions Mediated by Gastrointestinal Bacteria

Abstract

Synopsis

Rifaximin is a derivative of rifamycin which acts by inhibiting bacterial ribonucleic acid (RNA) synthesis. It is virtually unabsorbed after oral administration; thus it is used primarily to treat local conditions within the gastrointestinal tract. In vitro data indicate rifaximin possesses good activity against species of Staphylococcus, Streptococcus and Enterococcus but lesser activity against species of Enterobacteriaceae. Bacterial resistance during exposure to rifaximin has been reported but its clinical importance remains to be fully defined.

Results of comparative trials demonstrate that rifaximin is similar in efficacy to neomycin and lactulose in patients with hepatic encephalopathy and appears to be better tolerated. In 1 study, cyclical administration of rifaximin for 15 days per month was associated with progressive improvement over a 3-month period. In patients with infectious diarrhoea, rifaximin induces more rapid improvement in stool consistency and decreased frequency of faecal evacuations when compared with placebo, and is similar in efficacy to neomycin. Available data suggest rifaximin may be of some use in acute diverticulitis, but its use for the prevention of inflammatory complications or for control of common symptoms of diverticu-losis requires further study. Preoperative treatment with rifaximin as antibacterial prophylaxis in colorectal surgery shows some potential but should be further investigated.

Overall, rifaximin may be useful as an alternative therapy in hepatic encephalopathy but more data are needed to better define its clinical potential in infectious diarrhoea, diverticular disease and as antibacterial prophylaxis prior to colorectal surgery.

Antibacterial Activity

In common with other rifamycin antibacterial agents, rifaximin acts on the β subunit of the deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase enzyme of bacteria to inhibit bacterial RNA synthesis.

In vitro data indicate that the susceptibility of Gram-positive organisms to rifaximin is greater than that of Gram-negative organisms. Rifaximin possesses good inhibitory activity against species of Staphylococcus, Streptococcus and Enterococcus as well as Bacillus cereus, Moraxella catarrhalis and Haemophilus influenzae. Activity is lower against species of Enterobacteriaceae, Pseudomonas, Acinetobacter and Helicobacter, conflicting data exist for activity against Bacteroides spp. Because rifaximin undergoes essentially no systemic absorption, measurable plasma drug concentrations are very low; therefore, in vitro susceptibility data, expressed as minimum concentrations inhibitory to 50% (MIC50) or 90% (MIC90) of strains tested, may not accurately predict antibacterial activity in the gastrointestinal tract.

Administration of rifaximin 800 mg/day to 10 healthy volunteers for 5 days resulted in a marked reduction in the numbers of some enteric bacteria which subsequently normalised within 1 to 2 weeks.

Bacterial resistance rates of 30 to 90% have been reported after 5 days of rifaximin treatment. Within 1 to 2 weeks after treatment was halted, resistance rates had generally decreased to less than 20% in most strains tested. After 12 weeks, no resistant strains were detected.

Pharmacokinetic Properties

Rifaximin is used for localised action in the gastrointestinal tract and pharmacokinetic studies have aimed to verify its lack of systemic absorption after oral administration.

Rifaximin could not be detected in the plasma of 9 of 18 healthy men 4 hours after administration of a single 400mg dose, while drug concentrations were less than 6 μg/L in the remainder. Less than 0.025% of the rifaximin dose was recovered in urine after 48 hours; faecal rifaximin concentrations were not determined.

Bile samples from patients undergoing cholecystectomy who had received rifaximin 1200 mg/day for 2 preoperative days contained little or no drug, demonstrating a lack of hepatic distribution for rifaximin. This further indicates that rifaximin is essentially unabsorbed following oral administration.

At present, there is no information to indicate whether rifaximin undergoes gastrointestinal metabolism or inactivation, and data regarding the faecal excretion of rifaximin in humans are lacking.

Therapeutic Potential

The virtual lack of systemic absorption after oral administration indicates a potential role for rifaximin in localised conditions, mediated by susceptible bacteria, within the gastrointestinal tract. Rifaximin has been evaluated in the symptomatic management of hepatic encephalopathy, infectious diarrhoea, diverticular disease and as prophylaxis against postoperative complications following colorectal surgery.

Reductions in blood ammonia levels were reported in all groups of patients with hepatic encephalopathy after treatment with rifaximin, lactulose, neomycin or paromomycin. Although in double-blind trials a consistent differential response pattern was not always evident, rifaximin also appeared as effective as lactulose or neomycin in improving other parameters, such as mental state, electroencephalogram (EEG) irregularities and mental function test scores. In 1 study, cyclical administration of rifaximin for 15 days per month for 3 months was associated with progressive improvement in mental status over this time period.

After 5 to 7 days of treatment, improvement in diarrhoea and associated symptoms was evident in patients with infectious diarrhoea receiving rifaximin, neomycin or placebo. Symptomatic relief and normalisation of bowel function improved at a similar rate in rifaximin compared with neomycin recipients but more rapidly than in placebo recipients. These results require confirmation in well-controlled trials before definitive conclusions can be reached regarding the role of rifaximin in the management of infectious diarrhoea, where antibiotic therapy is deemed necessary.

Data from a small number of trials indicate that rifaximin, with or without various other strategies, may be of some benefit in patients with acute diverticulitis on the basis of symptomatic relief combined with an endoscopically verified decrease in mucosal swelling, hyperaemia, haemorrhagic suffusions and diffuse granules of the mucosa. The use of rifaximin for protection against the development of inflammatory complications in patients with symptomatic, uncomplicated diverticular disease or for symptomatic relief alone requires confirmation compared with more conservative measures.

The advantages of mechanical bowel cleansing plus antibacterial prophylaxis in patients undergoing colorectal surgery are well recognised and accepted. Results from a few small trials which have evaluated 3-day preoperative treatment with rifaximin showed some potential in this indication but further investigation is needed in trials comparing rifaximin with widely used 1-day preoperative treatments.

Tolerability

On the basis of clinical trial data, patient tolerability to rifaximin was as good as, and sometimes better than, that seen with comparative agents. Data extracted from those clinical trials that provided tolerability information indicated that gastrointestinal complaints, such as nausea, abdominal pain, flatulence and vomiting, occurred most frequently, each in less than 1% of the approximately 950 patients who received rifaximin. Persistent vomiting in 1 child resulted in the only documented treatment withdrawal. Urticarial rashes have occured infrequently after rifaximin administration.

Dosage and Administration

The recommended rifaximin dosage for adults and children older than 12 years is 10 to 15 mg/kg/day, while in younger children a higher daily dose of 20 to 30 mg/kg/day is suggested. Treatment duration should not exceed 7 days in children. Rifaximin should not be administered to patients with evidence of serious intestinal ulcerative lesions or obstruction.

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Correspondence to Jane C. Gillis.

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Various sections of the manuscript reviewed by: L. Bucci, ‘Brera’ Medical Department, Niguarda Cà Granda Hospital, Milan, Italy; R.G. Finch, Department of Microbial Diseases, The City Hospital, Nottingham, England; G. Gasbarrini, Facoltà di Medicina e Chirurgia ‘Agostino Gemelli’, Università Cattolica del Sacro Cuore, Rome, Italy; G. Gentiloni Silveri, Facoltà di Medicina e Chirurgia ‘Agostino Gemelli’, Università Cattolica del Sacro Cuore, Rome, Italy; R.N. Jones, Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA; S.D.R. Lang, Microbiology Laboratory, Middlemore Hospital, Auckland, New Zealand; M.J.S. Langman, Department of Internal Medicine, Edgbaston, Birmingham, England; C. Scarpignato, Cattedra di Farmacologia, Università degli Studi di Parma, Parma, Italy; E. Strauss, Clinic of Gastroenterology, Hospital Heliopolis, São Paulo, Brazil.

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Gillis, J.C., Brogden, R.N. Rifaximin. Drugs 49, 467–484 (1995). https://doi.org/10.2165/00003495-199549030-00009

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Keywords

  • Hepatic Encephalopathy
  • Neomycin
  • Diverticular Disease
  • Lactulose
  • Minimum Inhibitory Concentration