Rifaximin, a Poorly Absorbed Antibiotic: Pharmacology and Clinical Potential

Abstract

Rifaximin (4-deoxy-4′-methylpyrido[1′,2′-1,2]imidazo- [5,4-c]-rifamycin SV) is a synthetic antibiotic designed to modify the parent compound, rifamycin, in order to achieve low gastrointestinal (GI) absorption while retaining good antibacterial activity. Both experimental and clinical pharmacology clearly show that this compound is a nonsystemic antibiotic with a broad spectrum of antibacterial action covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. Being virtually nonabsorbed, its bioavailability within the GI tract is rather high with intraluminal and fecal drug concentrations that largely exceed the minimal inhibitory concentration values observed in vitro against a wide range of pathogenic organisms. The GI tract represents, therefore, the primary therapeutic target and GI infections the main indication. The appreciation of the pathogenic role of gut bacteria in several organic and functional GI diseases has increasingly broadened its clinical use, which is now extended to hepatic encephalopathy, small intestine bacterial overgrowth, inflammatory bowel disease and colonic diverticular disease. Potential indications include the irritable bowel syndrome and chronic constipation, Clostridium difficile infection and bowel preparation before colorectal surgery. Because of its antibacterial activity against the microorganism and the lack of strains with primary resistance, some preliminary studies have explored the rifaximin potential for Helicobacter pylori eradication. Oral administration of this drug, by getting rid of enteric bacteria, could also be employed to achieve selective bowel decontamination in acute pancreatitis, liver cirrhosis (thus preventing spontaneous bacterial peritonitis) and nonsteroidal anti-inflammatory drug (NSAID) use (lessening in that way NSAID enteropathy). This antibiotic has, therefore, little value outside the enteric area and this will minimize both antimicrobial resistance and systemic adverse events. Indeed, the drug proved to be safe in all patient populations, including young children. Although rifaximin has stood the test of time, it still attracts the attention of both basic scientists and clinicians. As a matter of fact, with the advancement of the knowledge on microbial-gut interactions in health and disease novel indications and new drug regimens are being explored. Besides widening the clinical use, the research on rifaximin is also focused on the synthesis of new derivatives and on the development of original formulations designed to expand the spectrum of its clinical use.

Rifaximin Re-treatment in Patients with Irritable Bowel Syndrome: Feels Like the First Time?

“…These observations are in line with previous studies reporting the broad antimicrobial effect of rifaximin, demonstrating that aerobic Gram-positive cocci are more prone to develop resistance compared to anaerobic and Gram-negative organisms [9]. Nonetheless, rifaximin is a poorly absorbed antibiotic reaching intestinal concentrations that are far above the MIC of tested bacteria, limiting the selection of resistant isolates.…”

Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double‐blind, placebo‐controlled trials

“…With many antibiotics, resistance is transmitted by mobile genetic elements, such as plasmids or transposons, which facilitate rapid development of antibiotic resistance among a population of bacteria. Antibiotic resistance to rifaximin appears to occur through chromosomal mutation that blocks the ability of the agent to inhibit bacterial DNA‐dependent RNA polymerase, and these mutations are rare 27. In patients treated with rifaximin for 5 days, resistant bacterial strains were recovered, but susceptibility to rifaximin was regained 1–12 weeks after treatment discontinuation 28.…”

Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells

“…Rifaximin has a broad-spectrum of activity against gram-positive and gram-negative aerobic and anaerobic enteric bacteria [36][37][38]. In addition to its anti-bacterial activity rifaximin exerts anti-inflammatory and immunomodulatory effects [38] in human tissues and in vivo. Despite the compound is poorly absorbed there is evidence that it penetrates intestinal cells.…”