In vitro activity of rifaximin, metronidazole and vancomycin against Clostridium difficile and the rate of selection of spontaneously resistant mutants against representative anaerobic and aerobic bacteria, including ammonia-producing species

Background: Rifaximin is a rifamycin derivative characterized by a wide ant ibacterial activity. This drug is neither absorbed by the gastrointestinal tract nor inactivated by gastric juices, and exerts its action entirely wit hin the intestinal lumen. Methods: In this study, the activity of this anti biotic was compared with that of metronidazole and vancomycin against 93 Cl ostridium difficile isolates. The rate of emergence of bacteria spontaneous ly resistant to the new compound was also evaluated in relation to represen tative gram-positive and gram-negative strains. In terms of MIC50 values, r ifaximin showed an intrinsic activity superior to that of the other agents. The emergence of spontaneously resistant strains was assessed with 46 aero bic (staphylococci, enterococci, Proteus spp., Citrobacter freundii, Provid encia rettgeri, enteropathogenic, enteroinvasive, enterotoxigenic and enter ohemorrhagic Escherichia coli, and Salmonella enteritidis) and anaerobic (C lostridium spp., Bacteroides spp., Fusobacterium nucleatum and Peptococcus spp.) pathogens, most of them also ammonium producers. Two different method s, broth and agar dilution, were employed. Results: When liquid medium was employed, bacteria capable of sustained growth in 100 mu g/ml of rifaximin were obtained after 2-5 transfers with grampositive aerobic cocci, 2-3 tran sfers with gram-negative aerobic strains and 2-5 transfers with anaerobic s pecies. At the highest dose used with the agar dilution method (8 x MIG), t he frequency of emergence of spontaneously resistant mutants ranged from <1 x 10(-9) to 1.6 x 10(-8) With gram-positive aerobic and anaerobic cocci, w hile with aerobic and anaerobic gram-negative bacteria, this value ranged f rom <1 x 10(-9) to 1.7 x 10(-7). C. difficile showed a particularly low inc idence of spontaneously resistant mutants (<1 x 10(-9)). The low incidence of resistant subpopulations selected by levels of 8 x MIC of rifaximin sugg ests that the high levels of the drug which were reached in the gastrointes tinal lumen may further prevent the selection of mutants. Conclusion: The l ow toxicity, broad antibacterial activity and very poor absorption from the gastrointestinal tract of rifaximin suggest a potential therapeutic use fo r this drug in gastrointestinal diseases, as well as in the management of p atients with cirrhosis and chronic portal-systemic encephalopathy. Copyrigh t (C) 2000 S. Karger AG, Basel.