In Vitro Activity and Single-Step Mutational Analysis of Rifamycin SV Tested against Enteropathogens Associated with Traveler's Diarrhea and Clostridium difficile

Abstract

Rifamycin SV is a broad-spectrum, poorly absorbed antimicrobial agent that, when coupled with MMX technology, is being targeted for the oral treatment of traveler's diarrhea (TD) and Clostridium difficileassociated disease (CDAD). Rifamycin SV was tested for activity against 911 TD-associated enteropathogens and 30 C. difficile isolates collected from several global surveillance studies. Rifamycin SV demonstrated similar antimicrobial activity levels against the Enterobacteriaceae, with MIC 50 values ranging from 32 to 128 g/ml for all but one strain (an enterotoxigenic Escherichia coli at >512 g/ml). For non-Enterobacteriaceae strains, MIC 50 values ranged from 2 to 8 g/ml, with the exception of Campylobacter spp., for which all strains had MIC values of >512 g/ml. Rifamycin SV also demonstrated excellent activity (MIC 50 of <0.03 g/ml) against most C. difficile strains (including one hypervirulent NAP1 strain), and this activity was even superior to the potency observed for vancomycin, metronidazole, and rifaximin. In mutational passaging studies, rifamycin SV induced stable resistance and showed a mutation frequency in E. coli similar to that of rifampin. This study presents the potency of rifamycin SV for enteropathogens commonly recovered from patients with TD and CDAD. Additional in vitro and in vivo studies appear necessary to determine the utility of rifamycin SV as an oral agent for the prevention and treatment of TD and CDAD.Rifamycin SV is a broad-spectrum semisynthetic antimicrobial agent of the rifamycin group with limited oral absorption that is active against Gram-positive bacteria and moderately active against . Coupled with the proprietary drug delivery system MMX (Cosmo Technologies Ltd., Dublin, Ireland), designed to release the antibiotic in the colonic lumen, rifamycin SV has been formulated as a tablet for treatment of colonic bacterial infections, including traveler's diarrhea (TD) and Clostridium difficile-associated disease (CDAD). As with all members of the rifamycin group, rifamycin SV inhibits DNA transcription by interfering with bacterial RNA polymerases (2,22).TD is the most common gastrointestinal (GI) illness contracted by persons from developed countries when they visit resource-poor countries; annually, it is estimated that 100 million persons travel internationally, with an estimated 30 to 40% of them developing TD and approximately 3% progressing to postinfectious irritable bowel syndrome (15,19). The most common bacterial etiologies of TD, accounting for nearly 60 to 80% of the cases, are pathogenic Escherichia coli, Salmonella spp., Shigella spp., and Campylobacter spp. although pathogenspecific prevalence rates do vary by geographic region (19).Current travel medicine treatment guidelines recommend the use of antimicrobials for TD, in addition to fluid replacement and antimotility drugs, especially for severe disease (10). These guidelines recommend the use of a fluoroquinolone (FQ) or azithromycin for most travelers worldwide although regional pockets have significant lev...

Competitive strategies differentiate closely related species of marine actinobacteria

“…CUA-766 using MALDI-TOF imaging mass spectrometry (Figure 6). Thirteen strains showing sensitivity to S. arenicola culture extracts were tested for sensitivity to commercially available rifamycin SV (the quinone analog of rifamycin S) and found to be sensitive at concentrations between 10-100 μg ml − 1 (data not shown), which is comparable to the MIC-50 values reported against a variety of enteropathogens (Farrell et al, 2011). Figure 5 Salinispora growth rates.…”

Resistance to rifampicin: a review

“…Resistance rates to rifamycins, determined in the laboratory, have ranged from 10 À10 to 10 À7 , depending on the organism and the methodology used. [1][2][3][4] RIF resistance was reported in different Gram-negative urinary tract pathogens, in vitro and in treated patients; 5 in gonococci and meningococci in the laboratory and the clinic; 2,6,7 and in tuberculosis patients who failed therapy when RIF was the only active drug administered. 8 When treating tuberculosis and other diseases, RIF is almost always combined with other active antimicrobials to prevent the emergence of resistance.…”

Targeting of Rifamycin SV to the Colon for Treatment of Travelers' Diarrhea: A Randomized, Double‐Blind, Placebo‐Controlled Phase 3 Study

“…9 In vitro, rifamycin SV is effective against the bacterial pathogens which most frequently cause TD and against Clostridium difficile. 10 In addition to its bactericidal activity, anti-inflammatory and immunomodulatory activities of rifamycin SV have been demonstrated using in vitro and in vivo models 11,12 and rifamycin SV has been used successfully to treat rheumatoid arthritis, suggesting that nonbactericidal actions may contribute to its clinical benefits. 13 Here we report on the efficacy and safety of RIF-MMX for treatment of TD from a randomized, placebo-controlled phase 3 study conducted in travelers to Latin America.…”