Rifaximin showed moderately high MICs (the MIC at which 90% of the isolates tested were inhibited ؍ 50 g/ml) for 145 bacterial enteropathogens from patients with traveler's diarrhea acquired in Mexico during the summers of 1997 and 1998. Rifaximin concentrations in stool the day after oral administration (800 mg daily for 3 days) were high (average, 7,961 g/g), proving the value of the drug.Bacterial agents are known to be the major cause of traveler's diarrhea. It has been shown that antibacterial agents are effective in the treatment and prevention of diarrhea among persons traveling from developed to developing countries (3, 4). Rifaximin is poorly absorbed after single or repeated oral administrations to humans, even in patients with a damaged colonic mucosa (2,7,11). It is a rifamycin derivative with activity against gram-positive, gram-negative, and anaerobic bacteria (8). Recently, we evaluated rifaximin in the treatment of traveler's diarrhea. It was shown to be superior to trimethoprim-sulfamethoxazole (5) , abstr. 2227, 1999).The objectives of this study were to determine the in vitro susceptibility to rifaximin of bacterial enteropathogens isolated from cases of traveler's diarrhea and to measure rifaximin concentrations in fecal samples after oral administration.The bacterial strains used were isolates from adults who contracted traveler's diarrhea during the summers of 1997 and 1998 in Guadalajara, Mexico. The strains were identified by standard procedures and were stored at Ϫ70°C. The following numbers of strains were tested: 120 enterotoxigenic strains of Escherichia coli (ETEC), 17 Shigella strains, and 8 Salmonella strains.MICs of rifaximin for each bacterial strain were determined by agar dilution testing according to the methods of the National Committee for Clinical Laboratory Standards (10). Agar dilution plates were prepared by making a stock solution of rifaximin with acetone and preparing twofold dilutions from 200 to 0.1 g/ml. Plates with rifaximin were inoculated with 10 4 bacteria and incubated at 37°C overnight.For quality control of antimicrobial potency, the rifaximin MICs for the recommended control strains (E. coli ATCC 25922, Staphylococcus aureus ATCC 29213, and Pseudomonas aeruginosa ATCC 27853) were determined daily with the test strains. MICs were defined as the lowest concentration of rifaximin that completely inhibited visible growth. A fine, barely visible haze or a single colony was disregarded.This study was part of a large clinical trial where rifaximin was compared with ciprofloxacin in the treatment of traveler's diarrhea (DuPont et al., 39th ICAAC). Thirty-nine adult patients were included in this part of the study. All patients (Ն18 years of age) had acute diarrhea but were otherwise in good health. The patients received 400-mg tablets of rifaximin every 12 h for 3 days consecutively. They were instructed to provide the next stool passed after the 3-day treatment period. One gram of each stool sample collected posttherapy was diluted with 1 ml of solution in ace...
Rifaximin is a poorly absorbed rifamycin derivative under investigation for treatment of infectious diarrhea. Adult students from the United States in Mexico and international tourists in Jamaica were randomized to receive either rifaximin (400 mg twice per day) or ciprofloxacin (500 mg twice per day) for 3 days, following a double-blinded model, from June 1997 to September 1998. A total of 187 subjects with diarrhea were studied. Time from initiation of therapy to passage of last unformed stool was comparable for those receiving rifaximin or ciprofloxacin (median, 25.7 hours versus 25.0 hours, respectively). There was no significant difference in the proportion of subjects in the 2 groups with respect to clinical improvement during the first 24 hours (P=.199), failure to respond to treatment (P=.411), or microbiological cure (P=.222). The incidence of adverse events was low and similar in each group. Rifaximin is a safe and effective alternative to ciprofloxacin in the treatment of traveler's diarrhea.
Background: A modification of the intestinal flora and an increased bacterial translocation is a common finding in patients with inflammatory bowel disease as well as in animal model of colitis. Rifaximin, a non-absorbable derivative of rifamycin, is an effective antibiotic that acts by inhibiting bacterial ribonucleic acid synthesis. Aims: In the present study, we investigated the effect of the administration of rifaximin (10, 30 and 50 mg/kg/day) or prednisolone (10 mg/kg/day) in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Methods: Colitis was induced in mice by intrarectal administration of TNBS (1.5 mg/mouse in 50% ethanol) and disease severity assessed clinically and by histologic scoring of colon damage, determination of interleukin (IL)-2, IL-12, interferon (IFN)-γ and tumor necrosis factor (TNF)-α (protein and mRNA and myeloperoxidase (MPO) activity in the colon. Cytokines production by the lamina propria mononuclear cells (LPMC) and luminal bacteria were also measured. Results: Rifaximin administration (30 or 50 mg/kg/day) increased survival rates of colitic mice and reduced colitis severity as demonstrated by improvement of wasting syndrome, histologic scores, decrease in colon IL-2, IL-12, IFN-γ and TNF-α (protein and mRNA) levels, and diminished colon MPO activity. Rifaximin administration caused a significant reduction of colon bacterial translocation towards mesenteric lymph nodes. LPMC obtained from rifaximin-treated mice released significantly lower amount of IFN-γ in response to ex vivo stimulation with agonistic anti-CD3 and anti-CD28 antibodies. Rifaximin (50 mg/kg/day) significantly accelerates recovery in mice with established colitis. Conclusions: Luminal bacterial microflora plays a role in the pathogenesis of TNBS-induced colitis in mice. Rifaximin administration reduces the development of colitis and accelerates healing of established disease by preventing bacterial translocation.
Background/Aims: Bacterial enteropathogens, the major cause of travelers’ diarrhea, are customarily treated with antibacterial drugs. Rifaximin, a nonabsorbed antimicrobial was examined as treatment for travelers’ diarrhea. Methods: A randomized, prospective, double-blind clinical trial was carried out in 72 US adults in Mexico. Patients with acute diarrhea received one of three doses of rifaximin (200, 400 and 600 mg t.i.d.) or trimethoprim/sulfamethoxazole (TMP/SMX, 160 mg/800 mg b.i.d.) for 5 days. Results were compared with data from 2 placebo-treated historical control populations. Results: The shortest duration of treated diarrhea was seen in the group receiving 200 mg rifaximin t.i.d (NS). Clinical failure to respond to treatment occurred in 6 of 55 (11%) rifaximin-treated subjects versus 5 of 17 (29%) of TMP/SMX-treated subjects (NS). Sixteen of twenty (80%) of the enteropathogens isolated from the rifaximin-treated subjects and 7 of 7 (100%) from the TMP/SMX group were eradicated by treatment (NS). Sixteen of twenty-four (67%) enteropathogens identified were susceptible to TMP and all 24 were inhibited by ≤50 µg/ml of rifaximin. Rifaximin reduced the number of unformed stools passed during the first 24 h of treatment when compared with 2 control placebo groups (3.3 versus 5.1; p = 0.008 and 0.0001) and led to a reduced duration of post-enrollment diarrhea (mean values of 43.1 versus 68.1 and 81.9 h; p = 0.001). Conclusions: Rifaximin shortened the duration of travelers’ diarrhea compared with TMP/SMX and 2 earlier studied placebo-treated groups. A poorly absorbed drug if effective in treating bacterial diarrhea has pharmacologic and safety advantages over the existing drugs.
In addition to inhibiting formation of prothrombotic eicosanoids, aspirin causes the acetylation of cyclooxygenase (COX)-2. The acetylated COX-2 remains active, and upon cell activation, initiates the generation of 15R-HETE, a lipid substrate for 5-lipoxygenase (LOX) leading to the formation of 15-epi-LXA4 (also termed "aspirin-triggered lipoxin," or ATL). Because ATL potently inhibits polymorphonuclear cell (PMN) function, we assessed the relative contribution of this lipid mediator in conjunction with another 5-LOX product, the leukotriene (LT)B4, to the pathogenesis of acute damage and gastric adaptation to aspirin. Data presented herein indicate that acute injury and gastric adaptation to aspirin is associated with ATL generation. Administration of COX inhibitors (celecoxib, indomethacin, ketoprofen) to aspirin-treated rats exacerbated acute injury and abolished adaptation to aspirin. Moreover, it inhibited ATL formation and caused a four- to fivefold increase in LTB4 synthesis. In contrast, licofelone, a COX/5-LOX inhibitor, did not exacerbate acute gastric injury nor did it interfere with gastric adaptation to aspirin. Although licofelone blocked ATL and LTB4 formation in aspirin-treated rats, it attenuated aspirin-induced gastric PMN margination. These findings indicate that the balance between the production of LTB4 and ATL modulates PMN recruitment/function and gastric mucosal responses to aspirin.
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