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Oral rifaximin, a semisynthetic rifamycin derivative, is an effective and well tolerated antibacterial for the management of adults with non-invasive traveller’s diarrhoea. Rifaximin was significantly more effective than placebo and no less effective than ciprofloxacin in reducing the duration of diarrhoea after treatment initiation for illness contracted during travel to diverse geographic locations. While rifaximin is effective in patients with Escherichia coli-predominant traveller’s diarrhoea, it appears ineffective in patients infected with inflammatory or invasive enteropathogens. Rifaximin has a broad spectrum of antibacterial activity in vitro and undergoes negligible systemic absorption (<0.4%). In contrast to systemically absorbed antibacterials, such as the fluoroquinolones and macrolides, the acquisition of resistance to rifaximin would have limited consequences for global public health, as rifaximin has no role in the management of systemic infections. Rifaximin shows promise as chemoprophylaxis against traveller’s diarrhoea and is a valuable new option for the management of traveller’s diarrhoea caused by non-invasive bacterial strains.
Pharmacological Properties and Antibacterial Activity
Rifaximin inhibits bacterial RNA synthesis by its action on the β-subunit of the DNA-dependent RNA polymerase. It is active against the bacterial enteropathogens from diverse global locations that commonly cause traveller’s diarrhoea including enterotoxigenic E. coli (ETEC), enteroaggregative E. coli(EAEC), Salmonella spp. and Shigella spp. Minimum inhibitory concentrations required to inhibit the growth of 90% of isolates (MIC90S) against these enteropathogens ranged from 4 to 64 mg/L in isolates from stool samples for patients with traveller’s diarrhoea.
Rifaximin does not appear to select for resistance among Gram-negative and -positive intestinal flora, although a small study reported the development of resistance to rifaximin (in vitro concentration threshold of 100 ji.g/mL) by aerobic and anaerobic bacteria, including E. coli, in the gastrointestinal tract; however, resistant strains were undetectable 12 weeks post-treatment (>75% of these strains were undetectable within 1–2 weeks).
Rifaximin undergoes negligible systemic absorption and does not appear to accumulate following repeated administration. Maximum plasma concentrations (Cmax) of rifaximin after administration of a single oral dose of rifaximin 400mg to healthy male volunteers were 3.80 ng/mL under fasting conditions and 9.63 ng/mL after a high fat meal. Mean Cmax values in volunteers treated with rifaximin 200mg three times daily for 3 days upon development of diarrhoea or dysentery after challenge with Shigella flexneri were 1.63 ng/mL on day 1 and 1.23 ng/mL on day 3. Rifaximin treatment was not effective in these volunteers; however, prophylactic rifaximin 200mg three times daily for 3 days was effective in preventing shigellosis in volunteers challenged with S. flexneri.
Rifaximin is excreted mainly in the faeces mostly as the unchanged drug. Faecal concentrations of rifaximin reached ≈8000 μg/g after oral administration of 400mg twice daily for 3 days, exceeding the MIC90 values of ETEC and EAEC by ≈250-fold. Because of this minimal systemic absorption, in vitro susceptibility data may not reliably predict antibacterial activity in the gastrointestinal tract.
Randomised, double-blind comparative trials have shown that oral rifaximin is significantly more effective than placebo, and no less effective than ciprofloxacin in shortening the duration of diarrhoea after initiation of treatment in non-indigenous travellers with traveller’s diarrhoea. In these trials, enteropathogen detection rates were generally low in pretreatment stool samples, with ETEC the most common pathogen identified in samples in which enteropathogens were detected.
The median time from the initiation of treatment to the passage of the last unformed stool (TLUS; primary endpoint) was significantly shorter (32.5 and 32.9 hours) in recipients of rifaximin 200 or 400mg three times daily for 3 days who contracted traveller’s diarrhoea during travel to Guatemala, Mexico or Kenya than in placebo recipients (60.0 hours). In adults with traveller’s diarrhoea contracted during travel to India, Mexico, Guatemala and Peru, median TLUS was 32.0 hours in recipients of rifaximin 200mg three times daily versus 65.5 hours in placebo recipients and 28.8 hours in recipients of ciprofloxacin 500mg twice daily.
Median TLUS was similar in patients with traveller’s diarrhoea contracted during travel to Mexico or Jamaica who received twice-daily rifaximin 400mg or ciprofloxacin 500mg (25.7 vs 25.0 hours).
Rifaximin appears ineffective in patients with fever and bloody stools and in patients with inflammatory or invasive pathogens in pretreatment stool samples (including patients infected with Campylobacter jejuni).
Prophylactic administration of rifaximin 200mg once, twice or three times daily for 2 weeks resulted in a significantly lower incidence of traveller’s diarrhoea (12%, 19% and 13%, respectively) than administration of placebo (54%) in travellers to Mexico. Again, ETEC was the most common enteropathogen identified in stool samples.
Oral rifaximin is well tolerated in adults with traveller’s diarrhoea, with the incidence and type of adverse events similar to that with placebo in clinical trials. Serious adverse event and treatment discontinuation rates were low: one rifaximin recipient experienced a serious adverse event (dysentery) that was considered unrelated to treatment and three rifaximin recipients discontinued treatment because of adverse events (possibly or probably treatment-related in one recipient).
Across the two largest trials, adverse events were commonly gastrointestinal, generally of mild or moderate intensity and occurred with an overall incidence of 44%, 24% and 54% in recipients of rifaximin 600 mg/day, ciprofloxacin 1000 mg/day or placebo. The rate of adverse events may be reflective of the severity of the underlying traveller’s diarrhoea: in participants of the largest trial, numerically more rifaximin and placebo recipients than ciprofloxacin recipients had faecal leukocyte-positive illness, and inflammatory or invasive pathogens or blood in baseline stool samples. In recipients of rifaximin 800 mg/day or ciprofloxacin 1000 mg/day enrolled in the other phase III trial, adverse events were mild and nonspecific, occurring in 33% and 36% of patients.
Across phase II and phase III trials, no clinically important changes in white blood cells, haemoglobin, platelets or liver enzyme levels were reported following rifaximin treatment.
KeywordsPlacebo Recipient Stool Sample Rifaximin Shigellosis Unformed Stool
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