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Xifaxanta for traveller’s diarrhoea

By Lucy Hedley, MRPharmS

Who it is for

graham briggs/Dreamstime.com Traveller’s diarrhoea (see Panel) affects up to 60 per cent of the 800 million plus travellers each year. In most cases the diarrhoea occurs in people who travel to areas with poor hygiene.

Symptoms usually occur around seven days into an overseas trip and usually resolve spontaneously, in three or four days. However, up to a quarter of affected travellers find their holiday or business activities interrupted.

Mild to moderate traveller’s diarrhoea should be treated with rehydration and, where needed, symptomatic therapy. Moderate to severe cases (at least three loose stools in 24 hours plus other enteric symptoms) or diarrhoea that has not responded to symptomatic treatment can be treated with antibiotics.

Xifaxanta (rifaximin; Norgine) has recently been launched in the UK for treating traveller’s diarrhoea associated with non-invasive strains of Escherichia coli — in other words, cases that are not associated with fever, bloody diarrhoea, eight or more loose stools in the previous 24 hours or occult blood or leucocytes in the stool.


 Traveller's diarrhoea


•    Classic traveller’s diarrhoea is defined as at least three loose towatery stools in 24 hours, with or without symptoms of abdominal cramps, fever, nausea, vomiting or blood in the stool.

•    Mild to moderate diarrhoea is one or two loose stools in 24 hours with or without another enteric symptom.

•    The causes of traveller’s diarrhoea depend on the destination, setting and season. Half to three quarters of cases are caused by bacteria, including Escherichia coli, Campylobacter, Salmonella, and Shigella species, with enterotoxigenic and enteroaggregative E coli being implicated in 5 to 45 per cent of cases. The remaining portion of cases are caused by viruses, parasites and food poisoning toxins.

•    Travel to the Middle East, Africa, Central and South America andmost of Asia tends to present the highest risk of traveller’s diarrhoea.

 

How it works

 

Rifaximin, a rifamycin, is a semi-synthetic, non-systemic structural analogue of rifampicin. It is not absorbed and acts within the gastrointestinal tract on the b-subunit of the bacterial enzyme DNA-dependent RNA polymerase enzyme and, consequently, inhibits bacterial RNA synthesis.

 

Research

Xifaxanta has been available in the US and other European countries since 2004. Many randomised placebo-controlled and comparative trials over the past 25 years have shown the efficacy of antibiotics in the treatment of traveller’s diarrhoea. Most indicate that an antibiotic taken as a single dose or for up to three days will improve the condition within 20 to 36 hours, shortening its duration by one or two days compared with placebo.

According to its summary of product characteristics, Xifaxanta may shorten the duration of diarrhoea associated with non-invasive strains of E coli: three multi-centre randomised controlled trials have demonstrated that it can reduce the duration of travellers’ diarrhoea by 27 to 36 hours.

Rifaximin had similar microbial eradication rates as placebo, but it produced higher clinical cure rates and shorter duration of diarrhoea. In clinical studies of patients with infectious diarrhoea, it demonstrated activity against both enterotoxigenic and enteroaggregative strains of E coli.

Rifaximin was also shown to be non-inferior to ciprofloxacin in a randomised double blind controlled trial of treatment in Mexico and Jamaica, where E coli-associated traveller’s diarrhoea was common (Clinical Infectious Diseases 2001;33:1807). It is less effective (and not recommended) when invasive agents, such as salmonella, campylobacter and shigella are the cause (ie, in up to 25 per cent of cases).

Bacterial resistance rates of 30 to 90 per cent have been reported after five days’ treatment. Within one or two weeks after treatment was stopped, resistance rates had generally decreased to less than 20 per cent in most strains tested; after 12 weeks, no resistant strains were detected (Drugs 1995;49:467). However, travel medicine expert and head of the school of pharmacy at De Montfort University Larry Goodyer, who did some consultative work for Norgine, does not believe that resistant strains are an issue for individuals or communities bearing in mind the levels of use of Xifaxanta in countries where it is unlikely to be available.

Administration

Rifaximin is taken orally as a 200mg tablet every eight hours for three days. It must not be used for more than three days. If symptoms continue or recur shortly afterwards, a second course of treatment should not be taken.

Dose adjustment for patients’ with hepatic or renal insufficiency is not necessary.

Safety

Rifaximin is contraindicated in patients who have had a hypersensitivity reaction to rifaximin, any component of the product, or other rifamycin antimicrobial agents.

Treatment should be discontinued if symptoms worsen because it is not effective against invasive enteric pathogens, or if Clostridium difficile-associated diarrhoea is suspected or confirmed.

Adverse events associated with short course therapy are usually mild. Side effects listed as common in the SPC include gastrointestinal effects, dizziness and headache.

There is no experience regarding administration of rifaximin to subjects who are taking another rifamycin to treat a systemic bacterial infection. Due to the lack of data and the potential for severe disruption of gut flora with unknown consequences rifaximin should not be administered concomitantly with other rifamycins.

Due to its negligible gastrointestinal absorption (less than 1 per cent), the potential for systemic drug interactions with Xifaxanta is low. In vitro data show that rifaximin is a weak inducer of the CYP3A4 isoenzyme of the P450 cytochrome. Drug-drug interaction studies investigating the clinical interaction between rifaximin and drugs metabolised by the human cytochrome P450 isoenzymes demonstrated that rifaximin does not significantly affect the pharmacokinetics of midazolam or an oral contraceptive containing ethinylestradiol and norgestimate. Therefore clinical interactions with drugs metabolised by these isoenzymes are not expected. The potential for drug-drug interactions to occur at the level of gut transporter systems has not been evaluated, however, and cannot be ruled out.

Cost

The basic price of a course of treatment, nine 200mg tablets, is £15.15. This is substantially more expensive than the current recommended first-line treatment and its alternative antibiotic: according to the Drug Tariff (online) a course of ciprofloxacin costs £0.63 and a course of azithromycin costs £4.50.

Place in therapy

Recent travel to any low income country should be considered a risk factor for infection. Current guidelines recommend that travellers’ diarrhoea can be evaluated in a general practice setting with referral to a specialist as required.

For those with moderate to severe diarrhoea or protracted symptoms, efforts should be made to try to identify a precise cause and empirical antibiotic treatment considered with a fluoroquinolone or azithromycin. Stool samples should be sent to microbiology, virology and parasitology laboratories. Those with fever or history of fever and who have returned from the tropics should have three sets of blood cultures and a blood film analysed for evidence of malaria parasites. Those with a history of antibiotic use and hospital contact should be tested for C. difficile infection.

Current first-line empirical antibiotic therapy is ciprofloxacin 500mg po bd for three days, with azithromycin 500mg po od for three days reserved for patients who have travelled to South East Asia (where campylobacter resistance to ciprofloxacin is prevalent) or who cannot tolerate quinolones.

Due to its lack of systemic absorption rifaximin has a more favourable interaction profile than the two currently prescribed agents. However, it is unlikely to be recommended as a suitable option for NHS-funded treatment of traveller’s diarrhoea. It has no demonstrated superior efficacy to the current recommended first-line therapies and has a similar microbial eradication rate to placebo. In addition, it is not licensed for use in patients under 18 years, nor is it available as a suspension.

Like ciprofloxacin, rifaximin may be prescribed as standby treatment for travellers [to high risk areas where access to medical assistance is poor and antibiotic prophylaxis is not a preferred option], Professor Goodyer said. However, this sort of prescribing has not been common in the UK. “I think that one of the reasons is that, conceptually, people don’t like to treat with a systemic product,” he explained. He said that he could see

Xifaxanta being prescribed privately, supplied by travel clinics and online pharmacies, especially those supplying antimalarials through patient group directions. “Some people will prefer to have an antibiotic that is not absorbed and not used for any other indication,” he told The Journal.

Professor Goodyer said that Xifaxanta can be used with loperamide. He pointed out that loperamide also should not be used to treat diarrhoea accompanied by blood in the stools and fever (dysentery) and travellers should be counselled on when use of either loperamide or an antibiotic is appropriate.

 

Citation: The Pharmaceutical Journal URI: 11087013

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