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. 2015 Apr 30;2015:0901.

Travellers' diarrhoea

Christopher Stewart Heather 1
PMCID: PMC4415508  PMID: 25928418

Abstract

Introduction

It is estimated that approximately 30% to 70% of international travellers will develop diarrhoea during their travels or after returning home.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute mild-to-moderate diarrhoea in adults from resource-rich countries travelling to resource-poor countries? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 24 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (empirical), antibiotics plus antimotility agents, antimotility agents, bismuth subsalicylate, diet, oral rehydration solutions, and racecadotril for travellers’ diarrhoea.

Key Points

Diarrhoea is an alteration in normal bowel movement, characterised by increased frequency, volume, and water content of stools, often defined clinically as an increase in stool frequency to three or more liquid or semi-formed motions in 24 hours.

It is estimated that approximately 30% to 70% of international travellers will develop diarrhoea during their travels or after returning home.

Risk of developing diarrhoea depends on destination, season of travel, and length of stay.

Travellers to resource-poor countries in Africa, Asia, the Middle East, and South America are at higher risk than travellers to high-income countries.

Travellers' diarrhoea is frequently self-limiting in otherwise-healthy adults and children and may require only supportive treatment unless symptoms are prolonged or severe.

However, treatment with the aim of reducing symptom duration and severity should be considered, given the potential inconvenience associated with diarrhoea while travelling.

This review examines the effects of treatments in adults with travellers' diarrhoea.

Antibiotics and antimotility agents seem to be effective in treating people from resource-rich countries who have travellers' diarrhoea.

  • Antibiotics plus antimotility agents may be more effective than antibiotics or antimotility agents alone at reducing the duration of diarrhoea and increasing cure rates in people with travellers' diarrhoea.

  • Although we searched for all antimotility agents, we only found evidence for loperamide in people with travellers' diarrhoea.

  • Efficacy of individual antibiotics could not be assessed due to the limited geographical restriction of most studies reviewed. Antibiotic efficacy may be affected by local antimicrobial resistance profiles and aetiological agent.

Bismuth subsalicylate is effective in treating travellers' diarrhoea, but less so than loperamide, and with more adverse effects (primarily black tongue and black stools).

We don't know the effectiveness of the antisecretory agent racecadotril, oral rehydration solutions, or restricting diet in reducing symptoms of diarrhoea in people travelling to resource-poor countries.

Clinical context

General background

Diarrhoea in travellers to resource-poor countries is common, with 30% to 70% of international travellers affected. Most cases of travellers' diarrhoea are non-severe and self-limiting, requiring only supportive management. Symptoms can cause inconvenience and anxiety, however, making treatment to reduce their severity and duration desirable. Travellers' diarrhoea has a range of aetiologies, including bacterial infection, viruses, and protozoa.

Focus of the review

Most therapy for travellers' diarrhoea is empirical, as microbiological diagnostic facilities are frequently not easily accessible at the time of disease onset. This review examines the efficacy of commonly used treatments for acute diarrhoea in travellers, including antimotility agents, antibiotics, and a combination of these, as well as antisecretory agents and supportive measures. The most pertinent outcomes were reduction in duration and decrease in severity of symptoms.

Comments on evidence

We found well-designed RCTs or systematic reviews covering most interventions reviewed. Most studies were geographically restricted with regards to travel destination. Given the multitude of interventions and travel destinations available, the findings of any one study should be generalised with caution. This is particularly the case with the use of antibiotics, where different agents may have differing efficacy depending on destination of travel and prevailing local antimicrobial resistance patterns.

Search and appraisal summary

The update literature search for this review was carried out from the date of the last search, January 2010, to September 2014. A search dating back to 1966 was performed for the new options added to the scope at this update. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 1565 studies. After deduplication, removal of conference abstracts, and appraisal of titles and abstracts, 1534 studies were excluded and 31 full publications were further reviewed. Of the 31 full articles evaluated, one systematic review and no RCTs were added at this update.

Additional information

While antimotility agents and antibiotics were found to be beneficial in the treatment of travellers' diarrhoea, this review did not consider complicated or severe diarrhoea, including enteritis due to Shiga-toxin-producing Escherichia coli. It should be noted that the use of these agents may not be appropriate in this setting. If diarrhoea in travellers is severe or prolonged, microbiological diagnosis is desirable. In this case, directed therapy may be substantially different from the empirical therapy reviewed here.

About this condition

Definition

Diarrhoea is an alteration in normal bowel movement, characterised by increased frequency, volume, and water content of stools. It is often clinically defined as an increase in stool frequency to three or more liquid or semi-formed motions in 24 hours. Acute diarrhoea is usually defined as diarrhoea of 14 days' duration or less, while persistent diarrhoea is of over 14 days' duration. Diarrhoea of over 30 days' duration is frequently defined as 'chronic'. This review examines the effects of treatments for travellers' diarrhoea in adults. For the purposes of this review, travellers' diarrhoea is defined as diarrhoea occurring during or shortly after travel in people who have crossed a national boundary from a resource-rich to a resource-poor country.

Incidence/ Prevalence

It is estimated that 30% to 70% of international travellers will develop a diarrhoeal illness during or after their travel. Incidence of diarrhoea in travellers is dependent on season of travel and destination country, with people travelling to Africa, Asia, Mexico, Central and South America, and the Middle East at highest risk. The epidemiology of travellers' diarrhoea is not well understood. Incidence is higher in travellers visiting resource-poor countries, but it varies widely by location and season of travel.

Aetiology/ Risk factors

The cause of diarrhoea depends on geographical location, standards of food hygiene, sanitation, water supply, and season. No pathogens are identified in more than half of people with diarrhoea. In returning travellers, about 50% of episodes are caused by bacteria such as enterotoxigenic Escherichia coli, Salmonella, Shigella, Campylobacter, Vibrio, enteroadherent E coli, Yersinia, and Aeromonas (see table 1 ).

Table 1.

Percentage of individuals with diarrhoea (cases) or controls with given aetiological agent found on stool testing

Population GP attendants in the Netherlands European and North American travellers in Kenya, India*, or Jamaica with diarrhoea
Age 15–29 years 30–59 years 60 years or over Age range not stated
Number (170 cases/72 controls) (313 cases/244 controls) (102 cases/102 controls) (1079 cases)
Percentage (%) positive for:
Adenovirus 1.0/0.0 0.6/1.4 0.3/0.0 2.8
Aeromonas species – – – 1.9
Astrovirus 0.6/0.0 0.6/0.0 3.9/2.0 –
Blastocystis hominis 27.2/34.7 23.9/34.4 16.7/37.3 –
Campylobacter species 14.7/0.0 10.5/1.2 7.8/0.0 4.2
Cryptosporidium species 3.0/0.0 0.6/0.0 0.0/0.0 0.6
Cyclospora species 0.6/0.0 0.3/0.0 0.0/0.1 –
Dientamoeba fragilis 8.3/18.1 8.9/17.4 9.8/13.7 –
Entamoeba histolytica/ dispar 0.0/2.8 1.0/0.8 1.0/0.0 1.5
Enterotoxigenic Escherichia coli – – – 25.5
Giardia lamblia 3.0/0.0 5.7/1.2 3.9/3.9 0.7
Norwalk-like virus 5.9/1.4 3.9/0.8 1.0/1.0 –
Plesiomonas species – – – 6.3
Rotavirus 4.1/1.4 1.9/1.6 2.9/0.0 2.6
Salmonella species 3.5/0.0 2.6/0.0 3.9/1.0 6.3
Sapporo-like virus 2.9/0.0 0.6/0.7 0.0/0.0 –
Shigella species 0.0/0.0 0.0/0.0 0.0/0.0 6.6
Vibrio species – – – 3.1
Verocytoxin-producing Escherichia coli 0.0/1.6 0.7/0.4 0.0/1.1 –
Yersinia species 1.2/0.0 0.3/1.6 2.0/2.0 –
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*In India, stool samples were not obtained from May to September because of lack of tourism.

Prognosis

Diarrhoea in travellers returning to resource-rich countries is usually self-limiting. However, severe or prolonged symptoms may develop in some people. Furthermore, travellers' diarrhoea may be incapacitating, causing significant inconvenience while travelling. It may, therefore, be desirable to treat mild-to-moderate diarrhoea in this setting.

Aims of intervention

To reduce the infectious period, length of illness, risk of dehydration, risk of transmission to others, and rates of severe illness, with minimum adverse effects.

Outcomes

Mortality; cure rates; duration of illness (time from start of treatment to last loose stool; time to first formed stool; duration of diarrhoea; duration of fever, duration of excretion of organisms); microbiological efficacy (eradication of pathogens); symptom control (number of loose stools a day; stool volume; relief of cramps, nausea, and vomiting; incidence of vomiting; incidence of severe illness; need for unscheduled fluids); for antibiotics: presence of bacterial resistance, rate of hospital admission; adverse effects.

Methods

BMJ Clinical Evidence search and appraisal September 2014. The following databases were used to identify studies for this systematic review, Medline 1966 to September 2014, Embase 1980 to September 2014, and The Cochrane Database of Systematic Reviews 2014, issue 9 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published RCTs and systematic reviews of RCTs in the English language, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the BMJ Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table 1.

GRADE evaluation of interventions for diarrhoea in adults (acute)

Important outcomes Symptom control, duration of illness, hospital admission rates, cure rates, adverse effects
Number of studies (participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of treatments for mild-to-moderate diarrhoea in adults from resource-rich countries travelling to resource-poor countries?
2 (277) Duration of illness Loperamide hydrochloride v placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (447) Cure rates Empirical antibiotics v placebo (multiple destination studies) 4 0 0 0 0 High
5 (1178) Duration of illness Empirical antibiotics v placebo (multiple destination studies) 4 0 0 0 0 High
9 (1315) Duration of illness Empirical antibiotics v placebo (Central America) 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (195) Symptom control Empirical antibiotics v placebo (North and West Africa) 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (47) Duration of illness Empirical antibiotics v placebo (Asia) 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (206) Cure rates Antibiotics (empirical) versus antimotility agents 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and lack of statistical analysis of between-group difference
2 (at least 206) Duration of illness Antibiotics (empirical) versus antimotility agents 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and lack of statistical analysis of between-group difference
1 (206) Microbiological efficacy Antibiotics (empirical) versus antimotility agents 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (206) Symptom control Antibiotics (empirical) versus antimotility agents 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and lack of statistical analysis of between-group difference
6 (unclear) Cure rates Antibiotics plus antimotility agents v antibiotics alone 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results; directness point deducted for heterogeneity among RCTs (regimens used, variable effects, and pathogens)
5 (unclear) Duration of illness Antibiotics plus antimotility agents v antibiotics alone 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results; directness point deducted for heterogeneity among RCTs (regimens used, variable effects, and pathogens)
1 (208) Cure rates Antibiotics plus antimotility agents v antimotility agents alone 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and lack of statistical analysis of between-group difference
2 (at least 208) Duration of illness Antibiotics plus antimotility agents v antimotility agents alone 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and lack of statistical analysis of between-group difference in one RCT
1 (208) Microbiological efficacy Antibiotics plus antimotility agents v antimotility agents alone 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and lack of a statistical assessment of the between-group difference
1 (208) Symptom control Antibiotics plus antimotility agents v antimotility agents alone 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (111) Symptom control Bismuth subsalicylate v placebo 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (245) Duration of illness Bismuth subsalicylate v placebo 4 0 0 0 0 High
1 (203) Duration of illness Bismuth subsalicylate v loperamide 4 0 0 0 0 High
1 (219) Symptom control Bismuth subsalicylate v loperamide 4 0 0 0 0 High
1 (105) Duration of illness Restricted diet v unrestricted diet 4 –1 0 –1 0 Low Quality point deducted for sparse data; directness point deducted for inclusion of intervention (different antibiotics)
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Type of evidence: 4 = RCT. Consistency: similarity of results across studies.Directness: generaliseability of population or outcomes.Effect size: based on relative risk or odds ratio.

Glossary

Acute diarrhoea

An episode of diarrhoea lasting 14 days or less.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Travellers' diarrhoea

Diarrhoea occurring during or shortly after travel in people who have crossed a national boundary.

Gastroenteritis in children

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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BMJ Clin Evid. 2015 Apr 30;2015:0901.

Antibiotics (empirical use)

Summary

CURE RATES Antibiotics compared with placebo (multiple destination studies): Antibiotics are more effective than placebo at increasing cure rates at 3 days ( high-quality evidence ). Antibiotics compared with antimotility agents: We don't know how rifaximin and loperamide compare at increasing clinical cure in people with travellers' diarrhoea ( low-quality evidence ). DURATION OF ILLNESS Antibiotics compared with placebo (multiple destination studies): The antibiotics rifaximin and ciprofloxacin are more effective than placebo at reducing the duration of diarrhoea in adults with travellers' diarrhoea (high-quality evidence). Antibiotics compared with placebo (Central America): Antibiotics seem more effective than placebo at reducing the duration of diarrhoea in adults with travellers' diarrhoea ( moderate-quality evidence ). Antibiotics compared with placebo (Asia): Pivmecillnam seems more effective than placebo at decreasing the duration of watery stools in people with travellers' diarrhoea (moderate-quality evidence). Antibiotics compared with antimotility agents: We don't know how empirical antibiotics and loperamide compare at reducing duration of diarrhoea in adults with travellers' diarrhoea as the evidence was weak and inconsistent (low-quality evidence). MICROBIOLOGICAL EFFICACY Antibiotics compared with antimotility agents: Rifaximin and loperamide seem to have equal microbiological efficacy in people with travellers' diarrhoea (moderate-quality evidence). SYMPTOM CONTROL Antibiotics compared with placebo (North and West Africa): Fleroxacin may be more effective at producing stools of normal consistency, at increasing the number of people with total relief of diarrhoea, and at curing all symptoms (low-quality evidence). 1-day and 2-day fleroxacin regimens may be equally effective at increasing the number of people cured of all symptoms (low-quality evidence). Antibiotics compared with antimotility agents: We don't know how rifaximin and loperamide compare at decreasing the mean number of unformed stools in people with travellers' diarrhoea (low-quality evidence). Antibiotics compared with antibiotics plus antimotility agents: Rifaximin alone seems to be less effective than rifaximin plus loperamide at decreasing the mean number of unformed stools in people with travellers' diarrhoea (moderate-quality evidence).

Benefits

We found two systematic reviews. The first review (search date 2003, 17 RCTs, 2867 people) compared a variety of antibiotics with placebo, a different dose of the same antibiotic, or another antibiotic, in adults travelling from resource-rich countries to resource-poor countries. Dose comparisons and comparisons of different antibiotics versus each other are not comparisons of interest for this BMJ Clinical Evidence review. The second review (search date 2010, 5 RCTs, 1349 people) evaluated the effects of rifaximin in the treatment and prevention of travellers' diarrhoea.

Antibiotics (empirical) versus placebo:

Multiple destination studies (Asia, Central America, South America, Africa):

The first systematic review identified one RCT (447 Swedish travellers to Africa, Asia, or Latin America with ,acute diarrhoea) which compared oral norfloxacin (400 mg twice-daily for 3 days) with placebo. It found that norfloxacin significantly increased cure rates for diarrhoea after 3 days (1 or less loose stools/24 hours without additional symptoms) compared with placebo (34/48 [74%] with norfloxacin v 18/48 [38%] with placebo; P <0.0001).

The second review identified two RCTs comparing rifaximin with placebo. The first RCT (380 adult tourists in Guatemala, Mexico, and Kenya with acute diarrhoea defined as 3 or more unformed stools in 24 hours plus one additional sign of enteric infection) compared three interventions: rifaximin (600 mg/day for 3 days), rifaximin (1200 mg/day for 3 days), and placebo. At 5 days' follow-up, rifaximin 600 mg/day and rifaximin 1200 mg/day significantly reduced median time since last unformed stool compared with placebo (32.5 hours with rifaximin 600 mg/day v 32.9 hours with rifaximin 1200 mg/day v 60.0 hours with placebo; P = 0.0001 for either rifaximin group v placebo). The second RCT (399 travellers to Mexico, Guatemala, India, or Peru) was a three-armed trial comparing rifaximin (200 mg 3 times a day) with ciprofloxacin (500 mg twice-daily plus placebo once daily) and with placebo (3 times daily). It found that both rifaximin and ciprofloxacin significantly reduced the duration of diarrhoea compared with placebo (median time to last unformed stool: 32 hours with rifaximin v 65.5 hours with placebo; P <0.001; 28.8 hours with ciprofloxacin v 65.5 hours with placebo; P <0.0003; intention-to-treat analysis).

Central America (Mexico, Belize):

We found one systematic review, which identified nine RCTs that met inclusion criteria for this BMJ Clinical Evidence review. The second and third RCTs compared ciprofloxacin with placebo. Both RCTs found that ciprofloxacin significantly reduced duration of illness compared with placebo (see table 2 ). The other seven RCTs were all carried out in the same centre in Guadalajara, Mexico, and are described in table 2 . Seven RCTs found that antibiotics significantly reduced the duration of illness compared with placebo.

Table 1.

Effects of antibiotics for travellers' diarrhoea

Ref Antibiotics Participants Duration of illness after start of treatment Adverse effects
Ciprofloxacin
Ciprofloxacin 250 mg bd for 3 days v placebo 17 travellers from Houston, Texas to Mexico with 4 or more loose stools or 2 or more loose stools plus any of: 38.0°C or more oral temperature, vomiting, or abdominal cramps during previous 24-hour period Mean time to cure: 26 hours with ciprofloxacin v 60 hours with placebo; P = 0.03 No adverse effects reported
  Ciprofloxacin 500 mg (single dose) v placebo 83 British troops having 1 or more loose stools in Belize Mean time to last liquid stool: 20.9 hours with ciprofloxacin v 50.4 hours with placebo; P <0.0001; mean time to last unformed stool: 24.8 hours with ciprofloxacin v 53.5 hours with placebo; P <0.0001) No adverse effects reported
Ofloxacin
  Ofloxacin 300 mg bd for 5 days v 3 days v placebo 232 adults (66 with ofloxacin for 5 days v 81 with ofloxacin for 3 days v 79 with placebo) (acute diarrhoea 4 or more unformed stools in 24 hours or 3 or more unformed stools in 8 hours, plus fever or other gastrointestinal complaint) Mean: 39 hours with ofloxacin for 5 days (P = NS compared with placebo) v 28 hours with ofloxacin for 3 days (P <0.05 compared with placebo) v 56 hours with placebo 3/68 (4%) with ofloxacin for 5 days v 4/84 (5%) with ofloxacin for 3 days (insomnia, dizziness, dysgeusia [2 each], sleep disorder, nausea, vaginitis [1 each]). Two people with ofloxacin discontinued (nausea and vaginitis, and headache and rash)
  Ofloxacin 400 mg single dose v ofloxacin 200 mg bd for 3 days v ofloxacin 400 mg single dose plus loperamide (4 mg then 2 mg after each loose stool) 166 adults (56 with ofloxacin single dose v 56 with ofloxacin bd v 54 with ofloxacin plus loperamide) (3 or more unformed stools in 24 hours plus 1 additional symptom of enteric disease) Median: 14 hours with ofloxacin single dose v 28 hours with ofloxacin bd v 0 hours with ofloxacin plus loperamide (P <0.001) No clinically important adverse reactions reported
Aztreonam
  Aztreonam 100 mg 3 times/day for 5 days v placebo 191 adults (98 with aztreonam v 93 with placebo) (acute diarrhoea 4 or more unformed stools in 24 hours or 3 in 8 hours, plus 1 or more additional symptoms of abdominal pain or cramps, nausea, vomiting, or fever) Median: 33 hours with aztreonam v 68 hours with placebo (P = 0.0001) 18/98 (18%) with aztreonam v 12/93 (13%) with placebo experienced adverse effects (mild gastrointestinal complaints: 4 with aztreonam v 2 with placebo; respiratory symptoms: 9 with aztreonam v 8 with placebo) (NS; P value not reported)
Trimethoprim-sulfamethoxazole (co-trimoxazole)
  TMP-SMX (320 mg/1600 mg) single dose v TMP-SMX (160 mg/800 mg) bd for 3 days v loperamide hydrochloride (4 mg initially, 2 mg after each loose stool, 16 mg/day or more) v TMP-SMX (160 mg/800 mg) bd for 3 days plus loperamide hydrochloride (4 mg initially, 2 mg after each loose stool, 16 mg/day or more) v placebo 227 adults (44 with TMP-SMX single dose v 45 with TMP-SMX for 3 days v 46 with loperamide v 47 with TMP-SMX bd plus loperamide v 45 with placebo) (3 or more unformed stools in 24 hours plus 1 additional symptom of enteric disease) Mean: 28 hours with TMP-SMX single dose v 36 hours with TMP-SMX for 3 days v 33 hours with loperamide v 16 hours with TMP-SMX bd plus loperamide v 58 hours with placebo (P less-than or equal to 0.005 compared with active treatments) 1 person taking TMP-SMX for 3 days had a self-limiting rash
  BW942C (20 mg initially then 10 mg 5 times/day) v TMP-SMX (160 mg/800 mg bd) v BW942C (20 mg initially then 10 mg 5 times/day) plus TMP-SMX (160 mg/800 mg bd) v placebo; for 72 hours 134 adults (31 with BW942C v 31 with TMP-SMX v 31 with BW942C plus TMP-SMX v 33 with placebo) (acute diarrhoea 4 or more unformed stools in 24 hours or 3 in 8 hours, plus 1 additional symptom of enteric disease) 24 hours with TMP-SMX v 59 hours with placebo (P = 0.001) 9/32 (28%) with BW942C v 2/31 (6%) with TMP-SMX v 3/33 (9%) with BW942C plus TMP-SMX v 1/33 (3%) with placebo (dizziness, light-headedness, restlessness, sleeplessness, difficulty concentrating, confusion or euphoria within the first 24 hours)
  Ciprofloxacin 500 mg v TMP-SMX (160 mg/800 mg) v placebo bd for 5 days 181 adults (60 with ciprofloxacin v 59 with TMP-SMX v 62 with placebo) (acute diarrhoea 4 or more unformed stools in 24 hours or 3 in 8 hours plus 1 or more symptom of enteric disease) Mean: 29 hours with ciprofloxacin v 20 hours with TMP-SMX v 81 hours with placebo (P less-than or equal to 0.001 compared with active treatment) 2 with ciprofloxacin (pruritus of the hands and eyes/swelling of hand and lips; vaginal infection) v 1 with TMP-SMX (halos around lights)
TMP-SMX (160 mg/800 mg bd for 5 days) v TMP (200 mg bd for 5 days) v placebo 110 adults (37 with TMP-SMX v 38 with TMP v 35 with placebo) (diarrhoea 4 or more unformed stools in 24 hours or 3 or more in 8 hours, plus 1 or more additional symptom of enteric disease) 29.2 hours with TMP-SMX v 30.7 hours with TMP v 92.8 hours with placebo (P <0.0001) 1 (3%) person with TMP had minimal self-limiting rash
Bicozamycin
  Bicozamycin (500 mg 4 times/day for 3 days) v placebo 140 adults (72 with bicozamycin v 68 with placebo) (acute diarrhoea 4 or more unformed stools in 24 hours plus 1 additional symptom of enteric disease) 28.2 hours with bicozamycin v 63.7 hours with placebo (P = 0.00009) Minor rash in 4/78 (5%) people with bicozamycin v 1/68 (1%) person with placebo (significance of difference between groups not reported). 1 person taking bicozamycin had an eruption (erythematous macular patches)
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bd, twice per day; NS, not significant; TMP, trimethoprim; TMP-SMX, trimethoprim-sulfamethoxazole (co-trimoxazole).

North and West Africa (Morocco, Egypt, the Gambia):

We found one RCT (195 tourists in the Gambia with acute diarrhoea, defined as one or more watery or soft stool plus abdominal cramps, vomiting, or nausea), which compared three interventions: fleroxacin (400 mg for 1 day), fleroxacin (400 mg/day for 2 days), and placebo. It found that both 1-day and 2-day fleroxacin were significantly more effective than placebo in producing normal stool consistency at 48 hours' follow-up (36/54 [67%] with 1 day v 34/48 [71%] with 2 day v 18/49 [37%] with placebo; P <0.01 for either dose of fleroxacin v placebo). It found no significant difference between different doses of fleroxacin (P value not reported). Both doses of fleroxacin significantly increased the proportion of people with total relief of diarrhoea compared with placebo, but there was no significant difference between different doses of fleroxacin (36 hours: 50% with 1 day v 50% with 2 days v 14% with placebo; 48 hours: 67% with 1 day v 71% with 2 days v 37% with placebo; absolute numbers not reported; P <0.05 between fleroxacin groups v placebo; no significant difference between different doses of fleroxacin; P value not reported). Fleroxacin at either dose significantly increased the proportion of people cured of all symptoms compared with placebo, but there was no significant difference between different doses of fleroxacin (48 hours: 28/54 [52%] with 1 day v 24/48 [50%] with 2 days v 14/49 [29%] with placebo; P <0.05 between fleroxacin groups v placebo; no significant difference between fleroxacin at different doses; P value not reported; 72 hours: >80% with 1 day v >80% with 2 days v 47% with placebo; absolute numbers not reported; P <0.01 between fleroxacin groups v placebo; no significant difference between fleroxacin groups; P value not reported).

Asia (India, Thailand):

We found one systematic review, which identified one RCT. The RCT (47 Danish tourists with diarrhoea in India) compared pivmecillinam (400 mg 3 times daily for 3 days) with placebo. It found that pivmecillinam significantly reduced the duration of watery stools compared with placebo (<24 hours' duration: 20/24 [83%] with pivmecillinam v 10/23 [43%] with placebo; 24–48 hours' duration: 6/24 [25%] with pivmecillinam v 8/23 [35%] with placebo; more than 48 hours' duration: 0/24 [0%] with pivmecillinam v 6/23 [26%] with placebo; P <0.05).

Antibiotics (empirical) versus antimotility agents:

One five-armed RCT (227 US school students attending summer school in Mexico) identified by the first review included the comparison of trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMX) with loperamide. The RCT found that the mean duration of diarrhoea was similar in both groups (33 hours with loperamide v 36 hours with TMP-SMX; significance not assessed).

One three-armed RCT (311 US students with travellers' diarrhoea in Mexico) identified by the second review compared rifaximin versus loperamide monotherapy versus combination therapy (results for comparison with combination treatment are reported in the relevant sections). People provided a pre-treatment stool, but results of the microbiological investigation did not influence treatment. The RCT found that rifaximin reduced the median time from start of treatment to last unformed stool compared with loperamide (32.5 hours with rifaximin v 69.0 hours with loperamide; significance between groups not assessed). In addition, a larger proportion of people receiving rifaximin achieved clinical cure (time from start of treatment to last unformed stool of <120 hours) compared with loperamide (77% with rifaximin v 58% with loperamide; significance between groups not assessed, absolute numbers not reported). The mean number of unformed stools passed during the first 72 hours of illness was similar between the two treatments (6.23 with rifaximin v 6.72 with loperamide; significance not assessed). The RCT found no significant difference between rifaximin and loperamide in microbiological efficacy, as defined by eradication rate (eradication rate of all pathogens: 76% with rifaximin v 67% with loperamide; OR 1.56; 95% CI 0.84 to 2.89; absolute numbers not reported).

Antibiotics versus antibiotics plus antimotility agents:

See Benefits of Antibiotics plus antimotility agents.

Harms

Antibiotics (empirical) versus placebo:

The first systematic review conducted a meta-analysis of five RCTs. There were significantly more adverse effects in people taking antibiotics compared with placebo (OR 2.37, 95% CI 1.50 to 3.75). However, the adverse effects were not serious and resolved on withdrawal from the drug.

Multiple destination studies (Latin America, South America, Africa, Asia):

The RCT included in the first review reported two adverse events with norfloxacin (constipation, heartburn: 2/19 [11%]) and seven adverse events in the placebo group (vertigo, headache, myalgia, constipation, and paraesthesia: 7/21 [33%]). None of the people had norfloxacin-resistant Escherichia coli before or after treatment; however, E coli resistant to other antibiotics was more frequent after treatment, particularly in the placebo group.

One of the RCTs included in the second review found no significant difference in non-serious adverse events (gastrointestinal-related, headache) between groups (74/125 [59.2%] with rifaximin 600 mg v 88/126 [69.8%] with rifaximin 1200 mg v 90/129 [69.7%] with placebo). Fatigue was reported significantly more with rifaximin 1200 mg (P = 0.023; absolute data not reported). The second RCT included in the review reported a similar rate of adverse events among the three groups. The most common adverse event was headache. There were no early withdrawals because of treatment-related adverse events in the rifaximin or placebo groups (no further information reported).

Central America (Mexico, Belize):

See table 2 for details of the adverse effects of treatment. Overall, these RCTs found that adverse effects with antibiotics were mild and self-limiting.

North and West Africa (Morocco, Egypt, the Gambia):

The RCT (106 people) reported more mild adverse effects with placebo than with norfloxacin (7 cases with norfloxacin v 18 cases with placebo; significance not reported). The second RCT (safety analysis on 190/195 people), found that adverse effects judged to be remotely, possibly, or probably related to the treatment were significantly more likely with 1-day fleroxacin or 2-day fleroxacin compared with placebo (36/61 [59%] with 1 day v 42/65 [65%] with 2 day v 25/64 [39%] with placebo; P <0.05 for either dose v placebo). The most common adverse event was fatigue. No adverse event was considered to be serious.

Asia (India, Thailand):

The RCT did not report on adverse effects.

Antibiotics (empirical) versus antimotility agents:

The RCT included in the second review evaluating loperamide and rifaximin found that a significantly larger proportion of people experienced vomiting after treatment with loperamide compared with rifaximin (12/104 [12%] with loperamide v 3/102 [3%] with rifaximin; OR 4.41; 95% CI 1.28 to 15).

Antibiotics versus antibiotics plus antimotility agents:

See Harms of Antibiotics plus antimotility agents for travellers' diarrhoea.

Comment

We found one RCT (598 people aged 12 years and under with acute diarrhoea lasting 5 days or less; only 70% of people had travellers' diarrhoea, the rest had non-travellers' diarrhoea) comparing norfloxacin 400 mg twice-daily with placebo. It found that norfloxacin significantly increased the proportion of people who were cured (1 loose stool or less/24 hours without additional symptoms) after 5 days compared with placebo (161/257 [63%] with norfloxacin v 130/254 [51%] with placebo; P = 0.003).

Clinical guide

Evidence supports the use of antibiotics in travellers with diarrhoea. Differences in effectiveness of antibiotics between regions are likely to be caused by local levels of antimicrobial resistance. As the prevalence of resistance steadily changes, it would be misleading to ascribe differences in efficacy to location.

First-line empirical therapy with TMP-SMX is not recommended due to high prevalence of resistance and common side effects.

Substantive changes

Antibiotics (empirical use) One systematic review added. Categorisation unchanged (likely to be beneficial).

BMJ Clin Evid. 2015 Apr 30;2015:0901.

Antibiotics plus antimotility agents

Summary

CURE RATES Antibiotics plus antimotility agents compared with antibiotics alone: Antibiotics plus loperamide may be more effective than antibiotics alone at increasing the proportion of people with clinical cure at 24 hours and 48 hours in people with travellers' diarrhoea, but not at 72 hours ( low-quality evidence ). Antibiotics plus antimotility agents compared with antimotility agents alone: We don't know how rifaximin plus loperamide and loperamide alone compare at increasing clinical cure in people with travellers' diarrhoea (low-quality evidence). DURATION OF ILLNESS Antibiotics plus antimotility agents compared with antibiotics alone: Antibiotics plus loperamide may be more effective than antibiotics alone at reducing the time to the last unformed stool in people with travellers' diarrhoea. However, results varied widely depending on the regimen used (low-quality evidence). Antibiotics plus antimotility agents compared with antimotility agents alone: Antibiotics plus loperamide may be more effective at reducing the duration of diarrhoea in people with travellers' diarrhoea (low-quality evidence). MICROBIOLOGICAL EFFICACY Antibiotics plus antimotility agents compared with antimotility agents alone: We don't know how rifaximin plus loperamide and loperamide alone compare at microbiological efficacy in people with travellers' diarrhoea (low-quality evidence). SYMPTOM CONTROL Antibiotics plus antimotility agents compared with antimotility agents alone: Rifaximin plus loperamide seems to be more effective than loperamide alone at decreasing the mean number of unformed stools in people with travellers' diarrhoea ( moderate-quality evidence ).

Benefits

Antibiotics plus antimotility agents versus antibiotics alone:

We found two systematic reviews, which compared antibiotic plus loperamide with the same antibiotic alone. In the first systematic review (search date 2007), antibiotics used included trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMX), ciprofloxacin, ofloxacin, rifaximin, and azithromycin. The second systematic review (search date 2010) reported only on rifaximin. The second review identified one RCT relevant for this comparison; the RCT was also identified by the first review.

The first review carried out a meta-analysis, the results of which are reported here. The review reported that the average age of participants ranged from 23 to 27 years and, although eligibility criteria varied with regard to fever and allowable symptom duration, all RCTs excluded people with dysenteric stools (bloody, mucoid, or both, stools). Clinical cure varied slightly among studies, but generally included resolution of loose stools and symptoms (fever, nausea, vomiting, cramps, myalgia, orthostatic hypotension, or a combination). The review found that antibiotic plus loperamide significantly increased clinical cure at 24 and 48 hours compared with antibiotic alone (24 hours: 6 RCTs; OR 2.58, 95% CI 1.84 to 3.61; 48 hours: 6 RCTs; OR 2.15, 95% CI 1.50 to 3.09; absolute numbers not reported for either analysis). It found no significant difference in clinical cure between groups at 72 hours (5 RCTs; OR 1.40, 95% CI 0.91 to 2.14; absolute numbers not reported). Included RCTs ranged in size from 104 to 310 people. The review reported that five RCTs all found that antibiotic plus loperamide significantly improved the time to last unformed stool compared with antibiotic alone (range in individual RCTs: shortest improvement, WMD –2 hours, 95% CI –0.3 hours to –3.7 hours; largest improvement, WMD –23 hours, 95% CI –21.5 hours to –24.5 hours; results presented graphically, absolute numbers not reported), but noted that there was significant heterogeneity among RCTs (P <0.001) and did not pool data for this comparison. The review did not explain the heterogeneity. Antibiotic regimens varied between RCTs, with three RCTs using a single-dose regimen and three RCTs using a 3-day regimen. Of the included studies, four RCTs were in US student travellers to Mexico, and two RCTs were in US military populations (1 RCT in Egypt and 1 RCT in Thailand).

Antibiotics plus antimotility agents versus antimotility agents alone:

We found one systematic review evaluating the effects of rifaximin (search date 2010, 1 RCT, 311 people) and one additional RCT assessing the combination of trimethoprim and sulfamethoxazole (TMP-SMX) and loperamide.

The RCT identified by the review (311 US students with travellers' diarrhoea in Mexico) found that rifaximin plus loperamide significantly reduced median duration of diarrhoea (time to last unformed stool) compared with loperamide alone (See table 3 .) The RCT also found that a larger proportion of people receiving rifaximin plus loperamide achieved clinical cure compared with those receiving loperamide alone (75% with rifaximin plus loperamide v 58% with loperamide alone; significance between groups not assessed, absolute numbers not reported). The mean number of unformed stools passed during illness was significantly lower in the rifaximin plus loperamide group compared with the group receiving loperamide alone (3.99 with rifaximin plus loperamide v 6.72 with loperamide alone; P = 0.002). Microbiological cure rate was similar between the two groups (68% with loperamide plus rifaximin group v 67% with loperamide; significance not assessed; absolute numbers not reported).

Table 1.

Effects of antibiotics plus antimotility agents for travellers' diarrhoea

Reference and population Intervention Comparison Outcome Results P value
Antibiotics plus antimotility agents versus antimotility agents alone
RCT (311 US students travelling in Mexico) Rifaximin (200 mg given thrice daily for 3 days) plus loperamide (4 mg given initially followed by 2 mg after each unformed stool for 3 days) Loperamide alone (4 mg given initially followed by 2 mg after each unformed stool for 3 days) Mean duration of diarrhoea (time to last unformed stool) 27.3 hours with rifaximin-loperamide v 69.0 hours with loperamide alone Significance between groups not assessed
RCT (227 US students travelling in Mexico) TMP-SMX (160 mg/800 mg twice daily for 3 days) plus loperamide (4 mg as a loading dose plus 2 mg after each loose stool) Loperamide alone (4 mg as a loading dose plus 2 mg after each loose stool) Mean duration of diarrhoea (time to last unformed stool) 16 hours with TMP-SMX plus loperamide v 33 hours with loperamide alone P <0.005
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NS, reported as not significant; TMP-SMX, trimethoprim-sulfamethoxazole (co-trimoxazole).

The additional RCT (227 US students travelling in Mexico) evaluating TMP-SMX plus loperamide found that the combination treatment significantly reduced mean duration of diarrhoea (time to last unformed stool) compared with loperamide alone. See table 3 .

Harms

Antibiotics plus antimotility agents versus antibiotics alone:

The first systematic review, which compared antibiotic plus loperamide with the same antibiotic alone, did not report on harms. The second review, which identified the same RCT as the first review, reported that a similar proportion of people in the rifaximin plus loperamide group and the rifaximin alone group experienced an adverse effect (66/104 [64%] with rifaximin plus loperamide v 70/102 [69%] with rifaximin alone; significance not assessed).

Antibiotics plus antimotility agents versus antimotility agents alone:

The RCT found that the proportion of people experiencing abdominal cramps or pain was significantly smaller in the rifaximin plus loperamide group compared with the loperamide alone group (14/104 [13%] with rifaximin plus loperamide v 34/104 [33%] with loperamide alone; P = 0.004). In addition, rifaximin plus loperamide was associated with a significantly lower rate of vomiting (4/104 [4%] with rifaximin plus loperamide v 12/104 [12%] with loperamide alone; OR 3.27, 95% CI 1.07 to 9.97). The RCT found that a smaller proportion of people experienced nausea in the rifaximin plus loperamide group compared with the loperamide alone group, but the difference between groups did not reach statistical significance (19/104 [18%] with rifaximin plus loperamide v 23/104 [22%] with loperamide alone; reported as not significant, P value not reported).

The RCT evaluating TMP-SMX plus loperamide reported on adverse effects; for details see Harms of Antimotility agents for travellers' diarrhoea.

Comment

The predominant pathogens found in the RCTs were different, with enterotoxigenic Escherichia coli being the predominant identified pathogen in the studies in Mexico and Egypt. Exploratory analyses in some of the studies suggested that the combination was most effective for enterotoxigenic E coli, but not for Shigella, Salmonella, or other invasive or cytopathic pathogens.

Clinical guide

The evidence seems to be in favour of antibiotic/loperamide combination therapy over antibiotics alone, effecting increased clinical cure rates at 24 and 48 hours. This effect is, however, variable across different antibiotics, with uncertain benefit for individual agents, and may further be related to the pathogens encountered.

Antimotility agents are not recommended for people with suspected shigellosis or Shiga-toxin-producing E coli.

Substantive changes

Antibiotics plus antimotility agents One systematic review added. Categorisation unchanged (likely to be beneficial).

BMJ Clin Evid. 2015 Apr 30;2015:0901.

Antimotility agents

Summary

CURE RATES Loperamide hydrochloride compared with antibiotics: We don't know how loperamide and rifaximin compare at increasing clinical cure in people with travellers' diarrhoea ( low-quality evidence ). Loperamide hydrochloride compared with antibiotics plus antimotility agents: We don't know how loperamide and rifaximin plus loperamide compare at increasing clinical cure in people with travellers' diarrhoea (low-quality evidence). Loperamide hydrochloride compared with bismuth subsalicylate: Loperamide is more effective than bismuth subsalicylate at reducing the time to last unformed stool ( high-quality evidence ). DURATION OF ILLNESS Loperamide hydrochloride compared with placebo: Loperamide hydrochloride seems to be more effective than placebo at reducing the duration of diarrhoea in adults with travellers' diarrhoea ( moderate-quality evidence ). Loperamide hydrochloride compared with antibiotics plus antimotility agents: Loperamide alone may be less effective than loperamide plus antibiotic at reducing the duration of diarrhoea in people with travellers' diarrhoea (low-quality evidence). Loperamide hydrochloride compared with antibiotics: We don't know how loperamide and empirical antibiotics compare at reducing duration of diarrhoea in adult with travellers' diarrhoea as the evidence was weak and inconsistent (low-quality evidence). MICROBIOLOGICAL EFFICACY Loperamide hydrochloride compared with antibiotics: Loperamide and rifaximin seem to have equal microbiological efficacy in people with travellers' diarrhoea (moderate-quality evidence). Loperamide hydrochloride compared with antibiotics plus antimotility agents: We don’t know how loperamide alone and loperamide plus rifaximin compare at eradicating pathogens in people with travellers' diarrhoea (low-quality evidence). SYMPTOM CONTROL Loperamide hydrochloride compared with antibiotics: We don't know how loperamide and rifaximin compare at decreasing the mean number of unformed stools in people with travellers' diarrhoea (low-quality evidence). Loperamide hydrochloride compared with antibiotics plus antimotility agents: Loperamide alone seems to be less effective than loperamide plus rifaximin at decreasing the mean number of unformed stools in people with travellers' diarrhoea (moderate-quality evidence). Loperamide hydrochloride compared with bismuth subsalicylate: Loperamide is more effective than bismuth subsalicylate at reducing the number of unformed stools at 0 to 48 hours (high-quality evidence).

Benefits

We found no systematic review but found two RCTs.

Antimotility agents versus placebo:

The first RCT (227 US school students attending summer school in Mexico, with 3 or more unformed stools in 24 hours, diarrhoea lasting 14 days or less, and at least one incidence of abdominal cramps, nausea, or vomiting) compared five interventions: loperamide hydrochloride 4 mg as loading dose and 2 mg on each loose bowel movement, single-dose trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMX) 300 mg/1600 mg, TMP-SMX 160 mg/800 mg twice-daily for 3 days, combination TMP-SMX 160 mg/800 mg twice daily for 3 days plus loperamide, and placebo. It found that loperamide significantly reduced mean duration of diarrhoea compared with placebo (33 hours with loperamide v 58 hours with placebo; P less than or equal to 0.05). Results from other arms of the RCT are presented under appropriate subheadings below. The second RCT (50 North American and Western European adult expatriates in Bangladesh, >3 unformed stools during previous 24 hours, and ill for <72 hours) compared loperamide 2 mg after each loose stool with placebo. It found that loperamide significantly reduced the number of stools on days 1 and 2 compared with placebo (results presented graphically).

Antimotility agents versus antibiotics:

See Benefits of Antibiotics for travellers' diarrhoea.

Antimotility agents versus antibiotics plus antimotility agents:

See Benefits of Antibiotics plus antimotility agents for travellers' diarrhoea.

Antimotility agents versus bismuth subsalicylate:

See Benefits of Bismuth subsalicylate for travellers' diarrhoea.

Harms

The first RCT reported only one important adverse reaction, namely a self-limiting rash occurring in a participant taking TMP-SMX. The second RCT reported that three people treated with loperamide had dizziness, and four people had constipation on loperamide compared with three taking placebo (significance not reported).

Antimotility agents versus antibiotics:

See Harms of Antibiotics for travellers' diarrhoea.

Antimotility agents versus antibiotics plus antimotility agents:

See Harms of Antibiotics plus antimotility agents for travellers' diarrhoea.

Antimotility agents versus bismuth subsalicylate:

See Harms of Bismuth subsalicylate for travellers' diarrhoea.

Comment

This review did not consider adverse events arising from enteritis due to Shiga-toxin-producing Escherichia coli (STEC). The use of antimotility agents in patients with STEC has been associated with increased risk of developing haemolytic uraemic syndrome (HUS).

Clinical guide

Treatment with antimotility agents reduces duration of symptoms compared with placebo.

If diarrhoea in travellers is severe or prolonged, microbiological diagnosis is desirable. In this case, directed therapy may be substantially different from the empirical therapy discussed in this section.

Treatment of patients who exhibit symptoms of STEC infection (bloody diarrhoea, abdominal pain, fever) with antimotility agents is not recommended.

Substantive changes

No new evidence

BMJ Clin Evid. 2015 Apr 30;2015:0901.

Bismuth subsalicylate

Summary

DURATION OF ILLNESS Bismuth subsalicylate compared with placebo: Bismuth subsalicylate is more effective than placebo at reducing the duration of diarrhoea ( high-quality evidence ). Bismuth subsalicylate compared with loperamide: Bismuth subsalicylate is less effective than loperamide at reducing the time to last unformed stool (high-quality evidence). SYMPTOM CONTROL Bismuth subsalicylate compared with placebo: Bismuth subsalicylate seems to be more effective than placebo at reducing the number of loose stools at 4 to 24 hours after treatment ( moderate-quality evidence ). Bismuth subsalicylate compared with loperamide: Bismuth subsalicylate is less effective than loperamide at reducing the number of unformed stools at 0 to 48 hours (high-quality evidence). NOTE The modest benefits of bismuth subsalicylate may be outweighed by large and frequent doses of the liquid preparation needed. Bismuth subsalicylate is associated with frequent minor adverse effects such as black tongue or black stools.

Benefits

We found no systematic review but found four RCTs of treatment of acute diarrhoea with bismuth subsalicylate compared with placebo or loperamide.

Bismuth subsalicylate versus placebo:

We found two RCTs. The first RCT (111 US students attending a Mexican university who developed diarrhoea) compared bismuth subsalicylate versus placebo. Students with three or four unformed stools in the preceding 24 hours received bismuth subsalicylate 30 mL every 30 minutes for eight doses; those with five or more unformed stools in 24 hours received 60 mL every 30 minutes for eight doses. The RCT found that both doses of bismuth subsalicylate significantly reduced the number of loose stools compared with placebo at 4 to 24 hours after treatment (109 with bismuth subsalicylate 30 mg v 165 with placebo; P <0.05; 39 with bismuth subsalicylate 60 mg v 77 with placebo; P <0.05). The second RCT (133 Europeans visiting West Africa and 112 US students in Mexico who had travellers' diarrhoea) compared bismuth subsalicylate 1050 mg suspension with placebo every hour up to four doses per day for 2 days for the West African study, and bismuth subsalicylate 525 mg versus placebo every 30 minutes up to eight doses per day for 2 days for the Mexican study. The RCT found that bismuth subsalicylate significantly reduced the duration of diarrhoea compared with placebo in both sites (West Africa: 25.8 hours with bismuth subsalicylate v 34.5 hours with placebo; P <0.01; Mexico: 24.2 hours bismuth subsalicylate v 31.4 hours with placebo; P = 0.02).

Bismuth subsalicylate versus loperamide:

We found two RCTs. The first RCT (219 students with acute diarrhoea while visiting 7 countries in Latin America) compared bismuth subsalicylate 30 mL every 30 minutes for eight doses for 2 days versus loperamide 4 mg followed by 2 mg after each unformed stool. The RCT found that bismuth subsalicylate was significantly less effective at reducing the number of unformed stools at 0 to 48 hours compared with loperamide (0–4 hours: 1.3 with bismuth subsalicylate v 0.9 with loperamide; P <0.0004; 4–24 hours: 2.4 with bismuth subsalicylate v 1.5 with loperamide; P <0.002; 24–48 hours: 1.0 with bismuth subsalicylate v 0.8 with loperamide; P <0.05). The number who received rescue treatment with antimicrobial drugs (trimethoprim-sulfamethoxazole [co-trimoxazole; TMP-SMX]) was similar between groups (28% with bismuth subsalicylate v 24% with loperamide; absolute numbers not reported). The second RCT (203 students in Mexico) compared bismuth subsalicylate 35 mL (612.5 mg) every 30 minutes up to eight doses versus loperamide liquid 20 mL (4 mg) followed by 2 mg after each unformed stool. The RCT found that bismuth subsalicylate was significantly less effective at reducing time to last unformed stool compared with loperamide (median: 13.9 hours with bismuth subsalicylate v 3.4 hours with loperamide; P = 0.001).

Harms

Bismuth subsalicylate versus placebo:

The first RCT gave no information on adverse effects. The second RCT reported that the main adverse reactions noted among people treated with bismuth subsalicylate were black tongue (22% with bismuth subsalicylate v 4% with placebo) and black stools (69% with bismuth subsalicylate v 11% with placebo).

Bismuth subsalicylate versus loperamide:

The first RCT reported that in the bismuth subsalicylate group, two people complained of tinnitus, three became nauseated after taking medication, one had dizziness, and one became constipated. In the loperamide group, eight people complained of constipation, four experienced headache, and two had drowsiness and dizziness. The second RCT reported that adverse effects were minimal, equally distributed between treatments, and for the most part indistinguishable from the symptoms commonly associated with diarrhoeal syndrome.

Comment

Clinical guide

There is evidence that bismuth is more effective than placebo, but less effective than loperamide. However, given the modest benefit and the frequent dosing and large volume required if using the liquid formulation, bismuth is a little-used clinical treatment option.

Substantive changes

No new evidence

BMJ Clin Evid. 2015 Apr 30;2015:0901.

Diet

Summary

DURATION OF ILLNESS Restricted diet compared with unrestricted diet: We don't know whether restricted diets are more effective than unrestricted diets at reducing the duration of diarrhoea ( low-quality evidence ).

Benefits

We found no systematic review but found one RCT comparing restricted with unrestricted diet. The RCT (105 US college students in Guadalajara) found no significant difference in duration of diarrhoea for students on a restricted diet versus students on an unrestricted diet (mean: 37 hours with restricted diet v 33 hours with unrestricted diet; P = 0.59). Adherence to both interventions was good. The students were part of studies investigating the effect of antibiotics on travellers' diarrhoea, and all received one of four antibiotics (levofloxacin, azithromycin, rifaximin, or ciprofloxacin). Participants were grouped to the same intervention according to the household in which they resided during their stay.

Harms

The RCT gave no information on adverse effects.

Comment

Clinical guide

Although commonly recommended, there is limited evidence that dietary restrictions are of any benefit.

Substantive changes

No new evidence

BMJ Clin Evid. 2015 Apr 30;2015:0901.

Oral rehydration solutions

Summary

We found no direct information from RCTs about the effects of oral rehydration solutions on acute mild-to-moderate diarrhoea in adults from resource-rich countries travelling to resource-poor countries.

Benefits

We found no systematic review or RCTs.

Harms

We found no RCTs.

Comment

One RCT (80 US students in Mexico) compared oral rehydration solution (500 mL initially, followed by 250 mL after each unformed stool, up to 1000 mL/day) plus loperamide (4 mg initially, followed by 2 mg after each unformed stool, up to 8 mg/day) with loperamide alone for 48 hours. It found no significant difference between groups in duration of diarrhoea or symptom control.

Clinical guide

Most clinicians believe that oral rehydration solution is the first-line treatment for diarrhoea.

Substantive changes

No new evidence

BMJ Clin Evid. 2015 Apr 30;2015:0901.

Racecadotril

Summary

We found no direct information from RCTs about the effects of racecadotril on acute mild-to-moderate diarrhoea in adults from resource-rich countries travelling to resource-poor countries.

Benefits

We found no systematic review or RCTs.

Harms

We found no systematic review or RCTs.

Comment

Racecadotril may not be available in all countries at the time this review was written.

Substantive changes

Racecadotril New option. Categorised as 'unknown effectiveness'.

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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