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. 2008 Mar 4;2008:0901.

Diarrhoea in adults (acute)

Guy de Bruyn 1
PMCID: PMC2907942  PMID: 19450323

Abstract

Introduction

An estimated 4000 million cases of diarrhoea occurred worldwide in 1996, resulting in 2.5 million deaths.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute diarrhoea in adults living in resource-rich countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults from resource-rich countries traveling to resource-poor countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults living in resource-poor countries? What are the effects of treatments for acute severe diarrhoea in adults living in resource-poor countries? We searched: Medline, Embase, The Cochrane Library and other important databases up to January 2007 (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 71 systematic reviews, RCTs, or observational 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, antimotility agents, antisecretory agents, bismuth subsalicylate, diet, intravenous rehydration, nasogastric tube rehydration, and oral rehydration solutions (amino acid oral rehydration solution, bicarbonate oral rehydration solution, reduced osmolarity oral rehydration solution, rice-based oral rehydration solution, standard oral rehydration solution).

Key Points

Diarrhoea is watery or liquid stools, usually with an increase in stool weight above 200 g daily and an increase in daily stool frequency.

  • An estimated 4000 million cases of diarrhoea occurred worldwide in 1996, resulting in 2.5 million deaths.

In people from resource-poor countries, antisecretory agents, such as racecadotril, seem to be as effective at improving symptoms of diarrhoea as antimotility agents, such as loperamide, but with fewer adverse effects.

Antisecretory agents, antibiotics, and antimotility agents also appear to be effective in treating people from resource-rich countries who are travelling to resource-poor countries.

For people from resource-poor countires with mild or moderate diarrhoea, antisecretory agents seem to be as beneficial as antimotility agents, and cause fewer adverse effects (particularly rebound constipation).

Oral rehydration solutions are considered to be beneficial in people from resource-poor countries who have severe diarrhoea.

We don't know whether intravenous rehydration is more beneficial than oral rehydration or enteral rehydration through a nasogastric tube.

About this condition

Definition

Diarrhoea is watery or liquid stools, usually with an increase in stool weight above 200 g daily and an increase in daily stool frequency. This review covers empirical treatment of suspected infectious diarrhoea in adults.

Incidence/ Prevalence

An estimated 4000 million cases of diarrhoea occurred worldwide in 1996, resulting in 2.5 million deaths. In the USA, the estimated incidence for infectious intestinal disease is 0.44 episodes per person per year (1 episode per person every 2.3 years), resulting in about one consultation with a doctor per person every 28 years. A recent community study in the UK reported an incidence of 19 cases per 100 person years, of which 3.3 cases per 100 person years resulted in consultation with a general practitioner. Both estimates derive from population-based studies, including both adults and children. 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. The incidence of diarrhoea in adults in resource-poor countries is largely unknown owing to the lack of large scale surveillance studies in these countries.

Aetiology/ Risk factors

The cause of diarrhoea depends on geographical location, standards of food hygiene, sanitation, water supply, and season. Commonly identified causes of sporadic diarrhoea in adults in resource-poor countries include Campylobacter, Salmonella, Shigella, Escherichia coli, Yersinia, protozoa, and viruses (see table 1 ). 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 E 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 (see text).

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 lablia 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

In resource-rich countries, death from infectious diarrhoea is rare, although serious complications, including severe dehydration and renal failure, can occur and may necessitate admission to hospital. Elderly people and those in long-term care have an increased risk of death. In resource-poor countries, diarrhoea is reported to cause more deaths in children under 5 years of age than any other condition. Few studies have examined which factors predict poor outcome in adults.

Aims of intervention

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

Outcomes

Illness duration (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); symptom control (number of loose stools a day; stool volume; relief of cramps, nausea and vomiting; incidence of vomiting; incidence of severe illness); microbiological efficacy (eradication of pathogens); presence of bacterial resistance; and rate of hospital admission.

Methods

BMJ Clinical Evidence search and appraisal January 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to January 2007, Embase 1980 to January 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2006, Issue 4. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We did not exclude studies that included people with HIV/AIDS. We use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table.

GRADE evaluation of interventions for diarrhoea in adults (acute)

Important outcomes Symptom control, duration of illness, hospitalisation 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 acute diarrhoea in adults living in resource-rich countries?
1 (152) Symptom control Diphenoxylate v placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (152 Duration of illness Diphenoxylate v placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
2 (670) Duration of illness Loperamide hydrochloride v placebo 4 0 0 0 0 High
2 (670) Duration of illness Loperamide hydrochloride v loperamide oxide 4 0 0 0 0 High
5 (1400) Duration of illness Loperamide oxide v placebo 4 0 0 0 0 High
1 (168)] Duration of illness Racecadotril v placebo 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (71) Symptom control Racecadotril v placebo 4 –1 0 0 0 Moderate Quality point deducted for sparse data
3 (288) Duration of illness Racecadotril v loperamide 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (157) Symptom control Racecadotril v placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
5 (676) Duration of illness Antibiotics v placebo 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
5 (676) Symptom control Antibiotics v placebo 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
4 (574) Cure rates Antibiotics v placebo 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for different results at different endpoints
1 (71) Duration of illness Restricted diets v unrestricted diets 4 –1 0 0 0 Moderate Quality point deducted for sparse data
What are the effects of treatments for mild-to-moderate diarrhoea in adults from resource-rich countries traveling 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
2 (227) Duration of illness Loperamide hydrochloride alone v trimethoprim-sulfamethoxazole 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 (142) Duration of illness Empirical antibiotics v each other (Multiple destination studies) 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (94) Duration of illness Empirical antibiotics v each other (Central America) 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (102) Symptom control Empirical antibiotics v each other (North and West Africa) 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (79) Duration of illness Empirical antibiotics v each other (Asia) 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
4 (639) Duration of illness Antibiotics plus antimotility agents v antibiotics alone 4 –2 –1 0 0 Very low Quality points deducted for incomplete reporting of results and for inclusion of single blind study. Consistency point deducted for conflicting results
1 (227) Duration of illness Antibiotics plus antimotility agents v antimotility agents alone 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (142) Duration of illness Different antibiotics plus antimotility agents regimens v each other 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and sparse data
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
2 (355) Duration of illness Zaldaride maleate v placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (179) Symptom control Zaldaride maleate v loperamide 4 –1 0 0 0 Moderate Quality point deducted for sparse data
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)
What are the effects of treatments for mild-to-moderate diarrhoea in adults living in resource-poor countries?
2 (185) Symptom control Antimotility agents v placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (945) Duration of illness Racecadotril v loperamide 4 0 0 0 0 High
2 (446) Symptom control Antibiotics v placebo 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and for no- intention-to-treat analysis
1 (57) Symptom control Citrate oral rehydration solution v bicarbonate oral rehydration solution 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
What are the effects of treatments for severe diarrhoea in adults living in resource-poor countries?
1 (88) Duration of illness Antibiotics plus antimotility agents v antibiotics 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (110) Duration of illness Racecadotril v placebo 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (110) Symptom control Racecadotril v placebo 4 –1 0 0 0 Moderate Quality point deducted for sparse data
2 (565) Duration of illness Berberine v placebo or no treatment 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for assessing different outcomes
2 (565) Duration of illness Berberine plus tetracycline v tetracycline 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for measuring different outcomes
1 (165) Symptom control Berberine v placebo or no treatment 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (46) Duration of illness Chlorpromazine v placebo 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for narrow inclusion criteria
1 (410) Symptom control Chlorpromazine v placebo 4 –1 0 –3 0 Very low Quality point deducted for incomplete reporting of results. Directness points deducted for assessing different outcomes and in a different population, and for additional interventions
2 (205) Symptom control Amino acid oral rehydration solution v standard oral rehydration solution 4 –2 0 –2 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for assessing different outcomes and generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
5 (817) Symptom control Rice based oral rehydration solution v standard oral rehydration solution 4 –1 0 –2 0 Very low Quality point deducted for incomplete reporting of results. Directness points deducted for additional interventions in one group and generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
1 (123) Duration of illness Rice based oral rehydration solution v standard oral rehydration solution 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
1 (123) Symptom control Rice-based oral rehydration solutions v low-glucose/low-sodium oral rehydration solution 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
1 (123) Duration of illness Rice-based oral rehydration solutions v low-glucose/low-sodium oral rehydration solution 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
1 (123) Duration of illness Low-sodium rice-based oral rehyration solution v rice-based oral rehydration solution 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
1 (123) Symptom control Low-sodium rice-based oral rehyration solution v rice-based oral rehydration solution 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
2 (310) Duration of illness Bicarbonate oral rehydration solution v standard oral rehydration solution 4 –1 0 –2 0 Very low Quality point deducted for incomplete reporting of results. Directness points deducted for additional intervention in one groups and generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
2 (310) Symptom control Bicarbonate oral rehydration solution v standard oral rehydration solution 4 –1 0 –2 0 Very low Quality point deducted for incomplete reporting of results. Directness points deducted for additional intervention in one groups and generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
1 (60) Duration of illness Bicarbonate oral rehydration solution v chloride standard oral rehydration solution 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness points deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
1 (60) Symptom control Bicarbonate oral rehydration solution v chloride standard oral rehydration solution 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness points deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
4 (575) ] Duration of illness Reduced osmolarity oral rehydration solution v standard oral rehydration solution 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness points deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
4 (575) Symptom control Reduced osmolarity oral rehydration solution v standard oral rehydration solution 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness points deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
1 (20) Duration of illness Intravenous rehydration v enteral rehydration 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness points deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
1 (20) Symptom control Intravenous rehydration v enteral rehydration 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness points deducted for generalisability of results (comparing response in people with cholera with less severe forms of diarrhoea)
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Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. 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.

Empirical treatment

Treatment guided by professional experience, or given before or without reference to the results of microbiologic investigations.

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.

Severe diarrhoea

A diarrhoeal illness associated with profuse or dehydrating stool losses, blood, fever, or illness in infants, elderly people, or immunocompromised people.

Travellers' diarrhoea

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

Very low-quality evidence

Any estimate of effect is very uncertain.

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. 2008 Mar 4;2008:0901.

Antimotility agents in resource-rich countries

Summary

DURATION OF ILLNESS Diphenoxylate compared with placebo: Diphenoxylate may be no more effective at increasing median time to last stool in adults with acute diarrhoea of less than 24 hours ( low-quality evidence ). Loperamide hydrochloride/oxide compared with placebo: Loperamide hydrochloride, and loperamide oxide are more effective at reducing the duration of diarrhoea in adults ( high-quality evidence ). Loperamide hydrochloride compared with loperamide oxide: Loperamide hydrochloride and loperamide oxide seem to be equally effective at reducing the duration of diarrhoea in adults (high-quality evidence). SYMPTOM CONTROL Diphenoxylate compared with placebo: Diphenoxylate may be more effective at reducing the rate of bowel actions 24 hours after treatment in adults with acute diarrhoea (low-quality evidence). ADVERSE EFFECTS Loperamide hydrochloride and loperamide oxide have been associated witih increased constipation-like periods.

Benefits

We found no systematic review but found six RCTs.

Difenoxin:

We found no RCTs.

Diphenoxylate:

We found one RCT (152 adults with acute diarrhoea for less than 24 hours) comparing diphenoxylate–atropine versus placebo. It found that diphenoxylate significantly reduced the rate of bowel actions in the 24 hours after treatment (P = 0.05). The RCT found no significant difference in median time to last loose stool (25 hours with diphenoxylate v 30 hours with placebo; P = 0.29).

Lidamidine:

We found no RCTs.

Loperamide hydrochloride:

We found two RCTs (409 and 261 adults with acute diarrhoea, defined as more than 2 watery or loose stools in the previous 24 hours) with four study arms each, comparing loperamide hydrochloride versus placebo and versus two doses of loperamide oxide (1 and 2 mg). Both RCTs found that loperamide hydrochloride significantly reduced duration of diarrhoea compared with placebo (first RCT: median time to complete relief of diarrhoea: 27 hours with loperamide hydrochloride v 45 hours and 15 minutes with placebo; P = 0.006; second RCT: median time to complete relief of diarrhoea: 17.5 hours with loperamide hydrochloride v 37 hours with placebo; P = 0.007). They found no significant difference among the groups on active treatment (first RCT: median time to complete relief of diarrhoea: 27 hours with loperamide hydrochloride v 23.5 hours with loperamide oxide 1 mg v 25.5 hours with loperamide oxide 2 mg; P more than 0.7; second RCT: median time to complete relief of diarrhoea: 17.5 hours with loperamide hydrochloride v 18 hours with loperamide oxide 1 mg v 18.5 hours with loperamide oxide 2 mg; P more than 0.8).

Loperamide oxide:

We found five RCTs comparing loperamide oxide versus placebo, versus loperamide hydrochloride, or comparing different doses of loperamide oxide. The first RCT (230 adults with more than 2 watery or loose stools in the previous 24 hours) had three study arms and compared two doses of loperamide oxide (1 and 2 mg) versus placebo. It found that both doses of loperamide oxide significantly reduced duration of diarrhoea compared with placebo (median time to complete relief of diarrhoea: 27 hours and 55 minutes with loperamide oxide 1 mg v 40 hours and 35 minutes with placebo; P = 0.022; 25 hours with loperamide oxide 2 mg v 40 hours and 35 minutes with placebo; P = 0.011). The second and third RCTs had four study arms each and compared two doses of loperamide oxide (1 and 2 mg) with placebo and loperamide hydrochloride. Both RCTs found that both doses of loperamide oxide significantly reduced duration of diarrhoea compared with placebo (first RCT: median time to complete relief of diarrhoea: 23.5 hours with loperamide oxide 1 mg v 45 hours and 15 minutes with placebo; P = 0.009; 25.5 hours with loperamide oxide 2 mg v 45 hours and 15 minutes with placebo; P = 0.007; second RCT: median time to complete relief of diarrhoea: 18 hours with loperamide oxide 1 mg v 37 hours with placebo; P = 0.003; 18 hours and 30 minutes with loperamide oxide 2 mg v 37 hours with placebo: P = 0.012) and found no significant difference between the groups on active treatment (see loperamide hydrochloride above). The fourth RCT (242 adults with acute diarrhoea, defined as more than 3 loose or watery stools in the previous 24 hours) compared two doses of loperamide oxide (0.5 and 1 mg) versus placebo. It found that both doses of loperamide oxide significantly reduced duration of diarrhoea compared with placebo (median time to complete relief of diarrhoea: 25 hours and 40 minutes with loperamide oxide 0.5 mg v 34 hours and 15 minutes with placebo; P = 0.041; 26 hours and 30 minutes with loperamide oxide 1 mg v 34 hours and 15 minutes with placebo; P = 0.044). Investigators' ratings of overall efficacy of loperamide oxide 1 mg, using a 5-point scale, were significantly better than placebo (P = 0.008) but the difference did not reach significance between loperamide oxide 0.5 mg and placebo (P = 0.096). Similarly, participants' overall evaluations of the efficacy of treatment, using a 100-point visual analogue scale, were significantly better with loperamide oxide 1 mg compared with placebo (P = 0.003) but the difference did not reach significance between loperamide oxide 0.5 mg and placebo (P value reported as not significant, CI not reported). The fifth RCT (258 adults with acute diarrhoea, defined as 4 or more watery or loose stools within the previous 24 hours, and with diarrhoea for no more than 72 hours) compared four interventions: loperamide oxide 1, 2, 4 mg, or placebo. All were given an initial dose of two tablets and told to take another tablet on experiencing symptoms. All doses of loperamide decreased median time to relief of diarrhoea compared with placebo, but there was no significant difference between the three loperamide groups (median time to first relief: 28 hours and 40 minutes with placebo v 10 hours with loperamide 1 mg v 12 hours and 45 minutes with loperamide 2 mg v 7.5 hours with loperamide 4 mg).

Harms

Difenoxin:

We found no RCTs.

Diphenoxylate:

The RCT comparing diphenoxylate–atropine versus placebo gave no details on adverse events and possible attribution/relationship to treatment.

Lidamidine:

We found no RCTs.

Loperamide hydrochloride:

The first RCT found that loperamide hydrochloride significantly increased the proportion of people with constipation-like periods compared with placebo (25% with loperamide hydrochloride v 7% with placebo; P less than or equal to 0.002). The second RCT (261 adults) compared loperamide oxide 1 mg with loperamide oxide 2 mg, with loperamide 2 mg, and with placebo. Adverse effects were mainly gastrointestinal (4 people on loperamide oxide 1 mg v 4 people on loperamide oxide 2 mg v 6 people on loperamide 2 mg v 8 people on placebo; gastrointestinal adverse effects not further specified). The significance of the difference between groups in adverse effects was not reported.

Loperamide oxide:

The first RCT found that few adverse effects were reported and all were mild or moderate (3/70 [4%] people on loperamide oxide 1 mg v 1/72 [1%] people on loperamide oxide 2 mg v 3/71 [4%] people on placebo). The second RCT found that loperamide oxide 2 mg significantly increased the proportion of people with constipation-like periods compared with placebo (24% with loperamide oxide 2 mg v 7% with placebo; P less than or equal to 0.002), but found no significant difference between loperamide oxide 1 mg and placebo (16% with loperamide oxide 1 mg v 7% with placebo; reported as not significant). The third RCT (261 adults) compared loperamide oxide 1 mg with loperamide oxide 2 mg, with loperamide 2 mg, and with placebo. Adverse effects were mainly gastrointestinal (4 people with loperamide oxide 1 mg v 4 people with loperamide oxide 2 mg v 6 people with loperamide 2 mg v people with placebo; gastrointestinal adverse effects not specified). The significance of the difference among groups in adverse effects was not reported. The fourth RCT (242 adults) found that more people on placebo than loperamide oxide reported adverse effects but significance was not reported (7/83 [8%] people with loperamide oxide 1 mg v 3/79 [4%] people with loperamide oxide 0.5 mg v 16/80 [20%] people with placebo). Abdominal cramps were the most frequently reported adverse effect in people taking placebo. In one person taking placebo, the cramps were noted as severe. The fifth RCT found that adverse effects of any kind reported after non-leading questions were 13/66 (20%) for placebo, 7/64 (11%) for loperamide oxide 1 mg, 13/63 (21%) for loperamide oxide 2 mg, and 14/65 (22%) for loperamide oxide 4 mg (significance of difference between groups not reported). The numbers of people having a constipation-like period for 48 hours or more were as follows: 11% with placebo, 10% with loperamide oxide 1 mg, 25% with loperamide oxide 2 mg, and 25% with loperamide oxide 4 mg. There was no significant difference between loperamide oxide and placebo.

Comment

Clinical guide:

There is evidence of benefit for antimotility agents, strongest for loperamide. However, antimotility agents are not recommended for people with suspected shigellosis or Shiga-toxin producing E coli.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antisecretory agents in resource-rich countries

Summary

DURATION OF ILLNESS Racecadotril compared with placebo: Racecadotril is more effective at reducing the duration of diarrhoea in people with acute diarrhoea ( moderate-quality evidence ). Racecadotril compared with loperamide: Racecadotril and loperamide seem to be equally effective at reducing the duration of diarrhoea in people with acute diarrhoea (moderate-quality evidence). SYMPTOM CONTROL Racecadotril compared with placebo: Racecadotril is more effective at reducing stool weight passed in the first 24 hours after treatment in people with acute diarrhoea (moderate-quality evidence). Racecadotril compared with loperamide: We don’t know whether racecadotril is more effective than loperamide at reducing the number of diarrhoeal stools passed until recovery in people with acute diarrhoea ( low-quality evidence ).

Benefits

We found no systematic review, but found five RCTs comparing racecadotril (previously called acetorphan) with placebo or loperamide.

Racecadotril versus placebo:

We found two RCTs comparing racecadotril with placebo. The first RCT (198 people with acute diarrhoea in France) found that racecadotril (200 mg loading dose, followed by 100 mg after each loose motion) significantly reduced mean duration of diarrhoea compared with placebo at 10–14 days (mean: 3.4 days with racecadotril v 4.4 days with placebo; P = 0.001). However, 30 people were not included in the analysis as they still had unformed stools 24 hours before follow-up (7 [7%] people with racecadotril v 23 [24%] people with placebo). The second RCT (71 people with acute diarrhoea in Tunisia) found that racecadotril (100 mg 3 times daily before meals) significantly reduced stool weight passed in the first 24 hours of treatment compared with placebo (mean: 355 g with racecadotril v 499 g with placebo; P = 0.025) and passed fewer stools (mean: 4.3 with racecadotril v 5.4 with placebo; P = 0.027).

Racecadotril versus loperamide:

We found three RCTs comparing racecadotril versus loperamide. The first RCT (69 people with acute diarrhoea) compared racecadotril (200 mg loading dose repeated at 12 hours, then 300 mg/day until well) versus loperamide (2 times 1.33 mg loading dose repeated at 12 hours, then 3 times 1.33 mg until well). The RCT found no significant difference between racecadotril compared with loperamide in duration of diarrhoea (2.2 days with racecadotril v 2.3 days with loperamide; reported as not significant). The second RCT (62 people with acute diarrhoea) found no significant difference between racecadotril (100 mg 3 times daily) and loperamide (2.0 mg twice daily) in mean duration of diarrhoea (19.5 hours with racecadotril v 13 hours with loperamide; P = 0.23). The third RCT (157 people with acute diarrhoea) found no difference between racecadotril (100 mg loading dose and 100 mg 3 times daily before to meals) compared with loperamide (4 mg loading dose and 2 mg after each loose stool) in the number of diarrhoeal stools passed until recovery (mean: 3.5 with racecadotril v 2.9 with loperamide; P value not reported) . The total duration of diarrhoea after initiation of treatment was similar for both groups (mean: 14.9 hours with racecadotril v 13.7 hours with loperamide; P value not reported).

Harms

Racecadotril versus placebo:

The frequency and nature of reported adverse effects were similar in the two treatment groups (35% with racecadotril v 36% with placebo) in one RCT. The adverse effects included nausea, thirstiness, vertigo, constipation, and headache. In the second RCT, adverse events included dizziness, malaise, backache, and abdominal distention requiring admission to hospital. The incidence of these events was similar in the racecadotril and placebo groups (3% with racecadotril v 5% with placebo).

Racecadotril versus loperamide:

Reported treatment-related adverse effects were constipation, bloody stool, skin itching, and abdominal pain on palpation in one RCT. The duration of abdominal distension, frequency of constipation after diarrhoea resolution, and duration of abdominal pain were higher in the loperamide group than in the racecadotril group (P = 0.1) in a second RCT. The incidence of adverse events was similar between treatment groups (7% with racecadotril v 12% with loperamide) in a third RCT. Rebound constipation was more frequent among people receiving loperamide (19%) than racecadotril (10%).

Comment

No antibiotics were given to participants in these RCTs.

Clinical guide:

There is modest published evidence for benefit with racecadotril compared with placebo in adults; racecadotril appears to have a similar efficacy to antimotility agents in comparative trials, although there may be a lower occurrence of rebound constipation with racecadotril therapy. Safety in people with renal or hepatic diseases is not established.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antibiotics (empirical use) in resource-rich countries

Summary

DURATION OF ILLNESS Compared with placebo: Antibiotics may be more effective than placebo at reducing the duration of diarrhoea, and fever in people with mild-to-moderate diarrhoea ( low-quality evidence ). SYMPTOM CONTROL Compared with placebo: Antibiotics may be more effective than placebo at reducing symptoms in people with mild-to-moderate diarrhoea (low-quality evidence). CURE RATES Compared with placebo: Antibiotics may be more effective than placebo at eradicating pathogens at 2 to 7 days (low-quality evidence).

Benefits

We found no systematic review but found five RCTs comparing empirical treatment with one or more antibiotics (ciprofloxacin, trimethoprim–sulfamethoxazole, nifuroxazide, ofloxacin, and pefloxacin) versus placebo or symptomatic treatment.

Duration of diarrhoea or fever:

The first RCT found that nifuroxazide significantly reduced mean duration of diarrhoea compared with placebo. The second RCT compared three interventions: ciprofloxacin, trimethoprim–sulfamethoxazole, and placebo. It found that ciprofloxacin significantly shortened the duration of diarrhoea compared with placebo and found similar duration of diarrhoea with trimethoprim–sulfamethoxazole and placebo in people identified as having a bacterial pathogen. The third RCT compared single-dose ofloxacin versus placebo. It found no significant difference between ofloxacin and placebo in the average duration of diarrhoea, but found that ofloxacin significantly reduced duration of fever compared with placebo. The fourth RCT compared ciprofloxacin versus placebo. It found that ciprofloxacin significantly reduced duration of diarrhoea and other gastrointestinal symptoms after treatment compared with placebo. The fifth RCT compared 5- and 7-day regimens of pefloxacin versus symptomatic treatment (described as standard supportive regimen). It found that both empirical pefloxacin regimens reduced the mean duration of fever days compared with symptomatic treatment. The RCT found no significant difference in the mean duration of fever days between the two pefloxacin regimens (see table 2 for all doses and full results).

Table 2.

Antibiotics (empirical use for mild-to-moderate diarrhoea).

Ref Comparison Participants Results Adverse effects
  Nifuroxazide (400 g bd for 5 days) v placebo. 102 adults in France with acute diarrhoea (less than 3 watery stools a day). Duration of diarrhoea Significant reduction in mean duration of diarrhoea with nifuroxazide (2.09 days with nifuroxazide v 3.26 days with placebo; P less than 0.004).Symptom control Significant reduction in number of bowel movements a day on days 1 and 2, did not reach significance on day 3: (day 1: 3.09 with nifuroxazide v 4.40 with placebo; P less than 0.015; day 2: 1.89 with nifuroxazide v 2.79 with placebo; P less than 0.008; day 3: 1.46 with nifuroxazide v 1.98 with placebo; NS).Microbiological efficacy Not reported. The RCT found no adverse effects
  Ciprofloxacin (500 mg bd for 5 days) v TMP–SMX (160–800 mg bd for 5 days) v placebo. 202 adults in the US with acute diarrhoea defined as more than 3 unformed stools in the previous 24 hours or more than 2 unformed stools in the 8 hours before presentation Duration of diarrhoea Ciprofloxacin significantly shortened the duration of diarrhoea compared with placebo (2.4 days with ciprofloxacin v 3.4 days with placebo; P less than 0.0005). Similar duration of diarrhoea with TMP–SMX and placebo in people identified as having a bacterial pathogen (days to last unformed stool: 4.2 days with TMP–SMX v 4.0 days with placebo; significance not reported). Symptom control Ciprofloxacin significantly increased the proportion of people cured or improved by days 1, 3, 4, and 5 compared with placebo (P less than 0.05). TMP–SMX increased the proportion of people cured or improved compared with placebo, only the difference on day 3 was significant (proportion of people cured or improved on day 3: 76% with TMP–SMX v 58% with placebo; P less than 0.05). Microbiological efficacy 61 pathogens (mainly Campylobacter, Shigella, and Salmonella) were isolated from 57/202 (28%) people. The RCT found that ciprofloxacin was significantly more effective in eradication of pathogens than placebo (number of negative stool samples: 14/17 [82%] with ciprofloxacin v 4/19 [21%] with placebo; P less than 0.001), or TMP–SMX (number of negative stool samples: 14/17 [82%] with ciprofloxacin v 12/25 [48%] with TMP–SMX; P less than 0.001). 20 adverse effects with ciprofloxacin (4 people with headache, 4 with myalgia, 3 with sleep disturbances, 3 with nausea, 2 with rash, 1 each with vaginitis, dysphagia, dizziness, and bitter taste).23 with TMP–SMX (8 people with headache, 4 with rash, 3 with dizziness, 3 with nausea, 2 with sleep disturbances, 1 each with dysuria, bloating, and a sour taste).12 with placebo (5 people with headache, 2 with nausea, 2 with dizziness, 1 each with myalgias, dysuria, and rash). Complaints were self-limiting; however, treatment was discontinued in people with rash. Bacterial resistance to ciprofloxacin developed in 2/10 (20%) people and to TMP–SMX in 3/14 (21%) people with Campylobacter isolates.
  Single-dose ofloxacin 400 mg v placebo. 117 adults in Spain with acute gastroenteritis, defined as more than 2 unformed stools in the previous 24 hours or more than 2 in the previous 8 hours with fever, abdominal pain, urgency, or other gastrointestinal complaints. Duration of diarrhoea or fever No significant difference between ofloxacin and placebo in the average duration of diarrhoea (2.51 days with ofloxacin v 3.41 days with placebo; P = 0.117), but found that ofloxacin significantly reduced duration of fever compared with placebo (0.63 days with ofloxacin v 1.05 days with placebo; P = 0.02). Symptom control No significant difference in the proportion of people with unchanged symptoms for more than 48 hours between ofloxacin and placebo (3/44 [7%] with ofloxacin v 6/46 [13%] with placebo; P = 0.485). Microbiological efficacy Pathogens (mainly Salmonella enteritidis) were isolated from 72/117 (62%) participants. Ofloxacin was significantly more effective in eradication of pathogens after 2 days of treatment compared with placebo (number of people with negative stool samples after 2 days: 36/53 (68%) with ofloxacin v 23/56 (41%) with placebo; P = 0.0018). The RCT found no significance difference in eradication of pathogens on day 15 with ofloxacin compared with placebo (number of people with negative stool samples on day 15: 33/43 [77%] with ofloxacin v 32/45 [71%] with placebo; P = 0.63). The RCT found no difference in adverse effects between treatment groups (1 person with headache with ofloxacin and 1 person with rash with placebo; no treatment required, P value not reported).
  Ciprofloxacin (500 mg bd for 5 days) versus placebo. 173 adults in the UK with severe acute gastroenteritis, defined as more than 4 fluid stools in 24 hours with at least 1 of the following symptoms: abdominal pain, fever, vomiting, myalgia, or headache. Duration of diarrhoea Ciprofloxacin significantly reduced duration of diarrhoea (2.2 days with ciprofloxacin v 4.6 days with placebo; P less than 0.0001) and other gastrointestinal symptoms after treatment compared with placebo (1.9 days with ciprofloxacin v 4.3 days with placebo; P less than 0.0001).Symptom control Ciprofloxacin significantly reduced the proportion of people with unresolved symptoms compared with placebo (3/81 [4%] with ciprofloxacin v 17/81 [21%] with placebo; P less than 0.001). Microbiological efficacy Pathogens (mainly Campylobacter and Salmonella species) were isolated from 141/162 (87%) of participants. Ciprofloxacin increased the proportion of people with negative stool samples on day 5 compared with placebo (59/69 [86%] people with ciprofloxacin v 23/67 [34%] with placebo; P value not reported). It found no significant difference in eradication of pathogens 6 weeks after treatment between the 2 groups (8/67 [12%] with ciprofloxacin v 8/65 [12%] with placebo; P value not reported). The RCT found 2 adverse effects with ciprofloxacin that could be attributed to the treatment (1 each with unpleasant taste and vaginal thrush); the number of adverse effects in the placebo was not reported. No bacterial resistance developed during treatment.
  Compared 5 and 7 day regimens of pefloxacin 400 mg once daily v symptomatic treatment (described as standard supportive regimen). 82 adults in Croatia with acute bacterial gastroenterocolitis, defined as more than 3 loose stools in 24 hours, fever more than 38 °C, and at least 1 of abdominal pain, nausea, or vomiting. Duration of fever Both empirical pefloxacin regimens reduced the mean duration of fever days compared with symptomatic treatment (3.3 days with 5-day pefloxacin v 5.0 days with symptomatic treatment; P less than 0.001; 3.0 days with 7-day pefloxacin v 5.0 days with symptomatic treatment; P less than 0.001). The RCT found no significant difference in the mean duration of fever days between the two pefloxacin regimens (P = 0.261). Symptom control Both pefloxacin regimens significantly reduced the average number of loose stools a day compared with symptomatic treatment (day 3: 3.0 with 5-day pefloxacin v 4.2 with symptomatic treatment, 3.0 with 7-day pefloxacin v 4.2 with symptomatic treatment; day 5: 1.5 with 5-day pefloxacin v 4.0 with symptomatic treatment, 1.6 with 7-day pefloxacin v 4.0 with symptomatic treatment; day 7: 1.2 with 5-day pefloxacin v 2.1 with symptomatic treatment, 1.4 with 7-day pefloxacin v 2.1 with symptomatic treatment; P less than 0.001). It found no significant difference in the average number of loose stools a day between the two pefloxacin regimens (P more than 0.23) .Microbiological efficacy Pathogens (mainly S enteritidis and Salmonella typhimurium) were isolated from all 82 (100%) participants. The RCT found that both pefloxacin regimens were significantly more effective in eradication of pathogens from day 5 onwards compared with symptomatic treatment (number of people with negative stool samples on day 5: 18/20 [90%] with 5-day pefloxacin v 21/35 [60%] with symptomatic treatment; P = 0.049; 23/27 [93%] with 7-day pefloxacin v 21/35 [60%] with symptomatic treatment; P = 0.017; day 7: 19/20 [95%] with 5-day pefloxacin v 22/35 [63%] with symptomatic treatment; 23/27 [93%] with 7-day pefloxacin v 22/35 [63%] with symptomatic treatment; P values reported as significant, CI not reported). Both pefloxacin regimens achieved eradication of pathogens in all 47 (100%) people 1 week after treatment compared with 29/35 (87%) people with symptomatic treatment (P value not reported). All participants had negative stool samples 4 weeks after treatment. The RCT found no adverse effects requiring discontinuation of treatment with pefloxacin.
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bd, twice a day; TMP–SMX, trimethoprim–sulfamethoxazole

Symptom control:

The first RCT found that nifuroxazide significantly reduced the number of bowel movements a day on days 1 and 2 compared with placebo, but the difference did not reach significance on day 3 of treatment. The second (three-armed) RCT found that ciprofloxacin significantly increased the proportion of people cured or improved by days 1, 3, 4, and 5 compared with placebo. Although trimethoprim–sulfamethoxazole increased the proportion of people cured or improved compared with placebo, only the difference on day 3 was significant. The third RCT found no significant difference in the proportion of people with unchanged symptoms for more than 48 hours between ofloxacin and placebo. The fourth RCT found that ciprofloxacin significantly reduced the proportion of people with unresolved symptoms compared with placebo. The fifth RCT found that both pefloxacin regimens significantly reduced the average number of loose stools a day compared with symptomatic treatment. It found no significant difference in the average number of loose stools a day between the two pefloxacin regimens (see table 2 for all doses and full results).

Microbiological efficacy:

In the second RCT, 61 pathogens (mainly Campylobacter, Shigella, and Salmonella) were isolated from participants. The RCT found that ciprofloxacin was significantly more effective in eradication of pathogens than placebo. In the third RCT, pathogens (mainly Salmonella enteritidis) were isolated from participants. The RCT found that ofloxacin was significantly more effective in eradication of pathogens after 2 days of treatment compared with placebo. However, it found no significant difference in eradication of pathogens on day 15 with ofloxacin compared with placebo. In the fourth RCT, pathogens (mainly Campylobacter and Salmonella species) were isolated from participants. The RCT found that ciprofloxacin increased the proportion of people with negative stool samples on day 5 compared with placebo. It found no significant difference in eradication of pathogens 6 weeks after treatment between the two groups. In the fifth RCT, pathogens (mainly S enteritidis and Salmonella typhimurium) were isolated from all 82 (100%) participants. The RCT found that both pefloxacin regimens were significantly more effective in eradication of pathogens from day 5 onwards compared with symptomatic treatment. Both pefloxacin regimens achieved total eradication of pathogens in all people 1 week after treatment. All participants had negative stool samples 4 weeks after treatment (see table 2 for full results).

Harms

See table 2 for all harms data.

Comment

The pathogenic organisms isolated from people in each study varied, and may partly explain variations in effect. Reported outcomes varied between trials, which precludes direct comparisons or summaries of treatment effect.

Clinical guide:

The use of empiric antibiotic therapy should be weighed for benefits and harms.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Diet in resource-rich countries

Summary

DURATION OF ILLNESS Restricted diet compared with unrestricted diet: Restricted diets and unrestricted diets seem to be equally effective at reducing the duration of watery and non-watery diarrhoea ( moderate-quality evidence ).

Benefits

We found no systematic review but found one RCT. The RCT (71 people with diarrhoea) found no significant difference in duration of watery and non-watery diarrhoea between unrestricted diet and restricted diet (watery diarrhoea, median: 14 hours with unrestricted diet v 13 hours with restricted diet; P = 0.46; non-watery diarrhoea, median: 18 hours with unrestricted diet v 42 hours with restricted diet; P = 0.15). People having an unrestricted diet were instructed to eat anything they liked and drink more than normal. People having a restricted diet were instructed not to take any solid food for 24 hours and encouraged to drink more than normal.

Harms

The RCT reported nausea occurred twice as often in the unrestricted diet group (19/37 (51%) with unrestricted diet v 6/26 (23%) with restricted diet; P = 0.02).

Comment

Adherence to the control regimen seemed to be lower than for the intervention group, although they were assessed differently.

Clinical guide:

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

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Oral rehydration solutions in resource-rich countries

Summary

We found no direct information about the effects of oral rehydration solutions in adults with acute diarrhoea living in resource-rich countries.

Benefits

We found no systematic review and no RCTs evaluating the effects of oral rehydration solutions for acute diarrhoea in adults living in resource-rich countries.

Harms

We found no RCTs.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antibiotics plus antimotility agents in resource-rich countries

Summary

We found no direct information about the effects of antibiotics plus antimotility agents in adults with acute diarrhoea living in resource-rich countries. The risk of increasing bacterial resistance should be taken into account when considering the use of antibiotics. see table .

Benefits

We found no systematic review or RCTs assessing the beneftis of antibiotics plus antimotility agents in adults with acute diarrhoea living in resource-rich countries.

Harms

We found no RCTs.

Comment

Clinical guide:

The risk of increasing bacterial resistance should be taken into account when considering the use of antibiotics. Differences between regions in effectiveness of antibiotics are likely to be caused, in part, by local levels of antimicrobial resistance.

Substantive changes

Antibiotics plus antimotility agents in resource-rich countries New option for which we found no systematic reviews or RCTs assessing antibiotics plus antimotility agents in adults with acute diarrhoea living in resource-rich countries; categorised as Unknown effectiveness.

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antimotility agents for travellers' diarrhoea

Summary

DURATION OF ILLNESS Loperamide hydrochloride compared with placebo: Loperamide hydrochloride is more effective at reducing the duration of diarrhoea in adults with travellers’ diarrhoea ( moderate-quality evidence ). Loperamide hydrochloride compared with trimethoprim-sulfamethoxazole: Loperamide hydrochloride and trimethoprim-sulfamethoxazole seem to be equally effective at reducing the duration of diarrohea in adults with travellers’ diarrhoea (moderate-quality evidence). Compared with antimotility agents plus antibiotics: Antimotility agents plus antibiotics seem to be more effective than antimotility agents alone at reducing the duration of diarrhoea in people with travellers’ diarrhoea (moderate-quality evidence).

Benefits

We found no systematic review but found two RCTs.

Loperamide hydrochloride 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 1 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 300/1600 mg, trimethoprim–sulfamethoxazole 160 mg/800 mg twice daily for 3 days, combination trimethoprim–sulfamethoxazole 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, more than 3 unformed stools during previous 24 hours, and ill for less than 72 hours) compared loperamide 2 mg after each loose stool with placebo.It found loperamide significantly reduced the number of stools on days 1 and 2 compared with placebo (figures presented graphically).

Loperamide hydrochloride alone versus trimethoprim–sulfamethoxazole:

The four-armed RCT (see above) found that mean duration of diarrhoea was similar in both groups (33 hours with loperamide v 36 hours with trimethoprim–sulfamethoxazole; significance not reported).

Antimotility agents versus antibiotics plus antimotility agents:

See benefits of antibiotics plus antimotility agents for travellers' diarrhoea.

Harms

The first RCT reported only one important adverse reaction, namely a self-limited rash occurring in a participant taking trimethoprim–sulfamethoxazole. The second RCT reported that three people treated with loperamide suffered from dizziness, and four people suffered from constipation on loperamide compared with three taking placebo (significance not reported).

Antimotility agents versus antibiotics plus antimotility agents:

See harms of antibiotics plus antimotility agents for travellers' diarrhoea.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antibiotics (empirical use) for travellers' diarrhoea

Summary

CURE RATES Compared with placebo (multiple destination studies): Antibiotics seem to be more effective at increasing cure rates at 3 days ( high-quality evidence ). DURATION OF ILLNESS Compared with placebo (mulitple destination studies): The antibiotics rifaximin, and ciprofloxacin seem to be more effective at reducing the duration of diarrhoea in adults with travellers' diarrhoea (high-quality evidence). Compared with placebo (Central America): Antibiotics seem to be more effective at reducing the duration of diarrhoea in adults with travellers' diarrhoea ( moderate-quality evidence ). Compared with placebo (Asia): Pivemecillinam is more effective at decreasing the duration of watery stools in people with travellers' diarrhoea (moderate-quality evidence). Antibiotics compared with each other (multiple destination studies): Norfloxacin and trimethoprim-sulfamethoxazole seem to be equally effective at reducing the duration of diarrhoea in people with travellers’ diarrhoea (moderate-quality evidence). Compared with each other (Central America): Furazolidone may be as effective as ampicillin at reducing the duration of illness in people with travellers’ diarrhoea (low-quality evidence). Compared with each other (Asia): Azithromycin and ciprofloxacin may be equally effective at decreasing the duration of illness in people with travellers’ diarrhoea (low-quality evidence). SYMPTOM CONTROL Compared with placebo (North and West Africa): Flexoraxacin 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 ).

Benefits

We found one systematic review (search date 2000, 19 RCTs, 3157 people), and two subsequent RCTs comparing a variety of antibiotics versus placebo, a different dose of the same antibiotic, or another antibiotic, in adults travelling from resource-rich countries to resource-poor countries.

Antibiotics (empirical) versus placebo:

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

The systematic review identified one RCT, and we found two subsequent RCTs. The RCT identified by the review (447 Swedish travellers to Africa, Asia, or Latin America with acute diarrhoea) compared oral norfloxacin (400 mg twice daily for 3 days) versus 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 less than 0.0001). The first subsequent RCT (380 adult tourists in Guatemala, Mexico, and Kenya with acute diarrhoea defined as 3 or more unformed stools in 24 hours plus 1 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 subsequent RCT (399 travellers to Mexico, Guatemala, India, or Peru) was a three-arm trial comparing rifaximin (200 mg three times a day) versus ciprofloxacin (500 mg twice daily plus placebo once daily) versus placebo (three 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 less than 0.001; 28.8 hours with ciprofloxacin v 65.5 hours with placebo; P less than 0.0003; intention to treat analysis)

Central America (Mexico, Belize):

We found one systematic review, which identified 10 RCTs. The second and third RCTs compared ciprofloxacin versus placebo. Both RCTs found that ciprofloxacin significantly reduced duration of illness compared with placebo (see table 3 ). The other 8 RCTs were all carried out in the same centre in Guadalajara, Mexico, and are described in table 3 . Seven RCTs found that antibiotics significantly reduced the duration of illness compared with placebo.

Table 3.

Effects of antibiotics for travellers' diarrhoea (see text).

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 less than 0.0001; mean time to last unformed stool: 24.8 hours with ciprofloxacin v 53.5 hours with placebo; P less than 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 less than 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 less than 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 symptom 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
  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 (28.1%) with BW942C v 2/31 (6.5%) with TMP–SMX v 3/33 (9.1%) with BW942C plus TMP–SMX v 1/33 (3.0%) 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 3 days) plus loperamide (4 mg then 2 mg after each loose stool, 16 mg/day or less, for 3 days) v TMP–SMX (320 mg/1600 mg single dose) plus loperamide (4 mg then 2 mg after each loose stool, 16 mg/day or less, for 3 days) v TMP–SMX (320/1600 mg loading dose then 160 mg/800 mg bd for 5 doses) plus loperamide (4 mg then 2 mg after each loose stool, 16 mg/day or less, for 3 days) 190 adults (62 with TMP–SMX bd plus loperamide v 64 with TMP–SMX single dose plus loperamide v 64 with TMP–SMX loading dose plus loperamide) (6 or more unformed stools in 24 hours) Time until 50% well: 11 hours with TMP–SMX bd plus loperamide v 4 hours with TMP–SMX single dose plus loperamide v 0 hours with TMP–SMX loading dose plus loperamide (P less than 0.09 favouring TMP–SMX loading dose plus loperamide); time until 75% well: 34 hours with TMP–SMX bd plus loperamide v 33 hours with TMP–SMX single dose plus loperamide v 12 hours with TMP–SMX loading dose plus loperamide (P less than 0.09 favouring TMP–SMX loading dose plus loperamide) No adverse effects reported
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 less than 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)
Furazolidone v ampicillin
  Furazolidone (100 mg 4 times/day for 5 days) v ampicillin (500 mg 4 times/day for 5 days) 94 adults (47 in each group) (4 or more unformed stools in 24 hours or 3 unformed stools in 8 hours) Mean: 57 hours with furazolidone v 72 hours with ampicillin (NS; P value not reported) 9/17 (52.9%) with furazolidone v 2/20 (10%) with ampicillin who had consumed alcohol had facial flushing. 12/47 (25.5%) with furazolidone had dark-yellow urine.
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bd, twice a day; NS, not significant; TMP, trimethoprim, TMP–SMX, trimethoprim–sulfamethoxazole

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

We found one RCT (195 tourists in the Gambia with acute diarrhoea, defined as 1 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- 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 less than 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 less than 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 less than 0.05 between fleroxacin groups v placebo; no significant difference between fleroxacin at different doses, P value not reported; 72 hours: more than 80% with 1 day v more than 80% with 2 days v 47% with placebo; numbers not reported, P less than 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) versus placebo. It found that pivmecillinam significantly reduced the duration of watery stools compared with placebo (less than 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 less than 0.05).

Antibiotics (empirical) versus each other:

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

We found one systematic review, which identified one RCT.The RCT (142 US male military personnel in South America and West Africa with acute diarrhoea) compared oral norfloxacin (400 mg twice daily for 5 days) versus oral trimethoprim–sulfamethoxazole (160 mg/800 mg twice daily for 5 days). It found no significant difference in duration of diarrhoea between norfloxacin and trimethoprim–sulfamethoxazole (mean number of days of diarrhoea after beginning treatment: 1.6 with norfloxacin v 1.8 with trimethoprim–sulfamethoxazole; P = 0.37). Bacterial enteropathogens in stool samples were identified in 36/73 (49%) of the norfloxacin group and 27/69 (39%) of the trimethoprim–sulfamethoxazole group. In vitro resistance was found to trimethoprim–sulfamethoxazole in 20/74 (27%) of isolates tested but not to norfloxacin.

Central America (Mexico, Belize):

One RCT found no significant difference in duration of illness between furazolidone and ampicillin.

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

We found one systematic review,which identified one RCT, comparing 1-day versus 2-day fleroxacin versus placebo. It found significant difference in the proportion of people cured of all symptoms between different doses of fleroxacin (48 hours: 28/54 [52%] with 1 day v 24/48 [50%] with 2 days; P value not reported, reported as not significant; 72 hours: more than 80% with 1 day v more than 80% with 2 days; absolute numbers and P value not reported, reported as not significant).

Asia (India, Thailand):

We found one systematic review, which identified one RCT. The RCT (79 US military personnel in Thailand with acute diarrhoea, defined as 3 or more liquid bowel movements in 24 hours or 2 liquid movements plus fever, cramps, nausea, or vomiting) compared azithromycin 500 mg versus ciprofloxacin 500 mg. It found that mean duration of illness was similar in both groups (36.9 hours with azithromycin v 38.2 hours with ciprofloxacin; reported as similar, P value not reported.

Antibiotics versus antibiotics plus antimotility agents:

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

Harms

Antibiotics (empirical) versus placebo:

The 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):

The RCT included in the 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. The first subsequent RCT found no significant difference in non-serious adverse events (gastrointestinal-related, headache) between groups (74/125 [59%] 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 subsequent RCT 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 rifamimin or placebo groups (no further information reported).

Central America (Mexico, Belize):

See table 3 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 less than 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 each other:

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

The first RCT stated that no adverse effects were reported. The second subsequent RCT 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 rifamimin group (no further information reported).

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

The RCT (safety analysis on 190/195 people), found that adverse effects judged to be remotely, possibly, or probably related to the treatment, were more likely in the 2-day fleroxacin than 1-day fleroxacin group (42/65 [65%] with 2 day v 36/61 [59%] with 1 day; P value and significance not reported). 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 versus antibiotics plus antimotility agents:

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

Comment

We found one RCT (598 people 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) versus 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.

Substantive changes

Antibiotics (empirical use) for travellers' diarrhoea One RCT added,which found that antibiotics reduced the duration of diarrhoea compared with placebo, and existing evidence reevaluated; categorisation changed from Trade off between benefits and harms to Likely to be beneficial.

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antibiotics plus antimotility agents for travellers' diarrhoea

Summary

DURATION OF ILLNESS Compared with antibiotics alone: We don't know whether antibiotics plus antimotility agents are more effective at reducing the duration of diarrhoea in people with travellers’ diarrhoea ( very low-quality evidence ). Compared with antimotility agents alone: Antibiotics plus antimotility agents seem to be more effective at reducing the duration of diarrhoea in people with travellers' diarrhoea ( moderate-quality evidence ). Different antibiotics plus antimotility regimens compared with each other: We don’t know whether a single dose of ciprofloxacin plus loperamide is more effective than loperamide plus ciprofloxacin taken for 3 days at decreasing the time to last unformed stool or at decreasing the mean number of liquid stools at 24–48 hours in people with travellers’ diarrhoea ( low-quality evidence ).

Benefits

Antibiotics plus antimotility agents versus antibiotics alone:

We found no systematic reviews but found four RCTs. See table 4 for full details of all RCTs. The first RCT (227 US students travelling in Mexico) was a five-arm trial comparing: (1) trimethoprim-sulfamethoxazole plus loperamide, (2) trimethoprim-sulfamethoxazole single dose, (3) trimethoprim-sulfamethoxazole for three days, (4) loperamide alone, and (5) placebo.It found that standard-dose trimethoprim-sulfamethoxazole plus loperamide significantly reduced mean duration of diarrhoea (time to last unformed stool) compared with standard-dose trimethoprim-sulfamethoxazole alone for 3 days. There was no significant difference in mean duration of diarrhoea between combination treatment and high single-dose trimethoprim-sulfamethoxazole, although duration was shorter in people receiving combined treatment.The second RCT (104 US soldiers deployed in Egypt who developed diarrhoea) compared ciprofloxacin for 3 days plus loperamide versus ciprofloxacin plus placebo. It found no significant difference between groups in the proportion of people who had improved or fully recovered at 24 or 48 hours, or in the mean number of liquid stools after 24 and 48 hours’ treatment.The third RCT (142 US soldiers deployed in Thailand who developed diarrhoea) was a three-arm trial comparing ciprofloxacin single dose plus loperamide versus ciprofloxacin for 3 days plus loperamide versus ciprofloxacin single dose plus placebo.It found no significant difference among treatment groups in the proportion of people fully recovered at 24, 48, and 72 hours, mean time to last unformed stool, or mean time to relief of all symptoms.The fourth RCT (single blind; 166 students from the US travelling to Mexico) was a three-arm trial comparing ofloxacin single dose plus loperamide versus ofloxacin single dose versus ofloxacin for three days.It found that ofloxacin plus loperamide significantly reduced median duration of diarrhoea compared with both ofloxacin single dose and ofloxacin for three days.

Table 4.

Effects of antibiotics plus antimotility agents for travellers' diarrhoea

Reference and population Intervention Comparison Outcome Results P value
Antibiotics plus antimotility agents versus antibiotics alone
RCT (227 US students travelling in Mexico) TMP–SMX (160 mg/800mg twice daily for three days) plus loperamide (4 mg as a loading dose plus 2 mg after each loose stool) TMP–SMX single dose 320 mg/1600 mg Mean duration of diarrhoea (time to last unformed stool); intention to treat analysis 16 hours with TMP–SMX for 3 days plus loperamide v 28 hours with TMP–SMX single dose NS
TMP–SMX (160 mg/800 mg twice daily for three days) plus loperamide (4 mg as a loading dose plus 2 mg after each loose stool) TMP–SMX 160 mg/800 mg twice daily for three days Mean duration of diarrhoea (time to last unformed stool); intention to treat analysis 16 hours with TMP–SMX for 3 days plus loperamide v 36 hours with TMP–SMX for 3 days P less than 0.005; intention to treat analysis
RCT (104 US soldiers deployed in Egypt) Ciprofloxacin (500 mg twice daily for three days) plus loperamide (4 mg as a loading dose plus 2 mg after each loose stool) Ciprofloxacin alone (500 mg twice daily for three days) Proportion of people who had improved (50% reduction in the daily number of stools compared with the previous 24 hours) or fully recovered (defined as absence of all symptoms) At 24 hours: 41/50 (82%) with ciprofloxacin plus loperamide v 36/54 (67%) with ciprofloxacin plus placebo; OR 2.3, 95% CI 0.8 to 6.3 P = 0.08
At 48 hours: 45/50 (92%) with ciprofloxacin plus loperamide v 48/54 (89%) with ciprofloxacin plus placebo; OR and CI not reported P less than 0.2
Mean number of liquid stools after 24 hours’ treatment 1.9 with ciprofloxacin plus loperamide v 2.6 with ciprofloxacin plus placebo P = 0.19
Mean number of liquid stools after 48 hours’ treatment 3.1 with ciprofloxacin plus loperamide v 4.0 with ciprofloxacin plus placebo P = 0.19
RCT (142 US soldiers deployed in Thailand who developed diarrhoea) Ciprofloxacin 750 mg single dose plus loperamide (4 mg as a loading dose plus 2 mg after each loose stool) Ciprofloxacin 750 mg single dose plus placebo Proportion of people fully recovered at 24 hours 36% with single-dose ciprofloxacin plus loperamide v 36% with single-dose ciprofloxacin plus placebo P values not reported; reported as not significant
Proportion of people fully recovered at 48 hours 70% with single-dose ciprofloxacin plus loperamide v 64% with single-dose ciprofloxacin plus placebo P values not reported; reported as not significant
Proportion of people fully recovered at 72 hours 83% with single-dose ciprofloxacin plus loperamide v 96% with single-dose ciprofloxacin plus placebo P values not reported; reported as not significant
Mean time to last unformed stool 34 hours with single-dose ciprofloxacin plus loperamide v 36 hours with single-dose ciprofloxacin plus placebo P value not reported
Mean time to relief of all symptoms 40 hours with single-dose ciprofloxacin plus loperamide v 38 hours with single-dose ciprofloxacin plus placebo P value not reported
Ciprofloxacin (500 mg twice daily for three days) plus loperamide (4 mg as a loading dose plus 2 mg after each loose stool) versus ciprofloxacin 750 mg single dose plus placebo. Ciprofloxacin 750 mg single dose plus placebo Proportion of people fully recovered at 24 hours 38% with 3-day ciprofloxacin plus loperamide v 36% with single-dose ciprofloxacin plus placebo P values not reported; reported as not significant
Proportion of people fully recovered at 48 hours 64% with 3-day ciprofloxacin plus loperamide v 64% with single-dose ciprofloxacin plus placebo P values not reported; reported as not significant
Proportion of people fully recovered at 72 hours 82% with 3-day ciprofloxacin plus loperamide v 96% with single-dose ciprofloxacin plus placeboide P values not reported; reported as not significant
Mean time to last unformed stool 44 hours with 3-day ciprofloxacin plus loperamide v 36 hours with single-dose ciprofloxacin plus placebo P value not reported
Mean time to relief of all symptoms 45 hours with 3-day ciprofloxacin plus loperamide v 38 hours with single-dose ciprofloxacin plus placebo P value not reported
RCT (single blind; 166 students from the US travelling to Mexico) Ofloxacin 400 mg single dose plus loperamide (4 mg loading dose plus 2 mg after each loose stool) Ofloxacin 400 mg single dose Median duration of diarrhoea (time to last unformed stool) 0 hours with ofloxacin plus loperamide v 14 hours with ofloxacin single dose P less than 0.001
Ofloxacin single dose plus loperamide (4 mg loading dose plus 2 mg after each loose stool) Ofloxacin 200 mg twice daily for 3 days Median duration of diarrhoea (time to last unformed stool) 0 hours with ofloxacin plus loperamide v 28 hours ofloxacin for 3 days P less than 0.001
Antibiotics plus antimotility agents versus antimotility agents alone
RCT (227 US students travelling in Mexico) TMP-SMX (160 mg/800 mg twice daily for three 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 withTMP-SMX plus loperamide v 33 hours with loperamide alone P less than 0.005
Different antibiotics plus antimotility agents regimens versus each other
RCT (142 US soldiers deployed in Thailand who developed diarrhoea) Ciprofloxacin 750 mg single dose plus loperamide (4 mg as a loading dose plus 2 mg after each loose stool) Ciprofloxacin (500 mg twice daily for three days) plus loperamide (4 mg as a loading dose plus 2 mg after each loose stool) Proportion of people fully recovered at 24 hours 36% with single-dose ciprofloxacin plus loperamide v 38% with 3-day ciprofloxacin plus loperamide P value not reported; reported as not significant
Proportion of people fully recovered at 48 hours 70% with single-dose ciprofloxacin plus loperamide v 64% with 3-day ciprofloxacin plus loperamide P value not reported; reported as not significant
Proportion of people fully recovered at 72 hours 83% with single-dose ciprofloxacin plus loperamide v 82% with 3-day ciprofloxacin plus loperamide P value not reported; reported as not significant
Mean time to last unformed stool 34 hours with single-dose ciprofloxacin plus loperamide v 44 hours with 3 day ciprofloxacin plus loperamide P value not reported
Mean time to relief of all symptoms 40 hours with single-dose ciprofloxacin plus loperamide v 45 hours with 3-day ciprofloxacin plus loperamide P value not reported
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NS, reported as not significant; TMP–SMX, Trimethoprim-sulfamethoxazole,

Antibiotics plus antimotility agents versus antimotility agents alone:

We found no systematic reviews but found one RCT.The RCT (227 US students travelling in Mexico) found that trimethoprim-sulfamethoxazole plus loperamide significantly reduced mean duration of diarrhoea (time to last unformed stool) compared with loperamide alone.

Different antibiotics plus antimotility agents regimens versus each other:

We found no systematic reviews but found one RCT.The RCT (142 US soldiers deployed in Thailand who developed diarrhoea) found no significant difference in the proportion of people fully recovered at 24, 48, and 72 hours between ciprofloxacin single dose plus loperamide compared with ciprofloxacin for 3 days plus loperamide. It also found no significant difference between groups in mean time until the last unformed stool, or mean time until all symptoms were relieved.

Harms

Only one RCTreported on adverse effects; for details see harms of antimotility agents for travellers' diarrhoea.

The other three RCTs gave no information on adverse effects.

Comment

The predominant pathogens found in the RCTs were different, with enterotoxigenic E 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 for a beneficial effect of combination therapy with antibiotics plus antimotility agents is uncertain, and may 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 for travellers' diarrhoea New option with four RCTs, two of which found that antibiotics plus antimotility agents reduced duration of diarrhoea compared with antibiotics alone and two of which found no significant difference between treatments; categorised as Unknown effectiveness.

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Bismuth subsalicylate for travellers' diarrhoea

Summary

DURATION OF ILLNESS Compared with placebo: Bismuth subsalicylate is more effective at reducing the duration of diarrhoea ( high-quality evidence ). Compared with loperamide: Bismuth subsalicylate is less effective at reducing the time to last unformed stool ( high-quality evidence ). SYMPTOM CONTROL Compared with placebo: Bismuth subsalicylate is more effective at reducing the number of loose stools at 4–24 hours after treatment (high-quality evidence). Compared with loperamide: Bismuth subsalicylate is less effective at reducing the number of unformed stools at 0–48 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 3–4 unformed stools in the preceding 24 hours received bismuth subsalicylate 30 mL every 30 minutes for 8 doses; those with five or more unformed stools in 24 hours received 60 mL every 30 minutes for 8 doses. The RCT found that both doses of bismuth subsalicylate significantly reduced the number of loose stools compared with placebo at 4–24 hours after treatment (109 with bismuth subsalicylate 30 mg v 165 with placebo; P less than 0.05; 39 with bismuth subsalicylate 60 mg v 77 with placebo; P less than 0.05). The second RCT (133 Europeans visiting West Africa and 112 American students in Mexico who had travellers' diarrhoea) compared bismuth subsalicylate 1050 mg suspension versus placebo every hour up to 4 doses a day for 2 days for the West African study, and bismuth subsalicylate 525 mg versus placebo every 30 minutes up to 8 doses a 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 less than 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 8 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 0–48 hours compared with loperamide (0–4 hours: 1.3 with bismuth subsalicylate v 0.9 with loperamide; P less than 0.0004; 4–24 hours: 2.4 with bismuth subsalicylate v 1.5 with loperamide; P less than 0.002; 24–48 hours: 1.0 with bismuth subsalicylate v 0.8 with loperamide; P less than 0.05). The number who received rescue treatment with antimicrobial drugs (trimethoprim–sulfamethoxazole) was similar between groups (28% with bismuth subsalicylate v 24% with loperamide; no absolute figures reported). The second RCT (203 students in Mexico) compared bismuth subsalicylate 35 mL (612.5 mg) every 30 minutes up to 8 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 may is a little-used clinical treatment option.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antisecretory agents for travellers' diarrhoea

Summary

DURATION OF ILLNESS Zaldaride maleate compared with placebo: High doses of zaldaride maleate may be more effective at reducing the time to passage of last unformed stool, but may be associated with cardiovascular symptoms ( low-quality evidence ). Zaldaride maleate compared with loperamide: Zaldaride maleate is less effective at reducing the mean number of unformed stools at 48 hours ( moderate-quality evidence ).

Benefits

We found no systematic review but found two RCTs of antisecretory agents among travellers.

Zaldaride maleate versus placebo:

One RCT (176 adult American students who developed acute diarrhoea while visiting Mexico) compared three doses of zaldaride maleate versus placebo. Participants received zaldaride maleate 5, 10, or 20 mg, or placebo four times daily for 2 days. The RCT found no significant difference in time for passage of last unformed stool between zaldaride maleate (5 or 10 mg) and placebo (median: 41.5 hours with zaldaride maleate 5 mg v 40.8 hours zaldaride maleate 10 mg v 42.5 hours with placebo, reported as not significant; P values not reported). However, the time to passage of last unformed stool was significantly shorter with zaldaride maleate 20 mg compared with placebo (median: 20.0 hours with zaldaride maleate 20 mg v 42.5 hours with placebo; P less than 0.01).

Zaldaride maleate versus loperamide versus placebo:

We found one RCT (179 adult American students travelling to Mexico who developed diarrhoea of less than 4 days' duration) comparing zaldaride maleate versus loperamide. People were randomised to zaldaride maleate (20 mg 4 times daily), loperamide (4 mg followed by 2 mg after each unformed stool), or placebo. The RCT found that zaldaride maleate was significantly less effective than loperamide in reducing the mean number of unformed stools during 48 hours (mean: 5.56 with zaldaride maleate v 2.74 with loperamide; P less than 0.0005). The RCT also found that both zaldaride maleate and loperamide significantly shortened duration of diarrhoea compared with placebo (median: 34.5 hours with zaldaride maleate v 45 hours with placebo; P = 0.034; median: 24 hours with loperamide v 45 hours with placebo; P less than 0.001).

Harms

The first RCT found 16 people with adverse effects, including headache, dizziness, chest pressure, and numbness in fingers and toes. The second RCT reported headache as the most common adverse effect, and it occurred in similar proportions in the three study groups.

Comment

Further development of zaldaride maleate has been halted because of concerns over cardiovascular symptoms related to higher doses.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Diet for travellers' diarrhoea

Summary

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

Benefits

We found no systematic review but found one RCT comparing restricted versus 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

None.

Clinical guide:

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

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Oral rehydration solutions for travellers' diarrhoea

Summary

We found no direct information 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) versus 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 of treatment for diarrhoea.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antimotility agents for mild-to-moderate diarrhoea in resource-poor countries

Summary

SYMPTOM CONTROL Compared with placebo: Lidamidine may be more effective at reducing the number of loose stools at 72 hours and mean stool weight at 29 hours in adults with acute diarrhoea. ( low-quality evidence ).

Benefits

Antimotility agents versus placebo:

We found no systematic review, but found two Mexican RCTs comparing antimotility agents versus placebo, versus each other, or comparing different doses of the same antimotility drug. The first RCT (30 adults with acute diarrhoea) found that lidamidine (2 or 4 mg) reduced the mean stool weight after 29 hours compared with placebo (435 g with lidamidine 4 mg v 364 g with lidamidine 2 mg v 576 g with placebo; P value not reported). The second RCT (105 adults with acute diarrhoea) compared three interventions: lidamidine, loperamide, and placebo. It found that fewer people had loose stools with lidamidine after 72 hours compared with placebo (8.5 stools with lidamidine v 3.9 stools with placebo; P value not reported).

Harms

The first RCT gave no information on adverse effects. Constipation occurred in one person taking lidamidine compared with no one taking placebo (1/35 [3%] with lidamidine v 0/35 [0%] with placebo).

Comment

Clinical guide:

There is evidence of benefit for antimotility agents. However, these agents are not recommended for patients with suspected shigellosis or Shiga-toxin producing E coli.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antisecretory agents for mild-to-moderate diarrhoea in resource-poor countries

Summary

DURATION OF ILLNESS Racecadotril compared with loperamide: Racecadotril and loperamide seem to be equally effective at reducing the duration of diarrhoea ( high-quality evidence ). NOTE Racecadotril has been associated with fewer side-effects compared with loperamide, particularly rebound constipation.

Benefits

We found no systematic review but found one RCT.

Racecadotril (acetorphan) versus loperamide:

We found one RCT (945 adults living in 14 resource-poor countries with acute diarrhoea) comparing racecadotril 100 mg twice daily versus loperamide 2 mg twice daily until resolution of diarrhoea. The RCT found no significant difference in the median duration of diarrhoea between groups (55 hours with racecadotril [95% CI 50 hours to 65 hours] v 55 hours with loperamide [95% CI 48 hours to 66 hours]).

Harms

The RCT found that that 44 people (9%) taking racecadotril and 87 (18%) taking loperamide had adverse experiences that were related to treatment. Adverse effects occurring in more than 1% of the study population included constipation (3% with racecadotril v 13% with loperamide), enlarged abdomen (2% with racecadotril v 6% with loperamide), anorexia (1% with racecadotril v 2% with loperamide), headache (2% with racecadotril v 0.4% with loperamide), and abdominal pain (0.2% with racecadotril v 2% with loperamide).

Comment

Clinical guide:

Racecadotril appears to have similar efficacy in adults compared to loperamide, possibly with fewer adverse effects.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antibiotics (empirical use) for mild-to-moderate diarrhoea in resource-poor countries

Summary

SYMPTOM CONTROL Compared with placebo: We don’t know whether antibiotics are more effective at reducing the number of unformed stools passed or at increasing the number of people who are well by 72 hours in people with acute mild-to-moderate diarrhoea ( low-quality evidence ).

Benefits

We found no systematic review but found an article reporting two Mexican RCTs that compared two different antibiotics versus placebo and versus trimethoprim–sulfamethoxazole. The first RCT (307 adults with 3 or more unformed stools in 24 hours, of less than 72 hours' duration and, if pre-treatment, stools contained 10 or more fecal leucocytes) compared trimethoprim–sulfamethoxazole 160 mg/800 mg twice daily versus clioquinol 250 mg three times daily versus placebo. The RCT found no significant difference in mean number of unformed stools passed during the 3-day study (4.2 with trimethoprim–sulfamethoxazole v 4.2 with clioquinol v 5.3 with placebo; P value not reported). Analysis was not intention to treat (20 [7%] people were excluded from the analysis). The second RCT (150 men with 4 or more unformed stools in the previous 24 hours, or 3 unformed stools in the previous 8 hours and 1 or more incidences of fever, abdominal pain, fecal urgency, nausea, or vomiting of no more than 60 hours' duration) compared three interventions: enoxacin, trimethoprim–sulfamethoxazole, and placebo. It found no significant difference in the proportion of people who were well by 72 hours with enoxacin, trimethoprim–sulfamethoxazole, or placebo (23/47 [49%] with enoxacin v 21/43 [49%] with trimethoprim–sulfamethoxazole v 16/49 [33%] with placebo; P more than 0.05). Analysis was not intention to treat (13 [8.7%] people were excluded from the analysis). Results were separated out into subgroups based on presence of pathogens before statistical analysis.

Harms

The first RCT did not report on adverse effects. The second RCT reported four people suffered from adverse effects leading to removal from the trial (one with light-headedness, vertigo, and photophobia, and one with moderate depression in the enoxacin group, and one person in the trimethoprim–sulfamethoxazole group with skin rash and one with moderate nervousness and abdominal pain).

Comment

Clinical guide:

Use of empiric antibiotic therapy should be weighed for benefits and harms.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antibiotics plus antimotility agents for mild-to-moderate diarrhoea in resource-poor countries

Summary

We found no direct information about antibiotics plus antimotility agents in adults with acute mild-to-moderate diarrhoea living in resource-poor countries.

Benefits

We found no systematic review or RCTs assessing antibiotics plus antimotility agents in adults with acute mild-to-moderate diarrhoea living in resource-poor countries.

Harms

We found no RCTs.

Comment

None.

Substantive changes

Antibiotics plus antimotility agents for mild-to-moderate diarrhoea in resource-poor countries New option, for which we found no systematic review or RCTs assessing antibiotics plus antimotility agents in adults with acute mild-to-moderate diarrhoea living in resource-poor countries; categorised as Unknown effectiveness.

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Oral rehydration solutions for mild-to-moderate diarrhoea in resource-poor countries

Summary

SYMPTOM CONTROL Citrate oral rehydration solution compared with bicarbonate oral rehydration solution: We don’t know whether citrate oral rehydration solutions are more effective at reducing stool output at 48 hours in adults with acute uncomplicated diarrhoea ( low-quality evidence ).

Benefits

We found no systematic review but found one RCT comparing citrate oral rehydration solution (ORS) versus bicarbonate ORS. The RCT (57 adults in Bangladesh with acute uncomplicated diarrhoea) found no significant difference between treatments in stool output over 48 hours (data reported as not significant). Three people were excluded from the citrate group and four people from the bicarbonate ORS group mainly as they were unable to be rehydrated orally because of persistent vomiting.

Harms

The RCT gave no information on adverse effects.

Comment

Clinical guide:

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

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antibiotics (empirical use) for severe diarrhoea in resource-poor countries

Summary

We found no direct information about the empirical use of antibiotics in treating severe diarrhoea in adults living in resource-poor countries.

Benefits

We found no systematic review and no RCTs evaluating the effects of empirical use of antibiotics in treating severe diarrhoea in adults living in resource-poor countries.

Harms

We found no RCTs.

Comment

See comment under oral rehydration solutions.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antimotility agents for severe diarrhoea in resource-poor countries

Summary

We found no direct information about antimotility agents in treating severe diarrhoea in adults living in resource-poor countries.

Benefits

We found no systematic review or RCTs evaluating the effects of antimotility agents in treating severe diarrhoea in adults living in resource-poor countries.

Harms

We found no RCTs.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antibiotics plus antimotility agents for severe diarrhoea in resource-poor countries

Summary

DURATION OF ILLNESS Antibiotics plus antimotility agents compared with antibiotics: Antibiotics plus antimotility agents are more effective at reducing the duration of diarrhoea and daily number of diarrhoeal stools in people with dysentry caused by the invasive bacterial pathogens, Shigella or enteroinvasive E coli but the combination seems to be no more effective than antbiotics alone in people infected with pathogens other than Shigella or enteroinvasive E coli ( moderate-quality evidence ). NOTE Antimotility agents are not recommended for people with suspected shigellosis or Shiga-toxin producing E coli.

Benefits

Antibiotics plus antimotility agents versus antibiotics plus placebo:

We found no systematic review but found one small RCT (88 adults admitted to hospital with dysentery in Thailand),] comparing ciprofloxacin 500 mg twice daily for three days plus loperamide (4 mg initial dose plus 2 mg after each loose stool) versus ciprofloxacin 500 mg twice daily for three days plus placebo. It found that, among people with invasive bacterial pathogens (Shigella or enteroinvasive E coli), ciprofloxacin plus loperamide significantly reduced duration of diarrhoea and daily number of diarrhoeal stools (median duration: 19 hours with ciprofloxacin plus loperamide v 42 hours with placebo; P = 0.028; median daily number of diarrhoeal stools: 2 with ciprofloxacin plus loperamide v 6.5 with placebo; P = 0.016). However, it found no significant difference between groups among people infected with other organisms (median duration of diarrhoea: 42 hours with ciprofloxacin plus loperamide v 43 hours with placebo; P = 0.99; median daily number of diarrhoeal stools: 6 with ciprofloxacin plus loperamide v 7.5 with placebo; P = 0.41).

Harms

Antibiotics plus antimotility agents versus antibiotics plus placebo:

The RCT reported that combination treatment was not associated with prolonged duration of fever and that no adverse effects were detected (further data not reported).

Comment

Clinical guide:

Despite the above findings, antimotility agents are not recommended for people with suspected shigellosis or Shiga-toxin producing E coli, therefore combination treatment would not generally be used in clinical practice.

Substantive changes

Antibiotics plus antimotility agents for severe diarrhoea in resource-poor countries New option, for which we found one RCT assessing combination treatment with ciprofloxacin plus loperamide compared with ciprofloxacin plus placebo, which was too small to draw firm conclusions from; categorised as Unknown effectiveness.

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Antisecretory agents for severe diarrhoea in resource-poor countries

Summary

DURATION OF ILLNESS Racecadotril compared with placebo: Racecadotril is no more effective at reducing the duration of diarrhoea in people with acute diarrhoea associated with severe dehydration ( moderate-quality evidence ). Berberine compared with placebo/no treatment: Berberine may be no more effective at reducing the duration of diarrhoea in people with non-cholera diarrhoea ( low-quality evidence ). Berberine plus tetracycline compared with tetracycline alone: Berberine plus tetracycline may be more effective at reducing the duration of diarrhoea in people with cholera (low-quality evidence). Chlorpromazine compared with no treatment: Chlorpromazine may be more effective at reducing the duration of diarrhoea in people with severe dehydration due to diarrhoea (low-quality evidence). SYMPTOM CONTROL Racecadotril compared with placebo: Racecadotril is no more effective at reducing mean total stool output or mean total rehydration solution intake in people with acute diarrhoea associated with severe dehydration (moderate-quality evidence). Berberine compared with placebo/no treatment: Berberine may be more effective at reducing mean stool volumes in people with cholera or in people with diarrhoea caused by Escherichia coli (low-quality evidence). Chlorpromazine compared with placebo: We don’t know whether chlorpromazine is more effective at reducing the need of fluids or volume loss in people with severe watery diarrhoea ( very low-quality evidence ).

Benefits

We found no systematic review, but found five RCTs of three interventions versus placebo or no treatment.

Racecadotril (acetorphan):

We found one RCT (110 people with acute diarrhoea associated with severe dehydration caused by Vibrio cholerae) comparing racecadotril (100 mg every 4 hours) versus placebo after initial rehydration. The RCT found no significant difference in duration of diarrhoea between treatment groups (mean: 35 hours with racecadotril v 32 hours with placebo; OR –3, 95% CI –7.37 to +3.04; P = 0.13). The RCT also found no significant difference between mean total stool output (315 g/kg with racecadotril v 280 g/kg with placebo; OR –35, 95% CI –108.9 to +38.18; P = 0.34) or mean total oral rehydration solution (ORS) intake (309 mL/kg with racecadotril v 311 mL/kg with placebo; OR +2.00, 95% CI –57.45 to +60.37; P = 0.96).

Berberine:

We found two RCTs comparing berberine versus placebo or no treatment. The first RCT (400 adults with acute watery diarrhoea) compared three interventions: berberine hydrochloride (100 mg tablet and 1 placebo capsule), tetracycline (500 mg capsule and 1 placebo tablet), berberine plus tetracycline (100 mg berberine tablet and 500 mg tetracycline capsule), or placebo (1 placebo tablet and 1 placebo capsule), given four times daily. The RCT found similar results among groups in mean duration of diarrhoea among people with non-cholera diarrhoea (37 hours with berberine v 37 hours with placebo; 50 hours with tetracycline v 42 hours with placebo; and 38 hours with berberine plus tetracycline v 42 hours with placebo; P values not reported). However, among people with cholera, tetracycline and tetracycline plus berberine both significantly reduced mean duration of diarrhoea compared with placebo (35 hours with tetracycline v 65 hours with placebo; P less than 0.001; 41 hours with tetracycline plus berberine v 65 hours with placebo; P less than 0.001). The second RCT (165 adults with acute diarrhoea caused by enterotoxigenic Escherichia coli [ETEC] and Vibrio cholerae) compared berberine sulphate versus no treatment. People with ETEC diarrhoea received berberine sulphate (400 mg orally as a single dose) or no treatment. People with cholera received berberine sulphate (400 mg as a single dose) or berberine (1200 mg; 400 mg 8-hourly) plus tetracycline 1 g, tetracycline 1 g alone, or no treatment. The RCT did not report on overall duration of illness, but found that berberine sulphate significantly reduced mean stool volumes during three consecutive 8-hour periods after treatment in people who had ETEC diarrhoea compared with no treatment (P less than 0.05). The RCT also found that, in people with ETEC, berberine sulphate significantly increased the proportion of people who stopped having diarrhoea at 24 hours compared with no treatment (42% with berberine sulphate v 20% with no treatment; P less than 0.05, absolute figures not reported). The RCT found that berberine sulphate significantly decreased mean stool volume at the second 8-hour period in people with cholera compared with no treatment (2.22 L with berberine sulphate v 2.79 L with no treatment; P less than 0.05). However, the RCT found people with cholera who received berberine sulphate 1200 mg plus tetracycline did not have a significant reduction in stool output compared with people who received tetracycline alone (no figures reported).

Chlorpromazine:

We found two RCTs comparing chlorpromazine versus placebo. The first RCT (410 people with severe watery diarrhoea aged under 2 years old, including 316 with cholera) compared a single dose of chlorpromazine 1 mg/kg versus placebo. All participants were also given tetracycline (500 mg every 6 hours for 2 days) plus a single dose of chlorpromazine or placebo (1 mg/kg body weight) 2 hours after admission. The RCT found similar results between chlorpromazine and placebo in duration of hospitalisation (children aged 2–8 years: 50 hours with chlorpromazine v 49 hours with placebo; adults: 43 hours with chlorpromazine v 44 hours with placebo; P values not reported), fluid requirements (children: 93.4 mL/kg with chlorpromazine v 104.3 mL/kg with placebo; adults: 100.2 mL/kg with chlorpromazine v 102.2 mL/kg with placebo; P values not reported) or volume loss (children: 250 mL/kg with chlorpromazine v 266 mL/kg with placebo; adults: 159 mL/kg with chlorpromazine v 189 mL/kg with placebo; P values not reported) in people with cholera. Results not reported for people in the non-cholera group. The second RCT (46 adult males with severe dehydration caused by cholera) compared four doses of chlorpromazine (1 or 4 mg/kg as a single dose, given by mouth or injection) versus no treatment. The RCT found that the duration of diarrhoea was significantly reduced among chlorpromazine treated people compared with no treatment (92.1 hours with im chlorpromazine 1 mg/kg v 99.0 hours with oral chlorpromazine 1 mg/kg v 94.6 hours with im chlorpromazine 4 mg/kg v 97.1 hours with oral chlorpromazine 4 mg/kg v 135.6 hours with no treatment; P values nor reported).

Harms

Racecadotril:

The RCT reported no drug-related adverse effects.

Berberine:

The two RCTs gave no information on adverse effects.

Chlorpromazine:

The first RCT gave no information on adverse effects. The second RCT reported a mild sedative effect for chlorpromazine.

Comment

People received initial intravenous rehydration, standard WHO ORS, to replace ongoing fluid losses, and doxycycline 300 mg or tetracycline 500 mg every 6 hours for 2 days (dose reduced to 250 mg for children aged under 8 years). In one study, to be eligible, people were required to have continued losses of over 200 mL/hour for 16 hours after admission. Fluid replacement was given intravenously. No oral rehydration solutions or antibiotics were given in this study.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Standard oral rehydration solution for severe diarrhoea in resource-poor countries

Summary

We found no clinically important results about oral rehydration compared with no rehydration in people with acute diarrhoea as RCTs assessing this intervention would be unethical. There is consensus that rehydration with standard oral rehydration solution is beneficial in people with severe diarrhoea.

Benefits

Standard oral rehydration solutions (ORS) versus no rehydration:

We found no systematic review or RCTs. RCTs comparing oral rehydration versus no rehydration would be considered unethical.

Harms

Standard oral rehydration solutions (ORS) versus no rehydration:

We found no systematic review or RCTs.

Comment

Clinical guide:

Response to ORS in people with cholera may not be comparable with response in people with less severe forms of diarrhoea.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Amino acid rehydration solutions for severe diarrhoea in resource-poor countries

Summary

SYMPTOM CONTROL Amino acid oral rehydration solution compared with standard oral rehydration solution: Amino acid oral rehydration solution may be more effective at reducing total volume of stool output in people with non-cholera diarrhoea, and at improving weight gain in people with cholera ( very low-quality evidence ).

Benefits

Amino acid oral rehydration solutions (ORS) versus standard ORS:

We found no systematic review but found two RCTs (97 men admitted to hospital with acute and severe dehydration from diarrhoea who received intravenous rehydration,108 men with diarrhoea under 48 hours’ duration and severe dehydration) comparing amino acid ORS versus standard ORS. In the RCT with intravenous rehydration, amino acid ORS was associated with a non-significant reduction in the total duration of diarrhoea and significantly reduced the total volume of stool compared with standard ORS. The other RCT found that amino acid ORS improved weight gain, but not stool volume, compared with standard ORS in people with cholera. For people with non-cholera diarrhoea, amino acid ORS was associated with a reduction in stool volume, but not in weight gain. See table 5 for all results .

Table 5.

Effects of oral rehydration solutions (ORS) in severe diarrhoea in adults living in resource-poor countries.

Trial People Aetiology Total duration of diarrhoea (hours) Total volume of stool
      Control Intervention Difference (95% CI) Control Intervention Difference (95% CI)
Intravenous fluid v ORS after initial intravenous fluids
  20 men over 20 years of age Cholera (100%) 44 37 7 (–6 to +20) 8.2 L 11.l L –2.9 L (NA)
Amino acid ORS v standard ORS
  97 males aged 6–59 years Cholera (60%) 52 44 8 (–1 to +14) 393 mL/kg 236 mL/kg 157 mL/kg (97  mL/kg to 298  mL/kg) P = 0.0003
  108 adult men, mean age 33 years Cholera (79%) Cholera 13 Non–cholera 15 Cholera 11 Non–cholera 13 Cholera 2 Non–cholera 2 Presented graphically Presented graphically Presented graphically
Bicarbonate ORS v chloride ORS
  60 adults Cholera 33 33 0 (NA) P = 0.98 4.1 mL/kg/hour 4.5 mL/kg/hour 0.4 mL/kg/hour (NA) P = 0.53
Bicarbonate ORS v standard ORS
  180 people aged 8–56 years Cholera, ETEC 48 48 0 (–0.5 to +8) P = 0.32 390 mL/kg 366 mL/kg 24 mL/kg (–18 mL/kg to 118 mL/kg) P = 0.10
  130 people Cholera 36 30 6 (NA) 6025 mL 4252 mL 1753 mL (NA) †
Reduced osmolarity ORS v standard ORS
  300 people Cholera 43 46 3 (0.8 to 7) 273 g/kg 284 g/kg +11 g/kg (–25 g/kg to +47 g/kg)
  34 adults Cholera 57 50 7 (NA) P = 0.126 481 mL/kg 303 mL/kg 178 mL/kg (NA) P = 0.001
  63 adult men Cholera 47 37 10 (4.2 to 15.2) 5.2 L 4.5 L +0.7 L (–0.04 L to +1.4 L)
  176 adults Cholera 43 44 Difference between groups reported as non-significant, P value not reported 3894 mL/kg 3792 mL/kg Difference between groups reported as non-significant, P value not reported
Rice-based ORS v standard ORS
  57 adults Cholera 47 37 10.4 (3.8 to 17) 5.2 L 4.0 L 1.2 L (0.3 L to 2.1 L)
  63 adults Cholera 47 29 18 (13.4 to 22.6) 5.2 L 3.1 L 2.1 L (1.3 L to 2.9 L)
  4 RCTs, 694 adults Cholera NA NA NA NA NA –51 mL/kg (–66 mL/kg to –36 mL/kg)†
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†For first 24 hours only. ETEC, enterotoxigenic Escherichia coli; L, litres; NA, not available.

Harms

Amino acid oral rehydration solutions (ORS) versus standard ORS:

One RCT reported no episodes of hypernatraemia or hyponatraemia in people taking amino acid ORS or standard ORS.

Comment

Clinical guide:

Response to ORS in people with cholera may not be comparable with response in people with less severe forms of diarrhoea.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Rice-based oral rehydration solution for severe diarrhoea in resource-poor countries

Summary

DURATION OF ILLNESS Rice-based oral rehydration solutions compared with standard oral rehydration solutions: Rice-based oral rehydration solutions (including low-sodium rice-based oral rehydration solutions) may be more effective at reducing duration of diarrhoea ( low-quality evidence ). Rice-based oral rehydration solution compared with low-glucose/low-sodium oral rehydration solution: Rice-based oral rehydration solutions (including low-sodium rice-based oral rehydration solutions) may be more effective at reducing duration of diarrhoea (low-quality evidence). Low-sodium rice-based oral rehydration solution compared with rice-based oral rehydration solution: Low-sodium rice-based oral rehydration solution may be more effective at reducing duration of diarrhoea (low-quality evidence). SYMPTOM CONTROL Rice-based oral rehydration solutions compared with standard oral rehydration solutions: Rice-based oral rehydration solutions (including low-sodium rice-based oral rehydration solutions) may be more effective at reducing stool output and 24 hour stool volume in adults with cholera ( very low-quality evidence ). Rice-based oral rehydration solution compared with low-glucose/low-sodium oral rehydration solution: Rice-based oral rehydration solutions (including low-sodium rice-based oral rehydration solutions) may be more effective at reducing stool output (low-quality evidence). Low-sodium rice-based oral rehydration solution compared with rice-based oral rehydration solution: Low-sodium rice-based oral rehydration solution may be more effective at reducing stool output (low-quality evidence).

Benefits

We found one systematic review (search date 1998, 4 RCTs) in people with cholera and non-cholera diarrhoea, which was withdrawn by the editor of the Cochrane Library as of Issue 4, 2005, pending a substantive update. We found one additional RCT (123 male adults with severe cholera who had received initial rehydration with intravenous Ringer's lactate solution), which was a four-arm trial comparing rice-based ORS (50 g/L rice plus 90 mmol/L sodium), low-sodium rice-based ORS (50 g/L rice plus 70 mmol/L sodium), low-glucose and low-sodium ORS, and standard ORS (WHO ORS). See table 5 .

Rice-based ORS versus standard ORS:

The review found that, in adults with cholera, rice-based ORS significantly reduced the 24 hour stool volume compared with standard ORS (4 RCTs, WMD –51 mL/kg, 95% CI –66 mL/kg to –36 mL/kg). All people with cholera received antibiotic treatment in addition to fluid treatment. Oral tetracycline or doxycycline were widely used, and were initiated at varying intervals after the start of oral rehydration.

The additional RCT found that, compared with standard ORS, both low-sodium rice-based ORS and rice-based ORS significantly reduced stool output (total stool output: 3.1 L with low-sodium rice-based ORS v 5.2 L with standard ORS; P less than 0.02; 4.0 L with rice-based ORS v 5.2 L with standard ORS; P less than 0.05) and duration of diarrhoea (36.5 hours with rice-based ORS v 28.9 hours with low-sodium rice-based ORS v 46.9 hours with standard ORS; P less than 0.05 or comparisons v standard ORS). See table 5 ..

Rice-based ORS versus low-glucose/low-sodium ORS:

The additional RCT found that both rice-based ORS and low-sodium rice-based ORS significantly reduced stool output compared with low-glucose/low-sodium ORS (total stool output: 3.1 L with low-sodium rice-based ORS v 5.2 L with low-glucose/low-sodium ORS; 4.0 L with rice-based ORS v 5.2 L with standard ORS; P less than 0.05) and duration of diarrhoea (36.5 hours with rice-based ORS v 28.9 hours with low-sodium rice-based ORS v 46.9 hours with standard ORS; P less than 0.05 or comparisons v standard ORS). See table 5 .

Low-sodium rice-based ORS versus rice-based ORS:

The additional RCT found that low-sodium rice-based ORS containing 70 mmol/L sodium significantly reduced stool output and duration of diarrhoea compared with rice-based ORS containing 90 mmol/L sodium (total stool output: 3.1 L with low-sodium rice-based ORS v 4.0 L with rice-based ORS; P less than 0.05). See table 5 ..

Harms

Information about harms for the withdrawn Cochrane review is unavailable at time of writing. The RCT gave no information about harms.

Comment

Clinical guide:

Response to ORS in people with cholera may not be comparable with response in people with less severe forms of diarrhoea.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Bicarbonate oral rehydration solution for severe diarrhoea in resource-poor countries

Summary

DURATION OF ILLNESS Bicarbonate oral rehydration solution compared with standard oral rehydration solution: We don’t know whether bicarbonate oral rehydration solution is more effective at reducing the duration of diarrhoea in people with cholera and non-cholera diarrhoea ( very low-quality evidence ). Bicarbonate oral rehydration solution compared with chloride oral rehydration solution: We don’t know whether bicarbonate oral rehydration solution is more effective at reducing the duration of diarrhoea in people with cholera and severe dehydration ( low-quality evidence ). SYMPTOM CONTROL Bicarbonate oral rehydration solution compared with standard oral rehydration solution: We don’t know whether bicarbonate oral rehydration solution is more effective at reducing volume of diarrhoea in people with cholera and non-cholera diarrhoea (very low-quality evidence). Bicarbonate oral rehydration solution compared with chloride oral rehydration solution: We don’t know whether bicarbonate oral rehydration solution is more effective at reducing total stool output in people with cholera and severe dehydration (low-quality evidence).

Benefits

Bicarbonate oral rehydration solution (ORS) versus standard ORS:

We found no systematic review but found two RCTs. The first RCT (180 men with diarrhoea lasting less than 48 hours) found no significant difference between treatments in the duration or volume of diarrhoea. The second RCT (130 people with cholera) did not assess the significance of the difference between groups, although bicarbonate ORS increased duration and volume of diarrhoea compared with standard ORS (see table 5 ).

Bicarbonate ORS versus chloride ORS:

We found no systematic review but found one small RCT (60 people with cholera and severe dehydration) comparing bicarbonate ORS versus an otherwise identical ORS, in which the bicarbonate was replaced with chloride. The RCT found no significant difference between treatments in total stool output or duration of diarrhoea (see table 5 ).

Harms

One RCT (130 people with cholera) reported that significantly more people taking standard ORS thought it tasted “bad” than those taking bicarbonate ORS (29% with standard ORS v 13% with bicarbonate ORS; CI not reported).

Comment

All people with cholera received antibiotic treatment in addition to fluid treatment. Oral tetracycline or doxycycline were widely used, and were initiated at varying intervals after the start of oral rehydration.

Clinical guide:

Response to ORS in people with cholera may not be comparable with response in people with less severe forms of diarrhoea.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Reduced osmolarity oral rehydration solution for severe diarrhoea in resource-poor countries

Summary

DURATION OF ILLNESS Low-glucose/low-sodium oral rehydration solution compared with rice-based oral rehydration solution: Low-glucose/low-sodium oral rehydration solution may be less effective at reducing duration of diarrhoea ( low-quality evidence ). Low-sodium rice-based oral rehydration solution compared with rice-based oral rehydration solution: Low-sodium rice-based oral rehydration solution may be more effective at reducing duration of diarrhoea (low-quality evidence). SYMPTOM CONTROL Low-glucose/low-sodium oral rehydration solution compared with rice-based oral rehydration solution: Low-glucose/low-sodium oral rehydration solution may be less effective at reducing stool output (low-quality evidence). Low-sodium rice-based oral rehydration solution compared with rice-based oral rehydration solution: Low-sodium rice-based oral rehydration solution may be more effective at reducing stool output (low-quality evidence). NOTE Reduced osmolarity oral rehydration solution has been associated with an increased risk of non-symptomatic hyponatraemia.

Benefits

Reduced osmolarity ORS versus standard ORS:

We found no systematic review but found four RCTs, which found a small and inconsistent effect on total volume of stool and duration of diarrhoea with reduced osmolarity ORS compared with standard ORS (see table 5) .

Reduced osmolarity ORS versus rice-based ORS:

See benefits of Rice-based oral rehydration solution: severe diarrhoea in resource-poor countries.

Harms

Reduced osmolarity ORS versus standard ORS:

Reduced osmolarity ORS significantly increased non-symptomatic hyponatraemia (OR 2.1, 95% CI 1.1 to 4.1) compared with standard ORS; in the RCTs evaluating symptomatic hyponatraemia, no cases were reported.

Reduced osmolarity ORS versus rice-based ORS:

See harms of Rice-based oral rehydration solution: severe diarrhoea in resource-poor countries.

Comment

Clinical guide:

Response to ORS in people with cholera may not be comparable with response in people with less severe forms of diarrhoea.

Substantive changes

Reduced osmolarity oral rehydration solution: severe diarrhoea in resource-poor countries One RCT added comparing reduced versus standard oral rehydration solution; categorisation unchanged (Unknown effectiveness).

BMJ Clin Evid. 2008 Mar 4;2008:0901.

Intravenous rehydration for severe diarrhoea in resource-poor countries

Summary

DURATION OF ILLNESS Intravenous rehydration compared with enteral rehydration: We don’t know whether intravenous rehydration is more effective at reducing duration of diarrhoea in people with cholera and severe dehydration ( low-quality evidence ). SYMPTOM CONTROL Intravenous rehydration compared with enteral rehydration: We don’t know whether reduced intravenous rehydration is more effective at reducing total volume of stool passed in people with cholera and severe dehydration (low-quality evidence). NOTE We found no clinically important results about oral rehydration solution alone compared with intravenous rehydration in people with acute diarrhoea.

Benefits

Intravenous rehydration versus oral rehydration solution:

We found no systematic review or RCTs comparing ORS alone versus intravenous rehydration.

Intravenous rehydration versus enteral rehydration:

We found one small RCT (20 adults with cholera and severe dehydration, who had received initial intravenous fluids for up to 90 minutes) comparing intravenous rehydration versus enteral rehydration through a nasogastric tube. All people with cholera received antibiotic treatment in addition to fluid treatment. Oral tetracycline or doxycycline were widely used, and were initiated at varying intervals after the start of oral rehydration. The RCT found no significant difference in the total duration of diarrhoea (44 hours with iv fluids v 37 hours with nasogastric fluids; difference +7 hours, 95% CI –6 hours to +20 hours), total volume of stool passed (8.2 L with iv fluids v 11 L with nasogastric fluids; difference –2.9 L), or duration of Vibrio excretion (1.1 days with iv fluids v 1.4 days with nasogastric fluids; difference 0.3 days, 95% CI 0 days to 1 day). See table 5) .

Harms

Intravenous rehydration versus oral rehydration solution:

We found no systematic review or RCTs comparing ORS alone versus intravenous rehydration.

Intravenous rehydration versus enteral rehydration:

The RCT reported that there was no unusual morbidity in either treatment group (no further data reported)..

Comment

Clinical guide:

Response to ORS in people with cholera may not be comparable with response in people with less severe forms of diarrhoea.

Substantive changes

No new evidence

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