Abstract
Introduction
Amoebic dysentery is caused by the protozoan parasite Entamoeba histolytica. It is transmitted in areas where poor sanitation allows contamination of drinking water and food with faeces. In these areas, up to 40% of people with diarrhoea may have amoebic dysentery.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of drug treatments for amoebic dysentery in endemic areas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2013 (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 6 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: diiodohydroxyquinoline (iodoquinol), diloxanide, emetine, metronidazole, nitazoxanide, ornidazole, paromomycin, secnidazole, and tinidazole.
Key Points
Invasive infection with the parasite Entamoeba histolytica can be asymptomatic, or can cause diarrhoea with blood and mucus, abdominal pains, and fever.
Amoebic dysentery is transmitted in areas where poor sanitation allows contamination of drinking water and food with faeces. In these areas, up to 40% of people with diarrhoea may have amoebic dysentery.
Fulminant amoebic dysentery is often fatal. Other complications include perforation of the colon, colonic ulcers, amoeboma, or chronic carriage.
Metronidazole may be less effective than tinidazole at reducing clinical symptoms, but may be as effective at clearing parasites. Metronidazole may be more likely than tinidazole to cause adverse effects such as nausea.
Ornidazole may be effective at curing amoebic dysentery compared with placebo, but can cause nausea and vomiting.
Secnidazole, tinidazole, and metronidazole may be as effective as ornidazole at curing amoebic dysentery.
Nitazoxanide is likely to be more effective than placebo at reducing clinical failure. Nitazoxanide may not be more effective than placebo at preventing parasitological failure.
We don't know whether emetine, paromomycin, diloxanide, or diiodohydroxyquinoline are effective in treating amoebic dysentery as we found no trials. However, paromomycin, diloxanide, and diiodohydroxyquinoline are luminal amoebicides and there is consensus that they have insufficient tissue penetration to be effective against invasive intestinal disease.
Clinical context
General background
Amoebiasis is caused by the parasite Entamoeba histolytica. Prevalence rates of amoebiasis are highest in developing countries in Asia, particularly the Indian subcontinent and Indonesia, sub-Saharan and tropical regions of Africa, and areas of Central and South America, although prevalence estimates are limited by a lack of studies. E histolytica infection can cause a spectrum of clinical symptoms, ranging from mild diarrhoea and abdominal pain to fulminant dysentery. It is estimated that only 10% to 20% of infected individuals develop symptoms. Fulminant amoebic dysentery is often fatal. Metronidazole is the established drug of choice for the treatment of amoebic dysentery in adults and children. Metronidazole is generally effective in treatment but has associated adverse effects and may be insufficient to fully eradicate infection.
Focus of the review
This review highlights the clinical evidence for the use of anti-amoebic therapeutic agents in the treatment of amoebic dysentery. We compare the efficacy and safety of amoebicides that penetrate the epithelium (e.g., metronidazole, tinidazole, ornidazole, secnidazole) and luminal amoebicides (e.g., paromomycin, diloxanide, diiodohydroxyquinoline) for treatment of amoebic dysentery.
Comments on evidence
The evidence for management of amoebic dysentery is generally limited by the poor methodological quality of trials, in particular in regards to randomisation and appropriate diagnostics. Randomised trials with accurate diagnostics for inclusion and standardised outcomes for clinical and parasitological failure are needed to completely compare the efficacy and safety of drug regimens for amoebic dysentery.
Search and appraisal summary
The update literature search for this review was carried out from the date of the last search, April 2010, to June 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved five studies. After deduplication and removal of conference abstracts, four records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of three studies and the further review of one full publication. Of the one full article evaluated, no systematic reviews nor RCTs were included at this update.
Additional information
Other amoebicides that penetrate the epithelium (tinidazole, ornidazole, secnidazole) may have similar efficacy as metronidazole at reducing parasitological or clinical failure, and have fewer reported adverse effects. Luminal amoebicides (paromomycin, diloxanide, diiodohydroxyquinoline) are not recommended for treatment of symptomatic amoebic infection. There is some evidence that treatment with luminal amoebicides after treatment with a tissue amoebicide, such as metronidazole, improves eradication of surviving parasites in the colon. Therefore, luminal amoebicides may have a role in reducing parasitological failure, preventing relapse, and interrupting transmission of parasite cysts.
About this condition
Definition
Amoebic dysentery is caused by the protozoan parasite Entamoeba histolytica. Invasive intestinal parasitic infection can result in symptoms of fulminant dysentery, such as fever, chills, bloody or mucous diarrhoea, and abdominal discomfort. The dysentery can alternate with periods of constipation or remission. This review focuses on amoebic dysentery only, and includes populations with both suspected and documented disease in endemic areas where levels of infection do not exhibit wide fluctuations through time. The term "amoebic dysentery" encompasses people described as having symptomatic intestinal amoebiasis, amoebic colitis, amoebic diarrhoea, or invasive intestinal amoebiasis. Extraintestinal amoebiasis (e.g., amoebic liver abscess) and asymptomatic amoebiasis are not covered.
Incidence/ Prevalence
We found no accurate global prevalence data for E histolytica infection and amoebic dysentery. Estimates on the prevalence of Entamoeba infection range from 1% to 40% of the population in Central and South America, Africa, and Asia, and from 0.2% to 10.8% in endemic areas of developed countries such as the US. However, these estimates are difficult to interpret, mainly because infection can remain asymptomatic or go unreported, and because many older reports do not distinguish E histolytica from the non-pathogenic, morphologically identical species Entamoeba dispar. Development and availability of more sophisticated methods (such as the enzyme-linked immunosorbent assay [ELISA]-based test) to differentiate the two species might give a more accurate estimate of its global prevalence. Infection with E histolytica is a common cause of acute diarrhoea in developing countries. One survey conducted in Egypt found that 38% of people with acute diarrhoea in an outpatient clinic had amoebic dysentery.
Aetiology/ Risk factors
Ingestion of cysts from food or water contaminated with faeces is the main route of E histolytica transmission. Low standards of hygiene and sanitation, particularly those related to crowding, tropical climate, contamination of food and water with faeces, and inadequate disposal of faeces, all account for the high rates of infection seen in developing countries. In developed countries, risk factors include communal living, oral and anal sex, compromised immune system, and migration or travel from endemic areas.
Prognosis
Amoebic dysentery may progress to amoeboma, fulminant colitis, toxic megacolon, and colonic ulcers, and may lead to perforation. Amoeboma may be mistaken for colonic carcinoma or pyogenic abscess. Amoebic dysentery may also result in chronic carriage and the chronic passing of amoebic cysts. Fulminant amoebic dysentery is reported to have 55% to 88% mortality. It is estimated that more than 500 million people are infected with E histolytica worldwide. Between 40,000 and 100,000 will die each year, placing this infection second to malaria in mortality caused by protozoan parasites.
Aims of intervention
To reduce the infectious period, length of illness, risks of dehydration, risks of transmission to others, and rates of severe illness; to prevent complications and death, with minimal adverse effects.
Outcomes
Mortality; complications (i.e., amoeboma, extension to pleural cavity, chronic cyst carriage); treatment effectiveness: therapeutic cure (defined as absence of parasites in stools, disappearance of symptoms, and healing of ulcers); clinical failure (defined as persistence of symptoms), and parasitological failure (defined as persistence of parasites in stools or in other diagnostic tests); and adverse effects of treatment.
Methods
Clinical Evidence search and appraisal June 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2013, Embase 1980 to June 2013, and The Cochrane Database of Systematic Reviews 2013, issue 2 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search run by an information specialist were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, including open studies, with no minimum number of participants. There was no minimum length of follow-up required for included studies, and no restriction applied based on number of withdrawals. We included systematic reviews of RCTs and RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Amoebic dysentery.
| Important outcomes | Adverse effects, Complications, Mortality, Treatment effectiveness | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of drug treatments for amoebic dysentery in endemic areas? | |||||||||
| 9 (at least 711 people) | Treatment effectiveness | Metronidazole versus tinidazole | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for methodological flaws (lack of blinding of RCTs and possible inclusion of duplicate study in analysis). Directness point deducted for uncertainty about diagnosis of amoebic dysentery |
| 8 (477) | Adverse effects | Metronidazole versus tinidazole | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for methodological flaws (lack of blinding of RCTs and possible inclusion of duplicate study in analysis) |
| 3 (128) | Treatment effectiveness | Metronidazole versus ornidazole | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and methodological weaknesses in included RCTs. Directness point deducted for uncertainty about diagnosis of amoebic dysentery |
| 1 (102) | Treatment effectiveness | Secnidazole versus ornidazole | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, no blinding, and no statistical assessment performed |
| 1 (55) | Treatment effectiveness | Ornidazole versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, uncertainty about randomisation, and no statistical assessment performed |
| 2 (66) | Treatment effectiveness | Ornidazole versus tinidazole | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and no statistical assessment performed. Directness point deducted for uncertainty about diagnosis of amoebic dysentery |
| 2 (167) | Treatment effectiveness | Nitazoxanide versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for uncertainty about diagnosis of amoebic dysentery |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Amoeboma
A granulomatous lesion of the caecum or ascending colon caused by localised chronic Entamoeba histolytica infection.
- Enzyme linked immunosorbent assay (ELISA)
A testing method using immune responses to detect substances such as hormones, bacterial antigens, and antibodies.
- Helminthiasis
The presence in the human gastrointestinal tract of nematode worms (i.e. roundworms) such as Ancylostoma duodenale, Ascaris lumbricoides, and Trichuris trichiura.
- 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.
- Very low-quality evidence
Any estimate of effect is very uncertain.
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.
Contributor Information
Chelsea Marie, University of Virginia School of Medicine, Charlottesville, USA.
William Arthur Petri Jr., University of Virginia, Charlottesville, USA.
References
- 1.Last JM (ed). A dictionary of epidemiology. 3rd ed. New York, NY: Oxford University Press; 1995. [Google Scholar]
- 2.Rivera WL, Tachibana H, Kanbara H. Field study on the distribution of Entamoeba histolytica and Entamoeba dispar in the northern Philippines as detected by the polymerase chain reaction. Am J Trop Med Hyg 1998;59:916–921. [DOI] [PubMed] [Google Scholar]
- 3.Haque R, Faruque ASG, Hahn P, et al. Entamoeba histolytica and Entamoeba dispar infection in children in Bangladesh. J Infect Dis 1997;175:734–736. [DOI] [PubMed] [Google Scholar]
- 4.Braga LL, Mendonca Y, Paiva CA, et al. Seropositivity for and intestinal colonization with Entamoeba histolytica and Entamoeba dispar in individuals in Northeastern Brazil. J Clin Microbiol 1998;36:3044–3045. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Chacin-Bonilla L, Bonillla E, Parra AM, et al. Prevalence of Entamoeba histolytica and other intestinal parasites in a community from Maracaibo, Venezuela. Ann Trop Med Parasitol 1992;86:373–380. [DOI] [PubMed] [Google Scholar]
- 6.Anonymous. Amoebiasis. Wkly Epidemiol Rec 1997;72:97–99. [PubMed] [Google Scholar]
- 7.Huston CD, Petri WA. Amoebiasis: clinical implications of the recognition of Entamoeba dispar. Curr Infect Dis Rep 1999;1:441–447. [DOI] [PubMed] [Google Scholar]
- 8.Abd-Alla MD, Ravdin JI. Diagnosis of amoebic colitis by antigen capture ELISA in patients presenting with acute diarrhoea in Cairo, Egypt. Trop Med Int Health 2002;7:365–370. [DOI] [PubMed] [Google Scholar]
- 9.Davis AN, Haque R, Petri WA Jr. Update on protozoan parasites of the intestine. Curr Opin Gastroenterol 2002;18:10–14. [DOI] [PubMed] [Google Scholar]
- 10.Lucas R, Upcroft JA. Clinical significance of the redefinition of the agent of amoebiasis. Rev Latinoam Microbiol 2001;43:183–187. [PubMed] [Google Scholar]
- 11.Petri WA Jr, Singh U. Diagnosis and management of amebiasis. Clin Infect Dis 1999;29:1117–1125. [DOI] [PubMed] [Google Scholar]
- 12.Stanley SL. Amoebiasis. Lancet 2003;361:1025–1034. [DOI] [PubMed] [Google Scholar]
- 13.Haque R, Huston CD, Hughes M, et al. Amebiasis. N Engl J Med 2003;348:1565–1573. [DOI] [PubMed] [Google Scholar]
- 14.Singh B, Moodley J, Ramdial PK. Fulminant amoebic colitis: a favorable outcome. Int Surg 2001;86:77–81. [PubMed] [Google Scholar]
- 15.Vargas M, Pena A. Toxic amoebic colitis and amoebic colon perforation in children: an improved prognosis. J Pediatr Surg 1976;11:223–225. [DOI] [PubMed] [Google Scholar]
- 16.Espinosa-Cantellano M, Martínez-Palomo A. Recent developments in amoebiasis research. Curr Opin Infect Dis 2000;13:451–456. [DOI] [PubMed] [Google Scholar]
- 17.Gonzales-Maria LM, Dans LF, Martinez EG. Antiamoebic drugs for treating amoebic colitis. In: The Cochrane Library, Issue 3, 2013. Chichester, UK: John Wiley & Sons, Ltd. Search date 2008. [Google Scholar]
- 18.Misra NP, Gupta RC. A comparison of a short course of single daily dosage therapy of tinidazole with metronidazole in intestinal amoebiasis. J Int Med Res 1977;5:434–437. [DOI] [PubMed] [Google Scholar]
- 19.Misra NP. A comparative study of tinidazole with metronidazole as a single daily dose for three days in symptomatic intestinal amoebiasis. Drugs 1978;15(suppl 1):19–22. [DOI] [PubMed] [Google Scholar]
- 20.Toppare MF, Kitapci F, Senses DA, et al. Ornidazole and secnidazole in the treatment of symptomatic intestinal amoebiasis in childhood. Trop Doct 1994;24:183–184. [DOI] [PubMed] [Google Scholar]
- 21.Apt W, Perez C, Miranda C, et al. Treatment of intestinal amebiasis and giardiasis with ornidazole. [In Spanish.] Rev Med Chil 1983;111:1130–1133. [PubMed] [Google Scholar]
- 22.Panggabean A, Sutjipto A, Aldy D, et al. Tinidazole versus ornidazole in amebic dysentery in children (a double blind trial). Paediatr Indones 1980;20:229–235. [PubMed] [Google Scholar]
- 23.Gupta YK, Gupta M, Aneja S, et al. Current drug therapy of protozoal diarrhoea. Indian J Pediatr 2004;71:55–58. [DOI] [PubMed] [Google Scholar]
- 24.Pantenburg B, Cabada MM, White AC Jr. Treatment of cryptosporidiosis. Expert Rev Anti Infect Ther 2009;7:385–391. [DOI] [PubMed] [Google Scholar]
- 25.Di Perri G, Strosselli M, Rondanelli EG. Therapy of entamebiasis. J Chemother 1989;1:113–122. [DOI] [PubMed] [Google Scholar]
- 26.Bhopale KK, Pradhan KS, Masani KB, et al. A comparative study of experimental caecal amoebiasis and the evaluation of amoebicides. Ann Trop Med Parasitol 1995;89:253–259. [DOI] [PubMed] [Google Scholar]