Antiamoebic drugs for treating amoebic colitis

  • Review
  • Intervention

Authors

  • Maria Liza M Gonzales,

    Corresponding author
    1. College of Medicine-Philippine General Hospital, University of the Philippines, Department of Pediatrics, Manila, National Capital Region, Philippines
    • Maria Liza M Gonzales, Department of Pediatrics, College of Medicine-Philippine General Hospital, University of the Philippines, Taft Avenue, Manila, National Capital Region, 1000, Philippines. lizmgonzales@yahoo.com.

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  • Leonila F Dans,

    1. Philippine General Hospital, University of the Philippines, Departments of Pediatrics and Clinical Epidemiology, Manila, National Capital Region, Philippines
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  • Elizabeth G Martinez

    1. College of Medicine-Philippine General Hospital, University of the Philippines, Department of Pediatrics, Manila, National Capital Region, Philippines
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Abstract

Background

Entamoeba histolytica infection is common in developing countries, and up to 100,000 individuals with severe disease die every year. Adequate therapy for amoebic colitis is necessary to reduce the severity of illness, prevent development of complicated disease and extraintestinal spread, and decrease transmission.

Objectives

To evaluate antiamoebic drugs for treating amoebic colitis.

Search methods

In September 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (2008, Issue 3), MEDLINE, EMBASE, LILACS, mRCT, and conference proceedings. We contacted individual researchers, organizations, and pharmaceutical companies, and checked reference lists.

Selection criteria

Randomized controlled trials of antiamoebic drugs given alone or in combination, compared with placebo or another antiamoebic drug for treating adults and children diagnosed with amoebic colitis.

Data collection and analysis

Two authors independently assessed the eligibility and methodological quality of trials, and extracted and analysed the data. We calculated clinical and parasitological failure rates, relapse, and adverse events as risk ratios (RR) with 95% confidence intervals (CIs), using a random-effects model. We determined statistical heterogeneity and explored possible sources of heterogeneity using subgroup analyses. We carried out sensitivity analysis using trial quality to assess the robustness of the results.

Main results

Thirty-seven trials, enrolling 4487 participants, met the inclusion criteria. Only one trial used adequate methods for randomization and allocation concealment, was blinded, and analysed all randomized participants. Only one trial used a E. histolytica stool antigen test. Tinidazole reduced clinical failure compared with metronidazole (RR 0.28, 95% CI 0.15 to 0.51; 477 participants, eight trials) and was associated with fewer adverse events. Compared with metronidazole, combination therapy resulted in fewer parasitological failures (RR 0.36, 95% CI 0.15 to 0.86; 720 participants, 3 trials).

Authors' conclusions

Tinidazole is more effective in reducing clinical failure compared with metronidazole and has fewer associated adverse events. Combination drug therapy is more effective in reducing parasitological failure compared with metronidazole alone. However, these results are based on trials with poor methodological quality so there is uncertainty in these conclusions. Further trials of the efficacy of antiamoebic drugs, with better methodological quality, are recommended. More accurate tests to detect E. histolytica are needed, particularly in countries where concomitant infection with other bacteria and parasites is common.

摘要

背景

用於治療阿米巴性結腸炎之抗阿米巴藥物

溶組織內阿米巴(Entamoeba histolytica)感染常見於開發中國家,且每年都有高達100,000人因嚴重疾病而死亡。茲需要對於阿米巴性結腸炎之適當治療,以降低疾病之嚴重性、預防發生重症及腸外感染、並減少疾病傳播。

目標

評估用於治療阿米巴性結腸炎之抗阿米巴藥物。

搜尋策略

2008年9月時我們搜尋Cochrane Infectious Diseases Group Specialized Register, CENTRAL (2008, Issue 3) 、MEDLINE、EMBASE、LILACS、mRCT,以及研討會手冊。此外還與本領域相關機構、藥廠及研究人員聯繫,並檢查參考資料清單。

選擇標準

針對診斷患有阿米巴性結腸炎之成人及兒童,比較單獨或組合投與之抗阿米巴藥物與安慰劑或是另一種抗阿米巴藥物的隨機對照試驗。

資料收集與分析

由2名作者獨立評估試驗之適用性及方法學品質,並摘錄及分析數據。我們使用隨機效果模型,將臨床及寄生蟲學失敗率、復發、及不良作用計算為風險比(risk ratio;RR)與95%信賴區間(confidence intervals;CIs)。我們使用亞族群分析判定統計異質性並探詢可能之異質性來源。茲使用試驗品質進行敏感性分析以評估結果之可靠度。

主要結論

共有招收4487名參與者之37項試驗符合收錄標準。其中僅有1項試驗使用了適當之方法進行隨機分派及分組隱匿,為遮盲試驗,並分析所有之隨機分派參與者。僅有1項試驗使用了溶組織內阿米巴(E. histolytica)糞便抗原試驗。Tinidazole相較於metronidazole可減少臨床失敗率(RR 0.28, 95% CI 0.15 to 0.51; 477名參與者,8項試驗),且其具有較少之不良作用。相較於metronidazole,組合治療可產生較少之寄生蟲性失敗(RR 0.36, 95% CI 0.15 to 0.86; 720名參與者,3項試驗)。

作者結論

Tinidazole相較於metronidazole可更有效的減少臨床失敗,並具有較少之不良作用。相較於單獨使用之metronidazole,組合藥物治療可減少寄生蟲性失敗。然而,此等結果係基於方法學品質不良之試驗,故此等結論仍有不確定性。建議應針對抗阿米巴藥物之功效進行具有較佳方法學品質之試驗。茲需要可偵測溶組織內阿米巴(E. histolytica)之更精確試驗,特別是在常見其他細菌及寄生蟲之伴隨感染的國家中。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

阿米巴性結腸炎係由寄生蟲溶組織內阿米巴(Entamoeba histolytica)造成。此種原蟲分布於全世界,且其常係經由攝入污染之食物或水而感染。估計共有約四至五千萬名感染溶組織內阿米巴(E. histolytica)之患者會發生阿米巴性結腸炎或腸外膿瘍,其可造成每年高達100,000人死亡。Metronidazole目前係用以治療成人及兒童之侵襲性阿米巴痢疾首選藥物,但其可能並不足以清除腸中之寄生蟲性囊腫。因此亦使用與其他藥物之組合。然而,尚未針對可支持組合治療之證據進行回顧。同時,亦必須考量metronidazole 在部分病患體內所產生之不良作用以及寄生蟲可能對metronidazole 具有抗藥性。本回顧係比較用於對抗阿米巴性結腸炎之不同藥物(包括單獨或組合使用者),並亦評估單劑療程對較長之療程。共收錄包括4487名參與者之37項試驗,而其中只有1項具有高方法學品質。Tinidazole 相較於metronidazole可更有效的減少臨床失敗,並具有較少之不良作用。相較於單獨使用之metronidazole,組合藥物治療可造成較少之寄生蟲性失敗。回顧作者歸結認為,tinidazole似乎可較metronidazole 更為有效的減少臨床失敗,並具有較少之不良作用。並無足夠之證據可取得關於其他抗阿米巴藥物功效之結論。然而,該等試驗一般皆不具有適當之方法學品質。同時,抗阿米巴藥物之選擇可能大量取決於藥物之可取得性。茲需要具有標準結果之較佳品質隨機試驗以評估藥物對於治療阿米巴性結腸炎之功效。亦需要可用於開發中國家之改良式可靠之診斷測試方法。

Plain language summary

Antiamoebic drugs for treating amoebic colitis

Amoebic colitis is caused by the parasite Entamoeba histolytica. This protozoan is distributed throughout the world and is commonly acquired by ingestion of contaminated food or water. It is estimated that about 40 to 50 million people infected with E. histolytica develop amoebic colitis or extraintestinal abscesses, which result in up to 100,000 deaths per year.

Metronidazole is currently the drug of choice for treating invasive amoebiasis in adults and children, but it may not be sufficient to eliminate parasite cysts in the intestine. Combinations with other drugs are therefore also used. However, the evidence to support combination therapy has not been reviewed. Also, some unpleasant adverse effects associated with metronidazole in some patients, and the possibility of parasite resistance to metronidazole has to be considered.

This review compares different drugs used against amoebic colitis, alone or in combination, and also assesses single-dose regimens versus longer regimens.

Thirty-seven trials with 4487 participants were included, and only one was of high methodological quality. Tinidazole reduced clinical failure compared with metronidazole and was associated with fewer adverse events. Combination therapy resulted in fewer parasitological failures than metronidazole alone.

The authors conclude that tinidazole appears more effective at reducing clinical failures than metronidazole, and has fewer associated adverse events. There is insufficient evidence to draw conclusions regarding the efficacy of the other antiamoebic drugs. However, the trials' methodological quality was generally inadequate. Also, the choice of antiamoebic drugs would depend largely on the availability and accessibility of drugs.

Better quality randomized trials with standardized outcomes are needed to evaluate the efficacy of drugs for treating amoebic colitis. There is also a need for improved, reliable diagnostic tests that can be used in developing countries.

Background

Epidemiology

Amoebiasis is a parasitic disease caused by Entamoeba histolytica, a protozoan parasite distributed throughout the world. It is estimated that about 40 to 50 million people infected with E. histolytica develop amoebic colitis or extraintestinal abscesses, which result in up to 100,000 deaths per year (Walsh 1986; Li 1996; WHO 1997; Petri 2000). Amoebiasis is second only to malaria in terms of mortality due to protozoan parasites (WHO 1997). Prevalence rates of amoebiasis are highest in developing countries in Asia, particularly the Indian subcontinent and Indonesia, the sub-Saharan and tropical regions of Africa, and areas of Central and South America (Petri 1999). In these areas, the prevalence rates vary with the population studied, differing between countries and areas with different socioeconomic conditions, and with the diagnostic test used.

Antibodies were detected by enzyme-linked immunosorbent assay (ELISA) in 14.7% to 32.7% of asymptomatic preschool children in an urban slum in Bangladesh (Haque 1999; Haque 2001), in 19.7% of individuals in a slum community in north-eastern Brazil (Braga 1996), and in 12.7% of individuals in an urban area in Vietnam (Blessman 2002). In a rural area in Ecuador, antibodies were detected using various serologic tests in 64.6% of elementary school students (Gatti 2002). In 1998, during an outbreak of amoebiasis in Tblisi, Georgia, 9% to 14% of asymptomatic individuals were positive for antibodies (Barwick 2002). More recent studies that used an ELISA test or polymerase chain reaction (PCR) reported that the incidence of intestinal amoebiasis in highly endemic areas ranged from 13% to 67% in individuals with diarrhoea (Haque 1997; Abd-Alla 2002; Tanyuksel 2005; Rivera 2006; Samie 2006) and from 1.0% to 13.8% in asymptomatic individuals (Haque 1997; Braga 1998; Rivera 1998; Haque 2001; Ramos 2005). In a four-year prospective study, 80% of asymptomatic schoolchildren aged two to five years and living in an urban slum in Bangladesh were infected with E. histolytica at least once, as determined by stool antigen detection test (Haque 2006).

Infection is commonly acquired by ingestion of food or water contaminated with cysts of E. histolytica, but transmission also occurs through oral and anal sex, and contaminated enema apparatuses (Li 1996; Haque 2003; Stanley 2003). In developed countries, infection occurs primarily among travellers to endemic regions, recent immigrants from endemic regions, homosexuals, immunosuppressed persons, and institutionalized individuals (Reed 1992; Petri 1999). One study found that 0.3% of travellers returning from tropical regions had positive amoebic serology (Weinke 1990), while another study found that 47% had positive stool cultures identified as E. histolytica by PCR and isoenzyme typing (Walderich 1997). Despite more frequent infection with nonpathogenic E. dispar in those with acquired immune deficiency syndrome (AIDS), E. histolytica remains an important diagnostic consideration in people with human immunodeficiency virus (HIV) presenting with bloody diarrhoea (Reed 1992; Ravdin 2005).

Clinical manifestations

About 90% of people infected with E. histolytica have no symptoms of disease and spontaneously clear their infection, while the remaining 10% develop invasive disease (Walsh 1986; Gathiram 1987; Haque 2002; Stanley 2003). About 3% to 10% of untreated individuals with asymptomatic infection coming from areas endemic for amoebiasis develop symptoms of invasive amoebic disease within one year (Gathiram 1985; Haque 2001; Blessman 2003b; Haque 2002).

Intestinal amoebiasis commonly presents as ulcers and inflammation of the colon. This results in a complete spectrum of colonic signs and symptoms ranging from non-bloody diarrhoea to dysentery (acute diarrhoea with bloody stools), and to necrotizing colitis (severe inflammation of the colon) with intestinal perforation and peritonitis (infection of the abdominal cavity membranes) (Patterson 1982; Petri 1999; Ravdin 2005). Clinical symptoms of amoebic colitis include abdominal pain or tenderness, urgency to defecate, fever, weight loss, and diarrhoea or loose stools with mucus, blood, or both (WHO 1997; Haque 2003).

Amoebic colitis includes two clinical forms defined by the WHO Expert Committee on Amoebiasis as "amoebic dysentery" and "nondysenteric amoebic colitis" (WHO 1969). Amoebic dysentery is diarrhoea with visible blood and mucus in stools and the presence of haematophagous trophozoites (trophozoites with ingested red blood cells) in stools or tissues; sigmoidoscopic examination reveals inflamed mucosa with or without discrete ulcers. Nondysenteric amoebic colitis presents as recurrent bouts of diarrhoea with or without mucus but no visible blood and presence of E. histolytica cysts or nonhaematophagous trophozoite (trophozoites with no ingested red blood cells) in stools, and the results of sigmoidoscopic examination are usually normal.

The most severe complication of amoebic colitis is fulminant or necrotizing colitis. It occurs in 0.5% of cases (Petri 1999) and as many as 6% to 11% of people with symptomatic infection (Pelaez 1966; Brooks 1985). In necrotizing colitis, there is profuse bloody diarrhoea, fever, and widespread abdominal pain, frequently progressing to severe injury of the bowel wall, intestinal haemorrhage, or perforation with peritonitis (Haque 2003; Stanley 2003). Among these people, the case-fatality rate is more than 40% (Ellyson 1986; Petri 1999; Chen 2004). Young children, malnourished individuals, pregnant women, immunocompromised individuals, and those receiving corticosteroids are at higher risk for invasive disease (Adams 1977; Ellyson 1986; Li 1996; Stanley 2003). Extraintestinal complications of amoebic infection include abscesses in various organs, empyema (accumulation of pus around the lungs), and pericarditis (inflammation of membranes surrounding the heart) (Petri 1999; Ravdin 2005). In the treatment of necrotizing colitis and extraintestinal amoebiasis, surgery and additional antibiotics may be required aside from specific antiamoebic drugs (WHO 1985; Stanley 2003).

Method of diagnosis

In many countries where amoebiasis is endemic, diagnosis of amoebic colitis is commonly made by identifying cysts or motile trophozoites in a saline wet mount of a stool specimen. Finding trophozoites containing ingested red blood cells in the stool is considered by many to be diagnostic for amoebic colitis (Gonzalez-Ruiz 1994; Haque 1997; Tanyuksel 2003). The limitations of this method include its low specificity because it is incapable of differentiating E. histolytica from nonpathogenic species such as E. dispar or E. moshkovskii (Petri 2000; Haque 2003). The accuracy of microscopic methods is highly dependent on the competence of the diagnostic laboratory. Specific and sensitive means to detect E. histolytica in stools include stool antigen detection test and PCR techniques based on the amplification of the target parasite RNA and DNA (Haque 1995; Haque 1998; Petri 2000; Nesbitt 2004). Ideally, stool samples positive for E. histolytica on microscopy should be confirmed with stool antigen or PCR before treatment starts. Unfortunately, these tests are not routinely used and are not widely available for the diagnosis of amoebic colitis in many developing countries.

Public health and socioeconomic impact

In addition to being a potentially fatal disease, invasive amoebiasis has important social and economic consequences. The peak incidence of amoebic colitis is among children less than 14 years of age and a second increase is seen in adults more than 40 years old (Gathiram 1985; Wanke 1988). Amoebic colitis is a temporarily incapacitating disease that may require hospitalization in some individuals presenting with severe diarrhoea or dysentery. Amoebic colitis affecting adults in the wage-earning group may require several weeks of hospitalization and up to two to three months for full recovery (WHO 1985; Walsh 1986). Pregnant and postpartum women appear to have an increased risk of severe disease and death (Li 1996; Stanley 2003; Ravdin 2005). Persistent infection can impair physical and mental growth, and affect the nutrition and general development of children. Children with E. histolytica-associated diarrhoea during the first two years of life were 2.93 times more likely to be malnourished and 4.69 times more prone to be stunted (Mondal 2006). Another study demonstrated that malnutrition and amoebic dysentery were associated with cognitive deficiencies (Tarleton 2006).

Antiamoebic drugs for treatment

The goals of treatment for amoebic colitis are to treat the invasive disease and to eradicate intestinal carriage of the organism (Li 1996). E. histolytica may be found in the bowel lumen, in the bowel wall, and in tissues, including the liver (WHO 1969). Antiamoebic drugs vary in efficacy at the three sites where the parasites commonly exist and are generally divided into two classes based on their main site of activity. The luminal amoebicides act principally in the bowel lumen and the tissue amoebicides act principally in the bowel wall and the liver; see Table 1 for examples.

Table 1. Amoebicide classes and examples
AmoebicideClassExample
LuminalArsenical compoundsCarbarsone, acetarsone or acetarsol, treparsol, diphetarsone, glycobiarsol or bismuth glycolylarsanilate, stovarsol, and thioarsenite, thiocarbarsone or thiocarabazone, arsthinol
Hydroxyquinoline derivativesChiniofon or quinoxyl, clioquinol or iodochlorhydroxyquin, and iodoquinol or diiodohydroxyquin
Dichloroacetamide derivativesDiloxanide furoate or entamide furoate, clefamide, eticlordifene or ethylchlordiphene or etofamide or etophamide, and quinfamide
Benzylamine derivativesTeclozan, chlorbetamide or mantomide, and chlorphenoxamide or mebinol
Antibiotic amoebicidesTetracycline, oxytetracycline, chlortetracycline, erythromycin, paromomycin, and fumagillin
Nithrothiazole salicylamideNitazoxanide
TissueEmetine and its derivativesEmetine hydrochloride, emetine bismuth iodide, dehydroemetine dihydrochloride, and dehydroemetine resinate
AminoquinolineChloroquine
Thiazole derivativeNiridazole
NitroimidazolesMetronidazole, tinidazole, ornidazole, secnidazole, and nimorazole

Metronidazole is considered as the drug of choice for treating invasive amoebiasis (WHO 1994; Medical Letter 2004; WHO 2005; AAP 2006). The standard regimen of metronidazole for the treatment of amoebic colitis is 500 to 750 mg given three times daily in adults and 30 to 50 mg/kg/day in children given for five to 10 days (WHO 1994; Medical Letter 2004; WHO 2005; AAP 2006). Although there are those who believe that this dose may have sufficient activity against both trophozoites and cysts (Powell 1970; WHO 1994; Li 1996), others believe that metronidazole is not reliably effective in eliminating cysts in the colonic lumen (Powell 1966; Powell 1967a; Powell 1967b; Powell 1969a; Powell 1969). Thus, the general recommendation is that patients with invasive amoebiasis should receive a luminal amoebicide after treatment with a tissue amoebicide, in order to eliminate any surviving organisms in the colon (WHO 1995; WHO 1997; Medical Letter 2004; AAP 2006). This recommendation is based on the assumption that drugs acting on different protozoal processes may enhance each other's effect. However, the evidence to support combination therapy has not been reviewed, and it is not known whether drug combinations reduce clinical symptoms or eradicate parasites more effectively compared with giving a tissue amoebicide alone. Furthermore, the increased complexity of combination regimens, additional drug costs, and possible increased adverse events, coupled with the unavailability of luminal agents in the market, act as major deterrents to compliance with this recommendation.

Adverse effects may occur even with conventional doses of metronidazole and include headaches, loss of appetite, nausea, metallic taste, and vomiting (WHO 1995; Tracy 2001). Individuals should avoid alcoholic drinks during metronidazole therapy because of vomiting, headache, flushing, and abdominal pain that may occur. Dizziness, convulsions, poor co-ordination, and numbness of the extremities are less common but more serious adverse effects that warrant discontinuation of metronidazole (Tracy 2001). Other nitroimidazole drugs with longer half lives, such as tinidazole, ornidazole, and secnidazole, allow shorter periods of treatment and appear to be better tolerated compared with metronidazole. These drugs have been used successfully when administered in shorter courses and have been recommended as alternative antiamoebic drugs to metronidazole (Haque 2003; Stanley 2003; Medical Letter 2004; WHO 2005; AAP 2006). Treatment failures have been reported with metronidazole with most failures attributed to incorrect diagnosis, unsuitable choice of drug, or failure to observe certain principles of treatment rather than drug resistance (Knight 1980; Wassman 1999). However, the induction of metronidazole-resistant E. histolytica strains in the laboratory suggests that indiscriminate use of antiamoebic drugs can result in an increased minimum inhibitory concentration against E. histolytica (Samarawickrema 1997; Wassman 1999).

A systematic review summarized the effects of different drug treatments for amoebic dysentery in endemic areas (Dans 2006). The systematic review included 12 randomized controlled trials and found that while ornidazole, secnidazole, and tinidazole were likely to be beneficial for treating amoebic dysentery, metronidazole was unlikely to be beneficial. The results of the trials were not combined, and no formal statistical methods were performed to determine summary measures of the effectiveness of the drugs.

Adequate therapy for amoebic colitis is necessary to reduce severity of illness, prevent the development of complicated disease and extraintestinal spread, and decrease infectiousness and transmission to others. In developing countries, where amoebiasis is common and most of the patients are treated in private practice or as hospital outpatients, the aim of treatment should be towards an effective, safe, and simple regimen that can be given on an outpatient basis.

A reliable summary of the evidence is needed to determine the best treatment for amoebic colitis. The occurrence of treatment failures and unpleasant adverse effects associated with metronidazole in some patients and the possibility of overt clinical resistance of E. histolytica to metronidazole make it imperative to investigate alternative treatment. The benefits of using combination regimens over monotherapy and single-dose regimens over longer regimens have to be determined. Furthermore, the effectiveness of potential new antiamoebic drugs has to be ascertained.

Objectives

To evaluate antiamoebic drugs for treating amoebic colitis. The review particularly aims to compare:

  1. single agent alternatives with metronidazole;

  2. any antiamoebic drug with placebo;

  3. combination regimens with monotherapy; and

  4. single-dose regimens with longer regimens.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials. We excluded quasi-randomized trials.

Types of participants

Adults and children with clinical symptoms of amoebic colitis (as outlined in WHO 1997 and Haque 2003) and the demonstration of E. histolytica cysts or trophozoites in a stool sample, or E. histolytica trophozoites in a tissue biopsy or ulcer scraping by histopathology. We included individuals with positive E. histolytica/E.dispar on stool examination confirmed by E. histolytica antigen detection test or PCR.

We excluded trials that include only individuals with: asymptomatic infection and those requiring surgery or additional antibiotic therapy, such as fulminant or necrotizing colitis; peritonitis, intestinal perforation, or haemorrhage; or evidence of extraintestinal amoebiasis including hepatic amoebiasis.

Types of interventions

Intervention

Antiamoebic drugs, administered alone or in combination.

Control

Placebo or another antiamoebic drug.

Types of outcome measures

Primary
  • Clinical failures, defined as the absence of E. histolytica in stools or scrapings but little or no relief of signs or symptoms, or with persistent rectal ulcerations on sigmoidoscopy (WHO 1969).

  • Parasitological failures, defined as the persistence of E. histolytica cysts or trophozoites in stools or colonic ulcer scrapings, with or without the presence of symptoms or rectal ulcers (WHO 1969).

  • Relapse, defined as reappearance of cysts or trophozoites of E. histolytica after the initial disappearance, with or without recurrence of clinical signs or symptoms of amoebic colitis after completion of treatment (Woodruff 1967).

Adverse events
  • Serious adverse events (death, life-threatening event, hospitalization required or duration of hospitalization prolonged, development of a persistent or significant disability or incapacity, having offspring with a congenital anomaly or birth defect, or development of cancer (Hutchinson 1997)).

  • Adverse events resulting in discontinuation of the treatment.

  • Other adverse events, including gastrointestinal adverse events, systemic symptoms such as weakness or fatigue, central nervous system effects such as headache or dizziness, and dermatologic effects such as skin rashes.

Search methods for identification of studies

We searched for all publications that described randomized controlled trials on antiamoebic drugs for treating amoebic colitis, regardless of language or publication status.

Databases

We searched the following databases using the search terms and strategy described in Appendix 1: the Cochrane Infectious Diseases Group Specialized Register (September 2008); the Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library (2008, Issue 3); MEDLINE (1966 to September 2008); EMBASE (1974 to September 2008); and LILACS (1982 to September 2008). We also searched the metaRegister of Controlled Trials (mRCT) using 'amoebic' and 'amoeba' as search terms (September 2008). Additional electronic searches of PubMed were made using the format for highly sensitive search strategies for identifying reports of randomized controlled trials (Higgins 2005), on 10 September 2006 and on 11 February 2008.

Conference proceedings

We searched the electronic databases of the conference proceedings listed in Appendix 2 for relevant abstracts.

Organizations and pharmaceutical companies

To help identify unpublished and ongoing trials, we contacted researchers working in the organizations listed in Appendix 3, and the pharmaceutical companies and associated databases listed in Appendix 4.

Reference lists

We checked the reference lists and bibliographies of all studies identified by the above methods.

Data collection and analysis

Selection of studies

Two authors (MLM Gonzales and LF Dans) independently assessed the results of the literature search to determine whether the title or abstract of each trial described a randomized controlled trial. We retrieved full reports of all trials considered by one or both authors to be potentially relevant, as well as those that were unclear. We used a standard eligibility form based on the inclusion criteria to independently assess the trials. We resolved any disagreements through discussion, or where this failed, by consulting the third author (EG Martinez). If eligibility was unclear due to unclear or inadequate information, we attempted to contact the trial authors for clarification. We noted the reasons for excluding studies.

Data extraction and management

Two authors (MLM Gonzales and EG Martinez) independently extracted data from the trials using pre-tested data extraction forms. We collected details regarding the inclusion and exclusion criteria for the participants, treatment intervention given, total number randomized, number of participants in each group for all outcomes, drop outs and withdrawals, and numbers experiencing each outcome. For dichotomous data, we extracted the number of participants who experienced the event of interest and the number of participants randomized and analysed in each treatment group. We resolved any disagreements by referring to the trial report and through discussion. Where data were insufficient or missing, we made attempts to contact the trial authors. MLM Gonzales entered data for analysis using double data entry.

Assessment of risk of bias in included studies

Two authors (MLM Gonzales and LF Dans) independently assessed the risk of bias in each trial using a prepared form. We assessed the generation of allocation sequence and allocation concealment as adequate, inadequate, or unclear according to Jüni 2001. We noted who was blinded, such as the trial participants, care providers, or outcome assessors, and assessed the inclusion of randomized participants in the analysis as adequate if 90% or greater, and inadequate if not.

Assessment of reporting biases

We determined publication bias by looking for asymmetry in a funnel plot. The presence of asymmetry in the funnel plot suggests possible publication bias, although it may also indicate heterogeneity or poor methodological quality of the trials.

Data synthesis

We analysed data collected using Review Manager 5. For dichotomous outcomes, we calculated risk ratios (RR) with 95% confidence intervals (CI).

Stratification of results

The main comparisons were between any single antiamoebic drug and metronidazole (current standard therapy), any antiamoebic drug and placebo, combination regimens and monotherapy, and any single-dose regimen and longer regimens. We included but did not pool data from other trials that compared any antiamoebic drug with another antiamoebic drug and did not address any particular pharmacological or clinical question relevant to this review.

For trials reporting results at multiple or varying time points, we performed separate analyses for outcomes measured from the end of treatment to 14 days and from 15 to 60 days after the end of treatment. In trials comparing drugs with different treatment durations, we measured the time point in relation to the last day of the longest treatment period. We did not consider outcomes that were measured during treatment or before completion of treatment. Likewise, we did not include outcomes measured beyond two months because this could be a reinfection rather than true failure or relapse.

Heterogeneity

We calculated summary RR from meta-analysis using both a fixed-effect model (Mantel-Haenszel method), which assumes trial homogeneity, and a random-effects model (DerSimonian and Laird method), which accounts for trial heterogeneity.

We reported results using the random-effects model when there were differences between trials that may potentially influence the size of the treatment effect or when significant statistical heterogeneity was detected. We determined the presence of statistical heterogeneity among the same interventions by inspecting the forest plots for overlapping confidence intervals and by applying the Chi2 test for heterogeneity (P value < 0.10 considered statistically significant) and the I2 statistic to quantify inconsistency across trials (I2 value of greater than 50% used to denote substantial heterogeneity). If heterogeneity was detected, but it was still considered clinically meaningful to combine trial data, we explored potential sources of heterogeneity using subgroup analysis. Only subtotals for each subgroup were presented if the pooled results showed significant heterogeneity. We determined clinical categories (amoebic dysentery, nondysenteric amoebic colitis, or unspecified amoebic colitis) and participant age (adults were those aged 15 years or more, and children were those aged less than 15 years) to be important subgroups even before data collection although we failed to specify this in the protocol. Subgroup analysis could not be undertaken as planned based on diagnostic tests because only one trial used a stool E. histolytica ELISA test. The post hoc sources of heterogeneity considered were types of intestinal infection (E. histolytica infection alone or mixed intestinal infection), criteria for determining outcome (based on WHO 1969 criteria or another criteria), and regimens used.

Sensitivity analysis

We performed sensitivity analyses to assess the robustness of the overall estimates by calculating the results using all trials and then excluding trials of a lower methodological quality (ie trials with inadequate generation of allocation sequence, allocation concealment, or blinding, or trials where less than 90% of randomized participants were analysed), and excluding trials that were sponsored by pharmaceutical companies. Although pharmaceutical-sponsored trials may publish only where demonstrating positive treatment effects, it may also be possible that pharmaceutical-sponsored trials were conducted with better methodological quality because of adequate funds. We determined the effect of date of publication on the overall pooled effect in a sensitivity analysis when there were large differences in the publication dates. It was unclear if two trials (Misra 1977; Misra 1978) reported the same results and attempts to contact the authors for clarification were not successful. We entered these two trials as separate trials and carried out sensitivity analysis to determine if exclusion of the later trial would have an effect on the overall estimate.

Results

Description of studies

Search results

We assessed 143 references included in the primary search until 23 September 2008 and excluded 112 trials (see 'Characteristics of excluded studies'). From additional searches of PubMed (September 2006 and February 2008), websites of relevant organizations and journals, reference lists and bibliographies of the retrieved trials, and contact with pharmaceutical companies, we considered 65 additional trials to be potentially relevant and retrieved the full reports; six trials were included. Of the 171 excluded trials, there were four trials that were duplicate publications of four other excluded trials (see 'Characteristics of excluded studies'). A total of 37 trials were included in the review (see 'Characteristics of included studies').

The 37 included trials enrolled a total of 4487 participants of which 1837 were adults, 1038 were children, and the rest were not identified separately as adults or children. All trial reports were in English, except for Huggins 1982 (Portuguese), Karabay 1999 (Turkish), and Donckaster 1964 (Spanish). The trials included in the review were published between 1967 and 2007.

Location

The trials were conducted in 15 different countries (see details in Appendix 5), 14 of which are considered to be highly endemic for amoebiasis. Eighteen trials were conducted in Asia: India (12), Indonesia (five), and Bangladesh (one). Six trials were conducted in Africa: Kenya (two), Egypt (two), Nigeria (one), and South Africa (one). Five trials were conducted in South America: Colombia (two), Brazil (two), and one trial in Chile (one). The other trials were conducted in the following countries: Mexico (two), Turkey (two), Iran (one), and Iraq (one). The remaining two trials were conducted in one industrialized country, Sweden.

The trials were conducted in a variety of settings (see details in Appendix 6): hospital setting (13), outpatient clinic (13), community (one), school (one). The study setting was not stated in eight trials. In one trial, most participants were treated as outpatients, but a few with severe symptoms were treated in the hospital (Toppare 1994).

Source of funding

Eighteen trials did not state the source of funding. Sixteen trials reported that a pharmaceutical company provided funding (Nnochiri 1967; Batra 1972; Naoemar 1973; Pudjiadi 1973; Panggabean 1980; Sitepu 1982; Tripathi 1986; Chunge 1989; Pamba 1990; Rossignol 2007) or supplied the study drugs (Kapadia 1968; Rubidge 1970; Misra 1974; Joshi 1975; Singh 1977; Davila 2002). At least one trial author was reported to be connected with the pharmaceutical company manufacturing the study drug in three trials (Asrani 1995; Salles 1999; Rossignol 2001), although the involvement of the company was not stated.

Participants' amoebic colitis

The trials used different inclusion criteria for the participants:

  • Clinical symptoms of intestinal amoebiasis, without distinguishing between amoebic dysentery and nondysenteric amoebic colitis (22 trials).

    • Three trials stratified the participants during the analysis of outcomes into those with acute amoebic dysentery and those with nondysenteric amoebic colitis (Botero 1974; Botero 1977; Swami 1977).

    • Two trials classified the participants as having invasive trophozoite forms and noninvasive cyst forms based on stool microscopy findings and analysed the two groups separately (Kapadia 1968; Pamba 1990).

    • Two trials categorized the participants as having acute amoebic dysentery, subacute amoebiasis, or chronic amoebiasis based on the severity of symptoms and whether trophozoites or cysts of E. histolytica were present but analysed the participants as one group (Joshi 1975; Mathur 1976).

    • Two trials classified the participants as having acute or chronic amoebiasis based on the duration of symptoms but analysed the participants as one group (Misra 1974; Tripathi 1986).

    • Thirteen trials recruited and analysed participants with symptoms of intestinal amoebiasis or amoebic colitis together, regardless of whether they presented with dysentery or not.

Participant age

Participant age ranged from seven months to 80 years; see Appendix 7 for details. Adults only (ie those aged more than 15 years) were recruited in 15 trials, while 10 trials recruited only children. Both adults and children were recruited in the remaining 10 trials. Participant age was not stated in two trials (Kapadia 1968; Batra 1972).

Methods used to diagnose amoebic colitis

Stool microscopy with direct smear was used as the predominant method for determining the presence of E. histolytica cysts or trophozoites in stools (details in Appendix 8): concentration methods for better detection of cysts (16 trials); flotation technique (two trials); and polyvinyl alcohol fixative for the detection of trophozoites (one trial). One trial used stool culture for E. histolytica in addition to stool microscopy to evaluate parasitological response, but it was not used as an inclusion criterion in the trial (Batra 1972). Only one trial used stool antigen-based ELISA test (Rossignol 2007).

Concomitant infection with other intestinal parasites

Aside from E. histolytica, concomitant infection with other intestinal parasites was identified in 10 trials: giardiasis (Singh 1977; Prasad 1985; Tripathi 1986; Rossignol 2001); intestinal helminth infection (Pudjiadi 1973; Panggabean 1980; Sitepu 1982); and other intestinal protozoa and helminth infection (Pehrson 1983; Salles 1999; Davila 2002). Three trials explicitly stated that stool bacterial culture was done before enrolment and excluded those found to be positive for pathogenic bacteria (Toppare 1994; Karabay 1999; Rossignol 2007). Concomitant infection with other intestinal pathogens or bacteria was not examined or not mentioned in the remaining trials. Since clinical symptoms may not have been exclusively caused by amoebiasis in those with concomitant intestinal parasites and the effect of concomitant infection on eradication of E. histolytica by antiamoebic drugs is not known, data for E. histolytica infection alone were used in assessment of outcomes except in those trials that did not separate the data for those with single and mixed infections. Separate analysis for clinical outcomes for those with E. histolytica alone and those with concomitant infection with Giardia and E. histolytica was carried out in three trials (Prasad 1985; Rossignol 2001; Davila 2002).

Drug comparisons

The included trials contained a variety of comparisons and involved over 30 individual drugs and combinations. As shown in Appendix 9, we grouped the trials into the following categories (some trials are included in more than one category):

  • single agent alternative versus metronidazole (17 trials);

  • any antiamoebic drug versus placebo (four trials);

  • combination regimen versus monotherapy (seven trials);

  • single-dose regimens versus longer regimens (five trials); and

  • other amoebic drug comparisons (nine trials).

More than two interventions were compared in six trials. Three trials compared different doses of the same drugs with standard or control groups: three dosages of quinfamide with placebo in Huggins 1982; two treatment durations of tinidazole with metronidazole in Awal 1979; and four dosages of MK-910 in Batra 1972. Ten different treatment groups were compared with placebo in Donckaster 1964, and three drugs used alone or in three different combinations were compared in Pamba 1990. Two brands of tinidazole and two brands of metronidazole were compared in one trial (Chunge 1989). For trials with more than two intervention groups, we combined multiple treatment arms as appropriate in one group and compared them collectively with the standard or control group. This is the recommended approach to avoid a unit of analysis error by not counting the placebo or control participants more than once in the same meta-analysis (Higgins 2008). For the trial comparing two brands of tinidazole and two brands of metronidazole, the two brands of tinidazole were combined as one group and compared with the two brands of metronidazole in the other group.

Duration of follow up

The follow-up period varied considerably between trials. Seventeen trials were followed up for about one month. Four trials were followed up only until the end of the treatment period (Kapadia 1968; Batra 1972; Pudjiadi 1973; Asrani 1995). Duration of follow up was less than 15 days in 10 trials (Huggins 1982; Sitepu 1982; Prasad 1985; Chunge 1989; Toppare 1994; Mohammed 1998; Padilla 2000; Rossignol 2001; Davila 2002; Rossignol 2007), while the longest period was 12 months (Nnochiri 1967).

Outcome measures

The primary outcomes in this review were clinical failure, parasitological failure, and relapse. Thirty-one trials evaluated both clinical and parasitological outcomes, and six trials evaluated parasitological outcomes only (Donckaster 1964; Nnochiri 1967; Pehrson 1983; Pehrson 1984; Padilla 2000; Davila 2002). The definition of clinical and parasitological cure or failure in the trials varied. Nine trials (Misra 1974; Joshi 1975; Mathur 1976; Misra 1977; Singh 1977; Swami 1977; Misra 1978; Awal 1979; Tripathi 1986) used the definitions set by the WHO Expert Committee on Amoebiasis (WHO 1969) where 'cure' was defined as symptom-free, ulcers healed, stools negative for E. histolytica, 'probable failure' was defined as persistent symptoms and rectal ulcerations despite disappearance of E. histolytica in stools or ulcer scrapings, and 'failure' was defined as positive E. histolytica with or without symptoms and rectal ulcers. For this review, 'probable failure' was interpreted as clinical failure and 'failure' was interpreted as parasitological failure based on the definitions given. Data for clinical and parasitological outcomes were presented as dichotomous data in most trials.

The duration of time from the start of treatment to resolution of diarrhoea and other clinical symptoms was also presented in seven trials (Batra 1972; Naoemar 1973; Pudjiadi 1973; Toppare 1994; Rossignol 2001; Mansour-Ghanaei 2003; Rossignol 2007), and the duration of time from start of treatment to disappearance of E. histolytica in stools in three trials (Naoemar 1973; Pudjiadi 1973; Karabay 1999). Two trials reported on the number of stools passed during treatment (Botero 1977; Tripathi 1986), and also on days seven and 21 after treatment (Botero 1977), while another reported average daily frequency of stools on admission and at the end of days five and 10 of treatment (Asrani 1995). One trial reported on cumulative daily clearance of E. histolytica from stools during treatment and on days 15, 30, and 60 after the start of treatment (Pamba 1990). One trial assessed clinical and parasitological outcomes jointly as 'cure' (Prasad 1985). Only dichotomous outcomes were included in the analysis because of inconsistent data in trials also reporting continuous data. Relapse or recurrence was reported in two trials (Naoemar 1973; Botero 1974) and described but not reported in another trial (Pamba 1990).

Measurements of clinical and parasitological outcomes were made at different time points. Thirteen trials reported outcomes between the end of treatment to 14 days, and 15 trials reported outcomes from 18 to 30 days after the end of treatment. Outcomes were measured repeatedly in nine trials and reported for two time points in six trials (Donckaster 1964; Nnochiri 1967; Naoemar 1973; Joshi 1975; Soedin 1985; Karabay 1999). Three trials reported results at one time point only because of high drop-out rates during the other follow-up periods (Panggabean 1980; Sitepu 1982; Pamba 1990).

Adverse events were reported in 33 trials and were not ascertained in the remaining four trials (Sitepu 1982; Chunge 1989; Karabay 1999; Mansour-Ghanaei 2003). Sixteen trials had incomplete data: 10 reported specific adverse events but not the number of participants who developed any adverse event (Nnochiri 1967; Kapadia 1968; Batra 1972; Botero 1974; Prasad 1985; Pamba 1990; Asrani 1995; Davila 2002; Padilla 2000; Rossignol 2007); two reported only the number of participants with adverse events severe enough to cause discontinuation of drug treatment (Pehrson 1983; Pehrson 1984); four did not report the actual number of participants who developed any adverse event (Rubidge 1970; Pudjiadi 1973; Soedin 1985; Toppare 1994); and one reported of adverse events only for the experimental group (Mohammed 1998).

Risk of bias in included studies

See Appendix 10 for an overview of the methodological quality assessment.

Only one trial reported using appropriate procedures to minimize or eliminate bias in allocation concealment, generation of the allocation sequence, blinding (of the care providers, participants, and outcome assessors), and inclusion of all randomized participants (Rossignol 2007).

Generation of allocation sequence

Only six trials reported adequate generation of the allocation sequence: four trials used a random-numbers table (Donckaster 1964; Awal 1979; Sitepu 1982; Mohammed 1998); one trial used computer-generated randomization (Rossignol 2007); and one trial used coin toss (Padilla 2000). The other trials did not describe the method used.

Allocation concealment

Two trials used identical coded drugs prepared independently at a site remote from the study site and had adequate allocation concealment (Pudjiadi 1973; Rossignol 2007). Two trials had inadequate allocation concealment as communicated by the primary author (Pehrson 1983; Pehrson 1984). The remaining 33 trials did not report on this.

Blinding

Only seven trials reported blinding of the participants, care providers, and outcome assessors (Nnochiri 1967; Naoemar 1973; Pudjiadi 1973; Prasad 1985; Rossignol 2001; Mansour-Ghanaei 2003; Rossignol 2007). One trial reported blinding of the participants and outcome assessors but not the care providers (Padilla 2000), one trial reported blinding only of the participants and microscopists assessing stool specimens (Chunge 1989), one trial reported blinding only of the care providers (Panggabean 1980), and another reported blinding only of the microscopists assessing stool specimens (Pamba 1990). Seven trials were reported to be 'double-blind' (Donckaster 1964; Botero 1974; Botero 1977; Huggins 1982; Sitepu 1982; Tripathi 1986; Davila 2002), but they did not describe the procedure for blinding, similarity of the appearance of drugs, or use of placebo. Five trials were also unclear regarding blinding (Kapadia 1968; Misra 1974; Misra 1977; Swami 1977; Misra 1978), and the other 14 were open label.

Inclusion of all randomized participants in the analysis

The number of participants followed up was adequate (greater or equal to 90%) in 32 trials for at least one outcome. Four trials reported losses of participants greater than 10% (Panggabean 1980; Sitepu 1982; Pamba 1990; Mohammed 1998), while in one trial, only the number analysed was reported but the actual number initially randomized, those lost to follow up, and those who were not compliant with the treatment protocol were not reported (Chunge 1989).

Effects of interventions

Details of the comparisons and interventions included in the review are shown in Appendix 9.

1. Single alternative drugs versus metronidazole

Sixteen trials compared alternative nitroimidazoles with metronidazole, and one trial compared praziquantel with metronidazole.

1.1.  Tinidazole versus metronidazole

For clinical failure 15 to 60 days after the end of treatment, tinidazole reduced clinical failure by 72% compared with metronidazole (RR 0.28, 95% CI 0.15 to 0.51; 477 participants, 8 trials, Analysis 1.2 and Figure 1). A sensitivity analysis evaluating quality in relation to allocation concealment and blinding was not possible. There was no significant change in the overall result when we excluded Misra 1978, which may be a duplicate publication of an earlier trial (Misra 1977) (RR 0.31, 95% CI 0.16 to 0.61, analysis not shown). Excluding four trials funded by pharmaceutical companies (Misra 1974; Joshi 1975; Mathur 1976; Singh 1977) also did not affect the overall result (RR 0.24, 95% CI 0.11 to 0.50, analysis not shown).

Figure 1.

Alternative drug vs metronidazole: clinical failure 15 to 60 days after end of treatment.

Results for parasitological failure did not show that tinidazole was more effective in eradicating E. histolytica compared to metronidazole (507 participants, 9 trials, Analysis 1.4 and Figure 2), although there was significant heterogeneity in the trials. A subgroup analysis to investigate possible sources of heterogeneity showed reduced heterogeneity in those with nondysenteric amoebic colitis and unspecified amoebic colitis (Analysis 6.1) and in those trials that used the WHO criteria (Analysis 6.4). Age and the presence or absence of other concomitant intestinal infection did not explain heterogeneity (Analysis 6.2 and Analysis 6.3).

Figure 2.

Alternative drug vs metronidazole: parasitological failure 15 to 60 days after end of treatment.

No data on relapse were reported.

Adverse events were incompletely reported. There were no serious adverse events or adverse events that necessitated drug withdrawal in the three trials that reported on this (Joshi 1975; Mathur 1976; Awal 1979). For the other adverse events, they were more common in those given metronidazole compared to those given tinidazole (RR 0.65, 95% CI 0.46 to 0.92; 477 participants, 8 trials, Analysis 1.6). The most common adverse events reported were nausea, vomiting, decreased appetite, altered taste or metallic taste, and abdominal discomfort (see Appendix 11 for other details).

1.2. Other drugs versus metronidazole

Other alternative drugs tested were ornidazole (128 participants, 3 trials), panidazole (44 participants, 1 trial), and satranidazole (40 participants, 1 trial). The number of trials was too small to detect any difference in clinical failure or parasitological failure compared with metronidazole (Analysis 1.1, Analysis 1.2, Analysis 1.3, and Analysis 1.4).

For relapse, data were reported for two trials, and both compared ornidazole with metronidazole. There were more relapses in those given ornidazole compared with metronidazole (RR 4.74, 95% CI 1.07 to 20.99; 135 participants, 2 trials, Analysis 1.5), but there were insufficient data to draw definite conclusions.

There were no serious adverse events or withdrawals resulting from adverse events in two trials that reported on this (Pehrson 1984; Tripathi 1986). One participant given ornidazole developed a temporary numbness of the hands and tongue with difficulty of speaking that disappeared after stopping treatment (Botero 1974). In another trial (Naoemar 1973), the daily dosage of ornidazole had to be reduced from 1500 mg to 1000 mg in two participants each in the ornidazole group and metronidazole group because of dizziness or nausea. No abnormalities in laboratory tests were seen in trials in which these tests were done (see Appendix 11 for other details).

2. Any antiamoebic drug versus placebo

Any antiamoebic drug was compared with placebo in four trials: versus two different luminal agents, nitazoxanide (167 participants, 2 trials) and quinfamide (96 participants, 1 trial); and versus 10 different drugs belonging to six drug classes (367 participants, 1 trial – Donckaster 1964).

Compared with placebo, the other antiamoebic drugs reduced clinical failure one to 14 days after the end of treatment by 73% (RR 0.27, 95% CI 0.13 to 0.57; 193 participants, 3 trials, Analysis 2.1) and reduced parasitological failure by 67% (RR 0.33, 95% CI 0.23 to 0.50; 630 participants, 4 trials, Analysis 2.2). There was significant heterogeneity among the trials so only subtotals are presented. Subgroup analysis using clinical categories did not explain heterogeneity (Analysis 7.1), but heterogeneity was reduced in trials that included adults only (Analysis 7.2 and Analysis 7.3). Excluding the single trial that used stool antigen-based ELISA test for confirming E. histolytica (Rossignol 2007) also reduced heterogeneity in the remaining trials (RR 0.36, 95% CI 0.23 to 0.56; 93 participants, 3 trials, analysis not shown). Sensitivity analysis was not possible using concealment and blinding because only one trial was concealed (Rossignol 2007) and only two trials were blinded (Donckaster 1964; Rossignol 2007).

No data on relapse were reported.

There were no serious adverse events or withdrawals due to adverse events in the two trials that reported on this (Rossignol 2001; Rossignol 2007).  For the other adverse events, there was no evidence of a difference in adverse events in those given antiamoebic drugs compared with placebo (530 participants, 3 trials, Analysis 2.3), although the results could be biased because of a great imbalance in the number of those given placebo compared to the active drugs. The most common adverse events were mild gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and headache. One individual given diiodohydroxyquinoline presented with severe intestinal colic (see Appendix 12 for details).

3. Combination regimen versus monotherapy

Three trials compared various combination regimens with metronidazole alone while four trials compared other combination regimens with alternative single drugs. 

3.1. Combination regimen versus metronidazole alone

Three trials that compared combination therapy with metronidazole alone showed that combination therapy reduced clinical failure one to 14 days after the end of treatment by 67% (RR 0.33, 95% CI 0.11 to 0.98; 1025 participants, 3 trials, Analysis 8.1). The heterogeneity seen in the trials could be due to the various combination regimens used: a combination of dehydroemetine, tetracycline, and diloxanide furoate (Rubidge 1970); a fixed-drug combination suspension of metronidazole and furazolidone (Prasad 1985); and a fixed-drug combination tablet of metronidazole and diiodohydroxyquinoline (Asrani 1995). Excluding one trial that was funded by a pharmaceutical company (Rubidge 1970) reduced heterogeneity, and the analysis showed that combination therapy significantly reduced clinical failure compared with metronidazole alone (RR 0.17, 95% CI 0.12 to 0.25; 986 participants, 2 trials, analysis not shown).

For parasitological failure, results showed a 64% reduction in parasitological failures one to 14 days after the end of treatment in those given the combination compared to metronidazole alone (RR 0.36, 95% CI 0.15 to 0.86; 720 participants, 3 trials, Analysis 8.2). There was no significant heterogeneity among the trials (see Figure 3). Excluding the trial funded by a pharmaceutical company (Rubidge 1970) did not significantly change the results (RR 0.25, 95% CI 0.13 to 0.46; 681 participants, 2 trials, analysis not shown).

Figure 3.

Combination regimen vs monotherapy: parasitological failure 1 to 14 days after end of treatment, subgrouped by intervention.

For both clinical and parasitological failure, sensitivity analysis was not possible because none of the trials were adequately concealed and only Prasad 1985 was double-blind. The overall results for both outcomes were driven by one trial (Asrani 1995) that analysed a large number of participants (896 participants analysed for clinical failure; 591 participants analysed for parasitological failure) compared to the other two trials. This trial was an open label trial with unclear allocation concealment and method of randomization, hence the high possibility of bias. A sensitivity analysis performed by excluding this trial significantly changed the overall results for both outcomes such that no difference between combination therapy and metronidazole alone was seen (RR 0.58, 95% CI 0.20 to 1.73; 129 participants, 2 trials, analysis not shown). The change in the overall result weakens the strength of the evidence for the advantage of combination therapy over metronidazole alone.

No data on relapse were reported.

Only one trial reported details for adverse events (Asrani 1995). One participant given a fixed-drug combination tablet of metronidazole and diiodohydroxyquinoline developed an unspecified allergic reaction on the first day necessitating withdrawal from the trial (see Appendix 13 for details).

3.2. Combination regimen versus other single drug regimens 

Four trials made this comparison. Two trials compared combination regimen with other nitroimidazoles: a combination of tetracycline and clioquinol with secnidazole alone (80 participants, 1 trial); and a combination of tinidazole and diloxanide furoate with tinidazole alone (41 participants, 1 trial). The third trial compared three different combinations (nimorazole and aminosidine, nimorazole and etophamide, and etophamide and aminosidine) with the same drugs given as monotherapy (400 participants, 1 trial). The fourth trial compared quinfamide and mebendazole with nitazoxanide (80 participants, 1 trial).

The trials could not be pooled because of different drug comparisons, but the data for clinical failure (Analysis 3.1) and parasitological failure (Analysis 3.2) are presented. The trials did not show any difference in clinical or parasitological failure rates between combination regimens and single drug regimens, except for two comparisons. One trial showed that secnidazole alone resulted in greater resolution of clinical symptoms and greater eradication of E. histolytica compared to the combination of tetracycline and clioquinol (80 participants, Soedin 1985, Analysis 3.1. and Analysis 3.2). Another trial showed that the combination of tinidazole and diloxanide furoate resulted in greater eradication of E. histolytica compared with tinidazole alone (41 participants, Pehrson 1984).

No data on relapse were reported.

None of the trials reported on serious adverse events. Recruitment of participants in the combination etophamide-aminosidine group was discontinued because of the high incidence of severe diarrhoea. No further details for adverse events were reported in the other trials.

4. Single-dose regimen versus longer regimen

Five trials compared a single-dose regimen with a multiple-dose regimen or longer durations of therapy.

4.1. Single-dose secnidazole versus longer duration of other drugs

Single-dose secnidazole was compared with tinidazole for two days (303 participants, Salles 1999), metronidazole for 10 days (44 participants, Karabay 1999), and a combination of tetracycline and clioquinol given for five days (80 participants, Soedin 1985).

Soedin 1985 showed that single-dose secnidazole resulted in greater resolution of clinical symptoms compared with five days of tetracycline and clioquinol (80 participants, 1 trial, Analysis 4.1). Salles 1999 did not show any difference between single-dose secnidazole and tinidazole given for two days (275 participants, 1 trial). Results for clinical failure could not be pooled because of difference in time of evaluation of clinical outcomes in the two trials (see Analysis 4.1).  

For parasitological failure, single-dose secnidazole resulted in lower parasitological failure compared with longer durations of therapy when the results from Soedin 1985 and Karabay 1999 were combined (RR 0.14, 95% CI 0.06 to 0.35; 124 participants, 2 trials, Analysis 4.2 and Analysis 9.1). Although there was no heterogeneity no conclusions can be made because both trials were small and did not use blinding. 

No data on relapse were reported.

Only Salles 1999 reported on adverse events. There were no serious adverse events or withdrawals from adverse events. The most common adverse events in those given single-dose secnidazole and longer durations of tinidazole for two days were bitter taste, nausea, vomiting, and abdominal pain, with no difference in frequency in the two groups (see Appendix 13 for details).

4.2. Single-dose quinfamide versus multiple doses of quinfamide or longer duration of another drug

Single-dose quinfamide was compared with two or three doses of quinfamide (96 participants, Huggins 1982) and with nitazoxanide for three days (105 participants, Davila 2002) (see Analysis 4.1 and Analysis 4.2). 

Huggins 1982 showed no difference in clinical failure in those given one dose compared to two or three doses of quinfamide (27 participants, Analysis 4.1).

For parasitological failure, there was a trend favouring longer duration compared to single-dose quinfamide in eradicating E. histolytica (RR 2.13, 95% CI 1.02 to 4.46; 97 participants, 2 trials, Analysis 9.1). Both trials were unclear regarding generation of the allocation sequence, concealment, and blinding. Results were not heterogenous, but the number of trials and participants were also too small to draw any definite conclusions. 

No data on relapse were reported.

Only Huggins 1982 reported on adverse events, which were based on only two symptoms, nausea and headache. There was no evidence of a difference in adverse events in those given single-dose quinfamide compared with two or three doses of quinfamide (see Appendix 13 for details).

5. Other antiamoebic drug comparisons

Nine trials studied different drug comparisons (see Appendix 9 for details) and data were not pooled. None of the trials were blinded or adequately concealed, and drop-out rates were high in two trials, with only 62.5% of those initially randomized analysed in one trial (Panggabean 1980) and 82% analysed in the other trial (Sitepu 1982).

Five trials assessed clinical failure one to 14 days after the end of treatment (Kapadia 1968; Batra 1972; Panggabean 1980; Sitepu 1982; Toppare 1994). Only chlorhydroxyquinoline was shown to be more effective than diiodohydroxyquinoline in reducing clinical failure (RR 0.24, 95% 0.11 to 0.53; 100 participants, 1 trial, Analysis 5.1). There was no evidence of a difference in the other antiamoebic drugs compared: ornidazole versus tinidazole (66 participants, 2 trials); and ornidazole versus secnidazole (102 participants, 1 trial). There were no clinical failures in any of the four dosage regimens of MK-910 studied (40 participants, 1 trial). 

Parasitological failure was assessed one to 14 days after the end of treatment in all nine trials. One trial also assessed parasitological failure 15 to 60 days after treatment (Nnochiri 1967). Only chlorhydroxyquinoline was more effective than diiodohydroxyquinoline in reducing parasitological failure (100 participants, 1 trial, Analysis 5.2). There was no evidence of any difference between groups in the other trials: quinfamide versus secnidazole (239 participants, 1 trial); ornidazole versus secnidazole (102 participants, 1 trial); and quinfamide versus nitazoxanide (24 participants, 1 trial). There were no parasitological failures in any of the four dosage regimens of MK- 910 studied (40 participants, 1 trial). One trial compared metronidazole and iodoquinol with the same combination plus Saccharomyces boulardii, and no difference was seen (54 participants, 1 trial). Another small trial that compared a fixed-drug combination of diloxanide furoate, tetracycline, and chloroquine with the fixed-drug combination without chloroquine showed no evidence of a difference between groups at the end of treatment (59 participants, Nnochiri 1967, Analysis 5.2), but there was a significant advantage for the combination containing chloroquine on follow up seven weeks after the end of treatment (RR 0.43, 95% CI 0.20 to 0.93; 59 participants, analysis not shown).

No data on relapse were reported.

None of the trials reported on serious adverse events. One trial reported that in two participants the higher dosage regimen of MK- 910 resulted in nausea, vomiting, and abdominal pain severe enough to require withdrawal from treatment (Batra 1972). One participant given ornidazole developed vomiting (Panggabean 1980). Three trials reported only on the specific adverse events but not the number of participants with adverse events (Nnochiri 1967; Kapadia 1968; Batra 1972; see Appendix 13 for details).

Funnel plot

We constructed a funnel plot for the one outcome measure with a sufficient number of trials and examined it visually for possible bias or heterogeneity: any antiamoebic drug versus metronidazole and measuring parasitological failure 15 to 60 days after the end of treatment (13 trials, Figure 4). This included nine trials that compared tinidazole with metronidazole. The funnel plot is asymmetrical due to the absence of smaller trials at the base and fewer trials to the right of the overall estimate. Although this may indicate the presence of publication bias, asymmetry in the funnel plot may also indicate inadequate methodological quality of the trials. Heterogeneity in the trials as a result of differences in study population, interventions, outcome measurements, trial design, and quality also have to be considered.

Figure 4.

Funnel plot. Alternative drug vs metronidazole: parasitological failure 15 to 60 days after end of treatment.

Discussion

Effectiveness of antiamoebic drugs

This systematic review examined the effectiveness of various antiamoebic drugs for treating amebic colitis by measuring improvements in both clinical and parasitological outcomes. The rapid relief of diarrhoea and other gastrointestinal symptoms associated with intestinal amoebiasis is an important concern of the individual with disease, while eradication of the parasite is important to prevent further invasion with damage to the intestinal mucosa and possible extraintestinal spread. The purpose of the review was to determine the best drug and treatment regimen required for effective treatment of amoebic colitis.

Tinidazole versus metronidazole

Metronidazole, the current recommended first-line drug for treating amoebic colitis, is a tissue amoebicide predominantly but with some activity against cysts in the bowel lumen. Among the other nitroimidazole drugs, only tinidazole had a sufficient number of trials to be able to draw any meaningful conclusions in the pooled results. The pooled results show that tinidazole demonstrated greater resolution of clinical symptoms, but there was inconclusive evidence of its advantage over metronidazole in eradication of E. histolytica in the stools. The comparable parasitological response could be attributed to similar activities of drugs belonging to the nitroimidazole drug class. In one trial, the poor eradication of parasites with tinidazole was attributed to its greater absorption and higher blood and tissue concentrations, possibly resulting in inadequate levels in the bowel lumen (Pehrson 1984). Lower concentrations of tinidazole could also be explained by the suboptimal dosing interval used in some trials (Misra 1974; Joshi 1975; Mathur 1976; Pehrson 1984). Tinidazole is better given as a single dose than divided doses because of its longer half life of approximately 12 to 14 hours resulting in longer concentrations in the body (Monro 1974; Looke 1987). In contrast, metronidazole has a shorter half life of about six to eight hours and is better if given in divided doses. Also, longer courses may lead to its re-excretion through the bile resulting in higher concentrations within the bowel lumen (Knight 1980; Tracy 2001). This is supported by the summary report of nine trials conducted in India where tinidazole given once daily was more effective compared with divided doses, and was also more effective than metronidazole given once daily (Bakshi 1978).

The incidence of mild to moderate gastrointestinal complaints was noted to be greater in those given metronidazole compared with tinidazole, particularly when it was given as a single dose. Again, this is similar to the summary report of Bakshi 1978, where the number of gastrointestinal adverse effects were greater in those given single-dose metronidazole compared with divided doses and compared with single daily administration of tinidazole. In both groups, the most frequently reported adverse effects were mild gastrointestinal side effects such as nausea, decreased appetite, vomiting, and metallic or bitter taste.

The calculation of the risk difference for clinical failure in those given tinidazole and those given metronidazole would give an absolute change in risk of 0.16 that is attributable to tinidazole. The inverse of the risk difference for clinical failure gave a number needed to treat to benefit (NNTB) of 6.25. Thus, we will need to treat seven people with tinidazole to reduce clinical failure in one more individual. However, this could not be applied to the parasitological failure because there appears to be no significant difference in eradication of E. histolytica in those given tinidazole compared with metronidazole.

Relapse can only be evaluated if stools are examined several times after the end of treatment. Data for relapse were only reported in two trials comparing ornidazole with metronidazole, with an increased risk in the ornidazole group compared with metronidazole; however, the available data were too few to draw any conclusions regarding the result.  

The funnel plot constructed from the trials comparing any antiamoebic drug versus metronidazole and measuring parasitological failure demonstrated asymmetry. Selection bias may arise when small studies reporting greater treatment benefit for the experimental drugs are more likely to be published (publication bias) and found (language and citation). Asymmetry could also result from poor methodological quality of the trials since greater treatment effect of the experimental drugs was seen in the smaller studies. Heterogeneity in treatment regimens used could also explain the asymmetry in the funnel plot. There was a trend favouring the experimental drugs in three trials (Singh 1977; Swami 1977; Awal 1979) where metronidazole was given at a dose of 2 g once daily for two or three days; a much lower dose compared to the recommended dose of 500 to 750 mg thrice daily in adults or 30 to 50 mg/kg/day in children for at least five days. This could account for the higher parasitological failure in those on metronidazole. When metronidazole was given at a dose of 2.4 g for five days, it was significantly more effective compared to tinidazole (Pehrson 1984). The presence of asymmetry in the funnel plot could lessen confidence in the results.

Antiamoebic drugs versus placebo

Antiamoebic drugs were shown to be more effective in reducing clinical symptoms of amoebic colitis and in eradicating E. histolytica in the stools compared with placebo. The significant heterogeneity in the pooled results could be attributed to factors such as differences in participant characteristics or the varied antiamoebic drugs used. Twelve different antiamoebic drugs were used and all, except for dehydroemetine, are more active for parasites found in the bowel lumen with no activity against invasive tissue forms. Since none of the participants were diagnosed as having amoebic dysentery, the significant response in those given these luminal drugs may result from the activity of these drugs against cysts in those with nondysenteric amoebic colitis or unspecified intestinal amoebiasis.

The disappearance of parasites in 50 out of 133 (38%) individuals while on placebo may result from spontaneous eradication of E. histolytica or infection with nonpathogenic amoeba. Several studies have shown that up to 90% of individuals with untreated E. histolytica infection spontaneously clear their infection within one year (Gathiram 1985; Haque 2001; Blessman 2003b; Haque 2002). It may have been possible that E. histolytica was misidentified in the trials utilizing stool microscopy as the only means for diagnosis.

Use of placebo as a comparison drug for individuals with symptomatic amoebic colitis may draw objections. Even in those with asymptomatic infection, approximately 3% to 10% of untreated individuals may still develop symptoms of invasive amoebiasis (Gathiram 1985; Haque 2001; Blessman 2003b; Haque 2002). For this reason, it is generally recommended that antiamoebic treatment be given to all individuals with definite E. histolytica, even those who are asymptomatic (WHO 1997; Medical Letter 2004; AAP 2006). Therefore, unless the diagnosis of E. histolytica infection is uncertain in an asymptomatic individual, the use of placebo as a comparison drug, particularly in cases with symptoms of invasive disease, may not be justifiable nor ethical.

Combination regimen versus metronidazole alone

For all forms of invasive disease, including amoebic colitis, the standard recommendation is to give a tissue amoebicide followed by a luminal amoebicide to eliminate surviving cysts in the bowel lumen (WHO 1995; WHO 1997; Medical Letter 2004; AAP 2006). The risk for parasitological failure was reduced by about one-third in those given combination therapy compared with metronidazole alone. The greater risk for failure with metronidazole when administered alone may result from its inconsistent effect in eliminating cysts in the bowel lumen and its failure to reach adequate therapeutic concentrations in the large intestines (Reed 1992; Petri 1999; Haque 2003; Stanley 2003). The advantage of combination therapy is attributed to the distinct activities of the different drugs against the cysts and trophozoites found at the different sites (WHO 1995; Tracy 2001; Medical Letter 2004).

Adverse events were incompletely reported, and it is not known whether combination therapy would lead to increased adverse events. Uncertainty also remains over which luminal agent is preferred in combination with metronidazole or another nitroimidazole to achieve eradication of cysts in the stools and to prevent relapse, since none of the trials were of sufficient size to determine this.

Comparison with other reviews

An earlier systematic review on amoebic dysentery concluded that metronidazole was "unlikely to be beneficial" since some ineffectiveness or associated harm was demonstrated in some trials and that ornidazole, secnidazole, and tinidazole were "likely to be beneficial", since effectiveness for these drugs, with no increased harms, was demonstrated in other trials (Dans 2006). In this current review, we concluded that although tinidazole may be more effective than metronidazole in reducing clinical failure, and was probably associated with fewer adverse effects, it did not show any significant advantage over metronidazole in reducing parasitological failure. For ornidazole and secnidazole, there was insufficient data to be able to draw any definite conclusions. The difference in conclusions could be due to important differences in methodology. The systematic review on amoebic dysentery used the Clinical Evidence search strategy (Dans 2006) and included 12 randomized controlled trials, defined therapeutic failure as persistence of symptoms or persistence of parasites or both, analysed outcomes reported at different time points together, and did not pool data to generate an overall summary measure.

Applicability of results

This review was limited only to symptomatic individuals with uncomplicated amoebic colitis. We did not study the effect of antiamoebic drugs on those with severe amoebic colitis, complicated disease, or extraintestinal amoebiasis. The potential effect of malnutrition, immune suppression, or AIDS on treatment is not known. Although asymptomatic infection with E. histolytica is more common than symptomatic disease, treatment of these individuals remains controversial because most will clear their infection within one year and only about 3% to 10% will manifest invasive disease (Gathiram 1987; Haque 2001; Blessman 2003b; Haque 2002).

The limited availability of many antiamoebic drugs must be addressed in the light of reports that newer nitroimidazole drugs may be as effective as, and better tolerated than, metronidazole and that there may be fewer clinical and parasitological failures when luminal agents are given in conjunction with tissue amoebicides. Metronidazole is widely used and may be the only available antiamoebic drug in many countries. Tinidazole and the other nitroimidazole drugs, such as ornidazole and secnidazole, and luminal agents such as diloxanide furoate, iodoquinol, and paromomycin, are not widely available and may only be purchased from certain pharmaceutical companies or requested from government agencies. Although tinidazole was shown to be probably more effective and better tolerated than metronidazole in this review, the limitations of the currently available evidence, and the limited availability of tinidazole in many regions, would make a widespread recommendation for its use impractical. Similarly, the evidence to recommend combination therapy is inadequate, and the limited availability of luminal agents in the market is a major deterrent to compliance with the general recommendation for combination therapy.

Limitations of the review

Limitations in study quality, the imprecise or sparse data in some outcomes, important inconsistencies across the trials, and a high probability of reporting or publication bias decrease the quality of evidence. Therefore the conclusions of the review should be interpreted with caution. Inaccurate diagnosis of E. histolytica infection by stool microscopy, absence of standardized classification of the various categories of amoebic colitis (particularly nondysenteric amoebic colitis), and variable timing and definition of outcome measurements would all lead to inaccuracy in assessing treatment effects. In areas highly endemic for amoebiasis, true treatment failures or relapse would be difficult to differentiate from reinfection without the benefit of finger typing or genotyping. Incomplete reporting of adverse events may lead to an inaccurate assessment of adverse events.

Authors' conclusions

Implications for practice

  • Antiamoebic drugs are indicated for treating individuals with amoebic colitis.

  • Tinidazole is probably more effective in reducing clinical failure and may be comparable to metronidazole in reducing parasitological failure, with fewer adverse events.

  • There is insufficient evidence to draw conclusions regarding efficacy of the other antiamoebic drugs.

  • Combination drug therapy may be more effective compared with metronidazole alone, but it is not known if this will lead to more adverse effects. There are insufficient data to recommend specific combinations to eradicate cysts in the stools and prevent relapse.

  • The trials were generally inadequate or unclear in the key components measuring methodological quality, so there is not enough evidence to be certain about the results.

  • The choice of antiamoebic drugs would depend largely on the availability and accessibility of drugs.

Implications for research

  • There is a need for more randomized controlled trials on the efficacy of drugs for treating amoebic colitis, with better methodological quality and using standardized definitions for evaluating outcomes.

  • Diagnosis of amoebic colitis should not rely solely on stool microscopy but should be confirmed by a reliable test that differentiates E. histolytica from nonpathogenic amoeba. There is a need to determine the most cost effective and accurate diagnostic test that can be used in developing countries.

  • Further information on the possible interaction of other intestinal pathogens affecting treatment response of E. histolytica would be important in areas where mixed infection with other intestinal pathogens and helminths are common.

  • Randomized controlled trials are also needed to determine which luminal agent would be the most effective in conjunction with metronidazole, or another nitroimidazole, for eradicating E. histolytica from the intestine and for decreasing relapse.

  • Finally, there is need for additional trials to compare single-dose or shorter regimens with multiple doses or longer durations of therapy.

Acknowledgements

This document is an output from a project under the Effective Health Care Research Programme Consortium (RPC) – Philippines, which is funded by the UK Department for International Development (DFID) for the benefit of developing countries. The views expressed are not necessarily those of DFID. The editorial base for the Cochrane Infectious Diseases Group is funded by DFID.

Data and analyses

Download statistical data

Comparison 1. Alternative drug vs metronidazole
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical failure: 1 to 14 days after end of treatment5375Risk Ratio (M-H, Random, 95% CI)0.41 [0.11, 1.64]
1.1 Ornidazole240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Praziquantel150Risk Ratio (M-H, Random, 95% CI)0.69 [0.17, 2.78]
1.3 Tinidazole2285Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.30]
2 Clinical failure: 15 to 60 days after end of treatment12679Risk Ratio (M-H, Random, 95% CI)0.39 [0.21, 0.73]
2.1 Ornidazole2118Risk Ratio (M-H, Random, 95% CI)3.00 [0.13, 71.89]
2.2 Panidazole144Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Satranidazole (GO 10213)140Risk Ratio (M-H, Random, 95% CI)0.8 [0.40, 1.60]
2.4 Tinidazole8477Risk Ratio (M-H, Random, 95% CI)0.28 [0.15, 0.51]
3 Parasitological failure: 1 to 14 days after end of treatment6419Risk Ratio (M-H, Random, 95% CI)1.05 [0.85, 1.29]
3.1 Ornidazole240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.2 Praziquantel150Risk Ratio (M-H, Random, 95% CI)0.69 [0.17, 2.78]
3.3 Secnidazole144Risk Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.12]
3.4 Tinidazole2285Risk Ratio (M-H, Random, 95% CI)1.01 [0.58, 1.74]
4 Parasitological failure: 15 to 60 days after end of treatment13 Risk Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Ornidazole2135Risk Ratio (M-H, Random, 95% CI)0.18 [0.02, 1.41]
4.2 Panidazole186Risk Ratio (M-H, Random, 95% CI)1.71 [0.81, 3.60]
4.3 Satranidazole (GO 10213)140Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.72]
4.4 Tinidazole9507Risk Ratio (M-H, Random, 95% CI)0.64 [0.25, 1.64]
5 Relapse (ornidazole)2 Risk Ratio (M-H, Random, 95% CI)Totals not selected
6 Adverse events11 Risk Ratio (M-H, Random, 95% CI)Subtotals only
6.1 Ornidazole120Risk Ratio (M-H, Random, 95% CI)0.67 [0.14, 3.17]
6.2 Panidazole1100Risk Ratio (M-H, Random, 95% CI)1.12 [0.87, 1.45]
6.3 Satranidazole (GO 10213)140Risk Ratio (M-H, Random, 95% CI)0.71 [0.27, 1.88]
6.4 Tinidazole8477Risk Ratio (M-H, Random, 95% CI)0.65 [0.46, 0.92]
Analysis 1.1.

Comparison 1 Alternative drug vs metronidazole, Outcome 1 Clinical failure: 1 to 14 days after end of treatment.

Analysis 1.2.

Comparison 1 Alternative drug vs metronidazole, Outcome 2 Clinical failure: 15 to 60 days after end of treatment.

Analysis 1.3.

Comparison 1 Alternative drug vs metronidazole, Outcome 3 Parasitological failure: 1 to 14 days after end of treatment.

Analysis 1.4.

Comparison 1 Alternative drug vs metronidazole, Outcome 4 Parasitological failure: 15 to 60 days after end of treatment.

Analysis 1.5.

Comparison 1 Alternative drug vs metronidazole, Outcome 5 Relapse (ornidazole).

Analysis 1.6.

Comparison 1 Alternative drug vs metronidazole, Outcome 6 Adverse events.

Comparison 2. Any antiamoebic drug vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical failure: 1 to 14 days after end of treatment3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Quinfamide140Risk Ratio (M-H, Random, 95% CI)0.35 [0.21, 0.60]
1.2 Nitazoxanide2153Risk Ratio (M-H, Random, 95% CI)0.21 [0.06, 0.81]
2 Parasitological failure: 1 to 14 days after end of treatment4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Nitazoxanide2167Risk Ratio (M-H, Random, 95% CI)0.25 [0.05, 1.27]
2.2 Quinfamide196Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.47]
2.3 10 different drugs belonging to 6 drug classes1367Risk Ratio (M-H, Random, 95% CI)0.37 [0.26, 0.53]
3 Other adverse events3 Risk Ratio (M-H, Random, 95% CI)Totals not selected
3.1 Nitazoxanide1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.2 Quinfamide1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.3 10 different drugs belonging to 6 drug classes1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Any antiamoebic drug vs placebo, Outcome 1 Clinical failure: 1 to 14 days after end of treatment.

Analysis 2.2.

Comparison 2 Any antiamoebic drug vs placebo, Outcome 2 Parasitological failure: 1 to 14 days after end of treatment.

Analysis 2.3.

Comparison 2 Any antiamoebic drug vs placebo, Outcome 3 Other adverse events.

Comparison 3. Combination regimen vs monotherapy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical failure: 1 to 14 days after end of treatment5 Risk Ratio (M-H, Random, 95% CI)Totals not selected
1.1 Dehydroemetine and tetracycline and diloxanide furoate vs metronidazole1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Metronidazole and diiodohydroxyquinoline vs metronidazole1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Metronidazole and furazolidone vs metronidazole1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.4 Combinations vs nimorazole, aminosidine, and etofamide1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.5 Tetracycline and clioquinol vs secnidazole1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2 Parasitological failure: 1 to 14 days after end of treatment6 Risk Ratio (M-H, Random, 95% CI)Totals not selected
2.1 Dehydroemetine and tetracycline and diloxanide furoate vs metronidazole1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.2 Metronidazole and diiodohydroxyquinoline vs metronidazole1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Metronidazole and furazolidone vs metronidazole1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.4 Combinations vs nimorazole, aminosidine, and etofamide1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.5 Quinfamide and mebendazole vs nitazoxanide (mixed infections only)1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.6 Tetracycline and clioquinol vs secnidazole1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 Combination regimen vs monotherapy, Outcome 1 Clinical failure: 1 to 14 days after end of treatment.

Analysis 3.2.

Comparison 3 Combination regimen vs monotherapy, Outcome 2 Parasitological failure: 1 to 14 days after end of treatment.

Comparison 4. Single dose regimen vs longer regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical failure: 1 to 14 or 15 to 60 days after end of treatment, combined3 Risk Ratio (M-H, Random, 95% CI)Totals not selected
1.1 Quinfamide: 1 dose vs 2 or 3 doses1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Secnidazole (1 dose) vs tetracycline and clioquinol (5 days)1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Secnidazole (1 dose) vs tinidazole (2 days)1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2 Parasitological failure: 1 to 14 days after end of treatment4 Risk Ratio (M-H, Random, 95% CI)Totals not selected
2.1 Quinfamide (1 dose) vs nitazoxanide (3 days)1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.2 Quinfamide: 1 dose vs 2 or 3 doses1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Secnidazole (1 dose) vs metronidazole (10 days)1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.4 Secnidazole (1 dose) vs tetracycline and clioquinol (5 days)1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 4.1.

Comparison 4 Single dose regimen vs longer regimen, Outcome 1 Clinical failure: 1 to 14 or 15 to 60 days after end of treatment, combined.

Analysis 4.2.

Comparison 4 Single dose regimen vs longer regimen, Outcome 2 Parasitological failure: 1 to 14 days after end of treatment.

Comparison 5. Other antiamoebic drug comparisons
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical failure: 1 to 14 days after end of treatment5 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Ornidazole vs tinidazole266Risk Ratio (M-H, Random, 95% CI)0.23 [0.03, 1.96]
1.2 Ornidazole vs secnidazole1102Risk Ratio (M-H, Random, 95% CI)0.95 [0.17, 5.45]
1.3 Chlorhydroxyquinoline vs diiodohydroxyquinoline1100Risk Ratio (M-H, Random, 95% CI)0.24 [0.11, 0.53]
1.4 MK-910 (4 dosages)140Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2 Parasitological failure: 1 to 14 days after end of treatment9 Risk Ratio (M-H, Random, 95% CI)Totals not selected
2.1 Ornidazole vs tinidazole2 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.2 Ornidazole vs secnidazole1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Chlorhydroxyquinoline vs diiodohydroxyquinoline1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.4 MK-910 (4 dosages)1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.5 Quinfamide vs secnidazole1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.6 Quinfamide vs nitazoxanide1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.7 Metronidazole and iodoquinol vs Saccharomyces boulardii or placebo1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.8 2 fixed-drug combinations of diloxanide furoate and tetracycline with or without chloroquine1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 5.1.

Comparison 5 Other antiamoebic drug comparisons, Outcome 1 Clinical failure: 1 to 14 days after end of treatment.

Analysis 5.2.

Comparison 5 Other antiamoebic drug comparisons, Outcome 2 Parasitological failure: 1 to 14 days after end of treatment.

Comparison 6. Subgroup analyses: alternative drug vs metronidazole
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure 15 to 60 days after end of treatment, by clinical category13768Risk Ratio (M-H, Random, 95% CI)0.81 [0.45, 1.48]
1.1 Amoebic dysentery3162Risk Ratio (M-H, Random, 95% CI)0.79 [0.07, 8.68]
1.2 Nondysenteric amoebic colitis389Risk Ratio (M-H, Random, 95% CI)1.63 [1.09, 2.42]
1.3 Amoebic colitis or intestinal amoebiasis, unspecified9517Risk Ratio (M-H, Random, 95% CI)0.56 [0.29, 1.10]
2 Parasitological failure 15 to 60 days after end of treatment, by age group13 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Adults (age ≥ 15 years)10622Risk Ratio (M-H, Random, 95% CI)0.63 [0.25, 1.54]
2.2 Children (age < 15 years)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Both adults and children3146Risk Ratio (M-H, Random, 95% CI)0.79 [0.34, 1.85]
3 Parasitological failure 15 to 60 days after end of treatment, single or mixed intestinal infection13 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Amoebic infection only10586Risk Ratio (M-H, Random, 95% CI)0.63 [0.25, 1.59]
3.2 Mixed intestinal infection3182Risk Ratio (M-H, Random, 95% CI)0.63 [0.10, 3.91]
4 Parasitological failure 15 to 60 days after end of treatment, by criteria13 Risk Ratio (M-H, Random, 95% CI)Subtotals only
4.1 WHO criteria9517Risk Ratio (M-H, Random, 95% CI)0.56 [0.29, 1.10]
4.2 Other criteria4251Risk Ratio (M-H, Random, 95% CI)1.31 [0.58, 2.94]
Analysis 6.1.

Comparison 6 Subgroup analyses: alternative drug vs metronidazole, Outcome 1 Parasitological failure 15 to 60 days after end of treatment, by clinical category.

Analysis 6.2.

Comparison 6 Subgroup analyses: alternative drug vs metronidazole, Outcome 2 Parasitological failure 15 to 60 days after end of treatment, by age group.

Analysis 6.3.

Comparison 6 Subgroup analyses: alternative drug vs metronidazole, Outcome 3 Parasitological failure 15 to 60 days after end of treatment, single or mixed intestinal infection.

Analysis 6.4.

Comparison 6 Subgroup analyses: alternative drug vs metronidazole, Outcome 4 Parasitological failure 15 to 60 days after end of treatment, by criteria.

Comparison 7. Subgroup analyses: any antiamoebic drug vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure 1 to 14 days after end of treatment, by clinical category4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Nondysenteric amoebic colitis196Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.47]
1.2 Amoebic colitis or intestinal amoebiasis, unspecified3534Risk Ratio (M-H, Random, 95% CI)0.33 [0.17, 0.62]
2 Clinical failure 1 to 14 days after end of treatment, by age group3193Risk Ratio (M-H, Random, 95% CI)0.27 [0.14, 0.51]
2.1 Adults (age ≥ 15 years)3143Risk Ratio (M-H, Random, 95% CI)0.31 [0.16, 0.60]
2.2 Children (age < 15 years)150Risk Ratio (M-H, Random, 95% CI)0.14 [0.04, 0.56]
3 Parasitological failure 1 to 14 days after end of treatment, by age group4630Risk Ratio (M-H, Random, 95% CI)0.33 [0.23, 0.48]
3.1 Adults (age ≥ 15 years)3213Risk Ratio (M-H, Random, 95% CI)0.34 [0.20, 0.56]
3.2 Children (age < 15 years)150Risk Ratio (M-H, Random, 95% CI)0.08 [0.01, 0.54]
3.3 Both adults and children1367Risk Ratio (M-H, Random, 95% CI)0.37 [0.26, 0.53]
Analysis 7.1.

Comparison 7 Subgroup analyses: any antiamoebic drug vs placebo, Outcome 1 Parasitological failure 1 to 14 days after end of treatment, by clinical category.

Analysis 7.2.

Comparison 7 Subgroup analyses: any antiamoebic drug vs placebo, Outcome 2 Clinical failure 1 to 14 days after end of treatment, by age group.

Analysis 7.3.

Comparison 7 Subgroup analyses: any antiamoebic drug vs placebo, Outcome 3 Parasitological failure 1 to 14 days after end of treatment, by age group.

Comparison 8. Subgroup analyses: combination regimen vs monotherapy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical failure: 1 to 14 days after end of treatment, by intervention5 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Combination vs metronidazole31025Risk Ratio (M-H, Random, 95% CI)0.33 [0.11, 0.98]
1.2 Combination vs alternative drugs2480Risk Ratio (M-H, Random, 95% CI)2.60 [0.20, 33.80]
2 Parasitological failure: 1 to 14 days after end of treatment, by intervention6 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Combination vs metronidazole3720Risk Ratio (M-H, Random, 95% CI)0.36 [0.15, 0.86]
2.2 Combination vs alternative drugs3577Risk Ratio (M-H, Random, 95% CI)1.84 [0.41, 8.37]
Analysis 8.1.

Comparison 8 Subgroup analyses: combination regimen vs monotherapy, Outcome 1 Clinical failure: 1 to 14 days after end of treatment, by intervention.

Analysis 8.2.

Comparison 8 Subgroup analyses: combination regimen vs monotherapy, Outcome 2 Parasitological failure: 1 to 14 days after end of treatment, by intervention.

Comparison 9. Subgroup analyses: any single dose regimen vs longer regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure: 1 to 14 days after end of treatment, by intervention4221Risk Ratio (M-H, Random, 95% CI)0.73 [0.11, 4.91]
1.1 Secnidazole single dose vs longer duration2124Risk Ratio (M-H, Random, 95% CI)0.14 [0.06, 0.35]
1.2 Quinfamide single dose vs longer duration297Risk Ratio (M-H, Random, 95% CI)2.13 [1.02, 4.46]
Analysis 9.1.

Comparison 9 Subgroup analyses: any single dose regimen vs longer regimen, Outcome 1 Parasitological failure: 1 to 14 days after end of treatment, by intervention.

Appendices

Appendix 1. Search methods: detailed search strategies

Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSb
1amoeb*amoeb*amoebiasisamoebiasisamoeb*
2EntamoebaEntamoeba histolyticaDYSENTERY, AMEBIC/DRUG THERAPYNITROIMIDAZOLE-DERIVATIVEEntamoeba
31 or 21 or 21 OR 2EMETINE1 or 2
4nitroimidazolesamoebicidesAMEBICIDES/THERAPEUTIC USEDILOXANIDE FUROATEnitroimidazoles
5emetineNITROIMIDAZOLESNITROIMIDAZOLEScarbarsoneemetine
6diloxanide furoateemetineEMETINEacetarsonediloxanide furoate
7quinfamidediloxanide furoatecarbarsoneacetarsolquinfamide
8etofamidequinfamideacetarsonediphetarsoneetofamide
9etophamideetofamideacetarsolglycobiarsoletophamide
10HYDROXYQUINOLINESetophamidediphetarsonestovarsolHYDROXYQUINOLINES
11chloroquineHYDROXYQUINOLINESglycobiarsolthioarsenitechloroquine
12tetracyclineARSENICALSstovarsoldiloxanide furoatetetracycline
13erythromycinchloroquinethioarsenitequinfamideerythromycin
14niridazoletetracyclinediloxanide furoateetofamideniridazole
15nitazoxanideoxytetracyclinequinfamideetophamidenitazoxanide
164-15/ORchlortetracyclineetofamidechiniofon4-15/OR
173 AND 16erythromycinetophamideclioquinol3 AND 16
18niridazoleHYDROXYQUINOLINESdichloroacetamide
19nitazoxanidechiniofonchlorbetamide
204-19/ORclioquinolchlorphenoxamide
213 AND 20dichloroacetamidechloroquine
22chlorbetamidetetracycline
23chlorphenoxamideerythromycin
24chloroquineoxytetracycline
25tetracyclinechlortetracycline
26erythromycinniridazole
27oxytetracyclinenitazoxanide
28chlortetracyclinenimorazole
29niridazolenitrimidazine
30nitazoxanide2-29/OR
31nimorazole1 AND 30
32nitrimidazineLimit 31 to human
334-32/OR
343 AND 33
35Limit 34 to human

aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2008); upper case: MeSH or EMTREE heading; lower case: free text term.

Appendix 2. Search methods: conference proceedings searched

Conference proceedingsDate and location of conference
International Congress of Chemotherapy24th: 4 to 6 June 2005, Manila, Philippines
25th: 31 March to 3 April 2007, Munich, Germany (joint conference with 17th European Congress of Clinical Microbiology and Infectious Diseases)
Interscience Conference on Antimicrobial Agents and Chemotherapy44th: 30 October to 2 November 2004, Washington DC, USA
45th: 16 to 19 December 2005, Washington DC, USA
46th: 27 to 30 September 2006, San Francisco, California, USA
Annual Meeting of the American Society of Tropical Medicine and Hygiene52nd: 3 to 7 December 2003, Philadelphia, Pennsylvania, USA
53rd: 7 to 11 November 2004, Florida, USA
54th: 11 to 15 December 2005, Washington DC, USA
55th: 12 to 16 November 2006, Atlanta, Georgia, USA
International Congress on Infectious Diseases11th: 4 to 7 March 2004, Cancun, Mexico
12th: 15 to 18 June 2006, Lisbon, Portugal
European Congress of Clinical Microbiology and Infectious Diseases15th: 2 to 5 April 2005, Copenhagen, Denmark
16th: 1 to 4 April 2006, Nice, France
17th (joint conference with 25th International Congress of Chemotherapy): 31 March to 3 April 2007, Munich, Germany
European Congress on Tropical Medicine and International Health5th: 24 to 28 May 2007, Amsterdam, the Netherlands (Workshop on Amoebiasis, Side Meeting, 24 to 25 May 2007)
Commonwealth Congress on Diarrhoea and Malnutrition7th (part of 2nd World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition): 3 to 7 July 2004, Paris, France
8th: 6 to 8 February 2006, International Centre for Diarrhoeal Diseases Research in Bangladesh (ICCDRB), Dhaka, Bangladesh
Seminars in Amebiasis14th: 27 to 30 November 2000, Mexico City, Mexico

Appendix 3. Search methods: organizations or institutions contacted for trials on amoebic colitis

OrganizationDate contacted
Department of Parasitology, College of Public Health, University of the Philippines, Manila, Philippines5 July 2005
Tropical Medicine, Mahidol University, Bangkok, Thailand7 July 2005
National Institute of Health, Manila, Philippines22 July 2005
South East Asian Ministers Education Organization (SEAMEO) TROPMED Network27 July 2005
Research Institute for Tropical Medicine, Alabang, Muntinglupa, Philippines5 September 2006
Waterborne and Parasitic Diseases, World Health Organization Regional Office for the Western Pacific, Manila, Philippines5 September 2006
National Institute of Cholera and Enteric Diseases, Calcutta, India24 September 2006
South African Medical Research Council, South Africa17 October 2006
Department of Medicine, University of Minnesota, Minneapolis, USA5 June 2006; 16 January 2008
International Centre for Diarrhoeal Diseases Research in Bangladesh (ICCDRB), Dhaka, Bangladesh7 July 2005; 3 February 2008
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, England1 February 2008
University of Guanajuato, Celaya, Mexico3 February 2008
Laboratory of Parasitic Diseases, NIAID, National Institutes of Health, Bethesda, USA3 February 2008
Department of Medicine, Washington University School of Medicine, St. Louis, Minnesota, USA3 February 2008
Department of Infectious Diseases, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, Japan3 February 2008
Department of Biotechnology, Indian Institute of Technology Roorkee, India5 February 2008
Infectious Diseases, Departments of Medicine Microbiology and Immunology, Stanford University, Stanford, California, USA6 February 2008
Department of Molecular Biology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany11 February 2008

Appendix 4. Search methods: pharmaceutical companies

CompanyRelevant drug(s)aDate(s) contacted/database searched
AventisSecnidazole (Flagentyl, Secnidal)22 September 2006; 3 February 2008
Boots Company PharmaceuticalsDiloxanide furoate (Furamide)22 September 2006
CIBA Pharmaceutical Company
(merged with Sandoz to form Novartis)
Niridazole (Ambilhar)22 September 2006; 3 February 2008
Glenwood LLCIodoquinol (Yodoxin)22 September 2006; 3 February 2008
Hoffmann-la Roche & Co. LtdOral and injectable dehydroemetine22 September 2006
International Federation of Pharmaceutical Manufacturers and Associationb3 June 2006, 22 September 2006, and 3 February 2008f
King Pharmaceuticals, Inc.Paromomycin (Humatin)31 May 2006; 3 February 2008
Novartis: Clinical Trial Results Databasesc3 June 2006, 22 September 2006, and 3 February 2008f
Presutti LaboratoriesTinidazole (Tindamax)3 June 2006
Pfizer

Metronidazole (Flagyl)

Etofamide (Kitnos)

22 September 2006; 3 February 2008
Roche: personal contactOrnidazole (Tiberal)22 September 2006; 3 February 2008
Roche: Clinical Trial Protocol Registryd; Clinical Trial Results Databasee3 June 2006, 22 September 2006, and 3 February 2008f
Romark Laboratories, IncNitazoxanide (Alinia)22 September 2006; 3 February 2008
SandozMetronidazole (Servizol)22 September 2006; 3 February 2008
SanvinQuinfamide22 September 2006

aTrade name in brackets.
bclinicaltrials-dev.ifpma.org.
cnovartis.com/about_novartis/en/clinical_trials.shtml.
dwww.roche-trials.com/registry.html.
dwww.roche-trials.com/results.html.
fSearch terms: 'amoebiasis or amebiasis,' 'amoebic dysentery or amebic dysentery,' and 'amoebic colitis or amebic colitis'.

Appendix 5. Region and country of trial

Appendix 6. Trial setting

Appendix 7. Participant age in included trials

Appendix 8. Methods used to diagnose amoebic colitis

MethodTechniqueNo. trialsTrials
Stool microscopyDirect smear20Nnochiri 1967; Kapadia 1968; Rubidge 1970; Batra 1972 a ; Naoemar 1973; Pudjiadi 1973; Joshi 1975; Mathur 1976; Botero 1977; Swami 1977; Awal 1979; Panggabean 1980; Sitepu 1982; Prasad 1985; Soedin 1985; Toppare 1994; Asrani 1995; Mohammed 1998; Karabay 1999; Mansour-Ghanaei 2003
Stool microscopy plusFormaline ether concentration methods16Donckaster 1964; Botero 1974; Misra 1974; Misra 1977; Singh 1977; Misra 1978; Huggins 1982; Pehrson 1983; Pehrson 1984; Tripathi 1986; Chunge 1989; Pamba 1990; Salles 1999; Padilla 2000; Rossignol 2001; Davila 2002
Flotation technique2Rubidge 1970; Mansour-Ghanaei 2003
Polvinyl alcohol fixative for detection of trophozoites1Donckaster 1964
Stool microscopy plus stool antigen-based ELISA test1Rossignol 2007

aStool culture was used in addition to stool microscopy to evaluate parasitological response, but not to diagnose amoebic colitis.

Appendix 9. Interventions and comparisons included in the trials

 No.ComparisonABTrial(s)

1.

 

 

 

 

 

 

 

 

Alternative drug (A) vs metronidazole (B)

 

 

 

 

 

 

 

 

Ornidazole (a nitroimidazole)MetronidazoleNaoemar 1973; Pudjiadi 1973; Botero 1974
PraziquantelMetronidazoleMohammed 1998
Tinidazole (a nitroimidazole)MetronidazoleMisra 1974; Joshi 1975; Mathur 1976; Misra 1977; Singh 1977; Swami 1977; Misra 1978; Awal 1979; Chunge 1989; Pehrson 1984
Secnidazole (a nitroimidazole)MetronidazoleKarabay 1999
Panidazole (a nitroimidazole)MetronidazoleBotero 1977
Satranidazole (GO 10213) (a nitroimidazole)MetronidazoleTripathi 1986
2.Any antiamoebic drug (A) vs placebo (B)QuinfamidePlaceboHuggins 1982
NitazoxanidePlaceboRossignol 2001; Rossignol 2007
10 different drugs belonging to 6 drug classes (dimethyl chlortetracycline, oxytetracycline, tetracycline, chlorphenoxamide, chlorbetamide, dehydroemetine, diiodohydroxyquinoline, iodohydroxyquinoline, phenanthronedione, bismuth glycoarsanilate)PlaceboDonckaster 1964

3.

 

 

 

 

 

 

Combination regimen (A) vs monotherapy (B)

 

 

 

 

 

 

Dehydroemetine and oral tetracycline and diloxanide furoateMetronidazoleRubidge 1970
Metronidazole and di-iodohydroxyquinoloneMetronidazoleAsrani 1995
Metronidazole and furazolidineMetronidazolePrasad 1985
Nimorazole and aminosidine, nimorazole and etofamide, etofamide and aminosidineNimorazole or aminosidine or etofamidePamba 1990
Tetracycline and clioquinolSecnidazoleSoedin 1985
Quinfamide and mebendazoleNitazoxanideDavila 2002 a (mixed infections only)
Tinidazole and diloxanide furoateTinidazolePehrson 1983

4.

 

 

 

 

Single dose regimen vs longer regimen

 

 

 

 

Quinfamide (1 dose)Quinfamide (2 or 3 doses)Huggins 1982
Secnidazole (1 dose)Tetracycline and clioquinol (5 days)Soedin 1985
Secnidazole (1 dose)Tinidazole (2 days)Salles 1999
Quinfamide (1 dose)Nitazoxanide (3 days)Davila 2002 a (Entamoeba infection only)
Secnidazole (1 dose)Metronidazole (10 days)Karabay 1999

5.

 

 

 

 

 

 

Other antiamoebic drug comparisons

 

 

 

 

 

 

OrnidazoleTinidazolePanggabean 1980; Sitepu 1982
OrnidazoleSecnidazoleToppare 1994
ChlorhydroxyquinolineDiiodohydroxyquinolineKapadia 1968
MK-910 low dose (0.5 mg/kg and 1 mg/kg) MK-910 high dose (2 mg/kg and 3 mg/kg)  Batra 1972
QuinfamideSecnidazolePadilla 2000
QuinfamideNitazoxanideDavila 2002 a (Entamoeba infection only)
Metronidazole and iodoquinol with Saccharomyces boulardiiMetronidazole and iodoquinol with placeboMansour-Ghanaei 2003
Fixed-drug combination of diloxanide furoate and tetracycline with chloroquineFixed-drug combination of diloxanide furoate and tetracycline without chloroquineNnochiri 1967

 6.

 

 

 

Not used, but mentioned in ‘Description of studies

 

 

 

SecnidazoleTinidazoleSalles 1999 b
Quinfamide (3 doses)PlaceboHuggins 1982 b
Tinidazole (2 durations)MetronidazoleAwal 1979 c
Tinidazole (2 brands)Metronidazole (2 brands)Chunge 1989 d

aDifferent interventions for single and mixed infections.
bTrial included in comparison 'single dose regimen vs longer regimen'.
cTrial included in comparison 'alternative drug vs metronidazole'.
dTwo brands of tinidazole compared with two brands of metronidazole and included in comparison 'alternative drug vs metronidazole'.

Appendix 10. Risk of bias assessmenta

TrialAllocation sequence generationAllocation concealmentBlindingInclusion of all randomized participants in analysis
Asrani 1995UnclearUnclearOpen labelAdequate
Awal 1979AdequateUnclearOpen labelAdequate
Batra 1972UnclearUnclearOpen labelAdequate
Botero 1974UnclearUnclearUnclearAdequate
Botero 1977UnclearUnclearUnclearAdequate
Chunge 1989UnclearUnclearBlinded: participants, and microscopists assessing stool specimens
Unclear: care providers and clinical outcome assessors
Unclear
Davila 2002UnclearUnclearUnclearAdequate
Donckaster 1964AdequateUnclearUnclearAdequate
Huggins 1982UnclearUnclearUnclearAdequate
Joshi 1975UnclearUnclearOpen labelAdequate
Kapadia 1968UnclearUnclearUnclearAdequate
Karabay 1999UnclearUnclearOpen labelAdequate
Mansour-Ghanaei 2003UnclearUnclearParticipants, care providers, and outcome assessors)Adequate
Mathur 1976UnclearUnclearOpen labelAdequate
Misra 1974UnclearUnclearUnclearAdequate
Misra 1977UnclearUnclearUnclearAdequate
Misra 1978UnclearUnclearUnclearAdequate
Mohammed 1998AdequateUnclearOpen labelInadequate
Naoemar 1973UnclearUnclearParticipants, care providers, and outcome assessors blindedAdequate
Nnochiri 1967UnclearUnclearParticipants, care providers, and outcome assessors blindedAdequate
Padilla 2000AdequateUnclearParticipants and outcome assessors blindedAdequate
Pamba 1990UnclearUnclearMicroscopists assessing stool specimens blindedInadequate
Panggabean 1980UnclearUnclearCare provider blindedInadequate
Pehrson 1983UnclearInadequateOpen labelAdequate
Pehrson 1984UnclearInadequateOpen labelAdequate
Prasad 1985UnclearUnclearParticipants, care providers, and outcome assessors blindedAdequate
Pudjiadi 1973UnclearAdequateParticipants, care providers, and outcome assessors blindedAdequate
Rossignol 2001UnclearUnclearParticipants, care providers, and outcome assessors blindedAdequate
Rossignol 2007AdequateAdequateParticipants, care providers, and outcome assessors blindedAdequate
Rubidge 1970UnclearUnclearOpen labelAdequate
Salles 1999UnclearUnclearOpen labelAdequate
Singh 1977UnclearUnclearOpen labelAdequate
Sitepu 1982AdequateUnclearUnclearInadequate
Soedin 1985UnclearUnclearOpen labelAdequate
Swami 1977UnclearUnclearUnclearAdequate
Toppare 1994UnclearUnclearOpen labelAdequate
Tripathi 1986UnclearUnclearUnclearAdequate

aDetails of methods used are reported in the 'Characteristics of included studies'.

Appendix 11. Adverse events: alternative drug vs metronidazole

Alternative drugTrialGeneral/systemicGastrointestinalDermatologicCentral nervous systemOthersLaboratory abnormalRemarks
TinidazoleAwal 1979Anorexia, nausea, vomiting, metallic taste in the mouth were reported in both groups, but exact numbers not statedVertigo: metronidazole (2 participants)No abnormalities in complete blood count, serum bilirubin, alkaline phosphatase, and aspartate aminotransferase were noted after treatment in both groupsMore adverse effects reported in the metronidazole group (14/23, 61%) compared with the tinidazole group (10/43, 23%). All were mild and transient
Joshi 1975No abnormalities in complete blood count, urinalysis, serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and blood urea during and after treatment in both groupsMild adverse effects such as general malaise, nausea, and vertigo not requiring any treatment or change in drug treatment: metronidazole (7 participants) and tinidazole (6 participants)
Mathur 1976No abnormalities in complete blood count, urinalysis, serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and blood urea during or after treatment in both groupsMild adverse effects such as metallic taste, anorexia, nausea, and giddiness, which did not require treatment of discontinuation of drug treatment: 9 participants in each group
Misra 1974Malaise: tinidazole (1 participant); metronidazole (0 participants)

Loss of appetite, nausea, and vomiting: tinidazole (1 participant)

Loss of appetite and nausea: tinidazole (2 participants); metronidazole (2 participants)

Vomiting: metronidazole (1 participant)

Altered taste: tinidazole (2 participants); metronidazole (2 participants)

No skin rashes were noted in either group

Vertigo: metronidazole (5 participants); tinidazole (2 participants)

Headache: metronidazole (1 participant)

Sleep disturbance: metronidazole (2 participants)

Blurring of vision and dysuria: metronidazole (1 participant)No abnormalities were seen in the complete blood count, urinalysis, serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea, and on electrocardiography after treatment in both groups

Tinidazole was better tolerated than metronidazole

Tinidazole group: 2 participants developed a total of 8 adverse effects

Metronidazole group: 9 participants developed a total of 17 adverse effects

Misra 1977No abnormalities were seen in the complete blood count, urinalysis, serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea, and on electrocardiography after treatment in both groups

Significantly more adverse effects reported in participants on metronidazole (16/30, 53.3%) compared to those on tinidazole (8/30, 26.7%) (P < 0.05)

40% of adverse effects in the metronidazole group were moderate in intensity while all side effects in the tinidazole group were mild

Most of the adverse effects were gastrointestinal complaints: nausea, anorexia, vomiting, abdominal discomfort

Misra 1978

Nausea: tinidazole (3 participants); metronidazole (15 participants)

Bitter taste: tinidazole (3 participants); metronidazole (1 participant)

Vomiting: tinidazole (1 participant)

Anorexia: metronidazole (8 participants)

Abdominal pain: metronidazole (1 participant)

Furry tongue: metronidazole (4 participants)

Diarrhoea: metronidazole (1 participant)

Dark urine: tinidazole (2 participants); metronidazole (2 participants)No abnormalities were seen in the complete blood count, urinalysis, and blood chemistry after treatment in both groups

Significantly more adverse effects were reported in participants on metronidazole (16/30, 53.3%) versus tinidazole (8/29, 27.6.%) (P < 0.01)

40% of adverse effects in the metronidazole group were moderate in intensity, while all side effects in the tinidazole group were mild

Pehrson 1984Not monitored

No participant had any adverse effects severe enough to cause cessation of treatment

Specific adverse effects were not reported

Singh 1977No abnormalities were seen in the complete blood count, urinalysis, alkaline phosphatase, transaminases, and blood urea after treatment in both groups

Adverse effects reported in 14/27 (51.9%) participants in the tinidazole group and in 22/29 (75.9%) participants in the metronidazole group

Adverse effects were referable to the gastrointestinal tract and consisted of anorexia, nausea, bitter taste, and vomiting

Adverse effects were mild in the tinidazole group and of mild to moderate intensity in the metronidazole group

Swami 1977General malaise: metronidazole (1 participant)

Metallic taste: tinidazole (9 participants)

Bitter taste: tinidazole (4 participants)

Anorexia: tinidazole (2 participants); metronidazole (3 participants)

Abdominal pain: tinidazole (2 participants); metronidazole (4 participants)

Nausea: tinidazole (1participant); metronidazole (7 participants )

Vomiting: tinidazole (1 participant); metronidazole (3 participants)

Diarrhoea: metronidazole (2 participants)

Excessive salivation: metronidazole (2 participants)

Pruritus: metronidazole (3 participants)

Skin rash: metronidazole (1 participant)

Vertigo: tinidazole (1 participant); metronidazole (2 participants)Dark coloured urine: tinidazole (2 participants); metronidazole (4 participants)No abnormalities were seen in the complete blood count, urinalysis, serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and blood urea during or after treatment in both groups

22 adverse effects were reported in 15/29 (51.7%) participants in the tinidazole group while 33 adverse effects were reported in 10/27 (37%) participants in the metronidazole group

Adverse effects were moderate in intensity in 2 participants on tinidazole and 8 participants on metronidazole

OrnidazoleBotero 1974Nausea or vomiting with or without dizziness: ornidazole (2 participants); metronidazole (5 participants)

Dizziness with or without headache: ornidazole (8 participants); metronidazole (4 participants)

Numbness of the hands and tongue, difficulty in speaking, and headache on day 6 of treatment, which disappeared after treatment was terminated: ornidazole (1 participant )

Joint and muscle pains: ornidazole (4 participants); metronidazole (6 participants)Not reportedThe first 20 participants were given complete cardiovascular, neurological, and laboratory workup but these were not specified or reported in detail
Naoemar 1973

Severe nausea: metronidazole (1 participant)

Nausea associated with hypersalivation, anorexia and dizziness: metronidazole (1 participant)

Both improved with rest and reduction in metronidazole dosage from 1500 mg to 1000 mg

Dizziness, which disappeared after reducing the dose from 1500 mg to 1000 mg daily: ornidazole (2 participants)

Slight dizziness, which disappeared with rest: metronidazole (1 participant)

No abnormalities were seen in the complete blood count, urinalysis, alanine aminotransferase, alkaline phosphatase, blood urea, and on electrocardiography after treatment in both groupsNo significant difference was observed in the adverse effects of the 2 drugs
Pudjiadi 1973No abnormalities were seen in the complete blood count, urinalysis, alanine aminotransferase, alkaline phosphatase, and on electrocardiography during and after treatment in both groupsNo clinical adverse effects (eg nausea, loss of appetite, neurological signs) observed
PanidazoleBotero 1977No significant changes from pre-treatment results were seen after treatment in the complete blood count, urinalysis, transaminases, blood urea, and on electrocardiography in both groups

37/50 (74%) participants on panidazole presented with ≥ 1 of following adverse effects in order of frequency: dizziness, nausea, headache, vomiting, epigastric pain, cutaneous rash, numbness of mouth and weakness

33/50 (66%) participants on metronidazole presented with ≥ 1 of following adverse effects in order of frequency: nausea, dizziness, headache, epigastric pain, vomiting, poor appetite, and metallic taste in the mouth

All symptoms were of low to medium intensity and disappeared after treatment was terminated

PraziquantelMohammed 1998Not monitored

Main adverse effects reported by participants on praziquantel were nausea and vomiting (5.3%) and dizziness (5.3%)

Other adverse effects encountered occasionally included mild fever, joint pain, sore throat, dysuria, retention of urine, and severe apprehension

No adverse events were reported for metronidazole

Satranidazole (GO 10213)Tripathi 1986Complete blood count, urinalysis, serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea, and electrocardiography were done after treatment, but results were not presented

7 participants in the metronidazole group and 5 participants in the satranidazole group presented with ≥ 1 of following adverse effects: nausea, vomiting, burning in the epigastrium, headache, abdominal distention, and generalized itching.

None were serious or necessitated withdrawal of treatment

Appendix 12. Adverse events: any antiamoebic vs placebo

TrialGeneral/systemicGastrointestinalDermatologicCentral nervous systemOthersLaboratory abnormalRemarks
Donckaster 1964

General adverse effects (headache, asthenia, vertigo, anorexia): antiamoebic drugs (34/339 participants, 10%); placebo (0)

Breakdown in general adverse effects in antiamoebic drugs: dimethylchlortetracycline (7 participants); oxytetracycline (1 participant); tetracycline (4 participants); chlorphenoxamide (6 participant); chlorbetamide (2 participants); dehydroemetine (9 participants); diiodohydroxyquinoline (1 participant); phenanthronedione (2 participants); bismuth glycoarsanilate (2 participants)

Gastrointestinal symptoms (nausea and vomiting, meteorism, hyperacidity, epigastric pain, intestinal colic, diarrhoea): antiamoebic drugs (114/339 participants, 34%); placebo (5/28 participants, 18%)

Breakdown in antiamoebic drugs: dimethylchlortetracycline (18 participants); oxytetracycline (7 participants); tetracycline (9 participants); chlorphenoxamide (18 participants); chlorbetamide (16 participants); dehydroemetine (27 participants); diiodohydroxyquinoline (5 participants); phenanthronedione (4 participants); bismuth glycoarsanilate (5 participants); iodochlorhydroxyquinoline (5 participants)

Cutaneous symptoms (anal pruritis, erythema): antiamoebic drugs (21/339, 6%); placebo (0)

Breakdown in antiamoebic drugs: dimethylchlortetracycline (5 participants); oxytetracycline (1 participant); tetracycline (2 participants); chlorphenoxamide (2 participants); chlorbetamide (2 participants); dehydroemetine (5 participants); phenanthronedione (3 participants); iodochlorhydroxyquinolone (1 participant)

Not monitoredNot monitored

Tolerance was classified as good, fair, and bad according to the number of symptoms presented and their intensity

Tolerance was rated as bad in 27% of participants given dehydroemetine and 23% of participants given dimethylchlortetracycline

1 participant given diiodochlorydroxyquinoline presented with intense and frequent intestinal colic

Huggins 1982Nausea: quinfamide (6/72 participants, 8%); placebo (1/24 participants, 4%)Headache: quinfamide (1/72 participants, 1%); placebo (2/24 participants, 8%)Complete blood count, urinalysis, total cholesterol, blood sugar, bilirubin, urea, creatinine, alkaline phophatase, transaminases, and serum calcium were examined, but results were not presented either before or after treatmentAdverse effects were based on participants' complaints, consisting of only 2 symptoms, nausea and headache
Rossignol 2001

Abdominal pain: nitazoxanide (1 participant); placebo (1 participants)

Nausea: nitazoxanide (1 participant)

Dyspepsia: nitazoxanide (2 participants)

Worsening diarrhoea: placebo (1 participant)

Headache: nitazoxanide (1 participant)

Dizziness: nitazoxanide (1 participant ); placebo (10 participants)

Drowsiness: nitazoxanide (2 participants); placebo (1 participant)

Dysuria: nitazoxanide (1 participant)Not monitored

9 adverse effects were reported in 6 participants in the nitazoxanide group, while 4 adverse effects were reported in 4 participants in the placebo group

All adverse effects were mild and transient with none resulting in discontinuation of therapy

Rossignol 2007

Drowsiness: nitazoxanide (4 participants)

Fatigue: nitazoxanide (1 participant); placebo (1 participant)

Abdominal pain: nitazoxanide (2 participants), placebo (1 participant)

Dyspepsia: nitazoxanide (1 participant)

Nausea: placebo (1 participant)

Vomiting: placebo (1 participant)

Headache: nitazoxanide (2 participants); placebo (1 participant)Yellowish urine: nitazoxanide (1 participant); placebo (1 participant)Not monitoredAll adverse effects were mild and transient with none requiring discontinuation of treatment

Appendix 13. Adverse events: other comparisons

ComparisonTrialGeneral/systemicGastrointestinalDermatologicCentral nervous systemOthersLaboratory abnormalRemarks
Ornidazole vs tinidazolePanggabean 1980Vomiting: ornidazole (1 participant)Not monitoredAdverse effects with both drugs were minimal; no specific details provided
Secnidazole vs tinidazoleSalles 1999Fever: secnidazole (1 participant)

Bitter taste: secnidazole (4 participants); tinidazole (8 participants)

Nausea: secnidazole (4 participants); tinidazole (7 participants)

Vomiting: secnidazole (4 participants); tinidazole (1 participants)

Abdominal pain: secnidazole (1 participant); tinidazole (1 participant)

Flatulence: secnidazole (1 participant)

Soft stools: secnidazole (1 participant)

Diarrhoea: tinidazole (1 participant)

Headache: secnidazole (2 participants); tinidazole (1 participant)

Dizziness: tinidazole (1 participant)

Pharyngeal erythema: secnidazole (1 participant)Not monitored

Adverse effects were reported in 12/156 (7.7%) participants on secnidazole and in 15/147 (10.2%) participants on tinidazole; all were mild to moderate in intensity

No statistically significant difference in frequency of adverse effects between the 2 groups

Secnidazole vs quinfamidePadilla 2000

Abdominal pain: secnidazole (18 participants); quinfamide (4 participants) (P < 0.05)

Nausea: secnidazole (20 participants); quinfamide (1 participant) (P < 0.05)

Unpleasant taste in the mouth: secnidazole(18 participants); quinfamide (0) (P < 0.0001)

Vomiting: secnidazole (3 participants); quinfamide (0)

Diarrhoea: secnidazole (3 participants); quinfamide (0)

Headache: secnidazole (2 participants); quinfamide (0)Not monitoredAdverse effects were significantly higher in the secnidazole group vs the quinfamide group as determined by chi-squared test (p value < 0.05 considered statistically significant)
Ornidazole vs secnidazoleToppare 1994Not monitoredNo adverse effects were seen; no further details provided
Quinfamide vs nitazoxanideDavila 2002Not monitoredBoth treatments were well tolerated by the participants; no further details given
Etophamide vs quinfamideOlaeta 1996Meteorism (developed during treatment period): etophamide (1 infant)Not monitoredNo participant needed to stop treatment because of adverse events; no further details were given
Chlorhydroxyquinoline vs diiodohydroxyquinolineKapadia 1968

Nausea: chlorhydroxyquinoline (1 participant)

Epigastric discomfort with vomiting: chlorhydroxyquinoline (6 participants)

None were reported for diiodohydroxyquinoline

Mild rash: chlorhydroxyquinoline (1 participant); diiodohydroxyquinoline (1 participant)

Coryza: diiodohydroxyquinoline (2 participants)

Conjunctivitis: diiodohydroxyquinoline (1 participant)

Liver function test before and after treatment remained within the normal range in both groups
Combination dehydroemetine, tetracycline and diloxanide furoate vs metronidazoleRubidge 1970Not monitoredTolerance of both regimens was reported to be "excellent" and no toxicity was encountered; tolerance was not defined and no further details were given
Combination metronidazole and diiodohydroxyquinoline vs metronidazoleAsrani 1995

Metallic taste: metronidazole alone (225); metronidazole plus diiodohydroxyquinoline (224)

Abdominal pain: metronidazole alone (45); metronidazole plus diiodohydroxyquinoline (46)

Vomiting: metronidazole alone (45); metronidazole plus diiodohydroxyquinoline (36)

Nausea: metronidazole alone (121); metronidazole plus diiodohydroxyquinoline (125)

Diarrhoea: metronidazole alone (5); metronidazole plus diiodohydroxyquinoline (5)

Headache: metronidazole alone (29); metronidazole plus diiodohydroxyquinoline (26)

Drowsiness: metronidazole alone (3); metronidazole plus diiodohydroxyquinoline (11)

Unspecified allergic reaction (and had to be withdrawn from trial): metronidazole plus diiodohydroxyquinoline (1 participant)Not monitoredOverall incidence of adverse effects was not statistically significant between the 2 groups
Fixed drug combination metronidazole and furazolidone vs metronidazolePrasad 1985Not monitored

Both regimens were well tolerated; adverse effects were usually mild in the form of distaste, flatulence, and nausea

Incidence of adverse effects was reported to be more with metronidazole suspension compared with the combination but no specific details were reported

Combination tetracycline and clioquinol vs secnidazoleSoedin 1985Not monitoredBoth treatment regimens were reasonably well tolerated and few adverse effects were reported; no further details were given
Combination tinidazole and diloxanide furoate vs tinidazolePehrson 1983Not monitoredNo adverse effects severe enough to cause cessation of treatment; no further details were given
Fixed drug combination diloxanide furoate, tetracycline with chloroquine vs fixed drug combination diloxanide furoate and tetracycline without chloroquineNnochiri 1967Flatulence and abdominal discomfort: 8 participants in both groups (unclear whether the adverse effects were seen in 8 participants in each of the two groups or in a total of 8 participants in both groups)No abnormalities were noted in complete blood count and urinalysis during or after treatment
Aminosidine, etophamide, nimorazole alone or in combinationPamba 1990Not monitored

Drug tolerance rated as poor in 1.0% of cases given aminosidine, 2.0% of cases given combination nimorazole and aminosidine, and in 76.5% of cases given etophamide and aminosidine

Recruitment of participants in the etophamide-aminosidine group was discontinued because of the high incidence of severe diarrhoea; no other details of adverse events were given

MK-910 low dose (0.5 mg/kg and 1 mg/kg) vs MK-910 high dose (2 mg/kg and 3 mg/kg)Batra 1972

Vague abdominal pain: 1 participant each in the low dosage groups (total of 2 participants); 3 participants each in the higher dosage groups (total of 6 participants)

Nausea and vomiting: 4 participants each in the higher dosage groups (total of 8 participants)

2 participants, 1 in each of the higher dosage groups had to be removed from the trial because of the severity of gastrointestinal symptoms

Not monitored

Contributions of authors

Dr MLM Gonzales is primarily responsible for conceiving and designing the review, and co-ordinating its development. Dr LF Dans advised Dr MLM Gonzales about the design and co-ordination of the review and, together with Dr MLM Gonzales, assessed the results of the literature search to determine trial eligibility and the risk of bias in each included trial. Dr EG Martinez extracted data from the included trials and resolved differences in the assessment of papers between the other two authors. Dr EG Martinez and Dr L Dans conducted the systematic review on drug therapy for amoebic dysentery (Dans 2006) that set the groundwork for this Cochrane Review.

Declarations of interest

Potential conflict of interest: Dr Elizabeth G Martinez is currently employed as Medical Manager in United Laboratories, Inc., a major pharmaceutical company in the Philippines. It manufactures and distributes an intravenous preparation of metronidazole. None of the trials included in the review were conducted or sponsored by United Laboratories, Inc., and Dr Elizabeth G Martinez was not involved in any trial involving antiamoebic drugs.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Department for International Development (DFID), UK.

Differences between protocol and review

Objectives

Four specific objectives were added to give a more focused direction to the review.

Search strategy

Aside from searching the databases mentioned in the protocol as described in Appendix 2, we conducted additional electronic searches of PubMed using the format for highly sensitive search strategies for identifying reports of randomized controlled trials (Higgins 2005), with the latest search conducted on 11 February 2008. We also conducted additional searches of the databases of ongoing or unpublished trials by pharmaceutical companies and other conference proceedings not originally mentioned in the protocol.

Data collection and analyses

Data synthesis

For trials with more than two intervention groups (eg two or more experimental interventions or different doses or preparations of the same drug), multiple treatment arms were combined as appropriate and compared collectively with the standard or control group in the review. This would avoid a unit of analysis error by not counting the placebo or control participants more than once in the same meta-analysis.

Stratification of results

In the protocol, separate analyses were planned for outcomes reported at the end of treatment until seven days after treatment and for outcomes reported eight to 21 days after the end of treatment. However, since many trials reported outcomes 28 days or one month after treatment, we decided to stratify the outcomes from the end of treatment to 14 days and from 15 to 60 days after the end of treatment instead.

Subgroup analyses

Clinical categories (amoebic dysentery or nondysenteric amoebic colitis) and participant age (adults and children) were determined to be important subgroups even before data collection, although we failed to specify this in the protocol. Severity of disease and response to treatment differ for those with amoebic dysentery compared to those with nondysenteric amoebic colitis. Participant age is also an important confounder that may influence treatment effect and would be valid to explore as a potential source of heterogeneity. In those comparisons with enough trials, age was included as a subgroup, with the participants categorized as adults (age 15 years or older) or children (age less than 15 years). Other sources of heterogeneity that were not mentioned in the protocol but included in the post hoc subgroup analysis were type of intestinal infection (E. histolytica infection alone or mixed intestinal infection), criteria for determining outcome (based on WHO 1969 criteria or another criteria), and regimens used.

Sensitivity analyses

We intended to explore validity by using the tests for diagnosing E. histolytica as a surrogate for trial quality. However, we could not carry out sensitivity analysis based on the diagnostic tests because only one trial used stool antigen-based ELISA test for confirming E. histolytica. In the review, additional sensitivity analyses were done to determine the possible effect of pharmaceutical-sponsored trials since this could have an effect on the quality of the trials.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Asrani 1995

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 100% for parasitological assessment; 93.4% (898/961) for clinical assessment

Participants

Number: 961 enrolled, 898/961 (93.4%) included in analysis of clinical outcome; 591/591 (100%) positive for E. histolytica on stool examination at baseline included in analysis of parasitological outcome; 63/961 (6.6%) lost to follow up or were protocol violators (33 in metronidazole group, 30 in combination therapy group); 1 participant in the combination group withdrawn from the study due to allergic reaction on the first day of treatment

Inclusion criteria: adult male and nonpregnant female patients > 12 years of age with clinical symptoms of intestinal amoebiasis and/or presence of trophozoites or cysts of E. histolytica in stool specimens; laboratory diagnostic method not specified

Exclusion criteria: history of alcohol abuse; hypersensitivity or contraindications to any of the study drugs; systemic amoebiasis; severe illness; and/or persistent vomiting

Interventions
  1. Metronidazole: 400 mg thrice daily orally for 5 days

  2. Metronidazole and diiodohydroxyquinoline: fixed-drug combination of metronidazole (200 mg) plus diiodohydroxyquinoline (325 mg) (Qugyl by Sil Pharma, Bombay, India) given as 2 tablets thrice daily for 5 days

Treatment period was extended to 10 days in both groups when 5 days treatment was inadequate to clear the stools of E. histolytica

Outcomes
  1. Parasitological cure: clearance of E. histolytica in stool specimens at end of treatment

  2. Clinical cure: remission of clinical symptoms on days 5 and 10 after start of treatment

  3. Adverse events: clinical adverse events monitored by study personnel during treatment

Not included in this review: average daily frequency of stools on admission and on day 5 and day 10 of treatment; overall clinical response (rated as "poor" if < 25% relief and not tolerated, "fair" if 25% to 49% relief and not well tolerated, "poor" if 50% to 74% relief and well tolerated, or "excellent" if 75% to 100% relief and well tolerated)

Notes

Location: various cities (not specified) in India

Date: 1995 (date of publication only; actual study period not reported)

Source of funding: not stated; one of the authors (Dr SJ Phaterpekar) is connected with Searle (India) Limited, Bombay, India

Several attempts were made to inquire about the study methods, but no response was obtained from the primary author

Awal 1979

Methods

Generation of allocation sequence: random-numbers table

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 100%

Participants

Number: 66 enrolled and analysed

Inclusion criteria: adults and children with clinical signs and symptoms of intestinal amoebiasis and motile haematophagous trophozoites of E. histolytica in fresh stool specimens and on sigmoidoscopy; laboratory diagnostic method for stool examination was not specified

Exclusion criteria: antiamoebic treatment during the previous 4 weeks; pregnant women; dehydrated patients; those with evidence of hepatic or renal dysfunction

Interventions
  1. Tinidazole: 2 g single oral dose daily for 3 days

  2. Tinidazole: 2 g single oral dose daily for 2 days

  3. Metronidazole: 2 g single dose for 2 days

Outcomes
  1. Parasitological cure: eradication of E. histolytica from stools on day 30 from start of therapy

  2. Clinical cure: resolution of baseline symptoms of intestinal amoebiasis on day 30 from start of therapy

  3. Adverse events: voluntary reporting of side effects by the participants; laboratory tests monitored before and after treatment including complete blood count, serum bilirubin, alkaline phosphatase, and liver transaminase (SGOT)

Notes

Location: hospital in Bangladesh

Date: 1979 (date of publication only; actual study period not reported)

Source of funding: not stated

Batra 1972

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 100%

Participants

Number: 40 enrolled; 40 analysed; 2 withdrawn from treatment because of severe gastrointestinal adverse effects

Inclusion criteria: acute amoebic dysentery and stool specimens positive for trophozoites of E. histolytica by saline and iodine smears

Exclusion criteria: pregnant women; critically ill patients; those with neurological and cardiac abnormalities or disturbed renal functions

Interventions

MK- 910: each arm used 1-methyl-2 -(4'fluorophenyl)-5-nitroimidazole (MK-910) at a different mg/kg body weight day in 3 divided doses orally for 10 days

  1. 0.5 mg/kg body weight

  2. 1.0 mg/kg body weight

  3. 2.0 mg/kg body weight

  4. 3.0 mg/kg body weight

Outcomes
  1. Parasitological response: disappearance of E. histolytica from stools on day 5 and day 10 of treatment, both on saline and iodine smear examination and on stool culture using NIH medium

  2. Clinical response: reduction in clinical signs and symptoms

  3. Adverse events: monitored by study personnel during treatment; laboratory tests monitored before and on day 5 and day 11 of treatment including complete blood count, platelet count, urinalysis, blood urea, blood sugar, serum bilirubin, alkaline phosphatase, liver transaminases (SGOT, SGPT), thymol turbidity tests, and 12-lead electrocardiogram

Not included in this review: number of hours from start of treatment to reduction in diarrhoea, tenesmus, and bloody stools; disappearance of colonic ulcers on sigmoidoscopic examination on day 5 and day 11 of treatment

Notes

Location: hospital in New Delhi, India

Date: 1972 (date of publication only; actual study period not reported)

Source of funding: Merck, Sharp and Dohme

Botero 1974

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear; reported as "double-blind", but blinding of participants, care provider, and outcome assessors not described

Inclusion of all randomized participants: 95.8% (115/120)

Participants

Number: 120 enrolled; 115 analysed; 5 lost to follow up; 1 participant in the Ro 7-0207 terminated treatment after day 6 because of adverse effects

Inclusion criteria: adult males with clinical symptoms of intestinal amoebiasis and confirmed by the presence of E. histolytica in the stools examined by direct and Ritchie formalin-ether concentration methods

Exclusion criteria: not stated

Interventions
  1. Ro 7-0207 (ornidazole): 2 x 250 mg capsules twice daily for 10 days

  2. Metronidazole: 2 x 250 mg capsules twice daily for 10 days

Outcomes
  1. Parasitological response: clearance of E. histolytica from stools at the end of treatment and on at weekly intervals on follow up for at least 1 month

  2. Relapse: reappearance of E. histolytica in the stools within 1 month after becoming negative at the end of treatment

  3. Clinical response: disappearance or improvement of clinical signs and symptoms on day 5, at the end of treatment, and at weekly intervals during follow up for at least 1 month

  4. Adverse events: clinical adverse events monitored for all participants but cardiovascular, neurological, and laboratory monitoring only for the first 20 participants (laboratory tests not specified)

Notes

Location: hospital in Medellin, Colombia

Date: 1974 (date of publication only; actual study period not reported)

Source of funding: not stated

Botero 1977

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear; reported as "double-blind", but blinding of participants, care provider, and outcome assessors not described

Inclusion of all randomized participants: 100%

Participants

Number: 100 enrolled and 100 analysed

Inclusion criteria: adult males with clinical symptoms of intestinal amoebiasis and stools positive for E. histolytica examined by direct and Ritchie formalin-ether concentration methods

Exclusion criteria: not stated

Concomitant intestinal infection: 26 participants in panidazole group and 27 participants in metronidazole group had concomitant infection with other enteric protozoa and intestinal helminths (Entamoeba coli, Endolimax nana, Iodamoeba butschlii, Ascaris lumbricoides, Trichuris trichiura, Necator americanus, Strongyloides stercoralis)

Interventions
  1. Panidazole: 2 x 250 mg tablets (500 mg), 4 times daily for 6 days

  2. Metronidazole: 2 x 250 mg tablets (500 mg), 4 times daily for 6 days

Outcomes
  1. Parasitological cure: eradication of parasites in any of the post-treatment laboratory examinations

  2. Clinical response: improvement or disappearance of symptoms during weekly follow up for 4 weeks after treatment

  3. Adverse events: clinical adverse events monitored during treatment and on follow up; laboratory tests monitored before and after treatment including complete blood count, erythrocyte sedimentation rate, blood urea nitrogen, liver transaminases, urinalysis, and electrocardiogram

Not included in this review: number of stools passed in 24 hours on day 3 and day 6 of treatment and on days 7 and 21 after treatment; clearance of E. histolytica in asymptomatic carriers

Notes

Location: Colombia

Date: 1977 (date of publication only; actual study period not reported)

Source of funding: not stated

Chunge 1989

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: double (only participants and laboratory staff examining stools were blinded)

Inclusion of all randomized participants: unclear; only those who completed the required stool examinations were included (225 participants) and number randomized not stated

Participants

Number: number enrolled and randomized not stated, 225 analysed

Inclusion criteria: adults and children presenting with at least any 4 of the following symptoms of intestinal amoebiasis: abdominal pain, diarrhoea, constipation, mucoid stools, malaise, flatulence, nausea, fever, tenesmus, and stool specimens positive for trophozoites or cysts of E. histolytica by direct smear or formol-ether concentration technique

Exclusion criteria: pregnant women

Interventions
  1. Tinidazole (Fasigyn): 2 g single oral dose daily for 3 days

  2. Tinidazole (Tynazole): 2 g single oral dose daily for 3 days

  3. Metronidazole (Flagyl): 400 mg thrice daily orally for 5 days

  4. Metronidazole (Metrozol): 400 mg thrice daily orally for 5 days

Outcomes
  1. Parasitological cure: absence of trophozoites or cysts from stool specimens on day 6 after start of treatment

  2. Clinical cure: absence of any 4 of the symptoms initially present at day 6 after start of treatment

Notes

Location: outpatient departments of 3 district hospitals in Kiambo, Kilifi, and Machakos in Kenya

Date: 1989 (date of publication only; actual study period not reported)

Source of funding: Farmitalia Carlo Erba

Davila 2002

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear; reported as "double-blind", but blinding of participants, care provider, and outcome assessors not described

Inclusion of all randomized participants: 100%

Participants

Number: 275 enrolled; 105/275 (38%) had E. histolytica or E. dispar infection (25 single infection and 80 mixed infection with other intestinal parasites) and were included in the review and analysed

Inclusion criteria: children with stool specimens positive for E. histolytica/E. dispar and/or other intestinal parasites by direct smear or Kato-Katz technique

Exclusion criteria: not stated

Interventions
  1. Nitazoxanide: 100 mg/5 mL twice daily orally for 3 days

  2. Quinfamide: 100 mg/5 mL single oral dose; mebendazole 100 mg/5 mL twice daily orally for 3 days was added to quinfamide when another parasite other than E. histolytica/E. dispar was observed

Not stated if placebo was used

Outcomes
  1. Parasitological cure: eradication of E. histolytica/E. dispar in stool examination 14 days after treatment

  2. Adverse events: only tolerance to the drugs reported

Data for parasitological cure were presented separately for nitazoxandie vs quinfamide for single infections and nitazoxanide vs quinfamide plus mebendazole for mixed infections, and included in a separate meta-analysis

Notes

Location: 3 communities in Colima, Mexico

Date: 2002 (date of publication only; actual study period not reported)

Source of funding: Instituto Mexicano del Seguro Social (IMSS); nitazoxanide was provided by Laboratories Columbia, S.A. de C.V., Mexico, D.F., Mexico

Several attempts were made to contact the primary author, but they were not successful

Donckaster 1964

Methods

Generation of allocation sequence: random-numbers table

Allocation concealment: unclear

Blinding: unclear; reported as "double-blind", but blinding of participants, care provider, and outcome assessors not described

Inclusion of all randomized participants: 100%

Participants

Number: 346 enrolled; 346 analysed initially; 21 cases who failed after administration of the primary drugs were randomized a second time to receive a different drug and were analysed twice together with the first group

Inclusion criteria: adults and children with clinical symptoms of intestinal amoebiasis and stool specimens positive for cysts and/or trophozoites of E. histolytica examined by the modified Telemann concentration technique (centrifugation with saline formol and ether) for cysts and the polyvinyl alcohol with fixative of Schaudin for the trophozoites

Exclusion criteria: those without a source of potable water at home; unable to dispose of their excrement properly; or have other non-parasitic infections and are taking other medications for their infections

Interventions
  1. Dimethychlortetracycline: once daily on an empty stomach for 10 days at the following oral daily doses – children 15 mg/kg and adults 900 mg

  2. Oxytetracycline: once daily on an empty stomach for 10 days at the following oral daily doses – children 25 mg/kg and adults 1500 mg

  3. Tetracycline: once daily on an empty stomach for 10 days at the following oral daily doses – children 25 mg/kg and adults 1500 mg

  4. Chlorphenoxamide: once daily after meals for 10 days at the following oral daily doses – children 125 mg for every 2 years of age and adults 1500 mg

  5. Chlorbetamide: once daily after meals for 10 days at the following oral daily doses – children 100 mg/kg and adults 4000 mg

  6. Racemic dehydroemetine: once daily after meals for 10 days at the following oral daily doses – children 5 mg for every 2 years of age and adults 40 mg

  7. Diiodohydroxyquinoline: once daily after meals for 21 days at the following oral daily doses – children 200 mg for every 2 years of age and adults 1800 mg

  8. Phenanthrondione: once daily after meals for 10 days at the following oral daily doses – children 25 mg for every 2 years of age and adults 300 mg

  9. Bismuth glycoarsanilate: once daily after meals for 10 days at the following oral daily doses – children 250 mg for every 2 years of age and adults 2000 mg

  10. Iodochlorhydroxyquinoline: once daily after meals for 21 days at the following oral daily doses – children 125 mg for every 2 years of age and adults 1000 mg

  11. Placebo (starch): once daily after meals for 10 days at the following oral daily doses – children 250 mg for every 2 years of age and adults 1500 mg

Not stated which among the drugs, if any, were identical in appearance to the placebo

Outcomes
  1. Parasitological failure: presence of cysts and/or trophozoites in the stool examinations done 10 and 40 days after start of treatment

  2. Adverse events: voluntary reporting of clinical adverse events by participants every 3 days during treatment and every 10 to 15 days after treatment

Notes

Location: outpatient clinic of the University of Chile in Santiago, Chile

Date: 1963 (date of publication only; actual study period not reported)

Source of funding: not stated

Huggins 1982

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear; reported as "double-blind", but blinding of participants, care provider, and outcome assessors not described

Inclusion of all randomized participants: 100%

Participants

Number: 96 enrolled and analysed

Inclusion criteria: adults with chronic intestinal amoebiasis and stool specimens positive for E. histolytica by direct smear with Lugol's stain according to the Teleman-Richter or Hoffman, Pons, and Janer methods

Exclusion criteria: not stated

Interventions
  1. Win 40.014 (quinfamide): 100 mg single oral dose

  2. Win 40.014 (quinfamide): 100 mg twice a day orally at 12-hourly intervals for 1 day

  3. Win 40.014 (quinfamide): 100 mg thrice a day orally at 8-hourly intervals for 1 day

  4. Placebo: 300 mg daily dose orally, no information given on the frequency of administration of placebo

Not stated if Win 40.014 (quinfamide) and placebo tablets were identical in appearance

Outcomes
  1. Parasitological cure: clearance of amoeba from stools on days 2 and 7 after treatment

  2. Clinical cure: disappearance of the 4 symptoms recorded at baseline (pain, colic, diarrhoea, and constipation) evaluated on days 2 and 7 after treatment

  3. Adverse events: only 2 symptoms (nausea and headache) solicited from participants; laboratory tests were done before and after treatment but results not presented

Notes

Location: Clinical Hospital of the Federal University of Pernambuco, Brazil

Date: 1982 (date of publication only; actual study period not reported)

Source of funding: not stated

Joshi 1975

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 100%

Participants

Number: 60 enrolled and analysed

Inclusion criteria: adults with clinical symptoms of intestinal amoebiasis and stool specimens positive for trophozoites or cysts of E. histolytica; laboratory diagnostic method not specified

Exclusion criteria: those who received antiamoebic treatment in the previous 1 month, pregnant women, dehydrated patients, and those with hepatic, renal, hematologic or EKG abnormalities

Interventions
  1. Tinidazole: 600 mg twice daily orally for 5 days

  2. Metronidazole: 400 or 800 mg thrice daily orally for 5 days

Treatment period was extended to 10 days in both groups when 5 days treatment was inadequate to relieve symptoms or clear the stools of E. histolytica

Outcomes
  1. Parasitological response: eradication of E. histolytica in stools on day 30 after start of treatment

  2. Clinical response: complete or partial relief of symptoms and healing of ulcers on sigmoidoscopy, when carried out

  3. Adverse events: voluntary reporting by participants; laboratory tests monitored before and after treatment including haemogram, urinalysis, serum bilirubin, serum transaminases (SGOT, SGPT), alkaline phosphatase, and blood urea

Not included in this review: clearance of E. histolytica on day 5 or 10 and day 20 after start of treatment; persistence of clinical symptoms on day 5 or 10 and day 20 after start of treatment

Notes

Location: Ahmedabad, India

Date: 1975 (date of publication only; actual study period not reported)

Source of funding: not stated

Tinidazole tablets (Fasigyn) were supplied by Pfizer Ltd.

Kapadia 1968

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear

Inclusion of all randomized participants: 100%

Participants

Number: 50 enrolled and analysed

Inclusion criteria: clinical symptoms of intestinal amoebiasis and stool specimens positive for trophozoites and/or cysts of E. histolytica; laboratory diagnostic method was not specified

Exclusion criteria: not stated

Interventions
  1. Chlorhydroxquinoline: 500 mg thrice daily orally for 10 days

  2. Di-diiodohydroxyquinoline: 500 mg thrice daily orally for 10 days

Not stated if chlorhydroxquinoline and di-diiodohydroxyquinoline were identical in appearance

Outcomes
  1. Parasitological cure: eradication of E. histolytica from stools at the end of the 10-day treatment period

  2. Clinical cure: improvement or disappearance of symptoms at the end of the 10-day treatment period

  3. Adverse events: clinical adverse events and liver function test monitored before and after treatment including total bilirubin, serum albumin and globulin, and zinc sulfate

Notes

Location: Bombay, India

Date: 1968 (date of publication only; actual study period not reported)

Source of funding: not stated

Supply of chlorhydroxquinoline (Quixalin) from Sarabhai Chemicals

Karabay 1999

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 100%

Participants

Number: 44 enrolled and analysed

Inclusion criteria: acute amoebic dysentery and stool specimens positive for E. histolytica cysts and/or trophozoites examined by 0.85% saline water, Lugol solution, and trichrome stain

Exclusion criteria: received treatment for diarrhoea in the last 10 days; those with pathogenic bacteria identified in stool culture

Interventions
  1. Secnidazole: 2 g single oral dose

  2. Metronidazole: 750 mg thrice daily orally for 10 days

Outcomes
  1. Parasitological response: clearance of E. histolytica from stools on days 14 and 21

Not included in this review: mean number of days from start of treatment to resolution of clinical symptoms

Notes

Location: military hospital in Erzurum, Turkey

Date: July 1998 to November 1998

Source of funding: not stated

Mansour-Ghanaei 2003

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: double (participants, care providers, and outcome assessors – from personal communication with primary author)

Inclusion of all randomized participants: 94.7% (54/57))

Participants

Number: 57 enrolled; 54 analysed; 3 noncompliant participants (2 from the group without Saccharomyces boulardii and 1 from the group with S. boulardii) were excluded from analysis

Inclusion criteria: amoebic dysentery presenting with mucous bloody diarrhoea, fever, and abdominal pain; stool specimens positive for haematophagous trophozoites of E. histolytica; laboratory diagnostic method was not specified

Exclusion criteria: pregnant women; those on maintenance haemodialysis, steroids, or chemotherapy

Interventions
  1. Metronidazole, iodoquinol, and placebo: metronidazole 750 mg and iodoquinol 650 mg given thrice daily orally with placebo tablets for 10 days

  2. Metronidazole, iodoquinol, and S. boulardii: 750 mg and iodoquinol 650 mg thrice daily orally for 10 days plus lyophilized S. boulardii 250 mg orally thrice daily for 10 days

S. boulardii and placebo were identical in appearance

Outcomes
  1. Parasitological failure: persistence of amoebic cysts in stool examinations at 4 weeks after treatment

Not included in this review: mean duration of diarrhoea, abdominal pain, fever, and headache from start of treatment to resolution of symptoms

Notes

Location: Shahid Beheshti Educational and Therapeutic Center in Shiraz, Iran

Date: 21 March 1995 to 21 March 1996

Source of funding: not stated

The author was contacted and kindly provided data on method of blinding; however, no response was obtained regarding method of allocation concealment despite several follow-up communications

Mathur 1976

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 100%

Participants

Number: 60 enrolled and 60 analysed

Inclusion criteria: adults and adolescents with clinical symptoms of intestinal amoebiasis and stool specimens positive for trophozoites or cysts of E. histolytica; laboratory diagnostic method was not specified

Exclusion criteria: received antiamoebic treatment in the previous 1 month; pregnant women; dehydrated patients; and those with hepatic, renal, hematologic or EKG abnormalities

Interventions
  1. Tinidazole: 600 mg twice daily orally for 5 days

  2. Metronidazole: 400 mg thrice daily orally for 5 days (for acute amoebic dysentery) or 800 mg thrice daily for 5 days (for other cases)

Treatment period was extended to 10 days in both groups when 5 days treatment was inadequate to relieve symptoms or clear the stools of E. histolytica

Outcomes
  1. Parasitological cure: eradication of E. histolytica from stools on day 30 after start of treatment

  2. Clinical cure: relief of presenting clinical signs and symptoms and healing of ulcers on sigmoidoscopy, when carried out

  3. Adverse events: voluntary reporting of clinical adverse events by participants; laboratory tests monitored before and after treatment including haemogram, urinalysis, serum bilirubin, transaminases (SGOT, SGPT), alkaline phosphatase, and blood urea

Notes

Location: India

Date: 1976 (date of publication only; actual study period not reported)

Source of funding: not stated

Tinidazole tablets (Fasigyn) were supplied by Pfizer Ltd.

Misra 1974

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear; reported as "single blind", but it was not stated who among the participants, care provider, or outcome assessor was blinded

Inclusion of all randomized participants: 100%

Participants

Number: 60 enrolled and analysed

Inclusion criteria: adults and children with clinical symptoms of intestinal amoebiasis and stool specimens positive for trophozoites or cysts of E. histolytica by direct smear or concentration method

Exclusion criteria: antiamoebic treatment in the preceding 1 month before enrolment; pregnant women; severe anaemia

Interventions
  1. Tinidazole: 600 mg twice daily orally for 5 days

  2. Metronidazole: 400 mg thrice daily orally for 5 days (for acute amoebic dysentery) or 800 mg thrice daily orally for 5 days (for chronic intestinal amoebiases if symptoms were more than 15 days duration)

Treatment period was extended to 10 days in both groups when 5 days treatment was inadequate to relieve symptoms or clear the stools of E. histolytica

Outcomes
  1. Parasitological cure: eradication of E. histolytica on follow-up stool examinations on day 30 after start of treatment

  2. Clinical cure: disappearance of presenting clinical symptoms and healing of ulcers on sigmoidoscopy on day 30 after start of treatment

  3. Adverse events: clinical adverse events monitored during treatment; laboratory tests monitored before and after treatment including complete blood count and platelet count, urinalysis, electrocardiogram, blood urea, serum bilirubin, alkaline phosphatase, and liver transaminases (SGOT, SGPT)

Notes

Location: Medical College Hospital in Bhopal, India

Date: 1974 (date of publication only; actual study period not reported)

Source of funding: Pfizer Ltd. for support and for supply of study drugs tinidazole (Fasigyn) and metronidazole (Flagyl)

Misra 1977

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear

Inclusion of all randomized participants: 100%

Participants

Number: 60 enrolled and analysed

Inclusion criteria: adults with clinical symptoms of intestinal amoebiasis and stool specimens positive for trophozoites or cysts of E. histolytica by direct smear or formol-ether concentration technique, sigmoidoscopy for colonic ulcers, and parasitological examination of sigmoidoscopic scrapings

Exclusion criteria: received antiamoebic treatment within the previous 4 weeks; pregnant women; dehydrated patients; evidence of hepatic, renal, hematologic, or EKG abnormalities

Interventions
  1. Tinidazole: 2 g single oral dose daily for 3 days

  2. Metronidazole: 2 g single oral dose daily for 3 days

Not stated if tinidazole and metronidazole were identical in appearance.

Outcomes
  1. Parasitological response: eradication of E. histolytica from stools on day 30 after start of treatment

  2. Clinical response: disappearance of presenting clinical symptoms on day 30 after start of treatment

  3. Adverse events: voluntary reporting of clinical adverse events by participants; laboratory tests monitored before and after treatment including urinalysis, complete blood count, serum bilirubin, alkaline phosphatase, liver transaminases (SGOT, SGPT), blood urea, and electrocardiogram

Notes

Location: hospital in Bhopal, India

Date: 1977 (date of publication only; actual study period not reported)

Source of funding: not stated

Unclear if Misra 1977 and Misra 1978 reported the results for same group of participants

Several attempts were made to contact the authors, but no response was obtained

Misra 1978

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear

Inclusion of all randomized participants: 98.3% (59/60)

Participants

Number: 60 enrolled; 59 analysed, 1 randomized to tinidazole group excluded because it was discovered later that he had a history of ulcerative colitis

Inclusion criteria: adults with clinical symptoms of intestinal amoebiasis and stool specimens positive for trophozoites and cysts of E. histolytica by direct smear or formol-ether concentration technique, sigmoidoscopy for colonic pathology

Exclusion criteria: received antiamoebic treatment in the previous 4 weeks before enrolment

Interventions
  1. Tinidazole: 2 g single oral dose daily for 3 days

  2. Metronidazole: 2 g single oral dose daily for 3 days

Not stated if tinidazole and metronidazole were identical in appearance

Outcomes
  1. Parasitological cure: eradication of E. histolytica from stools on day 30 after start of treatment

  2. Clinical cure: disappearance of presenting clinical symptoms on day 30 after start of treatment

  3. Adverse events: voluntary reporting of clinical adverse events by participants; laboratory monitoring done before and after treatment including complete blood count, urinalysis, and blood chemistry

Notes

Location: hospital in Bhopal, India

Date: 1978 (date of publication only; actual study period not reported)

Source of funding: not stated

Unclear if Misra 1977 and Misra 1978 reported the results for same group of participants

Several attempts were made to contact the author, but no response was obtained

Mohammed 1998

Methods

Generation of allocation sequence: random-numbers table

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 72.5% (50/69)

Participants

Number: 69 enrolled; 50 analysed; 19 lost to follow up (11 in the praziquantel group, 8 in the metronidazole group); 3 in praziquantel group withdrawn from treatment because of lack of response

Inclusion criteria: adults with clinical symptoms of intestinal amoebiasis and stool specimens positive for vegetative trophozoite forms (acute amoebic dysentery) or cysts of E. histolytica; laboratory diagnostic method was not specified; those who were cyst passers were treated with praziquantel alone and were not included in the review

Exclusion criteria: not stated

Interventions
  1. 1. Praziquantel: 40 mg/kg body weight divided into 2 doses orally and taken 4 to 6 hours apart

  2. 2. Metronidazole: 800 mg thrice daily orally for 5 days

Outcomes
  1. Parasitological response: disappearance of E. histolytica from stools 1 week after treatment

  2. Clinical response: disappearance of baseline clinical signs and symptoms at the end of treatment

  3. Adverse events: voluntary reporting of clinical adverse events by participants only for praziquantel

Notes

Location: outpatients in Iraq

Date: 1993 to 1995

Source of funding: not stated

Naoemar 1973

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: double (participants, care providers, and outcome assessors)

Inclusion of all randomized participants: 100% at end of treatment; 96.7% at 7 weeks after end of treatment

Participants

Number: 20 enrolled, 20 analysed

Inclusion criteria: adults and children with bloody diarrhoea and stools positive for motile haematophagous trophozoites of E. histolytica examined by eosin and iodine smears

Exclusion criteria: anaemia or other diseases but exact conditions not stated

Interventions
  1. Ro 7-0207 (ornidazole)

  2. Metronidazole

Both drugs given as follows: 2 to 6 years of age – 125 mg daily in 3 divided doses for 7 days; 7 to 12 years of age – 250 mg daily in 3 divided doses for 7 days; adults – 1500 mg daily in 3 divided doses for 5 days

Ro 7-0207 and metronidazole were identical in appearance (light yellow capsules) and kept in numbered bottles

Outcomes
  1. Parasitological response: clearance of E. histolytica from stools at the end of treatment and 1 month after end of treatment

  2. Relapse: reappearance of E. histolytica in stools 1 month after end of treatment

  3. Clinical cure: disappearance of symptoms at the end of treatment and at 1 month after end of treatment

  4. Adverse events: clinical adverse events monitored during treatment; laboratory tests monitored before and after the end of treatment including complete blood counts, liver transaminase (SGPT), alkaline phosphatase, urinalysis, blood urea, and electrocardiogram

Not included in this review: number of days from start of treatment to clearance of E. histolytica in stool specimens and disappearance of symptoms

Notes

Location: outpatient clinics in Jakarta, Indonesia

Date: 1973 (date of publication only; actual study period not reported)

Source of funding: Roche Far East Research Foundation for supply of drugs and support for the study

Nnochiri 1967

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: double (participants, care provider, and outcome assessors)

Inclusion of all randomized participants: 100% at end of treatment; 96.7% (58/60) at 7 weeks after end of treatment

Participants

Number: 60 with acute amoebic dysentery enrolled; 60 analysed at end of treatment, and 58 (96.8%) analysed 7 weeks after end of treatment

Inclusion criteria: military personnel and their families diagnosed with acute amoebic dysentery and stool specimens positive for E. histolytica examined by saline and iodine-stained smears

Exclusion criteria: not stated

Interventions
  1. Diloxanide furoate, tetracycline hydrochloride, and chloroquine phosphate (per capsule): diloxanide furoate (187.5 mg), tetracycline hydrochloride (125 mg), and chloroquine phosphate (50 mg) given in 3 dosage regimens of 2 capsules 4 times a day for 5 days, 2 capsules 4 times a day for 7 days, or 2 capsules 4 times a day for 10 days

  2. Diloxanide furoate and tetracycline hydrochloride (per capsule): diloxanide furoate (187.5 mg) and tetracycline hydrochloride (125 mg) given in 3 dosage regimens of 2 capsules 4 times a day for 5 days, 2 capsules 4 times a day for 7 days, or 2 capsules 4 times a day for 10 days

The 2 drug combinations with and without chloroquine were identical in appearance

Outcomes
  1. Parasitological response: clearance of E. histolytica cysts and trophozoites at end of treatment, then on follow up 7 weeks from completion of treatment; patients whose stools remained negative 7 weeks after treatment were followed up 3 and 6 months from completion of treatment

  2. Clinical response: recurrence of symptoms (results were not reported and could not be included in the meta-analysis)

  3. Adverse events: clinical adverse events monitored during treatment and on follow up; laboratory tests monitored before and after treatment including urine cytology and presence of protein, blood examination for haemoglobin, total erythrocyte and leucocyte counts and differential count

Not included in this review: clearance of E. histolytica from stools of 36 asymptomatic cyst carriers

Notes

Location: Yaba Military Hospital in Lagos, Nigeria

Date: August 1965 to July 1966

Source of funding: Messrs Boots Pure Drug Co., Ltd, Nottingham, England

Padilla 2000

Methods

Generation of allocation sequence: coin toss

Allocation concealment: unclear

Blinding: double blind (participants and outcome assessors for clinical and parasitological outcomes blinded; unclear if care provider (main investigator) who administered the medications was blinded)

Inclusion of all randomized participants: 100%

Participants

Number: 239 enrolled and analysed

Inclusion criteria: children with clinical symptoms of nondysenteric amoebic colitis with at least 1 of 3 stool specimens positive for E. histolytica cysts examined by direct smear using Faust concentration method

Exclusion criteria: history of sensitivity to clioquinol or to metronidazole and its derivatives; children who had received antibacterial and/or antiparasitic drugs in the 15 days before their entry into the study; those with amoebic dysentery

Interventions
  1. Secnidazole: 30 mg/kg body weight orally in a single dose

  2. Quinfamide: 4.3 mg/kg body weight orally in a single dose

Outcomes
  1. Parasitological response: clearance of E. histolytica cysts on days 5, 6, and 7 after administration of the drugs

  2. Adverse events: clinical adverse events were solicited by the investigators through direct questioning for the presence of abdominal pain, nausea, vomiting, headache, diarrhoea, and unpleasant taste in the mouth

Not included in this review: acceptability of taste

Notes

Location: 2 urban federal elementary schools in Celaya, Guanajuato, Mexico (Urban Federal Elementary schools 'Carmen Serdan' and 'Juan Jesus de los Reyes')

Date: 2000 (date of publication only; actual study period not reported)

Source of funding: not stated

Pamba 1990

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: single (only outcome assessor for parasitological response and rectosigmoidoscopy results were blinded; not stated if assessor for clinical response was blinded)

Inclusion of all randomized participants: 88.5% (369/417) 15 days after start of treatment, 67.6% (282/417) 30 days after start of treatment, and 51.3% (214/417) 60 days after start of treatment

Participants

Number: 417 enrolled; 369/417 (88.5%) analysed 15 days after start of treatment, 282/417 (67.6%) analysed 30 days after start of treatment, and 214/417 (51.3%) analysed 60 days after start of treatment; recruitment to the etophamide plus aminosidine group was discontinued because of high incidence of diarrhoea; withdrawals not stated for the other groups

Inclusion criteria: children with clinical symptoms of intestinal amoebiasis with stool specimens positive for E. histolytica by direct smear and a concentration method (not specified)

Exclusion criteria: pregnant women; known allergy to the drugs; those with co-existing extra-intestinal amoebiasis or other major diseases; treated with antiamoebic drugs in the 30 days before recruitment

Interventions
  1. Aminosidine (A): 500 mg twice daily orally for adults, 15 mg/kg body weight for children given orally for 5 days

  2. Etophamide (E): 600 mg twice daily orally for adults,15 mg/kg body weight for children given orally for 5 days

  3. Nimorazole (N): 1 g twice daily orally for adults, 20 mg/kg body weight for children given orally for 5 days

  4. Combination of nimorazole and aminosidine (NA): same doses as above for 5 days

  5. Combination of nimorazole and etophamide (NE): same doses as above for 5 days

  6. Combination of etophamide and aminosidine (EA): same doses as above for 5 days

Outcomes
  1. Parasitological cure: disappearance of any form of E. histolytica from stools or ulcer scrapings at the end of treatment

  2. Recurrence (relapse): reappearance of E. histolytica during follow up on days 15, 30, and 60 after initial disappearance; due to incomplete data on follow up; results could not be included in the meta-analysis

  3. Clinical cure: disappearance of all baseline symptoms at the end of treatment

  4. Adverse events: clinical adverse events monitored during treatment

Not included in this review: cumulative daily clearance of E. histolytica from stools during treatment, at the end of treatment, and on days 15, 30, and 60 after start of treatment; evolution of mild and severe amoebic ulcers seen on rectosigmoidoscopy; and anatomical cure (healing of previous ulceration)

Notes

Location: 3 district hospitals of Kiambo, Machakos and Kilifi in Kenya, Africa

Date: 1990 (date of publication only; actual study period not reported)

Source of funding: Farmitalia Carlo Erba

Panggabean 1980

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: reported as "double-blind", but only care provider was blinded; blinding of participants and outcome assessors not described

Inclusion of all randomized participants: 62.5% (25/40) 1 week after treatment, 42.5% (17/40) 2 weeks after treatment, 27.5% (11/40) 3 weeks after treatment, and 15% (6/40) 4 weeks after treatment

Participants

Number: 40 enrolled; 25/40 (62.5%) analysed 1 week after treatment, 17/40 (42.5%) analysed 2 weeks after treatment, 11/40 (27.5%) analysed 3 weeks after treatment, and 6/40 (15%) analysed 4 weeks after treatment

Inclusion criteria: children with amoebic dysentery presenting with bloody stools and motile haematophagous trophozoites of E. histolytica in stools examined by direct smear method with eosin 2% stain

Exclusion criteria: not stated

Concomitant intestinal infection: 35 participants included in the analysis had concomitant intestinal helminthic infection and groups were comparable for numbers and type of concomitant intestinal helminthic infection (tinidazole group: Ascaris lumbricoides 10, Trichuris trichiura 26, Ancylostoma 2; ornidazole group: Ascaris lumbricoides 12, Trichuris trichiura 12, Ancylostoma 3)

Interventions
  1. Tinidazole: 50 mg/kg body weight in a single oral dose daily for 3 days

  2. Ornidazole: 50 mg/kg body weight in a single oral dose daily for 3 days

Other interventions: children with concomitant intestinal helminthic infection were given single-dose pyrantel pamoate 10 mg/kg and those with trichuriasis were given mebendazole 1 tablet twice daily for 3 consecutive days

Outcomes
  1. Parasitological cure: disappearance of all forms of E. histolytica on stool examinations done weekly until 4 weeks after completion of treatment

  2. Reinfection: reappearance of E. histolytica after the second month

  3. Clinical cure: disappearance of blood and mucus from stools at follow-up examinations done weekly until 4 weeks after completion of treatment

  4. Adverse events: clinical adverse effects reported by participants during treatment

Notes

Location: outpatient clinic of the Sub-department of Gastroenterology, Department of Child Health Medical School, General Hospital, Medan, Indonesia

Date: January 1978 to June 1978

Source of funding: PT. Pfizer Indonesia and PT. Hoffman-La Roche

Pehrson 1983

Methods

Generation of allocation sequence: unclear (unrecalled by primary author during personal communication)

Allocation concealment: inadequate – no attempts to conceal treatment allocation (personal communication with primary author)

Blinding: open

Inclusion of all randomized participants: 100%

Participants

Number: 41 enrolled and analysed

Inclusion criteria: adults and children with clinical symptoms of intestinal amoebiasis but no signs of invasion (eg no fever or acute dysentery) and stool specimens positive for trophozoites or cysts of E. histolytica by direct smear or formol-ether concentration technique by Ridley and Hawgood; had not received any antiamoebic drug during the previous year

Exclusion criteria: acute dysenteric amoebiasis; liver abscess

Concomitant intestinal infection: 17 patients had concomitant infection with other intestinal organisms (Giardia lamblia 9, Campylobacter jejuni 2, Hymenolepsis nana 1, Ascaris lumbricoides 1, Trichuris trichiura 1, Salmonella paratyphi A 1), but the distribution in the 2 groups was not specified

Interventions
  1. Tinidazole: 40 mg/kg body weight in a single oral dose daily for 5 days

  2. Tinidazole plus diloxanide furoate: tinidazole 40 mg/kg body weight in a single oral dose daily for 5 days plus diloxanide furoate 20 mg/kg body weight divided into 3 daily doses for 10 days

Outcomes
  1. Parasitological response: clearance of E. histolytica in any of the 3 stool specimens evaluated 1 month after end of treatment

  2. Adverse events: only adverse events severe enough to result in cessation of therapy

Notes

Location: hospital in Stockholm, Sweden

Date: 1983 (date of publication only; actual study period not reported)

Source of funding: not reported

The author was contacted and kindly provided further data. Details on method of randomization could not be recalled by the trial author

Pehrson 1984

Methods

Generation of allocation sequence: unclear (unrecalled by primary author during personal communication)

Allocation concealment: inadequate – no attempts to conceal treatment allocation (personal communication with primary author)

Blinding: open

Inclusion of all randomized participants: 100%

Participants

Number: 30 enrolled and analysed

Inclusion criteria: adults with clinical symptoms of intestinal amoebiasis but no signs of invasion (eg no fever or acute dysentery) and stool specimens positive for trophozoites or cysts of E. histolytica examined by direct smear or formol-ether concentration technique

Exclusion criteria: not stated

Interventions
  1. Tinidazole: 600 mg twice daily orally for 5 days

  2. Metronidazole: 800 mg thrice daily orally for 5 days

Outcomes
  1. Parasitological cure: clearance of E. histolytica trophozoites or cysts in any of the 3 stool specimens taken 1 month after end of treatment

  2. Adverse events: only adverse events severe enough to result in cessation of therapy

Notes

Location: Stockholm, Sweden

Date: 1984 (date of publication only; actual study period not reported)

Source of funding: not reported

The author was contacted and kindly provided further data. Details on method of randomization could not be recalled by the trial author

Prasad 1985

Methods

Generation of allocation sequence: unclear

Allocation concealment: coded drug containers; code broken only at the end of the trial

Blinding: double (participants, care provider, and outcome assessor)

Inclusion of all randomized participants: 91.1% (164/180)

Participants

Number: 180 patients with amoebiasis or giardiasis or both were enrolled; 164/180 (91.1%) analysed, 90 with amoebiasis alone, 47 with giardiasis, and 27 with mixed infection with amoebiasis and giardiasis; 16/180 (8.9%) did not complete treatment and were dropped from the trial but not stated if those who dropped out had amoebiasis, giardiasis, or mixed infection

Inclusion criteria: children with clinical symptoms of intestinal amoebiasis or giardiasis (diarrhoea, abdominal pain, dysentery, gastrocolic urgency, etc.) and whose stools were positive for amoeba or giardia; laboratory diagnostic method was not specified

Exclusion criteria: not stated

Concomitant intestinal infection: Ascaris lumbricoides present in 20%, Ancylostoma duodanale 9.9%, Enterobius vermicularis 1.8%, but distribution in the 2 groups not reported

Interventions
  1. Metronidazole: 100 mg/5 mL suspension, given as 5 mL thrice daily for those 1 to 5 years of age and 10 mL thrice daily for those 6 to 15 years of age for 5 or 10 days depending on severity of disease

  2. Metronidazole plus furazolidone: fixed-drug combination suspension of (per 5 mL) metronidazole 75 mg plus furazolidone 25 mg, given as 5 mL thrice daily for those 1 to 5 years of age and 10 mL thrice daily for those 6 to 15 years of age for 5 or 10 days depending on severity of disease

Outcomes
  1. Parasitological and clinical response: evaluated jointly on day 7 after start of therapy; overall outcome was reported as complete cure, partial cure, and no cure but these terms were not defined

  2. Adverse events: clinical adverse events reported by participants during treatment

Not included in this review: clinical and parasitological response in those with mixed amoebiasis and giardiasis infection

Notes

Location: paediatric outpatient department of S.N. Medical College, Agra, India

Date: 1985 (date of publication only; actual study period not reported)

Source of funding: not stated

Attempts made to contact the authors were unsuccessful

Pudjiadi 1973

Methods

Generation of allocation sequence: unclear

Allocation concealment: sequentially numbered coded drug containers supplied by Roche Far East Research Foundation, Hong Kong; sealed envelope containing the list of the drugs only opened after the entire trial was finished

Blinding: double (participants, care providers, and outcome assessors)

Inclusion of all randomized participants: 100%

Participants

Number: 20 enrolled and analysed

Inclusion criteria: children with bloody diarrhoea and stools positive for E. histolytica examined by eosin and Lugol's solution

Exclusion criteria: not stated

Concomitant intestinal infection: Ascaris lumbricoides found in faeces of 6 participants, Trichuris trichiura found in feces of 6 participants, but distribution in the 2 groups not specified

Interventions
  1. Ro 7-0207 (ornidazole): 125 mg capsules

  2. Metronidazole: 125 mg capsules

Both drugs were given as follows: up to 2 years of age – 62.5 mg, 2 to 6 years of age – 125 mg, and 6 to 12 years of age 250 mg daily, divided into 3 daily doses for 7 days

Outcomes
  1. Parasitological response: clearance of E. histolytica from stools after 7 days of treatment

  2. Clinical response: disappearance of clinical symptoms after 7 days of treatment

  3. Adverse events: clinical adverse events monitored during treatment; laboratory tests monitored before, during and after treatment including complete blood count, urine analysis, electrocardiogram, liver transaminases (SGPT), and alkaline phosphatase

Not included in this review: number of days from start of treatment to disappearance of E. histolytica in the stools; number of days from start of treatment to disappearance of clinical symptoms

Notes

Location: hospital on the Department of Child Health, Medical School University of Indonesia, Jakarta, Indonesia

Date: 1973 (date of publication only; actual study period not reported)

Source of funding: Roche Far East Research Foundation for supply of drugs and study grant

Rossignol 2001

Methods

Generation of allocation concealment: unclear

Allocation concealment: unclear

Blinding: double (participants, care provider, and outcome assessors)

Inclusion of all randomized participants: 100%

Participants

Number: 91 enrolled but only 67 (74%) had Entamoeba histolytica (53 with single and 14 with mixed Giardia and Entamoeba infection); 67 analysed

Inclusion criteria: adults and children with diarrhoea and stool specimens positive for cysts or trophozoites of E. histolytica and/or E. dispar alone or with concomitant Giardia intestinalis by direct smear, concentration technique, Ziehl-Neelsen stain, and an immunofluorescent assay (MeriFluor Meridian Diagnostics)

Exclusion criteria: pregnant women; using any drug with antiprotozoal activity within 2 weeks of enrolment; and known to have or suspected of having acquired immunodeficiency syndrome (AIDS)

Concomitant intestinal infection: mixed Entamoeba histolytica and Giardia intestinalis infection in 6/36 (17%) of participants in the nitazoxanide group and 8/31 (26%) in the placebo group

Interventions
  1. Nitazoxanide: 500 mg twice daily orally for 3 days

  2. Placebo tablet (identical): twice daily orally for 3 days

Outcomes
  1. Parasitological response: clearance of E. histolytica from 2 stool specimens collected between days 7 and 10 after start of treatment

  2. Clinical response: disappearance of symptoms, resolution of diarrhoea and haematochezia on day 7 after start of treatment

  3. Adverse events: clinical adverse events monitored by study personnel

Not included in this review: median time from initiation of therapy to passage of the last unformed stools

Notes

Location: outpatient clinic of the Department of Hepatology, Gastroenterology, and Infectious Diseases of the Benha University Hospital, governorate of Kalubia, Nile delta, Egypt

Date: 2001 (date of publication only; actual study period not reported)

Source of funding: not stated

Rossignol 2007

Methods

Generation of allocation sequence: computer-generated randomization

Allocation concealment: unclear

Blinding: double (participants, care providers, outcome assessors)

Inclusion of all randomized participants: 100%

Participants

Number: 100 enrolled and 100 analysed; 2 participants in the placebo group lost to follow up and were considered treatment failures

Inclusion criteria: adults and children with diarrhoea; ≥ 1 enteric symptoms; E. histolytica/E. dispar trophozoites identified in stool by microscopic examination using direct smear and concentration technique; stool-positive for E. histolytica by antigen-based ELISA

Exclusion criteria: other enteric pathogens identified by Ziehl-Neelsen stain, immunofluorescent assay (MeriFluor Meridian Diagnostics) and stool culture; pregnant and lactating women; using any drug with antiprotozoal activity within 2 weeks of enrolment; and known to have or suspected of having acquired immunodeficiency syndrome (AIDS) or other immune deficiencies

Interventions
  1. Nitazoxanide: for 3 days; adults aged ≥ 12 years, 500 mg tablet twice daily; children 100 mg/5 mL suspension – 1 to 3 years received 5 mL twice daily, 4 to 11 years received 10 mL twice daily

  2. Placebo: matching placebo tablet or suspension twice daily for 3 days

Outcomes
  1. Parasitological response: clearance of E. histolytica from 2 stool specimens collected between days 7 to 10 after the start of treatment

  2. Clinical response: disappearance of symptoms, resolution of diarrhoea and hematochezia on day 7 after start of treatment

  3. Adverse events: monitored by patient diary

Not included in this review: time from first dose to passage of last unformed stools

Notes

Location: outpatient clinic of the Benha University Hospital, Benha, Egypt

Date: 17 February 2004 to 2 October 2005

Source of funding: Romark Laboratories, L.C.

Rubidge 1970

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 100%

Participants

Number: 39 enrolled and analysed

Inclusion criteria: children with amoebic dysentery presenting with acute onset of diarrhoea with blood, mucus and actively motile haematophagous trophozoites of E. histolytica in stool specimens examined by direct smear and zinc sulfate flotation technique

Exclusion criteria: not stated

Interventions
  1. Metronidazole: 50 mg per kg body weight orally for 7 days

  2. Dehydroemetine, tetracycline, and diloxanide furoate: dehydroemetine (2 mg/kg body weight daily by subcutaneous injection for 10 days), tetracycline (50 mg/kg body weight daily orally for 7 days), and diloxanide furoate (25 mg/kg body weight daily orally for 10 days)

Outcomes
  1. Parasitological response: clearance of E. histolytica at end of treatment and on subsequent stool specimens during follow up until 28 days after start of treatment

  2. Clinical response: disappearance of symptoms at end of treatment and during follow up until 28 days after start of treatment

  3. Adverse events: only tolerance to the drugs was reported

Notes

Location: hospital in Durban, South Africa

Date: 1970 (date of publication only; actual study period not reported)

Source of funding: not stated; metronidazole was supplied by Messrs. May and Baker, Ltd

Salles 1999

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 90.7% (275/303) included in evaluation for clinical efficacy, 99% (300/303) included in evaluation for parasitological efficacy

Participants

Number: 303 enrolled; 275/303 (90.7%) included in evaluation for clinical efficacy; 300/303 (99%) included in evaluation for parasitological efficacy

Inclusion criteria: children with clinical symptoms of intestinal amoebiasis with stool specimens positive for E. histolytica by direct smear using the Faust and Katz method and no history of intolerance to imidazole drugs

Exclusion criteria: history of vomiting in the last 48 hours; taken anti-emetic drugs in the last 24 hours; treated with antiamoebic drugs in the last 15 days; symptoms of extraintestinal amoebiasis

Concomitant intestinal infection: groups were comparable for presence of other intestinal parasites (Ascaris lumbricoides, Tricuris trichiura, Giardia lamblia, Necator americanus, Ancylostoma, Hymenolepsis nana, Schistosoma. Enterobius vermicularis, Endolimax nana) except for Strongyloides stercoralis which was more frequent in the tinidazole group (3 participants) compared with the secnidazole group (11 participants)

Interventions
  1. Secnidazole: 1 mL/kg body weight orally in a single dose

  2. Tinidazole: 0.5 mL/kg body weight once daily orally for 2 days

Outcomes
  1. Parasitological response: clearance of E. histolytica from stool specimens collected on days 7, 14, and 21 following treatment

  2. Clinical response: disappearance of all symptoms at the end of the study (day 21)

  3. Adverse events: solicited from the participants or their guardians during the follow-up visits

Notes

Location: 5 different centres in Brazil

Date: 1999 (date of publication only; actual study period not reported)

Source of funding: not stated

One author (Valfredo Costa) is connected with Rhodia Farma Ltd, the manufacturer of Secnidal (secnidazole)

Singh 1977

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 93.3% (56/60)

Participants

Number of participants randomized: 60 to 2 treatment groups

Number: 60 enrolled; 56 analysed; 3 participants in the tinidazole group and 1 in the metronidazole group did not comply with the regimen and were excluded from analysis

Inclusion criteria: adults with clinical symptoms of intestinal amoebiasis and stool specimens positive for trophozoites or cysts of E. histolytica by direct smear or formol-ether concentration technique

Exclusion criteria: received antiamoebic treatment in the previous 4 weeks before enrolment; pregnant women; dehydrated patients; evidence of hepatic, renal, hematologic, or EKG abnormalities

Concomitant intestinal infection: 12 had concomitant giardiasis, 6 in each group

Interventions
  1. Tinidazole: 500 mg tablets x 4 (2 g) single-dose daily for 3 days

  2. Metronidazole: 400 mg tablets x 5 (2 g) single-dose daily for 3 days

Outcomes
  1. Parasitological response: eradication of E. histolytica on follow-up stool examinations on day 30 after start of treatment

  2. Clinical response: disappearance of presenting clinical signs and symptoms on day 30 after start of treatment

  3. Adverse events: voluntary reporting of clinical adverse events by the participants; laboratory tests monitored before and after treatment including complete blood count, urinalysis, serum bilirubin, alkaline phosphatase, transaminases, and blood urea

Notes

Location: medical outpatient department of the Government Medical College and Hospital, Patiala India

Date: September 1982 to September 1983

Source of funding: not stated; tinidazole was supplied by Pfizer Ltd.

Sitepu 1982

Methods

Generation of allocation sequence: random-numbers table

Allocation concealment: unclear

Blinding: unclear; reported as "double blind", but procedure for blinding participants, care provider, and outcome assessor not described

Inclusion of all randomized participants: 82% (41/50) included in analysis on third day or 2 days after treatment, 36% (18/50) 1 week after treatment

Participants

Number: 50 enrolled; 41/50 (82%) analysed on the third day or 2 days after treatment, 18/50 (36%) were analysed 1 week after treatment

Losses to follow up: 9/51 (18%) were lost to follow up by the third day or 2 days after treatment, 7 participants in the tinidazole group and 2 in the ornidazole group; 32/50 (64%) were lost to follow up 1 week after treatment, 18 in the tinidazole group and 14 in the ornidazole group

Inclusion criteria: children with amoebic dysentery presenting with bloody diarrhoea and motile haematophagous trophozoites of E. histolytica in stools examined by direct smear method with eosin 1% stain

Exclusion criteria: not stated

Concomitant intestinal infection: trichuriasis (12 in tinidazole group and 15 in ornidazole group)

Interventions
  1. Tinidazole: 50 mg/kg body weight in a single oral dose

  2. Ornidazole: 50 mg/kg body weight in a single oral dose

Outcomes
  1. Parasitological response: clearance of E. histolytica from stools on subsequent follow-up visits on days 2 to 4 and 1 week after treatment

  2. Clinical response: disappearance of diarrhoea and faeces no longer contained mucus or red blood cells on days 2 to 4 and 1 week after treatment

Notes

Location: outpatient clinic of the Pediatric Gastroenterology Subdivision, Department of Child Health, School of Medicine, University of North Sumatra/Dr Pirngadi Hospital, Medan, Indonesia

Date: August 1978 to May 1979

Source of funding: PT. Pfizer Indonesia and PT. Hoffman-La Roche

Soedin 1985

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 100%

Participants

Number: 80 enrolled and analysed

Inclusion criteria: children with clinical symptoms of acute intestinal amoebiasis with stool specimens positive for trophozoites or haematophagous forms of E. histolytica; laboratory diagnostic method was not specified

Exclusion criteria: not stated

Interventions
  1. Secnidazole: 2 g orally in a single dose

  2. Tetracycline and clioquinol: tetracycline (750 mg) and clioquinol (1 g for 5 days)

Co-intervention: 2 cases on secnidazole group were given spasmolytics (unspecified) for stomach cramps

Outcomes
  1. Parasitological response: eradication of E. histolytica in stools examined on days 1 to 7, 7, 14, and 21 after start of treatment

  2. Clinical response: disappearance of clinical symptoms on days 1 to 7, 14, 21 and 28 after start of treatment

  3. Adverse events: clinical adverse events during follow up

Notes

Location: outpatient in the Padang Bulan Health Centre, Medan, Indonesia

Date: September 1982 to September 1983

Source of funding: not stated

Swami 1977

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear

Inclusion of all randomized participants: 93.3% (56/60)

Participants

Number: 60 enrolled; 56/60 (93.3%) analysed; 3/60 (5%) lost to follow up after day 4 (1 in tinidazole group, 2 in metronidazole group); 1 case in the metronidazole group subsequently found to have amoebic liver abscess was excluded from the final analysis

Inclusion criteria: adults with clinical symptoms of intestinal amoebiasis and stool specimens positive for trophozoites or cysts of E. histolytica; laboratory diagnostic method was not specified

Exclusion criteria: received antiamoebic treatment in previous 4 weeks; pregnant women; patients with marked dehydration; concomitant serious illness (not specified)

Type of amoebic colitis: tinidazole group: amoebic dysentery 20/29, nondysenteric amoebic colitis 9/29; metronidazole group: amoebic dysentery 22/27, nondysenteric amoebic colitis 5/27

Interventions
  1. Tinidazole: 2 g single-dose daily for 3 days

  2. Metronidazole: 2 g single-dose daily for 3 days

Treatment was extended if E. histolytica persisted in the stool on the day following the last treatment period

Outcomes
  1. Parasitological response: eradication of E. histolytica on follow-up stool examinations on day 30 after start of treatment

  2. Clinical response: relief of presenting clinical signs and symptoms on day 30 after start of treatment

  3. Adverse events: voluntary reporting of adverse events by participants; laboratory tests monitored before and after treatment including blood counts, urinalysis, serum bilirubin, alkaline phosphatase, transaminases (SGOT, SGPT), and blood urea

Not included in this review: number of participants who required extension of treatment beyond 3 days

Notes

Geographic location: Visakhapatnam, India

Date: 1977 (date of publication only; actual study period not reported)

Source of funding: not stated

Toppare 1994

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized participants: 100%

Participants

Number: 102 enrolled and analysed

Inclusion criteria: children with gastrointestinal symptoms and stool specimens positive for haematophagous trophozoites of E. histolytica; laboratory diagnostic method not specified

Exclusion criteria: not stated

Concomitant intestinal infection: all cases in both groups had negative stool cultures for pathogenic bacteria

Interventions
  1. Secnidazole: 30 mg/kg body weight as a single oral dose daily for 3 days

  2. Ornidazole 15 mg/kg body weight given twice daily orally for 10 days

Outcomes
  1. Parasitological cure: clearance of E. histolytica cyst or trophozoite from stools 10 days after completion of treatment

  2. Clinical response: range and mean number days from start of treatment to resolution of clinical symptoms

  3. Adverse events: method for obtaining information on adverse events, specific adverse events, and number of participants who developed any adverse events were not reported

Notes

Location: Medical Center Hospital, Ankara, Turkey

Date: 1994 (date of publication only; actual study period not reported)

Source of funding: not stated

Attempts to contact the authors were unsuccessful

Tripathi 1986

Methods

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear; reported as "double-blind", but procedure for blinding the participants, care provider, and outcome assessor not described

Inclusion of all randomized participants: 100%

Participants

Number: 40 enrolled and analysed

Inclusion criteria: adults with symptoms of intestinal amoebiasis and stool specimens positive for E. histolytica by direct smear and formol-ether concentration methods, sigmoidoscopy, colonic ulcer scrapings and positive stool culture on NIH media

Exclusion criteria: received amoebicidal drugs during the previous 4 weeks; pregnant women; dehydrated patients; liver abscess and any evidence of hepatic, renal, haematological, and ECG abnormalities

Concomitant intestinal infection: 4 in each group had concomitant Giardia lamblia in the stools

Interventions
  1. GO 10213 (satranidazole): 150 mg thrice daily for 10 days

  2. Metronidazole: 400 mg thrice daily for 10 days

Outcomes
  1. Parasitological response: eradication of E. histolytica on stool examinations on follow up 28 days after start of treatment

  2. Clinical response: relief of presenting clinical signs and symptoms and healing of ulcers on sigmoidoscopy on follow up 28 days after start of treatment

  3. Adverse events: volunteered by the participants; laboratory tests monitored before and after treatment including complete blood count, liver transaminases (SGOT, SGPT), serum bilirubin, blood urea, urinalysis, and electrocardiogram

Not included in this review: frequency of loose stools/day from start of treatment

Notes

Geographic location: hospital in Bhopal, India

Date: 1986 (date of publication only; actual study period not reported)

Source of funding: Ciba-Geigy India Limited

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    E. histolytica: Entamoeba histolytica; RCT: randomized controlled trial.

Abd-Rabbo 1969Not RCT
Abdallah 1969Not RCT
Achar 1967Not RCT
Ali Ata 1967Not RCT
Alterio 1968Not RCT
Amato Neto 1968Not RCT
Apt 1976Not RCT
Apt 1983Not RCT
Arredondo 1993Study population: RCT that compared medical treatment with medical treatment plus liver puncture in patients with amoebic liver abscess
Atias 1972Not RCT
Bakshi 1978Review of 17 RCTs conducted in India comparing tinidazole with metronidazole over a 2-year period
Banerjee 1976Not RCT
Baranski 1966Not RCT
Barroso 1969Not RCT
Bassily 1987Not RCT
Belkind 2004Study population: asymptomatic children positive for intestinal helminths or protozoa
Bezjak 1964Not RCT
Bhatia 1998Study population: RCT comparing metronidazole with secnidazole in treating patients with amoebic liver abscess
Biagi 1966The trial is an RCT comparing clefamide with placebo given not as treatment but as chemoprophylaxis for intestinal amoebiasis among asymptomatic carriers of E. histolytica. Both the primary trial and the subsidiary trial by Biagi are probably duplicate publications of the same study since the 2 trials are similar in all aspects of the study.
Biagi 1978Not RCT
Blanc 1965Not a RCT. Both reports (1965 and 1966) by Blanc are probably duplicate publications of the same study since the 2 trials are similar in all aspects of the study
Blessman 2002Study population: RCT comparing paromomycin with diloxanide furoate for the treatment of asymptomatic carriers of E. histolytica
Blessman 2003aIntervention and study population: RCT comparing metronidazole alone with ultrasound-guided needle aspiration of the abscess in addition to metronidazole in patients with amoebic liver abscess
Botero 1967Not RCT
Campos 1969Not RCT
Cardoso Salles 1970Not RCT: alternate allocation of patients with intestinal amoebiasis to receive 2 different doses of ethylchlordiphene
Cariry 1969Not RCT
Chari 1970Not RCT
Chaudhuri 1966Not RCT
Cho 1972Not reported to be randomized but described as a double-blind trial comparing Ro 7-0207 with metronidazole in treating participants with intestinal amoebiasis or E. histolytica asymptomatic carriers; repeated attempts to gather more details from the authors were unsuccessful because the primary author is deceased and the other authors cannot be contacted
Cohen 1975Study population: RCT comparing chloroquine and metronidazole for the treatment of amoebic liver abscess
da Cunha 1977Not RCT
Datta 1974Study population: amoebic liver abscess
de Carvalho 1965Not RCT
de la Rey 1989Intervention and study population: RCT that randomized patients with amoebic liver abscess to either metronidazole alone or ultrasound-guided aspiration of the abscess in addition to metronidazole
de Oliveira 1969Not RCT
Delgado 1971Not RCT
Devic 1974Not RCT
Dhariwal 1963Not RCT
Donckaster 1957Not RCT
dos Santos 1969Not RCT
Doshi 1968Not RCT
el Mofti 1965Not RCT
Esquivel 1979Study population: RCT that compared metronidazole, emetine, or both for treating patients with amoebic liver abscess
Ey 1977Not RCT
Felix 1966Not a RCT. Both reports by Felix are probably duplicate publications of the same study since the 2 trials are similar in all aspects of the study
Freeman 1990Intervention and study population: compared efficacy of antiamoebic drug therapy plus needle aspiration with antiamoebic drug therapy alone for patients with amoebic liver abscess
Gilman 1980Not RCT: diagnostic validity study comparing conventional and immunofluorescent techniques for detection of E. histolytica in rectal biopsies
Gorbea 1989Not RCT
Hatchuel 1975Study population: double-blind trial that compared tinidazole and metronidazole for treating patients with amoebic liver abscess
Hoekenga 1951Not RCT
Holz 1965Not RCT
Huggins 1965Not RCT
Huggins 1969Not RCT
Huggins 1974Not a RCT. Both reports by Huggins are probably duplicate publications of the same study since the 2 trials are similar in all aspects of the study
Huggins 1977Not RCT
Huggins 1980Not RCT
Huggins 1981Not RCT
Irusen 1992Study population: amoebic liver abscess
Islam 1975Not RCT
Islam 1978aStudy population: RCT that compared metronidazole and tinidazole for treating patients with amoebic liver abscess
Islam 1978bStudy population: amoebic liver abscess
Jain 1990Study population: open clinical trial that compared efficacy of various treatment regimens containing dehydroemetine and/or metronidazole for treating patients with hepatopulmonary amoebiasis
Jayawickrema 1975Study population: RCT that compared metronidazole with emetine and chloroquine in the treatment of patients with hepatic amoebiasis
Kaur 1972Not RCT
Khalil 1987Not RCT
Khokhani 1977Study population: RCT that compared metronidazole with emetine and chloroquine in the treatment of patients with hepatic amoebiasis
Khokhani 1978Study population: RCT that compared metronidazole with tinidazole in the treatment of patients with amoebic liver abscess
Konar 1963Not RCT
Krishnaiah 2003Not RCT: pharmacokinetic trial comparing 2 formulations of tinidazole given to healthy human volunteers
Kurt 2008Study population: RCT comparing metronidazole with single-dose ornidazole for treatment of dientamoebiasis
Laham 1951Not RCT
Levy 1967Not RCT
Martinez 1969Not RCT
Masters 1979Not RCT
Mathur 1974Not RCT
McAuley 1992Not RCT
Mendis 1984Study population: RCT that compared metronidazole with tinidazole in the treatment of patients with hepatic amoebiasis
Misra 1976aNot RCT
Misra 1976bCombination of a RCT involving 60 patients randomly assigned to either tinidazole or metronidazole, and a nonrandomized trial involving 30 patients given tinidazole 600 mg twice daily for 5 to 10 days and another 20 patients given tinidazole at 2 g once daily for 3 days. There was no separate analysis for the randomized patients only. Several attempts to contact the authors were unsuccessful
Morales 1975Study population: RCT that compared intravenous metronidazole with intramuscular emetine in treating patients with amoebic liver abscess
Murray 1980Intervention: did not study effect of any antiamoebic drug for treating amoebic colitis
Muzzafar 2006Study population: amoebic liver abscess
Nahrevanian 2008Study population and not RCT: study to determine prevalence of Cryptosporidium in immunocompromised patients
Naik 1968Not RCT
Nanavati 1965Not RCT
Nel 1985Intervention and study population: study to determine indications for aspiration of amoebic liver abscess
Nel 1986Intervention and study population: study to determine if aspiration influences course of amoebic liver abscess
O'Holohan 1972Not RCT
Okeniyi 2007Study population: no mention of amoebic colitis
Olaeta 1996Not RCT: alternate allocation of patients with intestinal amoebiasis to receive either quinfamide or etofamide
Omrani 1995Not RCT
Orozco 1975Study population: amoebic liver abscess
Padilla 1995Study population: asymptomatic amoebic infection
Padilla 1998Unclear if RCT
Padilla 2002Intervention and study population: RCT where children whose stools became negative for E. histolytica cysts and were asymptomatic after 1 or 2 doses of quinfamide were randomized into 3 groups to determine whether administering quinfamide every 3 to 6 months resulted in reduction in frequency of amoebic infection to below 27%
Pimparkar 1966Not RCT
Populaire 1980Pharmacokinetic study of secnidazole given to healthy human volunteers
Powell 1965aNot RCT
Powell 1965bStudy population: clinical trial of dehydroemetine, emetine, and chloroquine in treating patients with amoebic liver abscess
Powell 1965cStudy population: amoebic liver abscess
Powell 1965dNot RCT
Powell 1966aNot RCT
Powell 1966bNot RCT
Powell 1966cNot RCT
Powell 1967Study population: asymptomatic amoebic colitis
Powell 1968Report of 5 trials using metronidazole in different dosages and durations for the treatment of amoebic dysentery
Powell 1969aNot RCT
Powell 1969bReview of several clinical trials using several amoebicides including niridazole, alone or in combination, in the treatment of amoebic dysentery or amoebic liver abscess
Powell 1969cGuidelines on how to conduct drug trials in amoebiasis
Powell 1971aNot RCT
Powell 1971bLetter relaying observation of authors that no cases of liver abscess developed among patients with amoebic dysentery given chloroquine in addition to broad spectrum antibiotics or luminal amoebicides compared to those not given chloroquine
Powell 1972aReport of clinical trials of new nitroimidazole derivatives for treating patients with amoebic liver abscess
Powell 1972bReview on the evolution of drug therapy for amoebiasis and also presents the latest developments on niridazole, metronidazole, and other nitroimidazole drugs undergoing clinical trials at that time
Powell 1973Not RCT
Prakash 1974Not RCT: alternate allocation of patients with intestinal amoebiasis to receive either tinidazole or metronidazole
Qureshi 1994Not RCT
Qureshi 1997Not RCT
Rodrigues 1968Not RCT
Ruas 1973Study population: amoebic liver abscess
Ruchko 1978Not RCT
Saha 1966Not RCT
Saha 1970Not RCT
Salem 1964Not RCT
Salem 1967Not RCT
Sandia 1977Not RCT
Sangiuolo 1969Study population: RCT comparing the efficacy of a combination of canulase and iodochlorhydroxyquinoline (Septo-canulase) with placebo for the treatment of patients who had "acute gastroenteritis, food-borne gastroenteritis, chronic enterocolitis, or ulcerative colitis". There was no mention of amoebic colitis or laboratory diagnosis of amoebic colitis among the included patients
Sankale 1966Not RCT
Sankale 1969Not RCT
Sankale 1974Not RCT
Satpathy 1988Study population: amoebic liver abscess
Schapiro 1967Not RCT
Scragg 1968Study population: amoebic liver abscess
Scragg 1970Study population: amoebic liver abscess
Segal 1967Not RCT
Sharma 1989Intervention and study population: RCT that compared metronidazole alone with needle aspiration of the abscess in addition to metronidazole in patients with amoebic liver abscess
Shrotriya 1985Not RCT
Simjee 1985Study population: amoebic liver abscess
Simon 1967Not RCT
Sinuhaji 1986Preliminary report of a trial on children with acute amoebic dysentery randomized to receive a single dose of either metronidazole 50 mg/kg body weight/day or secnidazole 30 mg/kg body weight/day. There were incomplete results and no final published report of this trial. Attempts to contact the authors or the institution where the study was conducted were unsuccessful
Sladden 1964Not RCT
Soh 1980Study population: amoebic liver abscess
Spellberg 1969Study population: amoebic liver abscess
Spillman 1976Study population: RCT that compared metronidazole with tinidazole for treating those with asymptomatic E. histolytica infection and/or E. hartmanni infections
Sutrisno 1978Not RCT
Tandon 1997Intervention and study population: RCT that compared metronidazole alone with needle aspiration of the abscess in addition to metronidazole in patients with amoebic liver abscess
Thoren 1990aStudy population: RCT that compared metronidazole, tinidazole, and diloxanide furoate in treating asymptomatic homosexual carriers of E. histolytica
Thoren 1990bStudy population: asymptomatic E. histolytica homosexual carriers
Tjaij 1969Not RCT
Tjaij 1970Not RCT
Vaidya 1983Pharmacokinetic study of Go.10213 and does not compare the drug with placebo or another antiamoebic drug
Vakil 1967Not RCT: alternate allocation of children and adults with amoebic dysentery, nondysenteric intestinal amoebiasis, or hepatic amoebiasis to receive either intramuscular dehydroemetine or emetine
Vakil 1971Not RCT
Vakil 1974Summary report of several clinical trials of various amoebicidal drugs conducted in one medical centre in Bombay, India over the past 12 years
Valencia 1973Review on use of erythromycin stearate over the last 3 years on 500 patients with intestinal amoebiasis, patients with amoebic cysts, and those with other diseases of the colon
Vanijanonta 1985Study population: patients with amoebic liver abscess were treated with low dose tinidazole and needle aspiration
Viswanathan 1968Not RCT
Wang 1971aNot RCT
Wang 1971bReport of 2 cases of oxytetracycline resistant amoebic dysentery
Watson 1975Study population: amoebic infection of the eye
Welch 1978Not RCT
Widjaya 1991Intervention and study population: RCT that compared various antiamoebic drug combinations with percutaneous drainage in addition to combination drug therapy for treating patients with amoebic liver abscess
Wilmot 1962Not RCT
Wolfe 1973Not RCT
Wolfensberger 1968Not RCT
Zuberi 1973Not RCT

Characteristics of studies awaiting assessment [ordered by study ID]

Guevara 1980

MethodsUnclear (reported as double-blind in the title)
ParticipantsNondysenteric amoebic colitis (from abstract)
InterventionsQuinfamide given at 3 doses (300 mg, 600 mg, and 1200 mg) vs teclozan (from abstract)
OutcomesEradication of amoeba in stools and rectosigmoidoscopic findings (from abstract)
NotesFull paper not available

Soedin 1989

MethodsUnknown
Participantsintestinal amoebiasis
InterventionsSingle-dose secnidazole versus 5-day regimen of a combination of tetracycline and clioquinol
OutcomesUnknown
NotesFull paper not available; may possibly be the same study as Soedin 1985

Ancillary