ORIGINAL ARTICLE 10.1111/j.1469-0691.2008.02002.x

A comparison of metronidazole and single-dose ornidazole for thetreatment of dientamoebiasisO. Kurt, N. Girginkardesler, I. C. Balcioglu, A. Ozbilgin and U. Z. Ok

Department of Parasitology, School of Medicine, Celal Bayar University, Manisa, Turkey

A B S T R A C T

Recent reports of the pathogenic potential of Dientamoeba fragilis have underlined the need for aneffective treatment against this colon-dwelling protozoan. Metronidazole is a well-known andcommonly used anti-protozoal agent, but another 5-nitroimidazole derivative, ornidazole, may bepreferable, where available, because of its longer half-life and fewer side-effects. This study comparedthe efficacies of metronidazole and ornidazole in a group of 112 patients with dientamoebiasis. Patientswere randomised into two treatment groups: group 1 (n = 56) received metronidazole for 5 days,20 mg ⁄ kg ⁄ day for children and 1.5 g ⁄ day for adults, in three oral doses, while group 2 (n = 56) receiveda single oral dose of ornidazole, 30 mg ⁄ kg for children and 2 g for adults. Stool samples were examinedon the seventh and 14th days after treatment, and clinical symptoms were recorded to evaluate theefficacy of treatment. A statistically significant difference was recorded between the efficacies ofornidazole and metronidazole, both parasitologically (92.9% vs. 69.6%, p 0.001) and clinically (96.4% vs.76.8%, p 0.001). Patients in the metronidazole group reported more side-effects than patients in theornidazole group, none of whom required termination of treatment. These results suggest that single-dose ornidazole may be an important alternative agent for the treatment of dientamoebiasis.

Keywords Anti-protozoal agents, Dientamoeba fragilis, dientamoebiasis, metronidazole, ornidazole, treatment

Original Submission: 10 October 2007; Revised Submission: 17 January 2008; Accepted: 7 February 2008

Clin Microbiol Infect 2008; 14: 601–604

I N T R O D U C T I O N

Dientamoeba fragilis is an intestinal flagellate proto-zoan with a worldwide distribution in both ruraland urban regions. Currently, limited informationis available concerning many aspects of this tricho-monad, which, following its first description in1918, was regarded as a commensal for many years.In part, this is because it is present in asymptomaticindividuals and in patients co-infected with otherpathogenic microorganisms [1]. However, numer-ous clinical studies have now associated D. fragiliswith clinical symptoms that disappear followingthe elimination of the parasite with anti-protozoalagents [2–10].

A wide range of compounds has been used,with varying efficacies, in the treatment ofdientamoebiasis, including metronidazole [11],

iodoquinol [12], tetracycline [13], erythromycin[14], diphetarsone [15], paromomycin [16] andsecnidazole [2]. Chan et al. [17] used in-vitrosusceptibility tests on D. fragilis ATCC 30948 ina dixenic culture to reveal that iodoquinol,paromomycin and metronidazole were inhibitoryto D. fragilis, as they had limited or no activityagainst the associated bacteria. However, theabsence of an axenic culture is obviously a majorobstacle in determining whether D. fragilis or thebacterial flora was the real target of the therapeu-tic agents [1].

5-Nitroimidazole derivatives have been used inthe treatment of various intestinal protozoalinfections for many years. Among these agents,metronidazole is a common anti-protozoal agentthat is used worldwide, while ornidazole is arelatively new derivative that is used in somecountries in treating particular protozoal infec-tions, and that has higher patient compliancebecause of its longer half-life [18]. The aim of thepresent study was to compare the efficacies ofmetronidazole and single-dose ornidazole in

Corresponding author and reprint requests: O. Kurt, Depart-ment of Parasitology, School of Medicine, Celal Bayar Univer-sity, 45010 Manisa, TurkeyE-mail: oz1605@hotmail.com

� 2008 The AuthorsJournal Compilation � 2008 European Society of Clinical Microbiology and Infectious Diseases

patients with dientamoebiasis. The clinical symp-toms of the patients, as well as the side-effects ofboth treatments, were recorded.

M A T E R I A L S A N D M E T H O D S

Fresh stool samples of patients (produced within the preced-ing 30 min) were examined for D. fragilis trophozoites in theparasitology laboratory, on three consecutive days. The smearsprepared from these samples were immediately placed inSchaudinn’s fixative for trichrome staining (Wheatley modifi-cation). All samples were then examined by wet mount andformalin ethyl acetate concentration, as described previously[19]. Stool samples were also cultured to identify commonbacterial pathogens, e.g., Salmonella spp., Shigella spp. andEscherichia coli. Since data from virological analyses were notavailable for all individuals, these data were not included inthe study.

In total, 112 patients infected with D. fragilis who strictlyadhered to the study protocol were enrolled in the studyduring a 25-month period. A questionnaire concerning clinicalsymptoms before and after treatment was completed for eachpatient. Diarrhoea was defined as three or more soft or liquidstools per day for three or more days, while one formed stool aday was considered to indicate disappearance of diarrhoea.The patients were randomised to receive oral metronidazole(n = 56) or ornidazole (n = 56). Metronidazole 1.5 g daily for5 days was given in three equal doses to adults, while20 mg ⁄ kg was given to children aged 3–15 years. Ornidazole2 g was given as a single dose to adults, and 30 mg ⁄ kg wasgiven as a single dose to children. Metronidazole was given insuspension form to children aged <10 years; however, becauseof the unavailability of the suspension form of ornidazole inTurkey, children aged <10 years received ground ornidazoletablets with meals. Patients were asked not to consume otherantimicrobial agents for 1 week before and 2 weeks after bothtreatment regimens. On the seventh and 14th days after thecompletion of therapy, patients were invited to the laboratoryto submit fresh stool samples; these samples were examined,using the same methods, by microscopists who were unawareof the treatment groups.

Patients who failed to complete therapy and ⁄ or failed todeliver at least one stool sample for the follow-up wereexcluded. Patients found to be positive for D. fragilis in afollow-up examination received repeat treatment with thesame agent and dose and were then re-evaluated. Liverfunction tests were performed for patients who were stillinfected with D. fragilis after the second dose; unless there wasa contraindication, they then received the alternative agentaccording to its treatment regimen.

Effective treatment was defined as eradication of D. fragilisand resolution of the clinical symptoms in patients after thefirst treatment regimen. Disappearance of D. fragilis in follow-up stool examinations was considered to be a parasitologicalcure, while the absence of clinical symptoms, as reported bythe patient, at the second follow-up examination was consid-ered to be a clinical cure. Initial informed consent was obtainedfrom adult patients or from the parents of children. The studywas carried out in accordance with the Helsinki Declarationand was approved by the Ethics Committee of the Schoolof Medicine, Celal Bayar University (Registration number:2003-49).

The efficacies of the two drugs were compared bychi-squared tests (with Yates’ correction) and Fisher’s exact test.

R E S U L T S

The patients were aged between 3 and 84 years(mean 41.6 ± 18.5 years for ornidazole and35.5 ± 23.9 years for metronidazole; p 0.07), with25 (22.3%) patients being aged <15 years. Thepatients were randomised into two treatmentgroups, with no significant difference in termsof gender (p 0.36). No bacterial pathogens wereisolated from the stool samples of patients withD. fragilis infection. In both treatment groups,D. fragilis was the only pathogen in 60 (53.6%)cases, accompanied by the following protozoa:Blastocystis hominis (41 cases, 36.6%), Entamoebahistolytica ⁄ dispar (seven cases, 6.3%), Giardialamblia (three cases, 2.7%), and Entamoeba coliand Endolimax nana (one case, 0.9%). The mostfrequent clinical symptoms were fatigue (67.9%),flatulence (58.9%), abdominal pain (53.6%) anddiarrhoea (33.9%).

Parasitological and clinical cures after the firstregimen were achieved in 52 (92.9%) and 54(96.4%) patients, respectively, in the ornidazolegroup, and in 39 (69.6%) and 43 (76.8%) patients,respectively, in the metronidazole group(Table 1). Eradication of D. fragilis following thesecond regimen was confirmed in all four remain-ing patients in the ornidazole group, and in eightof the 17 remaining patients in the metronidazolegroup. Serum levels of alanine aminotransferaseand aspartate transaminase were within thenormal range in the remaining nine patients,who were then treated successfully with a single2-g dose of ornidazole.

Table 2 compares the efficacies of both treat-ment regimens according to the presence orabsence of other intestinal protozoa. In terms ofboth parasitological and clinical cures, ornidazolewas more effective than metronidazole, regard-less of whether other intestinal protozoa were alsopresent.

Table 1. Comparison of the efficacies of metronidazoleand ornidazole after the first treatment regimen

Agent

Treatment successn (%)

Treatment failuren (%)

Totaln (%) pParasitological Clinical Parasitological Clinical

Ornidazole 52 (92.9) 54 (96.4) 4 (7.1) 2 (3.6) 56 (100) 0.001Metronidazole 39 (69.6) 43 (76.8) 17 (30.4) 13 (23.2) 56 (100)

602 Clinical Microbiology and Infection, Volume 14 Number 6, June 2008

� 2008 The AuthorsJournal Compilation � 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14, 601–604

Few patients reported side-effects (Table 3),and none of these side-effects was sufficientlysevere to warrant termination of treatment.Parents of the children in both groups reportedno difficulty in delivering the agents to theirchildren.

D I S C U S S I O N

There is currently no consensus concerning thedefinitive treatment of dientamoebiasis, and allcurrent therapeutic regimens used for D. fragilisare considered to be investigational by the USFood and Drug Administration [1]. No large-scalerandomised trials of dientamoebiasis treatmenthave been reported previously. Iodoquinol andtetracycline are the most commonly used agentsfor the treatment of D. fragilis infection [1].Iodoquinol (diiodohydroxyquin) has been foundto be particularly effective in North America [4].Paromomycin is regarded as second-line therapy[11], with clinical and parasitological cure rates of87% and 80%, respectively, being reported in thetreatment of 15 Dientamoeba-infected children [16].

5-Nitroimidazoles are currently used inthe treatment of protozoal infections such asamoebiasis, giardiasis and trichomoniasis. Metro-nidazole has well-known efficacy against intesti-nal protozoa and anaerobic bacteria. Ornidazole isa relatively new derivative with a 1.7-fold longerhalf-life than metronidazole, thus enabling its useas a single dose and promoting patient compli-ance with treatment, which is particularly crucialamong children and the elderly [20]. As iodoqu-inol and paromomycin are currently unavailablein Turkey, and tetracycline, despite being effec-tive, has limited use because of its deleteriouseffects on dental development in children [1],metronidazole is the first choice for treatingD. fragilis infections. The efficacy of metronida-zole was reported to be only moderate in Swedishpatients with dientamoebiasis [21], but treatmentwith metronidazole 500–750 mg in three equaldoses a day for 5–7 days has been reported tobe effective in children with dientamoebiasis[11,22], and Preiss et al. [14] treated 70% ofD. fragilis-infected children with metronidazole.Secnidazole, another long-acting derivative of the5-nitroimidazoles, produced clinical and parasi-tological cures in 27 and 34, respectively, of 35children with dientamoebiasis [2].

In the present study, the parasitological andclinical efficacies of ornidazole (92.9% and96.4%, respectively) were significantly higherafter the initial regimen (p 0.001) than those ofmetronidazole (69.3% and 76.8%, respectively).The efficacy of ornidazole was also superior tothat of metronidazole, regardless of whetherother intestinal protozoa were present, includingB. hominis (90.0% vs. 71.4%), which is fre-quently detected with D. fragilis in symptomaticpatients [7,10]. Diarrhoea was resolved in allpatients, while the frequencies of abdominal pain

Table 2. Efficacies of ornidazoleand metronidazole according to thepresence or absence of other intesti-nal protozoa

Agent Accompanying intestinal protoza

Result

Treatment success (%) Treatment failure (%) Total (%)

Ornidazole None (Dientamoeba fragilis alone) 30 (100) – 30 (100)Blastocystis hominisa 18 (90) 2 (10) 20 (100)Giardia lamblia 1 (50) 1 (50) 2 (100)Entamoeba histolytica ⁄ dispar 3 (75) 1 (25) 4 (100)Total 52 (92.9) 4 (7.1) 56 (100)

Metronidazole None (D. fragilis alone) 19 (63.3) 11 (36.7) 30 (100)B. hominisa 15 (71.4) 6 (28.6) 21 (100)G. lamblia 1 (100) – 1 (100)E. histolytica ⁄ dispar 3 (100) – 3 (100)Entamoeba coli and Endolimax nana 1 (100) – 1 (100)Total 39 (69.6) 17 (30.4) 56 (100)

aSamples having ‡5 B. hominis cells under ·400 magnification.

Table 3. Side-effects of metronidazole and ornidazoleaccording to the reports of patientsa

Side-effect

Metronidazole

(n = 56)

Ornidazole

(n = 56)

n % n %

Nausea 4 7.1 3 5.4Vomiting 2 3.6 – –Anorexia 2 3.6 – –Headache – – 1 1.8Dizziness 1 1.8 2 3.6Dry mouth 4 7.1 – –Metallic taste 3 5.4 – –Insomnia 1 1.8 – –Vertigo 1 1.8 – –

aSome patients reported more than one side-effect.

Kurt et al. Treatment of dientamoebiasis 603

� 2008 The AuthorsJournal Compilation � 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14, 601–604

(53.6%) and flatulence (58.9%) declined to 1.1%and 3.4%, respectively, after therapy. Probablybecause of its possible multifactorial origin, thefrequency of fatigue also declined from 67.9%to 14.6% after treatment.

Agents used for the treatment of dientamoebi-asis have been associated with several side-effects. Diphetarsone has been associated withtransient liver function abnormalities [15], whiletetracycline is contraindicated in children becauseof its deleterious effects on dental development[1]. However, a recent study reported no side-effects following the use of paromomycin inpaediatric patients [16]. A few side-effects werereported in the present study, but none wassufficiently severe to require the termination oftreatment. Nausea was the most frequent side-effect in both groups (7.1% and 5.4% in themetronidazole and ornidazole groups, respec-tively), and some patients in the metronidazolegroup also complained of a dry mouth (7.1%) anda metallic taste (5.4%).

To our knowledge, this is the first time thatornidazole has been used for the treatment ofpatients with dientamoebiasis. A single dose ofornidazole was revealed to be effective and well-tolerated, with high compliance in all age groups.Co-infection with B. hominis had no significanteffect on outcome. Thus, ornidazole may beregarded as a novel drug of choice for thetreatment of D. fragilis infection.

A C K N O W L E D G E M E N T S

We would like to thank G. Dinc (Department of Public Health,School of Medicine, Celal Bayar University) for performing thestatistical analyses and evaluating the study data. This studywas supported financially by Celal Bayar University ResearchFund Accountancy (Registration No.: 2001-31). The authorsdeclare that they have no conflicting interests in relation to thiswork.

R E F E R E N C E S

1. Johnson EH, Windsor JJ, Clark CG. Emerging fromobscurity: biological, clinical and diagnostic aspects ofDientamoeba fragilis. Clin Microbiol Rev 2004; 17: 553–570.

2. Girginkardesler N, Coskun S, Balcioglu IC, Ertan P, OkUZ. Dientamoeba fragilis, a neglected cause of diarrhea,successfully treated with secnidazole. Clin Microbiol Infect2003; 9: 110–113.

3. Ayadi A, Bahri I. Dientamoeba fragilis: pathogenic flagel-late? Bull Soc Pathol Exot 1999; 92: 299–301.

4. Butler WP. Dientamoeba fragilis. An unusual intestinalpathogen. Dig Dis Sci 1996; 41: 1811–1813.

5. Crotti D, D’Annibale ML, Fonzo G et al. Dientamoebafragilis is more prevalent than Giardia duodenalis in childrenand adults attending a day care centre in Central Italy.Parasite 2005; 12: 165–170.

6. Grendon JH, Digiacomo RF, Frost FJ. Descriptive featuresof Dientamoeba fragilis infections. J Trop Med Hyg 1995; 98:309–315.

7. Stark D, Beebe N, Marriott D et al. Prospective study of theprevalence, genotyping, and clinical relevance of Dient-amoeba fragilis infections in an Australian population. J ClinMicrobiol 2005; 43: 2718–2723.

8. Windsor JJ, Rafay AM, Srenoy AK, Johnson EH. Theincidence of Dientamoeba fragilis in faecal samples sub-mitted for routine microbiological analysis. Br J Biomed Sci1998; 55: 172–175.

9. Stark DJ, Beebe N, Marriott D et al. Dientamoebiasis:clinical importance and recent advances. Trends Parasitol2006; 22: 92–96.

10. Lagace-Wiens PR, VanCaeseele PG, Koschik C. Dient-amoeba fragilis: an emerging role in intestinal disease. CanMed Assoc J 2006; 175: 468–469.

11. Cuffari C, Oligny L, Seidman EG. Dientamoeba fragilismasquerading as allergic colitis. J Pediatr Gastroenterol Nutr1998; 26: 16–20.

12. Spencer MJ, Chapin MR, Garcia LS. Dientamoeba fragilis: agastrointestinal protozoan infection in adults. Am J Gas-troenterol 1982; 77: 565–569.

13. Kean BH, Malloch CL. The neglected ameba: Dientamoebafragilis. A report of 100 ‘pure’ infections. Am J Dig Dis 1966;11: 735–746.

14. Preiss U, Ockert G, Broemme S et al. On the clinicalimportance of D. fragilis infections in childhood. J HygEpidemiol Microbiol Immunol 1991; 35: 27–34.

15. Keystone JS, Proctor E, Glenn C et al. Safety and efficacy ofdiphetarsone in the treatment of amoebiasis, non patho-genic amoebiasis and trichuriasis. Trans R Soc Trop MedHyg 1983; 77: 84–86.

16. Vandenberg O, Souayah H, Mouchet F et al. Treatment ofDientamoeba fragilis infection with paromomycin. PediatrInfect Dis J 2007; 26: 88–90.

17. Chan FT, Guan MX, Mackenzie AM et al. Susceptibilitytesting of Dientamoeba fragilis ATCC 30948 with iodoqui-nol, paromomycin, tetracycline, and metronidazole. Anti-microb Agents Chemother 1994; 38: 1157–1160.

18. Lamp KC, Freeman CD, Klutman NE et al. Pharmaco-kinetics and pharmacodynamics of the nitroimidazoleantimicrobials. Clin Pharmacokinet 1999; 36: 353–373.

19. Garcia LS, Bruckner DA. Macroscopic and microscopicexamination of fecal specimens. In: Garcia LS, BrucknerDA, eds, Diagnostic medical parasitology, 2nd edn.Washington, DC: American Society for Microbiology,1993; 501–535.

20. Pearson RD. Agents active against parasites and Pneumo-cystis carinii. In: Mandell GL, Bennett JE, Dolin R, eds, Basicprinciples in the diagnosis and management of infectiousdiseases, 5th edn. New York: Churchill Livingstone, 2000;505–539.

21. Norberg A, Nord CE, Evengard B. Dientamoeba fragilis—a protozoal infection which may cause severe boweldistress. Clin Microbiol Infect 2003; 9: 65–68.

22. Ito R, Sakagami J, Kataoka K et al. Chronic diarrhea andprotein-losing gastroenteropathy caused by Dientamoebafragilis. J Gastroenterol 2004; 39: 1117–1119.

604 Clinical Microbiology and Infection, Volume 14 Number 6, June 2008

� 2008 The AuthorsJournal Compilation � 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14, 601–604