A comparison of metronidazole and single-dose ornidazole for the treatment of dientamoebiasis

Authors


Corresponding author and reprint requests: Ö. Kurt, Department of Parasitology, School of Medicine, Celal Bayar University, 45010 Manisa, Turkey
E-mail: oz1605@hotmail.com

Abstract

Recent reports of the pathogenic potential of Dientamoeba fragilis have underlined the need for an effective treatment against this colon-dwelling protozoan. Metronidazole is a well-known and commonly used anti-protozoal agent, but another 5-nitroimidazole derivative, ornidazole, may be preferable, where available, because of its longer half-life and fewer side-effects. This study compared the efficacies of metronidazole and ornidazole in a group of 112 patients with dientamoebiasis. Patients were randomised into two treatment groups: group 1 (= 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 (= 56) received a single oral dose of ornidazole, 30 mg/kg for children and 2 g for adults. Stool samples were examined on the seventh and 14th days after treatment, and clinical symptoms were recorded to evaluate the efficacy of treatment. A statistically significant difference was recorded between the efficacies of ornidazole 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 the ornidazole 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.

Introduction

Dientamoeba fragilis is an intestinal flagellate protozoan with a worldwide distribution in both rural and urban regions. Currently, limited information is available concerning many aspects of this trichomonad, which, following its first description in 1918, was regarded as a commensal for many years. In part, this is because it is present in asymptomatic individuals and in patients co-infected with other pathogenic microorganisms [1]. However, numerous clinical studies have now associated D. fragilis with clinical symptoms that disappear following the elimination of the parasite with anti-protozoal agents [2–10].

A wide range of compounds has been used, with varying efficacies, in the treatment of dientamoebiasis, including metronidazole [11], iodoquinol [12], tetracycline [13], erythromycin [14], diphetarsone [15], paromomycin [16] and secnidazole [2]. Chan et al. [17] used in-vitro susceptibility tests on D. fragilis ATCC  30948 in a dixenic culture to reveal that iodoquinol, paromomycin and metronidazole were inhibitory to D. fragilis, as they had limited or no activity against the associated bacteria. However, the absence of an axenic culture is obviously a major obstacle in determining whether D. fragilis or the bacterial flora was the real target of the therapeutic agents [1].

5-Nitroimidazole derivatives have been used in the treatment of various intestinal protozoal infections for many years. Among these agents, metronidazole is a common anti-protozoal agent that is used worldwide, while ornidazole is a relatively new derivative that is used in some countries in treating particular protozoal infections, and that has higher patient compliance because of its longer half-life [18]. The aim of the present study was to compare the efficacies of metronidazole and single-dose ornidazole in patients with dientamoebiasis. The clinical symptoms of the patients, as well as the side-effects of both treatments, were recorded.

Materials and methods

Fresh stool samples of patients (produced within the preceding 30 min) were examined for D. fragilis trophozoites in the parasitology laboratory, on three consecutive days. The smears prepared from these samples were immediately placed in Schaudinn’s fixative for trichrome staining (Wheatley modification). All samples were then examined by wet mount and formalin ethyl acetate concentration, as described previously [19]. Stool samples were also cultured to identify common bacterial pathogens, e.g., Salmonella spp., Shigella spp. and Escherichia coli. Since data from virological analyses were not available for all individuals, these data were not included in the study.

In total, 112 patients infected with D. fragilis who strictly adhered to the study protocol were enrolled in the study during a 25-month period. A questionnaire concerning clinical symptoms before and after treatment was completed for each patient. Diarrhoea was defined as three or more soft or liquid stools per day for three or more days, while one formed stool a day was considered to indicate disappearance of diarrhoea. The patients were randomised to receive oral metronidazole (= 56) or ornidazole (= 56). Metronidazole 1.5 g daily for 5 days was given in three equal doses to adults, while 20 mg/kg was given to children aged 3–15 years. Ornidazole 2 g was given as a single dose to adults, and 30 mg/kg was given as a single dose to children. Metronidazole was given in suspension form to children aged <10 years; however, because of the unavailability of the suspension form of ornidazole in Turkey, children aged <10 years received ground ornidazole tablets with meals. Patients were asked not to consume other antimicrobial agents for 1 week before and 2 weeks after both treatment regimens. On the seventh and 14th days after the completion of therapy, patients were invited to the laboratory to submit fresh stool samples; these samples were examined, using the same methods, by microscopists who were unaware of the treatment groups.

Patients who failed to complete therapy and/or failed to deliver at least one stool sample for the follow-up were excluded. Patients found to be positive for D. fragilis in a follow-up examination received repeat treatment with the same agent and dose and were then re-evaluated. Liver function tests were performed for patients who were still infected with D. fragilis after the second dose; unless there was a contraindication, they then received the alternative agent according to its treatment regimen.

Effective treatment was defined as eradication of D. fragilis and resolution of the clinical symptoms in patients after the first treatment regimen. Disappearance of D. fragilis in follow-up stool examinations was considered to be a parasitological cure, while the absence of clinical symptoms, as reported by the patient, at the second follow-up examination was considered to be a clinical cure. Initial informed consent was obtained from adult patients or from the parents of children. The study was carried out in accordance with the Helsinki Declaration and was approved by the Ethics Committee of the School of Medicine, Celal Bayar University (Registration number: 2003-49).

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

Results

The patients were aged between 3 and 84 years (mean 41.6 ± 18.5 years for ornidazole and 35.5 ± 23.9 years for metronidazole; p 0.07), with 25 (22.3%) patients being aged <15 years. The patients were randomised into two treatment groups, with no significant difference in terms of gender (p 0.36). No bacterial pathogens were isolated from the stool samples of patients with D. 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%), Entamoeba histolytica/dispar (seven cases, 6.3%), Giardia lamblia (three cases, 2.7%), and Entamoeba coli and Endolimax nana (one case, 0.9%). The most frequent clinical symptoms were fatigue (67.9%), flatulence (58.9%), abdominal pain (53.6%) and diarrhoea (33.9%).

Parasitological and clinical cures after the first regimen were achieved in 52 (92.9%) and 54 (96.4%) patients, respectively, in the ornidazole group, and in 39 (69.6%) and 43 (76.8%) patients, respectively, in the metronidazole group (Table 1). Eradication of D. fragilis following the second regimen was confirmed in all four remaining patients in the ornidazole group, and in eight of the 17 remaining patients in the metronidazole group. Serum levels of alanine aminotransferase and aspartate transaminase were within the normal range in the remaining nine patients, who were then treated successfully with a single 2-g dose of ornidazole.

Table 1.   Comparison of the efficacies of metronidazole and ornidazole after the first treatment regimen
AgentTreatment success n (%)Treatment failure n (%)Total n (%)p
ParasitologicalClinicalParasitologicalClinical
Ornidazole52 (92.9)54 (96.4)4 (7.1)2 (3.6)56 (100)0.001
Metronidazole39 (69.6)43 (76.8)17 (30.4)13 (23.2)56 (100)

Table 2 compares the efficacies of both treatment regimens according to the presence or absence of other intestinal protozoa. In terms of both parasitological and clinical cures, ornidazole was more effective than metronidazole, regardless of whether other intestinal protozoa were also present.

Table 2.   Efficacies of ornidazole and metronidazole according to the presence or absence of other intestinal protozoa
AgentAccompanying intestinal protozaResult
Treatment success (%)Treatment failure (%)Total (%)
  1. aSamples having ≥5 B. hominis cells under ×400 magnification.

OrnidazoleNone (Dientamoeba fragilis alone)30 (100)30 (100)
Blastocystis hominisa18 (90)2 (10)20 (100)
Giardia lamblia1 (50)1 (50)2 (100)
Entamoeba histolytica/dispar3 (75)1 (25)4 (100)
Total52 (92.9)4 (7.1)56 (100)
MetronidazoleNone (D. fragilis alone)19 (63.3)11 (36.7)30 (100)
B. hominisa15 (71.4)6 (28.6)21 (100)
G. lamblia1 (100)1 (100)
E. histolytica/dispar3 (100)3 (100)
Entamoeba coli and Endolimax nana1 (100)1 (100)
Total39 (69.6)17 (30.4)56 (100)

Few patients reported side-effects (Table 3), and none of these side-effects was sufficiently severe to warrant termination of treatment. Parents of the children in both groups reported no difficulty in delivering the agents to their children.

Table 3.   Side-effects of metronidazole and ornidazole according to the reports of patientsa
Side-effectMetronidazole (= 56)Ornidazole (= 56)
n%n%
  1. aSome patients reported more than one side-effect.

Nausea47.135.4
Vomiting23.6
Anorexia23.6
Headache11.8
Dizziness11.823.6
Dry mouth47.1
Metallic taste35.4
Insomnia11.8
Vertigo11.8

Discussion

There is currently no consensus concerning the definitive treatment of dientamoebiasis, and all current therapeutic regimens used for D. fragilis are considered to be investigational by the US Food and Drug Administration [1]. No large-scale randomised trials of dientamoebiasis treatment have been reported previously. Iodoquinol and tetracycline are the most commonly used agents for the treatment of D. fragilis infection [1]. Iodoquinol (diiodohydroxyquin) has been found to be particularly effective in North America [4]. Paromomycin is regarded as second-line therapy [11], with clinical and parasitological cure rates of 87% and 80%, respectively, being reported in the treatment of 15 Dientamoeba-infected children [16].

5-Nitroimidazoles are currently used in the treatment of protozoal infections such as amoebiasis, giardiasis and trichomoniasis. Metronidazole has well-known efficacy against intestinal protozoa and anaerobic bacteria. Ornidazole is a relatively new derivative with a 1.7-fold longer half-life than metronidazole, thus enabling its use as a single dose and promoting patient compliance with treatment, which is particularly crucial among children and the elderly [20]. As iodoquinol and paromomycin are currently unavailable in Turkey, and tetracycline, despite being effective, has limited use because of its deleterious effects on dental development in children [1], metronidazole is the first choice for treating D. fragilis infections. The efficacy of metronidazole was reported to be only moderate in Swedish patients with dientamoebiasis [21], but treatment with metronidazole 500–750 mg in three equal doses a day for 5–7 days has been reported to be effective in children with dientamoebiasis [11,22], and Preiss et al. [14] treated 70% of D. fragilis-infected children with metronidazole. Secnidazole, another long-acting derivative of the 5-nitroimidazoles, produced clinical and parasitological cures in 27 and 34, respectively, of 35 children with dientamoebiasis [2].

In the present study, the parasitological and clinical efficacies of ornidazole (92.9% and 96.4%, respectively) were significantly higher after the initial regimen (p 0.001) than those of metronidazole (69.3% and 76.8%, respectively). The efficacy of ornidazole was also superior to that of metronidazole, regardless of whether other intestinal protozoa were present, including B. hominis (90.0% vs. 71.4%), which is frequently detected with D. fragilis in symptomatic patients [7,10]. Diarrhoea was resolved in all patients, while the frequencies of abdominal pain (53.6%) and flatulence (58.9%) declined to 1.1% and 3.4%, respectively, after therapy. Probably because of its possible multifactorial origin, the frequency of fatigue also declined from 67.9% to 14.6% after treatment.

Agents used for the treatment of dientamoebiasis have been associated with several side-effects. Diphetarsone has been associated with transient liver function abnormalities [15], while tetracycline is contraindicated in children because of its deleterious effects on dental development [1]. However, a recent study reported no side-effects following the use of paromomycin in paediatric patients [16]. A few side-effects were reported in the present study, but none was sufficiently severe to require the termination of treatment. Nausea was the most frequent side-effect in both groups (7.1% and 5.4% in the metronidazole and ornidazole groups, respectively), and some patients in the metronidazole group also complained of a dry mouth (7.1%) and a metallic taste (5.4%).

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

Acknowledgements

We would like to thank G. Dinc (Department of Public Health, School of Medicine, Celal Bayar University) for performing the statistical analyses and evaluating the study data. This study was supported financially by Celal Bayar University Research Fund Accountancy (Registration No.: 2001-31). The authors declare that they have no conflicting interests in relation to this work.

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