A comparative study of oral single dose of metronidazole, tinidazole, secnidazole and ornidazole in bacterial vaginosis.

OBJECTIVE: To compare the cure rates of oral single dose of metronidazole (2 g), tinidazole (2 g), secnidazole (2 g), and ornidazole (1.5 g) in cases of bacterial vaginosis.
MATERIALS AND METHODS: This was a prospective, comparative, randomized clinical trial on 344 Indian women (86 women in each group) who attended a gynecology outpatient department with complaint of abnormal vaginal discharge or who had abnormal vaginal discharge on Gynecological examination but they did not complaint of it. For diagnosis and cure rate of bacterial vaginosis, Amsel's criteria were used. Statistical analysis was done by Chi-square test of proportions. The cure rate was compared considering metronidazole cure rate as gold standard.
RESULTS: At 1 week, the cure rate of tinidazole and ornidazole was 100% and at 4 weeks, it was 97.7% for both drugs (P<0.001). Secnidazole had cure rate of 80.2% at 4 weeks (P=NS). Metronidazole showed a cure rate of 77.9% at 4 weeks, which is the lowest of all four drugs.
CONCLUSION: Tinidazole and ornidazole have better cure rate as compared to metronidazole in cases of bacterial vaginosis.

RCT Entities:   Population Interventions Outcomes

Introduction

Bacterial Vaginosis (BV) is the most common type of lower Reproductive Tract Infection (RTI), which is caused by replacement of the normal H2O2 producing Lactobacillus sp. in the vagina with high concentrations of anaerobic bacteria (eg, Prevotella sp. and Mobiluncus sp.), Gardnerella vaginalis and Mycoplasma hominis.[1] It has a high recurrence rate, which is difficult to treat. Many studies are under trial to replace abnormal vaginal flora with various strains of H2O2 producing lactobacilli but before inoculation, the vagina should be properly sterilized.[2] According to CDC 2006 guidelines, Metronidazole is the drug of choice for BV. Long-term follow-up shows relapse rate of 70% with Metronidazole.[3] Various studies have shown that new nitroimidazole derivative like tinidazole, secnidazole, and ornidazole are the best options for BV. Metronidazole, the five-nitroimidazole derivative, was originally introduced to treat Trichomonas vaginalis. Half-life of metronidazole is 7.9-8.8 hours.[4] Clinical success rate is about 84% with relapse rate of 60-70% after 3-12 months. Tinidazole has a structure similar to that of metronidazole, but longer half-life, about 14-14.7 hours.[4] It is useful in recurrent cases. It has a cure rate of about 97%. Secnidazole is the five-nitroimidazole derivative with a half-life of 17-29 hours and a cure rate of 59-96%.[5] Ornidazole is also of same group with a half-life of 14.1-16.8 hours with a cure rate of approximately 96%.[6]

This prospective, comparative, randomized clinical trial was conducted to compare the cure rates of oral single dose of Metronidazole (2 g), Tinidazole (2 g), Secnidazole (2 g), and Ornidazole (1.5 g) as well as its effect on vaginal flora in cases of BV.

Materials and Methods

This prospective, comparative, and randomized clinical trial consists of 344 Indian women (86 women in each group) who attended the gynecology Outpatient Department (OPD) unit with complaints of abnormal vaginal discharge or who were detected having abnormal vaginal discharge. The study period was from December 2008 to November 2009. The required sample size was 63 in each group, considering the cure rate of metronidazole about 70% and new nitroimidazole group about 90%. The power of the study was 80%. In order to compensate lost to follow-up cases, we recruited 86 patients in each group. Ethical clearance was obtained from All India Institute of Medical Sciences (AIIMS) ethics committee. This clinical trial was registered at the Clinical Trials Registry-India (CTRI; Reg. No: 2009 - 001093). Patients in the age group of 18-45 years with regular cycles and diagnosed as having BV were included in this study after receiving informed consent. Bacterial Vaginosis was diagnosed by Amsel's criteria[7] in both symptomatic and asymptomatic groups. The symptomatic group presented with complaints of vaginal discharge; the asymptomatic group did not complain of white discharge, but the disease was detected by a clinician on examination.

Amsel's criteria consist of four factors, namely, homogenous, milky or creamy vaginal discharge, pH of secretion above 4.5, fishy odor with or without addition of 10% KOH, and presence of clue cells on microscopic examination. Any three criteria out of four are necessary to diagnose bacterial vaginosis.[7] Menopausal and pregnant women, women with malignancy of reproductive tract, or those who have undergone delivery or abortion within last six weeks, women with history of severe allergic reactions and immunocompromised women were excluded from this study.

A detailed history including demographic profile of patients was noted. The patients were randomly divided into four groups, using computer-generated table, which guided the distribution of patients among the groups. Group 1 received Metronidazole (2 g), Group 2- Tinidazole (2 g), Group 3- Secnidazole (2 g), and Group 4- Ornidazole (1.5 g). All drugs were given as single oral dose.

In order to ensure uniformity of treatment, we used the same brand of medicine. All patients were blinded to the treatment, but the investigator was not blinded to the treatment. All patients received treatment in the presence of the gynecologist. At the beginning of the treatment, counseling about hygienic practices was done so that this factor could not contribute as failure of drug.

At the time of recruitment, vaginal pH was measured by directly dipping a pH strip (range: 0-6) in vagina. The pH strip used was a colour-fixed indicator stick, marketed by Sigma chemical company (USA). Vaginal smear was taken for Gram staining and wet mount, to look for clue cells and associated fungal or Trichomonas infection. On Gram staining, the effect of drug on vaginal flora was observed. Patients were called after one week and, thereafter, at four weeks. At each visit, vaginal pH, wet mount, and Gram staining examinations were performed. Cure rate, effect on vaginal flora, and recurrence rate were assessed in each category. For defining the cure rate, we preferred Amsel's criteria. Complete cure was considered when none of the four criteria were present. Improvement in the disease was considered when only one criterion was present. Partial cure was labelled when two criteria were present, and failure of treatment was labelled when three or four criteria were present.

For statistical analysis, Chi-square test of proportions was used. Cure rates of tinidazole, secnidazole, and ornidazole were compared with those of metronidazole. Value of P less than 0.05 was considered as significant.

Results

A detailed analysis revealed that the mean age of patients with BV was 27.9 ± 4.5 years, with a range of 20-40 years. Women educated in primary and secondary schools were the most commonly affected groups [123/344 (35.8%) and 154/344 (44.8%), respectively]. A majority of the patients were housewives (85.5%). Monthly family income of less than Rs 5000 was found in 147/344 (42.7%) women and a range of Rs 5000-10,000 was found in 87/344 (25.3%) of women. Common presenting symptom was abnormal vaginal discharge, which was found in 236/344 (68.6%) women, followed by backache and lower abdominal pain in 101/344 (29.4%) women. No complaint of vaginal discharge was found in 108/344 (31.4%) of women.

Of the 344 patients, four did not come for the second visit as they stayed very far away from the hospital [Figure 1]. Cure rate of different medicines, according to Amsel's criteria is depicted in Tables 1 and 2. At 1 week, the cure rate of tinidazole and ornidazole was 100% and at 4 weeks, it was 97.7% for both medicines. Metronidazole showed a cure rate of 88.4% at 1 week and 77.9% at 4 weeks, which was the lowest among all groups.

Figure 1

The parallel randomised trial of nitroimidazoles in bacterial vaginosis

Table 1

Cure rate of nitroimidazoles in bacterial vaginosis at one week

Table 2

Cure rate of nitroimidazoles in bacterial vaginosis at four weeks

Discussion

Metronidazole is the drug of choice for the treatment of BV. A long-term follow-up has shown recurrence of BV. Various other nitroimidazole groups of medicines are available in the market with different half-life. Metronidazole has the lowest half life (7.9-8.8 hours). Tinidazole and ornidazole have longer and similar half-life (14-14.7 and 14.1-16.8 hours, respectively). Secnidazole is the longest acting medicine with a half life of 17-29 hours. Proper antimicrobial agent should be preferred to kill unnatural anaerobic agents without harming the normal vaginal flora. In this regard, the half-life of nitroimidazole group of medicine is important.[8] Longer half life has adequate control over pathogenic bacteria.

The present study showed that metronidazole has a cure rate of 77.9% at 4 weeks, which is slightly more than the previous study by Larsson et al. Their study depicts a four-week cure rate of 60-70% and relapse rate of 70%.[3] This difference can be related to various other hygienic practices associated with treatment failure. A majority of patients were from low socioeconomic group and with lower education. Hence, failure rate was linked with poor hygienic practices. Tinidazole is a similar drug, which has been used previously in recurrent BV and found useful by Baylson et al.[9] Our study reveals that the four-week cure rate of tinidazole is 97.7%, which is higher than metronidazole (P<0.001). A multicenter, randomized study has shown that tinidazole has 97% success rate.[10] In this study, a single oral dose of 2 g tinidazole was compared with multiple-dose therapy of metronidazole.

Secnidazole is structurally related to 5-nitroimidazoles such as metronidazole and tinidazole. Its response in cases of BV is comparable to single-dose tinidazole or a seven-day treatment with metronidazole.[10] The present study reveals that a four-week cure rate for secnidazole is 80.2%. A Previous study by Gillis et al., which reports that 2-g single oral dose of secnidazole has a cure rate of approximately 59-96%.[11] Ornidazole is the newest 5-nitroimidazole derivative, which has been in use for the treatment of vaginitis for more than 10 years. As per Mayo clinic proceedings 1987 Nov, tinidazole and ornidazole have greater antimicrobial activity than metronidazole.[12] In the present study, the four-week cure rate for ornidazole was 97.7%. A study by Erkkola et al., conducted in Finland, showed that single oral dose ornidazole (1.5 g) has a 96% cure rate.[13] This is comparable to our study because the dose of ornidazole was same and patients were followed up at 7 and 28 days like that in our study. All four drugs did not affect normal vaginal flora as observed on Gram staining, and thus are safe for use since no significant untoward reaction was observed. Tinidazole and ornidazole proved significantly better than metronidazole (P<0.001), probably because they have similar half-life. The duration of action on a microbial agent is important in prevention of recurrence. In spite of having the longest half-life, secnidazole did not show the best cure. This could be because longer action might have disturbed the protective defence mechanism by natural floras.[14]

We could not classify different types of lactobacilli and the effect of each drug on these lactobacilli, which was a drawback of this study. However, from the evident results we conclude that tinidazole and ornidazole have a better cure rate as compared to that by metronidazole in cases of BV.