A Comparative Study of Oral Single Dose of Metronidazole, Tinidazole, Secnidazole and Ornidazole in Bacterial Vaginosis

Research Article

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

Jyoti Thulkar, Alka Kriplani, Nutan Agarwal

ABSTRACT

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. Department of Obstetrics and Materials and Methods: This was a prospective, comparative, randomized clinical trial on Gynecology, All India Institute of 344 Indian women (86 women in each group) who attended a gynecology outpatient department Medical Sciences, New Delhi, India with complaint of abnormal vaginal discharge or who had abnormal vaginal discharge on Received: 02-01-2011 Gynecological examination but they did not complaint of it. For diagnosis and cure rate of Revised: 28-08-2011 bacterial vaginosis, Amsel’s criteria were used. Statistical analysis was done by Chi‑square test of Accepted: 30-12-2011 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 Correspondence to: was 97.7% for both drugs (P<0.001). Secnidazole had cure rate of 80.2% at 4 weeks (P=NS). Dr. Jyoti Thulkar, Metronidazole showed a cure rate of 77.9% at 4 weeks, which is the lowest of all four drugs. E‑mail: [email protected] Conclusion: Tinidazole and ornidazole have better cure rate as compared to metronidazole in cases of bacterial vaginosis.

KEY WORDS: Bacterial vaginosis, metronidazole, ornidazole, secnidazole, tinidazole

Introduction about 84% with relapse rate of 60‑70% after 3‑12 months. Tinidazole has a structure similar to that of metronidazole, but Bacterial Vaginosis (BV) is the most common type of longer half‑life, about 14‑14.7 hours.[4] It is useful in recurrent lower Reproductive Tract Infection (RTI), which is caused by cases. It has a cure rate of about 97%. Secnidazole is the replacement of the normal H O producing Lactobacillus sp. 2 2 five‑nitroimidazole derivative with a half‑life of 17‑29 hours in the vagina with high concentrations of anaerobic bacteria and a cure rate of 59‑96%.[5] Ornidazole is also of same (eg, Prevotella sp. and Mobiluncus sp.), Gardnerella vaginalis group with a half‑life of 14.1‑16.8 hours with a cure rate of and Mycoplasma hominis.[1] It has a high recurrence rate, approximately 96%.[6] which is difficult to treat. Many studies are under trial to This prospective, comparative, randomized clinical trial replace abnormal vaginal flora with various strains of H O 2 2 was conducted to compare the cure rates of oral single dose producing lactobacilli but before inoculation, the vagina should of Metronidazole (2 g), Tinidazole (2 g), Secnidazole (2 g), and be properly sterilized.[2] According to CDC 2006 guidelines, Ornidazole (1.5 g) as well as its effect on vaginal flora in cases of BV. Metronidazole is the drug of choice for BV. Long‑term follow‑up shows relapse rate of 70% with Metronidazole.[3] Various Materials and Methods studies have shown that new nitroimidazole derivative like This prospective, comparative, and randomized clinical trial tinidazole, secnidazole, and ornidazole are the best options for BV. Metronidazole, the five‑nitroimidazole derivative, was consists of 344 Indian women (86 women in each group) who originally introduced to treat Trichomonas vaginalis. Half‑life attended the gynecology Outpatient Department (OPD) unit of metronidazole is 7.9‑8.8 hours.[4] Clinical success rate is with complaints of abnormal vaginal discharge or who were detected having abnormal vaginal discharge. The study period Access this article online was from December 2008 to November 2009. The required Quick Response Code: sample size was 63 in each group, considering the cure rate of Website: www.ijp-online.com metronidazole about 70% and new nitroimidazole group about DOI: 10.4103/0253-7613.93859 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.

Indian Journal of Pharmacology | April 2012 | Vol 44 | Issue 2 243 Thulkar, et al.: Bacterial vaginosis and treatment

No: 2009 ‑ 001093). Patients in the age group of 18‑45 years Rs 5000 was found in 147/344 (42.7%) women and a range of with regular cycles and diagnosed as having BV were included in Rs 5000‑10,000 was found in 87/344 (25.3%) of women. Common this study after receiving informed consent. Bacterial Vaginosis presenting symptom was abnormal vaginal discharge, which was was diagnosed by Amsel’s criteria[7] in both symptomatic and found in 236/344 (68.6%) women, followed by backache and asymptomatic groups. The symptomatic group presented with lower abdominal pain in 101/344 (29.4%) women. No complaint complaints of vaginal discharge; the asymptomatic group did of vaginal discharge was found in 108/344 (31.4%) of women. not complain of white discharge, but the disease was detected Of the 344 patients, four did not come for the second visit by a clinician on examination. as they stayed very far away from the hospital [Figure 1]. Cure Amsel’s criteria consist of four factors, namely, homogenous, rate of different medicines, according to Amsel’s criteria is milky or creamy vaginal discharge, pH of secretion above 4.5, depicted in Tables 1 and 2. At 1 week, the cure rate of tinidazole fishy odor with or without addition of 10% KOH, and presence and ornidazole was 100% and at 4 weeks, it was 97.7% for both of clue cells on microscopic examination. Any three criteria medicines. Metronidazole showed a cure rate of 88.4% at 1 week out of four are necessary to diagnose bacterial vaginosis.[7] and 77.9% at 4 weeks, which was the lowest among all groups. Menopausal and pregnant women, women with malignancy of Discussion reproductive tract, or those who have undergone delivery or abortion within last six weeks, women with history of severe Metronidazole is the drug of choice for the treatment of allergic reactions and immunocompromised women were BV. A long‑term follow‑up has shown recurrence of BV. Various excluded from this study. other nitroimidazole groups of medicines are available in the A detailed history including demographic profile of patients market with different half‑life. Metronidazole has the lowest was noted. The patients were randomly divided into four groups, half life (7.9‑8.8 hours). Tinidazole and ornidazole have longer using computer‑generated table, which guided the distribution and similar half‑life (14‑14.7 and 14.1‑16.8 hours, respectively). of patients among the groups. Group 1 received Metronidazole Secnidazole is the longest acting medicine with a half life of (2 g), Group 2‑ Tinidazole (2 g), Group 3‑ Secnidazole (2 g), 17‑29 hours. Proper antimicrobial agent should be preferred to kill unnatural anaerobic agents without harming the normal and Group 4‑ Ornidazole (1.5 g). All drugs were given as single vaginal flora. In this regard, the half‑life of nitroimidazole group oral dose. of medicine is important.[8] Longer half life has adequate control In order to ensure uniformity of treatment, we used the same over pathogenic bacteria. brand of medicine. All patients were blinded to the treatment, but The present study showed that metronidazole has a cure the investigator was not blinded to the treatment. All patients rate of 77.9% at 4 weeks, which is slightly more than the received treatment in the presence of the gynecologist. At the previous study by Larsson et al. Their study depicts a four‑week beginning of the treatment, counseling about hygienic practices cure rate of 60‑70% and relapse rate of 70%.[3] This difference was done so that this factor could not contribute as failure of drug. can be related to various other hygienic practices associated At the time of recruitment, vaginal pH was measured by with treatment failure. A majority of patients were from low directly dipping a pH strip (range: 0‑6) in vagina. The pH strip used socioeconomic group and with lower education. Hence, failure was a colour‑fixed indicator stick, marketed by Sigma chemical rate was linked with poor hygienic practices. Tinidazole is a company (USA). Vaginal smear was taken for Gram staining similar drug, which has been used previously in recurrent BV and wet mount, to look for clue cells and associated fungal or and found useful by Baylson et al.[9] Our study reveals that the Trichomonas infection. On Gram staining, the effect of drug on four‑week cure rate of tinidazole is 97.7%, which is higher than vaginal flora was observed. Patients were called after one week metronidazole (P<0.001). A multicenter, randomized study and, thereafter, at four weeks. At each visit, vaginal pH, wet has shown that tinidazole has 97% success rate.[10] In this mount, and Gram staining examinations were performed. Cure study, a single oral dose of 2 g tinidazole was compared with rate, effect on vaginal flora, and recurrence rate were assessed multiple‑dose therapy of metronidazole. in each category. For defining the cure rate, we preferred Amsel’s criteria. Complete cure was considered when none of the four Table 1: criteria were present. Improvement in the disease was considered Cure rate of nitroimidazoles in bacterial vaginosis at one week when only one criterion was present. Partial cure was labelled when two criteria were present, and failure of treatment was Name of medicine Cure rate by Amsel’s criteria (%) P value labelled when three or four criteria were present. Metronidazole 76/86 (88.4) For statistical analysis, Chi‑square test of proportions was Tinidazole 86/86 (100) P<0.001 used. Cure rates of tinidazole, secnidazole, and ornidazole were Secnidazole 78/86 (90.7) P=0.62 compared with those of metronidazole. Value of P less than 0.05 Ornidazole 86/86 (100) P<0.001 was considered as significant. Table 2: Results Cure rate of nitroimidazoles in bacterial vaginosis at four weeks 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. Name of medicine Cure rate by Amsel’s criteria (%) P value Women educated in primary and secondary schools were Metronidazole 67/86 (77.9) the most commonly affected groups [123/344 (35.8%) and Tinidazole 84/86 (97.7) P<0.001 154/344 (44.8%), respectively]. A majority of the patients Secnidazole 69/86 (80.2) P=0.71 were housewives (85.5%). Monthly family income of less than Ornidazole 84/86 (97.7) P<0.001

244 Indian Journal of Pharmacology | April 2012 | Vol 44 | Issue 2 Thulkar, et al.: Bacterial vaginosis and treatment

Figure 1: The parallel randomised trial of nitroimidazoles in bacterial vaginosis

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Secnidazole is structurally related to 5‑nitroimidazoles References such as metronidazole and tinidazole. Its response in cases 1. Bhalla P, Chawla R, Garg S, Singh MM, Raina U, Bhalla R, et al. Prevalence of of BV is comparable to single‑dose tinidazole or a seven‑day bacterial vaginosis among women in Delhi. Indian J Med Res 2007;125:167‑72. treatment with metronidazole.[10] The present study reveals 2. Eriksson K, Carisson B, Forsum U, Larsson PG. A double‑blind treatment study that a four‑week cure rate for secnidazole is 80.2%. A Previous of bacterial vaginosis with normal vaginal lactobacilli after an open treatment with study by Gillis et al., which reports that 2‑g single oral dose vaginal clindamycin ovules. Acta Derm Venereol 2005;85:42‑6. 3. Larsson PG, Forsum U. Bacterial vaginosis–A disturbed bacterial flora and [11] of secnidazole has a cure rate of approximately 59‑96%. treatment enigma. APMIS 2005;113:305‑16. Ornidazole is the newest 5‑nitroimidazole derivative, which 4. Mattila J, Mannisto PT, Mantyla R, Nykanen S, Lamminsivu U. Comparative has been in use for the treatment of vaginitis for more than pharmacokinetics of Metronidazole and Tinidazole as influenced by administration 10 years. As per Mayo clinic proceedings 1987 Nov, tinidazole route. Antimicrob Agents Chemother 1983;23:721‑5. 5. Gillis JC, Wiseman LR. Secnidazole. A review of its antimicrobial activity, and ornidazole have greater antimicrobial activity than pharmacokinetic properties and therapeutic use in the management of protozoal metronidazole.[12] In the present study, the four‑week cure rate infections and bacterial vaginosis. Drugs 1996;51:621‑38. for ornidazole was 97.7%. A study by Erkkola et al., conducted 6. Martin C, Bruguerolle B, Mallet MN, Condomines M, Sastre B, Gouin F. in Finland, showed that single oral dose ornidazole (1.5 g) has Pharmacokinetics and tissue penetration of a single dose of Ornidazole. [13] Antimicrob Agent Chemother 1990;34:1921‑4. a 96% cure rate. This is comparable to our study because 7. Chaijareenont K, Sirimai K, Boriboonhirunsarn D, Kiriwat O. Accuracy of Nugent’s the dose of ornidazole was same and patients were followed score and each Amsel’s criteria in the diagnosis of bacterial vaginosis. J Med up at 7 and 28 days like that in our study. All four drugs did Assoc Thai 2004;87:1270‑4. not affect normal vaginal flora as observed on Gram staining, 8. Kurt O, Girginkardeşler N, Balcioğlu IC, Ozbilgin A, Ok UZ. A comparison of and thus are safe for use since no significant untoward reaction metronidazole and single‑dose ornidazole for the treatment of dientamoebiasis. Clin Microbiol Infect 2008;14:601‑4. was observed. Tinidazole and ornidazole proved significantly 9. Baylson FA, Nyirjesy P, Weitz MV. Treatment of recurrent bacterial vaginosis with better than metronidazole (P<0.001), probably because they Tinidazole. Obstet Gynecol 2004;104:931‑2. have similar half‑life. The duration of action on a microbial 10. Schindler EM, Thamm H, Ansmann EB, Sarnow E, Schindler AE. Treatment agent is important in prevention of recurrence. In spite of having of bacterial vaginitis. Multicenter, randomized, open study with tinidazole in comparision with metronidazole. Fortschr Med 1991;109:138‑40. the longest half‑life, secnidazole did not show the best cure. 11. Gillis JC, Wiseman LR. Secnidazole. A review of its antimicrobial activity, This could be because longer action might have disturbed the pharmacokinetic properties and therapeutic use in the management of protozoal protective defence mechanism by natural floras.[14] infections and bacterial vaginosis. Drugs 1996;51:621‑38. We could not classify different types of lactobacilli and the 12. Rosenblatt JE, Edson RS. Symposium on antimicrobial agents. Metronidazole. effect of each drug on these lactobacilli, which was a drawback Mayo Clin Proc 1987;62:1013‑7. 13. Erkkola R, Jarvinen H. Single dose of Ornidazole in the treatment of bacterial of this study. However, from the evident results we conclude that vaginosis. Ann Chir Gynaecol Suppl 1987;202:94‑6. tinidazole and ornidazole have a better cure rate as compared 14. McFarland LV, Elmer GW. Pharmaceutical probiotics for the treatment of Anaerobic to that by metronidazole in cases of BV. and other infections. Anaerobe 1997;3:73‑8.

Acknowledgement Cite this article as: Thulkar J, Kriplani A, Agarwal N. A comparative study of We are thankful to Department of Science and Technology, oral single dose of metronidazole, tinidazole, secnidazole and ornidazole in New Delhi, India for supporting and funding this project (ID No: SR/ bacterial vaginosis. Indian J Pharmacol 2012;44:243-5. WOS‑ A/LS – 164/2007). Source of Support: Nil. Conflict of Interest: None declared.

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