Abstract
Objective
To compare the efficacy of two different doses of tinidazole with metronidazole for treatment of bacterial vaginosis and compare side effects of the drugs.
Study design
Women were randomized to metronidazole 500 mg BID, tinidazole 500 mg BID, or tinidazole 1 gm BID all for 7 days. Follow-up visits were conducted at day 14 and day 28.
Results
593 women were enrolled. There were no significant differences between the treatment arms. Overall cure rates were 76.8% at 14 days and 64.5% at one month. Women who admitted to engaging in sexual intercourse during the study were significantly more likely to have BV at follow-up. There were no significant differences in adverse events across treatment arms.
Conclusions
There were no differences in cure rates between metronidazole and either of the tinidazole dosing regimens studied. In addition, there were no important differences in the side effect profiles of metronidazole and tinidazole.
Keywords: bacterial vaginosis, metronidazole, tinidazole
Introduction
Bacterial vaginosis (BV) is the most prevalent cause of symptomatic vaginal discharge in the U.S.1 and has been associated with complications including preterm delivery of infants, pelvic inflammatory disease (PID), urinary tract infections (UTI) and acquisition/transmission of sexually transmitted diseases (STDs) including human immunodeficiency virus (HIV)2–4. Control of BV has been advocated as a means of decreasing the prevalence of these complications. However, available treatment regimens have been disappointing in terms of initial cure and recurrence rates5. Tinidazole was recently licensed in the U.S. for the treatment of trichomoniasis and BV. The indication for BV was based on a tinidazole versus placebo trial6. There are no data on the efficacy of multi-dose tinidazole versus metronidazole for treatment of this infection. Tinidazole has the potential of being a more efficacious drug for BV based on its longer half-life and its seemingly superior side effect profile as compared to oral metronidazole. We compared the efficacy of two different doses of tinidazole with oral metronidazole for the initial treatment of symptomatic BV as well as short-term recurrence rates. In addition side effect profiles of the two drugs were compared.
Material and Methods
Heterosexual women attending the Jefferson County Department of Health (JCDH) STD Clinic with symptomatic BV as defined by the Amsel criteria7 and no evidence of STD were invited to participate in this randomized, double-blinded study. To be eligible the subject had to report symptoms of vaginal discharge and/or vaginal odor and have a vaginal pH >4.5, positive “whiff” test, and clue cells on microscopy. Women with known HIV infection were excluded from the study.
The study was approved by the Institutional Review Board at the University of Alabama at Birmingham. Subjects were administered standardized questionnaires about symptoms and a comprehensive sexual history. A pelvic examination was performed and specimens collected for vaginal pH, microscopy, Gram stain, gonorrhea and chlamydia testing, and trichomonas culture.
Women were randomized to oral metronidazole 500 mg twice a day for 7 days, tinidazole 500 mg twice a day for 7 days, or tinidazole 1 gm twice a day for 7 days. The study was initiated prior to the FDA approval of tinidazole for BV thus dosing was based on review of the literature.
Follow-up visits were conducted at days 14 and 28 of the study, and then monthly for an additional 2 visits. At each of the follow-up visits, a standardized questionnaire was administered, a pelvic examination was conducted and specimens for the diagnosis of BV were collected. Women with symptomatic BV at the follow-up visits were treated with the current standard therapy of seven days of metronidazole and discontinued from the study at that time. Any woman found to have a positive screening test for gonorrhea and/or chlamydia was treated appropriately and discontinued from the study with the exception of women with positive culture tests for Trichomonas vaginalis as this infection would be adequately treated with either metronidazole or tinidazole. Women with intercurrent vaginal yeast infections were treated and continued in the study.
Microbiological cure was defined as a Nugent score of less than 7. Clinical improvement was defined as normalization of two of three criteria (pH, whiff test, and clue cells) and cure was defined as normalization of all three. The persistence of two or more abnormalities constituted clinical failure.
Microbiological Methods
Vaginal pH, amine odor (“whiff” test), and microscopy were performed as previously described8. Vaginal smears were gram stained and interpreted according to the method of Nugent et al9. Neisseria gonorrhoeae and Chlamydia trachomatis were Gen-Probe Aptima Combo 2 according to manufacturer's instructions. Trichomonas cultures were performed using the In Pouch TV test (BioMed Diagnostics Inc., White City, OR)10.
Statistical Considerations
Sample size and power
Sample size estimates were computed for the efficacy analysis based on the cure rates defined as 70% for the metronidazole group, 85 % for the tinidazole 500mg bid group and 90% for the tinidazole 1gm group. Assuming a 20% loss to follow-up overall, a sample size of 192 per group or a total N of 576 was randomized to the three treatment arms with an alpha level of 0.025. No formal comparison was planned for the two tinadazole arms. Based on 160 randomized subjects per group we would be able to detect a difference of 15% in side effects between the treatment arms. This would be an event proportion of approximately 15% in the two tinidazole arms with an alpha of 0.025.
Statistical analyses
The proportion cured of BV at the 14 day follow-up visit (7 days after completion of therapy) was compared between the metronidazole and 500mg tinidazole group using the chi-square test of proportions and exact confidence intervals were computed. The proportion cured was compared between the metronidazole and 1g-tinidazole groups in a similar fashion. Descriptive statistics of the population such as age, sexual history, STD history, etc. were compared between the treatment arms by the t test for compare continuous variables and the Fisher's exact test or the chi-square test will be used for nominal variables.
The short-term recurrence rates at 1month, 2 months, and 3 months among subjects that were successfully cured following the initial treatment (at the 14 day visit) were compared across treatment groups by the chi-square test. Confounding variables tested in a repeated measures model to predict BV included number of partners (>1 vs. 1, new partner (yes vs. no), consistent condom usage (yes vs. no), current douching (yes vs. no) and baseline BV score (≥ 7 vs. 4–7). For all analyses a p value of <0.05 was considered statistically significant.
Adverse events were categorized as gastrointestinal, vaginal/GYN, neurologic, and other. The proportion of women experiencing an event was compared across the three treatment groups by the Fisher' exact test for each type of event and for overall events. In addition the total numbers of events (more than one event possible per person) was compared across the three treatment groups in a similar fashion.
The study statistician was responsible for preparing computer-generated randomization lists for the clinical trial, and a blocked randomization scheme was employed in generating the list. The randomization scheme was provided only to the study pharmacist who was responsible for preparing the study medication in a blinded fashion. The actual randomization assignments were kept in a secured fashion by the Biostatistics Unit.
Results
Five hundred ninety-three patients were enrolled into the study between November, 2004 and October, 2009. The allocation of subjects for the trial up to and including the one month follow-up is shown in Figure 1. The most common reason for termination was loss to follow-up (158/593, 26.7%) followed by pre-existing protocol violation (57/593, 9.6%) of which 52/57 (91.2%) were presence of STD at baseline. The demographic and behavioral characteristics of subjects by randomized treatment group are shown in Table 1. There were no significant differences with respect to race, age, or behaviors such as douching and sexual behavior. Of note, nearly 97% of subjects reported a prior history of STD. 83% reported a prior history of BV.
Figure 1.
Enrollment and Analysis
At first follow-up, in the metronidazole group, 26 subjects were excluded from the analysis because 18 had a pre-existing protocol violation, 7 withdrew from the study, and 1 was withdrawn for pregnancy. In the tinidazole 1 gm twice a day group 25 subjects were excluded from the analysis because 15 had a pre-existing protocol violation, 8 withdrew from the study, 1 was withdrawn for pregnancy, and 1 discontinued the intervention due to side effects. In the tinidazole 500 mg twice a day group 21 subjects were excluded from the analysis because 19 had a pre-existing protocol violation and 2 discontinued the intervention due to side effects.
Table 1.
Demographic and behavioral characteristics of subjects by randomized treatment group (n (%)
| Characteristic | Metronidazole 500mg twice a day for 7 days | Tinidazole 1g twice a day for 7 days | Tinidazole 500mg twice a day for 7 days | P |
|---|---|---|---|---|
| Race | ||||
| African American | 181 (91.9) | 181 (92.4) | 187 (93.5) | 0.56 |
| White | 12 (6.1) | 1 (0.5) | 10 (5.0) | |
| Other | 4 (2.0) | 14 (7.1) | 1 (0.5) | |
| Education | ||||
| < 12 years | 42 (21.3) | 45 (23.0) | 40 (20.0) | 0.40 |
| 12 years | 70 (35.5) | 84 (42.9) | 84 (42.0) | |
| > 12 years | 85 (43.2) | 67 (34.2) | 76 (38.0) | |
| Condom use last 3 months | ||||
| Always | 28 (14.3) | 29 (14.8) | 33 (16.5) | 0.70 |
| Sometimes | 97 (49.5) | 86 (43.9) | 91 (45.5) | |
| Never | 68 (34.7) | 80 (40.8) | 72 (36.0) | |
| Don't know | 3 (1.5) | 1 (0.5) | 4 (2.0) | |
| How long since first had BV | ||||
| < 1 year | 21 (12.8) | 24 (14.7) | 38 (23.0) | 0.04 |
| 1–5 Years | 80 (48.8) | 80 (49.1) | 77 (46.7) | |
| >5 years | 63 (38.4) | 56 (34.4) | 50 (30.3) | |
| Don't know | 0 (0.0) | 3 (1.8) | 0 (0.0) | |
| Currently douche | ||||
| Yes | 78 (39.6) | 78 (39.8) | 79 (39.5) | 0.99 |
| No | 119 (60.4) | 118 (60.2) | 121 (60.5) | |
| History of STDs | ||||
| Yes | 187 (94.9) | 190 (96.9) | 196 (98.0) | 0.23 |
| No | 10 (5.1) | 6 (3.1) | 4 (2.0) | |
| Age | 28.0± 6.2 | 28.5 ± 6.8 | 28.3±6.6 | 0.70 |
| Age at first sex | 15.0 ± 2.5 | 15.3 ± 2.0 | 15.5 ± 2.0 | 0.11 |
| Number partners last 3 months | 1.5 ± 1.0 | 1.4 ± 0.7 | 1.3 ± 0.8 | 0.24 |
| Number partners last 30 days | 1.2 ± 0.7 | 1.1 ± 0.6 | 1.1 ± 0.6 | 0.25 |
Cure rates defined by Nugent score are shown in Table 2. Results are limited to the 14 day and one month visit as there was no change in trends at the two and three month visits and number of remaining subjects had diminished. There were no significant differences between the three treatment arms at any of the follow-up visits. Percent treatment failure rates and 95% confidence intervals for metronidazole, tinidazole 1 gm, and tinidazole 500 mg for the 14 day visit were 17.7 (11.2,24.1), 27.0 (19.6, 34.4) and 24.7 (17.9, 32.5) respectively. Overall the cure rate was 76.8% at the 14 day follow-up visit and 64.5% at the one month follow-up visit. Using a stricter Nugent criteria of cure defined as a score of <4, there were no significant differences in cure rates between the treatment arms with the overall cure rate at the 14 day visit being 53.7%. Neither baseline Nugent score, consistent use of condoms, sex with a new partner, or multiple partners was significantly associated with cure. There was no statistical difference in clinical cure or improvement as measured by individual Amsel criteria among the three treatment arms. Cure or improvement was seen in 80.3%, 82.5%, and 73.1% of the subjects in the metronidazole, tinidazole 1 gm, and tinidazole 500 mg arms respectively at the 14 day visit. For the 1 month follow-up visit the cure or improvement rates were 55.2%, 62.3% and 58.0% respectively.
Table 2.
Primary outcome, as defined by Nugent criteria, after completion of therapy by randomized treatment group (N (%))
| Nugent Score | Metronidazole | Tinidazole 1 gm | Tinidazole 500mg | P value |
|---|---|---|---|---|
| 14 day follow-up visit | ||||
| ≥7 | 24/136 (17.7) | 37/137 (27.0) | 36/146 (24.7) | 0.16 |
| 0.19* | ||||
| <7 | 112/136 (82.4) | 100/137 (73.0) | 110/146 (75.3) | 0.08+ |
| 1 month follow-up visit | ||||
| ≥7 | 42/117 (35.9) | 37/114 (32.5) | 45/118 (38.1) | 0.66 |
| 7 | 75/117 (64.1) | 77/114 (67.5) | 73/118 (61.9) |
P values are for the comparison of all three groups unless otherwise marked
p value for metronidazole versus tinidazole 500 mg
pvalue for metronidazole versus tinidazole 1 gm
Short term recurrence rates after initial cure are shown in Table 3. There were no significant differences in short term recurrence rates between the three treatment arms. Percent recurrence rates and 95% confidence intervals for metronidazole, tinidazole 1 gm, and tinidazole 500 mg for the 1 month visit were 33.3 (24.3, 43.4), 22.5 (14.3, 32.6), and 30.2 (21.3, 40.4) respectively. Overall recurrence rates were 28.9% and 31.2% at 1 and 2 months respectively. Women who admitted to engaging in sexual intercourse during the study were significantly more likely to have BV at follow-up (RR=1.76, (95% CI 1.25, 2.49)).
Table 3.
Short term recurrence rates, as defined by Nugent criteria, after completion of successful therapy by randomized treatment group (N (%))
| Nugent Score | Metronidazole | Tinidazole 1 gm | Tinidazole 500mg | P value |
|---|---|---|---|---|
| 500mg BID | BID | 500mg BID | ||
| 1 month follow-up | ||||
| ≥7 | 34/102 (33.3) | 20/89 (22.5) | 29/96 (30.2) | 0.24 |
| <7 | 68/102 (66.7) | 69/89 (77.5) | 67/96 (69.8) | |
| 2 month follow-up | ||||
| ≥7 | 19/56 (33.9) | 12/59 (20.3%) | 22/55 (40.0) | 0.07 |
| <7 | 4/56 (66.1) | 6/59 (79.7%) | 3/55 (60.0) |
Note. Women defined as failures at 14 day visit not included in the analysis
Adverse events associated with each treatment arm are displayed in Table 4. There were no significant differences in adverse events across treatment arms with the exception of an increased percentage of subjects reporting bad taste in the tinidazole 1 gm arm. The overall incidence of yeast infections was 15.3%.
Table 4.
Frequency of initial treatment emergent events by randomized treatment group among those reporting at least one adverse event*
| Event | Metronidazole 500mg n(%) | Tinidazole 1g n(%) | Tinidazole 500mg n(%) | p value |
|---|---|---|---|---|
| Yeast infection | 32 (29.3) | 27 (24.5) | 33 (25.0) | 0.67 |
| Nausea/vomiting | 22 (20.2) | 34 (30.9) | 26 (19.7) | 0.08 |
| Bad taste | 12 (11.0) | 46 (41.8) | 20 (15.2) | <0.001 |
| Diarrhea | 4 (3.7) | 6 (5.5) | 1 (0.8) | 0.10 |
| Anorexia | 1 (0.8) | 5 (4.5) | 7 (5.3) | 0.17 |
| Headache | 16 (14.7) | 27 (24.5) | 22 (16.7) | 0.13 |
| Total Number of Subjects with at Least 1 Adverse Event | 109 | 110 | 132 |
Subjects can experience more than one adverse event; the percents reperesent the number of subjects with that incident event out of the total number of individuals in each treatment group who experienced at least one adverse event.
Discussion
Bacterial vaginosis is the most common cause of vaginitis and is associated with several important reproductive health problems including preterm birth and acquisition/transmission of HIV/STD1, 2, 4, 7, 11. There is a lack of consensus on the etiologic agents or agents associated with BV; thus treatment has been based on empiricism12, generally with metronidazole or clindamycin which were chosen for their activity against many anaerobic organisms. Unfortunately, cure rates with these antibiotics range from 50–80% and recurrence rates are high5. Tinidazole, a 5-nitroimidazole similar to metronidazole but with a longer half-life and more favorable side effect profile has been used for decades in Europe. Recently it was licensed in the U.S. first for treatment of trichomoniasis and giardia and later for treatment of BV. Due to its pharmacokinetics there was optimism that tinidiazole would result in superior cure rates compared with metronidazole for the treatment of BV.
There have been 16 published studies encompassing over 1600 patients on the use of tinidazole for BV. The majority of the studies utilized a single 2g dose of tinidazole for BV treatment, all showing clinical efficacy. In both the reports comparing a single 2g dose of tinidazole to a single 2g dose of metronidazole, tinidazole produced higher efficacy rates. A report by Ekgren13 which compared a single 2g dose of tinidazole to a 2g × 2 day dose of tinidazole demonstrated higher efficacy with the 2 day dosing regimen. In that randomized, double-blind study report the 2 day dose produced an efficacy rate of 74% vs. 51% efficacy for the single 2g dose with only a small increase in the reported side effects (44% vs. 39%).
In two studies where a single 2g dose of tinidazole was compared to oral metronidazole at 500mg BID × 7 days, oral metronidazole produced slightly higher efficacy rates14, 15. In the Buranawarodmkul study, efficacy rates were 86% and 92% for tinidazole vs. metronidazole, respectively. The Sanz-Sanz study produced efficacy rates of 65% and 74% for tinidazole vs. metronidazole, respectively. Although a single 2g dose of tinidazole appears more effective than a single 2g dose of metronidazole, it may be slightly less effective than seven days of metronidazole.
A more recent double-blind, double-dummy, randomized, comparative trial of a single 2g dose of tinidazole vs. a single 2g dose metronidazole vs. a single 2g dose tinidazole with a vaginal acidifier showed superior efficacy with the single 2g dose tinidazole (without the acidifier) (88%) vs. metronidazole (73%) at 4 weeks post-therapy (p=0.06). The cure rate in the 2g tinidazole plus acidifier arm was 87%, indicating no benefit over 2g tinidazole alone16. Additionally, tinidazole showed a statistically superior lower relapse rate at 12 weeks (tinidazole (3%), metronidazole (30%), p=0.04).
The study conducted for FDA approval for the treatment of BV was conducted as a placebo controlled trial and used very strict FDA recommended criteria to determine cure6. In this study, at 21–30 days after treatment, tinidazole 1 gm daily for five days and 2 gms once daily for 2 days resulted in significantly improved cure rates compared to placebo (36.8% and 27.4% respectively). Due to the fact that FDA criteria for cure have changed over the years it is difficult to compare cure rates of tinidazole to other licensed products for the treatment of BV. In actuality, oral generic metronidazole was never evaluated by the FDA for the treatment of BV.
Although we anticipated that tinidazole would have superior efficacy to oral metronidazole our findings did not support that hypothesis. We found no differences in cure rates between metronidazole and either of the tinidazole dosing regimens we studied. Of note, our regimens were more intensive than those approved by the FDA. In addition, there were no significant differences in the side effect profiles of metronidazole and tinidazole.
Limitations to our study include the high lost to follow up rate as well as the high risk nature of this population for STD and BV. Eighty- three percent of the women had had at least one prior episode of BV and thus may represent a more difficult to cure group of women. Nonetheless, this randomized trial showed no difference in efficacy between metronidazole and tinidazole. New approaches to therapy for this common infection are needed.
Condensation.
Tinidazole was not found to be more efficacious for the treatment of bacterial vaginosis than metronidazole.
Acknowledgments
Financial Support: Support for this research was provided by the National Institutes of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) R01AI058033; tinidazole was provided by Mission Pharmacal Company (San Antonio, TX)
Footnotes
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Findings of this study were presented at the 37th Annual Scientific Meeting of the Infectious Diseases Society for Obstetrics and Gynecology, Santa Fe, New Mexico, August 7, 2010
References
- 1.Fleury FJ. Adult vaginitis. Clin Obstet Gynecol. 1981;24:407–38. doi: 10.1097/00003081-198106000-00008. [DOI] [PubMed] [Google Scholar]
- 2.Eschenbach DA. Bacterial vaginosis and anaerobes in obstetric-gynecologic infection. Clin Infec Dis. 1993;16:S282–S7. doi: 10.1093/clinids/16.supplement_4.s282. [DOI] [PubMed] [Google Scholar]
- 3.Hillier S. The vaginal microbial ecosystem and resistance to HIV. AIDS. 1998;14:17–21. [PubMed] [Google Scholar]
- 4.Martin H, Richardson BA, Nyange PM, Lavreys L, Hillier SL, Chohan B, et al. Vaginal lactobacilli, microbial flora, and risk of human immundodeficiency virus type 1 and sexually transmitted disease acquisition. J Infect Dis. 1999;180:1863–8. doi: 10.1086/315127. [DOI] [PubMed] [Google Scholar]
- 5.Joesoef MR, Schmid GP, Hillier SL. Bacterial vaginosis: review of treatment options and potential clinical indications for therapy. Clin Infect Dis. 1999;28:S57–S65. doi: 10.1086/514725. [DOI] [PubMed] [Google Scholar]
- 6.Livengood Cr, Ferris DG, Wiesenfeld HC, et al. Effectiveness of two tinidazole regimens in treatment of bacterial vaginosis: a randomized controlled trial. Obstet Gynecol. 2007;110:302–9. doi: 10.1097/01.AOG.0000275282.60506.3d. [DOI] [PubMed] [Google Scholar]
- 7.Amsel R, Totten PA, Spiegel CA, Chen KCS, Eschenbach D, Holmes KK. Non-specific vaginitis: diagnostic and microbial and epidemiological associations. Am J Med. 1983;74:14–22. doi: 10.1016/0002-9343(83)91112-9. [DOI] [PubMed] [Google Scholar]
- 8.Eschenbach DA, Hillier S, Critchlow C, Stevens C, DeRouen T, Holmes KK. Diagnosis and clinical manifestations of bacterial vaginosis. Am J Obstet Gynecol. 1988;158:819–28. doi: 10.1016/0002-9378(88)90078-6. [DOI] [PubMed] [Google Scholar]
- 9.Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of Gram stain interpretation. J Clin Microbiol. 1991;29:297–301. doi: 10.1128/jcm.29.2.297-301.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Draper D, Parker R, Patterson E, et al. Detection of Trichomonas vaginalis in pregnant women with the InPouch TV system. J Clin Microbiol. 1993;31:1016–8. doi: 10.1128/jcm.31.4.1016-1018.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Rein MF, Holmes KK. “Non-specific vaginitis,” vulvovaginal candidiasis, and trichomoniasis clinical features, diagnosis and management. Curr Clin Top Infec Dis. 1983;4:281–315. [Google Scholar]
- 12.Josey W, Schwebke J. The polymicrobial hypothesis of bacterial vaginosis causation: a reassessment. Int J STD AIDS. 2008;19:152–4. doi: 10.1258/ijsa.2007.007260. [DOI] [PubMed] [Google Scholar]
- 13.Ekgren J, Norling B, Degre M, Midret T. Comparison of tinidazole given as a single dose and on 2 consecutive days for the treatment of nonspecific bacterial vaginosis. Gynecol Obstet Invest. 1988;26:313–7. doi: 10.1159/000293712. [DOI] [PubMed] [Google Scholar]
- 14.Buranawarodomkul P, Chandeying V, Sutthijumroon S. Seven day metronidazole versus single dose tinidazole as therapy for nonspecific vaginitis. J Med Assoc Thai. 1990;73:283–7. [PubMed] [Google Scholar]
- 15.Sanz Sanz F, Hernanz A, Sancher E. Comparative trial of metronidazole versus tinidazole in the treatment of nonspecific vaginitis. Rev Esp Obst y Gin. 1985;44:717–20. [Google Scholar]
- 16.Milani MBE, Agnello A. Efficacy of the comparison of 2 g oral tinidazole and acidic buffering vaginal gel in comparison with vaginal clindamycin alone in bacterial vaginosis: a randomized, investigator-blinded, controlled trial. J Obstet Gynecol Reprod Biol. 2003;19:67–71. doi: 10.1016/s0301-2115(02)00478-5. [DOI] [PubMed] [Google Scholar]