OBJECTIVE: To assess the effectiveness at 21–30 days after treatment of tinidazole administered orally at 1 g once daily for 5 days and 2 g once daily for 2 days, compared with placebo, in the treatment of bacterial vaginosis, using rigorous U.S. Food and Drug Administration (FDA)–recommended criteria to define cure.
METHODS: A total of 235 women at 10 U.S. centers participated in this prospective, randomized, double-blinded, placebo-controlled trial. Presence or absence of all five following criteria was required to define diagnosis or cure of bacterial vaginosis: 1) clue cells were at least 20% of squamous cells in microscopic examination of vaginal fluid; 2) positive potassium hydroxide whiff test; 3) a homogeneous, thin, white-gray vaginal discharge; 4) vaginal pH greater than 4.5; and 5) Nugent score greater than or equal to 4 on Gram-stained vaginal fluid. Compliance, tolerability, and safety were assessed using patient diaries and interviews at 8–10 days and 21–30 days after treatment. Cochran-Mantel-Haenszel statistical analysis with Bonferroni adjustment was used to compare outcomes.
RESULTS: Superior efficacy was demonstrated by tinidazole for the 1 g once daily for 5 days regimen (36.8% cured, P<.001, number needed to treat 3.2) and for the 2 g once daily for 2 days regimen (27.4% cured, P<.001, number needed to treat 4.5), when compared with placebo (5.1% cured) in the primary endpoint analysis. Using more traditional criteria for cure, efficacy was greater. Compliance with study therapy and tolerability were comparable in the three treatment groups.
CONCLUSION: Both tinidazole regimens studied provided effective treatment for bacterial vaginosis.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00229216
LEVEL OF EVIDENCE: I
Tinidazole administered orally provides effective treatment for bacterial vaginosis when rigorous requirements for cure are applied.
From 1Duke University Medical Center, Durham, North Carolina; 2Medical College of Georgia, Augusta, Georgia; 3University of Pittsburgh School of Medicine/Magee-Women's Research Institute, Pittsburgh, Pennsylvania; 4Medical University of South Carolina, Charleston, South Carolina; 5Drexel University College of Medicine, Philadelphia, Pennsylvania; 6University of Washington, Seattle, Washington; 7Temple University College of Medicine, Philadelphia, Pennsylvania; 8Planned Parenthood of Houston and Southeast Texas, Houston, Texas; 9Wayne State University School of Medicine, Detroit, Michigan; 10Louisiana State University Health Sciences Center, New Orleans, Louisiana; 11Consultant, Mission Pharmacal Company, San Antonio, Texas; and 12Mission Pharmacal Company, San Antonio, Texas.
Funded by Mission Pharmacal Company, San Antonio, Texas.
Corresponding author: Charles H. Livengood III, MD, Room 242 Baker House, Box 3291 Duke Hospital, Durham, NC 27710; e-mail: email@example.com.
Financial Disclosure All authors received financial support from Presutti Labs, now Mission Pharmacal Co, for their contributions to this trial. Dr. Livengood provides clinical trial support to Merck Pharmaceuticals (Whitehouse Station, NJ), Curatek Pharmaceuticals (Elk Grove Village, IL), and Amgen (Thousand Oaks, CA). Dr. Ferris has received grant support from Curatek and 3M Pharmaceuticals (St. Paul, MN) for clinical trials, and was also a speaker. Dr. Wiesenfeld is on the Speaker's Bureau for 3M Pharmaceuticals and GlaxoSmithKline (Research Triangle Park, NC), serves as a consultant to K-V Pharmaceuticals (St. Louis, MO), performs research under contract with Mission Pharmacal Co, and is a speaker for Merck Pharmaceuticals. Dr. Hillier attended an advisory board meeting for and received an honorarium from Mission Pharmacal. Dr. Soper serves on the advisory board for Mission Pharmacal and received grant support for participating in this study. Dr. Nyirjesy has given talks for and received an honorarium from Mission Pharmacal, as well as consulted for and received honoraria from K-V Pharmaceuticals. Dr. Marrazzo is a consultant for TherRx, Quidel, and Mission Pharmacal. Dr. Sobel consulted for and received an honorarium from Mission Pharmacal. Dr. Wood was the director of this study as an employee of Presutti Laboratories and is a consultant to Mission Pharmacal. Dr. Kanalas is an employee of Mission Pharmacal. Drs. Chatwani, Fine, and Taylor have no other potential conflicts of interest to disclose.
Bacterial vaginosis results from replacement of the hydrogen peroxide-producing Lactobacillus species which dominate the normal vaginal flora by various anaerobic and facultative bacteria.1,2 Its pathogenesis is not clearly understood. The diagnosis of bacterial vaginosis is not standardized. Various combinations of the four clinical Amsel criteria3 (clue cells on microscopic examination of vaginal discharge in saline; vaginal pH more than 4.5; thin, homogeneous, white-gray discharge; and a fishy odor after addition of potassium hydroxide) are commonly used in clinical practice. Card tests for alkalinity, trimethylamine, and proline aminopeptidase are also used. Gram stain4 provides a reproducible microbiologic diagnosis, but correlates with the widely used clinical criteria in approximately 80% of cases,5–7 and requires a delay in diagnosis. Variations in diagnostic criteria employed in clinical trials of treatments for bacterial vaginosis are widespread as well.
Approved therapies for bacterial vaginosis in the United States include oral and topical metronidazole, and topical clindamycin. Tinidazole (Tindamax, Mission Pharmacal Company, San Antonio TX, 1-[2-(ethyl sulfonyl) ethyl]-2-methyl-5-nitroimidazole) was recently approved in the United States for treatment of giardiasis, amebiasis, and trichomoniasis. Tinidazole is a second-generation nitroimidazole that has been used in Europe, Asia, and Latin America since the 1970s for giardiasis, trichomoniasis, amebiasis, bacterial vaginosis, gingivitis, Helicobacter pylori infections, surgical prophylaxis, and other anaerobic infections. Compared with metronidazole, a first-generation nitroimidazole, tinidazole has a twice-longer serum half-life (12–14 hours compared with 6–7 hours,) and side-effects have been reported to occur one half as often with tinidazole as with metronidazole.8,9 Easier reduction of the nitro group is thought to make tinidazole a more potent agent than metronidazole. Additionally, the increased lipid solubility of tinidazole results in more efficient penetration into both female and male reproductive tissues than metronidazole.10
Previous studies of tinidazole as a treatment for bacterial vaginosis have found favorable results. We undertook this randomized, multicenter, double-blind, double-dummy, placebo-controlled study to examine the effectiveness of tinidazole at 21–30 days of treatment, administered orally at 1 g once daily for 5 days and 2 g once daily for 2 days in 10 centers across the United States. Rigorous criteria for diagnosis and cure of bacterial vaginosis were applied as recommended in the 1998 U.S. Food and Drug Administration (FDA) Guidance Document entitled “Bacterial Vaginosis—Developing Antimicrobial Drugs for Treatment.”11
MATERIALS AND METHODS
Women seen in the clinics of the participating institutions, given a diagnosis of bacterial vaginosis, and referred for consideration of participation were candidates for this trial. All of the following criteria were required of candidates for enrollment: 1) age at least 18 years; 2) capable of providing written informed consent; 3) a negative pregnancy test on the day of enrollment; 4) able to follow the study protocol; 5) willing to forego coitus for days 1–10 of study participation, and to use nonlubricated condoms with each episode of coitus from day 11 until study completion; 6) willing not to douche or use any intravaginal products throughout participation, including tampons, medications, and devices; 7) willing to avoid drinking any alcohol from 24 hours before through 72 hours after taking study medication; and 8) premenopausal status. Further, the diagnosis of bacterial vaginosis, made by study personnel, required all five of the following: 1) 20% or more of vaginal squamous cells were clue cells on microscopic examination in saline; 2) a homogeneous, thin, white-gray vaginal discharge; 3) pH of vaginal discharge more than 4.5; 4) emanation of fishy odor from vaginal discharge after addition of 10% potassium hydroxide (positive whiff test); and 5) confirmation of vaginal bacterial morphotypes consistent with bacterial vaginosis on Gram stain (Nugent score 4 or more), as determined by a single reference laboratory.
The following characteristics excluded participants from participation: 1) symptoms so severe as to make assignment to placebo unacceptable to the patient; 2) identification of fungal elements or trichomonads by microscopic examination of vaginal discharge, lesions caused by herpes simplex virus or human papillomavirus on gross examination, or a positive nucleic acid amplification test for Chlamydia trachomatis or Neisseria gonorrhoeae; 3) presence of another vaginal, vulvar, or medical condition which might confound assessment of response to study treatment; 4) treatment with any 5–nitroimidazole, antifungal agent, or clindamycin within 14 days of study entry, or with any investigational drug within 30 days of study entry; 5) history of hypersensitivity to 5–nitroimidazole agents; 6) under treatment for cervical neoplasia during participation; 7) presently breastfeeding; 8) menstruating at diagnosis; 9) currently being treated with lithium or anti-coagulant drugs; 10) treatment with disulfiram within two weeks before, during, or within one week after study treatment.
The protocol and consent were approved by the institutional review board at each participating institution. Study personnel obtained written informed consent and Health Insurance Portability and Accountability Act of 1996 authorizations from candidates who qualified for participation using the above criteria. Demographic information, medical history, vaginal symptoms, vital signs, and physical examination data were collected. During pelvic examination, vaginal discharge samples were collected for establishing the diagnosis of bacterial vaginosis (including a sample that was heat-fixed on a microscope slide and submitted to a central laboratory for Gram stain interpretation), and culture for Candida spp and Trichomonas vaginalis. Endocervical swabbings were tested by the nucleic acid amplification platform in use at each site for C trachomatis and N gonorrhoeae. Samples for cervical cytology were obtained. If clinically indicated, samples for herpes simplex virus culture were obtained. Urine and blood samples were obtained for urinalysis, pregnancy test, complete blood cell counts and differential, and liver and kidney function measures.
Participants were instructed about the study protocol, given a daily diary in which to record drug administration, vaginal symptoms, any potential adverse events, and concomitant medications and given a supply of nonlubricated condoms. A telephone call was scheduled for 8–10 days after the first day of study drug administration.
All participants meeting all entry criteria and no exclusion criteria were randomly assigned to study treatment using the method of permuted blocks. Blocks were of size 3, one participant to each treatment, and randomization was conducted at each study center separately. Randomization was accomplished with SAS PROC PLAN (SAS Institute Inc., Cary, NC), which uses a prime modulus multiplicative congruential random number generator. Allocation of participants to study treatment was accomplished by assigning each consecutive participant to the next study number and corresponding drug packet, provided by the sponsor, in sequence at each center. All those randomly assigned make up the Intent-To-Treat population. To form the modified Intent-To-Treat population, those whose Gram stain score did not provide microbiologic confirmation of the diagnosis of bacterial vaginosis were omitted from the Intent-to-Treat population. The Per Protocol population excluded modified Intent-To-Treat participants who had other genital tract infections not apparent on entry visit examination, took less than 4 doses of study treatment, did not follow protocol, or withdrew or were withdrawn from participation before study completion.
The three treatment arms consisted of tinidazole 1 g (two 500-mg tablets) by mouth once daily for 5 days (Group I); tinidazole 2 g (four 500-mg tablets) by mouth once daily for 2 days (Group II); and placebo tablets by mouth once daily for 5 days (Group III). To preserve blinding, each participant received a packet containing 14 identically appearing tablets for 5 days: a day 1 bottle containing four tablets, a day 2 bottle containing four tablets, and day 3–5 bottles each containing two tablets.
At the day 8–10 telephone call, participants were queried about vaginal symptoms, compliance with protocol procedures, and any potential adverse events. The final visit was scheduled at 21–30 days after the first day of treatment. During the final visit medical history and vaginal symptoms data were collected, vital signs and physical and pelvic examinations were repeated, and vaginal discharge samples were taken to reexamine for diagnostic criteria and Gram stain interpretation. T vaginalis culture was also repeated. Urine and blood samples were taken to repeat the same testing done at the entry visit. If clinically indicated, retesting for chlamydia, gonococcus, and herpes virus was done. Diaries were reviewed with participants to ensure all adverse events were recorded on the case report forms.
Therapeutic cure was defined in accordance with the 1998 FDA Guidance Document. Therefore, a therapeutic cure was characterized by resolution of all five diagnostic criteria used to establish the diagnosis of bacterial vaginosis at study entry, which were 1) clue cells 20% or more of squamous cells; 2) homogenous, thin white-gray discharge; 3) vaginal pH more than 4.5; 4) positive whiff test; and 5) Nugent score 4 or more. Adverse events were classified for relationship to study treatment by investigators, and were considered serious if they caused death, were life threatening, required hospitalization, caused a persistent or significant disability, or caused congenital anomaly.
Because of potential variation among centers, the Cochran-Mantel-Haenszel procedure (which adjusts for such variation) was used to test for efficacy of the tinidazole treatments. A priori, the one-tailed 0.025 alpha level was chosen for testing. Because each tinidazole treatment was compared with placebo (two comparisons), the Bonferroni adjustment was applied, thus making the alpha level 0.0125, one-tailed. Sample size determination was accomplished using the normal approximation of the binomial distribution, assuming a 25% success rate for placebo and a 55% success rate for tinidazole; with one-tailed alpha 0.0125 and power 80%, at least 50 modified Intent-To-Treat participants per treatment arm were needed. The primary efficacy analysis of a therapeutic cure compared the two tinidazole regimens with placebo in the modified Intent-To-Treat population. Secondary efficacy analyses using the same statistical method examined cure rates defined by resolution of four and three or more clinical (Amsel) criteria and microbiologic (Gram stain) criteria individually.
Ten geographically diverse centers in the United States participated, screened 379 candidates, and qualified and enrolled 235 participants from February 1, 2005, to January 11, 2006. Table 1 shows the disposition of participants by treatment arm. Centers enrolled 11–43 participants each. Table 2 shows that participants were evenly distributed among the three treatment arms, and that age, height, weight, ethnicity, entry Gram stain score, and vaginal pH were comparable as well. The mean Gram stain scores at entry in all three treatment arms were high (8.39, 8.24, and 8.35 in Groups I, II and III, respectively), as expected among women with clinical signs. Participants classified with recalcitrant bacterial vaginosis (three or more prior episodes within the previous 12 months) were comparable among the groups (19.2%, 20.0%, and 24.7% in Groups I, II, and III, respectively). Compliance with study therapy based on tablet count was 92.9%, 88.5%, and 89.1% for the three respective groups. Table 3 shows superior efficacy of both tinidazole regimens to placebo in the modified Intent-To-Treat population (primary endpoint), as well as in the Intent-To-Treat and Per Protocol populations when cure is defined by normalization of all four Amsel criteria and Gram stain score, by Gram stain score less than 4, and by resolution of four and three or more Amsel criteria. When normalization of the individual Amsel criteria by treatment arm for each population was examined, results very similar to those for resolution of three of four Amsel criteria were found (data not shown).
Adverse events (Table 4) occurred with comparable frequency in tinidazole and placebo recipients, except for dysgeusia, which was significantly more common in the tinidazole arms, and nausea, which was significantly more frequent in Group II. However, no difference was seen between the tinidazole and placebo groups in the number of participants experiencing one or more gastrointestinal symptoms. Comparing the proportion of participants experiencing any adverse event(s) in Group I (55.8%) and Group II (61.5%) to the placebo group (48.8%) by Fisher exact test gave values of P=.426 and P=.113, respectively. One serious adverse event, a perineal abscess in a placebo recipient, required withdrawal of the patient from the study. No patient withdrew because of unacceptability of tinidazole treatment. No clinically significant effect of tinidazole was seen on blood cell counts, liver or kidney function tests, or urinalysis results.
We are aware of 21 published clinical trials9,12–31 that have evaluated the efficacy of tinidazole in the treatment of bacterial vaginosis; most have been done outside the United States. Trial regimens range from 1–2 g daily for 1–5 days. All have found favorable results. Our present study, performed at 10 centers across the United States, demonstrates the efficacy and tolerability of tinidazole, both 1 g once daily for 5 days and 2 g once daily for 2 days, in the treatment of bacterial vaginosis when compared with placebo.
In trials evaluating treatments for bacterial vaginosis it has been common for studies to use some or all of the Amsel criteria, Gram stain results, or weighted combinations of the two to define diagnosis and cure. In 1998, the FDA issued a Guidance Document entitled “Bacterial Vaginosis—Developing Antimicrobial Drugs for Treatment,”11 which specifically called for investigators to define bacterial vaginosis in study participants as presence of all four Amsel criteria and a Gram stain score of 4 or more, to define cure as the absence of all four Amsel criteria and a Gram Stain score of 0–3, and to perform the examination for evaluation of therapeutic response at 21–30 days after the first day of treatment. Thomas et al32 are among few who have previously acknowledged these guidelines. They conclude that the rigor of the criteria can cause significant differences in treatment outcomes to be missed. Specifically, elimination of anaerobic overgrowth with consequent clearance of odor (amines) and clue cells is not appreciated by these criteria in participants who do not also reestablish Lactobacillus predominance to achieve a pH decrease. They note also that pH decrease does not correlate with greater durability of cure in existing literature. Our study confirms an improved cure rate when 3 of 4 Amsel criteria are used to define cure, but we did not find that eliminating the requirement for pH less than 4.5 yielded a higher cure rate than eliminating requirements for clue cells less than 20% or negative whiff test (data not shown).
We elected to use consistently the most rigorous criteria for the primary efficacy endpoint in our study. Specifically, we followed precisely the recommendations of the 1998 FDA Guidance Document, and applied them to the entire study population (modified Intent To Treat) meeting the diagnostic criteria. Using those methods we found that therapeutic cure rates of bacterial vaginosis for the 1 g once daily for 5 days group (36.8%, number needed to treat 3.2) and for the 2 g once daily for 2 days group (27.4%, number needed to treat 4.5) both reached high statistical significance in comparison with placebo (5.1%). Using the more traditional definitions of cure based only on clinical criteria predictably produced substantially higher cure rates for tinidazole (Table 3).
In the interest of our participants, we designed our protocol to exclude those with symptoms too severe to tolerate assignment to placebo, raising the possibility that only those with milder symptoms might be included in our study. Because our participants met all four Amsel criteria and Gram stain criteria for diagnosis, their Gram stain scores were high, and no patient at any center was excluded because of severe symptoms, we do not believe our findings are limited to milder cases.
Comparison of (particularly quantitative) results from one trial to those of another often leads to erroneous conclusions because of differences in study design, enrollment and outcome criteria, data collection, test methodology, selection of participants to include in the analyses, and a plethora of other seen and unseen confounders. Treatment trials for bacterial vaginosis are especially subject to such errors because of variations in the definitions of diagnosis and cure. However, because application of the FDA Guidance Document criteria effectively resets the reference standard for efficacy of therapy of bacterial vaginosis, we feel it may be useful to juxtapose our results to those available from trials of other agents which have used those criteria. These data are shown in Table 5.
Tinidazole therapy was well tolerated in this trial, as evidenced by the high compliance with therapy in both treatment arms. Compared with standard metronidazole given as 500 mg twice daily for 7 days, tinidazole therapy for bacterial vaginosis can reduce the total number of doses necessary by more than half. Additionally, the low incidence of posttreatment vaginal candidiasis seen in both tinidazole treatment arms compares favorably with current FDA-approved intravaginal and oral therapies. Finally, any gastrointestinal symptom(s) were seen with equal frequency in the tinidazole and placebo groups, and the incidence of nausea (a frequent complaint with oral metronidazole therapy) in the 1 g daily tinidazole treatment arm was not significantly different from that observed in the placebo arm.
Tinidazole by mouth, 1 g once daily for 5 days or 2 g once daily for 2 days, is an effective treatment for bacterial vaginosis in our rigorous therapeutic trial, and is competitive with available treatments. The 1 g once daily for 5 days regimen showed trends toward better efficacy and tolerability than the 2 g once daily for 2 days regimen. Although our study was not adequately powered to prove safety, we discovered no safety concerns with this use of tinidazole.
1. Hill GB. The microbiology of bacterial vaginosis. Am J Obstet Gynecol 1993;169:450–4.
2. Marrazzo JM. A persistent(ly) enigmatic ecological mystery: bacterial vaginosis. J Infect Dis 2006;193:1475–7.
3. Amsel R, Totten PA, Spiegel CA, Chen KC, Eschenbach D, Holmes KK. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations. Am J Med 1983;74:14–22.
4. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized version of gram stain interpretation. J Clin Microbiol 1991;29:297–301.
5. Mastrobattista JM, Bishop KD, Newton ER. Wet smear compared with gram stain diagnosis of bacterial vaginosis in asymptomatic pregnant women. Obstet Gynecol 2000;96:504–6.
6. Thomason JL, Gelbart SM, Anderson RJ, Walt AK, Osypowski PJ, Broekhuizen FF. Statistical evaluation of diagnostic criteria for bacterial vaginosis. Am J Obstet Gynecol 1990;162:155–60.
7. 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.
8. Welling PG, Monro AM. The pharmacokinetics of metronidazole and tinidazole in man. Arzneimittelforschung 1972;22:2128–32.
9. Mohanty KC, Deighton R. Comparison of 2 g single dose of metronidazole, nimorazole and tinidazole in the treatment of vaginitis associated with Gardnerella vaginalis. J Antimicrob Chemother 1987;19:393–9.
10. Mannisto P, Karhunen M, Mattila J, Koskela O, Suikkari AM, Heinonen P, et al. Concentrations of metronidazole and tinidazole in female reproductive organs after a single intravenous infusion and after a repeated oral administration. Infection 1984;12:197–201.
11. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: bacterial vaginosis—developing antimicrobial drugs for treatment. Draft guidance. July, 1998. Available at: www.fda.gov/cder/guidance/2572dft.pdf
. Retrieved May 24, 2007.
12. Bagnoli VR, Kesselring GL. Multicenter, double-blind, randomized, comparative study between secnidazole (single dose of 2g) and tinidazole (single dose of 2g) in the treatment of nonspecific vaginitis. Rev Bras Ginecol Obstet 1992;3:198–202.
13. Bardi M, Manenti G, Mattioni D, Lasala L. Metronidazole for non-specific vaginitis. Lancet 1980;1:1029–32.
14. Baylson FA, Nyirjesy P, Weitz MV. Treatment of recurrent bacterial vaginosis with tinidazole. Obstet Gynecol 2004;104:931–2.
15. 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.
16. Carmona O, Silva H, Acosta H. Vaginitis due to Gardnerella vaginalis: treatment with tinidazole. Curr Ther Res 1983;33:898–904.
17. de la Cabada FJ. Treatment of vaginitis due to Gardnerella vaginalis with tinidazole. Invest Med Int 1988;15:66–71.
18. Ekgren J, Norling B, Degre M, Midtvedt T. Comparison of tinidazole given as a single dose and on two consecutive days for the treatment of nonspecific bacterial vaginosis. Gynecol Obstet Invest 1988;26:313–7.
19. Heikkinen J, Vuopala S. Anaerobic vaginosis: treatment with tinidazole vaginal tablets. Gynecol Obstet Invest 1989;28:98–100.
20. Improda L, Nobler L, Chierego C, Iacona A. Is it necessary to treat the partner of a woman affected by bacterial vaginosis? Giorn It Ost Gin 1994;371–3.
21. Martins N. Ambulatory diagnosis of vaginitis: evaluation of 4903 patients treated with tinidazole with a single oral dose. Rev Bras Clin Terap 1985;14:94–8.
22. Milani M, Barcellona E, Agnello A. Efficacy of the combination 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. Eur J Obstet Gynecol Reprod Biol 2003;109:67–71.
23. Paavonen J, Vesterinen E, Purola E, Jokipii AM, Jokipii L, Holttinen K, et al. Single dose of tinidazole in the treatment of vaginal discharge. Scand J Urol Nephrol Suppl 1984;86:237–40.
24. Piot P, van Dyck E, Godts P, Vanderheyden J. Placebo-controlled, double-blind comparison of tinidazole and triple sulfonamide cream for the treatment of nonspecific vaginitis. Am J Obstet Gynecol 1983;147:85–9.
25. Sanz F, Arreaza L, Vidreales I. Concerning the different therapeutic options for bacterial vaginosis. Progres Obst Gin 1996;39:669–74.
26. Sanz Sanz F, Hernanz AD, Sanchez EA. Comparative trial of metronidazole versus tinidazole in the treatment of nonspecific vaginitis. Rev Esp Obst y Gin 1985;44:717–20.
27. Sanz Sanz F, Hernanz AD, Sanchez EA. Double-blind, randomized, comparative trial: ornidazole versus tinidazole for the treatment of nonspecific vaginitis. Chemioterapia 1985;4:218–21.
28. Schindler EM, Thamm H, Ansmann EB. Sarnow E, Schindler AE. Treatment of bacterial vaginosis. Multicenter, randomized, open study with tinidazole in comparison with metronidazole [in German]. Fortschr Med 1991;109:138–40.
29. van der Meijden W. Treatment of non-specific vaginitis with a single dose of tinidazole. Scand J Infect Dis Suppl 1983;40:85–9.
30. Villagrana-Zesati R, Reyna-Figueroa J, Ortiz-Ibarra J. Short-term therapy for mixed vaginal infections. Int J Gynaecol Obstet 2006;92:149–50.
31. Vutyavanich T, Pongsuthirak P, Vannareumol P, Ruangsri RA, Luangsook P. A randomized double-blind trial of tinidazole treatment of the sexual partners of females with bacterial vaginosis. Obstet Gynecol 1993;82:550–4.
32. Thomas KK, Sanchez S, Garcia PJ, Holmes KK. Why do different criteria for “cure” yield different conclusions in comparing two treatments for bacterial vaginosis? Sex Transm Dis 2005;32:526–30.