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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland; Clinica Ostetrica e Ginecologica, Ospedale S. Gerardo di Monza, Milan, Italy; and Pharmacia & Upjohn, Kalamazoo, Michigan.
Address reprint requests to: Jorma Paavonen, MD Department of Obstetrics and Gynecology University of Helsinki Haartmaninkatu 2 00290 Helsinki Finland E-mail: jpaavone{at}cc.helsinki.fi
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Abstract |
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Methods: Women with bacterial vaginosis received either 100-mg ovules of clindamycin (intravaginally for 3 consecutive days) plus placebo capsules (orally twice daily for 7 days) or metronidazole 500 mg (two 250-mg capsules orally twice daily for 7 days) plus placebo ovules (intravaginally for 3 consecutive days). The sample was determined prospectively to provide a probability of .84 of correctly concluding that the rate of success for clindamycin is not more than 15% less than the expected 75% success rate for metronidazole. Clinical outcome was determined on the basis of vaginal fluid amine odor and clue cells.
Results: Of the 399 patients enrolled, 233 could be evaluated for efficacy. Of those, 77 (68.1%) of 113 patients were cured with clindamycin, compared with 80 (66.7%) of 120 who were cured with metronidazole (95% confidence interval -10.6%, 13.4%; P = .810). Treatment-related adverse events were reported more frequently in the metronidazole treatment group. Systemic symptoms, such as nausea and taste perversion, accounted for most of the difference between groups.
Conclusion: A 3-day regimen of clindamycin, given as intravaginal ovules, was as effective as and better tolerated than a 7-day regimen of oral metronidazole 500 mg, given twice daily, for treatment of bacterial vaginosis.
Bacterial vaginosis is often characterized by malodorous vaginal discharge without symptoms or signs of vaginal inflammation.1 It is present in approximately 15% of private gynecologic patients, 10–30% of pregnant women, and 12–61% of women seen at clinics for sexually transmitted diseases.2 Although perceived as a mild medical problem, bacterial vaginosis can have potentially serious sequelae, including postoperative infection after hysterectomy,3 postpartum endometritis,4 and preterm labor.5
Metronidazole 500 mg administered orally twice daily for 7 days is a standard treatment for bacterial vaginosis.6 However, oral metronidazole is associated with adverse effects such as gastrointestinal symptoms, unpleasant taste, and a disulfiram-like effect with alcohol ingestion and should not be used during pregnancy unless alternative treatment has been inadequate.7
Clindamycin cream 2% administered topically for 7 days is as effective for treatment of bacterial vaginosis as oral metronidazole 500 mg given twice daily for 7 days.8–10 A 3-day regimen of topical clindamycin 2% vaginal cream is also a safe and effective treatment for bacterial vaginosis11,12 and offers the advantage of decreased risk of toxicity and increased compliance.
Clindamycin also has been formulated as solid vaginal ovules, a more convenient form. This study compared the efficacy and safety of clindamycin vaginal ovules given for 3 days with those of oral metronidazole given twice daily for 7 days for treatment of bacterial vaginosis. Oral metronidazole was chosen as the comparator because it is a standard treatment for bacterial vaginosis and because it made possible a fully masked trial.
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Materials and Methods |
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Subjects were excluded if they were pregnant or breast-feeding, previously had enrolled in the study, anticipated menstruating during treatment or follow-up visits, had received systemic or vaginal antimicrobial therapy in the 2 weeks before the study, or needed antibiotics not specified in the protocol. Additional exclusion criteria were positive tests for Neisseria gonorrhoeae, Candida albicans, Trichomonas vaginalis, or Chlamydia trachomatis; atrophic vaginitis; clinical evidence of genital herpes; and any other condition that precluded study participation in the investigator’s opinion. Written informed consent was obtained from each subject.
Eligible women were assigned randomly in a 1:1 ratio to receive clindamycin or metronidazole. Patients were assigned consecutively according to randomization schedules for each site that were generated before the study started and maintained by the sponsor. The code was not broken until after study completion. No plan was made to adjust for prognostic variables. Women in the clindamycin treatment group digitally inserted one 100-mg ovule of clindamycin (Cleocin/Dalacin Vaginal Ovule; Pharmacia & Upjohn Co., Peapack, NJ) intravaginally for 3 consecutive days and took two placebo capsules orally twice daily for 7 days. Women in the metronidazole treatment group took two 250-mg capsules of metronidazole (Flagyl; G.D. Searle and Co., Chicago, IL) twice daily for 7 days and inserted a placebo ovule intravaginally at bedtime for 3 consecutive days. Placebo ovules and capsules matched the active dosage forms to maintain masking. Women were instructed on vaginal administration of the ovules and not to douche or use topical contraceptive preparations. They were also encouraged to abstain from intercourse or have their partners use condoms provided by the sponsor.
At pretreatment (baseline) visits, subjects’ medical histories were taken, pelvic examinations were done, and vaginal discharges were described. Additional diagnostic tests consisted of determination of vaginal pH, a test of vaginal fluid for fishy odor after addition of 10% potassium hydroxide, and microscopic examination of wet mounts of vaginal fluid for clue cells. Tests for Trichomonas, Candida, Chlamydia, and Neisseria organisms also were done.
Women were to return for follow-up examinations 12–16 days and 28–42 days after the start of treatment. At each visit, a vulvovaginal examination was done and vaginal discharge was described. Diagnostic tests for pH level, odor, and clue cells were repeated. If a woman was symptomatic, tests for Trichomonas and Candida also were repeated. Adverse events and information on use of any other medications were recorded. Women for whom treatment had failed at the time of the first follow-up visit did not return for the second follow-up visit, because their participation was considered complete.
Women were able to be evaluated for treatment efficacy if they met selection criteria, did not menstruate during treatment or at follow-up visits, had no concomitant symptomatic genital infections or discharge of unknown etiology, returned for follow-up 18–52 days after the start of treatment, and received no antimicrobial therapy other than the study treatments. Those evaluated in the clindamycin treatment group had to have no lapses in their clindamycin regimens. Women evaluated in the metronidazole treatment group had to have ingested at least 21 metronidazole capsules over no more than 8 days and had to have no lapses in treatment of more than 1 day.
The primary efficacy measure was overall clinical outcome (cure, failure, nonassessable efficacy). Women were considered cured when they had resolution of amine odor and clue cells at both follow-up visits. They were considered to have treatment failure if they had no resolution of amine odor or clue cells at either follow-up visit. Efficacy was considered nonassessable when there were inadequate data to categorize an outcome as cure or failure. Women who did not complete the study therapy because of treatment-related adverse effects were considered to have a adverse-effect failure. All subjects who had clinical or adverse-effect failures could be evaluated unless they did not meet selection criteria.
Secondary measures of efficacy included clinical status (cured, having clinical failure, having adverse-effect failure, nonassessable status) at each follow-up visit, symptoms of vaginitis or cervicitis at each follow-up visit, and patient evaluation of efficacy (cure, improvement, failure) at second follow-up visits.
All participants were evaluated for treatment safety. At each visit after treatment initiation women were asked, "Since you began taking the investigational medication, have you had any health problems?" The investigator also reported all medical events directly or spontaneously reported by participants.
The planned sample (115 who could be evaluated per group) provided a probability of .84 of correctly concluding that the success rate for clindamycin ovules is not more than 15% less than the expected 75% success rate for metronidazole. All statistical tests were two-sided. The treatment-by-investigators interaction effect was evaluated with the Breslow test for homogeneity. In the presence of a significant treatment-by-investigator interaction, the primary efficacy measure was analyzed using a Cochran-Mantel-Haenszel test. In the absence of such an effect, the Pearson 
2 test was used. A confidence interval for the difference between cure rates of the groups was constructed using binomial distribution. The nonassessable category was not included in the analysis model. Secondary efficacy measures were analyzed using Pearson 2 tests.
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Results |
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), medical history, history of bacterial vaginosis, pelvic examination findings, and pretreatment diagnostic criteria and microbiologic results. The breakdown of subjects during the study is shown in Figure 1. With respect to total percentages of women who discontinued treatment and percentages of those who discontinued treatment, by specific reason, the two treatment groups were similar. Of the 399 women enrolled, 233 (113 in the clindamycin treatment group and 120 in the metronidazole treatment group) could be evaluated for treatment efficacy and 166 could not (Table 2).
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). There was no significant treatment-by-investigators interaction for overall clinical outcome (P = .437). Groups also did not differ in terms of cure rates at first or second visits (Table 3). Similar proportions of reporting participants in the two groups (78.3% [83 of 106] in the clindamycin treatment group and 79.6% [90 of 113] in the metronidazole treatment group) rated their vaginal infections as cured. The groups also did not differ significantly in the proportion of eligible women who had symptoms of vaginitis or cervicitis at the first follow-up visit, the second follow-up visit, or either follow-up visit. The results of analyses of efficacy outcomes were similar for the intent-to-treat population.
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). The incidence of conditions described by investigators as moniliasis was similar in the two groups. Two participants who received metronidazole discontinued therapy prematurely because of adverse effects. Both discontinued treatment on study day 2, one because of nausea and the other because of vulvovaginal itching and swelling.
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Discussion |
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Only 58% of the participants in this study could be evaluated for treatment efficacy. Patients were to be enrolled before fulfillment of inclusion criteria could be established, so it was anticipated that many would not be evaluated. Therefore, we enrolled more women than were needed to power the study adequately. The two groups were similar with regard to the percentages of women who could not be evaluated and the distribution of reasons for that.
In this double-masked trial, a double-placebo design was used to minimize bias. Overall cure was determined on the basis of the presence of clue cells, an objective measure, and the presence of amine odor, a subjective measure. As in most similar trials, no central laboratory was used for determination of the presence of clue cells, and that is a possible source of center-to-center variability. However, there was no reason to suspect any systematic shift that favored either group.
Clindamycin ovules were better tolerated than oral metronidazole in this study and treatment-related adverse events were reported by more women in the metronidazole treatment group than in the clindamycin treatment group. Systemic symptoms, such as nausea and altered taste, accounted for most of the difference between groups. Metronidazole has been associated with gastrointestinal effects and taste perversion in other studies as well.9,13 Intravaginal clindamycin offers the advantage of fewer systemic effects because exposure is minimal.14 Patient compliance, an important factor in treatment success, might be more likely with the clindamycin regimen than with the oral metronidazole regimen, because of the former’s shorter duration and convenient, once-daily dosing.
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Footnotes |
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This study was supported by a grant from Pharmacia & Upjohn, Peapack, New Jersey, which markets clindamycin ovules. Maureen A. Martin and Charles P. Wajszczuk are employees of Pharmacia & Upjohn and the latter owns stock and stock options in the company.
Received October 27, 1999. Received in revised form February 28, 2000. Accepted March 30, 2000.
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References |
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2. Mead PB. Epidemiology of bacterial vaginosis. Am J Obstet Gynecol 1993;169:446–9.[Medline]
3. Soper DE, Bump RC, Hurt WG. Bacterial vaginosis and trichomoniasis vaginitis are risk factors for cuff cellulitis after abdominal hysterectomy. Am J Obstet Gynecol 1990;163:1016–23.[Medline]
4. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. Bacterial vaginosis as a risk factor for postcesarean endometritis. Obstet Gynecol 1990;75:52–8.
5. Gravett MG, Nelson P, DeRouen T, Critchlow C, Eschenbach DA, Holmes KK. Independent associations of bacterial vaginosis and Chlamydia trachomatis infection with adverse pregnancy outcome. JAMA 1986;256:1899–903.[Abstract]
6. Joesoef MR, Schmid GP, Hillier SL. Bacterial vaginosis: Review of treatment options and potential clinical indications for therapy. Clin Infect Dis 1999;28(suppl 1):S57–65.
7. Physicians’ desk reference. 53rd ed. Montvale, New Jersey: Medical Economics Co., 1999.
8. Andres FJ, Parker R, Hosein I, Benrubi GI. Clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis: A prospective double-blind clinical trial. South Med J 1992;85:1077–80.[Medline]
9. Schmitt C, Sobel JD, Meriwether C. Bacterial vaginosis: Treatment with clindamycin cream versus oral metronidazole. Obstet Gynecol 1992;79:1020–3.
10. Fischbach F, Petersen EE, Weissenbacher ER, Martius J, Hosmann J, Mayer H. Efficacy of clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis. Obstet Gynecol 1993;82:405–10.
11. Ahmed-Jushuf IH, Shahmanesh M, Arya OP. The treatment of bacterial vaginosis with a 3 day course of 2% clindamycin cream: Results of a multicentre, double-blind, placebo controlled trial. B V Investigators Group. Genitourin Med 1995;71:254–6.[Medline]
12. Dhar J, Arya OP, Timmins DJ, Moss S, Mukembo S, Alawattegama AB, et al. Treatment of bacterial vaginosis with a three day course of 2% clindamycin vaginal cream: A pilot study. Genitourin Med 1994;70:121–3.[Medline]
13. Swedberg J, Steiner JF, Deiss F, Steiner S, Driggers DA. Comparison of single-dose vs one-week course of metronidazole for symptomatic bacterial vaginosis. JAMA 1985;254:1046–9.[Abstract]
14. Borin MT, Powley GW, Tackwell KR, Batts DH. Absorption of clindamycin after intravaginal application of clindamycin phosphate 2% cream. J Antimicrob Chemother 1995;35:833–41.
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