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A double-blind placebo-controlled trial of single-dose intravaginal versus single-dose oral metronidazole in the treatment of trichomonal vaginitis.

Since metronidazole is a mutagen in vitro, there is concern about the widespread systemic use of this drug in women with trichomoniasis, particularly those who are pregnant. A randomized, double-blind, placebo-controlled trial compared a single 2-g intravaginal dose of metronidazole cream with a single 2-g oral dose of metronidazole in patients with a culture positive for Trichomonas organisms. Of the 302 preenrollment cultures completed, 94 (31%) were positive. Sixty-one patients were enrolled in the study. Each received either oral placebo and intravaginal metronidazole or intravaginal placebo and oral metronidazole. Follow-up cultures were done on posttreatment day 3-5. Of the 53 evaluatable patients, 14 (50%) of 28 in the intravaginal group and 22 (88%) of 25 in the oral group were microbiologically cured (P = .0037). Single-dose intravaginal metronidazole is inferior to single-dose oral metronidazole and cannot be relied on as an alternative therapy.

Administration, Intravaginal↗

Progesterone stimulates luteinizing hormone secretion by acting directly on the pituitary.

To determine if progesterone (P) does affect gonadotropin secretion by acting directly on the pituitary, six women with hypothalamic gonadotropin deficiency were studied. They were treated with 17 beta-estradiol (E2; 2 mg/day, orally) to induce P receptors and maintain constant plasma E2 levels during two 15-day periods separated by 1 month. GnRH was administered iv at a dose of 10 microgram/pulse every 90 min during the last 5 days of E2 treatment. Either P (400 mg/day) or a placebo was administered intravaginally in a cross-over randomized design during the 5 days of pulsatile GnRH therapy. A baseline study of pulsatile LH secretion was performed, with sampling performed every 10 min for 8 h. The sampling was then repeated on day 15 of each study period at the end of pulsatile GnRH administration. Plasma levels of E2 and P were measured every day during the 5 days of either GnRH and P or GnRH and placebo treatment. In the six patients, the observed apulsatile pattern of LH during the baseline study confirmed the diagnosis of complete gonadotropin deficiency. Plasma E2 levels were not significantly different at the time of each pulse analysis (288 +/- 61 vs. 252 +/- 77 pmol/L). The plasma P level achieved with the vaginal pessaries was 22 +/- 5 nmol/L. P treatment resulted in all cases in a significant increase in the mean plasma LH level (5.2 +/- 0.9 vs. 3.6 +/- 0.7 IU/L after GnRH plus placebo; P less than 0.001). Furthermore, LH pulse amplitude was significantly increased by P compared to placebo (3.1 +/- 0.3 vs. 1.4 +/- 0.1 IU/L, respectively; P less than 0.01). Mean plasma FSH levels were significantly increased by GnRH regardless of whether P or placebo was present. In conclusion, these data indicate that a short exposure to physiological levels of P in the range of early luteal phase levels has a stimulatory effect on LH secretion by acting directly at the pituitary level.

Activity Cycles↗

Vaginal clindamycin and oral metronidazole for bacterial vaginosis: a randomized trial.

OBJECTIVE: To compare the efficacy and safety of clindamycin vaginal ovules with oral metronidazole for treatment of bacterial vaginosis. 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.

Administration, Intravaginal↗

Adjuvant effect of non-toxic mutants of E. coli heat-labile enterotoxin following intranasal, oral and intravaginal immunization.

Cholera toxin and Escherichia coli heat-labile enterotoxin (LT) are known to be very effective mucosal adjuvants, but their toxicity limits their use in humans. We genetically detoxified LT by substituting single residues in the active site of the enzymatic A subunit and obtained mutant molecules that retain mucosal adjuvant activity but are devoid of toxicity. These mutant LT molecules induce mucosal and systemic responses to antigens delivered intranasally, orally and intravaginally in mice. Furthermore, mucosal immunization with these molecules confers protection against systemic challenge with tetanus toxin (TT) and mucosal challenge with Helicobacter pylori.

Adjuvants, Immunologic↗

Single-dose oral fluconazole versus single-dose topical miconazole for the treatment of acute vulvovaginal candidosis.

OBJECTIVES: To compare efficacy, safety and patient preference of a single oral dose of 150 mg fluconazole with a single intravaginal dose of 1200 mg miconazole in vaginal candidosis. To investigate the effect of treatment on Candida colonization of throat and rectum. DESIGN: Double-blind, double-dummy, parallel, randomized trial. Ninety-nine patients with symptomatic and mycologically verified candidosis were given 150 mg fluconazole with an intravaginal dummy, or 1200 mg miconazole with an oral dummy. Patients with an inadequate short-term response were given a second dose. RESULTS: At each visit a patient self assessment and an investigators' global assessment were recorded, and cultures were set up. Adverse events were recorded and laboratory tests were performed. Clinical cure or improvement (investigators' assessment) was obtained in 100% (short-term) and 95% (long term) of the fluconazole group and in 94% and 90%, respectively, of the miconazole group. Patients considered the treatment excellent or good in 81% (short-term) and 88% (long-term) in the fluconazole group and in 84% and 76%, respectively, of the miconazole group. Mycological cure was achieved in 98% (short-term) and 73% (long-term) of the fluconazole group and in 96% and 82% respectively in the miconazole group. The differences in results were not significant. Both treatments significantly reduced the number of positive rectal cultures: neither treatment had a significant effect on throat cultures. Four percent of the patients preferred intravaginal therapy. CONCLUSION: A single dose fluconazole is as safe and effective as a single dose of miconazole.

Acute Disease↗

Salmon calcitonin plus intravaginal estriol: an effective treatment for the menopause.

OBJECTIVE: Intravaginal estriol (E3) effectively improves postmenopausal genito-urinary disturbances, without stimulating endometrial proliferation. The aim of the present study was to evaluate the effect of intravaginal estriol (E3) plus nasal spray salmon calcitonin (sCT), to improve neurovegetative symptoms and to prevent the decline of bone mineral density (BMD) of postmenopausal women. METHODS: Two hundred and fourteen (214) healthy postmenopausal women were treated for 12 months with: (1) E3 (0.5 mg every other day) + Ca (0.5 g/day); (2) E3 + Ca + sCT (50 IU x 2/day); (3) sCT + Ca; (4) Ca. Climacteric complaints, such as hot flushes and sweating, BMD at the distal 1/10 of the radius, analyzed by dual photon absorptiometry, urinary excretion of hydroxyproline and serum alkaline phosphatase were evaluated at baseline and every 6 months. At the same time, patient compliance and drug tolerability were evaluated. RESULTS: E3 but not sCT, improved hot flushes and sweating. E3 blunted but not completely counteracted the BMD decline observed in women treated with only Ca, and reduced urinary hydroxyproline excretion. sCT markedly increased BMD values and reduced both urinary hydroxyproline excretion and serum alkaline phosphatase. These effects were not potentiated by E3 coadministration. All treatments were well tolerated. CONCLUSIONS: Present data indicate that the combined administration of intravaginal E3 and sCT may represent an alternative therapeutic regimen for those postmenopausal women who do not accept or have contraindications to classical hormone replacement therapy.

Absorptiometry, Photon↗

Indomethacin for preterm labor: a randomized comparison of vaginal and rectal-oral routes.

OBJECTIVE: To compare the efficacy of intravaginal and intrarectal plus oral indomethacin for the treatment of preterm labor. METHODS: Between December 1996 and November 1998, 46 eligible gravidas admitted with singleton pregnancies and idiopathic preterm labor before 33 gestational weeks were randomized to receive 200 mg of intravaginal or intrarectal plus oral indomethacin. RESULTS: Twenty-three subjects were allocated to each study group. The interval from initiation of treatment to delivery was significantly longer in the intravaginal indomethacin group (26.5 +/- 5.7 versus 12.6 +/- 3.7 days; P =.007). Delivery was delayed by more than 7 days in 18 of 23 subjects (78%) in the intravaginal indomethacin group compared with ten (43%) in the intrarectal plus oral indomethacin group (P =.03). Birth weights were significantly higher (2306 +/- 436 versus 1862 +/- 232 g; P =.002) and hospitalization in a neonatal intensive care unit (NICU) (3.1 +/- 0.8 versus 9.3 +/- 3. 7 days; P =.001) and mechanical ventilation (1.4 +/- 0.2 versus 5.3 +/- 1.6 days; P =.001) were significantly shorter in the intravaginal indomethacin group. CONCLUSION: Intravaginal indomethacin is more effective than intrarectal plus oral application in delaying preterm labor and is associated with higher birth weights, shorter NICU stays, and shorter intervals of mechanical ventilation.

Administration, Intravaginal↗

Efficacy of clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis.

OBJECTIVE: To compare the efficacy and tolerance with 2% clindamycin vaginal cream versus oral metronidazole for the treatment of bacterial vaginosis. METHODS: This was a multicenter, randomized, double-blind study in which patients were randomly assigned to one of the following two regimens in a 1:1 ratio: clindamycin phosphate vaginal cream 2% (5 g intravaginally at bedtime for 7 days) plus two placebo capsules (twice a day for 7 days) or metronidazole 500 mg (two 250-mg capsules orally twice a day for 7 days) plus placebo vaginal cream (5 g intravaginally at bedtime for 7 days). The patients were seen for follow-up at 5-10 days and 25-39 days after completion of therapy. RESULTS: Seven investigators, four in Germany, two in Austria, and one in Switzerland, enrolled 407 patients. Four patients never received either protocol drug, leaving 403 evaluable for safety. Two hundred thirty-four patients were evaluable for efficacy. The analysis for all evaluable patients showed no significant difference between treatment groups. The cure or improvement rate at 1 month after therapy was 83% in the clindamycin group versus 78% in the metronidazole group. The incidence of drug-related adverse medical events was approximately 12% in both groups. CONCLUSIONS: Oral metronidazole and intravaginal clindamycin cream had a similar efficacy of 78 to 83%. Both drugs were tolerated, with vaginal candidiasis developing in 8.5 and 4.7% of the patients in the clindamycin and metronidazole groups, respectively.

Administration, Intravaginal↗

Uterine and fetal Doppler flow changes after misoprostol and oxytocin therapy for induction of labor in post-term pregnancies.

OBJECTIVES: To compare the effect of misoprostol vs. oxytocin on blood flow in uteroplacental circulation during labor induction. METHODS: Ninety-one women with indications for induction of labor were assigned to receive either misoprostol 50 microg per vagina every 4 h as needed or intravenous oxytocin by means of a randomization table generated by computer. Doppler velocimetry of umbilical, uterine and arcuate arteries was performed immediately before and 2-3 h after administration of misoprostol or oxytocin. Pulsatility index (PI), resistance index (RI) and systolic/diastolic (S/D) ratios were measured for these arteries. The SAS system was used to perform statistical analysis. RESULTS: There were no significant changes of PI, RI and S/D ratios in umbilical arteries during misoprostol and oxytocin inductions. Vaginal application of misoprostol significantly increased PI, RI and S/D ratios in arcuate arteries and S/D ratio in uterine arteries. CONCLUSIONS: Our results indicate that intravaginal misoprostol administration increases uteroplacental resistance but probably does not substantially affect placental perfusion.

Administration, Intravaginal↗

CpG oligodeoxynucleotides and mobilization of innate mucosal immunity: tasks and tactics.

The recent discovery of pathogen-associated molecular patterns (PAMPs) as potential ligands for the evolutionary conserved innate immune receptors termed Toll-like receptors has enabled a modern era of immunotherapy using synthetic mimics of pathogen molecules. Among the PAMPs, bacterial DNA or synthetic oligodeoxynucleotides (ODNs) that contain unmethylated CpG motif shows promising effect on activation of systemic innate immune response. We could document that CpG ODN is capable of mobilizing a potent innate immunity in the mucosal tissues. Thus, intravaginal, intrarrectal, or intragastric delivery of mice with CpG ODN elicits potent innate chemokine responses in the respective mucosal tissues. Interestingly, we could show that the immunostimulatory effect of CpG DNA is much improved when chemically conjugated to the non-toxic B subunit of cholera toxin.

Adjuvants, Immunologic↗

Effects of two types of hormonal contraception--oral versus intravaginal--on the sexual life of women and their partners.

BACKGROUND: Data relating to the influence of hormonal contraception on sexual life are conflicting and mostly they refer to oral contraceptives. In this randomized, controlled, prospective study we compared the effect of an intravaginal hormonal contraceptive with the effect of a combined oral contraceptive on sexual function. METHODS: Fifty-one healthy women with a permanent partner and an active sexual life were randomly divided in two groups according to a computer-generated randomization list: 26 women (group A) used an intravaginal contraceptive releasing 120 microg/day of etonogestrel and 15 microg/day of ethinylestradiol (EE) and 25 women (group B) used an oral contraceptive containing 20 microg di EE and 150 microg of desogestrel. Twenty-five women participated in the study as control group (group C). A specific questionnaire was completed by the patients and their partners at the start of the study and after cycles 3 and 6 of contraceptive use. RESULTS: Within 3 months of contraceptive use, women from both groups A and B reported a global improvement in sexual function. A statistically significant increase in sexual fantasy was reported only by patients of group A. Whereas partners of the women in both groups A and B reported an improvement in sexual function after 3 months of contraceptive intake, only patients' partners of group A reported a significant increase in sexual interest, complicity and sexual fantasy. CONCLUSIONS: Both hormonal contraceptives tested were seen to have a positive effect on some aspects of sexual function. The intravaginal contraceptive ring seems to exert a further positive effect on the psychological aspect of both women and their partners, which is evident from an improved complicity and sexual satisfaction.

Administration, Intravaginal↗

Metronidazole for bacterial vaginosis. A comparison of vaginal gel vs. oral therapy.

OBJECTIVE: To compare the efficacy and safety of 0.75% metronidazole vaginal gel with oral metronidazole for the treatment of bacterial vaginosis (BV). STUDY DESIGN: Nonpregnant women with BV were enrolled in a multicenter, randomized, investigator-blind treatment trial. Patients were randomly assigned to either 0.75% metronidazole vaginal gel (5 g twice daily for five days) or oral metronidazole (500 mg twice daily for seven days). Follow-up visits occurred approximately two and five weeks after initiation of therapy. RESULTS: BV was clinically eliminated at the first follow-up visit in 83.7% (36/43, 95% CI 72.3-95.1%) of the intravaginal group and 85.1% (40/47, 95% CI 74.6-95.6%) of the oral group. At the final visit, BV was eliminated in 70.7% (29/41, 95% CI 56.3-85.1%) of the intravaginal group and 71.1% (32/45, 95% CI 57.4-84.8%) of the oral group. Significantly more patients in the oral treatment group (51.8%) reported gastrointestinal complaints as compared to the intravaginal treatment group (32.7%, P = .04). CONCLUSION: The efficacy of 0.75% metronidazole vaginal gel twice daily for five days in treating BV was similar to that of standard oral metronidazole treatment and was associated with fewer gastrointestinal complaints.

Administration, Intravaginal↗

Vaginal misoprostol for cervical ripening and labour induction in late pregnancy.

BACKGROUND: Although not yet registered for such use, misoprostol has been widely used for obstetric and gynaecological indications, such as induction of abortion and of labour. OBJECTIVES: The objective of this review was to assess the effects of vaginal misoprostol for third trimester cervical ripening or induction of labour. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register and reference lists of articles were searched. SELECTION CRITERIA: Randomised trials comparing vaginal misoprostol with other methods of cervical ripening or labour induction, placebo or no treatment in women due for third trimester induction of labour. DATA COLLECTION AND ANALYSIS: Trial quality assessment and data extraction were done by both reviewers. MAIN RESULTS: Twenty-six studies were included. Compared to placebo, misoprostol was associated with increased cervical ripening (relative risk of unfavourable or unchanged cervix after 12 to 24 hours with misoprostol 0.20, 95% confidence interval 0.07 to 0.61). It was also associated with a reduced need for oxytocin (relative risk 0.47, 95% confidence interval 0.23 to 0.96). Misoprostol was more effective than prostaglandin E2 for labour induction (relative risk of failure to achieve vaginal delivery in 24 hours 0.70, 95% confidence interval 0.62 to 0.79). Oxytocin augmentation was used less often with misoprostol than with prostaglandin E2 (relative risk 0.64, 95% confidence interval 0.58 to 0.71). Uterine hyperstimulation and meconium stained liquor were more common with misoprostol than with prostaglandin E2. Lower doses of misoprostol compared to higher doses did not show significant differences except for more need for oxytocin augmentation and less uterine hyperstimulation without fetal heart rate changes. REVIEWER'S CONCLUSIONS: Vaginal misoprostol appears to be more effective in inducing labour than conventional methods of cervical ripening and labour induction. The apparent increase in uterine hyperstimulation is of concern. The studies were not large enough to exclude the possibility of rare but serious adverse effects.

Cervical Ripening↗

Effect of route of vaccination with vaccinia virus expressing HSV-2 glycoprotein D on protection from genital HSV-2 infection.

To evaluate the effects of the route of vaccination on protection against genital HSV infection guinea pigs were vaccinated twice with vaccinia recombinants expressing HSV-2 glycoprotein D or controls by intradermal, intranasal or intravaginal inoculation. Following HSV-2 intravaginal challenge, immunization by all 3 routes reduced vaginal HSV shedding and acute genital disease. The intravaginal vaccination, however, most effectively reduced primary and recurrent HSV disease. Vaccinia and HSV antibody titers were similar in all vaccinia gD immunized groups while the lymphoproliferative response was highest in the intradermal group. In a smaller follow-up experiment we demonstrated that intrarectal immunization with vaccinia gD could also induce antibody and T cell responses.

Administration, Intranasal↗

Comparative study on the effectiveness of antifungal agents in different regimens against vaginal candidiasis.

OBJECTIVE: A study was carried out to compare three treatment regimens for vaginal candidiasis. METHODS: A total of 150 women with clinical and mycological evidence of vaginal candidiasis were randomized to receive daily a 200-mg dose of oral itraconazole for 3 days (50 women), a single oral 150 mg dose of fluconazole (50 women), or daily 100 mg dose of intravaginal clotrimazole for 6 days (50 women). They were assessed at 5-15 days (short-term assessment) and again at 30-60 days (long-term assessment) after discontinuation of the treatment. RESULTS: At the short-term or long-term assessment, Candida species were completely eradicated from the vagina in 80 or 74% in the 3-day oral itraconazole group, 76 or 70% in the single oral fluconazole group, and 72 or 60% in the intravaginal clotrimazole group, respectively. The rates of clinical effectiveness were 92 or 88% in the 3-day oral itraconazole group, 80 or 76% in the single oral fluconazole group, and 72 or 58% in the intravaginal clotrimazole group, respectively. Treatment-related side effects were not found in any group. CONCLUSIONS: Our study suggests that the treatment of vaginal candidiasis with oral itraconazole or oral fluconazole would be effective and that an oral itraconazole or fluconazole therapy might be one choice in the treatment of vaginal candidiasis.

Administration, Intravaginal↗

Clinical and cervical cytokine response to treatment with oral or vaginal metronidazole for bacterial vaginosis during pregnancy: a randomized trial.

OBJECTIVE: To compare the efficacy of oral versus vaginal metronidazole treatment in pregnant women with bacterial vaginosis, and to compare cytokine profiles (interleukin-1beta, -6, and -8) in the cervical secretions of these women before and after treatment. METHODS: Pregnant women with bacterial vaginosis diagnosed both by Gram stain and clinical criteria were randomized to receive oral (n=52) or vaginal (n=50) metronidazole therapy. Cervical specimens for cytokine analysis and vaginal fluid for evaluation of bacterial vaginosis were obtained at baseline and 4 weeks after treatment. RESULTS: There was no significant difference in therapeutic cure rates (defined as a Gram stain score of 0-3 and the absence of all four clinical signs of bacterial vaginosis) between the two groups (71% and 70% for the oral and vaginal groups, respectively, P=1.0). Cervical levels of interleukin-1beta, -6, and -8 were significantly lower after treatment among the 72 women cured of bacterial vaginosis (P<.001, P=.001, and P=.02, respectively) but not among women who failed to respond to therapy. For interleukin-1beta and -6, a significant decrease in cytokine level was observed in both the oral and vaginal treatment groups. CONCLUSION: One week of oral metronidazole and 5 days of intravaginal metronidazole are equally efficacious for treatment of bacterial vaginosis during pregnancy. The decrease in cervical interleukin-1beta, -6, and -8 levels among women who established a normal flora after treatment but not among those with persistent bacterial vaginosis suggests a direct linkage between vaginal flora abnormalities and elevated cervical levels of interleukin-1beta, -6, and -8.

Administration, Intravaginal↗

Outpatient misoprostol cervical ripening without subsequent induction of labor to prevent post-term pregnancy.

BACKGROUND: Interventions that may help shorten the duration of pregnancy in an African setting where facilities for fetal monitoring in post-term pregnancy are limited, and induction is not without its hazards, are needed. AIM: To determine whether outpatient administration of intravaginal misoprostol safely decreases the interval to delivery in postdate pregnancies. DESIGN: Open randomized controlled trial. SETTING: Zonal district hospitals, Kwale, Southern Nigeria (August 2000 to October 2001). METHODS: Seventy-seven women were randomized at 40 weeks gestation to receive either 25 microg misoprostol intravaginally (38) or gentle cervical assessment only (39) on an outpatient basis. Subjects were then allowed to go into spontaneous labor unless an indication for induction developed. MAIN OUTCOME MEASURES: Interval to delivery, duration of labor, and incidence of side-effects. RESULTS: Misoprostol was associated with significant decrease in mean time to delivery (4.5 +/- 4.1 versus 7.4 +/- 5.2 days; P = 0.008), earlier gestational age at delivery (40.6 +/- 0.6 versus 41.4 +/- 0.05 weeks; P < 0.001) and shorter duration of active labor (6.1 +/- 4.0 versus 8.2 +/- 5.3 h; P = 0.028), without any significant increase in fetal distress, low Apgar score at delivery or other side-effects. CONCLUSION: Outpatient administration of low-dose misoprostol can safely shorten the length of gestation in postdate pregnancies.

Administration, Intravaginal↗

A pilot study of metronidazole vaginal gel versus oral metronidazole for the treatment of Trichomonas vaginalis vaginitis.

BACKGROUND: Trichomonas vaginalis is a common sexually transmitted pathogen. In the United States, oral metronidazole is the only officially sanctioned treatment option. OBJECTIVE: This study was undertaken to compare the efficacy and safety of 0.75% metronidazole vaginal gel with that of oral metronidazole for the treatment of trichomonal vaginitis. STUDY DESIGN: Women with trichomoniasis were enrolled in this randomized, open-label pilot study of 0.75% metronidazole vaginal gel twice daily for 7 days compared with 7 days of generic oral metronidazole, 250 mg, three times daily. Patients were seen for follow-up visits 5 to 7 days and 21 to 28 days after the last dose of medication. RESULTS: Using culture for test of cure, trichomonal infection was eliminated in all 15 women treated with oral metronidazole and 7 (44%) of 16 women treated with intravaginal metronidazole. Adverse events were similar, except that there were more taste-related adverse events in the oral metronidazole group. Significant reductions in genitourinary symptoms were seen in both the oral and intravaginal groups. CONCLUSION: This study has shown that 0.75% metronidazole vaginal gel is not effective as a single agent for the treatment of trichomoniasis. Future studies may define a role for metronidazole gel for symptomatic relief in patients intolerant of oral medication or as adjunctive treatment with oral metronidazole for the management of patients infected with metronidazole-resistant strains of T. vaginalis.

Administration, Intravaginal↗