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A Randomized, Double-Blind Clinical Trial of Vaginal Acidification versus Placebo for the Treatment of Symptomatic Bacterial Vaginosis

Holley, Robert L. MD*; Richter, Holly E. PhD, MD*; Varner, R. Edward MD*; Pair, Lisa MSN, CRNP*; Schwebke, Jane R. MD†

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Departments of *Obstetrics and Gynecology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama

Acetic acid and placebo gels were provided by Ortho-McNeil Pharmaceuatical Co., Raritan, NJ.

Correspondence: Jane R Schwebke, MD, Department of Medicine, University of Alabama at Birmingham, 703 19th Street South, ZRB 239, Birmingham, AL 35294-0007. E-mail: schwebke@uab.edu

Received for publication September 4, 2003,

revised November 17, 2003, and accepted November 25, 2003.

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Abstract

Background and Objectives: Vaginal acidification has been suggested as a means of normalizing the vaginal flora.

Goal: The purpose of this study was to determine the effectiveness of an acetic acid-based vaginal gel in the treatment of bacterial vaginosis (BV).

Study Design: Forty-four patients with BV were enrolled in a randomized, double-blind clinic trial. Of these, 29 were evaluable. Patients were randomized to receive either 5 mL acetic acid gel (n = 14) or placebo gel (n = 15) intravaginally twice daily for 7 days. Clinical criteria and vaginal Gram stain scores were compared between the initial visit and at 2 weeks after initiating therapy.

Results: No significant differences were noted when comparing drug and placebo in terms of subjective or clinical improvement or improvement in Gram stain smears for bacterial vaginosis.

Conclusion: Vaginal acidification with an acetic acid gel formulated to pH 3.9 to 4.1 was ineffective therapy for bacterial vaginosis.

BACTERIAL VAGINOSIS (BV), the most common vaginal infection among reproductive-aged women, is characterized by a profuse malodorous discharge and a shift from the normal flora dominated by lactobacilli to a flora in which increased quantities of Gardnerella vaginalis, anaerobic bacteria, and Mycoplasma hominis are present. 1,2 BV is associated with several potentially serious complications. These include pelvic inflammatory disease, posthysterectomy vaginal cuff cellulitis, postcesarean endometritis, chorioamnionitis, preterm labor and delivery, and an increased risk for acquisition and transmission of sexually transmitted diseases and HIV. 3–9

Oral metronidazole is recommended by the Centers for Disease Control and Prevention as the treatment of choice for BV with reported cure rates of 80% to 90%. 10 A concern with the use of systemic metronidazole is the potential for adverse effects during therapy, including nausea, vomiting, anorexia, heartburn, headache, and a metallic taste in the mouth. 11 Although the availability of intravaginal preparations has alleviated some of these concerns, adverse effects still could occur, especially vaginal candidiasis. Intravaginal metronidazole and clindamycin each achieve cure rates comparable to the oral regimen. 10

The potential for adverse effects with metronidazole and the less-than-optimal cure rates coupled with high recurrence rates of BV after treatment has prompted a search for alternative therapies. Case reports of successful cures of BV have been reported in pregnant and nonpregnant women using intravaginal yogurt and lactobacillus, respectively. 12,13 The association of BV with elevated vaginal pH makes logical the use of intravaginal acidic preparations in an attempt to recreate an environment unfavorable to the growth of pathogens. Although treatment of BV with a lactic acid gel has been reported to be successful in one study in pregnant women 14 and another study comparing lactic acid gel and metronidazole, 15 other studies have shown vaginal acidification to be ineffective treatment for BV. 16,17

In this study, we report the results of a randomized, double-blind clinical trial comparing an acetic acid-based vaginal gel versus a placebo gel in the treatment of symptomatic BV.

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Material and Methods

Subjects were recruited from the gynecology clinics at the University of Alabama at Birmingham and the Jefferson County Department of Health Sexually Transmitted Disease (STD) Clinic. Patients were eligible for participation in the study if they fulfilled at least 3 of the 4 clinical criteria of Amsel (malodorous discharge, pH above 4.5, detection of an amine odor after alkalinization of a specimen of vaginal discharge with 10% KOH, and the presence of clue cells in a saline wet smear) and complained of vaginal symptoms such as discharge and/or odor. Patients were excluded from the study if they had a concurrent STD, had taken antibiotic therapy within 7 days of the initial visit, or were pregnant. The study was approved by the Institutional Review Board for research involving humans at the University of Alabama at Birmingham.

Consenting subjects underwent a pelvic examination, including screening for gonorrhea and chlamydia. The presence or absence of homogenous vaginal discharge was noted. Vaginal pH was measured with indicator strips (colorpHast; E. M. Science, Gibbstown, NJ). Vaginal secretions were examined by wet mount microscopy for the presence of clue cells. A whiff test was also performed. A vaginal smear was obtained for Gram stain and graded for the presence of BV by the technique described by Nugent et al. 18

Patients were randomized by use of a computer-generated random number table to either of the 2 treatment schedules with 2 daily doses into the vagina for 7 days of regimen A: 5 mL of an acetic acid gel (Aci-Jel; OrthoMcNeil Pharmaceutical Co., Raritan, NJ) containing 0.92% acetic acid, 0.025% oxyquinoline sulfate, 0.7% ricinoleic acid, and 5% glycerin formulated to a pH of 3.9 to 4.1; or regimen B: 5 mL of placebo gel containing 96.2% purified water, 0.05% propylparaben, 3.15% tragacanth, 0.026% potassium hydroxide, 0.525% acacia, 0.015% stannous chloride, and 0.025% perfume formulated to pH = 4.9. The placebo was also supplied by the pharmaceutical company.

Two weeks after starting treatment, the subjects were seen again, questioned as to whether symptoms had improved, and the laboratory testing was repeated.

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Statistical Methods

To detect a significant difference between a 50% reduction in BV in the treated group versus 20% reduction in the placebo group with a power of 80% and a level of 0.05, the calculated sample size was 90 patients (45 in each group). However, in the first 29 patients, the overall prevalence of BV by Nugent score was 66% at follow up, similar to the 72% positivity rate by Nugent score found at baseline randomization, and thus the study was prematurely stopped. Results are reported for the first 29 patients, 14 in the acetic acid gel group and 15 in the placebo group. Statistical comparisons were made by using the Epi Info version 6 software program. 19 Fisher exact test was used to compare continuous variables.

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Results

After exclusion because of positive cultures for Chlamydia trachomatis (4 patients) and Neisseria gonorrhoeae (1 patient) or because the patient did not return for the 2-week follow-up visit (10 patients), 29 cases were available for evaluation. Interim analysis of the data to examine for trends or unanticipated complications revealed no significant differences between the 2 groups on any measure of treatment efficacy, and in fact, a trend of improvement of symptoms and Gram stain occurred with the placebo group; thus, the study was aborted for ethical considerations halfway before the projected sample size was reached.

A summary of the initial visit and 2-week follow-up data for evaluable subjects is presented in Table 1. There was no significant difference between the treatment and placebo groups in the distribution of Nugent scores. The mean age for patients randomized acetic acid gel was 29 years versus 32 years for those randomized to placebo gel (P = 0.007).

Table 1
Table 1
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At the 2-week follow-up visit, the vaginal pH had normalized in only 1 patient on acetic acid gel and in only 2 patients on placebo gel. Subjective improvement was reported by only 3 (21%) patients using acetic acid gel and by 5 (33%) patients using placebo gel. All 9 of the 14 patients randomized to acetic acid gel who had Gram stain evidence of BV at the initial visit also had BV on Gram stain at the second visit; of the 4 patients with intermediate flora at the initial visit, 1 progressed to BV, 1 regressed to normal, and 2 retained the same Gram stain score.

Among the 12 patients using placebo gel who were Gram stain-positive for BV at the initial visit, 9 remained Gram stain-positive for BV at the 2-week follow-up visit and 3 changed to an intermediate flora. Of the 2 women with intermediate flora on initial vaginal Gram stain, 1 remained unchanged during the course of the study, whereas the other developed normal flora. The mean Gram stain scores did not differ significantly between the 2 groups at the 2-week follow-up (acetic acid gel, 6.9; placebo gel, 6.5). Seventy-nine percent of the 14 patients using acetic acid gel required additional treatment with metronidazole as did 60% of the 15 patients using placebo gel.

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Discussion

Current evidence supports the role of a lactobacillus-predominant vaginal flora in protecting against BV and STDs, including HIV. 8,9 Mechanisms include production of lactic acid as well as production of hydrogen peroxide. 20 Thus, modalities to correct abnormal vaginal flora patterns such as BV could be desirable. Although currently recommended antibiotic regimens are helpful in many cases, cure rates remain suboptimal. Vaginal acidification is often prescribed by providers as a treatment for BV, but there is little data to support its use.

Two studies claim success in the treatment of BV by vaginal acidification. Holst and Brandberg reported a 100% cure rate in 10 pregnant women with BV treated with 5 mL lactate gel (pH = 3.8) at bedtime for 7 days. 14 Although not a randomized study, these authors concluded that this therapy might be preferable to oral antimicrobial therapy, especially during the first trimester of pregnancy. Andersch et al. in a randomized, nonblinded study treated 62 women with BV with 5 mL lactate gel (pH = 3.5) inserted into the vagina for 7 days. After 1 week of therapy, the lactate gel was as effective as 500 mg oral metronidazole twice daily for 7 days in relieving subjective symptoms as well as in suppressing the growth of anaerobes. 15

Other studies have reported poor results using vaginal acidification compared with oral metronidazole. Fredricksson et al., in a randomized clinical trail, obtained cures in only 3 of 17 cases treated with an acetic acid gel, whereas 13 of 14 were cured with oral metronidazole. 16 Likewise, Boeke et al. reported cure rates of 83%, 49%, and 47% using oral metronidazole, lactic acid suppositories, and placebo suppositories, respectively, 2 weeks after completion of therapy in a randomized, double-blind study. 17

In this randomized, double-blind clinical trial, we found vaginal acidification to be ineffective treatment for BV. Gram stain scores did not improve at the 2-week follow-up examination in subjects who received the acetic acid gel nor did subjective patient assessment. Although this study was terminated early, the trend was toward a higher prevalence of BV in the treatment arm. We conclude that vaginal acidification using an acetic acid based gel buffered to pH = 3.9 to 4.1 is not effective in discouraging the growth of BV-associated microorganisms or in promoting recolonization of the vagina with lactobacilli. This study confirms the work of other authors and casts considerable doubt on the benefit of intravaginal acidic preparations, including vinegar and water douches, in the treatment of BV.

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References

1. 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.

2. Thomason JL, Gelbart SM, Scaglione JJ. Bacterial vaginosis: Current review with indication for asymptomatic women. Am J Obstet Gynecol 1991; 165: 1210–1217.

3. Hillier SL, Kiviat NB, Hawes S, et al. Gynecology: Role of bacterial vaginosis associated microorganisms in endometritis. Am J Obstet Gynecol 1996; 175: 435–441.

4. Soper D, Brockwell N, Dalton H, Johnson D. Observations concerning the microbial etiology of acute salpingitis. Am J Obstet Gynecol 1994; 170: 1008–1017.

5. 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: 1016–1023.

6. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. Bacterial vaginosis as a risk factor for post-cesarean endometritis. Obstet Gynecol 1990; 75: 52–58.

7. Gravett M, Nelson H, DeRouen T, Chritchlow C, Eschenbach DA, Holmes K. Independent associations of bacterial vaginosis and Chlamydia trachomatis infection with adverse pregnancy outcome. JAMA 1986; 256: 1899–1903.

8. Wiesenfeld H, Hillier S, Krohn MA, Landers D, Sweet R. Bacterial vaginosis is a strong predictor of Neisseria gonorrhoeae and Chlamydia trachomatis infection. Clin Infect Dis 2003; 36: 663–668.

9. Martin H, Richardson B, Nyange P, et al. Vaginal Lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition. J Infect Dis 1999; 180: 1863–1868.

10. Centers for Disease Control and Prevention. 2002 sexually transmitted disease treatment guidelines. MMWR Morb Mortal Wkly Rep 2002; 51( No. RR-6): 42–44.

11. Schlicht J. Treatment of bacterial vaginosis. Ann Pharmacother 1994; 28: 483–487.

12. Neri A, Sabah G, Samra Z. Bacterial vaginosis in pregnancy treated with yoghurt. Acta Obstet Gynecol Scand 1993; 72: 17–19.

13. Hallen A, Jarstrand C, Pahlson C. Treatment of bacterial vaginosis with lactobacilli. Sex Transm Dis 1992; 19: 146–148.

14. Holst E, Brandberg A. Treatment of bacterial vaginosis in pregnancy with a lactate gel. Scand J Infect Dis 1990; 19: 146–148.

15. Andersch B, Forssman L, Lincoln K, Torstensson P. Treatment of bacterial vaginosis with an acid cream: A comparison between the effect of lactate-gel and metronidazole. Gynecol Obstet Invest 1986; 21: 19–25.

16. Fredricsson B, Englund K, Weintraub L, Olund A, Nord C. Bacterial vaginosis is not a simple ecological disorder. Gynecol Obstet Invest 1989; 28: 156–160.

17. Boeke A, Dekker J, van Eijk J, Kostense P, Bezemer P. Effect of lactic acid suppositories compared with oral metronidazole and placebo in bacterial vaginosis: A randomized clinical trial. Genitourin Med 1993; 69: 388–392.

18. 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.

19. Dean A, Dean J, Coulambeer D, Burton A, Brendel K, Smith D. Epi Info, version 6. A word processing database and statistics program for epidemiology in microcomputers. Atlanta: Centers for Disease Control and Prevention, 1994.

20. Hillier S. The vaginal microbial ecosystem and resistance to HIV. AIDS 1998; 14: 17–21.

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