Secondary Logo

Journal Logo

Articles

Comparison of Clindamycin Phosphate Vaginal Cream With Triple Sulfonamide Vaginal Cream in the Treatment of Bacterial Vaginosis

McCORMACK, WILLIAM M. MD,*; COVINO, JEAN M. MPA, PA-C,*; THOMASON, JESSICA L. MD,†; ESCHENBACH, DAVID A. MD,‡; MOU, SUSAN MD; KAPERNICK, PETER MD,‖‖; MCGREGOR, JAMES MD; REIN, MICHAEL F. MD,#; HILLIER, SHARON L. PhD**

Author Information
  • Free

Abstract

BACTERIAL VAGINOSIS is diagnosed frequently among women who seek treatment at gynecology clinics, sexually transmitted disease clinics, prenatal clinics, and physicians’ offices. Approximately 45% of all symptomatic, abnormal vaginal discharges are caused by this disease. 1 The most common presenting problem associated with bacterial vaginosis is a malodorous vaginal discharge. However, as many as 50% of women with bacterial vaginosis may be asymptomatic. 2 Until recently, bacterial vaginosis had been considered a benign condition. Bacterial vaginosis now has been linked with upper genital tract infection after gynecologic surgery and in association with pregnancy. 1,3,4 Metronidazole and erythromycin treatment of pregnant women with bacterial vaginosis at high risk for a premature delivery was associated with reduced rates of premature delivery, suggesting that bacterial vaginosis causes premature delivery. 5

The etiology of bacterial vaginosis is incompletely defined, although current evidence suggests that it is a polymicrobial condition involving Gardnerella vaginalis, Bacteroides species, Prevotella species, Mobiluncus species, Mycoplasma hominis, anaerobic cocci, and other microorganisms. 6–9 Conversely, lactobacilli are significantly decreased or absent among women with bacterial vaginosis. 10,11

Effective oral medications that treat bacterial vaginosis include metronidazole 500 mg twice a day for 7 days and clindamycin 300 mg twice a day for 7 days. 12–14 Intravaginal clindamycin and metronidazole also are effective and well tolerated. 15–18 Triple sulfonamide cream has been used for many years, although data concerning its efficacy are limited and inconclusive. 19,20

The purpose of this study was to compare the safety and efficacy of intravaginal clindamycin phosphate cream used once a day for 7 days to treat symptomatic bacterial vaginosis with that of intravaginal triple sulfonamide vaginal cream used twice a day for 7 days.

Materials and Methods

A double-blind, randomized, multicenter study compared 2% clindamycin phosphate vaginal cream (Cleocin Vaginal Cream; Upjohn Company, Kalamazoo, MI) with triple sulfonamide vaginal cream (Sultrin Triple Sulfa Cream; Ortho Pharmaceutical Corporation, Raritan, NJ) in the treatment of bacterial vaginosis. Nonpregnant, nonlactating, women 16 years of age or older with symptomatic bacterial vaginosis were studied. Exclusion criteria included allergy to clindamycin or sulfonamides, systemic or vaginal antimicrobial therapy within the preceding 2 weeks, a history of antibiotic-associated diarrhea, anticipation of menstruation during treatment or at the first follow-up visit, and the presence of other cervical or vaginal infection. All enrolled patients provided written informed consent as approved by each local institutional review board.

At the enrollment visit, participants were asked about their medical and sexual history. A vaginal examination was performed, and the vaginal fluid was examined for pH, odor after alkalinization with 10% potassium hydroxide, and microscopic appearance using the method of each participating center. The diagnosis of bacterial vaginosis was made if all three of the following were present: (1) pH of the vaginal fluid greater than 4.5; (2) a fishy, amine odor with the addition of 10% potassium hydroxide to the vaginal fluid; and (3) clue cells observed during microscopic examination of the vaginal fluid.

Gram-stained smears of the vaginal fluid were examined microscopically using published criteria to diagnose bacterial vaginosis. 21,22 Vaginal fluid was inoculated onto appropriate media and examined for Gardnerella vaginalis. Cultures for Neisseria gonorrhoeae and Chlamydia trachomatis were obtained from the endocervix, and cultures for Trichomonas vaginalis and yeast were obtained from the vaginal fluids of each patient. These specimens were examined using the routine methods of each laboratory.

The participants were assigned randomly to receive 2% clindamycin phosphate vaginal cream (Cleocin Vaginal Cream), 5 g intravaginally at bedtime for 7 days plus placebo vaginal cream, 5 g intravaginally in the morning for 7 days or triple sulfonamide cream (Sultrin Triple Sulfa Cream), 5 g intravaginally in the morning and at bedtime for 7 days.

The first return visit was scheduled 5 to 10 days after the completion of treatment, providing the patient was not menstruating, or the participants were asked to return when their menstruation ceased. The aforementioned clinical evaluation and laboratory determinations were repeated. The patients were considered clinically cured if a return to normal was found for all three diagnostic findings: vaginal pH, odor, and clue cells. A clinical improvement was defined as a return to normal for two of these three findings, whereas a clinical failure was a return to normal for one or none of these criteria. A patient who was unable to complete the protocol because of side effects was classified as a side effect failure.

Patients considered to be clinical failures at the first follow-up visit could, at the discretion of the investigator, be treated with an alternative therapy and discontinue participation in the study. Those who were clinical failures but did not receive alternative therapy were asked to return for the second follow-up visit. The same clinical assessments and diagnostic tests were used at the second follow-up visit, which was conducted 25 to 39 days after completion of therapy. Secondary efficacy parameters included Gram stain and the patient’s evaluation of efficacy.

Results

The seven collaborating investigators enrolled 281 women in the study. Another 48 patients enrolled by an eighth investigator were excluded from the analyses because the results obtained at this investigator’s site were significantly discordant statistically from the results of the other seven investigators. Of the 281 participants, 159 (56.6%) were assessable. Of the 122 nonassessable patients, 57 received clindamycin vaginal cream and 65 received triple sulfonamide vaginal cream. The 122 nonassessable patients were excluded because one or both follow-up visits occurred outside the designated time periods (97 patients), participants were lost to follow-up evaluation (23), medication was used for fewer than 6 or more than 9 days (44), entry criteria were violated (12), medical events resulted in discontinuation (24), other infections were detected at study entry (9), douches or vaginal medications were used (5), menstruation precluded evaluation (8), or other disallowed medications were taken (6). The participants may have had more than one reason for not being assessable. Of the 159 assessable participants, 80 received clindamycin vaginal cream and 79 received triple sulfonamide vaginal cream.

Assessable participants ranged in age from 16 to 51 years, with means of 27.4 years for the clindamycin treatment group and 28.8 years for the triple sulfonamide group, a difference that was not significant. Of the assessable participants, 83 (52.2%) were black, 69 (43.4%) were white and 7 (4.4%) were of other racial groups. Of the 159 assessable participating women, 26 (16.4%) were married. Most (76%) of the participants had been pregnant. The majority (94%) of assessable participants used some form of contraception, including condom use in approximately 20%. No statistically significant differences were found between the treatment groups regarding race, marital status, parity, or contraceptive method. Similarly, the treatment groups did not differ statistically in weight, number of sexual partners during the preceding 3 or 6 months, frequency of intercourse, or interval since the last sexual contact.

In all, 140 (88.1%) of the 159 participants reported prior gynecologic infections. No statistically significant differences were observed between the treatment groups regarding history of gonorrhea, pelvic inflammatory disease, syphilis, chlamydial infection, trichomoniasis, or vulvovaginal candidiasis. Of the 159 assessable patients, 88 (55.3%) reported a history of bacterial vaginosis: 37 (46.3%) in the clindamycin group and 51 (64.6%) in the triple sulfonamide group (P = 0.03).

No statistically significant differences were found between the treatment groups regarding frequency of intercourse, frequency of unprotected intercourse, new sexual partners, or douching between the first and second follow-up visits.

One woman discontinued treatment because of vaginal burning after using one applicator full of clindamycin vaginal cream. This patient was classified as a side-effect failure and excluded from the following analysis of efficacy. Table 1 summarizes the results at the first and second posttreatment visits. At the first visit, clinical cure or improvement was noted in 65 (82.3%) of the 79 patients who received clindamycin vaginal cream and in 56 (70.9%) of the 79 who received triple sulfonamide vaginal cream (P < 0.001). At the second posttreatment visit, clinical cure or improvement was noted in 63 (79.7%) of 79 clindamycin-treated women and in 35 (44.3%) of 79 women who used triple sulfonamide vaginal cream (P < 0.0001; odds ratio [OR], 4.9; 95% CI, 2.3–10.7). However, among participating women with no previous history of bacterial vaginosis, clindamycin and triple sulfonamide vaginal creams had similar efficacy. In contrast, treatment efficacy for clindamycin vaginal cream was significantly greater than for triple sulfonamide vaginal cream among women who reported prior bacterial vaginosis at the first (P < 0.001) and second (P < 0.001) follow-up visits.

Table 1
Table 1:
Response of Patients With Bacterial Vaginosis to Treatment Using Clindamycin Vaginal Cream or Triple Sulfonamide Vaginal Cream

Table 2 lists the overall treatment outcomes for the study participants. For this analysis, any patient classified as a failure at the first posttreatment visit was considered a failure regardless of the results, if any, at the second posttreatment visit. A patient regarded as cured at the 5- to 10-day visit and a failure at the 25- to 39-day visit was classified as a relapse. In all, 55 (69.6%) of 79 women who used clindamycin vaginal cream and 33 (41.8%) of 79 women who used triple sulfonamide vaginal cream were considered cured or improved (P < 0.0001; OR, 3.2; 95% CI, 1.6–6.5).

Table 2
Table 2:
Overall Outcome Among Women With Bacterial Vaginosis After Treatment Using Clindamycin Vaginal Cream or Triple Sulfonamide Vaginal Cream

Table 2 also presents the overall treatment outcomes among participants without and those with a history of bacterial vaginosis. Clindamycin vaginal cream and triple sulfonamide vaginal cream produced similar outcomes among women who did not report previous episodes of bacterial vaginosis (P = 0.3). In contrast, clindamycin cream was more effective than triple sulfonamide cream in women who provided a history of bacterial vaginosis. Only 6 (16.7%) of 36 clindamycin recipients with a history of bacterial vaginosis were classified as relapses or failures, whereas 33 (64.7%) of 51 such women who used triple sulfonamide vaginal cream were classified as relapses or failures (P < 0.0001; relative risk, 3.9; 95% CI, 1.8–8.3).

As shown in Table 3, most of the study participants reported that their symptoms had resolved or improved after treatment, regardless whether they used clindamycin vaginal cream or triple sulfonamide vaginal cream. More women who used sulfonamide cream reported persistent symptoms. Of the sulfonamide-using women self-classified as having persistent symptoms at the first and second posttreatment visits, a previous history of bacterial vaginosis was reported, respectively, by 7 of 8 and 10 of 12 participants.

Table 3
Table 3:
Evaluation of Symptoms by Patients With Bacterial Vaginosis Who Underwent Treatment Using Clindamycin Vaginal Cream or Triple Sulfonamide Vaginal Cream*

Table 4 details the evaluations of Gram-stained smears of vaginal fluids after treatment. These Gram-stained smears were used as an objective evaluation of response independent of the clinical scores and the patient’s symptoms. For all participants, clindamycin treatment was associated with fewer Gram stains consistent with bacterial vaginosis at both posttreatment visits. Among the participating women without a history of bacterial vaginosis, clindamycin treatment was significantly superior statistically to triple sulfonamide cream at the second but not at the first posttreatment visit. In contrast, among women with a history of bacterial vaginosis, clindamycin vaginal cream was significantly better than triple sulfonamide vaginal cream at both posttreatment visits. Most of the women who had Gram-stained smears consistent with bacterial vaginosis after treatment with triple sulfonamide vaginal cream at the first (17 of 24) and second (25 of 37) posttreatment visits reported previous bacterial vaginosis.

Table 4
Table 4:
Evaluation of Gram-Stained Smears of Vaginal Secretions After Treatment for Bacterial Vaginosis With Clindamycin Vaginal Cream or Triple Sulfonamide Vaginal Cream

Table 5 shows comparisons between Gram-stained vaginal smear evaluations and treatment outcomes for 151 patients seen at the second posttreatment visit. In 97 (64.2%) of the participants, the results were concordant. In 26 (17.2%) of the patients, the Gram-stain evaluation was worse than the clinical outcome, whereas in 28 (18.5%) of the patients, the Gram-stain result was better.

Table 5
Table 5:
Evaluation of Gram-Stained Vaginal Secretions Compared With Treatment Outcome at the Second Posttreatment Visit Among 151 Patients Treated for Bacterial Vaginosis Using Clindamycin Vaginal Cream or Triple Sulfonamide Vaginal Cream

Lactobacillus morphotypes were identified in baseline Gram stains of vaginal fluid from approximately 20% of the participants. At the first posttreatment visit, Lactobacillus morphotypes were seen in Gram stains from 42 (53.2%) of 79 women who used clindamycin vaginal cream, and in 55 (70.5%) of 78 women who used triple sulfonamide vaginal cream (P < 0.05). At the second posttreatment visit, Lactobacillus morphotypes were identified in Gram stains of vaginal fluid from 59 (75.6%) of 78 women who used clindamycin vaginal cream and from 42 (57.5%) of 73 women who used triple sulfonamide vaginal cream (P < 0.05). These data may indicate an initial suppression of lactobacilli by clindamycin.

Of the 281 enrolled patients, 277 received some study medication. At the follow-up visits, these patients completed a symptom checklist evaluating adverse events. Nearly half (48%) of the patients reported at least one adverse event. In the clindamycin group, 41 (30.1%) of 136 participants reported adverse events considered to be drug related, whereas 31 (22%) of 141 women who used triple sulfonamide cream reported a drug-related adverse event (P > 0.1). The adverse events reported by five or more participating women are listed in Table 6. No statistically significant differences were found between treatment groups in the incidence of any of these adverse events. Symptomatic vulvovaginal candidiasis developed after treatment in 15 women who received clindamycin cream and in 16 women who received triple sulfonamide cream.

Table 6
Table 6:
Adverse Experiences Reported by Five or More Patients Who Received Clindamycin Vaginal Cream or Triple Sulfonamide Vaginal Cream for the Treatment of Bacterial Vaginosis

Discussion

The purpose of this study was to compare clindamycin vaginal cream with triple sulfonamide vaginal cream in the treatment of bacterial vaginosis. Clindamycin vaginal cream was more effective than triple sulfonamide vaginal cream. After treatment with clindamycin vaginal cream, clinical cure or improvement was noted in approximately 70% of patients. Another multicenter study 16 that used similar diagnostic criteria to evaluate clinical outcomes reported similar results with intravaginal clindamycin cream.

Because more patients in the triple sulfonamide group reported previous episodes of bacterial vaginosis, the data were analyzed for patients with and those without a history of bacterial vaginosis. Most of the difference between treatment groups occurred in patients with prior bacterial vaginosis. Indeed, among patients who did not report a previous episode of bacterial vaginosis, clindamycin vaginal cream and triple sulfonamide vaginal cream efficacy rates were similar. In contrast, clindamycin cream was particularly more effective than triple sulfonamide cream among women who reported prior episodes of bacterial vaginosis. For example, only 6 (16.7%) of 36 clindamycin recipients with a history of bacterial vaginosis were classified as relapses or failures, as compared with 33 (64.7%) of 51 such women who used triple sulfonamide cream (Table 2).

Bacterial vaginosis can be diagnosed with the use of clinical criteria (pH, odor with 10% potassium hydroxide, clue cells), abbreviated clinical criteria, 21 or Gram-stained vaginal smears. 22 In this study, clindamycin vaginal cream was proved superior to triple sulfonamide vaginal cream in an evaluation of all the participants with either clinical or Gram-stain criteria. Interestingly, among women who had no history of previous bacterial vaginosis, clindamycin cream was proved superior to triple sulfonamide cream using Gram-stain criteria. For women who reported previous bacterial vaginosis, clindamycin cream was superior to triple sulfonamide cream whether clinical or Gram-stain criteria were used.

A comparison of clinical criteria with Gram-stain criteria at the second posttreatment visit showed concordance in about two thirds of the instances. Discordant pairs were equally likely to have Gram-stain results that were more abnormal or less abnormal than the clinical results. Thus, a bias toward overdiagnosis or underdiagnosis of bacterial vaginosis with the use of Gram-stain criteria does not explain the different results obtained with these methods among women who had no history of bacterial vaginosis.

Treatment of bacterial vaginosis reduces the components of the abnormal vaginal microflora that characterize this illness and allows hydrogen peroxide–producing lactobacilli to multiply and become reestablished as the primary vaginal microorganisms. Treatment failures may occur because lactobacilli do not repopulate the vagina after treatment, presumably because the host no longer is colonized with these microorganisms.

The current study may help to reconcile the differences between earlier reports such as those of Gardner and Dukes, 23 who found triple sulfonamide cream to be highly effective in the management of bacterial vaginosis, and more recent studies, 16,24–27 in which triple sulfonamide cream was found to have low cure rates. Clindamycin cream was found to be significantly superior to triple sulfonamide cream in the treatment of women with a history of bacterial vaginosis, whereas the preparations were similar in women without such a history. One explanation for this finding maintains that patients with a history of bacterial vaginosis are more difficult to treat, perhaps because prior treatment has an adverse effect on the vaginal microflora. Because most of Gardner’s patients would have been newly diagnosed and previously untreated, they would have been analogous to the current patients without previous bacterial vaginosis, and thus more likely to respond to treatment with triple sulfonamide cream.

References

1. 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: 819–828.
2. Thomason JL, Gelbart SM, Wilcoski LM, Peterson AK, Jilly BJ, Hamilton PR. Proline aminopeptidase activity as a rapid diagnostic test to confirm bacterial vaginosis. Obstet Gynecol 1988; 71: 607–611.
3. Hillier SL, Nugent RP, Eschenbach DA, et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. The Vaginal Infections and Prematurity Study. N Engl J Med 1995; 333: 1737–1742.
4. 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.
5. Hauth JC, Goldenberg RL, Andrews WW, DuBard MB, Cooper RL. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 1995; 333: 1732–1736.
6. Spiegel CA, Amsel R, Eschenbach DA, Schoenknecht F, Holmes KK. Anaerobic bacteria in nonspecific vaginitis. N Engl J Med 1980; 303: 601–607.
7. Spiegel CA, Eschenbach DA, Amsel R, Holmes KK. Curved anaerobic bacteria in bacterial (nonspecific) vaginosis and their response to antimicrobial therapy. J Infect Dis 1983; 148: 817–822.
8. Hillier SL, Krohn MA, Rabe LK, Klebanoff SJ, Eschenbach DA. The normal vaginal flora, H2O2-producing lactobacilli, and bacterial vaginosis in pregnant women. Clin Infect Dis 1993; 16: (suppl 4): S273–S281.
9. Martius J, Krohn MA, Hillier SL, Stamm WE, Holmes KK, Eschenbach DA. Relationship of vaginal Lactobacillus species, cervical Chlamydia trachomatis, and bacterial vaginosis to preterm birth. Obstet Gynecol 1988; 71: 89–95.
10. Redondo-Lopez V, Cook RL, Sobel JD. Emerging role of lactobacilli in the control and maintenance of the vaginal bacterial microflora. Rev Infect Dis 1990; 12: 856–872.
11. Eschenbach DA, Davick PR, Williams BL, et al. Prevalence of hydrogen peroxide-producing Lactobacillus species in normal women and women with bacterial vaginosis. J Clin Microbiol 1989; 27: 251–256.
12. Eschenbach DA, Critchlow CW, Watkins H, et al. A dose-duration study of metronidazole for the treatment of nonspecific vaginosis. Scand J Infect Dis 1983; 40: 73–80.
13. Swedberg J, Steiner JF, Deiss F, Steiner S, Driggers DA. Comparison of single-dose versus one-week course of metronidazole for symptomatic bacterial vaginosis. JAMA 1985; 254: 1046–1049.
14. Centers for Disease Control and Prevention. 1998 Guidelines for Treatment of Sexually Transmitted Diseases MMWR Morb Mortal Wkly Rpt 1998; 47 (No. RR-1):1–116.
15. Schmitt C, Sobel JD, Meriwether C. Bacterial vaginosis: treatment with clindamycin cream versus oral metronidazole. Obstet Gynecol 1992; 79: 1020–1023.
16. 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: 405–410.
17. Bistoletti P, Fredricsson B, Hagstrom B, Nord C-E. Comparison of oral and vaginal metronidazole therapy for nonspecific bacterial vaginosis. Gynecol Obstet Invest 1986; 21: 144–149.
18. Hillier SL, Lipinski C, Briselden AM, Eschenbach DA. Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol 1993; 81: 963–967.
19. Bhattacharyya MN, Jones BM. Haemophilus vaginalis infection: diagnosis and treatment. J Reprod Med 1980; 24: 71–75.
20. Piot P, Van Dyck E, Godts P, Vanderheyden J. A placebo-controlled, double-blind comparison of tinidazole and triple sulfonamide cream for the treatment of nonspecific vaginitis. Am J Obstet Gynecol 1983; 147: 85–89.
21. 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: 155–160.
22. 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: 293–301.
23. Gardner HL, Dukes CD. Haemophilus vaginalis vaginitis: a newly defined specific infection previously classified “nonspecific” vaginitis. Am J Obstet Gynecol 1955; 69: 962–976.
24. Pheifer TA, Forsyth PS, Durfee MA, Pollock HM, Holmes KK. Nonspecific vaginitis: role of Haemophilus vaginalis and treatment with metronidazole. N Engl J Med 1978; 298: 1429–1434.
25. Piot P, Van Dyck E, Godts P, Vanderheyden J. A placebo-controlled, double-blind comparison of tinidazole and triple sulfonamide cream for the treatment of nonspecific vaginitis. Am J Obstet Gynecol 1983; 147: 85–89.
26. Sobel JD, Chaim W, Thomason J, et al. Comparative study of intravaginal metronidazole and triple-sulfa therapy for bacterial vaginosis. Infect Dis Obstet Gynecol 1996; 4: 66–70.
27. Malouf M, Fortier M, Morin G, Dube J-L. Treatment of Haemophilus vaginalis vaginitis. Obstet Gynecol 1981; 57: 711–714.
© Copyright 2001 American Sexually Transmitted Diseases Association