Bunge, Katherine E. MD, MPH*; Beigi, Richard H. MD, MSC*; Meyn, Leslie A. MS†; Hillier, Sharon L. PHD*†
From the *Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh/Magee-Womens Hospital, Pittsburgh, PA; and †Magee-Womens Research Institute, Pittsburgh, PA.
Supported by an unrestricted research grant from 3M pharmaceuticals and NIH/NIAID U01 AI47785 (CRC MO1 RR00056).
Correspondence: Katherine Bunge, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital, 300 Halket Street, Pittsburgh, PA 15213. E-mail: email@example.com.
Received for publication February 2, 2009, and accepted May 15, 2009.
Few data exist regarding management strategies for women with early treatment failure for bacterial vaginosis. Cure rates after re-treatment were compared for two topical agents. The overall cure rate was 62%; rates between medications were comparable. Re-treatment with the same topical medication for early recurrence is an acceptable strategy.
Bacterial vaginosis is a common disruption of the vaginal microflora which affects a significant number of sexually active women. The most recent estimate of bacterial vaginosis prevalence comes from the National Health Examination and Nutrition Study.1 Nearly 4000 vaginal swabs were collected as part of this nationally representative sampling and assessed for bacterial vaginosis based on the Nugent Gram stain scoring system.2 The overall point prevalence of bacterial vaginosis among women aged 14 to 49 was 29%; half of these women were symptomatic suggesting that treatment of bacterial vaginosis is often indicated in American women.
The Centers for Disease Control’s (CDC) recommended treatments for bacterial vaginosis include oral metronidazole, topical metronidazole, and topical clindamycin.3 Published cure rates using these regimens vary significantly depending on what agent is used, how cure is defined, and the duration of follow-up. Cure rates at 1 month range from 68% to 74%, whereas cure rates at 1 year range from 34% to 51%.4 Importantly, nearly a quarter of women experience spontaneous resolution of signs and symptoms in the placebo group of randomized controlled studies.5,6
Despite the high prevalence of bacterial vaginosis and the high rates of recurrence, a paucity of data exists regarding the best management of early treatment failure. The CDC suggests that a treatment regimen different from the original may be used3; however, data supporting this approach are lacking. The objective of this investigation was to assess the efficacy of retreatment with the same medication.
A nested cohort study was performed as a secondary analysis on a subgroup of women enrolled in a randomized treatment trial comparing topical clindamycin to topical metronidazole for the treatment of bacterial vaginosis. The methods and results of this trial have been published previously.7 Briefly, women with a clinical diagnosis of bacterial vaginosis defined as having 3 of the 4 Amsel et al. criteria8 were randomized to receive either 3 days of topical clindamycin or 5 days of topical metronidazole. Clinical cure, defined as the presence of less than 2 Amsel’s criteria, was assessed at each of 3 follow-up visits: 7 to 9 days, 35 to 45 days, and 70 to 90 days after completing treatment. Treatment failures were retreated with the same medication prescribed at randomization. Basic demographic and behavioral characteristics of the cohort were assessed at baseline.
For this analysis, only women for whom clinical data were available for all 4 visits were included. Women were defined as an early treatment failure if they experienced an initial failure at either the 1 week or 1 month visit. The treatment failure group then was comprised of women who had initially responded to therapy and recurred and women who failed the initial therapy. The primary outcome was clinical cure at the next visit. An overall cure rate was calculated, and cure rates were compared between treatment arms, using Fisher exact test. Differences in demographic characteristics and the presence of antimicrobial resistant organisms in the vagina before initial therapy between those who were and were not cured after retreatment were evaluated using Student t and Fisher exact tests. All statistical tests were evaluated at the 2-sided 0.05 significance level.
Of 119 women enrolled in the original study, 104 participants had complete clinical data available. Of these, 51 women experienced an early treatment failure. Twenty-five had been randomized to topical clindamycin and 26 to topical metronidazole. Of 51 women, 34 (67%) were retreated with the same medication as per the protocol and 17 did not receive the same medication. The nested cohort’s (n = 34) mean age was 27.8 years; 76.5% were black. Fifty-three percent were current smokers, and 68% reported ever having douched. Twelve percent reported a new male partner in the month before enrollment.
Of 34 women retreated with the same medication, 21 experienced clinical cure at the next visit (61.8%, 95% CI: 43.6%–77.8%). By treatment group, 10 of 15 (66.7%, 95% CI: 38.3%–88.2%) women retreated with clindamycin experienced clinical cure and 11 of 20 (57.9%, 95% CI: 33.5%–79.7%) women retreated with metronidazole experienced clinical cure (P = 0.7) (Fig. 1). Those who were cured after retreatment did not differ from those who were not cured after retreatment by age, body mass index, smoking status, or baseline antimicrobial resistance (Table 1).
Seventeen women did not receive the same medication as they received at randomization for treatment of recurrent bacterial vaginosis. Reasons for protocol deviation included required oral treatment for concomitant Trichomonas vaginalis infection and participant refusal. This group of 17 did not differ from the 34 women who did receive the same medication by demographic and behavioral factors, nor baseline Nugent scores (Table 2). Of 17 women, 4 (23.5%) experienced clinical cure at the next visit. This was a statistically significant lower rate when compared to the cure rate for those treated with the same medication (23.5% vs. 61.8%; P = 0.017). Thirteen women experienced treatment failure at both the 1 week and 1 month visit. Two women received the same medication twice per protocol; neither was cured. Of the 11 women who did not get the same medication twice, only 1 was cured.
This study demonstrates that 62% of women retreated with the same topical medication after early treatment failure for bacterial vaginosis will experience clinical cure, a rate of cure comparable to the 54% cure rate observed 35 to 45 days after the initial treatment in the original study population.7 The 2006 CDC guidelines suggest that recurrent bacterial vaginosis may be treated with a different medication regimen3 presumably because recurrence may be due to medication resistance. However, in the current study, women who were treated with a different topical antimicrobicide had higher treatment failure rates. Whether early treatment failure of bacterial vaginosis represents resistance, reinfection, or relapse remains an important unanswered question.9 Studies demonstrating in vitro resistance among several organisms support the theory of microbial resistance, and at least 1 in vivo study suggests that resistance may play a role in treatment failure.7 Although our study does not directly address the etiology of early treatment failure for bacterial vaginosis, our finding that retreatment with the same topical medication produces an acceptable cure rate argues against resistance as the primary etiology for treatment failure. Importantly, this finding appears to be irrespective of the medication used. These data support pilot data demonstrating that 3 of 4 women who required retreatment with topical metronidazole after early treatment failure demonstrated clinical cure at the next visit.10
Reinfection as the etiology of early treatment failure and recurrence is supported by the association between abstinence or consistent condom use and a higher cure rate.11 However, the treatment of sexual partners does not appear to reduce recurrence rates for women with bacterial vaginosis.3 Furthermore, bacterial vaginosis has been documented in sexually inexperienced women12 suggesting that reinfection cannot account for all treatment failures.
Prospective microbiologic evaluations of women who experience treatment failure and recurrent bacterial vaginosis support relapse as the primary etiology. In a randomized study comparing metronidazole to a combination of metronidazole and azithromycin, women with more disturbed flora had lower cure rates than women with lower Nugent scores.11 These data suggest that recurrent bacterial vaginosis may be due to microbiologic relapse rather than reinfection.
One limitation of our study is that only 34 of 51 women who experienced early treatment failure were retreated with the same medication as outlined in the protocol. We considered the possibility that the women who were not treated with the same medication may have had more severe bacterial vaginosis; however, the baseline Nugent score for these women was similar to those who did receive the same medication suggesting this was not the case. A second limitation is the limited generalizability of these findings as we have restricted our analysis to women for whom complete data are available. Finally, a third limitation of the study is the limited follow-up period of 25 to 45 days; as such, the clinical cure rates represent short term cure rates of less than 3 months.
Interestingly, little data are available to inform the best management of women with persistent or recurrent bacterial vaginosis after treatment, though 2 studies have examined the role of suppressive intravaginal metronidazole for the prevention of recurrence. The first, a randomized placebo-controlled trial of a 4 month course of vaginal metronidazole gel, demonstrated a 32% reduction in the number of recurrent episodes of bacterial vaginosis by 28 weeks in the 0.75% metronidazole gel group as compared to the placebo group (HRR: 0.68, 0.49–0.93, P = 0.02).13 The second, a randomized, placebo-controlled trial of episodic intravaginal metronidazole failed to show a difference in recurrence frequency between groups.14 However, among HIV uninfected women, treatment with vaginal metronidazole was associated with restoration of normal vaginal flora. Both of these studies support the notion that repetitive use of the same product can successfully suppress the microorganisms associated with bacterial vaginosis.
Based on findings from this study, clinicians can counsel patients that retreatment with same topical medication offers a high likelihood of clinical cure and offer such treatment.
1. Koumans EH, Sternberg M, Bruce C, et al. The prevalence of bacterial vaginosis in the United States, 2001–2004; associations with symptoms, sexual behaviors, and reproductive health. Sex Transm Dis 2007; 34:864–869.
2. 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.
4. Bradshaw CS, Morton AN, Hocking J, et al. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis 2006; 193:1478–1486.
5. Livengood CH 3rd, McGregor JA, Soper DE, et al. Bacterial vaginosis: Efficacy and safety of intravaginal metronidazole treatment. Am J Obstet Gynecol 1994; 170:759–764.
6. Voorspoels J, Casteels M, Remon JP, et al. Local treatment of bacterial vaginosis with a bioadhesive metronidazole tablet. Eur J Obstet Gynecol Reprod Biol 2002; 105:64–66.
7. Beigi RH, Austin MN, Meyn LA, et al. Antimicrobial resistance associated with the treatment of bacterial vaginosis. Am J Obstet Gynecol 2004; 191:1124–1129.
8. Amsel R, Totten PA, Spiegel CA, et al. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations. Am J Med 1983; 74:14–22.
9. Eschenbach DA. Bacterial vaginosis: Resistance, recurrence, and/or reinfection? Clin Infect Dis 2007; 44:220–221.
10. Hillier SL, Lipinski C, Briselden AM, et al. Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol 1993; 81:963–967.
11. Schwebke JR, Desmond RA. A randomized trial of the duration of therapy with metronidazole plus or minus azithromycin for treatment of symptomatic bacterial vaginosis. Clin Infect Dis 2007; 44:213–219.
12. Yen S, Shafer MA, Moncada J, et al. Bacterial vaginosis in sexually experienced and non-sexually experienced young women entering the military. Obstet Gynecol 2003; 102:927–933.
13. Sobel JD, Ferris D, Schwebke J, et al. Suppressive antibacterial therapy with 0.75% metronidazole vaginal gel to prevent recurrent bacterial vaginosis. Am J Obstet Gynecol 2006; 194:1283–1289.
14. Taha TE, Kumwenda NI, Kafulafula G, et al. Intermittent intravaginal antibiotic treatment of bacterial vaginosis in HIV-uninfected and -infected women: A randomized clinical trial. PLoS Clin Trial 2007; 2:e10.