Treatment Considerations for Bacterial Vaginosis and the Risk of Recurrence

Abstract

Background:

Recommended regimens for the treatment of bacterial vaginosis (BV) have similar efficacy; thus, the choice of treatment should consider additional factors such as risk of BV recurrence and side effect profile. The purpose of this study was to investigate BV recurrence rates and rates of acquiring vulvovaginal candidiasis (VVC) after different BV treatments in a commercially insured population.

Methods:

Private administrative insurance claims from 2004 to 2006 were used. Study subjects were continuously enrolled females 12–50 years of age who filled prescriptions for BV treatment (n = 32,268). The four BV treatments (single-dose clindamycin vaginal cream (2%), multiple-dose clindamycin vaginal regimens, vaginal metronidazole, and oral metronidazole) were compared for rates of recurrent BV and VVC after treatment using multivariate analyses. Covariates included sociodemographic and clinical characteristics.

Results:

Overall, the rate of BV recurrence (2.7%), and VVC posttreatment (2.9%) were low. Women who were treated with single-dose clindamycin vaginal cream (2%) showed no significant difference from women treated with oral metronidazole in the likelihood of BV recurrence. However, women who received other vaginal treatments were significantly more likely to experience BV recurrence compared with women who received oral metronidazole (p < 0.01). Moreover, women who were treated with single-dose clindamycin vaginal cream (2%) and vaginal metronidazole were significantly less likely to have VVC compared with those treated with oral metronidazole (p < 0.01).

Conclusions:

This study suggests that single-dose clindamycin vaginal cream (2%) may be a good alternative to oral metronidazole for the treatment of BV, given the low rates of recurrence and subsequent VVC demonstrated in this analysis.

Introduction

Bacterial vaginosis (BV) is a highly prevalent condition affecting almost one third of reproductive women in the United States at some point in their lifetime.¹ It is the most common cause of vaginal irritation, more common than either vulvovaginal candidiasis (VVC) or trichomoniasis.^1,2 BV has been associated with many untoward reproductive sequelae, including spontaneous abortion, preterm labor and birth, postpartum endometritis, acquisition and transmission of numerous sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV) and pelvic inflammatory disease (PID), infections after gynecological surgeries, and urinary tract infections (UTIs).^1,2 In addition, a recent prospective study demonstrated that women treated for asymptomatic BV were less likely to acquire STDs.³ Thus, effective treatment regimens that minimize the risk for recurrence and are easily tolerated, with fewer side effects, are critically important.

Recommended treatments for BV include both intravaginal and oral formulations of the antibiotics clindamycin and metronidazole.² As current BV treatment regimens are reported to have similar initial clinical cure rates,^4

–8 the choice of treatment should also consider such factors as patient's preference of the route of administration, frequency of administration, and side effect profile. The recurrence rate of BV in the year after treatment has been reported to be as high as 58%.⁹ As the risk of recurrence may be related to the antimicrobial activity of the drug, this is another important determinant in the selection of BV treatment.

Intravaginal antimicrobial treatments for BV may be more advantageous than oral therapies because of less gastrointestinal side effects, such as nausea, vomiting, and taste aversion.^7,8 However, many women may dislike the inconvenience of repeatedly administering intravaginal therapy, leading to a negative impact on treatment compliance.⁴ Thus, an equally effective single-dose clindamycin vaginal cream may be beneficial for women who prefer vaginal treatments, as it has been demonstrated to improve compliance and tolerability.⁴

Little is known about the BV recurrence rate using different antimicrobial therapies. In addition, although antimicrobial treatment is a well-known risk factor for acquiring VVC,^10,11 no study to date has examined the risks of acquiring VVC after various antimicrobial treatments for BV. The purpose of this study was (1) to investigate the rates of BV recurrence after treatment using different antimicrobial therapies and (2) to assess the differential risk of acquiring VVC after use of these same standard BV antimicrobial therapies in a commercially insured population.

Materials and Methods

Administrative claims data were used from private insurers and large employers encompassing both fee-for-service and managed care health plans, covering approximately 8 million member lives across the southern, western, and midwestern United States between January 1, 2004, and December 31, 2006. Membership and health plan eligibility information were linked to claims from inpatient, outpatient, professional, pharmacy, emergency department, and ancillary sources. Data elements drawn from these databases included member demographics (age, gender, residence region, and enrollment), service dates, setting of the care episode (outpatient, inpatient, professional, or emergency care), diagnosis codes, procedure codes, and prescription medications dispensed or administered (date filled, days supplied, dosage, drug name, and therapeutic class).

Subject selection

Female health plan participants aged 12–50 years who filled one of the following prescriptions for treatment of BV: (1) single-dose clindamycin vaginal cream (2%), (2) multiple-dose vaginal clindamycin, (3) vaginal metronidazole, and (4) oral metronidazole were considered eligible as study subjects. Because oral metronidazole can be used for other reasons besides treatment of BV, a filled prescription of oral metronidazole was paired with the diagnosis of vaginitis and vulvovaginitis (ICD-9 CM code 616.10) in the 0–7 days preceding the prescription. Of note, oral clindamycin was not included in this analysis because of its common use for treatment of nonvaginitis conditions and the infrequency of its use for BV (<1%).¹² The index date was defined as the date the prescriptions were filled.

To accurately assess the baseline clinical characteristics and outcome of interest (e.g., recurrent BV) and ensure the completeness of the data, the study included only patients who were continuously enrolled in the health plan for both medical and pharmacy benefits for 52 weeks before and 28 weeks after the index date. The study excluded patients who had a diagnosis of or treatment for HIV or acquired immune deficiency syndrome (AIDS); had other infectious causes of vulvovaginitis, including trichomonal vaginitis, gonorrhorea, or Chlamydia, at any time during the 0–28 weeks after the index date; and were pregnant during the 52 weeks prior to the index date. In addition, patients who filled more than a 7-day supply of oral metronidazole (n = 1,342), vaginal metronidazole (n = 1,545), or multiple-dose vaginal clindamycin treatments (n = 320) and patients who filled more than a 1-day supply of single-dose vaginal clindamycin (2%) (n = 290) were excluded from the analyses. We excluded the women who filled more days of medication than indicated to minimize the possibility that taking more than the usual indicated course of the medication was a factor in preventing BV recurrence and to enable a fair comparison of the single-dose vaginal clindamycin (2%) with other therapies. After application of these inclusion and exclusion criteria, the study sample to assess BV treatment failure (i.e., treatment for BV in the first 3 weeks postindex date) was 32,268 women. To assess recurrent BV (i.e., treatment for BV in the 4–28 weeks postindex date), women who failed BV treatment in the first 3 weeks postindex were excluded from the analysis (n = 140), and the final sample size was 32,128. To assess the likelihood of acquiring VVC after BV treatment, women who were diagnosed or treated for VVC 0–7 days prior to the index date were excluded from the analyses (n = 2,611); the sample size for this cohort was 29,657.

Dependent variables

The outcomes of interest in this study were BV treatment failure, recurrent BV, and occurrence of VVC at 1–28 weeks after the index date. BV treatment failure and recurrent BV were defined as filling a vaginal or oral prescription for BV therapy in the first 3 weeks postindex date and 4–28 weeks postindex date, respectively.¹³ Again, for the prescription of oral metronidazole to count as treatment of BV, the diagnosis of vaginitis (ICD-9 code 616.10) had to be present in the 0–7 days preceding the prescription. The occurrence of VVC post-BV treatment was assessed by ICD-9 diagnosis code 112.1.

Main independent variables

The main independent variables of interest were four BV treatments: (1) single-dose clindamycin vaginal cream (2%), (2) multiple-dose vaginal clindamycin, (3) vaginal metronidazole, and (4) oral metronidazole. National drug codes (NDC) for these drug therapies were used to identify prescriptions in pharmacy claims.

Covariates

General covariates used in this study included age, median household income obtained by matching ZIP code to 2000 U.S. Census data, racial/ethnic composition of ZIP code obtained by matching with 2000 U.S. Census data (i.e., percent of whites living in the ZIP code), health plan region (south vs. other), Charlson Index, medication count, receipt of Papanicolaou test (Pap smear) in the baseline year, number of outpatient visits in the baseline year, and physician specialty (i.e., obstetrics/gynecology, other, or unknown specialty). The Charlson Index was calculated by a proprietary version of the Charlson algorithm specifically adapted for administrative datasets that has been shown to predict a variety of patient outcomes, including mortality, postoperative complications, length of stay, and hospital charges. A Charlson Index score of 0 indicates no comorbid diseases, and a higher score on the Charlson Index indicates a greater burden of comorbid diseases.^14,15 Medication count was measured by the total number of unique medication types (excluding study therapies) that each patient received during the baseline year. The receipt of Pap smear and number of outpatient visits in the baseline year were used as proxy measures for the likelihood of patients' healthcare use. Of note, the income measured is not an individual level variable. It is the median income of the community defined by the patient's ZIP code obtained using data published by the U.S. Census. Researchers often use area-based measure to estimate the effects of socioeconomic position and find it useful as a measure of community-wide characteristics and a strong predictor of health outcomes.^16

–19

The BV-specific covariates included history of recurrent BV, defined as having two or more episodes of BV in the year prior to the index date prescription. History of recurrent BV was controlled for because it was found to be highly significant in previous literature to predict the recurrence of BV.⁹ VVC-specific covariates include history of two or more episodes of VVC in the year prior to the index date, diabetes, any oral antibiotic use 1 month before index date, estrogen or estrogen-containing contraceptive use on the index date, and oral steroid use 2 months prior to the index date. Diabetes was defined among individuals with two or more claims of diabetes (ICD-9 diagnosis codes 250.xx, 357.2x, 362.0x, 366.41, 648.0x and DRG 294, 295) during the study period. Medications, such as antibiotics, contraceptives, and oral steroids, were captured using appropriate NDC codes. All the covariates were selected a priori based on literature review and expert opinions for their potential to predict recurrent BV or VVC.

Statistical analysis

Univariate descriptive statistics were calculated for variables of interest. Bivariate statistical tests (e.g., chi-square, ANOVA) were conducted between drug cohorts and outcomes. Multiple logistic regression models were used to examine the impact of drug therapies on BV treatment failure and BV recurrence while controlling for history of recurrent BV, age, community demographic and socioeconomic characteristics (i.e., median income, and ethnic composition), health plan region, comorbidity, healthcare use, medication burden, and physician specialty. A third multivariate logistic regression model was used to assess the impact of drug therapies on the occurrence of VVC after BV pharmacological therapy while controlling for history of recurrent VVC, age, community demographic and socioeconomic characteristics, health plan region, comorbidity, healthcare use, medication count, physician specialty, history of diabetes, antibiotic use 1 month before index date, estrogen or estrogen-containing contraceptive use on the index date, and oral steroid use 2 months prior to or on the index date. The results are presented as odds ratios (ORs) and p values.

Sensitivity analyses were conducted to confirm the robustness of the results. First, patients with VVC on the index date were included and then excluded in the study period to examine the impact of concurrent drug therapies for VVC on the recurrent BV in the study period of interest. Second, a Cox proportional hazard analysis was used to model the time to first event (i.e., recurrence of BV or occurrence of VVC after BV treatment). Third, to investigate the possibility that coding variation could contribute to the results, we defined BV treatment failure and recurrence using three other methods: (1) diagnosis of BV (i.e., ICD-9 diagnosis code 616.10) in a face-to-face visit in the outpatient setting, (2) diagnosis of BV in a face-to-face visit in the outpatient setting or the receipt of BV treatments, and (3) diagnosis of BV in a face-to-face visit in the outpatient setting, followed by receipt of BV treatment in the 0–7 days after the diagnosis. The results of all sensitivity analyses were consistent with the primary results presented herein. SAS proprietary software, release 9.1 (SAS Institute Inc., Cary, NC) and STATA (Statacorp, 2003, College Station, TX) were used for all statistical analyses.

Results

A total of 32,268 women were included in the claims study, and bivariate analyses revealed significant variation in almost all sociodemographic and clinical characteristics by drug cohorts (Table 1) and outcomes (Table 2). More women were prescribed metronidazole (vaginal, 48%; oral, 28%) for their index prescription compared with clindamycin (single-dose clindamycin vaginal cream (2%), 9%; multiple-dose vaginal clindamycin products, 15%) (Table 1). The mean age was 35. The median household income by ZIP code was $45,595 for the cohort, and women who were prescribed multiple-dose clindamycin had higher incomes on average ($47,912) than women who filled other BV treatments. Similarly, women who had BV treatment failure had higher incomes ($46,719) than women who did not (Table 2). Although 7% of women had two or more episodes of BV in the year previous to the index date, only 1% of women had two or more episodes of VVC in the same period (Table 1). Women who filled multiple-dose vaginal clindamycin prescriptions had the highest history of recurrent BV (10%) (Table 1).

Table 1.

Sociodemographic and Clinical Characteristics of Women Treated for Bacterial Vaginosis (BV)

Characteristic	Total (n = 32,268) (100%)	Single-dose vaginal clindamycin (n = 2,825) (8.8%)	Multiple-dose vaginal clindamycin (n = 4,871) (15.1%)	Vaginal metronidazole (n = 15,566) (48.2%)	Oral metronidazole (n = 9,006) (27.9%)
Demographic characteristics
Mean age (SD)^**	34.5 (9.6)	34.3 (9.4)	35.7 (9.5)	35.1 (9.5)	33.1 (9.8)
Median household income^a $ (SD)^**	$45,595 (15,457)	$45,579 (18,060)	$47,912 (16,231)	$45,091 (14,929)	$45,195 (15,043)
Percentage of whites (SD)^a,**	64.4 (27.2)	62.9 (26.3)	62.4 (28.7)	65.7 (26.5)	63.5 (27.8)
Region: South (%)^**	72.8	94.1	63.4	75.1	66.5
Healthcare utilization
Pap smear (%)^**	85.7	89.1	86.6	85.4	84.8
Mean number of outpatient visits (SD)^**	4.4 (4.4)	5.0 (4.6)	4.6 (4.7)	4.1 (4.1)	4.6 (4.8)
Mean medication count^b (SD)^**	5.8 (4.2)	6.5 (4.3)	5.9 (4.4)	5.5 (4.0)	6.1 (4.3)
Physician specialty^**
Obstetrics/gynecology (%)	35.5	44.3	38.0	33.5	35.1
Other specialty (%)	49.9	40.5	46.7	49.9	54.7
Missing (%)	14.6	15.2	15.3	16.6	10.2
Clinical characteristics
Charlson Comorbidity Index > 0 (%)^*	11.1	10.7	11.8	10.6	11.6
History of recurrent BV^c (%)^**	7.2	9.1	10.4	6.7	5.6
History of recurrent VVC^d (%)^**	1.4	1.4	1.4	1.1	1.7
Diabetes (%)	2.6	2.2	2.4	2.6	2.8
Antibiotic use (%)^**	13.6	12.9	15.9	13.2	13.2
Contraceptives (%)	23.9	24.7	24.1	23.8	23.5
Steroid use (%)	2.4	2.8	2.3	2.3	2.5

p < 0.05; ^** p < 0.01 using Pearson's chi-square test for categorical variables and ANOVA for continuous variables.

These were obtained by matching ZIP code with U.S. Census data; 8,631 members have missing ZIP code values.

Medication count was measured by the total number of unique medication types (excluding study therapies) that each patient received during the baseline year.

History of two or more episodes of BV in a year.

History of two or more episodes of vulvovaginal candidiasis (VVC) in a year.

Table 2.

Characteristics of Women with and without Bacterial Vaginosis (BV) Treatment Failure or Recurrence

Characteristic	BV treatment failure (n = 140) (0.43%)	BV recurrence (n = 873) (2.71%)	No BV treatment failure or recurrence (n = 31,255) (96.86%)
Antimicrobials received for BV treatment^**
Single-dose vaginal clindamycin cream (%)	10.0	9.1	8.7
Multiple-dose vaginal clindamycin treatments (%)	22.9	18.3	15.0
Vaginal metronidazole (%)	41.4	50.2	48.2
Oral metronidazole (%)	25.7	22.5	28.1
Demographic characteristics
Mean age (SD)^**	34.5 (9.8)	33.6 (9.0)	34.6 (9.6)
Median household income $ (SD)^a,**	46719 (17123)	46963 (16331)	45556 (15426)
Percentage of whites (SD)^a,**	70.9 (24.3)	60.4 (27.5)	64.5 (27.2)
Region: South (%)	70.7	74.7	72.7
Health care utilization
Pap smear (%)^*	78.6	85.3	85.8
Mean number of outpatient visits (SD)^**	5.2 (4.9)	4.8 (4.8)	4.4 (4.4)
Mean medication count^b (SD)^**	7.5 (4.9)	6.6 (4.8)	5.8 (4.2)
Physician specialty
Obstetrics/gynecology (%)	32.9	38.4	35.5
Other specialty (%)	52.9	49.1	49.9
Missing (%)	14.3	12.5	14.6
Clinical characteristics
Charlson Comorbidity Index > 0 (%)	13.6	10.7	11.1
History of recurrent BV^c (%)^**	19.3	21.3	6.7
History of recurrent VVC^d (%)^*	1.4	2.4	1.3
Diabetes (%)	1.4	2.6	2.6
Antibiotic use (%)^*	17.9	16.0	13.5
Contraceptives (%)	25.7	25.4	23.8
Steroid use (%)	4.3	2.2	2.4

p < 0.05; ^** p < 0.01 using Pearson's chi-square test for categorical variables and ANOVA for continuous variables.

These were obtained by matching ZIP code with U.S. Census data; 8,631 members have missing ZIP code values.

Medication count was measured by the total number of unique medication types (excluding study therapies) that each patient received during the baseline year.

History of two or more episodes of BV in a year.

History of two or more episodes of vulvovaginal candidiasis (VVC) in a year.

Overall, the rates of BV treatment failure (<1%), BV recurrence (2.7%), and VVC post-BV treatment (2.9%) were low (Table 3). Bivariate analyses showed significant variation with regard to BV treatment failure, BV recurrence, and VVC rates by treatment. Women who were treated with multiple-dose vaginal clindamycin products had the highest rate of treatment failure (0.6%) and BV recurrence (3.3%). Women treated with oral metronidazole had the highest rate of VVC post-BV treatment (3.6%).

Table 3.

Bacterial Vaginosis (BV) Treatment Outcomes by Antimicrobial Treatment

	Total	Single-dose vaginal clindamycin	Multiple-dose vaginal clindamycin	Vaginal metronidazole	Oral metronidazole
BV treatment failure^a,*	(n = 32,268) 0.43%	(n = 2,825) 0.50%	(n = 4,871) 0.66%	(n = 15,566) 0.37%	(n = 9,006) 0.40%
Recurrent BV^b,**	(n = 32,128) 2.72%	(n = 2,811) 2.81%	(n = 4,839) 3.31%	(n = 15,508) 2.82%	(n = 8,970) 2.19%
VVC^c,**	(n = 29,657) 2.94%	(n = 2,620) 2.37%	(n = 4,521) 3.07%	(n = 14,437) 2.65%	(n = 8,079) 3.58%

p < 0.05; **p < 0.01 using Pearson's chi-square test.

BV recurrence in the 1–3 weeks post-BV treatment.

BV recurrence in the 4–28 weeks post-BV treatment. Women with BV recurrence in the 1–3 weeks post-BV treatment were excluded in this analysis.

Vulvovaginal candidiasis (VVC) in the 0–28 weeks post-BV treatment (i.e., index date). Of note, women who were diagnosed or treated for VVC 0–7 days prior to index date were excluded from this analysis.

Multivariate analyses, using oral metronidazole as the reference drug, showed that there were no significant differences in the probability for treatment failure by BV therapies (Table 4). Significant predictors of BV treatment failure include prior history of recurrent BV. There were, however, differences observed in the probability for recurrent BV according to treatment therapies. Women who were treated with single-dose clindamycin vaginal cream (2%) showed no difference from women treated with oral metronidazole in the likelihood of BV recurrence. However, women who received multiple-dose vaginal clindamycin (OR 1.47, 95% CI 1.19-1.82, p < 0.001) or vaginal metronidazole (OR 1.36, 95 CI 1.14-1.61, p < 0.001) were significantly more likely to experience BV recurrence. Other significant predictors of BV recurrence include age, race area, sociodemographic measures, medication count, and prior history of recurrent BV. Of interest, middle-aged women (21–40 years) appear to have recurrent BV more after than younger or older women, and women who live in ZIP codes with higher percentages of minorities were significantly more likely to have recurrent BV.

Table 4.

Multivariate Logistic Regression Results of Bacterial Vaginosis (BV) and Vulvovaginal Candidiasis (VVC) Treatment Outcomes

	BV treatment failure OR (95% CI) (n = 32,268)	BV recurrence ^a OR (95% CI) (n = 32,128)	VVC ^b OR (95% CI) (n = 29,657)
Antimicrobial treatments (reference: oral metronidazole)
Single-dose vaginal clindamycin	1.26 (0.67-2.37)	1.19 (0.91-1.56)	0.66 (0.50-0.88)^**
Multiple-dose vaginal clindamycin	1.60 (0.99-2.59)	1.47 (1.19-1.82)^**	0.85 (0.69-1.04)
Vaginal metronidazole	0.97 (0.64-1.48)	1.36 (1.14-1.61)^**	0.79 (0.68-0.93)^**
Demographic and clinical characteristics and healthcare utilization
Age (reference 12–20 years)
21–30 years	1.13 (0.59-2.13)	1.52 (1.15-2.01)^**	1.15 (0.89-1.48)
31–40 years	1.14 (0.62-2.13)	1.31 (1.00-1.73)^*	0.94 (0.73-1.21)
41–50 years	0.88 (0.47-1.65)	0.94 (0.71-1.25)	0.89 (0.69-1.15)
Median income of ZIP code^c (reference: > $48,930)
<$36,930	0.92 (0.55-1.52)	0.82 (066-1.02)	0.95 (0.78-1.16)
$36,930–$48,930	0.90 (0.56-1.46)	1.07 (0.88-1.30)	0.83 (0.68-1.01)
% Whites in ZIP code^c (reference: > 83%)
< 60%	0.66 (0.40-1.10)	1.54 (1.24-1.90)^**	1.27 (1.04-1.56)^*
60%–83%	0.71 (0.44-1.15)	1.29 (1.04-1.59)^*	1.04 (0.85-1.28)
Missing ZIP code	0.82 (0.48-1.42)	1.63 (1.28-2.08)^**	1.33 (1.05-1.68)^*
Region: South	0.86 (0.57-1.31)	0.96 (0.80-1.15)	0.75 (0.63-0.88)^**
Receipt of Pap smear	0.59 (0.39-0.91)^**	0.91 (0.74-1.12)	1.48 (1.16-1.88)^**
Number of outpatient visits in 1 year (reference: 0–1)
2–5	1.01 (0.62-1.63)	0.84 (0.70-1.01)	1.14 (0.93-1.38)
>5	1.00 (0.57-1.75)	0.96 (0.77-1.20)	1.47 (1.17-1.85)^**
Number of distinct medications in 1 year (reference: 0–1)
2–5	1.17 (0.55-2.51)	1.46 (1.08-1.98)^*	0.85 (0.66-1.10)
>5	1.85 (0.84-4.09)	1.64 (1.18-2.26)^**	0.92 (0.70-1.22)
Treating physician specialty (reference: other specialty)
Obstetrics/gynecology	0.94 (0.64-1.37)	1.08 (0.93-1.25)	1.11 (0.96-1.30)
Missing specialty	0.93 (0.55-1.56)	0.85 (0.68-1.07)	1.16 (0.94-1.44)
Comorbidity	1.11 (0.67-1.84)	0.91 (0.73-1.15)	0.91 (0.72-1.16)
Recurrent BV	2.66 (1.71-4.12)^**	3.37 (2.83-4.02)^**	1.56 (1.25-1.94)^**
Recurrent VVC	–	–	4.69 (3.36-6.63)^**
Diabetes	–	–	0.92 (0.56-1.49)
Antibiotic use	–	–	1.09 (0.90-1.32)
Contraceptives	–	–	0.96 (0.82-1.14)
Steroid use	–	–	0.93 (0.59-1.45)

p < 0.05; ^** p < 0.01.

Women with BV recurrence in the 1–3 weeks post-BV treatment were excluded in this analysis.

VVC in the 0–28 weeks post-BV treatment (i.e., index date). Of note, women who were diagnosed or treated for VVC 0–7 days prior to index date were excluded from this analysis.

Income and percent whites were obtained by matching ZIP code with U.S. Census data and categorized into tertiles.

Differences were also observed in the likelihood of VVC occurrence according to treatment therapies. Women who were treated with single-dose clindamycin vaginal cream (2%) (OR 0.66, 95% CI 0.50-0.88, p < 0.01) and vaginal metronidazole (OR 0.79, 95% CI 0.68-0.93, p < 0.01) were significantly less likely to have VVC post-BV treatment compared with those treated with oral metronidazole, when controlling for covariates. The odds of VVC occurrence in women treated with multiple-dose vaginal clindamycin products did not differ significantly from those of women treated with oral metronidazole. Other significant predictors of VVC occurrence include race area, sociodemographic measure, region, utilization measures, and prior history of recurrent BV and VVC. Not surprisingly, although atypical and few in number (<1.4% of total study population), women with a history of two or more episodes of VVC in the past year were significantly more likely to experience VVC post-BV treatment.

Discussion

The similar likelihood for treatment failure across the treatment therapies observed in this study indirectly supports published findings that current BV treatments have similar initial clinical cure rates. However, the significant variations noted among the four treatment groups in the probability for recurrent BV and VVC occurrence at 4–28 weeks postindex treatment suggest that therapies may be differentiated from each other. This finding is relevant to both clinicians and patients when selecting which drug to prescribe and use in the management of BV.

This analysis demonstrates that women using single-dose clindamycin vaginal cream (2%) have a similar risk for BV recurrence to that of women treated with oral metronidazole even after controlling for important confounding factors, such as prior history of BV infection. Women treated with vaginal metronidazole or multiple-dose vaginal clindamycin were statistically more likely to have recurrent BV compared with women treated with oral metronidazole. This finding is supported by a recently published study, which showed single-dose vaginal clindamycin is more effective in reducing vaginal mobiluncus morphotypes than is vaginal metronidazle in patients with BV.⁵ In addition, women treated with single-dose clindamycin vaginal cream (2%) and vaginal metronidazole were less likely to have VVC in the 28 weeks posttreatment than women treated with oral metronidazole. Given the long-lasting effects of single-dose clindamycin, our data suggest that this new drug delivery system may have longer lasting beneficial effects on the vaginal flora. Further study is needed to investigate the microbiological effects of single-dose clindamycin on yeast colonization and infection rates.

Prior studies have suggested that single-dose clindamycin vaginal cream (2%) may cause fewer gastrointestinal side effects (i.e., nausea, vomiting, and taste perversion) and greater satisfaction when compared with oral antibiotic therapy^7,8,20 and improved compliance when compared with longer vaginal treatments.²¹ This investigation demonstrates that in addition to these benefits, single-dose clindamycin vaginal cream (2%) may be a good treatment option not only because of its similarity to oral metronidazole in the risk of BV recurrence (and lower risk than the other regimens) but also for its lower risk of posttreatment VVC when compared with oral metronidazole.

Notably, although in this study we could not measure the direct effect of race/ethnicity on BV recurrence, our findings, consistent with prior studies, suggest that minority populations were significantly more likely to have recurrent BV.¹ We also found that women who were more likely to use healthcare were also more likely to have complaints of VVC. This may be because VVC may be self-diagnosed and treated with over-the-counter (OTC) products by the patient. Thus, patients with VVC may be undercounted in this study.

It is acknowledged that the BV recurrence rate found in this study (2.72%) is substantially lower than the rates reported in studies that defined recurrence based on examination of the entire cohort of women using laboratory parameters.^9,22,23 Because in this study, BV recurrence is established by filled prescriptions for BV treatment, there may be some women who had BV recurrence but did not seek BV treatment. It is noteworthy, however, that despite the overall low rates based on the specific definition applied in this study, BV recurrence was documented and significant differences persisted across treatment therapies even after controlling for relevant confounding factors.

The etiology of recurrent BV is poorly understood, and there are many unproven theories. It is not clear whether BV recurs based on antibiotic failure to eradicate organisms, immune-mediated changes that predispose to recurrent BV, sexual partner reintroduction of pathogenic organisms, or failure of protective lactobacilli to recolonize. It is likely that all four of these possible explanations contribute to a predisposition for recurrence to varying degrees in different patients. It may also be hypothesized that diverse antimicrobial properties of the various agents used and the different mechanisms of therapeutic delivery (oral vs. vaginal dosing, prolonged release vs. immediate release of drug) may interface with the bacteria and inflammatory mediators in ways not completely understood to produce the differences in recurrence rates suggested herein. Nevertheless, BV recurrence is a challenging and highly understudied entity seen in clinical practice, and gaining an understanding of potential ways to minimize recurrence is an important undertaking. Thus, the findings in this investigation add to the small body of literature on this topic and deserve notice.

This study has some limitations. First, this study can only be generalized to women in the United States who have continuous commercial insurance coverage. Second, this is a claims-based analysis with certain potential biases, including coding variation between providers, imprecision of timing of symptoms, and missing data. However, to investigate the possibility that coding variation could contribute to the results, we defined BV treatment failure and recurrence using other methods, including BV diagnosis, BV diagnosis or filled prescription, and BV diagnosis code followed by filled prescription. We found that our results are consistent in our sensitivity analyses with these alternate definitions. Thus, we believe that the results presented are robust to coding variations. Third, there were important factors (e.g., race, education, smoking, sexual history, adherence to antimicrobials, self-treatment with OTC medication) that predict BV recurrence that are not available in administrative claims data and, thus, could not be controlled for in this study. Fourth, although we excluded women who filled more days of medication than indicated to minimize the possibility that taking more than the usual indicated course of the medication was a factor in preventing BV recurrence, this may be a source of bias. Lastly, as laboratory data confirming the diagnosis of BV or VVC were not available, it is possible that patients were misdiagnosed or miscoded. Nevertheless, administrative claims data have been used to effectively examine and document patterns of healthcare use,^24,25 detect opportunities to improve quality of care,²⁶ estimate incidence of disease,^27
–29 and even assess outcomes of pharmaceutical,³⁰ radiological,³¹ and surgical procedures,³² and thus provide useful and important insights.

In conclusion, women significantly differed in the risk of BV recurrence and VVC by BV treatments. In the discussion of BV treatment options with patients, healthcare providers should address not only the patients' preferred method of drug administration (oral vs. vaginal) and tolerance of side effects (e.g., gastrointestinal symptoms, posttreatment VVC) but also the risk of BV recurrence. This study demonstrates that single-dose clindamycin vaginal cream (2%) is similar to oral metronidazole and is superior to the other agents in terms of prevention of BV recurrence and, therefore, may be a good alternative to oral metronidazole, given its favorable side effect profile and lower risk of posttreatment VVC.

Footnotes

Acknowledgments

This study was funded by the Ther-Ex Corporation.

Disclosure Statement

The authors have no conflicts of interest to report.

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