Shelby Brigman, Mercer University College of Pharmacy
Bacterial vaginosis (BV) is characterized by vaginal malodor and increased white discharge. It is suggested in Phamacotherapy: a Pathophysiologic Approach that BV increases the risk of acquiring other genital infections such as chlamydia, gonorrhea, and trichomoniasis. Comparatively, vulvovaginal cadidasis (VVC) produces vaginal pruritus, burning, and irritation without malodor or increased discharge and commonly occurs in women with uncontrolled diabetes, debilitation, immunosuppression, or pregnancy.1
The United Kingdom national guideline for the management of recurring BV suggests using suppressive 0.75% metronidazole vaginal gel twice weekly as well as a daily probiotic. However, it is noted that receiving metronidazole has shown an increase in development of VVC.2 In guidelines on the management of vaginal discharge in non-genitourinary medicine settings, it is noted that evidence for other regimens for recurrent BV besides metronidazole gel is lacking. These guidelines also recommend an induction and maintenance treatment for up to six months for recurrent VVC. It is suggested that combined hormonal contraceptives increase the risk for recurrent VVC and switching to an alternative contraceptive method is recommended. The same is noted for recurrent BV and copper-bearing intrauterine devices.3
|Title: Randomized Trial of Periodic Presumptive Treatment With High-Dose Intravaginal Metronidazole and Miconazole to Prevent Vaginal Infections in Human Immunodeficiency Virus (HIV)-negative Women4|
|Design||Randomized, double-blind, placebo-controlled trial; N = 234|
|Objective||To test the efficacy of a novel regimen to prevent recurrent vaginal infections|
|Study Groups||Each group received either (1) intravaginal suppositories containing metronidazole 750 mg with miconazole 200 mg (n = 118) or (2) matching placebo suppositories (n = 116).|
|Methods||At screening, women had to have a vaginal infection including one or more of the following: bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), or Trichomonas vaginalis (TV). During screening, a pelvic exam including collection of genital specimens and a blood test for HIV were completed. Participants were allocated into treatment arms in a 1:1 ratio. Participants received a month-supply kit at each monthly visit. Each treatment arm was continued for five consecutive nights per month over a 12-month period. At each visit, tests were done for HIV, herpes simplex virus (HSV2), BV, TV, and VVC. BV was diagnosed based on a Nugent’s score greater than seven, and VVC was diagnosed based on the presence of both yeast forms on wet mount microscopy and a positive yeast culture. Presence of TV was tested using wet mount microscopy to identify budding yeast or hyphae.|
|Duration||April 2011 – August 2012|
|Primary Outcome Measure||Proportions of visits with BV or VVC, regardless of symptoms|
|Baseline Characteristics||The study arms were well balanced in terms of demographic, behavioral, obstetrical, medical, and laboratory characteristics with one exception; the few women who were not African or African American (N = 5) were all randomized to the control arm (p = .05). At enrollment, 82 (35.0%) participants had BV, 32 (13.7%) had VVC, and 16 (6.8%) had TV infection by NAAT. Eleven (4.7%) participants had more than one type of vaginal infection.|
|Results||Monthly treatment with intravaginal metronidazole plus miconazole reduced the relative risk of BV by Nugent’s criteria by 35% compared to placebo (RR 0.65, 21.2% occurrence on treatment vs. 32.5% placebo, p = 0.005).In contrast, the risk of VVC did not differ in the intervention versus placebo arm (RR 0.92, 10.4% occurrence on treatment vs. 11.3% placebo, p = 0.7). Overall, the risk of any vaginal infection (BV, VVC, or TV) was lower in the intervention arm compared to the placebo arm (RR 0.70, 32.6% occurrence on treatment vs. 46.5% placebo, p = 0.001).|
|Adverse Events||Common Adverse Events: upper respiratory tract infections (34%), vulvovaginal pruritis (31%), vaginal discharge (23%), headache (20%), back pain (18%), urinary tract infection (12%), vulvovaginitis (16%), respiratory tract infection (12%)|
|Serious Adverse Events: In the intervention arm, serious adverse events included a ruptured ectopic pregnancy (n = 1), soft tissue injuries in a motor vehicle accident (n = 1), and hospitalization for malaria (n = 1) and typhoid fever (n = 1). In the placebo arm, there was a pelvic fracture in a motor vehicle accident (n = 1). None were related to the study drug.|
|Percentage that Discontinued due to Adverse Events: none reported|
|Study Author Conclusions||Monthly treatment with five nights of intravaginal metronidazole 750 mg plus miconazole 200 mg significantly reduced the risk of BV, including both symptomatic and asymptomatic cases, compared to placebo during one year of presumptive treatment. A significantly lower rate of vaginal discharge was reported in intervention compared to control participants. This intervention did not produce the hypothesized reduction in VVC, despite including 200 mg of miconazole in each vaginal suppository.|
Strengths of this study include the design and the rate of retention of study participants. Due to the diversity of populations of women studied, the trial is highly generalizable. However, in order to maintain statistical power at 80%, the study required 117 participants in each study arm. Only 105 women in the treatment arm and 112 in the placebo arm completed the study all the way through to the end due to early discontinuations or being lost to follow-up. The study authors also noted that regimens for VVC are also typically dosed weekly, and that the dosing regimen may
1.) Marrazzo JM, Holmes KK. Sexually Transmitted Infections: Overview and Clinical Approach. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1130&Sectionid=79734209. Accessed June 02, 2015.
2.) Clinical Effectiveness Group, British Association for Sexual Health and HIV (BASHH). National guideline for the management of bacterial vaginosis. London (UK): British Association for Sexual Health and HIV (BASHH); 2012. 15 p.
3.) Faculty of Sexual and Reproductive Healthcare (FSRH), British Association for Sexual Health and HIV (BASHH). Management of vaginal discharge in non-genitourinary medicine settings. London (UK): Faculty of Sexual and Reproductive Healthcare (FSRH); 2012. 28 p.
4.) Mclelland SR, Balkus JE, Lee J, et. al. Randomized Trial of Periodic Presumptive Treatment With High-Dose Intravaginal Metronidazole and Miconazole to Prevent Vaginal Infections in HIV-negative Women. J Infect Dis. 2015;211(12):1875-1882. doi: 1093/infdis/jiu818