Reichman, Orna MD*; Akins, Robert PHD†; Sobel, Jack D. MD*
From the Division of Infectious Disease, *Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan; and †Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan
Correspondence: Jack D. Sobel, MD, Division of Infectious Diseases, Harper University Hospital, 3990 John R – 5 Hudson, Detroit, MI 48201. E-mail: email@example.com.
Received for publication March 11, 2009, and accepted May 12, 2009.
Background: Recurrent bacterial vaginosis (RBV) is extremely common and a source of frustration to patient and practitioners alike. In the absence of curative therapy, practitioners resort to retreating each individual episode. It has been suggested that vaginal biofilm in BV facilitates persistence of bacterial pathogens. Accordingly, topical boric acid (BA) aimed at biofilm removal was added to nitroimidazole induction and maintenance therapy creating a triple phase regimen to reduce symptomatic recurrence of BV in high-risk patients.
Method: Uncontrolled, nonrandomized, retrospective chart review of patients with RBV treated with 7 days of oral nitroimidazole; followed by 21 days of intravaginal BA 600 mg/day and if in remission treated with metronidazole gel twice weekly for 16 weeks. Outcome was determined using Amsel criteria.
Results: Fifty-eight women were treated for a total of 77 episodes of RBV. Sixty episodes of BV were available for a follow-up evaluation 4 to 12 weeks after enrollment, having completed both nitroimidazole and BA therapy and before initiating vaginal metronidazole gel. Cure after nitroimidazole and BA therapy ranged from 88% to 92%, 7 and 12 weeks after the initial visit, respectively. Cumulative cure at 12, 16, and 28 weeks from initial visit was 87%, 78%, and 65%, respectively. A failure rate of 50% was documented by 36 weeks of follow-up. No adverse effects of BA were observed.
Conclusion: Clinical experience with a triple phase maintenance regimen for women with RBV was encouraging but requires validation in a prospective randomized controlled study.
Bacterial vaginosis (BV) is the most common vaginal infection worldwide and in addition to vaginal symptoms is responsible for multiple complications.1–3 Although antimicrobial therapy selected with anaerobic activity, is effective short term in relieving symptoms, BV is associated with high posttreatment recurrence rates (30% in 3 months) responsible for enormous patient frustration.4–8 In 2006, Sobel et al. reported a long-term maintenance antimicrobial regimen of twice weekly vaginal metronidazole 0.75% gel which although not curative, resulted in reduced BV recurrence on therapy.7 Unfortunately, this suppressive regimen was still accompanied by a disappointing recurrence rate when the maintenance regimen was discontinued. We concluded that the high recurrence rate was in part a manifestation of relapse due to persistence of vaginal bacterial pathogens. Shortly thereafter, a BV - specific biofilm showing Gardnerella vaginalis adherent to epithelial cells and potentially protected from the antibacterial effects of metronidazole was reported.9,10 We postulated, that addition of intravaginal topical boric acid (BA) to the antimicrobial regimen might facilitate biofilm removal and enhance the eradication of G. vaginalis and other potential bacterial pathogens and result in reduced recurrence of symptomatic BV. This manuscript reports our experience with a moderate number of women with recurrent bacterial vaginosis (RBV) treated with an initial induction regimen of an oral nitroimidazole followed by sequential topical BA and finally metronidazole gel therapy with long-term follow-up.
MATERIALS AND METHODS
Women with recurrent BV were seen at the Wayne State University Vaginitis Clinic, Detroit, Michigan. RBV was defined as a history of at least 3 episodes of BV in the 12 months before enrollment. At the time of enrollment, all patients had florid symptomatic BV based on the clinical diagnosis of Amsel criteria with malodorous discharge and presence of >20% clue cells.11 Because these patients were symptomatic and our standard of care would involve maintenance metronidazole gel, they were offered the potential benefit of BA as an added component to their therapy. BA is a frequently administered intravaginally to treat vaginal candidiasis and hence was not considered an experimental agent. Accordingly, patients were given a prescription of either metronidazole or tinidazole, 500 mg bid for 7 days followed by nightly intravaginal insertion of a gelatin capsule containing 600 mg of BA for 21 days. Patients were given the option of delaying the aforementioned first 2 phases of therapy until after their next menses, so as not interrupt nightly BA therapy as a result of menstrual flow, tampons, etc. Hence the first follow-up visit could occur as early as 4 weeks after the enrollment visit but could occur as late as 8 and even 10 weeks after enrollment. Patients were encouraged to return for follow-up within 1 week of completing the BA regimen. Patients were evaluated at each visit by history, physical examination, measurement of vaginal pH, amine test, saline and 10% potassium hydroxide microscopy, and yeast culture.
At the first follow-up visit (visit 2), any patient with BV identified by the presence of at least 3 of 4 Amsel criteria and regardless of symptoms was categorized as a failure. Asymptomatic patients and without BV (<3 Amsel criteria) were prescribed intravaginal 0.75% metronidazole gel twice weekly for 2 to 3 months and asked to return for follow-up evaluation in 3 months or at any time in the presence of vulvovaginal symptoms.
Clinical and laboratory evaluation at visit 3 (2–3 months) was identical to that described earlier. Patients with BV were dropped from study and those in remission received a further prescription of twice weekly metronidazole gel for an additional 2 months. Identical assessment was undertaken during visit 4 at 6 months at the end of suppressive antibacterial therapy. Asymptomatic patients in remission were asked to return for further evaluation after additional 3 and 6 months of observation.
Any patient defined as a failure at visit 2 or subsequently, presenting with breakthrough BV at anytime during the induction or maintenance phases or after cessation of treatment, was offered the opportunity to reenter the study commencing once more with induction oral nitroimidazole therapy. Vaginal yeast cultures were obtained at each visit. Review of patient records was performed after obtaining Wayne State University Institutional Review Board approval.
A total of 77 episodes of BV were treated in 58 women over a 4-year period from February 2004 until January 2008. All patients met the definition of RBV and several had previously been enrolled in a maintenance suppressive study.7 Of the 58 women, 41 (71%) were black, 9 women (15%) were white, 1 Hispanic and 7 women (12%) were without documentation of race. The mean age was 32.7 years (range: 25.9–39.5).
Of 58 women treated with an oral nitroimidazole followed by boric acid, 45 women were treated for a single episode of BV, 7 women had 2 BV episodes and 6 women experienced and were treated with both modalities for 3 episodes of BV. Of the 77 episodes of BV, 12 episodes were first evaluated only after 13 weeks, 1 had incomplete data, and 4 were first evaluated while already on maintenance and were excluded from initial 12-week evaluation. Hence 60 episodes of BV were available for a follow-up evaluation 4 to 12 weeks after enrollment, having completed both nitroimidazole and BA therapy and before commencing maintenance vaginal metronidazole gel maintenance therapy. Forty-four women with a total of 49 episodes of acute BV were evaluated up to 7 weeks after enrollment. Cure was achieved in 45 episodes (92%). When all 60 episodes of BV in 51 women were evaluated at 12 weeks, 53 of 60 (88%) were cured, hence the cure rate of BV after nitroimidazole and BA therapy only ranged from 88% to 92% depending on the time evaluated from initial visit.
Fifty women experiencing 57 episodes of BV also received topical vaginal metronidazole gel for an intended maintenance period of 4 to 5 months. The 57 episodes were composed of the previous 53 episodes that achieved remission plus the addition of 4 episodes in women who had completed oral nitroimidazole followed by BA but were seen first while on maintenance metronidazole gel. Eight women failed to return for a follow-up visit while on the maintenance regimen. Among the remaining 49 episodes, cure at 6 months, corresponding to the completion of the maintenance metronidazole gel period, occurred in 34 of 44 (77.3%), 5 episodes were lost to follow-up at 6 months but were cured when last seen.
Figure 1 presents the cumulative proportion of women remaining free of BV for the total 60 episodes of acute BV evaluated after BA therapy. The cumulative proportion of cure after 12, 16, and 28 weeks from initial visit was 87%, 78%, and 65%, respectively. A failure rate of 50% was documented by 36 weeks (9 months) of follow-up. During the follow-up period 20 episodes were lost to follow-up (11 during the first 16 weeks, 3 between 16 and 28 weeks, and the rest after 28 weeks), all of them were cured when last seen. No adverse reactions were reported during BA vaginal therapy.
At the outset, we emphasize the limitations of this uncontrolled, pilot, single-center experience. Treatment was unblinded, lacked a control agent or placebo, and also lacked a rigid evaluation time. Furthermore, loss to follow-up over 12 months was not inconsiderable. The treatment regimen was derived from the frustration of women with severe RBV, often having already failed a previous protocol of maintenance metronidazole gel alone and the knowledge that no new antibacterial agents or strategies were available, as is the case today.
The use of BA was based upon the clinical observation of one of the investigators (J.D.S.) who used BA in combination with metronidazole in women with mixed infections of BV and Candida glabrata. Posttreatment interrogation was associated with a striking subjective patient sense of improvement, and objective clinical examinations of reduced or absent vaginal secretions and finally the relative absence of bacterial flora on saline microscopy of vaginal swab specimens. The recently reported presence of a vaginal biofilm in women with BV containing persistent G. vaginalis microorganisms adherent to epithelial cells led to our hypothesis that BA might influence the biofilm and enhance the antibacterial effect of conventional therapy.9,10 The biofilm reported was not found in healthy women without BV.10 BA is not effective as monotherapy (personal observation) nor was it used as an antibacterial agent in this study. We hypothesized that BA might remove bacterial mucus or biofilm and in so doing would remove pathogens able to escape the antibacterial effect of the nitroimidazole agents. A recent study investigating the in vitro activity of BA found a considerable inhibitory effect on prokaryotic organisms which could additionally contribute to the favorable results in our current study.12
It would be inappropriate to compare clinical efficacy of this triple phase regimen with previous studies even those involving a similar maintenance regimen.7 Study populations differed as did induction regimens, follow-up points, and duration of therapy, nevertheless some comparison may be reasonable. Early response at first follow-up visit after sequential induction therapy revealed failure in 8% in the current study which is similar to the 12% with metronidazole gel induction, both impressive outcomes.7 Breakthrough infections during metronidazole gel maintenance therapy was approximately 12% in the current study and 25% in the non BA study.7 Finally, late recurrence was 66% by 28 weeks in the previous study and approximately 45% at 32 weeks in the current study.
In summary, use of BA in combination with a nitroimidazole produced encouraging results, has a low cost, and a good safety profile. A prospective, randomized, masked multicenter comparative study incorporating BA into treatment seems reasonable. The therapeutic benefit of BA might be enhanced by administering BA simultaneous with oral nitroimidazole therapy rather than following the latter to facilitate exposure of exposed bacteria to the antimicrobial. This conclusion is particularly pertinent given the absence of alternative drugs or regimens to treat women with RBV.
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