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Maintenance Fluconazole Therapy for Recurrent Vulvovaginal Candidiasis

Background: There is no current long-term treatment for recurrent vulvovaginal candidiasis that is safe, convenient, and effective.

Objective: To determine if a regimen of fluconazole could prove to be the first safe and convenient regimen that is effective in preventing recurrent vulvovaginal candidiasis.

Methods: The study consisted of three parts. Patients who meet the inclusion and exclusion criteria of the study were knowingly given 150 mg of Diflucan every 72 hours orally for 9 days and were evaluated after 14 days. All patients had a vaginal examination and fungal culture and were eligible to continue if found to be cured of vulvovaginal candiasis. The next part of the study represented a double-blind, randomly assigned placebo controlled trial. The eligible patients were randomly assigned to receive Diflucan or placebo for 6 months. In the final phase patients were given no treatment for 6 months. The inclusion criteria were: age >18, active, acute candida vaginitis with a total severity score of 3 or more, a positive microscopical examination of vaginal secretions with 10 % potassium hydroxide, and 4 or more documented episodes of candida vaginitis in the previous 12 months. The exclusion criteria were: microscopical findings not confirmed by culture, pregnancy, mixed infections, HIV, and use of antifungal agents in the previous 2 weeks. 494 patients with acute symptomatic vulvovaginal candidiasis with a history of recurrent vulvovaginal candidiasis were initially enrolled. 387 women were randomly assigned to receive 150 mg of Fluconazole or the placebo weekly for 6 months. The study measured the proportion of women in clinical remission at the end of six months of therapy, mycologic outcome (i.e. fungal culture) at 6 months, and the results of clinical and mycologic examinations given monthly during the first 6 months and at 9 and 12 months during the observation phase. The power of the study was 80% with a two-sided alpha level of 0.05. A modified intent-to-treat-analysis was used.

Results: At six months 128 of 141 patients in the fluconazole group did not have clinical recurrence, while 51 of 142 patients in the placebo group did not have clinical recurrence. 13 of 141 patients in the fluconazole group and 91 of 142 patients in the placebo group showed symptomatic vulvovaginal candidiasis. This is a significant difference with p < 0.001 with a RR of 2.53 with a 95% confidence interval of 2.02 to 3.17. At 12 months 54 of 126 in the fluconazole group were cured while 30 of 137 in the placebo group where clinically cured. This is a significant difference with p < 0.001. The median time to clinical recurrence in the fluconazole group was 10.2 months and 4.0 months in the placebo group. This is a significant difference with p < 0.001. At 6 months 25 patients in the fluconazole group had at least 1 positive vaginal culture while 94 patients in the placebo group did. Mycologic eradication or suppression was documented in 82.1% of the fluconazole group and 28.2% of the placebo group. This was significant with p< 0.001. At 12 months 36 patients in the fluconazole group and 21 patients in the placebo group had negative cultures, which was a significant difference (p<0.02). The median time to mycologic relapse was 8.4 months in the fluconazole group and 1.9 months in the placebo group. This represented a significant difference with p < 0.001. The author concluded that fluconazole is a safe and convenient prophylaxis for recurrent candida vaginitis, but it is unable to retain its effect in many patients in the long term as illustrated by the significant increase in the rate of patients experiencing recurrance shortly after completing 6 months in the fluconazole group.

Strengths: The authors thoroughly discussed the study purpose and explained why Diflucan may be advantageous to other drugs. An appropriate design was used to get only patients who had recurrent candida into the study. Also the results were presented well and backed up with appropriate statistical tests.

Weaknesses: The study did not clearly state where the patients came from. Pfizer, which produces Diflucan, helped to fund the study, which could cause a bias in the results. It is difficult to understand the reasons different people withdrew from the study, because this information is touched on in so many different places in the study. There was no measure of compliance in the study. The study did not account for other factors that may be predisposing patients to recurrent infections.

Conclusions: Fluconazole is an excellent drug for prophylaxis of vulvovaginal candidiasis for a six month time period, but once treatment is stopped, there is a high rate of recurrence after this point. Its safety and convenience makes it an option to use for prophylaxis in women that have problems with this condition. However, its lack of long term efficacy and the hassles of once weekly dosing for long time periods may negate the benefits seen in some women. Therefore, it still may be more beneficial and effective to treat the individual infections as they happen. I believe this regimen may be useful in people having a very difficult time with this condition making it unreasonable to try to treat individual infections that come up. Opportunities exist to conduct future trials that may further define this drug’s role in therapy. A trial could be developed in which the treatment could be given over a longer period of time. Also different regimens of fluconazole could be used in future trials. For example, it could be given in a higher dose or be given more often than once a week.

Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance Fluconazole Therapy for Recurrent Vulvovaginal Candidiasis. The New England Journal of Medicine 2004 Aug;351:876-83.

William S. Kehayes, Pharm D Candidate