Original Commodity

Maintenance Fluconazole Therapy for Recurrent Vulvovaginal Candidiasis

Listing of authors.
  • Jack D. Sobel, M.D.,
  • Harold C. Wiesenfeld, One thousand.D.,
  • Mark Martens, M.D.,
  • Penny Danna, One thousand.D.,
  • Thomas M. Hooton, K.D.,
  • Anne Rompalo, Yard.D.,
  • Malcolm Sperling, M.D.,
  • Charles Livengood, III, M.D.,
  • Benson Horowitz, M.D.,
  • James Von Thron, G.D.,
  • Libby Edwards, One thousand.D.,
  • Helene Panzer, Ph.D.,
  • and Teng-Chiao Chu, Ph.D.

Abstract

Background

No safety and convenient regimen has proved to exist effective for the management of recurrent vulvovaginal candidiasis.

Methods

Subsequently inducing clinical remission with open-label fluconazole given in three 150-mg doses at 72-hour intervals, we randomly assigned 387 women with recurrent vulvovaginal candidiasis to receive treatment with fluconazole (150 mg) or placebo weekly for six months, followed by 6 months of ascertainment without therapy. The primary outcome measure out was the proportion of women in clinical remission at the end of the start half-dozen-month period. Secondary efficacy measures were the clinical outcome at 12 months, vaginal mycologic status, and time to recurrence on the basis of Kaplan–Meier analysis.

Results

Weekly treatment with fluconazole was effective in preventing symptomatic vulvovaginal candidiasis. The proportions of women who remained disease-complimentary at 6, 9, and 12 months in the fluconazole group were 90.eight per centum, 73.2 percent, and 42.9 pct, every bit compared with 35.ix percent, 27.viii percent, and 21.9 percent, respectively, in the placebo group (P< 0.001). The median time to clinical recurrence in the fluconazole group was ten.2 months, as compared with four.0 months in the placebo grouping (P<0.001). There was no bear witness of fluconazole resistance in isolates of Candida albicans or of superinfection with C. glabrata. Fluconazole was discontinued in one patient because of headache.

Conclusions

Long-term weekly handling with fluconazole tin can reduce the rate of recurrence of symptomatic vulvovaginal candidiasis. However, a long-term cure remains difficult to achieve.

Introduction

Since recurrent vulvovaginal candidiasis is estimated to occur in 5 to eight percent of women during their reproductive years, millions of women worldwide are afflicted by the status.1-3 Not considered a typical sexually transmitted infection, recurrent vulvovaginal candidiasis affects immunocompetent, salubrious women in all strata of society.two,4 Although the status has several causes, the majority of women with recurrent infection have no recognizable risk factors.5,6 Frequent recurrences of symptomatic vulvovaginitis effect in considerable suffering and cost and have a markedly negative effect on sexual relations.7

Management approaches include treatment of each individual episode or use of prophylactic antimycotic measures. Previously, several rubber regimens were advocated that involved the utilize of intravaginal antimycotic agents either daily or weekly or oral ketoconazole daily for approximately half-dozen months.8-17 Although these measures were effective in reducing the rate of recurrence of vulvovaginal candidiasis, they were inconvenient and expensive, and oral ketoconazole was associated with an unacceptable adventure of hepatotoxic effects.eighteen The availability of fluconazole as a safety, oral antifungal agent with both a favorable spectrum of antifungal activity and favorable pharmacokinetics offered an opportunity to report the effectiveness of the drug for suppressive maintenance prophylaxis in patients with recurrent vulvovaginal candidiasis.19 Afterward oral administration of a single dose of 150 mg of fluconazole, concentrations of fluconazole above the minimal inhibitory concentration (MIC) that inhibits the growth of 90 percent of candida species isolates (MIC90) are achieved for 72 to 96 hours in vaginal tissue and secretions — an efficacy that allows for weekly assistants.20 Nosotros performed a multicenter, prospective, randomized study to evaluate the clinical and mycologic efficacy of weekly treatment with fluconazole equally compared with placebo in reducing the frequency of clinical episodes of recurrent vulvovaginal candidiasis. Investigators participating in the study are listed in the Appendix.

Methods

Patients and Protocol

The written report, which took place from 1998 to 2002, was reviewed by the institutional review boards of all participating centers. Written informed consent was obtained from each patient. Eligible patients were at least eighteen years old; had active, acute candida vaginitis (full severity score, ≥three); had had a positive result on microscopical examination of vaginal secretions with 10 percent potassium hydroxide; and had had at least four documented episodes of candida vaginitis in the previous 12 months. The severity score was based on the presence of symptoms (east.g., pruritus, irritation, and burning) and vulvovaginal signs (east.thousand., erythema, edema, and excoriation, or fissures) as previously described.21 The severity of each sign or symptom was scored on a scale of 0 (absent or normal) to iii (severe). The level of vulvovaginal discharge was not scored. Patients were excluded from the written report if the microscopical findings could non exist confirmed by culture. Other exclusion criteria were pregnancy, mixed infections, known seropositivity for the human immunodeficiency virus (HIV), and receipt of antifungal agents in the previous iv weeks.

Later enrollment in the open-label induction phase, all patients received three sequential 150-mg doses of fluconazole (Diflucan, Pfizer) orally at 72-hr intervals and were requested to render for evaluation xiv days after enrollment. Patients were prohibited from using topical vaginal or other systemic antifungal agents and topical vaginal steroids at whatever time during the report. They were as well prohibited from using antibiotics during the induction phase. At the first follow-up visit, patients underwent a vaginal test, which included obtaining vaginal swabs for fungal civilization. All patients who were classified as being clinically cured (severity score, <3) were eligible for random assignment to the placebo-controlled, double-blind, rubber phase of the study.21 Patients were randomly assigned on the footing of a ane:1 ratio to receive either a single oral, 150-mg dose of fluconazole or an oral placebo tablet weekly for half dozen months. Thereafter, patients were followed without treatment for six months (i.due east., the observation phase). Patients were to render for evaluation visits monthly during the maintenance stage and at months nine and 12 during the observation phase.

At each follow-up visit, a detailed clinical history was obtained, a pelvic exam was performed, and a vaginal fungal civilization was obtained. Patients were to discontinue the assigned study handling if they had a recurrence of vulvovaginal candidiasis, except in cases in which the results of microscopical examination with 10 percent potassium hydroxide and a vaginal fungal civilisation were negative. In such cases, the patient remained in the study until the next visit, at which time the study treatment was discontinued if the clinical outcome was still considered to be a recurrence or continued if the clinical outcome was a cure. The report treatment was likewise discontinued if in that location was an adverse reaction to the prescribed drug therapy.

At each visit, vaginal swabs were obtained for culture. On receipt of clinical isolates, swab specimens were placed on Sabouraud'south dextrose agar and subsequently identified at the species level with the use of the API 20C system (BioMerieux). The clinical isolates were stored at –70°C and transferred as a grouping to Wayne Country University Mycology Laboratory for conclusion of their in vitro susceptibilities. In vitro susceptibilities of fluconazole were determined by a broth microdilution test according to the National Commission for Clinical Laboratory Standards M27-A method.22 Liver-function tests were performed at study entry, on mean solar day 14, and after three and six months of maintenance therapy.

Statistical Analysis

Bold that fluconazole therapy had a clinical success rate of 80 percent, it was estimated that 91 patients in each treatment group who could exist evaluated would be required to detect a treatment difference of 20 percent, with 80 per centum power and a ii-sided blastoff level of 0.05. The modified intention-to-treat population included all patients who had been randomly assigned to receive at least one dose of the written report medication (administered in a double-blind way) and who underwent at to the lowest degree one efficacy evaluation after receiving the first dose of the report medication. The population that could be evaluated for the efficacy assay, defined at each visit, included all women who met the criteria for inclusion, had not missed two or more consecutive doses of the written report drug before the visit, had not taken any prohibited medication, and underwent clinical and mycologic evaluations within the appropriate time frame. A prophylactic analysis included all patients who had taken at least one dose of the study medication.

The primary end point was the proportion of women in clinical remission at the terminate of the maintenance period (i.e., after half-dozen months), with cure defined as a clinical severity score of less than 3, and recurrence divers as a clinical severity score of 3 or more plus vaginal cultures that were positive for yeast.21 A secondary end point was the mycologic outcome at six months (i.e., the status on the footing of fungal culture, regardless of the microscopical findings with the employ of 10 pct potassium hydroxide). Other variables that were assessed included the results of monthly clinical and mycologic examinations during the maintenance phase and at each of two visits during the half dozen-calendar month observation phase. Statistical comparisons of the study groups were made at the completion of maintenance therapy and at months 9 and 12 with the use of Fisher's exact examination or the Cochran–Mantel–Haenszel chi-square examination, every bit appropriate.

Fourth dimension-to-recurrence data were analyzed by the Kaplan–Meier method and compared with the use of the log-rank exam. A logistic-regression model was used to identify host or microbial factors that were associated with success or failure, including in vitro MIC information for baseline Candida albicans isolates. Data analyses were performed by two of the authors (Drs. Chu and Sobel); all authors had full access to the original information, and all participated in decisions nigh the manuscript. Initially, the investigation was organized every bit two separate trials performed with identical protocols at 2 groups of institutions. Well-nigh halfway through the enrollment period (earlier the data were analyzed), the sponsor decided to combine the parallel trials into a unmarried trial.

Results

Study Population

Tabular array i. Table one. Identification of Vaginal Fungal Isolates.

A total of 494 patients with acute symptomatic vulvovaginal candidiasis who had a history of recurrent vulvovaginal candidiasis were enrolled and prescribed three doses of fluconazole to accomplish clinical remission. The average age of participants was 33.8 years (range, eighteen to 65). On the footing of investigators' assessment, 66.v percent of the patients were white, 25.6 pct black, and seven.9 per centum either Hispanic or of unknown ethnic background. Sixty-vii patients (13.6 percent) were withdrawn from the study considering afterward enrollment their baseline vaginal fungal cultures were negative and thus the diagnosis of vulvovaginal candidiasis could not be confirmed. The results of microbiologic analysis of the baseline vaginal isolates from the remaining 427 patients are shown in Tabular array 1. Of those isolates, 401 (93.ix percent) were identified as C. albicans and 13 (3.0 pct) as C. glabrata. Five patients dropped out of the study; of the remaining 422 patients who met the baseline criteria for enrollment, 387 (91.7 percent) had a clinical response with resolution of signs and symptoms and at 14 days were randomly assigned to receive either fluconazole or placebo. Four patients dropped out during the open-label consecration stage earlier randomization because of reported agin effects (none serious), iii patients were lost to follow-up, and seven were withdrawn because of protocol violations. Just nine patients did not have a total clinical remission.

Later randomization, 373 patients (96.iv percent of the patients who had a clinical response) were included in the modified intention-to-care for assay, and 343 patients (88.vi percentage) were included in the analysis of efficacy. Patients who were randomly assigned to receive fluconazole and those randomly assigned to receive placebo were similar with regard to age, race or ethnic background, and weight, every bit well as such predisposing factors as contraceptive method and coexisting illness (east.1000., 2 percent of the patients who received fluconazole and 5 per centum of the patients who received placebo had diabetes). The microbiologic status of the 2 study groups is shown in Table 1. Although more patients who received placebo had positive cultures (23 vs. 13 of those who received fluconazole), the difference was not statistically significant. Similarly, more than patients who received placebo were infected with species of candida other than C. albicans (14 vs. 6). The results were similar in a modified intention-to-treat assay (information not shown).

Table two. Tabular array 2. Clinical Outcome subsequently Randomization (Efficacy Assay).

During the half dozen-month blinded maintenance phase, patients who received placebo had a significantly higher charge per unit of clinical recurrence than did those receiving fluconazole (Tabular array 2). At half dozen months, 128 of 141 patients receiving fluconazole (90.eight percent) remained well without a clinical recurrence, as compared with 51 of 142 patients receiving placebo (35.ix percent). Symptomatic vulvovaginal candidiasis occurred in 13 of 141 patients receiving fluconazole and 91 of 142 patients receiving placebo (relative risk in the placebo group, two.53; 95 percent confidence interval, 2.02 to three.17; P<0.001).

Figure 1. Figure 1. Kaplan–Meier Analysis of the Time to Recurrence of Vulvovaginal Candidiasis amongst Patients Randomly Assigned to Fluconazole Prophylaxis or Placebo.

The median time to clinical recurrence in the fluconazole group was ten.2 months after randomization, as compared with iv.0 months in the placebo group (P<0.001) (Panel A). Although recurrence was prevented with fluconazole during the ascertainment catamenia, long-term cure remained difficult to achieve. The median time to mycologic recurrence was 8.4 months in the fluconazole group and 1.9 months in the placebo grouping (P<0.001) (Panel B).

During the vi-month ascertainment menstruation after the cessation of therapy (i.due east., in months 7 through 12), significantly more than episodes of clinical vulvovaginal candidiasis were observed in patients who had previously been protected by fluconazole than in those who had received placebo. However, at the completion of the 12-month study, 54 of 126 patients in the fluconazole group were clinically cured (42.ix percentage), every bit compared with 30 of 137 patients who had received placebo (21.ix percentage) (P<0.001). The modified intention-to-treat assay had similar results. The deviation between the two handling groups was also demonstrated in a Kaplan–Meier analysis (Effigy 1A). The median fourth dimension to a clinical recurrence in the fluconazole group was 10.ii months subsequently randomization, as compared with 4.0 months in the placebo group (P<0.001).

Asymptomatic patients whose cultures were positive were non withdrawn from the written report. At the finish of the six-month maintenance stage, 25 patients receiving fluconazole had had at least one positive vaginal civilization, equally compared with 94 patients in the placebo group. Mycologic eradication or suppression was documented in 82.1 percent of patients receiving fluconazole and in 28.2 percent of patients receiving placebo (P<0.001). After the abeyance of prophylaxis, the rate of a positive vaginal culture was significantly higher in the group that had previously been protected by fluconazole. At the end of one twelvemonth of written report, 36 patients in the fluconazole group had negative cultures, equally compared with 21 patients in the placebo group (P=0.02). The median time to mycologic relapse in the fluconazole group was eight.iv months subsequently randomization, as compared with 1.9 months in the placebo group (P<0.001) (Effigy 1B).

Amongst patients with any positive vaginal cultures during the 12-month written report period, in that location were no significant increases over time in the appearance of isolates of candida species other than C. albicans in either the fluconazole or the placebo grouping. Three patients who were randomly assigned to receive fluconazole initially had positive cultures for C. glabrata, and during the report, 4 additional patients became positive for C. glabrata. A similarly small increase in vaginal isolates identified as C. glabrata occurred in the placebo grouping. No fluconazole-resistant strains of C. albicans (MIC ≥64 μg per milliliter) were identified in either group, and no changes in MICninety values for fluconazole were detected (data not shown).

A stepwise logistic-regression assay was performed to assess the clan of the clinical response with the results of vaginal fungal civilization at baseline and with the presence or absenteeism of coexisting illnesses and other factors (including race or indigenous background, the presence or absence of a history of antibiotic and oral-contraceptive employ earlier entry in the study, and the presence or absence of diabetes). None of these prognostic variables were significantly associated with a clinical response, either at the cease of maintenance therapy or at the end of the study. The analysis of the time to clinical recurrence showed that amid the patients who were infected with C. albicans at baseline, 89.8 percentage of those who were treated with fluconazole remained clinically cured up to six months after the randomization, as compared with 41.three percentage of the placebo-treated patients. Twoscore-vi percent of the patients who received fluconazole remained clinically cured upwards to 12 months after randomization, as compared with 26.half dozen percentage who had received placebo (P<0.001). A positive vaginal culture for any candida species at any time during the maintenance phase predicted a clinical relapse after the abeyance of fluconazole therapy.

Agin Events

Table 3. Table 3. Agin Events.

During the maintenance phase, five patients in the fluconazole group (2.nine percentage) and two in the placebo group (1.two percent) reported at to the lowest degree ane agin event that led to discontinuation of the study drug. Unintended pregnancy (in iii patients in the fluconazole group and ane in the placebo group) was the most frequently reported reason for withdrawal. One patient in the placebo group withdrew after a motorcar accident. In just one patient was an adverse event (headache) leading to discontinuation thought to exist attributable to fluconazole. A patient in whom vulvar vestibulitis was diagnosed likewise discontinued fluconazole therapy. Liver-part tests were routinely performed at the completion of the induction phase and after three and six months. A mild elevation in aminotransferase levels was detected in but i patient during the maintenance phase (<one percent); the patient did not discontinue therapy. Adverse events not associated with discontinuation were uncommon (Table three).

Discussion

In our randomized, prospective, placebo-controlled report, weekly fluconazole administered during a half dozen-month menstruation reduced the frequency of recurrent vulvovaginal candidiasis by more than 90 percent. The results were non unexpected, since previous studies with other antimycotic agents had shown a similar reduction in episodes of candida vaginitis both in patients with HIV infection and in those without HIV infection.8-17,23 Previous studies, notwithstanding, used either intravaginal antimycotic agents, which were inconvenient to administer, or other oral antifungal regimens, which had toxic effects.eight-17,23 Fluconazole proved to be safety and convenient and did non outcome in the emergence of less susceptible strains of candida, particularly species other than C. albicans.

Our written report also indicates that effective suppressive prophylaxis, even over a six-calendar month period, does not guarantee a cure during the subsequent six months, after suppressive therapy has been discontinued. A full explanation of this circuitous miracle is even so not bachelor, but the data suggest that suppressive prophylaxis with an azole fails to achieve long-term vaginal eradication of candida organisms. Even though patients who are taking fluconazole may have negative cultures for a menstruum of several months, they may still have candida in numbers that are as well depression for detection by conventional civilisation methods. Two populations of patients receiving fluconazole prophylaxis can be identified: those in whom yeast eradication occurs and those in whom organisms persist in depression numbers, merely to increase when prophylaxis is stopped. Information technology is simplistic to attribute this miracle but to the properties of the azole agent, since undefined characteristics of the host and the microorganisms may contribute to persistence in spite of inhibitory drug concentrations. In improver, some patients who become civilisation-positive after the cessation of the fluconazole prophylaxis remain asymptomatically colonized, whereas others quickly become symptomatic. Previous studies take concluded that the development of symptoms in this context reflects a defective host response; however, the role of the pathogen has not been studied.4,6

In spite of the high rate of relapse of symptomatic vaginitis before long later on the cessation of suppressive therapy with fluconazole in our study, the number of patients who remained free of infection at i yr was significantly college in the fluconazole group than in the placebo group. The decision near how to care for patients whose infection recurs later the discontinuation of fluconazole therapy remains controversial. Clinical experience has indicated that a majority of patients elect to repeat the half dozen-month maintenance regimen with fluconazole; however, the optimal duration of secondary suppressive prophylaxis remains unknown, even though patients receiving the repeated regimen have had a level of protection that is similar to that in our study group. There have been anecdotal reports of women who became asymptomatic but dependent on fluconazole therapy and were monitored for several years, with no adverse effects.

The rubber of weekly fluconazole and its pharmacokinetic characteristics are major factors contributing to its overall clinical success. A business organisation about long-term therapy has been the possibility of the emergence of azole resistance in isolates of C. albicans or more frequent isolation of species other than C. albicans. Although azole-resistant recurrent oropharyngeal and esophageal candidiasis has been a trouble in patients with HIV infection and has been linked to long-term exposure to azoles, such findings did not emerge in our written report. Yet, given that a subpopulation of women with recurrent vulvovaginal candidiasis will probably receive fluconazole for a prolonged period of time, additional efficacy and safety studies are needed.

In decision, recurrent candida vaginitis, a common and poorly managed condition, tin be successfully and safely controlled by weekly suppressive therapy with fluconazole. A long-term cure, even so, remains elusive.

Funding and Disclosures

Supported by private institutional grants from Pfizer Pharmaceutical.

Dr. Sobel reports having received consultation or lecture fees from 3M, Pfizer, Merck, and Rostam and grant support from 3M, Johnson & Johnson, and Pfizer; Dr. Wiesenfeld lecture fees from 3M, GlaxoSmithKline, and Pfizer and grant support from Pfizer; Drs. Hooton and Horowitz lecture fees from Pfizer; Dr. Livengood lecture fees from 3M and Pfizer and grant support from Johnson & Johnson and Merck; and Dr. Von Thron lecture fees from Wyeth.

Author Affiliations

From the Partitioning of Infectious Diseases, Wayne Land Academy School of Medicine, Detroit (J.D.Southward.); the Section of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh Schoolhouse of Medicine, Pittsburgh (H.C.Westward.); the Section of Obstetrics and Gynecology, Hennepin Canton Medical Center, Minneapolis (Grand.G.); Doc Associates of Florida, Orlando (P.D.); the Division of Allergy and Communicable diseases, University of Washington, Seattle (T.Thousand.H.); the Sectionalisation of Infectious Diseases, Johns Hopkins University, Baltimore (A.R.); Edinger Medical Group and Research Center, Fountain Valley, Calif. (Thou.S.); the Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, Due north.C. (C.50.); SHE Medical Associates, Hartford, Conn. (B.H.); Insignia Intendance for Women, Tampa, Fla. (J.V.T.); Mid-Charlotte Dermatology and Research, Charlotte, N.C. (L.E.); and Pfizer Pharmaceuticals, New York (H.P., T.-C.C.).

Accost reprint requests to Dr. Sobel at the Sectionalisation of Infectious Diseases, Harper Infirmary, v Hudson, Rm. 5929, 3990 John R St., Detroit, MI 48201, or at [email protected].

Appendix

In addition to the authors, the following investigators participated in the study: P. Nyirjesy, Philadelphia; B.D. Reed, Ann Arbor, Mich.; W.E. Stamm, Seattle; Yard.West. Heine, Tucson, Ariz.; K. Moss, Seattle; J. Rosen, Coral Gables, Fla.; J. Schwebke, Tuscaloosa, Ala.; P. Siami, Evansville, Ill.; L. Smolenski, Memphis, Tenn.; and R. Jackson, Southfield, Mich.

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