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Treatment of vaginitis caused by glabrata: Use of topical boric acid and flucytosine

Jack D. Sobel, MD,a Walter Chaim, MD,b Viji Nagappan, MD,a and Deborah Leaman, RN, BSNa Detroit, Mich, and Beer Sheva, Israel

OBJECTIVE: The purpose of this study was to review the treatment outcome and safety of topical therapy with boric acid and flucytosine in women with Candida glabrata vaginitis. STUDY DESIGN: This was a retrospective review of case records of 141 women with positive vaginal cultures of C glabrata at two sites, Wayne State University School of Medicine and Ben Gurion University. RESULTS: The boric acid regimen, 600 mg daily for 2 to 3 weeks, achieved clinical and mycologic success in 47 of 73 symptomatic women (64%) in Detroit and 27 of 38 symptomatic women (71%) in Beer Sheba. No advantage was observed in extending therapy for 14 to 21 days. Topical flucytosine cream administered nightly for 14 days was associated with a successful outcome in 27 of 30 of women (90%) whose condition had failed to respond to boric acid and therapy. Local side effects were uncommon with both regimens. CONCLUSIONS: Topical boric acid and flucytosine are useful additions to therapy for women with azole- refractory C glabrata vaginitis. (Am J Obstet Gynecol 2003;189:1297-300.)

Key words: Vaginitis, Candida glabrata, boric acid, flucytosine

The increased use of vaginal cultures in the treatment Candida vaginitis studies have been insufficient to allow of women with chronic recurrent or relapsing vaginitis has separate consideration.6,7 Accordingly, practitioners have provided clinicians with new insights into the Candida been provided with relatively poor information regarding microorganisms that are responsible for vaginitis. treatment effectiveness, which is tainted further by Much attention has been directed at nonalbicans Candida accrual bias. In 1994, we reviewed our experience with with regard to epidemiologic makeup, clini- 40 women who were infected with C glabrata, some of cal manifestations, diagnosis, and treatment issues.1-5 In whom were treated successfully with topical boric acid.11 spite of suggestions of a significant trend to increased Because no new information has been published sub- occurrence of nonalbicans Candida ,4 more sequently, we reviewed the treatment outcomes with boric recent studies have failed to confirm an increased acid in 141 additional women at two geographic sites with incidence.6,7 The most common nonalbicans Candida differing patient demographics and report, for the first species reported is Candida glabrata, which has attracted time, the effectiveness of flucytosine in women whose attention because of it is known to reduce in vitro condition failed to respond to boric acid therapy. susceptibility to the entire class of and polyene agents.8-10 Methods Unfortunately, in spite of the increased awareness of We retrospectively reviewed the medical records of all vaginitis caused by C glabrata, cases are still too infrequent, patients, from whom C glabrata was isolated from vaginal especially at a single site, to permit the performance of swabs, who were seen at the Wayne State University a randomized prospective controlled study to establish Vaginitis Clinic between 1992 and 2001. Before record optimal treatment. Even multicenter studies have not review, approval was obtained from the Wayne State been forthcoming. Moreover, the numbers of women who University Investigational Review Board. In addition, one are infected with C glabrata and who are enrolled in author (W. C.) reviewed case records (n = 39) of women with C glabrata who were seen in a private clinic in Beer Sheba, Israel (1996-2002). None of the patients who are From the Division of Infectious Diseases, Wayne State University School of Medicine,a and the Department of Obstetrics and Gynecology, Ben described in the current study have been reported Gurion University.b previously. Received for publication January 28, 2003; revised April 8, 2003; Medical records were reviewed for demographic details accepted May 30, 2003. Reprint requests: Jack D. Sobel, MD, Division of Infectious Diseases, and treatment courses with boric acid, flucytosine, and Harper Hospital, 3990 John R, Detroit, MI 48201. E-mail: jsobel@ other antimycotics. C glabrata microorganisms were intmed.wayne.edu identified on the basis of negative chlamydospore and Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 germ-tube formation and carbon assimilation testing with doi:10.1067/S0002-9378(03)00726-9 use of API strips (Sherwood Medical, Plainview, NY).

1297 1298 Sobel et al November 2003 Am J Obstet Gynecol

Table. Comparative susceptibilities of vaginal C glabrata On saline microscopy, budding yeast without hyphal and C albicans to antifungal agents MIC 90 (lg/mL) formation were observed in 95 of 118 episode (81%). In 73 episodes of symptomatic vaginitis that were treated C albicans C glabrata with boric acid, 47 patients had improved symptoms and Amphoterecis B 0.25 1 became culture negative (64%), 23 patients remained 1 0.125 culture positive with residual symptoms (32%), and 3 0.03 2 0.03 0.25 patients were lost to follow-up. No difference in outcome 0.03 0.5 was found when patients who were treated for 14 and 21 0.03 4 days were compared. None of the patients stopped boric 0.03 1 0.03 2 acid therapy because of local or systemic effects, although 0.5 >64 occasional complaints of vaginal burning were docu- 0.03 1 mented ( <10%). Intravaginal flucytosine cream was offered to 30 patients, 26 of whom had previously received boric acid Boric acid was available as a gelatin capsule that con- therapy, with either short-term failure or relapse. Of the tained 600 mg of boric acid (Professional Compounding 30 patients, 27 patients achieved cure, 2 patients had Centers of America) and were administered through failure of therapy, and 1 patient was lost to follow-up. All the vagina once daily for either 14 or 21 days (non- patients completed and tolerated topical flucytosine randomized). Flucytosine cream was prepared as de- therapy. No staining of underclothing and sheets was scribed by Horowitz12 and administered as a nightly 5-g reported. Two patients had failure of flucytosine therapy, intravaginal dose for 14 days. Fourteen 500-mg capsules of both of whom subsequently received oral itraconazole flucytosine (Ancobon) were opened into a mortar and therapy followed by intravaginal suppositories. reduced to a fine powder. The powder was levigated with One of the 2 patients had successful eradication of C glycerin to form a smooth paste. The levigated mixture glabrata from the genital tract. was added to a hydrophilic ointment base or cold cream to Between 1996 and March 2002, 52 isolates of C glabrata 45 g. This mixture was blended until smooth, and two were cultured from 39 patients who were seen at a private 2-ounce ointment tubes were filled. Medical records were vaginitis clinic in Beer Sheba, Israel. Thirty patients were examined for documented side and adverse effects. Only Jewish, and 9 patients were Bedouin (median age, 31 symptomatic episodes were treated. years). Predisposing factors were similarly rare; only 1 In vitro susceptibility of all C glabrata isolates (Detroit) patient had diabetes mellitus; however, 8 women were were determined with the use of the N-27A microdilution pregnant. Thirty-eight episodes of symptomatic vaginitis National Committee for Clinical Laboratory Standards were treated with a 14-day course of boric acid (600 mg per method.13 day). Clinical and mycologic success was achieved in 27 of 38 patients (71%) whose cases were followed. No patients Results were treated with flucytosine. In the period between 1994 and 2001, 118 isolates of The in vitro susceptibility test results of 100 vaginal C glabrata were obtained on vaginal culture from 102 isolates of C glabrata that were obtained from the present patients at the Vaginitis Clinic, Wayne State University. Of study population are shown in the Table. The results of the 102 patients, 75 women were white, and 23 women azole susceptibility tests are compared with simulta- were black. The age range was 16 to 70 years (median neously tested C albicans vaginal isolates that were age, 41 years); 25 patients were older then 50 years. obtained from women in the same clinic over the same Predisposing gynecologic factors were rare without the period. C glabrata isolates are uniformly 10 to 100 times emergence of selective factors except for a past recent less susceptible to all azoles compared with C albicans. history of recurrent bacterial vaginosis (10 patients) and Similarly, reduced susceptibility of C glabrata to am- recent desquamative inflammatory vaginitis (10 patients). photericin B was evident. All of the C glabrata isolates Not all patients were symptomatic; 73 symptomatic pa- were susceptible to flucytosine at low concentrations tients received therapy with boric acid. Forty of the 73 (#0.25 lg/mL). Isolates of C glabrata were available from patients (55%) who were treated with boric acid were three patients for whom flucytosine therapy was un- referred to the clinic because of refractory yeast vaginitis, successful. Pretherapy susceptibility revealed minimal after having had failed repeated courses of azole therapy. inhibitory concentrations of 0.125 lg/mL; hence, no Twenty patients were receiving estrogen hormone replace- explanation for flucytosine treatment failure is forthcom- ment therapy; only 5 patients (5%) had diabetes mellitus. ing. Of interest, however, in one patient the posttreatment Clinical features during the symptomatic episodes of C C glabrata isolates had rapidly acquired resistance to glabrata vaginitis were indistinguishable from episodes flucytosine with a minimal inhibitory concentration of caused by other species. The median vaginal pH was 4.4. >32 lg/mL. Volume 189, Number 5 Sobel et al 1299 Am J Obstet Gynecol

Comment Although this retrospective case series was not designed In a busy referral clinic in Detroit, approximately 10 as an epidemiologic study, several features did emerge new patients with C glabrata infection were seen annually. and deserve further confirmation in prospective studies. Moreover, not all patients were symptomatic, qualified, Certainly in the Detroit review, C glabrata vaginitis was or willing to participate in a randomized study. A pro- often asymptomatic and had frequent coexistent vaginal spective, randomized, controlled single-site study was not pathologic condition (eg, recurrent bacterial vaginosis, 11 possible. Regrettably, all published data that are available desquamative inflammatory vaginitis). The higher currently are based on individual case reports or rare median age of patients (41 years) is notable compared case series.14 The current report is no exception, with patients in the clinic with C albicans (33 years; data although 111 patients who were not described previously not shown). Vaginal pH, although within the normal constitute by far the largest patient population to be range at 4.4, is on the high side and reflects the con- studied. comitant pathologic condition and the hypothesized pH In 1997, we published our experience in treating 26 preference of C glabrata. Finally, diabetes mellitus was episodes of vaginitis that were caused by C glabrata and observed rarely (5%). that were treated with a similar regimen of vaginal boric On the basis of our observations, topical flucytosine acid.11 In this considerably smaller series, the clinical appears more efficacious than boric acid, but no pro- spective controlled data are available. Accordingly, phy- response rate was slightly higher at 81% with mycologic sicians may choose to offer flucytosine as first-line therapy; eradication in 77% of cases. In the current series in however, the latter is expensive compared with boric acid. Detroit, cure rates were approximately 10% lower; White et al15 prepared flucytosine in , however, in addition to study size, uniform inclusion which may be synergistic and even more potent. and exclusion criteria were not implemented, except for Unfortunately, no comparative data in patients exist, the presence of positive vaginal cultures for C glabrata. and no animal model of C glabrata vaginitis is available for Nevertheless, the current larger series supports our comparative study. Resistance development to flucytosine original report that women whose condition fails to remains an additional concern. respond to conventional topical azole therapy can be In conclusion, when the conditions of patients with treated safely with boric acid and achieve cure in complicated Candida vaginitis7 from C glabrata fail to approximately two thirds of symptomatic episodes. respond to conventional azole therapy, treatment with The current report is the first case series to report boric acid vaginal capsules offers a reasonable success rate treatment outcome with intravaginal flucytosine. Flu- and is inexpensive and safe when administered by this cytosine has been recognized to have unique in vitro route. Topical flucytosine vaginal cream has emerged as activity against C glabrata.8 The topical preparation of a highly effective regimen but is not widely available. flucytosine that was used was based on a formulation used Vaginitis caused by C glabrata demands both special efforts 12 by Horowitz for the treatment of refractory C tropicalis. and challenge, and additional drugs must be developed to There are no other reports of its use for other species of provide effective and convenient treatment. Candida, apart from a recent report by White et al15 who reported success when flucytosine was compounded together with amphotericin B and used topically in three REFERENCES patients. Our experience with a 90% cure rate with 1. Fidel PL Jr, Vazquez JA, Sobel JD. Candida glabrata: review of flucytosine is extremely encouraging, and the regimen epidemiology, pathogenesis, and clinical disease with comparison to was well tolerated. The use of oral and parenteral flucyto- C albicans. Clin Microbiol Rev 1999;12:80-96. sine is known to cause gastrointestinal and bone marrow 2. Sobel JD, Faro S, Force RW, Foxman B, Ledger WJ, Nyirjesy PR, et al. Vulvovaginal : epidemiologic, diagnostic, and therapeutic toxicity, especially with prolonged use. Our brief vaginal considerations. Am J Obstet Gynecol 1998;178:203-11. use appeared safe, but no toxicity studies were performed. 3. Geiger AM, Foxman B, Sobel JD. Chronic vulvovaginal candidiasis: Long-term use of flucytosine is not recommended. These characteristics of women with , C glabrata and no candida. Genitourin Med 1995;71:304-7. results are particularly gratifying with the knowledge that 4. Horowitz BJ, Giaquinta D, Ito S. Evolving in vulvovaginal none of the newer are currently under study candidiasis: implications for patient care. J Clin Pharmacol 1992; for yeast vaginitis. The with excellent in 32:248-55. 5. Spinillo A, Capuzzo E, Egbe TO, Baltaro F, Nicola S, Piazzi G. vitro activity against all Candida species are not absorbed Torulopsis glabrata vaginitis. Obstet Gynecol 1995;85:993-8. by the oral route; topical preparations are not available.16 6. Sobel JD, Brooker D, Stein GE, Thomason JL, Wermeling DP, Weinstein L, et al. Single oral dose fluconazole compared with The newest generation of azoles (voriconazole, posa- conventional topical therapy of Candida vaginitis. Am J Obstet conazole, and ), although more active in Gynecol 1995;172:1263-8. vitro against C glabrata than earlier azoles, are still 7. Sobel JD, Kapernick PS, Zervos M, Reed BD, Hooton T, Soper D, et al. Treatment of complicated Candida vaginitis: comparison of single considerably less active against C glabrata than C albicans; and sequential doses of fluconazole. Am J Obstet Gynecol 2001; moreover, no studies in vaginitis are planned.10 185:363-9. 1300 Sobel et al November 2003 Am J Obstet Gynecol

8. Lynch ME, Sobel JD. Comparative in vitro activity of antimycotic 12. Horowitz BJ. Topical flucytosine therapy for chronic recurrent agents against pathogenic vaginal yeast isolates. J Med Vet Mycol . J Reprod Med 1986;31:821-4. 1994;32:267-74. 13. National Committee for Clinical Laboratory Standards 1994. De- 9. Redondo-Lopez V, Lynch M, Schmitt C, Cook R, Sobel JD. Torulopsis velopment of in vitro susceptibility testing criteria and quality control glabrata vaginitis: clinical aspects and susceptibility to antifungal parameters: approved guidelines M 27-A. Villanova (PA): National agents. Obstet Gynecol 1990;76:651-5. Committee for Clinical Laboratory Standards; 1994. 10. Pfaller MA, Messer SA, Hollis RJ, Jones RN, Diekema DJ. In vitro 14. Jovanovic R, Congema E, Nguyen HT. Antifungal agents vs. boric activities of ravuconazole and voriconazole compared with those of acid for treating chronic mycotic vulvovaginitis. J Reprod Med four approved systemic antifungal agents against 6,970 clinical 1991;36:593-7. isolates of Candida spp. Antimicrob Agents Chemother 2002;46: 15. White DJ, Habib AR, Vanthuyne A, Langford S, Symonds M. 1723-7. Combined topical flucytosine and amphotericin B for refractory 11. Sobel JD, Chaim W. Treatment of Torulopsis glabrata vaginitis: vaginal Candida glabrata infections. Sex Transm Infect 2001;77:212-3. retrospective review of boric acid therapy. Clin Infect Dis 1997;24: 16. Denning DW. Echinocandins: a new class of antifungal. J Antimicrob 649-52. Chemother 2002;49:889-91.