ORIGINAL RESEARCH ARTICLES: VULVA AND VAGINA
Non-albicans Candida Vulvovaginitis: Treatment Experience at a Tertiary Care Vaginitis Center Anna M. Powell, MD,1 Edward Gracely, PhD,2,3 and Paul Nyirjesy, MD1 Objectives: The aims of this study are to analyze a cohort of women with vulvovaginal symptoms and positive cultures for non-albicans Candida (NAC) to determine whether yeast was responsible for their symptoms and to evaluate the mycological effectiveness of various regimens. Methods: This observational study was performed from retrospective chart review of patients with positive NAC cultures between April 1, 2008, and January 31, 2011, at a tertiary care vaginitis center. Patient intake demographics were entered into a database. Follow-up visits were analyzed for data about patient treatments and outcomes. Patients were considered a clinical cure if their symptoms were significantly improved and mycologic cure (MC) if later yeast cultures were negative. If clinical symptoms improved at the same time as MC, the isolate was considered the proximate cause for the symptoms. Results: One hundred eight patients meeting entry criteria were analyzed. Boric acid was effective at obtaining MC in 32 (78%) of 41 patients with C. glabrata, 3 of 3 patients with C. tropicalis, and 3 of 3 patients with C. lusitaniae. Fluconazole was effective as initial treatment for 3 (60%) of 5 patients with C. glabrata and 13 (81%) of 16 patients with C. parapsilosis. In 52.7% of C. glabrata, 66.7% of C. parapsilosis, and 57.1% of C. tropicalis cases, effective antifungal therapy led to symptom improvement. Conclusions: In a tertiary care vaginitis center, NAC, when isolated on culture, caused clinically significant infections in approximately half of symptomatic patients. A majority of infections can be effectively treated with boric acid or fluconazole regardless of the non-albicans Candida species. Key words: non-albicans Candida, Candida glabrata, vulvovaginitis (J Lower Gen Tract Dis 2016;20: 85–89)
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ulvovaginal candidiasis (VVC) is one of the most frequent causes of vaginitis, which is associated with significant direct and indirect health-care costs. While Candida albicans is the most frequent causative agent, non-albicans Candida (NAC) species may also cause symptomatic yeast infections.1 Although women are led to believe that they can accurately self-diagnose VVC, only 11% who have never had an episode of VVC and 34% who have can accurately recognize the written description of VVC.2 Improper treatment of yeast vulvovaginitis may occur in the setting of frequent self-treatment with over-the-counter antifungals and empiric treatment with azoles by patients and providers.3–5 Because the use of broad-spectrum antibiotics has become more commonplace, the frequency of mucosal and systemic infections by NAC, especially Candida glabrata, has increased significantly,3 and higher percentages of NAC species (32%–40%) have
1 Drexel University College of Medicine, Department of Obstetrics and Gynecology; 2Drexel University College of Medicine, Department of Family, Community and Preventive Medicine; and 3Epidemiology and Biostatistics at Drexel School of Public Health, Philadelphia, PA Reprint requests to: Anna Powell, MD, 245 N 15th St MS 495, Philadelphia, PA 19102. E-mail: [email protected] Financial disclosures: Dr. Nyirjesy does report the following relationships with industry: Novadigm (consultant, research grant), Viamet Pharmaceuticals (consultant, research grant), and Becton-Dickinson (research grant). Dr. Powell and Dr. Gracely report no conflicts of interest. © 2015, American Society for Colposcopy and Cervical Pathology
been isolated in women with recurrent vulvovaginitis than in women with isolated episodes of vulvovaginal candidiasis (11%–20%).6–9 Eradication of NAC infections may be more difficult because of antimicrobial resistance to commonly used agents.3 Of the NAC species, C. glabrata has been reported most commonly. Risk factors identified for vulvovaginal C. glabrata infections include older age, underlying medical conditions such as diabetes, and douching.10 Candida glabrata is thought to carry few if any virulence factors compared with C. albicans but exhibits more azole resistance. The percentage of patients with C. glabrata infection treated effectively by practitioners with azoles alone is not known, but in vitro studies frequently show higher minimum inhibitory concentrations (MIC) for all available azoles compared with C. albicans.11 In clinical practice, this often necessitates treatment with vaginal boric acid, amphotericin B, flucytosine cream,12 or nystatin.13 Candida parapsilosis was initially considered nonpathogenic until a fatal case of endocarditis in a narcotic addict was reported in 1940.14 In vulvovaginal disorders, C. parapsilosis has been considered indolent by some14; on the other hand, Kennedy and colleagues concluded that 62.5% of isolates caused symptomatic vulvovaginal infections.12 Previously reported outcomes of vulvovaginal infections caused by C. krusei suggest this organism is implicated in refractory cases of vulvovaginits but clears with prolonged courses of clotrimazole or boric acid.15 Silverman and colleagues reported one case of refractory vulvovaginitis caused by C. lustianiae successfully treated with vaginal boric acid for 14 days.16 Although mycologic eradication with antifungal treatment can be difficult to achieve because of resistance issues, it is difficult to determine how often it is necessary to treat NAC. Although it had been previously assumed that the presence of NAC was indicative of a symptomatic infection, it is possible that symptomatic patients with a positive culture for NAC have symptoms because of another condition, for example, dermatitis, and that they are simply colonized with NAC. Thus, the role of NAC in causing symptomatic infection is vigorously debated, with some authors17 finding that vulvovaginal symptoms in women with NAC isolates resolve without antifungal treatment in up to 86% of cases. Given the controversies with regard to their role in causing vulvovaginal symptoms and the limited published data about effectiveness of various treatment regimens, we undertook a review of the NAC cases at our tertiary care vaginitis center to describe affected women, ascertain which treatments cleared the organism mycologically, and determine whether clearance of the organism resulted in relief or improvement of vulvovaginal symptoms.
METHODS This observational study consisted of a retrospective chart analysis of patients presenting with vulvovaginal symptoms, from whom NAC were isolated via vaginal yeast culture between April 2008 and January 2011. Institutional review board approval was obtained from Drexel University College of Medicine’s Office of Research (IRB Protocol No. 1203000971). Patients were seen
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at the Drexel Vaginitis Center, a tertiary care referral center for patients referred by their health-care providers because of persistent or recurrent vulvovaginal symptoms. The program sees an estimated 500 new and 4300 return annual patient visits. Each new patient undergoes a standardized history and examination, which includes testing for vaginal pH, amines, saline, and 10% KOH microscopy. Almost all patients have a baseline yeast culture sent to a commercial laboratory, which speciates positive organisms. Yeast cultures are repeated in patients with previous positive cultures or when a new yeast infection is suspected. Although follow-up visits were not mandated by protocol, patients are typically seen for reevaluation within 2 to 4 weeks of initiating treatment. Initial diagnosis was noted because a majority of patients seen at the Drexel University Vaginitis Center presented with multiple vulvovaginal complaints and may have had more than one underlying diagnosis. Diagnosis of yeast vaginitis was either made by presence of budding yeast or hyphae with KOH microscopy or by a positive yeast culture with corresponding symptoms. Antifungal minimum inhibitory concentration (MIC) via susceptibility is not recommended per CDC treatment guidelines and, therefore, was not routinely obtained.18 Patients with NAC were identified, and their electronic records were reviewed. Of note, our electronic medical record was implemented in April 2008, so patients with initial encounters before this date were excluded because of incomplete data. Study data were collected and managed using REDCap (Research Electronic Data Capture), an electronic data capture tool hosted at Drexel University College of Medicine.19 Study data were extracted from a database of 2396 patients with yeast cultures collected between 2008 and 2011. Data collected included demographics, medical history, symptoms, microscopic findings, yeast culture results, and treatments from the initial time when a positive culture was obtained until there was a negative one. All patients presenting for initial visit reported vulvovaginal symptoms (itching, burning, discharge, or dyspareunia). Interval visits between first positive and first negative NAC culture were also reviewed. Patient visits were conducted by center staff, either the center’s director (P.N.) or a dedicated nurse practitioner. A specific author (A.M.P.) reviewed charts to assess rates of clinical cure (CC) and mycological cure (MC) whether, at the completion of antifungal treatment for the NAC isolate, yeast was the organism responsible for symptoms. Clinical cure was defined as patients describing themselves as more than 50% better after a treatment course. Mycological cure was defined as a negative follow-up yeast culture; rates of MC with various treatment modalities were determined. If the patient remained symptomatic at the end of a successful treatment course or if the provider documented an alternative diagnosis, then symptoms were not attributed to yeast, and the patient was defined as being colonized with NAC. On the other hand, if MC correlated with CC, the patient was defined as having a true yeast infection, with the NAC being the likely cause for the symptoms. Unless an NAC infection with treatment failure was specifically documented by the visit provider, the alternative diagnosis is assumed to be the probable cause of vulvovaginal symptoms. The following treatments were used: boric acid 600 mg vaginal capsule given nightly for 14 days20; fluconazole 150 to 200 mg oral daily21; amphotericin B 50 mg vaginal suppository nightly22 with the addition of 600 mg vaginal capsules of boric acid in the morning (off label) for 14 days or, as a separate regimen, 4% with flucytosine 17% in a vaginal cream, 5 g nightly for 14 days23; compounded caspofungin vaginal cream (100 μg/4 g in sodium carboxy gel), 5 grams nightly for 14 days; nystatin 100,000 units given as a compounded tablet daily per vagina for at least 3 weeks; clotrimazole 1% vaginal cream18; or
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miconazole 2% vaginal gel18 for 7 to 14 days. It should be noted that, apart from the clotrimazole and miconazole preparations, all products were compounded and used off label. Initial treatment choice and subsequent order of therapy was decided by the clinic provider based on patient history, wet mount results, and clinical index of suspicion. Treatment courses are described by the initial antifungal used, followed by any additional antifungals that resulted in a negative yeast culture per episode, and total number of treatments required to achieve MC were recorded. In cases requiring more than 2 treatments, each treatment was reported.
RESULTS A total of initial 2396 patient charts were reviewed. Negative yeast cultures or those only positive for C. albicans were excluded. This left 298 patients whose cultures contained an NAC species. These patient charts were then reviewed and excluded from further analysis if the initial history and physical exam was not documented in the electronic medical record (n = 48), if the first patient visit was outside of the study date range (n = 51), or for incomplete data (n = 91). A total of 108 patients with 181 NAC isolates with complete data within the designated date range were available for review. Each woman had at least 2 clinic visits documented and may have had multiple positive NAC cultures. Demographic data and risk factors for recurrent VVC are listed in Table 1. The most frequent concomitant vulvovaginal disorders diagnosed on initial encounter were bacterial vaginosis (n = 24, 22%) and localized provoked vestibulodynia (n = 12, 11%). The most frequent NAC cultures were C. glabrata (n = 111, 63.4%), C. parapsilosis (n = 24, 20.6%), C. tropicalis (n = 9, 5.1%), C. lusitaniae (n = 6, 3.4%), and C. krusei (n = 5, 2.8%). Fifty-five patients had cultures positive for C. glabrata. In 29 (52.7%) of 55 patients, C. glabrata was retrospectively determined to be the cause of symptoms. Mycologic cure was not recorded for 5 patients who did not have further follow-up visits in our EMR; therefore, 50 patients were analyzed for effective treatment courses. Boric acid (600 mg intravaginally for 21–30 days) was the initial therapy used for 41 (82%) of 50 of patients, resulting in MC for 32 (78%) of 41 patients. Fluconazole was the second most commonly used initial treatment and was found to be the effective treatment in 3 (60%) of 5 patients receiving this therapy. A total of 9 patients had NAC isolates preceded by C. albicans; in these, six (67%) were determined to be asymptomatic after treatment of C. albicans. There were 9 associated treatment failures for patients initially treated with boric acid requiring additional antifungal treatments. Three patients who required subsequent treatment following boric acid were felt to have symptoms caused by yeast. One hundred percent of the patients treated and retrospectively determined to have symptoms caused by NAC achieved CC (Table 2). Four patients were noted to have refractory cases of C. glabrata requiring more than 2 distinct antifungal treatments. The first patient, a 62-year-old female patient with concurrent atrophic vaginitis and vulvodynia required boric acid 600 mg vaginal capsules for 30 days with subsequent maintenance therapy twice weekly, in addition to amphotericin B vaginal suppositories administered nightly for 14 days for 3 courses total and caspofungin given for 14 days for 2 courses to achieve MC. Retrospective analysis determined yeast was not responsible for symptoms. Caspofungin was reported as susceptible for this isolate. The second patient, a 41-year-old female patient with no concurrent vulvovaginal disorders required miconazole 2% vaginal gel nightly for 14 days 2 courses, fluconazole 200 mg twice weekly for 28 days, boric acid vaginal capsules © 2015, American Society for Colposcopy and Cervical Pathology
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Non-albicans Candida Vulvovaginitis
TABLE 1. Demographics and Risk Factors
No. patients with NCA isolate Mean age (SD) Vaginitis symptoms attributed to yeast White African American Race (other) Diabetes mellitus Previous vulvovaginal candidiasis Sexually active Premenopausal Postmenopausal Exogenous estrogen use Previous antibiotic use Previous antifungal use Topical corticosteroid use
C. glabrata
C. parapsilosis
C. tropicalis
C. lusitaniae
C. krusei
55 45.9 (15.5) 29/55 (52.7%) 36 (65.4%) 11 (20%) 5 (9.1%) 1 (1.8%) 29 (52.7%) 37 (67.3%) 35 (63.4%) 18 (32.7%) 6 (10.9%) 30 (54.5%) 36 (65.4%) 11 (20%)
24 45.4 (16.7) 16/24 (66.7%) 18 (75%) 5 (20.8%) 4 (16.7%) 0 11 (45.8%) 16 (66.7%) 12 (50%) 12 (50%) 5 (20.8%) 17 (70.8%) 15 (62.5%) 4 (16.7%)
7 53.1 (13.7) 4/7 (57.1%) 4 (57.1%) 2 (28.6%) 1 (14.3%) 1 (14.3%) 1 (14.3%) 5 (71.4%) 2 (28.6%) 5 (71.4%) 1 (14.3%) 4 (57.1%) 5 (71.4%) 0
5 39 (15.9) 3/5 (60%) 3 (60%) 2 (40%) 0 0 1 (20%) 5 (100%) 3 (60%) 2 (40%) 2 (40%) 4 (80%) 3 (60%) 1 (20%)
2 47 (9.8) 2/2 (100%) 2 (100%) 0 0 0 2 (100%) 1 (50%) 1 (50%) 1 (50%) 0 0 2 (100%) 1 (50%)
for 21 days, followed by compounded nystatin (100,000 units in 1 tablet) vaginally for 30 days’ total to achieve MC. Retrospective analysis determined yeast was responsible for symptoms in this case. Susceptibility testing was not performed. The third patient, a 47-year-old female patient without concurrent vulvovaginal disorders, required boric acid for 21 days, amphotericin B for 21 days, caspofungin for 28 days, and nystatin for 30 days to achieve MC. Retrospective analysis determined yeast was responsible for symptoms. The isolate was found susceptible to fluconazole, amphotericin B, and caspofungin but intermediately resistant to boric acid (MIC data not available). The fourth patient was a 47-year-old female patient with concurrent vulvodynia required boric acid vaginal capsules for 30 days, amphotericin B 50 mg vaginal suppository nightly and compounded flucytosine 15.5% vaginal cream nightly for 14 days, and compounded nystatin vaginal capsules for 30 days to achieve MC. Retrospective analysis determined yeast was not responsible for symptoms. Twenty-four patients had cultures positive for C. parapsilosis. Candida parapsilosis was retrospectively determined as the cause of symptoms in 16 (66.7%) of 24 patients. Fluconazole was initial treatment for 16 (66.7%) of 24 patients and resulted in MC in 13 (81.2%) of 16 patients with 3 associated treatment failures requiring further antifungal treatments. One patient determined to have NAC as the retrospective cause of symptoms did not receive treatment but obtained MC and CC at a visit 42 days after her initial visit. Boric acid was initial treatment for 4 patients, effective
for 3 (75%) of 4 of patients treated with 1 treatment failure. Amphotericin B was a first-line treatment for 1 patient, and 1 patient initially treated with miconazole did not achieve MC. Two patients required more than 2 treatment courses; the first was a 62-year-old female patient without concurrent vulvovaginal disease who required fluconazole 200 mg twice weekly 35 days, followed by compounded flucytosine 15.5% vaginal cream nightly for 14 days to achieve MC. Susceptibilities were reported twice: initially, fluconazole intermediate (MIC 32 μg/mL) and flucytosine sensitive and, subsequently, fluconazole resistant (MIC 64 μg /mL) and flucytosine and amphotericin B susceptible. Yeast was retrospectively determined to be the cause of symptoms. The second patient was a 59-year-old female patient without concurrent vulvovaginal disorders who required boric acid vaginal capsules nightly for 21 days and fluconazole 200 mg twice weekly continued as maintenance therapy for greater than 1 year to achieve MC. All treated patients determined to have NAC-attributable episodes achieved CC. Seven patients had cultures positive for C. tropicalis. Four (57.1%) of 7 patients were retrospectively determined to have yeast causing symptoms, and all achieved CC. Boric acid was first-line therapy for 3 of 3 patients with no treatment failures. Fluconazole was first-line therapy for one of 2 patients with 1 treatment failure. A combination of fluconazole and boric acid was administered for 2 patients. The patient with treatment failure was a 57-year-old with concurrent atrophic vaginitis who required fluconazole 200 mg twice weekly for 8 weeks, boric acid
TABLE 2. Treplatment Outcome of Patients with Vulvovaginal Symptoms (N = 108)
Total no. patients NAC causing symptoms Yeast colonization Positive KOH smear at initial visit Empirical treatment for VVC at initial visit Treated Most common treatment
C. glabrata
C. parapsilosis
C. tropicalis
C. lusitaniae
C. krusei
55 (50.9%) 29 (52.7%) 26 (47.2%) 23/55 (41.8%) 28/55 (51%) 55 (100%) Boric acid
24 (22%) 16 (67%) 8 (33%) 13/24 (54.2% ) 11/24 (45.8%) 22 (91.6%) Fluconazole
7 (6.5%) 4 (57.1%) 3 (42.8%) 3/7 (43%) 2/7 (28.6%) 7 (100%) Boric acid
5 (4.6%) 3 (60%) 2 (40%) 3/5 (60%) 4/5 (80%) 4 (80%) Boric acid
2 (1.8%) 2 (100%) 0 2/2 (100%) 1/2 (50%) 2 (100%) Boric acid, nystatin
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vaginal capsules for 21 days, compounded nystatin 100,000 units-triamcinolone ointment for 60 days, and compounded amphotericin B 4%/flucytosine 17% cream administered vaginally at night for 14 days to achieve MC. Five patients had cultures positive for C. lusitaniae. Yeast was retrospectively determined to cause symptoms in 3 (60%) of 5 patients, and all 3 women achieved CC. Boric acid resulted in MC for 4 (80%) of 5 treated episodes. No patients required more than 2 treatment modalities. Two patients had C. krusei identified in 2 cultures, and in both cases, yeast was retrospectively determined to cause symptoms. One patient required treatment with boric acid nightly for 73 days to achieve MC. The other patient achieved MC after treatment with boric acid 600 mg vaginal suppository inserted nightly for 21 days, followed by amphotericin B 50 mg vaginal suppository administered for 14 days and compounded nystatin 100,000 units vaginally for 30 days. Four patients grew other Candida species: C. zeylanoides (as above), C. famata, C. kefyr, and C. rugosa, respectively. The C. kefyr and C. zeylanoides isolates were noted to cause symptoms. The patients with C. kefyr and C. rugosa isolates achieved MC. The C. famata isolate was not treated. The patient with C. zeylanoides received maintenance fluconazole of 200 mg twice weekly for 3 weeks. The C. kefyr isolate was treated with boric acid 600 mg vaginal suppository for 21 days, and C. rugosa was treated with maintenance boric acid, 600 mg vaginal capsule applied 3 times per week for 12 weeks. Nine patients were found to have one of the following “other” yeast: Trichosporon species (n = 3), Saccharomyces cerevisiae (n = 2), Rhodotorula species (n = 2), Geotrichum species (n = 1), and Aureobasidium pullulans (n = 1). Trichosporon species did not cause symptoms; however, 2 patients received treatment, both with fluconazole 200 mg orally twice weekly for 13 weeks. Saccharomyces cerevisiae caused symptoms for 1 patient, who achieved MC after treatment with clotrimazole vaginal cream for 14 days. The other patient received maintenance fluconazole (200 mg twice weekly 4 weeks by mouth), followed by boric acid 600 mg vaginal capsules nightly for 30 days. The patient with Geotrichum species was retrospectively determined to cause symptoms for 1 patient, who achieved MC after treatment with fluconazole 200 mg by mouth twice weekly for 4 weeks. A. pullulans did not cause symptoms, but MC was achieved after treatment with fluconazole 150 mg PO twice weekly for 12 weeks.
DISCUSSION Candida albicans is the most frequently encountered isolate in VVC, accounting for 80% to 90% of cases, followed by C. glabrata, accounting for 7% to 16% of isolates.6 Previous studies suggest that NAC isolates, most commonly C. glabrata, only cause symptomatic infections in 15% to 20% of cases.12,24 Dennerstein and colleagues have even called into question the use of treating NAC isolates, as they found that symptoms and the yeast often resolved without specific antifungal treatment, suggesting these organisms tend to be innocent bystanders in the setting of other VVC complaints.17 Other studies have suggested they are indeed a cause for vulvovaginal symptoms, albeit infrequently.12,24 In our study, we found that C. glabrata, when present in symptomatic women with chronic vulvovaginal symptoms, was the cause of the symptoms 52% of the time, suggesting that it can function as a true pathogen. For other organisms such as C. parapsilosis, C. tropicalis, and C. krusei, our results again suggest that, when present in a symptomatic woman, they cause symptoms at least half of the time if not more.
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As noted with our results and by other authors, successfully eradicating yeast from the vagina can be difficult. An initial therapy which continues to be used by many experts25,26 is boric acid. Boric acid is a well-tolerated and cost-effective fungistatic agent that has shown efficacy in acute episodes of VVC and maintenance therapy.26,27 Small published reports of successful treatment of C. glabrata with amphotericin B suppositories (50 mg nightly) show successful treatment in up to 70% of patients who did not respond to azole treatment22; however, recent studies also suggest emerging resistance of these isolates to amphotericin B.28 In our study, the use of amphotericin B suppositories alone resulted in MC in 100% (3/3) of patients with C. glabrata isolates. Topical flucytosine is another treatment option and, in one study, was an effective treatment for 90% of patients who failed boric acid.29 White and colleagues23 report on the use of topical flucytosine and amphotericin B compounded together for refractory C. glabrata with MC obtained within 2 weeks of treatment with minimal side effects. In our study, 3 patients were treated with combination amphotericin B/flucytosine for C. glabrata, C. tropicalis, and C. parapsilosis, respectively. However, the expensive cost (currently more than $1000) limits the ability to use either of these regimens. One proposed mechanism for increased azole resistance by C. glabrata, and in some cases, C. albicans is altered susceptibility to decreasing medium pH.30 Test medium pH used for in vitro susceptibility testing can alter the azole MIC for Candida species. Vaginal pH is usually unchanged in VVC infections, but a low vaginal pH may affect treatment success. Danby and colleagues did not demonstrate an effect of pH on boric acid MIC for C. glabrata or fluconazole-sensitive and -resistant C. albicans but showed that amphotericin B and flucytosine have increasing MIC at lower pH.30 Based on these data, we treated certain recalcitrant patients with a combination of boric acid (a weak acid which raises vaginal pH to approximately 5.5) and amphotericin B suppositories. To the best of our knowledge, there are no previous reports of combination amphotericin B and boric acid for treatment of C. glabrata or other NAC isolates. In our study, boric acid was administered as a 600 mg vaginal suppository nightly, whereas amphotericin B was given as a 50 mg vaginal suppository in the morning. This combination was an effective treatment for 100% (4/4) of patients and was used as the initial treatment for 1 patient. In a patient population with multiple vulvovaginal complaints, assigning probable causality of symptoms to clearance of a particular yeast isolate from a culture can be difficult, but we tried to mitigate potential bias by having an investigator not involved with direct care of these patients make the determination through independent chart review. Time to both mycologic and clinical cure varied significantly, but interpretation of these measures was limited by the retrospective nature of the study. Each patient with symptomatic NAC isolates who underwent treatment eventually achieved CC, but some patients required more intensive treatment regimens. Clearly, a prospective trial with a designated treatment protocol would improve our ability to answer important questions about NAC infections, but such studies are limited by the relatively sporadic nature of these cases outside tertiary care referral vaginitis centers. The incidence and pathogenicity of NAC isolates in this study suggest that, in some cases, NAC yeast may indeed cause clinically significant infections and warrant attempts at treatment in symptomatic women. After the review of the entire NAC episode, which may include multiple positive cultures, the infections were felt to be causing symptoms in half of the cases. Our findings are similar to a previous report in the literature with a similar patient population.12 Patients seen at referral vaginitis clinics most © 2015, American Society for Colposcopy and Cervical Pathology
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likely have more multifactorial causes for their presenting symptoms and often multiple previous treatments; therefore, yeast cultures may be biased toward more complicated infections with NAC isolates. These findings add to the growing body of literature characterizing NAC isolates and their potential involvement in recurrent and often refractory VVC episodes. Until a prospective cohort study or randomized clinical trial can be performed, it seems reasonable to treat patients suspected of having symptomatic non-albicans Candida infections with either boric acid or fluconazole after ruling out other potential confounding vulvovaginal conditions.
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8. Nyirjesy P, Seeney SM, Grody MHT, et al. Chronic fungal vaginitis: The value of cultures. Am J Obstet Gynecol 1995;173:820–823. doi: 10.1016/0002-9378(95)90347-X.
25. Sobel JD. Management of recurrent vulvovaginal candidiasis: Unresolved issues. Curr Infect Dis Rep 2006;8:481–486. doi:10.1007/s11908-006-0023-7.
9. Holland J, Young ML, Lee O, et al. Vulvovaginal carriage of yeasts other than Candida albicans. Sex Transm Infect 2003;79:249–250. doi:10.1136/ sti.79.3.249. 10. Geiger AM, Foxman B, Sobel JD. Chronic vulvovaginal candidiasis: characteristics of women with Candida albicans, C glabrata and no candida. Genitourin Med 1995;71:304–307. doi:10.1136/sti.71.5.304. 11. Sobel JD, Faro S, Force RW, et al. Vulvovaginal candidiasis: Epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998;178: 203–211. doi:10.1016/S0002-9378(98)80001-X. 12. Kennedy MA, Sobel JD. Vulvovaginal Candidiasis caused by non-albicans Candida species: New insights. Curr Infect Dis Rep 2010;12:465–470. doi: 10.1007/s11908-010-0137-9. 13. Martins HPR, da Silva MC, Paiva LCF, et al. Efficacy of fluconazole and nystatin in the treatment of vaginal Candida species. Acta Derm Venereol 2012;92:78–82. doi:10.2340/00015555-1194.
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26. Sobel JD, Chaim W. Treatment of Torulopsis glabrata vaginitis: Retrospective review of boric acid therapy. Clin Infect Dis 1997;24: 649–652. 27. Iavazzo C, Gkegkes ID, Zarkada IM, et al. Boric acid for recurrent vulvovaginal candidiasis: the clinical evidence. J Womens Health (Larchmt) 2011;20:1245–1255. doi:10.1089/jwh.2010.2708. 28. Khan ZU, Ahmad S, Al-Obaid I, et al. Emergence of resistance to amphotericin B and triazoles in Candida glabrata vaginal isolates in a case of recurrent vaginitis. J Chemother 2008;20:488–491. 29. Sobel JD, Chaim W, Nagappan V, et al Treatment of vaginitis caused by Candida glabrata: Use of topical boric acid and flucytosine. Am J Obstet Gynecol 2003;189:1297–1300. doi:10.1067/S0002-9378(03)00726-9. 30. Danby CS, Boikov D, Rautemaa-Richardson R, et al. Effect of pH on in vitro susceptibility of Candida glabrata and Candida albicans to 11 antifungal agents and implications for clinical use. Antimicrob Agents Chemother 2012;56:1403–1406. doi:10.1128/AAC.05025-11.
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Non-albicans Candida Vulvovaginitis: Treatment Experience at a Tertiary Care Vaginitis Center Anna M. Powell, MD,1 Edward Gracely, PhD,2,3 and Paul Nyirjesy, MD1 Objectives: The aims of this study are to analyze a cohort of women with vulvovaginal symptoms and positive cultures for non-albicans Candida (NAC) to determine whether yeast was responsible for their symptoms and to evaluate the mycological effectiveness of various regimens. Methods: This observational study was performed from retrospective chart review of patients with positive NAC cultures between April 1, 2008, and January 31, 2011, at a tertiary care vaginitis center. Patient intake demographics were entered into a database. Follow-up visits were analyzed for data about patient treatments and outcomes. Patients were considered a clinical cure if their symptoms were significantly improved and mycologic cure (MC) if later yeast cultures were negative. If clinical symptoms improved at the same time as MC, the isolate was considered the proximate cause for the symptoms. Results: One hundred eight patients meeting entry criteria were analyzed. Boric acid was effective at obtaining MC in 32 (78%) of 41 patients with C. glabrata, 3 of 3 patients with C. tropicalis, and 3 of 3 patients with C. lusitaniae. Fluconazole was effective as initial treatment for 3 (60%) of 5 patients with C. glabrata and 13 (81%) of 16 patients with C. parapsilosis. In 52.7% of C. glabrata, 66.7% of C. parapsilosis, and 57.1% of C. tropicalis cases, effective antifungal therapy led to symptom improvement. Conclusions: In a tertiary care vaginitis center, NAC, when isolated on culture, caused clinically significant infections in approximately half of symptomatic patients. A majority of infections can be effectively treated with boric acid or fluconazole regardless of the non-albicans Candida species. Key words: non-albicans Candida, Candida glabrata, vulvovaginitis (J Lower Gen Tract Dis 2016;20: 85–89)
V
ulvovaginal candidiasis (VVC) is one of the most frequent causes of vaginitis, which is associated with significant direct and indirect health-care costs. While Candida albicans is the most frequent causative agent, non-albicans Candida (NAC) species may also cause symptomatic yeast infections.1 Although women are led to believe that they can accurately self-diagnose VVC, only 11% who have never had an episode of VVC and 34% who have can accurately recognize the written description of VVC.2 Improper treatment of yeast vulvovaginitis may occur in the setting of frequent self-treatment with over-the-counter antifungals and empiric treatment with azoles by patients and providers.3–5 Because the use of broad-spectrum antibiotics has become more commonplace, the frequency of mucosal and systemic infections by NAC, especially Candida glabrata, has increased significantly,3 and higher percentages of NAC species (32%–40%) have
1 Drexel University College of Medicine, Department of Obstetrics and Gynecology; 2Drexel University College of Medicine, Department of Family, Community and Preventive Medicine; and 3Epidemiology and Biostatistics at Drexel School of Public Health, Philadelphia, PA Reprint requests to: Anna Powell, MD, 245 N 15th St MS 495, Philadelphia, PA 19102. E-mail: [email protected] Financial disclosures: Dr. Nyirjesy does report the following relationships with industry: Novadigm (consultant, research grant), Viamet Pharmaceuticals (consultant, research grant), and Becton-Dickinson (research grant). Dr. Powell and Dr. Gracely report no conflicts of interest. © 2015, American Society for Colposcopy and Cervical Pathology
been isolated in women with recurrent vulvovaginitis than in women with isolated episodes of vulvovaginal candidiasis (11%–20%).6–9 Eradication of NAC infections may be more difficult because of antimicrobial resistance to commonly used agents.3 Of the NAC species, C. glabrata has been reported most commonly. Risk factors identified for vulvovaginal C. glabrata infections include older age, underlying medical conditions such as diabetes, and douching.10 Candida glabrata is thought to carry few if any virulence factors compared with C. albicans but exhibits more azole resistance. The percentage of patients with C. glabrata infection treated effectively by practitioners with azoles alone is not known, but in vitro studies frequently show higher minimum inhibitory concentrations (MIC) for all available azoles compared with C. albicans.11 In clinical practice, this often necessitates treatment with vaginal boric acid, amphotericin B, flucytosine cream,12 or nystatin.13 Candida parapsilosis was initially considered nonpathogenic until a fatal case of endocarditis in a narcotic addict was reported in 1940.14 In vulvovaginal disorders, C. parapsilosis has been considered indolent by some14; on the other hand, Kennedy and colleagues concluded that 62.5% of isolates caused symptomatic vulvovaginal infections.12 Previously reported outcomes of vulvovaginal infections caused by C. krusei suggest this organism is implicated in refractory cases of vulvovaginits but clears with prolonged courses of clotrimazole or boric acid.15 Silverman and colleagues reported one case of refractory vulvovaginitis caused by C. lustianiae successfully treated with vaginal boric acid for 14 days.16 Although mycologic eradication with antifungal treatment can be difficult to achieve because of resistance issues, it is difficult to determine how often it is necessary to treat NAC. Although it had been previously assumed that the presence of NAC was indicative of a symptomatic infection, it is possible that symptomatic patients with a positive culture for NAC have symptoms because of another condition, for example, dermatitis, and that they are simply colonized with NAC. Thus, the role of NAC in causing symptomatic infection is vigorously debated, with some authors17 finding that vulvovaginal symptoms in women with NAC isolates resolve without antifungal treatment in up to 86% of cases. Given the controversies with regard to their role in causing vulvovaginal symptoms and the limited published data about effectiveness of various treatment regimens, we undertook a review of the NAC cases at our tertiary care vaginitis center to describe affected women, ascertain which treatments cleared the organism mycologically, and determine whether clearance of the organism resulted in relief or improvement of vulvovaginal symptoms.
METHODS This observational study consisted of a retrospective chart analysis of patients presenting with vulvovaginal symptoms, from whom NAC were isolated via vaginal yeast culture between April 2008 and January 2011. Institutional review board approval was obtained from Drexel University College of Medicine’s Office of Research (IRB Protocol No. 1203000971). Patients were seen
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at the Drexel Vaginitis Center, a tertiary care referral center for patients referred by their health-care providers because of persistent or recurrent vulvovaginal symptoms. The program sees an estimated 500 new and 4300 return annual patient visits. Each new patient undergoes a standardized history and examination, which includes testing for vaginal pH, amines, saline, and 10% KOH microscopy. Almost all patients have a baseline yeast culture sent to a commercial laboratory, which speciates positive organisms. Yeast cultures are repeated in patients with previous positive cultures or when a new yeast infection is suspected. Although follow-up visits were not mandated by protocol, patients are typically seen for reevaluation within 2 to 4 weeks of initiating treatment. Initial diagnosis was noted because a majority of patients seen at the Drexel University Vaginitis Center presented with multiple vulvovaginal complaints and may have had more than one underlying diagnosis. Diagnosis of yeast vaginitis was either made by presence of budding yeast or hyphae with KOH microscopy or by a positive yeast culture with corresponding symptoms. Antifungal minimum inhibitory concentration (MIC) via susceptibility is not recommended per CDC treatment guidelines and, therefore, was not routinely obtained.18 Patients with NAC were identified, and their electronic records were reviewed. Of note, our electronic medical record was implemented in April 2008, so patients with initial encounters before this date were excluded because of incomplete data. Study data were collected and managed using REDCap (Research Electronic Data Capture), an electronic data capture tool hosted at Drexel University College of Medicine.19 Study data were extracted from a database of 2396 patients with yeast cultures collected between 2008 and 2011. Data collected included demographics, medical history, symptoms, microscopic findings, yeast culture results, and treatments from the initial time when a positive culture was obtained until there was a negative one. All patients presenting for initial visit reported vulvovaginal symptoms (itching, burning, discharge, or dyspareunia). Interval visits between first positive and first negative NAC culture were also reviewed. Patient visits were conducted by center staff, either the center’s director (P.N.) or a dedicated nurse practitioner. A specific author (A.M.P.) reviewed charts to assess rates of clinical cure (CC) and mycological cure (MC) whether, at the completion of antifungal treatment for the NAC isolate, yeast was the organism responsible for symptoms. Clinical cure was defined as patients describing themselves as more than 50% better after a treatment course. Mycological cure was defined as a negative follow-up yeast culture; rates of MC with various treatment modalities were determined. If the patient remained symptomatic at the end of a successful treatment course or if the provider documented an alternative diagnosis, then symptoms were not attributed to yeast, and the patient was defined as being colonized with NAC. On the other hand, if MC correlated with CC, the patient was defined as having a true yeast infection, with the NAC being the likely cause for the symptoms. Unless an NAC infection with treatment failure was specifically documented by the visit provider, the alternative diagnosis is assumed to be the probable cause of vulvovaginal symptoms. The following treatments were used: boric acid 600 mg vaginal capsule given nightly for 14 days20; fluconazole 150 to 200 mg oral daily21; amphotericin B 50 mg vaginal suppository nightly22 with the addition of 600 mg vaginal capsules of boric acid in the morning (off label) for 14 days or, as a separate regimen, 4% with flucytosine 17% in a vaginal cream, 5 g nightly for 14 days23; compounded caspofungin vaginal cream (100 μg/4 g in sodium carboxy gel), 5 grams nightly for 14 days; nystatin 100,000 units given as a compounded tablet daily per vagina for at least 3 weeks; clotrimazole 1% vaginal cream18; or
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miconazole 2% vaginal gel18 for 7 to 14 days. It should be noted that, apart from the clotrimazole and miconazole preparations, all products were compounded and used off label. Initial treatment choice and subsequent order of therapy was decided by the clinic provider based on patient history, wet mount results, and clinical index of suspicion. Treatment courses are described by the initial antifungal used, followed by any additional antifungals that resulted in a negative yeast culture per episode, and total number of treatments required to achieve MC were recorded. In cases requiring more than 2 treatments, each treatment was reported.
RESULTS A total of initial 2396 patient charts were reviewed. Negative yeast cultures or those only positive for C. albicans were excluded. This left 298 patients whose cultures contained an NAC species. These patient charts were then reviewed and excluded from further analysis if the initial history and physical exam was not documented in the electronic medical record (n = 48), if the first patient visit was outside of the study date range (n = 51), or for incomplete data (n = 91). A total of 108 patients with 181 NAC isolates with complete data within the designated date range were available for review. Each woman had at least 2 clinic visits documented and may have had multiple positive NAC cultures. Demographic data and risk factors for recurrent VVC are listed in Table 1. The most frequent concomitant vulvovaginal disorders diagnosed on initial encounter were bacterial vaginosis (n = 24, 22%) and localized provoked vestibulodynia (n = 12, 11%). The most frequent NAC cultures were C. glabrata (n = 111, 63.4%), C. parapsilosis (n = 24, 20.6%), C. tropicalis (n = 9, 5.1%), C. lusitaniae (n = 6, 3.4%), and C. krusei (n = 5, 2.8%). Fifty-five patients had cultures positive for C. glabrata. In 29 (52.7%) of 55 patients, C. glabrata was retrospectively determined to be the cause of symptoms. Mycologic cure was not recorded for 5 patients who did not have further follow-up visits in our EMR; therefore, 50 patients were analyzed for effective treatment courses. Boric acid (600 mg intravaginally for 21–30 days) was the initial therapy used for 41 (82%) of 50 of patients, resulting in MC for 32 (78%) of 41 patients. Fluconazole was the second most commonly used initial treatment and was found to be the effective treatment in 3 (60%) of 5 patients receiving this therapy. A total of 9 patients had NAC isolates preceded by C. albicans; in these, six (67%) were determined to be asymptomatic after treatment of C. albicans. There were 9 associated treatment failures for patients initially treated with boric acid requiring additional antifungal treatments. Three patients who required subsequent treatment following boric acid were felt to have symptoms caused by yeast. One hundred percent of the patients treated and retrospectively determined to have symptoms caused by NAC achieved CC (Table 2). Four patients were noted to have refractory cases of C. glabrata requiring more than 2 distinct antifungal treatments. The first patient, a 62-year-old female patient with concurrent atrophic vaginitis and vulvodynia required boric acid 600 mg vaginal capsules for 30 days with subsequent maintenance therapy twice weekly, in addition to amphotericin B vaginal suppositories administered nightly for 14 days for 3 courses total and caspofungin given for 14 days for 2 courses to achieve MC. Retrospective analysis determined yeast was not responsible for symptoms. Caspofungin was reported as susceptible for this isolate. The second patient, a 41-year-old female patient with no concurrent vulvovaginal disorders required miconazole 2% vaginal gel nightly for 14 days 2 courses, fluconazole 200 mg twice weekly for 28 days, boric acid vaginal capsules © 2015, American Society for Colposcopy and Cervical Pathology
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Journal of Lower Genital Tract Disease • Volume 20, Number 1, January 2016
Non-albicans Candida Vulvovaginitis
TABLE 1. Demographics and Risk Factors
No. patients with NCA isolate Mean age (SD) Vaginitis symptoms attributed to yeast White African American Race (other) Diabetes mellitus Previous vulvovaginal candidiasis Sexually active Premenopausal Postmenopausal Exogenous estrogen use Previous antibiotic use Previous antifungal use Topical corticosteroid use
C. glabrata
C. parapsilosis
C. tropicalis
C. lusitaniae
C. krusei
55 45.9 (15.5) 29/55 (52.7%) 36 (65.4%) 11 (20%) 5 (9.1%) 1 (1.8%) 29 (52.7%) 37 (67.3%) 35 (63.4%) 18 (32.7%) 6 (10.9%) 30 (54.5%) 36 (65.4%) 11 (20%)
24 45.4 (16.7) 16/24 (66.7%) 18 (75%) 5 (20.8%) 4 (16.7%) 0 11 (45.8%) 16 (66.7%) 12 (50%) 12 (50%) 5 (20.8%) 17 (70.8%) 15 (62.5%) 4 (16.7%)
7 53.1 (13.7) 4/7 (57.1%) 4 (57.1%) 2 (28.6%) 1 (14.3%) 1 (14.3%) 1 (14.3%) 5 (71.4%) 2 (28.6%) 5 (71.4%) 1 (14.3%) 4 (57.1%) 5 (71.4%) 0
5 39 (15.9) 3/5 (60%) 3 (60%) 2 (40%) 0 0 1 (20%) 5 (100%) 3 (60%) 2 (40%) 2 (40%) 4 (80%) 3 (60%) 1 (20%)
2 47 (9.8) 2/2 (100%) 2 (100%) 0 0 0 2 (100%) 1 (50%) 1 (50%) 1 (50%) 0 0 2 (100%) 1 (50%)
for 21 days, followed by compounded nystatin (100,000 units in 1 tablet) vaginally for 30 days’ total to achieve MC. Retrospective analysis determined yeast was responsible for symptoms in this case. Susceptibility testing was not performed. The third patient, a 47-year-old female patient without concurrent vulvovaginal disorders, required boric acid for 21 days, amphotericin B for 21 days, caspofungin for 28 days, and nystatin for 30 days to achieve MC. Retrospective analysis determined yeast was responsible for symptoms. The isolate was found susceptible to fluconazole, amphotericin B, and caspofungin but intermediately resistant to boric acid (MIC data not available). The fourth patient was a 47-year-old female patient with concurrent vulvodynia required boric acid vaginal capsules for 30 days, amphotericin B 50 mg vaginal suppository nightly and compounded flucytosine 15.5% vaginal cream nightly for 14 days, and compounded nystatin vaginal capsules for 30 days to achieve MC. Retrospective analysis determined yeast was not responsible for symptoms. Twenty-four patients had cultures positive for C. parapsilosis. Candida parapsilosis was retrospectively determined as the cause of symptoms in 16 (66.7%) of 24 patients. Fluconazole was initial treatment for 16 (66.7%) of 24 patients and resulted in MC in 13 (81.2%) of 16 patients with 3 associated treatment failures requiring further antifungal treatments. One patient determined to have NAC as the retrospective cause of symptoms did not receive treatment but obtained MC and CC at a visit 42 days after her initial visit. Boric acid was initial treatment for 4 patients, effective
for 3 (75%) of 4 of patients treated with 1 treatment failure. Amphotericin B was a first-line treatment for 1 patient, and 1 patient initially treated with miconazole did not achieve MC. Two patients required more than 2 treatment courses; the first was a 62-year-old female patient without concurrent vulvovaginal disease who required fluconazole 200 mg twice weekly 35 days, followed by compounded flucytosine 15.5% vaginal cream nightly for 14 days to achieve MC. Susceptibilities were reported twice: initially, fluconazole intermediate (MIC 32 μg/mL) and flucytosine sensitive and, subsequently, fluconazole resistant (MIC 64 μg /mL) and flucytosine and amphotericin B susceptible. Yeast was retrospectively determined to be the cause of symptoms. The second patient was a 59-year-old female patient without concurrent vulvovaginal disorders who required boric acid vaginal capsules nightly for 21 days and fluconazole 200 mg twice weekly continued as maintenance therapy for greater than 1 year to achieve MC. All treated patients determined to have NAC-attributable episodes achieved CC. Seven patients had cultures positive for C. tropicalis. Four (57.1%) of 7 patients were retrospectively determined to have yeast causing symptoms, and all achieved CC. Boric acid was first-line therapy for 3 of 3 patients with no treatment failures. Fluconazole was first-line therapy for one of 2 patients with 1 treatment failure. A combination of fluconazole and boric acid was administered for 2 patients. The patient with treatment failure was a 57-year-old with concurrent atrophic vaginitis who required fluconazole 200 mg twice weekly for 8 weeks, boric acid
TABLE 2. Treplatment Outcome of Patients with Vulvovaginal Symptoms (N = 108)
Total no. patients NAC causing symptoms Yeast colonization Positive KOH smear at initial visit Empirical treatment for VVC at initial visit Treated Most common treatment
C. glabrata
C. parapsilosis
C. tropicalis
C. lusitaniae
C. krusei
55 (50.9%) 29 (52.7%) 26 (47.2%) 23/55 (41.8%) 28/55 (51%) 55 (100%) Boric acid
24 (22%) 16 (67%) 8 (33%) 13/24 (54.2% ) 11/24 (45.8%) 22 (91.6%) Fluconazole
7 (6.5%) 4 (57.1%) 3 (42.8%) 3/7 (43%) 2/7 (28.6%) 7 (100%) Boric acid
5 (4.6%) 3 (60%) 2 (40%) 3/5 (60%) 4/5 (80%) 4 (80%) Boric acid
2 (1.8%) 2 (100%) 0 2/2 (100%) 1/2 (50%) 2 (100%) Boric acid, nystatin
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vaginal capsules for 21 days, compounded nystatin 100,000 units-triamcinolone ointment for 60 days, and compounded amphotericin B 4%/flucytosine 17% cream administered vaginally at night for 14 days to achieve MC. Five patients had cultures positive for C. lusitaniae. Yeast was retrospectively determined to cause symptoms in 3 (60%) of 5 patients, and all 3 women achieved CC. Boric acid resulted in MC for 4 (80%) of 5 treated episodes. No patients required more than 2 treatment modalities. Two patients had C. krusei identified in 2 cultures, and in both cases, yeast was retrospectively determined to cause symptoms. One patient required treatment with boric acid nightly for 73 days to achieve MC. The other patient achieved MC after treatment with boric acid 600 mg vaginal suppository inserted nightly for 21 days, followed by amphotericin B 50 mg vaginal suppository administered for 14 days and compounded nystatin 100,000 units vaginally for 30 days. Four patients grew other Candida species: C. zeylanoides (as above), C. famata, C. kefyr, and C. rugosa, respectively. The C. kefyr and C. zeylanoides isolates were noted to cause symptoms. The patients with C. kefyr and C. rugosa isolates achieved MC. The C. famata isolate was not treated. The patient with C. zeylanoides received maintenance fluconazole of 200 mg twice weekly for 3 weeks. The C. kefyr isolate was treated with boric acid 600 mg vaginal suppository for 21 days, and C. rugosa was treated with maintenance boric acid, 600 mg vaginal capsule applied 3 times per week for 12 weeks. Nine patients were found to have one of the following “other” yeast: Trichosporon species (n = 3), Saccharomyces cerevisiae (n = 2), Rhodotorula species (n = 2), Geotrichum species (n = 1), and Aureobasidium pullulans (n = 1). Trichosporon species did not cause symptoms; however, 2 patients received treatment, both with fluconazole 200 mg orally twice weekly for 13 weeks. Saccharomyces cerevisiae caused symptoms for 1 patient, who achieved MC after treatment with clotrimazole vaginal cream for 14 days. The other patient received maintenance fluconazole (200 mg twice weekly 4 weeks by mouth), followed by boric acid 600 mg vaginal capsules nightly for 30 days. The patient with Geotrichum species was retrospectively determined to cause symptoms for 1 patient, who achieved MC after treatment with fluconazole 200 mg by mouth twice weekly for 4 weeks. A. pullulans did not cause symptoms, but MC was achieved after treatment with fluconazole 150 mg PO twice weekly for 12 weeks.
DISCUSSION Candida albicans is the most frequently encountered isolate in VVC, accounting for 80% to 90% of cases, followed by C. glabrata, accounting for 7% to 16% of isolates.6 Previous studies suggest that NAC isolates, most commonly C. glabrata, only cause symptomatic infections in 15% to 20% of cases.12,24 Dennerstein and colleagues have even called into question the use of treating NAC isolates, as they found that symptoms and the yeast often resolved without specific antifungal treatment, suggesting these organisms tend to be innocent bystanders in the setting of other VVC complaints.17 Other studies have suggested they are indeed a cause for vulvovaginal symptoms, albeit infrequently.12,24 In our study, we found that C. glabrata, when present in symptomatic women with chronic vulvovaginal symptoms, was the cause of the symptoms 52% of the time, suggesting that it can function as a true pathogen. For other organisms such as C. parapsilosis, C. tropicalis, and C. krusei, our results again suggest that, when present in a symptomatic woman, they cause symptoms at least half of the time if not more.
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As noted with our results and by other authors, successfully eradicating yeast from the vagina can be difficult. An initial therapy which continues to be used by many experts25,26 is boric acid. Boric acid is a well-tolerated and cost-effective fungistatic agent that has shown efficacy in acute episodes of VVC and maintenance therapy.26,27 Small published reports of successful treatment of C. glabrata with amphotericin B suppositories (50 mg nightly) show successful treatment in up to 70% of patients who did not respond to azole treatment22; however, recent studies also suggest emerging resistance of these isolates to amphotericin B.28 In our study, the use of amphotericin B suppositories alone resulted in MC in 100% (3/3) of patients with C. glabrata isolates. Topical flucytosine is another treatment option and, in one study, was an effective treatment for 90% of patients who failed boric acid.29 White and colleagues23 report on the use of topical flucytosine and amphotericin B compounded together for refractory C. glabrata with MC obtained within 2 weeks of treatment with minimal side effects. In our study, 3 patients were treated with combination amphotericin B/flucytosine for C. glabrata, C. tropicalis, and C. parapsilosis, respectively. However, the expensive cost (currently more than $1000) limits the ability to use either of these regimens. One proposed mechanism for increased azole resistance by C. glabrata, and in some cases, C. albicans is altered susceptibility to decreasing medium pH.30 Test medium pH used for in vitro susceptibility testing can alter the azole MIC for Candida species. Vaginal pH is usually unchanged in VVC infections, but a low vaginal pH may affect treatment success. Danby and colleagues did not demonstrate an effect of pH on boric acid MIC for C. glabrata or fluconazole-sensitive and -resistant C. albicans but showed that amphotericin B and flucytosine have increasing MIC at lower pH.30 Based on these data, we treated certain recalcitrant patients with a combination of boric acid (a weak acid which raises vaginal pH to approximately 5.5) and amphotericin B suppositories. To the best of our knowledge, there are no previous reports of combination amphotericin B and boric acid for treatment of C. glabrata or other NAC isolates. In our study, boric acid was administered as a 600 mg vaginal suppository nightly, whereas amphotericin B was given as a 50 mg vaginal suppository in the morning. This combination was an effective treatment for 100% (4/4) of patients and was used as the initial treatment for 1 patient. In a patient population with multiple vulvovaginal complaints, assigning probable causality of symptoms to clearance of a particular yeast isolate from a culture can be difficult, but we tried to mitigate potential bias by having an investigator not involved with direct care of these patients make the determination through independent chart review. Time to both mycologic and clinical cure varied significantly, but interpretation of these measures was limited by the retrospective nature of the study. Each patient with symptomatic NAC isolates who underwent treatment eventually achieved CC, but some patients required more intensive treatment regimens. Clearly, a prospective trial with a designated treatment protocol would improve our ability to answer important questions about NAC infections, but such studies are limited by the relatively sporadic nature of these cases outside tertiary care referral vaginitis centers. The incidence and pathogenicity of NAC isolates in this study suggest that, in some cases, NAC yeast may indeed cause clinically significant infections and warrant attempts at treatment in symptomatic women. After the review of the entire NAC episode, which may include multiple positive cultures, the infections were felt to be causing symptoms in half of the cases. Our findings are similar to a previous report in the literature with a similar patient population.12 Patients seen at referral vaginitis clinics most © 2015, American Society for Colposcopy and Cervical Pathology
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Journal of Lower Genital Tract Disease • Volume 20, Number 1, January 2016
likely have more multifactorial causes for their presenting symptoms and often multiple previous treatments; therefore, yeast cultures may be biased toward more complicated infections with NAC isolates. These findings add to the growing body of literature characterizing NAC isolates and their potential involvement in recurrent and often refractory VVC episodes. Until a prospective cohort study or randomized clinical trial can be performed, it seems reasonable to treat patients suspected of having symptomatic non-albicans Candida infections with either boric acid or fluconazole after ruling out other potential confounding vulvovaginal conditions.
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