CHICAGO – Even though the numbers remain small, fluconazole-resistant Candida albicans vulvovaginitis appears to be emerging as a thorny clinical problem, one expert suggests.
Since its introduction in 1990 as a prophylactic antifungal agent after bone marrow transplantation, fluconazole (Diflucan) has become established as the dominant therapy for vulvovaginal candidiasis (VVC) worldwide. In North America alone, roughly 8 million cases of recurrent vulvovaginitis are reported annually, with more than 90% due to C. albicans.
"So the possibility of resistance is a tremendous problem and concern," asserted Dr. Jack D. Sobel, chief of the division of infectious diseases and professor of obstetrics and gynecology at Wayne State University in Detroit.
Women with recurrent vulvovaginitis are treated with induction and prolonged, low-dose maintenance fluconazole regimens to achieve an asymptomatic state. Successful control, not cure, is achieved in more than 90%. Susceptibility testing for C. albicans is not standard of care, so there is very little published data on prolonged fluconazole use, Dr. Sobel said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.
He and his colleagues published the only study to address the issue of resistance, and it failed to identify any evidence of fluconazole resistance in isolates of C. albicans after just 1 year of follow-up (N. Engl. J. Med. 2004;351:876-83).
Clinicians at Wayne State’s Vaginitis Clinic, however, have observed an uptick in the frequency of refractory Candida vulvovaginitis cases in the last 10 years among the more than 500 women with recurrent vulvovaginitis that they follow. The women present either on a maintenance fluconazole regimen with a breakthrough of symptoms accompanied by positive cultures or fail to resolve acute symptomatic vulvovaginitis with multidose fluconazole and have increased minimum inhibitory concentration (MIC) in vitro, Dr. Sobel explained.
A retrospective review of patients referred to the Vaginitis Clinic between 2000 and 2010 revealed 25 patients with clinically refractory fluconazole-resistant vulvovaginitis with confirmed in vitro resistance, with an MIC at least 2 mcg/mL (median 8 mcg/mL).
"Two-thirds of these patients were seen in the last 5 years, so the incidence is increasing," he said.
Eight patients had an MIC of 2 mcg/mL and 17 had MICs ranging from 4-128 mcg/mL. Cross resistance to itraconazole (Sporanox) was present in five women and to ketoconazole (Nizoral) in four.
The cohort consists of married, insured Caucasian women with an average or above average socioeconomic status. Their mean age was 43 years (range 32-56 years). All patients had significant consumption of and recent exposure to fluconazole, with 64% on low-dose, weekly maintenance fluconazole.
Significant risk factors for refractory Candida VVC included more than 10 lifetime sexual partners, recent use of antibiotics, and for mycological failure included increased fluconazole exposure and older age of VVC onset.
Management
Management of refractory VVC is possible, but can be extremely difficult, Dr. Sobel acknowledged.
"When you can’t use fluconazole, the closet is pretty empty," he said.
Dr. Sobel recommends initially using boric acid 600 mg per day for 14 days until an MIC is available. For those with low-level resistance, defined by an MIC of 2-4 mcg/mL, clinicians should increase the fluconazole dose to 150-200 mg twice weekly. Eleven of the 25 patients in the study cohort were controlled on this regimen, with five eventually discontinuing fluconazole.
"In patients with high level resistance, treatment depends on the presence of azole cross-resistance," he said.
Among eight such patients, three were successfully controlled on 200 mg per day of itraconazole, and four of five were controlled on ketoconazole 100 mg per day, both typically for several months. One patient required daily gentian violet for 14 days, with cure, and three patients were controlled on boric acid three times per week.
The novel, oral broad-spectrum antifungal, voriconazole (Vfend) is a possibility, but is rarely used because it is so poorly tolerated, Dr. Sobel said. Audience members questioned whether flucytosine (Ancobon), a synthetic antimycotic, can be employed. Specialty pharmacies can formulate it, but at $1,500 to $2,000 per tube is out of reach for most women.
The antifungal antibiotic nystatin, which was patented back in 1957 as the world’s first antifungal, is a far cheaper alternative, but should be given at 100,000 units daily per vagina only, Dr. Sobel said.
Nystatin also upstaged newer antifungal agents when used to treat vulvovaginal candidiasis caused by Candida glabrata in sequential, prospective clinical trials.
On day 7 to day 14 of follow-up, mycological cure of C. glabrata vulvovaginitis was achieved by 15 of 16 women (94%) treated with a nystatin vaginal suppository, compared with 8 of 19 (42%) given a miconazole nitrate vaginal suppository, 5 of 9 (56%) given oral fluconazole and 7 of 15 (47%) given oral itraconazole.