American Journal of Obstetrics and Gynecology (2005) 192, 200913

www.ajog.org

Treatment of non-albicans Candida vaginitis with

amphotericin B vaginal suppositories
Albert John Phillips, MD*
Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA

KEY WORDS
Amphotericin B
Vaginitis
Non-albicans Candida

Objective: This study was undertaken to investigate whether amphotericin B vaginal suppositories would be effective in the treatment of non-albicans Candida vaginitis in women who failed
conventional therapy.
Study design: Thirty-two patients were identified with non-albicans Candida vaginitis. These
patients were treated with conventional antifungal agents. Ten patients had persistence of the
non-albicans Candida infection after treatment. Amphotericin B 50-mg vaginal suppositories were
given nightly for 14 days to this subgroup of treatment failures.
Results: Of 10 women, 8 (80%) who were treated with amphotericin B vaginally initially showed
no further infection. One of the treatment successes had 2 recurrences and responded to a second
course of amphotericin B but failed a third course. If this patient is considered a treatment failure,
then amphotericin B vaginal suppositories were successful in 70% of patients. The medication
was well tolerated and local side effects were minimal.
Conclusion: Amphotericin B vaginal suppositories are a viable treatment option for refractory
vaginitis caused by non-albicans Candida.
2005 Mosby, Inc. All rights reserved.

Vaginitis is a common gynecologic condition and

accounts for more than 10 million oce visits each year.
Vaginal candidiasis is the second most frequent vaginal
infection in the United States.1 The majority of vaginal
candidiasis is due to Candida albicans.2 Over the last 30
years the incidence of other species of Candida, termed
non-albicans Candida, have steadily increased, with
C glabrata being the most common species of this
subgroup.3 C albicans responds to antifungal treatment
uniformly well, but the non-albicans Candida have
variable responses to conventional azole treatment.4
Presented at the 71st Annual Meeting of the Pacic Coast Obstetrical and Gynecological Society, October 19-24, 2004, Phoenix, Ariz.
* Reprint requests: Albert J. Phillips, MD, 1301 20th St, Suite 270,
Santa Monica, CA 90404.
E-mail: ajphillips@pol.net
0002-9378/$ - see front matter 2005 Mosby, Inc. All rights reserved.
doi:10.1016/j.ajog.2005.03.034

C glabrata has occasionally shown in vitro resistance

to azole medications.5 In candidiasis with uconazole
treatment failures, the critical independent factor inuencing therapeutic outcomes was if non-albicans Candida was isolated.6
Unfortunately with this rise in non-albicans Candida,
there are groups of patients who will not achieve clinical
cure despite treatment with multiple conventional
agents. Alternative treatments have been studied. Treatment of resistant C tropicalis with topical ucytosine
showed 93% cures.7 Treatment of azole refractory C
glabrata vaginitis with topical boric acid was successful
in 67%. A 90% cure rate occurred with topical ucytosine when used in those patients who had treatment
failures with boric acid.8 Three patients with highly
resistant azole C glabrata were successfully treated with
combined topical ucytosine and amphotericin B.9

2010

Phillips
Table Distribution of non-albicans Candida species in cultured patients

Figure C glabrata. Wet mount with potassium hydroxide.

Original magnication, !400.

This study was undertaken to determine whether

patients with non-albicans Candida vaginitis, who failed
conventional treatment with a topical azole and a
systemic azole (uconazole or ketoconazole), could benet from treatment with amphotericin B vaginal suppositories.

Materials and methods

With approval of Saint Johns Hospital Health Center/
John Wayne Cancer Institute Joint Institutional Review
Board, a review of the authors private practice patients
with non-albicans Candida vaginitis was conducted.
Between 1995 and 2004, 465 patients were seen with
symptoms of Candida vaginitis (pruritus, vulvar burning, discharge) and had a diagnosis of Candida vaginitis.
From within this group, were 32 patients (7%) found to
have non-albicans Candida vaginitis. These patients were
not pregnant and had an age range between 28 to 72
years. The majority (n = 20) was detected by identifying
the characteristic appearance for C glabrata (spores
without hyphae or pseudohyphae) on the potassium
hydroxide wet mount of the vaginal secretions (Figure).
The remainder was detected after failed azole treatment
when cultures were obtained. The distribution of the
non-albicans Candida species isolated in this group is
listed in the Table.
Vaginal specimens were obtained with sterile cotton
swabs and placed in a transport tube of Amies gel
without charcoal. Vaginal swabs were then plated onto
inhibitory mold agar with gentamicin (BBL, Becton
Dickinson, Franklin Lakes, NJ) and incubated at 30(C
for up to 4 weeks. Yeast identications were performed
with the use of the Viteck YBC system (BioMerieux,
Inc, Durham, NC) according to the manufacturers
instructions. The inoculated organism on the Vitek
cards was read by the instrument to determine the

Candida species

C
C
C
C
C
C

24
3
2
1
1
1

75
9
6
3
3
3

glabrata
parapsilosis
krusei
lusitaniae
tropicalis
pseudotropicalis

organisms ability to assimilate 23 carbon substrates, to

grow in the presence of cycloheximide, to assimilate
nitrate, and to hydrolyze urea. From these reactions the
organism was identied. Focus Technologies, Cypress,
Calif, performed fungal susceptibility testing for amphotericin B, uconazole, and ketoconazole using broth
microdilutions.
All patients were treated initially with a topical azole.
These included a wide variety of agents, including overthe-counter as well as prescription creams. Treatment
failures were dened as persistent symptoms and a wet
mount of vaginal discharge that continued to have
evidence of Candida vaginitis. The treatment failures
were then given uconazole or ketoconazole, depending
on MIC levels on the culture. Typical dosing was ketoconazole 200 mg daily for 1 to 2 weeks or uconazole 150
mg weekly for 2 to 4 weeks.
Amphotericin B suppositories were compounded by
suspending 50 mg of amphotericin B USP powder in 2 g
of polyethylene glycol suppository base. The polyethylene glycol was heated to 60(C until it melted. The base
is then allowed to cool for 5 minutes and the amphotericin B added. The compound is then placed into
vaginal suppository molds and refrigerated where they
would solidify. Patients were asked to place the suppositories high in the vagina with their ngers at bedtime.

Results
Ten patients (9 with C glabrata; 1 with C tropicalis) of
the original 32 patients with non-albicans Candida,
continued to demonstrate infection after treatment
with a topical azole, followed by systemic azole treatment with either uconazole or ketoconazole. These
patients were prescribed amphotericin B 50-mg suppositories nightly for 14 days. The MIC levels for amphotericin B of the group was in the sensitive range (between
0.5 and %0.06). All patients returned for follow-up after
treatment between 7 and 14 days after completion of
therapy. Cure was dened as resolution of symptoms
and a negative follow-up culture or potassium hydroxide wet mount for Candida.
Eight of the 10 patients (80%) treated with amphotericin B vaginal suppositories were cured at follow-up.

Phillips
Two patients with C glabrata failed to have fungal cure
after treatment. One of the 10 patients who had
responded to treatment had 2 additional episodes of
C glabrata vaginitis at 9 months and 14 months after
initial treatment. The rst reoccurrence responded to a
second treatment course of amphotericin B, but the
treatment failed after a third course of therapy. If this
patient is considered a treatment failure, the success rate
for amphotericin B vaginal suppositories drops to 70%.
The amphotericin B vaginal suppositories were well
tolerated and without serious side eects. One patient
had mild external irritation during treatment but completed the full course of treatment. Amphotericin B, due
to its large molecular size, is not absorbed systemically
through the vaginal mucosa. For conrmation, a serum
level for amphotericin was nondetectable on day 7 of
treatment in 1 patient.

Comment
Over the course of practice, the physician will encounter
patients who have from recurrent vaginal Candida
infections. This can be related to conditions that predispose the patient to candidiasis, including diabetes,
immunosuppression, estrogens, and antibiotic use.
Chronic infection can also be due to patients with
non-albicans Candida, who have resistance to treatment
with conventional azole agents. The incidence of vaginal
infections with non-albicans Candida and specically
C glabrata is increasing.10 Non-albicans Candida species
tend to have greater in vitro resistance to azole drugs.11
This increase in the prevalence of non-albicans Candida
species has been attributed to the lack of performing
cultures in patients, who have recurrent vaginitis, and
thus overlooking C glabrata cases that often require
dierent or unconventional treatment and the widespread use of over-the-counter azole antifungal drugs.12
Although in my practice the majority of C glabrata were
still susceptible to azole antifungal therapy, a signicant
percentage of cases were resistant to topical and systemic azole drugs. Alternative treatments with boric acid
and ucytosine have been previously shown to be
successful in these circumstances. This preliminary study
with amphotericin B vaginal suppositories also shows
promise for those patients who have failed conventional
treatments and continue to have infection. When compared with boric acid and ucytosine, amphotericin B
vaginal suppositories have a similar side eect prole,
treatment duration, and clinical ecacy. The cost of the
suppositories is approximately $5 per dose.
Azole drugs are fungistatic and act via inhibition of
ergosterol synthesis, resulting in the termination of fungal
cell membrane synthesis. Amphotericin B is a polyene
macrolide antibiotic and is fungicidal. The drug has
useful clinical activity to almost all fungal species. The

2011
antifungal activity of amphotericin B requires binding to
a sterol moiety that is present in the membrane of the
sensitive fungi. With this interaction of the drug and the
sterols of the membranes, pores or channels appear. This
increase in permeability of the membrane allows leakage
of small molecules and destruction of the organism.
Because of this dierent mechanism of action, amphotericin B potentially is a viable option for treatment in
those who have failed azole treatment courses. Amphotericin B given systemically is associated with many
serious side eects, e.g., nephrotoxicity. Because of its
large molecular structure, mucous membrane absorption
does not appreciably occur. This minimizes concerns for
systemic side eects. As was seen, vaginal amphotericin B
was well tolerated in the study group.
Amphotericin B has been used previously for vaginal
candidiasis in variable doses and duration. A preliminary report in 1958 using vaginal amphotericin B found
limited eectiveness in the treatment of Candida with
cure rates of only 46%.13 Subsequent literature have
reported more favorable treatment results. Nonrandomized comparative studies of amphotericin B and nystatin
in Candida vaginal infections showed amphotericin
B cure rates of 78% to 97%.14-16 Noncomparative,
nonrandomized studies that used only amphotericin
B treatment of Candida vaginitis found treatment cures
between 54% and 96%.17-19 Vaginal amphotericin B has
been used prophylactically to prevent candidiasis with
patients taking metronidazole for Trichomonas vaginitis.20 Amphotericin B has been combined with tetracycline for nonspecic treatment of Candida and other
types of vaginitis.21-25 All these previously published
studies used doses of 50 to 100 mg given between 4 and
15 days. Minimal side eects were encountered in all
studies. In the majority of these prior reports, vaginal
candidiasis was conrmed by vaginal culture of C
albicans.
There have been no prospective, randomized studies
looking at vaginal amphotericin B ecacy in the treatment of Candida vaginitis. This preliminary study was
not randomized. In the future, a randomized prospective
controlled study using vaginal amphotericin B should be
performed in for both C albicans and non-albicans
Candida vaginitis. Amphotericin B vaginal suppositories
appear to be a viable treatment option for patients who
have refractory vaginal infections with non-albicans
Candida, who have failed conventional therapy.

References
1. Kent HL. Epidemiology of vaginitis. Am J Obstet Gynecol
1991;65:1168-76.
2. Duerr A, Sierra MF, Feldman J, Clake LM, Ehrlich I, Dehovitz J.
Immune compromise and prevalence of Candida vulvovaginitis in
human immunodeciency virus-infected women. Obstet Gynecol
1997;90:252-6.

2012
3. Spinillo A, Capuzzo F, Egbe TO, Baltaro F, Nicola S, Piazzi G.
Torulopsis glabrata vaginitis. Obstet Gynecol 1995;85:993-8.
4. Nyirjesy P, Seeney SM, Grody MHT, Jordan CA, Buckley HR.
Chronic fungal vaginitis: the value of cultures. Am J Obstet
Gynecol 1995;173:820-3.
5. Ribeiro MA, Kietze R, Paula CR, Da Matte DA, Colombo AL.
Susceptibility prole of vaginal isolates from Brazil. Mycopathologia 2001;151:5-10.
6. Sobel JD, Kapernick PS, Zervos M, Reed BD, Hooton T, Soper
D, et al. Treatment of complicated Candida vaginitis: comparison
of single and sequential doses of uconazole. Am J Obstet Gynecol
2001;185:363-9.
7. Horowitz BJ. Topical ucytosine therapy for chronic recurrent
Candida tropicalis infections. J Reprod Med 1986;31:821-4.
8. Sobel JD, Chaim W, Napgappan V, Leaman D. Treatment of
vaginitis caused by Candida glabrata: use of topical boric acid and
ucytosine. Am J Obstet Gynecol 2003;189:1297-300.
9. White DJ, Habib AR, Vanthuyne A, Langford S, Symonds M.
Combined topical ucytosine and amphotericin B for refractory
vaginal Candida glabrata infections. Sex Transm Infect 200;77:
212-3.
10. Fidel PL Jr, Vazquez JS, Sobel JD. Candida glabrata: review of
epidemiology, pathogenesis, and clinical disease with comparison
to C. albicans. Clin Microbiol Rev 1999;12:80-96.
11. Sobel JD, Faro S, Force RW, Foxman B, Ledger WJ, Nyirjesy PR,
et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and
therapeutic consideration. Am J Obstet Gynecol 1998;178:203-11.
12. Chaim W. Fungal vaginitis caused by non-albicans species. Am J
Obstet Gynecol 1997;177:485-6.
13. Stough WV, Blank H. Vaginal candidiasis in South Florida. Obstet
Gynecol 1958;12:338-40.
14. Csonka GW. Comparison of amphotericin B and nystatin pessaries in Candida infection of the vagina. Br J Vener Dis 1967;43:
210-1.
15. Corkill BM, McCarthy NJ. Comparative trial of fungilin (amphotericin B) and pimafucin (natamycin) perssaries in the treatment of
vaginal candidiasis. Med J Aust 1972;2:33-4.
16. Mick R, Muller-Tyl E, Neufeld T. Comparison of the eectiveness
of nystatin and amphotericin B in female-mycoses. Wein Med
Wochenschr 1975;125:131-5.
17. Toth B, Simon J, Palos H. Analysis of results in the therapy of
vaginal moniliasis using an amphotericin B (Fungilin) pessary.
Zentralbl Gynakol 1973;95:463-9.
18. A new treatment for monilial vaginitis. Practitioner 1971;207:
236-8.
19. Valentova M, Klobusicky M. Fungilin in the therapy of vaginal
candidiasis. Bratisl Lek Listy 1971;56:203-10.
20. Oller LZ. Prevention of post-metronidazole condidosis with amphotericin B perssaries. Br J Vener Dis 1969;45:163-6.
21. Panaitescu D, Perju A, Balota V. Squibbs amphotericin B in
treatment of Candida albicans and Trichomonas infections. Arch
Roum Pathol Exp Microbiol 1971;30:79-86.
22. VanGijsegem M. Treatment of gynecologic infections by combined
tetracycline and amphotericin B. Brux Med 1971;51:391-3.
23. Brenciaglia MI, Ilari M, Lorino G, Luciano R, Mancini C, Spitali
R. Relationships between mycoplasma and vaginitis: experimental
clinical study of 400 cases of vaginal diseases treated with the
combination of amphotericin B and tetracycline. Minerva Ginecol
1980;32:223-7.
24. Patrono D, Antonini B, Santoro A, Ceccarini M. Importance of
infections of the primary female genital tract in obstetrical and
gynecological pathology: the combination of tetracycline and
amphotericin B in a new preparation in topical vaginal therapy.
Minerva Ginecol 1981;33:31-48.
25. Rubin A, Whitcomb M, Russell M, Amod ND. Tetracycline and
amphotericin B vaginal cream for mixed vaginal infections. S Afr
Med J 1983;63:395-7.

Phillips
Editors note: This manuscript was revised after these
discussions were presented.

Discussion
DR VERA STUCKY, San Marcos, Calif. Dr Phillips has
provided us with a retrospective review of 10 years of
oce practice identifying 30 patients with non-albicans
Candida vaginitis. Twenty patients were identied by
potassium hydroxide wet mount and 10 by culture after
they failed to respond to traditional topical azole treatment. The patients were then given either systemic
uconazole or ketoconazole, and if they continued to
have symptoms, they were given compounded amphotericin B suppositories. Dr Phillips does not elaborate on
the dose or duration of the oral agent used. Eight
patients were treated with amphotericin B, and there
were 7 cures at follow-up. One patient required a second
course of treatment 9 months after initial treatment.
C glabrata is becoming a signicant cause of vulvovaginitis. Sobel et al1 have proposed reasons for the
increase of non-albicans species as a cause of vulvovaginitis, including the use of short courses of either oral or
topical regimens, and the widespread use of over-the
counter antimycotics. These short and perhaps incomplete courses of therapy perhaps eliminate the albicans
species and select for the more azole-resistant species,
most notably C glabrata.1 The majority of cases are
identied by the use of vaginal cultures. There is little
accurate data about the precise frequency of C glabrata
and little about treatment response. Fidel et al2 provide
an excellent review of C glabrata microbiology and
point out that published experience in the management
reects a biased view of patients who have been referred
to specialized clinics after treatment failure, and this
may not be representative of treatment response in the
general oce setting. Dr Phillips provides us with his
oce experience, with 7% of patients having nonalbicans Candida vaginitis and of these, 27% not
responding to conventional therapy. This provides us
with some knowledge regarding the number of patients
we may encounter.
Because vulvovaginal candidiasis is a local infection,
local treatment is ideal and carries less risk than systemic
antifungal therapy. The question is which therapy is
best, and for how long should it be used?
As Dr Phillips points out, there are no prospective,
randomized studies looking at vaginal amphotericin B
ecacy in the treatment of resistant Candida vaginitis.
Dr Phillips review of the literature indicates variable
doses and duration of treatment and success rates
ranging between 54% and 96% with vaginal amphotericin B. Dr Phillips patients provide 8 additional cases
with 7 successes. Other recommended treatments have
included nonuconazole azoles for 7 to 14 days, boric