Vol.2, No.6, 513-518 (2010) Health
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Treatment of chronic vulvovaginal candidiasis with
posaconazole and ciclopiroxolamine
Hans-Jürgen Tietz
Fungal Infection and Microbiology Institute, Berlin, Germany; tietz@institut-fuer-pilzkrankheiten.de
Received 21 January 2010; revised 30 January 2010; accepted 2 February 2010.
Therapy of chronic recurrent vulvovaginal can-
didiasis (VVC) caused by Candida glabrata is
still rare in comparison to C. albicans infection,
but therapy remains more difficult. Combination
therapy with topical antifungals may improve
therapy outcome, but still standard agents as
fluconazole or itraconazole often fail. Posa-
conazole is a new systemic triazole with a wide
antifungal spectrum including rare Candida
species. Up to now, no clinical trials with posa-
conazole in chronic recurrent VVC have been
undertaken. Here, first results of the application
of a new therapy regimen consisting of oral
posaconazole in combination with topical ci-
clopiroxolamine are presented. 15 patients with
chronic recurrent VVC caused by C. glabrata
have been treated. 14 of these patients experi-
enced successful therapy, clinical and myco-
logical cure 30 days after begin of therapy has
been observed. Long-term results are promising,
as in 4 patients clinical and mycologic cure
persists for more than 1 year up to now.
Keywords: Chronic Recurrent Vulvovaginal
Candidiasis; VVC; Candida Glabrata; Posaconazole
Vulvovaginal candidiasis (VVC) is termed chronic if it
recurs four times or more per year at intervals of 8
weeks or less [1]. Literature data suggest that acute vul-
vovaginal candidiasis becomes chronic in 5-8 % of cases
[2,3]. Possible, but heatedly debated, risk factors for
vaginal thrush include prior antibiotic or corticosteroid
therapy, intrauterine contraceptive devices (coil), high-
sugar diet, and certain sexual practices [2]. The etiology
of chronic recurrent VVC is little understood even today.
Gastrointestinal tract as a reservoir for re-infection,
re-infection from sexual partner(s), and recurrent disease
as a result of persistent colonization have been postu-
lated. This last postulate is supported by studies showing
recurrent disease to be caused by identical strains in the
vast majority of cases [2].
Though C. albicans is the main pathogen in more than
95% of cases of acute infection [4], other species are
implicated in chronic infection, chiefly C. glabrata. The
characteristic features of Candida albicans and Candida
glabrata are listed in Table 1.
The pathogenic role of C. glabrata is disputed, but pa-
tients who present to a physician with fungal disease
caused by these atypical pathogens always report symp-
toms. Though vaginal discharge is rare, redness, agoniz-
ing itching, and a sour-smelling sticky discharge are
characteristic. A diagnosis of “harmless commensal” is
therefore both inappropriate and scientifically inaccurate.
Both organisms are biosafety class 1 organisms. Hence,
though low-virulence, they are not apathogenic—unlike
Saccharomyces cerevisiae.
The therapeutic goal in chronic recurrent VVC is the
eradication of the pathogen. The chances of achieving
that goal appear to be good. Unlike C. albicans, non-
albicans Candida organisms are located predominantly
vaginally. Measures to prevent recurrence should be ini-
tiated before starting therapy [5]. Oral and bowel con-
tamination in the patient (3 fecal samples taken on 3
different days) should be investigated, which may result
in measures such as professional dental and denture
cleaning and eradication of pathogens in the mouth and
bowel with amphotericin B or nystatin (C. glabrata) in
the form of lozenges or sugar-coated tablets. A hormonal
coil is a potential pathogen reservoir and should ideally
be removed before therapy. The sexual partner should be
involved in treatment too. Colonization of the prostate
(sperm sample) and contamination of dentures (smear
tests) in older partners should be investigated.
H. J. Tietz / HEALTH 2 (2010) 513-518
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Table 1. Characteristics of C. albicans and C. glabrata as or-
ganisms causing vaginal candidiasis.
Property C. albicans C. glabrata
Etiology Mostly intra partum Frequently iatrogenic
Course Acute Chronic
Virulence class 2 (high) 1 (low)
Pseudomycelium Yes No
Blastospores midsize, oval Small-cell, round
Chlamydospores Yes No
Hormone situation Dependent No
Antifungal Pathogen susceptibility (S= sensitive, R= re-
Clotrimazole S R
Nystatin S S
Ciclopiroxolamine S S
Fluconazole S R
Posaconazole S S
Drug of first choice:
- topical
- systemic
Drug therapy should encompass both a topical and a
systemic component. C. glabrata is located deep in
vaginal tissue-up to 10 layers deep-which explains the
high failure rate for local treatment attempts. C. glabrata
also thrives in surface locations–under the foreskin,
around the clitoris, in the anal folds and pubic hair–and
so the effectiveness of systemic therapy is limited.
Therefore, combination therapy seems to be necessary to
appropriately treat the patient and avoid recurrence of
infection. It needs to be stressed that in addition, patient
cooperation is crucial, as rigorous, reliable local treat-
ment is required in conjunction with properly adminis-
tered systemic therapy.
C. glabrata isolates have very low sensitivity to flu-
conazole and may be resistant in many cases. Secondary
resistance is mainly due to two factors: genetic variabil-
ity of the pathogen, which develops resistance to flu-
conazole at doses below 800 mg, and the fact that many
therapists administer fluconazole doses as low as 150 mg
[6]. In contrast, in vitro sensitivity to posaconazole is
high [7]. Until just a few years ago, systemic high-dose
treatment with 800 mg fluconazole was the treatment of
first choice [8]. Given the large number of current treat-
ment failures, the treatment approach is not advisable
today [5]. Nevertheless, the options for treating invasive
fungal infection of the kind are better now than ever. The
most promising agents according to the current state of
scientific knowledge are the triazole derivative posa-
conazole and the echinocandins caspofungin and anidu-
lafungin. The latter require intravenous dosing and are
associated with high treatment costs. Since vaginal can-
didiasis is usually treated in an ambulatory setting, these
agents are of lesser relevance for treatment.
Ciclopiroxolamine is the most effective local drug for
treating clotrimazole- and nystatin-resistant organisms
[8]. It is the antifungal with the broadest spectrum, as
well as showing deep penetration and sporicidal activity.
The mechanism of action is polyvalent. Ciclopiroxola-
mine’s activity is not limited to the level of ergosterol
synthesis. It also targets regions mitochondria and pro-
tein synthesis, making it the ideal combination partner
for all systemic antifungals. Inhibition of catalase pro-
duction is particularly effective, because it disables me-
tabolization of toxic H2O2 occurring in the fungal cell.
All clinically relevant Candida species are sensitive to
ciclopiroxolamine [8].
Posaconazole is a triazole derivative whose mecha-
nism of action is based on inhibiting ergosterol synthesis
[9]. It is effective against a variety of fungal pathogens.
These include all relevant Aspergillus species, the or-
ganisms responsible for mycetoma, coccidioidomycosis,
chromoblastomycosis, and refractory pathogens like
Mucor and Fusarium [10,11]. The spectrum of action
also includes Candida and especially the problem
pathogens C. glabrata and C. krusei [7,10] which are
resistant to fluconazole, itraconazole and voriconazole.
Posaconazole’s molecular structure gives it multiple
docking sites, so different mutations would have to oc-
cur simultaneously for it to be ineffective [12]. In con-
trast, a single mutation is enough to induce resistance to
fluconazole [12]. Posaconazole has linear kinetics up to
a dose of 800 mg [9]. Exposure can be increased by di-
vision into two divided doses of 400 mg (10 ml suspen-
sion BID), and is further enhanced by dosing together
with high-fat food, e.g. custard made with full-fat milk.
It has a high volume of distribution (1744 liters), sug-
gesting very good distribution. Posaconazole is metabo-
lized to a very slight extent and is primarily eliminated
with the feces. Posaconazole has the lowest potential for
interactions of all systemic azole derivatives, since in-
teractions with the CYP system are limited to CYP3A4
inhibition. The most common side effects reported in
studies involving a total of 2400 subjects and patients
were headache and nausea [9]. Posaconazole is approved
for prevention of systemic infection in high-risk he-
mato-oncology patients, for salvage therapy of certain
H. J. Tietz / HEALTH 2 (2010) 513-518
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
invasive mould infections and for the treatment of oro-
pharyngeal candidiasis [9]. Up to now, there is no clini-
cal data supporting efficacy in treatment of vaginal can-
didiasis. In a murine vaginal model, posaconazole re-
duced the fungal burden of both fluconazole-susceptible
and fluconazole-resistant Candida albicans strains [4].
The difficulty to treat chronic vaginal infections cau-
sed by C. glabrata lead to the development of a concept
comprising a posaconazole-ciclopiroxolamine combina-
tion therapy for patients, who seemed to have exhausted
all conventional treatment options.
Patients were eligible if they had a chronic vaginal can-
didiasis caused by C. glabrata, a history of therapy fail-
ure and reduced sensitivity towards licensed antifungals
indicated by susceptibility testing.
All patients were carefully examined, including mi-
crobiologic and dermatologic diagnosis, to exclude non-
fungal infections and a non-infectious dermatosis such
as lichen ruber, neurodermitis or psoriasis inversa. To
avoid recurrence, the patients’ surroundings were care-
fully examined mycologically by taking swabs or sam-
ples and cultivation on appropriate media (see Diagnos-
tic Procedures). This included the partner’s oral cavity,
penis and sperm, but also the patient’s oral cavity, vagina,
clitoris and faeces. Vaginal swabs of all patients were
taken and cultured before start of therapy for species
identification and susceptibility testing. Foreign objects
as Nuva-Ring or hormonal coil were removed before
start of therapy.
Therapy response was assessed by clinical and my-
cologic examination at 7 and 30 days after end of ther-
apy, respectively. For some patients, long-term results up
to 2 years after therapy are available. Patients who have
been treated here come from all over Germany, so that
long-term follow-up is not possible in every case. For
mycologic examination, vaginal and clitoris swabs were
taken and inoculated as described below. Further follow-
up visits are conducted regularly, about every 30 days,
the results are presented below.
A successful therapy outcome was defined as substan-
tial improvement of the patient’s clinical infection signs
and symptoms 7 days after start of treatment, as well as
persistent clinical and mycologic cure 30 days after be-
gin of therapy.
All patients were informed about the compassionate
use project in depth and about the existing database on
posaconazole in antifungal treatment. Health insurance
reimbursement was checked and agreed in advance for
all patients.
For species identification, swabs were inoculated onto
chromIDTM Candida agar, bioMérieux Deutschland GmbH,
Nürtingen, Germany, which is specific for yeast isolation
and direct identification of Candida albicans. Candida
albicans colonies are coloured blue by specific hydroly-
sis of a hexosaminidase chromogenic substrate after 2
day of incubation at 37°C. The species identification of
non-blue-coloured colonies like C. glabrata and C.
krusei were examined by their assimilation pattern with
the ID 32C yeast identification system, bioMérieux
Deutschland GmbH, Nürtingen, Germany. ID 32C sys-
tem consists of a single-use disposable plastic strip with
32 wells to perform 29 assimilation tests (carbohydrates,
organic acids, and amino acids), 1 assimilation test with
a negative control, 1 susceptibility test (cycloheximide),
and 1 colorimetric test (esculin) including a database of
63 different species. Results were recorded by direct
reading after 48 h of incubation at 30°C.
The susceptibility of all isolates towards itraconazole
and flucoanzole was tested routinely, as these are the
only systemic antifungal agents licensed to treat VVC.
FUNGITESTTM, Bio-Rad, Marnes-la Coquette, France
was used. In general, this test is used to study growth of
yeasts in the presence of 6 antifungal agents at 2 differ-
ent concentrations, among them fluconazole and itra-
conazole. Growth assessment is based on reduction of
the coloured indicator which turns the medium from blue
to pink. When growth is inhibited by the fungal agent,
the medium remains blue. Two growth and 2 negative
controls are included in the test system. The interpreta-
tion of the results was performed according the follow-
ing colour characteristics: Blue-blue = no growth, strain
inhibited by the antifungal agent, sensitive strain (“S”);
Pink-blue = low growth, intermediate strain (“I”); Pink-
pink = growth, strain not inhibited by the antifungal
agent, resistant strain (“R”). The breakpoints have been
chosen following the study of the distribution of the an-
tifungal agents MIC obtained with prototype microplates
used with the same procedure as FUNGITESTTM. If
susceptibility testing indicates intermediate susceptibility
or resistance towards fluconazole or itraconazole, ther-
apy attempts with these agents cannot expect to be suc-
cessful because of the genetic haploidy of C. glabrata.
All patients received a combination of systemic and
topical therapy (Table 1). For systemic therapy, posa-
conazole was administered for 15 days at a daily dose of
800 mg (10 ml BID). Topical therapy consisted of cicl-
opiroxolamine cream BID administered intravaginally
H. J. Tietz / HEALTH 2 (2010) 513-518
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
every morning and evening. 12 of the patients received
additional topical treatment with Nystatin Ovula (100,000
IU q.d.). Further measures were initiated in addition, if
required: shaving of pubic hair of both partners before
initiating therapy; antifungal decontamination of both
partners (mouth, bowel, sperm).
15 patients with chronic vaginal candidiasis caused by C.
glabrata were treated (Table 3). On average, they were
46.2 years old (range 20-76 years). For all patients,
vaginal control swabs at baseline were positive for Can-
dida glabrata, and most of the patients also had evidence
of C. glabrata below the clitoral hood. 13 of the 15 pa-
tients had a history of failed treatment with fluconazole,
2 of these patients received even more than one systemic
antifungal. Remaining 2 of the 15 patients had both been
pretreated topically with clotrimazole. Both patients
were infected with C. glabrata-strains that showed only
intermediate susceptibility to fluconazole and itracona-
In total, 7 of 15 C. glabrata strains were resistant to
fluconazole, 6 showed intermediate susceptibility and 2
results indicated susceptibility, although both patients
experienced clinical failure with fluconazole. All 7
strains resistant towards fluconazole were also itracona-
zole-resistant, and in addition, one of the strains exhi-
biting intermediate susceptibility towards fluconazole
tested itraconazole-resistant. No strain was itraconazole-
All patients received treatment with posaconazole and
ciclopiroxolamine in accordance with the regimen in
Table 2. 14 of the 15 patients were treated successfully
with this regimen: they experienced substantial clinical
improvement already after 7 days of treatment; no clini-
cal signs and symptoms of the infection could be dete-
cted 30 days after begin of therapy, and all mycologic
swabs were negative for Candida glabrata. 11 of the 14
patients with successful therapy outcome after 30 days
could be monitored for a longer time to detect a possible
recurrence of infection. No patient showed any sign or
symptom of recurrent fungal infection, and culture di-
agnostics have always been negative since. Clinical and
mycological cure persists for about 60 days in 4 patients,
for 90 days in 3 patients and for more than 1 year in 4 of
the patients. Clinical success of the applied therapy
regimen is documented photographically. One patient
(patient No. 7 in Table 3) experienced therapy failure.
This patient evidently failed to implement the treatment
processes. She was transferred to hospital for intrave-
nous treatment with an echinocandin, and topical therapy
has been stopped there. The patient experienced recur-
rence of infection. Posaconazole was well tolerated by
all patients, similarly to fluconazole.
Modern systemic antifungals such as posaconazole open
up prospects for successful and sustainable therapy. No
clinical data are available to date on posaconazole in the
treatment of chronic recurrent vaginal candidiasis. Pre-
clinical data suggest that posaconazole may be an option
for this difficult-to-treat infection [4,7,12]. Posacona-
zole activity against Candida species seems to be high
The key to a successful cure seems to be the combina-
tion of the highly active substances posaconazole and
ciclopiroxolamine. Since nystatin is effective against C.
glabrata, it may be included in the treatment regimen as
Posaconazole has been favoured as systemic combi-
nation partner over an echinocandin, although the main
indication of echinocandins is the therapy of Candida
Table 2. Regimen for treatment of refractory chronic vaginal fungal disease caused by C. glabrata (according to Tietz).
Treatment Conduct
Oral Posaconazole, 800 mg (suspension in 3 105-ml bottles)
400mg BID = 10ml BID with high-fat food (e.g. custard made with full-fat milk)
Local 1:
A) morning
Ciclopiroxolamine Cream 35 g
Introduce deep into the vagina and apply to labia, vaginal opening, under the foreskin/clitoral hood, and from perineum to anus
B) evening
Ciclopiroxolamine Cream 35 g (repeat as stated under A)
Additionally at night:
Nystatin Ovula, inserted at depth once daily
A) Pubic shaving of both partners before starting therapy
B) Mouth, bowel and sperm of both partners must be fungus-free
C) Remove IUD beforehand
1 Treatment takes place from treatment day 1 in parallel with systemic therapy. Patients are required to use up their full supply of drugs.
H. J. Tietz / HEALTH 2 (2010) 513-518
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Table 3. Therapy of chronic recurrent VVC in 15 patients with posaconazole and ciclopiroxolamine*.
Premedication Suceptibility testing
Itraconazole Fluconazole
No Age
Antimycotic Daily dosage
Last negative
culture result after
Clinical and
myclogical cure
1 43 Fluconazol 800 mg, 2 weeks X X 39 days +
2 76
400 mg, 10 days
400 mg, 6 days
50 mg, 21 days
100 mg, 10 days
50 mg, 14 days
X X 2 years +
3 45 Fluconazol 800 mg, 2 weeks X X 1 year +
4 24 Clotrimazol several times X X 92 days +
5 20 Fluconazol 150 mg, once X X 2 years +
6 52 Fluconazol
150 mg, once
400 mg, once X X 98 days +
7 72 Clotrimazol Several times X X non non
8 51 Fluconazol 800 mg, 2 weeks X X 56 days +
9 44 Fluconazol 800 mg, 2 weeks X X 90 days +
10 63 Fluconazol 400 mg, 2 weeks X X 1 year +
11 34 Fluconazol 400 mg, 2 weeks X X 60 days +
12 51 Fluconazol 800 mg, 2 weeks X X 60 days +
13 30 Fluconazol 800 mg, 2 weeks X X 35 days +
14 52 Fluconazol 150 mg, once X X 76 days +
15 37 Fluconazol 800 mg, 2 weeks X X 35 days +
* Patients had a history of treatment with 800 mg over a 2-week period
infections. Echinocandins are only available in intrave-
nous formulation, hence their application is complicated
and maybe too costly in an ambulatory setting.
On the basis of the current state of scientific knowl-
edge, it was possible to develop a treatment concept for
successful treatment of patients who had exhausted con-
ventional treatment options. From an ethical point of
view, too, it was appropriate not to withhold the drug
until marketing authorization. Unlike C. albicans fungal
disease, which typically is associated with a high risk of
re-infection, disease caused by C. glabrata was success-
fully cured. 14 of 15 patients in this drug use evaluation
achieved a cure. The follow-up period ranged from 90
days to 2 years in 11 of the 14 patients, no relapses oc-
curred. Concomitant topical treatment deserves merit as
the second mainstay of success; systemic antifungals on
their own will probably not reach all the remote niches
in which pathogens may be present.
Larger clinical trials should be conducted to further
study the efficacy of posaconazole in the treatment of
chronic recurrent vaginal candidiasis caused by rare
Candida species as C. glabrata and C. krusei.
[1] Mendling, W. (2006) Vaginose, vaginitis, zervizitis und
salpingitis. 2nd Edition, Springer Medizin Verlag, Hei-
[2] Watson, C. and Calabretto, H. (2007) Comprehensive re-
view of conventional and non-conventional methods of
management of recurrent vulvovaginal candidiasis. Aust
N Z J Obstet Gynaecol, 47(4), 262-272.
[3] Eschenbach, D.A. (2004) Chronic vulvovaginal candidi-
asis. New England Journal of Medicine, 351(9), 851-852.
[4] González, G.M., et al. (2007) Therapeutic efficacy of
posaconazole against isolates of Candida albicans with
different susceptibilities to fluconazole in a vaginal mo-
del. Medical Mycology, 45 (3), 221-224.
[5] Mendling, W., et al. (2008) Vulvovaginalkandidose.
Guideline of the German Society of Gynecology and Ob-
H. J. Tietz / HEALTH 2 (2010) 513-518
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
stetrics, German Dermatologic Society, German-Spea-
king Mycologic Society, Berlin.
[6] Czaika, V., et al. (2000) Antifungal susceptibility testing
in chronically recurrent vaginal candidosis as basis for
effective therapy. Mycoses, 43(Suppl 2), 45-50.
[7] Pfaller, M.A., et al. (2001) Vitro activities of posacona-
zole (Sch 56592) compared with those of itraconazole
and Fluconazole against 3,685 clinical isolates of Can-
dida spp. and Cryptococcus neoformans. Antimicrobial
Agents and Chemotherapy, 45(10), 2862-2864.
[8] Tietz, H.J. and Sterry W. (2006) Antimykotika von A-Z.,
Thieme, 4.Auflage, Stuttgart.
[9] Smith, W.J., Drew, R.H. and Perfect, J.R. (2009) Posa-
conazole’s impact on prophylaxis and treatment of inva-
sive fungal infections: an update. Expert Review of Anti-
Infective Therapy, 7(2), 165-181.
[10] Herbrecht, R. (2004) Posaconazole: A potent, extended
spectrum triazole antifungal for the treatment of serious
fungal infections. International Journal of Clinical Pra-
ctice, 58(6), 612-624.
[11] Schiller, D.S. and Fung, H.B. (2007) Posaconazole: An
extended spectrum triazole antifungal agent. Clinical Th-
erapeutics, 29(9), 1862-1886.
[12] Hof, H. (2008) Is there a serious risk of resistance de-
velopment to azoles among fungi due to the widespread
use and long-term application of azole antifungals in
medicine? Drug Resistance Updates, 11(1-2), 25-31.