Treatment of chronic vulvovaginal candidiasis with posaconazole and ciclopiroxolamine

doi:10.4236/health.2010.26077

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Vol.2, No.6, 513-518 (2010) Health

doi:10.4236/health.2010.26077

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.

ABSTRACT

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

1. INTRODUCTION

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.

2. TREATMENT OF PROBLEM FUNGI

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

514

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

Findings

Discharge

Redness

Pruritus

Redness

Pruritus

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-

sistant)

Clotrimazole S R

Nystatin S S

Ciclopiroxolamine S S

Fluconazole S R

Posaconazole S S

Drug of first choice:

- topical

- systemic

Clotrimazole

Fluconazole

Ciclopiroxolamine

Posaconazole

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

515

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.

3. PATIENTS

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.

4. DIAGNOSTIC PROCEDURES

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.

5. THERAPY

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

516

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).

6. RESULTS

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-

zole.

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-

susceptible.

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.

7. DISCUSSIONS

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

[7].

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

well.

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

Supportive

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

517

Table 3. Therapy of chronic recurrent VVC in 15 patients with posaconazole and ciclopiroxolamine*.

Premedication Suceptibility testing

Itraconazole Fluconazole

No Age

Antimycotic Daily dosage

S I R S I R

Last negative

culture result after

Clinical and

myclogical cure

1 43 Fluconazol 800 mg, 2 weeks X X 39 days +

2 76

Fluconazol

Voriconazol

Anidulafungin

Caspofungin

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

Itraconazol

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.

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