Abstract
Vulvo-vaginal candidiasis (VVC) is a common infection
among women. 5-8% of women with acute infection
experience recurrent vulvo-vaginal candidiasis (RVVC).
There is currently no gold standard treatment for RVVC.
Although antifungal agents such as imidazoles have been
successfully used as first-line treatment for acute VVC,
the effectiveness of these medications is limited for RVVC,
and various reasons have been postulated to contribute
to this. Here, we discuss the clinical features and pathogenesis
of RVVC, and its usual recommended treatment
regimens as well as newer upcoming potential alternative
therapies for this chronic condition.
Epidemiology
Candida is a yeast that is commonly found in the vagina
as part of normal flora, without causing symptoms.
However, in certain situations, Candida can change from
being a commensal organism to a pathogenic one, thereby
causing symptoms of vulvovaginal candidiasis (VVC).
Uncomplicated VVC affects 70-75% of women at least
once during their lives, most frequently in young women
of reproductive age. 40-50% of women will experience
a recurrence [1]. Recurrent Vulvo-vaginal Candidiasis
(RVVC) is usually defined as four or more episodes of
symptomatic VVC within 1 year and affects up to 5-8% of
adult women [2].
Microbiology
Most cases (85-95%) of uncomplicated VVC are
caused by Candida albicans. The remainder are caused by
non-albicans Candida spp, of which the most common is
Candida glabrata. In RVVC, these less common Candida
species may be implicated, and although clinically indistinguishable
from infection caused by Candida albicans,
they tend to be more resistant to treatment [2] .
Clinical Features (Indistinguishable between
symptoms caused by Candida albicans and non-albicans
species)
Common symptoms include vaginal discharge, vulvar
pruritus, dyspareuria and dysuria. On genital examination,
the labia and vulva are often swollen, erythematous,
with skin fissures commonly seen, and often accompanied
by a thick, white vaginal discharge.
Pathogenesis of RVVC
The pathogenesis of RVVC is multifactorial. RVVC
can be idiopathic or caused by several different mechanisms.
These include:
1. Host factors: Uncontrolled diabetes mellitus,
estrogen excess states (oral contraceptive pills,
hormone replacement therapy, local estrogen
administration, pregnancy), antibiotic-induced,
immunosuppressive states (Systemic lupus erythematosus,
human immunodeficiency virus,
long-term corticosteroid use 2. Genetic factors: Lewis blood group, African-
American ethnicity, polymorphism
3. Behavioural factors: Orogenital sexual activity,
contraceptive sponge/intrauterine contraceptive
device use
4. Microbial factors: Non-albicans Candida spp)
Theories for Development of RVVC
Three theories have been put forth to explain why
some women develop RVVC.
Intestinal Reservoir Theory
This theory suggests that persistence of Candida spp.
organisms in the gastrointestinal tract later leads to reinfection
of the vagina. This theory was originally based on
uncontrolled data in the late 1970s which showed candida
isolated from rectal cultures of women with RVVC being
almost 100% identical to candida isolated from vaginal
cultures, thereby suggesting the presence of a persistent
intestinal reservoir of yeast [3]. The mechanism for RVVC
was thus thought to be re-inoculation of the vagina from
the persistent rectal focus. However, other studies in the
literature have found a much lower concordance between
rectal and vaginal cultures in patients with RVVC. In addition,
2 controlled trials showed that nystatin treatment
given to reduce intestinal colonization with Candida albicans
failed to prevent recurrent symptoms of vaginal in fection [4,5]. Results from these later studies make it less
likely that the intestinal reservoir theory satisfactorily explains
the cause of RVVC.
Sexual Transmission Theory
This theory suggests that the sexual partner is the reservoir
or source for recurrent infection in the woman. A
study that supports this theory found that asymptomatic
colonisation of the male genitalia with candida was 4 times
more common in the sexual partners of infected women
than in those of non-infected women [6]. Also, strain typing
methods have indicated that infected partners often
harbour identical strains [7-9]. However, the role of sexual
transmission in vaginal infection is still yet unknown, and
treatment of the male partner does not appear to have an
effect on the woman’s risk of recurrence [10,11].
Vaginal Relapse Theory
20-25% of women who test negative for candida immediately
after treatment for vulvo-vaginal candidiasis
subsequently test positive at 30 days post-treatment. The
vaginal relapse theory thus postulates that the occurrence
of RVVC is due to persistence of some strains of yeast despite
anti-mycotic treatment, suggesting a vaginal rather
than intestinal reservoir of yeast. This is further supported
by studies showing that the Candida strains isolated before
and after treatment are identical in more than two-thirds of recurrences [12]. The recurrence is therefore thought
to be not caused by a new infection, but rather caused by
the persistence of organisms that increase in number and
cause a new clinical episode when the environment permits.
This is further promoted by certain exogenous factors
discussed above as well as the possibility of lowered
local vaginal immune response. The control of these factors
is thus an important aspect in management of women
with RVVC.
Treatment Options
There is currently no gold standard treatment for
RVVC. Treatment should be individualised based on a
comparison of effectiveness, convenience, potential side
effects and cost. Treatment should also be via a multipronged
approach, not limited to solely pharmacological
therapies, but also aiming to eliminate factors that predispose
an individual to vulvo-vaginal candidiasis. Before
therapy, mycological culture should be obtained to confirm
the diagnosis and to identify the specific Candida spp
involved.
General Advice and Lifestyle Changes
General advice includes the avoidance of local irritants
such as perfumed products and the maintenance
of good perineal hygiene. Tight fitting synthetic clothing
should also be avoided, although there is little evidence to support this. The patient should be advised to use a soap
substitute to clean the vulva area, and this should only be
done externally and not more than once daily. Vaginal
douching with feminine wash should be discouraged as
this will affect the protective effect of normal vaginal commensals.
In addition, an emollient can be used to moisturize
the vulva skin.
Medical Treatment
Although no gold standard treatment regimen for
RVVC currently exists, gynaecological experts have concurred
that the recommended treatment should include
the induction of clinical remission per acute episode, followed
by a period of up to 6 months of maintenance therapy.
This view is supported by a randomized controlled
trial proving that maintenance therapy with weekly fluconazole
for 6 months after clinical remission was superior
with regards to the reduction of clinical recurrence
[13]. However, regardless of which maintenance regime
is chosen, symptomatic relapse is often seen in half of
the women within a short time of cessation of treatment
[13,14].
Table 1 shows some of the recommended drug regimens
(induction and 6 months maintenance treatment)
for RVVC.
Table 1: Recommended drug regimens for RVVC.
Alternative Treatment Approach (6-Week
Regimen)
An alternative approach to treatment of RVVC proposed
is that of a six-week regimen with intravaginal
butozonazole 2% slow release (SR) gel. The rationale for
this proposed regimen is that of better patient compliance
and increased susceptibility of the Candida species
to this particular anti-mycotic drug. As discussed earlier,
one possible contributing factor to RVVC is the higher
prevalence of non-albicans species associated with RVVC
that have a 10-30-fold reduced sensitivity to fluconazole,
as well as lower susceptibility to other oral azoles (e.g. ketoconazole, itraconazole) [15]. As such, eradication of
these other types of non-albicans Candida species such as
C.glabrata and C. krusei is often difficult. However, one
study showed that eradication can be accomplished with
adequate treatment using butoconazole, clotrimazole or
miconazole. This particular study also showed that butoconazole
was superior to miconazole and clotrimazole,
with a low minimal inhibitory concentration of 90 at 24
and 48 hours against all species [16]. The difference between
butoconazole and other imidazoles is that the latter
play a major role in topical treatment and were developed
initially for dermatologic use, and then subsequently applied
to the treatment of vulvo-vaginal candidiasis.. In
contrast, butoconazole is a rare exception because it is
specifically developed for the treatment of vulvovaginal
candidiasis [17]. In addition, the SR formulation also
helps to improve treatment compliance, as it is less messy
and more convenient for patients, resulting in minimal
interruption to their daily routine. Besides its SR properties,
butoconazolealso provides significantly faster relief of
severe symptoms on the first post-treatment day [18,19].
It also avoids the main adverse effects of oral imidazoles
such as gastrointestinal symptoms like abdominal pain
and headache [20]. With oral medications, there is also
a risk of drug interactions if the patient is taking other
medications concurrently. Therefore, butoconazole has a
much better safety profile compared to oral azoles [21].
Nonetheless, although the use of butoconazole in acute
VVC compared to other forms of treatment has long been
accepted as superior against all species of Candida, its use
in RVVC still remains novel. A case report published by
Heng et al. in 2012 looked at treatment of RVVC with sustained-
release butoconazole pessary in two patients over a
6 week period, with achievement of good clinical and mycological
cure within 6 months [22]. The recommended
regimen was for an induction period of intravaginal butoconazole
SR twice weekly for the first two weeks, followed
by maintenance treatment of once a week for three to four
weeks. Randomised trials are required to further compare
and demonstrate the superiority of butoconazole to other
azoles in order to determine its long-term efficacy.
Alternative Therapies
Probiotics
A 1992 crossover study assessed the association between
the daily ingestion of yogurt containing Lactobacillus
acidophilus and the prevention of RVVC [23]. In
this study, women were assigned to a yogurt-free diet or
a yogurt-containing diet. Only 13 of the 21 women completed
the protocol, but it was found that women who ingested
yogurt had a three-fold reduction in infection. The
authors concluded that daily ingestion of an 8 oz of yogurt
containing Lactobacillus acidophilus decreased the rate of
candidal infection. More recently however, a review article
looking at the role of probiotics for prevention of RVVC
Agent Dosing regimen
Treatment for acute episode
Clotrimazole
Fluconazole
Ketoconazole
Terconazole cream
100mg vaginal pessary for 7 days
150mg orally single dose
200mg orally daily for 14 days
5g intravaginal for 3 days
Maintenance
Clotrimazole
Clotrimazole
Ketoconazole
Ketoconazole
Fluconazole
Fluconazole
Itraconazole
Two 100mg vaginal pessary twice weekly for 6 months
One 500mg pessary weekly for 6 months
Two 200mg oral tablets for 5 days after menses for 6 months
100mg daily for 6 months (low risk of idiosyncratic drug-induced
hepatitis. Monitor LFTs monthly)
150mg orally once a month for 6 months
100mg weekly for 6 months
200mg orally once a month for 6 months
found it to be controversial [24]. Some in-vitro studies and
clinical trials showed positive results with respect to the
effectiveness of some specific lactobacilli strains against
Candida albicans. However, most of the trials either included
a small sample of women or women with no confirmed
episodes of VVC or were not placebo-controlled in
nature. The review also noted that there were differences
among the trials regarding the strain of the tested probiotic,
its dosage and the duration of treatment, therefore
making it difficult to draw reliable conclusions from the
existing studies.
IM Depo-Provera
One study has suggested that the progestogen-only
injectable may reduce a woman’s susceptibility to RVVC,
possibly from its anovulatory effect and relative hypoestrogenism
[25]. More studies need to be done to investigate
the role of depo-provera as a preventive treatment for
RVVC.
Systemic Candida Antigen Hyposensitisation
via the Cutaneous Route
Meech et al. suggested that both Immunoglobulin E
(IgE)-mediated and/or cellular-mediated hypersensitivity
mechanisms may be involved in local candida infections
[26]. In addition, Witkin et al. demonstrated in their study
that the vaginal secretions of many women with RVVC
contained anti-Candida IgE antibodies and detectable
levels of prostaglandin E2, leading to a speculation that
a vaginal hypersensitivity response to Candida albicans
may be associated with increased levels of prostaglandin
E2, which is capable of suppressing localised vaginal cellmediated
immune responses [27]. The loss of this localised
vaginal defense mechanism can result in colonization
by yeast leading to repetitive infections. In a small and
limited uncontrolled study looking at hyposensitisation
with laboratory-prepared Candida antigen, Rosedale and
Browne achieved encouraging results [28]. This may be a
promising alternative treatment for patients who are unable
to tolerate maintenance azole suppressive treatment.
Treatment of Male Partners
There is currently no evidence to support treatment of
asymptomatic male partners, and therefore routine treatment
should therefore be deemed unnecessary [29].
Vaccine
Currently, a multicenter, double-blind, randomized,
placebo-controlled Phase 1b/2a clinical trial is underway
to evaluate the safety, tolerability, immunogenicity and efficacy
of a NDV-3 vaccine developed for the prevention of
episodes of VVC in patients with RVVC. This vaccine contains
a recombinant form of the Candida albicans surface
protein Als3, which faciltitates adherence to and invasion
of human endothelial cells. This trial follows a preclinical
study in a model of VVC, which demonstrated that NDV-
3 induced potent and protective immune responses, as
well as 2 successful Phase 1 studies, which demonstrated that NDV-3 was safe, well-tolerated and induced strong
antibody and T-cell immune responses in healthy adults.
188 patients have been enrolled into the Phase 1b/2a trial,
of which the results are currently pending. The estimated
study completion date is in May 2016.
Conclusion
In conclusion, RVVC is a highly troublesome condition
for women who experience it. There is currently no
optimal treatment for RVVC, but the approach to the
treatment of this condition should be multi-pronged in
view of its multifactorial pathogenesis. Research is currently
underway to develop new approaches besides that
of anti-mycotic treatment for the management of RVVC.