04 - Genital candidiasis

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Genital candidiasis
Jack D Sobel
Abstract
Vulvovaginal candidiasis (vaginal thrush) remains an extremely common
Pathogenesis3
Germination of candida enhances colonization and tissue inva-
Oestrogens: during pregnancy, the incidence of clinical attacks
reaches a maximum in the third trimester, but symptomatic
What’s new?
C Value of long-term maintenance fluconazole regimens
confirmed in additional studies
C No new widely available diagnostic tests
C No new antifungal agents
C Probiotic therapy largely ineffective both as prophylaxis and
therapy
C Emerging evidence of genetic contribution to genital candidi-
asis susceptibility
C Hormone replacement therapy (HRT) oestrogen responsible for
post-menopausal genital candidiasis
C Candida vaccine efficacy studies are underway in the USA
Factors associated with increased asymptomatic vaginal
colonization with candida and with candida vaginitis
C Genetic factors
C Pregnancy
C Uncontrolled diabetes mellitus
C High-oestrogen oral contraceptives
C Corticosteroid therapy
C Tight-fitting, synthetic underclothing (possibly)
C Antimicrobial therapy (oral, parenteral or topical)
C Use of IUD
C High frequency of coitusa
C Confectionery-eating bingesa
C HIV infection
a Vaginitis only.
Table 1
VAGINAL INFECTIONS
Jack D Sobel MD is a Distinguished Professor of Medicine and Chief of
the Division of Infectious Diseases, Department of Internal Medicine,
Wayne State University School of Medicine, Detroit, MI, USA. Competing
interests: none declared.
clinical problem, with both overdiagnosis and underdiagnosis and unreli-
able self-diagnosis. Occurring worldwide and affecting all strata of soci-
ety, this inflammatory condition usually presents with vulvovaginal
pruritus and irritation with a variable discharge. Little progress has
been made in providing diagnostic tests, and consequently inappropriate
antifungal therapy is common. New genetic susceptibility mechanisms are
emerging. A variety of highly effective topical and oral systemic antimy-
cotics agents are available. No new antifungal drug regimens have
recently appeared; accordingly, therapeutic recommendations are un-
changed. Antifungal drug resistance fortunately remains rare.
Keywords Azole antifungals; C. albicans; C. glabrata; candidosis;
genetic susceptibility; vaginal thrush; vulvovaginal candidiasis
Yeasts are microscopic, single-celled fungi that reproduce by
budding.1 Strains of Candida albicans constitute 90% of yeasts
isolated from the vagina. Of the remainder, the most common are
C. glabrata and C. tropicalis. Non-albicans Candida spp. can
induce vaginitis and are often more resistant to conventional
therapy. There is no evidence that the prevalence of non-albicans
Candida spp. causing vaginitis is increasing.
Candida is the second most common vaginal infection after
bacterial vaginosis. During the childbearing years, 75% of
women experience at least one episode of vulvovaginal candi-
diasis, and 40e50% of these women experience a second
episode.2 A small subpopulation of women (6e9%) suffer
repeated recurrent episodes of candida vaginitis.3
Asymptomatic candidiasis
Asymptomatic candidiasis is common; candida may be isolated
from the genital tract of about 20% of asymptomatic healthy
women of childbearing age. Candida gains access to the vaginal
lumen and secretions predominantly from the adjacent perianal
area, and then adheres to vaginal epithelial cells. The numbers of
C. albicans that adhere to the vaginal epithelial cells are signifi-
cantly greater than those of C. tropicalis, C. krusei and C.
glabrata.
Several factors are associated with increased prevalence of
asymptomatic vaginal colonization with candida (Table 1).4
The hormonal dependence of the infection is illustrated by the
fact that candida is seldom isolated from premenarchal girls, and
that the prevalence of candida vaginitis is lower after the
menopause, except in women taking hormone replacement
therapy (HRT).
MEDICINE 42:7 364
recurrences are common throughout pregnancy. It is generally
thought that the high level of reproductive hormones increases
the glycogen content of the vaginal environment and provides a
carbon source for candida growth and germination. Oestrogens
increase vaginal epithelial cell avidity for candida adherence, and
a yeast cytosol receptor or binding system for female reproductive
hormones has been documented. In addition, oestrogens increase
formation of yeast mycelia. Low-oestrogen oral contraceptives
Host factors
sion.1 Factors that facilitate germination (e.g. oestrogen therapy,
pregnancy) tend to precipitate symptomatic vaginitis; measures
that inhibit germination may prevent acute vaginitis in women
who are asymptomatic carriers of yeast. Other virulence factors
include proteolytic enzymes, toxins and phospholipase elabora-
tion. It is uncommon to find a precipitating factor that explains
the transformation from asymptomatic carriage to symptomatic
vaginitis.
� 2014 Published by Elsevier Ltd.
Clinical features8
� Vulvar pruritus is the most common symptom of candida
vulvovaginitis and is present in most symptomatic patients.
� Vaginal discharge is often minimal and sometimes absent.
Although described as being typically ‘cottage cheese-like’
in character, this discharge may vary from watery to ho-
mogeneously thick.
� Vaginal soreness, irritation, vulvar burning, dyspareunia
and external dysuria are common.
� If there is an odour, it is minimal and inoffensive.
� Characteristically, symptoms are exacerbated during the
week before the onset of menses. The onset of menstrual
flow brings some relief.
� Examination reveals erythema (Figure 1) and swelling of
the labia and vulva, often with discrete, pustulopapular,
peripheral lesions including fissures. The cervix is normal.
VAGINAL INFECTIONS
may also increase candida vaginitis. HRT, especially topical ther-
apy, may contribute to vaginitis in post-menopausal women.
Diabetes mellitus: vaginal colonization with candida is more
common in diabetes mellitus; uncontrolled diabetes predisposes
to symptomatic vaginitis. Glucose tolerance tests have been
recommended in women with recurrent vulvovaginal candidi-
asis; however, the yield is low, and testing is not justified in
otherwise healthy premenopausal women. Type 2 diabetes se-
lects for C. glabrata. Diets high in, or binges of, refined sugar may
precipitate symptomatic vaginitis.
Antibiotics: symptomatic vulvovaginal candidiasis often occurs
during or after use of systemic or intravaginal antibiotics possibly
as a result of eliminating the normal protective vaginal bacterial
flora. Although no antimicrobial agent is free from this compli-
cation, it is especially common following the use of broad-
spectrum antibiotics5 (e.g. tetracycline, ampicillin, cephalo-
sporin). It is hypothesized that Lactobacillus spp. in the natural
flora provide a colonization resistance mechanism and prevent
germination of candida. However, most women taking antibi-
otics do not develop candida vaginitis and women deficient in
lactobacilli are not at risk of developing candida vaginitis.
Environmental factors that predispose to candida vaginitis may
include tight, poorly ventilated clothing and nylon underclothing,
which increase perineal moisture levels and temperature.
Chemical contact, local allergy and hypersensitivity reactions
may also predispose to symptomatic vaginitis.6
Immunosuppression: in patients who are debilitated or immu-
nosuppressed, oral and vaginal thrush correlate well with
reduced cell-mediated immunity. This is evident in chronic
mucocutaneous candidiasis and AIDS. Lymphocytes might
therefore contributeto normal vaginal defence mechanisms,
preventing mucosal invasion by candida.
Genetic factors have an important role in determining the risk of
both vaginal yeast colonization and symptomatic episodes.
Recent studies suggest a role for mannose-binding lectin and toll-
like receptors (TLR) and cytokine gene polymorphisms.4
Recurrent and chronic candida vaginitis: various theories have
been proposed to explain recurrent vaginitis (Table 2).
Intestinal reservoir e the intestinal reservoir theory is based
on recovery of candida on rectal culture in almost 100% of
women with vulvovaginal candidiasis. DNA typing of vaginal
and rectal cultures obtained simultaneously usually reveals
identical strains. However, other studies have shown a lower
concordance between rectal and vaginal cultures in patients with
recurrent vulvovaginal candidiasis; also, oral nystatin, which
reduces intestinal yeast carriage, fails to prevent recurrence of
vulvovaginal candidiasis. Repeated re-introduction of yeast into
the vagina from the gut is therefore no longer considered a likely
cause of recurrent candida.
Sexual transmission e penile colonization with candida is
present in about 20% of male partners of women with recurrent
vulvovaginal candidiasis; infected partners usually carry iden-
tical strains. Oral colonization of partners with an identical strain
MEDICINE 42:7 365
of candida also occurs and may be a source of orogenital trans-
mission. However, in most studies involving treatment of part-
ners, there was no reduction in the frequency of episodes of
vaginitis, undermining this hypothesis.
Vaginal relapse e though antimycotic therapy may reduce
the number of candida in the lumen and alleviate the signs and
symptoms of inflammation, eradication or clearance of candida
from the vagina is incomplete in part because all of the anti-
mycotic agents are fungistatic. The small number of organisms
that persist in the vagina result in continued carriage of the or-
ganism, so that when host environmental conditions permit, the
colonizing organisms increase in number and undergo mycelial
transformation, resulting in a new clinical episode.
Drug resistance is seldom responsible for recurrent vulvova-
ginal candidiasis in women infected with C. albicans but has
been reported to be on the increase.7
Reduced host resistance e current theories of the pathogen-
esis of recurrent vulvovaginal candidiasis relate to genetic sus-
ceptibility, which enhances vaginal colonization, as well as to
deficient innate and altered cell-mediated immunity. However,
no evidence is available of any deficiency in vaginal lactobacilli,
and exogenous recolonization of the vagina with probiotic lac-
tobacilli is therefore not useful. Altered vaginal candida-specific
immunity may be responsible for recurrent infection in women
with a genetic predisposition.
Pathogenesis of recurrent vulvovaginal candidiasis
Source
C More frequent vaginal inoculation
Intestinal reservoir theory
Sexual transmission
C Vaginal relapse
Mechanism
C Increased candida virulence (seldom the result of antimycotic
drug resistance)
C Reduced mucosal immunity (cell-mediated immunity)
C Immediate hypersensitivity reaction (IgE)
C Loss of resistance to bacterial colonization
Table 2
� 2014 Published by Elsevier Ltd.
itish
discharge is present (Figure 2).
of 40
ilable
suppositories and coated tampons. There is little evidence that
the formulation of the topical antimycotic influences its clinical
efficacy (Table 4). Nystatin creams and vaginal suppositories
achieve a mycological cure rate of about 75e80%. The clinical
and mycological cure rates achieved by azole derivatives (about
85e90%) in acute, uncomplicated candida vaginitis appear to be
slightly higher than those achieved by the polyenes (e.g.
nystatin).9 There is little evidence that any one azole is superior.
Topical azoles are generally free from local and systemic adverse
effects, but the first application may be accompanied by burning
and discomfort.
Figure 2 Vaginal candidiasis.
VAGINAL INFECTIONS
for detecting candida, a positive culture does not necessarily
indicate that candida is responsible for the vaginal symptoms.
Serology
performed in suspicious cases with negative micros
Although vaginal culture is the most sensitive method ava
Patients with candida vaginitis have a normal vaginal pH (4.0
e4.5). A pH of more than 4.5 suggests the possibility of bacterial
vaginosis, trichomoniasis, atrophic vaginitis or a mixed infection.
Culture
Routine cultures are unnecessary, but vaginal culture should be
copy.
pH
e60%, and 10%potassiumhydroxide preparation ismore sensitive
in diagnosing the presence of germinated yeast, but almost half
the patients with vulvovaginal candidiasis aremicroscopy negative.
diagnosedon the basis of simplemicroscopic examinationof va
secretions. A wet mount or saline preparation has a sensitivity
Diagnosis8
Microscopy
In most symptomatic patients, vulvovaginal candidiasis is readily
ginal
Vaginal mucosal erythema with adherent wh
Figure 1 Typical vulvitis. (By courtesy of G R Kinghorn, Royal Hallamshire
Hospital, Sheffield, UK.)
There is no reliable serological technique for the diagnosis of
symptomatic vulvovaginal candidiasis.
Other
Commercial tests are less sensitive than culture and have no
advantages over microscopy. Newer tests involving DNA probes
and polymerase chain reaction analysis are now available and
are more sensitive, but are expensive and the results are not
quickly available.
Management
A classification of vaginal candidiasis is useful in facilitating the
choice and duration of therapy (Table 3).
Topical antimycotic agents
Topical antimycotic agents for acute candida vaginitis are avail-
able as creams, lotions, aerosol sprays, vaginal tablets,
MEDICINE 42:7 366
There has been a significant move towards using shorter
courses of treatment with progressively higher doses of anti-
fungal drugs, culminating in single-dose regimens. Short courses
and single-dose regimens are effective with most of the azole and
Classification of vaginal candidiasis
Feature Uncomplicated
(90% of cases)
Complicated (10% of cases)
Severity Mild or moderate Severe
Frequency Sporadic Recurrent
Organism Candida albicans Non-albicans Candida spp.
Host Normal Abnormal (e.g. uncontrolled
diabetes mellitus)
Table 3
� 2014 Published by Elsevier Ltd.
, pla-
Topical clotrimazole, 500 mg once weekly, can also be used.
Oral nystatin has little proven value in long-term prophylaxis.
Resistant vaginal yeast is seldom the cause of recurrent vul-
vovaginal candidiasis; however, in women who do not respond
to conventional therapy, unusual organisms may be involved
Figure 4 Mild recurrent candida balanoposthitis.
VAGINAL INFECTIONS
cebo-controlled study.11 After treatment of the initial infections
with three doses of fluconazole given every 3 days, women were
then randomized to a 6-month course of placebo or fluconazole,
150 mg once per week. During the 6-month treatment phase, 9%
of the fluconazole and 64% of the placebo group suffered a
relapse of infection. However, of the 126 fluconazole-treated
patients who were attack-free at the end of the treatment
phase, 57% developed a recurrence in the next 6 months. Most
women felt that suppressive fluconazole therapy was a major
advance in allowing them to control their frequent symptoms.
Similarly long-term maintenance therapy with oral fluconazole
has been confirmed in other studies.12
Because chronic therapy is required, oral treatme
convenient. Fluconazole was evaluated in a double-blind
Treatment of recurrent (complicated) vulvovaginalcandidiasis
Treatment of recurrent vulvovaginal candidiasis aims to control
rather than cure the infection. Vulvovaginal candidiasis is
considered to be recurrent if the patient has four or more attacks
per year.5 The diagnosis of recurrent vulvovaginal candidiasis
must be confirmed by culture, and reversible causes eliminated
when possible. However, in most women with recurrent vulvo-
vaginal candidiasis, no underlying or predisposing factor is
identified. Recurrent vulvovaginal candidiasis requires long-term
maintenance with a suppressive prophylactic regimen.
nt is
shown to be effective during pregnancy.
Pregnancy
Management of vulvovaginal candidiasis during pregnancy is
more difficult, because the clinical response tends to be slower
and recurrences are more frequent. Most topical antifungal
agents are effective, particularly when prescribed for 1e2 weeks;
however, single-dose therapy with clotrimazole has also been
studies indicate that limited fluconazole exposure may n
harmful.10
polyene antifungals. Although anecdotal evidence suggests that
individual failures are not uncommon, it seems reasonable to use
single-dose and short-course therapy in pregnant and non-
pregnant women with infrequent episodes of mild-to-moderate
severity (uncomplicated vaginitis). Moderate to severe vaginitis
requires more prolonged therapy.
In several countries, topical antimycotics are available over
the counter. This relies on patient self-diagnosis, and it is esti-
mated that 50% of women who buy these products do not have
candida vaginitis. Patients must be educated that self-limiting
vulvovaginal symptoms are common and often unrelated to
yeasts.
Oral antimycotic agents
Itraconazole, 200 mg/day for 3 days or 400 mg for 1 day, and flu-
conazole, 150 mg single daily dose, achieve clinical and mycolog-
ical cure in acute, uncomplicated candida vaginitis. Clinical results
with oral therapy are as good as, if not superior to, those with
conventional topical antimycotic therapy. Several studies indicate
that, given a choice, most women prefer oral therapy.
Any therapeutic advantage of oral therapy must be weighed
against the potential adverse effects and toxicity. Oral therapy is
still not recommended in pregnant women, although recent
ot be
MEDICINE 42:7 367
Figure 3 Superficial invasive candida balanoposthitis.
� 2014 Published by Elsevier Ltd.
positive for Candida spp. Treatment comprises topical anti-
mycotics or systemic azoles.
A milder but more common and particularly recurrent form of
balanitis is also described in which penile cultures may be
negative for candida. Symptoms of local erythema or rash and
pruritus typically appear soon after unprotected intercourse
(Figure 4). Clinical manifestations are transient and often
Topical azole therapy for vaginal candidiasis
Drug Formulation and dose
Butoconazole 2% cream, 5 g for 3 days
Clotrimazole 2% cream, 5 g for 7e14 days
10% cream, 5 g single application
VAGINAL INFECTIONS
(e.g. Saccharomyces cerevisiae, C. glabrata, C. tropicalis) that are
known to have relatively higher minimum inhibitory concen-
trations to azoles. Patients with these infections may respond to
oral imidazoles, topical 17% flucytosine or topical boric acid 600
mg/day in a gelatin capsule given vaginally.13 Topical flucytosine
should be limited to isolated cases, because there is a tendency
for resistance to develop. Because non-albicans spp. of candida
100 mg vaginal tablet, one for 7 days
100 mg vaginal tablet, two for 3 days
500 mg vaginal tablet, one once
Miconazole 2% cream, 5 g for 7 days
100 mg vaginal suppository, two for 7 days
200 mg vaginal suppository, two for 3 days
1200 mg vaginal suppository, one once
Econazole 150 mg vaginal tablet, one for 3 days
Fenticonazole 2% cream, 5 g for 7 days
Tioconazole 2% cream, 5 g for 3 days
6.5% cream, 5 g single-dose
Terconazole 0.4% cream, 5 g for 3 days
0.8% cream
Some of these preparations are unavailable in some countries.
Table 4
are less virulent than C. albicans, it is essential to ensure that the
isolated strain of non-albicans candida is the cause of symptoms
and not an innocent bystander.
Recurrent vulvovaginal candidiasis is not a useful marker of
HIV infection. HIV testing should be based on high-risk behav-
iour. There is little justification for treating the male partner,
because treatment is unhelpful. There exists preliminary evi-
dence that asymptomatic vaginal colonization and symptomatic
vaginitis may be associated with increased HIV transmission.
Balanitis
Two forms of balanoposthitis (balanitis) are associated with
Candida spp. Both may be acquired sexually.
A true superficial but invasive infection occurs particularly in
uncircumcised males and those with diabetes. It is characterized
by intense pruritus, discomfort, erythema and swelling that are
localized primarily to the glans, but may extend to involve the
penile shaft and scrotum (Figure 3). Cultures are invariably
MEDICINE 42:7 368
relieved by washing or topical corticosteroids. They represent a
proposed penile cutaneous immediate hypersensitivity reaction
to the presence of candida antigen in vaginal secretions, often of
asymptomatic women. Cure requires eradication of candida from
the female source. A
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� 2014 Published by Elsevier Ltd.
	Genital candidiasis
	Asymptomatic candidiasis
	Pathogenesis3
	Host factors
	Clinical features8
	Diagnosis8
	Microscopy
	pH
	Culture
	Serology
	Other
	Management
	Topical antimycotic agents
	Oral antimycotic agentsPregnancy
	Treatment of recurrent (complicated) vulvovaginal candidiasis
	Balanitis
	References