12/22/05njm

**Q. How do I manage patients with recurrent vulvovaginal candidiasis?**

A. First make sure of the correct diagnosis, then try these strategies

In this day and age of 'over the counter' vaginitis treatments, the
first step is to assure yourself and your patient that are actually
treating the correct organism.

(See also Clinical Features Diagnosis, Self diagnosis, and Differential
diagnosis below)\*\*

What is recurrent vulvovaginal candidiasis?

Recurrent vulvovaginal candidiasis is defined as four or more episodes
of infection per year; it occurs in 5 to 8 percent of healthy women.
Longitudinal DNA-typing studies suggest that repeated vaginitis occurs
in a significant number of women due to relapse or endogenous
reinfection with identical strains of susceptible C. albicans. Rarely,
there is infection with new strains of Candida.

On the other hand, what are considered 'complicated infections'?

Characteristics of complicated infections include:

  ![](media/image1.png){width="6.25e-2in"
height="7.291666666666667e-2in"} Porly controlled diabetes,
immunosuppression, other vulvovaginal disease, severe illness\
  ![](media/image1.png){width="6.25e-2in"
height="7.291666666666667e-2in"} History of recurrent
(![](media/image2.png){width="8.333333333333333e-2in"
height="9.375e-2in"}4/year) vulvovaginal candidiasis\
  ![](media/image1.png){width="6.25e-2in"
height="7.291666666666667e-2in"} Candida species other than C. albicans,
particularly C. glabrata\
  ![](media/image1.png){width="6.25e-2in"
height="7.291666666666667e-2in"} Pregnancy\
  ![](media/image1.png){width="6.25e-2in"
height="7.291666666666667e-2in"} Severe signs/symptoms

Women with severe inflammation or host factors suggestive of complicated
infection are less likely to respond to short courses of antimycotic
drugs and require seven to 14 days of topical therapy or two doses of
oral therapy 72 hours apart.

Complicated

One prospective study randomly assigned 556 women with severe or
recurrent candidiasis to therapy with a single dose of fluconazole (50
mg) or two sequential doses given three days apart. Severity of disease
was based upon a scoring system involving degree of pruritus and
physical signs (erythema, edema, excoriation/fissure formation). The two
dose regimen resulted in significantly higher clinical cure/improvement
rates at evaluation on day 14 (94 versus 85 percent) and day 35 (80
versus 67 percent) in women with severe, but not recurrent, disease.
However, the response to therapy was lower in the 8 percent of women
infected with nonalbicans Candida.

**C. glabrata** --- Treatment failure with azoles is not uncommon
(around 50 percent) in patients with C. glabrata vaginitis. Moderate
success (65 to 70 percent) in women infected with this organism can be
achieved with intravaginal boric acid (600 mg capsule once daily at
night for two weeks) and even better results (\>90 percent cure) are
achieved with intravaginal flucytosine cream (5 g nightly for two
weeks), although maintenance regimens remain unavailable.

**Sexual partner** --- As previously mentioned, sexual transmission of
candida can occur. However, partner treatment is not necessary since
this is not a primary route of transmission. Most experts do not
recommend treatment of sexual partners of women with recurrent
infections, although this is a matter of controversy (see below).

**Pregnancy** --- Treatment is indicated for relief of symptoms as
vaginal candidiasis is not associated with adverse pregnancy outcomes.
Topical azoles applied for seven days are recommended for treatment
during pregnancy.

[Now, back to recurrent vulvovaginal candidiasis.]{.underline}

We now know that recurrent vulvovaginal candidiasis is defined as four
or more episodes of infection per year; it occurs in 5 to 8 percent of
healthy women. Longitudinal DNA-typing studies suggest that repeated
vaginitis occurs in a significant number of women due to relapse or
endogenous reinfection with identical strains of susceptible C.
albicans. Rarely, there is infection with new strains of Candida.

Predisposing factors for recurrent infection are apparent in only a
minority of women, and include uncontrolled diabetes and
immunosuppressive therapy. In the remainder, factors that may predispose
to recurrent infection include abnormalities in local vaginal mucosal
immunity and genetic susceptibility: women with recurrent infections
have a higher frequency of certain Lewis blood group antigens compared
with controls. In women with recurrent vulvovaginal candidiasis who were
prescribed maintenance antifungal therapy, behavioral factors associated
with at least a two-fold increased risk of symptomatic episodes included
use of pantyliners, pantyhose, or sexual lubricants and consumption of
[cranberry](http://www.uptodateonline.com/application/topic.asp?file=nat_drug/47467&drug=true)
juice or acidophilus containing products.

There is no evidence that women with recurrent vulvovaginal candidiasis
have vaginal flora deficient in lactobacilli. Although there is a
popular belief that ingestion or vaginal administration of yogurt or
agents containing live
[Lactobacillus](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/139322&drug=true)
acidophilus decreases the rate of candidal colonization and symptomatic
relapse, the few studies in this area have a number of methodologic
flaws and small numbers of subjects. The value of administering live
lactobacilli to women with recurrent infection has been refuted in other
studies and this approach should be considered unproven. There are also
no data to support the concept of vaginal immunotherapy.

The role of sexual transmission in recurrent infection remains
unresolved. In one study, treatment of colonized male partners (evidence
of Candida in the oral cavity, penile coronal sulcus, or seminal fluid)
decreased the rate of recurrence compared with women who did not have a
colonized partner (16 versus 45 percent). In contrast, a second trial of
54 women with recurrent candida vaginitis that randomly treated one-half
of the male partners with
[ketoconazole](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/138286&drug=true),
200 mg per day for five days, found no significant difference in the
rate of relapse between women with untreated or treated partners. Many
providers do not treat sexual partners.

The incidence and persistence of vulvovaginal candidiasis are higher in
HIV seropositive than seronegative women. However, significantly
increased rates are confined to HIV infected women with very low CD4
counts and high viral load, a population likely to manifest other AIDS
related sentinel conditions. Moreover, recurrent candida vaginitis is
also a common condition in women without HIV infection. For these
reasons, routine HIV testing of women with recurrent vulvovaginal
candidiasis does not appear to be justified.

**Treatment recommendations** --- The treatment of women with recurrent
infections can be difficult and frustrating. Attempts should be made to
eliminate or reduce risk factors for infection (eg, improve glycemic
control, switch to lower dose OCP). Although not based upon data from
randomized studies, a trial of one or more behavioral changes may also
be beneficial for some women (eg, avoidance of pantyliners, pantyhose,
[cranberry](http://www.uptodateonline.com/application/topic.asp?file=nat_drug/47467&drug=true)
juice). Treatment should also be directed at the sexual dysfunction and
marital discord that frequently accompany chronic vaginitis.

Women with recurrent infections should receive longer initial therapy
(10 to 14 days of a topical agent or
[[fluconazole]{.underline}](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/105879&drug=true)
150 mg orally with a repeat dose 72 hours later). Antifungal maintenance
suppressive therapy taken for six months after an initial induction
regimen has resulted in negative cultures in multiple studies of women
with recurrent vulvovaginal candidiasis.

Regimens include
[ketoconazole](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/138286&drug=true)
(100 mg per day),
[itraconazole](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/137722&drug=true)
(100 mg per day or 400 mg once monthly),
[clotrimazole](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/63374&drug=true)
(500 mg vaginal suppositories administered once per week), and
fluconazole (see below). Patients receiving longterm ketoconazole should
be monitored for hepatotoxicity.

The safety and efficacy of
[fluconazole](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/105879&drug=true)
maintenance therapy was illustrated in a trial of 387 women with
recurrent vulvovaginal candidiasis treated with open-label fluconazole
(150 mg orally at 72 hour intervals for three doses) and then randomly
assigned to weekly doses of fluconazole (150 mg) or placebo for six
months. The maintenance therapy phase was begun two weeks after
initiation of treatment in patients who were clinically cured. Study
drugs were discontinued in patients diagnosed with recurrent candidal
infection during follow-up visits.

  ![](media/image1.png){width="6.25e-2in"
height="7.291666666666667e-2in"} The proportion of women who remained
disease-free was significantly higher in the fluconazole group (91
versus 36 percent at six months, 73 versus 28 percent at nine months,
and 43 versus 22 percent at twelve months).\
\
  ![](media/image1.png){width="6.25e-2in"
height="7.291666666666667e-2in"} The mean time to recurrence in the
fluconazole and placebo groups was 10.2 and 4.0 months, respectively.\
\
  ![](media/image1.png){width="6.25e-2in"
height="7.291666666666667e-2in"} Resistant isolates of Candida albicans
or superinfection with C. glabrata were not observed.

Although this regimen of maintenance
[fluconazole](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/105879&drug=true)
was convenient, safe, and as effective as other therapies, long-term
cure of recurrent vulvovaginal candidiasis was not achieved. Episodes of
recurrent candidiasis resumed when maintenance therapy was discontinued.

Alternatively,
[fluconazole](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/105879&drug=true)
150 mg orally may be given every 72 hours until the patient is
asymptomatic, with redosing weekly, tapered to every two weeks, and then
every three to four weeks as long as the woman remains asymptomatic.
Redosing once per month just before menses may be effective because this
is when most patients flare.

**\*\*****CLINICAL FEATURES** --- Vulvar pruritus is the dominant
feature of vulvovaginal candidiasis. Women may also complain of dysuria
(typically perceived to be external or vulvar rather than urethral),
soreness, irritation, and dyspareunia. There is often little or no
discharge; that which is present is typically white and clumpy
(curd-like).

Physical examination often reveals erythema of the vulva and vaginal
mucosa and vulvar edema. The discharge is classically described as
thick, adherent, and \"cottage cheese-like\". However, it may also be
thin and loose, indistinguishable from the discharge of other types of
vaginitis. Some patients, primarily those with C. glabrata infection,
have little discharge and often only erythema on vaginal examination.

**DIAGNOSIS** --- The general diagnostic approach to women with vaginal
complaints is reviewed separately.

The vaginal pH is typically 4 to 4.5, which distinguishes candidiasis
from trichomonas or bacterial vaginosis. The diagnosis is confirmed by
finding the organism on a wet mount of the discharge; adding 10 percent
potassium hydroxide destroys the cellular elements and may facilitate
recognition of budding yeast and hyphae (sensitivity 70 percent).

Microscopy is negative in up to 50 percent of patients with confirmed
vulvovaginal candidiasis. \[Although empiric therapy is often considered
in women with typical clinical features, a normal vaginal pH, and no
other pathogens visible on microscopy, a culture should be obtained to
confirm the diagnosis and avoid empiric therapy. Furthermore, culture
will show the species of organism, which will help in choosing the
correct antifungal agent. Culture should also be performed in patients
with persistent or recurrent symptoms because many of these women have
non-albicans infection that is resistant to azoles.

**Self diagnosis** --- There are serious doubts about the accuracy of
self-diagnosis of vulvovaginal candidiasis. This was illustrated in a
study that administered a questionnaire to 600 women to assess their
knowledge of the symptoms and signs of pelvic inflammatory disease,
bacterial vaginosis, acute cystitis, vaginal trichomoniasis, and
vulvovaginal candidiasis after reading classic case scenarios. Only 11
percent of women without a previous diagnosis of vulvovaginal
candidiasis made an accurate diagnosis of this infection; women who had
had a prior episode were slightly more accurate (35 percent correct),
but were likely to use over-the-counter preparations inappropriately to
treat other gynecologic conditions that were potentially more serious.

In another report, the actual diagnoses in 95 women who self-diagnosed
vulvovaginal candidiasis were: vulvovaginal candidiasis (34 percent),
bacterial vaginosis (19 percent), mixed vaginitis (21 percent), normal
flora (14 percent), trichomonas vaginitis (2 percent), and other (11
percent) . Women with a previous episode of vulvovaginal candidiasis and
those who read the package insert for their over-the-counter medication
were not more accurate in making a diagnosis than other women.

Some consequences of misdiagnosis and inappropriate therapy include a
delay in correct diagnosis and treatment, wasted monetary expenditure,
and precipitation of vulvar dermatitis.

**Differential diagnosis ---** Other conditions to be considered in the
differential diagnosis include hypersensitivity, allergic or chemical
reactions, and contact dermatitis. Failure to recognize the frequency of
local adverse reactions results in the empirical prescription of
additional topical agents, including high potency steroids, that further
aggravate symptoms. In addition, mechanical irritation due to
insufficient lubrication during coitus can result in vaginal discomfort
and discharge.

**Resources:**

Centers for Disease Control and Prevention. Sexually transmitted
diseases treatment guidelines 2002. MMWR 2002; 51:RR-6.

<http://www.cdc.gov/std/treatment/default.htm>

Candida vaginitis, UpToDate

[[http://www.uptodateonline.com/application/topic.asp?file=gen_gyne/27679&type=A&selectedTitle=1\~19]{.underline}](http://www.uptodateonline.com/application/topic.asp?file=gen_gyne/27679&type=A&selectedTitle=1~19)

Reef SE et al Treatment options for vulvovaginal candidiasis, 1993. Clin
Infect Dis 1995 Apr;20 Suppl 1:S80-90.

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7795112&query_hl>

Sobel JD et al Maintenance fluconazole therapy for recurrent
vulvovaginal candidiasis. N Engl J Med 2004 Aug 26;351(9):876-83.

[[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15329425&query_hl]{.underline}](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15329425&query_hl)