Fluconazole-Resistant Candida
albicans Vulvovaginitis
Dror Marchaim, MD, Leslie Lemanek, BS, Suchitha Bheemreddy,
and Jack D. Sobel, MD
OBJECTIVE: As a result of high recurrence rates of Candida
albicans vaginitis, successful suppressive fluconazole is
widely used, and drug resistance is considered rare. We
report increased occurrence of secondary fluconazole
resistance, analysis of risk factors thereof, and describe
management of fluconazole-refractory vaginitis.
METHODS: Patients referred to the Vaginitis Clinic
at Wayne State University with clinically refractory
fluconazole-resistant (minimum inhibitory concentration
[MIC] 2 micrograms/mL or greater) C albicans vaginitis
from 2000 to 2010 were enrolled. Patients completed
a questionnaire pertaining to demographics, comorbid-
ities, behavioral characteristics, exposure to antimicrobials
and antifungals, fluconazole consumption in defined daily
doses in the previous 6 months, management received,
and outcomes. With patients not located, data were
extracted from charts. Susceptibilities to antifungals were
determined by broth microdilution.
RESULTS: Twenty-five women with fluconazole-resistant
recurrent C albicans vaginitis were identified, and 16
returned filled questionnaires. Study cohort consisted
mainly of married, insured white women with more than
12 years of formal education and average or above aver-
age socioeconomic status. Median fluconazole MIC was 8
micrograms/mL (range 2–128 micrograms/mL). Risk fac-
tors for mycologic failure included increased fluconazole
consumption (P5.03) with 16 of 25 women exposed to
low-dose weekly fluconazole maintenance therapy.
From the Division of Infectious Diseases, Detroit Medical Center, Wayne State
University School of Medicine, Detroit, Michigan.
Presented at the Annual Meeting of the Infectious Diseases Society for Obstetrics
and Gynecology, August 7, 2011, Chicago, Illinois.
Corresponding author: Jack D. Sobel, MD, Division of Infectious Diseases,
Harper University Hospital, 3990 John R. Street, Detroit, MI, 48201; e-mail:
jsobel@med.wayne.edu.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2012 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/12
VOL. 120, NO. 6, DECEMBER 2012
MD, Keith S. Kaye, MD, MPH,
All patients were clinically controlled successfully,
although treatment was difficult and often prolonged.
CONCLUSION: Fluconazole-resistant C albicans vagini-
tis was previously considered rare. We report 25 cases
over an 11-year period, indicating an emerging problem.
All patients had fluconazole consumption in the previous
6 months. Management of fluconazole refractory disease
is extremely difficult with limited options, and new
therapeutic modalities are needed.
(Obstet Gynecol 2012;120:1407–14)
DOI: http://10.1097/AOG.0b013e31827307b2
LEVEL OF EVIDENCE: II
V
ulvovaginal candidiasis infection affects 75% of
women at least once in their lifetime.1,2 More
than 90% of vulvovaginal candidiasis infections are
caused by Candida albicans.2 Recurrent vulvovaginal
candidiasis infection, defined as four or more episodes
of vulvovaginal candidiasis infection in 1 year, affects
5–8% of women during their childbearing age, which
translates into disease affecting millions of women
worldwide.1–6 Recurrent vulvovaginal candidiasis infec-
tion is associated with considerable suffering, costs, and
interference with sexual relations.2–4 Acute episodes of
vulvovaginal candidiasis infection are frequently self-
diagnosed, self-treated with over-the-counter antimy-
cotics, or treated empirically by physicians without
obtaining cultures.2 As a result of low cure and high
recurrence rates, a long-term fluconazole maintenance
therapy regimen for recurrent vulvovaginal candidiasis
infection has been advocated.3,5,7 A low-dose regimen,
of 150 mg fluconazole taken once weekly for at least
6 months, has been shown in a randomized placebo-
controlled trial to be associated with reduced rate of
recurrences5 and is now considered the standard of
care.5–8 The frequent empiric prescription of flucona-
zole for sporadic vulvovaginal candidiasis infection,
coupled with over-the-counter availability of topical
azole agents and the widespread use of a low-dose
weekly fluconazole regimen for recurrent vulvovaginal
OBSTETRICS & GYNECOLOGY 1407
candidiasis infection, combines to create ideal condi-
tions for fluconazole-resistant C albicans strains causing
recurrent vulvovaginal candidiasis infection to evolve,
emerge, and spread. To date, reports of vulvovaginal
candidiasis infection caused by fluconazole-resistant
C albicans have been rare.5,9–11
In contrast to systemic infections, the definition of
in vitro C albicans nonsusceptibility to fluconazole in
the context of vaginal infections remains unvalidated.
Previous determination of Candida species break-
points was based on studies conducted on blood and
oropharyngeal isolates, ignoring specific pharmacoki-
netic considerations applicable to the vagina.12,13 The
breakpoint or measurement of in vitro fluconazole
resistance in C albicans had recently been reduced
by the Clinical and Laboratory Standards Institution
from 64 to 8 micrograms/mL.14,15 There are limited
clinical data, however, based on studies in women
with Candida vaginitis suggesting that fluconazole sus-
ceptibility be defined as 1 microgram/mL or less
instead of 2 micrograms/mL or less.16
The consequences of emergence of fluconazole-
resistant recurrent vulvovaginal candidiasis infection
are substantial, because few alternative therapeutics
agents are available. Study aims were to: 1. describe
the epidemiologic characteristics of the cohort of
patients with fluconazole-resistant recurrent vulvova-
ginal candidiasis infection; 2. analyze the risk factors
for clinical or mycologic failures or both among
patients with fluconazole-resistant recurrent vulvova-
ginal candidiasis infection; and 3. review therapeutic
options to treat refractory recurrent vulvovaginal
candidiasis infection.
PATIENTS AND METHODS
The outpatient Vaginitis Clinic at Wayne State
University admits approximately 400 new patients
and a total of 1,200 visits annually. Patients are
referred with complicated and difficult to manage
vaginal infections. The study cohort consisted of
patients with recurrent vulvovaginal candidiasis infec-
tion, who were admitted to the clinic from 2000 to
2010 who presented on admission or follow-up visits
with refractory Candida vaginitis and with a C albicans
isolate with fluconazole minimum inhibitory concen-
tration (MIC) 2 micrograms/mL or greater. Flucona-
zole refractory vulvovaginal candidiasis infection was
defined as culture positive symptomatic vulvovaginal
candidiasis infection, either breakthrough infection
while receiving 150 mg weekly fluconazole or unre-
sponsive to current multidose fluconazole administra-
tion. The study was retrospective and was approved
1408 Marchaim et al Fluconazole-Resistant C albicans Vulvovaginitis
by the Wayne State University institutional review
board before its initiation.
Patients with fluconazole-resistant recurrent vul-
vovaginal candidiasis infection were initially con-
tacted by phone, and after obtaining permission, an
informed consent and a questionnaire were mailed to
study participants accompanied by stamped returning
envelope. When the patient could not be located by
phone or had not returned the signed consent,
questionnaire, or both by mail, data were extracted
from charts. The epidemiologic questionnaire con-
sisted of data pertaining to patients’ demographics,
comorbidities, behavioral characteristics, exposure to
antimicrobials and antifungals, fluconazole consump-
tion in defined daily doses in the previous 6 months,
management received for the fluconazole-resistant
recurrent vulvovaginal candidiasis infection, and
outcomes.
Vaginal cultures were processed at the Wayne
State University infectious diseases research labora-
tory. Swabs were inoculated on Sabouraud dextrose
agar plates and incubated at 30°C for 48 hours. When
growth of yeast was detected, germ-tube and chla-
mydospore tests were performed. If both tests were
positive, the isolate was identified as C albicans. If
either one of the tests was negative, API 20C AUX
yeast identification strips were used to confirm identi-
fication of C albicans. Minimum inhibitory concentra-
tions to various antifungals were tested by using the
broth microdilution method conducted in accordance
with Clinical and Laboratory Standards Institution
criteria and breakpoints.17
All analyses were performed by using IBM SPSS
19. Univariate analyses were performed using the
Fisher’s exact and x2 tests for categorical variables and
the independent samples t test, analysis of variance,
and Mann–Whitney test for (for nonnormally distrib-
uted parameters for continuous variables). The x2 test
for trend was used to evaluate the prevalence and
incidence of fluconazole-resistant C albicans isolates
over the study period. All P values were two-sided.
RESULTS
Twenty-five patients were diagnosed with refrac-
tory vulvovaginal candidiasis infection caused by
fluconazole-resistant C albicans between 2000 and 2010
at the Wayne State University Vaginitis Clinic. As indi-
cated in Figure 1, although cases were identified
throughout the decade, 16 of 25 (64%) occurred in
the previous 5 years. Both the prevalence and inci-
dence (per 1,000 admissions) of cases increased over
the years, although insignificantly (P for trend5.16).
OBSTETRICS & GYNECOLOGY

vulvovaginitis cases (n)
Flucanozole-resistant
Fig. 1. Epidemiologic chart of fluco-
nazole-resistant vulvovaginitis cases,
2000–2010, Wayne State University,
Detroit, Michigan.
Marchaim. Fluconazole-resistant C albicans
vulvovaginitis. Obstet Gynecol 2012.
Twenty-one of the patients were contacted by
phone, and 16 returned questionnaires by mail and
signed consent forms. Patient characteristics are dis-
played in Table 1. The study cohort consisted primar-
ily of married, insured white women with more than
12 years of formal education and with an average or
above average socioeconomic status. All women
had recent extensive exposure to fluconazole and 16
of 25 (64%) women had received low-dose mainte-
nance weekly fluconazole in the 12 months before
isolation of the fluconazole-resistant strain. The level
of symptoms and disability reported by patients was
extremely high (Table 1).
The median fluconazole MIC was 8 micro-
grams/mL (range 2–128 micrograms/mL) (Table 2).
Eight patients (32%) had fluconazole MICs of 2 micro-
grams/mL, and 17 patients had MICs greater than
2 micrograms/mL (range 4–128 micrograms/mL).
Cross-resistance to itraconazole (0.5 micrograms/mL
or greater) was present in five patients and in four
isolates, cross-resistance to ketoconazole was evident.
Voriconazole resistance (2 micrograms/mL or greater)
was detected in five fluconazole-resistant isolates (20%).
There was no correlation between the fluconazole MIC
and pan-azole resistance phenotype.
Until susceptibility test results became available,
symptomatic patients initially seen with refractory
vulvovaginal candidiasis infection were most frequently
prescribed 600-mg intravaginal boric acid vaginal
suppositories per day for 2 weeks. Invariably, patients
became asymptomatic and microscopically negative
and maintenance antifungal therapy was recommended
at the next follow-up visit based on fluconazole
MIC results. In the event of low-level fluconazole
resistance of 2–4 micrograms/mL, patients were
restarted on fluconazole but at a higher dose of
150–200 mg twice weekly. A total of 11 patients
received a higher dose fluconazole maintenance regi-
men (median MIC of strains was 4 micrograms/mL)
VOL. 120, NO. 6, DECEMBER 2012
6 P for trend=.16
5
4
3
2
1
0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Year
and remained asymptomatic with negative vaginal yeast
cultures. Of the 11 women, maintenance fluconazole
was eventually discontinued in five, and all patients
remained asymptomatic and culture-negative.
Five women were treated with 100 mg ketocona-
zole daily based on in vitro susceptibility and a high
level of fluconazole resistance. Four women remained
asymptomatic and culture-negative with successful
discontinuation of therapy in two. Three patients were
successfully controlled on 200 mg maintenance itraco-
nazole daily and two additional patients did not tolerate
therapy. One woman failed to tolerate itraconazole and
ketoconazole and was maintained in clinical and
mycologic remission using a daily dose of 100 mg
fluconazole therapy. Three patients with a high level of
resistance to multiple azole drugs were treated effec-
tively with 600-mg boric acid capsules three times
weekly. One patient with high-level pan azole resis-
tance and clinically uncontrolled disease while on
boric acid, nystatin, and topical azoles was finally
controlled using daily gentian violet for 14 days. The
patient remained asymptomatic and culture-negative in
follow-up visits during the next 2 years.
Fifteen of the patients had additional C albicans
isolation at one of their follow-up visits, ie, mycologic
failures. Risk factors for mycologic failure included
older age (45 compared with 37 years, P 5.05), older
age at first vulvovaginal candidiasis infection attack
(37 compared with 25 years, P 5.04), and number
of fluconazole treatment courses in the 6 months
preceding the isolation of resistant strain (median of
six courses, interquartile range51.3–11 compared
with a median of one, interquartile range51–3.25,
P 5.03). As a result of low numbers, no multivariate
analysis was conducted.
After diagnosis of fluconazole resistance, it is
noteworthy that three patients initially controlled
with the aforementioned suppressive regimens did
subsequently recur with symptomatic vulvovaginal
Marchaim et al Fluconazole-Resistant C albicans Vulvovaginitis 1409
Table 1. Characteristics of Patients With Fluconazole-Resistant Candida albicans Vulvovaginitis, 2000–2010
Parameter

Demographics
Age (y) 43.1611.4
White 18 (75)
Patients having insurance 24 (96)
Married 17 (68)
More than 15 y of formal education 8 (53.3)
Average or above socioeconomic status 11 (73.4)
Background and chronic conditions
Other prior local vaginal or vulvar pathologies 9 (36)
Relatively constant intervals of menstrual cycles 17 (77.3)
Oral contraceptive pill usage in the year preceding the index isolation* 6 (28.6)
Hormone therapy in the year preceding the index isolation 3 (42.9)
No. of labors before index isolation 2 (0–4)
No. of pregnancies before index isolation 2 (0–5)
No. of sexual partners before index isolation
0 3 (13)
1–5 13 (56.5)
6–10 3 (13)
More than 10 4 (17.4)
Family history of vulvovaginitis in first-degree relative 7 (36.8)
Hospitalization in the year before index isolation 4 (16.7)
Surgery in the year before index isolation 6 (25)
Invasive gynecologic intervention or procedure in the year before index isolation 7 (28)
Antibiotic treatment for UTI in the year before index isolation 6 (26.1)
Number of UTI episodes in the year before index isolation 0 (0–3)
Diabetes mellitus or gestational diabetes 1 (4)
Human immunodeficiency virus 1 (4)
Sexually transmitted disease in the 3 y before index isolation 5 (20.8)
Bacterial vaginosis confirmed episodes 9 (39.1)
Glucocorticoid or steroid use (oral, topical, or both) in the 6 mo before index isolation 8 (32)
Other potential exacerbators of vulvovaginal candidiasis infection attacks
Consumptions of refined sugars 7 (46.7)
Increased sexual activity 6 (46.2)
Receptive oral sexual activity practices 1 (7.7)
Exposure to antimicrobials and antifungal agents
Systemic antimicrobials (no antifungal) in the 6 mo before index isolation 7 (29.2)
No. of antibiotic courses (no antifungal) in the 6 mo before index isolation 0 (0–3)
Any fluconazole exposure in the 6 mo before index isolation 25 (100)
Fluconazole treatment in the 6 mo before index isolation 24 (96)
Topical azole treatment in the 6 mo before index isolation 13 (56.5)
Weekly fluconazole maintenance therapy in the year before the index isolation 16 (66.7)
No. of months on weekly maintenance fluconazole therapy before index isolation 6.5 (1–16)
No. of fluconazole treatment courses in the 6 mo before index isolation 2 (1–20)
Defined daily doses of fluconazole in the 6 mo before index isolation 22 (3–150)
Factors related to the vulvovaginal disease state
Disease duration (y) 2 (0.17–40)
Age (y) when vulvovaginitis was first diagnosed 32 (12–59)
Subjective report of severity of symptoms (from 1 to 10) 8.161.6
Subjective report of mood disturbances (from 1 to 10) 6.762.9
Subjective report of general functionality (from 1 to 10) 5.962.9
Subjective report of sexual relation disturbances (from 1 to 10) 9.361.8
Subjective report of overall affect of all aspects in life (from 1 to 10) 8 (1–10)
Pregnant or up to 6 wk postpartum at the time of index isolation 0
Microbiology
MIC2 (micrograms/mL)
Fluconazole 8 (2–128)
Itraconazole 0.12 (0.03–128)
Voriconazole 0.25 (0.03–128)
(continued )

1410 Marchaim et al Fluconazole-Resistant C albicans Vulvovaginitis OBSTETRICS & GYNECOLOGY

Table 1. Characteristics of Patients With Fluconazole-Resistant Candida albicans Vulvovaginitis, 2000–2010
(continued )
Parameter
Ketoconazole
Clotrimazole
Amphotericin B
5-Fluorocytosine
Caspofungin
Management of resistant cases after the isolation of the resistant strain†
Boric acid vaginal capsules
Increased dosages of fluconazole
Ketoconazole
Itraconazole
Outcomes
Mycologic cure: additional vaginal isolation(s) of Candida albicans
Frequency of attacks: no. of symptomatic attacks since the index isolation
UTI, urinary tract infection; MIC, minimum inhibitory concentration.
Data are mean6standard deviation, n (%), or median (range).
* Percent is displayed as a “valid percent,” ie, excluding the missing.
†
Index isolation refers to the culture date of the first fluconazole-resistant isolate. Some of the patients had been treated with more than one
treatment regimen.
candidiasis infection caused by a fluconazole-suscep-
tible strain of C albicans. None of the 25 patients had
vaginal coinfection or sequential infections with
a non-albicans Candida species or had concomitant
bacterial infection.
DISCUSSION
Fluconazole was introduced into clinical use in 1993
and its use for recurrent vulvovaginal candidiasis
infection followed over the next few years.18,19 By
the end of the 1990s, only one case of fluconazole-
resistant C albicans vulvovaginitis had been isolated at
the Wayne State University clinic and reports else-
where were rare.9,10 In the past 10 years, an increase
in women with fluconazole-resistant recurrent vulvo-
vaginal candidiasis infection was observed in our cen-
ter although as yet not significantly different (Fig. 1).
To correlate fluconazole consumption with recur-
rent vulvovaginal candidiasis infection caused by
a fluconazole-resistant strain, a matched case–control
study design is mandatory.20,21 This case series analy-
sis revealed that all fluconazole-resistant patients con-
sumed high amounts of systemic fluconazole in the
previous 6 months with median defined daily doses
of 22 per patient. Increased fluconazole consumption
was especially evident in patients with longitudinal
mycologic failures. Matching a control group to
reflect the true background population from which
the cases arose, as per established criteria to study
the epidemiology of resistant strains, would be chal-
lenging for this clinical entity.20,21 In the absence of
a matched case–control study to quantify fluconazole
VOL. 120, NO. 6, DECEMBER 2012 Marchaim et al
0.03 (0.03–16)
0.13 (0.03–2)
0.13 (0–1)
0.13 (0.03–2)
0.5 (0.05–4)
12 (48)
16 (64)
5 (20)
5 (20)
9 (36)
6.5 (0–600)
consumption as a risk factor for fluconazole-resistant
recurrent vulvovaginal candidiasis infection, our data
are highly suggestive that frequent use of fluconazole
in some form or regimen can lead to emergence of
recurrent vulvovaginal candidiasis infection caused by
a fluconazole-resistant strain.
Primary or intrinsic azole resistance is rare in
C albicans isolates.13–15 Historical details available indi-
cate that only a minority of patients receiving
low-dose, long-term weekly fluconazole developed
secondary resistance presenting as breakthrough
symptomatic infections. In a previous prospective
controlled study, susceptibility profiles of C albicans
isolates in women who received weekly fluconazole
showed no increase in MIC values after 6 months of
fluconazole use.5 Nevertheless, in the present series,
women received considerably longer fluconazole reg-
imens and hence exposure often lasting several years.
Although not focusing on refractory vulvovaginal can-
didiasis infection or fluconazole resistance, two previ-
ous studies conducted in the same clinic reviewing
azole susceptibility reported a detectable and steady
creep or increase in MIC values over the past two
decades.22,23 It is noteworthy that in reviewing Candida
species responsible for candidemia, Lortholary et al24
reported that recent exposure to antifungals, especially
fluconazole, profoundly influenced species selection
and hence antifungal drug susceptibility.
At present, no information is available regarding
the biologic mechanism of fluconazole resistance in the
vaginal isolates and these studies are ongoing. Previous
studies in nonvaginal isolates indicate multiple steps
Fluconazole-Resistant C albicans Vulvovaginitis 1411
Table 2. Minimum Inhibitory Concentrations to Various Antifungals of 25 Fluconazole-Resistant Candida
albicans Unique Patient Vaginal Strains, 2000–2010
Minimum Inhibitory Concentration
Patient Ketocon- Clotri- Ampho- 5- Caspo-
No. Fluconazole Itraconazole Voriconazole azole mazole tericin-B Fluconazole fungin

1 8 0.25 0.5 0.25 0.125 1 1 0.125

2 4 0.125 0.06 0.03 0.25 0.03 2
3 4 0.125 0.25 0.125 0.5 0.03 0.25 0.25
4 2 0.03 0.25 0.03 0.03 0.06 0.5
5 32 0.03 0.25 0.03 0.03 0.125 0.5
6 16 0.06 1 0.125 0.06 0.06 0.5
7 16 0.25 0.5 0.125 0.5 0.125 0.25
8 2 0.25 0.06 0.03 0.5 0.25 0.125
9 2 0.06 0.03 0.03 0.125 0.125 0.5
10 2 0.03 0.03 0.03 0.03 0.25 0.5
11 128 0.03 16 0.06 1 0.25 0.125
12 16 0.25 0.25 0.125 1 0.125 0.5
13 8 0.125 0.25 0.03 0.06 0.125 4 4
14 2 0.25 0.06 0.03 0.03 0.25 0.125
15 8 0.5 0.5 0.25 0.25 0.06 1
16 32 0.06 0.03 0.03 0.125 0.125 0.5
17 128 32 32 16 2 0.06 0.125
18 2 0.06 0.03 0.03 0.06 0 0.25
19 128 128 128 8 0.25 0.25 0.125
20 128 32 32 0.5 0.5 0.25 0.25
21 2 0.125 0.125 0.03 0.03 0.25 0.125 0.5
22 2 0.03 0.25 0.03 0.03 0.25 0.125 0.5
23 4 0.25 0.03 0.03 0.06 0.25 16 2
24 128 128 32 16 1 0.25 0.125 2
25 32 0.125 0.25 0.06 0.06 0.05 8 0.05
Data are micrograms/mL.

are involved usually resulting in activation of both
CDR and MDR efflux pumps as well as ERG 11
mutation resulting in an increase in target 14-a-
demethylase enzyme activity.25,26 Although new Clin-
ical and Laboratory Standards Institution guidelines
consider a fluconazole MIC of 2 micrograms/mL or
less to reflect a drug-sensitive isolate of C albicans, this
determination did not consider any vaginitis clinical
data nor did it take into consideration the pharmaco-
kinetics of fluconazole achieving a peak value of no
more than 4 micrograms/mL in vaginal tissue and se-
cretions.27 Moreover, the low pH of vaginal tissue and
secretions during episodes of vulvovaginal candidiasis
infection is known to further reduce azole activity.28,29
A previous clinical study suggested that a breakpoint
MIC for Candida vaginal isolates of 1 microgram/mL
or less should be considered.16 In the present study, 8
of 25 isolates of women failing fluconazole therapy had
organisms with MIC values of 2 micrograms/mL sup-
porting the lower breakpoint value.
The treatment of women with refractory vulvo-
vaginal candidiasis infection, especially those with
recurrent episodes, is especially problematic given the
paucity of drug classes available.2,30 Long-term thera-
peutic decisions should be based on in vitro suscepti-
bility tests. In the short term, initially faced with an
acutely symptomatic patient with active vaginitis and
unknown azole susceptibility, topical boric acid or
nystatin suppositories prescribed for 10–14 days are
likely to provide rapid relief and provide time to
obtain susceptibility data.29 This allows for planning
of long-term therapy when indicated in women with
recurrent vulvovaginal candidiasis infection. Long-
term maintenance therapy with boric acid or nystatin
is possible but rarely used because of inconvenience,
unknown efficacy together with a paucity of safety
data. In considering azole use as maintenance prophy-
lactic therapy, decisions should be based entirely on
MIC data. Patients in the present study with flucona-
zole MIC values of 2 and 4 micrograms/mL could be
treated successfully by increasing fluconazole dosage
to 200 mg twice weekly. Clinical experience indicated
that with MIC value of 8 micrograms/mL or greater,
fluconazole use is precluded. At this juncture, cross-
resistance to itraconazole and ketoconazole should be
excluded, and, as shown in the present study, seven

1412 Marchaim et al Fluconazole-Resistant C albicans Vulvovaginitis OBSTETRICS & GYNECOLOGY

patients were treated effectively with long-term main-
tenance daily imidazole therapy. The latter regimens
do, however, require intermittent hepatic function
testing, not required with fluconazole use. Not infre-
quently, all maintenance antimycotic regimens were
successfully discontinued. Nevertheless, in the event
of severe recurrent vulvovaginal candidiasis infection,
when high-level pan azole resistance is present, ther-
apeutic measures are limited and achieving control of
symptoms was extremely difficult.
The current retrospective study has several limi-
tations. Given the duration of 11 years collecting data,
we were not able to contact or receive a response in
one-third of patients, hence the need for chart review.
However, in a clinic seeing 400 new cases annually
with less than 10% presenting with recurrent vulvo-
vaginal candidiasis infection, numbers did not allow
creation of a matched control group or estimation of
percentage of C albicans isolates resistant to flucona-
zole. Clinical and in vitro resistance is still uncommon,
but as this study reveals, it is certainly not rare. Any
further epidemiologic claims would be distorted by
the accrual bias of referred cases. In conclusion, fluco-
nazole resistance and reduced susceptibility C albicans
strains causing refractory vulvovaginal candidiasis
infection are increasingly emerging and responsible
for considerable suffering, especially when high-level
resistance exists. Given the likely causal role of fluco-
nazole exposure, unnecessary and inappropriate pre-
scription should be avoided and long-term use must
be based on diagnostic confirmation. Similarly, any
movement toward liberalizing public availability of
fluconazole should be discouraged. Fluconazole sus-
ceptibility trends require monitoring and new antimy-
cotic agents are urgently needed.
REFERENCES
1. Sobel JD. Epidemiology and pathogenesis of recurrent vulvo-
vaginal candidiasis. Am J Obstet Gynecol 1985;152:924–35.
2. Sobel JD. Vulvovaginal candidosis. Lancet 2007;369:1961–71.
3. Donders GG, Bellen G, Mendling W. Management of recurrent
vulvo-vaginal candidosis as a chronic illness. Gynecol Obstet
Invest 2010;70:306–21.
4. Foxman B, Marsh JV, Gillespie B, Sobel JD. Frequency and
response to vaginal symptoms among white and African American
women: results of a random digit dialing survey. J Womens Health
1998;7:1167–74.
5. Sobel JD, Wiesenfeld HC, Martens M, Danna P, Hooton TM,
Rompalo A, et al. Maintenance fluconazole therapy for recur-
rent vulvovaginal candidiasis. N Engl J Med 2004;351:876–83.
6. Sobel JD. Management of patients with recurrent vulvovaginal
candidiasis. Drugs 2003;63:1059–66.
7. Donders G, Bellen G, Byttebier G, Verguts L, Hinoul P,
Walckiers R, et al. Individualized decreasing-dose maintenance
VOL. 120, NO. 6, DECEMBER 2012 Marchaim et al
fluconazole regimen for recurrent vulvovaginal candidiasis
(ReCiDiF trial). Am J Obstet Gynecol 2008;199:613.e1-9.
8. Workowski KA, Berman SM. Sexually transmitted diseases
treatment guidelines, 2006. MMWR Recomm Rep 2006;55:
1–94.
9. Sobel JD, Vazquez JA. Symptomatic vulvovaginitis due to
fluconazole-resistant Candida albicans in a female who was
not infected with human immunodeficiency virus. Clin Infect
Dis 1996;22:726–7.
10. Dorrell L, Edwards A. Vulvovaginitis due to fluconazole resis-
tant Candida albicans following self treatment with non-
prescribed triazoles. Sex Transm Infect 2002;78:308–9.
11. Richter SS, Galask RP, Messer SA, Hollis RJ, Diekema DJ,
Pfaller MA. Antifungal susceptibilities of Candida species causing
vulvovaginitis and epidemiology of recurrent cases. J Clin Micro-
biol 2005;43:2155–62.
12. Rex JH, Pfaller MA, Galgiani JN, Bartlett MS, Espinel-
Ingroff A, Ghannoum MA, et al. Development of interpre-
tive breakpoints for antifungal susceptibility testing: concep-
tual framework and analysis of in vitro-in vivo correlation
data for fluconazole, itraconazole, and candida infections.
Subcommittee on Antifungal Susceptibility Testing of the
National Committee for Clinical Laboratory Standards. Clin
Infect Dis 1997;24:235–47.
13. Rex JH, Rinaldi MG, Pfaller MA. Resistance of Candida spe-
cies to fluconazole. Antimicrob Agents Chemother 1995;39:
1–8.
14. Pfaller MA, Andes D, Diekema DJ, Espinel-Ingroff A, Sheehan D;
CLSI Subcommittee for Antifungal Susceptibility Testing.
Wild-type MIC distributions, epidemiological cutoff values
and species-specific clinical breakpoints for fluconazole and
Candida: time for harmonization of CLSI and EUCAST
broth microdilution methods. Drug Resist Updat 2010;13:
180–95.
15. Pfaller MA, Espinel-Ingroff A, Boyken L, Hollis RJ, Kroeger J,
Messer SA, et al. Comparison of the broth microdilution
(BMD) method of the European Committee on Antimicrobial
Susceptibility Testing with the 24-hour CLSI BMD method for
testing susceptibility of Candida species to fluconazole, posaco-
nazole, and voriconazole by use of epidemiological cutoff val-
ues. J Clin Microbiol 2011;49:845–50.
16. Sobel JD, Zervos M, Reed BD, Hooton T, Soper D, Nyirjesy P,
et al. Fluconazole susceptibility of vaginal isolates obtained
from women with complicated Candida vaginitis: clinical
implications. Antimicrob Agents Chemother 2003;47:34–8.
17. CLSI. Performance standards for antimibrobial susceptibility
testing. Nineteenth informational supplement. Approved stan-
dard M100–S19. Wayne (PA): Clinical and Laboratory Stand-
ards Institute; 2009.
18. Brammer KW, Feczko JM. Single-dose oral fluconazole in the treat-
ment of vaginal candidosis. Ann N Y Acad Sci 1988;544:561–3.
19. Herzog RE, Ansmann FB. Treatment of vaginal candidiasis
with fluconazole. Mycoses 1988;32:204–8.
20. Harris AD. Control group selection is an important but
neglected issue in studies of antibiotic resistance. Ann Intern
Med 2000;132:925.
21. Kaye KS, Harris AD, Samore M, Carmeli Y. The case-case-
control study design: addressing the limitations of risk factor
studies for antimicrobial resistance. Infect Control Hosp Epide-
miol 2005;26:346–51.
22. Bulik CC, Sobel JD, Nailor MD. Susceptibility profile of vaginal
isolates of Candida albicans prior to and following fluconazole
introduction—impact of two decades. Mycoses 2011;54:34–8.
Fluconazole-Resistant C albicans Vulvovaginitis 1413
23. Shahid Z, Sobel JD. Reduced fluconazole susceptibility of Can-
dida albicans isolates in women with recurrent vulvovaginal
candidiasis: effects of long-term fluconazole therapy. Diagn
Microbiol Infect Dis 2009;64:354–6.
24. Lortholary O, Desnos-Ollivier M, Sitbon K, Fontanet A,
Bretagne S, Dromer F, et al. Recent exposure to caspofungin
or fluconazole influences the epidemiology of candidemia: a pro-
spective multicenter study involving 2,441 patients. Antimicrob
Agents Chemother 2011;55:532–8.
25. Sanglard D, Odds FC. Resistance of Candida species to anti-
fungal agents: molecular mechanisms and clinical consequen-
ces. Lancet Infect Dis 2002;2:73–85.
26. MacCallum DM, Coste A, Ischer F, Jacobsen MD, Odds FC,
Sanglard D. Genetic dissection of azole resistance mechanisms in
Candida albicans and their validation in a mouse model of dissem-
inated infection. Antimicrob Agents Chemother 2010;54:1476–83.
1414 Marchaim et al Fluconazole-Resistant C albicans Vulvovaginitis
27. Houang ET, Chappatte O, Byrne D, Macrae PV, Thorpe JE.
Fluconazole levels in plasma and vaginal secretions of patients
after a 150-milligram single oral dose and rate of eradication of
infection in vaginal candidiasis. Antimicrob Agents Chemother
1990;34:909–10.
28. Marr KA, Rustad TR, Rex JH, White TC. The trailing end
point phenotype in antifungal susceptibility testing is pH depen-
dent. Antimicrob Agents Chemother 1999;43:1383–6.
29. Danby CS, Boikov D, Rautemaa R, Sobel JD. Effect of pH on
in vitro susceptibility of Candida glabrata and Candida albicans to
eleven antifungal agents—implications for clinical use. Antimicrob
Agents Chemother 2012;56:1403–6.
30. Fan SR, Liu XP. In vitro fluconazole and nystatin susceptibility
and clinical outcome in complicated vulvovaginal candidosis.
Mycoses 2011;54:501–5.
OBSTETRICS & GYNECOLOGY