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Fluconazole-Resistant Candida

albicans Vulvovaginitis
Dror Marchaim, MD, Leslie Lemanek, BS, Suchitha Bheemreddy, MD, Keith S. Kaye, MD, MPH,
and Jack D. Sobel, MD

OBJECTIVE: As a result of high recurrence rates of Candida All patients were clinically controlled successfully,
albicans vaginitis, successful suppressive fluconazole is although treatment was difficult and often prolonged.
widely used, and drug resistance is considered rare. We CONCLUSION: Fluconazole-resistant C albicans vagini-
report increased occurrence of secondary fluconazole tis was previously considered rare. We report 25 cases
resistance, analysis of risk factors thereof, and describe over an 11-year period, indicating an emerging problem.
management of fluconazole-refractory vaginitis. All patients had fluconazole consumption in the previous
METHODS: Patients referred to the Vaginitis Clinic 6 months. Management of fluconazole refractory disease
at Wayne State University with clinically refractory is extremely difficult with limited options, and new
fluconazole-resistant (minimum inhibitory concentration therapeutic modalities are needed.
[MIC] 2 micrograms/mL or greater) C albicans vaginitis (Obstet Gynecol 2012;120:1407–14)
from 2000 to 2010 were enrolled. Patients completed DOI: http://10.1097/AOG.0b013e31827307b2
a questionnaire pertaining to demographics, comorbid- LEVEL OF EVIDENCE: II
ities, behavioral characteristics, exposure to antimicrobials

V
and antifungals, fluconazole consumption in defined daily ulvovaginal candidiasis infection affects 75% of
doses in the previous 6 months, management received, women at least once in their lifetime.1,2 More
and outcomes. With patients not located, data were
than 90% of vulvovaginal candidiasis infections are
extracted from charts. Susceptibilities to antifungals were
caused by Candida albicans.2 Recurrent vulvovaginal
determined by broth microdilution.
candidiasis infection, defined as four or more episodes
RESULTS: Twenty-five women with fluconazole-resistant of vulvovaginal candidiasis infection in 1 year, affects
recurrent C albicans vaginitis were identified, and 16 5–8% of women during their childbearing age, which
returned filled questionnaires. Study cohort consisted
translates into disease affecting millions of women
mainly of married, insured white women with more than
worldwide.1–6 Recurrent vulvovaginal candidiasis infec-
12 years of formal education and average or above aver-
tion is associated with considerable suffering, costs, and
age socioeconomic status. Median fluconazole MIC was 8
micrograms/mL (range 2–128 micrograms/mL). Risk fac-
interference with sexual relations.2–4 Acute episodes of
tors for mycologic failure included increased fluconazole vulvovaginal candidiasis infection are frequently self-
consumption (P5.03) with 16 of 25 women exposed to diagnosed, self-treated with over-the-counter antimy-
low-dose weekly fluconazole maintenance therapy. 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
From the Division of Infectious Diseases, Detroit Medical Center, Wayne State therapy regimen for recurrent vulvovaginal candidiasis
University School of Medicine, Detroit, Michigan. infection has been advocated.3,5,7 A low-dose regimen,
Presented at the Annual Meeting of the Infectious Diseases Society for Obstetrics of 150 mg fluconazole taken once weekly for at least
and Gynecology, August 7, 2011, Chicago, Illinois. 6 months, has been shown in a randomized placebo-
Corresponding author: Jack D. Sobel, MD, Division of Infectious Diseases, controlled trial to be associated with reduced rate of
Harper University Hospital, 3990 John R. Street, Detroit, MI, 48201; e-mail: recurrences5 and is now considered the standard of
jsobel@med.wayne.edu.
care.5–8 The frequent empiric prescription of flucona-
Financial Disclosure
The authors did not report any potential conflicts of interest. zole for sporadic vulvovaginal candidiasis infection,
coupled with over-the-counter availability of topical
© 2012 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins. azole agents and the widespread use of a low-dose
ISSN: 0029-7844/12 weekly fluconazole regimen for recurrent vulvovaginal

VOL. 120, NO. 6, DECEMBER 2012 OBSTETRICS & GYNECOLOGY 1407


candidiasis infection, combines to create ideal condi- by the Wayne State University institutional review
tions for fluconazole-resistant C albicans strains causing board before its initiation.
recurrent vulvovaginal candidiasis infection to evolve, Patients with fluconazole-resistant recurrent vul-
emerge, and spread. To date, reports of vulvovaginal vovaginal candidiasis infection were initially con-
candidiasis infection caused by fluconazole-resistant tacted by phone, and after obtaining permission, an
C albicans have been rare.5,9–11 informed consent and a questionnaire were mailed to
In contrast to systemic infections, the definition of study participants accompanied by stamped returning
in vitro C albicans nonsusceptibility to fluconazole in envelope. When the patient could not be located by
the context of vaginal infections remains unvalidated. phone or had not returned the signed consent,
Previous determination of Candida species break- questionnaire, or both by mail, data were extracted
points was based on studies conducted on blood and from charts. The epidemiologic questionnaire con-
oropharyngeal isolates, ignoring specific pharmacoki- sisted of data pertaining to patients’ demographics,
netic considerations applicable to the vagina.12,13 The comorbidities, behavioral characteristics, exposure to
breakpoint or measurement of in vitro fluconazole antimicrobials and antifungals, fluconazole consump-
resistance in C albicans had recently been reduced tion in defined daily doses in the previous 6 months,
by the Clinical and Laboratory Standards Institution management received for the fluconazole-resistant
from 64 to 8 micrograms/mL.14,15 There are limited recurrent vulvovaginal candidiasis infection, and
clinical data, however, based on studies in women outcomes.
with Candida vaginitis suggesting that fluconazole sus- Vaginal cultures were processed at the Wayne
ceptibility be defined as 1 microgram/mL or less State University infectious diseases research labora-
instead of 2 micrograms/mL or less.16 tory. Swabs were inoculated on Sabouraud dextrose
The consequences of emergence of fluconazole- agar plates and incubated at 30°C for 48 hours. When
resistant recurrent vulvovaginal candidiasis infection growth of yeast was detected, germ-tube and chla-
are substantial, because few alternative therapeutics mydospore tests were performed. If both tests were
agents are available. Study aims were to: 1. describe positive, the isolate was identified as C albicans. If
the epidemiologic characteristics of the cohort of either one of the tests was negative, API 20C AUX
patients with fluconazole-resistant recurrent vulvova- yeast identification strips were used to confirm identi-
ginal candidiasis infection; 2. analyze the risk factors fication of C albicans. Minimum inhibitory concentra-
for clinical or mycologic failures or both among tions to various antifungals were tested by using the
patients with fluconazole-resistant recurrent vulvova- broth microdilution method conducted in accordance
ginal candidiasis infection; and 3. review therapeutic with Clinical and Laboratory Standards Institution
options to treat refractory recurrent vulvovaginal criteria and breakpoints.17
candidiasis infection. 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
PATIENTS AND METHODS the independent samples t test, analysis of variance,
The outpatient Vaginitis Clinic at Wayne State and Mann–Whitney test for (for nonnormally distrib-
University admits approximately 400 new patients uted parameters for continuous variables). The x2 test
and a total of 1,200 visits annually. Patients are for trend was used to evaluate the prevalence and
referred with complicated and difficult to manage incidence of fluconazole-resistant C albicans isolates
vaginal infections. The study cohort consisted of over the study period. All P values were two-sided.
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 RESULTS
with refractory Candida vaginitis and with a C albicans Twenty-five patients were diagnosed with refrac-
isolate with fluconazole minimum inhibitory concen- tory vulvovaginal candidiasis infection caused by
tration (MIC) 2 micrograms/mL or greater. Flucona- fluconazole-resistant C albicans between 2000 and 2010
zole refractory vulvovaginal candidiasis infection was at the Wayne State University Vaginitis Clinic. As indi-
defined as culture positive symptomatic vulvovaginal cated in Figure 1, although cases were identified
candidiasis infection, either breakthrough infection throughout the decade, 16 of 25 (64%) occurred in
while receiving 150 mg weekly fluconazole or unre- the previous 5 years. Both the prevalence and inci-
sponsive to current multidose fluconazole administra- dence (per 1,000 admissions) of cases increased over
tion. The study was retrospective and was approved the years, although insignificantly (P for trend5.16).

1408 Marchaim et al Fluconazole-Resistant C albicans Vulvovaginitis OBSTETRICS & GYNECOLOGY


6 P for trend=.16

vulvovaginitis cases (n)


Flucanozole-resistant
5
4

Fig. 1. Epidemiologic chart of fluco- 3


nazole-resistant vulvovaginitis cases, 2
2000–2010, Wayne State University,
Detroit, Michigan. 1
Marchaim. Fluconazole-resistant C albicans
vulvovaginitis. Obstet Gynecol 2012. 0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Year

Twenty-one of the patients were contacted by and remained asymptomatic with negative vaginal yeast
phone, and 16 returned questionnaires by mail and cultures. Of the 11 women, maintenance fluconazole
signed consent forms. Patient characteristics are dis- was eventually discontinued in five, and all patients
played in Table 1. The study cohort consisted primar- remained asymptomatic and culture-negative.
ily of married, insured white women with more than Five women were treated with 100 mg ketocona-
12 years of formal education and with an average or zole daily based on in vitro susceptibility and a high
above average socioeconomic status. All women level of fluconazole resistance. Four women remained
had recent extensive exposure to fluconazole and 16 asymptomatic and culture-negative with successful
of 25 (64%) women had received low-dose mainte- discontinuation of therapy in two. Three patients were
nance weekly fluconazole in the 12 months before successfully controlled on 200 mg maintenance itraco-
isolation of the fluconazole-resistant strain. The level nazole daily and two additional patients did not tolerate
of symptoms and disability reported by patients was therapy. One woman failed to tolerate itraconazole and
extremely high (Table 1). ketoconazole and was maintained in clinical and
The median fluconazole MIC was 8 micro- mycologic remission using a daily dose of 100 mg
grams/mL (range 2–128 micrograms/mL) (Table 2). fluconazole therapy. Three patients with a high level of
Eight patients (32%) had fluconazole MICs of 2 micro- resistance to multiple azole drugs were treated effec-
grams/mL, and 17 patients had MICs greater than tively with 600-mg boric acid capsules three times
2 micrograms/mL (range 4–128 micrograms/mL). weekly. One patient with high-level pan azole resis-
Cross-resistance to itraconazole (0.5 micrograms/mL tance and clinically uncontrolled disease while on
or greater) was present in five patients and in four boric acid, nystatin, and topical azoles was finally
isolates, cross-resistance to ketoconazole was evident. controlled using daily gentian violet for 14 days. The
Voriconazole resistance (2 micrograms/mL or greater) patient remained asymptomatic and culture-negative in
was detected in five fluconazole-resistant isolates (20%). follow-up visits during the next 2 years.
There was no correlation between the fluconazole MIC Fifteen of the patients had additional C albicans
and pan-azole resistance phenotype. isolation at one of their follow-up visits, ie, mycologic
Until susceptibility test results became available, failures. Risk factors for mycologic failure included
symptomatic patients initially seen with refractory older age (45 compared with 37 years, P 5.05), older
vulvovaginal candidiasis infection were most frequently age at first vulvovaginal candidiasis infection attack
prescribed 600-mg intravaginal boric acid vaginal (37 compared with 25 years, P 5.04), and number
suppositories per day for 2 weeks. Invariably, patients of fluconazole treatment courses in the 6 months
became asymptomatic and microscopically negative preceding the isolation of resistant strain (median of
and maintenance antifungal therapy was recommended six courses, interquartile range51.3–11 compared
at the next follow-up visit based on fluconazole with a median of one, interquartile range51–3.25,
MIC results. In the event of low-level fluconazole P 5.03). As a result of low numbers, no multivariate
resistance of 2–4 micrograms/mL, patients were analysis was conducted.
restarted on fluconazole but at a higher dose of After diagnosis of fluconazole resistance, it is
150–200 mg twice weekly. A total of 11 patients noteworthy that three patients initially controlled
received a higher dose fluconazole maintenance regi- with the aforementioned suppressive regimens did
men (median MIC of strains was 4 micrograms/mL) subsequently recur with symptomatic vulvovaginal

VOL. 120, NO. 6, DECEMBER 2012 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 0.03 (0.03–16)


Clotrimazole 0.13 (0.03–2)
Amphotericin B 0.13 (0–1)
5-Fluorocytosine 0.13 (0.03–2)
Caspofungin 0.5 (0.05–4)
Management of resistant cases after the isolation of the resistant strain†
Boric acid vaginal capsules 12 (48)
Increased dosages of fluconazole 16 (64)
Ketoconazole 5 (20)
Itraconazole 5 (20)
Outcomes
Mycologic cure: additional vaginal isolation(s) of Candida albicans 9 (36)
Frequency of attacks: no. of symptomatic attacks since the index isolation 6.5 (0–600)
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- consumption as a risk factor for fluconazole-resistant


tible strain of C albicans. None of the 25 patients had recurrent vulvovaginal candidiasis infection, our data
vaginal coinfection or sequential infections with are highly suggestive that frequent use of fluconazole
a non-albicans Candida species or had concomitant in some form or regimen can lead to emergence of
bacterial infection. recurrent vulvovaginal candidiasis infection caused by
a fluconazole-resistant strain.
DISCUSSION Primary or intrinsic azole resistance is rare in
Fluconazole was introduced into clinical use in 1993 C albicans isolates.13–15 Historical details available indi-
and its use for recurrent vulvovaginal candidiasis cate that only a minority of patients receiving
infection followed over the next few years.18,19 By low-dose, long-term weekly fluconazole developed
the end of the 1990s, only one case of fluconazole- secondary resistance presenting as breakthrough
resistant C albicans vulvovaginitis had been isolated at symptomatic infections. In a previous prospective
the Wayne State University clinic and reports else- controlled study, susceptibility profiles of C albicans
where were rare.9,10 In the past 10 years, an increase isolates in women who received weekly fluconazole
in women with fluconazole-resistant recurrent vulvo- showed no increase in MIC values after 6 months of
vaginal candidiasis infection was observed in our cen- fluconazole use.5 Nevertheless, in the present series,
ter although as yet not significantly different (Fig. 1). women received considerably longer fluconazole reg-
To correlate fluconazole consumption with recur- imens and hence exposure often lasting several years.
rent vulvovaginal candidiasis infection caused by Although not focusing on refractory vulvovaginal can-
a fluconazole-resistant strain, a matched case–control didiasis infection or fluconazole resistance, two previ-
study design is mandatory.20,21 This case series analy- ous studies conducted in the same clinic reviewing
sis revealed that all fluconazole-resistant patients con- azole susceptibility reported a detectable and steady
sumed high amounts of systemic fluconazole in the creep or increase in MIC values over the past two
previous 6 months with median defined daily doses decades.22,23 It is noteworthy that in reviewing Candida
of 22 per patient. Increased fluconazole consumption species responsible for candidemia, Lortholary et al24
was especially evident in patients with longitudinal reported that recent exposure to antifungals, especially
mycologic failures. Matching a control group to fluconazole, profoundly influenced species selection
reflect the true background population from which and hence antifungal drug susceptibility.
the cases arose, as per established criteria to study At present, no information is available regarding
the epidemiology of resistant strains, would be chal- the biologic mechanism of fluconazole resistance in the
lenging for this clinical entity.20,21 In the absence of vaginal isolates and these studies are ongoing. Previous
a matched case–control study to quantify fluconazole studies in nonvaginal isolates indicate multiple steps

VOL. 120, NO. 6, DECEMBER 2012 Marchaim et al 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 paucity of drug classes available.2,30 Long-term thera-
CDR and MDR efflux pumps as well as ERG 11 peutic decisions should be based on in vitro suscepti-
mutation resulting in an increase in target 14-a- bility tests. In the short term, initially faced with an
demethylase enzyme activity.25,26 Although new Clin- acutely symptomatic patient with active vaginitis and
ical and Laboratory Standards Institution guidelines unknown azole susceptibility, topical boric acid or
consider a fluconazole MIC of 2 micrograms/mL or nystatin suppositories prescribed for 10–14 days are
less to reflect a drug-sensitive isolate of C albicans, this likely to provide rapid relief and provide time to
determination did not consider any vaginitis clinical obtain susceptibility data.29 This allows for planning
data nor did it take into consideration the pharmaco- of long-term therapy when indicated in women with
kinetics of fluconazole achieving a peak value of no recurrent vulvovaginal candidiasis infection. Long-
more than 4 micrograms/mL in vaginal tissue and se- term maintenance therapy with boric acid or nystatin
cretions.27 Moreover, the low pH of vaginal tissue and is possible but rarely used because of inconvenience,
secretions during episodes of vulvovaginal candidiasis unknown efficacy together with a paucity of safety
infection is known to further reduce azole activity.28,29 data. In considering azole use as maintenance prophy-
A previous clinical study suggested that a breakpoint lactic therapy, decisions should be based entirely on
MIC for Candida vaginal isolates of 1 microgram/mL MIC data. Patients in the present study with flucona-
or less should be considered.16 In the present study, 8 zole MIC values of 2 and 4 micrograms/mL could be
of 25 isolates of women failing fluconazole therapy had treated successfully by increasing fluconazole dosage
organisms with MIC values of 2 micrograms/mL sup- to 200 mg twice weekly. Clinical experience indicated
porting the lower breakpoint value. that with MIC value of 8 micrograms/mL or greater,
The treatment of women with refractory vulvo- fluconazole use is precluded. At this juncture, cross-
vaginal candidiasis infection, especially those with resistance to itraconazole and ketoconazole should be
recurrent episodes, is especially problematic given the 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- fluconazole regimen for recurrent vulvovaginal candidiasis
(ReCiDiF trial). Am J Obstet Gynecol 2008;199:613.e1-9.
tenance daily imidazole therapy. The latter regimens
do, however, require intermittent hepatic function 8. Workowski KA, Berman SM. Sexually transmitted diseases
treatment guidelines, 2006. MMWR Recomm Rep 2006;55:
testing, not required with fluconazole use. Not infre- 1–94.
quently, all maintenance antimycotic regimens were 9. Sobel JD, Vazquez JA. Symptomatic vulvovaginitis due to
successfully discontinued. Nevertheless, in the event fluconazole-resistant Candida albicans in a female who was
of severe recurrent vulvovaginal candidiasis infection, not infected with human immunodeficiency virus. Clin Infect
Dis 1996;22:726–7.
when high-level pan azole resistance is present, ther-
apeutic measures are limited and achieving control of 10. Dorrell L, Edwards A. Vulvovaginitis due to fluconazole resis-
tant Candida albicans following self treatment with non-
symptoms was extremely difficult. prescribed triazoles. Sex Transm Infect 2002;78:308–9.
The current retrospective study has several limi- 11. Richter SS, Galask RP, Messer SA, Hollis RJ, Diekema DJ,
tations. Given the duration of 11 years collecting data, Pfaller MA. Antifungal susceptibilities of Candida species causing
we were not able to contact or receive a response in vulvovaginitis and epidemiology of recurrent cases. J Clin Micro-
biol 2005;43:2155–62.
one-third of patients, hence the need for chart review.
However, in a clinic seeing 400 new cases annually 12. Rex JH, Pfaller MA, Galgiani JN, Bartlett MS, Espinel-
Ingroff A, Ghannoum MA, et al. Development of interpre-
with less than 10% presenting with recurrent vulvo- tive breakpoints for antifungal susceptibility testing: concep-
vaginal candidiasis infection, numbers did not allow tual framework and analysis of in vitro-in vivo correlation
creation of a matched control group or estimation of data for fluconazole, itraconazole, and candida infections.
Subcommittee on Antifungal Susceptibility Testing of the
percentage of C albicans isolates resistant to flucona- National Committee for Clinical Laboratory Standards. Clin
zole. Clinical and in vitro resistance is still uncommon, Infect Dis 1997;24:235–47.
but as this study reveals, it is certainly not rare. Any 13. Rex JH, Rinaldi MG, Pfaller MA. Resistance of Candida spe-
further epidemiologic claims would be distorted by cies to fluconazole. Antimicrob Agents Chemother 1995;39:
1–8.
the accrual bias of referred cases. In conclusion, fluco-
nazole resistance and reduced susceptibility C albicans 14. Pfaller MA, Andes D, Diekema DJ, Espinel-Ingroff A, Sheehan D;
CLSI Subcommittee for Antifungal Susceptibility Testing.
strains causing refractory vulvovaginal candidiasis Wild-type MIC distributions, epidemiological cutoff values
infection are increasingly emerging and responsible and species-specific clinical breakpoints for fluconazole and
for considerable suffering, especially when high-level Candida: time for harmonization of CLSI and EUCAST
broth microdilution methods. Drug Resist Updat 2010;13:
resistance exists. Given the likely causal role of fluco- 180–95.
nazole exposure, unnecessary and inappropriate pre- 15. Pfaller MA, Espinel-Ingroff A, Boyken L, Hollis RJ, Kroeger J,
scription should be avoided and long-term use must Messer SA, et al. Comparison of the broth microdilution
be based on diagnostic confirmation. Similarly, any (BMD) method of the European Committee on Antimicrobial
movement toward liberalizing public availability of Susceptibility Testing with the 24-hour CLSI BMD method for
testing susceptibility of Candida species to fluconazole, posaco-
fluconazole should be discouraged. Fluconazole sus- nazole, and voriconazole by use of epidemiological cutoff val-
ceptibility trends require monitoring and new antimy- ues. J Clin Microbiol 2011;49:845–50.
cotic agents are urgently needed. 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
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1414 Marchaim et al Fluconazole-Resistant C albicans Vulvovaginitis OBSTETRICS & GYNECOLOGY