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an emergent opportunist in vulvovaginitis
Rafael Buitrón-García-Figueroa,* Javier Araiza-Santibáñez,**
Erich Basurto-Kuba,*** and Alexandro Bonifaz-Trujillo**
Candida genus has various species. The incidence of C. glabrata has presented itself with more frequency over the
past years with clinical importance.Methods:
A case study was made to determine the frequency of C. glabrata in 468 patients who presented clinical symptomatology
for vulvovaginal candidiasis and the in vitro response for fluconazole using two methods: diffusion in agar plates and microdilution in
liquid medium [NCLSI (NCCLS) method].Results:
The frequency for this specie was 12.6%, almost double the frequency observed 10 years ago. The resistance of C.
glabrata to fluconazole treatment was confirmed in this study, representing 68.2% resistance in all strains on test plates and 51.2%
on NCLSI method with a MIC of 16 μg/ml.Conclusions:
The frequency of Candida glabrata has increased over the past years. It presents resistance to usual treatments,
which promotes the persistence and recurrence of genital and systemic infections.
candidiasis, Candida glabrata, resistance, vulvovaginitis.
is now frequently identified in our hospitals as
an agent of vaginal candidiasis or producing severe systemic
Infections by Candida
genus fungi (candidiasis) have increased
mycosis and candidemia in critical and immunocompromised
their prevalence in the last three decades and have become a
patients who present solid or hematologic neoplasms.3-6 C.
significant cause of morbimortality, especially when they evolve
is the second most frequently identified species (after
into hematic infections. Although Candida albicans
is still the
) in women with vaginitis and increased vaginal
most commonly found species, there has been a significant
discharge, having a prevalence between 0.6% and 36% with a
increase in the prevalence of other species known as non-albicans
mid-frequency between 15% and 20%.7-10 Some epidemic
: C. parapsilosis, C. tropicalis
and C. glabrata
outbreaks have been identified in ICUs and are regarded as
latter is commonly found in oral and vaginal cavities of healthy
nosocomial infections. Muriel et al.11 conducted a study including
individuals as well as in the hands of healthcare personnel.1
108 strains from gynecological samples (138 from neonatal ICUs
Infection from this yeast increases with extended hospital stays
and 71 from ICUs) identifying C. glabrata
in 19.4% of vaginal
and clinical deterioration of patients, representing the first sign
samples (regarded as community-acquired infections), 27.5% of
neonatal samples and 29.6% of ICU samples. These datademonstrate the prevalence of nosocomial infections overcommunity-acquired infections for that species.1,3,7,12
* Servicio de Ginecología y Obstetricia.
Because of the relevance and increase in vulvovaginal
*** Servicio de Cirugía General, Unidad 307.
candidiasis, it is important to determine its specific etiology with
Hospital General de México OD, México, D.F., Mexico
special attention to C. glabrata
identification, in order to have aprecise idea of its frequency in Mexico as well as its therapeutic
Correspondence and reprint requests to
:Rafael Buitrón García-Figueroa
behavior. The purpose of our study was to establish the frequency
Frontera 166-D, Col Roma, Del. Cuauhtémoc
of C. glabrata
in vaginal discharge cultures from patients with
vulvovaginal candidiasis signs and symptoms in three hospitals
in Mexico City and to evaluate C. glabrata
strain susceptibilityto fluconazole, one of the most frequently used azoles against
Received for publication:
4-16-2009Accepted for publication:
Materials and Methods
Results of direct exam and
We included 468 female patients from three hospitals in MexicoCity: Gynecology Service of the General Hospital of Mexico,
Women’s Hospital of Mexico City and Gynecology Service ofNovember 20th Hospital (ISSSTE). Patients were informed in
detail about the study and were willing to participate in the
research. We included patients >18 years old who presented signs
and symptoms of vulvovaginal candidiasis: erythema, edema,
leukorrhea, excoriations, pruritus and dyspareunia.
We obtained a complete clinical history from each patient along
S, pseudohyphae; B, blastoconidias; B3&4+, abundant blastoconidias (3 & 4
with gynecological exploration and vaginal samples that were tested
with 10% KOH to observe the following images: pseudohyphae,pseudohyphae + blastoconidias and only blastoconidias. We used
and parasitic image as well as species identification. Mycological
a gram-positive criteria for all described mycological images and
results are shown in Table 1. Of the negative cases (143), 95
regarded as normal flora the presence of yeasts (blastoconidias)
presented negative direct tests and cultures, whereas 48 presented
parasitic images but had positive cultures with few colonies.
These were regarded as part of the usual flora and account for
10.2% (48/468) of all included patients.
As shown in Table 1, 41/325 (12.6%) patients presented
Two discharge samples were taken using cotton swabs and
cultured in six media: two in Sabouraud dextrose agar, two in
. With obtained C. glabrata
strains, we carried outfluconazole sensitivity tests using two methods: agar plates (to
Sabouraud dextrose agar with antibiotics and two in BiGGY
obtain resistance/susceptibility cut-off points) and broth dilution
(Nickerson, Becton Dickinson, Franklin Lakes, NJ) agar,
according to NCLSI protocol (to identify resistant strains from
incubating them for 7 days at 28°C. They were observed macro-
obtained MICs. Of the strains, 68.2% (28/41) presented resistance
and microscopically to corroborate presence of yeast.
to fluconazole sensitivity test in agar plates because there were
Species were identified using the following methods: germina-
no visible inhibiting halos at the highest concentration (32 μg);
tion tubes in human serum at 37°C for 3 h, pseudohyphae and
51.2% (21/41) presented resistance to fluconazole in broth
Chlamydia conidia in corn flour media + Tween 80, and zymogram
dilution tests with an average of 16 μg/ml.
in commercial API-yeast-20 medium. Once species were identified,antifungal qualitative sensitivity tests were carried out usingfluconazole in agar plates and quantitative sensitivity using broth
dilution protocol from NCLSI (National Clinical and LaboratoryStandards Institute). Ethical and legal requirements were met
A 1996 epidemiological study including a high prevalence of
according to the Declaration of Helsinki recommendations (updated
candidemia in patients with neoplasms reported that 6/1000
in 1989, Hong Kong). Results were statistically analyzed using
admissions presented candidemia and, of these, 79% occurred
central trend, dispersion and percentage measures.
in ICU patients. This study confirmed the increase of non-albicansCandida
sp. prevalence, demonstrating that C. glabrata
responsible for 11% of sepsis related to central venous catheterand fluconazole prophylaxis. Candidemia is not a frequent
A total of 468 women were included in the study and were diagnosed
complication in AIDS patients and generally appears in late
with genital candidiasis. The following general data were reported:
phases; however, although C. albicans
is the most frequently
average age 35.96 years (±9.8 SD), 19 years old as the minimum
identified species, C. glabrata
has also been isolated.7,12,13
age and 69 years as the maximum age. Of these patients, 97.6%
is found in candiduria cases with an increasing
were mixed-race, whereas 2.4% were Caucasian.
frequency, especially in diabetic patients, patients who receive
Of the patients, 227(48.50%) reported having similar episodes
multi-antibiotic treatments or those patients who have a urinary
in the last 12 months. Clinical manifestations during the current
catheter. A retrospective study evaluating risk factors of
episode were 425 (90.8%) pruritus, 345 (69.4%) erythema, 451
nosocomial infections from C. glabrata
and C. albicans
(96%) leukorrhea, 269 (57.4%) edema, 143 (30.5%) excoriations
that fluconazole and quinolones were specifically associated with
candiduria. It has been questioned if the resistance
Of the cases, 143 were regarded as negative; therefore, the
to this antifungal drug presented by several strains produces C.
analyzed group was reduced to 325 cases with a positive culture
replacement or if this is an independent phenomenon.
Characteristics of C. glabrata infections
Immunosuppressed and weakened patientsAdmission to ICUs
Vascular catheter (candidemia)Broad-spectrum antibiotics
Previous fluconazole administrationProlonged hospitalization
Because of the above, this yeast is considered as an emergent
species-characteristic antigenic components have been described
opportunist in most publications.5 Table 2 specifies the most
such as factor 34, which is the basis of the commercial identification
relevant factors related to C. glabrata
belongs to Ascomycetes class, Saccharomycetales
strains do not assimilate inositol and do not contain
order, Saccharomycete family, Candida
carotenoid pigments and are inhibited by cycloheximide 0.01%.
genus was created to differentiate it from Candida
Maximum temperature for growth is 43-45ºC and optimal
because it lacks blastoconidias capable of forming pseudomycele
temperature for clinical strains is 35-37ºC. Differential
or true hyphae either in infected tissues or in cultures. Currently,
characteristics are shown in Table 3.
these characteristics are considered insufficient to differentiate
With 11 chromosomes and, because of its haploid character, C.
both genera, and its integration into Candida
genus has been
is considered to have a greater chance for mutations than
proposed since 1978, although both are regarded as synonymous.
other diploid species such as C. albicans
antigenic structure has been determined by several
Several studies that have isolated C. glabrata
authors, demonstrating there is a certain cross-reactivity level with
populations and areas report a higher prevalence in elderly patients
other more virulent species such as C. albicans, C. tropicalis, C.
(27%) and in those patients with stomatitis due to dental prostheses
guilliermondii, C. kefyr
and C. parapsilosis
. However, some
(22-25%). C. glabrata
has also been isolated in 5-25% of stomach
C. albicans and C. glabrata differential characteristics
G, glucose; S, saccharose; M, maltose; T, trehalose; GAL, galactose; A, arabinose; +, positive; -, negative; ±,occasional.
samples and in 5-30% of gynecological samples from women
Because C. glabrata
is a haploid yeast, this may favor the
without vaginitis. This species is seldom found in normal skin
development of secondary resistances. Cross-resistance with other
(1-2%), but is found in up to 36% of urine samples from
azoles such as itraconazole, ketoconazole and voriconazole is
frequent. However, contrary to other yeast genera, C. glabrata
isusually very sensitive to 5-fluorocytosine.
Using the Fungitest kit (Sanofi Diagnostics Pasteur, Paris,
France), which classifies strains as sensitive, intermediate and
The absence of some virulence factors such as pseudohyphae (that
resistant, 17.6% fluconazole-resistant strains have been isolated
increas fungus adherence and its ability to penetrate tissues) leads
in community-acquired vaginal infections, whereas samples from
us to think C. glabrata
is less virulent than other species such as
ICU discharged adults reported 21% resistance and neonatal ICU
or C. tropicalis
. This is true when using experimental
patients reported 1% resistance. Itraconazol resistances were
laboratory animal models; however, there are evidences that
higher: 23.5%, 26.3% and 1%, respectively. There were no cases
demonstrate a rapid spread of C. glabrata
of amphotericin B resistance.11 A previous study reported 13 C.
immunosuppressed patients who also present a high mortality rate.
cases with MIC >16 μg/ml for fluconazole, and 12
Although knowledge of virulence markers in this species is limited,
presented MIC >2 μg/ml for itraconazole. All strains were sensitive
some studies have confirmed that C. glabrata
to amphotericin B with MIC <0.5 μg/ml. For 5-fluorocytosine,
and that its cell surface hydrophobia is similar to C. albicans
MIC presented a range <0.06-0.125 μg/ml, confirming its high
ensures its adherence ability in host cells.
Some host alterations that contribute to C. glabrata
The clinical interpretation of C. glabrata in vitro
development are a decrease of vaginal secretory IgA, low
is controversial. However, it is considered that resistance
inflammatory response and a quantitative/qualitative decrease
contributes to therapeutic failure, and management of patients
of T-cells, which explains its higher prevalence in patients with
with resistant strains is frequently unsatisfactory. The next group
of antifungal drugs may contribute to improve prognosis for theseinfections.8-9,11,13,16,18,21-23
genus includes several species, with C. albicans
being prevalent. The latter have increased
Molecular mechanisms of resistance to antifungal drugs are not
their prevalence as clinically significant opportunist infections.6,8
yet well understood. C. glabrata
resistance to azoles is due to an
sp. constitute a heterogeneous group with
increased P450 cytochrome-dependent ergosterol synthesis and
>200 biological differences. Only some are associated with
the existence of an active fluconazole flow pump. When referring
human infections, which has become a challenge for diagnosis
to antifungal drug resistance, two concepts are often confused:
and treatment of candidiasis.19 One hundred years ago C. albicans
on one hand, absence of a clinical response for therapeutic dosages
was considered the only medically important Candida
and, on the other hand, the presence of high minimum inhibitory
and C. parapsilosis
, C. tropicalis
and C. guilliermondii
concentrations (MIC). In the first scenario, lack of therapeutic
considered occasional opportunists.7,19 Different species other
response may be associated with patient immunosuppression or
than C. albicans
have been isolated in infections since 1980 and,
an insufficient drug bioavailability. In the second scenario,
nowadays, the following are regarded as opportunists: C.
antifungal drug resistance may be primary (innate) or secondary
, C. krusei
and C. lusitania
(acquired). MIC results can vary according to the method used
incidence has increased during the last 40 years3
because of diverse factors such as the use of new treatments and
is generally sensitive to polyenes such as nystatin
procedures for neoplastic diseases and other pathologies, invasive
and amphotericin B. However, because of commercialization and
procedures for diagnosis, extended usage of broad-spectrum
intensive use of fluconazole and itraconazole, there have been
antibiotics, HIV and AIDS. In our study, C. glabrata
reported cases of in vitro
resistance and lack of response in patients
(12.6%) is twice that reported in similar studies 10 years ago.2
with candidiasis treated with these antifungal drugs. Several studies
This agrees with the increased frequency and resistance to
have been conducted in HIV-positive patients with oropharyngeal
antifungal drugs reported in several publications.
and esophageal candidiasis, either mixed or exclusive of C.
Fluconazole is one of the most widely used antifungal drugs
. C. glabrata
strains resistant to fluconazole are prevalent
used to treat systemic and superficial mycoses. C. glabrata
among HIV-positive patients, especially in those affected with
the ability to quickly develop resistance to this drug.17 Our study
oropharyngeal and esophageal candidiasis, although there are
shows a high fluconazole resistance percentage from C. glabrata
reported cases of resistant strains in vaginitis and systemic
(68.2% in plates and 51.2% in microdilutions).
infections of critical patients with or without neutropenia. Although
Resistance shown by C. glabrata
is related to its increased
primary fluconazole resistances are described, most are acquired.
prevalence and has converted it into an important factor for
nosocomial infections in ICUs. This favors the increase of C.
6. Fridkin SK, Jarvis WR. Epidemiology of nosocomial fungal infections. Clin
systemic infections during the last 10 years as well as the
persistence and recurrence of vulvovaginal infections.10,11,24 Hospital
7. Hazen KC. New and emerging yeast pathogens. Clin Microbiol Rev
epidemiological studies have recently demonstrated that C.
8. Pfaller M, Wenzel R. Impact of the changing epidemiology of fungal
is being replaced by C. glabrata
and C. parapsilosis
infections in the 1990s. Eur J Clin Microbiol Infect Dis 1992;11:287-291.
Results from our study show that C. albicans
is responsible for
9. Rex JH, Walsh TJ, Sobel JD, Filler SG, Pappas PG, Dismukes WE, et al.
67.6% of cases, whereas C. glabrata
has a prevalence of 12.6%.
Practice guidelines for the treatment of candidiasis. Clin Infect Dis
The widespread use of azoles may have contributed to the increase
10. Buitrón R, Romero R, Bonifaz A. Estudio de especies Candida
of C. glabrata
incidence because it presents a very limited in vitro
y su relación con candidiasis vulvovaginal recurrente. Ginecol Obstet Mex
resistance to these antifungal drugs. In the U.S. it is the second
most frequently isolated species after C. albicans
to cause systemic
11. Muriel MA, Vizcaíno MJ, Bilbao R, Herruzo N. Identificación de levaduras
candidiasis and candiduria. C. glabrata
and C. tropicalis
y sensibilidad in vitro a diversos antifúngicos. Enferm Infecc MicrobiolClin 2000;18:120-124.
species that show a frequent prevalence in vaginal, oral
12. Abi-Said D, Anaissie E, Uzun O, Raad I, Pinzcowski H, Vartivarian S. The
and gastrointestinal samples, whereas C. guilliermondii
epidemiology of hematogenous candidiasis caused by different Candida
are frequently found on skin.16,25
species. Clin Infect Dis 1997;24:1122-1128.
The most frequently found species in our study related to
13. Saballs-Radresa P, Torres-Rodríguez JM, Salvadó M, Sales P, Gimeno-
vulvovaginitis were C. albicans
(67.9%), C. glabrata
Bayón JL, Knobel H, et al. La candidemia en el síndrome deinmunodeficiencia adquirida. Estudio retrospectivo de nueve casos. Rev
(16%). It is important to establish the relationship
between recurrence of vulvovaginal candidiasis and non-albicans
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compared with reports from
London: Bailliere Tindall; 1988. pp. 7-15, 68-104.
previous years. Therefore, we consider this an emergent change
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and Candida albicans
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