Candida glabrata:
an emergent opportunist in vulvovaginitis
Rafael Buitrón-García-Figueroa,* Javier Araiza-Santibáñez,** Erich Basurto-Kuba,*** and Alexandro Bonifaz-Trujillo** Abstract
Background: 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.
Key words: candidiasis, Candida glabrata, resistance, vulvovaginitis.
C. glabrata 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 glabrata is the second most frequently identified species (after into hematic infections. Although Candida albicans is still the C. albicans) 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 Candida: C. parapsilosis, C. tropicalis and C. glabrata.1,2 The 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: 9-22-2009 Materials and Methods
Table 1. 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 glabrata. 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 Discussion
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 was 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% C. glabrata 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 reported (96%) leukorrhea, 269 (57.4%) edema, 143 (30.5%) excoriations that fluconazole and quinolones were specifically associated with C. glabrata 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 albicans replacement or if this is an independent phenomenon.
Table 2. 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 epidemiology infections.5 C. glabrata belongs to Ascomycetes class, Saccharomycetales C. glabrata strains do not assimilate inositol and do not contain order, Saccharomycete family, Candida genus, glabrata species.
carotenoid pigments and are inhibited by cycloheximide 0.01%.
Torulopsis 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 glabrata 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.2,16 C. glabrata antigenic structure has been determined by several Several studies that have isolated C. glabrata in different 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 Table 3. 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 C. albicans 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 infections in of amphotericin B resistance.11 A previous study reported 13 C. immunosuppressed patients who also present a high mortality rate.
glabrata 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 produces proteinases to amphotericin B with MIC <0.5 μg/ml. For 5-fluorocytosine, and that its cell surface hydrophobia is similar to C. albicans, which 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 infections The clinical interpretation of C. glabrata in vitro resistance 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 Candida genus includes several species, with C. albicans and non-albicans Candida 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 Non-albicans Candida 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 species, and, on the other hand, the presence of high minimum inhibitory and C. parapsilosis, C. tropicalis and C. guilliermondii were 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 glabrata, C. krusei and C. lusitania.8,19 (acquired). MIC results can vary according to the method used C. glabrata incidence has increased during the last 40 years3 because of diverse factors such as the use of new treatments and C. glabrata 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 frequency 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 glabrata. C. glabrata strains resistant to fluconazole are prevalent used to treat systemic and superficial mycoses. C. glabrata has 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 glabrata 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 tropicalis is being replaced by C. glabrata and C. parapsilosis.25 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 no albicans 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 are non- y sensibilidad in vitro a diversos antifúngicos. Enferm Infecc MicrobiolClin 2000;18:120-124.
albicans 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 and C. epidemiology of hematogenous candidiasis caused by different Candida parapsilosis 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 (12.6%) and Bayón JL, Knobel H, et al. La candidemia en el síndrome deinmunodeficiencia adquirida. Estudio retrospectivo de nueve casos. Rev C. tropicalis (16%). It is important to establish the relationship between recurrence of vulvovaginal candidiasis and non-albicans 14. Shin JH, Nolte FS, Holloway BP, Morrison CJ. Rapid identification of Candida species. Mycological tests should be carried out to Candida species in blood cultures by a clinically useful PCR method. J determine the species. If results report C. glabrata, long-term treatment will be justified to eradicate the mycosis or to perform 15. Peltroche-Llacsahuanga H, Schnitzler N, Lütticken R, Haase G. Rapid microbiological sensitivity tests to provide a specific treatment.
identification of Candida glabrata by using a dipstick to detect trehalose-generated glucose. J Clin Microbiol 1999;37:202-205.
In conclusion, our study shows a significant increase of 16. Odds F. Candida and Candidosis. A Review and Bibliography. 2nd ed.
vulvovaginitis from C. glabrata compared with reports from London: Bailliere Tindall; 1988. pp. 7-15, 68-104.
previous years. Therefore, we consider this an emergent change 17. Rex JH, Pfaller MA, Galgiani JN, et al. Development of interpretive for this species. Fortunately, available techniques to identify this breakpoints for antifungal susceptibility testing: conceptual framework and species are accessible and tests to determine antifungal drug analysis of in vitro-in vivo, correlation data for fluconazole, itraconazole,and Candida infections. Clin Infect Dis 1997;24:235-247.
susceptibility allow us to establish the presence of fluconazole- 18. Torres-Rodríguez JM, Madrenys N, Jiménez T, Saballs P. Concentraciones resistant strains. Our results show that 50% of C. glabrata strains mínimas inhibitorias de levaduras a cinco antifúngicos utilizando un were resistant to fluconazole. This suggests an opportune micrométodo de dilución estandarizado y el E-test. Rev Iberoam Micol therapeutic change to avoid treatment failures and the development 19. Pfaller MA. Nosocomial candidiasis: emerging species, reservoirs, and modes of transmission. Clin Infect Dis 1996;22:S89-S94.
20. Espinel-Ingrof A, Vázquez JA, Boikov D, Pfaller MA. Evaluation of DNA- based typing procedure for strain categorization of Candida spp. Diagn References
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