Global trends in the distribution of Candida species causing candidemia

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1 REVIEW / Global trends in the distribution of Candida species causing candidemia J. Guinea 1,2,3,4 1) Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Mara~non, Universidad Complutense de Madrid, Madrid, Spain, 2) Instituto de Investigacion Sanitaria Gregorio Mara~non, Madrid, Spain, 3) CIBER de Enfermedades Respiratorias (CIBER RES CB06/06/0058), Madrid, Spain and 4) Medicine Department, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain Abstract Only five species account for 92% of cases of candidemia (Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei); however, their distribution varies in population-based studies conducted in different geographical areas. C. albicans is the most frequent species, but considerable differences are found between the number of cases caused by C. glabrata and C. parapsilosis. Studies from Northern Europe and the USA reported a high number of cases caused by C. glabrata, whereas studies from Spain and Brazil demonstrated a lower number of cases caused by C. glabrata and a higher number of cases attributed to C. parapsilosis. Globally, the frequency of C. albicans is decreasing, while that of C. glabrata and C. krusei is stable, and C. parapsilosis and C. tropicalis are increasing. Patient characteristics and prior antifungal therapy also have a considerable influence on the distribution and frequency of Candida spp., regardless of the geographical area. C. albicans is more frequent in patients aged up to 18 years, the frequency of C. parapsilosis decreases with age, and C. glabrata is more common in the elderly. Finally, the presence of horizontal transmission of Candida spp. isolates (reported mainly in patients from the adult medical and post-surgical ICU, patients from oncology haematology units, and neonates) can affect species distribution. Keywords: C. albicans, C. glabrata, C. parapsilosis, candidemia, invasive candidiasis, outbreaks, population-based, species distribution Article published online: 10 February 2014 Clin Microbiol Infect 2014; 20 (Suppl. 6): 5 10 Corresponding author: J. Guinea, Servicio de Microbiologıa Clınica y Enfermedades Infecciosas-VIH, Hospital General Universitario Gregorio Mara~non, C/Dr. Esquerdo 46, Madrid, Spain jguineaortega@yahoo.es Background Fungal infections have become a major problem in hospitals, and the number of episodes of sepsis caused by fungi has been increasing since the early 1990s [1,2]. Candida spp. remains the most common cause of invasive fungal infections [3 5], and the incidence of candidemia, which is estimated at 72.8 cases per million inhabitants and year, clearly exceeds that of invasive aspergillosis and mucormycosis [6]. Candidemia is a consequence of advances in health care. During the last 20 years, we have observed an improvement in diagnostic procedures, the development and commercialization of new antifungal agents, and the implementation of strategies to prevent candidemia; nevertheless, the incidence of candidemia has increased [7]. Candidemia is generally diagnosed using blood cultures, although diagnosis remains a challenge for clinicians and microbiologists; in fact, half of all cases of invasive Candida infections go undetected in blood cultures [8]. Given these limitations, the true epidemiology and incidence of invasive candidiasis is imprecise. The incidence of candidemia expressed as cases per inhabitants has been reported to range from 1 to 8 cases [4]; in a study carried out in Brazil, incidence reported as cases per admissions was higher (249 cases per admissions) [9]. In a recent 1-year population-based study conducted in Spain (29 hospitals, 773 cases), the incidence of candidemia was 8.1 cases per inhabitants, which is similar to that reported in other European studies [10]. Candidemia has an attributable mortality of 15 35% for adults and 10 15% for neonates, and the hospitalization cost for each episode is approximately US$ [11 13]. The rates of Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases

2 6 Clinical Microbiology and Infection, Volume 20 Supplement 6, June 2014 CMI early and late mortality (7 days and 30 days after diagnosis, respectively) are different (13% vs. 30%). Whereas early mortality is associated with factors such as appropriate antifungal therapy and early removal of central venous catheters, late mortality is associated with factors related to the baseline condition of the host [10]. The mortality rate is clearly correlated with a delay in the initiation of appropriate antifungal treatment [14,15]. Incorrect treatment includes absence of antifungal treatment, a delay in initiation, or the use of an inactive agent. Therefore, efforts to minimize these three situations should help to reduce the mortality of candidemia. Knowledge of the frequency of causative species would facilitate appropriate selection of empirical antifungal treatment. The distribution of Candida spp. causing candidemia varies in population-based studies carried out in different geographical areas. Furthermore, notable differences can also be observed between hospital units. However, the frequency of Candida species causing candidemia is also dependent on the predisposing conditions of the patients infected, the antifungal agents they receive, and the local hospital-related factors. This review discusses global trends in the distribution of Candida spp. by looking at three main areas: influence of the geographic area, influence of predisposing conditions of the patients, and influence of local hospital epidemiology. Influence of the Geographical Area The list of Candida species causing candidemia is long and continues to expand as a consequence of more precise identification. The ARTEMIS DISK Global Antifungal Surveillance Study includes a large registry of invasive Candida isolates collected from 127 medical centers worldwide (39 countries). Data from this registry showed that only five species (C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei) accounted for 92% of cases of candidemia [16]. C. albicans was the most common cause of candidemia worldwide, accounting for 62% of cases [7,16]. However, the ranking of the abovementioned top 5 species is variable. Fig. 1 summarizes the proportion of cases 100% 90% 80% 70% 60% 50% C. albicans C. glabrata C. parapsilosis C. tropicalis C. krusei Other ,00 10, , % 30% 20% % 0% Iceland 2002 [18] Iceland 2013 [26] Finland 2003 [19] Norway 2006 [24] Denmark 2005 [22] Denmark 2011 [23] USA 1999 [17] USA 2004 [20] USA 2012 [25] Spain 2005 [21] Spain 2013 [10] FIG. 1. Proportion of the most relevant Candida species from population-based studies reporting on candidemia in different countries.

3 CMI Guinea Global trends in Candida species distribution 7 of candidemia involving the most relevant Candida species from population-based studies conducted in different countries [10,17 26]. C. albicans was the main cause of candidemia in all of them. However, considerable differences were found in the proportion of cases caused by C. glabrata and C. parapsilosis. This finding has an important clinical impact, as these species show diminished susceptibility to azoles and echinocandins, respectively. Studies from Northern Europe and the USA reported a high number of cases caused by C. glabrata and a low number of cases caused by C. parapsilosis. In contrast, reports from Spain and Brazil demonstrated a lower number of cases caused by C. glabrata and higher number of cases attributed to C. parapsilosis. The explanation for this finding is unknown, although it may be a consequence of the impact of climate, antifungal policy, or central venous catheter care procedures. Compiled data from the ARTEMIS DISK registry are useful when studying temporal changes in the frequency of invasive Candida spp isolates in large geographic areas from 1997 to 2007 [16,27,28] (Fig. 2). C. albicans remained the most frequent species worldwide, although this frequency was decreasing. The frequency of C. glabrata and C. krusei was stable, although an increase in the frequency of C. parapsilosis and C. tropicalis was reported. Influence of the Patient s Predisposing Conditions The kind of patient also has a considerable influence on the distribution and frequency of Candida spp., regardless of the geographic area. Malignancies and surgery are common predisposing factors for the development of candidemia, which is more frequent at age extremes. In addition, patients commonly carry central venous catheters and have received broad-spectrum antibiotics [10,21]. The differences in incidence between adults and children are also reflected in the species distribution. C. albicans is 100% 80% 60% C. albicans C. glabrata C. parapsilosis C. tropicalis C. krusei Other % % 0% FIG. 2. Data compiled from the ARTEMIS DISK registry on the temporal change in species distribution among invasive Candida isolates from 1997 to 2007.

4 8 Clinical Microbiology and Infection, Volume 20 Supplement 6, June 2014 CMI more frequent in patients aged up to 18 years. Interestingly, the frequency of C. parapsilosis decreases with age, whereas C. glabrata is more common in the elderly [29,30]. Differences have also been detected between neonates and adult patients: C. albicans and C. parapsilosis are more frequent in neonates (60% vs. 50% and 24% vs. 12%, respectively) [30]. Both species usually cause catheter-related candidemia, and catheters are widely used in neonates [10]. In contrast, the frequency of cases caused by azole-resistant species such as C. glabrata and C. krusei is much lower in neonates (3% vs. 23% and 0% vs. 2%), probably reflecting scant use of azoles in neonatology [30]. A recent study of children in Spain showed the high percentage of cases of candidemia caused by C. parapsilosis (47%), which even exceeded that of C. albicans (37%) [31]. Species distribution is highly dependent on the patient s underlying condition. C. glabrata is the most frequently detected species in stem cell recipients; C. krusei is also relevant in these patients, probably owing to the widespread use of azoles in this setting, which may promote infection by these two azole-resistant species. However, other patients, such as solid organ recipients, are infected mainly by C. albicans and C. glabrata [32 34]. A considerable number of episodes of candidemia are diagnosed in the intensive care unit (ICU) [21,35]. Comparison of patients admitted to the ICU with those admitted to other wards reveals no considerable variations in species distribution [35,36], probably because the species found in the ICU reflect those found in the rest of the hospital [37]. Finally, the use of antifungal agents also has an impact on the distribution of Candida spp., as shown in a study reporting a large number of patients collected from all over France [38]. Recent exposure to fluconazole or caspofungin affected the distribution of Candida spp. by promoting infection by C. glabrata and C. krusei (use of fluconazole) and infection by C. parapsilosis, C. glabrata, and C. krusei (use of caspofungin). Influence of Local Hospital Epidemiology Candida infections can be caused by strains of the patient s own microbiota [39,40]. The use of broad-spectrum antibiotics leads to overgrowth of Candida spp. in the gastrointestinal tract. Microorganisms can reach the bloodstream by translocation and cause candidemia, which is common in patients with mucositis or after disruption of the skin as a result of colonization. However, patients can also become infected by exogenous isolates that are not part of their own microbiota. Exogenous isolates can colonize the skin, intravenous catheters, and parenteral infusions and they are often involved in outbreaks where several patients become infected by the same isolate [41]. Horizontal transmission of exogenous isolates between patients admitted to the hospital increases the frequency of Candida spp. and, therefore, the frequency of invasive disease. Most reported outbreaks of candidemia involved patients from the adult medical and post-surgical ICU, patients from oncology haematology units, and neonates [41]. This finding probably reflects not only the high number of episodes of candidemia diagnosed in the units, but also the characteristics of these patients [7,42 47]. Relatively recent reports on outbreaks of infections caused by C. parapsilosis show that patients mainly had candidemia and were admitted to ICUs. Patients were both adult and paediatric, although neonates were also frequently involved. Typing of isolates from the patients involved and from the environment (including health care personnel) showed that genotypes from patients were commonly found on the hands of the health care workers, which are a common source of exogenous isolates [42,45,46,48 51]. Patients skin or central venous catheters can become infected by exogenous isolates after manipulation of medical devices by health care workers, particularly in the adult and neonatal ICU. Neonates and adult patients are also infected by C. albicans. Again, health care workers play a key role in transmission, and artificial nails have been reported to be a possible source of isolates causing an outbreak [52,53]. In a neonatal ICU, the first patient involved in an outbreak acquired the infection during delivery, and the isolate was transmitted to the other two patients during admission to the unit [54]. We recently typed 217 C. albicans isolates from 202 patients with candidemia admitted to the hospital during a 5-year period. We found 19 genotypes (11% of the total) that were epidemic and infected two or more patients. Clusters involved 2 6 patients each, and up to 25% of patients were infected by epidemic genotypes found in at least one other patient [55]. The same approach was adopted with C. parapsilosis isolates. We found 78 genotypes, of which 18% were epidemic and involved 14 clusters [56]. Epidemic genotypes were mostly detected in neonatology, suggesting more active horizontal transmission of these pathogens in both units. The higher frequency of nosocomial transmission may explain the higher frequency of these two species in neonates than in adult patients [30]. In conclusion, differences in the distribution of Candida spp can be found between geographical regions. However, underlying condition and antifungal agents received have a considerable effect on local epidemiology. The fact that C. albicans and C. parapsilosis are transmitted effectively from patient to patient may contribute to the high number of cases of candidemia caused by these two species.

5 CMI Guinea Global trends in Candida species distribution 9 Acknowledgements We would like to thank Thomas O Boyle for editing and proofreading the article. This study was presented in part at the 2nd ESCMID Conference on Invasive Fungal Infections, Rome, Italy, 16 18th January This work was supported by grants from Fondo de Investigacion Sanitaria (grants number PI11/00167). J. Guinea (MS09/00055) is supported by the Fondo de Investigacion Sanitaria. Transparency Declaration This study does not present any conflicts of interest for its authors. References 1. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through N Engl J Med 2003; 348: Lepak A, Andes D. Fungal sepsis: optimizing antifungal therapy in the critical care setting. Crit Care Clin 2011; 27: Azie N, Neofytos D, Pfaller M, Meier-Kriesche HU, Quan SP, Horn D. 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