Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002–2010)

On the basis of our analysis of a population whose characteristics are similar to those found in a recent multicenter study of septic shocks attributable to Candida spp. [16], a significant increasing incidence of candidemia was observed together with an increasing mortality rate in ICU. This was observed through a large prospective multicentric hospital-based surveillance program implemented over almost a decade in the Paris area. Even if we are fully aware that the epidemiology of candidemia is highly variable in Europe and elsewhere, these trends are worrisome in the context of expanded antifungal armamentarium, published management guidelines, and better diagnostic tools available at least in large tertiary care centers such as those involved in the present study [17, 18].

Of importance, similar incidence trends for candidemia and even other invasive fungal infections were observed recently using national registries in Europe [14, 19]. Indeed, the epidemiology of candidemia that we described here did not differ drastically from recently published data even if some differences can be noted. The global proportion of C. albicans was higher than in two recent North American studies (56 vs. 38–42.1 %) [20, 21]. That of C. glabrata was lower here (13.6 %) than in several recent studies reporting at least 20 % of C. glabrata among isolates causing fungemia [6, 20, 21]. C. parapsilosis ranked second in Spain, Brazil, and Italy and third here [13, 22, 23]. Of note, relative to ICU patients infected with C. albicans, those with C. parapsilosis were less likely to be hospitalized in ICU, those with C. tropicalis were more likely to have hematological disorders and less likely solid tumor, and those with C. krusei were more likely to have a solid tumor and solid organ transplantation but less recent surgery.

The increased incidence found here concerned two species (C. albicans and C. glabrata) at least in the overall population and only C. albicans in ICU. A specific increase in C. glabrata fungemia was recently reported in the USA, Europe, and Brazil [20, 24, 25]. We have no explanation for the increased incidence of C. albicans. We know that species involved can largely be influenced by ecosystems and local management of the patients at risk. In a recent study, 15 % of the patients were preexposed to antifungal, including fluconazole in 64 % and echinocandins in 15 % [7], while in another one, preexposure concerned up to 43.4 % of the patients [21] especially (more than 67 % of the cases) those with breakthrough episodes [12]. Here, preexposure concerned 10.6 % of patients hospitalized in ICU. Preexposure to fluconazole did not change over time, while that of caspofungin increased in ICU. We and others have previously evidenced the impact of prolonged prior fluconazole exposure on the distribution of Candida species [15, 24, 26]. Interestingly, in the current multinomial analysis performed in ICU patients with C. albicans as the reference, preexposure to fluconazole was an independent factor of infection with C. krusei, C. tropicalis, or C. glabrata, whereas preexposure to caspofungin was an independent factor of infection with C. parapsilosis, C. krusei, C. kefyr, C. glabrata, and mixed infections, thereby emphasizing the broader than expected ecological impact of echinocandin exposure [15, 27, 28]. It should also be remembered that in addition to the emergence of potentially more virulent Candida species induced by echinocandin exposure such as C. krusei and C. kefyr found here, the emergence of echinocandin resistance among usually susceptible Candida species is also worrisome [29, 30].

Our large database allowed us to focus on trends in death and look for explanations of the increased death rate over time in the overall population and in ICU. The first explanation could be the species involved. Here and in other studies [3, 13, 21, 31], C. parapsilosis and C. krusei/C. kefyr were associated with the lowest and highest death rates, respectively, while others found an increased death rate among patients with C. tropicalis or C. glabrata fungemia [32, 33]. However, the mortality trends cannot be explained by the evolving distribution of C. parapsilosis or C. krusei/C. kefyr. Another explanation might have been an increased proportion of elderly patients over time in ICU. However, it remained stable yet high (31.8 and 11.1 % of episodes occurred in patients aged at least 65 years and at least 80 years, respectively) as already noted by others with the highest incidence rates of candidemia in adults over 65 [7]. The death rate is also known to depend on underlying diseases or settings, as found here in ICU patients (51 %) and as already reported [14]. However, although mortality remained stable for the overall population, the most worrying finding is its increase in ICU. Several recent studies reported changes in the case-mix of critically ill patients. Nationwide trends of severe sepsis in the USA showed that from 2000 to 2007, more patients had at least three organ system failures [34]. In an Australian tertiary ICU, there was a significant increase in severity of illness and Charlson comorbidity index of the patients over a 16-year study period [35]. Finally, although we did not capture this information during our large prospective surveillance program, unpublished data from ICUs which participated in the present study indicate that the simplified acute physiology score II score and the percentage of mechanically ventilated patients increased from 37, 42 to 44, and from 41, 49, to 60 % in 2000, 2005, and 2010, respectively [CubRea Network (“Collège des Utilisateurs des Bases de Données en Réanimation”), Ile de France; Biostatistique et Informatique Médicale, Hôpital Ambroise Paré, Boulogne, France]. However, a recent study showed an average annual increase in the incidence of severe sepsis of 13 % between 2004 and 2009 while in-hospital death decreased from 35 to 25.6 % across the 6-year period [36]. In addition, a recent meta-analysis of 36 multicenter severe sepsis trials, with a total of 14,418 participants, found a decreasing mortality of 3.0 % annually (95 % CI, 0.8–5.0 %; p = 0.009), decreasing from 46.9 % during years 1991–1995 to 29 % during years 2006–2009 [37]. Thus, it can be speculated that more ICU patients now survive from bacterial sepsis and could be further exposed to life-threatening ICU-acquired candidemia.

The lack of overall diminution and a fortiori the increased death rate found in ICU patients are shocking knowing that new antifungals became available and that several guidelines for the management of candidemia were published during the same period. Among ICU patients, 55.4 % were treated with fluconazole and 26.2 % with an echinocandin, a percentage close to what was reported recently in the USA [7] even if more echinocandins were prescribed in one study [31]. Other studies found that receiving an antifungal was an independent factor decreasing both early and late death [22] and that echinocandins as first-line therapy reduced the death rate [38]. In the present study, outcome did not change according to initial antifungal therapy, and only lack of initial antifungal therapy impacted both overall and early deaths. Moreover, preexposure to caspofungin had a negative impact on the outcome. Although numerous other factors not captured here may have influenced the outcome, such as the delayed initiation of adequate antifungal therapy [8, 39, 40], although controversial [16], lack of consideration of antifungal dosing issues [40‐42], and inadequate source control as recently emphasized [16], both the strong ecological impact and potentially its deleterious effect on outcome emphasize the need for not only triazole but also echinocandin stewardship in our hospitals.

In conclusion we observed an increase in the incidence of candidemia and its death rate in ICU. The causes of these worrisome trends merit further studies.