Update from a 12-Year Nationwide Fungemia Surveillance: Increasing Intrinsic and Acquired Resistance Causes Concern

Abstract

New data from the years 2012 to 2015 from the Danish National Fungemia Surveillance are reported, and epidemiological trends are investigated in a 12-year perspective (2004 to 2015). During 2012 to 2015, 1,900 of 1,939 (98%) fungal bloodstream isolates were included. The average incidence was 8.4/100,000 inhabitants, and this appears to represent a stabilizing trend after the increase to 10.1/100,000 in 2011. The incidence was higher in males than females (10.0 versus 6.8) and in patients above 50 years, and those changes were mainly driven by an increasing incidence among 80-to-89-year-old males (65.3/100,000 in 2014 to 2015). The proportion of Candida albicans isolates decreased from 2004 to 2015 (64.4% to 42.4%) in parallel with a doubling of the proportion of Candida glabrata isolates (16.5% to 34.6%, P < 0.0001). C. glabrata was more common among females (34.0% versus 30.4% in males). Following an increase in 2004 to 2011, the annual drug use stabilized during the last 2 to 3 years of that time period but remained higher than in other Nordic countries. This was particularly true for the fluconazole and itraconazole use in the primary health care sector, which exceeded the combined national levels of use of these compounds in each of the other Nordic countries. Fluconazole susceptibility decreased (68.5%, 65.2%, and 60.6% in 2004 to 2007, 2008 to 2011, and 2012 to 2015, respectively, P < 0.0001), and echinocandin resistance emerged in Candida (0%, 0.6%, and 1.7%, respectively, P < 0.001). Amphotericin B susceptibility remained high (98.7%). Among 16 (2.7%) echinocandin-resistant C. glabrata isolates (2012 to 2015), 13 harbored FKS mutations and 5 (31%) were multidrug resistant. The epidemiological changes and the increased incidence of intrinsic and acquired resistance emphasize the importance of continued surveillance and of strengthened focus on antifungal stewardship.

Keywords: Candida glabrata; antifungal consumption; azole resistance; candidemia; echinocandin resistance; epidemiology; fungemia; multidrug resistance; population-based; surveillance.

FIG 1

Age- and gender-specific incidence rates per 100,000 population (pop.) in three 4-year intervals (2004 to 2015). The overall incidence rate for males was stable, whereas the overall incidence rate for females declined. Males had a slight decrease in the age group of 50 to 59 years (P = 0.04) and a significant increase in the age group of 80 to 89 years (P < 0.0001). Females had significant decreases in the age groups of 40 to 49 years and 60 to 69 years (and an increase only in the low-incidence age group of 20 to 29 years).

FIG 2

Species distribution (shown as percentages of isolates) over three 4-year periods during 2004 to 2015. The presented percentages are based on isolate numbers during the 4-year periods. Significant P values from a Chi-square test for trend are presented. (For C. dubliniensis, a P value of 0.01 was found due to an increase in isolates from 2014 to 2015.)

FIG 3

Species distribution of bloodstream infections among age groups in 2012 to 2015.

FIG 4

Annual consumption of systemic antifungal compounds in DDDs/1,000 inhabitants (inhab.) in 2004 to 2015. Hospital (Hosp) use data are shown in red, and data corresponding to use in the primary health care sector data are shown in orange. Data corresponding to the total annual consumption in Norway, Sweden, and Finland are inserted for comparison (dark gray, light gray, and white bars, respectively). DDD1, The DDD was 50 mg for caspofungin, whereas the DDD was 0.1 g for micafungin and anidulafungin. corrected use², for posaconazole, an enterotablet and an i.v. formulation were introduced on the Danish market in 2014. The licensed daily dose of these new formulations is 300 mg/day (after a loading dose), whereas the treatment dose of the suspension is 800 mg/day. The official defined DDD was 0.8 g for all three formulations (recently [in 2017] changed to 0.3 g). We have translated DDDs to reflect the actual use (for enterotablets and the i.v. formulation, 1 DDD of 0.3 g [red/white stripes]; for oral suspensions, 1 DDD of 0.8 g [solid red]). The total value for use in the Nordic countries and DK (uncorrected; gray line) is a DDD of 0.8 g.