We reexamined the attributable mortality of nosocomial candidemia 15 years after a retrospective cohort study performed at our hospital demonstrated an attributable mortality of 38%. For all episodes of nosocomial candidemia between 1 July 1997 and 30 June 2001, we matched control patients with case patients by age, sex, date of hospital admission, underlying disease(s), length of time at risk, and surgical procedure(s). We analyzed 108 matched pairs. There were no statistically significant differences in age, sex, underlying disease(s), time at risk, surgical procedure, or vital signs at admission between cases and controls. The crude mortality among case patients was 61% (66 of 108 patients), compared with 12% (13 of 108) among control patients, for an attributable mortality of 49% (95% CI, 38%-60%). Nosocomial candidemia is still associated with an extremely high crude and attributable mortality--much higher than that expected from underlying disease alone.

Echinocandin resistance is increasing, including among FLC-resistant isolates. The new Clinical and Laboratory Standards Institute clinical breakpoints differentiate wild-type from C. glabrata strains bearing clinically significant FKS1/FKS2 mutations. These observations underscore the importance of knowing the local epidemiology and resistance patterns for Candida within institutions and susceptibility testing of echinocandins for C. glabrata to guide therapeutic decision making.

A surveillance program (SENTRY) of bloodstream infections (BSI) in the UnitedStates, Canada, Latin America, and Europe from 1997 through 1999 detected 1,184 episodes of candidemia in 71 medical centers (32 in the United States, 23 in Europe, 9 in Latin America, and 7 in Canada). Overall, 55% of the yeast BSIs were due to Candida albicans, followed by Candida glabrata and Candida parapsilosis (15%), Candida tropicalis (9%), and miscellaneous Candida spp. (6%). In the United States, 45% of candidemias were due to non-C. albicans species. C. glabrata (21%) was the most common non-C. albicans species in the United States, and the proportion of non-C. albicans BSIs was highest in Latin America (55%). C. albicans accounted for 60% of BSI in Canada and 58% in Europe. C. parapsilosis was the most common non-C. albicans species in Latin America (25%), Canada (16%), and Europe (17%). Isolates of C. albicans, C. parapsilosis, and C. tropicalis were all highly susceptible to fluconazole (97 to 100% at <8 g/ml). Likewise, 97 to 100% of these species were inhibited by <1 g/ml of ravuconazole (concentration at which 50% were inhibited [MIC 50 ], 0.007 to 0.03 g/ml) or voriconazole (MIC 50 , 0.007 to 0.06 g/ml). Both ravuconazole and voriconazole were significantly more active than fluconazole against C. glabrata (MIC 90 s of 0.5 to 1.0 g/ml versus 16 to 32 g/ml, respectively). A trend of increased susceptibility of C. glabrata to fluconazole was noted over the three-year period. The percentage of C. glabrata isolates susceptible to fluconazole increased from 48% in 1997 to 84% in 1999, and MIC 50 s decreased from 16 to 4 g/ml. A similar trend was documented in both the Americas (57 to 84% susceptible) and Europe (22 to 80% susceptible). Some geographic differences in susceptibility to triazole were observed with Canadian isolates generally more susceptible than isolates from the United States and Europe. These observations suggest susceptibility patterns and trends among yeast isolates from BSI and raise additional questions that can be answered only by continued surveillance and clinical investigations of the type reported here (SENTRY Program).

There are limited data regarding the antifungal susceptibility of yeast causing vulvovaginal candidiasis, since cultures are rarely performed. Susceptibility testing was performed on vaginal yeast isolates collected from January 1998 to March 2001 from 429 patients with suspected vulvovaginal candidiasis. The charts of 84 patients with multiple positive cultures were reviewed. The 593 yeast isolates were Candida albicans (n ‫؍‬ 420), Candida glabrata (n ‫؍‬ 112), Candida parapsilosis (n ‫؍‬ 30), Candida krusei (n ‫؍‬ 12), Saccharomyces cerevisiae (n ‫؍‬ 9), Candida tropicalis (n ‫؍‬ 8), Candida lusitaniae (n ‫؍‬ 1), and Trichosporon sp. (n ‫؍‬ 1). Multiple species suggesting mixed infection were isolated from 27 cultures. Resistance to fluconazole and flucytosine was observed infrequently (3.7% and 3.0%); 16.2% of isolates were resistant to itraconazole (MIC > 1 g/ml). The four imidazoles (econazole, clotrimazole, miconazole, and ketoconazole) were active: 94.3 to 98.5% were susceptible at <1 g/ml. Among different species, elevated fluconazole MICs (>16 g/ml) were only observed in C. glabrata (15.2% resistant [R], 51.8% susceptible-dose dependent [S-DD]), C. parapsilosis (3.3% S-DD), S. cerevisiae (11.1% S-DD), and C. krusei (50% S-DD, 41.7% R, considered intrinsically fluconazole resistant). Resistance to itraconazole was observed among C. glabrata (74.1%), C. krusei (58.3%), S. cerevisiae (55.6%), and C. parapsilosis (3.4%). Among 84 patients with recurrent episodes, non-albicans species were more common (42% versus 20%). A >4-fold rise in fluconazole MIC was observed in only one patient with C. parapsilosis. These results support the use of azoles for empirical therapy of uncomplicated candidal vulvovaginitis. Recurrent episodes are more often caused by non-albicans species, for which azole agents are less likely to be effective.Limited data addressing the incidence of vulvovaginal candidiasis suggest approximately two-thirds of women experience at least one episode during their lifetime and nearly 50% of women have multiple episodes (3, 12). The majority of cases of vulvovaginal candidiasis are caused by Candida albicans; however, episodes due to non-albicans species of Candida appear to be increasing (15,22,29). Most non-albicans Candida species have higher azole MICs, and infections they cause are often difficult to treat (10,20,21,26).A possible explanation for more frequent isolation of nonalbicans species from vulvovaginitis patients may be the increased use of topical azole agents-available as over-thecounter preparations in the United States since 1992 (14, 24). Patients who see a physician usually receive empirical therapy; vaginal cultures are not routinely obtained, and susceptibility testing is rarely performed.Surveillance programs for candidemia have demonstrated that fluconazole resistance among C. albicans bloodstream isolates is rare (Յ1%) (16). The majority of studies analyzing yeast isolates from vulvovaginitis patients have also shown the recovery of fluconazole-resistant C. albicans isola...

Bloodstream infections due to Candida species cause significant morbidity and mortality. Surveillance for candidemia is necessary to detect trends in species distribution and antifungal resistance. We performed prospective surveillance for candidemia at 16 hospitals in the State of Iowa from 1 July 1998 through 30 June 2001. Using U.S. Census Bureau and Iowa Hospital Association data to estimate a population denominator, we calculated the annual incidence of candidemia in Iowa to be 6.0 per 100,000 of population. Candida albicans was the most common species detected, but 43% of candidemias were due to species other than C. albicans. Overall, only 3% of Candida species were resistant to fluconazole. However, Candida glabrata was the most commonly isolated species other than C. albicans and demonstrated some resistance to azoles (fluconazole MIC at which 90% of the isolates tested are inhibited, 32 g/ml; 10% resistant, 10% susceptible dose dependent). C. glabrata was more commonly isolated from older patients (P ‫؍‬ 0.02) and caused over 25% of candidemias among persons 65 years of age or older. The investigational triazoles posaconazole, ravuconazole, and voriconazole had excellent in vitro activity overall against Candida species. C. albicans is the most important cause of candidemia and remains highly susceptible to available antifungal agents. However, C. glabrata has emerged as an important and potentially antifungal resistant cause of candidemia, particularly among the elderly.

We examined the in vitro activity of caspofungin, posaconazole, voriconazole, ravuconazole, itraconazole, and amphotericin B against 448 recent clinical mold isolates. The endpoint for reading caspofungin was the minimum effective concentration (MEC). Among the triazoles, posaconazole was most active, inhibiting 95% of isolates at <1 g/ml, followed by ravuconazole (91%), voriconazole (90%), and itraconazole (79%). Caspofungin and amphotericin B inhibited 93% and 89% of isolates at <1 g/ml, respectively, with caspofungin demonstrating an MEC 90 of 0.12 g/ml. All three new triazoles and caspofungin inhibited >95% of Aspergillus spp. at <1 g/ml compared to 83% for itraconazole and 91% for amphotericin B. Amphotericin B inhibited only 38% of Aspergillus terreus isolates at <1 g/ml, whereas the three new triazoles and caspofungin inhibited all A. terreus at <0.5 g/ml. The new triazoles and caspofungin have excellent in vitro activity against a very large collection of recent clinical isolates of Aspergillus spp., and some in vitro activity against selected other filamentous fungi.Invasive infections due to Aspergillus spp. and other filamentous fungi have emerged as prominent causes of infectious morbidity and mortality in the United States and worldwide (6,7,20). Treatment of these infections with available antifungal agents still results in an unacceptably high associated mortality (18).Two new antifungal agents recently have been introduced for treatment of invasive aspergillosis or other invasive mold infections. Voriconazole and caspofungin offer new alternatives for therapy of these difficult infections (10, 11). In addition, the investigational triazoles ravuconazole and posaconazole have been demonstrated to have in vitro potency against Aspergillus spp. and selected other filamentous fungi (8,9,24).Since the availability of these agents represents an exciting opportunity for improving the outcome of invasive infections due to filamentous fungi, their in vitro activity against contemporary clinical isolates is of great interest. We performed a 2-year, 20-center survey of filamentous fungal infections from January 2000 through December 2001. We previously reported preliminary results of the activity of new triazoles against molds collected during the first year of this survey (24). We now report final 2-year results, including the in vitro activity of caspofungin, the new triazoles, amphotericin B, and itraconazole against over 400 recent clinical isolates of filamentous fungi collected from January 2000 through December of 2001. In the process, we present the largest collection of clinical mold isolates tested against caspofungin yet reported. MATERIALS AND METHODS Organisms.A total of 448 unique clinical isolates (one per patient, duplicate patient isolates excluded) of filamentous fungi were obtained from 20 different medical centers in the United States and Canada between January 2000 and December 2001. These centers were participants in the SENTRY Antimicrobial Surveillance Program. The isolates were obta...

An international program of surveillance of bloodstream infections (BSI) in the UnitedStates, Canada, and Latin America detected 306 episodes of candidemia in 34 medical centers (22 in the United States, 6 in Canada, and 6 in Latin America) in 1997 and 328 episodes in 34 medical centers (22 in the United States, 5 in Canada, and 7 in Latin America) in 1998. Of the 634 BSI, 54.3% were due to Candida albicans, 16.4% were due to C. glabrata, 14.9% were due to C. parapsilosis, 8.2% were due to C. tropicalis, 1.6% were due to C. krusei, and 4.6% were due to other Candida spp. The percentage of BSI due to C. albicans decreased very slightly in the United States between 1997 and 1998 (56.2 to 54.4%; P ‫؍‬ 0.68) and increased in both Canada (52.6 to 70.1%; P ‫؍‬ 0.05) and Latin America (40.5 to 44.6%; P ‫؍‬ 0.67). C. glabrata was the second most common species observed overall, and the percentage of BSI due to C. glabrata increased in all three geographic areas between 1997 and 1998. C. parapsilosis was the third most prevalent BSI isolate in both Canada and Latin America, accounting for 7.0 and 18.5% of BSI, respectively. Resistance to fluconazole (MIC, >64 g/ml) and itraconazole (MIC, >1.0 g/ml) was observed infrequently in both 1997 (2.3 and 8.5%, respectively) and 1998 (1.5 and 7.6%, respectively). Among the different species of Candida, resistance to fluconazole and itraconazole was observed in C. glabrata and C. krusei, whereas isolates of C. albicans, C. parapsilosis, and C. tropicalis were all highly susceptible to both fluconazole (98.9 to 100% susceptible) and itraconazole (96.4 to 100% susceptible). Isolates from Canada and Latin America were generally more susceptible to both triazoles than U.S. isolates were. Continued surveillance appears necessary to detect these important changes.

The echinocandin class of antifungal agents is considered to be the first-line treatment of bloodstream infections (BSI) due to Candida glabrata. Recent reports of BSI due to strains of C. glabrata resistant to both fluconazole and the echinocandins are of concern and prompted us to review the experience of two large surveillance programs, the SENTRY Antimicrobial Surveillance Program for the years 2006 through 2010 and the Centers for Disease Control and Prevention population-based surveillance conducted in 2008 to 2010. The in vitro susceptibilities of 1,669 BSI isolates of C. glabrata to fluconazole, voriconazole, anidulafungin, caspofungin, and micafungin were determined by CLSI broth microdilution methods. Fluconazole MICs of >64 g/ml were considered resistant. Strains for which anidulafungin and caspofungin MICs were >0.5 g/ml and for which micafungin MICs were >0.25 g/ml were considered resistant. A total of 162 isolates (9.7%) were resistant to fluconazole, of which 98.8% were nonsusceptible to voriconazole (MIC > 0.5 g/ml) and 9.3%, 9.3%, and 8.0% were resistant to anidulafungin, caspofungin, and micafungin, respectively. There were 18 fluconazole-resistant isolates that were resistant to one or more of the echinocandins (11.1% of all fluconazole-resistant isolates), all of which contained an acquired mutation in fks1 or fks2. By comparison, there were no echinocandin-resistant strains detected among 110 fluconazole-resistant isolates of C. glabrata tested in 2001 to 2004. These data document the broad emergence of coresistance over time to both azoles and echinocandins in clinical isolates of C. glabrata.