R. N. Jones

International Surveillance of Bloodstream Infections Due to Candida Species: Frequency of Occurrence and In Vitro Susceptibilities to Fluconazole, Ravuconazole, and Voriconazole of Isolates Collected from 1997 through 1999 in the SENTRY Antimicrobial Surveillance Program

ABSTRACT A surveillance program (SENTRY) of bloodstream infections (BSI) in the United States, 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 andCandida parapsilosis (15%), Candida tropicalis(9%), and miscellaneous Candida spp. (6%). In the United States, 45% of candidemias were due to non-C. albicansspecies. 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. parapsilosiswas the most common non-C. albicans species in Latin America (25%), Canada (16%), and Europe (17%). Isolates ofC. albicans, C. parapsilosis, and C. tropicaliswere all highly susceptible to fluconazole (97 to 100% at ≤8 μg/ml). Likewise, 97 to 100% of these species were inhibited by ≤1 μg/ml of ravuconazole (concentration at which 50% were inhibited [MIC50], 0.007 to 0.03 μg/ml) or voriconazole (MIC50, 0.007 to 0.06 μg/ml). Both ravuconazole and voriconazole were significantly more active than fluconazole against C. glabrata(MIC90s of 0.5 to 1.0 μg/ml versus 16 to 32 μg/ml, respectively). A trend of increased susceptibility of C. glabrata to fluconazole was noted over the three-year period. The percentage of C. glabrataisolates susceptible to fluconazole increased from 48% in 1997 to 84% in 1999, and MIC50s decreased from 16 to 4 μg/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).

Worldwide Prevalence of Antimicrobial Resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance Program, 1997–1999

The in vitro activities of numerous antimicrobials against clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis from patients with bloodstream and respiratory tract infections in the United States, Canada, Europe, Latin America, and the Asia-Pacific region were studied in the SENTRY Antimicrobial Surveillance Program. Penicillin resistance (minimum inhibitory concentration, > or =2 microg/mL) was noted in all 5 geographic regions, and a high and increasing rate of macrolide resistance among S. pneumoniae isolates was observed. Elevated rates of resistance to clindamycin, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline were seen. beta-Lactamase-mediated resistance in H. influenzae to amoxicillin and variable trimethoprim-sulfamethoxazole resistance by region were documented. Resistance to several drugs continues to emerge among pneumococci worldwide, but more stable resistance patterns have been noted for H. influenzae and M. catarrhalis. Continued surveillance of this pathogen group appears to be prudent.

Bloodstream Infections Due to Candida Species: SENTRY Antimicrobial Surveillance Program in North America and Latin America, 1997-1998

ABSTRACT An international program of surveillance of bloodstream infections (BSI) in the United States, 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 toC. 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 μg/ml) and itraconazole (MIC, ≥1.0 μg/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 ofCandida, 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.

Antifungal Activities of Posaconazole, Ravuconazole, and Voriconazole Compared to Those of Itraconazole and Amphotericin B against 239 Clinical Isolates of Aspergillus spp. and Other Filamentous Fungi: Report from SENTRY Antimicrobial Surveillance Program, 2000

ABSTRACT Posaconazole, ravuconazole, and voriconazole are new triazole derivatives that possess potent, broad-spectrum antifungal activity. We evaluated the in vitro activity of these investigational triazoles compared with that of itraconazole and amphotericin B against 239 clinical isolates of filamentous fungi from the SENTRY Program, including Aspergillus spp. (198 isolates), Fusarium spp. (7 isolates), Penicillium spp. (19 isolates), Rhizopus spp. (4 isolates), Mucor spp. (2 isolates), and miscellaneous species (9 isolates). The isolates were obtained from 16 different medical centers in the United States and Canada between January and December 2000. In vitro susceptibility testing was performed using the microdilution broth method outlined in the National Committee for Clinical Laboratory Standards M38-P document. Overall, posaconazole was the most active compound, inhibiting 94% of isolates at a MIC of ≤1 μg/ml, followed by voriconazole (91%), amphotericin B (89%), ravuconazole (88%), and itraconazole (70%). All three new triazoles demonstrated excellent activity (MIC, ≤1 μg/ml) against Aspergillus spp. (114 Aspergillus fumigatus, 22 Aspergillus niger, 13 Aspergillus flavus, 9 Aspergillus versicolor, 8 Aspergillus terreus, and 32 Aspergillus spp.): posaconazole (98%), voriconazole (98%), ravuconazole (92%), amphotericin B (89%), and itraconazole (72%). None of the triazoles were active against Fusarium spp. (MIC at which 50% of the isolates tested were inhibited [MIC50], >8 μg/ml) or Mucor spp. (MIC50, >8 μg/ml). Posaconazole and ravuconazole were more active than voriconazole against Rhizopus spp. (MIC50, 1 to 2 μg/ml versus >8 μg/ml, respectively). Based on these results, all three new triazoles exhibited promising activity against Aspergillus spp. and other less commonly encountered isolates of filamentous fungi. The clinical value of these in vitro data remains to be seen, and in vitro-in vivo correlation is needed for both new and established antifungal agents. Surveillance efforts should be expanded in order to monitor the spectrum of filamentous fungal pathogens and their in vitro susceptibility as these new antifungal agents are introduced into clinical use.

Activities of Caspofungin, Itraconazole, Posaconazole, Ravuconazole, Voriconazole, and Amphotericin B against 448 Recent Clinical Isolates of Filamentous Fungi

ABSTRACT 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 μg/ml, followed by ravuconazole (91%), voriconazole (90%), and itraconazole (79%). Caspofungin and amphotericin B inhibited 93% and 89% of isolates at ≤1 μg/ml, respectively, with caspofungin demonstrating an MEC 90 of 0.12 μg/ml. All three new triazoles and caspofungin inhibited >95% of Aspergillus spp. at ≤1 μg/ml compared to 83% for itraconazole and 91% for amphotericin B. Amphotericin B inhibited only 38% of Aspergillus terreus isolates at ≤1 μg/ml, whereas the three new triazoles and caspofungin inhibited all A. terreus at ≤0.5 μg/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.

Trends in Antifungal Susceptibility of Candida spp. Isolated from Pediatric and Adult Patients with Bloodstream Infections: SENTRY Antimicrobial Surveillance Program, 1997 to 2000

ABSTRACT From 1 January 1997 through 31 December 2000, 2,047 bloodstream infections (BSIs) due to Candida spp. were reported from hospitals in the United States, Canada, Latin America, and Europe participating in the SENTRY Antifungal Surveillance Program. Among individuals in four age groups (≤1, 2 to 15, 16 to 64, and ≥65 years) Candida albicans was the most common species, causing 60, 55, 55, and 50% of infections, respectively. C. glabrata caused 17 to 23% of BSIs in those ages 16 to 64 and ≥65 years, whereas it caused only 3% of BSIs in the individuals in the two younger age groups (P < 0.001). C. parapsilosis (which caused 21 to 24% of BSIs) and C. tropicalis (which caused 7 to 10% of BSIs) were more common than C. glabrata in individuals ages ≤1 year and 2 to 15 years. Isolates of Candida spp. showed a trend of decreasing susceptibility to fluconazole, itraconazole, and amphotericin B with increasing patient age (P ≤ 0.01). None of the C. glabrata isolates from individuals ≤1 year old were resistant to fluconazole, whereas they made up 5 to 9% of isolates from individuals ages 16 to 64 and ≥65 years. Isolates of C. tropicalis from patients ≤1 year old were more susceptible to flucytosine (MIC at which 90% of isolates are inhibited [MIC90], 0.5 μg/ml; 0% resistant isolates) than those from patients ≥65 years old (MIC90, 32 μg/ml; 11% resistant isolates). The investigational triazoles posaconazole, ravuconazole, and voriconazole were all highly active against all species of Candida from individuals in all age groups. These data demonstrate differences in the species distributions of pathogens and differences in antifungal resistance among isolates from individuals in the pediatric and adult age groups. Ongoing surveillance will enhance efforts to limit the extent of antifungal resistance in individuals in various age groups.

Survey of Bloodstream Infections Due to Gram-Negative Bacilli: Frequency of Occurrence and Antimicrobial Susceptibility of Isolates Collected in the United States,Canada, and Latin America for the SENTRY Antimicrobial Surveillance Program, 1997

During 1997, a total of 4,267 nosocomial and community-acquired bloodstream infections due to gram-negative organisms were reported from SENTRY hospitals in Canada (8 sites), the United States (30 sites), and Latin America (10 sites). Escherichia coli was the most common isolate (41% of all gram-negative isolates), followed by Klebsiella species (17.9%), Pseudomonas aeruginosa (10.6%), and Enterobacter species (9.4%). For all gram-negative isolates combined, the most active antimicrobials tested were meropenem, imipenem, and cefepime. The quinolones levofloxacin (MIC90, 2 microg/mL), ciprofloxacin (MIC90, 1 microg/mL), gatifloxacin (MIC90, 2 microg/mL), sparfloxacin (MIC90, 2 microg/mL), and trovafloxacin (MIC90, 2 microg/mL) were also active against most isolates. Bloodstream infection isolates from Latin America were uniformly more resistant to all classes of antimicrobial agents tested than were isolates from Canada or the United States. Resistance phenotypes consistent with extended-spectrum beta-lactamase production were also most common among E. coli and Klebsiella species from Latin America. Further investigation of the reasons for regional differences in resistance patterns is needed, as is ongoing surveillance to detect resistance trends and to guide antimicrobial use.

National Surveillance of Nosocomial Blood Stream Infection Due to Candida albicans: Frequency of Occurrence and Antifungal Susceptibility in the SCOPE Program

Surveillance of nosocomial blood stream infections (BSI) in the USA between April 1995 and June 1996 revealed that Candida was the fourth leading cause of nosocomial BSI, accounting for 8% of all infections. Fifty-two percent of 379 episodes of candidemia were due to Candida albicans. In vitro susceptibility studies using the 1997 National Committee for Clinical Laboratory Standards reference method demonstrated that 92% of C. albicans isolates were susceptible to 5-fluorocytosine and 90% were susceptible to fluconazole and itraconazole. Geographic variation in susceptibility of fluconazole and itraconazole was observed. Isolates from the Northwest and Southeast regions were more frequently resistant to fluconazole (13.3-15.5%) and to itraconazole (17.2-20.0%) than those from the Northeast and Southwest regions (2.9-5.5% resistant to fluconazole and itraconazole). Continued surveillance for infections caused by C. albicans and other species of Candida among hospitalized patients is recommended.

International surveillance of blood stream infections due to Candida species in the European SENTRY program: species distribution and antifungal susceptibility including the investigational triazole and echinocandin agents

The SENTRY Antimicrobial Surveillance Program, an international study of blood stream infections (BSIs), detected 170 episodes of candidemia in 20 European medical centers (13 nations) between January and December, 1997. Twenty-three percent of the candidal BSI occurred in patients hospitalized in an intensive care unit, 21% in patients in an internal medicine service, 13% in patients in a surgical service, and 9% in patients in an oncology service. Overall, 53% of the BSI were attributable to Candida albicans followed in prevalence by C. parapsilosis (21%), C. glabrata (12%), C. tropicalis (6%), C. famata (2%), C. krusei (1%), and C. inconspicua (1%). As observed previously in Canada and Latin America, C. parapsilosis and not C. glabrata, was the most common non-albicans species causing yeast BSI in Europe. The proportion of these candidemias attributable to C. albicans varied widely from 0-100% among the 20 European centers. Among the different species of Candida, resistance to fluconazole (MIC, > or = 64 micrograms/mL) and itraconazole (MIC, > or = 1.0 microgram/mL) was observed with C. glabrata and C. krusei and was observed more rarely among other species (e.g., C. inconspicua). Isolates of C. albicans, C. parapsilosis, C. tropicalis, and C. guilliermondii were all highly susceptible to both fluconazole and itraconazole. Furthermore, the investigational triazoles (BMS-207147, Sch 56592, and voriconazole) and an echinocandin (MK-0991) all demonstrated potent in vitro activity (MIC90s, 0.5, 0.5, 1.0, and 2.0 micrograms/mL, respectively) against these isolates. Continued surveillance at an international level will be important to monitor trends in species distribution and antifungal susceptibility among invasive strains of Candida.

In Vitro Activities of Ravuconazole and Voriconazole Compared with Those of Four Approved Systemic Antifungal Agents against 6,970 Clinical Isolates of Candida spp.

ABSTRACT The in vitro activities of ravuconazole and voriconazole were compared with those of amphotericin B, flucytosine (5FC), itraconazole, and fluconazole against 6,970 isolates of Candida spp. obtained from over 200 medical centers worldwide. Both ravuconazole and voriconazole were very active against all Candida spp. (MIC at which 90% of the isolates tested are inhibited [MIC90], 0.25 μg/ml; 98% of MICs were ≤1 μg/ml); however, a decrease in the activities of both of these agents was noted among isolates that were susceptible-dose dependent (fluconazole MIC, 16 to 32 μg/ml) and resistant (MIC, ≥ 64 μg/ml) to fluconazole. Candida albicans was the most susceptible species (MIC90 of both ravuconazole and voriconazole, 0.03 μg/ml), and C. glabrata was the least susceptible species (MIC90, 1 to 2 μg/ml). Ravuconazole and voriconazole were each more active in vitro than amphotericin B, 5FC, itraconazole, and fluconazole against all Candida spp. and were the only agents with good in vitro activity against C. krusei. These results provide further evidence for the spectrum and potency of ravuconazole and voriconazole against a large and geographically diverse collection of Candida spp.