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Abstract Background The emergence of antifungal resistance threatens effective treatment of invasive fungal infection (IFI). Invasive candidiasis is the most common health care–associated IFI. We evaluated the activity of fluconazole (FLU) against 20 788 invasive isolates of Candida (37 species) collected from 135 medical centers in 39 countries (1997–2016). The activity of anidulafungin, caspofungin, and micafungin (MCF) was evaluated against 15 308 isolates worldwide (2006–2016). Methods Species identification was accomplished using phenotypic (1997–2001), genotypic, and proteomic methods (2006–2016). All isolates were tested using reference methods and clinical breakpoints published in the Clinical and Laboratory Standards Institute documents. Results A decrease in the isolation of Candida albicans and an increase in the isolation of Candida glabrata and Candida parapsilosis were observed over time. Candida glabrata was the most common non–C. albicans species detected in all geographic regions except for Latin America, where C. parapsilosis and Candida tropicalis were more common. Six Candida auris isolates were detected: 1 each in 2009, 2013, 2014, and 2015 and 2 in 2016; all were from nosocomial bloodstream infections and were FLU-resistant (R). The highest rates of FLU-R isolates were seen in C. glabrata from North America (NA; 10.6%) and in C. tropicalis from the Asia-Pacific region (9.2%). A steady increase in isolation of C. glabrata and resistance to FLU was detected over 20 years in the United States. Echinocandin-R (EC-R) ranged from 3.5% for C. glabrata to 0.1% for C. albicans and C. parapsilosis. Resistance to MCF was highest among C. glabrata (2.8%) and C. tropicalis (1.3%) from NA. Mutations on FKS hot spot (HS) regions were detected among 70 EC-R isolates (51/70 were C. glabrata). Most isolates harboring FKS HS mutations were resistant to 2 or more ECs. Conclusions EC-R and FLU-R remain uncommon among contemporary Candida isolates; however, a slow and steady emergence of resistance to both antifungal classes was observed in C. glabrata and C. tropicalis isolates.

This analysis describes the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance) registry from 2004 to 2008. A total of 2,496 patients with non-albicans species of Candida isolates were identified. The identified species were C. glabrata (46.4%), C. parapsilosis (24.7%), C. tropicalis (13.9%), C. krusei (5.5%), C. lusitaniae (1.6%), C. dubliniensis (1.5%) and C. guilliermondii (0.4%); 111 infections involved two or more species of Candida (4.4%). Non-albicans species accounted for more than 50% of all cases of invasive candidiasis in 15 of the 24 sites (62.5%) that contributed more than one case to the survey. Among solid organ transplant recipients, patients with non-transplant surgery, and patients with solid tumors, the most prevalent non-albicans species was C. glabrata at 63.7%, 48.0%, and 53.8%, respectively. In 1,883 patients receiving antifungal therapy on day 3, fluconazole (30.5%) and echinocandins (47.5%) were the most frequently administered monotherapies. Among the 15 reported species, 90-day survival was highest for patients infected with either C. parapsilosis (70.7%) or C. lusitaniae (74.5%) and lowest for patients infected with an unknown species (46.7%) or two or more species (53.2%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in North America. The variability in species distribution in these centers underscores the importance of local epidemiology in guiding the selection of antifungal therapy.

Background. Candidemia remains a major cause of morbidity and mortality in the health care setting, and the epidemiology of Candida infection is changing. Methods. Clinical data from patients with candidemia were extracted from the Prospective Antifungal Therapy (PATH) Alliance database, a comprehensive registry that collects information regarding invasive fungal infections. A total of 2019 patients, enrolled from 1 July 2004 through 5 March 2008, were identified. Data regarding the candidemia episode were analyzed, including the specific fungal species and patient survival at 12 weeks after diagnosis. Results. The incidence of candidemia caused by non–Candida albicans Candida species (54.4%) was higher than the incidence of candidemia caused by C. albicans (45.6%). The overall, crude 12-week mortality rate was 35.2%. Patients with Candida parapsilosis candidemia had the lowest mortality rate (23.7%; P<.001) and were less likely to be neutropenic (5.1%; P<.001) and to receive corticosteroids (33.5%; P<.001) or other immunosuppressive drugs (7.9%; P=.002), compared with patients infected with other Candida species. Candida krusei candidemia was most commonly associated with prior use of antifungal agents (70.6%; P<.001), hematologic malignancy (52.9%; P<.001) or stem cell transplantation (17.7%; P<.001), neutropenia (45.1%; P<.001), and corticosteroid treatment (60.8%; P<.001). Patients with C. krusei candidemia had the highest crude 12-week mortality in this series (52.9%; P<.001). Fluconazole was the most commonly administered antimicrobial, followed by the echinocandins, and amphotericin B products were infrequently administered. Conclusions. The epidemiology and choice of therapy for candidemia are rapidly changing. Additional study is warranted to differentiate host factors and differences in virulence among Candida species and to determine the best therapeutic regimen.

Abstract Background Staphylococcus aureus is among the most common human pathogens, with therapy complicated by the epidemic spread of methicillin-resistant Staphylococcus aureus (MRSA). Methods The SENTRY Antimicrobial Surveillance Program evaluated the in vitro activity of >20 antimicrobials against 191 460 clinical S. aureus isolates collected from 427 centers in 45 countries from 1997 to 2016. Each center contributed isolates and clinical data for consecutive episodes of bacteremia, pneumonia in hospitalized patients, urinary tract infection, and skin and skin structure infection. Results Overall, 191 460 S. aureus isolates were collected, of which 77 146 (40.3%) were MRSA, varying geographically from 26.8% MRSA in Europe to 47.0% in North America. The highest percentage of MRSA was in nosocomial isolates from patients aged >80 years. Overall, MRSA occurrences increased from 33.1% in 1997–2000 to a high of 44.2% in 2005–2008, then declined to 42.3% and 39.0% in 2009–2012 and 2013–2016, respectively. S. aureus bacteremia had a similar trend, with nosocomial and community-onset MRSA rates peaking in 2005–2008 and then declining. Vancomycin activity against S. aureus remained stable (minimum inhibitory concentration [MIC]90 of 1 mg/L and 100% susceptibility in 2016; no increase over time in isolates with a vancomycin MIC >1 mg/L). Several agents introduced during the surveillance period exhibited in vitro potency against MRSA. Conclusions In a large global surveillance program, the rise of MRSA as a proportion of all S. aureus peaked a decade ago and has declined since, consistent with some regional surveillance program reports. Vancomycin maintained high activity against S. aureus, and several newer agents exhibited excellent in vitro potencies.

Candidemia and other forms of invasive candidiasis pose a significant diagnostic challenge. In order to provide the best treatment, it is important to accurately detect the fungal infection and identify the species. Historically, diagnosis of infections depended upon three classical laboratory approaches: microbiologic, immunologic, histopathologic; and now includes new methods such as radiographic techniques, molecular, proteomic and biochemical methods. The T2Candida Panel has introduced a new class of infectious disease diagnostics that can rapidly detect and identify the causative pathogen of sepsis directly from a patient blood sample in a culture-independent manner. This test enables detection of directly from the patient sample, a significant advance for the rapid and accurate diagnosis of invasive candidiasis.

Antifungal surveillance is an important tool to monitor the prevalence of uncommon fungal species and increasing antifungal resistance throughout the world, but data comparing results across several different Asian countries are scarce. In this study, 372 invasive molds collected in the Asia-Western Pacific region in 2011–2019 were susceptibility tested for mold-active triazoles (isavuconazole, posaconazole, voriconazole, and itraconazole). The collection includes 318 Aspergillus spp. isolates and 53 non-Aspergillus molds. The MIC values using CLSI methods for isavuconazole versus Aspergillus fumigatus ranged from 0.25 to 2 mg l−1. Isavuconazole, itraconazole, posaconazole, and voriconazole acted similarly against A. fumigatus. The mold-active triazoles exhibited a wildtype phenotype to most of the Aspergillus spp. isolates tested (>94%), but poor activity against Fusarium solani species complex and Lomentospora prolificans. Voriconazole was most active against the Scedosporium spp. and posaconazole was most active against the Mucorales. In summary, isavuconazole displayed excellent activity against most species of Aspergillus and was comparable to other mold-active triazoles against non-Aspergillus molds.

The SENTRY Antifungal Surveillance Program monitors global susceptibility rates of newer and established antifungal agents. We report the in vitro activity of seven antifungal agents against 496 contemporary clinical isolates of yeasts and molds. The isolates were obtained from 20 laboratories in the Asia-Western Pacific (APAC) region during 2010 through 2012. Anidulafungin, caspofungin, micafungin, fluconazole, itraconazole, posaconazole and voriconazole were susceptibility tested using CLSI methods and species-specific interpretive criteria. Sequencing of fks hot spots was performed for echinocandin-resistant strains. Isolates included 13 species of Candida ( n =460), 5 species of non- Candida yeasts (21), 5 species of Aspergillus (11) and 4 other molds. Echinocandin resistance was uncommon among eight species of Candida and was only detected in three isolates of Candida glabrata , two from Australia harboring mutations in fks1 (F625S) and fks2 (S663P). Resistance to the azoles was much more common and was observed among all species with the exception of Candida dubliniensis . Fluconazole resistance rates observed with C. glabrata (6.8%) was comparable to that seen with Candida parapsilosis (5.7%) and Candida tropicalis (3.6%). Cross resistance among the triazoles was seen with each of these three species. The mold-active azoles and the echinocandins were all active against isolates of Aspergillus fumigatus . Azole resistance was not detected among the isolates of Cryptococcus neoformans . Antifungal resistance is uncommon among isolates of fungi causing invasive fungal infections in the APAC region. As in other regions of the world, emerging resistance to the echinocandins among invasive isolates of C. glabrata bears close monitoring.

Ceftaroline fosamil, the prodrug form of the active metabolite ceftaroline, is a new broad-spectrum parenteral cephalosporin with antibacterial activity against the prevalent respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Bacterial resistance surveillance (5330 isolates) was conducted in the United States between 2008 and 2010 to assess the in vitro activity of ceftaroline and comparator antibacterial agents against invasive respiratory isolates of S. pneumoniae (3329 isolates), H. influenzae (1545 isolates), and M. catarrhalis (456 isolates). All organisms were cultured from patient infections in 71 US hospital laboratories and were submitted to a central reference monitor for broth microdilution testing by Clinical and Laboratory Standards Institute reference methods. Against S. pneumoniae, ceftaroline inhibited 98.7% of strains at the susceptible breakpoint of ≤0.25 μg/mL (50% minimum inhibitory concentration [MIC 50 ], 0.01 μg/mL; 90% MIC [MIC 90 ], 0.12 μg/mL) and was 16-fold more active than ceftriaxone (MIC 90 , 2 μg/mL). Among 70 ceftriaxone-resistant pneumococcal isolates, all were inhibited by ≤0.5 μg/mL of ceftaroline. Haemophilus influenzae (MIC 50 , ≤0.008 μg/mL; MIC 90 , 0.015 μg/mL) and M. catarrhalis (MIC 50 , 0.06 μg/mL; MIC 90 , 0.12 μg/mL) were very susceptible to ceftaroline regardless of β-lactamase production. Whereas the high-level of activity of ceftaroline was maintained against S. pneumoniae and H. influenzae from 2008 through 2010, increased rates of nonsusceptibility were observed for amoxicillin/clavulanate, erythromycin, and levofloxacin among S. pneumoniae and for trimethoprim/sulfamethoxazole and azithromycin among H. influenzae. In summary, ceftaroline resistance surveillance (Assessing Worldwide Antimicrobial Resistance Evaluation [AWARE] Program) in the United States (2008–2010) documented in vitro sustained potency and spectrum against Gram-positive and Gram-negative pathogens known to cause community-acquired bacterial pneumonia.

Abstract The activity of isavuconazole and other triazoles against non-fumigatus (non-AFM) Aspergillus causing invasive aspergillosis was evaluated. A total of 390 non-AFM isolates were collected (1/patient) in 2017–2021 from 41 hospitals. Isolates were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry and/or internal spacer region/β-tubulin sequencing and tested by Clinical and Laboratory Standards Institute (CLSI) broth microdilution. CLSI epidemiological cutoff values were applied, where available. Isavuconazole showed activity against Aspergillus sections Flavi (n = 122; minimum inhibitory concentration [MIC]50/90, 0.5/1 mg/L), Terrei (n = 57; MIC50/90, 0.5/0.5 mg/L), Nidulantes (n = 34; MIC50/90, 0.12/0.25 mg/L), Versicolores (n = 7; MIC50, 1 mg/L), and Circumdati (n = 2; MIC range, 0.12–2 mg/L). Similar activity was displayed by other triazoles against those Aspergillus sections. Most of the isolates from Aspergillus sections Fumigati (n = 9), Nigri (n = 146), and Usti (n = 12) exhibited elevated MIC values to isavuconazole (MIC50/90, 2/–, 2/4, and 2/8 mg/L), voriconazole (MIC50/90, 2/–, 1/2, and 4/8 mg/L), itraconazole (MIC50/90, 2/–, 2/4, and 8/>8 mg/L), and posaconazole (MIC50/90, 0.5/–, 0.5/1, and >8/>8 mg/L), respectively. Isavuconazole was active (MIC values, ≤1 mg/L) against Aspergillus parasiticus, Aspergillus tamarii, Aspergillus nomius, Aspergillus nidulans, Aspergillus unguis, Aspergillus terreus, Aspergillus alabamensis, and Aspergillus hortai, while isavuconazole MIC values between 2 and 8 mg/L were observed against cryptic isolates from Aspergillus section Fumigati. Isavuconazole inhibited 96.1% of Aspergillus niger and 80.0% of Aspergillus tubingensis at ≤4 mg/L, the CLSI wild-type cutoff value for A niger. Voriconazole, itraconazole, and posaconazole showed similar activity to isavuconazole against most cryptic species. Isavuconazole exhibited potent in vitro activity against non-AFM; however, the activity of triazoles varies among and within cryptic species.

Isavuconazole is the only US FDA-approved antifungal for treating invasive mucormycosis. We evaluated isavuconazole activity against a global collection of Mucorales isolates. Fifty-two isolates were collected during 2017–2020 from hospitals located in the USA, Europe, and the Asia-Pacific. Isolates were identified by MALDI-TOF MS and/or DNA sequencing and susceptibility tested by the broth microdilution method following CLSI guidelines. Isavuconazole (MIC50/90, 2/>8 mg/L) inhibited 59.6% and 71.2% of all Mucorales isolates at ≤2 mg/L and ≤4 mg/L, respectively. Among comparators, amphotericin B (MIC50/90, 0.5/1 mg/L) displayed the highest activity, followed by posaconazole (MIC50/90, 0.5/8 mg/L). Voriconazole (MIC50/90, >8/>8 mg/L) and the echinocandins (MIC50/90, >4/>4 mg/L) had limited activity against Mucorales isolates. Isavuconazole activity varied by species and this agent inhibited at ≤4 mg/L 85.2%, 72.7%, and 25% of Rhizopus spp. (n = 27; MIC50/90, 1/>8 mg/L), Lichtheimia spp. (n = 11; MIC50/90, 4/8 mg/L), and Mucor spp. (n = 8; MIC50, >8 mg/L) isolates, respectively. Posaconazole MIC50/90 values against Rhizopus, Lichtheimia, and Mucor species were 0.5/8 mg/L, 0.5/1 mg/L, and 2/- mg/L, respectively; amphotericin B MIC50/90 values were 1/1 mg/L, 0.5/1 mg/L, and 0.5/- mg/L, respectively. As susceptibility profiles varied among Mucorales genera, species identification and antifungal susceptibility testing are advised whenever possible to manage and monitor mucormycosis.