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Robert K Flamm - One of the best experts on this subject based on the ideXlab platform.

  • Antimicrobial activity of manogepix, a first-in-class antifungal, and comparator agents tested against contemporary invasive fungal isolates from an international surveillance programme (2018–2019)
    'Elsevier BV', 2021
    Co-Authors: Michael A Pfaller, Michael D Huband, Robert K Flamm, Paul A. Bien, Mariana Castanheira
    Abstract:

    ABSTRACT: Objectives: : Manogepix, the active moiety of the prodrug fosmanogepix, is a novel antifungal with activity against major fungal pathogens including Candida (except Candida krusei), Aspergillus and difficult-to-treat/rare moulds. We tested manogepix and comparators against 2669 contemporary (2018–2019) fungal isolates collected from 82 medical centres in North America (42.3%), Europe (37.9%), Asia-Pacific (12.3%) and Latin America (7.6%). Of these, 70.7% were Candida spp., 3.6% were non-Candida yeasts including 49 Cryptococcus neoformans var. grubii, 21.7% were Aspergillus spp. and 4.1% were other moulds. Methods: Isolates were tested for antifungal susceptibility by the CLSI reference broth microdilution method. Results: Manogepix (MIC50/90, 0.008/0.06 mg/L) was the most active agent tested against Candida spp. isolates; corresponding anidulafungin, micafungin and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, manogepix (MIC50/90, 0.5/2 mg/L) was ≥4-fold more active than anidulafungin, micafungin and fluconazole against C. neoformans var. grubii. Against Aspergillus spp., manogepix (MEC50/90, 0.015/0.03 mg/L) had comparable activity to anidulafungin and micafungin. Low manogepix concentrations inhibited uncommon species of Candida, non-Candida yeasts, and rare moulds including Scedosporium spp. and Lomentospora (Scedosporium) prolificans. Conclusion: Manogepix exhibited potent activity against contemporary fungal isolates, including echinocandin- and azole-resistant strains of Candida and Aspergillus spp., respectively. Although rare, Candida strains that were non-wild type for manogepix demonstrated resistance to fluconazole. However, the clinical relevance of this finding is unknown. The extended spectrum of manogepix is noteworthy for its activity against many less-common yet antifungal-resistant strains. Clinical studies are underway to evaluate the utility of fosmanogepix against difficult-to-treat resistant fungal infections

  • in vitro activity of minocycline against u s isolates of acinetobacter baumannii acinetobacter calcoaceticus species complex stenotrophomonas maltophilia and burkholderia cepacia complex results from the sentry antimicrobial surveillance program 2014 to 2018
    Antimicrobial Agents and Chemotherapy, 2019
    Co-Authors: Robert K Flamm, Helio S Sader, Mariana Castanheira, Dee Shortridge, Michael A Pfaller
    Abstract:

    We evaluated the activity of minocycline and comparator agents against a large number of Stenotrophomonas maltophilia (n = 1,289), Acinetobacter baumannii-Acinetobacter calcoaceticus species complex (n = 1,081), and Burkholderia cepacia complex (n = 101) isolates collected from 2014 to 2018 from 87 U.S. medical centers spanning all 9 census divisions. The isolates were collected primarily from hospitalized patients with pneumonia (1,632 isolates; 66.0% overall), skin and skin structure infections (354 isolates; 14.3% overall), bloodstream infections (266 isolates; 10.8% overall), urinary tract infections (126 isolates; 5.1% overall), intra-abdominal infections (61 isolates; 2.5% overall), and other infections (32 isolates; 1.3% overall). Against the A. baumannii-A. calcoaceticus species complex, colistin was the most active agent, exhibiting MIC50/90 values at ≤0.5/2 μg/ml and 92.4% susceptibility. Minocycline ranked second in activity, with MIC50/90 values at 0.25/8 μg/ml and susceptibility at 85.7%. Activity for these two agents was reduced against extensively drug-resistant and multidrug-resistant isolates of the Acinetobacter baumannii-Acinetobacter calcoaceticus species complex. Only two agents showed high levels of activity (susceptibility, >90%) against S. maltophilia, minocycline (MIC50/90, 0.5/2 μg/ml; 99.5% susceptible) and trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/1 μg/ml; 94.6% susceptible). Minocycline was active against 92.8% (MIC90, 4 μg/ml) of trimethoprim-sulfamethoxazole-resistant S. maltophilia isolates. Various agents exhibited susceptibility rates of nearly 90% against the B. cepacia complex isolates; these were trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/2 μg/ml; 93.1% susceptible), ceftazidime (MIC50/90, 2/8 μg/ml; 91.0% susceptible), meropenem (MIC50/90, 2/8 μg/ml; 89.1% susceptible), and minocycline (MIC50/90, 2/8 μg/ml; 88.1% susceptible). These results indicate that minocycline is among the most active agents for these three problematic potential pathogen groups when tested against U.S. isolates.

  • in vitro activity of apx001a manogepix and comparator agents against 1 706 fungal isolates collected during an international surveillance program in 2017
    Antimicrobial Agents and Chemotherapy, 2019
    Co-Authors: M A Pfaller, Michael D Huband, Paul Bien, Robert K Flamm, M Castanheira
    Abstract:

    Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during glycosylphosphatidylinositol anchor biosynthesis. APX001A is active against the major fungal pathogens, i.e., Candida (except Candida krusei), Aspergillus, and hard-to-treat molds, including Fusarium and Scedosporium In this study, we tested APX001A and comparators against 1,706 contemporary clinical fungal isolates collected in 2017 from 68 medical centers in North America (37.3%), Europe (43.4%), the Asia-Pacific region (12.7%), or Latin America (6.6%). Among the isolates tested, 78.5% were Candida spp., 3.9% were non-Candida yeasts, including 30 (1.8%) Cryptococcus neoformans var. grubii isolates, 14.7% were Aspergillus spp., and 2.9% were other molds. All isolates were tested by CLSI reference broth microdilution. APX001A (MIC50, 0.008 μg/ml; MIC90, 0.06 μg/ml) was the most active agent tested against Candida sp. isolates; corresponding anidulafungin, micafungin, and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, APX001A (MIC50, 0.25 μg/ml; MIC90, 0.5 μg/ml) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii Against Aspergillus spp., AXP001A (50% minimal effective concentration [MEC50], 0.015 μg/ml; MEC90, 0.03 μg/ml) was comparable in activity to anidulafungin and micafungin. Aspergillus isolates (>98%) exhibited a wild-type phenotype for the mold-active triazoles (itraconazole, posaconazole, and voriconazole). APX001A was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Scedosporium spp. (MEC values, 0.015 to 0.06 μg/ml). APX001A demonstrated potent in vitro activity against recent fungal isolates, including echinocandin- and fluconazole-resistant strains. The extended spectrum of APX001A was also notable for its potency against many less common but antifungal-resistant strains. Further studies are in progress to evaluate the clinical utility of the methyl phosphate prodrug, APX001, in difficult-to-treat resistant fungal infections.

  • tedizolid in vitro activity against gram positive clinical isolates causing bone and joint infections in hospitals in the usa and europe 2014 17
    Journal of Antimicrobial Chemotherapy, 2019
    Co-Authors: Cecilia G Carvalhaes, Helio S Sader, Robert K Flamm, Rodrigo E Mendes
    Abstract:

    BACKGROUND Despite the advances in current healthcare, bone and joint infections (BJIs) are a major clinical challenge that frequently involve prolonged systemic antibiotic use. Healthcare providers consider tedizolid an attractive candidate for therapy in adults and children with BJI. OBJECTIVES We tested tedizolid against a US and European collection of Gram-positive BJI isolates (n = 797) consecutively collected from 2014 to 2017. METHODS Organisms were tested by broth microdilution susceptibility methods following current CLSI guidelines and interpreted by both CLSI and EUCAST breakpoint criteria. RESULTS Staphylococcus aureus (59.3%; 58.6% in the USA and 60.4% in Europe) was the most common pathogen with a 29.6% MRSA rate and tedizolid MIC50/90 of 0.12/0.25 mg/L (100% susceptible). CoNS (15.0% of BJI in adults and 95%) for vancomycin, daptomycin and linezolid were observed and, based on MIC90 values, tedizolid (MIC90 0.12-0.25 mg/L) was 4- to 8-fold more potent than linezolid (MIC90 0.5-2  mg/L) against this collection of Gram-positive pathogens causing BJI. CONCLUSIONS This study showed that tedizolid had potent in vitro activity against contemporary Gram-positive cocci causing BJI in adults and children in US and European hospitals.

  • in vitro activity of plazomicin against gram negative and gram positive isolates collected from u s hospitals and comparative activities of aminoglycosides against carbapenem resistant enterobacteriaceae and isolates carrying carbapenemase genes
    Antimicrobial Agents and Chemotherapy, 2018
    Co-Authors: Mariana Castanheira, Rodrigo E Mendes, Andrew P Davis, Alisa W Serio, Kevin M Krause, Robert K Flamm
    Abstract:

    Plazomicin and comparator agents were tested by using the CLSI reference broth microdilution method against 4,825 clinical isolates collected during 2014 and 2015 in 70 U.S. hospitals as part of the ALERT (Antimicrobial Longitudinal Evaluation and Resistance Trends) program. Plazomicin (MIC50/MIC90, 0.5/2 μg/ml) inhibited 99.2% of 4,362 Enterobacteriaceae at ≤4 μg/ml. Amikacin, gentamicin, and tobramycin inhibited 98.9%, 90.3%, and 90.3% of these isolates, respectively, by applying CLSI breakpoints. The activities of plazomicin were similar among Enterobacteriaceae species, with MIC50 values ranging from 0.25 to 1 μg/ml, with the exception of Proteus mirabilis and indole-positive Proteeae that displayed MIC50 values of 2 μg/ml. For 97 carbapenem-resistant Enterobacteriaceae (CRE), which included 87 isolates carrying blaKPC, plazomicin inhibited all but 1 isolate at ≤2 μg/ml (99.0% and 98.9%, respectively). Amikacin and gentamicin inhibited 64.9% and 56.7% of the CRE isolates at the respective CLSI breakpoints. Plazomicin inhibited 96.5 and 95.5% of the gentamicin-resistant isolates, 96.9 and 96.5% of the tobramycin-resistant isolates, and 64.3 and 90.0% of the amikacin-resistant isolates according to CLSI and EUCAST breakpoints, respectively. The activities of plazomicin against Pseudomonas aeruginosa (MIC50/MIC90, 4/16 μg/ml) and Acinetobacter species (MIC50/MIC90, 2/16 μg/ml) isolates were similar. Plazomicin was active against coagulase-negative staphylococci (MIC50/MIC90, 0.12/0.5 μg/ml) and Staphylococcus aureus (MIC50/MIC90, 0.5/0.5 μg/ml) but had limited activity against Enterococcus spp. (MIC50/MIC90, 16/64 μg/ml) and Streptococcus pneumoniae (MIC50/MIC90, 32/64 μg/ml). Plazomicin activity against the Enterobacteriaceae tested, including CRE and isolates carrying blaKPC from U.S. hospitals, supports the development plan for plazomicin to treat serious infections caused by resistant Enterobacteriaceae in patients with limited treatment options.

Ronald N. Jones - One of the best experts on this subject based on the ideXlab platform.

  • telavancin in vitro activity against a collection of methicillin resistant staphylococcus aureus isolates including resistant subsets from the united states
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Rodrigo E Mendes, Helio S Sader, David J Farrell, Robert K Flamm, Ronald N. Jones
    Abstract:

    Telavancin had MIC50, MIC90, and MIC100 values of 0.03, 0.06, and 0.12 μg/ml, respectively, against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and non-multidrug-resistant (non-MDR) and MDR subsets. MRSA with elevated MIC values for vancomycin (2 to 4 μg/ml) or daptomycin (1 to 2 μg/ml) had telavancin MIC50 (0.06 μg/ml) values 2-fold higher than those of isolates with lower MIC results (MIC50, 0.03 μg/ml). However, telavancin had MIC90 and MIC100 results of 0.06 and 0.12 μg/ml (100% susceptible), respectively, regardless of the MRSA subset.

  • activity of oritavancin against gram positive clinical isolates responsible for documented skin and soft tissue infections in european and us hospitals 2010 13
    Journal of Antimicrobial Chemotherapy, 2015
    Co-Authors: Rodrigo E Mendes, Helio S Sader, David J Farrell, Robert K Flamm, Ronald N. Jones
    Abstract:

    Objectives To assess oritavancin activity in vitro against clinically relevant Gram-positive pathogens causing skin and soft-tissue infections (SSTIs) in European and US hospitals. Methods 13 262 consecutive and unique isolates deemed to be responsible for SSTIs were included. Isolates originated from 36 and 27 institutions in Europe (Israel included) and the USA, respectively, between 2010 and 2013. Results Oritavancin (98.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.03, 0.03 and 0.06 mg/L, respectively, for Staphylococcus aureus. CoNS from the USA (MIC50, 0.015 mg/L) demonstrated an MIC50 value of oritavancin slightly lower than those from Europe (MIC50, 0.03 mg/L). Overall, vancomycin-resistant (VanA-phenotype) Enterococcus faecalis had oritavancin MICs (MIC50/90, 0.25/0.5 mg/L) that were 16-fold higher than those obtained for vancomycin-susceptible isolates (MIC50/90, 0.015/0.03 mg/L; 99.2%-99.8% susceptible); nevertheless, oritavancin inhibited all VanA E. faecalis at ≤0.5 mg/L. Equivalent oritavancin MICs (MIC50/90, 0.004/0.008 mg/L) were noted for all VanB and vancomycin-susceptible Enterococcus faecium, while higher MICs (MIC50/90, 0.03/0.12 mg/L) were obtained for VanA strains. Oritavancin had low MICs against the overall populations of Streptococcus pyogenes (MIC50/90, 0.03/0.12 mg/L; 98.4%-98.6% susceptible), Streptococcus agalactiae (MIC50/90, 0.03/0.06 mg/L; 97.9%-98.0% susceptible) and the Streptococcus anginosus group (MIC50/90, 0.008/0.015 mg/L; 100.0% susceptible), with slightly higher MICs for Streptococcus dysgalactiae (MIC50/90, 0.06/0.25 mg/L; ≥98.3% susceptible). Conclusions Oritavancin had potent activity in vitro against this contemporary collection of European and US isolates causing SSTIs. These results describe oritavancin activity against Gram-positive pathogens collected shortly prior to its regulatory approval in the USA.

  • baseline activity of telavancin against gram positive clinical isolates responsible for documented infections in u s hospitals 2011 2012 as determined by the revised susceptibility testing method
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Rodrigo E Mendes, Helio S Sader, David J Farrell, Robert K Flamm, Ronald N. Jones
    Abstract:

    Telavancin had MIC50 and MIC90 values of 0.03 and 0.06 μg/ml (100.0% susceptible), respectively, against methicillin-resistant and -susceptible Staphylococcus aureus. Telavancin was active against vancomycin-susceptible Enterococcus faecalis (MIC50/90, 0.12/0.12 μg/ml; 100% susceptible) and Enterococcus faecium (MIC50/90, 0.03/0.06 μg/ml), while higher MIC values were obtained against vancomycin-resistant E. faecium (MIC50/90, 1/2 μg/ml) and E. faecalis (MIC50/90, >2/>2 μg/ml). Streptococci showed telavancin modal MIC results of ≤ 0.015 μg/ml, except against Streptococcus agalactiae (i.e., 0.03 μg/ml). This study reestablishes the telavancin spectrum of activity against isolates recovered from the United States (2011-2012) using the revised broth microdilution method.

  • ceftobiprole activity against over 60 000 clinical bacterial pathogens isolated in europe turkey and israel from 2005 to 2010
    Antimicrobial Agents and Chemotherapy, 2014
    Co-Authors: David J Farrell, Helio S Sader, Robert K Flamm, Ronald N. Jones
    Abstract:

    Ceftobiprole medocaril is a newly approved drug in Europe for the treatment of hospital-acquired pneumonia (HAP) (excluding patients with ventilator-associated pneumonia but including ventilated HAP patients) and community-acquired pneumonia in adults. The aim of this study was to evaluate the in vitro antimicrobial activity of ceftobiprole against prevalent Gram-positive and -negative pathogens isolated in Europe, Turkey, and Israel during 2005 through 2010. A total of 60,084 consecutive, nonduplicate isolates from a wide variety of infections were collected from 33 medical centers. Species identification was confirmed, and all isolates were susceptibility tested using reference broth microdilution methods. Ceftobiprole had high activity against methicillin-susceptible Staphylococcus aureus (MSSA) (100.0% susceptible), methicillin-susceptible coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci, and Streptococcus pneumoniae (99.3% susceptible), with MIC90 values of 0.25, 0.12, ≤0.06, and 0.5 μg/ml, respectively. Ceftobiprole was active against methicillin-resistant S. aureus (MRSA) (98.3% susceptible) and methicillin-resistant CoNS, having a MIC90 of 2 μg/ml. Ceftobiprole was active against Enterococcus faecalis (MIC50/90, 0.5/4 μg/ml) but not against most Enterococcus faecium isolates. Ceftobiprole was very potent against the majority of Enterobacteriaceae (87.3% susceptible), with >80% inhibited at ≤0.12 μg/ml. The potency of ceftobiprole against Pseudomonas aeruginosa (MIC50/90, 2/>8 μg/ml; 64.6% at MIC values of ≤4 μg/ml) was similar to that of ceftazidime (MIC50/90, 2/>16 μg/ml; 75.4% susceptible), but limited activity was observed against Acinetobacter spp. and Stenotrophomonas maltophilia. High activity was also observed against all Haemophilus influenzae (MIC90, ≤0.06 μg/ml) and Moraxella catarrhalis (MIC50/90, ≤0.06/0.25 μg/ml) isolates. Ceftobiprole demonstrated a wide spectrum of antimicrobial activity against this very large longitudinal sample of contemporary pathogens.

  • antimicrobial activity of ceftaroline tested against drug resistant subsets of streptococcus pneumoniae from u s medical centers
    Antimicrobial Agents and Chemotherapy, 2014
    Co-Authors: Robert K Flamm, Helio S Sader, David J Farrell, Ronald N. Jones
    Abstract:

    Streptococcus pneumoniae isolates (6,958) were collected from patients at 163 U.S. medical centers during 2009 through 2012. Isolates were evaluated for multidrug resistance (MDR) to penicillin, ceftriaxone, erythromycin, tetracycline, trimethoprim-sulfamethoxazole, and levofloxacin. Ceftaroline was 16-fold more potent than ceftriaxone (MIC50/MIC90, ≤0.25/2 μg/ml) against all isolates. For MDR isolates (35.2% of tested strains), ceftaroline (MIC50/MIC90, 0.06/0.25 μg/ml; 100.0% susceptible) was the most active agent tested, being 8-fold more potent than ceftriaxone (MIC50/MIC90, 0.5/2 μg/ml) and 16-fold more potent than penicillin (MIC50/MIC90, 1/4 μg/ml).

Mariana Castanheira - One of the best experts on this subject based on the ideXlab platform.

  • Antimicrobial activity of manogepix, a first-in-class antifungal, and comparator agents tested against contemporary invasive fungal isolates from an international surveillance programme (2018–2019)
    'Elsevier BV', 2021
    Co-Authors: Michael A Pfaller, Michael D Huband, Robert K Flamm, Paul A. Bien, Mariana Castanheira
    Abstract:

    ABSTRACT: Objectives: : Manogepix, the active moiety of the prodrug fosmanogepix, is a novel antifungal with activity against major fungal pathogens including Candida (except Candida krusei), Aspergillus and difficult-to-treat/rare moulds. We tested manogepix and comparators against 2669 contemporary (2018–2019) fungal isolates collected from 82 medical centres in North America (42.3%), Europe (37.9%), Asia-Pacific (12.3%) and Latin America (7.6%). Of these, 70.7% were Candida spp., 3.6% were non-Candida yeasts including 49 Cryptococcus neoformans var. grubii, 21.7% were Aspergillus spp. and 4.1% were other moulds. Methods: Isolates were tested for antifungal susceptibility by the CLSI reference broth microdilution method. Results: Manogepix (MIC50/90, 0.008/0.06 mg/L) was the most active agent tested against Candida spp. isolates; corresponding anidulafungin, micafungin and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, manogepix (MIC50/90, 0.5/2 mg/L) was ≥4-fold more active than anidulafungin, micafungin and fluconazole against C. neoformans var. grubii. Against Aspergillus spp., manogepix (MEC50/90, 0.015/0.03 mg/L) had comparable activity to anidulafungin and micafungin. Low manogepix concentrations inhibited uncommon species of Candida, non-Candida yeasts, and rare moulds including Scedosporium spp. and Lomentospora (Scedosporium) prolificans. Conclusion: Manogepix exhibited potent activity against contemporary fungal isolates, including echinocandin- and azole-resistant strains of Candida and Aspergillus spp., respectively. Although rare, Candida strains that were non-wild type for manogepix demonstrated resistance to fluconazole. However, the clinical relevance of this finding is unknown. The extended spectrum of manogepix is noteworthy for its activity against many less-common yet antifungal-resistant strains. Clinical studies are underway to evaluate the utility of fosmanogepix against difficult-to-treat resistant fungal infections

  • in vitro activity of minocycline against u s isolates of acinetobacter baumannii acinetobacter calcoaceticus species complex stenotrophomonas maltophilia and burkholderia cepacia complex results from the sentry antimicrobial surveillance program 2014 to 2018
    Antimicrobial Agents and Chemotherapy, 2019
    Co-Authors: Robert K Flamm, Helio S Sader, Mariana Castanheira, Dee Shortridge, Michael A Pfaller
    Abstract:

    We evaluated the activity of minocycline and comparator agents against a large number of Stenotrophomonas maltophilia (n = 1,289), Acinetobacter baumannii-Acinetobacter calcoaceticus species complex (n = 1,081), and Burkholderia cepacia complex (n = 101) isolates collected from 2014 to 2018 from 87 U.S. medical centers spanning all 9 census divisions. The isolates were collected primarily from hospitalized patients with pneumonia (1,632 isolates; 66.0% overall), skin and skin structure infections (354 isolates; 14.3% overall), bloodstream infections (266 isolates; 10.8% overall), urinary tract infections (126 isolates; 5.1% overall), intra-abdominal infections (61 isolates; 2.5% overall), and other infections (32 isolates; 1.3% overall). Against the A. baumannii-A. calcoaceticus species complex, colistin was the most active agent, exhibiting MIC50/90 values at ≤0.5/2 μg/ml and 92.4% susceptibility. Minocycline ranked second in activity, with MIC50/90 values at 0.25/8 μg/ml and susceptibility at 85.7%. Activity for these two agents was reduced against extensively drug-resistant and multidrug-resistant isolates of the Acinetobacter baumannii-Acinetobacter calcoaceticus species complex. Only two agents showed high levels of activity (susceptibility, >90%) against S. maltophilia, minocycline (MIC50/90, 0.5/2 μg/ml; 99.5% susceptible) and trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/1 μg/ml; 94.6% susceptible). Minocycline was active against 92.8% (MIC90, 4 μg/ml) of trimethoprim-sulfamethoxazole-resistant S. maltophilia isolates. Various agents exhibited susceptibility rates of nearly 90% against the B. cepacia complex isolates; these were trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/2 μg/ml; 93.1% susceptible), ceftazidime (MIC50/90, 2/8 μg/ml; 91.0% susceptible), meropenem (MIC50/90, 2/8 μg/ml; 89.1% susceptible), and minocycline (MIC50/90, 2/8 μg/ml; 88.1% susceptible). These results indicate that minocycline is among the most active agents for these three problematic potential pathogen groups when tested against U.S. isolates.

  • in vitro activity of plazomicin against gram negative and gram positive isolates collected from u s hospitals and comparative activities of aminoglycosides against carbapenem resistant enterobacteriaceae and isolates carrying carbapenemase genes
    Antimicrobial Agents and Chemotherapy, 2018
    Co-Authors: Mariana Castanheira, Rodrigo E Mendes, Andrew P Davis, Alisa W Serio, Kevin M Krause, Robert K Flamm
    Abstract:

    Plazomicin and comparator agents were tested by using the CLSI reference broth microdilution method against 4,825 clinical isolates collected during 2014 and 2015 in 70 U.S. hospitals as part of the ALERT (Antimicrobial Longitudinal Evaluation and Resistance Trends) program. Plazomicin (MIC50/MIC90, 0.5/2 μg/ml) inhibited 99.2% of 4,362 Enterobacteriaceae at ≤4 μg/ml. Amikacin, gentamicin, and tobramycin inhibited 98.9%, 90.3%, and 90.3% of these isolates, respectively, by applying CLSI breakpoints. The activities of plazomicin were similar among Enterobacteriaceae species, with MIC50 values ranging from 0.25 to 1 μg/ml, with the exception of Proteus mirabilis and indole-positive Proteeae that displayed MIC50 values of 2 μg/ml. For 97 carbapenem-resistant Enterobacteriaceae (CRE), which included 87 isolates carrying blaKPC, plazomicin inhibited all but 1 isolate at ≤2 μg/ml (99.0% and 98.9%, respectively). Amikacin and gentamicin inhibited 64.9% and 56.7% of the CRE isolates at the respective CLSI breakpoints. Plazomicin inhibited 96.5 and 95.5% of the gentamicin-resistant isolates, 96.9 and 96.5% of the tobramycin-resistant isolates, and 64.3 and 90.0% of the amikacin-resistant isolates according to CLSI and EUCAST breakpoints, respectively. The activities of plazomicin against Pseudomonas aeruginosa (MIC50/MIC90, 4/16 μg/ml) and Acinetobacter species (MIC50/MIC90, 2/16 μg/ml) isolates were similar. Plazomicin was active against coagulase-negative staphylococci (MIC50/MIC90, 0.12/0.5 μg/ml) and Staphylococcus aureus (MIC50/MIC90, 0.5/0.5 μg/ml) but had limited activity against Enterococcus spp. (MIC50/MIC90, 16/64 μg/ml) and Streptococcus pneumoniae (MIC50/MIC90, 32/64 μg/ml). Plazomicin activity against the Enterobacteriaceae tested, including CRE and isolates carrying blaKPC from U.S. hospitals, supports the development plan for plazomicin to treat serious infections caused by resistant Enterobacteriaceae in patients with limited treatment options.

  • antimicrobial activity of ceftobiprole and comparator agents when tested against contemporary gram positive and negative organisms collected from europe 2015
    Diagnostic Microbiology and Infectious Disease, 2018
    Co-Authors: M A Pfaller, Mariana Castanheira, Leonard R Duncan, Jennifer M Streit, Robert K Flamm, Helio S Sader
    Abstract:

    Abstract Susceptibility testing of ceftobiprole and comparators against 12,240 isolates was performed following CLSI/EUCAST guidelines. The percentage of susceptible MRSA isolates was higher for ceftobiprole (96.5% susceptible) than for ceftaroline (86.2% susceptible). Both ceftobiprole (MIC50/90, 0.5/2 mg/L) and ceftaroline (MIC50/90, 0.25/1 mg/L) demonstrated potent activity against coagulase-negative staphylococci. Ceftobiprole demonstrated good potency against Enterococcus faecalis (MIC50/90 values of 0.5/2 mg/L); ceftaroline (MIC50/90, 2/8 mg/L) was 4-fold less active against these strains. Ceftobiprole activity was comparable to that of the other β-lactam agents tested against S. pneumoniae (MIC90, 0.5 mg/L vs 0.12-2 mg/L [other β-lactams]), viridans-group streptococci (MIC90,0.25 mg/L vs 0.006-1 mg/L [other β-lactams]), and β-hemolytic streptococci (MIC90,0.03 mg/L vs 0.015–0.06 mg/L [other β-lactams]). Overall, 73.8% of Enterobacteriaceae isolates tested were susceptible to ceftobiprole. Ceftobiprole inhibited 70.4% of P. aeruginosa at ≤4 mg/L and all isolates of Haemophilus influenzae and Moraxella catarrhalis at ≤ 0.5 mg/L. Ceftobiprole was active in vitro against a broad range of clinically-relevant contemporary Gram-positive and Gram-negative bacterial isolates.

  • antimicrobial activities of aztreonam avibactam and comparator agents against contemporary 2016 clinical enterobacteriaceae isolates
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Rodrigo E Mendes, Michael A Pfaller, Dee Shortridge, Robert K Flamm, Mariana Castanheira
    Abstract:

    A total of 10,451 contemporary (2016) Enterobacteriaceae isolates from 84 U.S. medical centers and 116 metallo-β-lactamase- and/or OXA-48-like-producing Enterobacteriaceae isolates from other countries were tested against aztreonam-avibactam and comparators. All U.S. isolates were inhibited at aztreonam-avibactam MICs of ≤8 μg/ml (MIC50, ≤0.03 μg/ml; MIC90, 0.12 μg/ml), including Klebsiella pneumoniae carbapenemase-producing isolates (n = 102; MIC50, 0.25 μg/ml; MIC90, 0.5 μg/ml), multidrug-resistant isolates (n = 876; MIC50, 0.06 μg/ml; MIC90, 0.25 μg/ml), and extensively drug-resistant isolates (n = 111; MIC50, 0.12 μg/ml; MIC90, 0.5 μg/ml). The highest aztreonam-avibactam MIC value among ex-U.S. isolates was 4 μg/ml.

Helio S Sader - One of the best experts on this subject based on the ideXlab platform.

  • in vitro activity of minocycline against u s isolates of acinetobacter baumannii acinetobacter calcoaceticus species complex stenotrophomonas maltophilia and burkholderia cepacia complex results from the sentry antimicrobial surveillance program 2014 to 2018
    Antimicrobial Agents and Chemotherapy, 2019
    Co-Authors: Robert K Flamm, Helio S Sader, Mariana Castanheira, Dee Shortridge, Michael A Pfaller
    Abstract:

    We evaluated the activity of minocycline and comparator agents against a large number of Stenotrophomonas maltophilia (n = 1,289), Acinetobacter baumannii-Acinetobacter calcoaceticus species complex (n = 1,081), and Burkholderia cepacia complex (n = 101) isolates collected from 2014 to 2018 from 87 U.S. medical centers spanning all 9 census divisions. The isolates were collected primarily from hospitalized patients with pneumonia (1,632 isolates; 66.0% overall), skin and skin structure infections (354 isolates; 14.3% overall), bloodstream infections (266 isolates; 10.8% overall), urinary tract infections (126 isolates; 5.1% overall), intra-abdominal infections (61 isolates; 2.5% overall), and other infections (32 isolates; 1.3% overall). Against the A. baumannii-A. calcoaceticus species complex, colistin was the most active agent, exhibiting MIC50/90 values at ≤0.5/2 μg/ml and 92.4% susceptibility. Minocycline ranked second in activity, with MIC50/90 values at 0.25/8 μg/ml and susceptibility at 85.7%. Activity for these two agents was reduced against extensively drug-resistant and multidrug-resistant isolates of the Acinetobacter baumannii-Acinetobacter calcoaceticus species complex. Only two agents showed high levels of activity (susceptibility, >90%) against S. maltophilia, minocycline (MIC50/90, 0.5/2 μg/ml; 99.5% susceptible) and trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/1 μg/ml; 94.6% susceptible). Minocycline was active against 92.8% (MIC90, 4 μg/ml) of trimethoprim-sulfamethoxazole-resistant S. maltophilia isolates. Various agents exhibited susceptibility rates of nearly 90% against the B. cepacia complex isolates; these were trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/2 μg/ml; 93.1% susceptible), ceftazidime (MIC50/90, 2/8 μg/ml; 91.0% susceptible), meropenem (MIC50/90, 2/8 μg/ml; 89.1% susceptible), and minocycline (MIC50/90, 2/8 μg/ml; 88.1% susceptible). These results indicate that minocycline is among the most active agents for these three problematic potential pathogen groups when tested against U.S. isolates.

  • tedizolid in vitro activity against gram positive clinical isolates causing bone and joint infections in hospitals in the usa and europe 2014 17
    Journal of Antimicrobial Chemotherapy, 2019
    Co-Authors: Cecilia G Carvalhaes, Helio S Sader, Robert K Flamm, Rodrigo E Mendes
    Abstract:

    BACKGROUND Despite the advances in current healthcare, bone and joint infections (BJIs) are a major clinical challenge that frequently involve prolonged systemic antibiotic use. Healthcare providers consider tedizolid an attractive candidate for therapy in adults and children with BJI. OBJECTIVES We tested tedizolid against a US and European collection of Gram-positive BJI isolates (n = 797) consecutively collected from 2014 to 2017. METHODS Organisms were tested by broth microdilution susceptibility methods following current CLSI guidelines and interpreted by both CLSI and EUCAST breakpoint criteria. RESULTS Staphylococcus aureus (59.3%; 58.6% in the USA and 60.4% in Europe) was the most common pathogen with a 29.6% MRSA rate and tedizolid MIC50/90 of 0.12/0.25 mg/L (100% susceptible). CoNS (15.0% of BJI in adults and 95%) for vancomycin, daptomycin and linezolid were observed and, based on MIC90 values, tedizolid (MIC90 0.12-0.25 mg/L) was 4- to 8-fold more potent than linezolid (MIC90 0.5-2  mg/L) against this collection of Gram-positive pathogens causing BJI. CONCLUSIONS This study showed that tedizolid had potent in vitro activity against contemporary Gram-positive cocci causing BJI in adults and children in US and European hospitals.

  • antimicrobial activity of ceftobiprole and comparator agents when tested against contemporary gram positive and negative organisms collected from europe 2015
    Diagnostic Microbiology and Infectious Disease, 2018
    Co-Authors: M A Pfaller, Mariana Castanheira, Leonard R Duncan, Jennifer M Streit, Robert K Flamm, Helio S Sader
    Abstract:

    Abstract Susceptibility testing of ceftobiprole and comparators against 12,240 isolates was performed following CLSI/EUCAST guidelines. The percentage of susceptible MRSA isolates was higher for ceftobiprole (96.5% susceptible) than for ceftaroline (86.2% susceptible). Both ceftobiprole (MIC50/90, 0.5/2 mg/L) and ceftaroline (MIC50/90, 0.25/1 mg/L) demonstrated potent activity against coagulase-negative staphylococci. Ceftobiprole demonstrated good potency against Enterococcus faecalis (MIC50/90 values of 0.5/2 mg/L); ceftaroline (MIC50/90, 2/8 mg/L) was 4-fold less active against these strains. Ceftobiprole activity was comparable to that of the other β-lactam agents tested against S. pneumoniae (MIC90, 0.5 mg/L vs 0.12-2 mg/L [other β-lactams]), viridans-group streptococci (MIC90,0.25 mg/L vs 0.006-1 mg/L [other β-lactams]), and β-hemolytic streptococci (MIC90,0.03 mg/L vs 0.015–0.06 mg/L [other β-lactams]). Overall, 73.8% of Enterobacteriaceae isolates tested were susceptible to ceftobiprole. Ceftobiprole inhibited 70.4% of P. aeruginosa at ≤4 mg/L and all isolates of Haemophilus influenzae and Moraxella catarrhalis at ≤ 0.5 mg/L. Ceftobiprole was active in vitro against a broad range of clinically-relevant contemporary Gram-positive and Gram-negative bacterial isolates.

  • antimicrobial activity of oritavancin and comparator agents when tested against gram positive bacterial isolates causing infections in cancer patients 2014 16
    Journal of Antimicrobial Chemotherapy, 2018
    Co-Authors: M A Pfaller, Helio S Sader, M Castanheira, Robert K Flamm, Rodrigo E Mendes
    Abstract:

    Objectives The in vitro activity of oritavancin was assessed against clinically relevant Gram-positive pathogens causing infections in cancer patients in European and US hospitals. Methods A total of 1357 Gram-positive cocci (GPC) were included. Isolates were predominantly from bloodstream infections (54.6%). The most frequently isolated GPC were Staphylococcus aureus (43.6%), CoNS (14.4%) and Enterococcus spp. (22.0%). Results Oritavancin (99.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.015, 0.015-0.03 and 0.06 mg/L, respectively, when tested against S. aureus, regardless of methicillin susceptibility or geographical region. CoNS isolates from the USA demonstrated an MIC90 of oritavancin (MIC90, 0.12 mg/L) that was slightly higher than that for isolates from European countries (MIC90 0.06 mg/L). Oritavancin inhibited all Enterococcus faecalis and Enterococcus faecium, including VRE, at ≤ 0.25 mg/L. Oritavancin exhibited MIC50 results of 0.03 and 0.008-0.015 mg/L when tested against isolates of β-haemolytic streptococci and viridans group streptococci, respectively, regardless of geographical region. Conclusions Oritavancin had potent activity in vitro against this contemporary collection of European and US GPC isolates from cancer patients.

  • antimicrobial activities of aztreonam avibactam and comparator agents against contemporary 2016 clinical enterobacteriaceae isolates
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Rodrigo E Mendes, Michael A Pfaller, Dee Shortridge, Robert K Flamm, Mariana Castanheira
    Abstract:

    A total of 10,451 contemporary (2016) Enterobacteriaceae isolates from 84 U.S. medical centers and 116 metallo-β-lactamase- and/or OXA-48-like-producing Enterobacteriaceae isolates from other countries were tested against aztreonam-avibactam and comparators. All U.S. isolates were inhibited at aztreonam-avibactam MICs of ≤8 μg/ml (MIC50, ≤0.03 μg/ml; MIC90, 0.12 μg/ml), including Klebsiella pneumoniae carbapenemase-producing isolates (n = 102; MIC50, 0.25 μg/ml; MIC90, 0.5 μg/ml), multidrug-resistant isolates (n = 876; MIC50, 0.06 μg/ml; MIC90, 0.25 μg/ml), and extensively drug-resistant isolates (n = 111; MIC50, 0.12 μg/ml; MIC90, 0.5 μg/ml). The highest aztreonam-avibactam MIC value among ex-U.S. isolates was 4 μg/ml.

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  • Antimicrobial activity of manogepix, a first-in-class antifungal, and comparator agents tested against contemporary invasive fungal isolates from an international surveillance programme (2018–2019)
    'Elsevier BV', 2021
    Co-Authors: Michael A Pfaller, Michael D Huband, Robert K Flamm, Paul A. Bien, Mariana Castanheira
    Abstract:

    ABSTRACT: Objectives: : Manogepix, the active moiety of the prodrug fosmanogepix, is a novel antifungal with activity against major fungal pathogens including Candida (except Candida krusei), Aspergillus and difficult-to-treat/rare moulds. We tested manogepix and comparators against 2669 contemporary (2018–2019) fungal isolates collected from 82 medical centres in North America (42.3%), Europe (37.9%), Asia-Pacific (12.3%) and Latin America (7.6%). Of these, 70.7% were Candida spp., 3.6% were non-Candida yeasts including 49 Cryptococcus neoformans var. grubii, 21.7% were Aspergillus spp. and 4.1% were other moulds. Methods: Isolates were tested for antifungal susceptibility by the CLSI reference broth microdilution method. Results: Manogepix (MIC50/90, 0.008/0.06 mg/L) was the most active agent tested against Candida spp. isolates; corresponding anidulafungin, micafungin and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, manogepix (MIC50/90, 0.5/2 mg/L) was ≥4-fold more active than anidulafungin, micafungin and fluconazole against C. neoformans var. grubii. Against Aspergillus spp., manogepix (MEC50/90, 0.015/0.03 mg/L) had comparable activity to anidulafungin and micafungin. Low manogepix concentrations inhibited uncommon species of Candida, non-Candida yeasts, and rare moulds including Scedosporium spp. and Lomentospora (Scedosporium) prolificans. Conclusion: Manogepix exhibited potent activity against contemporary fungal isolates, including echinocandin- and azole-resistant strains of Candida and Aspergillus spp., respectively. Although rare, Candida strains that were non-wild type for manogepix demonstrated resistance to fluconazole. However, the clinical relevance of this finding is unknown. The extended spectrum of manogepix is noteworthy for its activity against many less-common yet antifungal-resistant strains. Clinical studies are underway to evaluate the utility of fosmanogepix against difficult-to-treat resistant fungal infections

  • in vitro activity of minocycline against u s isolates of acinetobacter baumannii acinetobacter calcoaceticus species complex stenotrophomonas maltophilia and burkholderia cepacia complex results from the sentry antimicrobial surveillance program 2014 to 2018
    Antimicrobial Agents and Chemotherapy, 2019
    Co-Authors: Robert K Flamm, Helio S Sader, Mariana Castanheira, Dee Shortridge, Michael A Pfaller
    Abstract:

    We evaluated the activity of minocycline and comparator agents against a large number of Stenotrophomonas maltophilia (n = 1,289), Acinetobacter baumannii-Acinetobacter calcoaceticus species complex (n = 1,081), and Burkholderia cepacia complex (n = 101) isolates collected from 2014 to 2018 from 87 U.S. medical centers spanning all 9 census divisions. The isolates were collected primarily from hospitalized patients with pneumonia (1,632 isolates; 66.0% overall), skin and skin structure infections (354 isolates; 14.3% overall), bloodstream infections (266 isolates; 10.8% overall), urinary tract infections (126 isolates; 5.1% overall), intra-abdominal infections (61 isolates; 2.5% overall), and other infections (32 isolates; 1.3% overall). Against the A. baumannii-A. calcoaceticus species complex, colistin was the most active agent, exhibiting MIC50/90 values at ≤0.5/2 μg/ml and 92.4% susceptibility. Minocycline ranked second in activity, with MIC50/90 values at 0.25/8 μg/ml and susceptibility at 85.7%. Activity for these two agents was reduced against extensively drug-resistant and multidrug-resistant isolates of the Acinetobacter baumannii-Acinetobacter calcoaceticus species complex. Only two agents showed high levels of activity (susceptibility, >90%) against S. maltophilia, minocycline (MIC50/90, 0.5/2 μg/ml; 99.5% susceptible) and trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/1 μg/ml; 94.6% susceptible). Minocycline was active against 92.8% (MIC90, 4 μg/ml) of trimethoprim-sulfamethoxazole-resistant S. maltophilia isolates. Various agents exhibited susceptibility rates of nearly 90% against the B. cepacia complex isolates; these were trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/2 μg/ml; 93.1% susceptible), ceftazidime (MIC50/90, 2/8 μg/ml; 91.0% susceptible), meropenem (MIC50/90, 2/8 μg/ml; 89.1% susceptible), and minocycline (MIC50/90, 2/8 μg/ml; 88.1% susceptible). These results indicate that minocycline is among the most active agents for these three problematic potential pathogen groups when tested against U.S. isolates.

  • surveillance of omadacycline activity tested against clinical isolates from the united states and europe as part of the 2016 sentry antimicrobial surveillance program
    Antimicrobial Agents and Chemotherapy, 2018
    Co-Authors: Michael A Pfaller, Michael D Huband, Dee Shortridge, Robert K Flamm
    Abstract:

    Omadacycline was tested against 21,000 bacterial isolates collected prospectively from medical centers in Europe and the United States during 2016. Omadacycline was active against Staphylococcus aureus (MIC50/MIC90, 0.12/0.25 mg/liter), including methicillin-resistant S. aureus (MRSA); streptococci (MIC50/MIC90, 0.06/0.12 mg/liter), including Streptococcus pneumoniae, viridans group streptococci, and beta-hemolytic streptococci; Enterobacteriaceae, including Escherichia coli (MIC50/MIC90, 0.5/2 mg/liter); Haemophilus influenzae (MIC50/MIC90, 1/1 mg/liter); and Moraxella catarrhalis (MIC50/MIC90, 0.25/0.25 mg/liter). Omadacycline merits further study in serious infections where resistant pathogens may be encountered.

  • antimicrobial activities of aztreonam avibactam and comparator agents against contemporary 2016 clinical enterobacteriaceae isolates
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Rodrigo E Mendes, Michael A Pfaller, Dee Shortridge, Robert K Flamm, Mariana Castanheira
    Abstract:

    A total of 10,451 contemporary (2016) Enterobacteriaceae isolates from 84 U.S. medical centers and 116 metallo-β-lactamase- and/or OXA-48-like-producing Enterobacteriaceae isolates from other countries were tested against aztreonam-avibactam and comparators. All U.S. isolates were inhibited at aztreonam-avibactam MICs of ≤8 μg/ml (MIC50, ≤0.03 μg/ml; MIC90, 0.12 μg/ml), including Klebsiella pneumoniae carbapenemase-producing isolates (n = 102; MIC50, 0.25 μg/ml; MIC90, 0.5 μg/ml), multidrug-resistant isolates (n = 876; MIC50, 0.06 μg/ml; MIC90, 0.25 μg/ml), and extensively drug-resistant isolates (n = 111; MIC50, 0.12 μg/ml; MIC90, 0.5 μg/ml). The highest aztreonam-avibactam MIC value among ex-U.S. isolates was 4 μg/ml.

  • activity of a long acting echinocandin cd101 and comparator antifungal agents tested against contemporary worldwide invasive fungal isolates
    Open Forum Infectious Diseases, 2016
    Co-Authors: Michael A Pfaller, S A Messer, Paul R Rhomberg, Sarah E Costello, Mariana Castanheira
    Abstract:

    Background: Echinocandins are important agents for treatment of invasive fungal infections. We evaluated the activity of CD101, a once-weekly echinocandin with extended half-life, and comparators against 606 invasive fungal isolates collected worldwide during 2014 using CLSI broth microdilution methods. Methods: 531 Candida spp. (7 species), 19 C. neoformans (CNEO) and 56 A. fumigatus (ASF) were susceptibility (S) tested for CD101, anidulafungin (ANF), caspofungin (CSF), micafungin (MCF) and azoles. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied. Isolates displaying echinocandin MIC>ECV were sequenced for fks hot spot (HS) mutations. Results: The activity of CD101 was similar to that of other echinocandins (Table). All C. albicans (CA), C. tropicalis (CTRO), C. krusei and C. dubliniensis (n=11) were inhibited by ≤0.12 μg/ml of CD101 and were S/wild-type to other echinocandins using CBP/ECV. Five C. glabrata (CGLA) displayed CD101 MIC >0.12 μg/ml (MIC, 1-4 μg/ml), elevated CSF (2->8 μg/ml), ANF (2-4 μg/ml) and MCF (2-4 μg/ml) results and carried mutations on fks1 HS1 S629P (3 isolates/2 also had HS2 S663P), HS2 F659S (1) or S663P (3 isolates). C. parapsilosis (CPRP; n=92) and C. orthopsilosis (n=10) displayed higher MIC values (ranges 0.5-4 and 0.12-2 μg/ml, respectively), but similar results were observed for other echinocandins. Fluconazole resistance was noted among 11.0% of CGLA, 4.3% CPRP and 2.0% CA and CTRO. Echinocandins had limited activity against CNEO. CD101 activity against ASF was similar to that of MCF, two-fold greater than CSF, but less than ANF. These moulds displayed MIC values below ECVs for the mould-active azoles (itraconazole, voriconazole and posaconazole). Conclusions: CD101 was as active as other echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life profile is very desirable for prevention and treatment of serious fungal infections, especially in patients that can then be discharged. INTRODUCTION Despite the broad utilization of echinocandins to treat invasive candidiasis (IC) in critically ill hospitalized patients, clinical resistance to these agents remains uncommon, although both breakthrough infections and acquired resistance mutations in some species of Candida have been noted. Whereas the currently available echinocandins are highly efficacious and relatively easy to use in the treatment of IC and other invasive fungal infections (IFI), they must be administered daily by intravenous infusion, potentially prolonging the hospitalization of patients undergoing therapy and limiting their use to the inpatient setting. The availability of an echinocandin with activity that is comparable to those presently in use but with a pharmacokinetic (PK) profile that allows for less frequent administration, would alter the standard-of-care therapy (e.g., echinocandin therapy) to be more easily administered in both inpatient and outpatient settings. CD101 IV is a novel echinocandin antifungal agent that displays chemical stability in plasma, aqueous solution, and at elevated temperature as well as possessing a long-acting PK. CD101 IV is being developed for once-weekly IV administration for the treatment and prevention of serious fungal infections. Less frequent administration while maintaining high exposure would alter hospital stays, improve compliance for outpatients and provide more convenient outpatient prophylaxis or maintenance treatment regimens. In the presented study, we determined the activity and potency of CD101 and comparator antifungal agents tested against 606 clinical fungal isolates collected worldwide from IFI (2014). MATERIALS AND METHODS Fungal organisms. A total of 606 non-duplicate prospectively collected fungal isolates from 38 medical centers located in North America (161 isolates; 10 sites), Europe (294; 17), the Asia-Pacific Region (82; 6) and Latin America (69; 5) were evaluated. Isolates selected were from the following sources: bloodstream, (379 strains), normally sterile body fluids, tissues or abscesses (22 strains), respiratory tract specimens (96 strains) and 109 were collected from other or non-specified body sites. Species identification. Yeast isolates were subcultured and screened using CHROMagar Candida (Becton Dickinson, Sparks, Maryland USA) to ensure purity and to differentiate Candida albicans/Candida dubliniensis, Candida tropicalis and Candida krusei. Isolates suspected to be either C. albicans or C. dubliniensis (green colonies on CHROMagar) were incubated at 45°C. All other yeast isolates were submitted to Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) using the MALDI Biotyper according to the manufacturer’s instructions (Bruker Daltonics, Billerica, Massachusetts USA). Isolates that were not identified by either phenotypic or proteomic methods were identified using sequencing-based methods as previously described. Antifungal susceptibility testing. All isolates were tested by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) methods outlined in documents M27-A3 and M38-A2. Frozen-form panels used RPMI 1640 broth supplemented with MOPS (morpholinepropane sulfonic acid) buffer and 0.2% glucose and inoculated with 0.5 to 2.5 X 103 cells/ml suspensions. MIC/MEC values were determined visually, after 24, 48 or 72 hours of incubation at 35oC, as the lowest concentration of drug that resulted in ≥50% inhibition of growth relative to the growth control or complete (100%) inhibition. CLSI clinical breakpoints were used for the five most common species of Candida (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) for echinocandins, fluconazole and voriconazole. Epidemiological cutoff values (ECV) were applied when available. Quality control was performed as recommended in CLSI documents M27-A3 and M38-A2 using strains C. krusei ATCC 6258, C. parapsilosis ATCC 22019, A. flavus ATCC 204304 and A. fumigatus MYA-3626. RESULTS • CD101 (MIC50/90, 0.03/0.06 μg/ml) inhibited all 251 C. albicans isolates at ≤0.12 μg/ml (Table 1). This compound displayed activity most similar to that of caspofungin (MIC50/90, 0.03/0.06 μg/ml). • CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml) inhibited 95 (95.0%) of the C. glabrata isolates at ≤0.12 μg/ml (Table 1). The activity of this investigational echinocandin was two-fold greater when compared to anidulafungin or caspofungin (MIC50 and MIC90, 0.06 and 0.12 μg/ml for both compounds) and two-fold less than the activity of micafungin (MIC50 and MIC90, 0.015 and 0.03 μg/ml; Table 1). • All C. parapsilosis isolates were inhibited by CD101 (MIC50 and MIC90, 1 and 2 μg/ml) at ≤4 μg/ml (Table 1). CD101 displayed similar activity to that of micafungin (MIC50/90, 1/2 μg/ml), slightly greater activity when compared to anidulafungin (MIC50/90, 2/4 μg/ml) and was two-fold less active than caspofungin (MIC50/90, 0.5/1 μg/ml; Table 1). • C. tropicalis isolates (n=51) were considered susceptible to the clinically available echinocandins and CD101 (MIC50/90, 0.015/0.06 μg/ml) inhibited all isolates at ≤0.06 μg/ml (Table 1). • CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml) was very active against 16 C. krusei and all isolates were inhibited at ≤0.06 μg/ml (Table 1). • The activity of CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml; Table 1) against C. dubliniensis isolates was comparable to that of caspofungin (MIC50 and MIC90, 0.03 and 0.06 μg/ml). • CD101 (MIC50 and MIC90, 0.5 and 1 μg/ml) activity against C. orthopsilosis was similar to the activity of anidulafungin and micafungin (MIC50/90, 0.5/1 μg/ml for both). Caspofungin was two-fold more active against C. orthopsilosis isolates (MIC50 and MIC90, 0.25 and 0.5 μg/ml; Table 1) when compared to other echinocandins. • The echinocandins, including CD101, had limited activity against C. neoformans var. grubii isolates (n=19; Table 1); all isolates had MIC values at ≥8 μg/ml for these compounds. • Echinocandins displayed good activity against A. fumigatus; CD101 (MEC50 and MEC90, 0.015 and 0.015 μg/ml) activity was two-fold greater than that of caspofungin (MEC50/90, 0.03/0.03 μg/ml) and similar to that of micafungin. Anidulafungin (MEC50/90, ≤0.008/0.015 μg/ml; Table 1) was slightly more active than the other compounds from the same class. • Among the five C. glabrata isolates displaying resistant MIC results for clinically available echinocandins, one harbored a mutation on fks1 HS1 encoding alteration S629P and another two carried alterations on fks2 HS1 F659S or S663P. The two remaining isolates were collected from the same patient in Edmonton, Canada and both strains carried alterations on fks1 HS1 S629P and fks2 HS1 S663P conferring elevated caspofungin MIC results (>8 μg/ml) and MIC results of 2-4 μg/ml for CD101, anidulafungin and micafungin (Table 2). • The activity of comparator agents tested against organisms/organism groups is displayed in Figure 1. Fluconazole resistance was noted among 2.0% of C. albicans and C. tropicalis, 11.0% of C. glabrata and 4.3% of C. parapsilosis. All C. neoformans var. grubii and A. fumigatus isolates were considered wild-type for the azoles. CONCLUSIONS • The activity of CD101 tested by reference methods against common fungal species isolated from invasive infections worldwide during 2014 was comparable to currently available echinocandins. • Further evaluation of CD101 against less common species is recommended, and expanded clinical development of this long-acting echinocandin is warranted.