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A total of 35,360 Enterobacterales isolates were consecutively collected from 75 US medical centers in 2018-2022. Among these isolates, 2612 (7.4%) were categorized as multidrug-resistant (MDR). Isolates were susceptibility tested by reference broth microdilution methods. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemase (CPE) genes by whole genome sequencing. The highest MDR rates was observed among Klebsiella pneumoniae (12.2%), followed by Raoultella spp. (10.9%) and Providencia stuartii (9.8%). Ceftazidime-avibactam and meropenem-vaborbactam were very active and showed identical susceptibility rates against MDR isolates (97.9%). Imipenem-relebactam (93.5% susceptible [S]) exhibited slightly lower susceptibility rates due to its limited activity against Morganellaceae family. The most active β-lactamase inhibitor combination (BLI) against CRE isolates (n = 310) was ceftazidime-avibactam (84.2%S), followed by meropenem-vaborbactam (81.9%S) and imipenem-relebactam (74.8%S). All 3 BLIs were very active against KPC producers and none were active against MBL producers. Ceftazidime-avibactam exhibited greater activity against OXA-48-type producers than meropenem-vaborbactam and imipenem-vaborbactam., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ceftaroline and comparators were tested against 9,268 Staphylococcus aureus isolates from 33 United States hospitals (2018-2020). Ceftaroline (MIC 50/90 , 0.25/1 mg/L) susceptibility ranged from 95.4% (pneumonia) to 98.5% (skin and skin structure) and was 97.2% overall. Ceftaroline retained potent and broad-spectrum activity against methicillin-resistant isolates, with a 93.4% overall susceptibility., (Copyright © 2022. Published by Elsevier Inc.)

As bone and joint infections (BJIs) frequently require prolonged, systemic antibiotic use, tedizolid is an attractive candidate for BJI therapy in adults and children. Tedizolid activity was evaluated against 1,193 Gram-positive isolates causing BJI in American (USA), European (EUR), Latin American (LATAM), and Asian-Pacific (APAC) medical centers. Isolates consecutively collected from 2015 to 2019 were susceptibility tested by CLSI broth microdilution. Staphylococcus aureus (69.2%) was the most common pathogen with a 25.9% MRSA rate and tedizolid MIC 50/90 of 0.12/0.25 mg/L (100% susceptible). Tedizolid exhibited MIC 50/90 values of 0.12/0.12 mg/L (98.9% susceptible) for CoNS (7.5% of BJI), 0.12/0.25 mg/L for streptococci, and 0.25/0.25 mg/L for enterococci. Overall, high susceptibility rates (100.0%) for linezolid, daptomycin, and vancomycin were observed. In summary, tedizolid had potent in vitro activity against contemporary Gram-positive cocci causing BJI in adults and children in USA, EUR, LATAM, and APAC hospitals., Competing Interests: Declaration of Competing Interest Cecilia Carvalhaes, Michael Pfaller, Rodrigo Mendes, and Jennifer Streit: Funding - This study was performed by JMI Laboratories and supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA., which included funding for services related to preparing this manuscript. Grants - JMI Laboratories was contracted to perform services in 2015-2019 for Achaogen, Inc., Albany College of Pharmacy and Health Sciences, Allecra Therapeutics, Allergan, AmpliPhi Biosciences Corp., Amicrobe Advanced Biomaterials, Amplyx, Antabio, American Proficiency Institute, Arietis Corp., Arixa Pharmaceuticals, Inc., Astellas Pharma Inc., Athelas, Basilea Pharmaceutica Ltd., Bayer AG, Becton, Dickinson and Company, bioMerieux SA, Boston Pharmaceuticals, Bugworks Research Inc., CEM-102 Pharmaceuticals, Cepheid, Cidara Therapeutics, Inc., CorMedix Inc., DePuy Synthes, Destiny Pharma, Discuva Ltd., Dr. Falk Pharma GmbH, Emery Pharma, Entasis Therapeutics, Eurofarma Laboratorios SA, US Food and Drug Administration, Fox Chase Chemical Diversity Center, Inc., Gateway Pharmaceutical LLC, GenePOC Inc., Geom Therapeutics, Inc., GlaxoSmithKline plc, Harvard University, Helperby, HiMedia Laboratories, F. Hoffmann-La Roche Ltd., ICON plc, Idorsia Pharmaceuticals Ltd., Iterum Therapeutics plc, Laboratory Specialists, Inc., Melinta Therapeutics, Inc., Merck & Co., Inc., Microchem Laboratory, Micromyx, MicuRx Pharmaceuticals, Inc., Mutabilis Co., Nabriva Therapeutics plc, NAEJA-RGM, Novartis AG, Oxoid Ltd., Paratek Pharmaceuticals, Inc., Pfizer, Inc., Polyphor Ltd., Pharmaceutical Product Development, LLC, Prokaryotics Inc., Qpex Biopharma, Inc., Roivant Sciences, Ltd., Safeguard Biosystems, Scynexis, Inc.,SeLux Diagnostics, Inc., Shionogi and Co., Ltd., SinSa Labs, Spero Therapeutics, Summit Pharmaceuticals International Corp., Synlogic, T2 Biosystems, Inc., Taisho Pharmaceutical Co., Ltd., TenNor Therapeutics Ltd., Tetraphase Pharmaceuticals, Theravance Biopharma, University of Colorado, University of Southern California-San Diego, University of North Texas Health Science Center, VenatoRx Pharmaceuticals, Inc., Viosera Therapeutics, Vyome Therapeutics Inc., Wockhardt, Yukon Pharmaceuticals, Inc., Zai Lab, Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Bone and joint infections (BJIs) present significant treatment challenges. Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus, is approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. In this study, the in vitro activity of ceftobiprole and comparators was evaluated against clinical isolates collected from BJIs in the USA from 2016 to 2020. Gram-positive pathogens made up 70.6% of all BJI isolates and included S. aureus (47.4% of all isolates), β-hemolytic streptococci, coagulase-negative staphylococci, and Enterococcus faecalis. Ceftobiprole was highly active against S. aureus (MIC 50/90 values, 0.5/1 mg/L; 99.6% susceptible using the European Committee on Antimicrobial Susceptibility Testing susceptibility breakpoint of ≤2 mg/L for the treatment of pneumonia patients) and exhibited potent activity against the other Gram-positive cocci and the predominant BJI Gram-negative groups. These results support the further evaluation of ceftobiprole for this potential indication., Competing Interests: Declaration of competing interest JIS is an employee of Basilea Pharmaceutica International Ltd. KAH was an employee of Basilea Pharmaceutica International Ltd. while this work was conducted. LRD, MAP, RKF, and REM have no conflicts to disclose. This study was funded in part by Basilea Pharmaceutica International Ltd., which was involved in the design and decision to present these results, and JMI Laboratories received compensation fees for services in relation to preparing the manuscript. JMI Laboratories contracted to perform services in 2021 for AbbVie Inc., Affinity Biosensors, AimMax Therapeutics, Inc., Alterity Therapeutics, Amicrobe, Inc., Arietis Pharma, Armata Pharmaceuticals, Inc., Astellas Pharma Inc., Basilea Pharmaceutica AG, Becton, Dickinson and Company (BD), bioMérieux, Inc., Boost Biomes, Brass Dome Ventures Ltd., Bravos Biosciences, Bugworks Research Inc., Centers for Disease Control and Prevention, Cerba Research, Cidara Therapeutics, Cipla Ltd., ContraFect Corp., CXC7, Diamond V, Enveda Biosciences, Fedora Pharmaceuticals, Inc., Fimbrion Therapeutics, First Light Diagnostics, Forge Therapeutics, Inc., Fox Chase Cancer Center, GlaxoSmithKline plc (GSK), Harvard University, Institute for Clinical Pharmacodynamics (ICPD), International Health Management Associates (IHMA), Inc., Iterum Therapeutics plc, Janssen Research & Development, Johnson & Johnson, Kaleido Biosciences, Inc., Laboratory Specialists, Inc. (LSI), Meiji Seika Pharma Co., Ltd., Melinta Therapeutics, Menarini Group, Merck & Co., Inc., MicuRx Pharmaceuticals Inc., Mutabilis, Nabriva Therapeutics, National Institutes of Health, Novome Biotechnologies, Omnix Medical Ltd., Paratek Pharma, Pattern Bioscience, Pfizer Inc., Prokaryotics Inc., Pulmocide Ltd., QPEX Biopharma, Inc., Roche Holding AG, Roivant Sciences, SeLux Diagnostics, Inc., Shionogi Inc., Sinovent Pharmaceuticals, Inc., SNIPR Biome ApS, Spero Therapeutics, Summit Therapeutics, Inc., T2 Biosystems, TenNor Therapeutics, Thermo Fisher Scientific, University of Southern California, University of Wisconsin, USCAST, U.S. Food and Drug Administration, Venatorx Pharmaceuticals, Inc., Weill Cornell Medicine, and Wockhardt Ltd., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to evaluate the in vitro activity of aztreonam plus imipenem-relebactam against clinical and isogenic strains of Escherichia coli and Klebsiella pneumoniae co-harboring NDM and >1 serine β-lactamase., Methods: Thirteen isolates were included: 4 clinical E. coli, 4 clinical K. pneumoniae, and 5 isogenic E. coli. Drugs were tested in time-kill analyses alone, in dual β-lactam combinations, and in triple drug combinations against all strains., Results: All isolates were resistant to imipenem and imipenem-relebactam, and 85% were aztreonam-resistant. Neither imipenem nor imipenem-relebactam was bactericidal alone while aztreonam was bactericidal against 54% of isolates. The combination of aztreonam+imipenem was bactericidal and synergistic against 7/13 and 10/13 isolates. The addition of relebactam to this combination resulted in synergy against all 11 aztreonam-resistant clinical isolates., Conclusion: Aztreonam plus imipenem-relebactam may be a viable treatment option for aztreonam-non-susceptible NDM and serine β-lactamase-producing E. coli and K. pneumoniae., Competing Interests: Declaration of competing interest E.W. serves on the speaker's bureau for Astellas Pharma, Melinta Therapeutics, and Allergan Plc and on the advisory board for GenMark Diagnostics and Shionogi. All other authors certify no potential conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We evaluated the antimicrobial susceptibility of Gram-negative bacteria recovered from ICU patients in US hospitals and compared them to those from non-ICU patients from the same hospitals during the same period. Overall, 4,680 isolates from ICU patients and 16,263 isolates from non-ICU patients were collected from 70 US medical centers in 2018-2020 and susceptibility tested by the broth microdilution method. Ceftazidime-avibactam and ceftolozane-tazobactam were the most active agents against P. aeruginosa and retained activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) isolates. Minocycline and trimethoprim-sulfamethoxazole were very active against S. maltophilia, whereas most antimicrobial agents exhibited low susceptibility to A. baumannii. Ceftazidime-avibactam and meropenem-vaborbactam were the most active agents against Enterobacterales, and retained potent activity against ESBL producers, carbapenem-resistant Enterobacterales (CRE), MDR, and XDR isolates. In summary, antimicrobial susceptibility was generally lower and the occurrence of ESBL, CRE, MDR, and XDR phenotypes were clearly higher among ICU compared to non-ICU isolates., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

A patient with a history of UTI acquired an isolate of Staphylococcus saprophyticus that was resistant to clindamycin, streptogramin A, pleuromutilins (LSPs), and oxacillin. A plasmid-located vga variant was identified in this pathogen, and the encoded protein showed a 39% to 67% identity to other previously characterized vga., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study updates dalbavancin activity against contemporary (2017-2019) isolates of indicated species/groups (n = 16,451). Isolates from 71 hospitals were tested by broth microdilution method. All isolates were susceptible to dalbavancin. Dalbavancin MIC 50/90 values remained stable for Staphylococcus aureus, vancomycin-susceptible Enterococcus faecalis, β-hemolytic streptococci, and Streptococcus anginosus group since its clinical approval., (Copyright © 2020. Published by Elsevier Inc.)

This study evaluated the in vitro activity of KHP-3757 (a novel LpxC inhibitor) and comparator agents against recent, geographically diverse, Pseudomonas aeruginosa isolates from a global surveillance program as well as molecularly characterized extended-spectrum-β-lactamase-positive, metallo-β-lactamase-positive, and colistin-resistant strains. KHP-3757 (MIC 50/90 , 0.25/0.5 mg/L; 97.4% inhibited at ≤0.5 mg/L) demonstrated potent in vitro activity based on MIC 90 values against P. aeruginosa isolates including extended-spectrum-β-lactamase-positive, metallo-β-lactamase-positive, and colistin-resistant strains outperforming other comparator agents., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Studies evaluating large series of pediatric patients with bloodstream infections (BSIs) are scarce. We evaluated the frequency and antimicrobial susceptibility of organisms isolated from pediatric patients with BSI and therapeutic options for BSI caused by multidrug-resistant (MDR) organisms. A total of 2423 organisms were consecutively collected from 33 US medical centers between 2014 and 2018, and susceptibility was tested by reference broth microdilution methods. Isolates with an extended-spectrum β-lactamase phenotype were screened for β-lactamase genes. Overall, 40.2% of organisms were Gram-negative bacteria, 57.0% Gram-positives, and 2.8% Candida spp. The 5 most common organisms were Staphylococcus aureus (26.0%), Escherichia coli (13.0%), coagulase-negative staphylococci (8.3%), Enterococcus faecalis (7.1%), and Klebsiella pneumoniae (6.9%). Among S. aureus, 26.0% were oxacillin-resistant and 99.8% were susceptible to ceftaroline (MIC 50/90 , 0.25/0.5 mg/L). Enterobacterales and Pseudomonas aeruginosa isolates combined represented >85% of Gram-negative bacteria, and all isolates (100.0%) were susceptible to ceftazidime-avibactam., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We evaluated different susceptibility testing media against 200 Klebsiella pneumoniae isolates that have been genetically characterized for the presence of polymyxin resistance mechanisms. The media evaluated included calcium enriched media that was described to promote separation of mcr-carrying Enterobacterales isolates and standard cation-adjusted Mueller-Hinton broth with and without polysorbate 80. The testing conditions evaluated did not show improvement in the separation of isolates carrying MgrB alterations and other mutation-driven polymyxin resistance mechanisms., (Copyright © 2020. Published by Elsevier Inc.)

Omadacycline and tigecycline MIC 90 values were 2 μg/mL and 0.25 μg/mL, respectively, against Staphylococcus aureus carrying tet(M), whereas the minocycline, tetracycline, and doxycycline values were > 8 μg/mL. Similarly, omadacycline and tigecycline remained active against Enterococcus faecalis and Streptococcus pneumoniae harboring tet(L)and/or tet(M)(MIC 90 , 0.06-0.25 μg/mL), whereas other tetracyclines were inactive (MIC 90 , >8 μg/mL). Omadacycline and tigecycline remained more potent than minocycline, tetracycline, and doxycycline against Enterobacteriaceae carrying tet. This study demonstrates the effectiveness of modern tetracyclines, omadacycline, and tigecycline against isolates with tetracycline resistance genes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ceftobiprole medocaril, the prodrug of ceftobiprole, is an advanced-generation cephalosporin that is approved in many European and non-European countries for the treatment of adults with hospital-acquired pneumonia (excluding ventilator-associated pneumonia) and community-acquired pneumonia and is currently being evaluated in a global phase 3 clinical trial of patients with Staphylococcus aureus bacteremia. This study investigated the in vitro activity of ceftobiprole and comparators against a total of 5466 gram-positive and -negative isolates from bloodstream infections (BSIs) that were collected in the United States during 2016 and 2017 as part of the SENTRY Antimicrobial Surveillance Program. Ceftobiprole was highly active (isolates were >99% susceptible) against S. aureus (including methicillin-resistant S. aureus), coagulase-negative staphylococci, Enterococcus faecalis, streptococci, and non-extended-spectrum β-lactamase (non-ESBL) phenotype Enterobacteriaceae. As expected, lower activities were observed against Enterococcus faecium, ESBL-phenotype Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. These results support further clinical evaluation of ceftobiprole for the treatment of BSIs caused by susceptible organisms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aminoglycoside-nonsusceptible isolates of Escherichia coli, Klebsiella, Proteus, and Enterobacter species (480/3675) from US hospitals collected during 2014-2015 were screened for 16S rRNA methyltransferase and aminoglycoside-modifying enzyme (AME) genes. Only 5 isolates had high aminoglycoside MICs and carried 16S rRNA methyltransferases. AME genes were observed among 89.7% (426/475) of isolates and the most common genes were aac(3)-IIa (n = 270) and aac(6')-Ib (n = 269). Among other genes, ant(2″)-Ia, aac(3)-Iva, and aph(3')-VIa were observed among 36, 23, and 3 isolates, respectively. Forty-nine (10.3%) isolates yielded negative results for the investigated AME genes. Plazomicin (MIC 50/90 , 0.5/1 μg/ml) inhibited 99.3% of the AME-carrying isolates at its susceptible breakpoint while amikacin, gentamicin, and tobramycin inhibited 90.1%, 20.9%, and 18.3%, respectively. Plazomicin was approved by the US Food and Drug Administration in June 2018 for the treatment of complicated urinary tract infections when limited treatment options are available. This agent displayed activity against isolates carrying AMEs that were resistance to other aminoglycosides and comparator agents., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pneumonia and skin and skin structure infections (SSSIs) caused by S. aureus can lead to serious bloodstream infections (BSIs). This study reports on potent telavancin in vitro activity (MIC 90 , 0.06 μg/mL; 100% susceptible) against 674 US S. aureus causing pneumonia or SSSI with associated BSI in hospitalized patients during 2012-2016., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Staphylococcus lugdunensis and Staphylococcus haemolyticus are unique among CoNS in that the former often causes aggressive disease, while the latter consistently exhibits high rates of multidrug resistance. We evaluated the in vitro susceptibility of contemporary (2012-2013) isolates from both pathogens to tedizolid and comparators, using standard methodology. Results were interpreted using CLSI and EUCAST breakpoints. Overall, 106 S. lugdunensis and 103 S. haemolyticus isolates were collected from 51 medical centers in the United States and 30 centers in 18 European countries. Tedizolid showed good activity against S. lugdunensis (MIC 50 /MIC 90 : 0.12/0.12 mg/L) and S. haemolyticus (MIC 50 /MIC 90 : 0.12/0.12 mg/L), inhibiting all isolates at MIC ≤0.25 mg/L. Based on the EUCAST breakpoint for staphylococci and when substituting the CLSI breakpoint for Staphylococcus aureus, all isolates were tedizolid susceptible. All isolates were also susceptible to linezolid, but the in vitro potency of tedizolid was 4-fold greater than that of linezolid against both S. lugdunensis and S. haemolyticus, based on MIC 90 values. S. lugdunensis exhibited ≥99% susceptibility to vancomycin, teicoplanin, gentamicin, levofloxacin, and trimethoprim-sulfamethoxazole; 7% of isolates were resistant to tetracycline, 11% to clindamycin, and 2% were methicillin-resistant. S. haemolyticus exhibited high rates of resistance to commonly used anti-staphylococcal agents: 71% of isolates were resistant to methicillin, 36%-37% to clindamycin, and 30%-50% to gentamicin. These in vitro findings suggest that tedizolid could be an alternative treatment option for infections due to these medically important CoNS pathogens. Additional clinical evaluation and continued surveillance of tedizolid in vitro activity against S. lugdunensis and S. haemolyticus are warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The in vitro activity of oritavancin was assessed against 44,715 gram-positive pathogens causing infections in European and United States (US) hospitals (2010-2014). There were no substantive differences (>±2-fold dilution) in oritavancin MIC 50 or MIC 90 values for different species/organism groups over time or by region. Oritavancin (99.9% susceptible) showed modal MIC, MIC 50 , and MIC 90 results of 0.03, 0.03, and 0.06-0.12 mg/L when tested against Staphylococcus aureus, regardless of methicillin susceptibility, year, or region. Coagulase-negative staphylococci from the US and Europe demonstrated equal MIC 50 values for oritavancin (MIC 50 , 0.03 mg/L). Oritavancin inhibited 99.9% of Enterococcus faecalis and all E. faecium at ≤0.5 mg/L, including vancomycin-resistant isolates. Oritavancin exhibited MIC 50 results of 0.03 and ≤0.008 mg/L when tested against β-hemolytic and viridans group streptococci isolates, respectively, regardless of geographical region. Oritavancin maintained potent activity in vitro against this contemporary collection of European and US gram-positive isolates over 5 years (2010-2014)., (Copyright © 2018. Published by Elsevier Inc.)

Telavancin was tested against a worldwide collection of Gram-positive pathogens (967) isolated from bone and joint infections (BJI). Most BJI isolates were from the United States (US) (49.9%) followed by Europe (26.4%), Latin America (LATAM; 14.4%), and Asia-Pacific (APAC; 9.3%). Organisms were tested by broth microdilution susceptibility methods. S. aureus (66.4%; range of 48.9% in APAC to 71.2% in LATAM) was the most common pathogen and had a 35.7% methicillin resistance (MRSA) rate and telavancin MIC 50/90 of 0.03/0.06μg/mL (100% susceptible). MRSA isolates that were daptomycin resistant (0.2%) were telavancin susceptible. CoNS (12.1% of BJI) had telavancin MIC 50/90 at 0.06/0.06μg/mL, and 13.7% were teicoplanin resistant. Enterococci had telavancin MIC 50/90 at 0.12/0.25μg/mL, but telavancin inhibited vancomycin-susceptible isolates at ≤0.25μg/mL. All streptococci were telavancin susceptible (MIC 90 , 0.03-0.06μg/mL). The in vitro results presented here warrant further investigations to access the role of telavancin for BJI/osteomyelitis treatment caused by Gram-positive cocci., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Oritavancin has been approved in the United States and European Union for the treatment of acute bacterial skin and skin structure infections caused by several Gram-positive pathogens including Staphylococcus aureus. In this study, the in vitro activity of oritavancin and comparator agents was assessed against 1008 isolates of contemporary invasive community- or healthcare-associated S. aureus (790 and 218 isolates, respectively). All sampled contemporary (2013-2014) S. aureus isolates were susceptible at ≤0.12μg/mL to oritavancin (MIC 50/90 values, 0.03/0.06μg/mL), regardless of origin or susceptibility phenotype., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Telavancin is approved in the United States and Europe for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia caused by Staphylococcus aureus. This study provides a current in vitro activity analysis for telavancin and comparators against 1353 United States S. aureus causing pneumonia in hospitalized patients during 2013-2014. Telavancin was found to exhibit potent activity (MIC 90 , 0.06μg/mL; 16-fold more active than vancomycin or linezolid) against all S. aureus isolates, including the HABP subset, multidrug-resistant isolates, and those less susceptible to vancomycin., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Among 8437 methicillin-resistant Staphylococcus aureus (MRSA) isolates collected from 143 medical centers in the United States (2012-2014), 7116 and 1321 were reported as community-acquired (CA) and hospital-acquired (HA) MRSA, respectively. CA-/HA-MRSA were most often isolated from patients with skin and skin structure infections (SSSI; 68.4/26.9%), pneumonia (13.7/49.0%) and bacteremia (10.0/17.7%). Overall, susceptibility rates were generally lower among HA-MRSA compared to CA-MRSA strains, especially for clindamycin (44.6 vs. 66.1%) and levofloxacin (21.4 vs. 35.5%). Also, susceptibility rates were lower for these two compounds among isolates from pneumonia compared to SSSI and bacteremia. Ceftaroline was broadly active against 98.0% of CA-MRSA and 94.3% of HA-MRSA (MIC50/90, 1μg/mL for both; no resistant isolate) overall, with little variation among infection type subsets., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A total of 1593 coagulase-negative staphylococci (CoNS) considered clinically significant were collected from 71 US medical centers in 2013-2014 and tested for susceptibility by CLSI broth microdilution methods. Species identification was performed by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Overall, 59.7% of isolates were oxacillin resistant (MRCoNS). Ceftaroline (MIC50/90, 0.25/0.5μg/mL) inhibited 99.2% of CoNS at ≤1μg/mL (susceptible breakpoint for Staphylococcus aureus), including 98.7% of MRCoNS, and the highest ceftaroline MIC value was 2μg/mL (13 isolates). Staphylococcus epidermidis represented 60.3% of the CoNS collection and was highly susceptible to ceftaroline (MIC50/90, 0.25/0.5μg/mL, 99.9% inhibited at ≤1μg/mL). All isolates of Staphylococcus capitis, Staphylococcus caprae, Staphylococcus hominis, Staphylococcus lugdunensis, Staphylococcus pettenkoferi, Staphylococcus simulans, and Staphylococcus warneri (MIC50/90, 0.06-0.25/0.25-0.5μg/mL) were inhibited at ceftaroline MIC of ≤1μg/mL. Staphylococcus haemolyticus represented only 4.8%, was atypically less susceptible to ceftaroline (MIC50/90, 0.5/2μg/mL, 87.0% inhibited at ≤1μg/mL), and accounted for 76.9% (10/13) of isolates with ceftaroline MIC >1μg/mL., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A total of 840 clinically relevant viridans group streptococci (VGS) isolates (1/patient episode) were collected from 71 US medical centers in 2013-2014. These organisms were tested for susceptibility by reference broth microdilution methods against ceftaroline and selected comparator agents. All isolates were speciated by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry and were primarily from skin/soft tissue (32.6%) and bloodstream (32.3%) infections. Ceftaroline was highly active against all VGS species/groups with MIC50 and MIC90 values ranging from ≤0.015 to 0.03μg/mL and ≤0.015 to 0.06μg/mL, respectively. The highest ceftaroline MIC value was only 0.5μg/mL (0.5% of strains) and ceftaroline (MIC50/90, 0.03/0.06μg/mL) was 8-fold more active than ceftriaxone (MIC50/90, 0.25/0.5μg/mL). The VGS groups most susceptible to ceftaroline were Streptococcus mutans and Streptococcus bovis (MIC90, ≤0.015μg/mL), whereas the highest ceftaroline MIC values were observed among Streptococcus mitis and Streptococcus sanguinis groups. In summary, ceftaroline exhibited potent in vitro activity against VGS, including many uncommonly isolated species/groups for which very limited susceptibility information is currently available to guide therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We evaluated the in vitro activity of tigecycline and selected comparator agents tested against carbapenem-resistant Enterobacteriaceae (CRE) isolated from European medical centers. A total of 14,286 clinically significant nonduplicate Enterobacteriaceae isolates were collected from 18 European countries in 2010-2013. Susceptibility testing was performed by CLSI broth microdilution method, and isolates with a meropenem or imipenem MIC at ≥4μg/mL were categorized as CRE. Selected CRE strains were screened for acquired carbapenemases by multiplex polymerase chain reaction and sequencing. Overall, 2.0% (280/14,286) of Enterobacteriaceae strains were CRE. The highest CRE occurrence was observed in Poland (17.3%; 70/405), followed by Italy (7.5%, 130/1,743), Greece (7.4%; 45/605), and Romania (5.0%; 8/157). The most common CRE species were Klebsiella pneumoniae (242; 86.4%) and Enterobacter cloacae (22; 7.9%), and the most common carbapenemases were KPC-2/3 (85.4%) and VIM-type (12.5%). Only tigecycline (88.6% susceptible) and colistin (73.9%) exhibited good in vitro activity (>70.0%) against CRE strains., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A total of 4533 isolates from community-acquired respiratory tract infections (CARTIs) and 8446 from skin and skin structure infections (SSSIs) were consecutively collected in 149 US medical centers in 2013. Strains were susceptibility tested by broth microdilution method against ceftaroline and numerous comparators. Ceftaroline (MIC(50/90), ≤0.015/0.12 μg/mL) was more potent than ceftriaxone (MIC(50/90), ≤0.06/1 μg/mL) against Streptococcus pneumoniae and highly active against ceftriaxone-nonsusceptible strains (n=201; MIC(90), 0.25 μg/mL). Ceftaroline was also very active against Haemophilus influenzae (MIC(50/90), 0.008/0.015 μg/mL), methicillin-susceptible (MIC(50/90), 0.25/0.25 μg/mL) and methicillin-resistant Staphylococcus aureus (MIC(50/90), 1/1 μg/mL), and β-hemolytic streptococci (highest MIC, 0.03 μg/mL). Ceftaroline exhibited good activity against non-extended-spectrum β-lactamase (ESBL) phenotype isolates of Klebsiella spp. and Escherichia coli (96.7% susceptible and MIC(90) of 0.25 μg/mL for both) but limited activity against ESBL phenotype isolates. In summary, ceftaroline exhibited potent in vitro activity against a large collection of bacterial isolates causing CARTI and SSSI in US medical centers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Dalbavancin (DAL) represents a recently approved addition for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Newly released antimicrobial agents are rarely found on commercial susceptibility testing devices, and surrogate testing may be an option for clinical microbiology laboratories. A total of 33,688 Staphylococcus aureus, 2800 viridans group streptococci (VGS), and 5722 β-hemolytic streptococci (BHS) were included in this cross-susceptibility (DAL versus vancomycin [VAN]) analysis as well as 4576 coagulase-negative staphylococci and 6515 enterococci (nonindicated species groups). Isolates were collected as part of the SENTRY Antimicrobial Surveillance Program for the United States (USA) and Europe (2011-2013). Susceptibility testing followed CLSI (M07-A9 and M100-S24) methods. USA Food and Drug Administration (DAL) and CLSI (VAN) breakpoint criteria were used for correlations between DAL and VAN susceptibility results. A categorical agreement (CA; susceptible) rate of 99.9% was observed between DAL and VAN when testing S. aureus. Only 48 (0.14%) very major (false-susceptible) errors were noted against VAN-susceptible isolates that displayed a DAL-nonsusceptible (MIC, 0.25 or 0.5 μg/mL) phenotype. When susceptible MIC correlations were analyzed against indicated BHS species (Streptococcus agalactiae and Streptococcus pyogenes), an overall CA rate of 97.7-100.0% was obtained. Complete (100.0%) CA was documented for S. pyogenes, as well as against all VGS isolates, including the indicated Streptococcus anginosus group (758 strains). In conclusion, high susceptible CA rates between DAL and VAN were observed when testing a contemporary collection of indicated clinical isolates found in ABSSSI. VAN-susceptible isolates can be inferred to be inhibited by DAL (97.7-100.0%) at the regulatory agency-approved susceptible interpretive breakpoint of ≤0.12 μg/mL., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The 2013 LEADER surveillance program monitored the in vitro activity of linezolid and comparator agents against Gram-positive bacteria at 60 medical centers in the United States. A total of 7183 pathogens were contributed from 6 predetermined pathogen groups. The groups were Staphylococcus aureus, coagulase-negative staphylococci, enterococci, Streptococcus pneumoniae, β-hemolytic streptococci, and viridans group streptococci. The MIC90 value for each of the 6 pathogen groups was 1 μg/mL. Susceptibility of "all organisms" to linezolid was 99.83%. Only 12 isolates (2 S. aureus, 3 Staphylococcus epidermidis, 1 Streptococcus sanguinis, 5 Enterococcus faecium, and 1 Enterococcus faecalis) were nonsusceptible to linezolid (0.17%). Three of these (2 S. aureus and 1 E. faecium) harbored the cfr resistance mechanism. The findings indicate that linezolid activity remains stable, although there are examples of clonal dissemination within several monitored institutions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A revised broth microdilution susceptibility testing method for telavancin was approved by the Food and Drug Administration (FDA). Telavancin activity was assessed against Gram-positive pathogens collected worldwide (2013) using the revised method. A total of 12,346 isolates from 90 sites were included as part of the Telavancin International Surveillance Program for the Americas, Europe, and Asia-Pacific. Telavancin had MIC50 and MIC90 values of 0.03 and 0.06 μg/mL, respectively, against staphylococci, regardless of methicillin susceptibility, and inhibited all Staphylococcus aureus at ≤0.12 μg/mL (revised FDA breakpoint). Telavancin was 8-fold more active than daptomycin (MIC50/90, 0.25/0.5 μg/mL) and 16- to 32-fold more active than vancomycin (MIC50/90, 1/1 μg/mL) and linezolid (MIC50/90, 1/1 μg/mL) against methicillin-resistant S. aureus. All 692 vancomycin-susceptible Enterococcus faecalis were inhibited by telavancin (MIC50/90, 0.12/0.12 μg/mL) at ≤0.25 μg/mL (FDA breakpoint), except for 1 strain (MIC, 0.5 μg/mL). All Enterococcus faecium and E. faecalis with telavancin MIC values of ≥0.5 and ≥1 μg/mL, respectively, had a VanA phenotype. A comparison data analysis based on the MIC90 demonstrated that telavancin was at least 8-fold more potent than comparators against vancomycin-susceptible enterococci. Streptococci showed telavancin MIC50 values of ≤0.015 μg/mL, except for Streptococcus agalactiae (MIC50, 0.03 μg/mL). These in vitro results obtained by the recently approved susceptibility testing method establish a new benchmark of telavancin activity worldwide., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

This study evaluated pneumococci cultured from blood or lower respiratory tract specimens from hospitalized patients in the USA (all age groups) during 2011-2012 (N = 1190) and compared findings with those from a similar study performed in 2008 (N = 694). Isolates were tested for susceptibility by broth microdilution and serotypes determined by cpsB sequencing, supplemented with multiplex PCR and capsular swelling assays. Relative percentages of 7-valent pneumococcal conjugate vaccine (PCV7) types were 6.3 and 4.9% in 2008 and 2011-2012, respectively, and the most common PCV7 serotypes (19F and 6B) comprised only 3.7% and 4.0% of all isolates from both periods, respectively. Thirteen-valent pneumococcal conjugate vaccine (PCV13) serotypes represented 42.9% of isolates in 2008 and 30.1% in the second period, and this decrease was driven by 19A and 7F. Non-PCV13 serogroups/serotypes 23A, 15B/15C, 7C, 8, and 31 increased. Penicillin non-susceptibility rates were 9.6-10.0% and 38.9-42.7% when applying the parenteral (i.e. ≥ 4 μg/mL) and oral breakpoints (i.e. ≥ 0.12 μg/mL), respectively. Ceftaroline was the most potent agent tested based on MIC50 and MIC90 values (≤ 0.015 and 0.12 μg/mL, respectively) for both time periods., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In the European component of the Regional Resistance Surveillance study for 2011, a total of 21 countries were monitored for antimicrobial resistance patterns including Belgium, Bulgaria (BU), Croatia, Czech Republic, France (F), Germany (GE), Greece (GR), Ireland (IR), Israel (IS), Italy (IT), Poland (PO), Portugal (PT), Romania (RO), Russia (RU), Slovakia (SK), Slovenia, Spain, Sweden (SW), Turkey (T), Ukraine, and United Kingdom. Results from testing 12,572 strains (100 [BU] to 1535 [F] per nation) were interpreted by contemporary published breakpoints. Samples from 47 hospitals were reference tested against agents such as amikacin (AMK), cefoperazone/sulbactam (C/S), colistin (COL), levofloxacin, linezolid (LZD), tigecycline (TIG), vancomycin (VAN), and 21 others. Among Staphylococcus aureus, LZD (MIC90, 2 μg/mL), TIG (MIC90, 0.12 μg/mL), and VAN (MIC90, 1 μg/mL) exhibited complete coverage and methicillin resistance rates among nations (average, 31%) ranged from 0.9% (SW) to 60.0-60.2% (PT, SK). Seven LZD-resistant coagulase-negative staphylococci (only 1.1% resistance overall) were noted in 5 nations, and a Staphylococcus simulans strain (MIC, 8 μg/mL from RO) had L3 mutations (N130D, G152A, F147S, A157R); also 6 LZD-resistant enterococci were detected in 3 countries (GE, IR, T). VAN-resistant enterococci (10% overall; 84% VanA) were found in 14 countries, highest in GE and IR (23.0%). The ESBL phenotype rate for Escherichia coli was 20.1% (range, 0.9% [SW] to 70.0-89.7% [BU, RU]), best inhibited by COL (100.0% S), TIG (100.0%), AMK (83.3-94.1%), C/S (81.0%), and carbapenems (>99.0%; resistant strains in IS and T). Klebsiella spp. had greater ESBL rates (45.7% overall, range 2.5-100.0%), as well as carbapenem resistance (8.3% overall, greatest in BU, GR, IS, IT, PO, RO, RU, T). Non-fermentative Gram-negative bacilli (Pseudomonas aeruginosa, Acinetobacter [ACB]) were generally less susceptible, except against COL (99.2-99.6% S) and TIG (95.0% inhibited at ≤2 μg/mL; ACB only). The following carbapenemases were detected: VIM-1 (2 countries); IMP-1 (1 from T); KPC-2 or -3 (2 countries); VIM-4 (1 from PO), NDM-1 (2 in RO; 2 centers); and OXA-48 or -162 (5 from T; 2 centers). European surveillance sampling demonstrates a wide array of resistant isolates, less prevalent among Gram-positive cocci that remain inhibited by several available agents. However, beta-lactamase-mediated mechanisms have spread widely among Gram-negative bacilli, especially across the Eastern and Southern European nations, severely limiting infection chemotherapy and necessitating escalated antimicrobial stewardship., (© 2014.)

Antimicrobial resistance (R) surveillance across Asia and especially in China has documented unique patterns and mechanisms. This 2011 study reports results for 2278 isolates from 12 hospitals in China (94-216 strains/site); most from bacteremia (20.4%), pneumonias (29.1%), or skin and skin structure infections (20.9%). Samples were tested by reference broth microdilution methods, interpreted by published susceptibility (S) breakpoints. The most common species were Staphylococcus aureus (343, 45.8% MRSA), Escherichia coli (EC; 288), Pseudomonas aeruginosa (PSA; 221), Klebsiella spp. (KSP; 208), acinetobacters (ACB; 178), enterobacters (155), Streptococcus pneumoniae (SPN; 154, 46.8% penicillin-S), and enterococci (ENT; 137). Among 849 Gram-positive (GP) cocci, linezolid, tigecycline (TIG), daptomycin, and vancomycin provided best antimicrobial coverage (≥99.7% S). Resistance patterns of concern were 0.3% VISA, 15.4% teicoplanin non-S coagulase-negative staphylococci, 1.5% vancomycin-R ENT (all Enterococcus faecium), 1.9% levofloxacin-R β-haemolytic streptococci, and 35.1 and 12.7% ceftriaxone-non-S rates for SPN and viridans group streptococci, respectively. For Gram-negative bacilli, R among Enterobacteriaceae was highest against β-lactams (extended spectrum β-lactamase-phenotype strains at 73.6 and 42.8% in EC and KSP, respectively; carbapenem-R was only 2.1-4.3% with KPC and IMP type enzymes detected in KSP). The widest spectrum agents were cefoperazone/sulbactam (79.5-86.1%), piperacillin/tazobactam (88.9-92.0%), TIG (98.6-100%), amikacin (AMK; 91.8-93.7%), and meropenem (95.7-97.1% S). PSA was most inhibited by AMK (90.5% S) and colistin (COL; 99.5%), with cefepime (67.9%) best among the tested β-lactams. Only COL (100% S) and TIG (MIC90, 2 μg/mL) showed significant potencies against ACB. In conclusion, R among pathogens from 12 Chinese hospitals illustrates several agents active against GP pathogens, but more serious R problems were noted among Enterobacteriaceae, PSA, and ACB. Combination treatment for the latter multidrug-R strains appears necessary, guided by local antibiograms and national surveillance results applying reference methods., (© 2013.)

Through a continuing resistance surveillance monitoring program, linezolid was shown to maintain its spectrum and potency against a collection of 8059 clinically relevant Gram-positive strains collected from patients at 79 medical centers in 33 countries and Hong Kong. Linezolid MIC90 values were 2 μg/mL for methicillin-resistant and -susceptible Staphylococcus aureus and enterococci, and the MIC90 value was 1 μg/mL for coagulase-negative staphylococci (CoNS), β-hemolytic streptococci, Streptococcus pneumoniae, and viridans group streptococci. Reference broth microdilution susceptibility testing for linezolid demonstrated a 99.83% susceptibility rate for all organisms. All S. aureus were inhibited by ≤2 μg/mL. Three (0.3%) of 928 strains of CoNS had a linezolid MIC of 4 μg/mL and contained the cfr resistance gene; 1 also had a mutation in L3. There were 14 linezolid-resistant strains detected from 7 countries (Brazil [5], France [1], Germany [2] Greece [2], Italy [2], Ireland [1], and Spain [1]) representing 5 species (E. faecium, S. capitis, S. epidermidis, S. hominis, S. lugdenensis). A mobile cfr gene was noted in 2 species having elevated linezolid MIC values; one was a S. haemolyticus isolate with a MIC at 4 μg/mL. Resistance rates were as follows for the 6 groups of organisms sampled in the 2011 ZAAPS Program: CoNS, 1.2%; enterococci, 0.39%; among S aureus, S. pneumoniae, viridans group streptococci, and β-hemolytic streptococci, no resistance was detected. As the activities of commonly used antimicrobials continue to be compromised by evolving resistance mechanisms in Gram-positive pathogens, linezolid-resistant strains remain uncommon and without increasing occurrence., (Copyright © 2013 Elsevier Inc. All rights reserved.)

International susceptibility testing breakpoint organizations and regulatory agencies have markedly differing interpretive criteria for the tetracycline class. Here we examined the magnitude of these differences for doxycycline and tetracycline hydrochloride (HCL) when tested against a collection of 13,176 Gram-positive cocci from a worldwide surveillance network (SENTRY Antimicrobial Surveillance Program, 2010). Clinical and Laboratory Standards Institute (CLSI) breakpoints are routinely higher, usually 4-fold, compared to those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST); however, CLSI recently (2013) modified Streptococcus pneumoniae breakpoints (≤ 2 μg/mL in 2012) to ≤ 0.25 and ≤ 1 μg/mL for doxycycline and tetracycline HCL, respectively. We report that these changes are a promising step toward international breakpoint harmonization, but lack a comprehensive approach needed for testing tetracyclines against all Gram-positive cocci. Generally, EUCAST breakpoint criteria showed i) lower spectrums (reduced susceptibility rates) for the tetracyclines, but highest for doxycycline versus all species examined; ii) greater test accuracy (lower predictive categorical errors), especially for tetracycline to predict doxycycline susceptibility (99.91%); and iii) zone diameter correlate breakpoints which are generally available online. Molecular tests for tet resistance genes demonstrate that tet (K) and tet (M) containing strains can occur in the susceptible population of MIC results by both CLSI and EUCAST breakpoint criteria. In summary, doxycycline continues to show greater comparative potency versus tetracycline HCL against all monitored Gram-positive species and the international harmonization of tetracycline breakpoints should be a priority, as the most recent CLSI update only addressed 1 streptococcal species and 2 tetracycline agents., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Tetracycline class agents vary widely in their activity against emerging important antimicrobial-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter spp. Also, published susceptibility breakpoints are discordant between the Clinical and Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST), and regulatory-approved documents. We have assessed the impact of these differences for tetracycline HCL and minocycline when tested against contemporary Gram-positive pathogens. The SENTRY Antimicrobial Surveillance Program (2011) compared minocycline and tetracycline HCL activity via reference methods (M07-A9) using a worldwide collection of S. aureus (SA; 4917 strains with 1955 MRSA), Streptococcus pneumoniae (SPN; 1899), S. pyogenes (GRA; 246), and S. agalactiae (GRB; 217). Regardless of applied categorical breakpoints, minocycline exhibited wider coverage (% susceptible) than tetracycline HCL of 4.5-11.8/0.5-2.6/1.4-2.3/0.4-0.4% for MRSA/SPN/GRB/GRA, respectively. Lower EUCAST susceptible breakpoints produced reduced susceptibility rates for minocycline ranging from no difference (≤0.5 μg/mL) for GRA to -8.9% (≤1 μg/mL) for MRSA (97.2% susceptible by CLSI; 88.3% by EUCAST). Use of tetracycline HCL-susceptible results to predict minocycline susceptibility was very accurate (99.0-100.0%), with absolute categorical agreement rates ranging from 92.1% to 98.4% (CLSI) to 98.4% to 99.6% (EUCAST) for streptococci; greatest predictive error was noted using the CLSI breakpoints (14.7%) compared to EUCAST criteria (only 5.0%; acceptable), both for MRSA testing dominated by false-resistant results for minocycline. In conclusion, minocycline demonstrates continued superior in vitro activity compared to tetracycline HCL when testing SA (especially MRSA) and pathogenic streptococci. When testing tetracyclines, laboratories must recognize the expanded spectrum of minocycline against certain pathogens and utilize methods minimizing interpretive error. We conclude that EUCAST breakpoint criteria (≤0.5 or ≤1 μg/mL) represent the most conservative (better recognize strains with tet resistance mechanisms) and accurate tetracycline breakpoint guidelines for testing contemporary isolates of Gram-positive cocci., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A 14-year longitudinal survey of Streptococcus pneumoniae (18,911) strains by the SENTRY Antimicrobial Surveillance Program shows significant increases in resistance to amoxicillin/clavulanate (18.9%), penicillin at a MIC of ≥ 4 μg/mL (14.8%), and ceftriaxone (11.7%) among 2011 isolates. Fluoroquinolones (levofloxacin; 98.8% susceptible) and ceftaroline (99.1-100.0% susceptible depending on breakpoint criteria) exhibited high levels of potency, as did linezolid, tigecycline, and vancomycin (100.0%). In summary, resistance rates to several antimicrobials continue to rise after introductions of both pneumococcal conjugate vaccines, as noted from these results for 1998 through 2011., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The epidemiology and molecular characteristics of vancomycin-resistant enterococci (VRE) from China deserve further investigation. This study reports on the molecular characterization of 101 unique VRE (96 E. faecium and 5 E. faecalis strains) recovered from diverse samples of 12 hospitals in China. MIC results were obtained by reference broth microdilution methods, and vancomycin resistance and virulence genes were screened by polymerase chain reaction. All strains were subjected to pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. E. faecalis exhibited vancomycin and teicoplanin MIC results at ≥256 μg/mL and harbored vanA, except for 1 vanB-carrying strain (MIC, 32 and 1 μg/mL, respectively). This strain had a unique PFGE pattern and was associated with ST410 (clonal complex [CC]4). E. faecium displayed vancomycin MIC values of ≥256 μg/mL with variable results for teicoplanin (1-256 μg/mL). One E. faecium had a teicoplanin MIC value of 1 μg/mL and carried a vanB, while the other 2 strains had teicoplanin MIC values of 4 and 8 μg/mL and harbored vanA. E. faecalis strains were susceptible to ampicillin, and all VRE displayed a susceptible phenotype to daptomycin, linezolid, and tigecycline. Four E. faecalis from a particular hospital were grouped within a single PFGE type and were associated with ST470 and ST471 (CC4), which are double- and triple-locus variants of ST410 and ST4, respectively. Overall, E. faecium displayed genetic variability, but clonal dissemination was noted within and among hospitals. All E. faecium belonged to STs associated with CC17, except for 1 strain (ST362; CC362). A total of 77.2% and 29.7% of all strains carried esp and hyl, respectively. In conclusion, these results show that vanA-carrying isolates predominated in strains from China, and E. faecium strains are usually associated with a common and human-adapted lineage (CC17). Unlike the majority of clinical E. faecalis (CC2 and CC9), strains included in this study showed ST profiles similar to ST4 (CC4), which has been associated with human infections in other Asia-Pacific countries., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The LEADER program monitors the in vitro activity of linezolid and comparator agents across the United States using reference broth microdilution and supportive molecular susceptibility-based investigations. This report summarizes the data from the 2010 program, the seventh consecutive year. A total of 61 medical centers from the USA including 7 medical centers specializing in children's healthcare provided a total of 6801 Gram-positive pathogens. The medical centers represented all 9 US Bureau of Census geographic regions. The organisms tested by reference broth microdilution were 3105 Staphylococcus aureus, 944 coagulase-negative staphylococci (CoNS), 934 Enterococci, 803 Streptococcus pneumoniae, 604 β-haemolytic streptococci, and 411 viridans group and other streptococci. The MIC(90) value for each of the above 6 targeted groups of organisms was 1 μg/mL. The "all organism" linezolid-resistant and nonsusceptible rate was 0.38%, which has been constant at 0.34% (2009) to 0.45% (2006) for the last 4 years. For Staphylococcus aureus, only 0.06% of the isolates were linezolid-resistant (MIC, ≥8 μg/mL); however, 2 additional methicillin-resistant Staphylococcus aureus had a cfr and a MIC of only 4 μg/mL. Resistance to linezolid was detected in 7 enterococci (0.75%) and 14 CoNS isolates (1.48%). This also represents a stable rate of resistance noted since the 2006 LEADER program report. Of note, for the first time in the 7 years of the Leader Program a linezolid-resistant Streptococcus pneumoniae was encountered. Overall, the results of the LEADER program demonstrate that linezolid maintains excellent in vitro activity against target Gram-positive pathogens across the USA. The LEADER program continues to provide valuable reference and molecular-level monitoring of linezolid activity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This study updates the activity of telavancin against Gram-positive pathogens collected from USA hospitals (2007-2009). Telavancin (MIC(50/90), 0.12/0.25 μg/mL) was active against coagulase-negative staphylococci and methicillin-resistant Staphylococcus aureus (100% susceptible), for which only daptomycin (MIC(50/90), 0.25/0.5 μg/mL; 99% susceptible) and quinupristin/dalfopristin (MIC(50/90), ≤ 0.25-0.5/0.5 μg/mL; 99% susceptible) exhibited similar activity. Telavancin (MIC(50/90), 0.25/0.5 μg/mL) inhibited 96.5% of Enterococcus faecalis at the Food and Drug Administration breakpoint (MIC, ≤ 1 μg/mL), where ampicillin (99.9% susceptible), daptomycin (99.9% susceptible), and linezolid (100% susceptible) also demonstrated high-level coverage. Telavancin inhibited, respectively, 100.0% and 91.7% of VanB-phenotype E. faecalis and E. faecium at ≤ 1 μg/mL, whereas it was less active against VanA strains. Telavancin was uniformly active against Streptococcus pneumoniae and resistant subsets, and demonstrated good potency (MIC(90), 0.06-0.12 μg/mL) against other streptococci, regardless of resistance to other drugs. This assessment reveals potent activity of telavancin against Gram-positive isolates collected from USA hospitals with no evidence of emergence of resistance., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We report a novel vga(A) detected in 3 methicillin-resistant Staphylococcus aureus ST398 recovered from swine and a swine caretaker in the United States. Strains were wild type for L3 and L4, but positive for vga(A) and tet(M). vga(A) was plasmid-located (ca. 24-kb) and demonstrated mobilization genes upstream and a transposase belonging to the IS3 family located downstream., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This study evaluated telavancin activity against 3868 Staphylococcus aureus and 1003 coagulase-negative staphylococci (CoNS) collected from 33 European hospitals (2009-2010). Studies of telavancin potency included analysis of strains with decreased susceptibility to glycopeptides. Telavancin (MIC(50/90), 0.12/0.25 μg/mL) showed high activity against S. aureus and CoNS, regardless of the stratification analysis performed (year sampled, infection source, or methicillin susceptibility). In addition, telavancin (MIC(50/90), 0.25/0.5 μg/mL) retained activity against S. aureus isolates with higher vancomycin (MIC, 2 μg/mL) or teicoplanin (MIC, 2-8 μg/mL) MIC results. Overall, telavancin exhibited higher potency (at least 2-fold greater) than tested comparators (vancomycin, daptomycin, and linezolid) against European staphylococci. Alongside published clinical data, the telavancin in vitro activity observed against these pathogens supports this drug as an option for treating S. aureus infections in Europe, including those infections caused by strains with decreased susceptibility to vancomycin and/or teicoplanin., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Linezolid is the only oxazolidinone agent approved for clinical use and has been administered to millions of patients over nearly a decade, becoming an important therapeutic alternative for infections caused by multidrug-resistant (MDR) Gram-positive pathogens. Resistance is due to mutations in 23S rRNA and the ribosomal proteins L3 and L4 and, more recently, the mobile cfr gene (causes resistance to several antimicrobial classes). Using reference broth microdilution methods in a central reference laboratory design, MIC values were obtained during the 2009 Zyvox® Annual Appraisal of Potency and Spectrum program (5754 sampled strains from 22 countries), and the following MIC(90) values were obtained for the leading pathogen or species groups: Staphylococcus aureus (2 μg/mL), coagulase-negative staphylococci (CoNS; 1 μg/mL), Enterococcus spp. (2 μg/mL), and 3 groups of streptococci (1 μg/mL) including Streptococcus pneumoniae. Linezolid-resistant strains (8 or 0.14% overall) that were not Staphylococcus aureus were observed in 5 nations and included CoNS (0.48%) having the mobile cfr gene. The results of this study demonstrate that linezolid continues to be effective in vitro against MDR pathogens, and the resistance rates appear stable., (Copyright © 2010 Elsevier Inc. All rights reserved.)

A total of 5127 Acinetobacter spp. were collected from 140 hospitals in 32 countries in North America (17.1%), Europe (22.9%), Latin America (25.2%), and the Asia-Pacific (APAC) region (34.8%). Tigecycline MIC distributions were bimodal against isolates from North America and APAC region, while a unimodal pattern was noted for strains from Latin America. A variable MIC distribution was noted in Europe. Only tigecycline (MIC(50/90), 0.5/2 μg/mL) and polymyxin B (MIC(50/90), 0.5/1 μg/mL; 98.6% susceptible) exhibited high activity against Acinetobacter spp. Overall, tigecycline inhibited at least 90.0% of Acinetobacter spp. isolates from all countries evaluated at ≤2 μg/mL, as well as 95.0% of those displaying multidrug resistance. Other tested agents showed limited activity and a significant (P < 0.001) trend toward decreased susceptibility during the study period., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Telavancin was approved in the United States and Canada for the treatment of adult patients with complicated skin and skin-structure infections (cSSSI) caused by susceptible Gram-positive isolates. In this study, telavancin and comparator antimicrobial activities were determined against a total of 24,017 clinical isolates, including Staphylococcus aureus, coagulase-negative Staphylococcus spp. (CoNS), Enterococcus spp., and various Streptococcus spp. Overall, telavancin was highly active across all geographic regions for S. aureus (MIC(50/90), 0.12/0.25 microg/mL; 100.0% susceptible), CoNS (MIC(50/90), 0.12/0.25 microg/mL), vancomycin-susceptible Enterococcus faecalis (MIC(50/90), 0.25/0.5 microg/mL; 100.0% susceptible), Enterococcus faecium (MIC(50/90), 0.06/0.12 microg/mL), Streptococcus pneumoniae (MIC(50/90), < or =0.015/0.03 microg/mL), viridans group Streptococcus spp. (MIC(50/90), 0.03/0.06 microg/mL; 100.0% susceptible), and beta-hemolytic Streptococcus spp. (MIC(50/90), 0.03/0.12 microg/mL; 99.8% susceptible). Telavancin had potent activity against vancomycin-nonsusceptible, teicoplanin-susceptible (VanB) E. faecalis (MIC(50/90), 0.25/0.5 microg/mL) and E. faecium (MIC(50/90), 0.06/0.25 microg/mL). These in vitro results show continued activity for telavancin, which represents an important alternative available for treating cSSSI., (Copyright 2010 Elsevier Inc. All rights reserved.)

Fusidic acid (CEM-102) is a steroidal antimicrobial agent with focused Gram-positive activity that acts by preventing bacterial protein synthesis via interacting with elongation factor G. A collection of 114 wild-type isolates (> 80 species) was used to define the contemporary limits of fusidic acid spectrum against Gram-positive and Gram-negative species. Reference broth microdilution and anaerobic agar dilution methods were performed. Modifications of standardized test methods included adding 10% human serum and adjusting the medium pH to 5, 6, and 8. Synergy was assessed by the checkerboard method and time-kill studies. Mutational rates to resistance were determined at 4 x, 8 x, and 16 x MIC. Against Gram-positive pathogens, fusidic acid MIC values ranged from 0.06 to 32 microg/mL with the greatest potency against Staphylococcus aureus, Corynebacterium spp., and Micrococcus luteus (MIC results, 0.25, < or = 0.12, and < or = 0.5 microg/mL, respectively). Enterococci and streptococci were less susceptible (MIC ranges, 2-8 and 16-32 microg/mL, respectively). Fusidic acid activity against Gram-negative species was more limited (all MIC values, > or = 2 microg/mL) except for Empedobacter brevis, Moraxella catarrhalis and Neisseria meningitidis. A 4-fold increase in fusidic acid MIC results was observed when 10% serum was added to the broth. Decreasing medium pH to 5.0 to 6.0 negated the protein binding effects. Among the 8 antimicrobial combinations tested, gentamicin and rifampin enhanced the activity when combined with fusidic acid (no antagonism). Fusidic acid in vitro activity was most improved when combined with rifampin. Single-step mutational rates ranged from 1.2 x 10(-6) for 4x MIC to 9.8 x 10(-8) for 16 x MIC. In conclusion, these in vitro results for fusidic acid tested against contemporary strains confirm a persisting antimicrobial spectrum, especially against staphylococci and some other Gram-positive species., (2010 Elsevier Inc. All rights reserved.)

The LEADER Program was initiated in 2004 and monitors emerging linezolid resistance in sampled US medical centers. This report summarizes the data obtained in 2008, the 5th consecutive year. A total of 57 institutions participated in 2008 representing all 9 US census regions with 100 target organisms per site (6113 isolates, 101.9% compliance to protocol design). The organisms tested by reference broth microdilution methods were Staphylococcus aureus (3156), coagulase-negative staphylococci (CoNS; 856), enterococci (901), Streptococcus pneumoniae (619), and viridans group (223) or beta-hemolytic streptococci (358); also, D-test was used to determine inducible clindamycin resistance in Staphylococcus aureus. Linezolid remained very potent against all sampled species with MIC(90) results ranging from 1 microg/mL (streptococci and CoNS) to 2 microg/mL (Staphylococcus aureus and enterococci). Only 0.36% of sampled strains were nonsusceptible to linezolid, a slight decrease from 0.45% and 0.44% in 2006 and 2007, respectively. The nonsusceptible strains (22) were Staphylococcus aureus (3), CoNS (14), and Enterococcus faecium (5) each with defined target mutations (G2576T in 19 strains; T2504A in 1 strain), mobile cfr element (1 strain Staphylococcus epidermidis with an identical pulsed-field gel electrophoresis pattern to a cfr-positive Staphylococcus epidermidis isolated from the same center in LEADER 2007), or an unknown (1 strain) mechanism. The mobile cfr resistance found in a Staphylococcus aureus strain in 2007 was not observed in 2008. In conclusion, linezolid activity sampled by the 5th year of this LEADER Program showed sustained potency and spectrum (99.64% susceptibility levels). The nonsusceptible strain isolation rates remained stable and the plasmid-mediated ribosomal-based resistance mechanism that emerged in Staphylococcus aureus and Staphylococcus epidermidis strains in 2007 showed no evidence of dissemination or increased prevalence. However, there was evidence of cfr persistence with the S. epidermidis strain. The LEADER Program continues to be an effective and sensitive surveillance tool to detect and monitor novel oxazolidinone resistance phenotypes and genotypes.

The emergence and rapid dissemination of extended-spectrum beta-lactamase (ESBL)-producing isolates among Enterobacteriaceae coupled with increasing prevalence of stably derepressed and plasmid-borne AmpC producers have rendered broad-spectrum cephalosporins and beta-lactam/beta-lactamase inhibitor combinations less effective. This scenario has required the use of carbapenems for treatment of infections caused by such organisms. In this study, the in vitro activities of doripenem and comparator agents against Enterobacteriaceae, including ESBL- and AmpC-producing strains, were evaluated. A total of 36 614 isolates collected from more than 60 medical centers (2000-2007) were included and tested for susceptibility using reference methods and interpretive criteria, except for doripenem (product package insert). Overall, doripenem inhibited 98.7% of all Enterobacteriaceae tested at

The LEADER Program (2007) monitors for emerging linezolid resistance in sampled US medical centers, initiated in 2004. For the current reported year, the number of sites participating was increased from 50 to 60 institutions representing all 9 US census regions with 100 target organisms per site (6305 isolates, 105.1% compliance to protocol design). The organisms tested by reference broth microdilution methods were Staphylococcus aureus (3318), coagulase negative staphylococci (CoNS, 1020), enterococci (705), Streptococcus pneumoniae (622), and viridans group (249) or beta-hemolytic streptococci (391); also, D-test was used to determine inducible clindamycin resistance in S. aureus strains. Linezolid remained very potent against all sampled species with MIC(90) results ranging from 1 microg/mL (streptococci and CoNS) to 2 microg/mL (S. aureus and enterococci). Only 0.44% of sampled strains were nonsusceptible to linezolid, compared with 0.45% in 2006. The nonsusceptible strains (23) were usually staphylococci (20) or Enterococcus faecium (8), each with defined target mutations (G2576T, 24 strains) or a novel mobile cfr element in staphylococci (2 strains). In conclusion, linezolid activity sampled by the 4th year of this LEADER Program showed sustained potency and spectrum (99.56% susceptibility). Although the nonsusceptible strain isolation rates remained stable, a new plasmid-mediated ribosomal-based resistance mechanism emerged in S. aureus and Staphylococcus epidermidis strains from Arizona and Ohio. The LEADER Program appears to be an effective and sensitive surveillance tool to detect novel resistance phenotypes and genotypes.