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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.)

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.)

Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound 79 . This molecule demonstrates potent antibacterial activity against diverse Gram-positive pathogens, inhibition of both DNA gyrase and topoisomerase IV, a low frequency of resistance, a favorable in vitro cardiovascular safety profile, and in vivo efficacy in a murine model of methicillin-resistant Staphylococcus aureus infection.

Contezolid, a new oxazolidinone antibacterial agent currently in development for the treatment of skin and skin structure infections, was susceptibility tested against Gram-positive clinical isolates ( n  = 1,211). Contezolid demonstrated potent activity against Staphylococcus aureus (MIC 50/90 , 0.5/1 mg/liter), coagulase-negative Staphylococcus (MIC 50/90 , 0.25/0.5 mg/liter), Enterococcus spp. (MIC 50/90 , 0.5/1 mg/liter), and streptococci (MIC 50/90 , 1/1 mg/liter). Moreover, methicillin-resistant S. aureus and vancomycin-resistant Enterococcus faecium isolates were all inhibited by contezolid at ≤1 mg/liter. These results support the clinical development of contezolid., (Copyright © 2020 American Society for Microbiology.)

Ceftobiprole medocaril is an advanced-generation cephalosporin prodrug that has qualified infectious disease product status granted by the US FDA and is currently being evaluated in phase 3 clinical trials in patients with acute bacterial skin and skin structure infections (ABSSSIs) and in patients with Staphylococcus aureus bacteremia. In this study, the activity of ceftobiprole and comparators was evaluated against more than 7,300 clinical isolates collected in the United States from 2016 through 2018 from patients with skin and skin structure infections. The major species/pathogen groups were S. aureus (53%), Enterobacterales (23%), Pseudomonas aeruginosa (7%), beta-hemolytic streptococci (6%), Enterococcus spp. (4%), and coagulase-negative staphylococci (2%). Ceftobiprole was highly active against S. aureus (MIC 50/90 , 0.5/1 mg/liter; 99.7% susceptible by EUCAST criteria; 42% methicillin-resistant S. aureus [MRSA]). Ceftobiprole also exhibited potent activity against other Gram-positive cocci. The overall susceptibility of Enterobacterales to ceftobiprole was 84.8% (>99.0% susceptible for isolate subsets that exhibited a non-extended-spectrum β-lactamase [ESBL] phenotype). A total of 74.4% of P. aeruginosa , 100% of beta-hemolytic streptococci and coagulase-negative staphylococci, and 99.6% of Enterococcus faecalis isolates were inhibited by ceftobiprole at ≤4 mg/liter. As expected, ceftobiprole was largely inactive against Enterobacterales that contained ESBL genes and Enterococcus faecium Overall, ceftobiprole was highly active against most clinical isolates from the major Gram-positive and Gram-negative skin and skin structure pathogen groups collected at U.S. medical centers participating in the SENTRY Antimicrobial Surveillance Program during 2016 to 2018. The broad-spectrum activity of ceftobiprole, including potent activity against MRSA, supports its further evaluation for a potential ABSSSI indication., (Copyright © 2020 American Society for Microbiology.)

Objectives: The in vitro antimicrobial activities of telavancin and comparator antimicrobials were evaluated against recent Staphylococcus aureus (S. aureus) clinical isolates collected in the United States of America (USA)., Methods: A total of 15882 S. aureus isolates were collected (2014-2016) as part of the SENTRY Antimicrobial Surveillance Program from sites located in all US Census Bureau divisions. Broth microdilution MIC values were measured using current reference methods. Data were stratified by year and census division, and resistance rates were analysed for significant trends. Previously published data on methicillin-resistant S. aureus (MRSA) and multidrug-resistant (MDR) MRSA isolates (collected 2011-2013) were merged with the current isolate set to examine longer term resistance trends., Results: Telavancin antimicrobial activity against MRSA and MDR MRSA isolates (MIC 50/90 values, 0.03/0.06μg/mL for both subsets) remained unchanged over the 3-year surveillance period, and all isolates were susceptible to telavancin. No difference in telavancin activity was noted when MIC data were stratified by year or US Census Bureau division. When merged data (2011-2016) were analysed, the MRSA rate decreased for the entire USA and six individual census divisions, although the overall rate remained considerable. The overall US MDR MRSA rate also remained considerable and was unchanged from 2011-2016., Conclusions: The sustained potent activity of telavancin against US S. aureus isolates (100% susceptible) and the high rates of MRSA and MDR MRSA in the USA support the continued use of telavancin to treat indicated serious infections caused by S. aureus., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This study evaluated the in vitro antimicrobial activity of telavancin against a large collection of Gram-positive pathogens of clinical importance, which were collected worldwide from 2015 through 2017, including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, Enterococcus spp., β-hemolytic streptococci (BHS), Streptococcus pneumoniae, and viridans group streptococci (VGS). This report completes 7 years of continuous surveillance data for telavancin using the approved reference method for in vitro testing methodology that includes the addition of polysorbate 80. For isolates collected from 2015 through 2017, telavancin exhibited potent activity against the following species and groups that have Clinical and Laboratory Standards Institute (CLSI)-approved interpretive criteria: MRSA (MIC90 value, 0.06 μg/mL; 100% susceptible), vancomycin-susceptible Enterococcus faecalis (MIC90 value, 0.25 μg/mL; 99.9% susceptible), BHS (MIC90 value, 0.03 μg/mL; 100% susceptible), and VGS (MIC90 value, 0.03 μg/mL; 99.0% susceptible). Importantly, telavancin maintained excellent antimicrobial activity against multidrug-resistant subsets of these pathogen groups and against ceftaroline-nonsusceptible (telavancin MIC90 value, 0.06 μg/mL; 100% susceptible) and ceftaroline-resistant (telavancin MIC90 value, 0.12 μg/mL; 100% susceptible) S. aureus isolates. [ABSTRACT FROM AUTHOR]

• 357 S. aureus isolates were collected from CF patients in 36 centers worldwide. • Results were compared with 725 S. aureus isolates from non-CF patients with pneumonia. • Susceptibility profiles were similar among isolates from CF and non-CF patients. • Dalbavancin showed potent activity and 100% coverage against CF and non-CF isolates. The activities of dalbavancin and comparator agents were evaluated against Staphylococcus aureus isolated from the lower respiratory tract of cystic fibrosis (CF) and non-CF patients with pneumonia. Bacterial isolates (n = 357) were collected from CF patients in 36 medical centers worldwide (2018–2019) and susceptibility tested using reference broth microdilution. Susceptibility results from these isolates were compared with those for 725 S. aureus isolates consecutively collected from non-CF patients with pneumonia from the same medical centers over the same period. Only isolates determined to be the probable cause of pneumonia were included in the study. Susceptibility profiles were very similar among isolates from CF and non-CF patients. Dalbavancin exhibited potent activity (MIC 50/90 , 0.03/0.03 mg/L) and complete coverage (100.0% susceptibility) against isolates from CF and non-CF patients. Ceftaroline (MIC 50/90 , 0.25/1 mg/L) was active against 97.8% and 98.1% of isolates from CF and non-CF patients, respectively. Oxacillin resistance (MRSA) rates were 27.7% among CF and 28.7% among non-CF patients. Among MRSA isolates from CF/non-CF patients (n = 99/208), susceptibility to ceftaroline, clindamycin, levofloxacin, and tetracycline were 91.9%/93.3%, 58.6%/64.4%, 40.4%/29.3%, and 83.8%/89.4%, respectively. Dalbavancin demonstrated high potency against S. aureus from CF and non-CF patients and may represent a valuable treatment option for CF patients with MRSA pulmonary infection. [ABSTRACT FROM AUTHOR]

Background: Many infections due to Gram-positive cocci (GPC; staphylococci, streptococci and enterococci) regularly involve prolonged systemic antibiotic use. Dalbavancin has demonstrated activity against GPC isolates and has been approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults.Objectives: To evaluate the activity of dalbavancin against GPC isolated from a variety of infection types in the USA and Europe.Methods: A total of 14 319 Staphylococcus aureus, 1992 CoNS, 3269 β-haemolytic streptococci (BHS), 2071 Enterococcus faecalis, 936 Enterococcus faecium, 71 Enterococcus gallinarum/casseliflavus and other Enterococcus spp., 3487 Streptococcus pneumoniae and 1063 viridans group streptococci (VGS) causing clinical infections were consecutively collected (2015-16) and tested for susceptibility by broth microdilution methods.Results: All S. aureus (36.4% MRSA) isolates were susceptible to dalbavancin, teicoplanin and vancomycin, while daptomycin and linezolid showed susceptibility rates of >99.9% (according to CLSI criteria). Dalbavancin MIC results were at least 16-fold lower than these comparators against all S. aureus. Dalbavancin was the most potent agent against CoNS [62.2%/59.6% methicillin-resistant (CLSI/EUCAST)], followed by daptomycin, linezolid and vancomycin. All vancomycin-susceptible E. faecalis isolates were inhibited by dalbavancin at ≤0.25 mg/L (FDA susceptible breakpoint). Dalbavancin was very active against BHS (MIC90 0.03 mg/L) and the most active agent against S. pneumoniae and VGS (highest MIC 0.25 mg/L). Ceftriaxone, daptomycin, levofloxacin and vancomycin were also active (93.5%-100.0% susceptible) against VGS, whereas clindamycin, erythromycin, penicillin and tetracycline had lower activity.Conclusions: Dalbavancin appears to be a viable candidate for treating serious infections caused by GPC. [ABSTRACT FROM AUTHOR]