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The absence of novel antibiotics for drug-resistant and biofilm-associated infections is a global public health crisis. Antimicrobial peptides explored to address this need have encountered significant development challenges associated with size, toxicity, safety profile, and pharmacokinetics. We designed PLG0206, an engineered antimicrobial peptide, to address these limitations. PLG0206 has broad-spectrum activity against >1,200 multidrug-resistant (MDR) ESKAPEE clinical isolates, is rapidly bactericidal, and displays potent anti-biofilm activity against diverse MDR pathogens. PLG0206 displays activity in diverse animal infection models following both systemic (urinary tract infection) and local (prosthetic joint infection) administration. These findings support continuing clinical development of PLG0206 and validate use of rational design for peptide therapeutics to overcome limitations associated with difficult-to-drug pharmaceutical targets. [ABSTRACT FROM AUTHOR]

Iclaprim is a novel diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and it is active against Gram-positive pathogens including emerging drug-resistant pathogens. In vitro activity of iclaprim and comparators against 1365 Gram-positive clinical isolates from patients with skin and skin structure infections (SSSI) from the United States, Asia Pacific, Latin America, Europe, Africa or Middle East collected between 2013 and 2017 were tested. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI criteria. MIC 90 for all S.aureus , methicillin-susceptible S. aureus , methicillin-resistant S. aureus , Streptococcus pyogenes, S. agalactiae, S. anginosus, S. constellatus , S. dysgalactiae and S. intermedius were 0.12, 0.12, 0.5, 0.03, 0.5, ≤0.004, ≤0.004, 0.12, and 0.008 μg/ml, respectively. The MIC for iclaprim was 8 to 32-fold lower than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all Gram-positive isolates including resistant phenotypes. Iclaprim demonstrated lower MICs than trimethoprim against a collection (2013–2017) of Gram-positive clinical isolates from patients with SSSI from the United States, Asia Pacific, Latin America, and Europe. [ABSTRACT FROM AUTHOR]

• 93.3% of Pseudomonas aeruginosa from Western Europe were ceftolozane/tazobactam-susceptible • 23.1% of P. aeruginosa from Western Europe were multidrug-resistant (MDR) • 72% of MDR P. aeruginosa in Western Europe were ceftolozane/tazobactam-susceptible • ∼30% of MDR P. aeruginosa in Western Europe were meropenem- or imipenem-susceptible • 16.6% of MDR P. aeruginosa carried a carbapenemase (8.8% MBL, 7.6% GES, 0.2% GPC) Multidrug-resistant (MDR) Pseudomonas aeruginosa infections compromise both empirical and definitive antimicrobial therapies. The Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program identified 943 MDR P. aeruginosa (from a total of 4086 P. aeruginosa isolates [23.1%]) collected at 32 clinical laboratories in six countries in Western Europe from 2017 to 2020. Minimum inhibitory concentrations (MICs) for ceftolozane/tazobactam and 10 comparator agents were determined by broth microdilution and interpreted using 2021 EUCAST breakpoints. β-lactamase genes were identified in selected isolate subsets. Most isolates of P. aeruginosa in Western Europe (93.3%) were ceftolozane/tazobactam-susceptible. A total of 23.1% of P. aeruginosa isolates were MDR. Of these, 72.0% were ceftolozane/tazobactam-susceptible, which is similar to that for ceftazidime/avibactam (73.6%) but >40% higher than for carbapenems, piperacillin/tazobactam, third- and fourth-generation cephalosporins, and levofloxacin. Metallo-β-lactamases (MBLs) were carried by 8.8% of molecularly characterized MDR P. aeruginosa , and 7.6% of molecularly characterized MDR isolates carried Guiana Extended Spectrum (GES) carbapenemases. MBLs were identified in isolates from all six countries, ranging from 3.2% of all P. aeruginosa isolates from Italy to 0.4% of all isolates from the United Kingdom. Acquired β-lactamases were not identified in 80.0% of molecularly characterized MDR P. aeruginosa isolates. Percentages of MDR isolates without detected β-lactamases were higher in the United Kingdom (97.7%), Spain (88.2%), France (88.1%), and Germany (84.7%) than in Portugal (63.0%) and Italy (61.3%), where carbapenemases were more prevalent. Ceftolozane/tazobactam is an important treatment option for patients infected with MDR P. aeruginosa that are not susceptible to first-line antipseudomonal agents. [ABSTRACT FROM AUTHOR]

Abstract: The Study for Monitoring Antimicrobial Resistance Trends has been monitoring the activity of antimicrobials indicated for the treatment of intra-abdominal infections since 2004. This report documents the in vitro activity of several recommended antimicrobials against 3449 gram-negative bacilli isolated from the 30 and 25 participating sites in North America in 2010–2011, respectively, and characterizes the extended-spectrum beta-lactamases (ESBL) identified in ESBL-positive and ertapenem-non-susceptible isolates of Enterobacteriaceae. Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Klebsiella oxytoca, Citrobacter freundii, Enterobacter aerogenes, Serratia marcescens, and Morganella morgannii were the most common species isolated. The incidence of beta-lactamase production was 8.8% and 8.9% for E. coli and K. pneumoniae, respectively. Overall the most active antimicrobials were amikacin, piperacillin-tazobactam, imipenem, and ertapenem, although beta-lactamase production reduced the activity of most agents. Characterization of beta-lactamase genes determined that bla SHV, bla CTX-M, bla AmpC, and bla KPC were commonly found in most beta-lactamase–positive isolates. [Copyright &y& Elsevier]

Objectives: To support the clinical development of mecillinam and pivmecillinam in the United States for the treatment of complicated and uncomplicated urinary tract infections (UTIs), this study investigated the activity of mecillinam compared with other antibiotics against Enterobacterales isolates from patients with UTIs in the United States during 2017 to 2020. Mecillinam is a first-in-class amidinopenicillin antibiotic, being the only β-lactam to exert its antibacterial activity through exclusive binding to penicillin-binding protein 2. Pivmecillinam is the oral prodrug of mecillinam and is recommended as a first-line therapy by the Infectious Disease Society of America guidelines for uncomplicated UTIs and is approved for the treatment of uncomplicated UTIs in Europe, Canada, and the United States., Methods: A total of 3303 isolates were collected and antimicrobial susceptibility determined according to Clinical Laboratory and Standards Institute (CLSI) guidelines., Results: Susceptibility was highest for fosfomycin (97.1% susceptible) and mecillinam (94.9% susceptible). Against extended-spectrum beta-lactamase (ESBL)-positive bacteria susceptibilities were highest for mecillinam (98.2% susceptible) and fosfomycin (97.3% susceptible) and against ESBL-positive K. pneumoniae only mecillinam and fosfomycin had > 80% susceptibility. Resistance to comparator antibiotics was highest for trimethoprim-sulfamethoxazole (27.1%), followed by ciprofloxacin (19.3%), ceftriaxone (19.2%), and nitrofurantoin (12.1%). Multi-drug-resistant isolates were most susceptible to mecillinam and fosfomycin., Conclusion: The data further support the clinical development and clinical utility of mecillinam. © 2024 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy., Competing Interests: Declaration of competing interest SH, NK, and FM are employees of IHMA Europe Sàrl. IM is a former employee of IHMA Europe Sàrl and is currently an independent consultant. ASH is a contractor for Utility Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study was performed to investigate the activity of the novel ß-lactam/ß-lactamase inhibitor combination cefepime/enmetazobactam, against recently circulating Enterobacterales isolates from Europe from 2019 to 2021., Methods: A total of 2627 isolates were collected, and antimicrobial susceptibility was determined according to the European Committee on Antimicrobial Susceptibility Testing guidelines. Isolates with phenotypic resistance to ceftriaxone and ceftazidime (but susceptible to meropenem) and isolates nonsusceptible to meropenem were screened for the presence of ß-lactamases., Results: Overall, susceptibility to third-generation cephalosporins was 77%, and 97.3% were susceptible to meropenem. Cefepime/enmetazobactam susceptibility was 97.9% (72% of these isolates were Klebsiella pneumoniae from Italy), compared with 80.0% susceptibility to piperacillin/tazobactam and 99.4% to ceftazidime/avibactam. A total of 320 isolates (12.2%) were resistant to third-generation cephalosporins but susceptible to meropenem, and virtually all (96.3%) carried an extended-spectrum ß-lactamase with or without an AmpC and these were all susceptible to cefepime/enmetazobactam. Most meropenem-nonsusceptible isolates carried a KPC (68%), which were not inhibited by cefepime/enmetazobactam but were inhibited by ceftazidime/avibactam. Additionally, most meropenem-nonsusceptible isolates carrying OXA-48 (9/12 isolates) were susceptible to cefepime/enmetazobactam., Conclusions: Cefepime/enmetazobactam was highly active against Enterobacterales isolates, especially those resistant to third-generation cephalosporins. These data suggest that cefepime/enmetazobactam could be used as a carbapenem-sparing agent to replace piperacillin/tazobactam., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The current study evaluated the in vitro activities of ceftolozane/tazobactam (C/T), imipenem/relebactam (IMI/REL), and comparators against recent (2017-2021) clinical isolates of gram-negative bacilli from two countries in southern Europe., Methods: Nine clinical laboratories (two in Greece; seven in Italy) each collected up to 250 consecutive gram-negative isolates per year from lower respiratory tract, intraabdominal, urinary tract, and bloodstream infection samples. MICs were determined by the CLSI broth microdilution method and interpreted using 2022 EUCAST breakpoints. β-lactamase genes were identified in select β-lactam-nonsusceptible isolate subsets., Results: C/T inhibited the growth of 85-87% of Enterobacterales and 94-96% of ESBL-positive non-CRE NME (non-Morganellaceae Enterobacterales) isolates from both countries. IMI/REL inhibited 95-98% of NME, 100% of ESBL-positive non-CRE NME, and 98-99% of KPC-positive NME isolates from both countries. Country-specific differences in percent susceptible values for C/T, IMI/REL, meropenem, piperacillin/tazobactam, levofloxacin, and amikacin were more pronounced for Pseudomonas aeruginosa than Enterobacterales. C/T and IMI/REL both inhibited 84% of P. aeruginosa isolates from Greece and 91-92% of isolates from Italy. MBL rates were estimated as 4% of Enterobacterales and 10% of P. aeruginosa isolates from Greece compared to 1% of Enterobacterales and 3% of P. aeruginosa isolates from Italy. KPC rates among Enterobacterales isolates were similar in both countries (7-8%). OXA-48-like enzymes were only identified in Enterobacterales isolates from Italy (1%) while GES carbapenemase genes were only identified in P. aeruginosa isolates from Italy (2%)., Conclusion: We conclude that C/T and IMI/REL may provide viable treatment options for many patients from Greece and Italy., (© 2024. Merck & Co., Inc., Rahway, NJ, USA and its affiliates and James A. Karlowsky, Sibylle H. Lob, Stephen P. Hawser, Nimmi Kothari, Daniel F. Sahm.)

ANT3310 is a novel broad-spectrum diazabicyclooctane serine β-lactamase inhibitor being developed in combination with meropenem (MEM) for the treatment of serious infections in hospitalized patients where carbapenem-resistant Gram-negative pathogens are expected. In this study, we evaluated the in vitro antibacterial activity of MEM in the presence of ANT3310 at 8 µg/mL against global clinical isolates that included Acinetobacter baumannii ( n = 905), carbapenem-resistant Enterobacterales (CRE), carrying either oxacillinase (OXA) ( n = 252) or Klebsiella pneumoniae carbapenemase (KPC) ( n = 180) carbapenemases, and Pseudomonas aeruginosa ( n = 502). MEM was poorly active against A. baumannii, as were MEM-vaborbactam, ceftazidime-avibactam, aztreonam-avibactam, cefepime-taniborbactam, cefepime-zidebactam, and imipenem-relebactam (MIC 90 values of ≥32 µg/mL). On the other hand, MEM-ANT3310 displayed an MIC 90 value of 4 µg/mL, similar to that observed with sulbactam-durlobactam, a drug developed to specifically treat A. baumannii infections. ANT3310 (8 µg/mL) additionally restored the activity of MEM against OXA- and KPC-producing CREs decreasing MEM MIC 90 values from >32 µg/mL to 0.25 and 0.5 µg/mL, respectively. The combination of 8 µg/mL of both MEM and ANT3310 prevented growth of 97.5% of A. baumannii and 100% of OXA- and KPC-positive CREs, with ~90% of P. aeruginosa isolates also displaying MEM MICs ≤8 µg/mL. Furthermore, MEM-ANT3310 was efficacious in both thigh and lung murine infection models with OXA-23 A. baumannii . This study demonstrates the potent in vitro activity of the MEM-ANT3310 combination against both carbapenem-resistant A. baumannii and Enterobacterales clinical isolates, a key differentiator to other β-lactam/β-lactamase combinations., Competing Interests: ANTABIO SAS paid for most of the studies presented in this manuscript. M.Z., P.A., A.L., D.D., S.L., C.S., A.L., J.B., J.C., C.L.,M.E., and M.L. were ANTABIO employees at the time this work was performed.

Objectives: To evaluate the in vitro activities of ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Gram-negative bacilli collected in four central and northern European countries (Belgium, Norway, Sweden, Switzerland) during 2017-21., Methods: Participating clinical laboratories each collected up to 250 consecutive Gram-negative isolates per year from patients with bloodstream, intraabdominal, lower respiratory tract or urinary tract infections. MICs were determined by CLSI broth microdilution and interpreted using 2022 EUCAST breakpoints. β-Lactamase genes were identified in select β-lactam-non-susceptible isolate subsets., Results: Ninety-five percent of all Enterobacterales ( n  = 4158), 95% of ESBL-positive non-carbapenem-resistant Enterobacterales (non-CRE) phenotype Escherichia coli and 85% of ESBL-positive non-CRE phenotype Klebsiella pneumoniae were ceftolozane/tazobactam susceptible. By country, 88% (Belgium), 91% (Sweden, Switzerland) and 96% (Norway) of ESBL-positive non-CRE phenotype Enterobacterales were ceftolozane/tazobactam susceptible. Greater than ninety-nine percent of non-Morganellaceae Enterobacterales and all ESBL-positive non-CRE phenotype Enterobacterales were imipenem/relebactam susceptible. Ceftolozane/tazobactam (96%) and imipenem/relebactam (95%) inhibited most Pseudomonas aeruginosa ( n  = 823). Both agents retained activity against ≥75% of cefepime-resistant, ceftazidime-resistant and piperacillin/tazobactam-resistant isolates; 56% and 43% of meropenem-resistant isolates were ceftolozane/tazobactam susceptible and imipenem/relebactam susceptible, respectively. By country, 94% (Belgium), 95% (Sweden) and 100% (Norway, Switzerland) of P. aeruginosa were ceftolozane/tazobactam susceptible and 93% (Sweden) to 98% (Norway, Switzerland) were imipenem/relebactam susceptible. Carbapenemase gene carriage among Enterobacterales and P. aeruginosa isolates was generally low (<1%) or completely absent with one exception: an estimated 2.7% of P. aeruginosa isolates from Belgium carried an MBL., Conclusions: Recent clinical isolates of Enterobacterales and P. aeruginosa collected in four central and northern European countries were highly susceptible (≥95%) to ceftolozane/tazobactam and imipenem/relebactam., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

This study determined the in vitro activity of finafloxacin against panels of bacterial strains, representative of those associated with infection in cystic fibrosis patients and predominately isolated from clinical cases of respiratory disease. Many of these isolates were resistant to various antimicrobials evaluated including the aminoglycosides, cephalosporins, carbapenems and fluoroquinolones. Broth microdilution assays were performed at neutral and acidic pH, to determine antimicrobial activity. Finafloxacin demonstrated superior activity at reduced pH for all of the bacterial species investigated, highlighting the requirement to determine the activity of antimicrobials in host-relevant conditions.

Objectives: To evaluate eravacycline (ERV) activity against Gram-negative and Gram-positive bacteria collected between 2017 and 2020 from worldwide locations., Methods: MIC determinations were performed using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology. ERV and tigecycline susceptibility was interpreted using United States Food and Drug Administration (FDA) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. Comparator susceptibility was interpreted using CLSI and EUCAST breakpoints., Results: ERV MIC 90 was 0.5 µg/mL against 12 436 Enterobacteriaceae isolates, which only increased to 1 µg/mL against multidrug-resistant (MDR) isolates (n = 2931) (23.6%). Similar activity was shown against 1893 Acinetobacter baumannii (MIC 90 1 µg/mL) and 356 Stenotrophomonas maltophilia (MIC 90 2 µg/mL). ERV was more active against Gram-positive bacteria: 415 Streptococcus pneumoniae (MIC 90 0.008 µg/mL), 273 S. anginosus group (MIC 90 0.015 µg/mL), 1876 Enterococcus faecalis and 1724 E. faecium (MIC 90 2 µg/mL), 2158 Staphylococcus aureus and 575 S. saprophyticus (MIC 90 0.12 µg/mL), 1143 S. epidermidis and 423 S. haemolyticus (MIC 90 0.25 µg/mL). ERV MIC 90 against methicillin-resistant staphylococci and vancomycin-resistant enterococci was similar to susceptible strains. However, ERV susceptibility varied between EUCAST or FDA against staphylococci, especially S. epidermidis (91.5% vs. 47.2%), and vancomycin-resistant E. faecalis (98.3% vs. 76.5%)., Conclusion: This study reaffirms ERV's consistent broad-spectrum activity, which has been evaluated since 2003. ERV remains a key agent for the treatment of bacterial infections, including resistant isolates, but urgent reassessment of clinical breakpoints is required for staphylococci and enterococci., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Antimicrobial susceptibility was determined for clinical gram-negative isolates from Czech Republic, Hungary, and Poland, where published data for ceftolozane/tazobactam (C/T) and imipenem/relebactam (IMI/REL) is scarce. C/T was active against 94.3% of Enterobacterales, 10-18% higher than the tested cephalosporins and piperacillin/tazobactam. IMI/REL was the most active tested agent against non-Morganellaceae Enterobacterales (99.7% susceptible). C/T was the most active among all studied agents except colistin against Pseudomonas aeruginosa (96.0% susceptible); susceptibility to IMI/REL was 90.7%. C/T maintained activity against 73.7-85.3% of β-lactam-resistant or multidrug-resistant P. aeruginosa subsets. C/T and IMI/REL could represent important treatment options for patients from these countries., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction. Piperacillin/tazobactam and carbapenems are important agents for the treatment of serious Gram-negative infections in hospitalized patients. Resistance to both agents is a significant concern in clinical isolates of Enterobacterales and Pseudomonas aeruginosa ; new agents with improved activity are needed. Gap Statement. Publication of current, region-specific data describing the in vitro activity of newer agents such as imipenem/relebactam (IMR) against piperacillin/tazobactam-resistant and carbapenem-resistant Enterobacterales and P. aeruginosa are needed to support their clinical use. Aim. To describe the in vitro activity of IMR against non- Morganellaceae Enterobacterales (NME) and P. aeruginosa isolated from bloodstream, intra-abdominal and urinary tract infection samples by hospital laboratories in Western Europe with a focus on the activity of IMR against piperacillin/tazobactam-resistant and meropenem-resistant isolates. Methodology. From 2018 to 2020, 29 hospital laboratories in six countries in Western Europe participated in the SMART global surveillance programme and contributed 9487 NME and 1004 P . aeruginosa isolates. MICs were determined by CLSI broth microdilution testing and interpreted by EUCAST (2021) breakpoints. β-Lactamase genes were identified in selected isolate subsets (2018-2020) and oprD sequenced in molecularly characterized P. aeruginosa (2020). Results. IMR (99.4 % susceptible), amikacin (98.0 %), meropenem (97.7 %) and imipenem (97.6 %) were the most active agents against NME; 83.1 % of NME were piperacillin/tazobactam-susceptible. Relebactam increased imipenem susceptibility of NME from Italy by 8.3 %, from Portugal by 2.9 %, and from France, Germany, Spain and the UK by <1 %. In total, 96.4 % of piperacillin/tazobactam-resistant ( n =1601) and 73.7 % of meropenem-resistant ( n =152) NME were IMR-susceptible. Also, 0.4 % of NME were MBL-positive, 0.9 % OXA-48-like-positive (MBL-negative) and 1.5 % KPC-positive (MBL-negative). Amikacin (95.4 % susceptible) and IMR (94.1 %) were the most active agents against P. aeruginosa ; 81.7 % of isolates were imipenem-susceptible and 79.6 % were piperacillin/tazobactam-susceptible. Relebactam increased susceptibility to imipenem by 12.5 % overall (range by country, 4.3-17.5 %); and by 30.7 % in piperacillin/tazobactam-resistant and 24.3 % in meropenem-resistant P. aeruginosa . In total, 1.6 % of P. aeruginosa isolates were MBL-positive. Seven of eight molecularly characterized IMR-resistant P. aeruginosa isolates from 2020 were oprD -deficient. Conclusion. IMR may be a potential treatment option for bloodstream, intra-abdominal and urinary tract infections caused by NME and P. aeruginosa in Western Europe, including infections caused by piperacillin/tazobactam-resistant and meropenem-resistant isolates.

The rapid worldwide spread of antimicrobial resistance highlights the significant need for the development of innovative treatments to fight multidrug-resistant bacteria. This study describes the potent antimicrobial activity of the novel peptide OMN6 against a wide array of drug-resistant Acinetobacter baumannii clinical isolates. OMN6 prevented the growth of all tested isolates, regardless of any pre-existing resistance mechanisms. Moreover, in vitro serial-passaging studies demonstrated that no resistance developed against OMN6. Importantly, OMN6 was highly efficacious in treating animal models of lung and blood infections caused by multidrug-resistant A. baumannii . Taken together, these results point to OMN6 as a novel antimicrobial agent with the potential to treat life-threatening infections caused by multidrug-resistant A. baumannii avoiding resistance.

Objectives: Ceftobiprole is approved for use in treatment of hospital-associated and community-acquired pneumonia in 16 different European countries and is currently undergoing clinical trials in the United States., Methods: Isolates were collected from hospital laboratories from 16 European countries during 2019 as part of an ongoing post-marketing surveillance study. MICs were determined using EUCAST broth microdilution methodology and interpreted using 2020 EUCAST breakpoints., Results: Ceftobiprole was active (MIC, ≤2 mg/L) against 100% and 99.3% of methicillin-susceptible Staphylococcus aureus and MRSA isolates collected in 2019. Against Streptococcus pneumoniae, ceftobiprole was active (MIC, ≤0.5 mg/L) against 98.4% of isolates. Overall, 77.4% of Enterobacterales were susceptible though isolate numbers in certain countries were notably low. In addition, based on non-species-related PK/PD breakpoints, 69.7% of Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. Analysis of data by geographical regions showed that susceptibility to ceftobiprole by region or country was not significantly varied though MRSA, S. pneumoniae, Enterobacterales and P. aeruginosa. Isolates from Italy had lower susceptibilities to ceftobiprole: 98% of MRSA, 94% of S. pneumoniae and 61% of Enterobacterales isolates were susceptible to ceftobiprole., Conclusion: The data for ceftobiprole for isolates from 2019 are encouragingly very similar to studies performed on isolates from earlier years showing that susceptibility to ceftobiprole has not changed and, importantly, that resistance emergence remains low throughout Europe., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study aimed to investigate third-generation cephalosporin (3GC) resistance determinants [extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases and OXA-type β-lactamases] in contemporary clinical Enterobacterales isolates and to determine the in vitro activity of β-lactams and β-lactam/β-lactamase inhibitor combinations, including the investigational combination of cefepime and the novel β-lactamase inhibitor enmetazobactam., Methods: Antibacterial susceptibility of 7168 clinical Enterobacterales isolates obtained between 2016-2018 from North America and Europe was determined according to CLSI guidelines. Phenotypic resistance to the 3GC ceftazidime (MIC ≥ 16 µg/mL) and/or ceftriaxone (MIC ≥ 4 µg/mL) but retaining susceptibility to meropenem (MIC ≤ 1 µg/mL) was determined. β-Lactamase genotyping was performed on clinical isolates with ceftazidime, ceftriaxone, cefepime or meropenem MIC ≥ 1 µg/mL., Results: Phenotypic resistance to 3GCs occurred in 17.5% of tested isolates, whereas 2.1% of isolates were resistant to the carbapenem meropenem. Within the 3GC-resistant subgroup, 60.1% (n = 752) of isolates encoded an ESBL, 25.6% (n = 321) encoded an AmpC-type β-lactamase and 0.9% (n = 11) encoded an OXA-type β-lactamase. Susceptibility of the subgroup to piperacillin/tazobactam (57.5%) and ceftolozane/tazobactam (71.3%) was <90% based on breakpoints established by the CLSI. Projected susceptibility to cefepime/enmetazobactam was 99.6% when applying the cefepime susceptible, dose-dependent breakpoint of 8 µg/mL. Against ESBL-producing isolates (n = 801) confirmed by genotyping, only susceptibility to meropenem (96.0%) and cefepime/enmetazobactam (99.9%) exceeded 90%., Conclusion: This study describes the antibacterial activity of important therapies against contemporary 3GC-resistant clinical Enterobacterales isolates and supports the development of cefepime/enmetazobactam as a carbapenem-sparing option for ESBL-producing pathogens., Competing Interests: Declaration of Competing Interest AB is a paid consultant for Allecra Therapeutics SAS; PK is an employee of Allecra Therapeutics SAS; IM, SH and NK are employees of IHMA Europe Sàrl., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Ceftobiprole was active (MIC, ≤2 mg/L) against most isolates (99.7%; 877/880) of methicillin-resistant Staphylococcus aureus from respiratory tract infections collected in 14 European countries during 2016-2017. Whole-genome sequence analysis showed that two of the three ceftobiprole-resistant (MIC, 4 mg/L) isolates identified were clonal complex 8 (CC8) and one was CC5, and that different mutations were present in genes encoding penicillin-binding proteins, mecA, and other proteins in each ceftobiprole-resistant isolate., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to demonstrate the efficacy of iclaprim in a neutropenic rat lung infection model with methicillin-resistant Staphylococcus aureus (MRSA) entrapped in alginate beads. An inoculum of 5.25 × 10 5 colony-forming units (CFU)/mL of S. aureus strain AH1252 was administered intratracheally to rats with prepared alginate bacteria suspensions. Beginning 2 h post-infection, rats received: (1) iclaprim 80 mg/kg (n = 16); (2) iclaprim 60 mg/kg (n = 16), or (3) vancomycin 50 mg/kg (n = 24), for 3 days via subcutaneous (SC) injection every 12 h. Twelve hours after the last treatment, rats were euthanized and lungs collected for CFU determination. Iclaprim administered at 80 mg/kg or 60 mg/kg or vancomycin 50 mg/kg SC twice a day for 3 days resulted in a 6.05 log 10 CFU reduction (iclaprim 80 mg/kg compared with control, p < 0.0001), 5.11 log 10 CFU reduction (iclaprim 60 mg/kg compared with control, p < 0.0001), and 3.42 log 10 CFU reduction, respectively, from the controls (p < 0.0001). Iclaprim 80 mg/kg and 60 mg/kg resulted in 2.59 and 1.69 log 10 CFU reductions, respectively, from vancomycin-treated animals (80 mg/kg iclaprim vs. vancomycin, p = 0.0005; 60 mg/kg iclaprim vs. vancomycin, p = 0.07). Animals receiving iclaprim, vancomycin, and controls demonstrated 100%, 91.7%, and 48.3% survival, respectively. In this neutropenic rat S. aureus lung infection model, rats receiving iclaprim demonstrated a greater CFU reduction than the controls or those receiving vancomycin.