Evaluation of the activity of cefepime/enmetazobactam against Enterobacterales bacteria collected in Europe from 2019 to 2021, including third-generation cephalosporin-resistant isolates.

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 in 2019 to 2021. METHODS: A total of 2,627 isolates were collected and antimicrobial susceptibility determined according to EUCAST guidelines. Isolates with phenotypic resistance to ceftriaxone and ceftazidime (but susceptible to meropenem), and isolates non-susceptible 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 to 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 ESBL with or without an AmpC and these were all susceptible to cefepime/enmetazobactam. Most meropenem-non-susceptible isolates carried a KPC (68%) which were not inhibited by cefepime/enmetazobactam but were inhibited by ceftazidime/avibactam. Most meropenem-non-susceptible isolates carrying OXA-48 (9/12 isolates) were susceptible to cefepime/enmetazobactam. CONCLUSION: 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.

Activity of ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected in Greece and Italy-SMART 2017-2021.

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. ß-lactamase genes were identified in select ß-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.

Activity of ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected in central and northern Europe (Belgium, Norway, Sweden, Switzerland)-SMART 2017-21.

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. ß-Lactamase genes were identified in select ß-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.

In vitro activity of eravacycline and comparators against Gram-negative and Gram-positive bacterial isolates collected from patients globally between 2017 and 2020.

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 MIC90 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 (MIC90 1 µg/mL) and 356 Stenotrophomonas maltophilia (MIC90 2 µg/mL). ERV was more active against Gram-positive bacteria: 415 Streptococcus pneumoniae (MIC90 0.008 µg/mL), 273 S. anginosus group (MIC90 0.015 µg/mL), 1876 Enterococcus faecalis and 1724 E. faecium (MIC90 2 µg/mL), 2158 Staphylococcus aureus and 575 S. saprophyticus (MIC90 0.12 µg/mL), 1143 S. epidermidis and 423 S. haemolyticus (MIC90 0.25 µg/mL). ERV MIC90 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.

In Vitro and In Vivo Antimicrobial Activity of the Novel Peptide OMN6 against Multidrug-Resistant Acinetobacter baumannii.

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.

Susceptibility of ceftobiprole against Gram-positive and Gram-negative clinical isolates from 2019 from different European territories.

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.

Surveillance of ceftobiprole against Gram-positive and Gram-negative clinical isolates from 2018 from different European territories.

OBJECTIVES: Ceftobiprole is approved for the treatment of hospital-acquired and community-acquired pneumonia in 17 different European countries and is currently undergoing clinical trials in the USA. METHODS: In this study, isolates were collected from hospital laboratories from 15 European countries during 2018 as part of an ongoing post-marketing surveillance study. Minimum inhibitory concentrations (MICs) were determined using European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution methodology and were interpreted using 2019 EUCAST breakpoints. RESULTS: Ceftobiprole was active (MIC, ≤2 mg/L) against 100% and 98.9% of methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) from 2018, respectively. Only six MRSA isolates (1.1%) were resistant to ceftobiprole and originated from four countries. Against Streptococcus pneumoniae, ceftobiprole was active (MIC, ≤0.5 mg/L) against 98.7% of isolates. Overall, 75.6% of Enterobacterales were susceptible, although isolate numbers in certain countries were notably low. In addition, based on non-species-related pharmacokinetic/pharmacodynamic breakpoints, 63.2% of Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. CONCLUSION: Data for ceftobiprole for isolates from 2018 are very similar to studies performed on isolates from earlier years, showing that susceptibility to ceftobiprole has remained high.

Third-generation cephalosporin resistance in clinical isolates of Enterobacterales collected between 2016-2018 from USA and Europe: genotypic analysis of ß-lactamases and comparative in vitro activity of cefepime/enmetazobactam.

OBJECTIVES: This study aimed to investigate third-generation cephalosporin (3GC) resistance determinants [extended-spectrum ß-lactamases (ESBLs), AmpC ß-lactamases and OXA-type ß-lactamases] in contemporary clinical Enterobacterales isolates and to determine the in vitro activity of ß-lactams and ß-lactam/ß-lactamase inhibitor combinations, including the investigational combination of cefepime and the novel ß-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. ß-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 ß-lactamase and 0.9% (n = 11) encoded an OXA-type ß-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.

In vitro activity of imipenem-relebactam against resistant phenotypes of Enterobacteriaceae and Pseudomonas aeruginosa isolated from intraabdominal and urinary tract infection samples - SMART Surveillance Europe 2015-2017.

Introduction. Infections attributable to carbapenem-resistant Gram-negative bacilli are increasing globally. New antimicrobial agents are urgently needed to treat patients with these infections.Aim. To describe susceptibility to the novel carbapenem-ß-lactamase inhibitor combination imipenem-relebactam and comparators of clinical isolates of non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas aeruginosa from intraabdominal infections (IAIs) and urinary tract infections (UTIs).Methods. Broth microdilution MICs were determined for isolates collected in 22 European countries in 2015-2017 and interpreted using EUCAST breakpoints; imipenem-relebactam MICs were interpreted using imipenem breakpoints.Results. For NPE, 98.4 % of isolates from IAIs (n=10,465) and 98.5 % of UTI isolates (n=7,446) were susceptible to imipenem-relebactam, as were 42.4 % of imipenem-nonsusceptible (n=474), 98.6 % of Klebsiella pneumoniae carbapenemase (KPC)-positive (n=138), and 93.9 % of multidrug-resistant (MDR) isolates (n=4,424) from IAIs and UTIs combined. Molecular analysis demonstrated that two-thirds of imipenem-nonsusceptible isolates rendered susceptible by relebactam carried KPCs; 96 % (261/271) of imipenem-nonsusceptible isolates of NPE that remained nonsusceptible in the presence of relebactam carried metallo-ß-lactamase (MBL)-type and/or OXA-48-like carbapenemases. Among P. aeruginosa, 94.4 % of IAI (n=1,245) and 93.0 % of UTI isolates (n=714) were susceptible to imipenem-relebactam, as were 74.4 % of imipenem-nonsusceptible (n=469) and 79.8 % of MDR isolates (n=595) from IAIs and UTIs combined. Among the 120 isolates of P. aeruginosa that remained nonsusceptible to imipenem upon addition of relebactam, 72 % carried MBLs. The distribution of NPE and P. aeruginosa carrying carbapenemases varied substantially across Europe, as did resistance to imipenem and imipenem-relebactam.Conclusions. Continued surveillance of antimicrobial resistance and resistance mechanisms, including the study of imipenem-relebactam as it approaches regulatory approval, appears warranted.

In vitro susceptibility testing of ceftobiprole against 880 European respiratory tract infection isolates of methicillin-resistant Staphylococcus aureus followed by whole genome sequencing of ceftobiprole-resistant isolates.

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.

Activity of imipenem/relebactam against MDR Pseudomonas aeruginosa in Europe: SMART 2015-17.

OBJECTIVES: Relebactam is a diazabicyclooctane non-ß-lactam inhibitor of Ambler class A and C ß-lactamases that is in clinical development in combination with imipenem/cilastatin. The current study evaluated the in vitro activity of imipenem/relebactam against 5447 isolates of Pseudomonas aeruginosa submitted to the SMART global surveillance programme in 2015-17 by 67 clinical laboratories in 22 European countries. METHODS: MICs were determined using the CLSI broth microdilution reference method (Eleventh Edition: M07, 2018). Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. MICs were interpreted using EUCAST clinical breakpoints (version 8.1); imipenem breakpoints were applied to imipenem/relebactam. RESULTS: Rates of susceptibility to imipenem and imipenem/relebactam (MIC ≤4 mg/L) were 69.4% and 92.4%, respectively, for all isolates of P. aeruginosa. Over one-third of all isolates (34.9%, 1902/5447) were MDR; lower respiratory tract isolates (38.3%, 1327/3461) were more frequently MDR than were intraabdominal (28.5%, 355/1245) or urinary tract (29.7%, 212/714) isolates. Of all MDR isolates, 78.2% were susceptible to imipenem/relebactam, a rate that was 50-77 percentage points higher than the rate of susceptibility to imipenem or any other ß-lactam tested; rates of susceptibility to imipenem/relebactam were similar for MDR isolates from lower respiratory tract (77.8% susceptible), intraabdominal (80.3%) and urinary tract (76.4%) infections. Overall, relebactam restored imipenem susceptibility to 75.2% (1254/1668) of imipenem-non-susceptible isolates of P. aeruginosa and to 69.6% (947/1361) of imipenem-non-susceptible isolates with an MDR phenotype. CONCLUSIONS: Relebactam restored in vitro susceptibility to imipenem for most imipenem-non-susceptible and MDR clinical isolates of P. aeruginosa from European patients.