Broad spectrum of β-lactamase coverage and potent antimicrobial activity of xeruborbactam in combination with meropenem against carbapenemase-producing Enterobacterales, including strains resistant to new β-lactam/β-lactamase inhibitor combinations.

Xeruborbactam is a broad-spectrum boronate-type β-lactamase inhibitor. We aimed to evaluate its activity in combination with meropenem and compare it with other β-lactam/β-lactamase inhibitor combinations against Enterobacterales. The following isolates were screened: (i) an isogenic collection of 94 isolates producing β-lactamases under wild-type and low-permeability conditions, (ii) 300 genetically diverse clinical Enterobacterales isolates producing the three main carbapenemase types (KPC-like, OXA-48-like, and metallo-β-lactamases), and (iii) two collections of isolates producing mechanisms of resistance to β-lactam/β-lactamase inhibitor combinations, such as KPC variants or PBP3 insertions combined with metallo-β-lactamases (MBLs).

Functional and structural analyses of amino acid sequence variation in PDC β-lactamase reveal different mechanistic pathways toward cefiderocol resistance in .

A wide variety of clinically observed amino acid alterations in the chromosomal β-lactamase AmpC (-derived cephalosporinase [PDC]) are associated with increased resistance to cefepime, ceftolozane/tazobactam, or ceftazidime/avibactam, but their impact on cefiderocol resistance is unclear. We took advantage of a previously engineered collection of wild-type (PAO1) and iron uptake-deficient (PAO Δ) isolates producing 19 distinct PDC variants with substitutions in key catalytic regions. While most variants had moderate effects on cefiderocol minimum inhibitory concentrations compared to PDC-1, the E219K (Ω-loop) and L293P (helix H10) variants significantly affected cefiderocol activity.

Rapid prediction of carbapenemases in by imipenem/relebactam and MALDI-TOF MS.

is a major nosocomial pathogen commonly involved in multidrug-resistant (MDR) infections that are very difficult to treat. Imipenem/relebactam is a new carbapenem/β-lactamase inhibitor combination with robust activity against . However, resistance is increasingly reported, and rapid detection is, therefore, crucial so that appropriate treatments can be prescribed.

Advancements in the fight against globally distributed OXA-48 carbapenemase: evaluating the new generation of carbapenemase inhibitors.

Carbapenemase OXA-48 and its variants pose a serious threat to the development of effective treatments for bacterial infections. OXA-48-producing Enterobacterales are the most prevalent carbapenemase-producing bacteria in large parts of the world. Although these bacteria exhibit low-level carbapenem resistance , the infections they cause are challenging to treat with conventional therapies, owing to their spread and complex detection in clinical settings.

Activity and resistance mechanisms of the third generation tetracyclines tigecycline, eravacycline and omadacycline against nationwide Spanish collections of carbapenemase-producing Enterobacterales and Acinetobacter baumannii.

Introduction: The rise in multidrug-resistant bacteria challenges clinical microbiology. Tigecycline, eravacycline, and omadacycline show promise against carbapenem-resistant Enterobacterales and Acinetobacter baumannii. This study evaluates their activity and resistance mechanisms.

Mutant prevention concentrations, resistance evolution dynamics, and mechanisms of resistance to imipenem and imipenem/relebactam in carbapenem-susceptible isolates showing ceftazidime/avibactam resistance.

carbapenemase (KPC) variants selected during ceftazidime/avibactam treatment usually develop susceptibility to carbapenems and carbapenem/β-lactamase inhibitors, such as imipenem and imipenem/relebactam. We analyzed imipenem and imipenem/relebactam single-step mutant frequencies, resistance development trajectories and differentially selected resistance mechanisms using two representative isolates that had developed ceftazidime/avibactam resistance during therapy (ST512/KPC-31 and ST258/KPC-35). Mutant frequencies and mutant prevention concentrations were measured in Mueller-Hinton agar plates containing incremental concentrations of imipenem or imipenem/relebactam.

emergence of resistance to ceftazidime/avibactam through modification of chromosomal AmpC β-lactamase in .

We describe the emergence of resistance to ceftazidime/avibactam via modification of AmpC in a clinical isolate during therapy with this combination. Paired ceftazidime/avibactam-susceptible/resistant isolates were obtained before and during ceftazidime/avibactam treatment. Whole genome sequencing revealed a differential mutation in AmpC (R148W) in the ceftazidime/avibactam-resistant isolate.

Impact of transferable β-lactamases and intrinsic AmpC amino acid substitutions on the activity of cefiderocol against wild-type and iron uptake-deficient mutants of Pseudomonas aeruginosa.

Objectives: We aimed to analyse the interplay between impaired iron uptake and β-lactamases on cefiderocol resistance in Pseudomonas aeruginosa.

Methods: Thirty-one transferable β-lactamases and 16 intrinsic P. aeruginosa AmpC (PDC) variants were cloned and expressed in wild-type (PAO1) and iron uptake-deficient (PAO ΔpiuC) P.

Impact of chromosomally encoded resistance mechanisms and transferable β-lactamases on the activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against Pseudomonas aeruginosa.

Objectives: We aimed to compare the stability of the newly developed β-lactams (cefiderocol) and β-lactam/β-lactamase inhibitor combinations (ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam) against the most clinically relevant mechanisms of mutational and transferable β-lactam resistance in Pseudomonas aeruginosa.

Methods: We screened a collection of 61 P. aeruginosa PAO1 derivatives.

In vitro development of imipenem/relebactam resistance in KPC-producing Klebsiella pneumoniae involves multiple mutations including OmpK36 disruption and KPC modification.

Objectives: In order to inform and anticipate potential strategies aimed at combating KPC-producing Klebsiella pneumoniae infections, we analysed imipenem/relebactam and ceftazidime/avibactam single-step mutant frequencies, resistance development trajectories, differentially selected resistance mechanisms and their associated fitness cost using four representative high-risk K. pneumoniae clones.

Methods: Mutant frequencies and mutant preventive concentrations were determined using agar plates containing incremental concentrations of β-lactam/β-lactamase inhibitor.