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.

Emergence of KPC-8-producing infection without prior exposure to ceftazidime/avibactam: the threat of infections by ceftazidime/avibactam-resistant KPC variants.

infections caused by ceftazidime/avibactam-resistant KPC variants are rarely reported. We characterize the evolution of a KPC-8-producing strain involved in a primary infection without previous ceftazidime/avibactam treatment. During a 15-month follow-up, changes in carbapenem susceptibility due to porin alterations were observed, remaining susceptible to meropenem/vaborbactam, imipenem/relebactam, and cefiderocol.

Regional distribution of carbapenemase-producing Acinetobacter baumannii isolates in southern Spain (Andalusia).

Objectives: This is the first study conducted in southern Spain to determine i) the population structure (PS) of carbapenem-resistant (CR) Acinetobacter baumannii isolates by multilocus sequencing typing (MLST) and core genome MLST (cgMLST) and ii) the association between the sequence type ST and the bla variant, capsule polysaccharide locus (KL) and lipooligosaccharide outer core locus (OCL) types.

Methods: Of 336 isolates submitted to the Andalusian reference laboratory (PIRASOA; December 2017-2020), 73 were subjected to WGS (MiSeq). The following analyses were performed: bacterial identification (ribosomal MLST), carbapenemase gene detection (Resfinder 4.

Evolution of ceftazidime/avibactam resistance and plasmid dynamics in OXA-48-producing Klebsiella spp. during long-term patient colonization.

Purpose: To prospectively monitor the evolution of the resistome of OXA-48-producing Klebsiella species in a patient with long-term colonization, with a particular focus into the plasmid dynamics and the evolution of ceftazidime/avibactam resistance.

Methods: All OXA-48-producing Klebsiella spp. isolates from a single patient admitted to a hospital during seven months were prospectively collected.

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.

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.

Molecular characterization of consecutive isolates of OXA-48-producing Klebsiella pneumoniae: changes in the virulome using next-generation sequencing (NGS).

Little is known about the clonality of consecutive OXA-48 producing-Klebsiella pneumoniae isolates from the same patient and the possibility of changes in their virulomes over time. We studied the molecular characteristics of twenty OXA-48-producing K. pneumoniae consecutive isolates from six patients using whole-genome sequencing.

Transmission of toxigenic Clostridiodes difficile between a pet dog with diarrhea and a 10-month-old infant.

We describe a case of interspecies transmission of toxigenic Clostridioides difficile involving a female and her dog, both with diarrhea without another diagnosis. Genomic analysis showed that isolates were grouped into MLST clade I, closely related to ribotype 020 and shared identical genotypes.