Exploring the Complexities of Intestinal and Pulmonary Microbiota in Cystic Fibrosis: A Multi-Omics Approach.

Background: We aimed to elucidate the cystic fibrosis (CF) microbiota composition (shotgun metagenomics) and functionality (short-chain fatty acids, SCFAs).

Methods: Fecal and sputum samples were recruited from 39 clinically stable CF subjects.

Results: Bacillota and Pseudomonadota were dominant in both gut and lung compartments, whereas Ascomycota were the most abundant fungi in feces, and Basidiomycota, especially Malassezia globosa, in sputum.

How do I manage Difficult-to-Treat Pseudomonas aeruginosa infections?: Key Questions for Today's Clinicians.

Background: Pseudomonas aeruginosa has a remarkable ability to develop resistance to antimicrobials in vivo, often leaving very limited therapeutic options and making treatment particularly challenging. In fact, P. aeruginosa infections with "difficult-to-treat resistance" are one of the most concerning contemporary bacterial infections.

An antisense peptide-conjugated peptide nucleic acid (PPNA) for peptidoglycan recycling inhibition reduces AmpC hyperproduction and β-lactam resistance in .

We performed a proof-of-concept study to validate a peptide-conjugated peptide nucleic acid (PPNA) directed to inhibit peptidoglycan recycling as strategy to reduce AmpC hyperproduction and β-lactam resistance in . Our -targeting PPNA at 2 µM decreased mRNA levels of and to about a quarter in the AmpC high-level hyperproducer mutant PAdacBΔD and a previously characterized clinical strain with similar features, causing low cytotoxicity on human A549 cells. Ceftazidime minimum inhibitory concentration decreased from 64 to 8 mg/L in both strains after combination with 2 µM PPNA (which showed significant synergy in checkerboard assays), suggesting that -targeting PPNAs can be explored as weapons to sensitize against β-lactams and return therapeutic value to these essential drugs.

Spanish nationwide survey of Pseudomonas aeruginosa cefiderocol susceptibility and resistance mechanisms.

Objective: Cefiderocol is a new siderophore-cephalosporin showing potent activity against Pseudomonas aeruginosa, including isolates showing extensively drug-resistant (XDR) or difficult-to-treat resistant (DTR) phenotypes. However, there is still a limited understanding of the potential resistance mechanisms. The objective of this study was to analyse the activity of cefiderocol in a nationwide Spanish survey, determine its stability against most relevant resistance mechanisms, and analyse potential drivers of resistance through whole-genome sequencing.

Corticosteroids modulate biofilm formation and virulence of .

Corticosteroids are anti-inflammatory drugs commonly administered to patients with chronic obstructive pulmonary disease (COPD), cystic fibrosis and similar lung pathologies, in which persistent infections with are frequent. However, their therapeutic value is debatable because of their adverse impact on host immunity. The aim of this work was to determine the impact of budesonide and fluticasone propionate on biology.

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.

Management of multidrug-resistant gram-negative bacilli infections in adult solid organ transplant recipients: GESITRA-IC/SEIMC, CIBERINFEC, and SET recommendations update.

Multidrug-resistant (MDR) Gram-negative bacilli (GNB) infections in solid organ transplant (SOT) recipients continue to pose a significant threat despite advances in diagnostics and treatments. The last international consensus guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) on the management of MDR GNB in adult solid organ transplant (SOT) recipients were published in 2018, underscoring the need for an update to incorporate recent advances, particularly the availability of new drugs that may improve the current standard of care. A working group consisting of members from the Study Group of Infection in Transplantation and Immunocompromised Hosts (GESITRA-IC) of SEIMC, the Center for Biomedical Research Network in Infectious Diseases (CIBERINFEC) and the Spanish Society of Transplantation (SET) developed consensus-based recommendations for managing MDR GNB infections during the transplant procedure.

Effects of different resistance mechanisms on bacterial response to meropenem, ciprofloxacin, and their combination described by next-generation mechanism-based modelling.

Objective: This study aimed to investigate the effects of different bacterial resistance mechanisms on the response of isogenic strains of Pseudomonas aeruginosa to meropenem and ciprofloxacin, in monotherapy and combination.

Methods: Seven isogenic P. aeruginosa strains were used: the PAO1 wild-type reference parent strain, PAΔAD (AmpC overexpression), PAOD1 (OprD porin loss), PAΔmexR (MexAB-OprM overexpression), and strains with two of these mutations (PAΔDMxR, PAOD1MxR, PAOD1ΔD).

Analysis of intrahospital and global dissemination and resistome dynamics of NDM-1-producing ST773 high-risk clone.

Objectives: To analyse the intrahospital and global dissemination and resistome dynamics of the concerning NDM-1 MBL-producing ST773 high-risk clone.

Methods: A total of 17 NDM-1-producing isolates recovered in 2022-24 from 10 patients at Hospital Clinic of Barcelona (HCB), Spain, were studied through susceptibility testing and WGS. Expression of resistance genes was analysed through quantitative (real-time) RT-PCR.

Ceftazidime-avibactam use selects multidrug-resistance and prevents designing collateral sensitivity-based therapies against Pseudomonas aeruginosa.

Ceftazidime-avibactam is a β-lactam/β-lactamase inhibitor combination restricted for the treatment of multidrug-resistant infections of Pseudomonas aeruginosa non-susceptible to ceftazidime and resistant to carbapenems. Crucially, it has not been studied if its use could allow the design or application of new or stablished evolution-based strategies that exploit the increased susceptibility that emerges when resistance is acquired (collateral sensitivity, CS). Works in the field have focused on the study of CS in model strains, but to be exploited it must robustly emerge in pre-existing resistant mutants that can coexist in a patient.

Whole Genome Sequencing Analysis of Isolates from Health Care-Associated Bacteremia of Urinary Origin in Spain: Findings from the Multicenter ITUBRAS-2 Cohort Study.

Background: The objective of this study was to assess the microbiological and clinical features of health care-associated bacteremia of urinary origin (HCA-BUO) in Spain, with a focus on third-generation cephalosporin-(3GCR-Kp) and carbapenem-resistant (CR-Kp) isolates.

Methods: A total of 96 (21.4%, 96/449) blood isolates were prospectively collected from patients with HCA-BUO (n = 443) from 12 tertiary care hospitals in Spain (2017-2019).

chronic infections in patients with bronchiectasis: a silent reservoir of carbapenemase-producing epidemic high-risk clones.

Objectives: is one of the major drivers of morbidity and mortality in patients with chronic underlying diseases. Whereas cystic fibrosis (CF) strains have been well studied, non-CF bronchiectasis isolates have received less scientific attention.

Methods: We determined the antibiotic susceptibility profiles of a collection of 100 isolates recovered from a total of 100 non-CF bronchiectasis patients attending a Catalonian hospital.

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.

Emerging resistance mechanisms to newer β-lactams in Pseudomonas aeruginosa.

Background: Although the introduction of novel β-lactams and/or combinations with β-lactamase inhibitors over the last decade is helping to mitigate the threat of extensively drug-resistant/difficult-to-treat-resistant (XDR/DTR) Pseudomonas aeruginosa infections, the problem is far from being solved, due to the capacity of this pathogen for developing resistance.

Objectives: This study aims to provide a comprehensive analysis of the emerging/evolving resistance mechanisms to the antipseudomonal β-lactams introduced over the last decade.

Sources: Sources include literature review of published studies before December 31 2024 analysing P.

Ceftazidime-avibactam plus aztreonam cocktail for the treatment of VIM-producing Pseudomonas aeruginosa infections: good enough to have another?

Background: Few active antibiotic options are available to treat MBL-producing Pseudomonas aeruginosa infections, and some of these options are either poorly tolerated or have pharmacokinetic limitations. The use of aztreonam monotherapy for treating MBL-producing P. aeruginosa remains controversial due to the risk of selecting resistant mutants during treatment.

Mutant prevention concentrations and phenotypic and genomic profiling of first-step resistance mechanisms to classical and novel β-lactams in .

A growing number of novel antipseudomonal β-lactams have been introduced in recent years, but the emergence of resistance is still a major concern in the treatment of infections. Here, we compared the mutant prevention concentrations (MPCs) and the nature of first-step resistant mutants to classical and novel β-lactams in . MPCs were determined in duplicate experiments for ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem, imipenem/relebactam, meropenem, meropenem/vaborbactam, aztreonam, aztreonam/avibactam, and cefiderocol in PAO1, PAOMS (Δ), and three extensively drug-resistant (XDR) clinical strains belonging to high-risk clones ST111, ST175, and ST235.

Pharmacodynamic interaction of apotransferrin and anti-pseudomonal antibiotics against extensively drug-resistant Pseudomonas aeruginosa in a dynamic PK/PD model.

Objectives: The rise of antibiotic resistance in clinical settings poses a major challenge. Apotransferrin has emerged as a potential non-traditional therapy for combating infections, potentially preventing resistance development while enhancing bactericidal effects. This study evaluated the efficacy of apotransferrin combined with antipseudomonal antibiotics against extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates.

Correction: Roson-Calero et al. Cyclic Peptide MV6, an Aminoglycoside Efficacy Enhancer Against . 2024, , 1147.

In the original publication [...

Addressing carbapenemase-producing extensively drug-resistant Pseudomonas aeruginosa: the potential of cefiderocol and ceftazidime/avibactam plus aztreonam therapy.

This study evaluated the activity of cefiderocol and the combination of ceftazidime/avibactam (CZA) plus aztreonam against carbapenemase-producing extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates. Nine clinical XDR P. aeruginosa isolates with different sequence types and class A (GES) or B (VIM, IMP or NDM) carbapenemases were analysed.

Study of the probability of resistance to phage infection in a collection of clinical isolates of s in relation to the presence of Pf phages.

is a bacterial pathogen that is a major cause of lung infections in cystic fibrosis (CF) and other patients. Isolates of from CF patients commonly carry filamentous phages (Pf phages), which constitute a family of temperate phages known to be related to biofilm production and antibiotic sequestration. In this study, we identified 12 new Pf phage genomes in a collection of clinical isolates of from CF patients.

Cyclic Peptide MV6, an Aminoglycoside Efficacy Enhancer Against .

: is a globally emerging pathogen with widespread antimicrobial resistance driven by multiple mechanisms, such as altered expression of efflux pumps like AdeABC, placing it as a priority for research. Driven by the lack of new treatments, alternative approaches are being explored to combat its infections, among which efficacy-enhancing adjuvants can be found. This study presents and characterizes MV6, a synthetic cyclic peptide that boosts aminoglycoside efficacy.

A multirange paper-based analytical device for identifying low, moderate, and high P. aeruginosa bacterial loads in sputum samples.

In this article we introduce a multirange analytical device that extends the dynamic range of nanoparticle-based immunoassays thanks to a multisensor design. Multirange devices contain low- and high-range sensors in the same analytical platform. The low-range sensor defines the limit of detection and quantifies low concentrated analytes, whereas the high-range sensor defines the upper limit of the dynamic range.

Differential contribution of PBP occupancy and efflux on the effectiveness of β-lactams at their target site in clinical isolates of Neisseria gonorrhoeae.

Neisseria gonorrhoeae exhibits alarming antibiotic resistance trends and poses a significant challenge in therapeutic management. This study aimed to explore the association of penA alleles with penicillin-binding protein (PBP) occupancy patterns and reduced outer membrane permeability, impacting susceptibility to last-line cephalosporins and potential β-lactam candidates. The whole genome sequence, the MICs and PBP IC50s were determined for 12 β-lactams and β-lactamase inhibitors in 8 clinical isolates with varying β-lactam sensitivity, 2 ATCC, and 3 WHO cephalosporin-resistant reference strains.

potentiation of tetracyclines in by RW01, a new cyclic peptide.

The pipeline for new drugs against multidrug-resistant remains limited, highlighting the urgent need for innovative treatments. New strategies, such as membrane-targeting molecules acting as adjuvants, aim to enhance antibiotic effectiveness and combat resistance. RW01, a cyclic peptide with low antimicrobial activity, was selected as an adjuvant to enhance drug efficacy through membrane permeabilization.