Long-Term Lung Function and Infection in Genotyped Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia is a rare genetic disorder characterized by progressive lung disease. is a major pathogen in this disease, known to impact lung function. Previous genotype-phenotype studies have been limited by cross-sectional designs, isolated adult or pediatric populations, small numbers, or short follow-up durations.

Macrolide resistance through uL4 and uL22 ribosomal mutations in Pseudomonas aeruginosa.

Macrolides are widely used antibiotics for the treatment of bacterial airway infections. Due to its elevated minimum inhibitory concentration in standardized culture media, Pseudomonas aeruginosa is considered intrinsically resistant and, therefore, antibiotic susceptibility testing against macrolides is not performed. Nevertheless, due to macrolides' immunomodulatory effect and suppression of virulence factors, they are used for the treatment of persistent P.

Clinical implications of innate immune exhaustion in cystic fibrosis.

Objectives: Lung disease progression in people with cystic fibrosis (pwCF) varies from one individual to another. Different immunological characteristics have been suggested to explain this variation, and we hypothesised that lung capacity may be associated with the innate immune response in pwCF. In an exploratory study, we aimed to investigate potential links between the innate immune response and lung function in pwCF using the standardised immune function assay TruCulture.

Metabolic specialization drives reduced pathogenicity in Pseudomonas aeruginosa isolates from cystic fibrosis patients.

Metabolism provides the foundation for all cellular functions. During persistent infections, in adapted pathogenic bacteria metabolism functions radically differently compared with more naïve strains. Whether this is simply a necessary accommodation to the persistence phenotype or if metabolism plays a direct role in achieving persistence in the host is still unclear.

Role of bacterial multidrug efflux pumps during infection.

Multidrug efflux pumps are protein complexes located in the cell envelope that enable bacteria to expel, not only antibiotics, but also a wide array of molecules relevant for infection. Hence, they are important players in microbial pathogenesis. On the one hand, efflux pumps can extrude exogenous compounds, including host-produced antimicrobial molecules.

Co-occurring microflora and mucin drive diversification and pathoadaptation.

While several environmental factors contribute to the evolutionary diversification of the pathogenic bacterium during cystic fibrosis lung infections, relatively little is known about the impact of the surrounding microbiota. By using experimental evolution we show that the presence of , or them both, prevent the evolution of loss of virulence, which repeatedly occurs in the absence of these species due to mutations in regulators of the Quinolone Signal quorum sensing system, and . Moreover, the strength of the effect of co-occurring species is attenuated through changes in the physical environment by the addition of mucin, resulting in selection for phenotypes resembling those evolved in the absence of the co-occurring species.

Widespread alterations in systemic immune profile are linked to lung function heterogeneity and airway microbes in cystic fibrosis.

Background: Excessive inflammation and recurrent airway infections characterize people with cystic fibrosis (pwCF), a disease with highly heterogeneous clinical outcomes. How the overall immune response is affected in pwCF, its relationships with the lung microbiome, and the source of clinical heterogeneity have not been fully elucidated.

Methods: Peripheral blood and sputum samples were collected from 28 pwCF and an age-matched control group.

Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance.

Mutations in mexZ, encoding a negative regulator of the expression of the mexXY efflux pump genes, are frequently acquired by Pseudomonas aeruginosa at early stages of lung infection. Although traditionally related to resistance to the first-line drug tobramycin, mexZ mutations are associated with low-level aminoglycoside resistance when determined in the laboratory, suggesting that their selection during infection may not be necessarily, or only, related to tobramycin therapy. Here, we show that mexZ-mutated bacteria tend to accumulate inside the epithelial barrier of a human airway infection model, thus colonising the epithelium while being protected against diverse antibiotics.

Ventriculostomy-associated infection (VAI) in patients with acute brain injury-a retrospective study.

Background: Ventriculostomy-associated infection (VAI) is common after external ventricular drains (EVD) insertion but is difficult to diagnose in patients with acute brain injury. Previously, we proposed a set of criteria for ruling out VAI in traumatic brain injury. This study aimed to validate these criteria.

Adaptive Evolution of Pseudomonas aeruginosa in Human Airways Shows Phenotypic Convergence Despite Diverse Patterns of Genomic Changes.

Selective forces in the environment drive bacterial adaptation to novel niches, choosing the fitter variants in the population. However, in dynamic and changing environments, the evolutionary processes controlling bacterial adaptation are difficult to monitor. Here, we follow 9 people with cystic fibrosis chronically infected with Pseudomonas aeruginosa, as a proxy for bacterial adaptation.

Predicting the primary infection source of Escherichia coli bacteremia using virulence-associated genes.

Purpose: To investigate the role of E. coli virulence-associated genes (VAGs) in predicting urinary tract infection (UTI) as the source of bacteremia in two distinct hospital populations, one with a large general catchment area and one dominated by referrals.

Methods: E.

Long-term evolution of antibiotic tolerance in lung infections.

Pathogenic bacteria respond to antibiotic pressure with the evolution of resistance but survival can also depend on their ability to tolerate antibiotic treatment, known as tolerance. While a variety of resistance mechanisms and underlying genetics are well characterized in vitro and in vivo, an understanding of the evolution of tolerance, and how it interacts with resistance in situ is lacking. We assayed for tolerance and resistance in isolates of from chronic cystic fibrosis lung infections spanning up to 40 years of evolution, with 3 clinically relevant antibiotics: meropenem, ciprofloxacin, and tobramycin.

Antimicrobial resistance of Pseudomonas aeruginosa in a cystic fibrosis population after introduction of a novel cephalosporin/β-lactamase inhibitor combination.

Ceftolozane-tazobactam is a new β-lactam/β-lactamase inhibitor combination approved by the U.S. Food and Drug Administration in 2019 for the treatment of hospital-acquired and ventilator-associated pneumonia.

New concepts in antimicrobial resistance in cystic fibrosis respiratory infections.

In this review, we summarize the main points that were raised and highlighted during the pre-conference meeting to the 17 European Cystic Fibrosis Society Basic Science Conference, held from 30 March to 2 April, 2022 in Albufeira, Portugal. Keynote lectures provided an update on the latest information regarding the phenomenon of antimicrobial resistance (AMR) in cystic fibrosis (CF). Traditional themes such as in vitro antibiotic susceptibility testing and its clinical value, AMR evolution in persistent Pseudomonas aeruginosa infection and the impact of biofilm on AMR were discussed.

Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a Cystic Fibrosis Patient Treated with β-Lactams.

Traditional studies on the evolution of antibiotic resistance development use approaches that can range from laboratory-based experimental studies, to epidemiological surveillance, to sequencing of clinical isolates. However, evolutionary trajectories also depend on the environment in which selection takes place, compelling the need to more deeply investigate the impact of environmental complexities and their dynamics over time. Herein, we explored the within-patient adaptive long-term evolution of a Pseudomonas aeruginosa hypermutator lineage in the airways of a cystic fibrosis (CF) patient by performing a chronological tracking of mutations that occurred in different subpopulations; our results demonstrated parallel evolution events in the chromosomally encoded class C β-lactamase ().

Macrolide therapy in Pseudomonas aeruginosa infections causes uL4 ribosomal protein mutations leading to high-level resistance.

Objectives: Pseudomonas aeruginosa colonizes the cystic fibrosis (CF) airways causing chronic bacterial lung infections. CF patients are routinely treated with macrolides, however, P. aeruginosa is considered insusceptible as consequence of inadequate susceptibility testing leaving resistance mechanism completely overlooked.

Polymicrobial infections can select against Pseudomonas aeruginosa mutators because of quorum-sensing trade-offs.

Bacteria with increased mutation rates (mutators) are common in chronic infections and are associated with poorer clinical outcomes, especially in the case of Pseudomonas aeruginosa infecting cystic fibrosis (CF) patients. There is, however, considerable between-patient variation in both P. aeruginosa mutator frequency and the composition of co-infecting pathogen communities.

Use of inhaled antibiotics among Danish patients with cystic fibrosis.

Background: Inhaled antibiotics are an important part of cystic fibrosis (CF) airway disease management and should be individualized to fit the microorganism and match patient needs. To investigate the implementation of personalized treatment, this study mapped the use of different types of inhaled antibiotics and adherence patterns.

Methods: We performed individual structured interviews in a cross-sectional study at the CF Centre in Copenhagen, Denmark.

Persistent Bacterial Infections, Antibiotic Treatment Failure, and Microbial Adaptive Evolution.

Antibiotic resistance is expected by the WHO to be the biggest threat to human health before 2050. In this overview, we argue that this prediction may in fact be too optimistic because it is often overlooked that many bacterial infections frequently 'go under the radar' because they are difficult to diagnose and characterize. Due to our lifestyle, persistent infections caused by opportunistic bacteria-well-known or emerging-show increasing success of infecting patients with reduced defense capacity, and often antibiotics fail to be sufficiently effective, even if the bacteria are susceptible, leaving small bacterial populations unaffected by treatment in the patient.