Clinical outcome after acquisition ofBurkholderia cepacia in patients with cystic fibrosis

McCloskey, M.; McCaughan, J.; Redmond, A.O.B.; Elborn, J.S.

doi:10.1007/bf03167716

Cited by 29 publications

(12 citation statements)

References 20 publications

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“…Consensus has not been met on the appropriate treatment regimen for Bcc lung infections, despite numerous studies examining antibiotic combination therapy [4, 11–13]. The differences in resistances between strains may make such a broad consensus impossible.…”

Section: Discussionmentioning

confidence: 99%

“…Colonization of the lung with Bcc is associated with an increased risk of accelerated pulmonary decline, early death, and often excludes Bcc infected patients from consideration for lung transplantation [2, 3]. Furthermore, Bcc respiratory infections in CF patients frequently lead to exacerbations, causing a significant and rapid decline in lung function that is often not reversible [4]. …”

Section: Introductionmentioning

confidence: 99%

“…Antimicrobial therapies for infection caused by Bcc are severely limited by the broad-spectrum resistance exhibited by most strains [8, 9]. Meropenem and tobramycin are two commonly used antimicrobial agents that are generally recommended to treat CF pulmonary exacerbation [10], however only a few reports describing treatments for CF patients infected with Bcc have been published [4, 11–14]. Though these antimicrobial agents cause a reduction in bacterial density, clinical improvement in lung function was not observed [11].…”

Section: Introductionmentioning

confidence: 99%

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Novel glycopolymer sensitizes Burkholderia cepacia complex isolates from cystic fibrosis patients to tobramycin and meropenem

et al. 2017

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Burkholderia cepacia complex (Bcc) infection, associated with cystic fibrosis (CF) is intrinsically multidrug resistant to antibiotic treatment making eradication from the CF lung virtually impossible. Infection with Bcc leads to a rapid decline in lung function and is often a contraindication for lung transplant, significantly influencing morbidity and mortality associated with CF disease. Standard treatment frequently involves antibiotic combination therapy. However, no formal strategy has been adopted in clinical practice to guide successful eradication. A new class of direct-acting, large molecule polycationic glycopolymers, derivatives of a natural polysaccharide poly-N-acetyl-glucosamine (PAAG), are in development as an alternative to traditional antibiotic strategies. During treatment, PAAG rapidly targets the anionic structural composition of bacterial outer membranes. PAAG was observed to permeabilize bacterial membranes upon contact to facilitate potentiation of antibiotic activity. Three-dimensional checkerboard synergy analyses were used to test the susceptibility of eight Bcc strains (seven CF clinical isolates) to antibiotic combinations with PAAG or ceftazidime. Potentiation of tobramycin and meropenem activity was observed in combination with 8–128 μg/mL PAAG. Treatment with PAAG reduced the minimum inhibitory concentration (MIC) of tobramycin and meropenem below their clinical sensitivity breakpoints (≤4 μg/mL), demonstrating the ability of PAAG to sensitize antibiotic resistant Bcc clinical isolates. Fractional inhibitory concentration (FIC) calculations showed PAAG was able to significantly potentiate antibacterial synergy with these antibiotics toward all Bcc species tested. These preliminary studies suggest PAAG facilitates a broad synergistic activity that may result in more positive therapeutic outcomes and supports further development of safe, polycationic glycopolymers for inhaled combination antibiotic therapy, particularly for CF-associated Bcc infections.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel glycopolymer sensitizes Burkholderia cepacia complex isolates from cystic fibrosis patients to tobramycin and meropenem

et al. 2017

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“…dolosa (3%), although there is significant variability based on geographic region and institution [5]. A number of studies have shown an association between infection with BCC and clinical pulmonary deterioration of CF patients [6–10]. The so-called “ cepacia syndrome” refers to the clinical presentation of fevers, leukocytosis, elevated erythrocyte sedimentation rate (ESR), and progressive severe pneumonia, sometimes with bacteremia, in CF patients occurring relatively soon after acquiring BCC, with a mortality rate initially reported at 62% [11].…”

Section: Introductionmentioning

confidence: 99%

An Oxygen-Sensing Two-Component System in the Burkholderia cepacia Complex Regulates Biofilm, Intracellular Invasion, and Pathogenicity

et al. 2017

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Burkholderia dolosa is a member of the Burkholderia cepacia complex (BCC), which is a group of bacteria that cause chronic lung infection in patients with cystic fibrosis (CF) and can be associated with outbreaks carrying high morbidity and mortality. While investigating the genomic diversity of B. dolosa strains collected from an outbreak among CF patients, we previously identified fixL as a gene showing signs of strong positive selection. This gene has homology to fixL of the rhizobial FixL/FixJ two-component system. The goals of this study were to determine the functions of FixLJ and their role in virulence in B. dolosa. We generated a fixLJ deletion mutant and complemented controls in B. dolosa strain AU0158. Using a fixK-lacZ reporter we found that FixLJ was activated in low oxygen in multiple BCC species. In a murine pneumonia model, the B. dolosa fixLJ deletion mutant was cleared faster from the lungs and spleen than wild-type B. dolosa strain AU0158 at 7 days post infection. Interestingly, the fixLJ deletion mutant made more biofilm, albeit with altered structure, but was less motile than strain AU0158. Using RNA-seq with in vitro grown bacteria, we found ~11% of the genome was differentially expressed in the fixLJ deletion mutant relative to strain AU0158. Multiple flagella-associated genes were down-regulated in the fixLJ deletion mutant, so we also evaluated virulence of a fliC deletion mutant, which lacks a flagellum. We saw no difference in the ability of the fliC deletion mutant to persist in the murine model relative to strain AU0158, suggesting factors other than flagella caused the phenotype of decreased persistence. We found the fixLJ deletion mutant to be less invasive in human lung epithelial and macrophage-like cells. In conclusion, B. dolosa fixLJ is a global regulator that controls biofilm formation, motility, intracellular invasion/persistence, and virulence.

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“…B. cepacia adopts an extracellular or intracellular lifestyle (23,24). This bacterium can survive within a variety of eukaryotic cells such as amoebae, epithelial cells, and macrophages (25)(26)(27)(28).…”

mentioning

confidence: 99%

Depletion of the Ubiquitin-binding Adaptor Molecule SQSTM1/p62 from Macrophages Harboring cftr ΔF508 Mutation Improves the Delivery of Burkholderia cenocepacia to the Autophagic Machinery

Abdulrahman

Khweek

Akhter

et al. 2013

Journal of Biological Chemistry

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Background: Cystic fibrosis is characterized by defective autophagy and increased Burkholderia cenocepacia infection. Results:The depletion of SQSTM1/p62 from ⌬F508 macrophages improves bacterial clearance via autophagy. Conclusion: p62 expression level determines the fate of B. cepacia infection in ⌬F508 macrophages. Significance: Our study reveals the role of p62 in diseases characterized by protein aggregates that compromise autophagy by consuming essential autophagy molecules.

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Clinical outcome after acquisition ofBurkholderia cepacia in patients with cystic fibrosis

Abstract: Acquisition of B. cepacia may be a cause of, rather than a marker for, a decrease in pulmonary function.

Cited by 29 publications

References 20 publications

Novel glycopolymer sensitizes Burkholderia cepacia complex isolates from cystic fibrosis patients to tobramycin and meropenem

Novel glycopolymer sensitizes Burkholderia cepacia complex isolates from cystic fibrosis patients to tobramycin and meropenem

An Oxygen-Sensing Two-Component System in the Burkholderia cepacia Complex Regulates Biofilm, Intracellular Invasion, and Pathogenicity

Depletion of the Ubiquitin-binding Adaptor Molecule SQSTM1/p62 from Macrophages Harboring cftr ΔF508 Mutation Improves the Delivery of Burkholderia cenocepacia to the Autophagic Machinery

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