Filamentous #bacteriophages are associated with chronic #Pseudomonas #lung #infections and #antibiotic resistance in #cysticfibrosis (Sci Transl Med., abstract)

[Source: Science Translational Medicine, full page: (LINK). Abstract, edited.]

Filamentous bacteriophages are associated with chronic Pseudomonas lung infections and antibiotic resistance in cystic fibrosis

Elizabeth B. Burgener1,*, Johanna M. Sweere2,3, Michelle S. Bach2, Patrick R. Secor4, Naomi Haddock3, Laura K. Jennings4, Rasmus L. Marvig5, Helle Krogh Johansen6,7, Elio Rossi6, Xiou Cao2, Lu Tian8, Laurence Nedelec9, Søren Molin10, Paul L. Bollyky2,3,† and Carlos E. Milla1,†

1 Center for Excellence in Pulmonary Biology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA. 2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA. 3 Stanford Immunology, Stanford University, Stanford, CA 94305, USA. 4 Division of Biological Sciences, University of Montana, Missoula, MT 59812, USA. 5 Center for Genomic Medicine, Rigshospitalet–Copenhagen University Hospital, Copenhagen, Denmark. 6 Department of Clinical Microbiology, Rigshospitalet, Copenhagen Ø, Denmark. 7 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark. 8 Biomedical Data Science Administration and Statistics, Stanford University, Stanford, CA 94305, USA. 9 Primary Care and Population Health, Stanford University, Stanford, CA 94305, USA. 10 The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark.

*Corresponding author. Email: eburgener@stanford.edu

† Co-senior authors.

Science Translational Medicine  17 Apr 2019: Vol. 11, Issue 488, eaau9748 / DOI: 10.1126/scitranslmed.aau9748

 

Infection-boosting phage

Chronic Pseudomonas aeruginosa infection is common in patients with cystic fibrosis (CF). Filamentous bacteriophage (Pf phage) can infect P. aeruginosa and has been shown to contribute to the virulence of infection in animal models. However, whether Pf phage plays a role in the pathogenicity of P. aeruginosa in CF is unknown. Now, Burgener et al. showed that Pf phage was abundantly expressed in sputum samples from two large cohorts of patients with CF. The presence of Pf phage was associated with increased antibiotic resistance and reduced lung function. The results suggest that Pf phage might play a role in the pathogenicity of P. aeruginosa infection in CF.

 

Abstract

Filamentous bacteriophage (Pf phage) contribute to the virulence of Pseudomonas aeruginosa infections in animal models, but their relevance to human disease is unclear. We sought to interrogate the prevalence and clinical relevance of Pf phage in patients with cystic fibrosis (CF) using sputum samples from two well-characterized patient cohorts. Bacterial genomic analysis in a Danish longitudinal cohort of 34 patients with CF revealed that 26.5% (n = 9) were consistently Pf phage positive. In the second cohort, a prospective cross-sectional cohort of 58 patients with CF at Stanford, sputum qPCR analysis showed that 36.2% (n = 21) of patients were Pf phage positive. In both cohorts, patients positive for Pf phage were older, and in the Stanford CF cohort, patients positive for Pf phage were more likely to have chronic P. aeruginosa infection and had greater declines in pulmonary function during exacerbations than patients negative for Pf phage presence in the sputum. Last, P. aeruginosa strains carrying Pf phage exhibited increased resistance to antipseudomonal antibiotics. Mechanistically, in vitro analysis showed that Pf phage sequesters these same antibiotics, suggesting that this mechanism may thereby contribute to the selection of antibiotic resistance over time. These data provide evidence that Pf phage may contribute to clinical outcomes in P. aeruginosa infection in CF.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
http://www.sciencemag.org/about/science-licenses-journal-article-reuse

This is an article distributed under the terms of the Science Journals Default License.

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Cystic fibrosis; Bacteriophages.

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#Antimicrobial Activity of #Ibuprofen Against #CysticFibrosis Associated Gram–Negative #Pathogens (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Antimicrobial Activity of Ibuprofen Against Cystic Fibrosis Associated Gram–Negative Pathogens

Parth N. Shah a, Kimberly R. Marshall-Batty c, Justin A. Smolen a, Jasur A. Tagaev b, Qingquan Chen a, Christopher A. Rodesney d,  Henry H. Le d, Vernita D. Gordon d, David E. Greenberg c and Carolyn L. Cannon a#

Author Affiliations: Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, College Station, Texas, USA{a}; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA{b}; Department of Internal Medicine and Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA{c}; Center for Nonlinear Dynamics and Department of Physics, The University of Texas at Austin, Austin, Texas, USA{d}

 

ABSTRACT

Clinical trials have demonstrated the benefits of ibuprofen therapy in cystic fibrosis (CF) patients, an effect that is currently attributed to ibuprofen’s anti-inflammatory properties. Yet, a few previous reports demonstrate an antimicrobial activity of ibuprofen as well, although none investigate its direct effects on the pathogens found in the CF lung, which is the focus of this work. Determination of ibuprofen’s in vitro antimicrobial activity against Pseudomonas aeruginosa and Burkholderia spp. strains through measurements of endpoint colony-forming units (CFU) and growth kinetics showed that ibuprofen reduces the growth rate and bacterial burden of tested strains in a dose-dependent fashion. In an in vitro Pseudomonas biofilm model, a reduction in the rate of biomass accumulation over 8-h of growth with ibuprofen treatment was observed. Next, an acute Pseudomonas pneumonia model was used to test this antimicrobial activity after oral delivery of ibuprofen. Following intranasal inoculation, ibuprofen-treated mice exhibited lower CFU counts and improved survival compared with control animals. Preliminary biodistribution studies performed after aerosolization of ibuprofen to mice demonstrated a rapid accumulation of ibuprofen in serum and minimum retention in lung tissue and bronchoalveolar lavage fluid. Therefore, ibuprofen-encapsulating polymeric nanoparticles (Ibu-NPs) were formulated to improve the pharmacokinetic profile. Ibu-NPs, formulated for aerosol delivery, inhibited the growth of P. aeruginosa in vitro and may provide a convenient dosing method. These results provide an additional explanation for the previously observed therapeutic effects of ibuprofen in CF patients, and further strengthen the argument for its use for these patients.

 

FOOTNOTES

#Address correspondence to Carolyn L. Cannon, cannon@medicine.tamhsc.edu.

Copyright © 2018 Shah et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Ibuprofen; Antibiotics; Cystic Fibrosis.

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#Microbiological #efficacy of early #MRSA #treatment in #cysticfibrosis in a randomised controlled trial (Thorax, abstract)

[Source: Thorax, full page: (LINK). Abstract, edited.]

Thorax doi:10.1136/thoraxjnl-2016-208949

Cystic fibrosis / Original article

Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial

Marianne Sponer Muhlebach1, Valeria Beckett2, Elena Popowitch3, Melissa B Miller3, Arthur Baines2, Nicole Mayer-Hamblett2,4, Edith T Zemanick5, Wynton C Hoover6, Jill M VanDalfsen2, Preston Campbell7, Christopher H Goss2,4,8, STAR-too study team

Author Affiliations: 1 Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA; 2 Seattle Children’s Research Institute, Seattle, Washington, USA; 3 Department of Microbiology, University of North Carolina, Chapel Hill, North Carolina, USA; 4 Department of Pediatrics, University of Washington, Seattle, Washington, USA; 5 Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA; 6 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA; 7 Cystic Fibrosis Foundation, Bethesda, Maryland, USA; 8 Department of Medicine, University of Washington, Seattle, Washington, USA

Correspondence to Dr Marianne S Muhlebach, Department of Pediatrics, University of North Carolina, 450 MacNider CB 7217, Chapel Hill, NC 27599, USA; Marianne_Muhlebach@med.unc.edu

Received 22 May 2016 – Revised 30 September 2016 – Accepted 12 October 2016 – Published Online First 15 November 2016

 

Abstract

Objective

To evaluate microbiological effectiveness, that is, culture negativity of a non-blinded eradication protocol (Rx) compared with observation (Obs) in clinically stable cystic fibrosis participants with newly positive methicillin resistant Staphylococcus aureus (MRSA) cultures.

Design

This non-blinded trial randomised participants ages 4–45 years with first or early (≤2 positive cultures within 3 years) MRSA-positive culture without MRSA-active antibiotics within 4 weeks 1:1 to Rx or Obs. The Rx protocol was: oral trimethoprim-sulfamethoxazole or if sulfa-allergic, minocycline plus oral rifampin; chlorhexidine mouthwash for 2 weeks; nasal mupirocin and chlorhexidine body wipes for 5 days and environmental decontamination for 21 days. The primary end point was MRSA culture status at day 28.

Results

Between 1 April 2011 to September 2014, 45 participants (44% female, mean age 11.5 years) were randomised (24 Rx, 21 Obs). At day 28, 82% (n=18/22) of participants in the Rx arm compared with 26% (n=5/19) in the Obs arm were MRSA-negative. Adjusted for interim monitoring, this difference was 52% (95% CI 23% to 80%, p<0.001). Limiting analyses to participants who were MRSA-positive at the screening visit, 67% (8/12) in the Rx arm and 13% (2/15) in the Obs arm were MRSA-negative at day 28, adjusted difference: 49% (95% CI 22% to 71%, p<0.001). Fifty-four per cent in the Rx arm compared with 10% participants in the Obs arm remained MRSA-negative through day 84. Mild gastrointestinal side effects were higher in the Rx arm.

Conclusions

This MRSA eradication protocol for newly acquired MRSA demonstrated microbiological efficacy with a large treatment effect.

Trial registration number NCT01349192.

Keywords: MRSA; Cystic Fibrosis.

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