18 results on '"Lucas, R."'
Search Results
2. Association Between Number of Intravenous Antipseudomonal Antibiotics and Clinical Outcomes of Pediatric Cystic Fibrosis Pulmonary Exacerbations
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Matthew P. Kronman, Anna V. Faino, Jonathan D Cogen, Lucas R. Hoffman, David P. Nichols, Margaret Rosenfeld, Frankline Onchiri, and Ronald L. Gibson
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Microbiology (medical) ,medicine.medical_specialty ,Cystic Fibrosis ,medicine.drug_class ,Antibiotics ,medicine.disease_cause ,Cystic fibrosis ,Forced Expiratory Volume ,Internal medicine ,medicine ,Humans ,Pseudomonas Infections ,Child ,Retrospective Studies ,Pseudomonas aeruginosa ,business.industry ,Hazard ratio ,Confounding ,Repeated measures design ,Retrospective cohort study ,Odds ratio ,medicine.disease ,Anti-Bacterial Agents ,Major Articles and Commentaries ,Infectious Diseases ,business - Abstract
Background Pulmonary exacerbations (PEx) in people with cystic fibrosis (PwCF) are associated with significant morbidity. While standard PEx treatment for PwCF with Pseudomonas aeruginosa infection includes two IV antipseudomonal antibiotics, little evidence exists to recommend this approach. This study aimed to compare clinical outcomes of single versus double antipseudomonal antibiotic use for PEx treatment. Methods Retrospective cohort study using the linked CF Foundation Patient Registry-Pediatric Health Information System dataset. PwCF were included if hospitalized between 2007 and 2018 and 6–21 years of age. Regression modeling accounting for repeated measures was used to compare lung function outcomes between single versus double IV antipseudomonal antibiotic regimens using propensity-score weighting to adjust for relevant confounding factors. Results Among 10,660 PwCF in the dataset, we analyzed 2,578 PEx from 1,080 PwCF, of which 455 and 2,123 PEx were treated with 1 versus 2 IV antipseudomonal antibiotics, respectively. We identified no significant differences between PEx treated with 1 versus 2 IV antipseudomonal antibiotics either in change between pre- and post-PEx percent predicted forced expiratory volume in one second (ppFEV1) (–0.84%, [95% CI –2.25, 0.56]; P = 0.24), odds of returning to ≥90% of baseline ppFEV1 within 3 months following PEx (Odds Ratio 0.83, [95% CI 0.61, 1.13]; P = 0.24) or time to next PEx requiring IV antibiotics (Hazard Ratio 1.04, [95% CI 0.87, 1.24]; P = 0.69). Conclusions Use of 2 IV antipseudomonal antibiotics for PEx treatment in young PwCF was not associated with greater improvements in measured respiratory and clinical outcomes compared to treatment with 1 IV antipseudomonal antibiotic.
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- 2021
3. Staphylococcus aureus Small-Colony Variants Are Independently Associated With Worse Lung Disease in Children With Cystic Fibrosis
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Wolter, Daniel J., Emerson, Julia C., McNamara, Sharon, Buccat, Anne M., Qin, Xuan, Cochrane, Elizabeth, Houston, Laura S., Rogers, Geraint B., Marsh, Peter, Prehar, Karandeep, Pope, Christopher E., Blackledge, Marcella, Déziel, Eric, Bruce, Kenneth D., Ramsey, Bonnie W., Gibson, Ronald L., Burns, Jane L., and Hoffman, Lucas R.
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- 2013
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4. Pseudomonas aeruginosa aggregation and Psl expression in sputum is associated with antibiotic eradication failure in children with cystic fibrosis.
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Morris, Amanda J., Yau, Yvonne C. W., Park, Subin, Eisha, Shafinaz, McDonald, Nancy, Parsek, Matthew R., Howell, P. Lynne, Hoffman, Lucas R., Nguyen, Dao, DiGiandomenico, Antonio, Rooney, Ashley M., Coburn, Bryan, Grana-Miraglia, Lucia, Wang, Pauline, Guttman, David S., Wozniak, Daniel J., and Waters, Valerie J.
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CYSTIC fibrosis ,SPUTUM ,ANTIBIOTICS ,PSEUDOMONAS aeruginosa ,TOBRAMYCIN ,IMMUNOGLOBULINS ,COUGH - Abstract
We previously demonstrated that P. aeruginosa isolates that persisted in children with cystic fibrosis (CF) despite inhaled tobramycin treatment had increased anti-Psl antibody binding in vitro compared to those successfully eradicated. We aimed to validate these findings by directly visualizing P. aeruginosa in CF sputum. This was a prospective observational study of children with CF with new-onset P. aeruginosa infection who underwent inhaled tobramycin eradication treatment. Using microbial identification passive clarity technique (MiPACT), P. aeruginosa was visualized in sputum samples obtained before treatment and classified as persistent or eradicated based on outcomes. Pre-treatment isolates were also grown as biofilms in vitro. Of 11 patients enrolled, 4 developed persistent infection and 7 eradicated infection. P. aeruginosa biovolume and the number as well as size of P. aeruginosa aggregates were greater in the sputum of those with persistent compared with eradicated infections (p < 0.01). The amount of Psl antibody binding in sputum was also greater overall (p < 0.05) in samples with increased P. aeruginosa biovolume. When visualized in sputum, P. aeruginosa had a greater biovolume, with more expressed Psl, and formed more numerous, larger aggregates in CF children who failed eradication therapy compared to those who successfully cleared their infection. [ABSTRACT FROM AUTHOR]
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- 2022
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5. Clinical Outcomes of Antipseudomonal versus Other Antibiotics among Children with Cystic Fibrosis without .
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Cogen, Jonathan D., Faino, Anna V., Onchiri, Frankline, Gibson, Ronald L., Hoffman, Lucas R., Nichols, David P., Rosenfeld, Margaret, and Kronman, Matthew P.
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ANTIBIOTICS ,RETROSPECTIVE studies ,CYSTIC fibrosis ,PSEUDOMONAS diseases ,RESEARCH funding ,PSEUDOMONAS ,LONGITUDINAL method ,DISEASE complications - Abstract
Rationale: Antibiotic selection for pulmonary exacerbation (PEx) management in children with cystic fibrosis is typically guided by prior respiratory culture results. Although antipseudomonal antibiotics are often used in children with chronic Pseudomonas aeruginosa (Pa) airway infection, no data exist to guide antibiotic selection in children who are culture negative for Pa for ≥1 year. Objectives: To determine among children classified as 1, 2, or 3 years' Pa negative if PEx treatment with at least one oral and/or intravenous antipseudomonal antibiotic is associated with improved clinical outcomes compared with treatment with antibiotics not effective against Pa. Methods: A retrospective cohort study was conducted using the linked Cystic Fibrosis Foundation Patient Registry-Pediatric Health Information System database. We included children 6-21 years old hospitalized between 2008 and 2018 consistently culture negative for Pa 1 year before a study PEx. Children were classified as 1 or 2 years' Pa negative if their last Pa-positive culture occurred in the 13-24 months or 25-36 months before a study PEx, respectively, with all subsequent cultures negative for Pa. Children classified as 3 years' Pa negative had no Pa-positive cultures in the 36 months before a study PEx. Inverse probability of treatment weighted linear or logistic regression models were used to compare clinical outcomes (pre- to post-PEx forced expiratory volume in 1 s, odds of returning to ≥90% of baseline lung function, and odds of having a future PEx) between antipseudomonal and non-antipseudomonal antibiotic strategies. Results: Among all children included in the linked data set, 1,290 children with 2,347 PExs were eligible for analysis. Among all study PExs, 530, 326, and 1,491 were classified as 1, 2, and 3 years' Pa negative, respectively, and antipseudomonal antibiotics were administered in 79%, 67%, and 66% of all PExs classified as 1, 2, and 3 years' Pa negative, respectively. For all Pa-negative groups, when compared with non-antipseudomonal antibiotic regimens, antipseudomonal antibiotic treatment was not associated with greater improvement in any studied clinical outcome. Conclusions: Despite their common use, including antibiotics effective against Pa may provide no additional benefit for PEx treatment among children who are Pa negative for at least 1 year prior. Prospective trials are warranted to directly test this hypothesis. [ABSTRACT FROM AUTHOR]
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- 2022
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6. The role of Psl in the failure to eradicate Pseudomonas aeruginosa biofilms in children with cystic fibrosis
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Kevin M. Guttman, Antonio DiGiandomenico, P. Lynne Howell, Daniel J. Wozniak, Courtney Reichhardt, Yvonne C. W. Yau, Lindsay Jackson, Trevor Beaudoin, Amanda J Morris, Dao Nguyen, David S. Guttman, Stephanie Uwumarenogie, Matthew R. Parsek, Valerie Waters, and Lucas R. Hoffman
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Multidrug tolerance ,Cystic Fibrosis ,medicine.drug_class ,Antibiotics ,Respiratory System ,macromolecular substances ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Microbiology ,Cystic fibrosis ,Article ,Microbial ecology ,Bacterial Proteins ,Pseudomonas infection ,medicine ,Tobramycin ,Humans ,Pseudomonas Infections ,Adhesins, Bacterial ,Child ,Clinical microbiology ,Antigens, Bacterial ,Pseudomonas aeruginosa ,business.industry ,Extracellular Polymeric Substance Matrix ,QR100-130 ,Biofilm ,Biofilm matrix ,medicine.disease ,Antibodies, Bacterial ,Anti-Bacterial Agents ,Biofilms ,business ,Biotechnology ,medicine.drug - Abstract
The exopolysaccharide Psl contributes to biofilm structure and antibiotic tolerance and may play a role in the failure to eradicate Pseudomonas aeruginosa from cystic fibrosis (CF) airways. The study objective was to determine whether there were any differences in Psl in P. aeruginosa isolates that were successfully eradicated compared to those that persisted, despite inhaled tobramycin treatment, in children with CF. Initial P. aeruginosa isolates were collected from children with CF undergoing eradication treatment, grown as biofilms and labeled with 3 anti-Psl monoclonal antibodies (Cam003/Psl0096, WapR001, WapR016) before confocal microscopy visualization. When grown as biofilms, P. aeruginosa isolates from children who failed antibiotic eradication therapy, had significantly increased Psl0096 binding compared to isolates from those who cleared P. aeruginosa. This was confirmed in P. aeruginosa isolates from the SickKids Eradication Cohort as well as the Early Pseudomonas Infection Control (EPIC) trial. Increased anti-Psl antibody binding was associated with bacterial aggregation and tobramycin tolerance. The biofilm matrix represents a potential therapeutic target to improve P. aeruginosa eradication treatment.
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- 2021
7. Association Between Number of Intravenous Antipseudomonal Antibiotics and Clinical Outcomes of Pediatric Cystic Fibrosis Pulmonary Exacerbations.
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Cogen, Jonathan D, Faino, Anna V, Onchiri, Frankline, Hoffman, Lucas R, Kronman, Matthew P, Nichols, David P, Rosenfeld, Margaret, and Gibson, Ronald L
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INTRAVENOUS therapy ,CONFIDENCE intervals ,LUNG diseases ,RETROSPECTIVE studies ,TREATMENT effectiveness ,CYSTIC fibrosis ,PSEUDOMONAS diseases ,DESCRIPTIVE statistics ,ANTIBIOTICS ,DISEASE exacerbation ,LONGITUDINAL method - Abstract
Background Pulmonary exacerbations (PEx) in people with cystic fibrosis (PwCF) are associated with significant morbidity. While standard PEx treatment for PwCF with Pseudomonas aeruginosa infection includes two IV antipseudomonal antibiotics, little evidence exists to recommend this approach. This study aimed to compare clinical outcomes of single versus double antipseudomonal antibiotic use for PEx treatment. Methods Retrospective cohort study using the linked CF Foundation Patient Registry-Pediatric Health Information System dataset. PwCF were included if hospitalized between 2007 and 2018 and 6–21 years of age. Regression modeling accounting for repeated measures was used to compare lung function outcomes between single versus double IV antipseudomonal antibiotic regimens using propensity-score weighting to adjust for relevant confounding factors. Results Among 10,660 PwCF in the dataset, we analyzed 2,578 PEx from 1,080 PwCF, of which 455 and 2,123 PEx were treated with 1 versus 2 IV antipseudomonal antibiotics, respectively. We identified no significant differences between PEx treated with 1 versus 2 IV antipseudomonal antibiotics either in change between pre- and post-PEx percent predicted forced expiratory volume in one second (ppFEV1) (–0.84%, [95% CI –2.25, 0.56]; P = 0.24), odds of returning to ≥90% of baseline ppFEV1 within 3 months following PEx (Odds Ratio 0.83, [95% CI 0.61, 1.13]; P = 0.24) or time to next PEx requiring IV antibiotics (Hazard Ratio 1.04, [95% CI 0.87, 1.24]; P = 0.69). Conclusions Use of 2 IV antipseudomonal antibiotics for PEx treatment in young PwCF was not associated with greater improvements in measured respiratory and clinical outcomes compared to treatment with 1 IV antipseudomonal antibiotic. [ABSTRACT FROM AUTHOR]
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- 2021
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8. Pyomelanin-producingPseudomonas aeruginosaselected during chronic infections have a large chromosomal deletion which confers resistance to pyocins
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Michael A. Jacobs, Benoît Valot, Patrick Plésiat, Laurence Rohmer, Xavier Bertrand, Alix Pantel, Elodie Bedel, Hemantha D. Kulasekara, Samuel I. Miller, Thilo Köhler, Didier Hocquet, Lucas R. Hoffman, and Marie Petitjean
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0301 basic medicine ,Genetics ,education.field_of_study ,Pseudomonas aeruginosa ,medicine.drug_class ,030106 microbiology ,Antibiotics ,Population ,Mutant ,Drug resistance ,Biology ,medicine.disease_cause ,Microbiology ,3. Good health ,Bacterial genetics ,03 medical and health sciences ,030104 developmental biology ,medicine ,education ,Gene ,Ecology, Evolution, Behavior and Systematics ,Chromosomal Deletion - Abstract
When bacterial lineages make the transition from free-living to permanent association with hosts, they can undergo massive gene losses, for which the selective forces within host tissues are unknown. We identified here melanogenic clinical isolates of Pseudomonas aeruginosa with large chromosomal deletions (66 to 270 kbp) and characterized them to investigate how they were selected. When compared with their wild-type parents, melanogenic mutants (i) exhibited a lower fitness in growth conditions found in human tissues, such as hyperosmolarity and presence of aminoglycoside antibiotics, (ii) narrowed their metabolic spectrum with a growth disadvantage with particular carbon sources, including aromatic amino acids and acyclic terpenes, suggesting a reduction of metabolic flexibility. Despite an impaired fitness in rich media, melanogenic mutants can inhibit their wild-type parents and compete with them in coculture. Surprisingly, melanogenic mutants became highly resistant to two intraspecific toxins, the S-pyocins AP41 and S1. Our results suggest that pyocins produced within a population of infecting P. aeruginosa may have selected for bacterial mutants that underwent massive gene losses and that were adapted to the life in diverse bacterial communities in the human host. Intraspecific interactions may therefore be an important factor driving the continuing evolution of pathogens during host infections.
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- 2016
9. Pseudomonas aeruginosa Phenotypes Associated With Eradication Failure in Children With Cystic Fibrosis
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Catherine R. Armbruster, Bonnie W. Ramsey, Margaret Rosenfeld, Lucas R. Hoffman, Hemantha D. Kulasekara, Nicole Mayer-Hamblett, Umer Khan, Bridget R. Kulasekara, Laura S. Houston, Christopher E. Pope, George Z. Retsch-Bogart, Samuel I. Miller, Ronald L. Gibson, Daniel J. Wolter, and Jane L. Burns
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Microbiology (medical) ,Exacerbation ,medicine.drug_class ,Pseudomonas aeruginosa ,business.industry ,Antibiotics ,Biofilm ,macromolecular substances ,medicine.disease_cause ,medicine.disease ,Phenotype ,Cystic fibrosis ,Quorum sensing ,Infectious Diseases ,Immunology ,Genotype ,medicine ,business - Abstract
Background. Pseudomonas aeruginosa is a key respiratory pathogen in people with cystic fibrosis (CF). Due to its association with lung disease progression, initial detection of P. aeruginosa in CF respiratory cultures usually results in antibiotic treatment with the goal of eradication. Pseudomonas aeruginosa exhibits many different phenotypes in vitro that could serve as useful prognostic markers, but the relative relationships between these phenotypes and failure to eradicate P. aeruginosa have not been well characterized. Methods. We measured 22 easily assayed in vitro phenotypes among the baseline P. aeruginosa isolates collected from 194 participants in the 18-month EPIC clinical trial, which assessed outcomes after antibiotic eradication therapy for newly identified P. aeruginosa. We then evaluated the associations between these baseline isolate phenotypes and subsequent outcomes during the trial, including failure to eradicate after antipseudomonal therapy, emergence of mucoidy, and occurrence of an exacerbation. Results. Baseline P. aeruginosa isolates frequently exhibited phenotypes thought to represent chronic adaptation, including mucoidy. Wrinkly colony surface and irregular colony edges were both associated with increased risk of eradication failure (hazard ratios [95% confidence intervals], 1.99 [1.03–3.83] and 2.14 [1.32–3.47], respectively). Phenotypes reflecting defective quorum sensing were significantly associated with subsequent mucoidy, but no phenotype was significantly associated with subsequent exacerbations during the trial. Conclusions. Pseudomonas aeruginosa phenotypes commonly considered to reflect chronic adaptation were observed frequently among isolates at early detection. We found that 2 easily assayed colony phenotypes were associated with failure to eradicate after antipseudomonal therapy, both of which have been previously associated with altered biofilm formation and defective quorum sensing.
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- 2014
10. Staphylococcus aureus Small-Colony Variants Are Independently Associated With Worse Lung Disease in Children With Cystic Fibrosis
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Bonnie W. Ramsey, Anne Marie Buccat, Jane L. Burns, Marcella Blackledge, Elizabeth Cochrane, Peter Marsh, Xuan Qin, Daniel J. Wolter, Geraint B. Rogers, Eric Déziel, Laura S. Houston, Lucas R. Hoffman, Sharon McNamara, Ronald L. Gibson, Julia Emerson, Christopher E. Pope, Kenneth D. Bruce, and Karandeep Prehar
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Male ,Microbiology (medical) ,Staphylococcus aureus ,Adolescent ,Cystic Fibrosis ,medicine.drug_class ,Antibiotics ,Population ,medicine.disease_cause ,Cystic fibrosis ,Pulmonary function testing ,Microbiology ,Antibiotic resistance ,Drug Resistance, Bacterial ,Pneumonia, Staphylococcal ,medicine ,Humans ,Child ,education ,Articles and Commentaries ,education.field_of_study ,Lung ,Pseudomonas aeruginosa ,business.industry ,Infant ,medicine.disease ,United States ,Anti-Bacterial Agents ,Treatment Outcome ,Infectious Diseases ,medicine.anatomical_structure ,Child, Preschool ,Carrier State ,Immunology ,Microbial Interactions ,Female ,business - Abstract
Lung disease associated with chronic airway infection is the main determinant of longevity and morbidity in people with cystic fibrosis (CF) [1]. Staphylococcus aureus is the bacterium cultured most commonly from the respiratory tracts of children with CF [2], and the earliest descriptions of CF lung infections focused on this species [3]. Subsequently, Pseudomonas aeruginosa was increasingly isolated from children with CF, and studies established an association between P. aeruginosa and CF lung disease [4, 5], largely shifting the focus of CF microbiological research and therapy. Recently, increases in S. aureus prevalence, both methicillin susceptible and methicillin resistant (MRSA), have been described in CF [6]. Recent studies of children with CF noted similar inflammation and lung function decline during infection with S. aureus compared with P. aeruginosa [7–9]. These observations have led to a reexamination of S. aureus and its role in CF lung disease [10]. Phenotypic variants of S. aureus called small-colony variants (SCVs) emerge during many chronic infections [11], including in CF [12–17]. Staphylococcus aureus SCVs grow slowly on most laboratory media due to metabolic defects, which also confer resistance to many antibiotics [11]. Staphylococcus aureus SCVs can be selected in vitro either by long-term exposure to specific antibiotics [11, 18] or growth with P. aeruginosa [19, 20], both of which occur commonly in CF airways. However, these various conditions select for phenotypically different SCVs, with distinct metabolic defects and antibiotic resistance profiles. As a result of their slow growth, S. aureus SCVs are difficult to detect unless specifically looked for. Currently, most clinical laboratories do not use culture methods required to detect SCVs or to estimate their prevalence and clinical impact. Recent studies of adults and children with CF in Europe [12–16] reported S. aureus SCV prevalences of between 8% [16] and 33% [13] and unadjusted associations with lower lung function [14, 15], but for several reasons those results cannot necessarily be extrapolated to other CF populations. For example, US and European CF centers differ substantially both in antibiotic treatment and prophylaxis practices [1, 2, 21, 22] and in rates of P. aeruginosa culture positivity [2, 6, 14, 22], 2 factors predicted to influence S. aureus SCV prevalence and antibiotic resistances. Children with CF also differ from adults in those 2 factors. We hypothesized that S. aureus SCVs would be common in US pediatric CF patients, but with different predicted antibiotic resistances from those found in previous (European) studies, warranting routine surveillance. To test these hypotheses, we performed a 2-year study of our hospital's CF population using specialized culture methods and detailed logs of antibiotic use. We focused on children due to their relatively mild disease, high rates of S. aureus, relatively little antibiotic exposure, and less frequent P. aeruginosa infection compared with adults, strengthening our ability to determine associations with specific selection pressures and disease severity.
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- 2013
11. Long-term cultivation-independent microbial diversity analysis demonstrates that bacterial communities infecting the adult cystic fibrosis lung show stability and resilience
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Franziska A. Stressmann, Peter Marsh, T. Daniels, Nilesh Patel, Christopher J. van der Gast, Benjamin John Forbes, Lucas R. Hoffman, Louic S. Vermeer, Kenneth D. Bruce, Geraint B. Rogers, and Mary P. Carroll
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Adult ,Male ,Pulmonary and Respiratory Medicine ,Cystic Fibrosis ,medicine.drug_class ,Respiratory System ,Antibiotics ,Biology ,medicine.disease_cause ,Cystic fibrosis ,medicine ,Humans ,Clinical significance ,Principal Component Analysis ,Community ,Pseudomonas aeruginosa ,Sputum ,Biodiversity ,medicine.disease ,Bacterial Load ,Anti-Bacterial Agents ,Metagenomics ,Immunology ,Disease Progression ,Metagenome ,Female ,Species richness ,medicine.symptom ,Polymorphism, Restriction Fragment Length - Abstract
Background Culture-independent analysis of the respiratory secretions of people with cystic fibrosis (CF) has identified many bacterial species not previously detected using culture in this context. However, little is known about their clinical significance or persistence in CF airways. Methods The authors characterised the viable bacterial communities in the sputum collected from 14 patients at monthly intervals over 1 year using a molecular community profiling technique—terminal restriction fragment length polymorphism. Clinical characteristics were also collected, including lung function and medications. Ecological community measures were determined for each sample. Microbial community change over time within subjects was defined using ecological analytical tools, and these measures were compared between subjects and to clinical features. Results Bacterial communities were stable within subjects over time but varied between subjects, despite similarities in clinical course. Antibiotic therapy temporarily perturbed these communities which generally returned to pretreatment configurations within 1 month. Species usually considered CF pathogens and those not previously regarded as such exhibited similar patterns of persistence. Less diverse sputum bacterial communities were correlated to lung disease severity and relative abundance of Pseudomonas aeruginosa . Conclusion Whilst not true in all cases, the microbial communities that chronically infect the airways of patients with CF can vary little over a year despite antibiotic perturbation. The species present tended to vary more between than within subjects, suggesting that each CF airway infection is unique, with relatively stable and resilient bacterial communities. The inverse relationship between community richness and disease severity is similar to findings reported in other mucosal infections.
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- 2012
12. Microbial Recognition of Antibiotics: Ecological, Physiological, and Therapeutic Implications
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Martin Bader, Lucas R. Hoffman, Samuel I. Miller, and David A. D'Argenio
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Soil bacteria ,medicine.drug_class ,Pseudomonas aeruginosa ,Microorganism ,fungi ,Antibiotics ,Disease ,Biology ,biology.organism_classification ,medicine.disease_cause ,Microbiology ,Bacillus anthracis ,medicine ,Robert koch - Abstract
Microbes release innumerable products into their environment, including many antibiotics. This fact has captivated scientists and clinicians for more than a century, and many of the details of the early history of antibiotics are familiar even to beginning students of microbiology and pharmacology. For example, the discovery in the late 1800s that microorganisms can cause disease was made concurrently with the finding that microbes can also prevent infections. After Robert Koch demonstrated that Bacillus anthracis is the causative agent of anthrax, Louis Pasteur showed that B. anthracis infection of animals could be prevented by simultaneous inoculation with soil bacteria. Other researchers later showed that cell-free preparations of Pseudomonas aeruginosa also conferred protection against anthrax infection, and this preparation was used to treat a variety of infectious diseases (with mixed results).
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- 2007
13. Exploratory Study of the Prevalence and Clinical Significance of Tobramycin-Mediated Biofilm Induction in Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients
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Danielle Elliott, Jane L. Burns, and Lucas R. Hoffman
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Adolescent ,Cystic Fibrosis ,medicine.drug_class ,Antibiotics ,Microbial Sensitivity Tests ,Drug resistance ,Biology ,medicine.disease_cause ,Cystic fibrosis ,Microbiology ,medicine ,Tobramycin ,Humans ,Pharmacology (medical) ,Mechanisms of Action: Physiological Effects ,Antibacterial agent ,Pharmacology ,Pseudomonas aeruginosa ,Aminoglycoside ,Biofilm ,medicine.disease ,Infectious Diseases ,Biofilms ,medicine.drug - Abstract
Exposure to aminoglycoside antibiotics induces biofilm formation by a laboratory strain of the cystic fibrosis (CF) pathogen Pseudomonas aeruginosa . Here, we detected this effect among about half of the clinical isolates from CF patients in a cross-sectional collection, suggesting that biofilm induction may represent a common mechanism of inducible aminoglycoside resistance in CF infections. This induction always occurred at the same tobramycin concentration regardless of MIC, suggesting that the mechanisms of killing and induction may be separable.
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- 2010
14. Nutrient Availability as a Mechanism for Selection of Antibiotic Tolerant Pseudomonas aeruginosa within the CF Airway
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Ferric C. Fang, Mikkel Klausen, Anthony R. Richardson, Samuel I. Miller, Daniel J. Hassett, David A. Stahl, Laura S. Houston, Lucas R. Hoffman, Hemantha D. Kulasekara, Willm Martens-Habbena, and Jane L. Burns
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Cystic Fibrosis ,Antibiotics ,Drug resistance ,medicine.disease_cause ,Cystic fibrosis ,Respiratory Medicine/Respiratory Infections ,Infectious Diseases/Bacterial Infections ,Tobramycin ,Biology (General) ,Lung ,0303 health sciences ,Microbiology/Microbial Evolution and Genomics ,Drug Resistance, Microbial ,respiratory system ,Respiratory Medicine/Respiratory Pediatrics ,Adaptation, Physiological ,Reactive Nitrogen Species ,3. Good health ,Pseudomonas aeruginosa ,Microbiology/Microbial Physiology and Metabolism ,medicine.drug ,Research Article ,QH301-705.5 ,medicine.drug_class ,Immunology ,Biology ,Microbiology ,03 medical and health sciences ,Antibiotic resistance ,Bacterial Proteins ,Virology ,Genetics ,medicine ,Humans ,Pseudomonas Infections ,Selection, Genetic ,Molecular Biology ,030304 developmental biology ,Infectious Diseases/Antimicrobials and Drug Resistance ,030306 microbiology ,Infectious Diseases/Respiratory Infections ,Microbiology/Medical Microbiology ,RC581-607 ,medicine.disease ,biology.organism_classification ,Chronic infection ,Food ,Mutation ,Trans-Activators ,Parasitology ,Immunologic diseases. Allergy ,Bacteria - Abstract
Microbes are subjected to selective pressures during chronic infections of host tissues. Pseudomonas aeruginosa isolates with inactivating mutations in the transcriptional regulator LasR are frequently selected within the airways of people with cystic fibrosis (CF), and infection with these isolates has been associated with poorer lung function outcomes. The mechanisms underlying selection for lasR mutation are unknown but have been postulated to involve the abundance of specific nutrients within CF airway secretions. We characterized lasR mutant P. aeruginosa strains and isolates to identify conditions found in CF airways that select for growth of lasR mutants. Relative to wild-type P. aeruginosa, lasR mutants exhibited a dramatic metabolic shift, including decreased oxygen consumption and increased nitrate utilization, that is predicted to confer increased fitness within the nutrient conditions known to occur in CF airways. This metabolic shift exhibited by lasR mutants conferred resistance to two antibiotics used frequently in CF care, tobramycin and ciprofloxacin, even under oxygen-dependent growth conditions, yet selection for these mutants in vitro did not require preceding antibiotic exposure. The selection for loss of LasR function in vivo, and the associated adverse clinical impact, could be due to increased bacterial growth in the oxygen-poor and nitrate-rich CF airway, and from the resulting resistance to therapeutic antibiotics. The metabolic similarities among diverse chronic infection-adapted bacteria suggest a common mode of adaptation and antibiotic resistance during chronic infection that is primarily driven by bacterial metabolic shifts in response to nutrient availability within host tissues., Author Summary Chronic infections are distinguished from many other infections in that they are difficult to eradicate with antibiotics. Thus, the microbes that cause chronic infections persist within host tissues for long periods despite our best treatment efforts. During the course of these chronic infections, the causative microbes often change genetically. For example, a bacterium that commonly infects the lungs of people with the genetic disease cystic fibrosis (CF) undergoes several known changes that affect the growth of this pathogen. However, the causes and clinical impact of the changes undergone by this and other chronically infecting microbes are unclear. We show that a common, early mutation found in bacteria isolated from chronically infected CF airways renders these bacteria better able to grow in the nutrients found in CF lung secretions. Interestingly, these same changes also confer resistance to several antibiotics used commonly to treat CF patients. Many of the characteristics conferred by this mutation are exhibited by other microbes found in chronic infections, suggesting that adaptation of these microbes to host tissue nutrient environments may be a common mechanism of antibiotic resistance in chronic infections.
- Published
- 2010
15. Selection for Staphylococcus aureus small-colony variants due to growth in the presence of Pseudomonas aeruginosa
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François Lépine, Bonnie W. Ramsey, David A. D'Argenio, Eric Déziel, Ronald L. Gibson, Julia Emerson, Sharon McNamara, Lucas R. Hoffman, and Samuel I. Miller
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Multidisciplinary ,Time Factors ,Pseudomonas aeruginosa ,medicine.drug_class ,Antibiotics ,Aminoglycoside ,Biology ,Biological Sciences ,medicine.disease_cause ,Microbiology ,Electron Transport ,Antibiotic resistance ,Staphylococcus aureus ,Immunology ,medicine ,Tobramycin ,Sputum ,Humans ,Pseudomonas Infections ,medicine.symptom ,Pathogen ,medicine.drug ,Cell Proliferation - Abstract
Opportunistic infections are often polymicrobial. Two of the most important bacterial opportunistic pathogens of humans, Pseudomonas aeruginosa and Staphylococcus aureus , frequently are coisolated from infections of catheters, endotracheal tubes, skin, eyes, and the respiratory tract, including the airways of people with cystic fibrosis (CF). Here, we show that suppression of S. aureus respiration by a P. aeruginosa exoproduct, 4-hydroxy-2-heptylquinoline- N -oxide (HQNO), protects S. aureus during coculture from killing by commonly used aminoglycoside antibiotics such as tobramycin. Furthermore, prolonged growth of S. aureus with either P. aeruginosa or with physiological concentrations of pure HQNO selects for typical S. aureus small-colony variants (SCVs), well known for stable aminoglycoside resistance and persistence in chronic infections, including those found in CF. We detected HQNO in the sputum of CF patients infected with P. aeruginosa , but not in uninfected patients, suggesting that this HQNO-mediated interspecies interaction occurs in CF airways. Thus, in all coinfections with P. aeruginosa , S. aureus may be underappreciated as a pathogen because of the formation of antibiotic-resistant and difficult to detect small-colony variants. Interspecies microbial interactions, analogous to those mediated by HQNO, commonly may alter not only the course of disease and the response to therapy, but also the population structure of bacterial communities that promote the health of host animals, plants, and ecosystems.
- Published
- 2006
16. Nutrient Availability as a Mechanism for Selection of Antibiotic Tolerant Pseudomonas aeruginosa within the CF Airway.
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Hoffman, Lucas R., Richardson, Anthony R., Houston, Laura S., Kulasekara, Hemantha D., Martens-Habbena, Willm, Klausen, Mikkel, Burns, Jane L., Stahl, David A., Hassett, Daniel J., Fang, Ferric C., and Miller, Samuel I.
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CYSTIC fibrosis , *DRUG resistance in microorganisms , *DRUG tolerance , *ANTIBIOTICS , *PSEUDOMONAS aeruginosa - Abstract
Microbes are subjected to selective pressures during chronic infections of host tissues. Pseudomonas aeruginosa isolates with inactivating mutations in the transcriptional regulator LasR are frequently selected within the airways of people with cystic fibrosis (CF), and infection with these isolates has been associated with poorer lung function outcomes. The mechanisms underlying selection for lasR mutation are unknown but have been postulated to involve the abundance of specific nutrients within CF airway secretions. We characterized lasR mutant P. aeruginosa strains and isolates to identify conditions found in CF airways that select for growth of lasR mutants. Relative to wild-type P. aeruginosa, lasR mutants exhibited a dramatic metabolic shift, including decreased oxygen consumption and increased nitrate utilization, that is predicted to confer increased fitness within the nutrient conditions known to occur in CF airways. This metabolic shift exhibited by lasR mutants conferred resistance to two antibiotics used frequently in CF care, tobramycin and ciprofloxacin, even under oxygen-dependent growth conditions, yet selection for these mutants in vitro did not require preceding antibiotic exposure. The selection for loss of LasR function in vivo, and the associated adverse clinical impact, could be due to increased bacterial growth in the oxygen-poor and nitrate-rich CF airway, and from the resulting resistance to therapeutic antibiotics. The metabolic similarities among diverse chronic infection-adapted bacteria suggest a common mode of adaptation and antibiotic resistance during chronic infection that is primarily driven by bacterial metabolic shifts in response to nutrient availability within host tissues. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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17. Growth phenotypes of Pseudomonas aeruginosa lasR mutants adapted to the airways of cystic fibrosis patients.
- Author
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D'Argenio, David A., Manhong Wu, Hoffman, Lucas R., Kulasekara, Hemantha D., Déziel, Eric, Smith, Eric E., Hai Nguyen, Ernst, Robert K., Freeman, Theodore J. Larson, Spencer, David H., Brittnacher, Mitchell, Hayden, Hillary S., Selgrade, Sara, Klausen, Mikkel, Goodlett, David R., Burns, Jane L., Ramsey, Bonnie W., and Miller, Samuel I.
- Subjects
PSEUDOMONAS aeruginosa ,CYSTIC fibrosis ,PATHOGENIC microorganisms ,MICROBIAL virulence ,GENETIC mutation ,PHENOTYPES ,ANTIBIOTICS ,DRUG resistance - Abstract
The opportunistic pathogen Pseudomonas aeruginosa undergoes genetic change during chronic airway infection of cystic fibrosis (CF) patients. One common change is a mutation inactivating lasR, which encodes a transcriptional regulator that responds to a homoserine lactone signal to activate expression of acute virulence factors. Colonies of lasR mutants visibly accumulated the iridescent intercellular signal 4-hydroxy-2-heptylquinoline. Using this colony phenotype, we identified P. aeruginosa lasR mutants that emerged in the airway of a CF patient early during chronic infection, and during growth in the laboratory on a rich medium. The lasR loss-of-function mutations in these strains conferred a growth advantage with particular carbon and nitrogen sources, including amino acids, in part due to increased expression of the catabolic pathway regulator CbrB. This growth phenotype could contribute to selection of lasR mutants both on rich medium and within the CF airway, supporting a key role for bacterial metabolic adaptation during chronic infection. Inactivation of lasR also resulted in increased β-lactamase activity that increased tolerance to ceftazidime, a widely used β-lactam antibiotic. Loss of LasR function may represent a marker of an early stage in chronic infection of the CF airway with clinical implications for antibiotic resistance and disease progression. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
18. Aminoglycoside antibiotics induce bacterial biofilm formation.
- Author
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Hoffman, Lucas R., D'Argenio, David A., MacCoss, Michael J., Zhang, Zhaoying, Jones, Roger A., and Miller, Samuel I.
- Subjects
- *
AMINOGLYCOSIDES , *BIOFILMS , *ANTIBIOTICS , *MICROBIAL ecology , *AMINO compounds , *PSEUDOMONAS aeruginosa - Abstract
Biofilms are adherent aggregates of bacterial cells that form on biotic and abiotic surfaces, including human tissues. Biofilms resist antibiotic treatment and contribute to bacterial persistence in chronic infections. Hence, the elucidation of the mechanisms by which biofilms are formed may assist in the treatment of chronic infections, such as Pseudomonas aeruginosa in the airways of patients with cystic fibrosis. Here we show that subinhibitory concentrations of aminoglycoside antibiotics induce biofilm formation in P. aeruginosa and Escherichia coli. In P. aeruginosa, a gene, which we designated aminoglycoside response regulator (arr), was essential for this induction and contributed to biofilm-specific aminoglycoside resistance. The arr gene is predicted to encode an inner-membrane phosphodiesterase whose substrate is cyclic di-guanosine monophosphate (c-di-GMP)—a bacterial second messenger that regulates cell surface adhesiveness. We found that membranes from arr mutants had diminished c-di-GMP phosphodiesterase activity, and P. aeruginosa cells with a mutation changing a predicted catalytic residue of Arr were defective in their biofilm response to tobramycin. Furthermore, tobramycin-inducible biofilm formation was inhibited by exogenous GTP, which is known to inhibit c-di-GMP phosphodiesterase activity. Our results demonstrate that biofilm formation can be a specific, defensive reaction to the presence of antibiotics, and indicate that the molecular basis of this response includes alterations in the level of c-di-GMP. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
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