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Bile signalling promotes chronic respiratory infections and antibiotic tolerance.

ABSTRACT: Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa, while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum samples demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease.

SUBMITTER: Reen FJ

PROVIDER: S-EPMC4949476 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Bile signalling promotes chronic respiratory infections and antibiotic tolerance.

Reen F Jerry FJ Flynn Stephanie S Woods David F DF Dunphy Niall N Chróinín Muireann Ní MN Mullane David D Stick Stephen S Adams Claire C O'Gara Fergal F

Scientific reports 20160719

Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates th ...[more]

PMID: 27432520

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Project description:The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we used in vitro evolution and analyzed the inpatient microevolution of Pseudomonas aeruginosa, an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistance in vitro, and we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections, P. aeruginosa first acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multidrug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections.IMPORTANCE Over the past decades, pan-resistant strains of major bacterial pathogens have emerged and have rendered clinically available antibiotics ineffective, putting at risk many of the major achievements of modern medicine, including surgery, cancer therapy, and organ transplantation. A thorough understanding of processes leading to the development of antibiotic resistance in human patients is thus urgently needed. We show that drug tolerance, the ability of bacteria to survive prolonged exposure to bactericidal antibiotics, rapidly evolves in the opportunistic human pathogen Pseudomonas aeruginosa upon recurrent exposures to antibiotics. Our studies show that tolerance protects P. aeruginosa against different classes of antibiotics and that it generally precedes and promotes resistance development. The rapid evolution of tolerance during treatment regimens may thus act as a strong driving force to accelerate antibiotic resistance development. To successfully counter resistance, diagnostic measures and novel treatment strategies will need to incorporate the important role of antibiotic tolerance.

Project description:Importance:Acute respiratory infections (ARIs) are the syndrome for which antibiotics are most commonly prescribed; viruses for which antibiotics are ineffective cause most ARIs. Objectives:To characterize antibiotic prescribing among outpatients with ARI during influenza season and to identify targets for reducing inappropriate antibiotic prescribing for common ARI diagnoses, including among outpatients with laboratory-confirmed influenza. Design, Setting, and Participants:Cohort study enrolling outpatients aged 6 months or older with ARI evaluated at outpatient clinics associated with 5 US Influenza Vaccine Effectiveness Network sites during the 2013-2014 and 2014-2015 influenza seasons. All patients received influenza testing by real-time reverse transcriptase-polymerase chain reaction for research purposes only. Antibiotic prescriptions, medical history, and International Classification of Diseases, Ninth Revision diagnosis codes were collected from medical and pharmacy records, as were group A streptococcal (GAS) testing results in a patient subset. Exposure:Visit for ARI, defined by a new cough of 7 days' duration or less. Main Outcomes and Measures:Antibiotic prescription within 7 days of enrollment. Appropriateness of antibiotic prescribing was based on diagnosis codes, clinical information, and influenza and GAS testing results. Results:Of 14?987 patients with ARI (mean [SD] age, 32 [24] years; 8638 [58%] women; 11?892 [80%] white), 6136 (41%) were prescribed an antibiotic. Among these 6136 patients, 2522 (41%) had diagnoses for which antibiotics are not indicated; 2106 (84%) of these patients were diagnosed as having a viral upper respiratory tract infection or bronchitis (acute or not otherwise specified). Among the 3306 patients (22%) not diagnosed as having pneumonia and who had laboratory-confirmed influenza, 945 (29%) were prescribed an antibiotic, accounting for 17% of all antibiotic prescriptions among patients with nonpneumonia ARI. Among 1248 patients with pharyngitis, 1137 (91%) had GAS testing; 440 of the 1248 patients (35%) were prescribed antibiotics, among whom 168 (38%) had negative results on GAS testing. Of 1200 patients with sinusitis and no other indication for antibiotic treatment who received an antibiotic, 454 (38%) had symptoms for 3 days or less prior to the outpatient visit, suggesting acute viral sinusitis not requiring antibiotics. Conclusions and Relevance:Antibiotic overuse remains widespread in the treatment of outpatient ARIs, including among patients with laboratory-confirmed influenza, although study sites may not be representative of other outpatient settings. Identified targets for improved outpatient antibiotic stewardship include eliminating antibiotic treatment of viral upper respiratory tract infections and bronchitis and improving adherence to prescribing guidelines for pharyngitis and sinusitis. Increased access to sensitive and timely virus diagnostic tests, particularly for influenza, may reduce unnecessary antibiotic use for these syndromes.

Project description:BackgroundAcute respiratory infections are the most common symptomatic reason for seeking care among patients in the US, and account for the majority of all antibiotic prescribing, yet a large fraction of antibiotic prescriptions are inappropriate.ObjectiveWe sought to identify the underlying factors driving variation in antibiotic prescribing across clinicians and settings.Design, participantsUsing electronic health data for adult ambulatory visits for acute respiratory infections to a retail clinic chain and primary care practices from an integrated healthcare system, we identified a random sample of clinicians for survey.Main measuresWe evaluated independent predictors of overall prescribing and imperfect antibiotic prescribing, controlling for clinician and site of care. We defined imperfect antibiotic prescribing as prescribing for non-antibiotic-appropriate diagnoses, failure to prescribe for an antibiotic-appropriate diagnosis, or prescribing a non-guideline-concordant antibiotic.Key resultsResponse rates were 34 % for retail clinics and 24 % for physicians' offices (N = 187). Clinicians in physicians' offices prescribed antibiotics less often than those in retail clinics (53 % versus 67 %; p < 0.01), but had a higher imperfect antibiotic prescribing rate (65 % versus 31 %; p < 0.01). Feeling rushed was associated with higher antibiotic prescribing (OR 1.34; 95 % CI 1.03, 1.75). Antibiotic prescribing was also associated with clinician disagreement that antibiotics are overused (OR 1.60, 95 % CI, 1.16, 2.20). Imperfect antibiotic prescribing was associated with receiving antibiotic prescribing feedback (OR 1.35, 95 % CI 1.04, 1.75) and disagreement that patient demand was a problem (OR 1.66, 95 % CI 1.00, 2.73). Imperfect antibiotic prescribing was less common with clinicians who perceived that they prescribed antibiotics less often than their peers (OR 0.63, 95 % CI 0.46, 0.87).ConclusionsPoor-quality antibiotic prescribing was associated with feeling rushed, believing less strongly that antibiotics were overused, and believing that patient demand was not an issue, factors that can be assessed and addressed in future interventions.

Project description:ObjectivesInappropriate antibiotic use for respiratory tract infection (RTI) is an ongoing problem linked to the emergence of drug resistance and other adverse effects. Less is known about the prescribing practices of individual physicians or the impact of physician prescribing habits on patient outcomes. We studied the prescribing practices of providers for acute RTIs in an integrated health system, identified patient factors associated with receipt of an antibiotic and assessed the relation between providers' adjusted prescribing rates and a number of patient outcomes.MethodsThis was a retrospective analysis of adults with an RTI visit to any primary care providers across the Cleveland Clinic Health System in 2011-2012. Patients with a history of chronic obstructive pulmonary disease or immunocompromised status were excluded. Logistic regression was used to examine patient factors associated with receipt of an antibiotic.ResultsOf 31,416 patients with an RTI, 54.8% received an antibiotic. Patient factors associated with antibiotic prescribing included white race (odds ratio [OR] 1.35, P < 0.001), presence of fever (OR 1.66, P < 0.001), and a diagnosis of bronchitis (OR 10.98, P < 0.001) or sinusitis (OR 33.85, P < 0.001). Among 290 providers with ≥10 RTI visits, adjusted antibiotic prescribing rates ranged from 0% to 100% (mean 49%). Antibiotics were prescribed more often for sinusitis (OR 33.85, P < 0.001), bronchitis (OR 10.98, P < 0.001), or pharyngitis (OR 1.76, P < 0.001) compared with upper respiratory tract infection. Patients who were prescribed antibiotics at the index visit were more likely to return for RTI within 1 year (adjusted OR 1.26, P < 0.001). Emergency department visits for respiratory complications were rare and not associated with antibiotic receipt.ConclusionsAntibiotic prescribing for RTI varies widely among physicians and cannot be explained by patient factors. Patients prescribed antibiotics for RTI were more likely to return for RTI.

Project description:BackgroundThe potential pathogenic role of Stenotrophomonas maltophilia in lung disease and in particular in cystic fibrosis is unclear. To develop further understanding of the biology of this taxa, the taxonomic position, antibiotic resistance and virulence factors of S. maltophilia isolates from patients with chronic lung disease were studied.ResultsA total of 111 isolates recovered between 2003 and 2016 from respiratory samples from patients in five different countries were included. Based on a cut-off of 95%, analysis of average nucleotide identity by BLAST (ANIb) showed that the 111 isolates identified as S. maltophilia by Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/MS) belonged to S. maltophilia (n = 65), S. pavanii (n = 6) and 13 putative novel species (n = 40), which each included 1-5 isolates; these groupings coincided with the results of the 16S rDNA analysis, and the L1 and L2 ß-lactamase Neighbor-Joining phylogeny. Chromosomally encoded aminoglycoside resistance was identified in all S. maltophilia and S. pavani isolates, while acquired antibiotic resistance genes were present in only a few isolates. Nevertheless, phenotypic resistance levels against commonly used antibiotics, determined by standard broth microbroth dilution, were high. Although putative virulence genes were present in all isolates, the percentage of positive isolates varied. The Xps II secretion system responsible for the secretion of the StmPr1-3 proteases was mainly limited to isolates identified as S. maltophilia based on ANIb, but no correlation with phenotypic expression of protease activity was found. The RPF two-component quorum sensing system involved in virulence and antibiotic resistance expression has two main variants with one variant lacking 190 amino acids in the sensing region.ConclusionsThe putative novel Stenotrophomonas species recovered from patient samples and identified by MALDI-TOF/MS as S. maltophilia, differed from S. maltophilia in resistance and virulence genes, and therefore possibly in pathogenicity. Revision of the Stenotrophomonas taxonomy is needed in order to reliably identify strains within the genus and elucidate the role of the different species in disease.

Project description:OBJECTIVES:To investigate if use of antibiotics was associated with bacterial complications following upper respiratory tract infections (URTIs). DESIGN:Ecological time-trend analysis and a prospective cohort study. SETTING:Primary, outpatient specialist and inpatient care in Stockholm County, Sweden. All analyses were based on administrative healthcare data on consultations, diagnoses and dispensed antibiotics from January 2006 to January 2016. MAIN OUTCOME MEASURES:Ecological time-trend analysis: 10-year trend analyses of the incidence of URTIs, bacterial infections/complications and respiratory antibiotic use. Prospective cohort study: Incidence of bacterial complications following URTIs in antibiotic-exposed and non-exposed patients. RESULTS:The utilisation of respiratory tract antibiotics decreased by 22% from 2006 to 2015, but no increased trend for mastoiditis (p=0.0933), peritonsillar abscess (p=0.0544), invasive group A streptococcal disease (p=0.3991), orbital abscess (p=0.9637), extradural and subdural abscesses (p=0.4790) and pansinusitis (p=0.3971) was observed. For meningitis and acute ethmoidal sinusitis, a decrease in the numbers of infections from 2006 to 2015 was observed (p=0.0038 and p=0.0003, respectively), and for retropharyngeal and parapharyngeal abscesses, an increase was observed (p=0.0214). Bacterial complications following URTIs were uncommon in both antibiotic-exposed (less than 1.5 per 10 000 episodes) and non-exposed patients (less than 1.3 per 10 000 episodes) with the exception of peritonsillar abscess after tonsillitis (risk per 10 000 tonsillitis episodes: 32.4 and 41.1 in patients with no antibiotic treatment and patients treated with antibiotics, respectively). CONCLUSIONS:Bacterial complications following URTIs are rare, and antibiotics may lack protective effect in preventing bacterial complications. Analyses of routinely collected administrative healthcare data can provide valuable information on the number of URTIs, antibiotic use and bacterial complications to patients, prescribers and policy-makers.

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Bile signalling promotes chronic respiratory infections and antibiotic tolerance.

Publications

Bile signalling promotes chronic respiratory infections and antibiotic tolerance.

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