Clinical characteristics of bacteraemia caused by burkholderia cepacia complex species and antimicrobial susceptibility of the isolates in a medical centre in taiwan.

Int J Antimicrob Agents. 2017 Jul 10;:

Authors: Chien YC, Liao CH, Sheng WH, Chien JY, Huang YT, Yu CJ, Hsueh PR

Abstract
This study investigated the clinical characteristics and outcomes of bacteraemia due to Burkholderia cepacia complex (BCC) species among 54 patients without cystic fibrosis from January 2013 to February 2015. BCC isolates were identified to the species level by the Bruker Biotyper MALDI-TOF MS system and by sequencing analysis of the 16S rRNA and recA genes. Antimicrobial susceptibilities of the isolates were determined by the agar dilution method. Sequencing of the recA gene in the 54 blood isolates revealed 37 (68.5%) isolates of B. cenocepacia, 9 (16.7%) B. cepacia, 4 (7.4%) isolates of B. multivorans and one isolate each of B. arboris, B. pseudomultivorans, B. seminalis, and B. vietnamiensis. The overall performance of the Bruker Biotyper MALDI-TOF MS system for correctly identifying the 54 BCC isolates to the species level was 79.6% that was better than that (16.7%) by 16S RNA sequencing analysis. Bacteraemic pneumonia (n=23, 42.6%) and catheter-related bacteraemia (n=21, 38.9%) were the most common types of infection. Higher rates of ceftazidime and meropenem resistance were found in B. cepacia isolates (33.3% and 22.2%, respectively) than in isolates of B. cenocepacia (21.6% and 10.8%, respectively) and other species (12.5% and 12.5%, respectively). Overall, the 30-day mortality rate was 38.9% (21/54). Bacteraemia caused by BCC species other than B. cenocepacia and B. cepacia (adjusted odds ratio [aOR] 20.005, P=0.024) and high SOFA score (aOR 1.412, P=0.003) were predictive of higher 30-day mortality. Different BCC complex species are associated with different outcomes of bacteraemia and exhibit different susceptibility patterns.

PMID: 28705667 [PubMed - as supplied by publisher]

Monitoring clinical and microbiological evolution of a cystic fibrosis patient over 26 years: experience of a Brazilian CF Centre.

BMC Pulm Med. 2017 Jul 14;17(1):100

Authors: da Costa Ferreira Leite C, Folescu TW, de Cássia Firmida M, Cohen RWF, Leão RS, de Freitas FAD, Albano RM, da Costa CH, Marques EA

Abstract
BACKGROUND: Burkholderia cepacia complex is a group of opportunistic pathogens in cystic fibrosis (CF) patients believed to be associated with poor prognosis and patient-to-patient transmissibility. Little is known about clinical outcomes after B. vietnamiensis chronic colonization/infection.
CASE PRESENTATION: A 33 yo male patient had diagnosis of CF by 7 yo, after recurrent pneumonia during infancy and lobectomy (left upper lobe) at 6 yo. Burkholderia cepacia complex (Bcc) was first isolated by 13 yo, and the patient fulfilled the criteria for chronic colonization by 15 yo. In the following 16 years (1997-2013), there was intermittent isolation of P. aeruginosa and continuous isolation of Bcc, identified as B. vietnamiensis. There was clinical and laboratorial stability for 16 years with annual rate of decline in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) of 1.61 and 1.35%, respectively. From 2013 to 2015, there was significant clinical and lung function deterioration: annual rate of decline in FEV1 and FVC was 3 and 4.1%, respectively while body mass index decreased from 18.1 to 17.1. Episodes of hemoptysis and respiratory exacerbations (with hospital admissions) became more frequent. CF related diabetes was diagnosed (fasting glycemia: 116 mg/dL, oral glucose tolerance test: 305 mg/dL). Because of the severity of the disease in the last years, in addition to traditional microbiological surveillance, microbiome analysis by next generation sequencing (NGS) was performed on respiratory secretions. The NGS showed that 97% of the sequencing data were attributed to genus Burkholderia.
CONCLUSIONS: We report the case of a 33-year-old male CF patient known to have chronic infection with B. vietnamiensis who remained clinically stable for 16 years and presented recent clinical and laboratorial deterioration. Microbiome analysis of respiratory secretions was performed in 3 samples collected in 2014-2015. Clinical deterioration overlapped with cystic fibrosis-related diabetes and microbiome composition revealed no significant differences when compared microbiome results to culture dependent methods.

PMID: 28705217 [PubMed - in process]

N-Chlorotaurine, a Promising Future Candidate for Topical Therapy of Fungal Infections.

Mycopathologia. 2017 Jul 12;:

Authors: Nagl M, Arnitz R, Lackner M

Abstract
N-Chlorotaurine (NCT) is a mild long-lived oxidant that can be applied to sensitive body regions as an endogenous antiseptic. Enhancement of its microbicidal activity in the presence of proteinaceous material because of transchlorination, a postantibiotic/postantifungal effect and antitoxic activity renders it interesting for treatment of fungal infections, too. This is confirmed by first case applications in skin and mucous membranes of different body sites. Recent findings of good tolerability of inhaled NCT suggest further investigations of this substance for treatment of bronchopulmonary diseases, where microorganisms play a role, particularly multi-resistant ones. The availability of a well-tolerated and effective inhaled antiseptic with anti-inflammatory properties could be a significant progress, in particular for chronic pulmonary diseases, such as chronic obstructive pulmonary disease or cystic fibrosis.

PMID: 28702855 [PubMed - as supplied by publisher]

Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis.

Sci Rep. 2017 Jul 12;7(1):5233

Authors: Zhang JT, Wang Y, Chen JJ, Zhang XH, Dong JD, Tsang LL, Huang XR, Cai Z, Lan HY, Jiang XH, Chan HC

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR), known as a cAMP-activated Cl(-) channel, is widely expressed at the apical membrane of epithelial cells in a wide variety of tissues. Of note, despite the abundant expression of CFTR in mammalian kidney, the role of CFTR in kidney disease development is unclear. Here, we report that CFTR expression is downregulated in the UUO (unilateral ureteral obstruction)-induced kidney fibrosis mouse model and human fibrotic kidneys. Dysfunction or downregulation of CFTR in renal epithelial cells leads to alteration of genes involved in Epithelial-Mesenchymal Transition (EMT) and kidney fibrosis. In addition, dysregulation of CFTR activates canonical Wnt/β-catenin signaling pathways, whereas the β-catenin inhibitor reverses the effects of CFTR downregulation on EMT marker. More interestingly, CFTR interacts with Dishevelled 2 (Dvl2), a key component of Wnt signaling, thereby suppressing the activation of β-catenin. Compared to wild type, deltaF508 mice with UUO treatment exhibit significantly higher β-catenin activity with aggregated kidney fibrogenesis, which is reduced by forced overexpression of CFTR. Taken together, our study reveals a novel mechanism by which CFTR regulates Wnt/β-catenin signaling pertinent to progression of kidney fibrosis and indicates a potential treatment target.

PMID: 28701694 [PubMed - in process]

Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients.

Diabetes Care. 2017 Jul 12;:

Authors: Shields BM, Shepherd M, Hudson M, McDonald TJ, Colclough K, Peters J, Knight B, Hyde C, Ellard S, Pearson ER, Hattersley AT, UNITED study team

Abstract
OBJECTIVE: Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating type 1 from non-type 1 diabetes, in a biomarker screening pathway for monogenic diabetes.
RESEARCH DESIGN AND METHODS: We studied patients diagnosed aged 30 years or younger, currently younger than 50 years, in two U.K. regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised three stages: 1) assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) if UCPCR was ≥0.2 nmol/mmol, measurement of GAD and IA2 islet autoantibodies; and 3) if negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes.
RESULTS: A total of 1,407 patients participated (1,365 with no known genetic cause, 34 with monogenic diabetes, and 8 with cystic fibrosis-related diabetes). A total of 386 out of 1,365 (28%) patients had a UCPCR ≥0.2 nmol/mmol, and 216 out of 386 (56%) were negative for GAD and IA2 and underwent molecular genetic testing. Seventeen new cases of monogenic diabetes were diagnosed (8 common Maturity Onset Diabetes of the Young [Sanger sequencing] and 9 rarer causes [next-generation sequencing]) in addition to the 34 known cases (estimated prevalence of 3.6% [51/1,407] [95%CI 2.7-4.7%]). The positive predictive value was 20%, suggesting a one-in-five detection rate for the pathway. The negative predictive value was 99.9%.
CONCLUSIONS: The biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed aged 30 years or younger.

PMID: 28701371 [PubMed - as supplied by publisher]

AJRCCM: 100-Year Anniversary. Homeward Bound: A Centenary of Home Mechanical Ventilation.

Am J Respir Crit Care Med. 2017 May 01;195(9):1140-1149

Authors: Hind M, Polkey MI, Simonds AK

Abstract
The evolution of home mechanical ventilation is an intertwined chronicle of negative and positive pressure modes and their role in managing ventilatory failure in neuromuscular diseases and other chronic disorders. The uptake of noninvasive positive pressure ventilation has resulted in widespread growth in home ventilation internationally and fewer patients being ventilated invasively. As with many applications of domiciliary medical technology, home ventilatory support has either led or run in parallel with acute hospital applications and has been influenced by medical and societal shifts in the approach to chronic care, the creation of community support teams, a preference of recipients to be treated at home, and economic imperatives. This review summarizes the trends and growing evidence base for ventilatory support outside the hospital.

PMID: 28459325 [PubMed - indexed for MEDLINE]

Swine models, genomic tools and services to enhance our understanding of human health and diseases.

Lab Anim (NY). 2017 Mar 22;46(4):167-172

Authors: Walters EM, Wells KD, Bryda EC, Schommer S, Prather RS

Abstract
The pig is becoming increasingly important as a biomedical model. Given the similarities between pigs and humans, a greater understanding of the underlying biology of human health and diseases may come from the pig rather than from classical rodent models. With an increasing need for swine models, it is essential that the genomic tools, models and services be readily available to the scientific community. Many of these are available through the National Swine Resource and Research Center (NSRRC), a facility funded by the US National Institutes of Health at the University of Missouri. The goal of the NSRRC is to provide high-quality biomedical swine models to the scientific community.

PMID: 28328880 [PubMed - indexed for MEDLINE]

Former Very Preterm Infants Show an Unfavorable Cardiovascular Risk Profile at a Preschool Age.

PLoS One. 2016;11(12):e0168162

Authors: Posod A, Odri Komazec I, Kager K, Pupp Peglow U, Griesmaier E, Schermer E, Würtinger P, Baumgartner D, Kiechl-Kohlendorfer U

Abstract
Cardiovascular disease is the leading cause of death worldwide. Evidence points towards an unfavorable cardiovascular risk profile of former preterm infants in adolescence and adulthood. The aim of this study was to determine whether cardiovascular risk predictors are detectable in former very preterm infants at a preschool age. Five- to seven-year-old children born at <32 weeks' gestational age were included in the study. Same-aged children born at term served as controls. Basic data of study participants were collected by means of follow-up databases and standardized questionnaires. At study visit, anthropometric data, blood pressure readings and aortic intima-media thickness were assessed. Blood samples were obtained after an overnight fast. In comparison to children born at term, former preterm infants had higher systolic and diastolic blood pressure readings (odds ratio [95% confidence interval] per 1-SD higher blood pressure level 3.2 [2.0-5.0], p<0.001 and 1.6 [1.1-1.2], p = 0.008), fasting glucose levels (OR [95% CI] 5.2 [2.7-10.1], p<0.001), homeostasis model assessment index (OR [95% CI] 1.6 [1.0-2.6], p = 0.036), and cholesterol levels (OR [95% CI] 2.1 [1.3-3.4], p = 0.002). Systolic prehypertension (23.7% vs. 2.2%; OR [95% CI] 13.8 [3.1-60.9], p = 0.001), elevated glucose levels (28.6% vs. 5.9%; OR [95% CI] 6.4 [1.4-28.8], p = 0.016), and hypercholesterolemia (77.4% vs. 52.9%; OR [95% CI] 3.0 [1.3-7.1], p = 0.010) were significantly more prevalent in the preterm group. As former very preterm infants display an unfavorable cardiovascular risk profile already at a preschool age, implementation of routine cardiovascular follow-up programs might be warranted.

PMID: 27959909 [PubMed - indexed for MEDLINE]

Spirometry Reference Equations for Indian Children: Create Local or Go Global?

Indian Pediatr. 2016 Sep 08;53(9):779-780

Authors: Guglani L, Weiner DJ

PMID: 27771644 [PubMed - indexed for MEDLINE]

Mucolytic Effectiveness of Tyloxapol in Chronic Obstructive Pulmonary Disease - A Double-Blind, Randomized Controlled Trial.

PLoS One. 2016;11(6):e0156999

Authors: Koppitz M, Eschenburg C, Salzmann E, Rosewich M, Schubert R, Zielen S

Abstract
OBJECTIVE: Mucoactive drugs should increase the ability to expectorate sputum and, ideally, have anti-inflammatory properties. The aim of the study was to evaluate the mucolytic activity of Tyloxapol compared to saline (0.9%) in COPD.
DESIGN: A randomized, placebo-controlled, double-blinded crossover, clinical trial was carried out. Patients were randomly assigned to either inhale 5 ml Tyloxapol 1% or saline 0.9% solution three times daily for 3 weeks and vice versa for another 3 weeks. 28 patients (18 male, 10 female, 47 to 73 years old, median age 63.50) were screened, 21 were treated and 19 patients completed the study per protocol.
RESULTS: A comparison of the two treatment phases showed that the primary endpoint sputum weight was statistically significant higher when patients inhaled Tyloxapol (mean 4.03 g, 95% CI: 2.34-5.73 g at week 3) compared to saline (mean 2.63 g, 95% CI: 1.73-3.53 g at week 3). The p-value at three weeks of treatment was 0.041 between treatment arms. Sputum cells decreased during the Tyloxapol treatment after 3 weeks, indicating that Tyloxapol might have some anti-neutrophilic properties. Lung function parameters (FVC, FEV1, RV, and RV/TLC) remained stable during the study, and no treatment effect was shown. Interestingly, there was a mean increase in all inflammatory cytokines (IL-1β, IL-6, and IL-8) during the saline treatment from day 1 to week 3, whereas during the Tyloxapol treatment, all cytokines decreased. Due to the small sample size and the large individual variation in sputum cytokines, these differences were not significant. However, analyses confirmed that Tyloxapol has significant anti-inflammatory properties in vitro. Despite the high number of inhalations (more than 1000), only 27 adverse events (20 during the Tyloxapol and seven during saline) were recorded. Eleven patients experienced AEs under Tyloxapol and six under saline treatment, which indicates that inhalation of saline or Tyloxapol is a very safe procedure.
CONCLUSION: Our study demonstrated that inhalation of Tyloxapol by patients with COPD is safe and superior to saline and has some anti-inflammatory effects.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02515799.

PMID: 27308826 [PubMed - indexed for MEDLINE]

FDA deems in vitro data on mutations sufficient to expand cystic fibrosis drug label.

Nat Biotechnol. 2017 Jul 12;35(7):606

Authors: Ratner M

PMID: 28700545 [PubMed - in process]

D-methionine interferes with non-typeable Haemophilus influenzae peptidoglycan synthesis during growth and biofilm formation.

Microbiology. 2017 Jul 12;:

Authors: Dawe H, Berger E, Sihlbom C, Angus EM, Howlin RP, Laver JR, Tebruegge M, Hall-Stoodley L, Stoodley P, Faust SN, Allan RN

Abstract
Non-typeable Haemophilus influenzae (NTHi) is an opportunistic pathogen that plays a major role in a number of respiratory tract infections, including otitis media, cystic fibrosis and chronic obstructive pulmonary disease. Biofilm formation has been implicated in both NTHi colonization and disease, and is responsible for the increased tolerance of this pathogen towards antibiotic treatment. Targeting metabolic pathways that are important in NTHi biofilm formation represents a potential strategy to combat this antibiotic recalcitrance. A previous investigation demonstrated increased expression of a putative d-methionine uptake protein following exposure of NTHi biofilms to the ubiquitous signalling molecule, nitric oxide. We therefore hypothesized that treatment with exogenous d-methionine would impact on NTHi biofilm formation and increase antibiotic sensitivity. Treatment of NTHi during the process of biofilm formation resulted in a reduction in biofilm viability, increased biomass, changes in the overall biofilm architecture and the adoption of an amorphous cellular morphology. Quantitative proteomic analyses identified 124 proteins that were differentially expressed following d-methionine treatment, of which 51 (41 %) were involved in metabolic and transport processes. Nine proteins involved in peptidoglycan synthesis and cell division showed significantly increased expression. Furthermore, d-methionine treatment augmented the efficacy of azithromycin treatment and highlighted the potential of d-methionine as an adjunctive therapeutic approach for NTHi biofilm-associated infections.

PMID: 28699879 [PubMed - as supplied by publisher]

Estimating Direct Cost of Cystic Fibrosis Care Using Irish Registry Healthcare Resource Utilisation Data, 2008-2012.

Pharmacoeconomics. 2017 Jul 11;:

Authors: Jackson AD, Jackson AL, Fletcher G, Doyle G, Harrington M, Zhou S, Cullinane F, Gallagher C, McKone E

Abstract
BACKGROUND: Understanding the determinants of cost of cystic fibrosis (CF) care and health outcomes may be useful for financial planning for the delivery of CF services. Registries contain information otherwise unavailable to healthcare activity/cost monitoring systems. We estimated the direct medical cost of CF care using registry data and examined how cost was affected by patient characteristics and CF gene (CF Transmembrane Conductance Regulator [CFTR]) mutation.
METHODS: Healthcare resource utilisation data (2008-2012) were obtained for CF patients enrolled with the Irish CF Registry by 2013 from linked registry and national hospitalisation database records. Mean annual hospitalisation and medication per-patient costs were estimated by demographic profile, CFTR mutation, clinical status, and CF co-morbidity, and were presented in 2014 euro values. A mixed-effects regression model was used to examine the effect of demographic, CFTR mutation, and clinical outcomes on the log10 cost of direct medical CF care.
RESULTS: Using 4261 observations from 1100 patients, we found that the median annual total cost per patient increased over the period 2008-2012 from €12,659 to €16,852, inpatient bed-day cost increased from €14,026 to €17,332, and medication cost increased from €5863 to €12,467. Homozygous F508-CFTR mutation (class II) cost was highest and milder mutation (class IV/V) cost was 49% lower. Baseline estimated cost in 2008 for a hypothetical underweight, homozygous F508del-CFTR 6-year-old female without chronic Pseudomonas aeruginosa/Staphylococcus aureus, CF-related diabetes (CFRD) or methicillin-resistant S. aureus (MRSA), and with a poor percent predicted forced expiratory volume in 1 s (ppFEV1) was €10,113, and was €21,082 in a 25-year-old with the same hypothetical profile. Chronic P. aeruginosa infection increased baseline cost by 39%, CF co-morbidity diabetes by 18%, and frequency of pulmonary exacerbation by 15%. Underweight, declining ppFEV1, chronic S. aureus colonisation, and time also influenced cost.
CONCLUSIONS: CFTR mutation is an important factor influencing the cost of CF care. Costs differ among cohorts of CF patients eligible to access new and emerging CFTR repair therapies. These findings support the evaluation of outcome-associated cost in CFTR mutation-specific CF patient groups.

PMID: 28699086 [PubMed - as supplied by publisher]

Peptide Nucleic Acids as miRNA Target Protectors for the Treatment of Cystic Fibrosis.

Molecules. 2017 Jul 08;22(7):

Authors: Zarrilli F, Amato F, Morgillo CM, Pinto B, Santarpia G, Borbone N, D'Errico S, Catalanotti B, Piccialli G, Castaldo G, Oliviero G

Abstract
Cystic Fibrosis (CF) is one of the most common life shortening conditions in Caucasians. CF is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene which result in reduced or altered CFTR functionality. Several microRNAs (miRNAs) downregulate the expression of CFTR, thus causing or exacerbating the symptoms of CF. In this context, the design of anti-miRNA agents represents a valid functional tool, but its translation to the clinic might lead to unpredictable side effects because of the interference with the expression of other genes regulated by the same miRNAs. Herein, for the first time, is proposed the use of peptide nucleic acids (PNAs) to protect specific sequences in the 3'UTR (untranslated region) of the CFTR messenger RNA (mRNA) by action of miRNAs. Two PNAs (7 and 13 bases long) carrying the tetrapeptide Gly-SerP-SerP-Gly at their C-end, fully complementary to the 3'UTR sequence recognized by miR-509-3p, have been synthesized and the structural features of target PNA/RNA heteroduplexes have been investigated by spectroscopic and molecular dynamics studies. The co-transfection of the pLuc-CFTR-3´UTR vector with different combinations of PNAs, miR-509-3p, and controls in A549 cells demonstrated the ability of the longer PNA to rescue the luciferase activity by up to 70% of the control, thus supporting the use of suitable PNAs to counteract the reduction in the CFTR expression.

PMID: 28698463 [PubMed - in process]

Cystic fibrosis: Priorities and progress for future therapies.

Paediatr Respir Rev. 2017 Jun 12;:

Authors: Kerem E

Abstract
Significant improvement in the survival of patients with CF has been achieved in the last decades. The improved clinical status of the patients is mainly the result of a better understanding of the natural course of infection and inflammation in CF that has led to the implementation of strategies that increase the life expectancy and quality of life of the patients. These strategies include prompt diagnosis, timely and aggressive nutritional support, augmentation of MCC and improved mucous drainage, initiation of antimicrobial and anti-inflammatory therapy as soon as possible, early treatment of acute exacerbations, implementation of effective hygienic measures in and outside CF centers and prompt identification and treatment of CF-related complications. Treatment at a specialized CF center by a multidisciplinary dedicated team, including frequent visits, and periodic routine tests are essential to detect and treat early changes. Adherence to these therapies is challenging. Maintaining patients in optimal status will allow them to benefit from future treatments designed to correct or modify the basic genetic defect associated with CFTR by gene replacement therapy or pharmacological interventions currently under development. These new therapies are expected to further increase life expectancy of the patients.

PMID: 28697970 [PubMed - as supplied by publisher]

Early Intervention of Cystic Fibrosis Pulmonary Exacerbations Based on Home Monitoring - "eICE Through the Looking Glass".

Am J Respir Crit Care Med. 2017 Jul 11;:

Authors: Bell SC

PMID: 28696781 [PubMed - as supplied by publisher]

Highlights from the 2016 North American Cystic Fibrosis Conference.

Pediatr Pulmonol. 2017 Jul 11;:

Authors: Zemanick ET, Daines CL, Dellon EP, Esther CR, Kinghorn B, Ong T, Muhlebach MS

Abstract
The 30th annual North American Cystic Fibrosis Conference (NACFC) was held in Orlando, FL, on October 27-29, 2016. Abstracts were published in a supplement to Pediatric Pulmonology. This review summarizes several major topic areas addressed at the conference: the pathophysiology of cystic fibrosis (CF) lung disease, clinical trials, clinical management issues, and quality improvement. We sought to provide an overview of emerging concepts in several areas of CF research and care, rather than a comprehensive review of the conference. Citations from the conference are by first author and abstract number or symposium number, as designated in the supplement.

PMID: 28696526 [PubMed - as supplied by publisher]

Optimised chronic infection models demonstrate that siderophore 'cheating' in Pseudomonas aeruginosa is context specific.

ISME J. 2017 Jul 11;:

Authors: Harrison F, McNally A, da Silva AC, Heeb S, Diggle SP

Abstract
The potential for siderophore mutants of Pseudomonas aeruginosa to attenuate virulence during infection, and the possibility of exploiting this for clinical ends, have attracted much discussion. This has largely been based on the results of in vitro experiments conducted in iron-limited growth medium, in which siderophore mutants act as social 'cheats:' increasing in frequency at the expense of the wild type to result in low-productivity, low-virulence populations dominated by mutants. We show that insights from in vitro experiments cannot necessarily be transferred to infection contexts. First, most published experiments use an undefined siderophore mutant. Whole-genome sequencing of this strain revealed a range of mutations affecting phenotypes other than siderophore production. Second, iron-limited medium provides a very different environment from that encountered in chronic infections. We conducted cheating assays using defined siderophore deletion mutants, in conditions designed to model infected fluids and tissue in cystic fibrosis lung infection and non-healing wounds. Depending on the environment, siderophore loss led to cheating, simple fitness defects, or no fitness effect at all. Our results show that it is crucial to develop defined in vitro models in order to predict whether siderophores are social, cheatable and suitable for clinical exploitation in specific infection contexts.The ISME Journal advance online publication, 11 July 2017; doi:10.1038/ismej.2017.103.

PMID: 28696423 [PubMed - as supplied by publisher]

Nontypeable Haemophilus influenzae releases DNA and DNABII proteins via a T4SS-like complex and ComE of the type IV pilus machinery.

Proc Natl Acad Sci U S A. 2017 Jul 10;:

Authors: Jurcisek JA, Brockman KL, Novotny LA, Goodman SD, Bakaletz LO

Abstract
Biofilms formed by nontypeable Haemophilus influenzae (NTHI) are central to the chronicity, recurrence, and resistance to treatment of multiple human respiratory tract diseases including otitis media, chronic rhinosinusitis, and exacerbations of both cystic fibrosis and chronic obstructive pulmonary disease. Extracellular DNA (eDNA) and associated DNABII proteins are essential to the overall architecture and structural integrity of biofilms formed by NTHI and all other bacterial pathogens tested to date. Although cell lysis and outer-membrane vesicle extrusion are possible means by which these canonically intracellular components might be released into the extracellular environment for incorporation into the biofilm matrix, we hypothesized that NTHI additionally used a mechanism of active DNA release. Herein, we describe a mechanism whereby DNA and associated DNABII proteins transit from the bacterial cytoplasm to the periplasm via an inner-membrane pore complex (TraC and TraG) with homology to type IV secretion-like systems. These components exit the bacterial cell through the ComE pore through which the NTHI type IV pilus is expressed. The described mechanism is independent of explosive cell lysis or cell death, and the release of DNA is confined to a discrete subpolar location, which suggests a novel form of DNA release from viable NTHI. Identification of the mechanisms and determination of the kinetics by which critical biofilm matrix-stabilizing components are released will aid in the design of novel biofilm-targeted therapeutic and preventative strategies for diseases caused by NTHI and many other human pathogens known to integrate eDNA and DNABII proteins into their biofilm matrix.

PMID: 28696280 [PubMed - as supplied by publisher]

Community composition determines activity of antibiotics against multispecies biofilms.

Antimicrob Agents Chemother. 2017 Jul 10;:

Authors: Tavernier S, Crabbé A, Tuysuz M, Stuer L, Henry S, Rigole P, Dhondt I, Coenye T

Abstract
In young cystic fibrosis (CF) patients, Staphylococcus aureus is typically the most prevalent organism, while in adults, Pseudomonas aeruginosa is the major pathogen. More recently, it was observed that also Streptococcus anginosus plays an important role in exacerbations of respiratory symptoms. These species are often co-isolated from CF lungs, yet little is known about whether antibiotic killing of one species is influenced by the presence of others. In the present study, we compared the activity of various antibiotics against S. anginosus, S. aureus and P. aeruginosa when grown in monospecies biofilms, with the activity observed in a multispecies biofilm. Our results show that differences in antibiotic activity against species grown in mono- and multispecies biofilms are species- and antibiotic-dependent. Less S. anginosus cells are killed by antibiotics that interfere with cell wall synthesis (amoxicillin+sulbactam, cefepime, imipenem, meropenem, and vancomycin) in presence of S. aureus and P. aeruginosa, while for ciprofloxacin, levofloxacin, and tobramycin, no difference was observed. In addition, we observed that the cell-free supernatant of S. aureus, but not that of P. aeruginosa biofilms, also caused this decrease in killing. Overall, S. aureus was more affected by antibiotic treatment in a multispecies biofilm, while for P. aeruginosa, no differences were observed between growth in mono- or multispecies biofilms.The results of the present study suggest that it is important to take the community composition into account when evaluating the effect of antimicrobial treatments against certain species in mixed biofilms.

PMID: 28696232 [PubMed - as supplied by publisher]