Comparative in vitro evaluation of four corticosteroid metered dose inhalers:Consistency of delivered dose and particle size distribution

SummaryIntroductionRecent developments concerning pressurized metered dose inhalers (pMDIs) with inhaled corticosteroids (ICS) are the introduction of ciclesonide and the replacement of propellants. As the results of in vivo studies depend on pMDIperformance, it is necessary to evaluate pMDIs in vitro for delivered dose and particle size distributions under different conditions.MethodsFluticasone 125μg, budesonide 200μg, beclomethasone HFA100μg, and ciclesonide 160μg were compared for delivered dose and particle size using laser diffraction analysis with inspiratory flow rates of 10, 20 and 30l/s.ResultsThe volume median diameter of budesonide was 3.5μm, fluticasone 2.8μm, beclomethasone and ciclesonide both 1.9μm. The mouthpiece retention was up to 30% of the nominal dose for beclomethasone and ciclesonide, 11–19% for the other pMDIs. Lifespan, flow rate, and air humidity had no significant influence on particle size distribution. The delivered dose of beclomethasone, budesonide, and ciclesonide remained constant over the lifespan. The delivered dose of fluticasone 125 decreased from 106% to 63%; fluticasone 250 also decreased whereas fluticasone 50 remained constant.ConclusionsThere is a significant difference in median particle size distribution between the different ICS pMDIs. Air humidity and inspiratory flow rate have no significant influence on particle size distribution. Ciclesonide 160 and beclomethasone 100 deliver the largest fine particle fractions of 1.1–3.1μm. The changes in delivered dose during the lifespan for the fluticasone 125 and 250 may have implications for patient care

The pharmacokinetics of antibiotics in cystic fibrosis

Introduction Dosing of antibiotics in people with cystic fibrosis (CF) is challenging, due to altered pharmacokinetics, difficulty of lung tissue penetration, and increasing presence of antimicrobial resistance. Areas covered The purpose of this work is to critically review original data as well as previous reviews and guidelines on pharmacokinetics of systemic and inhaled antibiotics in CF, with the aim to propose strategies for optimization of antibacterial therapy in both children and adults with CF. Expert opinion For systemic antibiotics, absorption is comparable in CF patients and non-CF controls. The volume of distribution (Vd) of most antibiotics is similar between people with CF with normal body composition and healthy individuals. However, there are a few exceptions, like cefotiam and tobramycin. Many antibiotic class-dependent changes in drug metabolism and excretion are reported, with an increased total body clearance for ss-lactam antibiotics, aminoglycosides, fluoroquinolones, and trimethoprim. We, therefore, recommend following class-specific guidelines for CF, mostly resulting in higher dosages per kg bodyweight in CF compared to non-CF controls. Higher local antibiotic concentrations in the airways can be obtained by inhalation therapy, with which eradication of bacteria may be achieved while minimizing systemic exposure and risk of toxicity

An International Prospective Cohort Study To Validate 2 Prediction Rules for Infections Caused by Third-generation Cephalosporin-resistant Enterobacterales

Background The possibility of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacterales (3GC-R-BSI) leads to a trade-off between empiric inappropriate treatment (IAT) and unnecessary carbapenem use (UCU). Accurately predicting 3GC-R-BSI could reduce IAT and UCU. We externally validate 2 previously derived prediction rules for community-onset (CO) and hospital-onset (HO) suspected bloodstream infections. Methods In 33 hospitals in 13 countries we prospectively enrolled 200 patients per hospital in whom blood cultures were obtained and intravenous antibiotics with coverage for Enterobacterales were empirically started. Cases were defined as 3GC-R-BSI or 3GC-R gram-negative infection (3GC-R-GNI) (analysis 2); all other outcomes served as a comparator. Model discrimination and calibration were assessed. Impact on carbapenem use was assessed at several cutoff points. Results 4650 CO infection episodes were included and the prevalence of 3GC-R-BSI was 2.1% (n = 97). IAT occurred in 69 of 97 (71.1%) 3GC-R-BSI and UCU in 398 of 4553 non–3GC-R-BSI patients (8.7%). Model calibration was good, and the AUC was .79 (95% CI, .75–.83) for 3GC-R-BSI. The prediction rule potentially reduced IAT to 62% (60/97) while keeping UCU comparable at 8.4% or could reduce UCU to 6.3% (287/4553) while keeping IAT equal. IAT and UCU in all 3GC-R-GNIs (analysis 2) improved at similar percentages. 1683 HO infection episodes were included and the prevalence of 3GC-R-BSI was 4.9% (n = 83). Here model calibration was insufficient. Conclusions A prediction rule for CO 3GC-R infection was validated in an international cohort and could improve empirical antibiotic use. Validation of the HO rule yielded suboptimal performance

Eradication of Pseudomonas aeruginosa in cystic fibrosis patients with inhalation of dry powder tobramycin

BACKGROUND: Pseudomonas aeruginosa (Pa) is the predominant pulmonary pathogen in patients with cystic fibrosis (CF). Tobramycin nebulization is used for the eradication of Pa infection. Nowadays, tobramycin dry powder inhalation (DPI) is available as well. This study reports the results of eradicating Pa with tobramycin DPI versus nebulization. METHODS: Adult CF patients with a Pa isolation between September 2010 and September 2017 from the University Medical Centre Groningen (UMCG), the Netherlands, were included in this retrospective study. RESULTS: In total 27 Pa isolations were recorded. In 13 of these, eradication was attempted with tobramycin, 7 with DPI and 6 with nebulization. DPI eradicated Pa successfully in six isolations (85.7%). Of these, one patient received additional oral ciprofloxacin and one received intravenous ceftazidime. Nebulization eradicated three Pa isolations (50.0%), in two of these, additional oral ciprofloxacin was given. CONCLUSION: Eradication rates of DPI tobramycin are comparable with those for nebulized tobramycin reported in the literature. This study suggests that DPI tobramycin is an alternative to nebulized tobramycin for eradication of Pa. TRIAL REGISTRATION: The Medical Ethics Committee of the UMCG granted a waiver (METC2017-349), as they concluded that this study was not subject to the Medical Research Involving Human Subjects Act. The reviews of this paper are available via the supplemental material section

Colistin dry powder inhalation with the Twincer (TM):An effective and more patient friendly alternative to nebulization

BACKGROUND: Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting. METHODS: This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer. RESULTS: Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63). CONCLUSION: Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates

The long-term safety of chronic azithromycin use in adult patients with cystic fibrosis, evaluating biomarkers for renal function, hepatic function and electrical properties of the heart

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation. Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively. Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed. Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication

An International Prospective Cohort Study To Validate 2 Prediction Rules for Infections Caused by Third-generation Cephalosporin-resistant Enterobacterales

[Background] The possibility of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacterales (3GC-R-BSI) leads to a trade-off between empiric inappropriate treatment (IAT) and unnecessary carbapenem use (UCU). Accurately predicting 3GC-R-BSI could reduce IAT and UCU. We externally validate 2 previously derived prediction rules for community-onset (CO) and hospital-onset (HO) suspected bloodstream infections.[Methods] In 33 hospitals in 13 countries we prospectively enrolled 200 patients per hospital in whom blood cultures were obtained and intravenous antibiotics with coverage for Enterobacterales were empirically started. Cases were defined as 3GC-R-BSI or 3GC-R gram-negative infection (3GC-R-GNI) (analysis 2); all other outcomes served as a comparator. Model discrimination and calibration were assessed. Impact on carbapenem use was assessed at several cutoff points.[Results] 4650 CO infection episodes were included and the prevalence of 3GC-R-BSI was 2.1% (n = 97). IAT occurred in 69 of 97 (71.1%) 3GC-R-BSI and UCU in 398 of 4553 non–3GC-R-BSI patients (8.7%). Model calibration was good, and the AUC was .79 (95% CI, .75–.83) for 3GC-R-BSI. The prediction rule potentially reduced IAT to 62% (60/97) while keeping UCU comparable at 8.4% or could reduce UCU to 6.3% (287/4553) while keeping IAT equal. IAT and UCU in all 3GC-R-GNIs (analysis 2) improved at similar percentages. 1683 HO infection episodes were included and the prevalence of 3GC-R-BSI was 4.9% (n = 83). Here model calibration was insufficient.[Conclusions] A prediction rule for CO 3GC-R infection was validated in an international cohort and could improve empirical antibiotic use. Validation of the HO rule yielded suboptimal performance.J. R.-B. receives funds for research from Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001), co-financed by the European Development Regional Fund “A Way to Achieve Europe,” Operative Program Intelligent Growth 2014-2020.Peer reviewe

Investigating mitochondrial DNA relationships in Neolithic Western Europe through serial coalescent simulations

Recent ancient DNA studies on European Neolithic human populations have provided persuasive evidence of a major migration of farmers originating from the Aegean, accompanied by sporadic hunter-gatherer admixture into early Neolithic populations, but increasing toward the Late Neolithic. In this context, ancient mitochondrial DNA data collected from the Neolithic necropolis of Gurgy (Paris Basin, France), the largest mitochondrial DNA sample obtained from a single archeological site for the Early/Middle Neolithic period, indicate little differentiation from farmers associated to both the Danubian and Mediterranean Neolithic migration routes, as well as from Western European hunter-gatherers. To test whether this pattern of differentiation could arise in a single unstructured population by genetic drift alone, we used serial coalescent simulations. We explore female effective population size parameter combinations at the time of the colonization of Europe 45000 years ago and the most recent of the Neolithic samples analyzed in this study 5900 years ago, and identify conditions under which population panmixia between hunter-gatherers/Early-Middle Neolithic farmers and Gurgy cannot be rejected. In relation to other studies on the current debate of the origins of Europeans, these results suggest increasing hunter-gatherer admixture into farmers' group migrating farther west in Europe.European Journal of Human Genetics advance online publication, 28 December 2016; doi:10.1038/ejhg.2016.180

Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease

Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O2). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Rα gene in preterms with nCLD and directly test the effect of PDGF-Rα haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O2. In the context of MV-O2, attenuated PDGF signal