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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.

Fine excipient particles or 'fines' have been shown to improve the dispersion performance of carrier-based formulations for dry powder inhalation. Mechanistic formulation studies have focussed mainly on explaining this positive effect. Previous studies have shown that higher drug contents may cause a decrease in dispersion performance, and there is no reason why this should not be true for fines with a similar shape, size and cohesiveness as drug particles. Therefore, the effects on drug detachment of 'fine lactose fines' (FLF, X50= 1.95 mm) with a similar size and shape as micronised budesonide were studied and compared to those of 'coarse lactose fines' (CLF, X50= 3.94 mm). Furthermore, interactions with the inhalation flow rate, the drug content and the mixing order were taken into account. The observed effects of FLF are comparable to drug content effects in that the detached drug fraction was decreased at low drug content and low flow rates but increased at higher flow rates. At high drug content the effects of added FLF were negligible. In contrast, CLF resulted in higher detached drug fractions at all flow rates and drug contents. The results from this study suggest that the effects of fines may be explained by two new mechanisms in addition to those previously proposed. Firstly, fines below a certain size may increase the effectiveness of press-on forces or cause the formation of strongly coherent fine particle networks on the carrier surface containing the drug particles. Secondly, when coarse enough, fines may prevent the formation of, or disrupt such fine particle networks, possibly through a lowering of their tensile strength. It is recommended that future mechanistic studies are based on the recognition that added fines may have any effect on dispersion performance, which is determined by the formulation and dispersion conditions. © 2014 Grasmeijer et al.

In Table 2, the data in row "600 min" shifted four columns to the left and the data in row "780 min" shifted six columns to the left. Please see the corrected Table 2 here: http://plosone.org/corrections/pone.0069263.t002.cn.tif

The drug content in adhesive mixtures for inhalation is known to influence their dispersion performance, but the direction and magnitude of this influence depends on other variables. In the past decades several mechanisms have been postulated to explain this finding and a number of possible interacting variables have been identified. Still, the role of drug content in the formulation of adhesive mixtures for inhalation, which includes its significance as an interacting variable to other parameters, is poorly understood. Therefore, the results from a series of drug detachment experiments are presented in which the effect of drug content and its dependence on flow rate, the mixing time and the type of drug is studied. Furthermore, it is investigated whether the effect depends on the range within which the drug content is changed. Quantitative and qualitative multiple order interactions are observed between these variables, which may be explained by a shifting balance between three different mechanisms. The results therefore demonstrate that accounting for (multiple order) interactions between variables has to be part of quality by design activities and the rational design of future experiments.