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Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 0 | General introduction InTroduCTIon, AIms & ouTlInE Cystic fibrosis Cystic fibrosis (CF) is a severe hereditary and life-threatening disease in the Caucasian population, affecting 70,000 patients worldwide. 1 In the 1950s, a child with CF would rarely live long enough to attend elementary school. Luckily, life expectancy... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 1 | Chapter ics play a key role in the eradication and chronic suppressive therapy of Pa infections. Currently, 3 inhaled antibiotics are registered for use in patients with CF: Tobramycin, Aztreonam Lysine and Colistin. Inhaled antibiotics First attempts of inhaling antibiotics, 50 years ago, were done by off label use of... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 2 | General introduction Colistin Nebulized colistin is frequently used for treatment of Pa lung infections in patients with CF despite very few controlled trials evaluated its efficacy. For eradication of early Pa infections, only the combination of nebulized colistin with oral ciprofloxacin has been investigated. Compare... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 3 | Chapter Despite the use of inhaled antibiotics and dornase alfa in CF, lung disease still progresses. It has been recognized that inhalation therapy using one of the above described drugs results in high concentrations of the drugs in sputum. 15,21 However, concentrations in the small airways after nebulization are lar... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 4 | General introduction is known to increase deposition of aerosol in the small airways. 24 Moreover, the Akita has shown to improve efficacy of inhaled dornase alpha by 70% compared with 10- 20% for the standard jet-nebulizer.25 The I-neb is another example of a smart electronic system in combination with a mesh nebulize... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 5 | Chapter ABsTrACT Dry powder inhalers (DPI) delivering antibiotics for the suppressive treatment of Pseu- domonas aeruginosa in cystic fibrosis patients were developed recently and are now increasingly replacing time-consuming nebuliser therapy. Noninferiority studies have shown that the efficacy of inhaled tobramycin d... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 6 | Inhaled antibiotics: dry or wet? InTroduCTIon Cystic fibrosis (CF) lung disease results in abnormal secretions in the lung that foster infec- tion and inflammation, even early in life.34,35 The vicious cycle of infection, inflammation and thick pulmonary secretions leads to early structural lung damage and to abnormal ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 7 | Chapter Forest Laboratories Inc., New York, NY, USA) has also recently been developed.18,50 Other antibiotics that are in development as DPI formulations are ciprofloxacin, levofloxacin, vancomycin and clarithromycin. 51-55 Regulatory studies of TIP and Colobreathe have shown non-inferiority relative to the nebulised s... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 8 | Inhaled antibiotics: dry or wet? on aerodynamic diameter is being used in the development of DPI drug formulations containing dry porous particles. Patient-related determinants of lung deposition and distribution within the airways in- clude, firstly, the diameter of the large airways. Children have smaller airways and... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 9 | Chapter deposition at the sites of obstruction. 59-61 The fourth patient-related factor is the abil- ity of the lung to expand. Recent modelling studies showed that lobes with substantial structural damage received less inhaled antibiotic.61 It is likely that structural abnormali- ties such as fibrosis in CF lungs have... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 10 | Inhaled antibiotics: dry or wet? airways. It should be kept in mind that drug bypassing the central airways is distributed over the vast surface area of the small airways. It is estimated that the total surface area of the small airways in adolescents is in the order of 1.2-1.3 m 2. For each consecutive airway generati... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 11 | Chapter the small airways and to more diseased regions with possibly subinhibitory concentra- tions. Secondly, low/subinhibitory concentrations in the more diseased and obstructed areas are not effective, and can lead to on-going infection in these regions. Hence, even when spirometry outcome measures improve during a ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 12 | Inhaled antibiotics: dry or wet? The recently introduced mesh nebulisers use either a vibrating or fixed membrane with a piezoelectric element with microscopic holes to generate an aerosol. Vibrating mesh devices have a number of advantages over jet nebuliser systems. They are very efficient because there is almost no ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 13 | Chapter For the nebulisation of aztreonam for treatment of chronic P. aeruginosa airway infec- tion, the Pari eFlow mesh nebuliser has been registered.The use of nebulisers has some well-recognised advantages. 1) They are a platform to deliver drugs that are only available as fluids. 2) They can be used for all ages fr... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 14 | Inhaled antibiotics: dry or wet? dPIs: ThE BAsICs In DPIs for antibiotics, the drug is present as a dry powder formulation in a capsule. The loading dose of the capsules for antibiotics is in the 20-150-mg range and, therefore, substantially higher than that of antiasthma drugs, which is mostly in the 50-200-μg range. ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 15 | Chapter DPIS: PrOS AND CONS DPIs have major advantages over nebulisers. 1) Administration is quick. For TIP , four capsules can be easily inhaled in 5 min. 2) DPIs do not require extensive cleaning after use. 3) Maintenance of the DPI is not required. 4) They are easy to carry around. 5) The capsules are packaged in se... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 16 | Inhaled antibiotics: dry or wet? sufficiently large fraction of small particles to treat the small airways effectively. For dry powder antibiotic formulations that are still in development, it will be important to edu- cate prescribing physicians and patients to understand the key characteristics of each formulation (a... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 17 | Inhaled antibiotics: dry or wet? disease; are all treated with the same regimen. It might well be that for more advanced disease, a higher dose is needed to cover all airway generations with antibiotic con- centrations above MIC. For TIP and TIS, a once daily double dose might result in larger areas with concentrations... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 18 | Chapter ABsTrACT Background: Chronic airway infections are an important factor in progressive lung disease in patients with cystic fibrosis (CF). These infections are most often treated with inhaled antibiotics of which deposition patterns have been extensively studied. However, the journey of aerosol particles does no... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 19 | Chapter Articles were selected based on the following inclusion criteria: (i) effect of CF sputum or (ii) bacterial factors on antibiotic efficacy; (iii) local efficacy determined by antibiotic concentration or number of molecules; (iv) liposomal formulations or co-medication to increase efficacy; (v) original research... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 20 | Chapter The following antibiotic classes were studied: aminoglycosides (n=28 studies), β-lactam antibiotics (n=12), fluoroquinolones (n=2), tetracyclines (n=1) and other anti - biotics (n=9). Table 2 – Impact per antibiotic class Factor Antibiotic class Impact CF mucus in general Aminoglycosides • Reduces diffusion• St... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 21 | Systematic review: fate of inhaled antibiotics Table 2 – Impact per antibiotic class (continued) Factor Antibiotic class Impact Other (Chloramphenicol) • Nitrate no effectAlginate Aminoglycosides • Reduces diffusion81, 111, 112, • Binding81, 112, 113, β-lactam AB • Reduces diffusionTetracyclines • Reduces diffusionOthe... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 22 | Chapter 1. d issolution of antibiotic in mucus layer (Table s4, part 1) After deposition on the mucus layer, local bioavailability of the inhaled antibiotic first depends on the solubility of the drug in the mucus. Within CF patients, the secretor and non-secretor phenotype are described: exocrine secretions between th... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 23 | Systematic review: fate of inhaled antibiotics 3. m ucus binding (Table s4, part 3) Apart from delaying the diffusion of antibiotics, macromolecules present in mucus can bind to certain antibiotics and drastically reduce their efficacy, as only free drug can be active against bacteria. In particular, the efficacy of am... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 24 | Chapter activity was inhibited to a greater extent by mucins than free aminoglycosides (up to 32-fold vs up to 8-fold).3.1.2 Co-treatment with dornase alfa Conflicting results were described for the co-treatment of aminoglycosides with dornase alfa. Dornase alfa was shown to increase free tobramycin in sputum by approx... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 25 | Systematic review: fate of inhaled antibiotics 4. Influence of oxygen level in mucus (Table s4, part 4) Thickened mucus layers in the lungs of CF patients contain areas of low oxygen ten- sion,107 with an anaerobic environment near the epithelial surface and higher oxygen levels at the top of the mucus layer.Aminoglyco... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 26 | Chapter 6. Barriers generated by Pseudomonas aeruginosa 6.1 Non-mucoid Pa, Mucoid Pa and alginate formation Pa has the ability to grow under aerobic and anaerobic circumstances and exists in both a mucoid and non-mucoid formation. Chronic Pa infections are associated with more mucoid variants that produce the polysacch... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 27 | Systematic review: fate of inhaled antibiotics 6.3 Biofilm formation Within biofilms, a subpopulation of persistent Pa cells is formed and characterised by reduced metabolic activity and tolerance to antibiotics. 106 It was shown that MBECs for three different Pa strains increased between 8 and 512 times for free amino... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 28 | Chapter In summary, co-treatment with AlgL and dornase alfa seems to increase the efficacy of aminoglycosides in the presence of alginate. Treatment of Pa growing in biofilms can be improved by co-treatment with iron binding drugs, dispersion compounds or mannitol. dIsCussIon To our knowledge, this is the first systema... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 29 | Systematic review: fate of inhaled antibiotics During the diffusion process the inhaled antibiotic may bind to mucus, thereby limit - ing the amount of free drug available to be efficacious against bacteria. Aminoglycosides showed substantial binding to mucus from CF patients 94 while this was not observed in β-lactam ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 30 | Systematic review: fate of inhaled antibiotics suPPlEmEnTAry TABlEs Table s1 – Critical appraisal table Criteria Additional information per criterion Study population CF patients (2), non-CF humans (1), animal study (0), in vitro/modelling study (0) Topics Direct answer or indirect answer to the research questions: dir... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 31 | Chapter Table s2 – Critical appraisal completed Study population[1] 0 0 0 0 0 0 0 0 Topics[2] 1 1 1 1 2 1 1 1 Study design[3] 0 0 0 0 0 0 0 0 Clearly stated aim? 2 2 2 2 2 2 2 2 Endpoints appropriate?[4] 2 2 2 2 2 2 2 2 Unbiased assessment of endpoint? 2 2 2 2 2 2 0 0 Methods reproducible? 2 2 1 2 2 1 1 1 Reporting bia... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 32 | Systematic review: fate of inhaled antibiotics Continuation Study population[1] 0 0 0 0 0 0 0 0 Topics[2] 1 1 1 1 2 2 1 1 Study design[3] 0 0 0 0 0 0 0 0 Clearly stated aim? 2 2 2 2 2 2 2 2 Endpoints appropriate?[4] 2 2 2 2 2 2 2 2 Unbiased assessment of endpoint? 2 2 0 2 2 2 2 2 Methods reproducible? 2 2 1 2 2 2 2 2 R... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 33 | Chapter Continuation Study population[1] 0 0 0 0 0 0 0 0 Topics[2] 1 1 1 1 1 2 2 2 Study design[3] 0 0 0 0 0 0 0 0 Clearly stated aim? 2 2 1 2 1 2 2 2 Endpoints appropriate?[4] 2 2 2 2 1 2 2 2 Unbiased assessment of endpoint? 2 2 2 2 2 2 2 2 Methods reproducible? 2 2 2 2 2 2 2 2 Reporting bias[5] 2 2 2 2 2 2 2 1 Result... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 34 | Systematic review: fate of inhaled antibiotics Continuation Study population[1] 0 0 0 0 0 0 0 Topics[2] 2 1 2 2 2 1 2 Study design[3] 0 0 0 0 0 0 0 Clearly stated aim? 1 2 2 2 2 2 2 Endpoints appropriate?[4] 2 2 2 2 2 2 2 Unbiased assessment of endpoint? 2 2 2 2 2 2 2 Methods reproducible? 2 2 1 2 2 2 1 Reporting bias[... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 35 | Chapter Continuation 4 (Excluded articles) Study population[1] 0 0 1 1 0 1 1 2 0 Topics[2] 1 1 2 0 1 1 1 0 2 Study design[3] 0 0 1 1 1 0 1 0 0 Clearly stated aim? 2 1 2 2 2 1 1 2 2 Endpoints appropriate?[4] 2 0 1 1 2 1 1 2 2 Unbiased assessment of endpoint? 1 1 0 1 1 1 1 2 2 Methods reproducible? 0 1 1 0 0 0 0 2 2 Repo... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 36 | Systematic review: fate of inhaled antibiotics Table s3 – Main results according to step in antibiotic pathway Step in antibiotic pathway number of studies Main results 1. dissolution in mucus layer 2 studies describing the same in vitro study • Tobramycin dissolves easier in mucus of secretors → more rapid effect (2 s... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 37 | Chapter Table s3 – Main results according to step in antibiotic pathway (continued) Step in antibiotic pathway number of studies Main results 6. diffusion through Pa alginate layer 10 in vitro studies • Aminoglycosides: o Inhibited in diffusion by alginate, stronger inhibition than β-lactam AB (3 studies) o 12-fold red... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 38 | Chapter ABsTrACT Background: Pseudomonas aeruginosa (Pa) infection is an important contributor to the progression of cystic fibrosis (CF) lung disease. The cornerstone treatment for Pa infection is the use of inhaled antibiotics. However, there is substantial lung disease heterogeneity within and between patients that ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 39 | Modeling of antibiotic concentrations in CF patients InTroduCTIon Cystic fibrosis (CF) is a severe hereditary and life-threatening disease in the Caucasian population. Most morbidity and mortality (>90% of deaths) is caused by progressive lung disease. 10 Important components of the pathophysiology of CF lung disease a... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 40 | Chapter Unfortunately, it is difficult to investigate the simultaneous influence of the above- mentioned factors on deposition in vivo. An in silico, patient-specific model based on computational fluid dynamics (CFD) has been developed to assess the behavior of inha- lation medication in airways. 129 This technique has... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 41 | Modeling of antibiotic concentrations in CF patients years. This retrospective study was approved by the Institutional Review Board of the Erasmus Medical Center in Rotterdam, the Netherlands (MEC-2013-078). Chest Computed Tomography (CT) Forty spirometer controlled CT-scans of consecutive CF-patients, acquired as part... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 42 | Chapter For each of the 40 CT-scan sets, the patient-specific lower airway model was con - nected to the selected nebulizer mouthpiece/upper airway model, maximizing the contribution of patient-specific information. All segmentation and 3D model operations were performed in commercially available validated software pac... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 43 | Modeling of antibiotic concentrations in CF patients Aerosol characteristics. Eleven different trials (Anderson Cascade impactor n=6, next generation impactor n=2, and laser diffraction n=3) studied the diameter distribution of AZLI nebulized via the Pari eFlow (Gilead data on file). The extremes and the median of thes... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 44 | Chapter description of the airway tree in infants, children and adolescents. 125 For every simula- tion, a Phalen model was constructed based on the height of the specific patient. Regional AZLI deposition was evaluated for both the particles depositing inside the model, in every separate zone indicated in Fig. 1; as w... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 45 | Chapter rEsulTs Study population Forty inspiratory and expiratory chest CT-scans were selected from 31 patients. Baseline characteristics are shown in Table 1. Thirty-nine (98%) CT-scans were spirometer con- trolled; the remaining scan was performed with technician guidance. There were no significant differences betwee... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 46 | Modeling of antibiotic concentrations in CF patients Significant differences between the lobes were found for all tested CF-CT subscores (bronchiectasis: x2 =21.70, p<0.001; airway wall thickness: x 2 =25.22, p<0.001; and air trapping: x2 =20.15, p<0.001). It was found that CF-CT subscores were generally higher in the ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 47 | Chapter Figure 3 – differences between lobes in AZlI concentrations Differences between lobes in AZLI concentrations for the scenario of thick airway surface liquid with largest aerosol diameter. Data are presented as median (range), unless otherwise indicated. Significant differences in AZLI concentrations were found ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 48 | Chapter The combination of thin ASL and smallest aerosol diameter resulted in AZLI concentra- tions above 10xMIC90 for both large and small airways. For the combination of thick ASL and largest aerosol diameter, 22% (0-49.79%) of the total area of small airways received AZLI concentrations below 10xMIC 90. The lowest A... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 49 | Modeling of antibiotic concentrations in CF patients dIsCussIon To our knowledge this is the first study that used CFD to estimate patient-specific inhaled antibiotic concentrations throughout the bronchial tree in CF. The most important finding was that the airway concentrations were highly dependent on patient-relate... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 50 | Chapter of 2.7 times the standard nebulized AZLI dose would have resulted in sufficiently high concentrations in the small airways. In the 'best-case' scenario, both large and small airways received AZLI concentrations above 10xMIC90. The observation that regional low concentrations can exist is of great importance, si... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 51 | Modeling of antibiotic concentrations in CF patients CFD allows detailed information on aerosol deposition at specific anatomical sites to be determined. Another advantage is that CFD allows estimation of AZLI concentrations throughout the bronchial tree, data that are extremely difficult to obtain in vivo. To date, gr... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 52 | Chapter Therefore it is not likely that this effect has a substantial effect on our data. We did not account for mucociliary and cough clearance, which further reduces AZLI concentrations in the airways, and this occurs within minutes after inhalation.153 Our model assumes that the microbiological effect of a β-lactam ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 53 | Chapter s1 TEXT. suPPlEmEnTAry mEThods. Chest computed tomography All routine chest CT scan sets were acquired using a 128-slice CT scanner (Somatom Definition Flash; Siemens, Erlangen, Germany). Thirty minutes prior to performing the CT scan, a lung function technician trained the study subjects by practicing the requ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 54 | Modeling of antibiotic concentrations in CF patients points. In the CF-CT scoring method, the CF-CT composite score is calculated by sum- ming the component scores per lobe. Instead of using the CF-CT composite score, the component scores per lobe were used for analysis. The lobar specific component scores were express... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 55 | Chapter s1 Figure – Breathing profiles (high – Average – low) Inhalation part of breathing profiles. Low breathing profile: tidal volume of 6 ml/kg (228 ml) and respiration rate of 14 breaths per minute. Average breathing profile: tidal volume of 10 ml/kg (380 ml) and respiration rate of 18 breaths per minute. High bre... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 56 | Modeling of antibiotic concentrations in CF patients Table s1. P-values of pairwise comparison of AZLI concentrations between lobes, accompanying figure lobe Comparison with other lobes (p-values) rul rml rll lul lll RUL - 0.002 1.4E-09 0.156 2.7E-RML 0.002 - 2.7E-10 5.6E-06 2.7E-RLL 1.4E-09 2.7E-10 - 6.8E-11 5.3E-LUL ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 57 | Chapter ABsTrACT Background: Inhaled tobramycin is important in the treatment of Pseudomonas aerugi- nosa (Pa) infections in cystic fibrosis (CF). However, despite its use it fails to attenuate clinical progression of CF-lung disease. The bactericidal efficacy of tobramycin is known to be concentration-dependent and he... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 58 | Can we dose once daily? InTroduCTIon Inhaled tobramycin is important in the treatment of Pseudomonas aeruginosa (Pa) infec- tions in cystic fibrosis (CF) and is used to both eradicate early, and suppress chronic Pa infections.22 As tobramycin exhibits concentration-dependent bactericidal activity, the highest possible ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 59 | Chapter eFlow). Therefore, the results of this study cannot be simply extrapolated to tobramycin nebulization. Our study aimed to predict aerosol deposition patterns of inhaled tobramycin after once- and twice-daily dosing in CF lungs. We used patient-specific airway models and CFD simulations to determine the local co... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 60 | Can we dose once daily? population. The upper airway model was scaled twice, once for the 6 youngest patients and once for the 6 oldest patients. These models were connected to the mouthpiece of the PARI-LC® Sprint nebulizer, which was further connected to the patient-specific lower airway model (Figure S1). reconstruc... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 61 | Chapter investigating the required delivered doses of different nebulizers to obtain an equivalent lung dose to the PARI-LC® Plus nebulizer.167,168 Due to the efficiency of the Akita®, the delivered dose for this system was set to be much lower. However, the reduced loss of drug in the central airways meant that concen... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 62 | Can we dose once daily? in the epithelial lining fluid (ELF) were computed as follows; the fraction of deposited inhaled aerosol in an airway multiplied by the delivered dose, was divided by, the surface area of that airway multiplied by the ELF thickness. A range of ELF thickness was used and based on studies in CF (3... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 63 | Chapter 84316-94957 μg/ml when dosed twice daily and 168633-189916 μg/ml when dosed once daily. Figure 1 shows tobramycin concentrations in the small airways calculated for the median ELF. Simulations with the Akita® resulted in tobramycin concentrations of 1770 μg/ml when dosed twice daily and 3541 μg/ml when dosed on... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 64 | Chapter and MMAD influence tobramycin concentrations in the small airways for the PARI-LC® Plus. Specifically, lower tobramycin concentrations in the small airways were observed with higher tidal volumes and the largest MMAD. Small airways concentrations for all ELF thicknesses are shown in Figure S2 of the Supplementa... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 65 | Can we dose once daily? Hence for wildtype Pa (MIC2 μg/ml), effective killing can be easily achieved as concentra - tions 381-1500x MIC 2 μg/ml were observed in the small airways for the twice-daily dose and 762-2999x MIC 2 μg/ml for the once-daily dose. However, for Pa strains with in vitro MICs above 2 μg/ml (i.e. ac... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 66 | Can we dose once daily? Although our study supports the use of the once-daily treatment regimen of nebulized tobramycin, drug safety issues need to be considered when increasing nebulized doses of aminoglycosides. A pharmacokinetic study in patients with CF showed that inhalation of a double tobramycin dose with either... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 67 | Chapter Figure s2 – small airway tobramycin concentrations calculated for different lining fluid thickness Thin lining fluid (3 µm) Small airways tobramycin concentrations calculated for the thin epithelial lining fluid of 3 µm. Con- centrations after nebulization of the once-daily dose (boxplot on the left) are higher... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 68 | Can we dose once daily? tained with the Akita® and PARI-LC® Plus nebulized with a lower tidal volume and small MMAD of 3.4 µm. For the PARI-LC® Plus, higher concentrations are obtained with the small MMAD of 3.4 µm than the large MMAD of 4.93 μm. MMAD = mass median aerosol diameter. Thick lining fluid (7 µm) Small airw... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 69 | Chapter Nebuliser and tidal volume used for simulation Pari LC Plus with higher tidal volume Pari LC Plus with lower tidal volume Pari LC Plus with mean tidal volume Akita 4.93 mcm (Pari LC Plus) 3.4 mcm (Pari LC Plus) 3.6 mcm (Akita) MMAD MIC: 5120 mcg/ml Page Figure s3 – Boxplot small airways concentrations once-dail... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 70 | Chapter ABsTrACT Background: Small airways disease (SAD) progresses with age in most cystic fibrosis (CF) patients in spite of maintenance therapy including inhaled dornase alfa. In a clinical study, efficient targeting of dornase alfa to the small airways using a smart nebulizer improved SAD in stable patients with CF... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 71 | Modeling of dornase alfa concentrations in CF patients InTroduCTIon Cystic fibrosis (CF) lung disease is characterized by chronic early lung infection and inflammation. As part of this process, deoxyribonucleic acid (DNA) is released from inflammatory cells and bacteria that lyse within the airways. DNA significantly i... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 72 | Chapter tory tract exacerbation. CF patients hospitalized for an exacerbation were randomized to small or large airway deposition of dornase alfa using the Akita nebulizer. In this study, for safety reasons, half the dose of dornase alfa was given (1.25 mg) which was estimated to result in a lung dose that would be 1.5... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 73 | Modeling of dornase alfa concentrations in CF patients PARI-LC Plus, and Akita - PARI-LC Sprint combination a digital CAD model of the PARI-LC Sprint mouthpiece was used as the mouthpieces of the PARI-LC Plus and PARI-LC Sprint are equivalent. The patient-specific lower airway model was connected to the nebulizer mouth... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 74 | Chapter For the Akita targeting the small airways (Akita Small), the inhalation time and volume per breath varied between 3.8-7.5 seconds and 0.75-1.5 L, respectively. The breathing profile had an inspiration-expiration ratio of 1:1.5. The inspiration part was stepwise and expiration part sinusoidal (Supplementary figu... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 75 | Modeling of dornase alfa concentrations in CF patients A loading dose of 2.5 mg was used in simulations for the PARI-LC Plus and eFlow sys- tems. The delivered dose for PARI-LC Plus has been shown to be 0.570 mg and for eFlow 0.567 mg.188 Both inspiration and expiration were modelled. Unlike the Akita, circulating part... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 76 | Chapter rEsulTs Study population Forty inspiratory and expiratory chest CT-scans were selected from 31 patients, of which 39 CT-scans were spirometry controlled and 1 scan was performed with lung technician guidance. Baseline characteristics are shown in Table 1. Table 1 – Baseline characteristics Value IQ range Male 3... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 77 | Modeling of dornase alfa concentrations in CF patients Nebulizer eFlowPARI-LC PlusAkita SmallAkita Large Figure 1 – dornase alfa concentrations in the large airways for the different nebulizers Dornase alfa concentrations in the large airways calculated for the median epithelial lining fluid (5 µm) after inhalation wit... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 78 | Chapter Concentrations in all small airways combined were 46-80 fold the effective dose of 2.9 μg/ml for the Akitalarge, 29-53 fold 2.9 μg/ml for the Akitasmall, and 1-3 fold 2.9 μg/ml for the PARI-LC Plus and eFlow. When looking at separate lung lobes, the total area of small airways received dornase alfa concentratio... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 79 | Modeling of dornase alfa concentrations in CF patients Figure 3 – differences between lobes in dornase alfa concentrations for the different nebulizers Small airways concentrations of dor- nase alfa in the separate lung lobes, calculated for the median epithelial lin- ing fluid (5 µm). Boxplot a) represents all nebuliz... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 80 | Chapter dIsCussIon This study aimed to investigate whether specific targeting of dornase alfa to the small airways using a smart nebulizer would result in sufficiently high concentrations in the small airways in patients differing in disease severity. Using CFD, we determined the per- Figure 4 – relative dornase alfa c... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 81 | Modeling of dornase alfa concentrations in CF patients centage of airways that received suboptimal dornase alfa concentrations when dornase alfa was nebulized using a conventional PARI-LC Plus nebulizer, an eFlow nebulizer, or the smart Akita nebulizer set to target the large or small airways. The main finding was that... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 82 | Chapter the larger aerosol particle size. There might be several explanations for this discrepancy. Firstly, CFD computes deposited drug in the segmented airways and airways are seg- mented up to the 5 th-9th generation.63 Drug that bypasses the segmented airways is as- sumed to distribute homogeneously throughout the ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 83 | Modeling of dornase alfa concentrations in CF patients Figure s2 – Breathing profile with the Akita nebulizer targeted on the small airways Breathing profile used for simulations with the Akita nebulizer targeted to the small airways (Akitas- mall). The inspiration part is stepwise and expiration part sinusoidal. Graph... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 84 | Chapter Figure s4 – deposition of dornase alfa in the extrathoracic region with the Akita nebulizer Dornase alfa concentrations in the mouth and upper airway calculated for the median epithelial lining fluid (5 µm) after inhalation with the Akita large and Akita small. Extrathoracic concentration is a combination from ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 85 | Chapter ABsTrACT Background: Cystic fibrosis (CF) caregivers focus on correct inhalation technique for nebulisers as this is essential to optimize efficacy of inhaled drugs. However, little is known on this nebuliser technique of patients at home. methods: Three "hidden" video registrations were made of 32 children wit... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 86 | Daily nebuliser technique in children with CF InTroduCTIon New treatments lead to improved survival in patients with cystic fibrosis (CF). 195 Unfor- tunately, this improved survival comes at the cost of a complex treatment regime. 195,196 One to two hours per day are spent on inhalation therapy. This treatment burden ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 87 | Chapter mEThods Study population Patients, ages 6-18 years, were included in this prospective, observational study if they had a confirmed diagnosis of CF and used nebulisation therapy. Patients were recruited from the Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands. There were no exclusion criteria. ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 88 | Daily nebuliser technique in children with CF nebuliser and medication. All parents were instructed to continue the regular routine of nebulisation therapy. Thus, parents did only actively participate in the treatment if this was their regular routine. At the second home visit the investigator recorded a fourth nebulis... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 89 | Chapter videos of 2 patients were used for training and excluded for further analyses of inhala- tion technique. The surveys regarding cleaning procedure of these 2 patients remained included. Scoring rules were drawn up in a written consensus. The remaining videos were scored by all observers. Observers independently ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 90 | Daily nebuliser technique in children with CF Statistical analysis Approximately 80 patients met the inclusion criteria. We aimed to include 30 patients (15 aged 6-11 years and 15 aged 12-18 years). Patients were approached by telephone following the order of an alphabetical list. Patient characteristics were summarize... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 91 | Chapter Two patients were used for the training sessions. Hence, the videos of 30 patients were used for scoring inhalation technique. A very good agreement was found for the total score between observer 1 vs observer 3; ICC 0.81. Observer 2 showed a moderate agreement with observer 1 and 3 (ICC 0.45 and 0.51 respectiv... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 92 | Daily nebuliser technique in children with CF step regarding correct exhalation showed a poor agreement between observer 1 and 3 (ICC 0.38), while the other steps showed a moderate to good agreement (all above 0.47). This item was considered less important for lung deposition than the other items. For this reason we ex... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 93 | Chapter association was found between overall duration of nebuliser therapy and inhalation technique (estimate - 0.382, SE 0.172, p = 0.037). Also, a moderate negative correlation was found for the I-neb between duration of the nebulisation session and inhalation technique (r = - 0.531, p = 0.023). However, when correc... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 94 | Daily nebuliser technique in children with CF nually, a nebulisation session is shown within the outpatient clinic followed by direct positive feedback. The good inhalation technique in this study shows that our instructions on nebuliser use were effective for most patients. Unfortunately, still one in seven children h... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 95 | Chapter to maintain nebuliser function. The compliance with cleaning and disinfection recom- mendations in the present study was high. However, recommendations regarding weekly maintenance of the I-neb were poorly adhered to. Lack of maintenance can result in clogging of the apertures of the vibrating mesh. This leads ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 96 | Daily nebuliser technique in children with CF Figure s2 – shapes of the nebuliser mouthpieces used in the study From left to right this picture shows the mouthpiece of the Sidestream, I-neb and Akita® nebuliser. Table s1 - Cleaning recommendations for nebulisers Procedure Frequency Instruction Cleaning After every inha... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 97 | Chapter Table s2 – Nebuliser checklists for scoring of video registrations Score movie Score movie Score movie Items on checklists of all three nebulisers 1. Transfer medication into drug container 2. Correctly put nebuliser together 3. Turn on nebuliser 4. Sit upright or stand 5. Hold nebuliser: o I-neb: horizontally ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 98 | Daily nebuliser technique in children with CF Table s3 - Mistakes in cleaning, disinfection and weekly maintenance procedures % Mistakes in cleaning* 31. - No washing in soapy water 15. - No direct cleaning after use 6. - Only tap water rinse 6. - Dishwasher 3. - Dry with kitchen towel 6.mistakes in disinfection 28. - ... | Erasmus |
Erasmus | Erasmus_BosAukje_2016-11-23_161123_Bos-Aukje-Catharina.pdf | 99 | ChAPTEr Pharmacokinetics and tolerability of once daily double dose tobramycin inhalation in cystic fibrosis using controlled and conventional nebulization Aukje C. Bos*, Annelies J. van Velzen*, Daan J. Touw, Harm A.W.M. Tiddens, Harry G.M. Heijerman, Hettie M. Janssens *Both authors contributed equally to this manusc... | Erasmus |
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