Respirable Range Research Articles

Bacillus thuringiensis as a surrogate for Bacillus anthracis in aerosol research

Characterization of candidate surrogate spores prior to experimental use is critical to confirm that the surrogate characteristics are as closely similar as possible to those of the pathogenic agent of interest. This review compares the physical properties inherent to spores of Bacillus anthracis (Ba) and Bacillus thuringiensis (Bt) that impact their movement in air and interaction with surfaces, including size, shape, density, surface morphology, structure and hydrophobicity. Also evaluated is the impact of irradiation on the physical properties of both Bacillus species. Many physical features of Bt and Ba have been found to be similar and, while Bt is considered typically non-pathogenic, it is in the B. cereus group, as is Ba. When cultured and sporulated under similar conditions, both microorganisms share a similar cylindrical pellet shape, an aerodynamic diameter of approximately 1μm (in the respirable size range), have an exosporium with a hairy nap, and have higher relative hydrophobicities than other Bacillus species. While spore size, morphology, and other physical properties can vary among strains of the same species, the variations can be due to growth/sporulation conditions and may, therefore, be controlled. Growth and sporulation conditions are likely among the most important factors that influence the representativeness of one species, or preparation, to another. All Bt spores may, therefore, not be representative of all Ba spores. Irradiated spores do not appear to be a good surrogate to predict the behavior of non-irradiated spores due to structural damage caused by the irradiation. While the use of Bt as a surrogate for Ba in aerosol testing appears to be well supported, this review does not attempt to narrow selection between Bt strains. Comparative studies should be performed to test the hypothesis that viable Ba and Bt spores will behave similarly when suspended in the air (as an aerosol) and to compare the known microscale characteristics versus the macroscale response.

Supercritical fluid assisted production of chitosan oligomers micrometric powders

Chitosan oligomers (O-chitosan) micrometric particles were produced from aqueous solution using a novel process, i.e. supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer (SAA-HCM). Hydrodynamic cavitation was introduced to enhance mass transfer and facilitate the mixing between SC-CO2 and liquid solution for fine particles formation. Well defined, separated and spherical microparticles were obtained, and the particles size could be well controlled with narrow distribution ranging from 0.5μm to 3μm. XRD patterns showed amorphous structure of O-chitosan microparticles. FTIR, TGA and DSC analyses confirmed that no change in molecular structure and thermal stability after SAA-HCM processing, while the water content was between 5.8% and 8.4%. Finally, tap densities were determined to be below 0.45g/cm3 indicating hollow or porous structures of microparticles. By tuning process parameters, theoretical mass median aerodynamic sizes lied inside respirable range of 1–2μm, which presented the potential of the O-chitosan microparticles in application as inhaled dry powders. SAA-HCM was demonstrated to be very useful in particle size engineering.

Longitudinal Evaluation of Compressor/Nebulizer Performance

Inhaled medications are the mainstay of treatment for maintenance of lung health in patients with cystic fibrosis (CF). Compressor/nebulizer units are used an average of 100-120 min/d by patients with CF. Each compressor/nebulizer has unique flow/pressure characteristics that affect particle size distribution and drug output rate. Few data are available regarding longitudinal performance of compressor/nebulizers. We hypothesized that their use over a 24-wk period under conditions similar to those of patients with CF would affect their performance. Four new units of compressor/reusable nebulizers from 3 brands (Pari Vios/Pari LC Plus, Pulmo-Aide 5650D/Viox, and Inspiration Elite/SideStream Plus) commonly used by patients with CF were tested. Compressor/nebulizers were operated for 1 h twice daily 5 d/wk for 24 wk. Compressor flow/pressure characteristics were measured every 6 wk. Maximal flow was recorded without and with the nebulizer (MF and MF/NEB, respectively). Pressure was recorded at zero flow (MP) and at MF/NEB (P/NEB). Particle size distribution, inhaled mass (IM), and IM in respirable range were evaluated at baseline and every 12 wk. Vios had statistically significant declines in MP and P/NEB at each measurement compared with baseline (45.8 and 32.6 psi for MP and 16.7 and 14.3 psi for P/NEB at wk 0 and 24, respectively, P < .05), but other compressors did not. MF and MF/NEB were stable over time but significantly varied among brands. Vios had the greatest slope of flow/pressure relationship (Vios > Pulmo-Aide > Inspiration Elite). Two Vios units stopped working at wk 11 and 24, respectively. All compressors maintained baseline IM, IM in respirable range, and aerosol characteristics. Long-term use of compressor/nebulizers in a regimen similar to that of patients with CF affected their performance. Pari Vios was the most affected brand, with declines in MP and P/NEB and 2 units that stopped working. Measurement of MF and MF/NEB could help identify compressors that are likely to fail.

Occupational Exposure Assessment for Engineered CaCO3 Nanoparticles

Background: Engineered nanoparticles (ENPs) are intentionally produced materials with specific properties. Emerging toxicological studies have demonstrated that exposure to ENPs could induce pulmonary diseases in animals. Little is known about the potential health effects in humans due to a lack of sufficient exposure information. To improve understanding of occupational exposure of ENPs, an exposure assessment was conducted in a CaCO3 nanoparticle manufacturing facility. Aims: The objectives of this research include characterizing job-based exposure and promoting understanding of metric suitable for nanoparticle exposure and epidemiological research. Methods: Personal and area air sampling was performed to estimate exposure of respirable dust. On-line instruments were used to measure the number concentrations and lung deposited surface area concentrations for manufacturing processes. Particle size, shape, element and degree of coagulation were assessed by SEM analysis. Results: Geometric mean of respirable mass concentrations ranged from 7.24 to 3195.86 ?g/m^3 for area sampling and 44.69 to 6023.21?g/m^3 for personal sampling. Nanoparticles dominate in the workplace, which consists of 90-98% of respirable number concentration. There are three levels of emission sources. The highest exposure of nanoparticles occurs at modification process, identified to be single emission origin. The number concentrations in nanosized range vary with the distance to this source. The second form of nanoparticle release is related to specific process, which is intermittent and sparse. In addition, combustion and welding could produce nanoparticles as well. Respirable mass is not correlated with number concentration in respirable range (r =0.0090). The number concentration in nanoscale is modestly correlated with surface area deposited in alveolar (r=0.46) and TB (r=0.66) region. Conclusions: A complete exposure characterization of nanoparticles needs to be conducted in both bulk- and nano-form. (The abstract is subject to change with added epidemiological findings.)

Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation

The aim of this study was to design, develop, and optimize respirable tacrolimus microparticles and nanoparticles and multifunctional tacrolimus lung surfactant mimic particles for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced at different pump rates by advanced spray-drying particle engineering design from organic solution in closed mode. In addition, multifunctional tacrolimus lung surfactant mimic dry powder particles were prepared by co-dissolving tacrolimus and lung surfactant mimic phospholipids in methanol, followed by advanced co-spray-drying particle engineering design technology in closed mode. The lung surfactant mimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]. Laser diffraction particle sizing indicated that the particle size distributions were suitable for pulmonary delivery, whereas scanning electron microscopy imaging indicated that these particles had both optimal particle morphology and surface morphology. Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size. X-ray powder diffraction patterns and differential scanning calorimetry thermograms indicated that spray drying produced particles with higher amounts of amorphous phase. X-ray powder diffraction and differential scanning calorimetry also confirmed the preservation of the phospholipid bilayer structure in the solid state for all engineered respirable particles. Furthermore, it was observed in hot-stage micrographs that raw tacrolimus displayed a liquid crystal transition following the main phase transition, which is consistent with its interfacial properties. Water vapor uptake and lyotropic phase transitions in the solid state at varying levels of relative humidity were determined by gravimetric vapor sorption technique. Water content in the various powders was very low and well within the levels necessary for dry powder inhalation, as quantified by Karl Fisher coulometric titration. Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung. These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine.

Emission Characteristics of Microbial Aerosols in a Municipal Sewage Treatment Plant in Xi’an, China

To characterize the emission of microbial aerosols from the widely used municipal sewage treatment plants (MSTP) in China, an Andersen six-stage impactor and the culture method were employed to determine the concentrations and size distributions of airborne viable bacteria, fungi and actinomycetes in a sewage treatment plant with an oxidation ditch process in Xi’an in summer. The results showed that the concentrations and size distributions of each of the airborne microorganisms varied greatly at different phases of sewage treatment process. The highest bacteria (7866 ± 970 CFU/m 3 ) and actinomycetes concentrations (2139 ± 229 CFU/m 3 ) were found in the sludge-dewatering house while the highest fungi concentration (2156 ± 119 CFU/m 3 ) at the oxidation ditch. The particle size distributions showed that similar singlepeak pattern for airborne actinomycetes, bacteria and fungi. Another important finding was that about 52% of airborne bacteria, 62% of airborne fungi and 65% of airborne actinomycetes were in respirable size range (less than 3.3 μm), indicating that most microbial aerosols from MSTP could easily penetrate into the human alveolus. Finally, the order of the count median diameters of different microbial aerosols was found to be similar at each phase, that is, airborne bacteria > airborne fungi > airborne actinomycetes. This implied that airborne actinomycetes emitted from MSTP might have a more significant effect on public health and urban air quality than bacteria and fungi.

Nebulization of mycophenolate mofetil inhalation suspension in rats: Comparison with oral and pulmonary administration of Cellcept®

In this study, a suspension of mycophenolate mofetil (MMF) suitable for inhalation was developed using the emulsion template process and characterized for particle size and aerosolization performance. To evaluate the benefits of this suspension over a solution, the IV Cellcept(®) solution was also characterized in vitro. Both formulations exhibited excellent aerosolization performance. The aerodynamic diameters for the solution and the suspension were within the respirable range (below 5μm) and their fine particle doses were nearly equivalent, suggesting the same drug exposure during in vivo experiments. Single dose 24-h pharmacokinetic studies following inhalation of the formulations and oral administration of oral Cellcept(®) were performed in rats. Following oral administration, MMF was completely and rapidly metabolized into its active metabolite, mycophenolic acid (MPA) and partial metabolism was observed following pulmonary administration. Inhaled MMF suspension displayed more favorable pharmacokinetics than inhaled IV Cellcept(®) solution, but the MPA drug levels in each compartment were much lower than those obtained with oral Cellcept(®). The dose normalized MPA levels in the lung, thymus gland and plasma following inhalation of the MMF suspension with the oral control suggested that pulmonary delivery of a MMF suspension could be beneficial in preventing lung allograft rejection.

Nicotine delivery to rats via lung alveolar region-targeted aerosol technology produces blood pharmacokinetics resembling human smoking.

Nicotine is a heavily used addictive drug acquired through smoking tobacco. Nicotine in cigarette smoke is deposited and absorbed in the lungs, which results in a rapidly peaked slowly declining arterial concentration. This pattern plays an important role in initiation of nicotine addiction. A method and device were developed for delivering nicotine to rodents with lung alveolar region-targeted aerosol technology. The dose of delivery can be controlled by the nicotine aerosol concentration and duration of exposure. Our data showed that, in the breathing zone of the nose-only exposure chamber, the aerosol droplet size distribution was within the respirable diameter range. Rats were exposed to nicotine aerosol for 2 min. The arterial blood nicotine concentration reached 43.2 ± 15.7 ng/ml (mean ± SD) within 1-4 min and declined over the next 20 min, closely resembling the magnitude and early pharmacokinetics of a human smoking a cigarette. The acute inhalation toxicity of nicotine: LC50 = 2.3mg/L was determined; it was affected by pH, suggesting that acidification decreases nicotine absorption and/or bioavailability. A noninvasive method and toolkit were developed for delivering nicotine to rodents that enable rapid delivery of a controllable amount of nicotine into the systemic circulation and brain-inducing dose-dependent pharmacological effects, even a lethal dose. Aerosol inhalation can produce nicotine kinetics in both arterial and venous blood resembling human smoking. This method can be applied to studies of the effects of chronic intermittent nicotine exposure, nicotine addiction, toxicology, tobacco-related diseases, teratogenicity, and for discovery of pharmacological therapeutics.

Evaluation of potential for toxicity from subacute inhalation of tire and road wear particles in rats

Tire and road wear particles (TRWP) are a component of ambient particulate matter (PM) produced from the interaction of tires with the roadway. Inhalation of PM has been associated with cardiopulmonary morbidities and mortalities thought to stem from pulmonary inflammation. To determine whether TRWP may contribute to these events, the effects of subacute inhalation of TRWP were evaluated in rats. TRWP were collected at a road simulator laboratory, aerosolized, and used to expose male and female Sprague-Dawley rats (n = 10/treatment group) at ~10, 40, or 100 μg/m3 TRWP via nose-only inhalation for 6 h/day for 28 days. Particle size distribution of the aerosolized TRWP was found to be within the respirable range for rats. Toxicity was assessed following OECD guidelines (TG 412). No TRWP-related effects were observed on survival, clinical observations, body or organ weights, gross pathology, food consumption, immune system endpoints, serum chemistry, or biochemical markers of inflammation or cytotoxicity. Rare to few focal areas of subacute inflammatory cell infiltration associated with TWRP exposure were observed in the lungs of one mid and four high exposure animals, but not the low-exposure animals. These alterations were minimal, widely scattered and considered insufficient in extent or severity to have an impact on pulmonary function. Furthermore, it is expected that these focal lesions would remain limited and may undergo resolution without long-term or progressive pulmonary alterations. Therefore, from this study we identified a no-observable-adverse-effect-level (NOAEL) of 112 μg/m3 of TRWP in rats for future use in risk assessment of TRWP.

Cosuspensions of Microcrystals and Engineered Microparticles for Uniform and Efficient Delivery of Respiratory Therapeutics from Pressurized Metered Dose Inhalers

Engineered porous phospholipid microparticles with aerodynamic diameters in the respirable range of 1-2 μm were cosuspended in 1,1,1,2-tetrafluoroethane, a propellant, with microcrystals of glycopyrrolate, formoterol fumarate dihydrate, or Mometasone furoate-three drugs with different solubilities in the propellant, and different physical, chemical, and pharmacological attributes. The drug microcrystals were added individually, in pairs, or all three together to prepare different cosuspensions, contained in a pressurized metered dose inhaler (pMDI). The drug microcrystals irreversibly associated with the porous particles, and the resultant cosuspensions possessed greatly improved suspension stability compared with suspensions of drug microcrystals alone. In general, all cosuspensions showed efficient dose delivery of the drugs, with fine particle fractions of more than 60% for a wide range of doses, including those as low as 300 ng per inhaler actuation. In the cosuspension pMDIs, comparable fine particle fractions were delivered for all tested drugs, whether or not they were emitted from an inhaler containing one, two, or three drugs. We demonstrate that the cosuspension approach solves at least three long-standing problems in the clinical development of pMDI-based products: (1) dose and drug dependent delivery efficiency, (2) inability to formulate dose strengths below 1 μg to fully explore drug efficacy and safety, and (3) combination suspensions delivering a different fine particle fraction than individual drug suspensions.

Synergistic combination dry powders for inhaled antimicrobial therapy: Formulation, characterization and in vitro evaluation

In combination antimicrobial therapy, the desired outcome is to broaden the antimicrobial spectrum and to achieve a possible synergistic effect. However, adverse antagonistic species may also emerge from such combinations, leading to treatment failure with serious consequences. It is therefore imperative to screen the drug candidates for compatibility and possible antagonistic interactions. The aim of this work was to develop a novel synergistic dry powder inhaler (DPI) formulation for antimicrobial combination therapy via the pulmonary route. Binary (ciprofloxacin hydrochloride and gatifloxacin hydrochloride, SD-CIP/GAT) and ternary (ciprofloxacin hydrochloride, gatifloxacin hydrochloride, and lysozyme, SD-CIP/GAT/LYS) combinations were prepared via spray-drying on a BUCHI® Nano Spray Dryer B-90. The powder morphologies were spherical with a slightly corrugated surface and all within the respirable size range. The powders yielded fine particle fractions (of the loaded dose) of over 40% when dispersed using an Aerolizer® at 60L/min. Time-kill studies carried out against the respiratory tract infection-causing bacteria Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia, and Acinetobacter baumannii at 1×the minimum inhibitory concentration (MIC) over 24h revealed no antagonistic behavior for both the binary and ternary combinations. While the interactions were generally found to be indifferent, a favorable synergistic effect was detected in the dual combination (SD-CIP/GAT) when it was tested against P. aeruginosa bacteria.

Challenges with Developing In Vitro Dissolution Tests for Orally Inhaled Products (OIPs)

The purpose of this article is to review the suitability of the analytical and statistical techniques that have thus far been developed to assess the dissolution behavior of particles in the respirable aerodynamic size range, as generated by orally inhaled products (OIPs) such as metered-dose inhalers and dry powder inhalers. The review encompasses all analytical techniques publicized to date, namely, those using paddle-over-disk USP 2 dissolution apparatus, flow-through cell dissolution apparatus, and diffusion cell apparatus. The available techniques may have research value for both industry and academia, especially when developing modified-release formulations. The choice of a method should be guided by the question(s) that the research strives to answer, as well as by the strengths and weaknesses of the available techniques. There is still insufficient knowledge, however, for translating the dissolution data into statements about quality, performance, safety, or efficacy of OIPs in general. Any attempts to standardize a dissolution method for compendial inclusion or compendial use would therefore be premature. This review reinforces and expands on the 2008 stimulus article of the USP Inhalation Ad Hoc Advisory Panel, which "could not find compelling evidence suggesting that such dissolution testing is kinetically and/or clinically crucial for currently approved inhalation drug products."

Nebulisation of vancomycin injection – efficacy of the nebulisation process for pulmonary delivery

ObjectivesTo evaluate if vancomycin injections can be successfully nebulised via the Pari LC Plus and eFlow rapid nebulisers, by measuring particle size of droplets produced, proportion and concentration of drug...

Influence of Suspending Liquid, Impactor Type, and Substrate on Size-Selective Sampling of MS2 and Adenovirus Aerosols

Size-selective sampling methods for detecting viral aerosols are needed to assess the risk of airborne transmission of disease. Andersen and MOUDI nonviable cascade impactors were used to separate test aerosols containing MS2 bacteriophage or adenovirus into size fractions spanning much of the human respirable range. Culture-based methods and a fluorescent tracer dye allowed quantification of the viral particles that remained infective after being aerosolized into a test apparatus and collected by the impactors. In addition, various suspension fluids and impaction surfaces were evaluated for their effect on virus viability. Both the Andersen and MOUDI impactors were able to sample live viruses from test aerosols, although the relative recovery rate of MS2 was higher than adenovirus (P < 0.001). The MS2 and adenovirus aerosols were sensitive to different test factors. MS2 recovery was dependent on the suspension fluid (P < 0.0001) and RH (P = 0.001), whereas adenovirus recovery was dependent on aerodynamic...

An eddy interaction model for particle deposition

Deposition of mono-disperse aerosols is studied numerically on a simplified human upper airway model (UAM). This paper presents new correction functions for eddy interaction model (EIM) in an attempt to improve the accuracy of predicting aerosol deposition in the UAM. Based on an Euler-Lagrange methodology, the fluid phase is solved using RANS (Reynolds Averaged Navier Stokes equation) and employing low-Reynolds SST k-ω turbulence model. The particle phase is solved using Lagrangian approach and employing an EIM model. Mono-disperse particle sizes of 3 and 6μm are considered for breathing rates of 30 and 60L/min. The proposed method of correction functions to EIM (“helicity EIM”) is compared to the classical EIM assuming isotropy (“isotropic EIM”) and to the EIM incorporating correction functions of Wang & James (1999) (“Wang and James EIM”). All three EIM methods are validated against experimental data of deposition efficiencies reported for a 90° bend pipe and for the UAM. In the latter case, total as well as compartmental deposition efficiencies are used for validation purposes. In both geometries, the present approach (“helicity EIM”) predicts the deposition efficiency better than the “isotropic EIM”. The results obtained with “helicity EIM” are of similar accuracy compared to those of “Wang and James EIM”. Considering that the “helicity EIM” does not require the estimation of y+ for each case, we suggest that this could be the preferred EIM correction method for simulation of respirable range aerosol particle deposition in the mouth-throat.

Physicochemical Characterization and Water Vapor Sorption of Organic Solution Advanced Spray-Dried Inhalable Trehalose Microparticles and Nanoparticles for Targeted Dry Powder Pulmonary Inhalation Delivery

Novel advanced spray-dried inhalable trehalose microparticulate/nanoparticulate powders with low water content were successfully produced by organic solution advanced spray drying from dilute solution under various spray-drying conditions. Laser diffraction was used to determine the volumetric particle size and size distribution. Particle morphology and surface morphology was imaged and examined by scanning electron microscopy. Hot-stage microscopy was used to visualize the presence/absence of birefringency before and following particle engineering design pharmaceutical processing, as well as phase transition behavior upon heating. Water content in the solid state was quantified by Karl Fisher (KF) coulometric titration. Solid-state phase transitions and degree of molecular order were examined by differential scanning calorimetry (DSC) and powder X-ray diffraction, respectively. Scanning electron microscopy showed a correlation between particle morphology, surface morphology, and spray drying pump rate. All advanced spray-dried microparticulate/nanoparticulate trehalose powders were in the respirable size range and exhibited a unimodal distribution. All spray-dried powders had very low water content, as quantified by KF. The absence of crystallinity in spray-dried particles was reflected in the powder X-ray diffractograms and confirmed by thermal analysis. DSC thermal analysis indicated that the novel advanced spray-dried inhalable trehalose microparticles and nanoparticles exhibited a clear glass transition (T(g)). This is consistent with the formation of the amorphous glassy state. Spray-dried amorphous glassy trehalose inhalable microparticles and nanoparticles exhibited vapor-induced (lyotropic) phase transitions with varying levels of relative humidity as measured by gravimetric vapor sorption at 25°C and 37°C.

Infection prevention and control in cystic fibrosis

This review will discuss recent studies of the virulence of cystic fibrosis (CF) pathogens, including epidemic strains, a more complex understanding of droplet transmission, bacterial contamination of CF clinics, and identifying and overcoming barriers to implementation of infection control guidelines. Both morbidity and mortality are associated with methicillin-resistant Staphylococcus aureus (MRSA). Thus, clinicians are attempting eradication strategies for MRSA using combinations of oral, aerosolized, intravenous, and topical antibiotics, with some success. However, household contacts may be colonized with MRSA, which can impact the durability of eradication. Epidemic strains of Pseudomonas aeruginosa are also associated with increased morbidity and mortality and some clones are detected in CF patients throughout the world presumably due to social networks among patients. Recent experimental and clinical data have suggested that CF patients can generate droplet nuclei in the respirable range and that infectious particles can be cultured from room air minutes to hours after patients have left. Although these observations regarding droplet nuclei have not been linked to transmission, they do challenge the safety of the '3-foot rule' and suggest the potential role of masks. Additional research is needed to develop strategies to improve infection control practices among healthcare professionals, CF patients, and families.

Effect of crystallisation conditions and feedstock morphology on the aerosolization performance of micronised salbutamol sulphate

Salbutamol sulphate (SS) used in dry powder inhalers requires drug particles in the respirable size range of 1–5 μm to achieve a suitable therapeutic effect. The aim of this study was therefore to determine strategies for controlling drug substance characteristics pre and post-crystallisation to facilitate the production of micronised SS with desirable particle attributes for optimal delivery as an inhaled aerosol. SS batches were crystallised using an antisolvent method to produce a range of crystal morphologies. Air jet milling was then used to reduce the size of crystallised SS particles. Starting materials and micronised batches of SS were characterised in the solid state using a range of techniques with subsequent assessment of aerosol properties. Assessment of the aerodynamic characteristics of micronised SS delivered by DPI (without any carrier) indicated that fine particle fraction and emitted dose as a percentage of the total recovered dose were dependent on the quality attributes of the micronised SS, which were directly linked to the degree of imperfections and the morphology of the crystalline feedstock used in micronisation. Aerosolization performance of micronised SS can be optimised by manipulation of feedstock characteristics through crystal engineering and through definition of optimal processing conditions for micronisation.

Effects on Aerosol Performance of Mixing of Either Budesonide or Beclomethasone Dipropionate With Albuterol and Ipratropium Bromide

Mixing of nebulized drugs is common in real life, but its consequences on aerosol output and granulometry are poorly known. In an in vitro study I evaluated the effects on aerosol output, drug output, and aerosol particle size characteristics of mixing either beclomethasone dipropionate or budesonide with albuterol and ipratropium bromide. I tested the SideStream and VentStream-Pro nebulizers, run with the AirClinic compressor. Using the same fill volume in all experiments, I nebulized and evaluated each studied drug alone, and 2 drug mixtures: beclomethasone plus albuterol plus ipratropium; and budesonide plus albuterol plus ipratropium. I measured aerosol output via gravimetrics. I measured drug delivery by collecting the aerosol on a filter in the inspiratory limb, and the residual solution in the reservoir and the circuit after nebulization, and assayed those liquids with chromatography. I measured particle size distribution via cascade impaction. Mixing tended to reduce drug output and to increase mass median aerodynamic diameter with the SideStream, but not always with the VentStream-Pro. However, the drug output always remained satisfactory and the mass median aerodynamic diameters were within the respirable range. When nebulized alone, the respirable mass of bronchodilators ranged from 18% to 40% of the nominal dose; when mixed, it ranged from 13% to 37%. When nebulized alone, the respirable mass of corticosteroids ranged from 10% to 24% of the nominal dose; when mixed, it ranged from 10% to 17%. Both the SideStream and VentStream-Pro have good aerosol performance in nebulizing budesonide or beclomethasone dipropionate alone, and when mixed with albuterol and ipratropium bromide.

Aerosol survival of Staphylococcus epidermidis

Recent studies have suggested that aerosol dispersal might play a role in the dissemination of meticillin-resistant Staphylococcus aureus (MRSA). Relatively little has been published about the ability of staphylococci to survive in aerosols. This study measured the survival of Staphylococcus epidermidis, a surrogate for S. aureus, in aerosols and investigated the effect of relative humidity on survival. We used a Goldberg drum to assess survival at relative humidities of <20%, 40-60%, 70-80% and >90%. We controlled for the effects of aerosol dilution and physical decay by comparing the recovery of S. epidermidis with that of the aerosol-stable spores of Bacillus atrophaeus, using the ratio of their recovery rates to estimate biological degradation of S. epidermidis over time. At all relative humidities investigated 13% [95% confidence interval (CI): 10.1-16.2%] of the initial aerosol was recovered after 5h (300 min). The mean percentage survival ratio (% S. epidermidis:% B. atrophaeus) after 5h was 47% (95% CI: 33.5-60.5%). Overlapping 95% CIs of mean percentage survival ratios at each humidity level indicated that humidity did not have a significant effect on the survival in aerosol form of S. epidermidis. Additional experiments indicated that S. epidermidis was recoverable after five days at 76% humidity. The sizes of particles within the bacterial aerosol were well within the respirable range (<2.1 μm). The survival of aerosolised S. epidermidis demonstrated in this study suggests that staphylococci have the potential for aerosol dissemination in hospitals.