Effects of the deformation and size of the upper airway on the deposition of aerosols.

Aerosol drug delivery in the human airway is significantly affected by the morphology and size of the airway. This work developed a CFD-DEM model to simulate and analyze air flow and powder dynamics in combined inhaler-airway systems with different degrees of airway deformation (non-deformed, 50%, and 75% deformed) and sizes (adult, 0.80, and 0.62 scaled). The airways were generated based on a regular airway constructed from the MRI images through finite element method (for deformed airways) or scaling-down (for smaller airways). The airways were connected to Turbuhaler® through a connector. The results showed that under the same flow rate, the variation in the airway geometry and size had a minimum impact on the flow field and powder deposition in the device and the connector. However, deformation caused more particle deposition in the deformed region. Notably, the airway with 50% deformation had the most particles passing through the airway with the largest particle sizes due to its lower air velocity in the deformed area. Reducing airway size resulted in more powder deposition on the airway, particularly at the pharynx and mouth regions. This was because, with the same flow rate, the flow velocity in the smaller airway was higher, causing more particle-wall collisions in the mouth and pharynx regions. More importantly, the deposition efficiency in the 0.62-scaled airway was significantly higher than the other two airways, highlighting the importance of the different administration of aerosol drugs for young children.

Nanoscale colocalized thermal and chemical mapping of pharmaceutical powder aerosols.

Inhalation of pharmaceutical aerosol formulations is widely used to treat respiratory diseases. Spatially resolved thermal characterization offers promise for better understanding drug release rates from particles; however, this has been an analytical challenge due to the small particle size (from a few micrometers down to nanometers) and the complex composition of the formulations. Here, we employ nano-thermal analysis (nanoTA) to probe the nanothermal domain of a pharmaceutical aerosol formulation containing a mixture of fluticasone propionate (FP), salmeterol xinafoate (SX), and excipient lactose, which is widely used to treat asthma and chronic obstructive pulmonary disease (COPD). Furthermore, atomic force microscopy-infrared spectroscopy (AFM-IR) and AFM force measurements are performed to provide nanochemical and nanomechanical information to complement the nanothermal data. The colocalized thermal and chemical mapping clearly reveals the surface heterogeneity of the drugs in the aerosol particles and demonstrates the contribution of the surface chemical composition to the variation in the thermal properties of the particles. We present a powerful analytical approach for in-depth characterization of thermal/chemical/morphological properties of dry powder inhaler particles at micro- and nanometer scales. This approach can be used to facilitate the comparison between generics and reference inhalation products and further the development of high-performance pharmaceutical formulations.

Optimizing in vitro phage-ciprofloxacin combination formulation for respiratory therapy of multi-drug resistant Pseudomonas aeruginosa infections.

Respiratory infection caused by multi-drug resistant (MDR) Pseudomonas aeruginosa is challenging to treat. In this study, we investigate the optimal dose of anti-pseudomonas phage PEV31 (103, 105, and 108 PFU/mL) combined with ciprofloxacin (ranging from 1/8× MIC to 8× MIC) to treat the MDR P. aeruginosa strain FADD1-PA001 using time-kill studies. We determined the impact of phage growth kinetics in the presence of ciprofloxacin through one-step growth analysis. Single treatments with either phage PEV31 or ciprofloxacin (except at 8× MIC) showed limited bactericidal efficiency, with bacterial regrowth observed at 48 h. The most effective treatments were PEV31 at multiplicity of infection (MOI) of 0.1 and 100 combined with ciprofloxacin at concentrations above 1× MIC, resulting in a >4 log10 reduction in bacterial counts. While the burst size of phage PEV31 was decreased with increasing ciprofloxacin concentration, robust antimicrobial effects were still maintained in the combination treatment. Aerosol samples collected from vibrating mesh nebulization of the combination formulation at phage MOI of 100 with 2× MIC effectively inhibited bacterial density. In summary, our combination treatments eradicated in vitro bacterial growth and sustained antimicrobial effects for 48 h. These results indicated the potential application of nebulization-based strategies for the combination treatment against MDR lung infections.

Understanding the effects of inhaler resistance on particle deposition behaviour - A computational modelling study.

BACKGROUND AND OBJECTIVE: Understanding the impact of inhaler resistance on particle transport and deposition in the human upper airway is essential for optimizing inhaler designs, thereby contributing to the enhancement of the therapeutic efficacy of inhaled drug delivery. This study demonstrates the potential effects of inhaler resistance on particle deposition characteristics in an anatomically realistic human oropharynx and the United States Pharmacopeia (USP) throat using computational fluid dynamics (CFD). METHOD: Magnetic resonance (MR) imaging was performed on a healthy volunteer biting on a small mockup inhaler mouthpiece. Three-dimensional geometry of the oropharynx and mouthpiece were reconstructed from the MR images. CFD simulations coupled with discrete phase modelling were conducted. Inhaled polydisperse particles under two different transient flow profiles with peak inspiratory flow rates (PIFR) of 30 L/min and 60 L/min were investigated. The effect of inhaler mouthpiece resistance was modelled as a porous medium by varying the initial resistance (Ri) and viscous resistance (Rv). Three resistance values, 0.02 kPa0.5minL-1, 0.035 kPa0.5minL-1 and 0.05 kPa0.5 minL-1, were simulated. The inhaler outlet velocity was set to be consistent across all models for both flow rate conditions to enable a meaningful comparison of models with different inhaler resistances. RESULT: The results from this study demonstrate that investigating the effect of inhaler resistance by solely relying on the USP throat model may yield misleading results. For the geometrically realistic oropharyngeal model, both the pressure and kinetic energy profiles at the mid-sagittal plane of the airway change dramatically when connected to a higher-resistance inhaler. In addition, the geometrically realistic oropharyngeal model appears to have a resistance threshold. When this threshold is surpassed, significant changes in flow dynamics become evident, which is not observed in the USP throat model. Furthermore, this study also reveals that the impact of inhaler resistance in a geometrically realistic throat model extends beyond the oral cavity and affects particle deposition downstream of the oral cavity, including the oropharynx region. CONCLUSION: Results from this study suggest that key mechanisms underpinning the working principles of inhaler resistance are intricately connected to their complex interaction with the pharynx geometry, which affects the local pressure, local variation in velocity and kinetic energy profile in the airway.

CFD-DEM investigation of the effects of aperture size for a capsule-based dry powder inhaler.

Capsule based dry powder inhalers (DPIs) often require piercing of the capsule before inhalation, and the characteristics of the apertures (punctured holes) affect air flow and the release of powders from the capsule. This work develops a numerical model based on the two-way coupling of computational fluid dynamics and discrete element method (CFD-DEM) to investigate the effect of aperture size on powder dispersion in the Aerolizer® device loaded with only carrier particles (lactose). Powders (carrier particles) in the size range 60-140 µm (d50: 90 µm and span: 0.66) were initialized in a capsule which had a circular aperture at each end. Boundary conditions corresponding to an air flow rate of 45 L/min were specified at each inlet to the mixing chamber (i.e., a total flow rate 90 L/min), and a capsule spin speed of âˆ¼ 4050 rpm. The velocity magnitudes inside the capsule were considerably lower than those in the mixing chamber in the vicinity of the rotating capsule, with the exception of the capsules featuring 2.5 mm and 4 mm apertures. Larger apertures reduced the capsule emptying time and increased the particle evacuation velocity; the fluid drag force on the particles issuing from the capsule peaked for an aperture of 1.3 mm. Inside the capsule, particle-particle (PP) collisions were more frequent than particle-wall (PW) collisions due to high concentration of powder, but PP collisions had smaller (median) impact energy than PW collisions. Larger apertures resulted in fewer collisions in the capsule with higher PW and virtually unchanged PP collision energies. Outside the capsule (i.e., in the inhaler mixing chamber), PW collisions occurred more frequently than PP collisions with median collision energies typically two orders of magnitude higher than inside the capsule. Larger apertures resulted in more collisions with slightly reduced collision energy, but this effect plateaued for aperture sizes larger than 1.3 mm. Powder dispersion, expressed as the fine particle fraction (FPF) of the powder, was predicted using an empirical equation based on carrier PW collisions. Therefore, consistent with the model prediction of the effect of aperture sizes on the chamber collision frequency, FPF increased with aperture size but plateaued beyond 1.3 mm.

Stability of bacteriophages in organic solvents for formulations.

Bacteriophages or phages used as an alternative therapy for treating multi-drug resistant infections require formulation consideration. Current strategies to produce phage formulations involving organic solvents are based on empirical practices without a good understanding of phage stability during formulation development. In this study, we investigated the effect of common formulation organic solvents (ethanol, isopropyl alcohol, tetrahydrofuran (THF) and dimethyl sulfoxide (DMSO)) on the stability of Pseudomonas aeruginosa-specific myovirus (PEV1, PEV20) and podovirus (PEV31) phages using biological assay, transmission electron microscopy (TEM) and scattering near field optical microscopy (SNOM). The three phages were mixed with the solvents at different concentrations (25%, 50%, and 75% (v/v)) for 20 min. All phages were fully viable in the organic solvents at 25% (v/v) showing negligible titre changes. At the higher solvent concentration of 50% (v/v), the myoviruses PEV1 and PEV20 remained relatively stable (titre loss 0.4-1.3 log10), whereas the podovirus PEV31 became less stable (titre loss 0.25-3.8 log10), depending on the solvent used. Increasing the solvent level to 75% (v/v) caused increased morphological changes in TEM and decreased viability as indicated by the titre loss (0.32-7.4 log10), with DMSO being the most phage-destabilising solvent. SNOM spectra showed differences in the signal intensity and peak positions in the amide I and amide II regions, revealing altered phage proteins by the solvents. In conclusion, the choice of the solvents for phage formulation depends on both the phages and solvent types. Our results showed (1) the phages are more stable in the alcohols than DMSO and THF, and (2) the myoviruses tend to be more stable than the podovirus in the solvents. Overall, a low to moderate (25-50 % v/v) level of organic solvents (except 50% THF) can be used in formulation of the phages without a substantial titre loss.

Stability Considerations for Bacteriophages in Liquid Formulations Designed for Nebulization.

Pulmonary bacterial infections present a significant health risk to those with chronic respiratory diseases (CRDs) including cystic fibrosis (CF) and chronic-obstructive pulmonary disease (COPD). With the emergence of antimicrobial resistance (AMR), novel therapeutics are desperately needed to combat the emergence of resistant superbugs. Phage therapy is one possible alternative or adjunct to current antibiotics with activity against antimicrobial-resistant pathogens. How phages are administered will depend on the site of infection. For respiratory infections, a number of factors must be considered to deliver active phages to sites deep within the lung. The inhalation of phages via nebulization is a promising method of delivery to distal lung sites; however, it has been shown to result in a loss of phage viability. Although preliminary studies have assessed the use of nebulization for phage therapy both in vitro and in vivo, the factors that determine phage stability during nebulized delivery have yet to be characterized. This review summarizes current findings on the formulation and stability of liquid phage formulations designed for nebulization, providing insights to maximize phage stability and bactericidal activity via this delivery method.

Numerical analysis of airflow and particle deposition in multi-fidelity designs of nasal replicas following nasal administration.

BACKGROUND AND OBJECTIVE: An improved understanding of flow behaviour and particle deposition in the human nasal airway is useful for optimising drug delivery and assessing the implications of pollutants and toxin inhalation. The geometry of the human nasal cavity is inherently complex and presents challenges and manufacturing constraints in creating a geometrically realistic replica. Understanding how anatomical structures of the nasal airway affect flow will shed light on the mechanics underpinning flow regulation in the nasal pharynx and provide a means to interpret flow and particle deposition data conducted in a nasal replica or model that has reduced complexity in terms of their geometries. This study aims to elucidate the effects of sinus and reduced turbinate length on nasal flow and particle deposition efficiencies. METHODS: A complete nasal airway with maxillary sinus was first reconstructed using magnetic resonance imaging (MRI) scans obtained from a healthy human volunteer. The basic model was then modified to produce a model without the sinus, and another with reduced turbinate length. Computational fluid dynamics (CFD) was used to simulate flow in the nasal cavity using transient flow profiles with peak flow rates of 15 L/min, 35 L/min and 55 L/min. Particle deposition was investigated using discrete phase modelling (DPM). RESULTS: Results from this study show that simplifying the nasal cavity by removing the maxillary sinus and curved sections of the meatus only has a minor effect on airflow. By mapping the spatial distribution of monodisperse particles (10 µm) in the three models using a grid map that consists of 30 grids, this work highlights the specific nasal airway locations where deposition efficiencies are highest, as observed within a single grid. It also shows that lower peak flow rates result in higher deposition differences in terms of location and deposition quantity, among the models. The highest difference in particle deposition among the three nasal models is ∼10%, and this is observed at the beginning of the middle meatus and the end of the pharynx, but is only limited to the 15 L/min peak flow rate case. Further work demonstrating how the outcome may be affected by a wider range of particle sizes, less specific to the pharmaceutical industries, is warranted. CONCLUSION: A physical replica manufactured without sections of the middle meatus could still be adequate in producing useful data on the deposition efficiencies associated with an intranasal drug formulation and its delivery device.

The role of capsule aperture size on the dispersion of carrier-based formulation at different air flowrates.

The effect of capsule aperture size on the aerosol performance of lactose blend formulation was studied using Foradil® (containing 12 µg of formoterol fumarate (FF1) and 24 mg of lactose) dispersed with a powder inhaler Aerolizer® at increasing air flowrates. Apertures sizes of 0.4, 1.0, 1.5, 2.5, and 4.0 mm were introduced at the opposite ends of the capsule. The formulation was dispersed into a Next Generation Impactor (NGI) at 30, 60 and 90 L/min, with the fine particle fractions (FPFrec and FPFem) measured by chemical assay of FF and lactose using high-performance liquid chromatography. Particle size distribution (PSD) of FF particles dispersed in wet media was also characterized by laser diffraction. FPFrec showed a stronger dependency on the flowrate than the capsule aperture size. The most efficient dispersion was achieved at 90 L/min. At a given flowrate, FPFem remained broadly constant across different aperture sizes. The laser diffraction studies demonstrated the presence of large agglomerates.

Effects of the mouthpiece and chamber of Turbuhaler® on the aerosolization of API-only powder formulations.

Powder dispersion in dry powder inhalers (DPIs) is affected by powder formulations as well as the design of a device. This paper conducted a numerical investigation based on the coupled computational fluid dynamics (CFD) and discrete element method (DEM) to evaluate the changes of the design of a commercial DPI device Turbuhaler® on the aerosolization of an API-only formulation. Six different designs were proposed by modifying the mouthpiece and chamber of the original geometry which was reconstructed from a CT-scan of the Turbuhaler, and their performances in terms of powder deposition in the device and fine powder fraction (FPF) were evaluated. The resistance of the device was observed to vary with different designs. For the change of the mouthpiece, the device with a cylindrical mouthpiece had the least resistance and the lowest FPF emitted among all the devices, confirming the important role of the spiral mouthpiece on powder dispersion. Reducing the mouthpiece size caused more powder deposition in the inhaler due to higher airflow velocity, but FPF emitted increased compared to the original design as more powder dispersion occurred inside the mouthpiece. The half-length mouthpiece design reduced device resistance to increase airflow velocity and average collision energy, resulting in an increase in FPF loaded but a decrease in the number of collisions. For the change of the chamber, the domed chamber design increased the powder dispersion time and thus enhanced the frequency and energy of particle collisions, which eventually led to an increase in FPF loaded. At fixed flow rates, the powder dispersion efficiency was a function of the device resistance with higher device resistance causing an increase in the FPF loaded. However, it is important for the patient's attainable pressure drop to be considered in this context. Correlations between the aerosolization efficiency and the ratio of the average collision energy and cohesion energy were established based on model-predicted quantities.

Bacteriophage endolysin powders for inhaled delivery against pulmonary infections.

Endolysins are bacteriophage-encoded enzymatic proteins that have great potential to treat multidrug-resistant bacterial infections. Bacteriophage endolysins Cpl-1 and ClyJ-3 have shown promising antimicrobial activity against Streptococcus pneumoniae, which causes pneumonia in humans. This is the first study to investigate the feasibility of spray-dried endolysins Cpl-1 and ClyJ-3 with excipients to produce inhalable powders. The two endolysins were individually tested with leucine and sugar (lactose or trehalose) for spray drying method followed by characterization of biological and physico-chemical properties. A complete loss of ClyJ-3 bioactivity was observed after atomization of the liquid feed solution（before the drying process）, while Cpl-1 maintained its bioactivity in the spray-dried powders. Cpl-1 formulations containing leucine with lactose or trehalose showed promising physico-chemical properties (particle size, crystallinity, hygroscopicity, etc.) and aerosol performances (fine particle fraction values above 65%). The results indicated that endolysin Cpl-1 can be formulated as spray dried powders suitable for inhaled delivery to the lungs for the potential treatment of pulmonary infections.

Pharmacokinetics/pharmacodynamics of phage therapy: a major hurdle to clinical translation.

BACKGROUND: The increasing emergence of antimicrobial resistance worldwide has led to renewed interest in phage therapy. Unlike antibiotics, the lack of pharmacokinetics/pharmacodynamics (PK/PD) information represents a major challenge for phage therapy. As therapeutic phages are biological entities with the ability to self-replicate in the presence of susceptible bacteria, their PK/PD is far more complicated than that of antibiotics. OBJECTIVES: This narrative review examines the current literature on phage pharmacology and highlights major pharmacological challenges for phage therapy. SOURCES: Included articles were identified by searching PubMed and Google Scholar till June 2022. The search terms were 'bacteriophage', 'antimicrobial', 'pharmacokinetics' and 'pharmacodynamics'. Additional relevant references were obtained from articles retrieved from the primary search. CONTENT: In this review, phage PK is first discussed, focusing on absorption, distribution, metabolism, and elimination. Key factors affecting phage antimicrobial activities are reviewed, including multiplicity of infection, passive and active phage therapy, and the involvement of the human immune system. Importantly, we emphasize the impact of phage self-replication on the PK/PD and the fundamental phage characteristics that are required for PK/PD modelling and clinical translation. IMPLICATIONS: Recent progress in phage pharmacology has shown that we are in a far better position now to treat infections with phage therapy than a century ago. However, phage therapy is still in its infancy when compared to antibiotics due to the scarce pharmacological knowledge (e.g. PK/PD). Optimization of phage PK/PD is key for translation of phage therapy in patients.

Cannabidiol for the Treatment of Brain Disorders: Therapeutic Potential and Routes of Administration.

The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.

Optical photothermal infrared spectroscopy for nanochemical analysis of pharmaceutical dry powder aerosols.

The aim of this research was to chemically analyse the distribution of drugs and excipients in pharmaceutical dry powder inhalation (DPI) aerosol particles of various sizes in solid state. The conventional wet assay of the chemical composition of particles after collection in a cascade impactor lacks the capability to differentiate spatially resolved morphology and chemical composition of particles in complex DPI formulations. In this proof-of-concept study, we aim to demonstrate the feasibility of using optical photothermal infrared spectroscopy (O-PTIR) to characterize micro- to nano-scale chemical composition of size-segregated particles of pharmaceutical DPI formulations. These formulations were prepared by spray drying a solution or a suspension comprising an inhaled corticosteroid fluticasone propionate, a long-acting ß2-agonist salmeterol xinafoate, and excipient lactose. The active ingredients fluticasone propionate and salmeterol xinafoate are widely used for the treatment of asthma and chronic obstructive pulmonary disease. Spatially resolved O-PTIR spectra acquired from the particles collected from stages 1-7 of a Next Generation Impactor (NGI) for both formulations confirmed the presence of peaks related to fluticasone propionate (1746 cm-1, 1702 cm-1, 1661 cm-1 and 1612 cm-1), salmeterol xinafoate (1582 cm-1), and lactose (1080 cm-1). There was no significant difference in the drug to lactose peak ratio among various size fractions of particles spray dried from solution indicating a homogeneity in drug and lactose content in the aerosol formulation. In contrast, the suspension-spray dried formulation showed the drug content increased while the lactose content decreased in the particles collected down the NGI from stage 1 to stage 7, indicating heterogeneity in the ratio of drug-excipient distribution. The qualitative chemical compositions from O-PTIR were comparable to conventional wet chemical assays of various size fractions, indicating the suitability of O-PTIR to serve as a valuable analytical platform for screening the physicochemical properties of DPIs in solid state.

Quantifying Agglomerate-to-Wall Impaction in Dry Powder Inhalers.

PURPOSE: The probability of agglomerate-to-wall collision was quantified using a unique image processing technique applied to high-speed microscopic images. The study aimed to investigate the effects of flow rate and particle size on the percentage of colliding agglomerates detected within an in-house powder dispersion device. METHOD: The device consists of a swirl chamber and two tangential inlets in various configurations, designed to emulate the geometric features of commercial devices such as the Aerolizer® and Osmohaler®. The test cases were conducted with constant flow rates of 30 SLPM and 60 SLPM. Four powder samples were tested, including carrier Respitose® SV010 (median volume diameter 104 µm, span 1.7) and mannitol of three constituent primary particle sizes (3 µm, 5 µm and 7 µm; span 1.6 - 1.9). RESULTS: At the lower flow rate of 30 SLPM, collision frequencies were significantly different between powders of different constituent particle sizes, but the effects of powder properties diminished on increasing the flow rate to 60 SLPM. At the higher flow rate, all powders experienced a significant increase in the proportion of colliding particles. CONCLUSION: Analysis of collision events showed that the probability of collision for each agglomerate increased with agglomerate diameter and velocity. Experimental data of agglomerate-to-wall collision were utilised to develop a logistic regression model that can accurately predict collisions with various powders and flow rates.

Engineering the right formulation for enhanced drug delivery.

Dry powder inhalers (DPIs) can be used with a wide range of drugs such as small molecules and biologics and offer several advantages for inhaled therapy. Early DPI products were intended to treat asthma and lung chronic inflammatory disease by administering low-dose, high-potency drugs blended with lactose carrier particles. The use of lactose blends is still the most common approach to aid powder flowability and dose metering in DPI products. However, this conventional approach may not meet the high demand for formulation physical stability, aerosolisation performance, and bioavailability. To overcome these issues, innovative techniques coupled with modification of the traditional methods have been explored to engineer particles for enhanced drug delivery. Different particle engineering techniques have been utilised depending on the types of the active pharmaceutical ingredient (e.g., small molecules, peptides, proteins, cells) and the inhaled dose. This review discusses the challenges of formulating DPI formulations of low-dose and high-dose small molecule drugs, and biologics, followed by recent and emerging particle engineering strategies utilised in developing the right inhalable powder formulations for enhanced drug delivery.

Advancements in Particle Engineering for Inhalation Delivery of Small Molecules and Biotherapeutics.

Dry powder inhalation formulations have become increasingly popular for local and systemic delivery of small molecules and biotherapeutics. Powder formulations provide distinct advantages over liquid formulations such as elimination of cold chain due to room temperature stability, improved portability, and the potential for increasing patient adherence. To become a viable product, it is essential to develop formulations that are stable (physically, chemically and/or biologically) and inhalable over the shelf-life. Physical particulate properties such as particle size, morphology and density, as well as chemical properties can significantly impact aerosol performance of the powder. This review will cover these critical attributes that can be engineered to enhance the dispersibility of inhalation powder formulations. Challenges in particle engineering for biotherapeutics will be assessed, followed by formulation strategies for overcoming the hurdles. Finally, the review will discuss recent examples of successful dry powder biotherapeutic formulations for inhalation delivery that have been clinically assessed.

Simulating the effect of individual upper airway anatomical features on drug deposition.

This study aims to systematically isolate different anatomical features of the human pharynx with the goal to investigate their independent influence on airflow dynamics and particle deposition characteristics in a geometrically realistic human airway. Specifically, the effects of the uvula, epiglottis and soft palate on drug particle deposition are studied systematically, by carefully removing each of these anatomical features from reconstructed models based on MRI data and comparing them to a benchmark realistic airway model. Computational Fluid Dynamics using established turbulence models is employed to simulate the transport of mono-dispersed particles (3 µm) in the airway at two flow-rates. The simulations suggest three findings: 1) widening the space between the oral cavity and oropharynx and where the soft palate is situated leads to the most dramatic reduction in drug deposition in the upper airway; 2) exclusion of the uvula and epiglottis: a) affects flow dynamics in the airway; b) alters regional deposition behaviour; c) does not significantly affect the total number of particles deposited in the pharynx; and 3) the space adjacent to the soft palate is a key determinant for aerosol deposition in the extrathoracic region and is related to mechanisms of flow acceleration, diversion and recirculation.

Novel antimicrobial agents for combating antibiotic-resistant bacteria.

Antibiotic therapy has become increasingly ineffective against bacterial infections due to the rise of resistance. In particular, ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have caused life-threatening infections in humans and represent a major global health threat due to a high degree of antibiotic resistance. To respond to this urgent call, novel strategies are urgently needed, such as bacteriophages (or phages), phage-encoded enzymes, immunomodulators and monoclonal antibodies. This review critically analyses these promising antimicrobial therapies for the treatment of multidrug-resistant bacterial infections. Recent advances in these novel therapeutic strategies are discussed, focusing on preclinical and clinical investigations, as well as combinatorial approaches. In this 'Bad Bugs, No Drugs' era, novel therapeutic strategies can play a key role in treating deadly infections and help extend the lifetime of antibiotics.