Inhalable Dry Powders of Antimicrobial Agents in Respiratory Diseases

Abstract

Background

Respiratory infections remain a major global health burden despite advances in systemic antimicrobial therapy. Antimicrobial dry powder inhalers (DPIs) have emerged as precision-engineered pulmonary delivery platforms capable of achieving high local drug concentrations while minimizing systemic toxicity.

Objective

This review examines the historical evolution, pharmacological landscape, particle engineering technologies, translational challenges, and clinical progress of antibacterial, antiviral, and antifungal DPIs.

Content

We trace the evolution of antimicrobial DPIs from early aerosolized therapies to contemporary engineered systems, integratingdisease targets, pharmacological agents, particle and formulation engineering, inhaler technologies, patents, clinical development andregulatory milestones. Particular emphasis is placed on formulations supported by in vivo efficacy, clinical investigation or regulatoryapproval, highlighting advances in tuberculosis, chronic bacterial infections, viral respiratory diseases and pulmonary fungal infections.

Conclusions

Antimicrobial DPIs are evolving toward precision pulmonary therapies, highlighting their expanding role in chronic infections, pandemic preparedness, and next-generation pulmonary anti-infective therapy. Overcoming dose, deposition, stability, andtranslational barriers will be critical for broader clinical adoption.

Introduction

Respiratory infections remain a dominant contributor to global morbidity and mortality, encompassing a diverse spectrum of diseases such as Tuberculosis, Influenza, COVID-19, bacterial pneumonias, and invasive fungal infections. The clinical management of a broad pathogen spectrum, ranging from Mycobacterium tuberculosis (Mtb) and SARS-CoV-2 to highly resistant bacterial pneumonias and invasive aspergillosis, is increasingly complicated by the limitations of conventional pharmacotherapy. Despite the widespread availability of potent systemic antimicrobial therapies, clinical outcomes are frequently undermined by physiological barriers inherent to the respiratory tract, inadequate drug penetration into pulmonary infection sites, dose-limiting systemic toxicity, suboptimal adherence, and the accelerating emergence of antimicrobial resistance (AMR) [1, 2].

The fundamental challenge in treating deep-lung infections lies in the pharmacokinetic (PK) mismatch of systemic administration. To achieve therapeutic concentrations within the epithelial lining fluid, systemic dosing must often be escalated to levels that approach the Maximum Tolerated Dose (MTD) [3]. This is particularly problematic for antimicrobials with narrow therapeutic indices, where suboptimal biophase concentrations at the infection site lead to “sanctuary sites” that facilitate pathogen persistence [4]. Furthermore, high systemic exposure frequently triggers dose-limiting nephrotoxicity and hepatotoxicity, undermining patient adherence and clinical outcomes [5].

Pulmonary drug delivery offers a compelling mechanical alternative by enabling the direct deposition of therapeutics into the lung parenchyma [6, 7]. This localized approach maximizes the Target Site Concentration (TCS) while minimizing systemic absorption, thereby effectively widening the therapeutic window [6]. Among available inhalation platforms, dry powder inhalers (DPIs) have emerged as particularly advantageous relative to nebulizers and pressurized metered-dose inhalers (pMDIs) [8, 9]. DPIs offer superior physicochemical stability by avoiding aqueous formulations, eliminate cold-chain requirements, and support rapid, portable, and breath-actuated drug administration [10, 11]. These attributes collectively position DPIs as a robust platform for delivering antimicrobial agents in both acute and chronic respiratory settings.

Although inhaled antibiotics have demonstrated clinical utility in diseases such as cystic fibrosis and bronchiectasis, the broader application of inhalable antimicrobial powders, including antivirals and antifungals remains comparatively underexplored [12, 13]. Recent advances in particle engineering, aerosol science, and formulation technologies have revitalized interest in this domain, enabling more precise control over aerodynamic behavior, lung deposition, and drug release kinetics. At the same time, evolving regulatory pathways and increasing patent activity underscore a growing translational momentum that warrants critical examination.

In this context, the present review provides a comprehensive synthesis of the field, spanning the historical evolution, mechanistic underpinnings, formulation strategies, disease-specific applications, clinical development landscape, and translational challenges associated with antimicrobial dry powder inhalers for respiratory diseases.

Historical Development of Inhaled Antimicrobial Therapy

The concept of delivering antimicrobials directly to the respiratory tract predates modern aerosol science and emerged from a clear clinical need to manage persistent endobronchial infections, particularly in diseases such as Cystic Fibrosis (CF) and Bronchiectasis [14]. Early efforts in the 1940s and 1950s relied on rudimentary nebulization systems to aerosolize systemic liquid formulations of antibiotics, including Penicillin and Streptomycin [14]. While these pioneering studies established the foundational proof-of-concept for localized pulmonary therapy, their clinical utility was limited by prolonged administration times, cumbersome device designs, and the inherent instability of aqueous formulations. A significant advancement occurred in the 1980s with the introduction of inhaled Tobramycin solutions, which demonstrated that high therapeutic concentrations could be achieved at the site of infection while minimizing systemic toxicities, including nephrotoxicity commonly associated with aminoglycosides [15].

The transition from nebulized liquid formulations to DPIs was driven by the need to reduce treatment burden, improve portability, and enhance formulation stability through solid-state design. A defining milestone in this evolution was the regulatory approval of Zanamivir (Relenza^®) in 1999, marking the first successful deployment of an antimicrobial (antiviral) DPI [16]. This approval established the feasibility of breath-actuated platforms for delivering therapeutics in acute respiratory infections and catalyzed broader interest in inhalable antimicrobial powders. The subsequent decade witnessed rapid progress in particle engineering and formulation science, enabling the design of powders with controlled aerodynamic properties and improved lung deposition. Between 2010 and 2016, notable preclinical advances were achieved in the development of inhalable therapies for Tuberculosis, including dry powder formulations of Isoniazid, Rifabutin, and investigational agents such as PA-824 [17–20]. These studies demonstrated sustained pulmonary pharmacokinetics and efficacy in advanced animal models, highlighting the potential of DPI systems to target intracellular pathogens and granulomatous lesions. Concurrently, the scope of inhaled antimicrobial therapy expanded beyond conventional antibiotics to include antifungal agents and treatments targeting multidrug-resistant pathogens.

A central challenge during this period was the precise engineering of particles with optimal aerodynamic behavior, particularly in terms of flowability, moisture sensitivity, and control over aerodynamic diameter (d_ae). Advances in spray drying and the development of engineered porous particles enabled the reproducible generation of respirable powders within the ideal aerodynamic size range of 1–5 μm, facilitating deep lung deposition. These technological breakthroughs culminated in the approval of the TOBI^® Podhaler^® (tobramycin inhalation powder) in 2013, followed by the development of dry powder formulations of Colistimethate sodium (Colobreathe^®) [21, 22]. These milestones marked a decisive shift from traditional lactose-based carrier systems to advanced carrier-free, high-dose formulations optimized for pulmonary delivery. More recently, the global urgency created by the COVID-19 pandemic accelerated innovation in inhaled antiviral therapies, including the rapid exploration of spray-dried formulations of repurposed agents such as Ivermectin and other emerging antiviral compounds [23–27].

In parallel with formulation advancements, inhaler device technology has undergone substantial evolution. Early capsule-based systems were limited in their ability to efficiently disperse the relatively high powder masses required for antimicrobial therapy. Modern inhaler platforms now incorporate high-resistance designs and optimized airflow pathways to enable effective powder deagglomeration even at lower inspiratory flow rates [28]. The introduction of multi-dose systems, excipient-minimized formulations, and digitally integrated inhalers has further improved dose consistency, patient adherence, and therapeutic precision [29]. Collectively, these developments reflect a broader transition from empirical aerosol therapy to highly engineered pulmonary delivery systems capable of addressing the complex pharmacological and pathological challenges associated with respiratory infections. Figure 1 illustrates the evolution of inhaled antimicrobial therapies spanning multiple technological and translational phases.

Fig. 1.

Historical milestones in the development of antimicrobial DPIs for respiratory infections. The evolution of inhaled antimicrobial therapy spans early nebulized antibiotics (1940–1990), the first DPI approval (zanamivir, 1999), and subsequent antibacterial DPI approvals including tobramycin (2013) and colistimethate sodium (European Union). Recent decades have seen expansion into TB, fungal, MDR, and antiviral therapies, with strong preclinical progress but limited clinical translation. Abbreviations: DPI, Dry powder inhaler; NHP, Non-human primates; CF, Cystic fibrosis; INH, Isoniazid; VAP, Ventilator associated pneumonia; HAP, Hospital-acquired pneumonia; NTM, Non-tuberculous mycobacteria; MRSA, Methicillin-resistant Staphylococcus aureus. Created with BioRender.com; elements generated using Nano Banana 2, Gemini and curated by the authors

Rationale for Delivery of Antimicrobial Dry Powder Inhalers

The clinical efficacy of antimicrobial DPIs is fundamentally governed by a multiscale interplay between the particle physicochemical properties, the complex branching architecture of the respiratory tree, and the biological niche of the target pathogen. The mechanistic basis of the aerosol deposition, pharmacokinetics, and site-specific drug delivery in respiratory diseases is illustrated in Fig. 2.

Fig. 2.

Mechanistic pathways of DPI deposition, uptake, and systemic absorption. Inhaled dry powder particles deposit in distinct lung regions based on aerodynamic diameter and inhalation dynamics. Following deposition, antimicrobials dissolve in lung lining fluid and interact with disease-specific microenvironments, enabling local antimicrobial activity and, in some cases, absorption into systemic circulation via the alveolar–capillary interface. Created with BioRender.com; elements generated using Nano Banana 2, Gemini and curated by the authors

Principles of Aerodynamic Engineering and Deposition

The therapeutic performance of antimicrobial DPIs is fundamentally governed by the relationship between the particle’s aerodynamic diameter (d_ae) and the complex architecture of the respiratory tree. Unlike the geometric diameter, d_ae accounts for particle density and shape, defining how a particle behaves in an airstream. We can mathematically describe this relationship as:

1

(Where is geometric diameter, is particle density, is unit-density of sphere (1 g/cm³), and is the shape factor).

By rationally tuning d_ae, particles can be engineered for spatially resolved delivery across distinct anatomical regions. Particles in the 5–10 μm range preferentially deposit within the tracheobronchial tree, making them suitable for infections localized to conducting airways, such as Pseudomonas aeruginosa colonization in bronchiectasis [30, 31]. In contrast, particles within the 1–5 μm range penetrate deeper into the alveolar region, which is critical for targeting distal pathologies including bacterial pneumonia and invasive fungal infections [30, 31]. Submicron particles (< 1 μm), although susceptible to exhalation, are increasingly being explored for specialized applications such as intracellular delivery or systemic translocation [30].

Achieving such topographical targeting requires leveraging the three primary mechanisms of aerosol deposition which are inertial impaction, gravitational settling (i.e. sedimentation), brownian motion (i.e. diffusion). Inertial impaction dominates for particles > 10 μm in the oropharyngeal region and results in coughing. Gravitational settling (i.e. sedimentation) governs smaller particles that escape inertia but succumb to gravity which are for most therapeutic inhaled particles entering the lungs including the bronchioles and bronchiolar regions where reduced airflow velocities enable particle settling by gravity onto the epithelial lining fluid, representing the optimal regime for deep lung targeting in pneumonia and invasive fungal infections [30]. Brownian motion (i.e. diffusion) becomes significant for very small particles < 1 μm such as nanoparticles where stochastic motion facilitates access to peripheral alveolar spaces, supporting intracellular delivery and potential systemic translocation despite partial exhalation losses [30].

Tailoring Solubility to Pathogen Biology

A critical, often overlooked rationale in DPI design is the modulation of particle dissolution kinetics to match with pathogen-specific microenvironments. This concept of “residence niche matching” provides a mechanistic basis for optimizing therapeutic efficacy. For intracellular pathogens such as Mtb, which reside within alveolar macrophages, poorly soluble or controlled-release particulate systems are advantageous [32, 33]. These formulations are engineered for efficient phagocytic uptake, enabling the formation of intracellular drug depots that directly target pathogen sanctuaries. Conversely, extracellular pathogens located within the epithelial lining fluid (ELF) require rapid pharmacological intervention. In such cases, highly soluble formulations are preferred, delivering an immediate concentration surge that maximizes the peak concentration-to-minimum inhibitory concentration (C_max/MIC) ratio, a key determinant of antimicrobial efficacy against rapidly proliferating organisms [34, 35].

Overcoming Systemic Limitations

Systemic antimicrobial therapy is often constrained by the inefficiency of drug transport across the blood-air barrier. Achieving therapeutically relevant concentrations within the ELF frequently necessitates plasma exposures that approach or exceed the MTD, thereby increasing the risk of systemic toxicity. Localized pulmonary delivery via DPIs provides a strategy to decouple pharmacodynamic efficacy from systemic exposure [36]. By depositing high drug concentrations directly at the site of infection, inhaled powders circumvent vascular transport limitations. This advantage is particularly pronounced in pathological conditions characterized by impaired perfusion, such as granulomatous lesions in tuberculosis or dense fungal aggregates, where systemic therapies exhibit poor penetration [1, 36]. Direct deposition ensures that even poorly vascularized or necrotic regions are exposed to bactericidal or fungicidal concentrations [36].

Systemic Delivery Via the Lung

Beyond localized therapy, the lung represents a highly efficient interface for systemic drug delivery. The alveolar region offers an expansive surface area (~ 100 m²) coupled with an ultrathin epithelial barrier (~ 0.1–0.2 μm) and extensive vascularization, enabling rapid drug absorption into the bloodstream. By engineering particles with rapid dissolution and favorable permeability characteristics, DPIs can function as non-invasive, needle-free delivery systems for systemic antimicrobials especially for biologics [37, 38]. This approach is particularly valuable for compounds with poor oral bioavailability or for clinical scenarios requiring rapid onset of action. In such contexts, pulmonary delivery can achieve systemic exposure profiles approaching those of intravenous administration, while maintaining the convenience and safety of a non-invasive route.

Biological and Pathophysiological Barriers

Despite their theoretical advantages, inhaled particles must traverse a complex and often hostile pulmonary microenvironment [39]. Mucus hypersecretion and pathogen-derived biofilms act as physical and electrostatic barriers, impeding particle diffusion and limiting epithelial access [40]. Disease-induced alterations in lung architecture, including airway obstruction and ventilation heterogeneity, further contribute to uneven deposition and the formation of poorly accessible “dead zones” [39, 40]. Additionally, the high relative humidity of the respiratory tract (~ 99.5%) poses a significant challenge for hygroscopic powders, which may undergo premature moisture uptake, leading to particle growth, agglomeration, and unintended deposition in proximal airways [40, 41]. Accordingly, successful DPI design requires an integrated understanding of aerosol physics, microbial pathogenesis, and pulmonary pathophysiology. Only through such multidisciplinary optimization can a formulation transition from a merely “respirable” system to one capable of delivering a clinically effective, site-specific therapeutic dose.

Disease Targets and Translational Developments of Antimicrobial DPIs

Respiratory infections comprise a heterogeneous spectrum of diseases defined by distinct pathogen biology, anatomical localization, and host-pathogen interactions. The therapeutic suitability of antimicrobial DPIs is therefore inherently disease-specific, dictated by the accessibility of the infected compartment and the pharmacokinetic limitations of systemic therapy. Localized delivery via DPIs allows decoupling of pulmonary efficacy from systemic toxicity, providing a mechanistically rational approach to treating “perfusion-limited” infectious niches. The current translational landscape of antimicrobial DPIs across major respiratory infectious diseases is summarized in Fig. 3.

Fig. 3.

Translational landscape of antimicrobial DPIs across respiratory infectious diseases. The schematic summarizes the current state of antimicrobial DPI development across major respiratory infections, including tuberculosis, CF, bronchiectasis, VAP, viral infections, and invasive fungal diseases. The figure highlights differences in clinical translation, regulatory approval, preclinical validation, and technological maturity among antibacterial, antiviral, and antifungal inhalation therapies. Created with BioRender.com; elements generated using Nanobanana, Gemini

Bacterial Infections

Pulmonary Tuberculosis and Non-Tuberculous Mycobacteria (NTM)

Pulmonary tuberculosis remains a major contributor to global infectious mortality and represents the most compelling clinical case for the development of antimicrobial DPIs. The pathophysiology of Mtb infection is characterized by the formation of complex granulomatous lesions containing regions of caseous necrosis, a surrounding fibrotic rim, and cavitation [42]. These highly organized pathological structures create profound physiological barriers to systemic drug delivery. In chronic or cavitary pulmonary tuberculosis, these regions are poorly vascularized, leading to “perfusion-limited” drug penetration where systemic plasma concentrations, even at the MTD fail to reach the MIC within the necrotic cores [20].

DPIs provide a mechanistically rational strategy to overcome these barriers through localized pulmonary deposition. Unlike oral or intravenous administration, which relies on extravasation from the pulmonary vasculature into the ELF, inhaled particles with d_ae below 5 μm deposit directly within distal respiratory regions, generating steep local concentration gradients that facilitate diffusion into granulomatous and cavitary lesions [20, 43, 44]. Furthermore, a substantial proportion of the Mtb bacilli population resides within alveolar macrophages, particulate systems can be engineered to exploit macrophage phagocytosis [20, 44, 45]. Particles within the 1–3 μm aerodynamic range are particularly favorable for macrophage uptake, enabling the formation of intracellular drug depots that directly target the pathogen within its primary host-cell environment [44].

Over the past two decades, extensive preclinical work has demonstrated the feasibility of pulmonary delivery of antitubercular agents including rifampicin, isoniazid, ethionamide, D-cycloserine, capreomycin, clofazimine, and emerging nitroimidazole derivatives [17, 18, 45–51]. These formulations have shown enhanced pulmonary deposition, prolonged lung residence, macrophage targeting, and sustained pharmacokinetic exposure in multiple animal models, including non-human primates and Phase I clinical studies [17, 51]. Nevertheless, despite substantial preclinical progress, no antitubercular DPI has yet achieved regulatory approval, highlighting a persistent translational gap driven by challenges associated with high-dose powder delivery, multidrug combination therapy, and long-term pulmonary safety. Importantly, clinical translation has advanced beyond conceptual feasibility. Early-phase clinical studies involving high-dose DPI of amikacin (Cyclops™) and capreomycin platforms have demonstrated the safety and tolerability of pulmonary delivery at doses approaching 1000 mg while achieving rapid local concentrations above the MIC [51] (www.pureims.com). In addition, Phase II evaluations of multidrug DPI regimens (including isoniazid and rifampicin) have shown accelerated symptomatic relief and reduced contagiousness, despite comparable long-term culture conversion rates to standard care [52]. As newer agents progress through inhalation-focused development pipelines, formulation research continues to address key translational barriers including powder mass limitations, cough induction, aerosol stability, and dose reproducibility. Collectively, these studies establish a strong mechanistic and translational foundation for the integration of inhaled antimicrobial powders into future TB treatment paradigms.

CF and Bronchiectasis

CF and non-CF bronchiectasis represent the most clinically advanced indications for antimicrobial DPIs [53, 54]. Both diseases are characterized by impaired mucociliary clearance, chronic airway inflammation, and persistent bacterial colonization, particularly with Pseudomonas aeruginosa, resulting in mucus-rich and biofilm-dominated microenvironments that limit the efficacy of systemic antibiotics [55]. In this setting, inhaled antimicrobial powders enable exceptionally high local airway drug concentrations while minimizing systemic exposure and associated toxicities. The clinical success of tobramycin inhalation powder as TOBI^® Podhaler™ (www.tobipodhaler.com) and colistimethate sodium DPI as Colobreathe^® (www.colobreathe.co.uk) has established the therapeutic feasibility of DPI-based antimicrobial delivery, while substantially reducing administration times compared with conventional nebulized therapies of these antibiotics [56]. Although these products are primarily approved for chronic Pseudomonas aeruginosa infections in CF, they are increasingly utilized in non-CF bronchiectasis as suppressive inhaled therapies [56]. Importantly, the broader clinical landscape of inhaled antimicrobials in these diseases extends beyond DPIs and includes several nebulized antibiotic platforms, such as aztreonam lysine as Cayston^® (www.cayston.com), levofloxacin as Quinsair^® (www.quinsairadmin.ca), and liposomal amikacin as Arikayce^® (www.arikaycehcp.com) formulations, which remain important therapeutic options for chronic pseudomonal and non-tuberculous mycobacterial infections.

Ventilator-Associated Pneumonia (VAP)

VAP represents a severe nosocomial respiratory infection associated with high morbidity, mortality, and the increasing prevalence of multidrug-resistant (MDR) pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (MRSA) [57]. Systemic antibiotic therapy in mechanically ventilated patients is frequently limited by altered pharmacokinetics, impaired pulmonary perfusion, and inadequate ELF concentrations, particularly within consolidated or poorly ventilated lung regions [57]. These limitations have driven substantial interest in inhaled antimicrobial therapies capable of delivering high local antibiotic concentrations directly to infected airways [58, 59]. To date, clinical implementation has largely relied on nebulized aminoglycosides, colistin, and liposomal amikacin formulations integrated into ventilator circuits [59–61]. DPIs for VAP has emerged as a promising but technically demanding frontier in critical care pharmacology [62]. Current research focuses on high-dose, actively dispersed powder systems designed to deliver antibiotics such as amikacin and colistin independent of patient inspiratory effort. Pharmacokinetic and pharmacodynamic modeling suggests that these approaches may achieve substantially higher ELF drug concentrations than intravenous administration, potentially improving bacterial eradication while limiting systemic toxicity and resistance emergence. However, successful translation remains constrained by challenges associated with ventilator-associated humidity-induced particle aggregation, ventilator synchronization, and reproducible powder dispersion within mechanically ventilated systems.

Collectively, antibacterial DPIs represent the most clinically advanced and translationally mature class of inhaled antimicrobial therapies. Development efforts have expanded from chronic suppressive therapies for cystic fibrosis and bronchiectasis to investigational platforms targeting pulmonary tuberculosis, non-tuberculous mycobacterial infections, multidrug-resistant pneumonia, and ventilator-associated infections. Advances in particle engineering technologies, including spray drying, thin-film freezing, porous particle engineering, and nanoparticle-based systems, have enabled the generation of high-payload inhalable formulations optimized for deep lung deposition and sustained pulmonary exposure. Representative antibacterial DPI systems spanning approved products, clinical-stage candidates, and preclinical platforms are summarized in Table 1.

Table 1.

Antibacterial DPI systems for pulmonary infections: approved products, clinical development, and preclinical platforms

Antibacterial agent	Target disease	DPI technology/formulation	Development status	Key notes	References
Tobramycin	CF, Bronchiectasis	Spray-dried porous particles (PulmoSphere™)	FDA-approved (TOBI® Podhaler™)	Landmark antibacterial DPI	www.tobipodhaler.com
Colistimethate sodium	CF, Bronchiectasis	Carrier-free DPI	Approved in EU/UK (Colobreathe®)	Chronic P. aeruginosa suppression	www.colobreathe.co.uk
Colistin	CF, Bronchiectasis	Spray-Drying	Granted Orphan drug designation (ODD) by EMA and FDA (Colistin Cyclops®)	Improved patient convenience (reduced cough), reduced treatment burden, and superior formulation delivery (high-dose efficiency, low powder loss due to device)	www.pureims.com/products/ / [63]
Ciprofloxacin	Non-CF Bronchiectasis	PulmoSphere™ spray-dried DPI	Phase III completed	Phase III (RESPIRE 2) study failed to meet primary endpoints of extending time to first exacerbation and an increased risk of antibiotic resistance	[64, 65]
Levofloxacin	CF, Bronchiectasis, Combined antitubercular DPI therapy	iSPERSE™ spray-drying technology	Preclinical	DPI translation still limited. Note: Quinsair® is an approved, nebulized levofloxacin formulation for treating chronic Pseudomonas aeruginosa lung infections in adults with cystic fibrosis	[66, 67]
Aztreonam	CF	Spray-drying	Nebulizer approved; DPI exploratory	DPI formulations remain investigational, however, nebulized product Cayston® (Aztreonam lysine) is FDA approved.	[68]
Fosfomycin/Tobramycin	COPD, bronchiectasis	Co-spray drying	Patent of fixed combination granted (US20110124589A1)	Dual-antibiotic inhalation platform. Safety and efficacy of dual combination evaluated in CF patients with P. aeruginosa infection.	[69]
Amikacin	CF, VAP, NTM, Drug susceptible tuberculosis	High-dose inhalable powders delivered via Cyclops™	Preclinical/device-development	PureIMS initiated phase I clinical trial (NCT04249531) to evaluate PK and local tolerability of Amikacin Cyclops™ in patients with drug susceptible tuberculosis. Note: Arikayce® is an FDA approved liposomal suspension as nebulizer.	www.pureims.com/products/
Vancomycin	CF with MRSA infection	Aero Vanc DPI using Spray-drying	Phase II/III	The development of AeroVanc has been halted by Savara Pharmaceuticals following the failure of its Phase III AVAIL trial. The trial did not meet its primary end point of showing no statistically significant improvement in lung function or a significant reduction in pulmonary exacerbations.	[70] www.cysticfibrosisnewstoday.com/aerovanc-vancomycin-inhalation-powder-lung-infections-cystic-fibrosis/
Fixed dose combination of Isoniazid, Rifampicin, Pyrazinamide and Levofloxacin	Tuberculosis	Spray-dried microparticles	Phase II	Patients using the DPI of this fixed dose combination as an add-on to oral therapy experienced reduced coughing and lower TB transmission compared with the control groups, indicating promising safety and efficacy	[52]
Isoniazid	Tuberculosis	Porous spray-dried particles	Preclinical	Sustained pulmonary exposure	[71]
Isoniazid+ Rifabutin	Tuberculosis	Spray-dried microparticles	Advanced Preclinical	A 90 days PK and biodistribution study showed DPI achieved targeted and sustained drug delivery to the non-human primate lungs. DPI formulation effectively extends the half-life of the drugs due to slow elimination and slow release from lung macrophages.	[17, 18]
Capreomycin	MDR-TB	Spray-dried DPI	Phase I completed	Phase I clinical studies demonstrated that a single dose escalating DPI formulation (upto 300 mg) was safe and well tolerated in healthy individuals.	[51]
Rifabutin	Tuberculosis	Polymeric microparticles and Spray-drying	Preclinical	Intracellular macrophage delivery. DPI Combination delivery with Isoniazid resulted in relapse-free cure in experimental mice and guinea pigs.	[18]
Clofazimine	MDR-TB, NTM	Airjet milling, Nanocluster DPIs, Spray-drying	Preclinical	MannKind Corporation has planned Phase I clinical trials of clofazimine formulation (MNKD-102) for treating NTM lung disease.	[47, 72] www.mannkindcorp.com
Sutezolid	MDR-TB	Polymeric inhalable particles	Preclinical	In vivo studies in mice have shown that adjunct therapy with DPI of sutezolid can reduce its oral efficacious dose	[49]
Gentamicin	Pneumonic Plague & Pneumonia	Spray-drying	Preclinical	Murine models show high efficacy against Yersinia pestis and P. aeruginosa	[73]
Azithromycin	Chronic lower respiratory infections	Spray-drying	Preclinical	DPI achieves high local concentration in murine models	[74]

Viral Infections

Respiratory viral infections represent an increasingly important target for antimicrobial DPIs (Antiviral DPIs), particularly following the global impact of influenza outbreaks and the COVID-19 pandemic [75]. Because respiratory viruses replicate primarily within airway and alveolar epithelial cells, localized pulmonary delivery offers the potential to achieve rapid and high antiviral concentrations directly at the site of infection while minimizing systemic exposure [75, 76]. The clinical feasibility of this approach was first established by zanamivir (Relenza^®), the first FDA-approved antiviral DPI for influenza A and B, delivered using a lactose-based Diskhaler^® platform [77]. Subsequently, laninamivir octanoate (Inavir^®), a long-acting neuraminidase inhibitor DPI approved in Japan, further demonstrated the clinical utility of inhaled antiviral powders for influenza management (www.daiichisankyo.com) [78]. Inhaled antiviral therapies such as ribavirin (Virazole^®) (www.ir.bauschhealth.com) for severe pediatric respiratory syncytial virus (RSV) infections is available, but relies on nebulized administration through specialized systems such as the SPAG-2.

Recent research has expanded beyond neuraminidase inhibitors toward broad-spectrum antiviral and host-directed pulmonary therapies [75]. Advances in spray drying, thin-film freezing, and nanoparticle-in-microparticle engineering have enabled the development of inhalable formulations of remdesivir, molnupiravir, favipiravir, and oseltamivir designed to enhance ELF exposure while reducing systemic toxicity [75, 79–83]. In parallel, increasing attention has focused on antiviral peptides, inhaled interferon-β, siRNA, and mRNA-based platforms aimed at either suppressing viral replication or augmenting innate pulmonary immunity. The COVID-19 pandemic substantially accelerated interest in high-payload antiviral DPIs suitable for rapid outpatient deployment and pandemic preparedness. Despite strong mechanistic rationale and intense preclinical activity, most antiviral DPI systems remain in early translational stages, underscoring ongoing challenges related to formulation stability, dose reproducibility, and the narrow therapeutic window required for effective antiviral intervention.

Table 2 summarizes antiviral agents developed as DPIs for respiratory viral diseases, including approved therapies, investigational clinical-stage products, and preclinical formulations with demonstrated aerosolization or pulmonary delivery potential.

Table 2.

Antiviral DPI systems for respiratory viral infections: approved products, clinical development, and preclinical platforms

Antiviral agent	Viral target/indication	DPI technology/platform	Developmental status	Key notes	References
Zanamivir	Influenza A/B	Lactose-blended DPI	FDA-approved (Relenza® Diskhaler®)	First approved antiviral DPI for treatment of acute and uncomplicated influenza A and B in patients aged 7 years and older	www.accessdata.fda.gov/drugsatfda_docs/label/2023/021036s034lbl.pdf
Laninamivir octanoate	Influenza A/B	Lactose blended DPI packaged into specialized disposable powder delivery device (TwinCaps® inhaler)	Approved in Japan (Inavir®)	Single-dose (40 mg) neuraminidase inhibitor DPI approved in both adults and children above 10 years of age	www.daiichisankyo.com
Ribavirin	Respiratory Syncytial Virus (RSV)	DPI prepared using advanced particle engineering, such as Particle Replication in Nonwetting Templates (PRINT)	Available as FDA approved inhalation solution for nebulization (Virazole®) Phase I clinical studies on PRINT DPI for treatment of viral respiratory infections in COPD	DPI research aimed at reducing treatment burden Phase I studies demonstrated safety and PK in healthy participants and those with COPD (NCT03243760 and NCT03235726)	[84]
Remdesivir	COVID-19/broad-spectrum coronaviruses	Thin-film freezing (TFF), spray-dried DPI	Preclinical	Major pandemic-era DPI focus with robust data in murine models validating the PK and lung distribution profiles	[81]
Favipiravir	Influenza/COVID-19	Spray-dried DPI; Spray-freeze dried DPI; Lactose blending	Preclinical	The DPI generated high drug concentrations in the BALF, with mice receiving inhaled doses at approximately one twenty-fifth of the human-equivalent oral dose achieving higher BALF drug concentrations than orally treated mice.	[82, 83]
Oseltamivir	Influenza	Spray dried DPI	Preclinical	PK studies in rats established reducing dosing frequency on inhalation as DPI as compared to oral route.	[85]
COVIRIX broad-spectrum antiviral	Emerging respiratory viruses	Orbital™ high-payload DPI	Investigational	Pandemic-response inhalation platform	https://aptar.com/en-us/news-events/aptar-pharma-and-covirix-medical-partner-to-develop-inhalable-antiviral-treatments

Fungal Infections

Pulmonary fungal infections represent an important yet comparatively underdeveloped target for antimicrobial DPIs (Antifungal DPIs) [86]. Diseases such as invasive pulmonary aspergillosis and chronic pulmonary aspergillosis are associated with poor clinical outcomes due to limited pulmonary penetration and systemic toxicities of conventional antifungal therapies [86–88]. As of now, there are no FDA-approved DPIs or nebulized antifungal products specifically indicated for pulmonary fungal infections, instead inhaled antifungal therapy has historically relied on the off-label nebulization of intravenous amphotericin B formulations, particularly in immunocompromised and transplant populations [89]. Localized pulmonary delivery nevertheless remains highly attractive for achieving elevated antifungal concentrations directly at infected airway and alveolar sites while minimizing systemic nephrotoxicity and hepatotoxicity.

Recent translational efforts have focused on investigational inhaled antifungal platforms, including opelconazole (PC945), a long-residence triazole currently in Phase 3 development [89, 90]; Pulmazole™ (PUR1900) an itraconazole DPI based on the iSPERSE™ technology platform (www.pulmatrix.com/pipeline.html) [91]; and thin-film freezing (TFF)-engineered voriconazole powders designed to enhance lung bioavailability [92, 93]. Additional preclinical and early clinical studies have explored inhalable posaconazole and nanoparticle-based antifungal systems targeting multidrug-resistant fungal infections [94]. Advances in spray drying, thin-film freezing, and lipid-based particle engineering have been particularly important for overcoming the poor aqueous solubility and solid-state instability of many antifungal agents [94, 95]. In particular, maintenance of the amorphous state is critical for rapid dissolution within the limited volume of ELF, while optimized particle engineering is required to deliver the high powder masses for antifungal efficacy [1]. Furthermore, surfactant interactions, cough induction, and bronchospasm remain important translational considerations for highly hydrophobic compounds such as amphotericin B [96]. Collectively, these developments highlight both the growing momentum and the substantial formulation challenges associated with pulmonary antifungal drug delivery.

Table 3 summarizes antifungal agents developed as DPIs for pulmonary fungal diseases, including investigational clinical-stage systems and preclinical proof-of-concept formulations demonstrating pulmonary delivery feasibility or antifungal efficacy.

Table 3.

Investigational and clinical-stage antifungal DPIs for pulmonary fungal infections

Antifungal agent	Target indication	DPI technology/platform	Translational status	Key notes	References
Itraconazole	Allergic bronchopulmonary aspergillosis	iSPERSE™ DPI technology	Phase II	DPI of Itraconazole known as PUR1900 or Pulmazole was developed by Pulmatrix and later on transferred to Cipla Ltd. for development outside USA for Phase II clinical trials to evaluate long term efficacy, safety and pulmonary function	www.pulmatrix.com/pipeline.html
Opelconazole	Pulmonary aspergillosis	Spray drying	Preclinical	Opelconazole (PC945) nebulized formulation developed by Pulmocide Ltd. is in Phase III clinical trials (NCT05238116) for treating invasive pulmonary aspergillosis whereas the DPI formulation is in the experimental pipeline	www.pulmocide.com/portfolio/
Posaconazole	Resistant fungal infections	Spray-dried DPI; Wet milling	Preclinical	In vivo studies established that nanocrystal based DPIs achieves higher lung concentrations and lower systemic exposure as compared to approved oral suspension	[94]
Amphotericin B	Aspergillosis prophylaxis	Spray-dried powders, lipid-based DPI	Preclinical	Nektar Therapeutics UK Ltd. was earlier in 2006 granted an orphan drug designation for amphotericin B DPI to prevent pulmonary fungal infections but the program was discontinued. Nebulized amphotericin B including liposomal formulations for IV use is used in clinical practices as an ‘Off-label” therapy	https://ir.nektar.com/news-releases/news-release-details/nektar-announces-us-fda-has-granted-orphan-drug-designation
Voriconazole	Invasive fungal disease	Spray drying; TFF; Jet milling	Preclinical	In vivo study in a murine model showed DPI provided higher concentrations in the lung while minimizing systemic exposure ad toxicity	[92, 93]

Technological Landscape of Antimicrobial DPIs

The translational evolution of antimicrobial DPIs has been driven not only by advances in antimicrobial pharmacology, but also by major innovations in aerosol engineering, particle fabrication technologies, formulation architecture, and inhaler device design [97–100]. In contrast to conventional inhaled therapies for asthma and COPD, antimicrobial DPIs frequently require delivery of substantially higher powder masses while maintaining efficient aerosolization, deep lung deposition, physicochemical stability, and reproducible dose emission [101–103]. Consequently, antimicrobial DPI development has emerged as a highly interdisciplinary field integrating pharmaceutical sciences, aerosol physics, pulmonary biology, materials engineering, and inhaler device technology. Recent progress has shifted the field from conventional micronized carrier-based powders toward precision-engineered inhalable systems optimized for disease-specific pulmonary targeting, intracellular delivery, and scalable clinical translation. The contemporary technological ecosystem governing antimicrobial DPI development is illustrated in Fig. 4, highlighting the convergence of advanced particle engineering, formulation science, and inhaler device technologies required for efficient pulmonary antimicrobial delivery.

Fig. 4.

Technological landscape of antimicrobial DPIs. The schematic summarizes major technological domains involved in antimicrobial DPI development, including particle engineering technologies, formulation architectures, inhaler device platforms, and integrated pulmonary delivery outcomes. Advanced antimicrobial DPI systems increasingly incorporate engineered porous particles, nanoparticle-enabled formulations, carrier-free architectures, and smart inhaler technologies to optimize pulmonary deposition, antimicrobial efficacy, and translational performance. Created with BioRender.com; some elements were generated using Nanobanana, Gemini

Particle Engineering Technologies

Particle engineering forms the technological foundation of antimicrobial DPI development. Early inhalable antimicrobial powders relied predominantly on micronization and jet milling approaches, where coarse crystalline drug materials were mechanically reduced to respirable aerodynamic diameters within the 1–5 μm range. Although these strategies enabled the first clinically translated inhaled antimicrobial products, including zanamivir and early tobramycin formulations, micronized particles frequently exhibited strong interparticulate cohesion, poor flowability, electrostatic interactions, and inconsistent aerosol dispersion. These limitations became especially problematic for antimicrobial therapies requiring high powder-dose administration. Figure 5 summarizes the progression of particle engineering platforms currently employed in antimicrobial DPI development, including spray drying, TFF, PRINT, nanoengineering, and advanced inhalable carrier systems designed to optimize aerosol performance and pulmonary deposition [95, 100, 104–106].

Fig. 5.

Evolution of particle engineering technologies for antimicrobial DPIs. The figure illustrates the progression of antimicrobial DPI particle fabrication approaches from conventional micronization and spray drying technologies toward precision particle engineering platforms including thin-film freezing, nano spray drying, electrospraying, microfluidics, and nanoembedded inhalable systems. Modern antimicrobial DPI engineering increasingly focuses on controlling particle morphology, density, porosity, and intracellular targeting to improve aerosol performance and pulmonary drug delivery. Abbreviations: PRINT, Particle Replication in Non-wetting Templates; TFF, thin-film freezing. Created with BioRender.com; some elements were generated using Nanobanana, Gemini

The introduction of spray drying transformed antimicrobial DPI engineering by enabling simultaneous control over particle morphology, density, porosity, and surface composition. Spray-dried particles demonstrated improved dispersibility, reduced cohesion, and enhanced aerodynamic performance, particularly through the generation of porous low-density microparticles. Technologies such as PulmoSphere™ particles exemplified this transition and enabled the successful development of TOBI^® Podhaler™, establishing the feasibility of high-dose antibiotic powder delivery with improved patient usability [107, 108]. Beyond conventional spray drying, advanced particle fabrication approaches including nano spray drying, electrospraying, and supercritical fluid-assisted processing further expanded the capability to engineer particles with tightly controlled aerodynamic and structural properties [33, 99, 104, 106, 108]. For example, iSPERSE™, an advanced particle engineering platform is designed to optimize drug delivery by producing small, dense, and highly dispersible microparticles (www.pulmatrix.com/isperse.html). This technology enables consistent, efficient deposition within the deep lung, facilitating improved localized pulmonary administration.

Among emerging technologies, thin-film freezing (TFF) has become one of the most influential particle engineering platforms for poorly water-soluble antiviral and antifungal agents [79, 95, 109]. TFF enables the production of brittle, highly porous amorphous matrices characterized by exceptional dispersibility and rapid dissolution within the limited volume of epithelial lining fluid. This platform has shown particular promise for inhalable remdesivir, itraconazole, and voriconazole formulations [79, 109]. Similarly, spray freeze drying has enabled the fabrication of highly porous biologic and peptide powders while minimizing thermal degradation, whereas microfluidic particle engineering and PRINT^® technologies have introduced the possibility of producing monodisperse particles with highly tunable aerodynamic, shape specific particles, and biological characteristics [106, 110, 111]. A recent application of this technology is the FDA-approved YUTREPIA™ (Treprostinil). Developed by Liquidia Corporation (https://liquidia.com/technology), this DPI utilizes a unique trefoil-shaped, monodisperse particle design to treat pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease [112].

Nanotechnology-enabled pulmonary systems now represent a major frontier in antimicrobial DPI development. Nanoembedded microparticles, nanoparticle-in-microparticle systems, and macrophage-targeted inhalable carriers have been extensively investigated for tuberculosis, multidrug-resistant bacterial infections, and invasive fungal diseases [113–115]. These systems are specifically designed to overcome biological barriers including mucus entrapment, biofilm penetration, macrophage sequestration, and intracellular pathogen persistence [115, 116]. In parallel, lipid-based inhalable systems, including phospholipid-coated particles and liposomal dry powders, have demonstrated improved pulmonary biocompatibility, intracellular uptake, and sustained lung retention while minimizing local irritation and systemic exposure [117].

Formulation Architecture and Solid-State Design

The formulation architecture of antimicrobial DPIs has progressively evolved from conventional lactose-carrier blends toward sophisticated carrier-free and multifunctional inhalable systems tailored for pulmonary infectious diseases [118]. Traditional carrier-based formulations utilize coarse lactose excipients to improve powder flowability and metering reproducibility; however, the high drug payloads required for antimicrobial therapy frequently limit the practicality of carrier-dependent approaches [118, 119]. Consequently, carrier-free architectures composed of porous low-density microparticles have become increasingly dominant in advanced antimicrobial DPI platforms [118, 119]. A major challenge across antibacterial, antiviral, and antifungal DPI systems involves balancing aerosol performance with long-term solid-state stability. Many antimicrobial agents exhibit unfavorable physicochemical properties including hygroscopicity, crystallization tendencies, poor aqueous solubility, and thermal instability. To address these limitations, co-amorphous systems and amorphous solid dispersions have emerged as important stabilization strategies capable of improving dissolution kinetics while minimizing recrystallization during storage and aerosolization. These approaches have been particularly important for triazole antifungals and inhaled antiviral formulations developed using TFF technologies [95, 109].

Additional formulation advances include phospholipid-based particles designed to mimic endogenous pulmonary surfactant, leucine surface-modified powders that reduce interparticle cohesion, and stimulus-responsive inhalable systems capable of triggered drug release within disease-specific microenvironments [120]. Increasingly, formulation optimization is also being guided by computational modeling and artificial intelligence-assisted approaches capable of predicting aerodynamic behavior, powder dispersibility, and regional lung deposition profiles.

Inhaler Device Platforms

Advances in inhaler hardware have evolved in parallel with formulation technologies and remain critical determinants of clinical translation [121]. Antimicrobial DPIs impose unique engineering challenges because they frequently require delivery of high powder masses, multidose regimens, and administration to patients with compromised inspiratory capacity resulting from severe respiratory disease [121, 122]. Early capsule-based single-dose inhalers provided simple and effective powder dispersion mechanisms but were often limited by variable deagglomeration efficiency and strong inspiratory flow dependence [9, 29].

Modern antimicrobial DPI devices increasingly incorporate optimized airflow resistance, engineered turbulence chambers, and multidose reservoir- or blister-based platforms designed to maximize powder dispersion efficiency while minimizing oropharyngeal deposition [9, 123]. High-resistance breath-actuated inhalers capable of efficient aerosolization at lower inspiratory flow rates have become particularly important for cystic fibrosis, tuberculosis, and critically ill patient populations [29, 124, 125]. Furthermore, active dispersion systems and ventilator-compatible powder delivery platforms are now being explored for mechanically ventilated patients with VAP, where passive inhalation is not feasible [126].

Digital inhalers and smart monitoring technologies represent an emerging direction in pulmonary delivery [127, 128]. Integrated sensors capable of monitoring inspiratory flow patterns, inhalation technique, adherence, and dose administration may become especially valuable for prolonged antimicrobial regimens such as tuberculosis therapy, where poor adherence contributes significantly to treatment failure and antimicrobial resistance [128]. Collectively, these technological advances illustrate the transition of antimicrobial DPIs from conventional aerosol dosage forms toward precision-engineered pulmonary delivery systems capable of addressing increasingly complex infectious disease challenges.

Translational Challenges and Regulatory Considerations

Despite major advances in aerosol engineering and pulmonary drug delivery, the clinical translation of antimicrobial DPIs remains limited by significant formulation, biological, engineering, and regulatory barriers. Many anti-infective agents possess unfavorable physicochemical properties, including poor aqueous solubility, hygroscopicity, thermal instability, and crystallization tendencies, complicating aerosol formulation and long-term storage stability. These challenges are particularly relevant for hydrophobic antifungals, aminoglycosides, and emerging antiviral compounds. Biological barriers within the infected lung further compromise pulmonary delivery efficiency. Mucus hypersecretion, impaired mucociliary clearance, biofilm formation, altered regional ventilation, and intracellular pathogen localization contribute to heterogeneous aerosol deposition and variable therapeutic exposure. Such limitations are especially pronounced in cystic fibrosis, bronchiectasis, tuberculosis, and ventilator-associated pneumonia.

Another critical translational challenge involves the delivery of high antimicrobial payloads while maintaining patient tolerability and inhaler usability. Many anti-infective therapies require tens to hundreds of milligrams of powder per dose, creating substantial engineering constraints related to powder dispersibility, inspiratory resistance, cough induction, and device retention efficiency. While porous particle engineering and carrier-free systems have improved aerosol performance for high-dose delivery, the scalability and manufacturing reproducibility of these advanced platforms remain important industrial considerations. In mechanically ventilated patients, additional complexities arise from humidity-induced particle aggregation and synchronization of aerosol release within ventilator circuits, limiting the current feasibility of DPI therapy for critical care applications.

From a regulatory perspective, antimicrobial DPIs continue to face evolving and relatively underdefined approval pathways. Unlike systemic anti-infectives, pulmonary antimicrobial therapies require demonstration of both aerosol performance and clinically meaningful local PK/PD relationships within the lung. However, standardized in vitro-in vivo correlation (IVIVC) models for inhaled anti-infectives remain limited, and currently available animal infection models often fail to accurately reproduce the complexity of human pulmonary disease. The absence of universally accepted pulmonary PK endpoints, clinically predictive deposition models, and harmonized regulatory frameworks continues to complicate translational development and cross-platform comparisons. Addressing these barriers will be essential for expanding antimicrobial DPI technologies beyond their current niche applications toward broader implementation across chronic, acute, and emerging respiratory infectious diseases.

Future Outlook and Concluding Remarks

The future of antimicrobial DPIs is likely to be shaped by the convergence of precision particle engineering, nanomedicine, pulmonary immunopharmacology, and digitally integrated inhalation technologies. Although the field has already achieved important translational success in chronic bacterial airway infections, next-generation antimicrobial DPIs are increasingly being developed as highly engineered pulmonary therapeutic platforms rather than simple reformulated inhalation products. Advances in nanoparticle-in-microparticle systems, macrophage-targeted carriers, mucus-penetrating particles, and stimulus-responsive formulations are expected to improve pulmonary targeting of intracellular and biofilm-associated pathogens, particularly in tuberculosis, chronic Pseudomonas infections, and invasive fungal diseases.

In parallel, the therapeutic landscape is progressively expanding beyond conventional small-molecule anti-infectives toward biologic and host-directed pulmonary therapies. Inhalable siRNA, mRNA, antiviral peptides, monoclonal antibodies, bacteriophages, and immunomodulatory cytokines are increasingly being investigated as next-generation inhaled therapeutics for respiratory viral and multidrug-resistant infections. The rapid expansion of inhaled antiviral research during the COVID-19 pandemic further highlighted the strategic importance of pulmonary delivery as a rapid-response platform capable of achieving high local drug concentrations while minimizing systemic toxicity.

Emerging computational and digital technologies are also expected to accelerate translational development. Artificial intelligence-assisted formulation optimization, computational fluid dynamics, and patient-specific aerosol modeling may improve prediction of pulmonary deposition and therapeutic exposure, while smart inhalers incorporating adherence monitoring and inhalation analytics could enhance long-term management of chronic infectious diseases such as tuberculosis and bronchiectasis. Simultaneously, greater harmonization of pulmonary PK/PD frameworks, standardized in IVIVC models, and clinically predictive infection models will be essential for streamlining regulatory translation and enabling meaningful cross-platform comparisons.

Author Contributions

H.S.: conceptualization, methodology, formal analysis, investigation, writing-original draft, writing-review and editing, visualization. D.E.B.: conceptualization, methodology, formal analysis, investigation, writing-original draft, writing-review and editing. Y.P.D.: resources, writing-review and editing, funding acquisition. H.M.M.: Conceptualization, methodology, resources, writing-review and editing, supervision, project administration, funding acquisition.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.