Abstract
The management of difficult-to-treat acute and chronic respiratory infections (infections in cystic fibrosis, non-cystic fibrosis bronchiectasis, immunocompromised and mechanically ventilated patients) and difficult-to-treat pathogens (including multidrug-resistant strains) has become a challenge in clinical practice. The arsenal of conventional antibiotic drugs can be limited by tissue penetration, toxicities, or increasing antibiotic resistance. Inhaled antimicrobials are an interesting therapeutic approach for optimizing the management of respiratory infections. Due to extensive developments in liposome technology, a number of inhaled liposome-based antibiotic and antifungal formulations are available for human use and many products are undergoing clinical trials. Liposomes are biocompatible, biodegradable, and nontoxic vesicles able to encapsulate and carry antimicrobials, enhancing the therapeutic index of various agents and retention at the desired target within the lung. Liposomes reduce drug toxicity and improve tolerability, leading to better compliance and to decreased respiratory side effects. The aim of this article was to provide an up-to-date overview of nebulized liposomal antimicrobials for lung infections (with a special focus on liposomal amikacin, tobramycin, ciprofloxacin, and amphotericin B for inhalation), discussing the feasibility and therapeutic potential of these new strategies of preventing and treating bacteria, mycobacterial and fungal infections.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Liposomes are biocompatible, biodegradable, and nontoxic vesicles able to encapsulate and carry drugs, and have been used in a broad range of pharmaceutical applications, including for nebulized antibiotic delivery |
Use of inhaled liposomal antimicrobial treatment in lung Infections results in targeting of the antimicrobial agent at the site of infection to the infectious organism, increasing intracellular antibiotic concentrations, reducing drug toxicity, and improving tolerability |
The most important liposomal antimicrobial drugs for inhalation include amikacin, tobramycin, ciprofloxacin, and amphotericin B |
New avenues of research in the delivery of lung-targeted liposomal antimicrobials alone or in association with other treatment alternatives are being investigated |
1 Introduction
Over recent years, there has been a worldwide increase in the prevalence of multidrug-resistant (MDR) and difficult-to-treat pathogens [1, 2]. This issue has forced clinicians to rediscover old drugs with suboptimal pharmacokinetics and toxicity issues and has resulted in significant research efforts, with few new molecules proposed for use in clinical practice. In addition, alternative novel therapies have been developed including monoclonal antibodies, vaccines, stem cells, bacteriophages, and liposomes [3]. Lung infections include a challenging spectrum of clinical conditions, ranging from acute to chronic infections, and new therapeutic approaches are warranted for optimizing treatment in difficult-to-treat infections, cystic fibrosis (CF), non-cystic fibrosis bronchiectasis (NCFB), and immunocompromised and mechanically ventilated patients.
Liposomes are safe and suitable carriers for a variety of drugs and have been used in a broad range of pharmaceutical applications [4]. The use of antibiotic liposomal delivery systems result in targeting of the antimicrobial agent at the site of infection to the infectious organism, increasing intracellular antibiotic concentrations, reducing drug toxicity, and improving tolerability [5].
The aim of this article was to provide an up-to-date overview of inhaled liposomal antimicrobials for lung infections, discussing the feasibility and therapeutic potential of these new strategies of preventing and treating bacterial, mycobacterial, and fungal infections.
2 Liposomal Antimicrobials for Lung Infections and Inhaled Drug-Delivery Systems
Liposome administration to humans has been principally used for drug delivery, vaccine adjuvants, medical diagnostics, and cosmetics. Liposomes, first discovered in the mid-1960s, are sphere-shaped vesicles (typically in the range of 20 nm–20 μm) consisting of one or more phospholipid bilayers of natural or synthetic origin enclosing an internal aqueous space. Liposomes are biocompatible, biodegradable, and nontoxic vesicles and are able to encapsulate and carry both hydrophilic and lipophilic drugs, allowing a precise release of the drug at the site of infection (Fig. 1) [6]. The liposomal encapsulation efficiency varies depending on the physicochemical characteristic of the drug (hydrophobic antibiotics can be intercalated in the phospholipid bilayer and hydrophilic antibiotics can be loaded in the aqueous core), the therapeutically feasible concentration of the drug into liposomes, the characteristics of the liposome vesicles (lipid composition, surface charge, size distribution, and lamellarity) and the preparation methods [5]. In addition, the size of liposomes plays an important role in the clearance.
Liposomal antibiotic drug delivery
The most common routes of liposomal drug delivery are oral, topical, and parenteral. In addition, inhaled drug delivery for treatment of respiratory diseases is an interesting alternative treatment option and has been used increasingly over the last few decades. Targeting antibiotics to the lungs via aerosolization can offer a way to achieve high exposure of antibiotics directly at the site of infection, including for antibiotics with poor lung penetration and tissue distribution (β-lactams, colistin, aminoglycosides, and glycopeptides). Optimal drug deposition is dynamic and is associated both with particle-related and with patient-related factors. Particle deposition patterns are critically dependent on size (ideally particles between 1 and 5 µm), proper viscosity (inversely proportional to the rate of aerosolization) and shape. Patient-related determinants include the diameter of the large airways (relative to age), the quality of the inhalation technique in spontaneously breathing and mechanically ventilated patients, the presence of structural abnormalities (including mucus of the airways), and the ability of the lung [7]. Theoretically inhaled drugs may allow high drug concentration that exceed the minimal inhibitory concentration (MIC) for MDR pathogens as well as reduce the potential for development of drug resistance [8]. However, depending on the amount of drug inhaled and on the aerosol characteristics, a wide range of sputum concentrations exist throughout the lung with lower concentrations in the small airways and the risk of therapeutic levels below the MIC [9, 10]. Low concentrations below the MIC can lead to the development of high mutation rates and hence resistant subpopulations of bacteria that cannot be eradicated [10].
In addition, there are several factors that influence the clinical efficacy of inhaled antibiotics after delivery, especially for CF patients, although antibiotics may display activity against planktonic bacteria in vitro. Firstly, the antimicrobial aerosol particles need to dissolve in the epithelial lining fluid and in mucus. Secondly, the need for antibiotic diffusion toward the bacteria depends on the site, since in the case of CF with Pseudomonas aeruginosa chronic infections the location is most likely intraluminal within the mucus. Thirdly, microorganisms may have specific mechanisms to overcome antibiotic activity, including resistant mucoidal strains and increased biofilm production, and the environment of sputum-containing factors produced by the host and the microbes can reduce antibiotic activity [7, 11].
The properties of an inhaled antibiotic can be modified by use of liposomes, which enhance the therapeutic index of various agents, mainly through alterations in their pharmacokinetics and pharmacodynamics (PK/PD) enhancing drug delivery and retention at the desired target within the lung. Liposomes reduce drug toxicity and improve tolerability, leading to better compliance and to decreased respiratory side effects [12, 13].
Most inhaled antibiotics and antifungals have a short half-life in the lungs and require two- or three-times-daily administration. An important benefit of an inhaled liposome formulation is to provide a slow release of the antibiotic, which reduces the dosing frequency and continuously maintains high drug concentrations in the lung above the MIC.
Liposomes can also deposit drug within alveolar macrophages via phagocytosis to improve treatment of intracellular infections (although many chronic lung infections reside in the conducting airways of the lung lumen) and can have the ability penetrate biofilms to enhance activity against P. aeruginosa and other biofilm producer bacteria and fungi [14]. Previous studies have demonstrated that liposomes are stable in the presence of sputum and inhibitory factors, with the ability to protect the antibiotic from inactivation, although the sputum may act as a barrier to larger liposomes [11].
Despite the advantages of a liposome vehicle for nebulized drug delivery, there are some additional factors that need to be considered. Liposome nebulization can lead to changes in their physical properties and deposition of liposomes within alveolar macrophages may affect their functions, although there is no evidence of changes in lipid content of pulmonary surfactant or lung immune response [15, 16]. With the current dearth of safety and tolerability data of liposomal inhaled antibiotics and antifungals, caution should be exercised, although the most common adverse events are local mild pulmonary effects [16, 17] (Table 1).
Modern technologies involving pulmonary drug delivery have employed new devices with liposomal formulations that should be aerosolized into particles that have a high fine particle fraction to achieve improved delivery throughout the lung.
There are four types of devices that are used for the pulmonary delivery of liposomes: pressurized metered-dose inhalers, dry powder inhalers, soft mist inhalers, and medical nebulizers [18].
Medical nebulizers are the most commonly used inhalation devices to deliver liposomes. Compared to other inhalation devices, nebulizers are particularly useful for diseases that require high pulmonary doses, with no need to perform drying procedures or to involve propellants, and are useful for patients who are unable to coordinate or achieve flow rates [18]. Nebulizers can be categorized into four general types: air jet, ultrasonic, vibrating mesh, and static mesh nebulizers [8]. The air jet type nebulizer is the most commonly used aerosolized delivery system in the world and is the best-established nebulizer for delivering liposomes. Vibrating mesh nebulizers have become increasingly popular, especially in pharmaceutical-sponsored studies, and have demonstrated excellent suitability in delivering vesicles in fine-particle fractions, including large liposomes and liposome aggregates [18]. Compared with jet nebulizers, vibrating mesh nebulizers are more efficient (less residual antibiotic in the nebulizer reservoir), but are more expensive to manufacture [19]. Vibrating mesh nebulizers have not been consistently shown to be superior to jet nebulizers in terms of pulmonary drug delivery, clinical outcome, and safety [20, 21]. The ultrasonic nebulizer has generally been shown to be the least suitable to deliver liposomes [19].
3 Inhaled Treatment for Acute and Chronic Infections and Possible Role for Liposomal Antimicrobials
Use of inhaled antimicrobials is an interesting therapeutic approach for optimizing respiratory tract infections in difficult-to-treat acute and chronic respiratory infections and for difficult-to-treat pathogens, including MDR bacteria, typical and atypical mycobacteria, and potential inhaled biowarfare agents. The possible role of liposomal inhaled preparations in different clinical settings is discussed below.
CF patients have a deficiency in mucociliary clearance, which makes the airways susceptible to infections that typically become chronic and lifelong [22]. CF registry data confirm that P. aeruginosa typically becomes the predominant organism cultured from the respiratory tract by adulthood and chronic P. aeruginosa infection is linked to progressive pulmonary function decline. The eradication and treatment of this organism from CF airways is particularly challenging. NCFB results from a permanent and progressive destruction of the airways leading to poor lung function, and is characterized by recurrent lung infection. Patients with NCFB and chronic infections with P. aeruginosa have a high risk of hospitalization, reduced quality of life, and increased mortality [23]. Current guidelines recommend inhaled tobramycin for individuals with CF and persistent P. aeruginosa infection who are aged 6 years or older [24]. Trials with long-term inhaled antibiotics in NCFB have indicated some benefits, but not in the way anticipated from trials in CF [25]. The new European Respiratory Society (ERS) guidelines for the management of bronchiectasis recognize the place of inhaled antibiotics, yet there is no international agency approval for NCFB [21, 26]. In these patients, the effectiveness of classical inhaled antibiotics is limited by poor penetration into infection sites, inactivation by sputum, non-penetration of biofilm, emergent resistance, bacterial phenotypic changes, and bacterial retention in mucous plugs. These limitations could be theoretically overcome with liposomal inhaled preparations and are discussed in the next paragraph with a focus on specific antimicrobials.
The global spread of MDR pathogens and limited efficacy of currently available intravenous antibiotics for the treatment of pneumonia in hospitalized and mechanically ventilated patients are also a growing cause for concern [13]. Despite lacking high-quality efficacy and safety data, and lack of international guideline recommendations, clinicians worldwide are increasingly using antibiotic nebulization for respiratory infections in critically ill adult patients. The role of liposomal antibiotics is yet to be defined in this setting [8, 21, 27, 28].
Aspergillus spp. is the most common cause of invasive fungal pulmonary infection in lung transplant recipients (LTR) and hematological patients, and despite the advances in antifungal drugs is associated with persistently high mortality. Inhaled antifungal agents have been investigated as antifungal prophylaxis and as adjunctive agents to systemic antifungals. In addition, inhaled antibiotics have been largely used off-label to prevent and treat bacterial in LTR, mainly in patients with devascularized anastomotic infections, history of MDR infections, and to prevent donor to host transmission [16, 29,30,31].
Use of nebulized antibiotics for tuberculous (TB) or nontuberculous mycobacterial (NTM) infections remains a very active area of research. Inhaled antibiotics for TB and NTM have the potential to reduce dosage (up to ten times less used for the standard oral treatment of care), to limit side effects, and to result in higher drug concentrations, potentially overcoming drug resistance [32]. Liposomal formulations have the ability to be more readily and effectively phagocytosed by alveolar macrophages within the airways and alveoli, with in vitro and in vivo therapeutic advantages for TB and NTM treatment [32, 33].
There are a number of other severe infections including melioidosis (endemic to South East Asia), potential inhaled biowarfare agents including Francisella tularensis, Yersinia pestis, and Coxiella burnetiid, and anthrax, which also do not have approved inhaled antibiotic therapies for prevention or treatment [34]. Limited data on the role of liposomal formulation are available in this setting but may improve treatment of intracellular infections [35].
4 Liposomal Antimicrobial Drugs for Lung Infections
Due to extensive developments in liposome technology, a number of liposome-based antibiotic and antifungal formulations are available for human use and many products are undergoing different clinical trials [12].
In vitro studies with animal models are the first step to evaluate new drugs essentially based on acute infection models and reduction of bacterial loads. However, there are no good animal models available for chronic lung infections. Despite this limitation, in vitro and in vivo studies, pharmacokinetic and pharmacodynamic characteristics, clinical efficacy, and the safety profile of liposomal drugs for lung infections are discussed with regard to liposomal amikacin, tobramycin, ciprofloxacin, and amphotericin B. In addition, limited in vitro and animal model data have been published for the use of nebulized liposomal formulations of gentamicin [36], capreomycin [37, 38], streptomycin [39], polymyxin B [40], isoniazid [41], rifampicin, [42], pyrazinamide, and ethambutol [39].
Table 1 summarizes available treatment options.
4.1 Liposomal Amikacin for Inhalation
Liposomal amikacin for inhalation (LAI) (trade name Arikayce ™) is a unique formulation that encapsulates aqueous amikacin in charge-neutral liposomes composed of dipalmitoyl phosphatidyl choline and cholesterol, which is very similar to surfactant [43, 44]. These lipids have a neutral charge, shielding the positively charged amikacin from the characteristic negatively charged components of CF sputum [45]. In addition, the small diameter (~ 300 nm) and uniform size of the liposomes permits the molecule to penetrate the meshwork of P. aeruginosa biofilm in CF sputum.
The activity of LAI has been studied extensively both in vitro and in vivo. LAI has been shown to have deposition of higher local concentrations and a prolonged lung half-life of several hours relative to liposome-free antibiotics [46]. LAI reduced and eradicated P. aeruginosa in a rat lung model more effectively than inhaled free amikacin and has shown in a macrophage model significant activity against NTM (Mycobacterium avium complex, MAC, and Mycobacterium abscessus) [44], without being associated with macrophage defects in immune function [47, 48].
Initial Phase I and Phase II studies in CF patients with chronic P. aeruginosa infections demonstrated that LAI was a safe drug with no clear dose-dependent pulmonary adverse events. In addition, LAI resulted in significant improvements in lung function after 14–28 days of treatment [14, 15]. Phase III studies of LAI compared to tobramycin inhalation solution in CF patients with P. aeruginosa infection did not demonstrate its superiority over conventional tobramycin inhalation, showing a comparable increase in forced expiratory volume in 1 s (FEV 1) at the end of three cycles [49].
In addition, LAI has other potential applications in the management of difficult-to-treat pulmonary infections including NTM. In the COVERT trial, LAI has proven statistically significant improvement in bacterial clearance when added to guideline-based therapy (GBT) therapies in refractory MAC patients, leading to increased sputum conversion (29% vs. 9%) [33]. Although current evidence for efficacy is limited to microbiological outcomes, LAI has received US Food and Drug Administration (FDA) approval for adult patients with MAC lung disease refractory to conventional therapy and with limited or no alternative treatment options. Furthermore, the CONVERT and extension trials are ongoing, with final results awaited to establish clinical benefit [50].
4.2 Liposomal Tobramycin for Inhalation
Many studies have described the efficacy of inhaled tobramycin (TOB) in lowering P. aeruginosa pulmonary infection in CF patients and the CF guidelines recommend chronic use of inhaled TOB in patients 6 years of age and older with moderate to severe lung disease and chronic Pseudomonas colonization [24]. The high dose required and the prolonged use of tobramycin has raised investigators’ concerns about its toxicity.
In vitro studies show that encapsulation of TOB in liposomes enhances bacterial killing and increases efficacy against both P. aeruginosa and Burkholderia cepacia complex when compared with the corresponding conventional form [51, 52]. Bismuth-ethanedithiol (BiEDT) has been shown to inhibit the exopolysaccharide, lipopolysaccharide, and alginate production by P. aeruginosa and has been incorporated into a liposome-loaded tobramycin formulation (LipoBiEDT-TOB). A study on rats chronically infected with P. aeruginosa showed that the MIC of LipoBiEDT-TOB was 16-fold lower than the MIC of tobramycin alone and fourfold lower than the MIC of free BiEDT-TOB. In addition, LipoBiEDT-TOB has been shown shown to reduce the production of quorum-sensing molecules and virulence factors [53, 54]. There are limited data and no randomized clinical trial ongoing on the in vivo role of liposomal TOB for inhalation. In contrast, research has focused on tobramycin formulated as a dry powder (tobramycin inhalation powder or TIP), which is currently being investigated [55].
4.3 Liposomal Ciprofloxacin for Inhalation
Liposomal ciprofloxacin is prepared using negatively charged liposomes (liposome surfaces coated with polyethylene glycol or PEG) and is delivered by inhalation or intravenous routes. In preclinical studies liposomal ciprofloxacin has shown great promise in the treatment of P. aeruginosa and MAC lung infections, since it was able to infiltrate established biofilms and penetrate infected macrophages [56,57,58]. The in vivo release profile after intratracheal instillation in mice confirmed that the liposomal formulation satisfied the requirement for sustained levels of ciprofloxacin in the lung for a duration of 24 h, having a lung clearance half-life after inhalation of approximately 12 h (compared with 1 h for free ciprofloxacin).
There are two types of liposomal ciprofloxacin formulation commercially available: rapid-release formulations (Lipoquin™ or ARD-3100) and slow release formulations CF (Pulmaquin™ or ARD-3150). Lipoquin™ consists of ciprofloxacin active-loaded in a liposomal formulation, while Pulmaquin™ is a dual-release ciprofloxacin formulation for inhalation containing Lipoquin™ mixed with a solution of free ciprofloxacin for inhalation in order to provide an initially high peak of ciprofloxacin in the lung. In a clinical Phase II trial involving 22 adult CF patients, Lipoquin™ was shown to be safe and well tolerated when administered once daily for 14 days at a 300 mg dose [59]. It was the remarkable tolerability in CF that encouraged the exploration of Lipoquin™ in NCFB patients colonized with P. aeruginosa, since this population of patients historically failed to show a positive clinical response to inhaled antibiotics, in contrast to CF patients [60].
Further Phase II clinical trials (ORBIT-1 for Lipoquin™ and ORBIT-2 for Pulmaquin™) to evaluate the efficacy and safety of liposomal ciprofloxacin in adults with chronic P. aeruginosa lung infection by ciprofloxacin-sensitive strains and CF/NCFB have proven that a once-daily inhaled dose had strong antipseudomonal microbiological efficacy, was well tolerated, and delayed the risk P. aeruginosa exacerbation [59, 61]. Based on the totality of the preclinical and clinical evidence, 6 mL of once-daily Pulmaquin™ was selected for the Phase III program in NCFB, with the ORBIT-3 and ORBIT-4 trials [57]. Pulmaquin™ led to a significantly longer median time to first pulmonary exacerbation compared with placebo in ORBIT-4, but not in ORBIT-3 or the pooled analysis. Inconsistency between the trials and disappointing results suggest the need for further research, but could support the rationale for the use of inhaled ciprofloxacin in this specific setting [62].
4.4 Liposomal Amphotericin B for Inhalation
Amphotericin B has broad activity against various yeasts, molds, and dimorphic fungi, including Aspergillus species.
The first stage in the pathogenesis of Aspergillus spp. disease includes inhalation of spores, colonization of Aspergillus spp. in the airways, and its proliferation. In patients with altered local or systemic defense mechanisms, colonization may cause invasive pulmonary aspergillosis (IPA).
Several types of nebulized amphotericin B preparations are available. The unique particle structure and size of each amphotericin B product is inversely related to the aerosolized particle size. To achieve aerosolization, the large molecules of the various intravenous amphotericin B formulations—deoxycholate (AmBd), liposomal (L-AmB), colloid dispersion (ABCD), and lipid complex (ABLC)—result in small-aerosolized particle sizes ranging from 0.90 to 2.43 μm. The variable sizes of these different aerosolized amphotericin B formulations influence the extent of alveolar distribution and the half-life of the drug in the lungs [63].
Current clinical evidence for the use of liposomal aerosolized delivery in preventing fungal infections is limited to L-AmB, with few data on ABLC [64, 65]. Other publications have reported good tolerance to n‐LAB and an optimal safety profile with no evidence of significant systemic absorption, effects on respiratory function, or changes in lipid content of pulmonary surfactant, permitting long‐term administration [16, 66]. After comparing nebulized L-AmB and nonliposomal amphotericin B deoxycholate, rates of IPA were low and comparable between the two treatment groups, but the liposomal form was better tolerated and had a longer half-life. In addition drug concentrations after nebulized L-AmB remained high and adequate for Aspergillus spp. prophylaxis over 14 days, a convenient administration interval [67].
Current clinical evidence for the use of aerosolized delivery is limited to amphotericin B products for prophylaxis against IPA in patients with LTR, but rigorous randomized controlled trials evaluating their use after transplant have not been conducted [68]. Moreover, prophylactic inhalation of L-AmB has been proven to also significantly reduce the incidence of IPA in hematological patients with chemotherapy-induced prolonged neutropenia (≥ 10 days) [16, 69].
L-AmB may serve also as an alternative method of treatment for patients with pulmonary fungal infections either used alone or in combination with systemic treatment. Nebulized L-AmB has been used as adjunctive treatment in devascularized anastomotic infections in LTR and for fungal infections other than aspergillosis [70]. Furthermore, L-AmB may have a place in the treatment of patients with corticosteroid-dependent allergic bronchopulmonary aspergillosis [71].
5 Conclusions
The potential use of liposomal compounds for the treatment of acute and severe infections has recently emerged. Liposomes are safe and suitable for delivery of variety of antibiotics and antifungals to improve the therapeutic index of encapsulated agents and reduce drug toxicity. The combination of specifically designed drug formulations and modern, high efficiency delivery devices has the potential to overcome current challenges with aerosolized treatment. Their effects on infected macrophages and biofilms have promising applications in CF, NFCF, and pulmonary NTM infections. However, the promise of liposomal aerosol formulations has partially fulfilled the developed expectations. New avenues of research in the delivery of lung-targeted liposomal antimicrobials alone or in association with other treatment alternatives are needed.
References
Weiner LM, Webb AK, Limbago B, Dudeck MA, Patel J, Kallen AJ, Edwards JR, Sievert DM. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the national healthcare safety network at the centers for disease control and prevention, 2011–2014. Infect Control Hosp Epidemiol. 2016;37(11):1288–301.
Bassetti M, Russo A, Carnelutti A, La Rosa A, Righi E. Antimicrobial resistance and treatment: an unmet clinical safety need. Expert Opin Drug Saf. 2018;17(7):669–80.
Rello J, Parisella FR, Perez A. Alternatives to antibiotics in an era of difficult-to-treat resistance: new insights. Expert Rev Clin Pharmacol. 2019;12(7):635–42.
Karlowsky JA, Zhanel GG. Concepts on the use of liposomal antimicrobial agents: applications for aminoglycosides. Clin Infect Dis. 1992;15(4):654–67.
Alipour M, Suntres ZE. Liposomal antibiotic formulations for targeting the lungs in the treatment of Pseudomonas aeruginosa. Therap Deliv. 2014;5(4):409–27.
Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Joo SW, Zarghami N, Hanifehpour Y, Samiei M, Kouhi M, Nejati-Koshki K. Liposome: classification, preparation, and applications. Nanosc Res Lett. 2013;8(1):102.
Bos AC, Passe KM, Mouton JW, Janssens HM, Tiddens HA. The fate of inhaled antibiotics after deposition in cystic fibrosis: how to get drug to the bug? J Cyst Fibrosis. 2017;16(1):13–23.
Sweeney DA, Kalil AC. Why Don't We have more inhaled antibiotics to treat ventilator-associated pneumonia? Clin Microbial Infection. 2019;20:20.
Tiddens HA, Bos AC, Mouton JW, Devadason S, Janssens HM. Inhaled antibiotics: dry or wet? Eur Respire J. 2014;44(5):1308–18.
Bos AC, van Holsbeke C, de Backer JW, van Westreenen M, Janssens HM, Vos WG, Tiddens HA. Patient-specific modeling of regional antibiotic concentration levels in airways of patients with cystic fibrosis: are we dosing high enough? PLoS One. 2015;10(3):e0118454.
Alipour M, Suntres ZE, Halwani M, Azghani AO, Omri A. Activity and interactions of liposomal antibiotics in presence of polyanions and sputum of patients with cystic fibrosis. PLoS One. 2009;4(5):e5724.
Nisini R, Poerio N, Mariotti S, De Santis F, Fraziano M. The multirole of liposomes in therapy and prevention of infectious diseases. Front Immunol. 2018;9:155.
Bassetti M, Luyt CE, Nicolau DP, Pugin J. Characteristics of an ideal nebulized antibiotic for the treatment of pneumonia in the intubated patient. Ann Intensive Care. 2016;6(1):35.
Clancy JP, Dupont L, Konstan MW, Billings J, Fustik S, Goss CH, Lymp J, Minic P, Quittner AL, Rubenstein RC, et al. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax. 2013;68(9):818–25.
Waters V, Ratjen F. Inhaled liposomal amikacin. Expert review of respiratory medicine. 2014;8(4):401–9.
Peghin M, Monforte V, Martin-Gomez MT, Ruiz-Camps I, Berastegui C, Saez B, Riera J, Ussetti P, Sole J, Gavalda J, et al. 10 years of prophylaxis with nebulized liposomal amphotericin B and the changing epidemiology of Aspergillus spp. infection in lung transplantation. Transpl Int. 2016;29(1):51–62.
Peghin M, Monforte V, Martin-Gomez MT, Ruiz-Camps I, Berastegui C, Saez B, Riera J, Sole J, Gavalda J, Roman A. Epidemiology of invasive respiratory disease caused by emerging non-Aspergillus molds in lung transplant recipients. Transplant Infect Dis. 2016;18(1):70–8.
Rudokas M, Najlah M, Alhnan MA, Elhissi A. Liposome delivery systems for inhalation: a critical review highlighting formulation issues and anticancer applications. Med Principles Pract. 2016;25(Suppl 2):60–72.
Najlah M, Parveen I, Alhnan MA, Ahmed W, Faheem A, Phoenix DA, Taylor KM, Elhissi A. The effects of suspension particle size on the performance of air-jet, ultrasonic and vibrating-mesh nebulisers. Int J Pharm. 2014;461(1–2):234–41.
Lehofer B, Bloder F, Jain PP, Marsh LM, Leitinger G, Olschewski H, Leber R, Olschewski A, Prassl R. Impact of atomization technique on the stability and transport efficiency of nebulized liposomes harboring different surface characteristics. Eur J Pharm Biopharm. 2014;88(3):1076–85.
Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O'Grady NP, Bartlett JG, Carratala J, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61–e111.
Ehsan Z, Clancy JP. Management of Pseudomonas aeruginosa infection in cystic fibrosis patients using inhaled antibiotics with a focus on nebulized liposomal amikacin. Future Microbiol. 2015;10(12):1901–12.
Paredes Aller S, Quittner AL, Salathe MA, Schmid A. Assessing effects of inhaled antibiotics in adults with non-cystic fibrosis bronchiectasis—experiences from recent clinical trials. Expert Rev Respir Med. 2018;12(9):769–82.
Smith S, Rowbotham NJ, Regan KH. Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis. Cochrane Database Syst Rev. 2018;3:CD001021.
Laska IF, Crichton ML, Shoemark A, Chalmers JD. The efficacy and safety of inhaled antibiotics for the treatment of bronchiectasis in adults: a systematic review and meta-analysis. Lancet Respir Med. 2019;7(10):855–69.
Polverino E, Goeminne PC, McDonnell MJ, Aliberti S, Marshall SE, Loebinger MR, Murris M, Canton R, Torres A, Dimakou K, et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J. 2017;50:3.
Wenzler E, Fraidenburg DR, Scardina T, Danziger LH. Inhaled antibiotics for gram-negative respiratory infections. Clin Microbiol Rev. 2016;29(3):581–632.
Rello J, Sole-Lleonart C, Rouby JJ, Chastre J, Blot S, Poulakou G, Luyt CE, Riera J, Palmer LB, Pereira JM, et al. Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbial Infect. 2017;23(9):629–39.
Quon BS, Goss CH, Ramsey BW. Inhaled antibiotics for lower airway infections. Ann Am Thorac Soc. 2014;11(3):425–34.
Suhling H, Rademacher J, Greer M, Haverich A, Warnecke G, Gottlieb J, Welte T. Inhaled colistin following lung transplantation in colonised cystic fibrosis patients. Eur Respire J. 2013;42(2):542–4.
Ruiz I, Gavalda J, Monforte V, Len O, Roman A, Bravo C, Ferrer A, Tenorio L, Roman F, Maestre J, et al. Donor-to-host transmission of bacterial and fungal infections in lung transplantation. Am J Transplant. 2006;6(1):178–82.
Traini D, Young PM. Drug delivery for tuberculosis: is inhaled therapy the key to success? Therap Deliv. 2017;8(10):819–21.
Griffith DE, Eagle G, Thomson R, Aksamit TR, Hasegawa N, Morimoto K, Addrizzo-Harris DJ, O'Donnell AE, Marras TK, Flume PA, et al. Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT). A prospective, open-label, randomized study. Am J Respire Crit Care Med. 2018;198(12):1559–69.
Cipolla D, Blanchard J, Gonda I. Development of liposomal ciprofloxacin to treat lung infections. Pharmaceutics. 2016;8:1.
Hamblin KA, Armstrong SJ, Barnes KB, Davies C, Laws T, Blanchard JD, Harding SV, Atkins HS. Inhaled liposomal ciprofloxacin protects against a lethal infection in a murine model of pneumonic plague. Front Microbiol. 2017;8:91.
Burton AJ, Giguere S, Arnold RD. Pharmacokinetics, pulmonary disposition and tolerability of liposomal gentamicin and free gentamicin in foals. Equine Vet J. 2015;47(4):467–72.
Garcia-Contreras L, Muttil P, Fallon JK, Kabadi M, Gerety R, Hickey AJ. Pharmacokinetics of sequential doses of capreomycin powder for inhalation in guinea pigs. Antimicrob Agents Chemother. 2012;56(5):2612–8.
Ricci M, Giovagnoli S, Blasi P, Schoubben A, Perioli L, Rossi C. Development of liposomal capreomycin sulfate formulations: effects of formulation variables on peptide encapsulation. Int J Pharm. 2006;311(1–2):172–81.
Justo OR, Moraes AM. Incorporation of antibiotics in liposomes designed for tuberculosis therapy by inhalation. Drug Deliv. 2003;10(3):201–7.
He J, Abdelraouf K, Ledesma KR, Chow DS, Tam VH. Pharmacokinetics and efficacy of liposomal polymyxin B in a murine pneumonia model. Int J Antimicrob Agents. 2013;42(6):559–64.
Chimote G, Banerjee R. In vitro evaluation of inhalable isoniazid-loaded surfactant liposomes as an adjunct therapy in pulmonary tuberculosis. J Biomed Mater Res B Appl Biomater. 2010;94(1):1–10.
Patil JS, Devi VK, Devi K, Sarasija S. A novel approach for lung delivery of rifampicin-loaded liposomes in dry powder form for the treatment of tuberculosis. Lung India. 2015;32(4):331–8.
Okusanya OO, Bhavnani SM, Hammel J, Minic P, Dupont LJ, Forrest A, Mulder GJ, Mackinson C, Ambrose PG, Gupta R. Pharmacokinetic and pharmacodynamic evaluation of liposomal amikacin for inhalation in cystic fibrosis patients with chronic pseudomonal infection. Antimicrob Agents Chemother. 2009;53(9):3847–54.
Meers P, Neville M, Malinin V, Scotto AW, Sardaryan G, Kurumunda R, Mackinson C, James G, Fisher S, Perkins WR. Biofilm penetration, triggered release and in vivo activity of inhaled liposomal amikacin in chronic Pseudomonas aeruginosa lung infections. J Antimicrob Chemother. 2008;61(4):859–68.
Weers J, Metzheiser B, Taylor G, Warren S, Meers P, Perkins WR. A gamma scintigraphy study to investigate lung deposition and clearance of inhaled amikacin-loaded liposomes in healthy male volunteers. J Aerosol Med Pulmon Drug Deliv. 2009;22(2):131–8.
Li Z, Zhang Y, Wurtz W, Lee JK, Malinin VS, Durwas-Krishnan S, Meers P, Perkins WR. Characterization of nebulized liposomal amikacin (Arikace) as a function of droplet size. J Aerosol Med Pulmon Drug Deliv. 2008;21(3):245–54.
Castellani C, Duff AJA, Bell SC, Heijerman HGM, Munck A, Ratjen F, Sermet-Gaudelus I, Southern KW, Barben J, Flume PA, et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibrosis. 2018;17(2):153–78.
Doring G, Conway SP, Heijerman HG, Hodson ME, Hoiby N, Smyth A, Touw DJ. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J. 2000;16(4):749–67.
Bilton D, Pressler T, Fajac I, Clancy JP, Sands D, Minic P, Cipolli M, Galeva I, Sole A, Quittner AL, et al. Amikacin liposome inhalation suspension for chronic Pseudomonas aeruginosa infection in cystic fibrosis. J Cyst Fibrosis. 2019;20:20.
Liposomal Amikacin for Inhalation (LAI) for Nontuberculous Mycobacteria. US National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT01315236
Halwani M, Mugabe C, Azghani AO, Lafrenie RM, Kumar A, Omri A. Bactericidal efficacy of liposomal aminoglycosides against Burkholderia cenocepacia. J Antimicrob Chemother. 2007;60(4):760–9.
Marier JF, Brazier JL, Lavigne J, Ducharme MP. Liposomal tobramycin against pulmonary infections of Pseudomonas aeruginosa: a pharmacokinetic and efficacy study following single and multiple intratracheal administrations in rats. J Antimicrob Chemother. 2003;52(2):247–52.
Gungor N, Knaapen AM, Munnia A, Peluso M, Haenen GR, Chiu RK, Godschalk RW, van Schooten FJ. Genotoxic effects of neutrophils and hypochlorous acid. Mutagenesis. 2010;25(2):149–54.
Forier K, Messiaen AS, Raemdonck K, Nelis H, De Smedt S, Demeester J, Coenye T, Braeckmans K. Probing the size limit for nanomedicine penetration into Burkholderia multivorans and Pseudomonas aeruginosa biofilms. J Control Release. 2014;195:21–8.
Waters V, Smyth A. Cystic fibrosis microbiology: advances in antimicrobial therapy. J Cyst Fibros. 2015;14(5):551–60.
Banaschewski B, Hofmann T: Inhaled Antibiotics for Mycobacterial Lung Disease. Pharmaceutics 2019, 11(7).
Khatib I, Khanal D, Ruan J, Cipolla D, Dayton F, Blanchard JD, Chan HK. Ciprofloxacin nanocrystals liposomal powders for controlled drug release via inhalation. Int J Pharm. 2019;566:641–51.
Blanchard JD, Elias V, Cipolla D, Gonda I, Bermudez LE. Effective treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus species infections in macrophages, biofilm, and mice by using liposomal ciprofloxacin. Antimicrob Agents Chemother. 2018;62:10.
Serisier DJ, Bilton D, De Soyza A, Thompson PJ, Kolbe J, Greville HW, Cipolla D, Bruinenberg P, Gonda I. investigators O-: Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial. Thorax. 2013;68(9):812–7.
Rubin BK. Aerosolized antibiotics for non-cystic fibrosis bronchiectasis. J Aerosol Med Pulm Drug Deliv. 2008;21(1):71–6.
Chalmers JD, Smith MP, McHugh BJ, Doherty C, Govan JR, Hill AT. Short- and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2012;186(7):657–65.
Haworth CS, Bilton D, Chalmers JD, Davis AM, Froehlich J, Gonda I, Thompson B, Wanner A, O'Donnell AE. Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials. Lancet Respir Med. 2019;7(3):213–26.
Le J, Schiller DS. Aerosolized delivery of antifungal agents. Curr Fungal Infect Rep. 2010;4(2):96–102.
Borro JM, Sole A, de la Torre M, Pastor A, Fernandez R, Saura A, Delgado M, Monte E, Gonzalez D. Efficiency and safety of inhaled amphotericin B lipid complex (Abelcet) in the prophylaxis of invasive fungal infections following lung transplantation. Transpl Proc. 2008;40(9):3090–3.
Gavalda J, Martin MT, Lopez P, Gomis X, Ramirez JL, Rodriguez D, Len O, Puigfel Y, Ruiz I, Pahissa A. Efficacy of nebulized liposomal amphotericin B in treatment of experimental Pulmonary aspergillosis. Antimicrob Agents Chemother. 2005;49(7):3028–30.
Monforte V, Ussetti P, Lopez R, Gavalda J, Bravo C, de Pablo A, Pou L, Pahissa A, Morell F, Roman A. Nebulized liposomal amphotericin B prophylaxis for Aspergillus infection in lung transplantation: pharmacokinetics and safety. J Heart Lung Transplant. 2009;28(2):170–5.
Monforte V, Ussetti P, Gavalda J, Bravo C, Laporta R, Len O, Garcia-Gallo CL, Tenorio L, Sole J, Roman A. Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation. J Heart Lung Transplant. 2010;29(5):523–30.
Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, et al. Practice guidelines for the diagnosis and management of Aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dise. 2016;63(4):e1–e60.
Rijnders BJ, Cornelissen JJ, Slobbe L, Becker MJ, Doorduijn JK, Hop WC, Ruijgrok EJ, Lowenberg B, Vulto A, Lugtenburg PJ, et al. Aerosolized liposomal amphotericin B for the prevention of invasive Pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis. 2008;46(9):1401–8.
Godet C, Cateau E, Rammaert B, Grosset M, Le Moal G, Beraud G, Martellosio JP, Iriart X, Cadranel J, Roblot F. Nebulized liposomal amphotericin B for treatment of pulmonary infection caused by Hormographiella aspergillata: case report and literature review. Mycopathologia. 2017;182(7–8):709–13.
Kuiper L, Ruijgrok EJ. A review on the clinical use of inhaled amphotericin B. J Aerosol Med Pulm Drug Deliv. 2009;22(3):213–27.
Acknowledgement
Open access funding provided by Università degli Studi di Genova within the CRUI-CARE Agreement.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of Interest
Matteo Bassetti reports grants and personal fees from Pfizer, MSD, and Cidara and personal fees from Astellas and Gilead outside the submitted work.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
About this article
Cite this article
Bassetti, M., Vena, A., Russo, A. et al. Inhaled Liposomal Antimicrobial Delivery in Lung Infections. Drugs 80, 1309–1318 (2020). https://doi.org/10.1007/s40265-020-01359-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40265-020-01359-z