Abstract
Nontuberculous mycobacterial (NTM) pulmonary disease is a chronic respiratory infection associated with declining lung function, radiological deterioration and significantly increased morbidity and mortality. Patients often have underlying lung conditions, particularly bronchiectasis and COPD. NTM pulmonary disease is difficult to treat because mycobacteria can evade host defences and antimicrobial therapy through extracellular persistence in biofilms and sequestration into macrophages. Management of NTM pulmonary disease remains challenging and outcomes are often poor, partly due to limited penetration of antibiotics into intracellular spaces and biofilms. Efficient drug delivery to the site of infection is therefore a key objective of treatment, but there is high variability in lung penetration by antibiotics. Inhalation is the most direct route of delivery and has demonstrated increased efficacy of antibiotics like amikacin compared with systemic administration. Liposomes are small, artificial, enclosed spherical vesicles, in which drug molecules can be encapsulated to provide controlled release, with potentially improved pharmacokinetics and reduced toxicity. They are especially useful for drugs where penetration of cell membranes is essential. Inhaled delivery of liposomal drug solutions can therefore facilitate direct access to macrophages in the lung where the infecting NTM may reside. A range of liposomal drugs are currently being evaluated in respiratory diseases.
Abstract
Liposome-encapsulated antibiotics can optimise respiratory disease treatment. Amikacin liposomal inhalation suspension is effective in nontuberculous mycobacterial pulmonary disease that has failed to convert following oral guideline-based therapy. https://bit.ly/3f3ixIu
Introduction
Nontuberculous mycobacterial (NTM) pulmonary disease is a serious, chronic, infectious disease that often presents in patients with underlying chronic pulmonary diseases such as bronchiectasis, cystic fibrosis (CF) or COPD [1]. NTM pulmonary disease is associated with a decline in lung function [2], radiological deterioration, reduced quality of life and significant increases in morbidity and mortality [3–7].
NTM consist of more than 200 species and sub-species, separated into two groups according to growth rate [8, 9]. The most common slow-growing NTM linked with human pulmonary disease are the Mycobacterium avium complex (MAC) species, which include M. avium, Mycobacterium intracellulare and Mycobacterium chimaera [10]. The most common fast-growing species causing NTM pulmonary disease is the Mycobacterium abscessus complex (MABC), which includes M. abscessus subsp. abscessus, M. abscessus subsp. massiliense and M. abscessus subsp. bolletii [1].
NTM are environmental microorganisms and geographical distribution of species differs within and across countries, climates, latitudes [11, 12] and water sources [13, 14]. Furthermore, mycobacterial species vary in their clinical relevance and capacity to cause NTM pulmonary disease [15–18] and in their resistance phenotypes and associated clinical treatment outcomes [19].
Pathophysiology of NTM pulmonary disease
The pathophysiology and factors involved in the occurrence of NTM pulmonary disease are largely unknown. Airway infection probably occurs by inhalation or aerosolisation of particles or droplets containing NTM, but the mechanisms through which NTM establish persistent infection in the lung, bronchus and alveoli remain hypothetical (figure 1). NTM pulmonary disease is a difficult-to-treat infection because of its ability to evade host defences and antimicrobial therapy through extracellular persistence in biofilms [21–23] and sequestration into macrophages inside membrane vesicles where NTM can replicate unhindered [24–26]. Once NTM enter the lung, whether disease follows is related to the propensity for NTM within macrophages to resist the bactericidal response of alveolar macrophages and the inflammatory response of the host, which is sometimes readily present as in the context of CF or bronchiectasis [20, 25, 27, 28]. Recent studies have highlighted that suboptimal inflammatory responses to NTM exposure may predispose to NTM pulmonary disease [29, 30]. Failure of NTM killing by macrophages sets up a cycle of NTM uptake and release, leading to a cycle of chronic infection. Survival of M. avium within eukaryotic cells such as macrophages has been extensively studied and there is also increasing research into the potential role of environmental amoebae as a source of disease [26, 31–34]. Amoebae are prevalent in the environment; interaction of M. avium with amoebae facilitates an increase in virulence [35] and may also select for NTM species best suited to survival within macrophages. M. avium grown in amoebae has also demonstrated enhanced infectivity in a mouse infection model [29, 31, 35, 36]. Recently, M. abscessus has also been shown to persist within macrophages [37] and amoebae, and its interaction with amoebae, as for M. avium, increases its virulence [38].
M. avium and M. abscessus also demonstrate morphological heterogeneity that contributes to the intrinsic virulence of each species. For M. avium, three distinct morphotypes exist (smooth transparent, smooth opaque and rough), thought in part to be dependent on the presence or absence of surface glycopeptidolipids and degree of glycosylation [20, 31, 39]. Only the smooth transparent and rough forms of M. avium multiply in macrophages and have demonstrated virulence in mice or can be cultured from clinical samples [40]. It is worth noting, however, that all three morphotypes may be present inside the host simultaneously. Additional morphotypic switches exist within smooth transparent forms of MAC, which also appear to play a part in driving increased virulence [41]. For M. abscessus, two morphotypes exist (smooth and rough), with the potential for transition between smooth and rough [42] during lung disease [43, 44] and in animal models. In the case of M. avium and M. abscessus, the R form (rough form) appears more virulent in experimental models [31]. Once sequestered within macrophages, both M. avium and M. abscessus can block phagosome maturation and phagolysosomal fusion [37, 45, 46]. For M. avium, this is through inhibition of vacuolar ATPase to prevent acidification and lysosomal enzyme release [45, 47], and for M. abscessus this is via activation of the type VII secretion system encoded by the esx4 locus [48].
NTM species, including M. avium, can also mediate the development of biofilms in airways, providing a persistent extracellular environment that can evade host defences, activate macrophages to facilitate phagocytosis [23, 49], reduce susceptibility to antibiotics and increase virulence [50–53]. It has also been postulated that the ability of M. avium to form biofilms may be correlated with their ability to invade bronchial epithelial cells and it is conceivable that colony morphotype may also play a role in this correlation [54].
Together, macrophages and biofilms play an important role in propagating NTM, evading host defences and preventing elimination by antimicrobial compounds, and their involvement explains the chronic nature of, and the difficulty in treating, infections caused by NTM [55, 56]. As NTM pulmonary disease involves airways, intracellular and even bronchiole-epithelial infection in some cases, it presents a highly challenging disease for treatment [21, 57, 58].
In addition to macrophage sequestration and biofilm development, mycobacteria are characterised by thick, lipid-rich, hydrophobic cell walls, incorporating polysaccharides, proteins and lipids, including glycopeptidolipids, which render them impermeable to hydrophilic nutrients and resistant to antibiotics [54, 59]. Consequently, NTM are intrinsically resistant to a wide spectrum of antibiotic agents, including most drugs used to treat tuberculosis [60–62]. In addition, NTM utilise further mechanisms to inhibit antibiotic efficacy, including the production of drug-converting and target-protecting enzymes, extrusion of antibiotics via efflux pumps and acquired resistance through gene mutations [60, 62–66].
Treatment challenges of NTM pulmonary disease
Given the difficulties of biofilm penetration, macrophage sequestration and mycobacterial characteristics, management of NTM pulmonary disease with antibiotics remains challenging [1, 24, 67]. Treatment of NTM pulmonary disease usually consists of a combination of several oral and parenteral antibiotics administered for an extended period of 18–24 months or for at least 12 months after culture conversion is achieved, with the aim of achieving and sustaining culture conversion [19, 68]. Treatment success for NTM pulmonary disease is variable, with a recent study in MAC [16] demonstrating treatment failure in 35.3% of patients due to treatment termination, recurrence, re-infection, treatment failure and relapse. Treatment success for MAC disease was estimated in a meta-analysis as 52.3% (95% CI 44.7–59.9%) [6]. Other studies show that treatment success for MAC pulmonary disease is lower in patients with fibrocavitary disease than in those with nodular-bronchiectatic MAC pulmonary disease [18]; treatment success in this latter group exceeds 80% [18, 69], with macrolide-containing regimens in macrolide-sensitive organisms more likely to succeed [70, 71]. The 5-year all-cause mortality rate also varies between 5% and 42% across MAC studies, with death more likely in those with fibrocavitary disease compared with nodular-bronchiectatic disease [6]. Treatment is even more challenging in those infected with MABC, with success rates of between 45.1% and 51% [72, 73].
The poor treatment outcomes in NTM pulmonary disease are probably attributable to the intrinsic resistance of the infecting organisms and the limited penetration of antibiotics into intracellular spaces and biofilms [1, 67]. Ensuring efficient lung penetration to the site of infection, including intracellularly and into biofilms, is therefore a key objective of treatment. Efficient lung penetration by antibiotics is determined by the characteristics of the antibiotics themselves as well as the delivery mechanisms. Lung penetration at the site of infection by systemically administered antibiotics is typically evaluated in humans through the analysis of the epithelial lining fluid (ELF), and antibiotic penetration is measured as a ratio of concentration of drug in serum versus concentration in ELF. Among antibiotics there is a high variability in penetration [74–76]. As demonstrated in pneumonia studies, macrolides and tigecycline have relatively good penetration into ELF; oxazolidinones, fluoroquinolones and ethambutol have moderate penetration; and beta-lactam antibiotics, rifampicin and vancomycin demonstrate lower concentrations within ELF (table 1) [75, 76].
As well as good penetration into ELF, macrolide antibiotics have also demonstrated effective penetration with retained concentration in macrophages, and as such form the backbone of current NTM pulmonary disease recommendations [68]. In other in vitro and ex vivo studies, tetracyclines such as minocycline have demonstrated effective penetration of lung tissue and macrophages, and subsequent reductions in MAC bacterial load [77]. Drugs such as aminoglycosides, however, are considered to have low penetration into the lung. Indeed, a recent study in pneumonia demonstrated that standard clinical doses of amikacin provide insufficient antibacterial levels in ELF [78].
Overview of liposomes
Lung antibiotic concentrations are the result of a complex interplay between drug delivery, drug absorption, and mucociliary and macrophage clearance. For organisms evading host detection and elimination in biofilms and macrophages, the use of liposomes may be of particular benefit. Liposomes are small, artificial, enclosed spherical vesicles separating one aqueous medium from another by a phospholipid bilayer [79, 80], which can effectively encapsulate hydrophilic molecules in the internal aqueous core or sequester hydrophobic drugs in the lipid bilayer and provide a controlled release system [81]. Liposomes are widely used as drug delivery nanocarriers, with the ability to transport agents to target sites while minimising systemic exposure [79, 82–85]. They are classified by type (conventional, theranostic, PEGylated and ligand-targeted [83]), size, lamellarity and surface charge [79, 82–85] (figure 2).
Being constructed from mammalian cell membrane-like constituents, liposome formulations are biocompatible and biodegradable [79] and can penetrate biofilms [86] and intracellular spaces including macrophages [67, 87]. Liposomes are attractive for drug delivery for a range of reasons, including their pharmacological inactivity, ability to self-assemble, large aqueous centre to carry large drug “payloads”, controlled drug release and potential for improved pharmacokinetics and reduced toxicity [88]; they are especially useful for drugs where penetration of cell membranes is essential [67, 87].
Liposomal technology: rationale for use in infection
A range of liposomal drugs are currently used in clinical practice, such as amphotericin B and doxorubicin, or are being explored in studies in a number of diseases, including cytotoxic drugs in lung cancer, vasodilators for pulmonary arterial hypertension, antibacterial drugs for chronic lung infections, and corticosteroids and budesonide for asthma, acute lung injury and acute respiratory distress syndrome [82, 89–93]. A Cochrane analysis has also determined that systemic administration of liposomal amphotericin B has efficacy across a wide range of patients with fungal infections, with reduced nephrotoxicity compared with non-liposomal formulations [94].
Systemic administration of liposomes results in reticuloendothelial system accumulation, predominantly in the liver, spleen, lungs, kidney, bone marrow and lymph nodes [83, 95]. Accumulation of liposomes in the reticuloendothelial system triggers clearance by macrophage phagocytosis through direct liposome‒macrophage interaction. The accumulation of liposomes in the reticuloendothelial system, coupled with high levels of this system in the lungs, suggests that direct delivery of liposome-encapsulated antibiotics to the lung might be advantageous for respiratory disease, particularly to combat organisms residing in the intracellular space.
Intravenously administered liposome-encapsulated amikacin has been shown in preclinical models to effectively penetrate the lung [96] and macrophages after a single dose [97, 98]. However, in clinical management, effective treatment of lung infections faces the challenge of achieving delivery of sufficient antibiotic concentrations to the site of infection. Targeting the lung directly with inhaled formulations of antibiotics achieves high pulmonary concentrations with potentially limited systemic exposure and so potentially less likelihood of systemic toxicity [99]. Liposomal encapsulation of inhaled antibiotics provides the additional benefit of potential for macrophage and biofilm penetration [67]. Studies in the early 2000s explored liposomal encapsulation of antibiotics, including amikacin, for systemic delivery and demonstrated rapid intracellular accumulation with a prolonged half-life and accumulation in the reticuloendothelial system [83, 95, 100]. However, the ability of systemically delivered liposomes to reach the point of NTM infection remains low despite this, and accumulation in the kidney following systemic delivery of liposomal amikacin suggests the potential for nephrotoxicity. Furthermore, it is likely that liposome-encapsulated antibiotics such as amikacin, if delivered systemically, would need to be given at sufficiently high doses in order to reach the lungs. Liposomal encapsulated formulations of amikacin and ciprofloxacin have demonstrated a greater ability to penetrate biofilms of Pseudomonas aeruginosa and MAC than non-liposomal drugs [67, 86, 101]. In an in vitro study, liposome-encapsulated amikacin has demonstrated effective penetration of both macrophages and biofilms infected with M. avium [67], and nebulisation in mice demonstrated that effective lung deposition was greater than for nebulised free amikacin, with liposomal amikacin being retained in the lungs for longer after dosing than free amikacin [67]. Inhalation of antibiotics, including liposomal amikacin, provides high lung concentrations of antibiotics that exceed the required minimum inhibitory concentration (MIC) and with demonstrated low systemic exposure [67, 102]. In a preclinical animal study in mice, administration of nebulised liposomal amikacin was associated with a 10-fold higher deposition in the lung than intravenous amikacin, and the mean peak plasma concentration was lower than with systemic delivery [67].
Inhalation is the most effective and direct route of delivery to the lung [79]. Advantages of inhaled antibiotic administration include the potential to deliver high drug concentrations to the site of infection that exceed the MIC, the bypassing of systemic circulation and reduction of systemic exposure compared with parenteral or oral antibiotics, as well as prolonged drug residence time in the lung [92, 103–107]. Inhaled delivery of medications, including antibiotics such as non-liposomal nebulised amikacin, has been shown to be more effective than systemic delivery in ventilator-associated pneumonia where it has been explored for use against highly resistant pathogens such as Acinetobacter baumannii and P. aeruginosa, but pivotal phase 3 studies have not been successful [99, 106–108]. Several other inhaled formulations have also been used, including tobramycin in CF [109] and bronchiectasis [110].
Inhaled liposomal drug delivery in research and clinical practice
Treating lung diseases with liposomes requires effective and deep lung penetration and, for NTM pulmonary disease, the targeting of biofilms and uptake into macrophages. Inhaled liposomal drugs can be effectively delivered to the lung and intracellular space through a range of inhalation devices, including pressurised metered dose inhalers, dry powder inhalers, soft mist inhalers and nebulisers [80]. Effective lung deposition of inhaled liposomes requires droplets to be <5 μm in diameter [92, 111]. Nebulisers are the most used device to deliver liposomes in aerosolised droplets at the correct size [80, 92]. Increasing target localisation provides options to maximise efficacy at lower drug doses, prevent the systemic degradation of antibiotics and protect them from pulmonary clearance [79, 83, 112–114].
Examples of inhaled liposomal antibiotics evaluated in respiratory diseases include ARD-3150 and amikacin liposomal inhalation suspension (ALIS; in Europe this is known as amikacin liposomal inhalation dispersion). ARD-3150 is an inhaled combination of liposomal ciprofloxacin and free ciprofloxacin, which has been explored in a range of studies in non-CF bronchiectasis [115–117]. Most recently, ARD-3150 demonstrated mixed results in two replicate phase 3 studies, meeting the primary outcome of prolonged time to first exacerbation in ORBIT-4 but demonstrating no statistically significant benefit in ORBIT-3. Anti-pseudomonal activity of the liposomal formulation was demonstrated in both studies, suggesting that the inconsistent results may be related to patient population and design factors rather than formulation.
ARD-3150 has not been evaluated in clinical studies in NTM disease, but potential has been demonstrated in animal models [118]. Most NTM species, particularly MAC, are susceptible to aminoglycoside antibiotics (i.e. amikacin and streptomycin [60]) and these are recommended as part of current guideline-based therapy (GBT) [17, 68]. However, amikacin accumulates poorly in cells such as macrophages, which can limit its use against intracellular infections such as NTM [98]; furthermore, improving access to the lung by dose and duration changes results in an increase in systemic exposure, with the associated adverse events of ototoxicity and nephrotoxicity [119, 120]. Systemic exposure to aminoglycosides, cumulative and daily area under the curve (AUC), and frequent dosing (at least twice daily) are associated with an increased risk of nephrotoxicity, while cumulative amikacin exposure and duration of treatment have been associated with ototoxicity risk [121–123].
ALIS is a nebulised liposomal formulation of amikacin, which was developed in recognition of the benefit that inhaled amikacin would have on reducing systemic exposure, and because encapsulation into liposomes has the potential to access the intracellular space where MAC resides. The liposomes in ALIS are mostly unilamellar [124] and neutrally charged and have a diameter of 250–300 nm; they are stable and can withstand the high sheer forces through the vibrating mesh Pari e-flow nebuliser (Pari GmbH, Germany) [86, 124, 125]. Their composition closely resembles that of lung surfactant, with a 2:1 ratio of dipalmitoylphosphatidylcholine (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and cholesterol [86, 124]. Uptake of liposomal amikacin into the intracellular space of macrophages has been evaluated using fluorescently tagged amikacin [67]. In these macrophages, mean fluorescence intensity was four-fold greater with liposome-encapsulated amikacin compared with non-encapsulated, free amikacin, an effect that was maintained at all concentrations of amikacin exposure (32, 64 or 128 μg·mL−1).
ALIS increases lung exposure to amikacin compared with intravenous administration of non-liposomal amikacin by 42-fold in lung tissues, 69-fold in airways and 274-fold in macrophages [67] and has been shown to penetrate MAC biofilms in vitro [67, 86]. Lung deposition has been demonstrated in an experimental human study with ALIS [126], with 43% of the dose loaded into the nebuliser reaching the lungs; of this, 79% was retained at 1 h and more than half retained at 24 h [126, 127]. Furthermore, lung distribution in patients with NTM pulmonary disease and healthy volunteers has been shown to be comparable, although penetration into cavities was not apparent in patients with treatment-refractory NTM pulmonary disease [126, 128].
ALIS is authorised for use in the USA as “Arikayce” and in Europe as “Arikayce liposomal”. Efficacy demonstrated in phase 2 [129] and phase 3 studies in patients with refractory MAC pulmonary disease [130, 131] formed the basis for new drug applications in both locations. In the phase 2 study, patients received ALIS (590 mg once daily; n=44) or placebo (n=45) for 84 days in a double-blind phase with an option for a further 84 days of open-label treatment. The primary end-point was change from baseline in mycobacterial growth, with secondary end-points of sputum culture conversion at day 84 and changes from baseline in 6-min walk test and health-related quality of life. In this study, the primary end-point was not reached (p=0.072), although 32% of patients demonstrated at least one negative sputum culture compared with 9% of placebo-treated patients. Patients with sputum culture conversion were most commonly infected with MAC (19 out of 23; 82.6%). Sputum culture conversion was sustained for 1 year after treatment cessation in 64% of patients infected with MAC [129].
In the phase 3 CONVERT study, patients with refractory MAC pulmonary disease received nebulised ALIS (590 mg once daily) plus GBT (n=224) or GBT alone (n=112) [130]. In this study, ALIS-treated patients were more likely to achieve sputum culture conversion within 6 months than those receiving GBT alone (n=112; 29% versus 8.9%, respectively; odds ratio 4.22, 95% CI 2.08–8.57; p<0.001). Patients who converted were treated with ALIS for a further 12 months. Of patients who converted by month 6, 63.1% (41 out of 65) remained converted when receiving ALIS for a further 12 months during the follow-up period, compared with 30% (three out of 10) of patients treated with GBT alone [131]. When all treatment was removed at the end of the follow-up period, patients were evaluated at 3 months to explore the durability of clinical response. At 3 months post treatment, 41 of the 65 patients who converted at 6 months remained converted in the absence of all antibiotic treatment (63.1% of the original converted cohort), compared with 0% in patients who received GBT alone [131].
ALIS plus GBT and GBT alone were generally well tolerated, with a comparable number of treatment-emergent adverse events reported (98.2% versus 91.1%). Most treatment-related adverse events were respiratory related, as could be expected, and most were mild to moderate in severity with few (17.4%) leading to discontinuation of ALIS. The most common adverse events in >10% of the patient population (regardless of treatment arm) were dysphonia, cough, dyspnoea and haemoptysis [130]. No new safety signals were apparent with long-term treatment [131], which was comparable with the original study [130]. In patients treated with ALIS in both phase 2 and phase 3 studies, there was low systemic exposure to amikacin, with plasma concentrations below desired trough levels [127, 129]. The incidence of typical amikacin adverse events of ototoxicity was higher in patients treated with ALIS plus oral GBT than in those treated with GBT alone, which might be expected as the GBT alone regimens were not permitted to contain amikacin. It is known that amikacin ototoxicity is associated with cumulative exposure and duration of treatment with AUC values that exceed 50 mg·L−1·h [122, 123, 130]. Population pharmacokinetic analysis of ALIS in the phase 3 CONVERT and phase 2 study demonstrated a relatively low exposure to amikacin, with once-daily dosing of ALIS of <2 mg·L−1 and a median AUC from 0–24 h of <20 mg·L−1·h [132]. The median AUC from day 1 to day 168 (6 months) is within <10%, suggesting that systemic exposure remains stable and similar regardless of treatment duration and is notably lower than that seen with parenteral amikacin [132]. Given the inhaled nature of ALIS, the risks of systemic exposure are perhaps not surprising, and confirm early data where deposition of ALIS was confined primarily to the lung with limited transfer into the bloodstream outside of the lung [67]. The most common ototoxicity-related adverse event reported with ALIS in CONVERT was tinnitus [130]. One-half of all reported audiological adverse events resolved with continued treatment with ALIS plus oral GBT by month 6 [130].
Challenges
Challenges to the development of effective treatments for NTM pulmonary disease still exist and include a need for new antimicrobials or targeted delivery of currently available antibiotics, as well as development of preclinical models that improve drug candidate evaluation.
Many drugs that have performed well in preclinical studies have underperformed or failed in clinical trials. This suggests the need for a complementary series of models that can replicate aspects of respiratory disease and be effectively validated for use. In NTM pulmonary disease specifically, there is a need to develop models that can accurately replicate aspects of disease such as cavitation or granuloma formation. There is also growing interest in animal-free models, such as the hollow-fibre model used by Ruth et al. [77] to evaluate the pharmacodynamics of minocycline in NTM-infected macrophages.
Drug delivery is clearly one aspect open to scrutiny in treatments for NTM pulmonary disease. Inhaled formulations of antibiotics may have demonstrated disappointing results in ventilator-associated pneumonia, with several recent reviews noting the difficulties in clinical trial design, patient selection and optimising administration in ventilated patients, which may have contributed to the limited benefit shown in these studies [133, 134]. In NTM pulmonary disease, however, inhaled formulations are being explored with some published success. For example, inhalation of clofazimine suspension in an in vitro model of NTM demonstrated MIC values for MAC and M. abscessus of 0.125 μg·mL−1 and 2 μg·mL−1, respectively, with good tolerability over repeated dosing and escalating doses shown in mice [135]. Similarly, a small case series of paediatric patients with CF and M. abscessus demonstrated potential clinical utility of inhaled imipenem/cilastatin [136]. In a recent study in a mouse model of M. abscessus, inhaled tigecycline was highly efficacious and demonstrated intracellular activity within macrophages, an important finding given the limitations posed by intravenous tigecycline toxicity [137]. These studies, along with established data of lung penetration of inhaled non-liposomal amikacin, support the rationale that inhaled drug delivery can provide targeted delivery with the potential to limit systemic exposure.
Although inhalation of nebulised antibiotics provides effective access to the lung, solution formulations may not provide adequate uptake into the intracellular space (i.e. macrophages). In these cases, liposomal technology may be advantageous [83]. Targeted lung delivery of new or existing antibiotics through inhalation of liposomal formulations could help to improve pharmacodynamic properties to treat lung diseases [80]. Pharmacokinetic analysis of drugs involved in the treatment of MAC has an important role in informing drug selection and duration of therapy. Targeted delivery with liposomes might be attractive for drugs that require prolonged time above the MIC in order to be effective, such as beta-lactams and oxazolidinones, or where time-kill analyses against MAC or M. abscessus highlight a rationale for poor treatment outcomes [121, 138, 139]. Furthermore, the use of liposomes with ampicillin to limit antibiotic resistance in Staphylococcus aureus has recently been explored and suggests that antibiotic activity can be successfully increased through liposomal encapsulation and coating with a cationic polymer [140].
The horizon for NTM pulmonary disease is looking promising, updated guidelines have been launched in 2020 [68] and new antimicrobial approaches are being explored. In tandem with these advances are approaches to monitor the course of disease and involve patients in their treatment through the use of patient-reported outcomes (PROs) [141]. To these ends, methods such as blood-based monitoring, serodiagnosis for early signs of disease, or assessments of humoral and cell-mediated NTM-driven immune responses, may become routine [142, 143], as might PROs to understand the impact of treatment from the patient's perspective with the recently published NTM Module, which attempts to provide a validated PRO for treatment response [144].
Conclusions
NTM pulmonary disease and MAC pulmonary disease present a significant clinical challenge due to the ability of mycobacteria to evade host mechanisms and antibiotic therapy through biofilm formation and sequestration into macrophages. While systemic administration of macrolides demonstrates effective uptake into the lung and penetration into extracellular space, some other antibiotics used for NTM pulmonary disease treatment demonstrate low rates of lung penetration and poor uptake into macrophages. As a result, treatment outcomes for NTM pulmonary disease remain suboptimal and there is an urgent need for new medications, new approaches to delivery, and new treatment regimens to tackle NTM pulmonary disease.
Inhaled delivery of antibiotics can increase drug concentrations in the lung but does not guarantee efficient penetration of biofilms or macrophages. Liposomal technology provides an opportunity to deliver drugs more effectively to the point of infection, with the additional benefit of improvement in pharmacokinetics and tolerability. Uptake of liposomes in the reticuloendothelial system provides an opportunity for effective uptake into macrophages and, when nebulised, a further chance to secure direct access to macrophages in the lung, where the infecting NTM may reside. Given the ability of NTM to sequester within biofilms and intracellular spaces including macrophages, it is imperative that antibiotics demonstrate effective targeting of bacterial species regardless of their location. Inhalation of ALIS demonstrated uptake into macrophages and biofilms in preclinical models, and these data are supported by clinical findings showing robust, sustained culture conversion in patients with refractory MAC pulmonary disease. Specific and effective targeting of the intracellular space in NTM pulmonary disease with ALIS suggests the potential to break the vicious cycle of chronic NTM infection, whereby evasion of host defences in the macrophage can continue to propagate disease.
Acknowledgements
Medical writing assistance and editorial support was provided by Highfield (Oxford, UK). This assistance was sponsored by Insmed.
Footnotes
Provenance: Submitted article, peer reviewed.
Author contributions: All authors conceived, drafted and reviewed the manuscript, and approved the final draft.
Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca,
Conflict of interest: Boehringer Ingelheim, GlaxoSmithKline and Insmed; grants from Gilead Sciences and Grifols; and personal fees from Chiesi, Novartis and Zambon, outside the submitted work.
Conflict of interest: J. van Ingen reports advisory board membership from Insmed, outside the submitted work.
Conflict of interest: R. van der Laan is an employee of Insmed.
Conflict of interest: J-L. Herrmann has nothing to disclose.
- Received January 11, 2021.
- Accepted May 1, 2021.
- Copyright ©The authors 2021
This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org