1Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

Abstract: Mycobacterium avium complex (MAC) is the most prevalent pathogen among slow-growing Nontuberculous mycobacteria (NTM), and the global incidence of MAC pulmonary disease (MAC-PD) continues to rise steadily. Its intrinsic resistance to conventional anti-mycobacterial agents poses a major therapeutic obstacle. Currently, macrolide-based multidrug regimens remain the standard of care; however, treatment options for macrolide-resistant MAC-PD are critically limited, leading to poor outcomes. Refractory MAC-PD is conventionally defined as persistent sputum culture positivity after at least six months of guideline-based macrolide-containing therapy. As a novel targeted preparation, amikacin liposome inhalation suspension (ALIS) utilizes liposomal encapsulation technology to deliver high and sustained intracellular drug concentrations within alveolar macrophages, while significantly reducing systemic toxic and side effects. It is currently the first and only approved inhaled formulation specifically indicated for refractory MAC-PD, and the addition of ALIS to guideline-based therapy significantly improved sputum culture conversion (Phase III CONVERT trial: 29.0% versus 8.9%,). This review systematically dissects the pharmacological rationale, summarizes pivotal clinical trials, including Phase 2/3 clinical trial data and post-marketing real-world evidence, and further discusses the existing limitations and unresolved clinical challenges. Based on the latest research advances, this review aims to provide a comprehensive and practical reference for clinical decision-making in refractory MAC-PD management.

Keywords: Mycobacterium avium complex, amikacin liposome inhalation suspension, refractory pulmonary disease, therapeutic advances

Introduction

The discovery of Mycobacterium avium complex (MAC) dates back to the 1880s, when M. avium was first isolated from avian hosts; subsequent investigations gradually established the pathogenic potential of MAC in humans and led to its formal taxonomic designation.1 MAC is classified among the slowly growing, nonchromogenic Nontuberculous mycobacteria (NTM) and represents the most widely distributed and clinically prevalent species. Globally, the incidence and prevalence of NTM pulmonary disease (NTM-PD) have increased steadily over the past two decades, representing a growing public health concern. Epidemiological studies have reported an annual increase of approximately 4.0% in both NTM infection and disease incidence across different regions. Among NTM species, Mycobacterium avium complex (MAC) remains the predominant pathogen, accounting for approximately 70.0–80.0% of NTM-PD cases in many regions, including North America, Europe, and East Asia. This increasing disease burden highlights an urgent need for effective targeted therapies, particularly for patients with refractory MAC-PD, for whom current treatment options remain limited.2,3 Importantly, MAC demonstrates intrinsic resistance to first-line antituberculous agents, markedly restricting available treatment options.4 Amikacin liposome inhalation suspension (ALIS) received regulatory approval in the United States and the European Union in 2018 for the treatment of refractory MAC pulmonary disease (PD).5 Over recent years, a growing body of clinical evidence supporting the use of ALIS in this setting has continued to accumulate. This review provides a comprehensive overview of refractory MAC-PD and the therapeutic application of ALIS, with the aim of informing evidence-based clinical practice. Despite guideline-recommended macrolide-based triple therapy, treatment failure and the emergence of macrolide resistance in MAC-PD have increasingly been reported in real-world cohorts and systematic analyses.6–9 Meta-analytic studies indicate that sustained sputum culture conversion is achieved in only approximately 39.0–61.4% of MAC-PD patients receiving standard multidrug therapy.6,8,10 Furthermore, macrolide resistance develops in approximately 8.3–21.0% of patients with previous treatment exposure,11,12 and once resistance emerges, culture conversion rates remain poor, reaching only approximately 21.0% despite prolonged multidrug salvage regimens.7 The limited effectiveness of current therapeutic strategies is driven by multiple interconnected factors, including the ability of MAC to persist intracellularly within alveolar macrophages, which restricts effective intracellular drug exposure; rifamycin-mediated induction of cytochrome P450 3A enzymes, which reduces macrolide bioavailability; and the limited bactericidal activity of ethambutol, which may facilitate the selection and persistence of resistant subpopulations during prolonged treatment.13–15 Collectively, these challenges highlight a critical unmet need for adjunctive inhaled therapies capable of enhancing pulmonary and intracellular drug delivery while improving treatment outcomes in refractory MAC-PD.

Refractory MAC-PD: A Condition Warranting Clinical Attention

Despite guideline-based multidrug therapy, treatment outcomes remain suboptimal, particularly among patients with refractory disease. In the pivotal phase III CONVERT trial, only 8.9% of patients receiving guideline-based therapy alone achieved sputum culture conversion by month 6, highlighting the limited efficacy of conventional therapy in this population. Furthermore, macrolide resistance has emerged as a major therapeutic challenge, with resistance reported in treatment-experienced cohorts and associated with poor outcomes. A systematic review and meta-analysis demonstrated that patients with macrolide-resistant MAC-PD achieved a pooled sputum culture conversion rate of only 21.0% despite multidrug salvage therapy. These findings provide the clinical rationale for evaluating adjunctive therapies, including ALIS, in patients with refractory MAC-PD.(CONVERT/ALIS evidence;16 Macrolide-resistant MAC-PD outcomes;7 Development of resistance during refractory disease12) In recent years, the global incidence and prevalence of NTM infection and NTM-PD have risen steadily.2,3,17 MAC ranks among the most prevalent and widely distributed slowly growing NTM, comprising more than 20 subspecies, with M. avium, M. intracellulare, and M. chimaera serving as the principal representative members. This complex can cause pulmonary, lymph node, cutaneous, and disseminated infections.18 A meta-analysis enrolling predominantly adult cohorts with MAC-PD reported a 5-year all-cause mortality of approximately 27.0% (95% CI: 21.3–37.8%),19 highlighting the substantial long-term clinical burden of this disease.

Refractory MAC-PD, defined as disease that remains sputum culture–positive following 6 months of standardized guideline-based therapy,4 is characterized by a protracted disease course, limited therapeutic options, and poor prognosis, thereby imposing a substantial disease burden on affected patients.20

Current Clinical Management of MAC-PD

The clinical manifestations of MAC-PD are often nonspecific and may overlap considerably with other chronic pulmonary conditions, including pulmonary tuberculosis, bronchiectasis, and chronic pulmonary aspergillosis, thereby complicating accurate diagnosis and timely initiation of appropriate therapy.21–24 which results in inappropriate anti-tuberculosis regimens and delayed targeted intervention for MAC infection.18 Furthermore, there are significant differences among different MAC subspecies in terms of pathogenicity, clinical characteristics and drug susceptibility. The clinical diagnosis and treatment of MAC-PD face multiple dilemmas, including difficult diagnosis, marked subspecies heterogeneity, coexistence of inherent and acquired drug resistance, and limited available therapeutic agents. Therefore, novel therapeutic approaches are urgently needed.25–27

Macrolides are currently the only drugs for which in vitro drug susceptibility test results have been proven to correlate with clinical therapeutic responses, and they serve as the core and foundation of the current therapeutic regimens for MAC-PD. For refractory MAC-PD, the 2020 clinical practice guidelines for NTM jointly issued by the ATS/ERS/ESCMID/IDSA first recommended the addition of ALIS to the three-drug regimen consisting of a macrolide, rifamycin, and ethambutol, marking the first time that ALIS has been recommended for the treatment of refractory MAC-PD.4

Guideline-recommended triple therapy for MAC pulmonary disease (MAC-PD), consisting of a macrolide combined with a rifamycin and ethambutol, remains the cornerstone of treatment; however, its effectiveness is limited by suboptimal microbiological outcomes and the emergence of drug resistance. In a pooled analysis by Diel et al, the standard three-drug regimen recommended by the American Thoracic Society achieved a sustained sputum culture conversion rate of 61.4% among macrolide-susceptible, treatment-naïve patients who completed at least 12 months of therapy. When considering all macrolide-containing regimens across heterogeneous MAC-PD populations, the pooled treatment success rate was only 52.3%, with substantially poorer outcomes observed among patients with refractory disease.8 Recent meta-analytic evidence has further highlighted ongoing uncertainties regarding the contribution of individual components within multidrug regimens. Nguyen et al reported that, among patients with disseminated MAC infection, omission of rifamycin-containing therapy was associated with an increased risk of acquired macrolide resistance (OR, 2.99; P = 0.03), emphasizing the potential role of rifamycins in preventing resistance emergence.28 Furthermore, Park et al demonstrated that macrolide resistance has been reported in approximately 15.0–30.0% of treatment-experienced MAC-PD cohorts, and once resistance occurs, treatment outcomes remain poor, with pooled culture conversion rates of only approximately 21.0% despite multidrug salvage therapy.7

Collectively, these findings demonstrate that although guideline-based triple therapy remains the standard of care, persistent limitations in achieving durable microbiological response and the increasing challenge of macrolide-resistant MAC underscore the unmet need for adjunctive therapeutic approaches. These clinical challenges provide the rationale for the development and incorporation of inhaled amikacin liposome inhalation suspension (ALIS) into the management of refractory MAC-PD.

Formulation Characteristics and Drug Delivery Advantages of ALIS

ALIS is a sterile aqueous suspension of amikacin sulfate encapsulated within liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and cholesterol.29,30 These liposomes are artificially engineered spherical vesicles approximately 300 nm in diameter, in which aqueous compartments are separated by phospholipid bilayers. This structure enables efficient encapsulation of hydrophilic molecules within the internal aqueous core and retention of hydrophobic agents within the lipid bilayer, thereby functioning as a controlled-release system.31 The ALIS formulation is optimized to an amikacin concentration of 70 mg/mL, with a lipid-to-amikacin weight ratio of 0.60–0.79.32,33 Administration of the recommended dose requires approximately 14 minutes of nebulization, enabling efficient delivery to the lungs.32

ALIS is administered using the Lamira™ nebulizer system.34 The resulting aerosol has a mass median aerodynamic diameter (MMAD) of approximately 4.7 μm, which is within the respirable range (<5 μm) and thereby promotes efficient pulmonary deposition.32 During nebulization, approximately 70.0% of amikacin remains encapsulated within liposomes, whereas approximately 30.0% is released as free amikacin; thus, the lungs receive a mixture of free and liposome-associated amikacin.16 Chalmers et al demonstrated that liposomal drug delivery systems substantially enhance both pulmonary antibiotic distribution and intracellular delivery. Compared with conventional intravenous amikacin, ALIS achieved 42-fold, 69-fold, and 274-fold higher drug exposure in lung tissue, airway lumens, and alveolar macrophages, respectively.35

Pharmacokinetic Characteristics of ALIS

After nebulization, ALIS is distributed extensively throughout the lungs, with most of the dose retained in liposomal form. This results in high local drug concentrations while markedly minimizing systemic exposure.36 In patients with MAC-PD, approximately 43.0% of the delivered dose is deposited in the lungs. ALIS liposomes distribute broadly across both central and peripheral lung regions at an approximate ratio of 2:1; however, deposition appears comparatively limited in cavitary lesions and air-trapped regions.5

ALIS undergoes minimal metabolism in humans body. Unabsorbed drug is eliminated primarily through mucociliary clearance and expectoration,33 whereas only 7.4% of the administered dose is excreted in urine - a fraction substantially lower than the 94.0% urinary excretion observed after intravenous administration.35 Multiple clinical studies and population pharmacokinetic models have consistently confirmed that systemic amikacin exposure remains low after ALIS inhalation, with no appreciable drug accumulation after repeated once-daily dosing5,33,35,37 (Table 1).

Table 1 Sputum and Serum Amikacin Concentrations in Patients with Refractory MAC-PD After Once-Daily Inhalation of 590 mg ALIS5,35,37

A population pharmacokinetic model derived from the CONVERT trial demonstrated that systemic amikacin exposure remained stable during 6 months of once-daily ALIS inhalation. The median peak plasma concentration (Cmax) was 1.85 mg/L, and the median 24-hour area under the concentration-time curve (AUC0-24) was 16.7 μg·h/mL. Notably, the median difference in AUC0-24 between day 1 and month 6 was less than 10.0%, indicating that prolonged therapy does not increase systemic drug exposure.37 Clinical studies in patients with MAC-PD further confirmed that after 3 months of once-daily ALIS inhalation, the mean serum Cmax of amikacin was only 2.8 μg/mL (range, 1.0–4.4 μg/mL), with an AUC24 of approximately 76 μg·h/mL - values substantially lower than systemic exposures observed in healthy adults receiving intravenous amikacin.38 Ethnicity-stratified analyses revealed no statistically significant differences in serum amikacin exposure between White and Japanese patients, suggesting favorable interethnic applicability.38 ALIS achieves prolonged pulmonary retention. Studies indicate that 79.0% of the initially lung-deposited dose remains in the lungs at 1 hour post-dose, with 53.0% retained at 24 hours, providing a strong basis for sustained antimicrobial activity.38 Both in vivo and in vitro studies have demonstrated that ALIS achieves substantially greater amikacin exposure in the lungs, airways, and macrophages compared with free amikacin. In rats, ALIS was able to increase amikacin concentrations in alveolar macrophages by 5–8 fold at 2, 6, and 24 hours; concentrations in airways and lung tissue were also markedly higher at all assessed time points, with this advantage maintained at 24 hours. In vitro experiments using human macrophages showed that ALIS substantially enhanced intracellular drug uptake at both 4 and 24 hours, with uptake at 24 hours approximately 4-fold higher than that of free amikacin, thereby sustaining local drug exposure and providing a pharmacological basis for prolonged antibacterial activity.39

Overall, the pharmacokinetic profile of ALIS, characterized by low systemic exposure, absence of systemic accumulation, and prolonged pulmonary retention, provides a core support for its long-term and safe clinical application.

Antimicrobial Susceptibility Characteristics

ALIS enhances drug penetration into intracellular persisters and biofilms, thereby augmenting its inhibitory activity against MAC.36 Its mechanism of action involves binding to the bacterial 30S ribosomal subunit and inhibiting protein synthesis.37 In vitro studies have demonstrated that ALIS has superior antimicrobial activity against MAC compared with conventional intravenous amikacin, including the ability to penetrate MAC biofilms and markedly increase macrophage uptake of amikacin, with intracellular drug accumulation substantially exceeding that of free amikacin.39

Regarding phenotypic susceptibility testing and its correlation with clinical efficacy, the minimum inhibitory concentration (MIC) breakpoint for ALIS has been established at 128 µg/mL, which is higher than the 64 µg/mL breakpoint designated for parenteral amikacin.40 This distinction was further supported in the phase III ALIS trial:16 among patients receiving ALIS plus guideline-based therapy (GBT), 23 harbored MAC isolates with amikacin MICs >64 µg/mL, a level that would conventionally indicate resistance to the injectable formulation. Notably, 2 of these 23 patients (approximately 8.7%) nevertheless achieved sputum culture conversion despite amikacin resistance. By contrast, all three patients in the GBT-alone arm with MAC isolates exhibiting amikacin MICs >64 µg/mL failed to achieve culture conversion.

Clinical Efficacy of ALIS

The Phase II trial showed that sputum culture conversion rates in the ALIS-containing group increased progressively with treatment duration, reaching 23.0% (10/44), 25.0% (11/44), and 32.0% (14/44) at days 28, 56, and 84, respectively, each of which exceeded the corresponding rate in the control group.41

The phase III CONVERT trial (N=336) reported a 6-month sputum culture conversion rate of 29.0% (65/224) in the ALIS-GBT group, significantly exceeding the 8.9% (10/112) observed in the GBT-alone group (adjusted odds ratio [OR], 4.22; 95% CI:2.08–8.57; P < 0.001).36 Extended follow-up revealed that culture conversion rates in the ALIS group reached 80.0% at the end of treatment (maximum duration, 16 months), 63.1% at 3 months after treatment discontinuation, and 53.8% at 12 months after treatment discontinuation; each rate was significantly higher than that in the control group. These findings support a durable and sustained microbiological response with ALIS, with potential implications for reducing relapse and reinfection.

Real-world cohort studies have further corroborated these efficacy data, reporting 6-month sputum culture conversion rates ranging from approximately 56.8% to 100.0% with ALIS-containing regimens in patients with refractory MAC-PD.42–44 Cavitary disease, macrolide resistance, elevated C-reactive protein levels, and a body mass index <18.5 kg/m2 have been identified as factors associated with treatment failure.44,45

Safety Profile of ALIS

ALIS, when combined with standard therapy, demonstrates a favorable overall safety profile. In phase II41 and phase III16 clinical trials, the incidence of treatment-emergent adverse events (TEAEs) was comparable between the ALIS and control groups (93.2% vs 88.9%; 98.2% vs 91.1%, respectively). The most frequently reported adverse events were local respiratory reactions, including dysphonia, cough, and oropharyngeal pain. The incidences of serious TEAEs were 18.2% and 20.2%, respectively, whereas discontinuation rates due to TEAEs were 15.9% and 17.5%, respectively. No treatment-related deaths were reported. The categories and incidences of adverse reactions observed with ALIS are summarized in Table 2. Dysphonia was the most common adverse reaction, with an incidence of 43.2–66.7%; symptomatic management, including throat hydration and oral hygiene measures, led to improvement in 84.6% of affected patients.

Table 2 Types and Incidence of Adverse Reactions Associated with ALIS Therapy for MAC-PD

Pulmonary adverse events warrant particular vigilance during ALIS therapy, notably drug-induced interstitial lung disease (DIILD) and hypersensitivity pneumonitis. Hashimoto et al47 reported a case of refractory MAC-PD in which fever, cough, and pulmonary infiltrates developed approximately 3 weeks after ALIS initiation. The condition resolved after drug discontinuation and corticosteroid therapy, and a positive drug provocation test confirmed ALIS-induced DIILD. This case underscores the need for close monitoring of respiratory symptoms and radiographic changes after ALIS initiation, as well as prompt differentiation between infectious exacerbation and drug-induced pulmonary injury.

Clinical Management of ALIS

Clinical interventions can meaningfully mitigate ALIS-related adverse events. Throat hydration and oral hygiene measures improved dysphonia in 84.6% of patients; combined airway clearance, pretreatment with short-acting bronchodilators, and temporary dose interruption or dosing-frequency adjustment alleviated increased sputum production in 75.0% of patients and cough in 72.7%; and bronchodilator pretreatment improved dyspnea in 90.9% of patients.48

For patients receiving concomitant bronchodilators, administration before ALIS inhalation is recommended. In individuals with airway hyperresponsiveness, chronic obstructive pulmonary disease, asthma, or a history of bronchospasm, pretreatment with a short-acting selective β2-agonist is advised. ALIS is contraindicated in patients with a history of hypersensitivity to any aminoglycoside. In addition, because of potential pharmacodynamic interactions, ALIS should be avoided in combination with agents associated with ototoxicity, nephrotoxicity, or neurotoxicity.49 These prescribing recommendations provide a framework for rational clinical use; however, the long-term tolerability, safety, and overall clinical value of ALIS require further investigation.

Low body mass index, hypoalbuminemia, and a fibrocavitary radiographic pattern are significant risk factors for early discontinuation of ALIS. These findings underscore the importance of maintaining adequate nutritional status as an integral component of successful multidrug antimicrobial therapy for NTM pulmonary disease. Clinicians should carefully evaluate these factors before initiating ALIS and intensify monitoring and nutritional support when needed to optimize treatment adherence and outcomes.50

If treatment with ALIS needs to be discontinued due to intolerable adverse reactions or treatment failure during the course of therapy, an alternative antibacterial regimen should be promptly initiated to ensure continuous treatment of refractory MAC-PD. Chen et al reported a case of refractory MAC-PD in which ALIS-GBT was unsuccessful; subsequent transition to a sitafloxacin(STFX)-based combination regimen, which eventually achieved sustained sputum culture conversion, relief of hemoptysis, and long-term clinical stability.51

Health Economic Evaluation

In addition to improving clinical efficacy in patients with refractory MAC-PD, ALIS may reduce hospitalization risk and healthcare resource utilization. Aksamit et al conducted a retrospective cohort study using real-world data to evaluate the impact of ALIS initiation on healthcare resource utilization (HCRU).52 The study enrolled 331 patients with refractory MAC-PD who had received at least one dose of ALIS. Compared with baseline, all-cause hospitalization rates decreased by 4.3% and 10.3% during months 0–6 and 7–12 after ALIS initiation, respectively (P = 0.04). Respiratory disease-related hospitalization rates also declined significantly, to 19.3% during months 0–6 (P < 0.01) and 15.4% during months 7–12 (P < 0.0001). Moreover, the frequencies of both all-cause and respiratory-related hospitalizations decreased significantly after ALIS initiation, highlighting its potential to alleviate healthcare burden.

Perspectives

The global prevalence of NTM-PD continues to rise, posing an increasingly urgent public health challenge. As the most common subtype of NTM-PD, MAC-PD presents substantial clinical obstacles, including intrinsic antimicrobial resistance, complex pathogenic mechanisms, and suboptimal therapeutic outcomes. The approval of ALIS represents a landmark advance in this field. By leveraging liposomal encapsulation technology to achieve lung-targeted drug delivery, ALIS substantially enhances local drug concentrations while minimizing systemic exposure. Its efficacy and manageable safety profile in refractory MAC-PD offer renewed promise for the clinical management of this challenging condition. Nevertheless, several limitations constrain the broader clinical application of ALIS. Real-world evidence remains limited by relatively small sample sizes; subgroup analyses stratified by individual MAC subspecies are lacking; and the relationships between microbiological endpoints and patient-reported quality of life, as well as long-term prognostic outcomes, remain incompletely defined. Future priorities should include large-scale, long-term real-world studies to comprehensively evaluate the impact of ALIS on quality of life and overall survival; dedicated investigations to elucidate differential efficacy across MAC subspecies, thereby informing individualized therapeutic strategies; and development of comprehensive pharmacoeconomic models to systematically assess cost-effectiveness and provide an evidence-based framework for clinical decision-making. In parallel, the integration of host-directed therapies with ALIS-containing regimens warrants exploration as a novel strategy to further improve outcomes in refractory MAC-PD.

Patents

The authors declare no patents resulting from the work reported in this manuscript.

Data Sharing Statement

No new data were created or analyzed in this study. All data are included in the published article.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This research was funded by the 2024 National Distinguished Physician Program (Phase I) for High-Level Medical Talents (Guo Shuliang).

Disclosure

The authors declare no conflicts of interest.

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