In this study, 7 of 12 (58.3%) patients with refractory MAC-PD achieved sputum culture conversion with ALIS under GBT. However, the sputum negative conversion rate was unsatisfactory in patients with cavitary lesions, CLA-resistant isolates, and prolonged pre-ALIS initiation treatment duration. In the CONVERT study, 65 of 224 (29%) patients with refractory MAC-PD achieved sputum culture conversion at 6 months with ALIS treatment [3]. Subsequently, 24 of 90 (26.7%) patients with refractory MAC-PD and no prior ALIS exposure, and who did not achieve sputum culture conversion, achieved sputum culture conversion at 6 months of ALIS treatment [9]. The comparatively higher rates of sputum culture conversion in our study vs. these reports can be attributed to the inclusion of patients who were easier to treat than in the CONVERT study with shorter pre-ALIS treatment duration (2.1 vs. 4.5 years).
Contrarily, the proportion of CLA-resistant isolates was comparable to that of the CONVERT study [25% (3 of 12) vs. 22.9% (51 of 224)]. In the CONVERT study, sputum culture conversion was achieved by 7 of 51 (13.7%) and 58 of 173 (33.5%) patients with CLA-resistant and susceptible isolates, respectively. In this study, sputum culture conversion was achieved by 0 of 3 (0%) and 7 of 9 (77.8%) patients with CLA-resistant and susceptible isolates, respectively. This demonstrates that CLA sensitivity is also an important factor in the therapeutic efficacy of ALIS. All isolates in our study were AMK-sensitive, while in the CONVERT study 222/223 (99.6%) strains had an MIC of AMK < 64µg/mL, so the effect of AMK-resistant isolates on treatment efficacy could not be examined. It has been reported that prior treatment with other AMK formulations can lead to AMK resistance [11]. In our study, 2 of 5 isolates showed elevated AMK MIC after 6 months of inhaled AMK, but none reached 128µg/mL, the ALIS breakpoint proposed by the CLSI [8].
Further, the CONVERT study did not investigate differences in treatment efficacy by MAC-PD type. MAC-PD is comprehensively classified into nodular bronchiectatic (NBE) and fibrocavitary (FC) types, both known to affect treatment outcomes [12]. Another study reported poorer prognosis in MAC-PD patients with cavitary lesions regardless of type, than those without cavitary lesions [13]. Also, our study found lower sputum conversion rates for MAC-PD patients with cavitary lesions. Nevertheless, 2 of 5 patients in the non-conversion group with cavitary lesions showed improved chest CT findings including cavitary lesions. One of 2 patients with improved chest CT findings in the non-conversion group also had weight gain. Thus, sputum culture conversion alone may not correspond to whole effectiveness of ALIS. Long-term ALIS treatment may be recommended for patients with improved chest CT findings, regardless of sputum culture conversion status. Conversely, 2 of 7 patients in the culture conversion group had worsened chest CT findings and weight loss. In these patients, MAC lesions were present in central airways predominantly which might be eradicated by ALIS inhalation. Thus, improved CT findings do not always correspond to sputum culture conversion. The fact that the use of ALIS achieved an MICD of CAT score in approximately 60% of cases, with or without sputum culture conversion, suggests that this may reflect a decrease in bacterial abundance due to ALIS with or without culture conversion.
In addition to ALIS, several other drugs have been reported to be effective in the treatment of MAC-PD, including intravenous (IV)-AMK, Streptomycin (SM), moxifloxacin, sitafloxacin, and clofazimine [14–18]. There is limited data available on the use of these agents in refractory MAC-PD, however, a 2020 guideline recommends the treatment of refractory MAC-PD by adding ALIS, IV-AMK, and SM to GBT [1]. A study of the duration of aminoglycoside use (IV-AMK and SM) reported that use for 3 to 7.4 months contributed to increased treatment success, but longer use did not [19]. Conversely, the use of ALIS beyond 6 months for more than 12 months has been reported to further increase the rate of sputum culture conversion [20]. One suggestion for the use of ALIS versus IV-AMK and SM is that patients with CLA-resistant strains or FC-type who are considering surgery in the future should be treated with short courses of IV-AMK or SM. If the patient is not planning for surgery and is considering long-term use of an aminoglycoside, ALIS should be selected.
Adverse events were observed in 11 of 12 (91.7%) patients in this study. Severe adverse events leading to ALIS treatment discontinuation were observed in 2 (16.7%) patients (hypersensitivity pneumonitis and ototoxicity). In the CONVERT study, 219 of 224 patients (98.2%) in the ALIS + GBT arm reported some form of adverse events; in 17.4% of patients this led to ALIS discontinuation. According to Morita et al., while 9 of 11 (81.8%) patients reported some adverse events, no serious adverse event was observed [21]. The proportion of these adverse events is very similar.
In our study, dysphonia was observed in 8 of 12 (66.7%) patients; 7 cases occurred within the first month. Dysphonia was the most reported adverse event in the CONVERT study, seen in 47% of patients [3] and also noted in 73.1% (19/26) and 72.7% (8/11) from other reports [21, 22]. In this study, dysphonia improved with warm water gargle before and after ALIS inhalation for all patients. A previous study describes satisfactory management of dysphonia using lozenges, warm water or glycerin gargle, changing ALIS administration time to evening, and reducing or briefly interrupting dosing frequency [22].
Hypersensitivity pneumonitis was reported in 3.1% of patients in another CONVERT study [23]. It showed hypersensitivity pneumonitis with fever and dyspnea that developed 2 weeks after ALIS initiation, but imaging findings improved at 2 weeks post-withdrawal [24]. In this study, 1 patient had chest CT findings suggestive of hypersensitivity pneumonitis at 9 months after initiation. There were no added symptoms such as dyspnea, and chest CT findings subsequently improved at 3 months after withdrawal of ALIS.
In the CONVERT study, AMK-induced ototoxicity was observed in 17 of 223 (7.6%) patients with hearing loss in 10 of 223 (4.5%) [3]. In this study, 2 of 12 (16.7%) patients developed ototoxicity, an adverse event that should be monitored cautiously.
This study has limitations. As a single-center study in a small number of patients, the findings may not be generalizable to a larger, more diverse population. Also, the study duration was short, long-term follow up might further highlight potential issues with resistant isolates.