Amikacin Inhalation as Salvage Therapy for Refractory Nontuberculous Mycobacterial Lung Disease

Abstract

Although guidelines recommend amikacin (AMK) inhalation therapy for difficult-to-treat nontuberculous mycobacterial lung disease (NTM-LD), data are limited regarding the safety and clinical efficacy of this salvage therapy. We retrospectively evaluated the treatment outcomes of 77 patients with refractory NTM-LD caused by complex (MABC) or complex (MAC) who initiated AMK inhalation therapy between February 2015 and June 2016. MABC was the most common etiology ( = 48, 62%), followed by MAC ( = 20, 26%) and mixed infections ( = 9, 12%). Isolates with macrolide resistance and baseline AMK resistance were identified in 63 (82%) patients and 5 (6%) patients, respectively. At 12 months after AMK inhalation therapy, 49% of patients had symptomatic improvement, whereas 42% had radiological improvement. Conversion to a negative sputum culture occurred in 14 (18%) patients, and the culture conversion rate was higher in patients infected with macrolide-susceptible isolates (7/14, 50%) than in those infected with macrolide-resistant isolates (7/63, 11%) ( = 0.003). Significant decreases in sputum semiquantitative culture positivity occurred after AMK inhalation therapy ( < 0.001). On multivariate analysis, conversion to a negative sputum culture was associated with mixed infections ( = 0.009), a forced expiratory volume in 1 s of greater than 60% ( = 0.008), and the absence of macrolide resistance ( = 0.003). Thirty-eight percent of patients experienced adverse effects, with ototoxicity ( = 15) being the most common. AMK inhalation salvage therapy may improve the treatment responses in some patients with refractory NTM-LD. However, considering the common adverse effects, further evaluation of the optimal dosage and intervals for AMK inhalation therapy is needed.

Nontuberculous Mycobacteria in Cystic Fibrosis

“…These high levels of adverse events raise questions as to the tolerability of inhaled amikacin. 89 These findings were similar to a smaller study by Olivier et al, in which in 20 patients (15 with MABS and 5 with MAC) treated with inhaled amikacin 25% achieved sputum conversion, 30% had radiographic improvement, and 35% stopped treatment due to side effects. 90 The high incidence of side effects of inhaled amikacin commonly associated with IV administration (ototoxicity, nephrotoxicity, hemoptysis, and dysphonia) has led to the development of amikacin as a liposome inhalation suspension (ALIS; ARIKAYCE, Insmed) designed to reduce systemic exposures and improve intracellular killing.…”

“…97 In the studies of Olivier et al and Jhun et al, no patient with either MAC or MAB and resistance to amikacin were able to achieve culture conversion with either IV or inhaled amikacin. 89,90 Break points for both IV and liposomal inhaled amikacin for MAC have recently been published by the Clinical and Laboratory Standards Institute and summarized in ►Table 5. 98 The linkage between these break points and clinical outcomes for clarithromycin and amikacin provides strong evidence that susceptibility testing should be performed as part of primary treatment for MAC and MABS.…”

Nontuberculous Mycobacterial Lung Diseases Caused by Mixed Infection with Mycobacterium avium Complex and Mycobacterium abscessus Complex

“…Antibiotic treatment. In patients with mixed infections with MAC and MABC, administration of three oral antibiotics (macrolide, EMB, and RIF) and/or fluoroquinolone and/or clofazimine and/or inhaled amikacin was performed after 2 or 4 weeks of intravenous antibiotics in the hospital (16,18,31,(38)(39)(40). In some patients with mixed infections with MAC and M. massiliense, three oral antibiotics without initial hospitalization were continuously used, especially in those with noncavitary nodular bronchiectatic disease who could not be hospitalized due to economic or family problems (41).…”

Treatment ofMycobacterium aviumComplex Pulmonary Disease

“…Case series using different doses and frequencies of administration of inhaled amikacin in refractory cases with MAC or M. abscessus infections showed variable culture conversion rates (25%–43%) and adverse drug reaction rates (8%–35%)6566. Recently, in a large cohort study from South Korea involving 77 patients with refractory NTM-PD ( M. abscessus , n=48; MAC, n=20; mixed infection, n=9), all of whom received amikacin inhalation therapy, culture conversion was achieved in 18% of the cases overall and 15% of the MAC-PD cases67. In the same study, adverse drug reactions such as ototoxicity to the amikacin inhalation therapy developed in 38% of all patients, and this therapy was discontinued in 27% of patients67.…”

“…Recently, in a large cohort study from South Korea involving 77 patients with refractory NTM-PD ( M. abscessus , n=48; MAC, n=20; mixed infection, n=9), all of whom received amikacin inhalation therapy, culture conversion was achieved in 18% of the cases overall and 15% of the MAC-PD cases67. In the same study, adverse drug reactions such as ototoxicity to the amikacin inhalation therapy developed in 38% of all patients, and this therapy was discontinued in 27% of patients67. Although these studies showed clinical and microbiologic improvements in some patients, the treatment was associated with common adverse reactions.…”