What is the evidence for use of conventional (non-liposomal) inhaled amikacin for Mycobacterial infection?

What is the evidence for use of conventional (non-liposomal) inhaled amikacin for Mycobacterial infection?

Comment by InpharmD Researcher

Published evidence describes conventional (non-liposomal) inhaled amikacin as an adjunct to multidrug therapy for refractory NTM pulmonary disease, although the available data are limited and heterogeneous. In observational studies, parenteral amikacin administered by inhalation ranged from 250-500 mg once daily to 15 mg/kg once daily and was generally added to an existing multidrug regimen. Notably, joint societal guidelines do not recommend conventional inhaled amikacin as initial therapy but consider it a reasonable alternative when liposomal amikacin is unavailable for patients with refractory disease after at least 6 months of guideline-based therapy.

Background

According to the 2020 joint American Thoracic Society (ATS)/European Respiratory Society (ERS)/European Society of Clinical Microbiology and Infectious Diseases (ESCMID)/Infectious Diseases Society of America (IDSA) guidelines on the treatment of nontuberculous mycobacterial disease, inhaled conventional (parenteral formulation) amikacin is not recommended as part of the initial treatment regimen for newly diagnosed macrolide-susceptible Mycobacterium avium complex (MAC) pulmonary disease because available evidence is limited and of very low certainty. In patients with treatment-refractory MAC pulmonary disease who remain culture-positive after at least 6 months of guideline-based therapy, the guidelines recommend adding amikacin liposome inhalation suspension. However, when the liposomal formulation is unavailable, the guidelines state that addition of inhaled parenteral amikacin is a reasonable alternative. In these guidelines, evidence for conventional inhaled amikacin comes primarily from five retrospective case series (see Tables 1-5) involving 138 patients, including 55 with MAC pulmonary disease. Doses of commercially available parenteral amikacin administered by inhalation ranged from 250-500 mg once daily to 15 mg/kg once daily and were generally added to an existing multidrug regimen. Among patients with treatment-refractory MAC pulmonary disease, reported clinical response rates ranged from 20% to 100%, while sputum culture conversion occurred in 18% to 67% of patients. Reported adverse effects occurred in 8% to 38% of patients and included hoarseness, throat irritation, bitter taste, and oral thrush. Ototoxicity occurred in 0% to 19%, with nephrotoxicity reported in one patient and vertigo in two patients. The guidelines emphasize that inhaled amikacin should be used as part of a salvage regimen in patients whose MAC isolates retain in vitro susceptibility to amikacin, rather than as initial therapy. [1]

Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the evidence for use of conventional (non-liposomal) inhaled amikacin for Mycobacterial infection?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-6 for your response.

Aerosolized amikacin for treatment of pulmonary Mycobacterium avium infections: an observational case series
Design	Observational case series N= 6
Objective	To assess the safety, tolerability and preliminary clinical benefits of the addition of aerosolized amikacin to a standard macrolide-based oral treatment regimen for nontuberculous mycobacterial pulmonary infection
Study Groups	All patients (n= 6)
Inclusion Criteria	HIV-negative patients with Mycobacterium avium intracellulare pulmonary infections who had failed standard therapy
Exclusion Criteria	Not specified
Methods	Patients were administered aerosolized amikacin at 15 mg/kg daily in addition to standard multi-drug macrolide-based oral therapy. Patients were monitored clinically and serial sputum cultures were obtained to assess response to therapy. Symptomatic improvement with radiographic stabilization and eradication of mycobacterium from sputum were considered markers of success
Duration	Not specified
Outcome Measures	Symptomatic improvement, radiographic stabilization, eradication of mycobacterium from sputum
Baseline Characteristics		All patients (n= 6)
	Sex	All female
	Age, years	52 to 73
	NTM Species	MAC, M. chelonae
	Radiographic Pattern	Bronchiectasis, nodular infiltrates, cavitary lesions
	Duration of therapy prior to starting amikacin, months	0.5 to 96
Results		Response to Therapy	Sputum Culture Status
	1	Improvement	Negative for 21 months; now positive (MAC)
	2	Progressive disease; died	Persistent positive at death
	3	Improvement	Negative for 6 months; now positive (M. chelonae)
	4	Improvement	Negative for 7 months; now positive (MAC)
	5	Improvement	Negative for 6 months
	6	Improvement	No cough sputum
Adverse Events	Voice hoarseness, sore throat (transient), oral candidiasis. No evidence of nephrotoxicity, ototoxicity or vestibular toxicity.
Study Author Conclusions	Aerosolized delivery of amikacin is a promising adjunct to standard therapy for pulmonary nontuberculous mycobacterial infections. Larger prospective trials are needed to define its optimal role in therapy of this disease.
Critique	The study is limited by its small sample size and observational design, which may affect the generalizability of the findings. The lack of a control group and the variability in prior treatment durations among patients are additional limitations. However, the study provides valuable preliminary data on the potential benefits and safety of aerosolized amikacin in this patient population.

Table 1 References:
[2] Davis KK, Kao PN, Jacobs SS, Ruoss SJ. Aerosolized amikacin for treatment of pulmonary Mycobacterium avium infections: an observational case series. BMC Pulm Med. 2007;7:2. Published 2007 Feb 23. doi:10.1186/1471-2466-7-2

Aerosolized amikacin in patients with difficult-to-treat pulmonary nontuberculous mycobacteriosis
Design	Retrospective study N= 9
Objective	To evaluate the safety and feasibility of aerosolized amikacin (aeAmk) in combination with oral anti-NTM drugs for patients with difficult-to-treat pulmonary nontuberculous mycobacteriosis (pNTM)
Study Groups	All patients (N= 9)
Inclusion Criteria	Patients with pNTM who failed to show clinical improvement or had radiographic worsening after 3 months of oral antimicrobial treatment, or were unable to tolerate oral agents due to toxicity or interactions
Exclusion Criteria	Not specified
Methods	Patients received aerosolized amikacin (aeAmk) in combination with one or two oral agents to which NTM showed in vitro susceptibility. AeAmk was administered as 100 mg twice-daily, increased to 300 mg twice-daily if tolerated. Patients received inhaled beta-agonist bronchodilators before and after therapy
Duration	2004 to 2009
Outcome Measures	Primary: Clinical response and resolution of symptoms Secondary: Safety and toxicity profile
Baseline Characteristics		All patients (n= 9)
	Age, years	63 ± 9
	Solid-organ cancer	56%
	Acute myelogenous leukemia	11%
	APACHE II score	6 ± 3
	High-dose systemic corticosteroids	33%
	Bilateral lung involvement	67%
	Lingula involvement	44%
Results	Patient no.	Response	Duration of aeAmk therapy
	1	Complete response (CR)	92 days
	2	CR	75 days
	3	CR	201 days
	4	CR	133 days
	5	CR	54 days
	6	PR	18 days
	7	CR	59 days
	8	CR	38 days
	9	CR	277 days
Adverse Events	Self-limiting hoarseness of voice, throat irritation, and bitter taste occurred in one patient each. Persistent throat irritation and cough improved after dose reduction.
Study Author Conclusions	Aerosolized amikacin was well-tolerated and showed clinical improvement in patients with difficult-to-treat pNTM disease, suggesting its potential as a treatment option. However, validation through randomized trials is necessary.
Critique	The study is limited by its small sample size and retrospective design, which may affect the generalizability of the findings. The lack of a control group and potential selection bias are additional limitations. Despite these, the study provides valuable insights into the potential use of aerosolized amikacin for pNTM.

Table 2 References:
[3] Safdar A. Aerosolized amikacin in patients with difficult-to-treat pulmonary nontuberculous mycobacteriosis. Eur J Clin Microbiol Infect Dis. 2012;31(8):1883-1887. doi:10.1007/s10096-011-1516-3

Inhaled Amikacin for Treatment of Refractory Pulmonary Nontuberculous Mycobacterial Disease
Design	Retrospective study N= 20
Objective	To review the efficacy and toxicity of inhaled amikacin in patients with treatment-refractory nontuberculous mycobacterial lung disease
Study Groups	All patients (N= 20)
Inclusion Criteria	Patients who met the diagnostic criteria for pulmonary nontuberculous mycobacterial disease as established by the American Thoracic Society guidelines, treated with aerosolized amikacin, and had a baseline and at least one follow-up visit
Exclusion Criteria	Patients not on an ATS guidelines–based treatment regimen with persistently positive mycobacterial cultures
Methods	Records were queried to identify patients who had inhaled amikacin added to failing regimens. Lower airway microbiology, symptoms, and CT scan changes were assessed together with reported toxicity. Commercial amikacin sulfate 250 mg/ml solution was diluted with 3 ml of saline and placed in a jet nebulizer for inhalation. Patients were generally started at 250 mg once daily and titrated to twice daily if tolerated.
Duration	Data collection from 2003 through 2010
Outcome Measures	Primary: Microbiologic improvement (negative cultures) Secondary: Symptomatic improvement, CT scan changes, reported toxicity
Baseline Characteristics		All patients (n= 20)
	Sex, female, n (%)	16 (80%)
	Age, mean (SD), yr	56 (16)
	CFTR carriers	3 (15%)
	Cystic fibrosis	2 (10%)
	Chronic obstructive pulmonary disease	2 (10%)
	CT findings - Initial score, mean (SD)	6 (3)
	Cavitary disease, n (%)	9 (45%)
	Mycobacterium species - Mycobacterium abscessus group	15 (75%)
	Mycobacterium species - Mycobacterium avium complex	5 (25%)
	Months on mycobacterial treatment (before amikacin), median (range)	60 (6, 190)
Results		All patients (n= 20)
	At least one negative culture	8 (40%)
	Persistently negative cultures	5 (25%)
	Decrease in smear quantity	9 (45%)
	Decrease in mycobacterial culture growth	10 (53%)
	Symptom scores improved	9 (45%)
	Improvement on CT scans	6 (30%)
	Stopped amikacin due to toxicity	7 (35%)
Adverse Events	Ototoxicity in two (10%), hemoptysis in two (10%), nephrotoxicity, persistent dysphonia, and vertigo in one each
Study Author Conclusions	Inhaled amikacin was associated with microbiologic and/or symptomatic improvement in some patients with treatment-refractory pulmonary nontuberculous mycobacterial disease, but toxicity was common. Prospective evaluation is warranted
Critique	The study highlights the potential of inhaled amikacin as an adjunctive treatment for refractory nontuberculous mycobacterial lung disease, showing some microbiologic and symptomatic improvements. However, the retrospective design, small sample size, and lack of a control group limit the ability to draw definitive conclusions. The high rate of toxicity also raises concerns about the safety of this treatment approach

Table 3 References:
[4] Olivier KN, Shaw PA, Glaser TS, et al. Inhaled amikacin for treatment of refractory pulmonary nontuberculous mycobacterial disease. Ann Am Thorac Soc. 2014;11(1):30-35. doi:10.1513/AnnalsATS.201307-231OC

Amikacin Inhalation as Salvage Therapy for Refractory Nontuberculous Mycobacterial Lung Disease
Design	Retrospective study N= 77
Objective	To evaluate the treatment outcomes and safety of salvage therapy with amikacin inhalation in patients with refractory NTM-LD caused by MAC or MABC
Study Groups	Mycobacterium abscessus complex (MABC; n= 48) M. avium complex (MAC; n= 20) Mixed infections (n= 9)
Inclusion Criteria	Patients with refractory MAC- or MABC-LD who initiated AMK inhalation therapy between February 2015 and June 2016
Exclusion Criteria	None specified
Methods	Retrospective evaluation of 77 patients with refractory NTM-LD who received AMK inhalation therapy. Patients were treated with 500 mg AMK inhalation daily, later adjusted to three times weekly due to adverse effects. Treatment outcomes were assessed based on symptomatic, radiological, and microbiological responses
Duration	February 2015 to June 2016
Outcome Measures	Primary: Symptomatic improvement, radiological improvement, sputum culture conversion Secondary: Decrease in sputum semiquantitative culture positivity
Baseline Characteristics		All patients (n= 77)
	Median age, years (IQR)	60 (53-69)
	Female	53 (69%)
	Median BMI, kg/m2 (IQR)	19.8 (18.1-21.8)
	Nonsmokers	60 (78%)
	Previous pulmonary tuberculosis	57 (74%)
	Chronic cavitary pulmonary aspergillosis	17 (22%)
	Chronic obstructive pulmonary disease	9 (12%)
	M. abscessus complex	48 (62%)
	M. avium complex	20 (26%)
	Mixed infections	9 (12%)
	Nodular bronchiectatic form	47 (61%)
	Fibrocavitary form	30 (39%)
	AFB smear-positive sputum	51 (66%)
	Macrolide resistance	63 (82%)
	Amikacin resistance	5 (7%)
Results		Total (n= 77)	MABC (n= 48)	MAC (n= 20)	Mixed (n= 9)	p-value
	Symptomatic improvement	38 (49%)	21 (44%)	11 (55%)	6 (67%)	0.242
	Radiological improvement	32 (42%)	16 (33%)	10 (50%)	6 (67%)	0.154
	At least one negative culture	26 (34%)	14 (29%)	5 (25%)	7 (78%)	0.015
	Sputum culture conversion	14 (18%)	6 (13%)	3 (15%)	5 (56%)	0.019
Adverse Events	Thirty-eight percent of patients experienced adverse effects, with ototoxicity (n= 15) being the most common. Other adverse effects included fatigue, tinnitus, and cough.
Study Author Conclusions	AMK inhalation salvage therapy may improve 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.
Critique	The study provides valuable insights into the potential benefits of AMK inhalation therapy for refractory NTM-LD, highlighting its role in symptomatic and radiographic improvement. However, the retrospective design and lack of objective measures for symptomatic and radiographic improvement limit the robustness of the findings. Additionally, the high rate of adverse effects suggests a need for further research to optimize dosing regimens.

Table 4 References:
[5] Jhun BW, Yang B, Moon SM, et al. Amikacin Inhalation as Salvage Therapy for Refractory Nontuberculous Mycobacterial Lung Disease. Antimicrob Agents Chemother. 2018;62(7):e00011-18. Published 2018 Jun 26. doi:10.1128/AAC.00011-18

The efficacy, safety, and feasibility of inhaled amikacin for the treatment of difficult-to-treat non-tuberculous mycobacterial lung diseases
Design	Retrospective chart review N= 26
Objective	To evaluate the efficacy, safety, and feasibility of inhaled amikacin therapy in patients with difficult-to-treat non-tuberculous mycobacterial lung diseases
Study Groups	All patients (N= 26)
Inclusion Criteria	Patients with NTM lung diseases who received combination therapy, including inhaled amikacin (AMK) therapy, at Keio University Hospital from January 2014 through May 2016
Exclusion Criteria	Not explicitly stated
Methods	Patients received inhaled AMK therapy using injectable AMK sulfate solution (100 mg/mL) at a dose of 15 mg/kg/day once a day for 30 min using a compressor nebulizer. The duration of therapy was determined by efficacy and adverse events, with at least 3 months scheduled. Serum AMK trough levels were monitored, and adverse events were recorded
Duration	January 2014 through May 2016
Outcome Measures	Primary: Sputum conversion (at least three consecutive negative sputum cultures) Secondary: Improvement in clinical symptoms, HRCT imaging
Baseline Characteristics		All patients (N= 26)
	Age, years (median [IQR])	65.5 [60.0-70.5]
	Female	22 (84.6%)
	Weight, kg (median [IQR])	44.0 [41.7-47.7]
	BMI, kg/m2 (median [IQR])	18.0 [17.3-19.4]
	Mycobacterium avium complex	23 (88.5%)
	Mycobacterium abscessus complex	3 (11.5%)
Results		All patients (N= 26)
	Sputum conversion	10 (43.5%)
	Improvement in HRCT findings	7 (30.4%)
	Reduction in clinical symptoms (cough and sputum)	Significant
Adverse Events	No severe systemic adverse events such as renal toxicity. One patient (3.8%) experienced auditory toxicity (tinnitus), which was reversible. Other adverse events included uncomfortable sensations in the oral cavity (46.2%), oral candidiasis (3.8%), and hoarseness (19.2%).
Study Author Conclusions	Inhaled AMK therapy is an effective and feasible therapy for difficult-to-treat NTM lung disease.
Critique	The study is limited by its retrospective design and small sample size, which may not fully capture the long-term effectiveness and safety of inhaled AMK therapy. Additionally, the lack of a control group makes it difficult to attribute improvements solely to the inhaled AMK therapy. Further randomized controlled trials are needed to confirm these findings.

Table 5 References:
[6] Yagi K, Ishii M, Namkoong H, et al. The efficacy, safety, and feasibility of inhaled amikacin for the treatment of difficult-to-treat non-tuberculous mycobacterial lung diseases. BMC Infect Dis. 2017;17(1):558. Published 2017 Aug 9. doi:10.1186/s12879-017-2665-5

Outcomes of Inhaled Amikacin-Containing Multidrug Regimens for Mycobacterium abscessus Pulmonary Disease
Design	Prospective observational cohort study N= 82
Objective	To evaluate the outcomes of treatment-naive patients with Mycobacterium abscessus pulmonary disease treated with inhaled amikacin-containing multidrug regimens
Study Groups	M massiliense-PD (n= 46) M abscessus-PD (n= 36)
Inclusion Criteria	Patients with M abscessus-PD who started inhaled amikacin with or without clofazimine between March 2015 and June 2018
Exclusion Criteria	Previously treated with inhaled amikacin or clofazimine as salvage therapy, treated for M abscessus-PD for more than 1 month, withdrew consent, or treated for less than 12 months
Methods	Patients received IV amikacin, imipenem (or cefoxitin), and oral azithromycin initially. Clofazimine was added for M abscessus or M massiliense with cavitary lesions. Amikacin was changed to inhalational form during continuation phase. Sputum examinations and chest CT scans were performed to evaluate outcomes.
Duration	March 2015 to June 2018
Outcome Measures	Primary: Cure rate at 12 months Secondary: Symptomatic and radiologic improvements, culture conversion, microbiologic cure
Baseline Characteristics		Total (N = 82)	M massiliense (n = 46)	M abscessus (n = 36)	P Value
	Age, y (range)	57 (52-66)	56 (51-66)	58 (52-65)	.904
	Sex, female (%)	70 (85)	38 (83)	32 (89)	.425
	BMI, kg/m2 (range)	20.1 (18.6-21.7)	20.2 (18.6-21.7)	19.8 (18.4-21.8)	.902
	Never smoker (%)	70 (85)	37 (80)	33 (92)	.314
	Previous TB treatment (%)	42 (51)	26 (57)	16 (44)	.278
	Positive sputum AFB smear (%)	40 (49)	23 (50)	17 (47)	.803
Results		Total (N = 82)	M massiliense (n = 46)	M abscessus (n = 36)	P Value
	Symptomatic response - Improved (%)	72 (88)	44 (96)	28 (78)	.047
	Radiographic response on CT scan - Improved (%)	64 (78)	42 (93)	22 (61)	.002
	Culture conversion (%)	56 (68)	44 (96)	12 (33)	< .001
	Microbiologic cure (%)	55 (67)	44 (96)	11 (31)	< .001
	Cure (%)	53 (65)	42 (91)	11 (31)	< .001
Adverse Events	Adverse effects from inhaled amikacin (23%), clofazimine (33%), and linezolid (41%) led to discontinuation or dose reduction. Ototoxicity was the most frequent adverse event related to inhaled amikacin. Skin discoloration and GI disturbance were common with clofazimine. Peripheral neuropathy was common with linezolid.
Study Author Conclusions	Inhaled amikacin with or without clofazimine provides favorable treatment outcomes in M massiliense-PD. However, more effective treatments are needed for M abscessus-PD.
Critique	The study provides valuable insights into the treatment of M abscessus-PD with inhaled amikacin-containing regimens. However, the generalizability may be limited due to geographic specificity. The short duration of the initial phase and exclusion of certain patients may have influenced outcomes. Additionally, the lack of drug level monitoring for inhaled amikacin and the exclusion of reinfection or relapse evaluation are limitations.

Table 6 References:
[7] Kang N, Jeon K, Kim H, et al. Outcomes of Inhaled Amikacin-Containing Multidrug Regimens for Mycobacterium abscessus Pulmonary Disease. Chest. 2021;160(2):436-445. doi:10.1016/j.chest.2021.02.025