Early-Phase Adverse Effects and Management of Liposomal Amikacin Inhalation for Refractory Mycobacterium avium Complex Lung Disease in Real-World Settings

Figures & data

Table 1 Patient Background Data (n=11)

Backgrounds	Median [Interquartile Range] or Number (%)
Age, years	64.6 [60.0–75.1]
Sex, Male/Female	2 (18.2)/9 (81.8)
Time from diagnosis until the initiation of treatment, years	13.7 [6.3–15.8]
Weight, kg	49.4 [44.7–51.5]
BMI, kg/m^2	19.8 [16.4–22.4]
Smoking history	2 (18.2)
Medical history
Bronchial asthma	2 (18.2)
Malignancy	2 (18.2)
Diabetes mellitus	1 (9.1)
Mycobacterium species
M. avium	10 (90.9)
M. intracellulare	1 (9.1)
Presence of cavitary lung lesions	4 (36.4)
Radiological pattern
NB/FC/NB+FC/unclassified	8 (72.7)/0 (0)/3 (27.3)/0 (0)
Number of GBT drugs in regimen (at baseline)
0/1/2/3/4 or more	0 (0)/0 (0)/5 (45.5)/4 (36.4)/2 (18.2)
Drug class (at baseline)
Macrolide	9 (81.8)
Ethambutol	10 (90.9)
Rifamycin	8 (72.7)
Fluoroquinolone	3 (27.3)
Others	0 (0)
Generic name of drug (at baseline)
Clarithromycin	3 (27.3)
Azithromycin	3 (27.3)
Erythromycin	3 (27.3)
Ethambutol	10 (90.9)
Rifampicin	8 (72.7)
Sitafloxacin	3 (27.3)

Abbreviations: FC, fibrocavitary type; GBT, guideline-based therapy; NB, nodular bronchiectatic type.

Table 2 Clinical Characteristics of Patients with Mycobacterium avium Complex Receiving ALIS

Case	Sex	Age	Species	MIC of CLA (μg/mL)	MIC of AMK (μg/mL)	Radiological Pattern	Prior Treatment	Total Treatment Duration Before ALIS (Year)	Drugs at ALIS Initiation	Sputum Culture Results Before ALIS Initiation	Sputum Culture Results 1 Month After ALIS Initiation
#1	F	56	M.avium	>32	4	NB	CLA, EB, RFP, RFB, EM, STFX	4.5	EB, RFP	+	+
#2	F	69	M.avium	4	1	NB+FC	CLA, EB, RFP, KM	19.8	CLA, EB, RFP	+	+
#3	M	76	M.avium	>32	16	NB	CLA, EB, RFP, EM	13.7	EB, RFP, EM	+	–
#4	F	69	M.avium	0.5	2	NB	CLA, EB, AZM	3.9	EB, AZM	+	–
#5	F	63	M.avium	>32	>16	NB+FC	CLA, EB, RFP, AMK div, AMK inh, STFX, LVFX	15.8	EB, RFP, STFX	+	+
#6	F	75	M.avium	0.5	16	NB	CLA, EB, RFP, RFB, AZM, AMK div, AMK inh	9.9	EB, AZM	+	–
#7	F	79	M.avium	>32	4	NB	CLA, EB, RFP	13.9	CLA, RFP	+	+
#8	F	64	M.avium	>32	>16	NB	CLA, EB, RFP, EM, SM, AMK div, AMK inh, STFX, SPFX, CPFX, ope	21.3	EB, RFP, EM, STFX	+	+
#9	M	61	M.avium	>32	8	NB	CLA, EB, RFP, EM, AMK div, STFX	7.3	EB, RFP, EM, STFX	+	+
#10	F	60	M.avium	2	8	NB+FC	CLA, EB, RFP, AZM, SM, CZM, LVFX	8.4	CLA, EB, RFP	+	+
#11	F	56	M.intracellulare	0.25	4	NB	CLA, EB, RFP, AZM	6.3	EB, AZM	+	+

Note: Sputum culture “+” denotes positive and “-” denotes negative.

Abbreviations: ALIS, amikacin liposome inhalation suspension; MIC, minimum inhibitory concentration; M, male; F, female; M.avium, Mycobacterium avium; M.intracellulare, Mycobacterium intracellulare; div, intravenous drip; inh, inhalation (non-liposomal); ope, operation; CLA, clarithromycin; EB, ethambutol; RFP, rifampicin; RFB, rifabutin; EM, erythromycin; STFX, sitafloxacin; KM, kanamycin; AZM, azithromycin; AMK, amikacin; LVFX, levofloxacin; SM, streptomycin; SPFX, sparfloxacin; CPFX, ciprofloxacin; CZM, clofazimine; NB, nodular bronchiectatic type; FC, fibrocavitary type.

Figure 1 Sputum smear results over time and duration of adverse effects in each case. Halftone pattern indicates the period during ALIS treatment. Smear results are shown as (-) to (3+) depending on the amount of bacteria based on the bacterial collection method. The end point of the solid arrow indicates the day when the side effect disappeared, and the end point of the dotted arrow indicates a state of general improvement.

Table 3 Adverse Event Profiling of ALIS (n=11)

Adverse Event	n (%)
Uncomfortable feeling in the oral cavity	5 (45.5)
Hoarseness	8 (72.7)
Dysphonia	5 (45.5)
Hypersensitivity pneumonitis	2 (18.2)
Hemoptysis	1 (9.1)
Digestive symptom	1 (9.1)
Vertigo	1 (9.1)
Renal toxicity	0 (0)
Auditory toxicity	0 (0)

Abbreviation: ALIS, amikacin liposome inhalation suspension.

Table 4 Clinical Symptoms Before and After ALIS (Number [%])

Clinical Symptom	Before Treatment (n=11)	After Treatment (n=11)	P value^a
Cough	9 (81.8)	7 (63.6)	0.1573
Sputum	10 (90.9)	8 (72.7)	0.1573
Dyspnea	3 (27.3)	3 (27.3)	0.5637
Hemoptysis	3 (27.3)	2 (18.2)	1.0000
Fever	1 (9.1)	1 (9.1)	1.0000

Note: ^aMcNemar’s test.

Abbreviation: ALIS, amikacin liposome inhalation suspension.

Table 5 Serum Amikacin Concentrations (n=11)

Serum Amikacin Concentrations (μg/mL)	n (%)
(A) Serum amikacin concentrations 1 h after the start of the first ALIS inhalation (peak concentration)
< 0.8	0 (0)
0.8 to <1.6	8 (72.7)
1.6 to <2.4	3 (27.3)
2.4 to <3.2	0 (0)
3.2 to <4.0	0 (0)
≥ 4.0	0 (0)
(B) Serum amikacin concentrations just before the start of the third ALIS inhalation (trough concentrations)
< 0.8	9 (81.8)
0.8 to <1.2	2 (18.2)
≥ 1.2	0 (0)
(C) Serum amikacin concentrations 1 h after the start of the third ALIS inhalation (peak concentration)
< 0.8	1 (9.1)
0.8 to <1.6	1 (9.1)
1.6 to <2.4	4 (36.4)
2.4 to <3.2	2 (18.2)
3.2 to <4.0	2 (18.2)
≥ 4.0	1 (9.1)

Abbreviation: ALIS, amikacin liposome inhalation suspension.