Supplemental Digital Content
Figure S1.Rates of clinical response by weeks 6 and 12 (blue and red bars, respectively) according to the certainty of diagnosis as per the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) criteria.
Figure S2.Comparison of the corrected QT interval from baseline to week 2 after the initiation of isavuconazole therapy in the 39 patients with repeated 12-lead electrocardiograms available.
Table S1. Comparison of efficacy and safety outcomes across different types of solid organ transplantation.
Study outcome, n (%) Kidney/kidney pancreas
(n = 29)
Liver (n = 15)
Lung (n = 23)
Heart (n = 11)
Small bowel/
multivisceral (n = 3)
P
Efficacy outcomes
Clinical response by week 6 16 (55.2) 9 (60.0) 12 (52.2) 4 (36.4) 2 (66.7) 0.772 Clinical response by week 12 17 (58.6) 9 (60.0) 12 (52.2) 4 (36.4) 2 (66.7) 0.723
All-cause mortality by week 6 8 (27.6) 4 (26.7) 2 (8.7) 3 (27.3) 1 (33.3) 0.483
All-cause mortality by week 12 8 (27.6) 5 (33.3) 7 (30.4) 5 (45.5) 1 (33.3) 0.876 IMD-attributable mortality by week 6 7 (24.1) 3 (20.0) 2 (8.7) 3 (27.3) 1 (33.3) 0.580 IMD-attributable mortality by week 12 7 (24.2) 3 (20.0) 3 (13.0) 4 (36.4) 1 (33.3) 0.607 Safety outcomes
Occurrence of ≥1 TEAE 4 (13.8) 3 (20.0) 5 (21.7) 2 (18.2) 0 (0.0) 0.865
TEAE requiring premature
discontinuation of therapy 3 (10.3) 0 (0.0) 2 (8.7) 0 (0.0) 0 (0.0) 0.552
IMD, invasive mould disease; TEAE, treatment-emergent adverse event.
Table S2. Univariate analysis of factors predicting clinical response by week 6 after the initiation of isavuconazole therapy (primary efficacy outcome).
Clinical response by week 6
(n = 43)
No clinical response by week 6
(n = 38)
Univariate Multivariate
OR (95% CI) P OR (95% CI) P
0.847 0.54 (0.22 – 1.33) 0.177 0.66 (0.27 – 1.60) 0.355
6.19 (1.27 – 30.04) 0.013 – –
0.586 0.39 (0.11 – 1.39) 0.137 1.65 (0.44 – 6.16) 0.451 0.55 (0.05 – 6.37) 1.000 2.41 (0.42 – 13.98) 0.412 0.69 (0.27 – 1.75) 0.431 1.94 (0.54 – 7.06) 0.307 1.07 (0.45 – 2.58) 0.873 1.52 (0.62 – 3.75) 0.359 1.03 (0.41 – 2.58) 0.949 Age at diagnosis of IMD, mean ± SD, years
Male gender, n (%)
Thoracic organ transplantation, n (%)a Previous solid organ transplantation, n (%) Time interval from transplantation to diagnosis of IMD, median (IQR), days
Donation after circulatory death donor, n (%) Induction with T-cell-depleting agents, n (%) Corticosteroids at diagnosis, n (%)
Tacrolimus at diagnosis, n (%) MMF/MPS at diagnosis, n (%) mTOR inhibitor at diagnosis, n (%) Chronic lung disease, n (%) Chronic renal disease, n (%) Diabetes mellitus, n (%)
60.0 ± 11.4 30 (69.8) 16 (37.2) 11 (25.6) 226 (51 – 2201)
4 (9.3) 7 (16.3) 41 (95.3) 41 (95.3) 27 (62.8) 8 (18.6) 20 (46.5) 19 (44.2) 15 (34.9)
59.5 ± 10.7 21 (55.3) 18 (47.4) 2 (5.3) 304 (68.5 – 1401.5)
8 (21.1) 4 (10.5) 37 (97.4) 34 (89.5) 27 (71.1) 4 (10.5) 17 (44.7) 13 (34.2) 13 (34.2)
5 (11.6) 2 (5.3) 2.37 (0.43 – 12.99) 0.439
1 (2.3) 7 (18.4) 0.11 (0.01 – 0.90) 0.023 0.07 (0.01 – 0.72) 0.025
8 (18.6) 9 (23.7) 0.74 (0.25 – 2.15) 0.575
12 (27.9) 18 (47.7) 0.43 (0.17 – 1.08) 0.070 34 (79.1) 25 (65.8) 1.96 (0.73 – 5.31) 0.180
5.8 (4.3 – 10.2) 6.0 (3.5 – 11.4) 0.891
4.2 (2.9 – 6.8) 5.3 (2.9 – 10.6) 0.159
0.8 (0.4 – 1.6) 0.4 (0.2 – 1.0) 0.009
15 (34.9) 25 (65.8) 0.27 (0.11 – 0.69) 0.005 – –
1.4 (0.9 – 2.0) 1.3 (0.7 – 2.3) 0.551
17.5 (12.8 – 31.8) 22.0 (14.0 – 62.0) 0.132
ECMO, n (%)b
Disseminated IMD, n (%) Breakthrough IMD, n (%)
Combination antifungal therapy, n (%) Isavuconazol as first-line therapy, n (%) WBC count, median (IQR),c x 109 cells/L Neutrophil count, median (IQR),c x 109 cells/L Lymphocyte count, median (IQR),c x 109 cells/L Lymphocyte count <0.7 x 109 cells/L, n (%)c Creatinine, median (IQR),c mg/dL
ALT, median (IQR),c U/L
AST, median (IQR),cU/L 19.0 (14.0 – 29.0) 27.0 (18.0 – 59.8) 0.024
17 (42.5) 20 (66.7) 0.37 (0.14 – 0.99) 0.045 0.25 (0.08 – 0.76) 0.015
84.0 (62.0 – 159.0) 129.0 (83.5 – 267.5) 0.022
17 (43.6) 18 (62.1) 0.47 (0.18 – 1.26) 0.132
55.0 (26.8 – 162.5) 74.0 (43.0 – 361.0) 0.297
AST >22.0 U/L, n (%)c ALP, median (IQR),cU/L ALP >100.0 U/L, n (%)c GGT, median (IQR)cU/L
Bilirubin, median (IQR),cmg/dL 0.5 (0.3 – 0.9) 0.6 (0.3 – 1.0) 0.630
aIncludes lung and heart transplantation.
bWithin the 3 months prior to the diagnosis of IMD.
cAt diagnosis of IMD.
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CMV, cytomegalovirus; ECMO, extracorporeal membrane
oxygenation; GGT, gamma-glutamyl transferase; HCV, hepatitis C virus; IMD, invasive mould disease; IQR, interquartile range; MMF/MPS, mycophenolate mofetil / mycophenolate sodium;
mTOR, mammalian target of rapamycin; OR, odds ratio; WBC: white blood cell.
Table S3. Univariate analysis of factors predicting clinical response by week 12 after the initiation of isavuconazole therapy (primary efficacy outcome).
Clinical response by week 12
(n = 44)
No clinical response by week 12
(n = 37)
Univariate Multivariate
OR (95% CI) P OR (95% CI) P
0.893 0.76 (0.31 – 1.88) 0.549 0.60 (0.25 – 1.47) 0.264
5.83 (1.20 – 28.32) 0.017 – –
0.909 0.55 (0.16 – 1.90) 0.340 2.52 (0.62 – 10.29) 0.187 0.58 (0.05 – 6.70) 1.000 2.55 (0.44 – 14.76) 0.404 0.74 (0.29 – 1.89) 0.528 1.83 (0.51 – 6.66) 0.352 0.80 (0.33 – 1.93) 0.623 1.74 (0.70 – 4.31) 0.232 1.19 (0.47 – 2.99) 0.711 Age at diagnosis of IMD, mean ± SD, years
Male gender, n (%)
Thoracic organ transplantation, n (%)a Previous solid organ transplantation, n (%) Time interval from transplantation to diagnosis of IMD, median (IQR), days
Donation after circulatory death donor, n (%) Induction with T-cell-depleting agents, n (%) Corticosteroids at diagnosis, n (%)
Tacrolimus at diagnosis, n (%) MMF/MPS at diagnosis, n (%) mTOR inhibitor at diagnosis, n (%) Chronic lung disease, n (%) Chronic renal disease, n (%) Diabetes mellitus, n (%)
59.9 ± 11.2 29 (65.9) 16 (36.4) 11 (25.0) 230.5 (51 – 2203.3)
5 (11.4) 8 (18.2) 42 (95.5) 42 (95.5) 28 (63.6) 8 (18.2) 19 (43.2) 20 (45.4) 16 (36.4)
59.6 ± 10.9 22 (59.5) 18 (48.6) 2 (5.4) 248 (63 – 1163.5)
7 (18.9) 3 (8.1) 36 (97.3) 33 (89.2) 26 (70.3) 4 (10.8) 18 (48.6) 12 (32.4) 12 (32.4)
5 (11.4) 2 (5.4) 2.24 (0.41 – 12.31) 0.445
1 (2.3) 7 (18.9) 0.10 (0.01 – 0.85) 0.021 0.06 (0.01 – 0.67) 0.022
9 (20.5) 8 (21.6) 0.93 (0.32 – 2.72) 0.898
12 (27.3) 18 (48.6) 0.39 (0.16 – 0.99) 0.047 – –
36 (81.8) 23 (62.2) 2.74 (0.99 – 7.55) 0.048 – –
5.7 (4.4 – 9.3) 6.2 (3.5 – 11.7) 0.753
4.3 (2.9 – 6.8) 5.5 (2.7 – 10.7) 0.124
0.8 (0.4 – 15.3) 0.4 (0.2 – 1.0) 0.008
16 (36.4) 24 (64.9) 0.31 (0.12 – 0.77) 0.011 – –
1.4 (0.8 – 1.9) 1.4 (0.7 – 2.3) 0.876
18.0 (13.0 – 30.0) 22.0 (14.0 – 64.5) 0.103
ECMO, n (%)b
Disseminated IMD, n (%) Breakthrough IMD, n (%)
Combination antifungal therapy, n (%) Isavuconazol as first-line therapy, n (%) WBC count, median (IQR),c x 109 cells/L Neutrophil count, median (IQR),c x 109 cells/L Lymphocyte count, median (IQR),c x 109 cells/L Lymphocyte count <0.7 x 109 cells/L, n (%)c Creatinine, median (IQR),cmg/dL
ALT, median (IQR),c U/L
AST, median (IQR),cU/L 19.0 (14.0 – 29.0) 27.0 (19.0 – 90.0) 0.010
17 (41.5) 20 (69.0) 0.32 (0.12 – 0.87) 0.023 0.24 (0.07 – 0.79) 0.019
83.5 (62.0 – 158.5) 131.5 (86.0 – 269.3) 0.007
16 (40.0) 19 (67.9) 0.32 (0.12 – 0.87) 0.024 – –
54.0 (27.0 – 141.0) 75.0 (45.3 – 378.8) 0.191
AST >22.0 U/L, n (%)c ALP, median (IQR),cU/L ALP >100.0 U/L, n (%)c GGT, median (IQR),cU/L
Bilirubin, median (IQR),cmg/dL 0.4 (0.3 – 0.9) 0.6 (0.3 – 1.1) 0.315
aIncludes lung and heart transplantation.
bWithin the 3 months prior to the diagnosis of IMD.
cAt diagnosis of IMD.
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CMV, cytomegalovirus; ECMO, extracorporeal membrane oxygenation; GGT, gamma-glutamyl transferase; HCV, hepatitis C virus; IMD, invasive mould disease; IQR, interquartile range; MMF/MPS, mycophenolate mofetil / mycophenolate sodium; mTOR, mammalian target of rapamycin; OR, odds ratio; WBC, white blood cell.