TDM-Based Approach for Properly Managing Intravenous Isavuconazole Treatment in a Complex Case Mix of Critically Ill Patients
Abstract
1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Study Design
4.2. Data Collection
4.3. Outcome Definition
4.4. Isavuconazole Dosing Regimens, Sampling Procedure, and Definition of Optimal Exposure
4.5. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variables | Overall Patients (n = 32) |
---|---|
Demographics | |
Age (yrs; Median; [IQR]) | 62.0 (51.0–65.0) |
Gender (male/female; n [%]) | 25/7 (78.1/21.9) |
Weight (kg; Median; [IQR]) | 73.0 (60.8–85.8) |
Body mass index (kg/m2; Median; [IQR]) | 25.5 (22.3–27.8) |
Obesity (n; [%]) | 5 (15.6) |
Underlying disease (n; [%]) | |
Solid organ transplant recipient | 21 (65.6) |
Hematological malignancies | 6 (18.8) |
CAPA | 5 (15.6) |
Pathophysiological conditions | |
SOFA score (Median; [IQR]) | 8 (5–11) |
Vasopressors (n; [%]) | 19 (59.4) |
Mechanical ventilation (n; [%]) | 25 (78.1) |
PaO2/FiO2 ratio (Median; [IQR]) | 166.0 (122.8–197.3) |
PaO2/FiO2 ratio < 200 (n; [%]) | 24 (75.0) |
Continuous renal replacement therapy (n; [%]) | 16 (50.0) |
Cytosorb hemoadsorption (n; [%]) | 2 (6.3) |
Extracorporeal membrane oxygenation (n; [%]) | 0 (0.0) |
Serum albumin (g/dL; Median; [IQR]) | 2.8 (2.5–3.1) |
Patients with moderate/severe hypoalbuminemia (n; [%]) | 22 (68.7) |
Concomitant use of CYP3A4 strong inducers * (n; [%]) | 1 (3.1) |
Concomitant use of CYP3A4 strong inhibitors * (n; [%]) | 0 (0.0) |
IFI classification ** (n; [%]) | |
Proven | 1 (3.1) |
Probable | 25 (78.1) |
Possible | 2 (6.3) |
No IFI | 4 (12.5) |
Documentation of IFI | |
Patients with Aspergillus spp. isolated from BAL (n; [%]) | 6 (18.7) |
Patients with positive galactomannan antigen on BAL (n; [%]) | 28 (87.5) |
Patients with positive galactomannan antigen on serum (n; [%]) | 3 (9.4) |
Galactomannan antigen index on BAL in positive patients (Median; [IQR]) | 2.6 (2.0–4.2) |
Galactomannan antigen index on serum in positive patients (Median; [IQR]) | 2.9 (2.0–7.4) |
Type of isavuconazole treatment (n; [%]) | |
First-line therapy | 6 (18.7) |
Second-line therapy | 22 (68.7) |
First-line prophylaxis | 2 (6.3) |
Second-line prophylaxis | 2 (6.3) |
Isavuconazole treatment regimens and PK/PD target attainment | |
Isavuconazole MD (mg/die; Median; [IQR]) | 200 (200–200) |
Treatment duration (days; Median; [IQR]) | 35.0 (12.5–47.75) |
Overall TDM-guided ECPA | 166 |
TDM-guided ECPA per patient (Median; [IQR]) | 4 (2–7) |
Average isavuconazole Cmin (mg/L; Median; [IQR]) | 3.5 (2.1–4.6) |
(patients; n; [%]) | 29 (90.6) |
Below desired range (patients; n; [%]) | 2 (6.3) |
Above desired range (patients; n; [%]) | 1 (3.1) |
Within desired range (ECPA; n; [%]) | 131 (78.9) |
Below desired range (ECPA; n; [%]) | 7 (4.2) |
Above desired range (ECPA; n; [%]) | 28 (16.9) |
Outcome (n; [%]) | |
HTD occurrence with no baseline alteration (n; [%]) | 5 (15.6) |
Reduction ≥50% from baseline of galactomannan antigen on BAL within 14 days *** | 16/23 (69.6) |
Breakthrough IFI | 0 (0.0) |
30-day mortality rate | 10 (31.3) |
Variables | Patients with No Isavuconazole Cmin Below Desired Range (n = 30) | Patients with Isavuconazole Cmin Below Desired Range (n = 2) | p Value |
---|---|---|---|
Demographics | |||
Age (yrs; Median; [IQR]) | 62.5 (51.0–65.0) | 53.0 (50.5–55.5) | 0.21 |
Gender (male/female; n [%]) | 23/7 (76.7/23.3) | 2/0 (100.0/0.0) | 0.99 |
Weight (kg; Median; [IQR]) | 72.5 (60.3–85.0) | 95.5 (83.3–107.8) | 0.24 |
Body mass index (kg/m2; Median; [IQR]) | 25.5 (22.0–27.7) | 30.1 (26.6–33.6) | <0.001 |
Obesity (n; [%]) | 4 (13.3) | 1 (50.0) | 0.29 |
Underlying disease (n; [%]) | |||
Solid organ transplant recipient | 21 (70.0) | 0 (0.0) | 0.11 |
Hematological malignancies | 5 (16.7) | 1 (50.0) | 0.34 |
CAPA | 4 (13.3) | 1 (50.0) | 0.29 |
Pathophysiological conditions | |||
SOFA score (Median; [IQR]) | 8.5 (5.25–11.0) | 6.5 (5.75–7.25) | 0.48 |
Vasopressors (n; [%]) | 17 (56.7) | 2 (100.0) | 0.50 |
Mechanical ventilation (n; [%]) | 23 (76.7) | 2 (100.0) | 0.99 |
PaO2/FiO2 ratio (Median; [IQR]) | 166.0 (122.25–195.5) | 181.5 (171.75–191.25) | 0.56 |
PaO2/FiO2 ratio < 200 (n; [%]) | 23 (76.7) | 1 (50.0) | 0.44 |
Continuous renal replacement therapy (n; [%]) | 15 (50.0) | 1 (50.0) | 0.99 |
Use of cytosorb hemoadsorption (n; [%]) | 1 (3.3) | 1 (50.0) | 0.12 |
Extracorporeal membrane oxygenation (n; [%]) | 0 (0.0) | 0 (0.0) | 0.99 |
Serum albumin (g/dL; Median; [IQR]) | 2.9 (2.6–3.1) | 2.4 (2.2–2.5) | 0.15 |
Patients with moderate/severe hypoalbuminemia (n; [%]) | 20 (66.7) | 2 (100.0) | 0.99 |
Concomitant use of CYP3A4 strong inducers * (n; [%]) | 0 (0.0) | 1 (50.0) | 0.06 |
IFI classification ** (n; [%]) | |||
Proven | 1 (3.3) | 0 (0.0) | 0.99 |
Probable | 24 (80.0) | 1 (50.0) | 0.40 |
Possible | 2 (6.7) | 0 (0.0) | 0.99 |
No IFI | 3 (10.0) | 1 (50.0) | 0.24 |
Type of isavuconazole treatment (n; [%]) | |||
First-line therapy | 6 (20.0) | 0 (0.0) | 0.99 |
Subsequent line of therapy | 21 (70.0) | 1 (50.0) | 0.53 |
First-line prophylaxis | 1 (3.3) | 1 (50.0) | 0.12 |
Second-line prophylaxis | 2 (6.7) | 0 (0.0) | 0.99 |
Isavuconazole treatment regimens and outcome | |||
Isavuconazole MD (mg/die; Median; [IQR]) | 200 (200–200) | 250 (200–300) | <0.001 |
Treatment duration (days; Median; [IQR]) | 37.0 (13.25–49.25) | 19.0 (15.0–23.0) | 0.37 |
HTD occurrence with no baseline alteration (n; [%]) | 5 (16.7) | 0 (0.0) | 0.99 |
Reduction ≥ 50% from baseline of galactomannan antigen on BAL within 14 days *** (n; [%]) | 15/21 (71.4) | 1/2 (50.0) | 0.53 |
Breakthrough IFI (n; [%]) | 0 (0.0) | 0 (0.0) | 0.99 |
30-day mortality rate (n; [%]) | 9 (30.0) | 1 (50.0) | 0.53 |
Isavuconazole Cmin (mg/L) | Day < 7 | Day 7–28 | Day > 28 | p Value |
---|---|---|---|---|
<1.0 (n; [%]) | 4/38 (10.5%) | 3/70 (4.3%) | 0/58 (0.0%) | <0.001 |
1.0–5.1 (n; [%]) | 32/38 (84.2%) | 58/70 (82.9%) | 41/58 (70.7%) | |
>5.1 (n; [%]) | 2/38 (5.3%) | 9/70 (12.8%) | 17/58 (29.3%) |
Variables | SOT Patients (n = 21) | Non-SOT Patients (n = 11) | p Value |
---|---|---|---|
Demographics | |||
Age (yrs; Median; [IQR]) | 62.0 (51.0–64.0) | 64.0 (54.5–65.0) | 0.55 |
Gender (male/female; n [%]) | 17/4 (81.0/19.0) | 8/3 (72.7/27.3) | 0.67 |
Weight (kg; Median; [IQR]) | 68.5 (60.0–80.0) | 84.0 (68.0–100.0) | 0.10 |
Body mass index (kg/m2; Median; [IQR]) | 24.2 (21.1–26.6) | 27.4 (23.5–30.4) | 0.10 |
Obesity (n; [%]) | 2 (9.5) | 3 (27.3) | 0.31 |
Pathophysiological conditions | |||
SOFA score (Median; [IQR]) | 8.0 (5.0–10.0) | 8.0 (6.5–11.0) | 0.56 |
Vasopressors (n; [%]) | 12 (57.1) | 7 (63.6) | 0.99 |
Mechanical ventilation (n; [%]) | 16 (76.2) | 9 (81.8) | 0.99 |
PaO2/FiO2 ratio (Median; [IQR]) | 180.0 (135.0–209.0) | 136.0 (91.5–179.0) | 0.10 |
PaO2/FiO2 ratio < 200 (n; [%]) | 15 (71.4) | 9 (81.8) | 0.68 |
Continuous renal replacement therapy (n; [%]) | 12 (57.1) | 4 (36.4) | 0.46 |
Use of cytosorb hemoadsorption (n; [%]) | 1 (4.8) | 1 (9.1) | 0.99 |
Extracorporeal membrane oxygenation (n; [%]) | 0 (0.0) | 0 (0.0) | 0.99 |
Serum albumin (g/dL; Median; [IQR]) | 2.88 (2.63–3.11) | 2.73 (2.41–3.22) | 0.76 |
Patients with moderate/severe hypoalbuminemia (n; [%]) | 14 (66.7) | 8 (72.7) | 0.99 |
Concomitant use of CYP3A4 strong inducers * (n; [%]) | 0 (0.0) | 1 (9.1) | 0.34 |
IFI classification ** (n; [%]) | |||
Proven | 1 (4.8) | 0 (0.0) | 0.99 |
Probable | 18 (85.7) | 7 (63.6) | 0.20 |
Possible | 2 (9.5) | 0 (0.0) | 0.53 |
Prophylaxis | 0 (0.0) | 4 (36.4) | 0.009 |
Type of isavuconazole treatment (n; [%]) | |||
First-line therapy | 4 (19.0) | 2 (18.2) | 0.99 |
Subsequent line of therapy | 17 (81.0) | 5 (45.4) | 0.06 |
Prophylaxis | 0 (0.0) | 4 (36.4) | 0.009 |
Isavuconazole treatment regimens and outcome | |||
Isavuconazole MD (mg/die; Median; [IQR]) | 200 (200–200) | 200 (200–200) | 0.33 |
Treatment duration (days; Median; [IQR]) | 42 (31–50) | 13 (8–26) | 0.02 |
Average isavuconazole Cmin (mg/L; Median; [IQR]) | 3.44 (2.41–4.03) | 2.20 (1.36–2.70) | 0.006 |
No. of TDM with isavuconazole underexposure *** (n; [%]) | 2/137 (1.5) | 5/29 (17.2) | 0.002 |
No. of TDM with isavuconazole overexposure *** (n; [%]) | 27/137 (19.7) | 0/29 (0.0) | 0.005 |
HTD occurrence in pts with normal baseline values (n; [%]) | 4 (19.0) | 1 (9.1) | 0.64 |
Reduction ≥ 50% from baseline of galactomannan antigen on BAL within 14 days **** (n; [%]) | 10/16 (62.5) | 6/7 (85.7) | 0.37 |
Breakthrough IFI (n; [%]) | 0 (0.0) | 0 (0.0) | 0.99 |
30-day mortality rate (n; [%]) | 5 (23.8) | 5 (45.5) | 0.21 |
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Gatti, M.; Rinaldi, M.; De Paola, R.; Siniscalchi, A.; Tonetti, T.; Viale, P.; Pea, F. TDM-Based Approach for Properly Managing Intravenous Isavuconazole Treatment in a Complex Case Mix of Critically Ill Patients. Antibiotics 2025, 14, 777. https://doi.org/10.3390/antibiotics14080777
Gatti M, Rinaldi M, De Paola R, Siniscalchi A, Tonetti T, Viale P, Pea F. TDM-Based Approach for Properly Managing Intravenous Isavuconazole Treatment in a Complex Case Mix of Critically Ill Patients. Antibiotics. 2025; 14(8):777. https://doi.org/10.3390/antibiotics14080777
Chicago/Turabian StyleGatti, Milo, Matteo Rinaldi, Riccardo De Paola, Antonio Siniscalchi, Tommaso Tonetti, Pierluigi Viale, and Federico Pea. 2025. "TDM-Based Approach for Properly Managing Intravenous Isavuconazole Treatment in a Complex Case Mix of Critically Ill Patients" Antibiotics 14, no. 8: 777. https://doi.org/10.3390/antibiotics14080777
APA StyleGatti, M., Rinaldi, M., De Paola, R., Siniscalchi, A., Tonetti, T., Viale, P., & Pea, F. (2025). TDM-Based Approach for Properly Managing Intravenous Isavuconazole Treatment in a Complex Case Mix of Critically Ill Patients. Antibiotics, 14(8), 777. https://doi.org/10.3390/antibiotics14080777