Efficacy and Safety of Combination Antifungals as Empirical, Preemptive, and Targeted Therapies for Invasive Fungal Infections in Intensive-Care Units

Figures & data

Table 1 Demographics and Outcomes of All Intensive Care Unit Patients Receiving CAS, VOR or the Combination Therapy for Invasive Fungal Infections^a

Demographics and Outcomes	CAS (n = 53)	VOR (n = 56)	CAS+VOR (n = 55)	P-value
Sex (male/female)	36/17	28/28	34/21	0.151
Median age (range) (years)	65 (28–97)	65 (30–95)	55 (19–92)	0.011
Median hospitalization days (range)	18 (8–71)	19 (7–58)	21 (7–77)	0.713
Median duration of antifungal agents therapy (range)	11 (7–32)	11 (7–28)	12 (8–27)	0.283
IFI diagnosis
Definite (Candida.spp/Aspergillus.spp/others)	23 (20/2/1)	29 (20/9/0)	21 (15/5/1)	0.347
Probable	30	27	34	0.347
Hypoproteinemia (%)	45 (84.9)	43 (76.8)	41 (76.4)	0.386
Continuous renal replacement therapy (%)	15 (28.3)	17 (30.4)	12 (21.8)	0.572
Liver function (Child-Pugh A/B/C)	22/26/5	23/30/3	18/33/4	> 0.05
Median creatinine clearance rate (range) (mL/min)	81.3 (7.7–592.0)	106.5 (26.6–587.1)	86.9 (10.0–478.7)	0.136
Median APACHE II score (range)	25 (7–42)	19 (6–34)	21 (7–30)	0.100
Median SOFA score (range)	12 (2–18)	8 (1–19)	11 (5–14)	0.623
Increase in neutrophils (On admission/ infection occurs/at the end of treatment)	39/44/34	44/51/43	35/42/38	> 0.05
Steroid use before or during therapy (%)	39 (73.6)	40 (71.4)	49 (89.1)	0.051
Mechanical ventilation during therapy (%)	34 (64.2)	48 (85.7)	43 (78.2)	0.028
Prophylactic antifungal treatment prior to infection (%)	14 (26.4)	12 (21.4)	22 (40.0)	0.085
Breakthrough infection (%)	1 (1.9)	0 (0)	1 (1.8)	0.548
Response to therapy (%)	37 (69.8)	34 (60.7)	31 (56.4)	0.340
IFI-associated death within 90 days (%)	7 (13.2)	8 (14.3)	1 (1.8)	0.035
All deaths within 90 days (%)	15 (28.3)	14 (25.0)	19 (34.5)	0.547
All adverse events (%)	12 (22.6)	30 (53.6)	19 (34.5)	0.003
Liver (%)	4 (7.5)	11 (19.6)	7 (12.7)	0.187
Renal (%)	4 (7.5)	15 (26.8)	7 (12.7)	0.021

Notes: ^aThe total number of all intensive care unit patients receiving CAS, VOR or the combination therapy was 164.

Table 2 Demographics and Outcomes of Intensive Care Unit Patients Receiving Empirical or Preemptive Therapy of CAS, VOR or the Combination for Invasive Fungal Infections^a

Demographics and Outcomes	CAS (n = 30)	VOR (n = 27)	CAS+VOR (n = 34)	P-value
Sex (male/female)	21/9	12/15	23/11	0.092
Median age (range) (years)	58.5 (28–97)	60 (38–95)	53 (19–85)	0.061
Median hospitalization days (range)	19.5 (8–71)	19 (8–41)	18 (7–77)	0.591
Median duration of antifungal agents therapy (range)	11 (7–32)	11 (7–19)	8.5 (7–27)	0.087
Hypoproteinemia (%)	25 (83.3)	19 (70.4)	28 (82.4)	0.445
Continuous renal replacement therapy (%)	6 (20.0)	8 (29.6)	6 (17.6)	0.506
Liver function (Child-Pugh A/B/C)	14/14/2	15/10/2	12/21/1	> 0.05
Median creatinine clearance rate (range) (mL/min)	81.0 (11.5–592.0)	104.4 (26.6–556.4)	84.9 (10.0–400.1)	0.231
Median APACHE II score (range)	23 (7–39)	18 (6–25)	21 (7–25)	0.232
Median SOFA score (range)	10 (2–16)	7 (1–15)	10 (5–12)	0.503
Increase in neutrophils (On admission/ infection occurs/at the end of treatment)	20/24/18	21/24/23	20/23/23	> 0.05
Steroid use before or during therapy (%)	20 (66.7)	20 (74.1)	32 (94.1)	0.014
Mechanical ventilation during therapy (%)	15 (50.0)	24 (88.9)	25 (73.5)	0.005
Prophylactic antifungal treatment prior to infection (%)	6 (20.0)	5 (18.5)	15 (44.1)	0.052
Breakthrough infection (%)	0 (0)	0 (0)	0 (0)	—
Response to therapy (%)	24 (80.0)	16 (59.3)	16 (47.1)	0.025
IFI-associated death within 90 days (%)	0 (0)	1 (3.7)	0 (0)	0.297
All deaths within 90 days (%)	8 (26.7)	7 (25.9)	16 (47.1)	0.130
All adverse events (%)	6 (20.0)	17 (63.0)	11 (32.4)	0.003
Liver (%)	2 (6.7)	8 (29.6)	4 (11.8)	0.058
Renal (%)	2 (6.7)	7 (25.9)	4 (11.8)	0.115

Note: ^aThe total number of intensive care unit patients receiving empirical or preemptive therapy of CAS, VOR or the combination was 91.

Table 3 Demographics and Outcomes of Intensive Care Unit Patients Receiving Targeted Therapy of CAS, VOR or the Combination for Invasive Fungal Infections^a

Demographics and Outcomes	CAS (n = 23)	VOR (n = 29)	CAS+VOR (n = 21)	P-value
Sex (male/female)	15/8	16/13	11/10	0.654
Median age (range) (years)	69 (28–87)	67 (30–86)	66 (25–92)	0.208
Median hospitalization days (range)	18 (8–70)	19 (7–58)	28 (7–58)	0.097
Median duration of antifungal agents therapy (range)	11 (7–27)	11 (7–28)	12 (7–26)	0.969
Infection type (Candida.spp/Aspergillus.spp/others)	23 (20/2/1)	29 (20/9/0)	21 (15/5/1)	> 0.05
Hypoproteinemia (%)	20 (87.0)	24 (82.8)	13 (61.9)	0.097
Continuous renal replacement therapy (%)	9 (39.1)	9 (31.0)	6 (28.6)	0.730
Liver function (Child-Pugh A/B/C)	8/12/3	8/20/1	6/12/3	> 0.05
Median creatinine clearance rate (range) (mL/min)	81.5 (7.7–428.7)	108.6 (36.5–271.1)	106.5 (15.1–478.7)	0.473
Median APACHE II score (range)	37 (9–42)	21 (10–34)	25 (12–30)	0.201
Median SOFA score (range)	15 (6–18)	11 (7–19)	12 (9–14)	0.753
Increase in neutrophils (On admission/ infection occurs/at the end of treatment)	19/23/15	20/27/19	16/20/15	> 0.05
Steroid use before or during therapy (%)	19 (82.6)	20 (69.0)	17 (81.0)	0.504
Mechanical ventilation during therapy (%)	19 (82.6)	24 (82.8)	18 (85.7)	1.000
Prophylactic antifungal treatment prior to infection (%)	8 (34.8)	7 (24.1)	7 (33.3)	0.689
Breakthrough infection (%)	1 (4.3)	0 (0)	1 (4.8)	0.514
Response to therapy (%)	13 (56.5)	18 (62.1)	15 (71.4)	0.587
IFI-associated death within 90 days (%)	7 (30.4)	7 (24.1)	1 (4.8)	0.084
All deaths within 90 days (%)	7 (30.4)	7 (24.1)	3 (14.3)	0.504
All adverse events (%)	6 (26.1)	13 (44.8)	8 (38.1)	0.377
Liver (%)	2 (8.7)	3 (10.3)	3 (14.3)	0.805
Renal (%)	2 (8.7)	8 (27.6)	3 (14.3)	0.212

Note: ^aThe total number of intensive care unit patients receiving targeted therapy of CAS, VOR or the combination was 73.

Table 4 Demographics and Outcomes of All Intensive Care Unit Patients Receiving CAS, L-AmB or the Combination Therapy for Invasive Fungal Infections^a

Demographics and Outcomes	CAS (n = 53)	L-AmB (n = 20)	CAS+L-AmB (n = 22)	P-value
Sex (male/female)	36/17	9/11	13/9	0.196
Median age (range) (years)	65 (28–97)	51 (25–79)	54 (21–87)	0.004
Median hospitalization days (range)	18 (8–71)	23 (8–92)	23 (7–59)	0.514
Median duration of antifungal agents therapy (range)	11 (7–32)	10 (7–30)	9 (7–44)	0.179
IFI diagnosis
Definite (Candida.spp/Aspergillus.spp/others)	23 (20/2/1)	4 (3/1/0)	10 (6/3/1)	0.149
Probable	30	16	12	0.149
Hypoproteinemia (%)	45 (84.9)	15 (75.0)	14 (63.6)	0.128
Continuous renal replacement therapy (%)	15 (28.3)	4 (20.0)	7 (31.8)	0.707
Liver function (Child-Pugh A/B/C)	22/26/5	9/11/0	5/16/1	> 0.05
Median creatinine clearance rate (range) (mL/min)	81.3 (7.7–592.0)	122.8 (12.2–210.7)	89.4 (16.5–482.2)	0.095
Median APACHE II score (range)	25 (7–42)	16 (4–28)	27 (6–38)	0.200
Median SOFA score (range)	12 (2–18)	7 (1–14)	15 (5 −20)	0.722
Increase in neutrophils (On admission/ infection occurs/at the end of treatment)	39/44/34	13/13/9	15/19/14	> 0.05
Steroid use before or during therapy (%)	39 (73.6)	14 (70.0)	22 (100.0)	0.008
Mechanical ventilation during therapy (%)	34 (64.2)	6 (30.0)	12 (54.5)	0.033
Prophylactic antifungal treatment prior to infection (%)	14 (26.4)	10 (50.0)	9 (40.9)	0.132
Breakthrough infection (%)	1 (1.9)	0 (0)	0 (0)	1.000
Response to therapy (%)	37 (69.8)	16 (80.0)	15 (68.2)	0.679
IFI-associated death within 90 days (%)	7 (13.2)	2 (10.0)	3 (13.6)	1.000
All deaths within 90 days (%)	15 (28.3)	4 (20.0)	4 (18.2)	0.721
All adverse events (%)	12 (22.6)	9 (45.0)	8 (36.4)	0.144
Liver (%)	4 (7.5)	4 (20.0)	1 (4.5)	0.229
Renal (%)	4 (7.5)	3 (15.0)	4 (18.2)	0.309

Note: ^aThe total number of all intensive care unit patients receiving CAS, L-AmB or the combination therapy was 95.

Table 5 Demographics and Outcomes of Intensive Care Unit Patients Receiving Empirical and Preemptive Therapy of CAS, L-AmB or the Combination for Invasive Fungal Infections^a

Demographics and Outcomes	CAS (n = 30)	L-AmB (n = 16)	CAS+L-AmB (n = 12)	P-value
Sex (male/female)	21/9	8/8	9/3	0.316
Median age (range) (years)	58.5 (28–97)	50.5 (25–68)	59.5 (27–74)	0.178
Median hospitalization days (range)	19.5 (8–71)	20.5 (8–92)	21.5 (7–48)	0.981
Median duration of antifungal agents therapy (range)	11 (7–32)	8.5 (7–30)	12.5 (7–44)	0.195
Hypoproteinemia (%)	25 (83.3)	12 (75.0)	7 (58.3)	0.237
Continuous renal replacement therapy (%)	6 (20.0)	1 (6.3)	3 (25.0)	0.376
Liver function (Child-Pugh A/B/C)	14/14/2	8/8/0	5/7/0	> 0.05
Median creatinine clearance rate (range) (mL/min)	81.0 (11.5–592.0)	130.8 (12.2–210.7)	89.4 (61.7–324.1)	0.124
Median APACHE II score (range)	23 (7–39)	14 (4–21)	22 (6–27)	0.256
Median SOFA score (range)	10 (2–16)	6 (1–12)	13 (5 −18)	0.223
Increase in neutrophils (On admission/ infection occurs/at the end of treatment)	20/24/18	9/9/5	6/10/9	> 0.05
Steroid use before or during therapy (%)	20 (66.7)	11 (68.8)	12 (100)	0.058
Mechanical ventilation during therapy (%)	15 (50.0)	3 (18.8)	5 (41.7)	0.139
Prophylactic antifungal treatment prior to infection (%)	6 (20.0)	9 (56.3)	6 (50.0)	0.028
Breakthrough infection (%)	0 (0)	0 (0)	0 (0)	—
Response to therapy (%)	24 (80.0)	14 (87.5)	9 (75.0)	0.681
IFI-associated death within 90 days (%)	0 (0)	0 (0)	0 (0)	—
All deaths within 90 days (%)	8 (26.7)	2 (12.5)	1 (8.3)	0.409
All adverse events (%)	6 (20.0)	6 (37.5)	5 (41.7)	0.297
Liver (%)	2 (6.75)	4 (25.0)	1 (8.3)	0.237
Renal (%)	2 (6.7)	1 (6.3)	2 (16.7)	0.587

Note: ^aThe total number of intensive care unit patients receiving empirical and preemptive therapy of CAS, L-AmB or the combination was 58.

Table 6 Demographics and Outcomes of Intensive Care Unit Patients Receiving Targeted Therapy of CAS, L-AmB or the Combination for Invasive Fungal Infections^a

Demographics and Outcomes	CAS (n = 23)	L-AmB (n = 4)	CAS+L-AmB (n = 10)	P-value
Sex (male/female)	15/8	1/3	4/6	0.253
Median age (range) (years)	69 (28–87)	54.5 (41–79)	43 (21–87)	0.031
Median hospitalization days (range)	18 (8–70)	39.5 (27–57)	25 (8–59)	0.037
Median duration of antifungal agents therapy (range)	11 (7–27)	12.5 (10–25)	7.5 (7–27)	0.119
Infection type (Candida.spp/Aspergillus.spp/others)	23 (20/2/1)	4 (3/1/0)	10 (6/3/1)	> 0.05
Hypoproteinemia (%)	20 (87.0)	3 (75.0)	7 (70.0)	0.366
Continuous renal replacement therapy (%)	9 (39.1)	4 (100.0)	4 (40.0)	0.730
Liver function (Child-Pugh A/B/C)	8/12/3	1/3/0	0/9/1	> 0.05
Median creatinine clearance rate (range) (mL/min)	81.5 (7.7–428.7)	107.8 (62.0–144.8)	122.3 (16.5–478.7)	0.545
Median APACHE II score (range)	37 (9–42)	21 (7–28)	29 (10–38)	0.512
Median SOFA score (range)	15 (6–18)	9 (3–14)	17 (7 −20)	0.198
Increase in neutrophils (On admission/ infection occurs/at the end of treatment)	19/23/15	4/4/4	9/9/5	> 0.05
Steroid use before or during therapy (%)	19 (82.6)	3 (75.0)	10 (100.0)	0.347
Mechanical ventilation during therapy (%)	19 (82.6)	3 (75.0)	7 (70.0)	0.138
Prophylactic antifungal treatment prior to infection (%)	8 (34.8)	1 (25.0)	7 (70.0)	0.689
Breakthrough infection (%)	1 (4.3)	0 (0)	0 (0)	1.000
Response to therapy (%)	13 (56.5)	2 (50.0)	6 (60.0)	1.000
IFI-associated death within 90 days (%)	7 (30.4)	2 (50.0)	3 (30.0)	0.762
All deaths within 90 days (%)	7 (30.4)	2 (50.0)	3 (30.0)	0.762
All adverse events (%)	6 (26.1)	3 (75.0)	3 (30.0)	0.168
Liver (%)	2 (8.7)	0 (0)	0 (0)	1.000
Renal (%)	2 (8.7)	2 (50.0)	2 (20.0)	0.104

Note: ^aThe total number of intensive care unit patients receiving targeted therapy of CAS, L-AmB or the combination was 37.

Figure 1 Composition flowchart of ICUs. ICUs: intensive-care units; CAS, caspofungin; VOR, voriconazole; L-AmB, amphotericin B liposome. The bold texts represent the number of patients receiving empirical therapy, preemptive therapy and targeted therapy of CAS, VOR, CAS+VOR, L-AmB and CAS+L-AmB, respectively.

Figure 2 Estimated cumulative incidence curves of invasive fungal infection (IFI) associated death within 90 days (A), and all deaths within 90 days (B) for ICU patients receiving CAS, VOR or the combination therapy (For all patients, n = 164).

Figure 3 Estimated cumulative incidence curves of invasive fungal infection (IFI) associated death within 90 days (A), and all deaths within 90 days (B) for ICU patients receiving CAS, L-AmB or the combination therapy (For all patients, n = 95).