Intensive care unit-related fluconazole use in Spain and Germany: patient characteristics and outcomes of a prospective multicenter longitudinal observational study

Figures & data

Figure 1 Predefined definitions of successful therapy according to individual treatment arm.

Abbreviation: IV, intravenous.

Table 1 General patient characteristics

Parameter	All	Prophylaxis	Empiric therapy	Preemptive therapy	Definitive therapy
Total number of patients	303	29	140	85	49
Characteristic Age	n (%)	n (%)	n (%)	n (%)	n (%)
<65 years	162 (54%)	21 (72%)	84 (60%)	34 (40%)	23 (47%)
≥65 years	303 (47%)	8 (28%)	56 (40%)	51 (60%)	26 (53%)
Gender
Male	209 (69%)	22 (76%)	102 (73%)	52 (61%)	33 (67%)
Female	94 (31%)	7 (24%)	38 (27%)	33 (39%)	16 (33%)
Weight
<70 kg	79 (26%)	11 (38%)	29 (21%)	20 (24%)	19 (39%)
≥70 kg	224 (74%)	18 (62%)	111 (79%)	65 (76%)	30 (61%)
APACHE II score at start of antifungal treatment (mean ± SD)	19 ± 10	16 ± 7	19 ± 7	19 ± 8	21 ± 15
SOFA score at start of antifungal treatment (mean ± SD)	9 ± 5a	10 ± 5	8 ± 5	9 ± 4	7 ± 3
Neutropenic status at ICU admission < 500 cells/μL	20 (7%)	3 (10%)	14 (10%)	2 (2%)	1 (2%)
Mechanical ventilation at study entry	248 (82%)	22 (76%)	109 (78%)	75 (88%)	42 (86%)
Medical conditions before start of fluconazole therapy
<3	94 (31%)	14 (48%)	50 (36%)	19 (22%)	11 (23%)
Risk factors for developing fungal infections
<5	98 (32%)	4 (14%)	49 (35%)	28 (33%)	17 (35%)
Active malignancy	60 (20%)	11 (38%)	27 (19%)	10 (12%)	12 (25%)
Acute renal failure	141 (47%)	11 (38%)	62 (44%)	45 (53%)	23 (47%)
AIDS/HIV infection	9 (3%)	2 (7%)	5 (4%)	2 (2%)	0
Broad-spectrum antibiotic use immediately prior to IV fluconazole	287 (95%)	29 (100%)	130 (93%)	81 (95%)	47 (96%)
Recent use of central venous catheter	293 (97%)	29 (100%)	134 (96%)	81 (96%)	49 (100%)
Diabetes mellitus	92 (31%)	8 (28%)	37 (27%)	27 (32%)	20 (41%)
CRRT	96 (32%)	10 (35%)	42 (30%)	32 (38%)	12 (25%)
Immunosuppressive medication	51 (17%)	13 (45%)	25 (18%)	11 (13%)	2 (4%)
Neutropenia (ANc < 500 cells/μL)	20 (7%)	3 (10%)	14 (10%)	2 (2%)	1 (2%)
Recent parenteral nutrition	204 (67%)	21 (72%)	88 (63%)	60 (71%)	35 (71%)
Organ transplantation	26 (9%)	13 (45%)	10 (7%)	2 (2%)	1 (2%)
Prior fungal colonization	34 (11%)	1 (3%)	15 (11%)	13 (15%)	5 (10%)
Major surgery (within 30 days)	210 (69%)	25 (86%)	95 (68%)	54 (64%)	36 (74%)
Trauma	42 (14%)	4 (14%)	21 (15%)	12 (14%)	5 (10%)

Notes: Data are % of patients, unless otherwise indicated; ^an = 148.

Abbreviations: AIDS/HIV, acquired immunodeficiency syndrome/human immunodeficiency virus; ANC, absolute neutrophil count; APACHE II, Acute Physiology and Chronic Health Evaluation II; CRRT, (continuous) renal replacement therapy including hemodialysis; ICU, intensive care unit; IV, intravenous; SOFA, Sequential Organ Failure Assessment.

Table 2 Pathogens (n = 407) isolated at initiation or on intravenous fluconazole treatment in 251 patients with mycology results available

Pathogen	Number of isolates	%	% of all specified Candidaa
Candida	393	96.5
C. albicans	190	46.6	67.4
C. glabrata	38	9.3	13.5
C. krusei	9	2.2	3.2
C. tropicalis	25	6.1	8.9
C. parapsilosis	19	4.7	6.7
C. guillermondii	1	0.3	0.3
C. not specified	111	27.3
Aspergillus	10	2.5
Other fungib	4	1.0
Total	407	100.0

Notes: ^aIncludes C. albicans, C. glabrata, C. krusei, C. tropicalis, C. parapsilosis, C. guillermondii (n = 282);

b includes Mucor, Scedosporium, Trichosporon.

Table 3 Antifungal therapy characteristics by treatment group

Characteristic	All	Prophylaxis	Empiric therapy	Preemptive therapy	Definitive therapy
Time from hospital admission to antifungal therapy (days)	20.1 ± 16.8	12.3 ± 13.2	22.4 ± 20.1	19.3 ± 13.1	19.2 ± 12.4
Time from first ICU admission to initial IV fluconazole therapy (days)	15.3 ± 15.1	7.9 ± 10.3	16.3 ± 17.4	16.2 ± 13.4	15.6 ± 11.8
Initiation of IV fluconazole therapy
First-line	298 (100%)	29 (100%)	140 (100%)	84 (99%)	45 (92%)
Number of IV fluconazole treatment cycles	1.1 ± 0.3	1.0 ± 0.2	1.1 ± 0.3	1.1 ± 0.3	1.1 ± 0.3

Abbreviations: ICU, intensive care unit; IV, intravenous.

Table 4 Treatment response by sensitivity to fluconazole treatment in 152 patients with proven Candida infection only

Treatment response to IV fluconazole	Potentially sensitive	Potentially resistant	Total	P*
Prophylaxis
Failure	3	1	4	0.32
Success	6	2	8	0.16
Total	9	3	12
Empiric therapy
Failure	18	12	30	0.27
Success	25	9	34	0.01
Total	43	21	64
Preemptive therapy
Failure	12	8	20	0.37
Success	17	5	22	0.01
Total	29	13	42
Definitive therapy
Failure	12	8	20	0.37
Success	10	4	14	0.11
Total	22	12	34
Total
Failure	45	29	74	0.06
Success	58	20	78	<0.01
Total	103	49	152

Notes: *H0:proportion = 0.5. Potentially sensitive to fluconazole treatment: C. albicans, C. parapsilosis, and C. guillermondii. Potentially resistant to fluconazole treatment: C. glabrata, C. krusei, and C. tropicalis. Patients suffering from both species potentially sensitive and potentially resistant to fluconazole treatment were counted in the latter group.

Abbreviation: IV, intravenous.

Figure 2 Complete response rates by treatment arm.

Table 5 Multivariate logistic regression for predictors of successful empiric therapy

Predictor	Point estimate (OR)	95% confidence limits
Female gender	1.54	0.55; 4.34
colonization with Candida not specified as C. albicans	0.21	0.08; 0.54
Antibiotic use	3.93	0.43; 35.54
Major surgery within 30 days	1.70	0.60; 4.80
Immunosuppressive medication	0.37	0.10; 1.47
Recent parenteral nutrition	0.87	0.33; 2.34
CRRT	0.24	0.08; 0.70
Prior fungal colonization	9.36	1.50; 58.19
Recent use of central venous catheter	1.03	0.06; 16.59
Age ≥ 65 years	0.59	0.23; 1.52
APACHE II score	0.95	0.89; 1.01
Organ transplantation	1.26	0.13; 12.40
Diabetes mellitus	3.08	0.98; 9.70
Mechanical ventilation	0.54	0.17; 1.70
Number of fluconazole treatment cycles	5.60	0.77; 40.67
NeutropeniaANC < 500 cells/mL	4.87	0.57; 41.73

Note: Model predictors were determined based on literature review and expert clinical opinion.

Abbreviations: ANC, absolute neutrophil count; APACHE, Acute Physiology and Chronic Health Evaluation; CRRT, (continuous) renal replacement therapy including hemodialysis; OR, odds ratio.