Introduction 1 4 Voriconazole follows itraconazole as the second triazole-antifungal agent with an enhanced spectrum of activity against numerous clinically important fungi. This activity is achieved by inhibition of fungal cytochrome P450-mediated 14α-lanosterol demethylase, a key enzyme in ergosterol biosynthesis. Subsequent loss of ergosterol in the fungal cell wall and accumulation of 14α-methyl sterols are the primary mode of action of voriconazole. Candida 5 7 Aspergillus 8 10 Fusarium 8 13 Scedosporium 14 Cryptococcus 7 Trichosporon Blastomyces Histoplasma capsulatum Coccidioides immitis 14 15 16 Scedosporium apiospermum Fusarium 17 18 21 Methods Participating investigators were asked to document all patients receiving voriconazole via online electronic data capture. Data were collected retrospectively after treatment completion. Collected data comprised demographic information, underlying disease, indication for treatment, earlier antifungal treatment, risk factors for invasive fungal infection, clinical outcome (including results of diagnostic imaging, microbiology, lab results, vital signs and survival), occurrence of adverse events, concurrent medication, and evaluation of response. Treatment outcome was evaluated by the investigator. Data were monitored electronically and manually for plausibility and completeness and queries were raised to the investigators in cases that were unclear or incomplete. 19 Results N 1 Table 1 N a 59 (24–84) Female 37 (37%) Mean weight in kg (±SD) 76.2 (±14.7) b  Acute myeloid leukemia 72  Acute lymphoblastic leukemia 9  Low grade non-Hodgkin lymphoma 4  Other hematological malignancy 9  Other non-malignant hematological disease 5  Solid tumors 3 Stem cell transplantation 15  Unrelated donor 8  Sibling donor 4  Autologous 3 Graft-versus-host disease 8 Isolation  Reverse isolation 48 c 27  No isolation 14  LAF 9 c 2 Treatment indication  Primary prophylaxis 3  Empirical therapy 21  Suspected or proven IFI 57  Secondary prophylaxis 19 Days on voriconazole (±SD) 26.7 (±43.3) a b c N N 1 N N N N N Geotrichum capitatum N N N N N N 2 Table 2 N a  Lung 55 (96.5%)  Blood (fungemia) 2 (3.5%)  Sinus 2 (3.5%)  CNS 1 (1.8%)  Liver 1 (1.8%) Risk factors  Diabetes mellitus 4 (7%)  HIV 1 (1.8%) b 43 (75.4%)  Mucositis 25 (43.9%)  Prior IFI 7 (12.28%)  Central venous catheter 39 (68.4%)  Dust exposure 47 (82.5%)  Surgery 1 (1.8%)  Cytarabine 14 (24.6%)  Purine analogues 7 (12.3%)  Steroids 10 (17.5%)  Other immunosuppressant 4 (7%) Days with fever (±SD) 7.6 (±6.54) Total days on antibiotic treatment (±SD) 29.3 (±18.30) Days on voriconazole (±SD) 26.6 (±26.76) Average initial voriconazole mg/kg (range) 6.8 (3.125 – 13.559) Route of administration  Oral only 27 (47.4%)  Switch to oral 21 (36.8%)  Switch to intravenous 4 (7.0%) c  Complete response 19 (33.3%)  Partial response 16 (28.1%)  Stable disease 11 (19.3%)  Progressive disease 11 (19.3%) Switch to other antifungal 15 (26.3%)  Liposomal amphotericin B 8 (14.0%)  Caspofungin 5 (8.8%)  Other 2 (3.5%) a b c 16 20 21 3 Table 3 N  Investigator assessment 16 20 21 Proven 3/57 (5.3) 2/57 (3.5) 2/57 (3.5) Probable 26/57 (45.6) 35/57 (61.4) 4/57 (7.0) Possible 14/57 (24.6) 1/57 (1.8) 32/57 (56.1) Not defined 14/57 (24.6) 19/57 (33.3) 19/57 (33.3) Values in parenthesis are in percentage N N N N 4 Table 4 Voriconazole dosing and treatment outcome  N N Average initial voriconazole dose in mg/kg (range) 5.7 (2.469–10.870) 5.7 (3.3–7.5) Route of administration  Oral only 16 (76.2%) 18 (94.7%)  Switch to oral 2 (9.5%) 0  Switch to intravenous – 1 (5.3%) Days with fever (±SD) 11.6 (±11.17) n. a. Days on antibiotic treatment (±SD) 29.8 (±13.55) n. a. Days on voriconazole (±SD) 9.7 (±6.94) 48.8 (±84.31) Breakthrough IFI n. a. 4 (21.1%) a  Progressive disease 4 (19.1%) n. a.  Stable disease 6 (28.6%) n. a.  Partial response 1 (4.8%) n. a.  Complete response 10 (47.6%) n. a. Switch to other antifungal 8 (38.1%) 7 (36.8%)  Liposomal amphotericin B 3 (14.3%) 2 (10.1%)  Caspofungin 4 (19.1%) 5 (26.3%)  Liposomal amphotericin B + caspofungin 1 (4.8%) 0 N N N 5 Table 5 N Visual disturbance 6 Nausea 3 Rash 3 Hallucination 2 Vomiting 2 Diarrhea 1 Drug fever 1 Edema 1 Adverse events at least possibly related to voriconazole by judgment of the investigator N N N 6 6 Table 6 Highest grade of treatment-emergent renal and hepatic adverse events 19 Grade-1 (%) Grade-2 (%) Grade-3 (%) Grade-4 (%) N Liver  GOT (AST) 29 (31.5) 5 (5.4) 2 (2.2) 2 (2.2) 92 a a a a  GPT (ALT) 20 (20.2) 4 (4) 1 (1) 1 (1) 99 a a a a  GGT 14 (15.7) 14 (15.7) 11 (12.4) 0 (0) 89 a a a a  AP 17 (19.5) 4 (4.6) 2 (2.3) 0 (0) 87 a a a a  Bilirubin 10 (11) 5 (5.5) 4 (4.4) 2 (2.2) 91 a a a a Kidney  Creatinine 11 (11) 6 (6) 2 (2) 2 (2) 100 a a a a Values given in parenthesis are in percentage a Discussion 16 22 16 22 16 22 Analysis of survey data did not reveal yet unknown toxicities of voriconazole. Treatment-related grade 3 or 4 hepatotoxicity was observed in 15 patients. Further frequent adverse events were visual disturbances (6%), rash (3%) and nausea (3%). 22 21 21 23 25 21 In the above clinical situations, voriconazole offers a flexible and tolerable treatment option. Still, the many difficulties in the diagnosis and treatment of invasive fungal infections should not be used as a carte blanche in clinical decision making. Physicians should strive towards establishing the most accurate diagnosis possible and then treat according to current evidence.