Article Figures & Data
Tables
- TABLE 1.
Demographic and clinical characteristics of patients
Patienta Sex Age (yr) VRC administrationb Dosec Therapy day Interval between last VRC administration and death (h) CRRTd IFI definitione Diagnosisf Interval between death and sampling (h) Cause of death Daily (mg) By wt (mg/kg) Cumulative (mg) 1 Female 58 i.v. 200 (single) 3.33 (single) 200 1 36.0 − Proven Pancreatitis, liver failure, COPD, CMP, and Candida sepsis 13 Liver failure, pancreatitis 2 Male 52 os 300 q24h 1.85 q24h 2,500 6 18.0 + Possible Sepsis, pneumonia, ARF, and ALL 12 Septic shock 3 Female 57 i.v. 300 q12h 2.63 q12h 4,800 8 8.5 + Probable Sepsis, ARF, GvHD, and AML 21 Septic shock 4 Male 35 os 200 q12h 2.94 q12h 3,800 10 12.0 − Possible Sepsis, pneumonia, DLBCL, and St. p. alloSCT 62 Septic shock 5 Male 67 i.v. 300 q12h 3.70 q12h 2,500 4 41.7 + Probable Sepsis, ARF, LF, DM, CVD 10 Septic shock 6 Male 47 i.v. 200 q12h 3.77 q12h 10,000 25 85.0 + Possible Sepsis, pneumonia, ARF, and multiple myeloma 60 Septic shock, multiorgan failure 7 Male 24 i.v. 300 q12h 4.00 q12h 3,500 6 5.5 − Possible Sepsis, pneumonia, and Hodgkin's disease 66 Respiratory failure 8 Male 75 i.v. 350 q12h 4.17 q12h 7,500 10 25.0 + Probable Sepsis, pneumonia, ARF, and oropharynx cancer 26 Septic shock Median 55 300 3.52 3,650 7 21.5 23.5 Interquartile range 22 100 1.1 3,650 5 28.6 48.5 ↵a Patient 1 received only a single-dose of VRC. Patient 2 received VRC every 24 h because of hepatic impairment. In patient 3 (body weight, 114 kg; body mass index, 40.4), the dosage was guided by the adjusted body weight.
↵b i.v., intravenous; os, oral suspension.
↵c q12h, dose administered every 12; q24h, dose administered every 24 h.
↵d CRRT, continuous renal replacement therapy. +, patient on CRRT; −, patient off CRRT.
↵e IFI, invasive fungal infection. The definition of IFI is based on EORTC-MSG criteria, including the following clinical mycological criteria and host factors (7): microbiology for patient 1, Candida glabrata from central venous line and Candida tropicalis in bile; patient 3, A. fumigatus in bronchoalveolar lavage; patient 5, A. fumigatus in bronchial aspirate and C. glabrata from central venous line; patient 8, mycelium (and C. glabrata) in bronchoalveolar lavage; patients 2, 4, 6, and 7, no microbiological or histopathological findings of a fungal infection. There was postmortem histopathological confirmation of proven or probable IFI in patients 1 (lung, kidney, and pancreas), 3 (lung), and 5 (lung). All detected pathogens were VRC sensitive: the MIC for A. fumigatus was <4 μg/ml, and the MIC for C. glabrata was <2 μg/ml.
↵f CMP, cardiomyopathy; COPD, chronic obstructive pulmonary disease; DLBCL, diffuse large B-cell lymphoma; St. p. allo SCT, status post-allogeneic stem cell transplantation; ARF, acute renal failure; LF, liver failure; DM, diabetes mellitus; CVD, cardiovascular disease; ALL, acute lymphoblastic leukemia; GvHD, graft versus host disease; AML, acute myeloid leukemia.
- TABLE 2.
Routine laboratory results for patients
Patient Laboratory resulta Creatinine (mg/dl) Urea (mg/dl) Bilirubin (mg/dl) AST (U/liter) ALT (U/liter) GGT (U/liter) PT (%) WBC (109 cells/liter) Hb (g/liter) PLT (109 cells/liter) Baseline testing 1 0.40 46.6 6.12 55 40 1,317 86 27.0 95 185 2 0.88 69.7 11.00 60 149 686 70 10.6 77 106 3 0.73 60.8 9.75 61 50 148 50 11.8 97 24 4 1.47 83.2 0.95 20 40 480 90 7.1 99 21 5 1.12 76.1 8.63 235 214 2,534 72 9.1 79 136 6 0.68 81.1 1.14 33 22 232 76 4.5 89 21 7 0.64 47.1 0.28 15 9 35 90 16.9 91 241 8 0.92 62.0 0.93 50 40 433 77 5.2 91 296 Median 0.81 65.9 3.63 53 40 457 77 9.9 91 121* Interquartile range 0.36 24.7 8.25 34 69 812 17 8.2 12 191 Final testing 1 0.40 46.6 6.12 55 40 1,317 86 27.0 95 185 2 1.99 106.7 9.29 221 109 1,129 67 13.5 84 15 3 0.62 80.5 15.33 107 75 180 51 9.5 101 12 4 0.98 57.1 3.45 43 66 338 89 7.0 74 18 5 0.89 60.5 7.93 205 186 1,827 70 6.2 87 112 6 1.53 183.1 0.46 31 20 209 108 3.1 73 28 7 3.07 250.7 0.36 1,079 667 102 25 39.9 108 108 8 2.45 100.5 1.00 56 29 656 82 6.6 88 177 Median 1.26 90.5 4.79 82 71 497 76 8.25 88 82* Interquartile range 1.47 86.1 7.88 164 113 1,029 29 13.9 19 128 ↵a The results from routine laboratory tests on the first day of VRC treatment (baseline testing) and final routine laboratory test results are shown as follows: serum creatinine, normal range, 0.51 to 1.17 mg/dl; urea, normal range 18 to 55 mg/dl; plasma bilirubin, normal range, 0.00 to 1.29 mg/dl; aspartate aminotransferase (AST), normal range, 10 to 50 U/liter; alanine aminotransferase (ALT), normal range, 10 to 50 U/liter; γ-glutamyl transferase (GGT), normal range, 6 to 71 U/liter; prothrombin time (PT), normal range 70 to 130%; white blood cell (WBC) count, normal range, 4.0 × 109 to 10.0 × 109 cells/liter; hemoglobin (Hb), normal range, 120 to 177 g/liter; and platelet (PTL) count, normal range, 150 × 109 to 380 × 109 cells/liter. *, significant differences between the first and last testings (Wilcoxon matched-pairs test). No significant increases in liver and renal function tests were observed during VRC therapy. Since all patients were on sedoanalgesia, neurotoxicity of VRC could not be assessed.
- TABLE 3.
Voriconazole concentrations in 128 tissue samples from eight patients
Patient VRC concn (μg/ml) ina: Lung Brain Liver Spleen Kidney Myocardium 1b 0.74 (0.72-0.76) <0.25 2.14 (1.86-2.42) 1.31 (1.29-1.34) 1.97 (1.69-2.26) <0.25 2 4.44 (3.64-5.20) 1.67 (1.38-2.06) 6.28 (6.22-6.34) 5.93 6.05 (5.99-6.10) 2.04 (1.96-2.13) 3 6.57 (6.12-6.78) 6.54 (5.77-6.95) 19.83 (19.58-20.08) 5.72 (5.60-5.84) 4.88 (4.83-4.92) 7.55 (6.53-8.57) 4 1.98 (1.47-2.04) 3.36 (3.08-3.56) 4.21 (3.67-4.76) 2.95 (2.92-2.99) 6.89 (6.84-6.93) 2.44 (2.27-2.62) 5 5.94 (4.14-7.86) 2.27 (2.25-3.79) 8.69 (7.44-9.95) 2.22 (2.22-2.22) 2.89 (2.76-3.02) 3.17 (3.10-3.23) 6 6.59 (4.74-9.38) 2.72 (2.57-3.35) 2.98 (2.83-3.12) 6.10 (5.46-6.74) 8.89 (8.64-9.13) 13.47 (13.11-13.84) 7 20.26 (19.82-20.87) 27.72 (26.78-34.70) 35.53 (35.04-36.03) 18.73 (17.98-19.47) 13.58 (11.10-16.05) 25.79 (25.54-26.05) 8 13.68 (12.04-15.07) 20.09 (17.43-23.13 40.04 (37.77-42.31) 14.27 (13.71-14.83) 14.81 (13.55-16.08) 19.85 (19.53-20.18) Median 6.26 3.41 6.89 5.60 6.47 7.55 Interquartile range 7.87 16.72 24.16 11.49 6.19 16.91 ↵a Shown are median VRC concentrations (with ranges in parentheses). Multiple sampling was performed from different sites as follows: lung, four samples (upper and lower lobe, left and right); brain, five samples (cortex, hippocampus, nucleus caudatus, medulla oblongata, and cerebellum); liver, two samples from different sites; spleen, two samples from different sites; kidney, two samples (left and right); and myocardium, two samples (ventricular septum and anterior wall).
↵b Patient 1 received only a single dose of VRC.
