title: How common is subsequent central nervous system toxicity in asymptomatic patients with haematologic malignancy and supratherapeutic voriconazole serum levels?
abstract: OBJECTIVE
  We sought to determine the frequency at which patients with elevated voriconazole (VRC) levels but no clinically evident central nervous system (CNS) toxicity subsequently develop CNS toxicity.
  
  
  METHODS
  We retrospectively reviewed the records of adult patients with haematolologic malignancy who had a VRC serum level >5.5 μg/mL at MD Anderson Cancer Center (January 2010 to December 2015). Patients with any documented CNS toxicity at the time the VRC level was obtained or patients whose VRC was discontinued as a response to high VRC level were excluded. Neurologic status was assessed using standard grading scales. Demographic and clinical characteristics, including potentially interacting medications, were correlated with the development of toxicity.
  
  
  RESULTS
  We identified 320 such patients (mean age, 57 ± 15 years; 202 male (63%)). Subsequent CNS toxicity was documented in only 16 patients (5%). The most common CNS toxicities were visual disturbances (9/16, 56%), depressed consciousness (5/16, 31%) and cognitive disturbance (4/16, 19%). Patients with CNS toxicity tended to be older than those without (64 ± 8 vs 57 ± 15 y, p 0.08). The use of one or more neurotoxic drugs was common in patients with subsequent CNS toxicity (14/16, 88%). Reduction of VRC dose associated with the high VRC level did not correlate with less subsequent CNS toxicity.
  
  
  CONCLUSIONS
  Development of subsequent CNS toxicity is uncommon in haematolologic malignancy patients with elevated VRC levels who had no evidence of toxicity at the time the level was obtained. Automatic reduction of VRC dose out of concern for impending CNS toxicity might not be warranted.
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Infectious Diseases, Jeju National University School of Medicine, Jeju, South Korea.
authors.forename: S T
authors.initials: ST
authors.lastname: Heo
authors.affiliation: Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Aitken
authors.affiliation: Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: F P
authors.initials: FP
authors.lastname: Tverdek
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: dkontoyi@mdanderson.org.
authors.forename: D P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000935:Antifungal Agents / Q000097:blood / Q000633:toxicity*; D002490:Central Nervous System / Q000187:drug effects*; D060825:Cognitive Dysfunction / Q000139:chemically induced; D003244:Consciousness Disorders / Q000139:chemically induced; D005260:Female; D019337:Hematologic Neoplasms / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014786:Vision Disorders / Q000139:chemically induced; D065819:Voriconazole / Q000097:blood / Q000633:toxicity*
chemical_list: D000935:Antifungal Agents; D065819:Voriconazole
keywords: Central nervous system; Haematologic malignancy; Neurotoxicity; Serum levels; Voriconazole