Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies

Abstract

Voriconazole plasma concentrations (VPCs) vary widely, and concentrations outside the therapeutic range are associated with either worse outcome in invasive aspergillosis (IA) or increased toxicity. The primary goal of this cohort study conducted in a real-life setting was to identify potential factors associated with inadequate VPCs in ICU patients and patients with hematological malignancies. Within a period of 12 months, trough VPCs were obtained and analyzed with high-performance liquid chromatography, and the adequate range was defined as 1.5 to 5.5 mg/liter. VPCs of <1.5 mg/liter were defined as low, whereas VPCs of >5.5 mg/liter were defined as potentially toxic. A total of 221 trough VPCs were obtained in 61 patients receiving voriconazole, and 124/221 VPCs (56%) were found to be low. Multivariate analysis revealed that low VPCs were significantly associated with clinical failure of voriconazole, prophylactic use, younger age, underlying hematological malignancy, concomitant proton pump inhibitor (PPI) (pantoprazole was used in 88% of the patients), and absence of side effects. Low VPCs remained an independent predictor of clinical failure of voriconazole. The defined adequate range was reached in 79/221 (36%) VPCs. In 18 samples (8%), potentially toxic levels were measured. Multivariate analysis revealed higher body mass index (BMI), absence of hematological malignancy, therapeutic application, and diarrhea as factors associated with potentially toxic VPCs. Neurotoxic adverse events occurred in six patients and were mostly associated with VPCs in the upper quartile of our defined adequate range. In conclusion, potential factors like younger age, prophylaxis, underlying hematological malignancy, BMI, and concomitant PPI should be considered within the algorithm of voriconazole treatment.

Variability of Voriconazole Plasma Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Cytochrome P450 Polymorphisms and Comedications on Initial and Subsequent Trough Levels

“…However, our data and those from other studies (6,42) did not support such an interaction, and in the present study, steroid use induced no significant change in VRC C min both in the overall analysis performed with all VRC C min and in the pairwise patient analysis. These conflicting results could be explained by the heterogeneity of the studied populations and the type and dose of the glucocorticoid.…”

“…Thus, a therapeutic target of between 1 and 4 to 6 mg/liter for VRC C min has recently been proposed by the British Society for Medical Mycology (5). However, the VRC C min is frequently below this efficacy threshold in patients suffering from hematologic malignancies (6,7), notably in AHSCT patients (8).…”

“…Younger age (3,6,12), oral administration of VRC (3), and concomitant medication with enzyme inducers like phenytoin, rifampin, or glucocorticoids (3,13) are associated with decreased VRC C min . In this context, therapeutic drug monitoring (TDM) of VRC is of particular interest.…”

Novel Tests for Diagnosis of Invasive Aspergillosis in Patients with Underlying Respiratory Diseases

“…Azoulay and colleagues previously reported that up to two-thirds of patients receiving antifungal therapy in the ICU setting have no evidence for IFIs (46). Overtreatment with antifungals is not only associated with a huge financial burden but also bears the risk of side effects, drug-drug interactions, and even development of resistance (47,48). Thus, using the LFD test may be an effective way to reduce unnecessary antifungal treatment.…”

Performance of Galactomannan, Beta- d -Glucan, Aspergillus Lateral-Flow Device, Conventional Culture, and PCR Tests with Bronchoalveolar Lavage Fluid for Diagnosis of Invasive Pulmonary Aspergillosis

“…Due to the crude mortality of 80 to 90% in the absence of adequate treatment, timely diagnosis and early start of antifungal therapy are key factors in the successful treatment of IPA, as delayed antifungal therapy has a negative impact on the survival of these patients (6). Various studies have shown that early diagnosis and initiation of antifungal therapy may improve IFI survival to Ͼ80% (7)(8)(9). Diagnosing IFI, however, remains difficult, as clinical signs and symptoms, as well as radiological findings, are often unspecific, and conventional culture methods display low sensitivities (8).…”