Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study

Soler‐Palacín, Pere; Frick, Marie Antoinette; Martin‐Nalda, Andrea; Lanaspa, Miguel; Pou, Leonor; Roselló, E.; Heredia, Cristina Diaz de; Figueras, Concepció

doi:10.1093/jac/dkr517

Cited by 78 publications

(86 citation statements)

References 25 publications

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“…This nonlinearity also makes the half-life and the time to steady state dependent on the dose and concentration, complicating the ability to compare steady-state trough concentrations to the accepted therapeutic range of 1 to 6 mg/liter (17) and resulting in either unnecessary delays in sampling or premature sampling and misinterpreted concentrations. Furthermore, intuitive or empirical voriconazole dose adjustments result in prolonged patient exposure to voriconazole outside the therapeutic range in up to half or more of children and adults (6,10).In this paper, we first present a nonparametric population model of voriconazole in children and adolescents aged 2 to 18 years and then use it to accurately predict both the measured concentrations and doses required to generate those concentrations in pediatric patients receiving voriconazole for clinical purposes. …”

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“…Numerous reports of studies in both adults (1)(2)(3)(4)(5)(6)(7), including a prospective randomized trial (8), and children (9)(10)(11) have documented improved outcomes when trough concentrations are maintained above 1 mg/liter, which is a readily measured clinical surrogate for the full area under the concentration-time curve (AUC) that drives efficacy (12)(13)(14)(15).…”

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Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Neely

Margol

et al. 2015

Antimicrob Agents Chemother

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f Despite the documented benefit of voriconazole therapeutic drug monitoring, nonlinear pharmacokinetics make the timing of steady-state trough sampling and appropriate dose adjustments unpredictable by conventional methods. We developed a nonparametric population model with data from 141 previously richly sampled children and adults. We then used it in our multiplemodel Bayesian adaptive control algorithm to predict measured concentrations and doses in a separate cohort of 33 pediatric patients aged 8 months to 17 years who were receiving voriconazole and enrolled in a pharmacokinetic study. Using all available samples to estimate the individual Bayesian posterior parameter values, the median percent prediction bias relative to a measured target trough concentration in the patients was 1.1% (interquartile range, ؊17.1 to 10%). Compared to the actual dose that resulted in the target concentration, the percent bias of the predicted dose was ؊0.7% (interquartile range, ؊7 to 20%). Using only trough concentrations to generate the Bayesian posterior parameter values, the target bias was 6.4% (interquartile range, ؊1.4 to 14.7%; P ‫؍‬ 0.16 versus the full posterior parameter value) and the dose bias was ؊6.7% (interquartile range, ؊18.7 to 2.4%; P ‫؍‬ 0.15). Use of a sample collected at an optimal time of 4 h after a dose, in addition to the trough concentration, resulted in a nonsignificantly improved target bias of 3.8% (interquartile range, ؊13.1 to 18%; P ‫؍‬ 0.32) and a dose bias of ؊3.5% (interquartile range, ؊18 to 14%; P ‫؍‬ 0.33). With the nonparametric population model and trough concentrations, our control algorithm can accurately manage voriconazole therapy in children independently of steady-state conditions, and it is generalizable to any drug with a nonparametric pharmacokinetic model. (This study has been registered at ClinicalTrials.gov under registration no. NCT01976078.) V oriconazole is the approved first-line therapy for aspergillosis in patients who are at least 12 years of age in the United States and at least 2 years of age elsewhere. Numerous reports of studies in both adults (1-7), including a prospective randomized trial (8), and children (9-11) have documented improved outcomes when trough concentrations are maintained above 1 mg/liter, which is a readily measured clinical surrogate for the full area under the concentration-time curve (AUC) that drives efficacy (12-15).However, the pharmacokinetic behavior of voriconazole is complex and nonlinear, such that in many patients, small dose changes are associated with disproportionately large changes in the plasma concentrations of the drug. While it is more common in adults, nonlinear, saturated pharmacokinetic behavior is readily observed in children who receive doses higher than those that have been approved by regulatory agencies (16). This nonlinearity also makes the half-life and the time to steady state dependent on the dose and concentration, complicating the ability to compare steady-state trough concentrations to the accepted therapeu...

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Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Neely

Margol

et al. 2015

Antimicrob Agents Chemother

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“…This is particularly important for children, as there is very wide variability in the voriconazole dose required to achieve a target level between 1 and 5.5 mg/ L. In one study, Spanish investigators followed 196 voriconazole trough levels in 30 children with IFI and found that 98 (50%) of the samples were reported as <1 mg/L and 14 (7%) were >5.5 mg/L. 90 The majority of patients (73%) required dose adjustment after the voriconazole trough was measured; a median voriconazole dose of 38 mg/kg/day for children < 5 y in contrast to a median dose of 15 mg/kg/day for children 5 y was also noted. The authors were unable to demonstrate a correlation between subtherapeutic level and poor outcome due to the small sample size.…”

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Antifungal stewardship considerations for adults and pediatrics

2016

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Antifungal stewardship refers to coordinated interventions to monitor and direct the appropriate use of antifungal agents in order to achieve the best clinical outcomes and minimize selective pressure and adverse events. Antifungal utilization has steadily risen over time in concert with the increase in number of immunocompromised adults and children at risk for invasive fungal infections (IFI). Challenges in diagnosing IFI often lead to delays in treatment and poorer outcomes. There are also emerging data linking prior antifungal exposure and suboptimal dosing to the emergence of antifungal resistance, particularly for Candida. Antimicrobial stewardship programs can take a multi-pronged bundle approach to ensure suitable prescribing of antifungals via postprescription review and feedback and/or prior authorization. Institutional guidelines can also be developed to guide diagnostic testing in at-risk populations; appropriate choice, dose, and duration of antifungal agent; therapeutic drug monitoring; and opportunities for de-escalation and intravenous-to-oral conversion.

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“…The Infectious Diseases Society of America (IDSA) recommend a 6-mg/kg loading dose, administered intravenously every 12 h for 1 day, followed by an intravenous dose of 4 mg/kg every 12 h or an oral dose of 200 mg every 12 h (9). However, Soler-Palacin et al (10) found that for patients aged 5 years and older, the median intravenous dose needed to achieve therapeutic levels was 15 mg kg Ϫ1 day Ϫ1 . Surgery is generally required when there is evidence of spinal cord (nerve root) compression or vertebral bony destruction (7,9).…”

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Vertebral Aspergillosis in a Patient with Autosomal-Dominant Hyper-IgE Syndrome

Kuang

et al. 2013

Clin. Vaccine Immunol.

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bWe present a report of an autosomal-dominant hyper-IgE syndrome patient with vertebral aspergillosis. Early diagnosis and antifungal therapy with surgery are crucial for improving the outcome of this aggressive condition. CASE REPORTA n 8-year-old boy was admitted for a mass in the neck with numbness in the right upper extremity. He had no fever, night sweating, weight loss, or fatigue. At presentation, the patient appeared malnourished but had no facial abnormalities. Marked growth retardation was noticed (height, 113 cm; weight, 19 kg (both less than the third percentile [1])). His medical history included a delay in primary tooth shedding, recurrent oral ulcers, and pulmonary infections of unidentified etiology. Vital sign measurements were within the normal ranges. On physical examination, a 4-cm by 3-cm soft mass was palpable in the right nuchal region, without tenderness or ulceration. His neurological functions were normal except for right extremity numbness. Blood tests showed elevated white blood cell (WBC) counts (10.4 ϫ 10 9 /liter; normal range, 4 ϫ 10 9 to 10 ϫ 10 9 /liter) with an increase in the percentage of eosinophils (14.2%; normal range, 0.5% to 5%), a high erythrocyte sedimentation rate (ESR; 90 mm/h; normal range, 0 to 15 mm/h), and an elevated C-reactive protein (CRP) concentration (52.7 mg/liter; normal range, 0 to 5.2 mg/ liter). The results of the tuberculin skin test and blood test for anti-tuberculin antibody were negative. Magnetic resonance imaging (MRI) confirmed a 4-cm by 3.5-cm by 3-cm mass located in the right nuchal region. Additionally, a space-occupying lesion in the left pulmonary hilum was revealed by computed tomography (CT) (Fig. 1A, B, and C).A working diagnosis of malignant neurogenic tumor was considered. Needle aspiration of the neck lesion was not performed because of the risk of metastasis. Surgical decompression with debridement of the neck mass was performed, which revealed pus in the mass and spinal canal. The pus culture (Sabouraud dextrose agar; Bio-caring) results were negative. Histological examination revealed purulent inflammation without malignant tumor cells. Cefathiamidine was started for presumed bacterial infection. The patient experienced symptom relief after the surgery. Two weeks later, however, the patient complained of new-onset back pain, and reappearance of the mass in the same nuchal region was observed. Needle aspiration performed, and 1 week later, Aspergillus fumigatus was detected on pus culture. Enzyme-linked immunosorbent assay for Aspergillus galactomannan (GM test; Platelia Aspergillus enzyme immunoassay [EIA] [Bio-Rad]; cutoff value, 0.5 ng/ml) and screening for 1,3-␤-D-glucans (G-test; Fungitell [Associates of Cape Cod]; cutoff value, 80 pg/ml) in the plasma were performed. The GM test value was 1.45 ng/ml, and the G test value was 227 pg/ml. Vertebral aspergillosis was suspected, and the patient was given chemotherapy (voriconazole, at a loading dose of 6 mg/kg of body weight, intravenously every 12 h for 1 day, followed by 4 mg/kg,...

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Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study

Cited by 78 publications

References 25 publications

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

Antifungal stewardship considerations for adults and pediatrics

Vertebral Aspergillosis in a Patient with Autosomal-Dominant Hyper-IgE Syndrome

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