The prognosis for patients with respiratory syncytial virus (RSV) or parainfluenza virus type 3 (PIV3) respiratory tract infection post allogeneic haematopoietic progenitor cell transplant (HPCT) is historically poor. The use of oral ribavirin (RBV) has not been widely studied in this patient population. We examined the outcomes of 15 consecutive patients (RSV, n ¼ 13 and PIV3, n ¼ 2) treated with oral RBV post HPCT. Oral RBV was commenced at a starting dose of 10 mg/kg/day, increasing to a maximum dose of 60 mg/kg/day depending on response and tolerance. At diagnosis, seven patients had upper respiratory tract infection (URTI) and eight had lower respiratory tract infection (LRTI). The starting RBV dose of 10 mg/kg/day did not prevent the progression of URTI to LRTI in any patient. However, with dose escalation, six of the seven patients responded to RBV therapy and survived their infective episode. Of the eight patients presenting with LRTI, six patients survived their infection, again after dose escalation of RBV. There was no dose-limiting toxicity seen in any patient. Our results indicate that oral RBV has clinical efficacy in the treatment of RSV/PIV3 infection post HPCT. However, a starting dose of 10 mg/kg/day appears ineffective; we recommend a starting dose of 20 mg/kg/day in this patient group.
i Bayesian methods for voriconazole therapeutic drug monitoring (TDM) have been reported previously, but there are only sparse reports comparing the accuracy and precision of predictions of published models. Furthermore, the comparative accuracy of linear, mixed linear and nonlinear, or entirely nonlinear models may be of high clinical relevance. In this study, models were coded into individually designed optimum dosing strategies (ID-ODS) with voriconazole concentration data analyzed using inverse Bayesian modeling. The data used were from two independent data sets, patients with proven or suspected invasive fungal infections (n ؍ 57) and hematopoietic stem cell transplant recipients (n ؍ 10). Observed voriconazole concentrations were predicted whereby for each concentration value, the data available to that point were used to predict that value. The mean prediction error (ME) and mean squared prediction error (MSE) and their 95% confidence intervals (95% CI) were calculated to measure absolute bias and precision, while ⌬ME and ⌬MSE and their 95% CI were used to measure relative bias and precision, respectively. A total of 519 voriconazole concentrations were analyzed using three models.
Voriconazole is a triazole antifungal that exhibits broad-spectrum activity and is a first-line agent for the treatment of Candida sp. infections (1), invasive aspergillosis (2), and other serious fungal infections. With increasing numbers of at-risk immunocompromised populations, such as those undergoing solid-organ transplantation or those with HIV infections, the incidence of invasive mycoses is on the rise (3, 4). Despite the advent of newer antifungals, Aspergillus sp. and Candida sp. infections have exhibited high mortality rates of 60% and 30%, respectively (5, 6).Recent published studies of voriconazole have shed light on the clinical relevance of therapeutic drug monitoring (TDM) for optimization of dosing based on voriconazole's highly variable pharmacokinetics (PK) and the resultant poor predictability of plasma concentrations (7,8). Subtherapeutic concentrations have been linked to higher failure rates in patients with life-threatening invasive fungal infections, and supratherapeutic concentrations are associated with neurological and hepatic toxicity (9-19). Voriconazole is primarily metabolized by CYP2C19, which commonly exhibits genetic polymorphism, leading to variable PK and leaving certain populations susceptible to decreased metabolism and increased plasma concentrations of voriconazole (20-23). Patients of Asian descent with polymorphisms in CYP2C19 have up to a 20% incidence of being poor metabolizers while this value is up to 5% for Caucasian and African American individuals (24). Poor metabolizers can have a PK exposure up to four times higher than that of homozygous comparators.Nonlinearity in voriconazole PK relating to saturable clearance mechanisms has been reported (8), which together with its extensive variability makes dosing profoundly challenging, especially when higher doses are used. Conve...
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