At this point, it is essential to determine whether the duration of drug therapy is sufficient for the patient to benefit from clinical pharmacokinetic monitoring.
The appropriate duration of therapy for voriconazole or any antifungal agent for an invasive fungal infection is not well established. Given the high mortality and morbidity associated with fungal infections, and the inherent difficulty of eradicating fungal pathogens, treatment of such infections may last from weeks to months, depending on the type of pathogen, the site and extent of the infection, and the patient’s immune status. For invasive pulmonary aspergillosis, the recommended treatment duration is a minimum of 6 to 12 weeks, whereas chronic pulmonary aspergillosis may require treatment with voriconazole for several months. Rarely would a patient be receiving voriconazole for less than 2 weeks, especially given that empiric therapy with voriconazole in febrile neutropenia is not recommended. In summary, if TDM is indicated (as determined by earlier steps in the algorithm shown in Figure 1), the duration of voriconazole therapy is adequate and appropriate to allow TDM to be performed and patient therapy to benefit.
UTILITY OF DRUG MONITORING IN CLINICAL DECISION-MAKING
Finally, the clinician must determine whether the results of the drug assay will make a significant difference in clinical decision-making (by providing more information than sound clinical judgement alone). viagra 50 mg
Many trials have suggested a possible association between plasma concentration of voriconazole and the efficacy and toxic effects of the drug. However, because the available evidence does not support any definitive relation at this time, it is unlikely that routine TDM of voriconazole can provide any additional therapeutic advantage in the clinical setting. In addition, several other gaps in knowledge (e.g., sampling time for optimal drug monitoring, thresholds that correlate with clinical efficacy and toxic effects) must be filled before TDM of voriconazole can be fully utilized. As Bruggemann and others suggested in a recent review article, the indication to use voriconazole TDM as a means to ensure optimal drug concentrations after intravenous- to-oral step-down is probably weak. Nonetheless, this approach is supported by the results of a randomized study of patients with invasive aspergillosis, in which 71% of the patients receiving voriconazole but only 58% of those receiving amphotericin B had treatment success at the 12-week follow-up, despite intravenous-to-oral therapy step-down (from 4 mg/kg IV twice daily to 200 mg PO twice daily) after a median of 10 days of IV therapy, regardless of plasma concentration of the drug.
However, selective monitoring of voriconazole concentration may be considered under certain circumstances when lack of response or toxic effects related to external and internal patient factors (e.g., drug interactions, CYP2C19 genetic polymorphism, hepatic impairment) are present or strongly suspected in a critically ill patient. An extremely low or high concentration of voriconazole in such a setting may help the clinician to rule out or verify a particular diagnosis and may provide guidance in making the most logical and clinically sound decision.
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Voriconazole has demonstrated efficacy in the treatment of invasive fungal infections caused by a variety of fungal pathogens. It is preferred over amphotericin B for the treatment of aspergillosis, given its comparable efficacy and lower incidence of toxic effects. HPLC appears to be the most widely accepted analytic method for quantification of voriconazole concentration in the plasma, but in light of the requirement for specialized equipment and associated high costs, this type of assay is not readily accessible to all institutions. The wide variability in exposure to voriconazole, both within and between individuals, secondary to saturable metabolism, genetic polymorphism, drug interactions, disease state, and other pharmacokinetic factors provides the rationale for TDM. Duration of therapy with voriconazole for invasive fungal infections will generally last for weeks if not months, which allows adequate time to realize the benefits of TDM. However, the correlation between plasma concentrations of voriconazole and the drug’s efficacy and toxic effects remain inconclusive. While a lower target threshold of 0.25 to 2 mg/L and an upper target of 4 to 6 mg/L have been suggested, studies to date have not been appropriately designed or powered to definitively determine any association. Routine TDM with voriconazole is therefore not recommended. On the contrary, clinicians should monitor patients for attributable signs and symptoms, such as resolution of serologic, clinical, or radiologic findings, as a means of determining the efficacy of antifungal therapy. Ultimately, under certain circumstances, such as the lack of response to therapy or occurrence of toxic effects, selective monitoring of voriconazole concentration, in concert with other available tools, may be considered to assist clinical decision-making. In such cases, TDM may offer some benefit, but clinicians should interpret the results with caution. Although the subject of voriconazole TDM has sparked much clinical and academic interest and discussion, a well-designed, randomized trial with fixed sampling time points may not be feasible and is unlikely to be performed, as it would be difficult to recruit study participants from this patient population and the sample would almost certainly be heterogeneous. Apcalis Oral Jelly