Posaconazole is indicated for prophylaxis and salvage therapy of invasive fungal infections. Based on pharmacokinetic-pharmacodynamic data, a minimum serum concentration higher than 0.5 mg/L and 1.0 mg/L has been proposed for prophylaxis and therapy, respectively. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. In fact only few reports correlate posaconazole plasma concentrations (PPCs) with breakthrough infection.
In this retrospective single center study we evaluated the correlation of PPCs with breakthrough invasive mould infections (IMIs) in 50 patients with acute myeloid leukaemia (AML) who underwent chemoterapy (induction or salvage therapy) between July 2009 and March 2012. To measure the posaconazole concentration in human plasma, we developed and validated a rapid and simple high-performance liquid chromatography method. The method involved a solid-phase extraction of posaconazole using Oasis HLB cartridges, a reversed-phase liquid chromatography on an XTerra RP18 column with a mobile phase consisting of acetonitrile/ammonium acetate and ultraviolet detection.
Patient characteristics and microbiological data such galactomannan detection and TDM were collected retrospectively.
A total of 454 PPCs were measured before and 4 hours after administration in 50 patients with AML receiving posaconazole prophylaxis at dose of 200 mg 3 times/day. When plasma levels were below 0.5 mg/L, the dose was increased to 200 mg 4 times/day.
Average levels below the target of 0.5 μg/mL were detected in 38 (76%) out of 50 cases; 5 out of 38 cases showed plasma concentrations <0.20 μg/mL. Six patients (12%) receiving PCZ prophylaxis met the criteria of breakthrough infection (5 possible and 1 probable). Noteworthy, none of these patients achieved a complete remission after chemotherapy. Prior to development of IMIs, PPCs were below the target in 4 out of 6 (66%) cases experiencing breakthrough infection (between 0.2 and 0.5 μg/mL). Interestingly, only one patient had galactomannan positivity in the bronchoalveolar lavage fluid whereas none of the cases had serum galactomannan. Furthermore, out of 13 patients with resistant disease who did not develop IMIs, 8 (62%) presented PCPs < 0.5 μg/mL.
Our data demonstrate that low PPCs are common in patients receiving posaconazole prophylaxis during chemotherapy for AML. However, in spite of low PPCs, the rate of IMIs was low. This is possibly due to the good lung bioavailability of the drug, despite the presence of low drug serum levels. In addition, our data seems to confirm that refractory disease is a strong risk factor for the development of IMIs. Even in this high risk group, low PPCs did not correlate with high IMIs' incidence. A prospective evaluation of TDM of posaconazole is needed.
No relevant conflicts of interest to declare.
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