Antifungal Prophylaxis with Posaconazole Delayed-Release Tablet and Oral Suspension in a Real-Life Setting: Plasma Levels, Efficacy, and Tolerability

We continuously determined posaconazole plasma concentrations (PPCs) in 61 patients with hematological malignancies receiving posaconazole (PCZ) delayed-release tablets (DRT; 48 patients; median duration of intake, 92 days) and PCZ oral solution (OS; 13 patients; median duration of intake, 124 days). PCZ DRT and OS antifungal prophylaxis was efficient and well tolerated. Thirty-four of 48 patients (71%) receiving DRT always had PPCs of >0.7 mg/liter, while 14 of 48 patients (29%) had at least one PPC of ≤0.7 mg/liter. In patients receiving OS, 4 of 13 patients (31%) always had PPCs of >0.7 mg/liter, 6 of 13 patients (46%) had at least one PPC of ≤0.7 mg/liter, and 3 (23%) patients never reached a PPC of 0.7 mg/liter. In patients with at least one determined PPC, the mean proportion of all PPCs of >0.7 mg/liter was 91% for PCZ DRT, whereas it was 52% for PCZ OS (P = 0.001). In the per sample analysis, PPCs were significantly more likely to be >0.7 mg/liter in patients receiving DRT than in patients receiving OS (PPCs were >0.7 mg/liter in 91.4% [297/325] of patients receiving DRT versus 70.3% [85/121] of patients receiving OS; P < 0.001). Patients receiving PCZ DRT had higher proportions of PPCs of >0.7 mg/liter than patients receiving OS both in the per patient and in the per sample analyses. Two patients (3%) had side effects during PCZ prophylaxis, and one (2%) had fungal breakthrough infection. Therapeutic drug monitoring enables detection of extended periods of PPCs of ≤0.7 mg/liter (e.g., due to nonadherence or graft-versus-host disease), which may also be associated with the loss of protective intracellular PCZ concentrations, regardless of the PCZ formulation

Demographic data and clinical characteristics of study patients.

<p>ICU patients were all intubated and mechanically ventilated.</p

Relative abundance of fungal microbiota in lower respiratory tract samples.

<p>Healthy adults (bar group 1a), patients with healthy respiratory tract but with antibiotic therapy for extrapulmonary infection (bar group 1b), non-neutropenic intubated and mechanically ventilated ICU patients without antibiotic therapy (bar group 2a), non-neutropenic intubated and mechanically ventilated ICU patients with antibiotic therapy for extrapulmonary infection (bar group 2b), and patients with antibiotic therapy due to pneumonia (bar group 3b). Fungi are shown at genus level. Yellow bars represent the sum of <i>Candida</i> sequences across all samples per group related to the total number of detected fungal sequences within each of the groups. By conventional culture <i>Candida spp</i>. were detected in 0/8 (group 1a), 0/7 (group 1b), 1/7 (group 2a), 3/6 (group 2b), and 11/26 (group 3b) patients. No other fungi were cultured.</p

Relative abundance of bacterial microbiota in consecutively sampled patients.

<p>Consecutive lower respiratory tract samples of 4 intubated and mechanically ventilated patients with pneumonia. Bacteria are shown at genus level. Unclassified sequences in sample 304-3B-ASP-0 revealed <i>Escherichia/Shigella sp</i>. using a confidence threshold of 0.63. Comparison of these sequences with reference sequences using BLAST yielded uncultured <i>Shigella sp</i>. 16s rRNA genes. Unclassified sequences in sample 313-3B-VAP-0 revealed <i>Enterobacter sp</i>. using a confidence threshold of 0.63. Comparison of these sequences with reference sequences using BLAST yielded uncultured proteobacterium 16s rRNA genes. VAP = Ventilator associated pneumonia, ASP = aspiration pneumonia, NAP = nosocomial acquired pneumonia.</p