Efficacy, Safety, and Breakthrough Infections Associated with Standard Long-Term Posaconazole Antifungal Prophylaxis in Allogeneic Stem Cell Transplantation Recipients

Abstract

Based on favorable results from randomized clinical trials, oral posaconazole has been approved for prophylaxis in neutropenic patients and stem cell transplantation (SCT) recipients. However, routine use of a prophylactic drug may yield different results than those from clinical trials. We collected data on the efficacy, safety, breakthrough infections, and antimicrobial resistance associated with standard long-term posaconazole prophylaxis in adult allogeneic SCT recipients at the UCLA Medical Center. Oral posaconazole (200 mg 3 times daily) was started on day 1 after SCT and continued until day 100. After day 100, posaconazole was continued in patients who still required corticosteroids for prevention or treatment of graft-versus-host disease. From January 2007 through December 2008, 106 consecutive patients received prophylactic posaconazole. Breakthrough invasive fungal infections on posaconazole occurred in 8 patients (7.5%) within 6 months after SCT; 3 additional patients developed invasive fungal infection after discontinuation of prophylactic posaconazole. The infective organisms were Candida (8 cases), Aspergillus (2 cases), and Aspergillus plus Coccidioides immitis (1 case). There were no Zygomycetes infections. Only 2 (both Candida glabrata) of 9 infecting isolates tested were resistant to posaconazole (minimal inhibitory concentration >1 μg/mL). Mortality from invasive fungal infection occurred in 4 patients (3.7%). Except for nausea in 9 patients, no clinical adverse event or laboratory abnormality could be attributed to posaconazole. Mean peak and trough plasma posaconazole concentrations were relatively low (<400 ng/mL) in neutropenic patients with oral mucositis and other factors possibly affecting optimal absorption of posaconazole. These results demonstrate that standard long-term oral posaconazole prophylaxis after allogeneic SCT is safe and associated with few invasive mold infections. However, breakthrough infections caused by posaconazole-susceptible organisms (frequently Candida) may occur at currently recommended prophylactic doses. Thus, strategies to improve posaconazole exposure, including the use of higher doses, administration with an acidic beverage, and restriction of proton pump inhibitors, need to be considered when using prophylactic posaconazole.

Posaconazole Serum Concentrations among Cardiothoracic Transplant Recipients: Factors Impacting Trough Levels and Correlation with Clinical Response to Therapy

“…The median trough posaconazole level among our patients (0.50 g/ml) was similar to levels described among HSCT recipients, as was the percentage of patients who did not achieve levels Ͼ0.5 g/ml (9, 10, 17). At the same time, however, factors that classically impact the absorption of posaconazole in HSCT recipients, such as mucositis, acute graft-versushost disease (GVHD), and chronic diarrhea, were not relevant in our patients (9,10,18). Rather, lower serum levels of posaconazole were correlated by multivariate analysis with concomitant receipt of PPI and higher levels with increased age and oral rather than tube feed administration.…”

Comparative cost-effectiveness analysis of voriconazole and fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants

“…This study estimated a rate of breakthrough IFIs at 6 months for those given posaconazole prophylaxis (7.5%) that was similar to the rate observed in the BMT CTN 0101 clinical trial for voriconazole (7.3%). 28 However, in the posaconazole observational study, only 7% of the study population had AML as the underlying disease, whereas in the BMT CTN 0101 clinical trial, 44% of the voriconazole prophylaxis arm had AML as the underlying disease. Thus, the available data are not sufficient to determine the comparative effectiveness and cost-effectiveness of prophylaxis with voriconazole and posaconazole in those undergoing allogeneic HCT.…”

Profilaktyka zakażeń grzybiczych u dzieci poddawanych transplantacjom komórek hematopoetycznych

“…Na 106 pacjentów poddanych profilaktyce pozakonazolem w UCLA (University of California Los Angeles, USA) infekcje przełamujące (gł. Candida sp., n = 6) pojawiły się u pacjentów z czynnikami ryzyka gorszego wchłaniania leku, takich jak stosowanie inhibitorów pompy protonowej, biegunka czy mucositis [27]. Stosowanie worikonazolu jest ograniczone przez potencjalne toksyczności w zakresie skóry czy też układu nerwowego [28].…”