Comparative Pharmacodynamics of Posaconazole in Neutropenic Murine Models of Invasive Pulmonary Aspergillosis and Mucormycosis

Scopulariopsis is an emerging opportunistic fungus characterized by its high resistance to antifungal therapies. We have developed a murine model of disseminated infection in immunosuppressed animals by intravenous inoculation of Scopulariopsis brevicaulis and Scopulariopsis brumptii, the most clinically relevant species, in order to evaluate their virulence and their responses to conventional antifungal treatments. Survival and tissue burden studies showed that S. brumptii was more virulent than S. brevicaulis. The three drugs tested, liposomal amphotericin B, posaconazole, and voriconazole, prolonged the survival of mice infected with S. brumptii, but none showed efficacy against S. brevicaulis. The different therapies were only able to modestly reduce the fungal burden of infected tissue; however, in general, despite the high serum levels reached, they showed poor efficacy in the treatment of the infection. Unfortunately, the most effective therapy for Scopulariopsis infections remains unresolved.

“…Only PSC and VRC concentrations in serum were above the respective MICs, which agrees with previous studies (30,31,32). Despite that, they were only effective against S. brumptii.…”

Section: Discussionsupporting

confidence: 92%

Virulence and Resistance to Antifungal Therapies of Scopulariopsis Species

Paredes

Capilla

Mayayo

et al. 2016

“…Most breakthrough IFIs in the prior studies were due to mold species, similar to our study. Lewis and colleagues demonstrated that the AUC/MIC ratio was directly related to PCZ treatment efficacy in a mouse model of mold infection (17). Although it is unclear what pharmacodynamic parameter is relevant to prophylaxis against mold infection, the PCZ tablets provide a much greater AUC than the suspension with the current FDA-approved dosing, due to improved absorption of the tablets (13,18).…”

Section: Discussionmentioning

confidence: 99%

Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses

Tverdek

Heo

Aitken

et al. 2017

Self Cite

Posaconazole is the preferred mold-active azole for prophylaxis against invasive fungal infections (IFIs) in patients with hematological malignancy. Delayedrelease tablet and intravenous formulations of posaconazole have recently become available, but clinical data are limited. We sought to examine the real-world pharmacokinetics and prophylactic effectiveness of the new formulations of posaconazole given as prophylaxis for patients with hematological malignancy. A retrospective cohort of all consecutive adult inpatients with hematological malignancy who received Ն3 days of tablet or intravenous posaconazole therapy for primary IFI prophylaxis at the M. D. Anderson Cancer Center between 1 December 2013 and 31 December 2015 was established. Clinical information was collected and correlated with low posaconazole serum levels (Ͻ700 ng/ml). Rates of IFIs and safety events were assessed. A total of 1,321 courses of posaconazole were administered at the M. D. Anderson Cancer Center during the study period, of which 343 courses were assessed for prophylactic safety and effectiveness. Seventy-nine patients (23%) had posaconazole serum level measurements available for interpretation. Acute myeloid leukemia was the primary malignancy (62%), with 20% of all patients having previously received a stem cell transplant. The median posaconazole level was 1,380 ng/ml (interquartile range, 864 to 1,860 ng/ml). Low posaconazole levels (Ͻ700 ng/ml) were observed for 14 patients (18%). Proven or probable breakthrough IFIs occurred in 8 patients (2%); posaconazole therapeutic drug monitoring (TDM) was performed for 6 of those patients, all with levels above 700 ng/ml. Overall, 19% of patients experienced grade 3 or 4 liver injury, manifesting primarily as hyperbilirubinemia and being correlated with serum levels of Ͼ1,830 ng/ml. Although hepatotoxicity in a small percentage of patients is of concern, posaconazole tablets appeared to be generally safe and effective. As all breakthrough IFIs for which TDM was performed occurred in patients with levels of Ͼ700 ng/ml, and a posaconazole level of Ͼ1,830 ng/ml was correlated with grade 3 or 4 liver toxicity, further studies are needed to assess the role of TDM.KEYWORDS posaconazole, hematological malignancy, prophylaxis, cancer, antifungal I nvasive fungal infections (IFIs) continue to be a significant cause of morbidity and death among patients with hematological malignancy (1). The triazole posaconazole (PCZ) has in vitro, preclinical, and clinical activities against a variety of yeasts and molds (2). Since its introduction 15 years ago, PCZ has been widely used for the prevention and treatment of IFIs in patients with leukemia and in hematopoietic stem cell

“…The doses for ISA and POS were chosen because of prior demonstration of activity in murine pulmonary mucormycosis (20,21). Drugs were given orally three times a day (t.i.d.)…”

mentioning

confidence: 99%

Prophylaxis with Isavuconazole or Posaconazole Protects Immunosuppressed Mice from Pulmonary Mucormycosis

Gebremariam

Alkhazraji

Baldin

et al. 2017

We assessed prophylactic or continuous therapy of isavuconazole, posaconazole, or voriconazole in treating pulmonary murine mucormycosis. In the prophylaxis studies, only isavuconazole treatment resulted in significantly improved survival and lowered tissue fungal burden of immunosuppressed mice infected with Rhizopus delemar. In the continuous treatment studies, isavuconazole and posaconazole, but not voriconazole, equally prolonged survival time and lowered tissue fungal burden compared to placebo-treated mice. These results support the use of isavuconazole and posaconazole in prophylaxis treatment.