Pharmacy & Therapeutics- July 2008 - (Page 393) DRUG FORECAST IN VIVO ANIMAL EFFICACY STUDIES Cacciapuoti et al., 200610 Potential, theoretical, and different but complementary mechanisms of action of posaconazole and caspofungin were investigated. Immunocompetent mice infected with Aspergillus fumigatus and Aspergillus flavus were treated with a combination of posaconazole and caspofungin (Cancidas). The MIC90 of posaconazole ranged from 0.03 to 0.125 mcg/mL against all strains of Aspergillus species. The MIC90 for caspofungin ranged from 32 to 128 mcg/mL, and minimum effective concentrations (MECs) ranged from 0.03 to 0.06 mcg/mL. The combination of posaconazole and caspofungin was synergistic or indifferent for A. fumigatus and was indifferent for A. flavus isolates. No antagonism was observed with the concomitant use of posaconazole and caspofungin in mice infected with Aspergillus species. Barchiesi et al., 200711 significantly prolonged survival rates, compared with control mice (P = 0.001). Mice that were infected with A. corymbifera and that were treated by both posaconazole and amphotericin B had longer survival rates than controls (P < 0.05). Prophylaxis with both drugs was effective at reducing the size of foci in kidneys infected by R. oryzae (P < 0.05), but neither drug was effective in the brain. Both drugs reduced the numbers and sizes of infectious foci in kidneys and brain tissues of mice infected with A. corymbifera, suggesting a prophylaxis potential of posaconazole for zygomycosis. Cornely et al., 200713 IN VIVO HUMAN EFFICACY STUDIES Prophylaxis for Febrile Neutropenia and Invasive Fungal Infections Ullmann et al., 200612 Zygomycosis manifests as rhino cerebral, pulmonar y, gastrointestinal, and cutaneous disseminated disease. It is a rare but highly aggressive fungal infection associated with a high mortality rate. Most common zygomycetes that are identified as etiological pathogens in humans are Rhizopus, Rhizomucor, Mucor, and Absidia species. Zygomycosis usually affects immunocompromised hosts, including patients with diabetes mellitus or neutropenia and those taking chronic corticosteroids. Therapy usually includes surgical debridement and high doses of IV amphotericin B. Because posaconazole has shown activity against zygomycetes in vitro, it was compared with amphotericin B for prophylaxis against Rhizopus oryzae and Absidia corymbifera in an experimental model of neutropenic mice. In vitro susceptibilities of Rhizopus species for posaconazole and amphotericin B ranged from 1 to 2 mcg/mL and from 0.5 to 4 mcg/mL, respectively. The susceptibilities for A. corymbifera were 0.25 to 2 mcg/mL for posaconazole and 1 to 2 mcg/mL for amphotericin B, respectively. The survival rate for mice that were infected with R. oryzae and treated with posaconazole was not improved, but mice treated with amphotericin B had The efficacy and safety of different dosing regimens of posaconazole oral suspension were evaluated in a multicenter, randomized, open-label, parallelgroup study in patients with possible, probable, and proven refractory invasive fungal infections (IFIs) or febrile neutropenia (FN). Overall, 66 subjects with FN and 32 patients with IFIs were randomly assigned to one of three posaconazole schedules: • 200 mg four times a day for nine doses, followed by 400 mg twice daily (regimen 1) • 400 mg four times a day for nine doses, followed by 600 mg twice daily (regimen 2) • 800 mg twice a day for five doses, followed by 800 mg once daily (regimen 3) Therapy was continued for up to six months in patients with IFIs or until neutrophil count recovery in patients with FN. In all, successful clinical responses were observed in 43% of patients with IFIs: 56% with regimen 1, 17% with regimen 2, and 50% with regimen 3. The overall successful response rate in patients with FN was 77%: 74% of patients receiving regimen 1, 78% receiving regimen 2, and 81% receiving regimen 3. Treatmentrelated adverse events occurred in 24% of recipients and were mostly gastrointestinal. Patients with FN caused by aggressive chemotherapy for acute myelogenous leukemia and myelodysplastic syndrome are at increased risk for fatal IFIs. In this randomized, multicenter, singleblinded study, the investigators compared the efficacy and safety of posaconazole with that of fluconazole or itraconazole. A total of 304 subjects received antifungal prophylaxis with each cycle of chemotherapy until recovery from neutropenia and complete remission. If fungal infection occurred during therapy, antifungal treatment was continued for up to 12 weeks. The incidence of proven or probable IFIs was compared for posaconazole versus fluconazole or itraconazole-treated groups. Proven or probable fungal infections were reported in seven patients (2%) in the posaconazole group and in 25 patients (8%) in the fluconazole or itraconazole group, thus revealing the superiority of posaconazole: absolute reduction, –6%; 95% confidence interval (CI), –9.7 to –2.5% (P < 0.001). Significantly fewer patients in the posaconazole group (two patients, 1%) had invasive aspergillosis (20 patients, 7%) (P < 0.001). Survival was significantly higher among the posaconazole-treated subjects than among recipients of fluconazole or itraconazole (P = 0.04). Ullmann et al., 200714 In an double-blind, randomized, international trial, the Ullmann team investigated the incidence of IFIs in 600 patients after allogeneic hematopoietic stem-cell transplantation (HSCT). Oral posaconazole or fluconazole was administered as prophylaxis against IFIs in patients with graft-versus-host disease (GVHD) who were receiving immunosuppressive therapy. The incidence of proven or probableIFIs was recorded for up to 112 days. Posaconazole was found to be as effective as fluconazole in preventing all IFIs, with an incidence of 5.3% and 9%, respectively (P = 0.07). It was also superior to fluconazolein preventing proven or probable invasive aspergillosis (2.3% vs. 7%, respectively) (P = 0.006). Overall mortality rates were similar in thetwo groups, but the number of deaths from IFIs was lower with posaconazole treatment (1%) than with fluconazole (4%) (P = 0.046). Vol. 33 No. 7 • July 2008 • P&T® 393
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