MSG-10: a Phase 2 study of oral ibrexafungerp (SCY-078) following initial echinocandin therapy in non-neutropenic patients with invasive candidiasis.

OBJECTIVES: To evaluate the safety and efficacy of two dosing regimens of oral ibrexafungerp (formerly SCY-078), a novel orally bioavailable ß-glucan synthase inhibitor, in subjects with invasive candidiasis versus the standard of care (SOC) and to identify the dose to achieve target exposure (15.4 µM·h) in >80% of the intended population. METHODS: In a multinational, open-label study, patients with documented invasive candidiasis were randomized to receive step-down therapy to one of three treatment arms: two dosing regimens of novel oral ibrexafungerp or the SOC treatment following initial echinocandin therapy. Plasma samples were collected to evaluate exposure by population pharmacokinetic (PK) modelling. Safety was assessed throughout the study and global response at the end of treatment. RESULTS: Out of 27 subjects enrolled, 7 received ibrexafungerp 500 mg, 7 received ibrexafungerp 750 mg and 8 received the SOC. Five did not meet criteria for randomization. Population PK analysis indicated that an ibrexafungerp 750 mg regimen is predicted to achieve the target exposure in ∼85% of the population. The rate of adverse events was similar among patients receiving ibrexafungerp or fluconazole. Similar favourable response rates were reported among all groups: 86% (n = 6) in the ibrexafungerp 750 mg versus 71% (n = 5) in both the fluconazole and ibrexafungerp 500 mg treatment arms. The one subject treated with continued micafungin had a favourable global response. CONCLUSIONS: The oral ibrexafungerp dose estimated to achieve the target exposure in subjects with invasive candidiasis is 750 mg daily. This dose was well tolerated and achieved a favourable global response rate, similar to the SOC.

Secukinumab in plaque psoriasis--results of two phase 3 trials.

BACKGROUND: Interleukin-17A is considered to be central to the pathogenesis of psoriasis. We evaluated secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: In two phase 3, double-blind, 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), we randomly assigned 738 patients (in the ERASURE study) and 1306 patients (in the FIXTURE study) to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly). The objective of each study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator's global assessment (coprimary end points). RESULTS: The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (P<0.001 for each secukinumab dose vs. comparators). The proportion of patients with a response of 0 or 1 on the modified investigator's global assessment at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinumab, 27.2% with etanercept, and 2.8% with placebo (P<0.001 for each secukinumab dose vs. comparators). The rates of infection were higher with secukinumab than with placebo in both studies and were similar to those with etanercept. CONCLUSIONS: Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target. (Funded by Novartis Pharmaceuticals; ERASURE and FIXTURE ClinicalTrials.gov numbers, NCT01365455 and NCT01358578, respectively.).

Case study: posaconazole treatment of disseminated phaeohyphomycosis due to Exophiala spinifera.

A 41-year-old woman with no known immunosuppression experienced a 12-year period of a relapsing phaeohyphomycosis. Despite administration of multiple courses of therapy with standard antifungals, sustained clinical remission was not achieved. A partial response was seen initially with the combination of itraconazole and flucytosine therapy, but the patient did not respond to subsequent treatment. During the patient's pregnancy, the mycosis became disseminated, with lymphadenopathy and fever, and was considered life threatening. Despite receipt of parenteral amphotericin B therapy, the patient did not show a clinical response. After premature delivery by cesarean section, treatment with oral posaconazole suspension (800 mg/day) was started. The patient's condition improved within 1 week after initiating treatment; therapy was continued for 13 months. During posaconazole treatment, the patient showed a complete clinical response, with negative results of fungal cultures.

Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study.

We conducted a retrospective, multicenter study evaluating the safety of discontinuing maintenance therapy for cryptococcal meningitis after immune reconstitution. Inclusion criteria were a previous definitive diagnosis of cryptococcal meningitis, a CD4 cell count of >100 cells/microL while receiving highly active antiretroviral therapy (HAART), and the subsequent discontinuation of maintenance therapy for cryptococcal meningitis. The primary end point was relapse of cryptococcal disease. As of July 2002, 100 patients were enrolled. When maintenance therapy was discontinued, the median CD4 cell count was 259 cells/microL and the median plasma virus load was <2.30 log10 copies/mL, and serum cryptococcal antigen was undetectable in 56 patients. During a median follow-up period of 28.4 months (range, 6.7-64.5; 262 person-years), 4 events were observed (incidence, 1.53 events per 100 person-years; 95% confidence interval, 0.42-3.92). Three of these patients had a CD4 cell count of >100 cells/microL and a positive serum cryptococcal antigen test result during the recurrent episode. In conclusion, discontinuation of maintenance therapy for cryptococcal meningitis is safe if the CD4 cell count increases to >100 cells/microL while receiving HAART. Recurrent cryptococcal infection should be suspected in patients whose serum cryptococcal antigen test results revert back to positive after discontinuation of maintenance therapy.

[Interruption of antifungal secondary prophylaxis in AIDS-related histoplasmosis]. / Interrupción de la profilaxis secundaria antifúngica en la histoplasmosis asociada al sida.

The clinical data of 21 patients, suffering AIDS-related histoplasmosis, who were able to interrupt antifungal secondary prophylaxis, after achieving a partial restoration of the cell mediated immunity by HAART administration, are presented. They were 16 males and five females, whose ages varied between 32 and 54 years (mean = 38.5 years). All of them presented disseminated progressive forms of histoplasmosis, with multiple locations (skin, mucous membranes, liver, spleen, lymph nodes and lungs). The majority of the cases suffered other concomitant diseases (specially tuberculosis and Kaposi sarcoma), 66.6 % of the patients had less than 50 CD4+ cells/microl at the start of treatment and the average viral burden was 278,385 RNA copies/ml. The initial treatment consisted in 400 mg/day of itraconazole, by oral route, in 14 cases and the remaining seven patients were treated with amphotericin B, intravenously, at a daily dose of 0.7 mg/kg of body weight. One patient who did not tolerate amphotericin B and presented a partial response to itraconazole, was treated with posaconazole orally at a daily dose of 800 mg. Fourteen patients received oral itraconazole at a daily dose of 200 mg as a secondary prophylaxis, the remaining three patients were treated with intravenous amphotericin B, 50 mg twice a week. After HAART for an average lapse of 16.7 months (10 to 32 months), five cases showed CD4+ cells counts above 150 cells/microl and the remaining 16 presented more than 200 cells/microl; 18 of them had undetectable viral burden and all cases were asymptomatic. The follow up after secondary prophylaxis discontinuation varied between six months and six years (mean= 33.6 months). Twenty out of 21 patients (95 %) were clinically stable, without any manifestation of relapses, including two patients who abandoned HAART. One patient, who discontinued HAART, contracted a fatal bacterial pneumonia. Even though the limited number of cases, the data presented in this study seem to suggest that it is possible to interrupt antifungal secondary prophylaxis of histoplasmosis, when the patient is clinically asymptomatic and the CD4+ cells counts are above 150 cells/microl.

Micetomas en el Hospital de Infecciosas Francisco Javier Muniz de la ciudad de Buenos Aires, Argentina / Mycetomas in the Muniz Hospital of Buenos Aires City

Se presentam las características clínicas, microbiológicas y los resultados terapéuticos de 54 casos de micetoma, disgnosticados en los ultimos 10 anos en le Hospital Muniz. Treita y dos fueron varones y 22 mujeres, la edad promedio fue de 43.4 anos (20-27 anos). La mayoria de los enfermos adquirió la infección en el norte de la Argentina (Santiago del Estero 2o casos, Chaco 9, Formosa 3, Salta 2 y Catamarca1) y 6 pacientes de evolución de la enfermedad fue de 9.1 anos (6 meses a 30 anos)...