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Treatment outcomes in patients with proven/probable vs possible invasive mould disease (IMD; 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG] criteria) needed further assessment. The Phase III SECURE trial compared isavuconazole vs voriconazole for treatment of IMD. This post hoc analysis assessed all-cause mortality (ACM) through day 42 (primary endpoint) and day 84, overall and clinical success at end of treatment (EOT), and drug-related treatment-emergent adverse events (TEAEs) in subgroups with proven/probable or possible IMD. Of 516 randomised patients, 304 (58.9%) had proven/probable IMD and 164 (31.8%) had possible IMD as per EORTC/MSG criteria; 48 did not have IMD. Across treatment groups, day 42 and day 84 ACM were numerically lower for possible vs proven/probable IMD (day 42: 17.1% vs 21.1%; P=0.3, day 84: 26.2% vs 32.6%; P=0.15). Overall and clinical success at EOT were significantly higher for possible IMD compared with proven/probable IMD (48.2% vs 36.2%; P=0.01, 75.0% vs 63.1%; P=0.01 respectively). Fewer drug-related TEAEs were reported with isavuconazole compared with voriconazole in patients with either proven/probable or possible IMD. Compared with patients with proven/probable IMD, those with possible IMD demonstrated higher overall and clinical success rates, supporting early initiation of antifungal treatment.

Objectives: A two-part (Phase 1B/3), sequential, open-label, multicentre study evaluated the pharmacokinetics (PK) and safety of intravenous (iv) posaconazole given as antifungal prophylaxis to neutropenic patients with AML or myelodysplastic syndrome (MDS) or to recipients at risk of invasive fungal disease (IFD) after allogeneic HSCT. Methods: Patients (N=237) received 300mg of posaconazole iv twice daily on day 1, followed by 300mg of posaconazole iv once daily for 4-28 days. After at least 5 days, patients were randomly assigned to receive posaconazole oral suspension, 400mg twice daily or 200mg three times daily, to complete a 28 day treatment course. Primary PK parameters were steady-state average concentration over the dosing interval (C-avg) and posaconazole trough levels (C-min). Results: Mean posaconazole C-min was 1320 ng/mL (day 6) and 1297 ng/mL (day 8); steady-state C-min was 1090 ng/mL (day 10). Mean steady-state posaconazole C-avg was 1500 ng/mL (day 10 or 14) and was similar in HSCT recipients (1560 ng/mL) and AML/MDS patients (1470 ng/mL). The most commonly reported treatment-related adverse events were diarrhoea (8%), nausea (5%) and rash (5%). IFD was reported in 3/237 patients (1%; 2 proven, 1 probable). Conclusions: Intravenous posaconazole at 300mg was well tolerated, resulted in adequate steady-state systemic exposure and was associated with a low incidence of IFD in this population at high risk.

Background. Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. Methods. A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. Results. Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P < .001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P < .001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P < .001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated. Conclusions. Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis

Background Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. Methods This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1: 1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. Findings 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1.0% (95% CI -7.8 to 5.7). Because the upper bound of the 95% CI (5.7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0.122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69

Viral infections are important causes of morbidity and mortality in patients after hematopoietic stem cell transplantation. The monitoring by PCR of Herpesviridae loads in blood samples has become a critical part of posttransplant follow-up, representing mounting costs for the laboratory. In this study, we assessed the clinical performance of the multiplex PCR DNA microarray Clart Entherpex kit for detection of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6) as a screening test for virological follow-up. Two hundred fifty-five blood samples from 16 transplanted patients, prospectively tested by routine PCR assays, were analyzed by microarray. Routine PCR detected single or multiple viruses in 42% and 10% of the samples, respectively. Microarray detected single or multiple viruses in 34% and 18% of the samples, respectively. Microarray results correlated well with CMV and EBV detections by routine PCR (kappa tests = 0.79 and 0.78, respectively), whereas a weak correlation was observed with HHV-6 (0.43). HHV-7 was also detected in 48 samples by microarray. In conclusion, the microarray is a reliable screening assay for a posttransplant virological follow-up to detect CMV and EBV infections in blood. However, positive samples must be subsequently confirmed and viral loads must be quantified by PCR assays. Limitations were identified regarding HHV-6 detection. Although it is promising, is easy to use as a first-line test, and allows a reduction in the cost of analysis without undue delay in the reporting of the final quantitative result to the clinician, some characteristics of this microarray should be improved, particularly regarding quality control and the targeted virus panel, such that it could then be used as a routine test., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

0, info:eu-repo/semantics/published

Background. Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. Methods. A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. Results. Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P < .001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P < .001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P < .001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated. Conclusions. Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis