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Item does not contain fulltext BACKGROUND: Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. FINDINGS: Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. INTERPRETATION: Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. FUNDING: Cidara Therapeutics and Mundipharma.

Introduction: Cytomegalovirus (CMV) infection is a well-known factor associated with invasive aspergillosis in immunocompromised hosts. However, its association with COVID-19-associated pulmonary aspergillosis (CAPA) has not been described. We aimed to examine the possible link between CMV replication and CAPA occurrence. Methods: A single-center, retrospective case–control study was conducted. A case was defined as a patient diagnosed with CAPA according to 2020 ECMM/ISHAM consensus criteria. Two controls were selected for each case among critically ill COVID-19 patients. Results: In total, 24 CAPA cases were included, comprising 14 possible CAPA and 10 probable CAPA. Additionally, 48 matched controls were selected. CMV replication was detected more frequently in CAPA than in controls (75.0% vs. 35.4%, p = 0.002). Probable CMV end-organ disease was more prevalent in CAPA (20.8% vs. 4.2%, p = 0.037). After adjusting for possible confounding factors, CMV replication persisted strongly associated with CAPA (OR 8.28 95% CI 1.90–36.13, p = 0.005). Among 11 CAPA cases with CMV PCR available prior to CAPA, in 9 (81.8%) cases, CMV replication was observed prior to CAPA diagnosis. Conclusions: Among critically ill COVID-19 patients, CMV replication was associated with CAPA and could potentially be considered a harbinger of CAPA. Further studies are needed to confirm this association.

The authors report interim results of the WHO Solidarity trial of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with Covid-19. Effects on overall mortality, initiation of ventilation, and duration of hospital stay are compared. Background World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). Methods We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. Results At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. Conclusions These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ; ClinicalTrials.gov number, .)

The aim of the study was to analyse the epidemiology and prognosis of candidaemia in elderly patients. We performed a comparison of clinical presentation of candidaemia according to age and a study of hazard factors within a prospective programme performed in 29 hospitals. One hundred and seventy-six episodes occurred in elderly patients (>75 years), 227 episodes in middle-aged patients (61-75 years) and 232 episodes in younger patients (16-60 years). Central venous catheter, parenteral nutrition, neutropenia, immunosuppressive therapy and candidaemia caused by Candida parapsilosis were less frequent in elderly patients. These patients received inadequate antifungal therapy (57.3%) more frequently than middle-aged and younger patients (40.5% P < .001). Mortality during the first week (20%) and 30 days (42%) was higher in elderly patients. The variables independently associated with mortality in elderly patients during the first 7 days were acute renal failure (OR: 2.64), Pitt score (OR: 1.57) and appropriate antifungal therapy (OR: 0.132). Primary candidaemia (OR: 2.93), acute renal failure (OR: 3.68), Pitt score (OR: 1.38), appropriate antifungal therapy (OR: 0.3) and early removal of the central catheter (OR: 0.47) were independently associated with 30-day mortality.In conclussion, inadequate antifungal treatment is frequently prescribed to elderly patients with candidaemia and is related with early and late mortality.

Background Since 2011, several cases of health care-related disseminated Mycobacterium chimaera infection outbreaks have been reported subsequent to cardiac surgery. Diagnosis is difficult and the prognosis is extremely poor despite long-term antibiotic treatment and surgery. Case summary We report a Spanish case of M. chimaera infective endocarditis (IE) with disseminated infection. The patient was treated with long-term antibiotic therapy, valve replacement, and the novel use of interferon-gamma as adjuvant therapy. In addition, [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) was used in combination with computed tomography (CT) to facilitate the diagnosis as well as to determine the duration of antibiotics and success of treatment. Discussion Diagnosing M. chimaera IE is difficult and requires a high index of clinical suspicion. Controlling the infection is even more difficult. Interferon-g used adjuvant to surgery and antibiotic therapy could be useful in achieving this goal. Given that the appropriate duration of antibiotics is unknown, FDG PET/CT could also be a valuable tool for determining when antibiotic therapy can be withdrawn.

Summary Objective To assess the current clinical features and determinants of outcome of Candida tropicalis bloodstream infection (BSI). Methods A population-based surveillance on Candida BSI was conducted from May 2010 to April 2011 in 29 Spanish hospitals. Antifungal susceptibility testing (EUCAST methodology) was centrally performed. The characteristics and outcome of C. tropicalis BSI episodes were compared with those due to other species. Results Fifty-nine out of 752 episodes (7.8%) were due to C. tropicalis (annual incidence: 0.62 cases per 100,000 population). Resistance to fluconazole and voriconazole was found in 23.2% and 26.8% of isolates. Breakthrough BSI occurred in 10.5% of episodes. Risk factors for C. tropicalis BSI were age (odds ratio [OR]: 1.01; P -value = 0.05), underlying leukaemia (OR: 4.77; P -value = 0.001) and chronic lung disease (OR: 2.62; P -value = 0.002). There were no differences in clinical failure (persistent BSI for ≥72 h after initiation of therapy and/or 30-day all-cause mortality) between C. tropicalis (39.6%) and non- C. tropicalis groups (45.6%). The appropriateness of antifungal therapy or the fluconazole MIC values had no significant impact on outcome, whereas early central venous catheter removal exerted a protective effect. Conclusions C. tropicalis BSI was associated with advanced age, haematological malignancy and respiratory comorbidity. We found no correlation between the unexpectedly high resistance rate to azoles observed and outcome.

To analyse the clinical presentation of candidaemia in elderly patients.A comparison of clinical presentation of candidaemia cases was carried out in a Spanish tertiary hospital between January 2010 and September 2015.Forty-five cases (32%) corresponded to elderly patients (≥ 75 years) and 95 cases (68%) to non-elderly patients (16-74 years). A higher proportion of elderly patients presented solid tumour (51% versus 32%, p=0.026) and a lower proportion had undergone solid or hematopoietic transplantation (0% versus 28%, p0.001). Fewer elderly patients (16 patients, 36%) had a central venous line inserted than non-elderly patients (81 patients, 85%, p0.001). Isolation of Candida parapsilosis was significantly lower among elderly (13.3%) than among non-elderly patients (32%, p=0.015). Fundoscopy was carried out in 20 elderly (44%) and in 64 younger patients (67%, p=0.009). The proportion of patients who underwent echocardiography was similar in both groups (56% vs 66%, respectively; p=0.218). Adequate antifungal treatment within the first 48 hours was administered in16 elderly patients (36%) and 58 younger patients (61%, p=0.005). Catheter removal was carried out in 9 elderly patients (68.1%) and in 40 non-elderly patients (49%, p=0.544). Mortality was higher among elderly patients (55.6%) than non-elderly patients (36.8%; p=0.037).Elderly patients account for a substantial proportion of patients suffering from candidaemia in recent years. The clinical management of these patients was less appropriate than in younger patients with respect to fundus examination and the prescription of appropriate antifungal treatment. Mortality in elderly patients was higher than in younger patients.

A prospective, multicentre, population-based surveillance programme for Candida bloodstream infections was implemented in five metropolitan areas of Spain to determine its incidence and the prevalence of antifungal resistance, and to identify predictors of death. Between May 2010 and April 2011, Candida isolates were centralized to a reference laboratory for species identification by DNA sequencing and for susceptibility testing by EUCAST reference procedure. Prognostic factors associated with early (0–7 days) and late (8–30 days) death were analysed using logistic regression modelling. We detected 773 episodes: annual incidence of 8.1 cases/100 000 inhabitants, 0.89/1000 admissions and 1.36/10 000 patient-days. Highest incidence was found in infants younger than 1 year (96.4/100 000 inhabitants). Candida albicans was the predominant species (45.4%), followed by Candida parapsilosis (24.9%), Candida glabrata (13.4%) and Candida tropicalis (7.7%). Overall, 79% of Candida isolates were susceptible to fluconazole. Cumulative mortality at 7 and 30 days after the first episode of candidaemia was 12.8% and 30.6%, respectively. Multivariate analysis showed that therapeutic measures within the first 48 h may improve early mortality: antifungal treatment (OR 0.51, 95% CI 0.27–0.95) and central venous catheter removal (OR 0.43, 95% CI 0.21–0.87). Predictors of late death included host factors (e.g. patients' comorbid status and signs of organ dysfunction), primary source (OR 1.63, 95% CI 1.03–2.61), and severe sepsis or septic shock (OR 1.77, 95% CI 1.05–3.00). In Spain, the proportion of Candida isolates non-susceptible to fluconazole is higher than in previous reports. Early mortality may be improved with strict adherence to guidelines.

This study was partially financed by the CIBER de Enfermedades Respiratorias (CIBERES) from the ISCIII (CB06/06/0058) and by Fundación BBVA-FundacioóCarolina (research fellowship of Maricela Valerio)., Muñoz, P; Kestler, M; De Alarcon, A; Miro, JM; Bermejo, J; Rodriguez-Abella, H; Farinas, MC; Belaustegui, MC; Mestres, C; Llinares, P; Goenaga, M; Navas, E; Oteo, JA; Tarabini, P; Bouza, E.

We aimed to develop a simple prediction score to identify fluconazole non-susceptible (Flu-NS) candidaemia using simple clinical criteria. A derivation cohort was extracted from the CANDIPOP study, a prospective, multicentre, population-based surveillance programme on candidaemia conducted in 29 hospitals in Spain from April 2010 to May 2011. The score was validated with an external, multicentre cohort of adults with candidaemia in six tertiary hospitals in three countries. The prediction score was based on three variables selected by a logistic regression model together with the severity of disease. In total, 617 and 297 cases of candidaemia were included in the derivation and validation cohorts, respectively; of these, 134 (21.7%) and 57 (19.2%) were caused by Flu-NS strains. Factors independently associated with Flu-NS were transplant recipient status (adjusted odds ratio (AOR) 2.13; 95% CI 1.01–4.55; p 0.047), hospitalization in a unit with a high prevalence (≥15%) of Flu-NS strains (7.53; 4.68–12.10; p

A prospective, population-based surveillance on candidaemia was implemented in five metropolitan areas of Spain from May 2010 to April 2011. We aimed to describe the distribution and susceptibility pattern of Candida species, and to evaluate risk factors for mortality in patients with oncological (solid tumours) and haematological malignancies. Adults (≥16 years) with cancer were included in the present report. Impact of therapeutic strategies on 7- and 30-day mortality were analysed by logistic regression, adjusting for propensity score by inverse weighting probability of receiving early antifungal treatment and catheter removal. We included 238 (32.6%) patients (195 oncological, 43 haematological). Compared with oncological patients, haematological patients were more likely to have received chemotherapy (53.5% versus 17.4%, p