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Despite this complication, several promising new agents, including entirely new classes of molecules, have entered clinical trials in the past decade.6,8 But even before they reach the market after years of development and clinical trials, fungicides with similar modes of action are developed by the agrochemical industry resulting in cross-resistance for critical priority pathogens such as A fumigatus.8 We are back where we started in terms of the future sustainability of treating azole-resistant A fumigatus with currently available antifungals. NPG was supported by the National Institute for Health and Care Research (NIHR; grant numbers NIHR134342 and NIHR303140) with UK international development funding from the UK Government to support global health research; has received grants from the US Centers for Disease Control and Prevention, Bill & Melinda Gates Foundation, and Medical Research Council (UK); has participated on a data safety monitoring board for the ACACIA trial; and is a council member of the Federation of Infectious Diseases Societies of Southern Africa. FH has received support for attending a conference from the International Society for Human and Animal Mycology (ISHAM); is Treasurer of the Netherlands Society for Medical Mycology; is Vice President of ISHAM; is Chair of the Division of Microbial Genomics of the Royal Netherlands Society for Microbiology; and has received diagnostic kits for validation from CHROMagar, Bruker Daltonics, Pathonostics, OLM Diagnostics, and Altona Diagnostics.

About the Authors: Joshua Griffiths Affiliation: The University of Manchester, Manchester, United Kingdom Arnaldo Lopes Colombo Affiliation: Division of Infectious Diseases, Universidade Federal de São Paulo, São Paulo, Brazil David W. Denning * E-mail: ddenning@manchester.ac.uk, ddenning@GAFFI.org Affiliations The University of Manchester, Manchester, United Kingdom, National Aspergillosis Centre, Wythenshawe Hospital, Manchester Academic Health Science Centre, Manchester, United Kingdom, Global Action Fund for Fungal Infections, Geneva, Switzerland ORCID logo http://orcid.org/0000-0001-5626-2251 Introduction The World Health Organization’s (WHO) neglected tropical disease (NTD) portfolio is a diverse group of diseases with profound impacts on affected populations. Public health impact and association with poverty Previous reviews of the epidemiology of PCM have attempted to estimate the incidence of the disease using case series [5,10]. Additionally, patients usually present with pulmonary lesions (a feature of the chronic form, which otherwise is almost the exclusive form affecting those over 30 years old) as well as generalised lymphadenopathy, splenomegaly, bone lesions, and skin lesions as a result of haematogenous dissemination (a feature of the acute/subacute form of the disease, which tends to affect children) [26]. First WHO report on neglected tropical diseases.

Caspofungin is a new echinocandin drug that has activity against the cell wall of candida species. This double-blind trial evaluated whether caspofungin is as effective as amphotericin B, which has substantial toxicity. Among 224 patients with invasive candidiasis, the outcomes were successful in 73.4 percent of those treated with caspofungin and in 61.7 percent of those treated with amphotericin B. The frequency of nephrotoxic effects was lower with caspofungin than with amphotericin B. The optimal first-line treatment for serious candida infections is a controversial issue. Amphotericin B has served as standard treatment for five decades, 1 – 3 but toxic effects often limit its use. 2 Fluconazole has a role in the treatment of candidemia. 4 – 10 Prospective, randomized studies have shown that fluconazole is as effective as amphotericin B, with superior safety, for the treatment of candidemia in patients without neutropenia. 11 – 13 However, certain non-albicans candida species, which account for over half the cases of candidemia, are less susceptible to fluconazole. 14 – 18 The need remains for new agents to treat serious candida infections. One alternative is . . .

Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.

Tolerance to antifungal drug concentrations above the minimal inhibitory concentration (MIC) is rarely quantified, and current clinical recommendations suggest it should be ignored. Here, we quantify antifungal tolerance in Candida albicans isolates as the fraction of growth above the MIC, and find that it is distinct from susceptibility/resistance. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, and correlates inversely with intracellular drug accumulation. Many adjuvant drugs used in combination with fluconazole, a widely used fungistatic drug, reduce tolerance without affecting resistance. Accordingly, in an invertebrate infection model, adjuvant combination therapy is more effective than fluconazole in treating infections with highly tolerant isolates and does not affect infections with low tolerance isolates. Furthermore, isolates recovered from immunocompetent patients with persistent candidemia display higher tolerance than isolates readily cleared by fluconazole. Thus, tolerance correlates with, and may help predict, patient responses to fluconazole therapy. The authors show that antifungal tolerance, defined as the fraction of growth of a fungal pathogen above the minimal inhibitory concentration, is due to the slow growth of subpopulations of cells that overcome drug stress, and that high tolerance is often associated with persistent infections.

Candidemia is a growing problem in hospitals all over the world. Despite advances in the medical support of critically ill patients, candidiasis leads to prolonged hospitalization, and has a crude mortality rate around 50%. We conducted a multicenter surveillance study in 16 hospitals distributed across five regions of Brazil to assess the incidence, species distribution, antifungal susceptibility, and risk factors for bloodstream infections due to Candida species. From June 2007 to March 2010, we studied a total of 2,563 nosocomial bloodstream infection (nBSI) episodes. Candida spp. was the 7th most prevalent agent. Most of the patients were male, with a median age of 56 years. A total of 64 patients (46.7%) were in the ICU when candidemia occurred. Malignancies were the most common underlying condition (32%). The crude mortality rate of candidemia during the hospital admission was 72.2%. Non-albicans species of Candida accounted for 65.7% of the 137 yeast isolates. C. albicans (34.3%), Candida parapsilosis (24.1%), Candida tropicalis (15.3%) and Candida glabrata (10.2%) were the most prevalent species. Only 47 out of 137 Candida isolates were sent to the reference laboratory for antifungal susceptibility testing. All C. albicans, C. tropicalis and C. parapsilosis isolates were susceptible to the 5 antifungal drugs tested. Among 11 C. glabrata isolates, 36% were resistant to fluconazole, and 64% SDD. All of them were susceptible to anidulafungin and amphotericin B. We observed that C. glabrata is emerging as a major player among non-albicans Candida spp. and fluconazole resistance was primarily confined to C. glabrata and C. krusei strains. Candida resistance to echinocandins and amphotericin B remains rare in Brazil. Mortality rates remain increasingly higher than that observed in the Northern Hemisphere countries, emphasizing the need for improving local practices of clinical management of candidemia, including early diagnosis, source control and precise antifungal therapy.

Chromoblastomycosis (CBM), represents one of the primary implantation mycoses caused by melanized fungi widely found in nature. It is characterized as a Neglected Tropical Disease (NTD) and mainly affects populations living in poverty with significant morbidity, including stigma and discrimination. In order to estimate the global burden of CBM, we retrospectively reviewed the published literature from 1914 to 2020. Over the 106-year period, a total of 7,740 patients with CBM were identified on all continents except Antarctica. Most of the cases were reported from South America (2,619 cases), followed by Africa (1,875 cases), Central America and Mexico (1,628 cases), Asia (1,390 cases), Oceania (168 cases), Europe (35 cases), and USA and Canada (25 cases). We described 4,022 (81.7%) male and 896 (18.3%) female patients, with the median age of 52.5 years. The average time between the onset of the first lesion and CBM diagnosis was 9.2 years (range between 1 month to 50 years). The main sites involved were the lower limbs (56.7%), followed by the upper limbs (19.9%), head and neck (2.9%), and trunk (2.4%). Itching and pain were reported by 21.5% and 11%, respectively. Malignant transformation was described in 22 cases. A total of 3,817 fungal isolates were cultured, being 3,089 (80.9%) Fonsecaea spp., 552 (14.5%) Cladophialophora spp., and 56 Phialophora spp. (1.5%). This review represents our current knowledge on the burden of CBM world-wide. The global incidence remains unclear and local epidemiological studies are required to improve these data, especially in Africa, Asia, and Latin America. The recognition of CBM as NTD emphasizes the need for public health efforts to promote support for all local governments interested in developing specific policies and actions for preventing, diagnosing and assisting patients.

Purpose Clinical data on patients with intra-abdominal candidiasis (IAC) is still scarce. Methods We collected data from 13 hospitals in Italy, Spain, Brazil, and Greece over a 3-year period (2011–2013) including patients from ICU, medical, and surgical wards. Results A total of 481 patients were included in the study. Of these, 27 % were hospitalized in ICU. Mean age was 63 years and 57 % of patients were male. IAC mainly consisted of secondary peritonitis (41 %) and abdominal abscesses (30 %); 68 (14 %) cases were also candidemic and 331 (69 %) had concomitant bacterial infections. The most commonly isolated Candida species were C. albicans ( n  = 308 isolates, 64 %) and C. glabrata ( n  = 76, 16 %). Antifungal treatment included echinocandins (64 %), azoles (32 %), and amphotericin B (4 %). Septic shock was documented in 40.5 % of patients. Overall 30-day hospital mortality was 27 % with 38.9 % mortality in ICU. Multivariate logistic regression showed that age (OR 1.05, 95 % CI 1.03–1.07, P  < 0.001), increments in 1-point APACHE II scores (OR 1.05, 95 % CI 1.01–1.08, P  = 0.028), secondary peritonitis (OR 1.72, 95 % CI 1.02–2.89, P  = 0.019), septic shock (OR 3.29, 95 % CI 1.88–5.86, P  < 0.001), and absence of adequate abdominal source control (OR 3.35, 95 % CI 2.01–5.63, P  < 0.001) were associated with mortality. In patients with septic shock, absence of source control correlated with mortality rates above 60 % irrespective of administration of an adequate antifungal therapy. Conclusions Low percentages of concomitant candidemia and high mortality rates are documented in IAC. In patients presenting with septic shock, source control is fundamental.

Invasive infections caused by Trichosporon spp. have increased considerably in recent years, especially in neutropenic and critically ill patients using catheters and antibiotics. The genus presents limited sensitivity to different antifungal agents, but triazoles are the first choice for treatment. Here, we investigated the biofilm production and antifungal susceptibility to triazoles and amphotericin B of 54 Trichosporon spp. isolates obtained from blood samples (19), urine (20) and superficial mycosis (15). All isolates and 7 reference strains were identified by sequence analysis and phylogenetic inferences of the IGS1 region of the rDNA. Biofilms were grown on 96-well plates and quantitation was performed using crystal violet staining, complemented with Scanning Electron Microscopy (SEM). Susceptibility tests for fluconazole, itraconazole, voriconazole and amphotericin B were processed using the microdilution broth method (CLSI) for planktonic cells and XTT reduction assay for biofilm-forming cells. Our results showed that T. asahii was the most frequent species identified (66.7%), followed by T. faecale (11.1%), T. asteroides (9.3%), T. inkin (7.4%), T. dermatis (3.7%) and one T. coremiiforme (1.8%). We identified 4 genotypes within T. asahii isolates (G1, G3, G4 and G5) and 2 genotypes within T. faecale (G1 and G3). All species exhibited high adhesion and biofilm formation capabilities, mainly T. inkin, T. asteroides and T. faecale. Microscopy images of high biofilm-producing isolates showed that T. asahii presented mainly hyphae and arthroconidia, whereas T. asteroides exhibited mainly short arthroconidia and few filaments. Voriconazole exhibited the best in vitro activity against all species tested. Biofilm-forming cells of isolates and reference strains were highly resistant to all antifungals tested. We concluded that levels of biofilm formation by Trichosporon spp. were similar or even greater than those described for the Candida genus. Biofilm-forming cells were at least 1,000 times more resistant to antifungals than planktonic cells, especially to voriconazole.

Background Candidemia is an increasing problem in tertiary care hospitals worldwide. Here, we report the first outbreak of candidemia caused by fluconazole-resistant C. parapsilosis (FRCP) strains in Brazil. Methods This was a cross-sectional study of clinical and microbiological data of all candidemic episodes diagnosed from July 2011 to February 2012 in a 200-bed tertiary care hospital. Initial yeast identification and susceptibility testing were performed using the VITEK 2 - System. Isolates of Candida spp . resistant to fluconazole were sent to a reference laboratory (LEMI-UNIFESP) for further molecular identification and confirmation of resistance by CLSI microdilution test. A multivariate analysis was conducted to identify factors associated with FRCP infection. Results We identified a total of 40 critically ill patients with candidemia (15 women) with a median age of 70 years. The incidence of candidemia was 6 cases/1,000 patients admissions, including 28 cases (70 %) of infection with C. parapsilosis , 21 of which (75 %) were resistant to fluconazole. In only 19 % of FRCP candidemia cases had fluconazole been used previously. The results of our study indicated that diabetes is a risk factor for FRCP candidemia ( p  = 0.002). Overall, mortality from candidemia was 45 %, and mortality from episodes of FRCP infections was 42.9 %. Conclusions The clustering of incident cases in the ICU and molecular typing of strains suggest horizontal transmission of FRCP. Accurate vigilant monitoring for new nosocomial strains of FRCP is required.