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Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Background: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma., Methods: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126., Findings: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation., Interpretation: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients., Funding: Janssen Research & Development., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We report the isolation of a novel agent of subcutaneous mycosis from a 45-year-old Indian male immigrant in the United States. Phylogenetic analysis of partial small ribosomal subunit and large ribosomal subunit, internal transcribed spacer, partial translation elongation factor (TEF1), and RNA polymerase second largest subunit (rPB2) loci revealed that the strain was identical to another isolate previously reported as "Madurella mycetomatis." Both strains clustered in the order Pleosporales, nested in the family Arthopyreniaceae/Roussoellaceae. The fungus differed from known species and hence a new taxon, Roussoella percutanea, is introduced, typified by a strain that showed delayed production of pycnidial conidiomata. Antifungal susceptibility testing suggested that the new species is resistant to echinocandins and flucytosine, with variable results with azoles and amphotericin B., (© The Author 2014. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Management of postoperative pain remains an important clinical problem throughout the world. Using the PAIN-OUT acute pain registry database to examine perioperative pain management in orthopedic surgery patients, we compared patient-reported outcomes (PROs) in a pooled sample obtained from four American hospitals (N = 473) with PROs in a pooled sample of 20 European institutions (N = 8799). Most American hospitals consistently assess acute pain in surgical patients due to Joint Commission accreditation guidelines. Therefore, we hypothesized that this practice would create a climate of clinical staff sensitivity to patients' pain and a greater readiness to intervene when pain is higher than one would find in Europe as a whole. American institutions might then provide better control of postoperative pain after orthopedic surgery than European institutions. Because of the large sample sizes, our analyses focused on effect size rather than statistical significance. Evaluation of the pain PROs revealed that European patients reported much lower Worst Pain on the first day after orthopedic surgery than American patients. The mean Worst Pain (± SD) for Europeans was 5.4 (2.5) but for Americans the mean was 7.4 (2.7), p < .0001, a large effect size. Europeans also reported significantly less emotional discomfort, less interference of pain with activity and lower Least Pain. Nonetheless, 98.3% of American patients received opioids on the ward on the first postoperative day compared to 70.2% of European patients, and 41.1% received regional analgesia on the ward while 15.9% of European patients received regional analgesia (both small effect sizes). Overall, the results are clear in demonstrating much better pain control in the ensemble of European countries as compared to the United States.

Background: Aspergillus terreus causes invasive aspergillosis (IA) in immunocompromised individuals and can be the leading cause of IA in certain medical centers. We examined a large isolate collection (n = 117) for the presence of cryptic A. terreus species and employed a genome scanning method, Inter-Simple Sequence Repeat (ISSR) PCR to determine A. terreus population structure., Results: Comparative sequence analyses of the calmodulin locus revealed the presence of the recently recognized species A. alabamensis (n = 4) in this collection. Maximum parsimony, Neighbor joining, and Bayesian clustering of the ISSR data from the 113 sequence-confirmed A. terreus isolates demonstrated that one clade was composed exclusively of isolates from Europe and another clade was enriched for isolates from the US., Conclusions: This study provides evidence of a population structure linked to geographical origin in A. terreus.

With increasing numbers of immune-compromised patients with malignancy, hematologic disease, and HIV, as well as those receiving immunosupressive drug regimens for the management of organ transplantation or autoimmune inflammatory conditions, the incidence of fungal infections has dramatically increased over recent years. Definitive diagnosis of pulmonary fungal infections has also been substantially assisted by the development of newer diagnostic methods and techniques, including the use of antigen detection, polymerase chain reaction, serologies, computed tomography and positron emission tomography scans, bronchoscopy, mediastinoscopy, and video-assisted thorascopic biopsy. At the same time, the introduction of new treatment modalities has significantly broadened options available to physicians who treat these conditions. While traditionally antifungal therapy was limited to the use of amphotericin B, flucytosine, and a handful of clinically available azole agents, current pharmacologic treatment options include potent new azole compounds with extended antifungal activity, lipid forms of amphotericin B, and newer antifungal drugs, including the echinocandins. In view of the changing treatment of pulmonary fungal infections, the American Thoracic Society convened a working group of experts in fungal infections to develop a concise clinical statement of current therapeutic options for those fungal infections of particular relevance to pulmonary and critical care practice. This document focuses on three primary areas of concern: the endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections of special concern for immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections.

Emergency situations only recently have come to include terrorist threats, such as radiation, biological and chemical attacks, and bombings. The importance of emergency preparedness in health care facilities has increased as a result of recent terrorist threats. Perioperative leaders must meet the challenge of preparing their departments for a wide range of potential disasters. This article describes how a facility can prepare for both natural and man-made disasters and reviews modifications to the Joint Commission on Accreditation of Healthcare Organizations' disaster preparedness standards.

The inhalation of conidia of Blastomyces dermatitidis, a fungus found in soil, causes disease in humans and animals. We studied the genetic diversity of this pathogen by extracting DNA yeasts and analyzing them with a polymerase chain reaction (PCR)-based typing system we developed, which used restriction fragment analysis of amplicons from the regions between the rDNA repeats and allowed us to class isolates into 3 major groups. Strains were further differentiated by use of PCR fingerprinting with 3 different primers. Fifty-nine isolates collected over 35 years from 15 regions (United States, India, Africa, Canada) were analyzed. Genotypic groups A, B, and C contained 17, 23, and 19 isolates, which were divided into 5, 15, and 12 types, respectively. All 16 isolates from North America in group A were from the upper midwestern United States or Canada, whereas 0 of 20 isolates from the southeastern United States were in group A. Studies of the largest collection from 1 locale (Eagle River, WI), revealed that the soil isolates studied were not responsible for the majority of cases in this outbreak, as previously proposed, and that >1 strain was present in the environment and in patients. Overall, these results provide a tool for the epidemiological study of blastomycosis and illuminate the genetic and geographic diversity of this important pathogen.

The objective of the present study was to conduct a comparative genotypic analysis of Candida albicans isolates from the United States, Europe, and Southeast Asia to determine whether differences between isolates might be associated with geographic locations. The genotypes of 86 unrelated isolates of C. albicans (from the United States and Europe) and 26 isolates from Singapore were examined by three DNA typing methods. Computer-assisted methods were used to analyze the gel patterns for all isolates. A dendrogram based on the overall similarity of the patterns obtained by restriction endonuclease analysis (REA) with EcoRI clustered the U.S. and European isolates into two major groups (groups A and B). The Singaporean isolates demonstrated unique REA profiles, with nine isolates having both or neither of the REA-characteristic 3.7- and 4.2-kb bands present in groups A and B. By REA profiles, the Singaporean isolates were related to each other with similarity values (S(AB)s) of > 0.80, but only one isolate mixed with the U.S. and European isolates at this S(AB) (an arbitrary threshold for genetic similarity). Randomly amplified polymorphic DNA (RAPD) analysis generated DNA profiles that clustered the C. albicans isolates into approximately the same number of distinct typing groups as REA. However, isolates identical to each other by REA were generally different from each other by RAPD analysis. In a composite dendrogram prepared from the results obtained by RAPD analysis, the isolates from the United States and Europe clustered in major groups with S(AB)s of > 0.85, while Singaporean isolates connected to these clusters at S(AB)s of > or = 0.75. Pulsed-field gel electrophoresis was less discriminatory, discerning about one-third as many distinct subtypes as REA or RAPD analysis; the Singaporean isolates were distributed randomly with the U.S. and European isolates. These results suggest that a high degree of genetic diversity exists between C. albicans isolates from Southeast Asia and those from the United States and Europe.

Itraconazole has emerged as an important new oral agent in the treatment of systemic fungal infections. This paper summarizes the data available on its use in aspergillosis, cryptococcosis and histoplasmosis, compiled in the United States with particular attention to the immunocompromised host. Data have been accrued in open-label studies including 57 patients with cryptococcal disease where the overall response rate among patients with meningitis was 86%, and in 28 patients (8 with acquired immune deficiency syndrome (AIDS) or human immunodeficiency virus (HIV) infection) with invasive aspergillosis where the overall response rates were 80% in patients without AIDS and 86% in patients with AIDS. Data are summarized on 6 patients with allergic bronchopulmonary aspergillosis, 5 of whom demonstrated marked improvement on therapy, and 12 patients with histoplasmosis including 8 with AIDS, 11 of whom responded and 1 recrudesced on therapy. In summary, itraconazole showed activity in human studies of aspergillosis, cryptococcosis and histoplasmosis with minimal toxicity. Itraconazole offers a new oral alternative to conventional amphotericin B therapy in these infections. Comparative studies are needed to clarify its role.

The application of methods of Candida albicans DNA fragment length polymorphism analysis to correlations with phenotype and to questions in the epidemiology of Candida is shown. Twenty-nine different DNA types, in two broad classes, have thus far been demonstrated in 91 isolates. One type, IA2, was easily the most common (41% of isolates). A type is constant after multiple generations in vivo, as demonstrated in a mouse model. Isolates from individual medical centers were polymorphic, and DNA types were widely distributed geographically. Persons colonized with and/or having disease due to C. albicans at two or more body sites almost always had the same individual type. Sex partners studied had the same type in genital isolates. There was neither tight concordance nor random association of DNA type with previously described phenotypic groups. Likewise, some phenotypic characteristics were significantly associated with DNA type. Urogenital isolates were significantly associated with DNA type IA2. Colonizing and invading isolates included many different and overlapping DNA types. A cluster of cases in a hospital, previously reported to have been caused by a single organism (based on phenotypic studies), was shown to be due to multiple types. Phenotype switching, associated with transition from colonization to invasion, is suggested in these studies. The present series of studies demonstrates the application of DNA typing methods to classification and clinical problems.

Candida albicans isolates from 402 patients with no prior history of treatment with 5-fluorocytosine were collected at five medical centers from different areas of the United States. Isolates could be separated into four groups based on their minimum inhibitory concentrations (MICs) to 5-fluorocytosine. Group I isolates (60%) had MICs less than or equal to 12.5 micrograms/ml after 7 days, whereas groups II (22%), III (14%), and IV (4%) demonstrated MICs greater than 12.5 micrograms/ml on days 7, 2, and 1, respectively. Serotypes A and B accounted for 50.7 and 49.3%, respectively, of the 398 isolates typed. Serotype B was less prevalent in group I (26%), but predominated in the more resistant groups, groups II (85%), III (86%), and IV (53%). The common practice of identifying as "resistant" those isolates with MICs greater than 12.5 micrograms/ml after 48 h of incubation would yield a resistance rate in the United States of 11.5 to 15.5% in four centers and 35% in the fifth. Although serotype B and small agar disk diffusion zone sizes correlated with poor 5-fluorocytosine susceptibility, their ability to predict tube dilution MICs was limited. The true predictive value of such tests awaits correlation with in vivo studies.

A trial of the killed Coccidioides immitis spherule vaccine was undertaken with 151 healthy skin test negative adult volunteers and controls to evaluate the safety of selected regimens, the induction of humoral and cell-mediated immune responses, and to determine if there were immunogenetic differences in these responses. The vaccine was given as three intra-deltoid doses over 8 weeks. No severe systemic symptoms were noted, although 3% of 3.5 mg doses (but no 1.75 mg doses) were associated with severe local reactions. Half the vaccinees had skin test conversions, which generally persisted greater than or equal to 6 months, two-thirds showed boosting of lymphocyte transformation in vitro, and 16% given three 3.5 mg doses developed antibody. There was an association between degree of local adverse vaccine reaction and immunostimulation, and a trend to immune response in persons of O blood type and with some HLA phenotypes. There was no evidence of deficient response to vaccination in subpopulations known to respond to coccidioidal infection poorly. A regimen of three 1.75 mg doses appears to be safe and without reduced immunogenicity, and there is no evidence dosage modification for certain subpopulations would be necessary in efficacy studies.