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Background The use of iliac vein stenting for the treatment of pelvic pain secondary to pelvic venous insufficiency has significantly increased. In women of childbearing age, the effect of the gravid uterus on stent function and patency is unclear. The purpose of this investigation was to determine the effect of pregnancy on stent patency and reintervention rate in women with iliac vein stents. Methods A retrospective chart review and email survey was performed to identify women treated at the Center for Vascular Medicine who were treated with iliac vein stenting and who had subsequent pregnancies. Medical and surgical comorbidities, stent type, location, length, number of stents, reintervention rates, number of pregnancies after stenting, anticoagulation usage during pregnancy, and type of delivery were assessed. Results From January 2014 to December 2020, 15 women with 16 iliac vein stents and who had 17 subsequent pregnancies were identified. The average age at stenting was 35.3 ± 4.13 years. The average interval between stenting and conception was 350 ± 287 days. Before pregnancy, stent location was in the right common/right external iliac veins in 1 patient and left common/external iliac veins in 14 patients. The average stent diameter and length were 19.6 ± 3 and 79.5 ± 20.3 mm, respectively. Thirteen Boston Scientific Wallstents and three Bard Venovo stents were used before pregnancy. One patient with a Wallstent required a stent extension before pregnancy and one patient had two stents placed at the initial procedure. Two women were pregnant twice after stenting for a total of 17 pregnancies. There were 16 term and 1 premature delivery of single infants. Patients were treated with enoxaparin (Lovenox) for stent-related thrombosis prophylaxis in 11 of 17 pregnancies, 5 had no prophylaxis, and the status of 1 pregnancy is unknown. One asymptomatic patient underwent a stent venoplasty after delivery. Conclusions Iliac vein stents tolerate a gravid uterus well. No stents thrombosed during or after pregnancy and none required reintervention secondary to pregnancy-related compression. Anticoagulation with low-molecular-weight heparin should be considered for stent thrombosis prophylaxis. Potential pregnancy should not be considered a contraindication to iliac vein stenting for the treatment of symptomatic pelvic venous insufficiency.

Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including fungi resistant to standard of care antifungals. This multicenter, open-label, single-arm study evaluated FMGX safety and efficacy for treatment of candidemia and/or invasive candidiasis caused by Candida auris .

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.

Background Rezafungin is a next-generation, once-weekly echinocandin in development for treatment of candidemia and invasive candidiasis (IC), and for prevention of invasive fungal diseases caused by Candida, Aspergillus, and Pneumocystis in allogeneic blood and marrow transplant recipients (Fig 1). ReSTORE (NCT03667690) is a global, double-blind, double-dummy, 1:1 randomized, controlled, Phase 3 non-inferiority trial that evaluated the efficacy and safety of rezafungin once weekly (QWk) versus caspofungin once daily (QD) in patients with candidemia and/or IC. This analysis of the completed ReSTORE trial was conducted to evaluate outcomes by baseline pathogen and susceptibility. Methods In ReSTORE, adults (≥18 y) with systemic signs and mycological confirmation of candidemia and/or IC received either rezafungin QWk (400 mg Week 1, then 200 mg QWk) or caspofungin QD for ≥14 days (up to 4 weeks) with optional oral fluconazole step-down in the caspofungin arm. The primary endpoints were global cure at day (D) 14 (per Data Review Committee confirmation of investigator-assessed clinical cure [and radiological cure for IC) + mycological eradication]) and all-cause mortality (ACM) at D30 (Fig 2). Secondary endpoints included mycological eradication at D14. For this analysis, D14 global cure and mycological eradication by treatment group were analyzed by Candida species and in vitro susceptibility at baseline (CLSI broth microdilution MIC values; M27 Ed4) (Fig 3). Results A total of 204 Candida isolates were recovered in 187 patients across both treatment groups. Of the 204 isolates, C. albicans was the most common species, followed by C. glabrata, C. tropicalis, and C. parapsilosis; 61% of all baseline isolates were non-albicans Candida (Fig 3). The rates of D14 global cure and mycological eradication by pathogen are shown in Tables 1 and 2. Overall, outcomes by Candida species and MIC did not appear to be affected by MIC values for either rezafungin or caspofungin (Table 3). Conclusion Rezafungin was efficacious across multiple Candida species in the Phase 3 ReSTORE trial that demonstrated non-inferiority of rezafungin to caspofungin. There was no clear correlation between increased MIC values and clinical outcomes. Disclosures George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Alex Soriano, MD, MSD, Pfizer, Shionogi, Angelini, Menarini, Gilead: Honoraria Oliver A. Cornely, Prof. Dr., Abbott: Honoraria|Abbvie: Advisor/Consultant|Actelion: Board Member|Al-Jazeera Pharmaceuticals: Honoraria|Allecra Therapeutics: Board Member|Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Honoraria|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|Biocon: Advisor/Consultant|Biosys: Advisor/Consultant|BMBF: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Board Member|Cidara: Expert Testimony|Cidara: Grant/Research Support|CoRe Consulting: Stocks/Bonds|Da Volterra: Advisor/Consultant|DLR: Grant/Research Support|DZIF: Grant/Research Support|Entasis: Board Member|EU Directorate-General for Resarch and Innovation: Grant/Research Support|F2G: Grant/Research Support|German Patent and Trade Mark Office: German patent (DE 10 2021 113 007.7)|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Grupo Biotoscana/United Medical/Knight: Honoraria|Hikma: Honoraria|IQVIA: Board Member|Janssen: Board Member|Matinas: Advisor/Consultant|Matinas: Grant/Research Support|MedPace: Advisor/Consultant|MedPace: Grant/Research Support|MedScape: Honoraria|MedUpdate: Honoraria|Menarini: Advisor/Consultant|Merck/MSD: Grant/Research Support|Merck/MSD: Honoraria|Molecular Partners: Advisor/Consultant|MSG-ERC: Advisor/Consultant|Mundipharma: Grant/Research Support|Mylan: Honoraria|Noxxon: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Grant/Research Support|Paratek: Board Member|Pardes: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Projektträger Jülich: Grant/Research Support|PSI: Advisor/Consultant|PSI: Board Member|Pulmocide: Board Member|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support|Seres: Advisor/Consultant|Shionogi: Board Member|Wiley (Blackwell): Editor-in-Chief, Mycoses Bart-Jan Kullberg, MD, FRCP, FIDSA, Cidara: Independent Data Review Committee Jeffrey B. Locke, PhD, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds Taylor Sandison, MD, MPH, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds.

Cryptococcal antigen (CrAg) detection could direct the timely initiation of antifungal therapy. We searched MEDLINE and Embase for studies where CrAg detection in serum/cerebrospinal fluid (CSF) and CSF fungal culture were done on adults living with human immunodeficiency virus (HIV) who had suspected cryptococcal meningitis (CM). With Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), we evaluated the risk of bias in 11 included studies with 3600 participants, and used a random-effects meta-analysis to obtain summary sensitivity and specificity of serum and CSF CrAg, as well as agreement between CSF CrAg and CSF culture. Summary sensitivity and specificity of serum CrAg were 99.7% (97.4–100) and 94.1% (88.3–98.1), respectively, and summary sensitivity and specificity of CSF CrAg were 98.8% (96.2–99.6) and 99.3% (96.7–99.9), respectively. Agreement between CSF CrAg and CSF culture was 98% (97–99). In adults living with HIV who have CM symptoms, serum CrAg negativity may rule out CM, while positivity should prompt induction antifungal therapy if lumbar puncture is not feasible. In a first episode of CM, CSF CrAg positivity is diagnostic.

Invasive fungal infections continue to increase as at-risk populations expand. The high associated morbidity and mortality with fungal diseases mandate the continued investigation of novel antifungal agents and diagnostic strategies that include surrogate biomarkers. Biologic markers of disease are useful prognostic indicators during clinical care, and their use in place of traditional survival end points may allow for more rapid conduct of clinical trials requiring fewer participants, decreased trial expense, and limited need for long-term follow-up. A number of fungal biomarkers have been developed and extensively evaluated in prospective clinical trials and small series. We examine the evidence for these surrogate biomarkers in this review and provide recommendations for clinicians and regulatory authorities.

In this article, the editors of Clinical Infectious Diseases review some of the most important lessons they have learned about the epidemiology, clinical features, diagnosis, treatment and prevention of SARS-CoV-2 infection and identify essential questions about COVID-19 that remain to be answered., This article reviews important lessons learned to this day, October 15, 2020, about the epidemiology, clinical virology, presentation, complications, diagnosis, treatment and prevention of SARS-CoV-2 infection and identifies essential questions about the COVID-19 pandemic that remain to be answered.

Background Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC). Methods Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up. Results Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. In total, 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS. Conclusions RZF was safe and efficacious in the treatment of candidemia and/or IC. Clinical Trials Registration NCT02734862, In a phase 2, randomized, double-blind, multicenter clinical trial conducted to evaluate rezafungin compared with caspofungin followed by fluconazole for primary treatment of patients with proven candidemia or invasive candidiasis, rezafungin demonstrated favorable safety and efficacy.

Invasive fungal diseases cause significant morbidity and mortality, in particular affecting immunocompromised patients. Resistant organisms are of increasing importance, yet there are many notable differences in the ability to both perform and interpret antifungal susceptibility testing compared with bacteria. In this review, we will highlight the strengths and limitations of resistance data of pathogenic yeasts and moulds that may be used to guide treatment and predict clinical outcomes.

Antibody immunity has not been studied in organ transplant recipients (OTRs) with cryptococcosis. We determined serum antibody levels in OTRs: 23 cryptococcosis cases and 21 controls. Glucuronoxylomannan immunoglobulin M (IgM) and laminarin IgM were lower in cases than controls, were inversely associated with cryptococcosis status, and may hold promise as markers of cryptococcosis.

Coronavirus disease 2019 (COVID-19) can become complicated by secondary invasive fungal infections (IFIs), stemming primarily from severe lung damage and immunologic deficits associated with the virus or immunomodulatory therapy. Other risk factors include poorly controlled diabetes, structural lung disease and/or other comorbidities, and fungal colonization. Opportunistic IFI following severe respiratory viral illness has been increasingly recognized, most notably with severe influenza. There have been many reports of fungal infections associated with COVID-19, initially predominated by pulmonary aspergillosis, but with recent emergence of mucormycosis, candidiasis, and endemic mycoses. These infections can be challenging to diagnose and are associated with poor outcomes. The reported incidence of IFI has varied, often related to heterogeneity in patient populations, surveillance protocols, and definitions used for classification of fungal infections. Herein, we review IFI complicating COVID-19 and address knowledge gaps related to epidemiology, diagnosis, and management of COVID-19–associated fungal infections.

Objectives To evaluate the safety and efficacy of two dosing regimens of oral ibrexafungerp (formerly SCY-078), a novel orally bioavailable β-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.

Background Candida species are a major cause of invasive and mucocutaneouls infections. There are limited oral treatment options available for patients with Candida infections who are unresponsive to or who are intolerant of currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. We present an analysis of patient outcomes from the FURI study by fungal disease type. Table 1: FURI Outcomes by Fungal Disease Methods FURI patients were eligible for enrollment if they have proven or probable, severe mucocutaneous candidiasis, invasive candidiasis or invasive aspergillosis,other fungal diseases and evidence of failure to, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or can not receive approved oral antifungal options (e.g., susceptibility of the organism) and a continued IV antifungal therapy is clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 74 patients enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total of 39 (52.7%) patients had invasive candidiasis, 32 (43.2%) had mucocutaneous candidiasis and 3 (4.5%) patients had invasive aspergillosis. The percent of patients who were determined to have a complete response (CR), partial response (PR), clinical improvement (CI) was 63.5%, stable disease (SD) was 23.0%, patients with progression of disease 6.8% and 4 patients were indeterminate. Additionally, there was 1 death in the FURI study that was not related to fungal disease. Table 1 shows outcomes by fungal disease type as determined by the DRC. Conclusion Analysis of 74 patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options. Disclosures Peter G. Pappas, MD, Astellas (Research Grant or Support)Cidara (Research Grant or Support)F2G (Consultant)Matinas (Consultant, Scientific Research Study Investigator)Mayne Pharma (Research Grant or Support)Scynexis (Research Grant or Support) Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker's Bureau)Astellas Pharma (Speaker's Bureau)Euopean Confederation of Medical Mycology (Speaker's Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker's Bureau)MSD (Speaker's Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker's Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Barbara D. Alexander, MD, MHS, SCYNEXIS, Inc. (Consultant) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker's Bureau)Pfizer (Scientific Research Study Investigator, Speaker's Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker's Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, Mayne Pharma (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Marisa Miceli, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Martin Hoenigl, MD, Astellas (Grant/Research Support)Gilead (Grant/Research Support)Pfizer (Grant/Research Support) Martin Hoenigl, MD, Astellas (Individual(s) Involved: Self): Grant/Research Support; F2G (Individual(s) Involved: Self): Grant/Research Support; Gilead (Individual(s) Involved: Self): Grant/Research Support; Pfiyer (Individual(s) Involved: Self): Grant/Research Support; Scýnexis (Individual(s) Involved: Self): Grant/Research Support Thomas F. Patterson, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Background Cryptococcosis due to Cryptococcus neoformans and Cryptococcus gattii varies with geographic region, populations affected, disease manifestations, and severity of infection, which impact treatment. Methods We developed a retrospective cohort of patients diagnosed with culture-proven cryptococcosis during 1995–2013 from 5 centers in North America and Australia. We compared underlying diseases, clinical manifestations, treatment, and outcomes in patients with C. gattii or C. neoformans infection. Results A total of 709 patients (452 C. neoformans; 257 C. gattii) were identified. Mean age was 50.2 years; 61.4% were male; and 52.3% were white. Time to diagnosis was prolonged in C. gattii patients compared with C. neoformans (mean, 52.2 vs 36.0 days; P Conclusions This study emphasizes differences in species-specific epidemiology and outcomes of patients with cryptococcosis, including underlying diseases, site of infection, and mortality. Species identification in patients with cryptococcosis is necessary to discern epidemiologic patterns, guide treatment regimens, and predict clinical progression and outcomes.

In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting.

Background The largest health care–associated infection outbreak in the United States occurred during 2012–2013. Following injection of contaminated methylprednisolone, 753 patients developed infection with a dematiaceous mold, Exserohilum rostratum. The long-term outcomes of these infections have not been described. Methods This retrospective cohort study of 440 of a total of 753 patients with proven or probable Exserohilum infection evaluated clinical and radiographic findings, antifungal therapy and associated adverse effects, and outcomes at 6 weeks, 3, 6, 9, and 12 months after diagnosis. Patients were grouped into 4 disease categories: meningitis with/without stroke, spinal or paraspinal infections, meningitis/stroke plus spinal/paraspinal infections, and osteoarticular infections. Results Among the 440 patients, 223 (51%) had spinal/paraspinal infection, 82 (19%) meningitis/stroke, 123 (28%) both, and 12 (3%) osteoarticular infection. Of 82 patients with meningitis/stroke, 18 (22%) died; among those surviving, 87% were cured at 12 months. Only 7 (3%) of 223 patients with spinal/paraspinal infection died, but at 12 months, 68% had persistent or worsening pain and only 47% were cured. For the 123 patients with both meningitis/stroke and spinal/paraspinal infection, 10 (8%) died, pain persisted in 72%, and 52% were cured at 12 months. Only 37% of those with osteoarticular infection were cured at 12 months. Adverse events from antifungal therapy were noted at 6 weeks in 71% of patients on voriconazole and 81% on amphotericin B. Conclusions Fungal infections related to contaminated methylprednisolone injections culminated in death in 8% of patients. Persistent pain and disability were seen at 12 months in most patients with spinal/paraspinal infections.

Background Antibiotic use is a well-known risk factor for acquisition of drug-resistant bacteria and community antibiotic prescribing can drive high rates of resistance within the hospital setting. Owing to concerns over increasing fluoroquinolone (FQ) resistance among Gram-negative organisms at UAB Hospital, our stewardship program implemented a pre-authorization policy. The goal of this study was to assess the relationship between hospital fluoroquinolone use and antibiotic resistance. Methods In 2006, the inpatient formulary was consolidated to only ciprofloxacin and moxifloxacin with implementation of guidelines for use to limit inpatient prescribing. Any use outside of these guidelines required approval from an infectious diseases physician. Organism-specific data were obtained from the clinical microbiology database and FQ use was obtained from the hospital database. Correlations were calculated using Pearson’s coefficient. Results From 1998 to 2004, FQ use peaked at 173 days of therapy (DOT)/1,000 patient-days, but has remained below 60 DOT/1,000 patient-days since restriction implementation (Figure 1). FQ susceptibility was documented for five common Gram-negative isolates, P. aeruginosa, Acinetobacter spp., Enterobacter cloacae, E. coli, and K. pneumoniae, over an 18-year period (1998–2016). Common hospital acquired pathogens, including Pseudomonas aeruginosa, Acinetobacter spp. and Enterobacter cloacae improved in their susceptibilities to fluoroquinolones. Acinetobacter went from 35% to over 50% susceptible in the preceding 10 years after the policy. Pseudomonas improved from 50% susceptible to over 70% and Enterobacter improved from less than 50% to over 90% susceptible. Interestingly this improvement was not seen for E. coli which continued to show a decline in susceptibility from over 90% to near 60% in 2016. Conclusion In a large academic hospital setting, FQ susceptibility for common hospital-acquired GNRS improved significantly with the introduction of a restricted use program. A continued decline in E. coli FQ susceptibility suggests resistance rates may be driven by outpatient and community antibiotic use and thus, outpatient stewardship programs are necessary to prevent further spread of FQ resistance. Disclosures All authors: No reported disclosures.

Background Reflux in the ovarian veins, with or without an obstructive venous outflow component, is reported to be the primary cause of pelvic venous insufficiency (PVI). The degree to which venous outflow obstruction plays a role in PVI is currently ill-defined. Methods We retrospectively reviewed the charts of 227 women with PVI who presented to the Center for Vascular Medicine from January 2012 to September 2015. Assessments and interventions consisted of an evaluation for other causes of chronic pelvic pain by a gynecologist; preintervention and postintervention visual analog scale (VAS) pain score; complete venous duplex ultrasound examination; and Clinical, Etiology, Anatomy, and Pathophysiology classification. All patients underwent diagnostic venography of their pelvic and left ovarian veins as well as intravascular ultrasound of their iliac veins. Patients were treated in one of six ways: ovarian vein embolization (OVE) alone (chemical ± coils), OVE with staged iliac vein stenting, OVE with simultaneous iliac vein stenting, iliac vein stenting alone, OVE with venoplasty, and venoplasty alone. Results Of the 227 women treated, the average age and number of pregnancies was 46.4 ± 10.4 years and 3.36 ± 1.99, respectively. Treatment distribution was the following: OVE, n = 39; OVE with staged stenting, n = 94; OVE with simultaneous stenting, n = 33; stenting alone, n = 50; OVE with venoplasty, n = 8; and venoplasty alone, n = 3. Seven patients in the OVE and stenting groups (staged) and one patient in the OVE + venoplasty group required a second embolization of the left ovarian vein. Eighty percent (181/227) of patients demonstrated an iliac stenosis >50% by intravascular ultrasound. Average VAS scores for the entire cohort before and after intervention were 8.45 ± 1.11 and 1.86 ± 1.61 (P ≤ .001). In the staged group, only 9 of 94 patients reported a decrease in the VAS score with OVE alone. VAS score decreased from 8.6 ± 0.89 before OVE to 7.97 ± 2.10 after OVE. After the planned staged stenting, VAS score decreased to 1.33 ± 2.33 (P ≤ .001). Similarly, in the simultaneous group, preintervention scores were 8.63 ± 1.07 and decreased to 2.36 ± 2.67 after OVE + stenting (P ≤ .001). Conclusions The majority of patients in our series (80%) demonstrated a significant iliac vein stenosis. These observations indicate that the incidence of iliac vein outflow obstruction in PVI is greater than previously reported. In patients with combined ovarian vein reflux and iliac vein outflow obstruction, our data suggest that pelvic venous outflow lesions should be treated first and that ovarian vein reflux should be treated only if symptoms persist. In women with an outflow lesion, ovarian vein reflux, and a large pelvic reservoir, we recommend simultaneous treatment.

Background C-itra is the drug of choice for treatment of most non-CNS, non-life-threatening forms of endemic mycoses (EM), including histoplasmosis, blastomycosis, coccidioidomycosis, sporotrichosis and talaromycosis. SUBA represents a new formulation of itraconazole that utilizes nanotechnology to improve bioavailability when administered orally. SUBA is formulated as nanoparticles allowing for absorption in the small bowel while not relying on gastric acidity for optimal absorption. MSG-15 is an open-label, comparative clinical trial comparing SUBA to c-itra for the treatment of EM. Herein we report the final PK and AE profiles of these two compounds. Methods Subjects with proven and probable EM were eligible this open-label comparative study. The protocol allowed up to 14 d of prior therapy with any antifungal for this episode of EM. Subjects were randomized to receive either SUBA 130 mg po bid or c-itra 200 mg po bid for up to 6 months. Follow up occurred at 7, 14, 28, 42, 84 and 180 d post-enrollment. PK samples were obtained at 7, 14, and 42 d. Clinical assessment, including symptom assessment, AEs, overall drug tolerance, and quality of life were assessed at each visit. We used descriptive statistics for this analysis. Results 89 subjects with EM entered the trial, including 43 on SUBA and 46 on c-itra. We measured PK serum levels of itra and hydroxyl-itra at days 7, 14, and 42 and these data are depicted in Figures 1-3. There were no significant differences in these levels, including combined itra/hydroxyl-itra levels, among the two study arms. AUC for itra and hydroxyl-itra were similar for both arms. AEs as assessed at each study evaluation were also quite similar among the two study arms. Overall, any AE occurred in 74% vs 85% of SUBA and c-itra recipients, respectively (NS). Drug-related AEs occurred in 35% vs 41% of SUBA and itra recipients, respectively (NS). Most common drug-related AEs included cardiovascular (edema and hypertension), nausea and loss of appetite. Combined Itraconazole and Hydroxy-itraconazole Concentration Over Time Conclusion Compared to c-itra, SUBA demonstrates almost identical serum levels despite being dosed at roughly 60% standard dosing for c-itra (130 mg po bid vs 200 mg po bid). SUBA is slightly better tolerated than c-itra, although the specific AEs are similar. Disclosures Peter G. Pappas, MD, Astellas (Research Grant or Support)Cidara (Research Grant or Support)F2G (Consultant)Matinas (Consultant, Scientific Research Study Investigator)Mayne Pharma (Research Grant or Support)Scynexis (Research Grant or Support) Andrej Spec, MD, MSCI, Mayne Pharma (Grant/Research Support) Marisa Miceli, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) George R. R. Thompson III, III, MD, Amplyx (Consultant, Grant/Research Support)Appili (Consultant)Astellas (Consultant, Grant/Research Support)Avir (Grant/Research Support)Cidara (Consultant, Grant/Research Support)F2G (Consultant, Grant/Research Support)Mayne (Consultant, Grant/Research Support)Merck (Scientific Research Study Investigator)Pfizer (Advisor or Review Panel member)

Objectives To identify the frequency of micafungin resistance among clinically significant isolates of Candida stored at our institution from 2005 to 2015. Chart review of patients with resistant isolates then informed the clinical setting and outcomes associated with these infections. Methods Clinical Candida isolates had been stored at -80°C in Brucella broth with 20% glycerol from 2005. Isolates were tested using broth microdilution to determine micafungin MICs. All Candida glabrata isolates and all isolates demonstrating decreased susceptibility to micafungin were screened for FKS mutations using a Luminex assay. Results In total, 3876 Candida isolates were tested for micafungin resistance, including 832 C. glabrata isolates. Of those, 33 isolates from 31 patients were found to have either decreased susceptibility to micafungin and/or an FKS mutation. C. glabrata accounted for the majority of these isolates. While bloodstream infections were found to have a very high mortality rate, isolates from other sites were uncommonly associated with 30-day mortality. Overall resistance rates were very low. Conclusions Echinocandin resistance in C. glabrata has been increasingly reported but rates at our institution remain very low. We hypothesize that a focus on antifungal stewardship may have led to these observations. Knowledge of local resistance patterns is key to appropriate empirical treatment strategies.

Background Blood cultures are approximately 50% sensitive for diagnosing invasive candidiasis. The T2Candida nanodiagnostic panel uses T2 magnetic resonance and a dedicated instrument to detect Candida directly within whole blood samples. Methods Patients with Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, or Candida krusei candidemia were identified at 14 centers using diagnostic blood cultures (dBCs). Follow-up blood samples were collected concurrently for testing by T2Candida and companion cultures (cBCs). T2Candida results are reported qualitatively for C. albicans/C. tropicalis, C. glabrata/C. krusei, and C. parapsilosis. T2Candida and cBCs were positive if they detected a species present in the dBC. Results Median time between collection of dBC and T2Candida/cBC samples in 152 patients was 55.5 hours (range, 16.4-148.4). T2Candida and cBCs were positive in 45% (69/152) and 24% (36/152) of patients, respectively (P < .0001). T2Candida clinical sensitivity was 89%, as positive results were obtained in 32/36 patients with positive cBCs. Combined test results were both positive (T2+/cBC+), 21% (32/152); T2+/cBC-, 24% (37/152); T2-/cBC+, 3% (4/152); and T2-/cBC-, 52% (79/152). Prior antifungal therapy, neutropenia, and C. albicans candidemia were independently associated with T2Candida positivity and T2+/cBC- results (P values < .05). Conclusions T2Candida was sensitive for diagnosing candidemia at the time of positive blood cultures. In patients receiving antifungal therapy, T2Candida identified bloodstream infections that were missed by cBCs. T2Candida may improve care by shortening times to Candida detection and species identification compared to blood cultures, retaining sensitivity during antifungal therapy and rendering active candidemia unlikely if results are negative. Clinical Trials Registration NCT01525095.

Background Chronic venous disorders (CVDs) have been estimated to affect up to 20 million Americans. Despite this huge prevalence, the signs, symptoms, and treatment outcomes in patients 65 years of age and older are not well defined. Our goal was to determine the presentation and treatment outcomes in elderly patients compared with a cohort of patients younger than 65 years. Methods From January 2015 to December 2016, we retrospectively reviewed prospectively collected data from 38,750 patients with CVD from the Center for Vein Restoration's electronic medical record (NextGen Healthcare Information Systems, Irvine, Calif). We divided patients into two groups; group A patients were younger than 65 years, and group B patients were 65 years of age or older. Medical and surgical history, presenting symptoms, treatment modalities, and revised Venous Clinical Severity Score before and after intervention were evaluated. A multivariate logistic regression analysis was performed to determine the predictive value of presenting and associated symptoms. Groups A and B were subdivided by Clinical, Etiology, Anatomy, and Pathophysiology class for subgroup analysis. Data were analyzed with GraphPad Prism (GraphPad Software Inc, La Jolla, Calif) or SAS version 9.4 statistical software package (SAS Institute, Cary, NC). Results There were 27,536 patients in group A and 11,214 in group B. Women constituted 78% of all patients. Group B demonstrated a higher incidence of chronic diseases compared with group A (P ≤ .003). As initial presenting symptoms, pain, heaviness, fatigue, and aching were more common in group A than in group B (61% vs 55%, 30% vs 27%, 27% vs 24%, and 17% vs 12%, respectively; P ≤ .001). Swelling, skin discoloration, and venous ulceration were more common in group B than in group A (29% vs 23%, 12% vs 6%, and 5% vs 2%; P ≤ .001). Ablations were more commonly performed in group B patients with C4 to C6 disease (P ≤ .004). The revised Venous Clinical Severity Scores before and 1 month after intervention were similar between groups. Treatment improvement was statistically significant in both groups (P ≤ .001). Multivariate logistic regression analysis indicated that varices, bleeding, swelling, skin changes, venous ulceration, aching, heaviness, pain, fatigue, cramping, and restless legs were associated with the presence of CVD (P ≤ .001). Conclusions Medicare beneficiaries presented with more chronic diseases and more severe disease. Initial and associated symptoms were highly associated with the presence of CVD. Despite requiring more interventions than patients younger than 65 years, Medicare beneficiaries demonstrated the same degree of clinical improvement. Medicare should not develop coverage policy decisions that prevent access to therapies that alleviate CVD-induced symptoms.

Candida species are one of the leading causes of nosocomial infections. Because much of the treatment for Candida infections is empirical, some institutions do not identify Candida to species level. With the worldwide emergence of the multidrug-resistant species Candida auris , identification of Candida to species level has new clinical relevance. Species should be identified for invasive candidiasis isolates, and species-level identification can be considered for selected noninvasive isolates to improve detection of C. auris .

Patient: Male, 44 Final Diagnosis: Cerebral toxoplasmosis after HSCT Symptoms: Hemiparesis • muscle weakness Medication: — Clinical Procedure: — Specialty: Hematology Objective: Unusual clinical course Background: Toxoplasmosis is an uncommon but potentially fatal complication following allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant toxoplasmosis is often a reactivation of prior infection and typically occurs within the first 6 months of transplant. Herein, we report that cerebral toxoplasmosis may occur 22 months after allogeneic hematopoietic stem cell transplantation. Case Report: We describe a case of cerebral toxoplasmosis that occurred 22 months after an allogeneic HCT while the patient was on aerosolized pentamidine for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. The disease was only diagnosed after brain biopsy because of atypical MRI appearance of the cerebral lesion and negative Toxoplasma gondii IgG antibody test result in the cerebrospinal fluid (CSF). The patient received pyrimethamine and sulfadiazine treatment, with dramatic improvement after several months. The patient is alive 2 years after infection diagnosis, with no evidence of disease and is off Toxoplasma prophylaxis. Conclusions: Cerebral toxoplasmosis can occur late after allogeneic HCT while patients are on immunosuppression therapy, with atypical features on imaging studies and negative Toxoplasma gondii IgG antibody test result in the CSF. Pre-transplant serologic screening for T. gondii antibodies in allogeneic transplant candidates is warranted. Brain biopsy can be a helpful diagnostic tool for cerebral lesions.

Background Rezafungin (RZF) is a novel echinocandin in Phase 3 development for treatment of candidemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis in blood and marrow transplant recipients. This analysis of the completed Phase 2 STRIVE trial (NCT02734862) of RZF treatment was conducted to evaluate outcomes based on baseline pathogen and susceptibility. Methods In STRIVE, adults (≥ 18 y) with systemic signs and mycological evidence of candidemia and/or IC were randomized to either RZF once weekly or caspofungin (CAS) once daily for ≥ 14 days (Fig. 1). The primary efficacy endpoint was Overall Response (resolution of clinical signs of infection + mycological eradication) at Day 14. For this analysis, outcomes by treatment group were stratified by Candida species and by its in vitro susceptibility (CLSI broth microdilution MIC values; M27-Ed4). Figure 1. Treatment Groups of the Phase 2 STRIVE Trial Results A total of 196 Candida isolates were recovered from 183 patients across all treatment groups (Fig. 2). C. albicans was the most common species, followed by C. glabrata, C. parapsilosis, and C. tropicalis; non-albicans Candida comprised 54% of all baseline isolates (Fig. 2). Among all clinical isolates, MIC distributions and ranges for RZF were generally lower than or comparable to those for CAS (Table 1). The rate of Overall Response (as defined above) against C. parapsilosis was lower for CAS than for RZF (Table 2). Overall, outcomes by Candida species and MIC did not appear to be affected by MIC values for either RZF or CAS (Table 1). Figure 2. Candida Species Distribution and MIC ranges in the Phase 2 STRIVE Trial (mITT) Table 1. Overall Response Rates (%) for Most Frequently Isolated Candida Species at Baseline by Treatment Group and MIC Values (mITT) Table 2. Overall Response Rates (%) for Most Frequently Isolated Candida Species at Baseline by Treatment Group (mITT) Conclusion This analysis demonstrated RZF efficacy across multiple Candida species. RZF outcomes were similar to or better than those for CAS regardless of species identified. There was no clear correlation between increased MICs and clinical outcomes although, based on MICs, all isolates exhibited a wild-type in vitro susceptibility profile. These findings from STRIVE, together with future analyses from the ongoing Phase 3 trial of RZF treatment of candidemia and IC (ReSTORE; NCT03667690), will further our understanding of the relationships between MIC values and clinical outcomes in patients with candidemia or IC. Disclosures Jeffrey B. Locke, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Rolando Viani, MD, Cidara Therapeutics, Inc. (Employee, Shareholder) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Mahmoud Ghannoum, PhD, Amplyx (Grant/Research Support)Cidara (Grant/Research Support)Scynexis (Consultant, Grant/Research Support) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder)

Background C-ITC is a drug of choice for non-life-threatening, non-CNS histoplasmosis, blastomycosis, sporotrichosis, coccidioidomycosis and other EM. Oral C-ITC is problematic due to inconsistent absorption often leading to sub-therapeutic serum levels. SUBA-ITC is an FDA approved formulation which utilizes nanotechnology to provide more consistent absorption when compared to C-ITC. We performed an open-label RCT comparing SUBA-ITC to C-ITC for non-life-threatening non-CNS EM, and is the first US based RCT examining SUBA-ITC. Herein we report the PK during the first 6 wks of study therapy (rx) and drug-related AEs and tolerability throughout the course of rx. Methods Subjects with a proven or probable EM, who had received Results 62 subjects are included in this analysis (31 each in SUBA-ITC and C-ITC, respectively). Median serum levels of ITC + hydroxy-ITC at d 7, 14 and 42 were consistently higher in the SUBA-ITC arm (Fig 1, p=0.8, NS). Combined AUC (ITC+hydroxy-ITC) were 2951 and 2845 for SUBA-ITC and C-ITC, respectively (NS). 4 subjects in each arm had sub-therapeutic d 7 levels (< 1000ng/ml). Drug-related AEs and tolerability were similar in both arms (Table 1). Lower extremity edema, hypertension, nausea, and anorexia were the most common AEs. Premature study withdrawal was seen in 12 (19%) subjects overall (5 and 7 subjects, respectively on SUBA-ITC and C-ITC). Figure 1 Conclusion SUBA-ITC dosed at 130 mg BID PO is safe, well-tolerated, and consistently leads to combined serum ITC/hydroxy-ITC levels and AUC that are higher (NS) when compared to C-ITC 200 mg BID. Moreover, compared to C-ITC, SUBA-ITC achieves these serum levels when administered at substantially lower daily doses (130mg BID vs 200 mg BID). Disclosures Peter G. Pappas, MD, Mayne Pharma (Scientific Research Study Investigator) Andrej Spec, MD, MSCI, Mayne (Consultant, Grant/Research Support) Marisa H. Miceli, MD, FIDSA, SCYNEXIS, Inc. (Advisor or Review Panel member) Laurie Proia, MD, Mayne Pharma (Scientific Research Study Investigator) Ana Belen Arauz, MD, Mayne Pharma (Scientific Research Study Investigator) Justin Hayes, MD, Mayne Pharma (Grant/Research Support) Alisa Peinhardt, MAIS, BSN, Mycoses Study Group Education and Research Consortium (Consultant)

Background: Methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization has been a well-established risk for developing MRSA pneumonia. In previous studies, the MRSA nasal screening test has shown an excellent negative predictive value (NPV) for MRSA pneumonia in patients without exclusion criteria such as mechanical ventilation, hemodynamic instability, cavitary lesions, and underlying pulmonary disease. MRSA nasal screening can be used as a stewardship tool to de-escalate broad antibiotic coverage, such as vancomycin. Objective: The purpose of this study was to determine whether implementation of a MRSA nasal screening questionnaire improves de-escalation of vancomycin for patients with pneumonia. Methods: A retrospective review was performed on 250 patients from October 2018 to January 2019 who received MRSA nasal screening due to their prescriber choosing only “respiratory” on the vancomycin dosing consult form. Data obtained included demographics and clinical outcomes. Statistical analyses were performed, and P < .05 was considered significant. Results: Of the 250 patients screened, only 19 patients (8%) were positive for MRSA. Moreover, 40% of patients met exclusion criteria. In 149 patients without exclusion criteria, the MRSA nasal swab had a 98% NPV. Although not statistically significant, vancomycin days of therapy (DOT) based on MRSA nasal swab result was 1 day shorter in those with negative swabs (3.49 days negative vs 4.58 days positive; P = .22). Vancomycin DOT was significantly reduced in pneumonia patients without exclusion criteria (3.17 days “no” vs 4.17 days “yes”; P = .037). Conclusions: The implementation of an electronic MRSA nasal screening questionnaire resulted in reduced vancomycin DOT in pneumonia patients at UAB Hospital. The MRSA nasal swab is an effective screening tool for antibiotic de-escalation based on its 98% NPV for MRSA pneumonia if utilized in the correct patient population.Funding: NoneDisclosures: Rachael Anne Lee reports a speaker honoraria from Prime Education, LLC.

Background Fosmanogepix (FMGX) is a first-in-class antifungal agent, with a unique MOA targeting the fungal enzyme Gwt1, that has broad-spectrum activity against both yeasts, molds, and dimorphic fungi, including fungi resistant to other antifungal agents. FMGX has a favorable safety profile, reduced potential for clinically significant drug-drug interactions, and is formulated for IV and oral administration. Methods This global, multicenter, open-label, non-comparative study evaluated the safety and efficacy of FMGX for first-line treatment of candidemia. Patients with a recent diagnosis of candidemia defined as positive blood culture for Candida spp. within 96 hrs prior to study entry, with ≤2 days of prior antifungal treatment were eligible. Patients with neutropenia, C. krusei infection, or deep-seated Candida infections were excluded. Patients were treated with FMGX for up to 14 days: 1000 mg IV BID for 1 day, then 600 mg IV QD for at least 2 days, followed by either 600 mg IV QD or 700 mg PO QD. Short-term fluconazole (or appropriate alternative) could follow if treatment was required beyond 14 days. Patients with a diagnosis of candidemia within 96 hrs of start of study drug who received at least 1 dose of FMGX were included in the mITT population. The primary efficacy endpoint was outcome at end of study treatment (EOST) as determined by an independent data review committee (DRC). Successful outcome was defined as clearance of Candida from blood cultures with no additional antifungal treatment and survival at EOST. All Candida isolates were tested for antifungal susceptibility. Results A total of 21 subjects were enrolled in the study: 20 were included in the mITT. Median duration of FMGX was 11 days (range 5–14). All subjects received IV FMGX, 48% (10/21) received PO FMGX. The DRC-assessed success rate at EOST was 80% (16/20). Survival at day 30 was 85% (17/20); 3 deaths were not related FMGX. FMGX was well-tolerated with no treatment-related serious adverse events or discontinuations. FMGX had potent in vitro activity against all study Candida spp. (EUCAST MIC range 0.001–0.03 µg/ml) including those resistant to other antifungal agents. Conclusion FMGX was safe, well-tolerated, and demonstrated proof of concept with a high level of treatment success in patients with candidemia. Disclosures Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Bart Jan Kullberg, MD, FRCP, FIDSA, Amplyx (Advisor or Review Panel member) Galia Rahav, MD, AstraZeneca (Scientific Research Study Investigator) Mickaël Aoun, MD, Amplyx Pharmaceuticals (Scientific Research Study Investigator) Pierre Bulpa, MD, Amplyx Pharmaceuticals (Scientific Research Study Investigator) Ricard Ferrer, MD, PhD, Shionogi B.V. (Advisor or Review Panel member) Todd P. McCarty, MD, Amplyx (Scientific Research Study Investigator)Cidara (Scientific Research Study Investigator) Sara Barbat, BSN, RN, Amplyx Pharmaceuticals (Employee) Pamela Wedel, BSc, Amplyx Pharmaceuticals (Employee) Iwonka Oborska, PhD, Amplyx Pharmaceuticals (Consultant, Independent Contractor) Haran T. Schlamm, MD, Amplyx (Consultant) Michael Hodges, BSc. MD, Amplyx Pharmaceuticals Inc. (Employee)

Background There is increasing evidence of antifungal underdosing in the treatment of invasive disease, particularly in special populations such as the obese. Body size is often an important variable affecting drug exposure, and pharmacokinetic (PK) models of antifungal dosing have suggested size-based dose adjustments to achieve target drug exposure. Rezafungin (RZF) is a novel echinocandin in Phase 3 development for treatment of candidemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis in blood and marrow transplant recipients. Distinctive PK properties of RZF (e.g., long half-life, extensive tissue distribution, and front-loaded drug exposure) lend themselves to RZF once-weekly (QWk) dosing and antifungal efficacy. In this sub-analysis of the Phase 2 STRIVE trial of RZF in the treatment of candidemia and/or IC, outcomes based on patient BMI were evaluated. Methods The STRIVE trial (NCT02734862) compared the safety and efficacy of RZF QWk compared with once-daily caspofungin (Fig. 1). For this subanalysis, data were stratified by BMI categories of < 30 kg/m2 and ≥ 30 kg/m2. Efficacy (overall response [resolution of clinical signs of infection + mycological eradication], mycological response, and investigator assessment of clinical response) and safety (treatment-emergent adverse events [TEAEs]) endpoints by treatment group were evaluated, as well as PK data (area under the curve [AUC]) from RZF-treated patients. Figure 1. Results Mean BMI values were similar across treatment arms (26.9 kg/m2 in RZF Group 1 and 26.8 kg/m2 in RZF Group 2 and CAS arms). Efficacy outcomes at Day 14 were similar between BMI categories (Table 1). Rates of TEAEs were generally similar between BMI categories as well (Table 2), with no concerning safety trends. Following one dose of RZF 400 mg (Week 1), the ranges of AUCs by BMI category overlapped and there was a minor mean difference of ~20% (lower for those with BMI ≥ 30 kg/m2) (Fig. 2). Table 1 Table 2 Figure 2. Conclusion The safety, efficacy, and PK of RZF in the Phase 2 STRIVE trial was consistent across BMI categories. These results suggest that dose adjustments in obese patients are not necessary. These findings contribute to the evaluation of RZF in a range of patient populations and its ongoing development. Disclosures Shawn Flanagan, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder) Patrick M. Honore, MD, PhD, FCCM, Cidara Therapeutics, Inc. (Scientific Research Study Investigator)

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Background Chronic venous disease (CVD) affects >20 million people in the United States. Despite this huge prevalence, there are few data on whether the effectiveness of current CVD therapies for symptomatic superficial vein reflux is affected by race. The goal of this investigation was to evaluate CVD treatment outcomes in various races in the United States. Methods From January 2015 to December 2017, we retrospectively reviewed and prospectively collected data from 66,621 patients who presented for CVD evaluation. We divided patients into five racial groups: African American, Asian, Hispanic, other (race not recorded), and white. Presenting signs and symptoms, treatment modalities, number of procedures per patient, and preintervention and postintervention revised Venous Clinical Severity Scores (rVCSSs) were evaluated. All racial groups were stratified by Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) class for subgroup analysis. Results The average age of the entire cohort was 56.8 ± 14.7 years, with 51,393 women (77%) and 15,228 men (23%). Prevalence by race was 17% African American, 3% Asian, 18% Hispanic, 8% others, and 55% white. There was a higher incidence of C0 disease in whites (44%) and African Americans (31%); C1 and C2 disease in whites (46% and 55%) and Hispanics (28% and 25%); and C3, C4, C5, and C6 disease in whites (60%, 57%, 58%, and 61%) and African Americans (19%, 17%, 19%, and 21%). Pain as an initial presenting symptom was more common in African Americans, Asians, and Hispanics (29%, 29%, and 31%). Swelling was highest in African Americans (18%) and cramping in Hispanics (14%). Skin changes and venous ulcers were most common in African Americans (16% and 21%) and whites (63% and 61%). With regard to the average number of procedures performed, Hispanics (1.98 ± 1.24) and others (2.07 ± 1.25) required fewer stand-alone ablations compared with whites (2.31 ± 1.56), Asians (2.36 ± 1.58), and African Americans (2.27 ± 1.56; P ≤ .0001. With the addition of phlebectomies to ablations, Hispanics (3.78 ± 2.08) continued to require fewer procedures, and Asians required the greatest number of phlebectomies compared with all groups (P ≤ .001). When ultrasound-guided foam sclerotherapy was added to ablation and phlebectomy, African Americans required more procedures compared with all races (4.38 ± 2.59; P ≤ .01). For stand-alone ablations, Hispanics (2.18 ± 2.34) and Asians (1.91 ± 2.35) demonstrated lower postprocedure rVCSSs compared with African Americans (2.79 ± 2.88) and whites (2.8 ± 2.85; P ≤ .0001). For ablations with phlebectomies, all races demonstrated similar results except for Hispanics (2.19 ± 2.14), who did better than whites (2.85 ± 2.75; P ≤ .002). For ablations with phlebectomies and ultrasound-guided foam sclerotherapy, all races had similar results (P ≤ .0001). Conclusions In the United States, CVD is primarily observed in white women. There are differences in the incidence and prevalence of disease severity and symptom presentation based on race. The incidence of CVD decreases with age in all racial groups except whites. Hispanics required the fewest procedures and African Americans required the most for optimal results. Postintervention rVCSSs equalized in all races when ablations were combined with phlebectomies and ultrasound-guided foam sclerotherapy.

We report the case of a 61-year-old female with Crohn’s disease dependent on total parenteral nutrition who developed a central venous catheter bloodstream infection and septic arthritis, complicated further by osteomyelitis and persistent Candida glabrata fungemia. Fluconazole treatment led to persistent infection, and micafungin therapy failed with development of FKS -associated resistance. Infection responded after initiation of amphotericin B plus voriconazole.

We report the case of a 61-year-old female with Crohn’s disease dependent on total parenteral nutrition who developed a central venous catheter bloodstream infection and septic arthritis, complicated further by osteomyelitis and persistent Candida glabrata fungemia. Fluconazole treatment led to persistent infection, and micafungin therapy failed with development of FKS-associated resistance. Infection responded after initiation of amphotericin B plus voriconazole. Echinocandin resistance is increasingly recognized, suggesting a role for alternative antifungal therapies.

Elevated intracranial pressure in patients with cryptococcal meningitis is common and associated with poor outcomes. This study evaluated factors at the time of diagnosis of cryptococcal meningitis that were associated with need ventriculo-peritoneal shunting., Objective Increased intracranial pressure (ICP) is an important complication of cryptococcal meningitis (CM) and impacts morbidity and mortality. Factors associated with permanent ventriculoperitoneal (VP) shunt placement are poorly characterized. Method We conducted a retrospective cohort study of patients with CM at the University of Alabama at Birmingham from 1996 through 2015. Characteristics of patients at time of CM diagnosis who did and did not receive a VP shunt were compared with use of the 2-group chi-square test or Fisher exact test for categorical variables and the 2-group t test for continuous variables. Stepwise logistic regression analysis was used to determine predictors of shunt placement. Results Of 422 patients with cryptococcosis, 257 (60.9%) had CM. Mean age was 47.7 years, 71.6% were male, and 44.4% were African American. The most common underlying conditions were HIV (42.4%), solid organ transplantation (29.6%), and corticosteroid use (34.2%). Forty-four (17.1%) received a VP shunt a median of 17 days (range, 1–320 days) post-diagnosis. By multivariable analysis, baseline opening pressure >30 cm H2O (OR, 9.4; 95% CI, 3.0, 28.8; P < .0001), being a normal host (OR, 6.3; 95% CI, 1.5, 26.1; P = .011) and hydrocephalus (OR, 4.9, 95% CI, 1.3, 17.9); P = .017) were associated with increased odds of shunting (Table 2). In contrast, age (OR, 0.96; 95% CI, 0.92, 0.99; P = .037) and male gender (OR, 0.18; 95% CI, 0.06, 0.55; P = .023) were associated with decreased odds of shunting. Conclusions Identification of factors at time of CM diagnosis associated with need for permanent VP shunt placement may allow for earlier, more aggressive treatment and potentially improve outcomes associated with increased ICP from cryptococcal meningitis.

Background Open lumbar spine stabilization surgery often requires mobilization of the left and right common iliac veins (CIVs) and the placement of plates and screws that can impinge on them. We reviewed our venography experience of the past 3 years to determine whether there is an association between spine stabilization surgery and the development of symptomatic iliac vein outflow lesions. Methods A retrospective chart review of prospectively collected data from our electronic medical record system was performed to identify patients who underwent venography with or without venous stenting and had a history of previous lumbar spine stabilization. Patients' demographics, medical comorbidities, venograms, and intravascular ultrasound (IVUS) data were collected and analyzed. The senior author reviewed all venograms and IVUS images of patients with previous spine stabilization procedures. Results From January 2014 to April 2018, venography was performed in 1713 limbs in 1245 patients at the Center for Vascular Medicine. Of the 1245 patients, 18 patients had a history of lumbar spine stabilization procedures: five anterior-posterior and 13 posterior. Nine had single-level and eight had two- or three-level fusions. All 18 patients demonstrated pelvic lesions. These included 1 left CIV aneurysm, 5 left CIV stenoses, 3 bilateral CIV stenoses, 2 left CIV and inferior vena cava occlusions, and 2 external iliac vein stenoses. The aneurysm patient was treated with anticoagulation, 8 patients underwent stenting, 1 patient refused stenting because of relocation to another country, 1 inferior vena cava-CIV occlusion could not be crossed, fear of dislodging a thrombus and the proximity to a protruding posteriorly placed screw prevented stenting in 2 patients, and 4 patients had a venoplasty alone because of undersizing of a stenosis or missed lesions with IVUS after review by a blinded reviewer. Lesions in anterior lumbar interbody fusion patients were extremely stenotic, required predilation, and resulted in a residual stenosis requiring venoplasty at a second setting in one patient. Conclusions Lumbar spine stabilization surgery may be a risk factor for development of symptomatic venous outflow obstruction lesions. During venography and stenting in patients with anterior lumbar interbody fusion approaches, significant scarring may be encountered, resulting in a residual stenosis after stent placement. Predilation venoplasty, before stent deployment, is recommended to prevent stent migration. Furthermore, a history of spine stabilization surgery in patients presenting with pelvic symptoms, lower extremity pain or swelling, or post-thrombotic symptoms should prompt consideration of a pelvic venous duplex ultrasound examination to determine whether an iliac venous outflow lesion is present.

BACKGROUND: Infections with Histoplasma can range from asymptomatic to life-threatening acute pulmonary or disseminated disease. Histoplasmosis can be challenging to diagnose and is widely under-recognized. We analyzed insurance claims data to better characterize histoplasmosis testing and treatment practices and its burden on patients. METHODS: We used the IBM® MarketScan® Research Databases to identify patients with histoplasmosis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 115.00–115.99) during 2012–2014. We analyzed claims in the 3 months before to the 1 year after diagnosis and examined differences between probable (hospitalized or >1 outpatient visit) and suspect (1 outpatient visit) patients. RESULTS: Among 1,935 patients (943 probable, 922 suspect), 54% had codes for symptoms or findings consistent with histoplasmosis and 35% had ≥2 healthcare visits in the 3 months before diagnosis. Overall, 646 (33%) had any fungal-specific laboratory test: histoplasmosis antibody test (n= 349, 18%), Histoplasma antigen test (n=349, 18%), fungal smear (n=294, 15%), or fungal culture (n=223, 12%); 464 (24%) had a biopsy. Forty-nine percent of probable patients and 10% of suspect patients were prescribed antifungal medication in the outpatient setting. Total, 19% were hospitalized. Patients’ last histoplasmosis-associated healthcare visits occurred a median of 6 months after diagnosis. CONCLUSIONS: Some histoplasmosis patients experienced severe disease, apparent diagnostic delays, and prolonged illness, whereas other patients lacked symptoms and were likely diagnosed incidentally (e.g., via biopsy). Low rates of histoplasmosis-specific testing also suggest incidental diagnoses and low provider suspicion, highlighting the need for improved awareness about this disease.

Background Invasive candidiasis (IC) is a common cause of mortality in solid organ transplant recipients (OTRs), but knowledge of epidemiology in this population is limited. Method The present analysis describes data from 15 US centers that prospectively identified IC from nearly 17,000 OTRs. Analyses were undertaken to determine predictors of infection and mortality. Results A total of 639 cases of IC were identified. The most common species was Candida albicans (46.3%), followed by Candida glabrata (24.4%) and Candida parapsilosis (8.1%). In 68 cases >1 species was identified. The most common infection site was bloodstream (44%), followed by intra-abdominal (14%). The most frequently affected allograft groups were liver (41.1%) and kidney (35.3%). All-cause mortality at 90 days was 26.5% for all species and was highest for Candida tropicalis (44%) and C. parapsilosis (35.2%). Non-white race and female gender were more commonly associated with non-albicans species. A high rate of breakthrough IC was seen in patients receiving antifungal prophylaxis (39%). Factors associated with mortality include organ dysfunction, lung transplant, and treatment with a polyene antifungal. The only modifiable factor identified was choice of antifungal drug class based upon infecting Candida species. Conclusion These data highlight the common and distinct features of IC in OTRs. This article is protected by copyright. All rights reserved.