Search

Introduction Viral suppression prevents HIV transmission and disease progression, but socio-economic and clinical factors can hinder the goal of suppression. We evaluated factors associated with viral non suppression (VNS) and persistent viremia (PV) in people living with HIV (PLHIV) receiving antiretroviral therapy (ART) in Guatemala. Methods We conducted a cross sectional analysis using data from an ongoing cohort of PLHIV attending the largest HIV clinic in Guatemala. Univariable and multivariable analyses were conducted between PLHIV with viral suppression and detectable viremia. VNS was defined as most recent HIV RNA ≥ 200 copies/ml and PV as two consecutive HIV RNA ≥ 200 copies/ml. Results Of 664 participants, 13.3% had VNS and 7.1% had PV. In univariable analysis disaggregated by gender, low income, poor education, perceived difficulty attending healthcare, and alcohol use were associated with VNS in men while low CD4 at diagnosis, multiple prior ART regimens and treatment interruptions were significant in both genders. Multiple prior ART regimens (adjusted Odds Ratio (aOR) 2.82, [95% confidence interval (CI) 1.59, 4.99], p p p p p Conclusions We conclude that socio-economic and clinical factors influence viral suppression in our cohort and vary between men and women. Gender specific approaches are necessary to achieve the 90% suppression goal.

Clinical predictive models (CPM) serve to identify and categorize patients into risk categories to assist in treatment and intervention recommendations. Predictive accuracy and practicality of models varies depending on methods used for their development, and should be evaluated. The aim of this study was to summarize currently available CPM for invasive candidiasis, analyze their performance, and assess their suitability for use in clinical decision making. We identified studies that described the construction of a CPM for invasive candidiasis from PubMed/MEDLINE, EMBASE, SCOPUS, Web of Science, Cochrane Library databases, and Clinicaltrials.gov. Data extracted included: author, data source, study design, recruitment period, characteristics of study population, outcome types, predictor types, number of study participants and outcome events, modelling method, and list of predictors used in the final model. Calibration and discrimination in the derivative datasets were used to assess the performance of each model. Ten articles were identified in our search and included for full text review. Five models were developed using data from ICUs, and five models included all hospitalized patients. The findings of this review highlight the limitations of currently available models to predict invasive candidiasis, including lack of generalizability, difficulty in everyday clinical use, and overly optimistic performance. There are significant concerns regarding predictive performance and usability in every day practice of existing CPM to predict invasive candidiasis.Clinical predictive models may assist in early identification of patients at risk for invasive candidiasis to initiate appropriate treatment. The findings of this systematic review highlight the limitations of currently available models to predict invasive candidiasis.

Few large cohorts have examined histoplasmosis in both immunocompromised and immunocompetent patients. We describe the differences in presentations and outcomes of histoplasmosis by immune and dissemination status. We assembled a retrospective cohort of adult patients diagnosed with histoplasmosis from 2002 to 2017. Patients were grouped by immune status: people living with HIV (PLWH), patients who were HIV negative but had other-immunocompromise (OIC), and immunocompetent patients. Patients were further classified into asymptomatic lung nodule (ALN), localized and disseminated disease groups, and outcomes were compared across patients by these immune status categories We identified 261 patients with histoplasmosis: 54 (21%) PLWH, 98 (38%) OIC, and 109 (42%) immunocompetent. Disseminated disease was more common among PLWH than among other groups (P

BACKGROUND: Determining the extent of Cryptococcal disease (CD) is key to therapeutic management. Treatment with fluconazole is only recommended for localized pulmonary disease. Induction therapy with amphotericin B (AmB) and flucytosine is recommended for disease at other sites, irrespective of central nervous system (CNS) involvement, but this is not often followed in patients without meningitis. In this study, we compared treatment and mortality between patients with CD of the CNS and other extrapulmonary (OE) sites. METHODS: This is a retrospective, single-center study of all hospitalized patients with non-pulmonary Cryptococcal infection from 2002 to 2015 who underwent lumbar puncture. Demographics, predisposing factors, comorbidities, clinical presentation, laboratory values, antifungal treatment, and mortality data were collected to evaluate 90-day mortality and treatment differences between patients with OE and CNS CD. Survival analysis was performed using multivariable Cox Regression analysis. RESULTS: Of 193 patients analyzed, 143 (74%) had CNS CD and 50 (26%) had OE CD. Ninety-day mortality was 23% and similar between the OE and CNS CD groups (22% vs 23%, P=0.9). In the comorbidity adjusted multivariable Cox Regression model, mortality risk was similar in the OE and CNS groups. Fewer patients with OE CD received induction therapy with AmB and flucytosine compared to those with CNS disease (28% vs 71.3%, P

Highlights • National TB cohort analyzing risk factors associated with MDR-TB and mortality in Guatemala. • Indigenous ethnicity and prior TB treatment were associated with increased risk of mortality and MDR-TB. • HIV/Unknown HIV status were associated with increased mortality and diabetes with risk for MDR-TB., Background Risk factors for mortality and MDR-TB in Guatemala are poorly understood. We aimed to identify risk factors to assist in targeting public health interventions. Methods We performed a retrospective study of adults with pulmonary TB reported to the Guatemalan TB Program between January 1, 2016 and December 31, 2017. The primary objective was to determine risk factors for mortality in pulmonary TB. The secondary objective was to determine risk factors associated with MDR-TB. Results Among 3,945 patients with pulmonary TB, median age was 39 years (IQR 25–54), 59% were male, 25% of indigenous ethnicity, 1.1% had MDR-TB and 3.9% died. On multivariable analysis, previous TB treatment (odds ratio [OR] 3.57, CI 2.24–5.68 [p

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.

The field of infectious diseases currently takes a reactive approach and treats infections as they present in patients. Although certain populations are known to be at greater risk of developing infection (eg, immunocompromised), we lack a systems approach to define the true risk of future infection for a patient. Guided by impressive gains in “omics” technologies, future strategies to infectious diseases should take a precision approach to infection through identification of patients at intermediate and high-risk of infection and deploy targeted preventative measures (ie, prophylaxis). The advances of high-throughput immune profiling by multiomics approaches (ie, transcriptomics, epigenomics, metabolomics, proteomics) hold the promise to identify patients at increased risk of infection and enable risk-stratifying approaches to be applied in the clinic. Integration of patient-specific data using machine learning improves the effectiveness of prediction, providing the necessary technologies needed to propel the field of infectious diseases medicine into the era of personalized medicine., Translational systems immunology approaches to infectious diseases will enable the switch from reactive to precision treatment of patients, which will improve clinical outcomes while reducing the use of prophylactic antibiotics and incidence of infection in high-risk individuals.

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug–drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01611-0.

The mold Thyronectria austroamericana is a plant pathogen that causes canker in honey locust trees. We describe the first case of this mold causing septic arthritis in humans.

Summary Background Candida bloodstream infection is associated with high mortality. Infectious disease consultation improves outcomes in several infections, including Staphylococcus aureus and cryptococcosis, as well as multidrug-resistant organisms. We aimed to examine the association between infectious disease consultation and differences in management with mortality in candida bloodstream infections. Methods In this retrospective, single-centre cohort study, we reviewed the medical charts of all patients admitted to Barnes-Jewish Hospital (St Louis, MO, USA), a tertiary referral centre, aged 18 years or older with candida bloodstream infection from 2002 to 2015. We collected data for demographics, comorbidities, predisposing factors, all-cause mortality, antifungal use, central-line removal, and ophthalmological and echocardiographic evaluation to assess 90-day all-cause mortality between individuals with and without an infectious disease consultation. For the survival analysis we used Cox proportional hazards model with inverse weighting by propensity score to assess the effects of infectious disease consultation on mortality and differences in management. Findings Between Jan 1, 2002, and Dec 31, 2015, of 1794 patients assessed for eligibility, we analysed 1691 patients with candida bloodstream infection; 776 (45·9%) who had an infectious disease consultation and 915 (54·1%) who did not have an infectious disease consultation. All 1691 patients were included in the analysis. None were missing data. Most underlying comorbidities were evenly distributed between groups. 90-day mortality was lower in the infectious disease consultation group than in patients who did not receive an infectious disease consultation (29% [222/776] vs 51% [468/915]; p Interpretation Patients with candida bloodstream infection receiving an infectious disease consultation have lower mortality. This finding might be attributable to these individuals receiving a higher number of non-pharmacological, evidence-based interventions and lower amounts of non-treatment. These data suggest that an infectious disease consultation should be an integral part of clinical care of patients with candida bloodstream infection. Funding Astellas Global Development Pharma, Washington University Institute of Clinical and Translational Sciences, and the Agency for Healthcare Research and Quality.

The use of immunomodulatory and immunosuppressive therapies in multiple sclerosis (MS) has allowed practitioners to regulate MS disease activity, with the caveat that these potent medications may render patients susceptible to opportunistic infections. The approval of fingolimod presented the first oral option for relapsing MS. Since 2015, postmarketing safety data have documented several published cases of cryptococcal meningitis and disseminated cryptococcosis associated with fingolimod use. However, surveillance mechanisms for opportunistic infections and management of active demyelinating disease with ongoing infection have not been adequately addressed. We present a case of isolated pulmonary cryptococcosis with the use of fingolimod to highlight the hurdles in balancing efficacious disease-modifying therapies for MS while treating an opportunistic infection associated with that therapy.

Candida infective endocarditis (CIE) is a rare but serious complication of candidemia. Incidence and risk factors associated with CIE among candidemic patients are poorly defined from small cohorts. Identification of clinical predictors associated with this entity may guide more judicious use of cardiac imaging. We conducted a retrospective analysis of all inpatients aged ≥18 years diagnosed with candidemia at our institution. CIE was diagnosed by fulfilling two of the major Duke criteria: specifically a vegetation(s) on echocardiogram and positive blood cultures for Candida spp. We used univariable and multivariable regression analyses to identify risk factors associated with CIE. Of 1,873 patients with candidemia, 47 (2.5%) were identified to have CIE. In our multivariable logistic model, existing valvular heart disease was associated with a higher risk for CIE (adjusted odds ratio [aOR], 7.66; 95% confidence interval [CI], 2.95–19.84). Predictors that demonstrated a decreased risk of CIE included infection with C. glabrata (aOR, 0.17; 95% CI, 0.04–0.69), hematologic malignancy (aOR, 0.09; 95% CI, 0.01–0.68), and receipt of total parenteral nutrition (aOR, 0.38; 95% CI, 0.16–0.91). The 90-day crude mortality for CIE was 48.9%, similar to the overall non-CIE mortality of 41.9% (P = .338). We identified a set of clinical factors that can predict the presence of CIE among patient with candidemia. These findings may reduce the need for unnecessary expensive and invasive imaging studies in a subset of patients with a lower risk profile for endocarditis and alternative infection source.

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: Candidemia is the most common clinical presentation of invasive candidiasis and is a major cause of morbidity and mortality. Candiduria is a predictor for candidemia; however, patient characteristics that are associated with concurrent candidemia in the setting of candiduria are unclear. Identifying these characteristics could aid in the early detection of systemic disease. METHODS: We performed a retrospective cohort analysis of hospitalized patients with candiduria at our institution over a 13-year period. Our evaluation of patient characteristics included demographics, comorbidities, medications, procedures, devices, vital signs, and laboratory values. We developed a multivariable logistic model to identify factors associated with candidemia in patients with candiduria. RESULTS: We identified 4,240 patients with candiduria, 263 (6.2%) of whom had candidemia. Predictors for increased risk of candidemia with candiduria included hospitalizations greater than 12 days, central venous catheter, parenteral nutrition, hematological and gynecological malignancy, and receipt of β-lactam/β-lactamase inhibitors. Vital signs and laboratory values associated with candidemia included elevated heart rate, temperature, and creatinine, along with neutropenia and neutrophilia. Factors that demonstrated a decreased risk of candidemia included diabetes mellitus, gastrostomy, and urinary catheter with antibiotic use. The c-statistic was 0.741 (95% CI, 0.710 – 0.772). CONCLUSION: We identified a set of clinical characteristics that can predict the presence of candidemia with candiduria.

This retrospective single-center study of a cohort of adult patients who received voriconazole with a steady-state trough concentration measured during therapy evaluated the rate of therapeutic trough attainment using adjusted body weight (AdjBW)-based and total body weight (TBW)-based dosing in overweight and obese patients. Of the 130 patients included, 45 patients received TBW-based dosing and 85 patients received AdjBW-based dosing. Therapeutic trough attainment was significantly improved with AdjBW-based dosing compared to TBW-based dosing (64.7% versus 46.7%; P = 0.047).

Liposomal amphotericin B (LAmB) is used for various fungal infections, but it is unclear which dosing weight to use in obese patients. The purpose of this study was to compare clinical outcomes of adjusted body weight (adjBW) versus total body weight (TBW) dosing of LAmB. This single-center, retrospective cohort study included patients who received LAmB for definitive therapy and whose TBW exceeded 120% of their ideal body weight (IBW). Analyses were conducted for 3 mg/kg for adjBW versus TBW and 5 mg/kg for adjBW versus TBW. A total of 238 patients were included. For the 68 patients who received LAmB at 3 mg/kg, there were no differences in safety or efficacy outcomes. For the 170 patients who received LAmB at 5 mg/kg, significantly more patients in the TBW group experienced the primary outcome of nephrotoxicity (57% versus 35% [P value of 0.016]) and had significantly higher rates of early discontinuation of LAmB due to toxicity (33% versus 17% [P = 0.030]). There was a trend toward increased 90-day mortality in the adjBW group (60% versus 45% [P = 0.079]); however, adjBW dosing was not associated with increased mortality in an adjusted model. Given the lower rates of nephrotoxicity but a possible trend toward increased mortality in patients whose TBW exceeds 120% of their IBW, dosing LAmB by adjBW may be reasonable in patients who are not critically ill and who have lower-risk infections. In critically ill patients or those with fungal pathogens or sites of infection associated with higher mortality risk, dosing by TBW can be considered.

Conventional itraconazole (C-ITZ) suffers from absorption variability. SUBA-itraconazole (S-ITZ) is more bioavailable than C-ITZ at steady state in a fed condition, but there are no data comparing the two under a fasted state. An open-label, single-dose, randomized, bioequivalence study was performed comparing S-ITZ to C-ITZ capsules under fasted and fed conditions in healthy adults measuring itraconazole and hydroxyitraconazole plasma levels. This study demonstrated less variability of S-ITZ compared to C-ITZ capsules under fasted conditions.

Histoplasmosis is a common opportunistic infection in people with HIV (PWH), however, no study has looked at factors associated with the long-term mortality of histoplasmosis in PWH. We conducted a single-center retrospective study on the long-term mortality of PWH diagnosed with histoplasmosis between 2002 and 2017. Patients were categorized into three groups based on length of survival after diagnosis: early mortality (death &lt, 90 days), late mortality (death ≥ 90 days), and long-term survivors. Patients diagnosed during or after 2008 were considered part of the modern antiretroviral therapy (ART) era. Insurance type (private vs. public) was a surrogate indicator of socioeconomic status. Out of 54 PWH infected with histoplasmosis, overall mortality was 37%, 14.8% early mortality and 22.2% late mortality. There was no statistically significant difference in survival based on the availability of modern ART (p = 0.60). Insurance status reached statistical significance with 38% of survivors having private insurance versus only 8% having private insurance in the late mortality group (p = 0.05). High mortality persists despite the advent of modern ART, implicating a contribution from social determinants of health, such as private insurance. Larger studies are needed to elucidate the role of these factors in the mortality of PWH.

A nonimmunocompromised patient developed life-threatening soft tissue infection with Trichosporon asahii, Fusarium, and Saksenaea that progressed despite maximum antifungal therapies and aggressive debridement. Interleukin-7 immunotherapy resulted in clinical improvement, fungal clearance, reversal of lymphopenia, and improved T-cell function. Immunoadjuvant therapies to boost host immunity may be efficacious in life-threatening fungal infections.

Rapid information dissemination is critical in a world changing rapidly due to global threats. Ubiquitous internet access has created new methods of information dissemination that are rapid, far-reaching, and universally accessible. However, inaccuracies may accompany rapid information dissemination, and rigorous evaluation of primary data through various forms of peer review is crucial. In an era in which high-quality information can save lives, it is critical that infectious diseases specialists are well versed in digital strategy to effectively disseminate information to colleagues and the community and diminish voices spreading misinformation. In this study, we review how social media can be used for rapid dissemination of quality information, benefits and pitfalls of social media use, and general recommendations for developing a digital strategy as an infectious diseases specialist. We will describe how the Infectious Diseases Society of America has leveraged digital strategy and social media and how individuals can amplify these resources to disseminate information, provide clinical knowledge, community guidance, and build their own person brand. We conclude in providing guidance to infectious diseases specialists in aiming to build and preserve public trust, consider their audience and specific goals, and use social media to highlight the value of the field of infectious diseases.

International audience; The global burden of the endemic mycoses (blastomycosis, coccidioidomycosis, emergomycosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and talaromycosis) continues to rise yearly and these infectious diseases remain a leading cause of patient morbidity and mortality worldwide. Management of the associated pathogens requires a thorough understanding of the epidemiology, risk factors, diagnostic methods and performance characteristics in different patient populations, and treatment options unique to each infection. Guidance on the management of these infections has the potential to improve prognosis. The recommendations outlined in this Review are part of the "One World, One Guideline" initiative of the European Confederation of Medical Mycology. Experts from 23 countries contributed to the development of these guidelines. The aim of this Review is to provide an up-to-date consensus and practical guidance in clinical decision making, by engaging physicians and scientists involved in various aspects of clinical management.

Background: Echinocandins are used as first-line therapy for suspected and confirmed Candida spp, and its indiscriminate use may drive selection for echinocandin resistance. We evaluated patterns of use of micafungin to identify opportunities for antifungal stewardship. Methods: We identified all micafungin completed orders and microbiological test result data from July 2018 to November 2020 among hospitalized patients in Barnes-Jewish Hospital. Continuous micafungin courses with Candida spp, (2) patients with recovery of yeast or Candida spp from tracheal aspirates, and (3) patients with recovery of yeast or Candida spp from urine cultures. We only included micafungin courses if they were initiated within 5 days of blood culture collection or up to 4 days after tracheal or urine culture collection to account for incubation and decision to initiate treatment. Results: We found 3,381 micafungin courses in 3,287 admissions. Of these, 2,532 courses had blood culture collection around micafungin initiation and were included in the first analysis: 1,879 (74%) were negative, 149 (6%) had Candida spp isolated in the blood, and 504 (20%) had positive blood cultures for other organisms. Micafungin was given for a median duration of 3 days (IQR, 2–7) to those with negative blood cultures and for 3 days (IQR, 1–5) to those with positive blood cultures without candidemia (p < 0.001), and prolonged durations of more than 5 days was seen in 768/1879 (41%) and 143/504 (28%) of courses, respectively (p Conclusions: Echinocandin treatment courses did not differ when a yeast was identified from a tracheal isolate or urine specimen. However, a substantial proportion of treatment courses were prolonged in those with negative Candida spp in the blood, suggesting opportunities for antifungal stewardship interventions.Funding: NoDisclosures: None

Background Cryptococcal meningitis is a major cause of death among people with human immunodeficiency virus (PWH). Cryptococcal antigen (CrAg) testing of asymptomatic patients is an important public health measure to reduce mortality in high-incidence areas. However, limited data exist on CrAg prevalence in Central America. Methods We conducted a prospective cohort study at the 2 largest human immunodeficiency virus (HIV) clinics and hospitals in Honduras. Cryptococcal antigen in serum and cerebrospinal fluid was performed in individuals with HIV who had CD4 ≤100 cells/mm3 between 2017 and 2018. After CrAg testing, individuals were observed for 12 months to assess mortality using adjusted Cox proportional hazard models. Results A total of 220 PWH were tested for CrAg, 12.7% (n = 28) of which tested positive. Cryptococcal antigen prevalence was higher among hospitalized individuals in 40% (n = 10 of 25) of the cases. The proportion (35.8%) of individuals taking antiretroviral therapy was significantly (P, This cohort study shows a high prevalence of CrAg among Honduran individuals with HIV. Individuals testing CrAg positive were at a higher risk of death during a 12-month period compared with individuals who tested CrAg negative.

Uncommon, or rare, yeast infections are on the rise given increasing numbers of patients who are immunocompromised or seriously ill. The major pathogens include those of the genera Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon (ie, basidiomycetes) and Kodamaea, Malassezia, Pseudozyma (ie, now Moesziomyces or Dirkmeia), Rhodotorula, Saccharomyces, and Sporobolomyces (ie, ascomycetes). A considered approach to the complex, multidisciplinary management of infections that are caused by these pathogens is essential to optimising patient outcomes; however, management guidelines are either region-specific or require updating. In alignment with the One World-One Guideline initiative to incorporate regional differences, experts from diverse geographical regions analysed publications describing the epidemiology and management of the previously mentioned rare yeasts. This guideline summarises the consensus recommendations with regards to the diagnostic and therapeutic options for patients with these rare yeast infections, with the intent of providing practical assistance in clinical decision making. Because there is less clinical experience of patients with rare yeast infections and studies on these patients were not randomised, nor were groups compared, most recommendations are not robust in their validation but represent insights by use of expert opinions and in-vitro susceptibility results. In this Review, we report the key features of the epidemiology, diagnosis, antifungal susceptibility, and treatment outcomes of patients with Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon spp infections.

Background Cryptococcosis is one of the most common life-threatening opportunistic mycoses worldwide. Insidious presentation and slow onset of symptoms make it difficult to recognize, complicating the diagnostic process. Delays in diagnosis may lead to increased mortality. We aim to determine the frequency of missed opportunities for diagnosis of cryptococcosis and its effects on mortality. Methods To estimate the proportion of individuals with a potentially missed diagnosis for cryptococcosis in hospitalized patients, we conducted a retrospective cohort study using the Healthcare Cost and Utilization Project State Inpatient Databases from 2005 to 2015 from eight states. All hospitalized adult patients diagnosed with cryptococcal infection or cryptococcal meningitis were included. Potentially missed diagnoses were defined as admissions coded for a procedure or diagnosis suggestive of cryptococcosis in the 90-days prior to the initial cryptococcosis admission. Generalized estimating equations models were used to evaluate the association between underlying comorbidities and potential missed diagnosis of cryptococcosis and 90-day all-cause in-hospital mortality. Findings Of 5,354 patients with cryptococcosis, 2,445 (45·7%) were people living with HIV (PLWH). Among PLWH, 493/2,445 (20·2%) had a potentially missed diagnosis, of which 83/493 (16·8%) died while hospitalized compared with 265/1,952 (13·6%) of those without a potentially missed diagnosis (relative risk [RR] 1·04, 95% CI 0·99–1·09). Among HIV-negative patients, 977/2,909 (33·6%) had a potentially missed diagnosis, of which 236/977 (24·2%) died while hospitalized compared with 298/1,932 (15·4%) of those not missed (RR 1·12, 95% CI 1·07–1·16). Interpretation Missed opportunities to diagnose cryptococcosis are common despite highly efficacious diagnostic tests and are associated with increased risk of 90-day mortality in HIV-negative patients. A high index of clinical suspicion is paramount to promptly diagnose, treat, and improve cryptococcosis-related mortality. Funding National Center for Advancing Translational Sciences, Washington University Institute of Clinical and Translational Sciences, and the Agency for Healthcare Research and Quality.

Outpatient parenteral antimicrobial therapy (OPAT) is a safe, effective, and convenient treatment strategy for patients receiving intravenous antimicrobials in the outpatient setting; however, data are limited describing the use and safety of liposomal amphotericin B (L-AMB). Records of patients receiving L-AMB OPAT between 1/1/2015 and 7/31/2018 were retrospectively reviewed. The primary objective was to describe the OPAT patient population discharged on L-AMB and evaluate factors associated with readmission and adverse events (AEs). Analysis was performed to evaluate for predictors of worse outcomes. Forty-two patients (67% male, median age 50 years) were identified, most of whom were treated for histoplasmosis. The most common doses of L-AMB were 3 mg/kg (n = 16, 38%) or 5 mg/kg (n = 14, 33%) based on actual body weight. Twenty-six (62%) patients completed their anticipated course of L-AMB. Twenty-two (52%) patients were readmitted within 30 days of discharge; median time to readmission was 11 days (interquartile range [IQR] 5 to 18). While hypokalemia and acute kidney injury (AKI) were common, occurring in 26 (62%) and 20 (48%) patients, respectively, only 5 (12%) were readmitted to the hospital due to L-AMB-associated AEs. Ninety percent of patients achieved at least partial renal recovery within 30 days after L-AMB discontinuation. Factors significantly associated with AKI include higher L-AMB dose, lower serum potassium levels after therapy initiation, and receipt of potassium supplementation at discharge. L-AMB is associated with significant AEs; however, these results suggest that treatment is feasible in the outpatient setting with close monitoring, as the majority of AEs were managed effectively in an outpatient without long-term sequelae.

Background Itraconazole is the preferred azole for histoplasmosis in the current Infectious Diseases Society of America guidelines. Voriconazole is increasingly used as treatment for histoplasmosis; it has in vitro activity against Histoplasma capsulatum and has shown success in case reports and small case series, but may have a lower barrier to resistance. No comparative studies have been published. Methods We constructed a single-center, retrospective cohort of adult patients diagnosed with histoplasmosis from 2002 to 2017. Individual charts were reviewed to gather clinical information, including demographics, clinical features, immune status, treatments, and mortality. Patients were categorized based on the choice of azole and use as an initial treatment or as a step-down therapy from amphotericin B. Initial therapies with other azoles were excluded. Mortality was compared using a multivariable Cox proportional hazards with Heaviside function at 42 days. Results We identified 261 cases of histoplasmosis from 2002 to 2017. After excluding patients not treated with itraconazole or voriconazole, 194 patients remained. Of these, 175 (90%) patients received itraconazole and 19 (10%) received voriconazole. There were no significant demographic differences between patient populations receiving either azole as their initial azole treatment. Death at 180 days occurred in 41 patients (23.4%) in the itraconazole group and 6 patients (31.6%) in the voriconazole group. Patients on voriconazole had a statistically significant increase in mortality during the first 42 days after initiation of treatment when compared to patients receiving itraconazole (hazard ratio, 4.30; 95% confidence interval, 1.3–13.9; P = .015), when controlled for other risk factors. Conclusions Voriconazole in histoplasmosis was associated with increased mortality in the first 42 days when compared to itraconazole.

Cryptococcal epidemiology is shifting toward HIV-negative populations who have diverse presentations. Cryptococcal antigen (CrAg) testing is also changing, with development of the lateral flow assay (LFA) having reported increased sensitivity and specificity, but with minimal knowledge in the HIV-negative population. In this study, we evaluate the real-life performance of CrAg testing in patients with cryptococcal disease. We conducted a retrospective review of patients with cryptococcosis from 2002 to 2019 at Barnes-Jewish Hospital. Latex agglutination (LA) was used exclusively until April 2016, at which point LFA was used exclusively. Demographics, presentations, and testing outcomes were evaluated. Serum CrAg testing was completed in 227 patients with cryptococcosis. Of 141 HIV-negative patients, 107 had LA testing and 34 had LFA testing. In patients with disseminated disease, serum CrAg sensitivity by LA was 78.1% compared to 82.6% for LFA. In patients with localized pulmonary disease, serum CrAg sensitivity was 23.5% compared to 90.9% for LFA. Of 86 people living with HIV (PLWH), 76 had LA testing, and 10 had LFA testing. Serum CrAg sensitivity for LA was 94.7% compared to 100% for LFA in patients with disseminated disease. We noted a significant improvement in sensitivity from LA testing to LFA testing, predominantly in those with localized pulmonary disease. However, both LFA and LA appear to be less sensitive in HIV-negative patients than previously described in PLWH.

Knowledge dissemination during COVID19 has been notable for the rise of pre-prints and publication by press release, favoring speed over accuracy. We stress the importance of journals in this landscape and highlight the value of editorial judgment and peer review.

The treatment of invasive fungal infections remains challenging due to limitations in currently available antifungal therapies including toxicity, interactions, restricted routes of administration, and drug resistance. This review focuses on novel therapies in clinical development, including drugs and a device. These drugs have novel mechanisms of action to overcome resistance, and some offer new formulations providing distinct advantages over current therapies to improve safety profiles and reduce interactions. Among agents that target the cell wall, 2 glucan synthesis inhibitors are discussed (rezafungin and ibrexafungerp), as well as fosmanogepix and nikkomycin Z. Agents that target the cell membrane include 3 fourth-generation azoles, oral encochleated amphotericin B, and aureobasidin A. Among agents with intracellular targets, we will review olorofim, VL-2397, T-2307, AR-12, and MGCD290. In addition, we will describe neurapheresis, a device used as adjunctive therapy for cryptococcosis. With a field full of novel treatments for fungal infections, the future looks promising., The treatment of invasive fungal infections remains challenging. Current antifungal therapies have several limitations, including toxicities, interactions and drug-resistant fungi continue to arise. New antifungals in the pipeline will be discussed in this review.

Early HIV diagnosis remains a challenge in many regions with delayed diagnosis resulting in increased morbidity and mortality. We conducted a retrospective cohort study of people living with HIV receiving outpatient care at a large tertiary referral center in Guatemala to describe the proportion of late presenters (LP) and missed opportunities for HIV diagnosis. Of 3686 patients, 2990 (81.1%) were LP who were more likely to be male (60.2% vs. 48.0%, p

No clinical trials for histoplasmosis have been performed with the newer azoles, leaving itraconazole as the azole of choice. In vitro studies suggest that Histoplasma capsulatum from patients that relapse on fluconazole has higher minimum inhibitory concentrations (MICs) to fluconazole and voriconazole but not itraconazole and posaconazole. The newest azole, isavuconazole, shares structural similarity to voriconazole, but to date nobody has explored emergence of resistance. In vitro susceptibilities to isavucoanzole and fluconazole were performed on previously obtained isolates from the patients who relapsed on fluconazole therapy. Susceptibilities were determined by NCCLS method M27A developed for yeasts, as modified for H. capsulatum. The change in the MIC from the primary to the relapse isolate was tested using Wilcoxon Rank-Sum for paired data. Among the primary isolates, the median MICs were 1.0 (range 0.25 to 4.0) μg/ml for fluconazole and ≤0.007 (range ≤0.007 to 0.015) μg/ml for isavuconazole. In the group of relapsed isolates, the median MICs rose to 8.0 (range 0.25 to 64.0) μg/ml for fluconazole and remained unchanged at ≤0.007 (range ≤0.007 to 0.015) μg/ml for isavuconazole (P < .001). Only one isolate exhibited a nonsignificant increase in MIC to isavuconazole. Histoplasma isolates from patients who relapsed on fluconazole did not have an elevation in MICs to isavuconazole. This differs from the results previously seen with voriconazole and suggests that despite a closer structural similarity to voriconazole than itraconazole and posaconazole, isavuconazole has a higher barrier to resistance and may be effective as therapy for histoplasmosis.

Cryptococcal disease is most often thought of in the context of HIV infection. Much of our knowledge of the disease originates from its management in the HIV-positive population over the last 30 years. While the majority of cases globally continue to occur in the setting of advanced HIV, Cryptococcus species is increasingly responsible for disease in HIV-negative populations including those considered normal hosts and these HIV-negative populations will be the focus of this review. Currently available data indicated that significant differences exist in epidemiology, clinical presentation, management and outcomes of cryptococcal disease in HIV-negative populations when compared to those living with HIV. Further research is required to improve our knowledge of cryptococcal disease in particular in HIV-negative cohorts so as to optimise management of the disease in the future.

Background Histoplasmosis in transplant recipients is understudied. We reviewed a large cohort of histoplasmosis in patients with solid organ and stem cell transplants in an endemic area to describe the epidemiology, clinical findings and outcomes. Methods We performed a single-center retrospective cohort study of patients diagnosed with histoplasmosis between 2002 and 2017. Demographic data, clinical findings, diagnostic methods, treatment, and mortality were collected. We compared the characteristics of patients with history of transplant to non-transplant (NT) patients. Results We identified 261 patients with histoplasmosis. Of those, 28(11%) were transplant recipients; 8(29%) liver, 8(29%) lung, 6(21%) kidney, 3(11%) heart, and 3(11%) stem cell. Median time from symptom onset to diagnosis was 6 vs 34 days in transplant vs NT groups (p=0.001). Lung was the most common organ involvement (89% in transplants vs 78% in NT, p=0.168). Spleen involvement was more commonly found in transplant patients (29 vs 14%, p=0.039). In patients with disseminated disease, urine antigen was 100% sensitive in transplant patients compared to 78% in the NT group (p=0.038). Duration of treatment was 13 vs 6 months in transplant vs NT patients (p= 0.003). Mortality was comparable between groups (14 vs 15% in transplant vs NT, p=0.918). Median time from transplant to diagnosis was 4.21 years. However, five patients (18%) developed histoplasmosis within 6 months. For these early diagnosed patients, ICU admission rate was 80 vs 30% (p=0.04) and rate of mechanical ventilator use was 80 vs 22% (p=0.011) compared to patients diagnosed later. Table 1: Patient characteristics Table 2: Organ involvement Table 3: Diagnostic test positivity Conclusion Transplant recipients with histoplasmosis are likely to be diagnosed early and be treated longer. Urine antigen is highly sensitive for diagnosis of disseminated disease. Histoplasmosis that occurs within the first 6 months after transplantation tends to be more severe. Disclosures Andrej Spec, MD, MSCI, Astellas (Grant/Research Support)Mayne (Consultant)Scynexis (Consultant)

Background Histoplasmosis is a common opportunistic infection afflicting people living with HIV (PLWH) globally. There are no data on long term survival of PLWH with histoplasmosis. Methods We conducted a single-center retrospective cohort study of PLWH diagnosed with histoplasmosis between 2002 and 2017. Data collected included demographics, clinical characteristics, treatment, and mortality. Patients were categorized into three groups based on length of survival after diagnosis: early mortality (death within 90 days), late mortality (death at or after 90 days), and survivors. Between group differences in demographic and clinical characteristics were assessed using Chi square for categorical variables and Mann-Whitney U non-parametric tests for continuous variables. Mortality was compared using Cox proportional hazards. Insurance type (i.e. private versus public option) served as a surrogate indicator of socioeconomic status (SES). Patients diagnosed with histoplasmosis in or after 2008 were considered a part of the modern ART era, regardless of treatment regimen. Results Our review found 54 PLWH infected with histoplasmosis from 2002-2017. Overall mortality was 37%, with 14.8% early mortality and 22.2% late mortality. Median survival time in the early mortality group was 13.5 days (IQR 2.5-41 days), and 338 days (IQR 180.5-803.3) in the late mortality group. Compared to the late mortality group, survivors were over 6 times more likely to have suppressed HIV viral load at last observation (HR 6.19, p=0.013). Median HIV viral load at last observation was lower among the survivors (2 log copies/ml, IQR 0, 4.5) compared to the late mortality group (4.1 log copies/ml, IQR 2.6,5.5) (p=0.010). Survivors were twice as likely to have private insurance, but this did not reach statistical significance (HR 2.19, p=0.14). There was no statistically significant difference in survival based on the availability of modern ART (p=0.85). The year of diagnosis made no difference with regards to survival (p=0.914). Baseline Characteristics of PLWH with Histoplasmosis HIV-related Characteristics of PLWH with Histoplasmosis Conclusion Histoplasmosis continues to be associated with high mortality among PLWH. Improved long-term survival is seen in patients with suppressed HIV viral loads. Disclosures Andrej Spec, MD, MSCI, Astellas (Grant/Research Support)Mayne (Consultant)Scynexis (Consultant)

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 IDSA guidelines on candidemia recommend fluconazole as first-line therapy in patients considered low risk for fluconazole resistant infections. However, there is currently no mechanism to determine risk of resistance, and most community hospitals cannot perform rapid sensitivity testing, leading to prolonged use of echinocandin therapy. This study aims to develop a clinical predictive model to identify patients at low risk for fluconazole resistance where first-line use of fluconazole therapy would be acceptable without requiring resistance testing. Methods We performed a retrospective cohort analysis of all hospitalized adult patients with a positive blood culture for Candida spp. from 2013 to 2018. Fluconazole resistance was determined using Sensititre™ YeastOne™ YO9 AST Plate, with cutoffs defined for each Candida species based on Clinical and Laboratory Standards Institute performance standards for antifungal testing (M60) in all patients. Using backwards stepwise regression, we developed a multivariable logistic regression model to identify factors associated with fluconazole resistance in patients in Candida bloodstream infection, including only variables with clinical plausibility and p < 0.1 in bivariable analysis. Stepwise regression was performed on bootstrapped samples to test individual variable stability and estimate confidence intervals. We used graphs of observed vs expected values to assess model performance across the probability spectrum. Results We identified 539 patients with Candida bloodstream infection from 2013–2018, of which 13.4% (72/539) were fluconazole resistant. Increased risk of fluconazole resistance was associated with age (1.12 [1.01, 1.24]), bacterial septicemia (2.14 [1.20, 3.79]), receipt of previous azole therapy (5.47 [2.92, 10.26]), bone marrow transplant (2.63 [1.31, 5.29]), and myelodysplastic syndrome (3.13 [1.14, 8.60]). The model predicted fluconazole sensitivity well (c-statistic 0.788) and all the variables were stable (Figure 1). Figure 1. Graph comparing observed versus expected probability of fluconazole resistance. Bars included on the top parameter of the graph indicate the number of individuals, illustrating the distribution of the sample. Conclusion The presented model provides a potential tool for identifying the 80% of patients at low enough risk for fluconazole resistance to receive empiric therapy with azoles and reduce use of echinocandins. Disclosures Margaret A. Olsen, PhD, MPH, Merck (Grant/Research Support)Pfizer (Consultant, Grant/Research Support) Dustin Stwalley, MA, AbbVie Inc (Shareholder)Bristol-Myers Squibb (Shareholder) Andrej Spec, MD, MSCI, Astellas (Grant/Research Support)Mayne (Consultant)Scynexis (Consultant)

BACKGROUND The prevalence of cryptococcosis in people living with HIV (PLWH) in the developed world has decreased considerably in the modern antiretroviral therapy (ART) era. Although early mortality of PLWH with opportunistic infections is well understood, overall mortality has not been previously evaluated. METHODS We conducted a retrospective cohort study of cryptococcosis in PLWH from January 1, 2002, to July 1, 2017. Data were also evaluated before and after 2008 to evaluate the possible effect of modern ART on outcomes. Death date was obtained from the hospital's medical informatics database and the Social Security Death Index. Participants were grouped as survivors, early-mortality (death

The innervation of taste buds is an excellent model system for studying the guidance of axons during targeting because of their discrete nature and the high fidelity of innervation. The pregustatory epithelium of fungiform papillae is known to secrete diffusible axon guidance cues such as BDNF and Sema3A that attract and repel, respectively, geniculate ganglion axons during targeting, but diffusible factors alone are unlikely to explain how taste axon terminals are restricted to their territories within the taste bud. Nondiffusible cell surface proteins such as Ephs and ephrins can act as receptors and/or ligands for one another and are known to control axon terminal positioning in several parts of the nervous system, but they have not been studied in the gustatory system. We report that ephrin-B2 linked β-galactosidase staining and immunostaining was present along the dorsal epithelium of the mouse tongue as early as embryonic day 15.5 (E15.5), but was not detected at E14.5, when axons first enter the epithelium. Ephrin-B1 immunolabeling was barely detected in the epithelium and found at a somewhat higher concentration in the mesenchyme subjacent to the epithelium. EphB1 and EphB2 were detected in lingual sensory afferents in vivo and geniculate neurites in vitro. Ephrin-B1 and ephrin-B2 were similarly effective in repelling or suppressing outgrowth by geniculate neurites in vitro. These in vitro effects were independent of the neurotrophin used to promote outgrowth, but were reduced by elevated levels of laminin. In vivo, mice null for EphB1 and EphB2 exhibited decreased gustatory innervation of fungiform papillae. These data provide evidence that ephrin-B forward signaling is necessary for normal gustatory innervation of the mammalian tongue.

Background HIV infection and antiretroviral therapy (ART) can lead to metabolic abnormalities associated with increased cardiovascular disease risk, some of these abnormalities (central obesity, elevated fasting glucose, triglycerides, and blood pressure and low HDL cholesterol) are in metabolic syndrome (MetS). The prevalence of MetS increases with age. Currently, the status of MetS in people with HIV (PWH) Guatemala is unknown. We assessed the prevalence of MetS and potential predictors in PWH participating in prospective cohort study at Hospital Roosevelt in Guatemala City. Methods We performed a cross-sectional analysis of PWH under 40 years old receiving ART for at least 6 months from July 2019 to March 2020. The harmonized criteria for MetS and the cut-off for waist circumference recommended by the Latin American Diabetes Association were used. Association between MetS and gender, place of residency, ethnicity, educational level, baseline and current CD4 count, smoking, alcohol consumption, physical activity, viral load, body mass index (BMI) and ART exposure was assessed in bivariate analysis. Potential predictors (p-value < 0.1) were included in a multivariate binary logistic regression model. Results Of total cohort of 757 participants enrolled390 (51.5%) were younger than 40 years. Of those under < 40 years, 150 (38.5%) were women, 59 (15.1%) Mayan, median age was 32 years (IQR 27, 37). 93 (23.8%) had MetS. Between group differences in Table 1. Of those with Met, 51 (54.8%) had elevated waist circumference, 87 (93.5%) elevated triglycerides, 83 (89.2%) low HDL-c, 56 (60.2%) elevated blood pressure and 35 (37.6%) elevated fasting glucose. Body mass index (BMI) ≥ 25 kg/m2 or higher and 2 years or more of cumulative non-nucleoside reverse transcription inhibitors (NNRTI) where more common in those < 40 years with MetS compared to those without MetS. On multivariable regression, MetS was associated with current CD4 count < 200 (OR 3.1; IC 1.51, 6.34; p-value < 0.01) and BMI ≥ 25 kg/m2 (OR; 6.53; IC 3.64, 11.73; p-value < 0.01). Table1. Between group differences (No MetS vs MetS) Conclusion Nearly one in every four PWH under 40 years old in our cohort was affected by MetS. Dyslipidemia (elevated triglycerides and low HDL-c) was the main driver of MetS. Lower CD4 count and overweight were predictors for MetS in PWH under 40. Disclosures Andrej Spec, MD, MSCI, Astellas (Grant/Research Support)Mayne (Consultant)Scynexis (Consultant)

Background Invasive fungal infections (IFI) following traumatic injury are devastating complications that threaten life and limb. In military combat wounds, post-traumatic IFI patients have up to 6 times higher mortality rates and 2.6-5.1 times higher rate of high-level amputations compared to non-IFI patients, though no such data exists for the civilian population. This study is the first cohort to analyze a post-traumatic civilian population for IFI, its epidemiology and outcomes. Methods We conducted a single-center retrospective cohort study of all trauma patients over the age of 18 years admitted to a large tertiary referral hospital between 2004 to 2015 who required surgery for their injury and had operative cultures submitted from their wounds. Patient demographics, comorbid conditions, mechanisms of trauma, environmental exposures, and laboratory data were included for analysis. Patients with positive culture for fungus from a site compatible with IFI were considered IFI patients. Data was analyzed using descriptive statistics with p≤0.05 considered significant. Results Our cohort includes 1,107 patients that met inclusion criteria. Of these, 120 patients had a positive culture for fungus, 454 patients had a positive culture for bacteria and 533 patients had no positive culture from a site of interest. Basic patient demographics, geographical setting of the trauma, and anatomical site of injury were not significantly associated with having a positive fungal culture. Necrosis was present in 19 (15.8%) IFI vs. 74 (7.5%) non-IFI patients (p=0.002). Soil contamination of a wound was present in 6 (5.0%) IFI vs. 11 (1.1%) non-IFI patients (p=0.001). 55.8% of 120 IFI wounds penetrated below fascial layers compared to 26.7% of 987 non-IFI wounds (p< 0.001). Presence of IFI increased likelihood of requiring amputation (6.7% vs. 2.7%, p=0.02) and prolonged hospitalization >14 days (77.5% vs. 57.4%, p< 0.001) compared to those without. Conclusion IFI significantly increased patient risk for amputation and prolonged hospital length of stay following traumatic injury in a civilian population. Presence of IFI was associated with wounds penetrating below the fascial layer, presence of wound necrosis, and soil contamination of a wound. Disclosures Andrej Spec, MD, MSCI, Astellas (Grant/Research Support)Mayne (Consultant)Scynexis (Consultant)

Background Candida infections resistant to currently available antifungals are an emerging global threat. 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 oral ibrexafungerp (FURI) (Clinicaltrials.gov NCT03059992) is ongoing for the treatment of patients (≥18 years) with fungal diseases who are intolerant of or refractory to standard antifungal therapies. Methods An independent Data Review Committee (DRC) provided an assessment of treatment response for 41 patients. Patients were enrolled in 22 centers from 6 countries. Patients were eligible for enrollment if they had proven or probable, invasive or severe mucocutaneous candidiasis and documented evidence of failure of, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or could not receive approved oral antifungal options (e.g., susceptibility of the organism) and a continued IV antifungal therapy was undesirable or unfeasible. Results The 41 patients assessed had the following infection types: intra-abdominal abscesses, oropharyngeal candidiasis, esophageal candidiasis, candidemia, and others. The DRC adjudicated 23 patients (56%) as achieving complete or partial response, 11 patients (27%) maintaining stable disease, 6 patients (15%) with progression of disease and one case was considered as indeterminate. The efficacy of oral ibrexafungerp by pathogen is shown in Table 1. Ibrexafungerp was well-tolerated with the most common treatment-related adverse events being of gastrointestinal origin. No deaths due to progression of fungal disease were reported. Table 1: Ibrexafungerp Outcomes by Pathogen Conclusion Preliminary analysis of these 41 cases indicate that oral ibrexafungerp provides a favorable therapeutic response in the majority of patients with difficult to treat Candida spp. infections, including those caused by non-albicans Candida species. Disclosures Barbara D. Alexander, MD, MHS, SCYNEXIS, Inc. (Employee, Scientific Research Study Investigator, Research Grant or Support) Oliver Cornely, Prof., Actelion (Grant/Research Support)Actelion (Other Financial or Material Support, Personal fees)Al Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Other Financial or Material Support, Personal fees)Amplyx (Other Financial or Material Support, Personal fees)Amplyx (Grant/Research Support)Astellas (Grant/Research Support)Astellas (Other Financial or Material Support, Personal fees)Basilea (Other Financial or Material Support, Personal fees)Basilea (Grant/Research Support)Biosys UK Limited (Other Financial or Material Support, Personal fees)Cidara (Other Financial or Material Support, Personal fees)Cidara (Grant/Research Support)Da Volterra (Grant/Research Support)Da Volterra (Other Financial or Material Support, Personal fees)Entasis (Other Financial or Material Support, Personal fees)F2G (Other Financial or Material Support)F2G (Grant/Research Support)Gilead (Grant/Research Support)Gilead (Other Financial or Material Support, Personal fees)Grupo Biotoscana (Other Financial or Material Support, Personal fees)Janssen Pharmaceuticals (Grant/Research Support)Matinas (Other Financial or Material Support, Personal fees)Medicines Company (Grant/Research Support)MedPace (Grant/Research Support)MedPace (Other Financial or Material Support, Personal fees)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche (Other Financial or Material Support, Personal fees)Merck/MSD (Other Financial or Material Support, Personal fees)Merck/MSD (Grant/Research Support)Mylan Pharmaceuticals (Consultant)Nabriva Therapeutics (Other Financial or Material Support, Personal fees)Octapharma (Other Financial or Material Support, Personal fees)Paratek Pharmaceuticals (Other Financial or Material Support, Personal fees)Pfizer (Other Financial or Material Support, Personal fees)Pfizer (Grant/Research Support)PSI (Other Financial or Material Support, Personal fees)Rempex (Other Financial or Material Support, Personal fees)Roche Diagnostics (Other Financial or Material Support, Personal fees)Scynexis (Other Financial or Material Support, Personal fees)Scynexis (Grant/Research Support)Seres Therapeutics (Other Financial or Material Support, Personal fees)Tetraphase (Other Financial or Material Support, Personal fees) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Luis Ostrosky-Zeichner, MD, Amplyx (Scientific Research Study Investigator)Astellas (Consultant, Scientific Research Study Investigator, Other Financial or Material Support, Non-branded educational speaking)Biotoscana (Consultant, Other Financial or Material Support, Non-branded educational speaking)Cidara (Consultant, Scientific Research Study Investigator)F2G (Consultant)Gilead (Consultant)Mayne (Consultant)Octapharma (Consultant)Pfizer (Other Financial or Material Support, Non-branded educational speaking)Scynexis (Consultant, Grant/Research Support, Scientific Research Study Investigator)Stendhal (Consultant)Viracor (Consultant) Andrej Spec, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator, Advisor or Review Panel member) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) Robert Krause, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Caryn Morse, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) John W. Sanders, III, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) David Andes, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator, Advisor or Review Panel member) George Lyon, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Francisco M. Marty, MD, Allovir (Consultant)Amplyx (Consultant)Ansun (Scientific Research Study Investigator)Avir (Consultant)Cidara (Scientific Research Study Investigator)F2G (Consultant, Scientific Research Study Investigator)Kyorin (Consultant)Merck (Consultant, Grant/Research Support, Scientific Research Study Investigator)New England Journal of Medicine (Other Financial or Material Support, Honorarium for Video)Regeneron (Consultant, Scientific Research Study Investigator)ReViral (Consultant)Scynexis (Scientific Research Study Investigator)Symbio (Consultant)Takeda (Scientific Research Study Investigator)United Medical (Consultant)WHISCON (Scientific Research Study Investigator) Marisa H. Miceli, MD, FIDSA, SCYNEXIS, Inc. (Advisor or Review Panel member) Thomas F. Patterson, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Martin Hoenigl, MD, SCYNEXIS, Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Cryptococcal epidemiology is changing in the modern antiretroviral era, and immune status informs outcomes. We describe the differences in clinical presentation and mortality of cryptococcosis by immune status in the antiretroviral therapy era.We conducted a single-center retrospective cohort study of patients diagnosed with cryptococcosis from 2002 through 2017. Data included demographics, clinical features, diagnostics, and mortality.We identified 304 patients with Cryptococcus neoformans infections: 105 (35%) were people living with human immunodeficiency virus (HIV), 41 (13%) had a history of transplantation, and 158 (52%) were non-HIV nontransplant (NHNT). Age analysis showed that people living with HIV were younger (40 years) than transplant (53 years) and NHNT (61 years) (P.001). Fevers and headache were more common in people living with HIV (70% and 57%) than in transplant (49% and 29%) and NHNT (49% and 38%) (P = .003 and P = .001), respectively. Meningitis was more common in people living with HIV (68%) than in transplant recipients (32%) or NHNT (39%, P.001). Disseminated cryptococcosis was more common in people living with HIV (97%) as compared with transplant (66%) or NHNT (73%) (P.001). Time to diagnosis from hospitalization was longer for transplant (median 2 days, interquartile range [IQR] ± 9 days) and NHNT patients (median 2 days, IQR ± 7 days) as compared with people living with HIV (median 1 day, IQR ± 2 days) (P = .003). NHNT patients had a higher risk of 90-day mortality (hazard ratio 3.3; 95% confidence interval, 1.9-5.8) as compared with people living with HIV.The majority of cryptococcosis occurs in NHNT patients. NHNT patients had more localized pulmonary cryptococcosis and significantly higher 90-day mortality. Cryptococcosis in NHNT patients appears to be a distinct entity that needs further study and requires a higher level of clinical suspicion than it currently receives.

Cryptococcocis is an opportunistic fungal infection with high morbidity and mortality. Guidelines to aid clinicians regarding diagnosis, management, and treatment can be extensive and challenging to comply with. There is no tool to measure guideline adherence. To create such a tool, we reviewed current guidelines from the Infectious Diseases Society of America, the World Health Organization, the American Society of Transplantation, and recent significant publications to select the strongest recommendations as vital components of our scoring tool. Items included diagnostic tests (blood, tissue, and cerebrospinal fluid cultures, Cryptococcus antigen, India ink, histopathology with special fungal stains, central nervous system imaging), pharmacological (amphotericin B, flucytosine, azoles) and nonpharmacological treatments (intracranial pressure management, immunomodulation, infectious disease consultation), and follow-up of central nervous system complications. The EQUAL Cryptococcus Score 2018 weighs and aggregates the recommendations for the optimal management of cryptococcosis. Providing a tool that could measure guideline adherence or facilitate clinical decision-making.

Background Candida krusei bloodstream infection (CK BSI) is associated with high mortality, but whether this is due to underlying comorbidities in affected patients or the organism itself is unknown. Identifying patient characteristics that are associated with CK BSI is crucial for clinical decision-making and prognosis. Methods We conducted a retrospective analysis of hospitalized patients with Candida BSI at our institution between 2002 and 2015. Data were collected on demographics, comorbidities, medications, procedures, central lines, vital signs, and laboratory values. Multivariable logistic and Cox regression were used to identify risk factors associated with CK and mortality, respectively. Results We identified 1873 individual patients who developed Candida BSI within the study period, 59 of whom had CK BSI. CK BSI was predicted by hematologic malignancy, gastric malignancy, neutropenia, and the use of prophylactic azole antifungals, monoclonal antibodies, and β-lactam/β-lactamase inhibitor combinations. The C-statistic was 0.86 (95% confidence interval, 0.81–0.91). The crude mortality rates were 64.4% for CK BSI and 41.4% for non-CK BSI. Although CK was associated with higher mortality in univariable Cox regression, this relationship was no longer significant with the addition of the following confounders: lymphoma, neutropenia, glucocorticoid use, chronic liver disease, and elevated creatinine. Conclusions Six patient comorbidities predicted the development of CK BSI with high accuracy. Although patients with CK BSI have higher crude mortality rates than patients with non-CK BSI, this difference is not significant when accounting for other patient characteristics.

Cryptococcal meningitis remains a significant cause of morbidity and mortality amongst patients living with human immunodeficiency virus (HIV). The prevalence in the developed world has decreased as HIV is being diagnosed earlier, but is still significant, and the prevalence in resource-limited settings is exceedingly high. The presenting symptoms usually include a headache, fever, and, less often, cranial nerve abnormalities. Space-occupying lesions do occur, but are rare. Once diagnosed, patients should be treated with a combination of amphotericin and flucytosine, with step-down therapy to fluconazole for a minimum of a year, or until the CD4 count is above 100 cells/μL, whichever is longer. In the acute phase of treatment increased opening pressure is common, which should be managed aggressively with frequent lumbar punctures, or through neurosurgical interventions (lumbar drains, ventriculoperitoneal shunts) if those fail. Antiretrovirals should be delayed at least 2 weeks, but maybe as many as 10 weeks, after initiation of antifungal therapy in order to prevent clinical or subclinical immune reconstitution inflammatory syndrome (IRIS), which may lead to increased mortality. However, if IRIS does develop, there is no role for antiretroviral interruption, and the condition should be managed supportively by use of anti-inflammatories and aggressive management of elevated opening pressure, if present. Steroids should be administered for specific indications only (IRIS or cryptococcoma with cerebral edema and risk of herniation) as routine use of steroids increases mortality in cryptococcal meningitis.

Background The guideline-preferred azole for histoplasmosis (HP) is itraconazole (IC). While voriconazole (VC) has shown success in in-vitro and in retrospective analyses, there has not been enough data to include newer generation azoles as first-line treatment for infections with Histoplasma capsulatum. Methods We conducted a single-center retrospective cohort study of adult patients diagnosed with HP from 2002 through 2017. Data included demographics, clinical features and sites of infection, immune status, treatments, and mortality. Patients were categorized into two groups based on initial choice of azole (IC or VC) and mortality was compared between these two groups. The treatment groups were defined based on the first azole received, either IC or VC, as initial or as step-down therapy from amphotericin. Patients initiated on other azoles were excluded. Results We identified 263 cases of HP from 2002 to 2017. After excluding patients initiated on other azoles, 194 patients remained. 175 (90%) patients were started on IC and 19 (10%) were started on VC, either as stepdown or initial choice of antifungal. There were no significant demographic differences between patients receiving IC compared with VC as their initial azole treatment. Patients with hematologic malignancies tended to be prescribed VC more frequently but this was not statistically significant (OR 3.1 [0.77–12.4]). Death occurred in 40 (23%) patients from the IC and 5 (26%) patients from the VC group. The hazard ratio for mortality with the use of VC was 1.21 (CI 0.4–3.6, P = 0.73). Conclusion IC is the mainstay in the treatment for HP. It appears that VC has comparable outcomes to IC and can be considered an alternative treatment option for HP, at least for patients with contraindications to IC treatment. Disclosures All authors: No reported disclosures.