bluuebunny/crossref_metadata_2025_split huggingface dataset:
Public Health Response to US Cases of Candida auris, a Globally Emerging, Multidrug-Resistant Yeast, 2013–2017
Authors: Tsay Sharon , Welsh Rory M , Adams Eleanor H , Chow Nancy A , Gade Lalitha , Berkow Elizabeth L , Lutterloh Emily , Quinn Monica , Chaturvedi Sudha , Fernandez Rafael , Giardina Rosalie , Greenko Jane , Southwick Karen , Kerins Janna L , Black Stephanie , Kemble Sarah K , Barrett Patricia M , Greeley Rebecca , Barton Kerri , Shannon Dj , Kallen Alexander , Shugart Alicia , Litvintseva Anastasia P , Lockhart Shawn , Chiller Tom , Jackson Brendan R , Vallabhaneni Snigdha 
Published: October 2017

Abstract

Background
Candida auris is an often multidrug-resistant yeast that causes invasive infections and, unlike most Candida species, spreads in healthcare facilities. CDC released a clinical alert in June 2016 requesting reporting of C. auris cases. We investigated cases to contain transmission and inform prevention measures for this novel organism.

Methods
Clinical cases were defined as C. auris from any clinical specimen from a patient in the United States. Response to cases included implementation of infection control measures, enhanced cleaning and disinfection, and testing of close contacts for C. auris colonisation (isolation from a person’s axilla or groin was defined as a screening case). Microbiology records were reviewed at reporting facilities for missed cases. All isolates were forwarded to CDC for confirmation, antifungal susceptibility testing, and whole-genome sequencing (WGS).

Results
As of April 13, 2017, 61 clinical cases of C. auris were reported from six states: New York (39), New Jersey (15), Illinois (4), Indiana (1), Maryland (1), and Massachusetts (1). All but two occurred since 2016 (Figure). An additional 32 screening cases were identified among contacts. Median age of clinical case-patients was 70 years (range 21–96); 56% were male. Nearly, all had underlying medical conditions and extensive exposure to healthcare facilities before infection. Most clinical isolates were from blood (38, 62%), followed by urine (8, 13%) and respiratory tract (5, 8%). Among the first 35 isolates, 30 (86%) were resistant to fluconazole, 15 (43%) to amphotericin B, and one (3%) to caspofungin. No isolate was resistant to all three. WGS revealed isolates from each state were highly related and different from other states, suggestive of transmission. Microbiology record reviews did not identify additional cases before 2016.

Conclusion
C. auris is an emerging pathogen, with similarities to multidrug-resistant bacteria, that has been transmitted in US healthcare settings. CDC and public health partners are committed to prompt and aggressive action through investigation of cases and heightened infection control practices to halt its spread.

Disclosures
All authors: No reported disclosures.
Time Trends in the Burden of Hospitalizations with Invasive Aspergillosis in the United States, 2004–2013
Authors: Zilberberg Marya D , Harrington Rachel , Spalding James , Shorr Andrew F 
Published: October 2017

Abstract

Background
Invasive aspergillosis (IA) remains a burdensome illness and is associated with substantial mortality. With increasing use of aggressive chemotherapy and immunomodulatory treatments, the prevalence of IA is likely to have grown. However, little is known about the current US burden of IA-related hospitalizations.

Methods
Using aggregated data available on the interactive website from the Agency of Healthcare Research and Quality’s Health Care Utilization Project Net, we examined the annual volume of IA-related hospitalizations in the United States, based on the presence of the ICD-9-CM codes 117.3, 117.9, and 484.6. Age-adjusted volumes were derived through population incidence calculated using year-specific censal and intercensal US population estimates available from the US Census Bureau. We additionally determined time trends in IA as the principal diagnosis (PD) and its associated charges.

Results
Between 2004 and 2013, the number of annual hospitalizations with IA grew from 29,774 (standard error, SE 2,425) to 51,870 (SE 2,642), a 74.2% overall increase. This increase was most notable among those aged 45–64 and 65–84 years. Regionally, the South contributed the plurality of the cases (40%), and the Northeast the fewest (17%) with the remainder split evenly between the West and the Midwest. When age-adjusting to year 2013, the growth in the volume of cases was slightly more modest (44.2%), going from 35,968 cases in 2004 to 51,870 in 2013. The proportion of IA hospitalizations in which IA was the PD dropped, from 14.4% in 2004 to 9.3% in 2013. Despite mean hospital length of stay (LOS) decreasing from 13.3 (SE 0.07) in 2004 to 11.5 (SE 0.6) days in 2013, the corresponding mean hospital charges rose from $71,164 (SE $5,248) to $123,005 (SE $9,738). The aggregate US inflation-adjusted hospital charges for IA PD rose from $436,074,445 in 2004 to $592,358,369 in 2013.

Conclusion
The rate of growth in IA-related hospitalizations in the United States between 2004 and 2013 was substantial. The plurality of cases appears to arise in the South. Despite a moderate decrease in LOS during the time period studied, there was a modest rise in the corresponding hospital charges. The aggregate US annual hospital bill for IA PD discharges is over $0.5 billion.

Disclosures
M. D. Zilberberg, Astellas Pharma Global Development, Inc.: grant investigator, research support R. Harrington, Astellas Pharma Global Development, Inc.: employee, former employee and salary J. Spalding, Astellas Pharma Global Development, Inc.: employee, salary A. F. Shorr, Astellas Pharma Global Development, Inc.: Consultant and Speaker’s Bureau, consulting fee, research support and speaker honorarium Cidara: consultant, consulting fee Merck: consultant, scientific advisor and Speaker’s Bureau, research support and speaker honorarium
Primary or Secondary Prophylaxis with Voriconazole Compared with Posaconazole for Prevention of Invasive Fungal Infections After Hematopoietic Stem Cell Transplantation
Authors: Jansen Jeffrey W , Pande Anupam , Romee Rizwan , Lawrence Steven J , Powderly William 
Published: October 2017

Abstract

Background
Invasive fungal infections (IFI) remain a serious complication in hematopoietic stem cell transplantation (HSCT) patients and are associated with increased costs, morbidity, and mortality. Posaconazole (PCZ) and voriconazole (VCZ) are frequently utilized as antifungal prophylaxis in this population. To date, no direct comparison between PCZ and VCZ exists for the prevention of IFI in adult HSCT patients.

Methods
A retrospective cohort analysis of HSCT patients aged ≥18 years who received ≥28 continuous days of primary (PPPx) or secondary (SPPx) antifungal prophylaxis with either VCZ or PCZ between February 26, 2003 and September 30, 2015 at Barnes-Jewish Hospital was conducted. Patients who received PPPx or SPPx with both VCZ and PCZ were analyzed following intention to treat of the initial agent received. Patients who received both PPPx and SPPx were included once for both PPPx and SPPx. The primary outcome of interest was development of possible, probable, or proven IFI as defined by EORTC/MSG guidelines. In the SPPx patients, development of IFI was confirmed as a distinct event from primary IFI based on manual chart review and radiographic evidence.

Results
Overall, there were 472 patients included; 402 in the VCZ group and 70 in the PCZ group. At baseline, patients in the PCZ group had more graft vs. host disease (GVHD) prior to prophylaxis (27.1% vs. 16.7%, P = 0.04) and were more likely to be on SPPx (60% vs. 41%, P &lt; 0.01). There were 22 and 1 IFI events in the VCZ and PCZ groups, respectively, which corresponded to a crude incidence rate of 0.345 and 0.077 per 1000 person-days of prophylaxis. Figure 1 displays the Cox proportional hazard model which was completed in the backwards stepwise method accounting for gender, transplant type, GVHD prior to prophylaxis, disease remission, and PPPx or SPPX. The hazard ratio for development of IFI while on prophylaxis between VCZ and PCZ was 5.22 (95% CI: 0.69–39.4; P = 0.11) after controlling for PPPx or SPPx.

Conclusion
There was not a significant difference between rates of IFI in HSCT patients who received antifungal prophylaxis with VCZ compared with PCZ. Our data trends towards favoring PCZ but is limited by low rates of IFI. Larger, prospective analyses are necessary to confirm our findings.

Disclosures
W. Powderly, Merck: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Gilead: Scientific Advisor, Consulting fee. Astellas: Grant Investigator, Research grant
Posaconazole-Induced Hypertension and Hypokalemia: Mechanistic Evaluation
Authors: Thompson George R , Chang Diana , Wittenberg Rebecca , Mchardy Ian , Semrad Alison 
Published: October 2017

Abstract

Background
Recent studies have shown the new posaconazole delayed-release tablets have superior bioavailability compared with the liquid suspension formulation. As higher serum posaconazole concentrations have been associated with improved clinical responses, this formulation has been a welcome addition to available treatment options. However, higher serum and tissue levels are likely to reveal previously undescribed toxicity as adverse events attributed to “off-target” effects are observed.

Methods
We prospectively identified two patients with new onset hypertension, hypokalemia, and alkalosis after starting posaconazole tablets. Patient vital signs and laboratory values were within normal limits prior to starting posaconazole; however, following over 30 days of therapy both patients became newly hypertensive (mean systolic BP increase 59 mmHg). Serum posaconazole levels were 4.3–4.6 μg/ml. Complete suppression of renin and aldosterone, with increased 11-deoxycortisol, estradiol levels, and cortisol/cortisone ratios were observed in both patients. The TTKG in both patients was inappropriately elevated.

Results
Posaconazole-induced disruption of the steroid biosynthesis pathway in patients has not previously been described, but has been suggested by in vitro studies. Our patients’ laboratory results show clinically significant inhibition of 11β-hydroxysteroid dehydrogenase enzyme type 2 isoform (11β-HSD2) as evidenced by: the elevated 11-deoxycortisol (with subsequent suppression of renin and aldosterone), the highly elevated cortisol/cortisone ratio, and the inappropriately elevated TTKG in the setting of hypokalemia. The normal deoxycorticosterone confirms normal function of 11β-hydroxylase and the observed effects in our patients are thus downstream from this enzyme.

Conclusion
Our findings support in vitro predictions and highlight the clinical sequelae of posaconazole-mediated inhibition of 11β-HSD2. Additional studies are necessary to determine the frequency of posaconazole induced apparent mineralocorticoid excess syndrome and whether other azole antifungals can be associated with this phenomenon.

Disclosures
All authors: No reported disclosures.
Presentation and Outcome of Cryptococcal Infection Varies by Predisposing Illness
Authors: Raval Krunal , Powderly William , Spec Andrej 
Published: October 2017

Abstract

Background
Better treatment for HIV has led to the changing epidemiology of cryptococcosis. Important differences in outcomes have recently been demonstrated based on immune status. In this study, we describe the differences in presentation and outcome of cryptococcal infection by immune status in the post-HAART era.

Methods
We conducted a retrospective cohort study of patients diagnosed with cryptococcosis from 2002 through 2014 at our institution. Data included demographics, clinical features, diagnostics, and outcomes. Comparisons were made with χ 2 and one-way ANOVA. Survival analysis was performed with Cox regression with survival censored at 90 days.

Results
We enrolled 243 patients with cryptococcosis: 91 (37.4%) with HIV, 24 (9%) with prior organ transplantation, and 128 (52.6%) with non-HIV non-transplant (NHNT). Age analysis showed HIV patients were younger (40 years) than transplant (53 years) and NHNT (60 years) (P &lt; 0.001). Fevers and headache were more common in HIV (71 and 52%, P = 0.001) than in transplant (33 and 25%, P 0.001) and NHNT (51 and 39%, P 0.001), respectively. Meningitis (71%) was more common in HIV+ than in transplant recipients (45%) or NHNT (43%, P &lt; 0.001). NHNT (37.5%) and transplant (45.8%) had more pulmonary cryptococcosis than HIV (10%, P &lt; 0.001). Patients with NHNT had a higher risk of mortality (HR 2.642, 95% CI 1.481–4.713) as compared with HIV+. However, transplant recipients with cryptococcosis had risk of 90-day mortality (HR 0.99, 95% CI 0.33–2.99) similar to HIV+ patients.

Conclusion
Cryptococcosis in HIV+ and transplant recipients was less common than in NHNT in our institution and the presentation was different, with meningitis being less prominent. Cryptococcosis in NHNT was associated with higher risk of death than HIV+ patients or transplant recipients. NHNT patients comprise an important group that requires a high degree of clinical suspicion.
Survival curve of 243 patients with cryptococcosis by immune status: blue (NHNT), green (HIV), and red (any transplant). Patients in non-HIV non-transplant cohort had a higher mortality than those with HIV or transplant. Vertical dashes represent censored data (P &lt; .001).

Disclosures
A. Spec, Astellas Pharma US, Inc.: Grant Investigator, Research grant
Erythema Sweetobullosum a Rare Presentation of Coccidioidomycosis
Authors: Heidari Arash , Abukamleh Hisham , Petersen Greti 
Published: October 2017

Abstract

Background
Erythema nodosum (EN) and erythema multiforme (EM) are known reactive cutaneous manifestations of acute infection with coccidioidomycosis. In endemic area, these findings could be diagnostic in the presence of proper clinical presentation. In our experience at Kern Medical similar to our colleagues in Arizona we have observed unique form of cutaneous manifestation of acute coccidioidiomycosis with blisters. This form of skin eruption was given different names such as toxic erythema in 1940 and recently sweet syndrome in 2005. The term erythema sweetobullosum (ESB) was suggested first by David J. Elbaum in 1998 in San Joaquin Valley California in a nine case series. This study showed in contrast to sweet syndrome in ESB histology appears to change based on when the patient is seen. Early on ESB shows lymphocytic dominance, later will be neutrophil rich and eventually histiocytic phase and even granulomatous.

Methods
Retrospective chart review.

Results
Six cases are identified. Upon presentation they were between 27 and 47 years old half male and other half female. In all cases, ESB lesions were present as multiple tense erythematous plaques base with central crusting and surrounding cluster of vesicular formation. ESB lesions were located on bilateral upper and lower arms in all cases (Figures 1–3). IgM immunodiffusion serology was positive in all cases. Chest X-ray was positive for infiltration or nodule or cavity in five cases. Eosinophilia was present in four cases (800–1600). All cases had EM and two cases had EN present. Histopathology in one case described as subepidermal vesicular dermatitis with lymphocytes and histocytes. No evidence of dissemination was found in all six cases. One case lost follow-up but rest had significant clinical, radiological and serological response to fluconazole therapy with complete resolution of all skin manifestations.

Conclusion
We are describing six cases of acute pulmonary coccidioidomycosis with unique reactive skin manifestation described as erythema sweetobullosum. The acknowledgment of skin findings assists in prompt clinical suspicious to make diagnosis and initiate treatment.

Disclosures
All authors: No reported disclosures.
Disseminated Coccidioidomycosis Among Children in Central California: A Retrospective Review
Authors: Naeem Fouzia , Mhaissen Mohammad Nael , McCarty James , Rongkavilit Chokechai 
Published: October 2017

Abstract

Background
The burden of coccidioidomycosis in central California is significant among children. Yet, the literature on such infection is limited, particularly on disseminated coccidioidomycosis (DC) in children.

Objectives
Review the natural history, treatment and outcomes of DC in a tertiary children’s hospital.

Methods
Retrospective review of patients ≤21 years old with DC seen at our facility during 1/1/07–12/31/16.

Results
Eighty cases were identified. Median age was 8.5 years (IQR 4.3–14.6); majority was hispanic (66%) and without comorbid conditions (85%). Pulmonary disease with other organ involvement occurred in 69%; 19% had meningitis. Overall, 82% had resolved and/or stable disease (RS), whereas 14% experienced relapse and/or progressive disease (RP). Meningitis more commonly seen in older age group (14.3 vs. 6.9 years, P = 0.04) and had low eosinophil’s (0.8 vs. 2.1%, P &lt; 0.01). More organ involvement (64% vs. 35%, P = 0.03) and RP disease (22% vs. 5%, P = 0.04) commonly seen in children 10 years or older. Non-Hispanics also found to be older than Hispanics (12.2 vs. 7.4 years, P &lt; .01); received multiple drug therapy (48% vs. 18%, P = 0.02). Although not significant, Non-Hispanics were more likely to have meningitis (30% vs. 13%, P = 0.07), coccidioidal complement fixation (CF) titers ≥ 32 (92% vs. 73%, P = 0.07), and RP disease (24% vs. 7%, P = 0.06) than Hispanics. No significant association was found between gender and age, CF titers, and/or outcomes. Higher CF titers were seen with &gt;1 organ involvement (1:256 vs. 1;64, P &lt; 0.01) and more antifungal therapy (1:256 vs. 1:32, P &lt; 0.01). Coccidioides EIA antibody was positive in 50% of cases and 48% with negative/indeterminate results were positive by Immunodiffusion. On multivariate analysis, age remained independently associated with RP (OR = 1.2, 95% CI 1.0–1.5, P = 0.02); age (OR = 1.1, 95% CI 1.0–1.3, P = 0.01) and more antifungal therapy (OR = 3.7, 95% CI 1.4–9.5, P &lt; 0.01) with non-Hispanics.

Conclusion
To our knowledge this is the largest series for pediatric DC. We identify older age group, non-Hispanics and higher CF titers as potential risk factors for DC, which require early intervention. Prospective studies are needed to identify predictors for adverse outcomes in pediatric DC.

Disclosures
All authors: No reported disclosures.
Real-World Use – Isavuconazole at a Large Academic Medical Center
Authors: Hassouna HabiBA , Brizendine Kyle , Athans Vasilios 
Published: October 2017

Abstract

Background
Invasive fungal infections cause significant mortality and morbidity. Isavuconazole (ISV) is a new triazole approved for treatment of mucormycosis and aspergillosis. Data on its effectiveness outside clinical trials and in patients receiving prior triazole prophylaxis are lacking.

Methods
We conducted a retrospective cohort study on all patients at the Cleveland Clinic 6/1/2015–1/31/2017 who received ISV to determine 6-week response in a population with varying underlying diseases, and previous triazole prophylaxis or treatment. Descriptive statistics and univariate associations were calculated.

Results
Thirty-three patients were identified including organ transplant recipients (5), hematopoietic cell transplant recipients (7), and acute leukemia (18). Twenty-five had lung involvement while 13 had rhino-orbital-cerebral disease. In 13 cases, a fungal pathogen was identified: Mucorales (7) and Aspergillus (6). Fifteen received triazole prophylaxis prior to initiating ISV. Twenty-four received antifungal therapy immediately prior to switching to ISV: amphotericin B (1), fluconazole (1), voriconazole (16), posaconazole (4), and micafungin (2). Switching was often to broaden empiric coverage (18). Six-week response according to subgroups is presented in Figure 1 patients had therapeutic drug monitoring (TDM). Median level (IQR) was 6.75 (5.6–7.0) g/ml. Patients given ISV following triazole prophylaxis, those undergoing TDM, and those with an identified fungal pathogen had increased odds of complete or partial response, but this did not reach statistical significance (Figure 2). At 6 weeks mortality was 36%; complete or partial response observed in 45%. No ISV-related adverse effects reported.

Conclusion
To our knowledge, this is the first study to assess a real-world setting and a heterogeneous population with previous triazole prophylaxis or treatment. Our 6-week response (45%) compares favorably to published trials (35% Aspergillus; 11% Mucorales). Mortality in our study (36%) is similarly comparable to trial results (19% Aspergillus; 35% Mucorales). No major safety signal was observed. Larger cohorts are needed to describe additional real-world ISV use and determine associations with patient outcomes.

Disclosures
All authors No reported disclosures.
Epidemiology and Clinical Features of Invasive Fungal Disease in a US Healthcare Network
Authors: Webb Brandon , Ferraro Jeffrey , Rea Susan , Kammerer Jennifer , Kaufusi Stephanie , Goodman Bruce , Martin Greta , Spalding James 
Published: October 2017

Abstract

Background
A better understanding of the epidemiology and clinical features of invasive fungal disease (IFD) is integral to improving outcomes. Here we aimed to describe the incidence, clinical features and outcomes of IFD in a large US healthcare network.

Methods
We developed a novel method of IFD cohort discovery to query all available records in the Intermountain Healthcare electronic data warehouse from 2006 to 2015 for clinical data associated with IFD (Figure 1). Resulting data were overlaid in 124 different combinations to identify high-probability IFD cases. The cohort was manually reviewed and exclusions applied. EORTC/MSG definitions were adapted to categorize IFD in a broad patient population. Linear regression was used to model variation in incidence over time.

Results
3,391 IFD episodes occurred in 3,171 patients. Mean incidence was 27.4 cases/100,000 patients per year (Figure 2). Estimated mean annual increase was 0.24 cases/100,000 patients (r2 = 0.09, P = 0.21). Candidiasis was most common (56%). Dimorphic fungi, primarily Coccidioides, comprised 24%, followed by aspergillosis (9%). Mean age was 50 years; pediatric cases accounted for 13%. 19.2% of patients had an active malignancy or primary immunodeficiency, 6.9% were transplant recipients, and 27.5% were on immunosuppression. Lymphopenia preceded IFD in 24.4% of patients. Hospital admission occurred in 75%; median length of stay was 12 days. All-cause mortality was 17% at 42 days and 28.6% at 1 year. 42-day mortality was highest in aspergillosis (27.5%), 20.5% for Candida, and lowest for dimorphic fungi (7.5%).

Conclusion
In this population, IFD was not uncommon, affected a broad spectrum of patients and had high observed mortality.

Disclosures
B. Webb, Astellas Pharma Global Development, Inc.: Grant Investigator, Research grant. J. Ferraro, Astellas Pharma Global Development, Inc.: Grant Investigator, Research support. S. Rea, Astellas Pharma Global Development, Inc.: Grant Investigator, Research support. J. Kammerer, Astellas Pharma Global Development, Inc..: Employee, Salary. S. Kaufusi, Astellas Pharma Global Development, Inc.: Grant Investigator, Research support. B. Goodman, Astellas Pharma Global Development, Inc.: Grant Investigator, Research support. G. Martin, Astellas Pharma Global Development, Inc.: Grant Investigator, Research support. J. Spalding, Astellas Pharma Global Development, Inc.: Employee, Salary