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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.

The Accelerate Pheno and BacT/Alert Virtuo systems may improve bacteremia management. Here, we evaluated the impact of both devices on outcomes in patients with sepsis and concurrent Gram-negative bacteremia. This quasiexperimental study included a retrospective preimplementation and a prospective postimplementation group. Patients ≥18 years old with Gram-negative bacteremia were included. Patients with neutropenia, pregnant patients, those who were transferred from an outside hospital with active bloodstream infections, and those with polymicrobial bacteremia were excluded. Blood culture incubation in the BacT/Alert 3D device and microdilution antimicrobial susceptibility testing from culture plate growth were used prior to implementation of the BacT/Alert Virtuo and Accelerate Pheno systems. Matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) identification directly from blood culture was used pre- and postimplementation. Time to Gram stain results, identification, susceptibility reporting, initiation of narrow-spectrum Gram-negative therapy at 72 h, 30-day inpatient mortality, sepsis resolution, and length of hospital stay were evaluated. A total of 116 patients were included (63 preimplementation, 53 postimplementation). Median times to Gram stain and susceptibility results were significantly shorter postimplementation (P

Case We describe a case of biopsy-proven blastomycosis in a patient residing in Upstate New York with osseous and skin lesions and no pulmonary or constitutional symptoms. The patient had a rapid resolution of symptoms after the initiation of antifungal treatment, followed by curettage and cementation of her distal femoral lesion. Conclusions Orthopaedic surgeons should be aware of the presence of blastomycosis in nonendemic areas, especially since bone involvement may be the predominant manifestation. Tissue should be submitted for both histologic and microbiologic analysis. Antifungal therapy and surgical management if needed can result in a good outcome.

Background The Centers for Disease Control and Prevention and New York State Department of Health recently identified the Capital District of New York (CDNY) as an emerging endemic area for blastomycosis. However, no clinical or epidemiological description of blastomycosis in the CDNY has been published. Methods We performed a retrospective analysis of blastomycosis cases at Albany Medical Center (AMC) and Albany Stratton Veterans Affairs Medical Center (VAMC) from January 1, 2000, through June 1, 2019. Patients were identified via an institution-approved informatics system at the hospital's microbiology laboratory. Results We identified 20 patients diagnosed with blastomycosis over the past 2 decades. There was a nearly 9-fold increase in the annual number of cases in 2016–2019 compared with 2000–2015. The majority of patients resided in the CDNY (90%), and 65% lived within the Mohawk River valley. Most cases (85%) were assumed to be malignancies or non-mycotic infections prior to diagnosis, with median time between presentation and diagnosis of 53 days. Conclusions Our data support recent reports that blastomycosis is an emerging disease in the CDNY. Most patients were misdiagnosed as malignancy or non-mycotic infection, which led to treatment delays.

Combination therapy with vancomycin and piperacillin/tazobactam (TZP) has been associated with increased risk of acute kidney injury (AKI) compared with monotherapy with either agent. This retrospective, matched cohort study was conducted to assess the comparative incidence of AKI due to combination therapy in patients receiving vancomycin and TZP in combination or as monotherapy. Patients aged ≥18 years admitted to Albany Medical Center (Albany, NY) between September 2013 and August 2014 who had received therapy for at least two consecutive days were included. Patients who were pregnant, neutropenic, had AKI on admission or with cystic fibrosis were excluded. Patients were matched on baseline risk of AKI. The main outcome of interest was AKI, defined as an increase in serum creatinine of ≥0.3 mg/L or ≥50% within 48 h. Secondary outcomes evaluated were length of hospital and ICU stay and inpatient mortality associated with AKI. The risk of AKI was 7.0%, 8.5% and 26.8% in the vancomycin monotherapy, TZP monotherapy and combination groups, respectively (P0.001). In the multivariate analysis, combination therapy was independently associated with an increased odds of AKI (adjusted odds ratio = 4.406, 95% confidence interval 1.472-13.188) compared with vancomycin monotherapy. The excess risk of combination therapy was 11.3%. In this matched cohort study, there was an increased incidence of AKI in patients receiving vancomycin and TZP combination therapy. Further research is needed to determine the individual strategies to best prevent inpatient AKI in patients receiving this combination therapy.

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

Purpose Antimicrobial stewardship programs (ASPs) can be aided by using rapid diagnostics (RDT). However, there are limited data evaluating the impact of ASPs and RDT on sepsis outcomes in the setting of the new Sepsis-3 guidelines. This study evaluates the impact of a low-resource method for ASPs with RDT on sepsis outcomes. Methods This was a prospective, quasi-experimental study with a retrospective double pretest. Patients ≥ 18 years old with sepsis and concurrent bacteremia or fungemia were included; patients who were pregnant, had polymicrobial septicemia or who were transferred from an outside hospital were excluded. In the first pretest (O1), polymerase chain reaction was used to identify Staphylococcal species from positive blood cultures, and traditional laboratory techniques were used to identify other species. Matrix-assisted laser desorption ionization time-of-flight mass spectroscopy and FilmArray were implemented in the second pretest (O2), and twice daily blood culture review was implemented in the posttest (O3). Results A total of 394 patients (157 in O1, 176 in O2, 61 in O3) were enrolled. Clinical response was 73.2%, 83.5%, and 88.5% in O1, O2, and O3, respectively, p = 0.013. By Cox regression, the O3 was associated with improved time to clinical response (hazard ratio, 1.388; 95% confidence interval, 1.004-1.919) as compared with O1. Mortality, hospital length of stay, and intensive care unit length of stay were unchanged between groups. Conclusion Twice-daily blood culture review may be useful for implementing rapid diagnostics within low-resource ASPs. Further research is needed to identify the optimal method of blood culture follow-up within low-resource settings.

Objectives To characterize the number of granulocytes needed to count on peripheral smear to identify diagnostic anaplasmosis morulae. Methods Retrospective case study where the peripheral smears of 14 confirmed cases of anaplasmosis were examined. The granulocytes were counted up to 100 and 200 until a morula was identified. The mean counts of three pathologists were calculated to determine the minimum number of granulocytes needed to count for identifying diagnostic morulae. Results Morulae were identified before a count of 100 granulocytes in 11 (78.6%) cases and between 100 and 200 granulocytes in 3 (21.4%) cases. All 14 (100%) cases had morulae identified before counting 200 granulocytes. Conclusions Peripheral smears are a useful, cost-effective, and time-effective tool for diagnosing anaplasmosis. In positive cases, diagnostic morulae can be identified with a count of 200 granulocytes.

To report use of intravenous foscarnet or cidofovir for the treatment of refractory acute retinal necrosis (ARN).Retrospective chart review.Four immunocompetent men aged 45-90 years presented with ARN from 2008-2014. One patient with two prior episodes of herpes simplex virus (HSV) ARN developed ARN after 6 years of antiviral prophylaxis. His condition worsened on acyclovir followed by intravenous foscarnet but responded to intravenous cidofovir (final VA in involved eye 20/20). Another patient with HSV ARN had received prolonged acyclovir prophylaxis for HSV keratitis; ARN improved after switching from acyclovir to intravenous foscarnet (final VA 20/125). Two patients with varicella zoster virus (VZV) ARN initially responded to acyclovir but developed fellow eye involvement 2-8 weeks later that worsened on acyclovir but responded to intravenous foscarnet (fellow eye final VA 20/20, 20/40).Cases of HSV or VZV ARN that worsen despite intravenous acyclovir treatment may respond to intravenous foscarnet or cidofovir.

Background Blastomycosis is a commonly misdiagnosed infection caused by Blastomyces spp. It is not reportable in New York State (NYS), but where reportable, yearly incidence is 1–2/100,000 persons. In October 2017, a physician notified the NYS Department of Health (NYSDOH) of six blastomycosis cases seen during April 2016–July 2017 in the nonendemic eastern upstate area known as the Capital District (CD). NYSDOH investigated to determine the possibility of locally acquired blastomycosis. Methods NYS hospital blastomycosis discharge codes from the January 2007–December 2016 Statewide Planning and Research Cooperative System dataset were reviewed. To better understand illness in the area of highest incidence, NYSDOH contacted CD physicians to identify patients diagnosed with blastomycosis during April 2016–February 2018. Chart reviews and interviews were conducted to obtain travel and disease progression details. Results During 2007–2016, there were 279 blastomycosis diagnoses in NYS. Mean annual blastomycosis diagnoses during 2007–2015 was 24 (incidence: 0.1/100,000 persons); in 2016, there were 59 blastomycosis diagnoses (incidence: 0.3/100,000 persons). A CD county had the highest state incidence, with a rate increase from 2.0/100,000 persons during 2007–2015 to 4.1/100,000 persons during 2016. CD physicians provided contact and clinical information for the six initially-identified patients and two additional patients seen during April 2016–February 2018. All experienced delays in diagnosis, seven lacked travel history, two had cutaneous blastomycosis, three had pulmonary blastomycosis, and three had disseminated blastomycosis. One died from blastomycosis and another required long-term ventilator support. Seven cases were identified by culture or histopathology; the diagnostic method for one was unknown. Conclusion One CD county had blastomycosis rates similar to known endemic areas; patients lacked travel history to endemic areas, indicating locally acquired blastomycosis might have occurred. To improve prompt diagnosis, NYS clinicians and laboratorians should consider blastomycosis in patients with pneumonia, even without travel history to endemic areas. Further evaluation is needed to determine whether the endemic area of NYS has expanded. Disclosures All authors: No reported disclosures.

Pasteurella multocida is a common cause of soft tissue infections in humans and usually results from a bite by a domestic or wild animal. Pasteurella supraglottitis is rare and likely results from a non-bite animal exposure. We report a case of P. multocida supraglottitis resulting in bacteremia and seeding of a vascular homograft resulting in pseudoaneurysm formation. After surgical repair of the graft and 6 weeks of postoperative antibiotic therapy, the patient resumed normal activities and has continued to do well after 1 year of follow-up. This case illustrates the potential for P. multocida to cause non-bite–associated infections. This is the first report of this zoonotic infection involving a vascular homograft.

Purpose To report successful treatment of exogenous Fusarium and Aspergillus endophthalmitis with new antifungal agents. Design Interventional case report. Methods Treatment of two cases is reviewed. Results A 64-year-old man developed post-cataract Fusarium moniliforme endophthalmitis. Infection persisted despite removal of the intraocular lens, three vitrectomies, and five intravitreal injections of amphotericin. Inflammation resolved and vision improved from 20/80 to 20/40 on 6 months of oral voriconazole. A 55-year-old man developed post-cataract intraocular inflammation. After three vitrectomies and removal of the intraocular lens, Aspergillus fumigatus endophthalmitis was diagnosed. Intravitreal amphotericin and systemic voriconazole were given, but one week later there were early signs of recurrence. Intravenous caspofungin was added and the eye improved. Caspofungin was continued for 6 weeks and voriconazole for 6 months. Vision improved from counting fingers to 20/80 at 6 months and 20/25 at 23 months. Conclusion Voriconazole is a promising new therapy for Fusarium and Aspergillus endophthalmitis. Caspofungin may act synergistically with voriconazole in treating Aspergillus endophthalmitis.

Diseases 10 1.6 Current Approach to Diagnosis of Infections 11 1.7 Infectious Diseases: Nanobiosensing Interface 121.7.1 Photonic Biosensing: Semiconductors 14 1.7.2 Quantum Dot Semiconductors and Infectious Diseases Biosensing 151.7.2.1 Quantum Dots and Virus Detection 17 1.7.2.2 Quantum Dot Biosensing and Human Immunodeciency Virus..... 17 1.7.2.3 Quantum Dot Biosensing and Respiratory Syncytial Virus 18 1.7.2.4 Quantum Dot Biosensing and Inuenza Virus 19 1.7.2.5 Quantum Dot Biosensing and Hepatitis Viruses 20 1.7.2.6 Quantum Dot Biosensing and Other Viruses 201.7.3 Quantum Dots, Bacteria, and Bacterial Toxin Detection 21 1.7.3.1 Quantum Dot Biosensing and Bacteria: General Principles 21 1.7.3.2 Quantum Dot Biosensing and Biolms 23 1.7.3.3 Quantum Dot Biosensing and Food-Borne Bacteria 24 1.7.3.4 Quantum Dot Biosensing and Syphilis 25 1.7.3.5 Quantum Dot Biosensing and Mycobacteria 25 1.7.3.6 Quantum Dot Biosensing and Bacterial Toxins 261.7.4 Quantum Dot Biosensing and Fungi 27 1.7.5 Quantum Dot Biosensing and Parasites 28 1.7.6 Quantum Dot Biosensing: Conclusions 291.8 Plasmonic Nanobiosensing: Emphasis on Infectious Diseases 30 1.8.1 Plasmonics: Basic Principles 30 1.8.2 Surface Plasmon Resonance Biosensing Scheme 1: Detection of LightScattering 31 1.8.3 Surface Plasmon Resonance Biosensing Scheme 2: Colorimetric Detection ... 32 1.8.4 Surface Plasmon Resonance Biosensing Scheme 3: Surface PlasmonWave-Based Detection 34 1.8.5 Surface Plasmon Resonance Biosensing Scheme 4: Surface-EnhancedRaman Scattering-Based Detection 36 1.8.6 Plasmonic Nanobiosensing: Conclusions 37It has long been an axiom of mine that the little things are innitely the most important.

Background Blood cultures (BC) are the diagnostic gold standard for candidemia, but sensitivity is Methods Candidemic adults were identified at 14 centers by diagnostic BC (dBC). Follow-up blood samples were collected from all patients (pts) for testing by T2 and companion BC (cBC). T2 was run-in batch at a central lab; results are reported qualitatively for three groups of spp. (Candida albicans/C. tropicalis (CA/CT), C. glabrata/C. krusei (CG/CK), or C. parapsilosis (CP)). T2 and cBC were defined as positive (+) if they detected a sp. identified in dBC. Results 152 patients were enrolled (median age: 54 yrs (18–93); 54% (82) men). Candidemia risk factors included indwelling catheters (82%, 125), abdominal surgery (24%, 36), transplant (22%, 33), cancer (22%, 33), hemodialysis (17%, 26), neutropenia (10%, 15). Mean times to Candida detection/spp. identification by dBC were 47/133 hours (2/5.5 d). dBC revealed CA (30%, 46), CG (29%, 45), CP (28%, 43), CT (11%, 17) and CK (3%, 4). Mean time to collection of T2/cBC was 62 hours (2.6 d). 74% (112) of patients received antifungal (AF) therapy prior to T2/cBC (mean: 55 hours (2.3 d)). Overall, T2 results were more likely than cBC to be + (P Conclusion T2 was sensitive for diagnosing candidemia at the time of + cBC, and it was significantly more like to be + than cBC among AF-treated patients. T2 is an important advance in the diagnosis of candidemia, which is likely to be particularly useful in patients receiving prophylactic, pre-emptive or empiric AF therapy. Disclosure D. P. Kontoyiannis, Pfizer: Research Contractor, Research support and Speaker honorarium; Astellas: Research Contractor, Research support and Speaker honorarium; Merck: Honorarium, Speaker honorarium; Cidara: Honorarium, Speaker honorarium; Amplyx: Honorarium, Speaker honorarium; F2G: Honorarium, Speaker honorarium; L. Ostrosky-Zeichner, Astellas: Consultant and Grant Investigator, Consulting fee and Research grant; Merck: Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium; Pfizer: Grant Investigator and Speaker’s Bureau, Grant recipient and Speaker honorarium; Scynexis: Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient; Cidara: Grant Investigator and Scientific Advisor, Consulting fee and Research grant; S. Apewokin, T2 biosystems: Investigator, Research support; Astellas: Scientific Advisor, Consulting fee

Oculoglandular syndrome and swelling of the parotid gland are unusual manifestations of cat-scratch disease. Although exposure to cats is considered an important part of the patient history, an actual cat scratch is not required to establish the diagnosis. Oral fluoroquinolones show promise in the treatment of the infection.

Six years after kidney-pancreas transplant, a 47-year-old white man developed multiple subcutaneous and tenosynovial nodules of hands and wrists, limiting mobility. Biopsy of multiple nodules showed fibrosing, sarcoidal granulomas, some of which contained pigmented material. Microbiology, immunohistochemistry, scanning electron microscopy with backscattered electron imaging and energy dispersive X-ray analysis and polymerase chain reaction assays failed to show any infectious agents or foreign material. There was no historical, clinical or laboratory evidence of systemic sarcoidosis. It is not known whether the donor had sarcoidosis. Despite empiric antimycobacterial therapy and ongoing immunosuppressive therapy (corticosteroids, mycophenolate, cyclosporine), the man has progressively developed more nodules, limiting hand function. Sarcoidosis occurring in non-donor tisssue post-transplantation is an exceedingly rare complication of transplantation. We discuss this case and review the literature on sarcoidal tenosynovitis and sarcoidosis occurring post-transplantation.

Dengue is the most important arthropod-borne viral disease, and it is a major public health problem in subtropical and tropical regions. The virus is transmitted to humans by the bite of infected female mosquitoes of the genus Aedes . The global resurgence of dengue is thought to be due to failure to control the Aedes populations, uncontrolled urbanization, population growth, climate change, and increased airplane travel. In this paper we describe the methods used to detect dengue virus infection in a patient who presented to a hospital in New York State. The patient was a 21-year-old female who had recently traveled from Thailand. Serologic testing, viral culture, and molecular methods, including reverse transcription-PCR (RT-PCR) and real-time RT-PCR, were tools used for diagnosis. Enzyme-linked immunosorbent assay and immunofluorescence assay of serum specimens indicated flavivirus infection. Conventional RT-PCR and sequencing, in addition to real-time RT-PCR of serum samples and nasal and throat swabs from the patient, confirmed dengue virus 1 (DEN-1) infection. A cytopathic effect was observed in virus cultures of the acute-phase serum samples and nasal swabs. DEN-1 was subsequently detected by RT-PCR from cell culture supernatants and by direct fluorescent-antibody assay staining of the cell culture monolayer. We show that a multipronged approach to the laboratory diagnosis of dengue infections can be used to successfully diagnose and differentiate the dengue virus serotypes. In addition, we show that both dengue viral RNA and infectious virus can be detected in respiratory specimens from an infected patient.

We identified an emerging infectious disease of the genitoperineum caused by community associated, methicillin resistant Staphylococcus aureus.We report our experience with severe genital infections caused by community associated, methicillin resistant S. aureus occurring in 3 individuals who lacked any of the risk factors associated with traditional methicillin resistant S. aureus infection. Two cases were limited to scrotal abscesses that required only incision and drainage plus antimicrobial therapy. To our knowledge the third case represents the first and only reported case to date of Fournier's gangrene caused by community associated, methicillin resistant S. aureus.The prevalence of community associated, methicillin resistant S. aureus complicated skin and skin structure infections is increasing throughout the United States and other countries. Community associated, methicillin resistant S. aureus contains unique virulence factors but retains sensitivity to various nonbeta-lactam antibiotics. Historical risk factors associated with methicillin resistant S. aureus appear not to apply to infections associated with community associated, methicillin resistant S. aureus. Infections due to the latter cause have been identified in healthy individuals of all ages, races and ethnicities. Surgical and antimicrobial approaches to management are presented.Community associated, methicillin resistant S. aureus infections of the genitoperineum are likely to increase in incidence, necessitating heightened awareness on the part of the urologist.

Klebsiella pneumoniae carbapenemases (KPCs) have previously been identified in distinct geographic locations. We report the spread of KPC-2 to upstate New York. Our intention is to alert clinicians to problems encountered in identifying KPC-containing isolates. Possible errors as a result of inferring susceptibility of untested carbapenems from the routine antibiogram using agar-based methodology or microdilution testing are discussed.

BACKGROUND Polymerase chain reaction (PCR) is becoming more common in diagnostic laboratories. In some instances, its value has been established. In other cases, assays exist, but their beneficial use has not been determined. This article summarizes findings from 3485 patients who underwent testing over a 6-year period in our laboratory. METHODS A panel of PCR assays was used for the detection of a range of viruses associated with central nervous system (CNS) infections. PCR results were analyzed in conjunction with information about patient age and sex, the time between onset and specimen collection, and other variables. Medical chart review was conducted for 280 patients to gain diagnostic and epidemiologic insight with regard to cases of unresolved encephalitis. RESULTS A total of 498 PCR-positive samples (14.3%) were detected. Enteroviruses accounted for the largest number (360 [72.3%]) of positive PCR results, followed by herpes simplex virus (76 [15.3%]), varicella-zoster virus (29 [5.82%]), and West Nile virus (WNV) (18 [3.61%]). Of 360 patients who tested positive for enterovirus, only 46 met the Centers for Disease Control and Prevention's encephalitis definition. It resulted in the greatest decrease (87.2%) in positive PCR results. Overall, the PCR positivity rate for specimens collected within 5 days after illness onset was 17.2%, compared with 8.6% for specimens collected > or =6 days after onset. CONCLUSIONS The value of PCR in the diagnosis of viral infections has been established. PCR is of lower value in the detection of WNV in CNS, compared with serological testing, but is of greater value in the detection of other arboviruses, particularly viruses in the California serogroup. Medical chart reviews indicated that apparent CNS infection resolves in approximately 50% of cases.

A 42-year-old woman developed eosinophilic meningitis after exposure to cats. Brain magnetic resonance imaging showed numerous areas of abnormal enhancement. A lung nodule contained eosinophilic infiltrates. Toxocara antibodies were present in serum and cerebrospinal fluid. Meningoencephalit

Background Hospitalized patients are at increased risk for candidemia and invasive candidiasis (C/IC). Improved therapeutic regimens with enhanced clinical and pharmacoeconomic outcomes utilizing existing antifungal agents are still needed. Methods An open-label, non-comparative study evaluated an intravenous (IV) to oral step-down strategy. Patients with C/IC were treated with IV anidulafungin and after 5 days of IV therapy had the option to step-down to oral azole therapy (fluconazole or voriconazole) if they met prespecified criteria. The primary endpoint was the global response rate (clinical + microbiological) at end of treatment (EOT) in the modified intent-to-treat (MITT) population (at least one dose of anidulafungin plus positive Candida within 96 hours of study entry). Secondary endpoints included efficacy at other time points and in predefined patient subpopulations. Patients who stepped down early (≤ 7 days’ anidulafungin) were identified as the "early switch" subpopulation. Results In total, 282 patients were enrolled, of whom 250 were included in the MITT population. The MITT global response rate at EOT was 83.7% (95% confidence interval, 78.7–88.8). Global response rates at all time points were generally similar in the early switch subpopulation compared with the MITT population. Global response rates were also similar across multiple Candida species, including C. albicans, C. glabrata, and C. parapsilosis. The most common treatment-related adverse events were nausea and vomiting (four patients each). Conclusions A short course of IV anidulafungin, followed by early step-down to oral azole therapy, is an effective and well-tolerated approach for the treatment of C/IC. Trial registration ClinicalTrials.gov: NCT00496197

Objective. —To evaluate the safety and efficacy of p55 tumor necrosis factor receptor fusion protein, a recombinant chimeric protein of human p55 (type I) tumor necrosis factor receptor (CD120a) extracellular domain and lgG1 sequences (referred to as p55-lgG), in the treatment of patients with severe sepsis or septic shock. Design. —Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. Setting. —Forty-four community and university-affiliated hospitals in the United States and Europe. patients. —There were 498 patients enrolled in this clinical trial. Intervention. —Patients prospectively stratified within each site into refractory shock or severe sepsis groups were randomized to receive a single infusion of p55IgG, 0.083 mg/kg, 0.042 mg/kg, or 0.008 mg/kg, or placebo. Patients received standard aggressive medical/surgical care during the 28-day postinfusion period. Outcome Measure. —Twenty-eight—day all-cause mortality. Results. —The distribution of variables describing demographics, organ system dysfunction or failure, infecting microorganisms, predicted mortality, plasma interleukin 6 levels, and plasma tumor necrosis factor α (TNF-α) levels were similar among patients in the p55-lgG and placebo treatment arms. A planned interim analysis was performed after 201 patients were enrolled. Because a statistically nonsignificant trend toward increased mortality was present in patients who had received 0.008 mg/kg, this treatment arm was discontinued, and the study continued with 3 arms. Among all infused patients, there was a statistically nonsignificant trend toward reduced 28-day all-cause mortality in those who received p55-lgG compared with placebo-treated patients (5% reduction, 0.042 mg/kg vs placebo; 15% reduction, 0.083 mg/kg vs placebo;P=.30). However, in patients with severe sepsis and early septic shock (n=247), therapy with p55-lgG, 0.083 mg/kg, was associated with a 36% reduction in 28-day all-cause mortality compared with placebo (P=.07): 20 (23%) of 87 patients died among those treated with p55-lgG, 0.083 mg/kg; 30 (37%) of 82 among those treated with p55-lgG, 0.042 mg/kg; and 28 (36%) of 78 in the placebo group. A prospectively planned logistic regression analysis to assess treatment effect on 28-day all-cause mortality by means of predicted mortality and serum interleukin 6 levels as continuous covariates demonstrated a significant improvement in outcome for the patients with severe sepsis treated with p55-lgG, 0.083 mg/kg, compared with placebo (P=.01). Serious adverse events, including death and the development of new organ system dysfunction, were reported in 65% of patients infused with placebo, with no increased frequency (56%) present in the 2 p55-lgG treatment arms. There were no reports of immediate hypersensitivity reactions caused by p55-lgG. Conclusions. —In this dose-finding study, there was no decrease in mortality between placebo and p55-lgG in all infused patients. In the prospectively defined population of patients with severe sepsis who received p55-lgG, 0.083 mg/kg, there was a trend toward reduced mortality at day 28 that became significant when predicted mortality and plasma interleukin 6 levels were included in a logistic regression analysis.

A histochemical steroid hormone receptor assay was performed on a number of cases of primary recurrent and metastatic breast cancer and then these findings were correlated with more expensive biochemical assays and patients response to endocrine therapies. The histochemical procedure used ligand-conjugates composed of 17 beta-estradiol and 11 alpha-hydroxyprogesterone covalently linked to bovine serum albumin and labeled with fluorescein isothiocyanate for measuring estrogen receptor (ER) and progesterone receptor (PR) respectively. When results from the histochemical assay were compared with determinations from conventional biochemical receptor assay they correlated for ER in 92% of the 313 tumors and for PR in 86% of the 86 specimens. Various endocrine therapies performed in 40 women with Stage 4 disease were correlated with ER and PR determinations in terms of clinical response. In 80% of cases including 8 which could not be fully analyzed by biochemical methods the histochemical assay gave successful prediction of clinical response.

An intravenous glucose tolerance test (GTT) was given to 116 women--82 nondiabetic subjects (NDS) and 34 diabetes suspects--before they received Ovulen for oral contraception. Subjects were followed for 1 to 4 years during Ovulen therapy. Twenty women using an intrauterine device showed no changes in glucose tolerance. Prompt, significant decline in tolerance was noted in NDS, persisting for the duration of the study. At least one abnormal test, indicating chemical diabetes, was noted in 13 per cent of the NDS. Similarly, prompt decline in tolerance, although not statistically significant, was observed in the suspect group. Fifteen per cent of suspects had at least one abnormal test. Chemical diabetes persisted during Ovulen therapy in suspects but not in NDS. No overt diabetes occurred. Based on greater concern regarding suspects, a procedure for monitoring carbohydrate tolerance is proposed for this group.

Estrogen and progesterone receptor determinations were performed on 518 specimens at the Surgical Research Laboratory of the Maimonides Medical Center. Of these, 41% were ERP and PgRP positive; 17% were ERP positive and PgRP negative; 38% were ERP negative and PgRP negative, and 3.9% were ERP negative, PgRP positive. Sixty-two patients with advanced breast cancer were treated with either an endocrine ablative procedure or with antihormonal therapy. In the two treatment groups the overall response rate when both receptors were positive was 79%, with a higher percentage of responders in the endocrine ablative group (88% vs. 69%). In addition, a greater duration of response was achieved in those patients treated with endocrine ablation. The overall predictability of response was achieved in those patients treated with endocrine ablation. The overall predictability of response or failure to hormonal therapy is 91% if the progesterone receptor alone is utilized to select treatment and an endocrine ablative procedure is performed. The predictability of response based on the estrogen receptors presence or absence is 70%.

This report describes three patients with both multiple intestinal polyps and tumors of neural crest origin. This combination of findings may represent a new clinical syndrome. The embryologic relationships between tumors derived from endoderm and tumors derived from neurocrest are described. An inherent defect in tissue proliferation or repair is postulated to explain the abnormal growth in these two different cell lines.

The identification of steroid receptors in human breast cancer tissues has provided biochemical markers to predict hormone responsiveness. Analysis of tumors from 328 patients for the estrogen receptor protein (ERP) revealed significant levels in 225 patients (68%). Fifty-five patients with advanced disease were subjected to hormonal manipulation. Thirty patients underwent ablative surgery consisting of adrenalectomy or adrenalectomy and oophorectomy. Twenty-five patients were treated with additive therapy utilizing the new antiestrogen Tamoxifen. The ECOG criteria for an objective response were applied to all patients. Fifteen of the 24 estrogen receptor-positive patients (63%) subjected to endocrine ablation responded. Eleven of twenty (55%) ERP-positive patients responded to Tamoxifen therapy. Only one ERP-negative patient responded in the total group. Simultaneous analysis of these same specimens for the progesterone receptor protein (PgRP) revealed that 151 patients were ERP and PgRP positive (46%); 74 (23%) were ERP positive and PgRP negative; 90 (27%) were ERP and PgRP negative, and 13 (4%) were ERP negative and PgRP positive. In the two treatment groups the overall response rate when both receptors were positive was 77% with a higher percentage of responders in the endocrine ablative group (88% vs. 64%). In addition, a greater duration of response was achieved in those patients treated with endocrine ablation.

A review of the current literature on immunohistologic and histochemical methods for the detection of steroid hormone binding sites in breast cancer, reveals that many, but not all of the criteria for establishing hormone-receptor binding interactions have been met. These include tissue specificity, binding between labeled ligands and soluble receptor in vitro, correlations between histochemical and biochemical assays, as well as between histologic procedures and tumor hormone responsiveness. However, histochemical binding phenomena do not appear to follow classical receptor dogma in regard to the concentration of ligand required, or specificity of binding as determined by competitive binding assays. It is concluded that these histologic techniques may be detecting classical receptor that may be reacting differently than would be expected from biochemical analyses, Types II and III binding sites, and/or organelle and membrane-bound receptors. Certainly no current method should presently be promoted as a laboratory method for the detection of classical receptor. New immunocytologic procedures employing specific, antireceptor sera currently under development, may obviate many of the criticisms leveled against earlier methods.

The introduction of receptor protein studies as markers for hormone dependence of breast carcinomas has had a profound effect on the management of advanced disease. All breast carcinomas, regardless of stage, should have receptor binding protein studies for estrogen and progesterone by the sucrose gradient method or by the dextran-coated charcoal method as a good alternative. A simpler test is needed. In cases of primary advanced disease or in recurrent disease, receptor binding protein studies effectively identify the subgroup of hormone-dependent tumors that should be managed by surgical hormone ablation or endocrine manipulation. These tests are even more effective in identifying patients that should not receive hormone therapy and respond better to chemotherapy. In primary, potentially surgically curable disease, receptor studies may serve as a therapeutic guide to adjuvant hormone or chemotherapy. In all breast cancers, ER and PgR receptor studies should be performed and the information should be stored for possible future use. If possible, tisssue should be stored in a freezer in anticipation of future tests and for confirmation of hormone dependence in the event of recurrence.