bluuebunny/crossref_metadata_2025 huggingface dataset:
809. Empiric Antifungal Therapy Is Not Associated with Improved Survival Outcome among Intensive Care Units (ICU) Patients
Authors: Wong Lauren , Zelenkov Dimitar , Campion Maureen , Foong Kap Sum , Doron Shira , Vazquez Gabriela Andujar
Published: November 2023

Background

In recent years, ICU at Tufts Medical Center (TMC) have a higher utilization rate of antifungal agents compared to nationwide ICU data reported to the National Health and Safety Network. The role of empiric antifungal therapy in reducing ICU patient mortality remains controversial. Prudent use of antifungals is needed to mitigate the risk of further antifungal resistance development. Our study aimed to evaluate empiric antifungal use among ICU patients and its association with ICU 30-day all-cause mortality.

Methods

We conducted a retrospective study of all adult ICU patients at TMC who had received fluconazole (F) or micafungin (M) between August 2022 and February 2023. We collected demographics, comorbidities, Candida score, indication for empiric antifungal therapy, use of mechanical ventilation (MV) and broad spectrum antibiotic use. Univariable and multivariable logistic regression analyses were conducted to identify predictors associated with ICU 30-day all-cause mortality among ICU patients who received antifungal therapy.

Results

A total of 77 ICU patients received antifungal treatment, (F: 22 patients, M: 55 patients). The median treatment duration was the same for both therapies, 2 days [1-4]. Only 4 (5%) of patients had positive blood cultures for Candida sp. The median Candida score was 3 [2-4]. Antifungal therapy was initiated for suspected infection in 52 (68%) of patients per prescriber orders indications. The majority of patients were ventilated (63, 81.8%), of these, 15 (23.8%) were on extracorporeal membrane oxygenation. The 30-day all-cause mortality was 58 (75%). Multivariable logistic regression analysis showed antifungal therapy for ≥ 48 hours was not associated with improved ICU mortality (adjusted odds ratio, 0.276; 95% confidence interval, 0.31-2.44). Chronic heart failure was associated with an increased risk for ICU mortality (adjusted odds ratio, 19.91; 95% confidence interval, 1.32-299.72).

Conclusion

A high 30-day all-cause mortality among ICU patients who received empiric antifungal treatment was observed. Similar to national trends, the incidence of fungemia was low despite moderate candida scores. Empiric antifungal therapy ≥48 hours was not associated with improved mortality outcome in this population.

Disclosures

Maureen Campion, PharmD, BCIDP, Shinoigi: Speaker
812. Bacterial endosymbionts are frequently found among Mucorales clinical isolates. Should we screen for their presence in patients with Mucormycosis?
Authors: Leon Dora Edith Corzo , Harrison Jamie , Uehling Jessie , López-Jácome Luis Esaú , Borman Andy , Ballou Elizabeth
Published: November 2023

Background

Soil-associated Mucorales fungi frequently host bacterial endosymbionts that produce damaging endotoxins important for plant pathology. Our work and clinical reports suggest an important and unanticipated role for endosymbionts in human disease. The endosymbiont Mycetohabitants rhizoxinica was associated with bacteriemia in an immunocompromised individual where its host Rhizopus microsporus caused mucormycosis. Our data demonstrate the endosymbiont Ralstonia pickettii can impact virulence of its R. microsporus host. Together, these data suggest Mucorales endosymbionts can influence both fungal and bacterial infections; however, their frequency and diversity in Mucormycosis is unknown. This project investigates the frequency and diversity of bacterial endosymbionts in Mucorales clinical isolates.

Methods

Mucorales isolates from mucormycosis patients via the UK National Mycology Reference Laboratory and the Instituto Nacional de Rehabilitacion, Mexico, were identified by ITS1/2 PCR or MALDI-TOF. Fungal isolates (YPG agar, 5 days, 30 oC) were subjected to phenol/chloroform DNA extraction. Bacterial presence was assessed by 16s RNA PCR, and resulting bands identified by nanopore sequencing. In parallel, WGS of total DNA confirmed bacterial presence and identity. Bacteria were also physically isolated from homogenized fungal mycelia (nutrient broth, 80rpm, 37oC, 4 days) harvested under sterile conditions. Bacteria from supernatants (LB, Blood agar, 30 and 37 oC ± 5% CO2, 4-10 days) were identified by 16s RNA PCR and Nanopore sequencing.

Results

In total, 27 Mucorales isolates (R. arrhizus/delemar n=7; R. microsporus n=6; Lichtheimia corymbifera n=4; L. ramosa n=3; Mucor circinelloides n=4; others n=3) were evaluated for bacteria presence. 17/27 (62%) were 16s RNA positive. Culture identified 6 bacterial species (R. pickettii, Niallia circulans, Peribacillus simplex, Roseomonas mucosa, Micrococcus luteus, Staphylococcus pasteuri). Mucorales isolates originated from cutaneous 11/27 (41%); respiratory 8/27 (29%); and sinus-orbital diseases 7/27 (26%).

Conclusion

The presence of bacterial endosymbionts in clinical isolates of Mucorales is frequent, diverse and can potentially influence fungi in causing disease among individuals at risk.

Disclosures

All Authors: No reported disclosures
814. Impact of Testing Turnaround Times on Clinical Outcome in Hospitalized Patients with Histoplasmosis and Blastomycosis
Authors: Dalton Liam , Richards Blair , Miceli Marisa H
Published: November 2023

Background

Patients (pt) with histoplasmosis (histo) and blastomycosis (blasto) requiring hospitalization have unacceptably high mortality rates. In part, this is due to a delay in diagnosis. Serum (S) and urine (U) antigen (Ag) testing are often crucial for timely antifungal therapy. Clinical observations suggested delays in ordering samples to be sent to reference labs upon admission and prolonged turnaround time (TAT) for test results can lead to delays in starting therapy and poor outcomes. We sought to determine the impact of TAT for histo and blasto Ag testing on clinical outcomes of hospitalized patients (pt) at our institution.

Methods

Retrospective evaluation of all adult inpatients with histo or blasto diagnosed by positive U or S Ag tests from 1/1/15-12/31/22 was conducted. TAT from admission to result (TAT-AR) and from sample collection to result (TAT-CR) for the earliest positive test were calculated. Clinical data, including treatment & outcomes were collected. Only pt who received antifungal therapy or had a postmortem diagnosis were included. The relationship between TAT-AR and TAT-CR and outcome was evaluated.

Results

Of 39 pt (mean age 47±19 yr), 26 (67%) were men and 33 (85%) were immunocompromised: solid organ transplant recipients, 15; hematologic malignancy, 3; autoimmune/inflammatory disease on treatment, 12; others, 3. Thirty-five pt had pulmonary (8) or disseminated histo (27); 4 had disseminated blasto. Nine pt (23%) died within 4 months of diagnosis, including 8 pt with histo and 1 with blasto. Mean TAT-AR for these 9 deceased pt was 14.7± 19.5 days (d) vs 6.1±3.1 d for 30 survivors (p=.02). Mean TAT-CR for these 9 deceased pt was 5.4±1.5 d vs 3.9±1.3 d for 30 survivors (p=.003). Of the 32 pt who required IV amphotericin B (29) or died before any antifungal therapy was given (3), mean TAT-CR was 5.4±1.5 d for those who died vs 3.7±1.1 d for those who survived (p=.0013). ICU transfers, 30-d readmissions, and length of stay were not impacted by TAT-AR or TAT-CR.

Conclusion

Delays in TAT for initiating testing and obtaining results were associated with increased mortality of hospitalized pt with newly diagnosed histo or blasto. These findings highlight the importance of early testing and timely test results to guide treatment for hospitalized pt with these diseases.

Disclosures

Marisa H. Miceli, MD, Astellas: Advisor/Consultant|F2G: Grant/Research Support|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support
818. Therapeutic Drug Monitoring of Triazole Antifungals for Coccidioidal Meningitis
Authors: Fang Michelle , Torres Bianca , Kooner Lovedip , Dunn Chelsea , Redgrave Jessica , Kuran Rasha , Heidari Arash , Johnson Royce H
Published: November 2023

Background

Coccidioidal meningitis (CM) is a potentially devastating manifestation of disseminated infection caused by Coccidioides spp., generally requiring lifelong therapy with triazole antifungals (TA). Given the complexity of assessing treatment response in coccidioidomycosis, which can be impacted by host immune response, pharmacokinetics, antifungal pharmacodynamics, and medication adherence, therapeutic drug monitoring (TDM) of TA therapy, which is not currently common practice for most TA, has been proposed to improve clinical evaluation of such variables. Consistent TDM is anticipated to increase the probability of a successful CM treatment outcomes.

Methods

This is a retrospective review of patients with CM who received adjunctive TA TDM at the Valley Fever Institute at Kern Medical from November 2019 to December 2022. Approval and a waiver of consent were obtained from the Institutional Review Board. The combination of a patient and TA was considered a unique therapy regimen, with each TA course evaluated separately for patients who received multiple triazoles over the course of their CM treatment. The primary endpoint was improvement in the cerebrospinal fluid (CSF) score, which was derived from the Mycoses Study Group scoring system for meningeal disease, over the available follow-up period.Table 1.CSF Score (based on the Mycoses Study Group scoring system for meningeal disease)

Results

Twenty-seven TA regimens were found to be eligible for inclusion in this study, with fluconazole comprising the majority of these courses (52%) and the remainder divided between isavuconazole (22%), voriconazole (11%), itraconazole (7%), and posaconazole (7%). Of the serum triazole levels obtained, 34% were considered to be therapeutic, 45% were subtherapeutic, and 21% were supratherapeutic. Greater improvements were noted in CSF scores of TA regimens with the higher serum levels compared to TA regimens resulting in lower serum levels (see figure 1).

Figure 1. CSF Scores on Fluconazole: Lowest vs. Highest Quartile

CSF scores of fluconazole regimens resulting in the lowest quartile (Q1, n=4) of serum fluconazole levels over 24 months were compared to regimens resulting in the highest quartile (Q4, n=4) of serum levels. A decrease in the CSF score generally represent improvement in meningeal disease.

Conclusion

TA TDM is expected to advantage the care of patients with CM. The possible correlation between higher TA serum levels and improvements in CSF parameters shown in this study emphasizes the potential role of TDM for maximizing TA efficacy in CM, in addition to discernment of medication nonadherence or suboptimal pharmacokinetics.

Disclosures

All Authors: No reported disclosures
819. Experience with Isavuconazole Use for Treatment of Invasive Fungal Infections
Authors: Gow-Lee Vanessa , Chesdachai Supavit , Harris Courtney E , Abu Saleh Omar M
Published: November 2023

Background

The treatment of invasive fungal infections (IFI) is often complicated by drug-drug interactions, toxicities, and host comorbidities. Isavuconazole (ISA) has a favorable side effect profile and has FDA approval for invasive aspergillosis and mucormycosis, but there are fewer data on its efficacy for other microbes and non-pulmonary infections. We report our experience of ISA in IFI treatment, with a particular focus on non-pulmonary sites and other microbial etiologies.

Methods

We identified patients who received ISA as part of IFI treatment from 1/1/2015–4/1/2020 at Mayo Clinic. We categorized them by organ involvement and by pathogens, and identified patterns of ISA use and clinical outcomes.

Results

A total of 131 patients were identified. Similar to the existing literature, the majority were pulmonary infections (60%), with 12% invasive sinus infection, 12% central nervous system (CNS) infection, and 7% fungemia. Aspergillus was the most common pathogen (39%), yeast comprised 19%, dimorphic fungi 15%, Mucormycosis 12%, phaeohyphomycosis 5%, and other molds 3%.

ISA was used as secondary/salvage therapy in 89% of cases. The response rate varied by organ involvement and pathogen. ISA had complete/partial resolution or achieved stability in 57% of fungemia cases, 63% of invasive sinus infections, 64% of pulmonary infections, and 73% of CNS infections. Aspergillus species had a 67% response rate, with 72% response in yeast infections, 65% rate in dimorphic fungi, 53% for mucormycosis, and 86% in dematiaceous molds.

Conclusion

Although limited by a small sample size, the subgroup review based on organ site and microbial etiology did seem to show roughly similar results to approved uses. The CNS infections treated with ISA were particularly of interest, given the limited options available with reliable CNS penetration.

The current available literature has little to say on the efficacy of ISA in these off-label uses, with the majority being similar case series. This report highlights the importance of prospective trials comparing ISA to other antifungals in a greater variety of indications to better identify when this better-tolerated agent can be safely used.

Disclosures

Courtney E. Harris, MD, Dynamed: Advisor/Consultant
822. Is the Juice Worth the Squeeze: Ophthalmologist Examination for All Hospitalized Patients with Candidemia in a Rural Community
Authors: Kim Hyun Sue , Baffoe-Bonnie Anthony
Published: November 2023

Background

Candidemia is a common cause of bloodstream infections in hospitalized patients in the United States. Ocular manifestations of candidemia include chorioretinitis and endophthalmitis, which can lead to the loss of vision. Currently, there are opposing recommendations on whether all patients with candidemia should have a dilated ophthalmologic examination. We describe a rural patient population with candidemia who underwent an ophthalmology consultation and the associated clinical features and risk factors for an abnormal eye exam. We analyze the impact of ophthalmology consults on the treatment, management, and outcome.

Methods

We conducted a retrospective cross-sectional study of consecutive candidemia cases from 2015 to 2023. We abstracted patient demographics, clinical, and microbiologic data.

Results

We found that 218 candidemia patients with an average age of 54 years (range, 5-94) underwent an ophthalmologic evaluation. The average duration between hospital admission and consultation was 12 days. 24% of patients reported visual symptoms at the time of the consult and of those, 49% reported decreased visual acuity. Age, insurance status, and the number of days between hospital admission and consultation were strongly associated with positive findings.

Conclusion

Abnormal eye findings were not uncommon and were seen more frequently in certain demographic groups. In resource-limited settings, a more nuanced consultation strategy informed by local data may be reasonable.

Disclosures

All Authors: No reported disclosures
823. Clinical Outcomes of Coccidioidomycosis in Patients Requiring Intensive Care Unit Hospitalization
Authors: Lim James Ray M , Scott Ashley , Wig Rebecca , Tan Rachel V , Harnois Emily R , Zangeneh Tirdad , Al-Obaidi Mohanad
Published: November 2023

Background

Coccidioidomycosis is an endemic mycosis in the southwestern United States. While most infections are mild or asymptomatic, severe cases are associated with high morbidity and mortality. We aimed to evaluate the clinical outcomes of patients admitted to the intensive care unit (ICU) with proven culture-positive coccidioidomycosis.

Methods

After institutional review board approval, we retrospectively included ICU patients with positive Coccidioides spp. culture within a multi-healthcare system between 10/01/2017 – 07/01/2022. Clinical information was collected by chart review.

Results

Of the 392 hospital encounters with positive Coccidioides spp. culture, 145 patients required ICU stay. The median age was 51 (32-62), with 100 (68.9%) male, 56 (38.6%) White non-Hispanics, and 25 (17.2%) Blacks. Fifty-seven (39.3%) received azole antifungals before hospitalization. Seventy-two (49.7%) had another fungal, bacterial, or viral infection during their hospitalization, and 41 (28.3%) had extrapulmonary coccidioidomycosis. The majority, 131 (90.3%), received antifungal therapy during their hospital stay. The median hospital length of stay was 18 days (10-37). Almost half (48.3%) died during the study period, with liver cirrhosis and age ( >60 years) resulting in statistically significant mortality, 12/13 (92.3%), p-value < 0.001, and 31/43 (72.1%) p-value =0.001, respectively. Mechanical ventilation and/or intravenous vasopressor support was associated with a high risk of mortality 66/113 (58.4%, p-value=< 0.001). Failure to receive antifungal therapy before ICU admission was associated with increased mortality, 46/70 (65.7%, p-value=0.002).

Conclusion

Patients with coccidioidomycosis admitted to the ICU face an increased risk of mortality. Risk factors associated with ICU mortality include advanced age, cirrhosis, and delay in the administration of antifungal therapy. Future studies are needed to evaluate these risks further.

Disclosures

Tirdad Zangeneh, DO, AiCuris: Grant/Research Support Mohanad Al-Obaidi, MD, MPH, La Jolla Pharmaceuticals: Honoraria
825. Cryptococcosis in the Immunocompetent Patient: Incidence and Outcomes
Authors: Mani Valli , Zimilover Adam , Hsieh Ji-Cheng , Ghani Maham , Kashfi Simon , Chen Richie , Islam Iffath , Donaghy Henry
Published: November 2023

Background

Cryptococcosis is a fungal infection that can cause pulmonary, central nervous system, or disseminated disease in immunosuppressed individuals. Although pulmonary cryptococcosis is known to rarely affect immunocompetent patients, there is limited research comparing the incidence and clinical outcomes of cryptococcosis in immunocompetent versus immunocompromised patients.

Methods

A retrospective analysis was performed on patients with confirmed positive CSF PCR, CSF antigen, or serum cryptococcal antigen tests from 8 hospitals in New York from 2017-2022. Patients were classified as immunocompromised if they had HIV, an organ transplant, active cancer, or were on immunosuppressive medications at the time of diagnosis. Baseline demographic information, comorbidities, and clinical outcomes were recorded. Statistical methods performed include t-test, Chi-square, and Fisher exact test.

Results

37 cases were identified with 9 cases (24%) in immunocompetent patients. There were no significant differences in age (p=0.82), gender (p=0.61), or BMI (p=0.15) amongst immunocompetent vs immunocompromised patients. Immunocompetent patients were more likely to have diabetes compared to immunocompromised patients (44% vs 21%, p = 0.04). Immunocompetent patients presented with meningitis more frequently (78% vs 41%, p = 0.05) with decreased mortality (11% vs 18%, p = 0.04) and no significant differences in rates of fungemia (21% vs 22%, p = 0.28). The majority of immunocompetent patients were treated inpatient and discharged on fluconazole without documented relapsed infection (77%). When assessing patients before and after 3/30/2020, the midpoint of our data timeline and beginning of the COVID pandemic, the proportion of immunocompetent cases increased (12% vs 35%, p = 0.03) while the total number of cases was relatively unchanged.

Conclusion

Meningitis was a more common presentation than pulmonary disease in immunocompetent patients. Immunocompetent patients also had better outcomes with decreased mortality. Overall, the number of immunocompetent patients increased over the study period. Additional information about cryptococcosis in immunocompetent patients, as well as the role of diabetes and COVID infection as potential risk factors, warrants further study.

Disclosures

All Authors: No reported disclosures
832. Epidemiology, Clinical Characteristics, Treatment and Outcome of Mucormycosis during COVID-19 Pandemic in the VA Health System
Authors: Muthukumarasamy Nirmal , Suzuki Hiroyuki
Published: November 2023

Background

Mucormycosis is associated with high mortality rates, ranging between 40 to 90%. COVID-19 associated mucormycosis (CAM) has garnered much attention during the COVID-19 pandemic. As most of the reports of CAM are case reports, it is difficult to estimate the true incidence and characteristics of CAM compared to non-CAM cases. Our study aims to describe and compare CAM and non-CAM cases during the COVID-19 pandemic within the Veterans Health Administration (VHA) system.

Methods

A retrospective chart review was conducted of all inpatients with a diagnostic code of mucormycosis (ICD-10: B46) among VHA hospitals from 1/1/2020 to 12/31/2022. We classified CAM as mucormycosis with a preceding COVID-19 diagnosis within 3 months. Data collected include demographics, comorbidities, COVID-19 diagnosis within 3 months, type of mucormycosis, surgical treatment and 90-day mortality.

Results

During the study period, 61 patients were identified, and after a manual chart review a total of 47 patients from 29 hospitals were included in the descriptive analysis. The median age of patients was 68 years, with 46/47 (97.9%) being male. 33/46 (70.2%) were White. Most common comorbidities were diabetes mellitus (72.3%), chronic obstructive pulmonary disease (57.5%), and chronic kidney disease (40.4%). Pulmonary mucormycosis was the most common manifestation in 20 (42.6%), followed by rhino-cerebral in 15 (31.9%), cutaneous in 7 (14.9%) and musculoskeletal in 4 (8.5%) of patients.

There were 11 (23.4%) patients with CAM. Most of these cases occurred in the second half of 2021 during the Delta variant wave (8 patients), followed by 2 cases in 2022 (during the Omicron variant wave) and 1 case in 2020. More than half of patients with CAM had pulmonary disease compared with about one-third in non-CAM cases (63.6% versus 36.1%, p=0.16). CAM cases were significantly less likely to be confirmed with a biopsy (45.5% versus 80.6%, p=0.02). Mortality was higher in CAM cases (54.6% versus 30.6%, p=0.17) although the difference was not statistically significant.

Comparison of CAM and Non-CAM cases during the study period

Conclusion

CAM cases seemed to be quite different from non-CAM cases in clinical characteristics, treatment and outcome in our VHA cohort although a definitive conclusion cannot be made due to the limited number of cases.

Disclosures

All Authors: No reported disclosures
834. A Single-center Experience of Cardiovascular Histoplasmosis: An Emerging Complication of Histoplasmosis
Authors: Ordaya Eloy E , Lawrence Sarah A , Conley Elyse L , Padang Ratnasari , Enzler Mark
Published: November 2023

Background

Histoplasmosis is an endemic mycosis associated with a wide range of clinical presentations. Cardiovascular histoplasmosis (CVH) was rarely seen at our center before 2007 but has increased in frequency over the last 15 years. Herein, we describe the clinical characteristics of our recent CVH cases.

Methods

We identified all adults diagnosed with CVH at Mayo Clinic in Rochester, MN, between May 2007 and February 2023.

Results

Ten cases of CVH were identified, all of whom resided in the Midwest (Table). The majority were male, with a median age of 72 years. Five patients had prosthetic valves, two endovascular grafts, one a prosthetic valve and aortic graft, and one was a heart-kidney transplant recipient. Patients most frequently presented with prolonged night sweats, fever, and dyspnea. Cytopenias, pulmonary nodules, and splenomegaly were common laboratory and imaging findings. The diagnosis was suspected based on a positive Histoplasma antibody (100%) and/or antigen (80%) testing and confirmed by positive culture (blood 60%, explanted valve/graft 20%) and/or histopathology (60%). Identified clinical syndromes included: prosthetic valve endocarditis (PVE; 50%), native valve endocarditis (10%), mycotic aortic aneurysm (10%), aortic graft infection (10%), PVE and aortic graft infection (10%), and myocarditis (10%). Most patients received combined medical and surgical treatment (50%). Three patients (30%) received medical treatment only, including one patient with myocarditis. Two patients (20%) presented progressive clinical decline and were not considered antifungal treatment or surgical candidates. The overall mortality within one year of diagnosis was 50%. Patients with endocarditis and/or graft infection who received only medical treatment had higher mortality than those who received combined medical and surgical treatment (100% vs 20%, respectively).Table.Clinical characteristics of patients presenting with cardiovascular histoplasmosis (N=10)

*Patient frequently had more than one comorbidity, symptom, laboratory or imaging finding, positive histoplasmosis testing, or affected valve. **Two patients did not receive treatment given their critical status, and were transitioned to comfort care.

Conclusion

CVH is being seen more frequently at our institution. One-year mortality of CVH was high, but combined medical and surgical management conferred better outcomes than medical treatment alone. We suggest a high index of suspicion of CVH in patients residing in Histoplasma endemic regions with a history of prior cardiac or vascular surgery presenting with prolonged fevers and/or new cardiomyopathy.

Disclosures

All Authors: No reported disclosures
837. Isavuconazole in the Treatment of Chronic Forms of Coccidioidomycosis
Authors: Heidari Arash , Sharma Rupam , Shakir Qusai , Shah Madiha , Donnelly Monica , Reynolds Trina , Trigg Kate , Joliff Jeff , Kuran Rasha , Johnson Royce H , Thompson George R
Published: November 2023

Background

Coccidioidomycosis is a fungal infection with a range of clinical manifestations. Currently used antifungal agents exhibit variable efficacy and toxicity profiles necessitating evaluation of additional therapeutic options.

Methods

Patients with coccidioidomycosis who received Isavuconazole were identified by cross-indexing ICD-9 and ICD-10 codes from patients and data abstracted. Responses to Isavuconazole therapy were measured using a modified Mycoses Study Group Coccidioidomycosis Scoring system as described previously.

Results

82 patients met the criteria for inclusion. Over half of the patient exhibited pulmonary involvement 45/82 (55%), although meningitis 32/82 (39%), bone and joint disease 14/82 (17%) and skin/soft tissue infection 7/82 (9%) were also seen. The majority of patients experienced a decrease in their MSG score following initiation of Isavuconazole therapy (median MSG score change across all patient groups 7 → 2, p< 0.0001). Overall improvement was noted in 58/82 (71%) patients, while no change was observed in 19/82 (23%) and 5/82 (6%) who were unresponsive to antifungal changes.

Conclusion

Isavuconazole demonstrated efficacy in the majority of patients treated, with failures observed only in a subgroup of patients with coccidioidal meningitis.

Disclosures

Rupam Sharma, PGY-1/MD, Astellas: Grant/Research Support George R. Thompson, III, MD, Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Mayne: Advisor/Consultant|Mayne: Grant/Research Support|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Mundipharma: Advisor/Consultant|Mundipharma: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support
839. Insights into Histoplasmosis in India: A Tertiary Care Centre Experience
Authors: SONI J I N A L , Jindal Anmol , Aggarwal Anivita , Batra Tanvi , GOGIA A T U L
Published: November 2023

Background

Serious fungal infections have a significant global impact, affecting millions of lives. Histoplasmosis, commonly reported from the Gangetic Plains of India, presents as a spectrum of varied clinical courses ranging from an acute pulmonary illness to a progressive disseminated histoplasmosis. It is probably underreported due to low index of suspicion, expensive and invasive tests, especially in resource-limited settings like India. In a high tuberculosis burden country, its clinico- radiological resemblance often makes the diagnosis and treatment further challenging for clinicians.This study was conducted to provide deeper insights into the varied clinical presentation and outcomes of Histoplasmosis from a tertiary centre in India.

Methods

We conducted a retrospective observational study including all adult patients who were diagnosed with Histoplasmosis between July 2019 and March 2023 admitted in the Department of Internal Medicine at Sir Ganga Ram Hospital, New Delhi. Their details were collected using electronic records and analysed. They were followed up till the completion of treatment or recent follow up.

Results

We found 8 patients with confirmed histoplasmosis. Majority of the cases were males (87.5%), farmers (37.5%) and belonged to Uttar Pradesh (37.5%),Table 1, Figure 1. Only one patient did not have any attributable underlying risk factor. Fever (100%) and weight loss (50%) were the most common symptoms, Table 2. Anemia, leucopenia and splenomegaly were among the common abnormalities detected, Table 3. Organ-specific involvements were identified by histopathological examination on specific biopsy, Figure 2. Most of the patients (75%) received an initial intravenous course of Liposomal Amphotericin B for 2-3 weeks followed by oral Itraconazole therapy. There were two in-hospital mortalities, out of which one patient expired before the initiation of treatment. Rest of the patients (75%) had clinical recovery on follow up.

Abbreviations: HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome

Abbreviations: MODS, multiorgan dysfunction syndrome; HLH, hemophagocytic histiocytosis

Abbreviations: FDG, fluorodeoxyglucose

Conclusion

Majority of the cases depicted in our study had peculiar diagnostic dilemmas and required a strong clinical suspicion with subsequent invasive procedures to establish the diagnosis. Our study adds to the paucity of data on histoplasmosis and improves the understanding of the disease course among the Indian population.

Distribution of 8 cases of histoplasmosis reported from different states of India

Disclosures

All Authors: No reported disclosures
855. Distinguishing between drug-susceptible and resistant Neisseria gonorrhoeae from urine samples by image recognition AI.
Authors: Ariizumi Reiichi , Inagaki Tsubasa , Ozaki Hiroaki , Nakada Mitsutaka , Maeta Shogo , Nakajima Masakazu , Taketani Makoto
Published: November 2023

Background

Gonorrhea is a major public health concern because it causes complications that can seriously affect maternal and newborn health, including infertility and neonatal eye infections leading to blindness. Antimicrobial resistance (AMR) of the causative pathogen, Neisseria gonorrhoeae (Ng), emerged shortly after the introduction of antimicrobial agents. This has continued to grow over the past 80 years, culminating in the current outbreak of the gonorrhea superbugs, a broad spectrum of drug-resistant strains of Ng. Gonorrhea superbugs can be a major challenge inducing prolonged complications of gonococcal infection and increasing the number of patients with complications.

Here, we demonstrated whether resistant Ng can be morphologically distinguished from susceptible Ng using our artificial intelligence (AI) assisted image recognition of Gram-stained specimens, which are inexpensive and can be diagnosed in the clinical setting.

Methods

As shown in Figure1, three groups of standard bacterial strains were used for the study; (1) a drug-susceptible Ng (ATCC 49226), (2) two drug-resistant Ng (NCTC13480 and NCTC13821), and (3) other GNC (ATCC13120: Neisseria flavescens and ATCC49143: Moraxella catarrhalis). Each bacterial strain was dissolved in female human urine and Gram stained. Image data were collected using a Nikon Eclipse Si microscope at 1000x magnification and iPhone 11.

In total, approximately 600 images were collected, with 60% used for training and 20% for validation. As a final test, 20% of the images were used to test accuracy.

Results

As shown in Table 1, our preliminary AI model achieved 95.3% sensitivity and 96.5% specificity. Since we use Gram-staining, its limit of detection is in theory 1 × 10^5 cells/ml and we confirmed it experimentally.

The classification prediction results.

The trained AI was tested on 139 images divided into three groups; (1)Drug-resistant Neisseria gonorrhoeae(DR-Ng), (2)Drug-susceptible Ng (DS-Ng) and (3)other commensal gram-negative cocci (other GNC)

Conclusion

Our preliminary AI model was able to distinguish not only drug-resistant Ng from drug-susceptible Ng, but also other commensal GNC with Gram-stained specimens, demonstrating the potential for low-cost point-of-care diagnosis of Ng. Such a diagnosis will promote the proper use of antimicrobial agents, which can help to prevent the spread of drug-resistant Ng.

Disclosures

Masakazu Nakajima, B. Engineering, Soiken Holdings: Board Member|Welby Inc.: Board Member|Welby Inc.: Ownership Interest|Welby Inc.: Stocks/Bonds
859. The Role of Procalcitonin in Antimicrobial De-escalation and Stewardship Program in Febrile Neutropenic Cancer Patients
Authors: Dagher Hiba , Chaftari Anne-Marie , Hachem Ray Y , Jiang Ying , Philip Ann , Mulanovich Patricia , Haddad Andrea , Lamie Peter , Dib Rita Wilson , John Teny , Garnes Natalie J Dailey , Chaftari Patrick , Raad Issam I
Published: November 2023

Background

Serial procalcitonin (PCT) measurement has been adopted as an adjunct to clinical judgement to guide antibiotic therapy, prevent antibiotics overuse and endorse antimicrobial stewardship programs. PCT peaks at 24 to 48 hours, and declines with infection resolution. In this prospective study we explored the role of PCT used as a biomarker in adjunct to the clinical judgment to guide antibiotic course.

Methods

We prospectively enrolled cancer patients with febrile neutropenia (FN) to receive empiric intravenous broad-spectrum antibiotics (IV-BSA) for at least 48 hours. PCT was measured at baseline and 48-72 hours after initiation of study drug. A PCT drop at 48-72 hours after study drug initiation was defined as a drop by ≥30 % from baseline (start of therapy) or a level of < 0.25 ng/ml. De-escalation was defined as a switch of IV-BSA to oral or simplified once a day IV therapy.

Results

A total of 80 patients were enrolled between October 2021 and April 2023, of whom 74 had serial PCT measurements. Median age was 59 years, 57% were male, and 66% had hematological malignancies. A PCT drop at 48-72 hours was observed in 68% of patients who de-escalated to oral or IV therapy. In this PCT guided study, the median time to de-escalation was 62 hours (< 3 days). Furthermore, 64% of these patients de-escalated within 3 days after initiation of therapy, 79% de-escalated by day 4, 85% by day 5 and 92% by day 7. Patients with PCT drop had a shorter median duration of antibiotic compared to those without PCT drop (54.8 hours vs 106.4 hours; p=0.003). Furthermore, the antibiotic therapy de-escalation occurred sooner in patients with PCT drop (75% occurred prior or at 72 hours in the PCT drop group vs 41% in the non-PCT drop group; p=0.017). Patients who had a documented bacteremia had a significantly higher median PCT level at baseline than those without bacteremia (3.92 ng/ml vs 0.37 ng/ml; p=0.001).

Conclusion

In this PCT guided study, the median time to de-escalation of IV-BSA was < 3 days and most of the cancer patients with FN who de-escalated had a PCT drop within 3 days of initiating therapy. Patients with a PCT drop had an earlier de-escalation and a shorter course of antibiotic therapy.

Disclosures

Natalie J Dailey Garnes, MD, MPH, AlloVir: Grant/Research Support Issam I. Raad, Distinguished Professor, Novel Anti-Infective Technologies, LLC: Technology License
860. Molecular Characterization of Isolated Staphylococcus aureus Specimens Using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS)
Authors: Dawning Amber , Lin Xiting , Jerris Robert C , Thornton Kevin , Mohamed Noor , Immergluck Lilly
Published: November 2023

Background

Staphylococcus aureus (S. aureus) is a common cause of skin and soft tissue infections (SSTIs). Both the β-lactam resistant form, methicillin resistant S. aureus (MRSA), and non-resistant form, methicillin susceptible S. aureus (MSSA) are associated with disparate infections across age and race; community-associated infections are often due to S. aureus US300. Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) is a used in clinical microbiology laboratories to identify bacterial species, but limited data is available on if this tool can identify different strains of S. aureus. We hypothesize that MALDI-TOF MS can be used to identify strain-specific peaks of S. aureus USA300.

Methods

Children were enrolled from emergency departments and swabbed for S. aureus (anterior nares, axilla, perirectal, oropharyngeal, and wounds) during two time periods (2006-2008 and 2015-2016). MALDI-TOF MS was performed on S. aureus cultured from study participants. Default parameters used for variance stability, smoothing, baseline subtraction, and normalization in R 4.4.3. and MALDIquant v1.22 were applied to raw data. Peak detection and alignment were performed with a signal-to-noise ratio of three and tolerance of 300 ppm. Binning and machine learning algorithms were used to identify intensity differences of each peak identified; significance of peaks was determined using Chi Square statistical analyses, comparing MRSA and MSSA, and then between all S. aureus isolates compared to USA300. Statistical significance was considered with p-value < 0.05 using R and SAS 9.4.

Results

From 57 MRSA and 53 MSSA isolates, 320 peaks were identified. 31 significant peaks were identified, with 14 unique peaks for MRSA and 17 for MSSA. With S. aureus USA300, eight of the 31 peaks remained statistically significant.

Conclusion

MALDI-TOF MS can identify unique peak differences between MRSA and MSSA. This tool can be potentially used to distinguish S. aureus at the strain level in a clinical setting. MALDI-TOF MS can be an impactful and rapid diagnostic tool to detect antibiotic resistance in S. aureus in a clinical setting.

Disclosures

Lilly Immergluck, MD,MS, Melinta: Grant/Research Support|Melinta: Grant/Research Support
861. Development and Clinical Validation of a Custom Modified Two-Tier Testing Algorithm for Serodiagnosis of Lyme Disease
Authors: Gaylord Michelle A , Baranova Danielle , Pride Michael W , Simon Raphael , Anderson Annaliesa S , Kalina Warren Vincent
Published: November 2023

Background

Diagnosis of Lyme Disease has relied on measuring the serological response to Borrelia sp. Over the years the rigor of serological diagnosis has evolved to meet the needs of the clinic and vaccine manufacturers, where the latter require especially sensitive and specific tests to measure efficacy. Likewise, current US guidelines recommend a two-tier testing approach to diagnose Lyme Disease. Among a constellation of commercially available in vitro diagnostics, two highly sensitive immunoassays with Borrelia sp. antigenic diversity were characterized for utility as a custom Modified Two-Tier Testing (MTTT) algorithm. This custom algorithm consists of a first tier assay from Bio-Rad and a second tier assay from Zeus Scientific, and was developed to capture cases of Lyme Disease.

Methods

The BioPlex 2200 Lyme Total assay from BioRad and VlsE1/pepC10 IgG/IgM ELISA from Zeus Scientific were evaluated as the first and second tier assays in the custom MTTT, respectively. The MTTT was clinically assessed for diagnostic accuracy and compared to the highly characterized CDC Pre-Marketing Panel, which is composed of samples from US donors diagnosed with Lyme Disease, “look-alike” diseases or healthy individuals. Other clinically relevant sample populations were benchmarked off the predicate FDA-approved MTTT, also from Zeus Scientific.

Results

The custom MTTT, described here, was more clinically specific than either test alone and was more clinically sensitive than the only other FDA-approved MTTT. When matched against the FDA-approved predicate method, sensitivity and specificity was 100%. The custom MTTT also detected fewer “look-alike” disease samples than either test alone, or the FDA-approved MTTT. Furthermore, detection of early Lyme Disease in the CDC Pre-Marketing panel was 80% sensitive. In addition, the custom MTTT identified Lyme disease in 98.6% of Lyme Disease samples collected from samples that originated in Europe.

Conclusion

The clinically validated custom MTTT method, described here, has utility as a Lyme Disease diagnostic and is a highly specific tool for assessing efficacy of Lyme Disease vaccines currently in development.

Disclosures

Michelle A. Gaylord, PhD, Pfizer Inc.: Stocks/Bonds Danielle Baranova, PhD, Pfizer Inc: Stocks/Bonds Michael W. Pride, PhD, Pfizer: Stocks/Bonds Raphael Simon, PhD, Pfizer: Stocks/Bonds Annaliesa S. Anderson, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Warren Vincent. Kalina, PhD, Pfizer: Stocks/Bonds
867. Diagnostic test accuracy of TRAIL, IP-10 and C-RP biomarker combination (MeMed BV test) for discrimination of viral vs. bacterial infections among Emergency Department patients with febrile illness: A Systematic Review and Meta-analysis
Authors: Kandula Manasa , Farrell John J
Published: November 2023

Background

Infections (eg. RSV, influenza & Streptococcus pyogenes) have surged following discontinuation of social distancing and masking. Emergency Department (ED) providers feel pressure to prescribe antibiotics for common presentations such as fever for fear of missing a case of Group A Strep, which can lead to antibiotic misuse. Multiplex PCR assays are costly and cultures take 1-2 days to result, and lack sensitivity when antibiotics have already been started. There is a need for a rapid, affordable, and accurate method to distinguish bacterial from viral infections. Some prospective studies have demonstrated that a diagnostic assay that combines CRP with IP-10 and TRAIL can effectively assist ED providers with decisions regarding antibiotic therapy in patients with a febrile illness.

Forrest plot of the individual and composite direct odds ratios (DOT) respectively for the nine studies included in the meta-analysis

Summary Receiver Operating Characteristic (SROC) analysis of the diagnostic accuracy of the MeMed BV test. The SROC analysis was applied to the data which was pooled from all nine studies included in this meta-analysis

Methods

The analysis was registered with PROSPERO prior to following PRISMA-DTA framework, which yielded 9 studies with 4X4 tables for sensitivity, specificity, and diagnostic accuracy of the BV test for bacterial vs. viral infection. Articles were searched in PubMed, Medline, Google Scholar and Ovid. Random effects models were used to calculate pooled proportions. The estimated total effect sizes, test for heterogeneity and moderator effect, and ROC curve are reported using R software.

Results

9 prospective studies were included with a total of 4084 patients (3271 cases and 813 controls). The proportion of the random effect model was 0.841 (95% CI, 0.788 to 0.882). The total effect sizes of all nine studies are shown. The OR of the random effect model is 124.2 (95% CI, 77.3 to 199.4) and p-value < 0.0001, meaning the OR of a positive BV test result among persons with disease was approximately 124 times higher than the OR for a positive test among persons with no disease. The bivariate diagnostic random-effects meta-analysis for viral vs. bacterial infection AUC = 0.973.

Conclusion

Across 9 studies performed over 8 years, the combination of TRAIL, IP-10 and C-RP biomarkers (BV test) accurately distinguished between bacterial and viral infections in patients with febrile illness. The test has the potential to be used to facilitate timely diagnosis and antimicrobial treatment decisions. Further large scale studies are needed to establish its role in antimicrobial stewardship.

Disclosures

All Authors: No reported disclosures
871. Clinical Detection of Intestinal Protozoa in Digitized Modified Trichrome-Stained Stool Specimens using a Deep Convolutional Neural Network Assisted Workflow
Authors: Morris Heather Rose , Pritt Bobbi S , Norgan Andrew
Published: November 2023

Background

Deep convolutional neural networks (DNN) have been successfully applied to the detection and segmentation of objects in gigapixel digital slides. In this study, trained laboratory technologists utilized a DNN-assisted digital workflow (Techcyte, Inc.; Orem, UT) to evaluate clinical stool specimens for the presence and identification of protozoan parasites.

Methods

Slides were prepared from 142 stool specimens by spreading a thin layer of concentrated stool onto a slide, staining with modified-trichrome, and coverslipping with permanent mounting medium. Slides were then scanned using a NanoZoomer 360 digital slide scanner (Hamamatsu Photonics K.K., Japan) at 40x apparent magnification and prospectively analyzed by the Techcyte DNN. Objects of interest were identified and classified by the DNN (protozoa, leukocytes, erythrocytes) and presented to a laboratory technologist for interpretation. (See example image below.) DNN-assisted results were compared to those from conventional microscopic examination. To determine analytical sensitivity, slides were prepared from serial, 2-fold dilutions of 3 unique stool specimens (6 slides at each dilution/specimen) and analyzed by the DNN-assisted method and conventional microscopy.

Example of Techcyte DNN analysis review screen

Objects of interest most likely to be significant are presented to the technologist for review in an intuitive web-based format. Parasites are confirmed as present or absent by a trained technologist after reviewing these images.

Results

Digital analysis was highly reproducible, showing 100% slide level agreement (positive/negative) within and between runs using positive and negative slides. There was 98.7% and 98.3% positive and negative agreement, respectively, between conventional and DNN-assisted results. Of the 142 slides conventional microscopy detected parasites in 82, while the DNN-assisted method detected 83. The DNN-assisted method also detected more slides with leukocytes (29 vs 24) and erythrocytes (12 vs 8). All discrepant results were confirmed by repeat conventional microscopy. Analytical sensitivity of the DNN-assisted method was equivalent or superior to conventional microscopy review, detecting down to 1:64 dilutions in 6/6 slides per specimen (conventional = 1:32 to 1:64), extending for some slides to detection at dilutions of 1:2048.

Conclusion

The DNN-assisted method facilitates rapid screening of negative specimens, while providing sensitive and accurate detection and classification of protozoa.

Disclosures

All Authors: No reported disclosures