bluuebunny/crossref_metadata_2025_split huggingface dataset:
989. Isavuconazonium Sulfate Treatment of Blastomycosis: A Case Series
Authors: Scolarici Michael J , Saddler Christopher , Smith Jeannina , Gauthier Gregory 
Published: December 2021

Abstract

Background
Blastomyces fungi, endemic to the Ohio and Mississippi River Valleys, cause pneumonia and disseminated disease in both immunocompetent and immunocompromised patients. Prolonged antifungal therapy is commonly complicated by hepatic toxicity, QT prolongation, and drug interactions. Isavuconazonium sulfate is dosed once daily, does not prolong the QT interval, and has fewer drug interactions, but there is a paucity of data for its use in blastomycosis.

Methods
This case series of blastomycosis treated with isavuconazonium sulfate at the University of Wisconsin Hospital and Clinics from 2015 to December 2019 focuses on long term outcomes. Inclusion criteria were adults, that received at least one day of isavuconazole. Exclusion criteria was no blastomycosis diagnosis.

Results
Of 14 cases, median age was 53 years, 6/14 were female, 11/14 White, 2/14 Black, 1/14 Hmong, 6/14 had a solid organ transplant (4 renal, 1 heart, 1 bilateral lung), 1/14 on a TNF-alpha inhibitor (infliximab). Most cases, 9/14 had moderate severity illness requiring inpatient care, 2/14 required ICU level care, and 3/14 were outpatient. Most cases, 11/14, were initially treated with Liposomal Amphotericin B (LAMB) for a median duration of 14 days, 9/14 cases received itraconazole, 8/14 voriconazole, 1/14 posaconazole. Isavuconazonium sulfate was started after adverse drug effects with other azoles in 10/14 cases, prolonged QT interval in 3/14, drug interactions in 2/14, subtherapeutic azole levels in 2/14. Isavuconazonium sulfate was well tolerated and used for median duration of 255 (average 68% total treatment course). 3/14 cases had adverse reactions to isavuconazonium sulfate: nausea, rash, elevated liver enzymes. There was only one death during therapy from a fatal hemorrhagic stroke, and 2/14 cases were still on therapy at end of data collection. 11/14 were cured after treatment course.

Conclusion
This is the largest case series treating Blastomycosis with isavuconazonium sulfate, and it adds to the evidence that isavuconazonium sulfate can be safely used to treat pulmonary and disseminated blastomycosis. Prospective data is needed to compare isavuconazonium sulfate to other antifungals for the treatment of Blastomycosis.

Disclosures
All Authors: No reported disclosures
990. Fungal Malignant Otitis Externa: Clinical and Therapeutic Features
Authors: Hammami Fatma , Koubaa Makram , Chakroun Amal , Rekik Khaoula , Marrakchi Chakib , Smaoui Fatma , Jemaa Mounir Ben 
Published: December 2021

Abstract

Background
Fungal malignant otitis externa is a rare, but a serious infection that might lead to death if not promptly diagnosed and treated. We aimed to study the clinical, therapeutic and evolutionary features of fungal malignant otitis externa.

Methods
We conducted a retrospective study including all cases of fungal malignant otitis externa hospitalized in the infectious diseases department between 2003 and 2020.

Results
We included 35 patients with a mean age of 68±11 years. There were 18 males (51.4%). All patients were diabetics, and 7 patients had a previous medical history of otitis externa (20%). The use of topical corticosteroids was noted in 10 cases (28.5%). The revealing symptoms were otalgia (97.1%), otorrhea (82.9%) and cephalalgia (54.3%). Physical examination revealed tenderness to palpation of the mastoid bone in 21 cases (60%) and the temporomandibular joint in 16 cases (45.7%). Facial paralysis was noted in 14.3% of the cases. Otoscopic examination revealed stenosis of the external auditory canal (94.3%), granulation tissue (34.3%) and a polyp (31.4%). Candida species were isolated in 22 cases (62.8%) represented by Candida parapsilosis in 15 cases (42.8%) and Candida albicans in 5 cases (14.2%). Serological tests detecting Candida were positive in 12 cases (34.2%). Aspergillus species were isolated in 13 cases (37.1%) represented mainly by Aspergillus flavus in 7 cases (20%). Positive serology results for Aspergillus were noted in 8 cases (22.8%). A polyp or granulation tissue biopsy, performed in 12 cases (34.2%), revealed non-specific inflammatory reaction (28.5%) and the presence of fungal hyphae and spores (5.7%). After empirical antibiotics treatment, patients received fluconazole in 18 cases (51.4%) and voriconazole in 17 cases (48.6%). The median duration of treatment was 3 [1.5-12] months. Both surgery and hyperbaric oxygen therapy were indicated in one case (2.8%). Complications including the onset of contralateral otitis (14.3%) and endocranial extension (8.6%) were noted. The disease evolution was favorable in 65.7% of the cases. Four patients were dead (11.4%).

Conclusion
Involvement of fungal species in malignant otitis externa should be considered in front of the absence of improvement with antibiotic. Prompt treatment might prevent complications.

Disclosures
All Authors: No reported disclosures
991. Blockade of the PD-1/PD-L1 Immune Checkpoint Pathway Improves Mortality, Infection Severity, and Fungal Clearance in an Immunosuppressed Murine Model of Invasive Pulmonary Mucormycosis
Authors: Wurster Sebastian , Albert Nathaniel D , Kontoyiannis Dimitrios P 
Published: December 2021

Abstract

Background
Emerging experimental evidence suggests that immune checkpoint inhibitors (ICIs) enhance antifungal immunity. In addition, there is anecdotal evidence of potential benefit of adjunct PD-1 pathway blockade in patients with intractable mucormycosis. However, proof-of-concept data in animal models are lacking. Therefore, we compared the efficacy of PD-1 and PD-L1 inhibition in an immunosuppressed murine model of invasive pulmonary mucormycosis (IPM).

Methods
Female 8-9-week-old BALB/c mice were immunosuppressed with cyclophosphamide (150 mg/kg on days -4 and -1, 100 mg/kg on day +3) and cortisone acetate (300 mg/kg on day -1) and infected intranasally with 50,000 Rhizopus arrhizus spores (clinical isolate Ra-749, day 0). On days 0, +2, +4, and +6, mice received intraperitoneal injections of 250 µg/kg PD-1 or PD-L1 blocking antibodies versus (vs.) 250 µg/kg of the corresponding isotype antibodies (all antibodies from Leinco Technologies). Survival was monitored for 7 days post-infection. Infection severity was scored using the murine sepsis score (MSS, 0 = healthy to 3 = moribund). Fungal burden in lung tissue was determined by an 18S quantitative PCR assay on day +7 or upon death. 20 mice per treatment were assessed in 2 independent experiments.

Results
Control mice with IPM receiving either of the unspecific isotype antibodies developed severe infection (median MSS on day 7, 2.5-3.0) and had a high 7-day mortality (50-55%). Compared to the corresponding isotype control, PD-L1 inhibition provided a strong therapeutic benefit, significantly improving morbidity (median MSS = 1.0 vs. 2.5, p = 0.002), 7-day mortality (15% vs. 50%, p = 0.02), and fungal burden (3.6k vs. 27.2k spore equivalents/lung, p &lt; 0.001). In contrast, blockade of-PD-1 modestly yet non-significantly reduced infection severity (median MSS = 2.1 vs. 3.0, p = 0.48), 7-day mortality (35% vs, 55%, p = 0.12), and fungal burden (5.6k vs. 40.7k spore equivalents/lung, p = 0.09) compared to isotype control.

Conclusion
Even without concomitant antifungals, blockade of PD-L1 and to a lesser extent of PD-1 improved mortality, infection severity, and fungal clearance in immunosuppressed mice with IPM. Immune phenotyping studies are in progress to better understand the protective antifungal activity of ICIs in IPM.

Disclosures
Dimitrios P. Kontoyiannis, MD, Astellas (Consultant)Cidara Therapeutics (Advisor or Review Panel member)Gilead Sciences (Consultant, Grant/Research Support, Other Financial or Material Support, Honoraria)
994. Comparison of Lactate, Procalcitonin and a Gene Signature Assay Alone or in Combination to Differentiate Sepsis from Non-infectious Systemic Inflammation in ICU Patients
Authors: Hassan Erkan , Davis Roy , Sampson Dayle , Miller Russell 
Published: December 2021

Abstract

Background
Procalcitonin (PCT) and serum lactate (L) are measures of bacterial infection and tissue hypoxia, respectively, but also used to discern sepsis from infection negative systemic inflammation (INSI). However, improved tools are needed to enhance this differentiation. A previously validated gene signature assay (SeptiCyte RAPID) and its correlated score (SeptiScore (SS)) has been reported to effectively differentiate sepsis from INSI.

Objective
To compare early L, PCT and SS results (alone or in combination) in differentiating sepsis from INSI in adult intensive care unit (ICU) patients (Pt).

Methods
Data from a previously reported, prospective study (8 sites). Inclusion criteria: (i) ICU admission with ≥ 2 signs of systemic inflammatory response syndrome; (ii) Therapeutic antibiotic administration; (iii) external 3-physician clinical review classifying each Pt as sepsis or INSI with ≥ 2 reviewer agreement; (iv) L, PCT & SS values within 24 hrs of ICU admission; (v) Statistical Analysis; (iv) Area under the receiving operator curve (AUROC), 95% confidence intervals (CI) via generalized linear models for: (i) Each parameter alone (L, PCT, SS); (ii) Combinations (L + PCT, L + SS, PCT + SS, All 3); (iii) AUROC discriminated Sepsis from INSI model: (a) &lt; 0.7 Sub-Optimal; (b) 0.7-0.8 Good; (c) &gt; 0.8 Excellent. Comparisons conducted via paired t-test.

Results
222 pts, sepsis=113; INSI=109 Similar demographics between groups (NS). Mean age (SD) = 57.9 (17.1) yrs; 58.1% male). Overall mechanically ventilated 60.8% and hospital mortality 17.1%. AUCROC (95% CI) in Table and Figure; AUCROC of L, PCT or SS alone or in combination

L, PCT, SS Comparison of Sepsis vs INSI

Conclusion
L is sub-optimal in discriminating sepsis from INSI. PCT with or without L was acceptable but not as robust as SS. SS alone or in any combination provided superior and significant discrimination between sepsis and INSI. Incorporation of SS into the clinical assessment process for suspected sepsis pts should be evaluated to determine the impact on early detection and Pt management.

Disclosures
Erkan Hassan, Pharm.D., FCCM, Immunexpress (Consultant) Roy Davis, M.D&gt;, Immunexpress (Consultant)Immunexpress (Consultant, Shareholder) Dayle Sampson, Ph.D., Immunexpress (Employee, Shareholder)
995. A Murine Model of Klebsiella pneumoniae Gastrointestinal Colonization with Parenteral Vancomycin Administration
Authors: Cheung Bettina , Lebrun-Corbin Marine , Hauser Alan R 
Published: December 2021

Abstract

Background
As a leading cause of nosocomial infections, Klebsiella pneumoniae poses a significant threat due to its propensity to acquire resistance to many classes of antibiotics, including carbapenems. Gastrointestinal (GI) colonization by K. pneumoniae is a risk factor for subsequent infection as well as transmission to other patients. To study this crucial step in pathogenesis, we developed a mouse model of K. pneumoniae GI colonization using a clinically relevant parenteral antibiotic regimen.

Methods
To improve the clinical relevance of our model, we elected to use intraperitoneal injections of vancomycin, one of the most highly utilized antibiotics in the United States.

Results
To optimize dosage in C57bl/6 mice, we injected 20mg/kg, 350mg/kg, or vehicle (PBS) for three days prior to gastric gavage with 108 colony forming units (CFU) of a low-resistance strain of K. pneumoniae. The mice who received 350mg/kg (a mouse equivalent of a human dose of 1g/day calculated through the FDA guidelines for estimating safe dosing) shed about 107 CFU/g of feces at Day 7 while those receiving the lower dose or vehicle shed 104 CFU/g. Next, we compared 3- or 5-day pre-treatments with vancomycin prior to inoculation with an ST258 (epidemic carbapenem-resistant) strain. At Day 7 post-inoculation, mice who received 5 days shed 1010 CFU/g feces while those who received vancomycin for 3 days or vehicle for 5 days (PBS) shed 106 or 104 CFU/g feces respectively. Thus, we chose 5 days of 350mg/kg vancomycin injection as our regimen for inducing robust GI colonization in mice. Finally, we tested the durability of colonization by following fecal shedding in mice up to Day 60 post-inoculation with a second ST258 strain. Shedding during the first 7 days occurs at about 1010 CFU/g feces, and from day 14 to day 60 fecal loads are stable around 107 CFU/g feces. Results are comparable between male and female mice.

Conclusion
In conclusion, we have developed a mouse model of robust, prolonged GI colonization with multiple strains of K. pneumoniae using controlled dosing of a clinically relevant antibiotic. This model may be used to study a key step in K. pneumoniae pathogenesis and infection prevention in the future.

Disclosures
All Authors: No reported disclosures
119. A Humanized Antibody Targeting the CotH Invasins is Protective Against Murine Mucormycosis
Authors: Gu Yiyou , Alqarihi Abdullah , Singh Shakti , Gebremariam Teclegiorgis , Alkhazraji Sondus , Youssef Eman , Andes David , Ibrahim Ashraf S 
Published: December 2021

Abstract

Background
Despite antifungal therapy and surgical debridement, overall mortality of invasive mucormycosis is &gt;40%. Currently the world is witnessing an explosion in mucormycosis in India among COVID-19 patients with an official count of 28,252 cases as of 06/07/2021. Thus, novel therapeutic modalities are needed. We previously reported on a mouse monoclonal antibody (C2) targeting CotH invasins being protective against mucormycosis. Here, we humanized C2 MAb and assessed its efficacy in vitro and in vivo.

Methods
The C2 (IgG1) paratopes of the heavy chain and light chain were grafted on the most suitable human IgG1 with back mutations in the paratopes needed to restore binding of humanized clones to CotH3 (by biolayer interferometry using Gator). Clones were compared to C2 in their ability to prevent Rhizopus delemar-induced injury to A549 alveolar epithelial and primary human endothelial cells and for enhancing human neutrophil killing of the fungus in vitro. C2 and the humanized clones were also compared for their ability to protect neutropenic mice from mucormycosis induced by R. delemar or Mucor cicrinelloides with and without antifungal therapy.

Results
Three humanized clones showed 10-fold enhanced binding affinity to CotH3 protein (~5 nM for humanized vs. ~50 nM for C2). One humanized clone (VX01) doubled the ability of neutrophils to kill R. delemar and resulted in ~50% reduction in host cell damage. A single low dose of VX01 (30 µg) given 24 h post infection resulted in comparable survival of 60-70% in mice infected intratracheally with either R. delemar or M. cicrinelloides vs. placebo mice (0% survival, P &lt; 0.02). Importantly, VX01 acted synergistically in protecting mice when combined with liposomal amphotericin B or posaconazole in a severe model of mucormycosis with treatment starting 48 h post infection (~70% survival for combination vs. 0-20% survival for monotherapy and reduced lung fungal burden by 1.5 log, P&lt; 0.001). GLP-tissue cross reactivity studies of VX01 showed favorable safety profiles.

Conclusion
VX01 shows enhanced binding to CotH3 protein and maintained the protective features of C2 MAb against murine mucormycosis. Clinical testing of combination therapy of VX01 + antifungals is warranted. VX01 is currently in manufacturing.

Disclosures
Yiyou Gu, PhD, Vitalex Biosciences (Shareholder) Ashraf S. Ibrahim, PhD, Vitalex Biosciences (Shareholder)
996. CD4+ T-Cell Lymphopenia Associated with Frequent Plateletpheresis in Healthy Donors
Authors: Cunningham Phoebe H , Mitre Xhoi , Pierre Djenane , Montesano Christina , Woods Tenaizus , Oganezova Karina , Krauss Jonathan H , Von Salena S , Kupelian John A , Gothing Jon A , Jane Kleinjan , Caldara Lise Ann , Sherman Amy C , Walsh Stephen R , Kaufman Richard M , Baden Lindsey R , Desjardins Michaël 
Published: December 2021

Abstract

Background
Frequent plateletpheresis using the Time Accel leukoreduction system chamber may result in lymphopenia in healthy donors, with increased donation in the previous year associated with CD4+ T-cell count of less than 200 cells/µL. However, this finding has not been replicated and the clinical significance of plateletpheresis-associated lymphopenia remains unclear.

Methods
A prospective observational study of healthy plateletpheresis donors aged 18 or older who donated at least once in the previous 365 days was conducted at the Kraft Blood Center at Brigham and Women’s Hospital/Dana Farber Cancer Institute, where the Time Accel system is used exclusively. Blood was drawn immediately before plateletpheresis or at least 2 weeks after the last donation to assess for total lymphocyte and CD4+ T-cell counts.

Results
A total of 86 participants were enrolled: 23 had 1-5 donations, 36 had 6-19 donations, and 27 had 20-24 donations within the previous 365 days (Figure 1). For the low-, medium-, and high-frequency donation groups, the median age was 53 years (IQR 43-64), 61 years (IQR 53-68), and 61 years (IQR 55-65), respectively. The median total lymphocyte count was 1.5 (IQR 1.3-1.9), 1.2 (IQR 0.9-1.5), 0.8 (IQR 0.6-0.9) 103 cells/µL, and the median CD4+ T-cell count was 648 (IQR 531-843), 525 (IQR 348-698), and 220 (IQR 184-347) cells/µL. CD4+ T-cell counts were &lt; 200 cells/µL in 0/23 (0%), 3/36 (8%), and 9/27 (33%) participants across the three groups. Total lymphocyte and CD4+ T-cell counts were inversely correlated with the number of platelet donations in the prior 365 days, R2 = 0.384 (Fig 2) and 0.402 (Fig 3) respectively.

Conclusion
Frequent plateletpheresis using Time Accel leukoreduction system chamber is associated with CD4+ T-cell lymphopenia, with counts below 200 cells/µL seen in one third of those who donated 20-24 times in the previous year. Vaccine immunogenicity studies are ongoing to evaluate the clinical significance of this finding.

Disclosures
Stephen R. Walsh, MDCM, Janssen Vaccines (Scientific Research Study Investigator)Regeneron (Scientific Research Study Investigator)Sanofi Pasteur (Scientific Research Study Investigator)
1000. Serotype 3 pneumococci evade activation of the classical complement pathway
Authors: Lapidot Rotem , Ramirez Mario , Lee Dayeun , Scully Ingrid L , Gessner Bradford D , pelton stephen 
Published: December 2021

Abstract

Background
Complement classical pathway (CCP) activation is the major mechanism leading to opsonophagocytic pneumococcal killing. Following immunization with 13-valent pneumococcal conjugate vaccine (PCV13), opsonophagocytic titers are lowest against serotype 3 among the 13 vaccine serotypes. Post licensure surveillance indicated early declines in serotype 3 invasive pneumococcal disease (IPD) were not sustained over time

Methods
Using flow cytometry, we measured C3 and C4 deposition on serotype 3 strains from children with IPD or nasopharyngeal [NP] carriage, and analyzed by clade. C4 deposition is an indicator of CCP, while C3 deposition is common to all complement pathways. We measured C3/C4 deposition on serotype 3 pneumococcal strains incubated with antibody depleted complement alone or with complement and the following antibodies: mouse monoclonal anti-capsular IgG or IgM, rabbit polyclonal serotype 3 antisera (IgG + IgM) [RPS3A] and RPS3A combined with anti-rabbit IgM, which blocks IgM function, leaving only polyclonal IgG

Results
Serotype 3 strains demonstrated high variability in C3 binding when incubated with complement alone. RPS3A (containing both IgM+IgG) and monoclonal IgM activated CCP in all strains. Anti- serotype 3 monoclonal IgG and polyclonal IgG demonstrated absent or limited CCP activation; but activated alternative pathway in some strains. When analyzing complement deposition by clade, a lower proportion of clade II NP serotype 3 strains bound C3 when incubated with complement or monoclonal IgG, compared to clade Ia NP strains. Differences between clade Ia and II IPD strains were not apparent.

Conclusion
Serotype 3 strains did not demonstrate activation of the CCP in the presence IgG and varied in C3 deposition. Pneumococcal strains that evade CCP activation may be less sensitive to opsonophagocytosis. Our findings suggest a mechanism by which serotype 3 carriage and disease may persist despite immunization with conjugate vaccine containing serotype 3 polysaccharide.

Disclosures
Rotem Lapidot, MD MSCI, Pfizer (Consultant, Grant/Research Support, Advisor or Review Panel member) Mario Ramirez, PhD, GlaxoSmithKline (Advisor or Review Panel member)Merck Sharp & Dohme (Advisor or Review Panel member)Pfizer (Speaker’s Bureau) Ingrid L. Scully, PhD, Pfizer (Employee, Shareholder) Bradford D. Gessner, MD, MPH, Pfizer Inc. (Employee) stephen pelton, MD, Merck Vaccines (Advisor or Review Panel member, Research Grant or Support)Pfizer, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support)Sanofi pasteur (Advisor or Review Panel member, Research Grant or Support, DSMB)Seqirus (Consultant)
1003. Cytokine Levels in Sepsis and TNFα Association with Mortality but not Sepsis Severity or Infection Source: a Systematic Review and Meta-analysis
Authors: Gharamti Amal , Samara Omar , Monzon Anthony , Barahona Lilian Vargas , Scherger Sias , DeSanto Kristen , Chastain Daniel B , Sillau Stefan , Franco-Paredes Carlos , Henao Martínez Andrés F , Shapiro Leland 
Published: December 2021

Abstract

Background
Sepsis is a global health problem associated with significant morbidity and mortality and is attributed to a “cytokine storm.”. However, anti-cytokine therapies have failed to lower sepsis mortality in clinical trials. Linking cytokine excess to sepsis pathogenesis requires quantification of cytokine levels in sepsis. This systematic review and meta-analysis characterizes levels of key cytokines in the circulation of sepsis patients and relates TNFα levels to mortality and patient characteristics.

Methods
Medline, Embase, Cochrane Library, and Web of Science Core Collection databases were searched from 1946 to May 2020 for studies in English disclosing cytokine levels in sepsis. Keywords included sepsis, septic shock, purpura fulminans, and tumor necrosis factor (TNF)α. We related cytokine amounts to 28-day mortality. Data analyses were performed using a random-effects model to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). This systematic review is registered in PROSPERO under number CRD42020179800.

Results
A total of 3656 records were identified. After exclusions, 103 studies were included. Among these studies, 72 disclosed TNFα levels, 25 showed interleukin (IL)-1β levels, and 6 presented interferon (IFN)γ levels. The pooled estimate mean TNFα concentration in sepsis patients was 58.4 pg/ml (95% CI, 39.8-85.8 pg.ml; I2 = 99.4%). Pooled estimate means for IL-1α and IFNγ in sepsis patients were 21.8 pg/ml (95% CI, 12.6-37.8 pg.ml; I2 =99.8%) and 63.3 pg/ml (95% CI, 19.4-206.6 pg/ml; I2 = 99.7%), respectively. Elevated TNFα concentrations were associated with increased 28-day mortality (P=0.001). In a subgroup analysis, TNFα levels did not relate to sepsis source, sepsis severity, or sequential organ failure assessment (SOFA) score (figure 1). In a metaregression, TNFα associated with age, percentage of females and mortality at 28 days.
Figure 1: A: TNFa levels according to sepsis source. B: TNFa levels according to measurement technique. C: TNFa levels according to presence or absence of cardiovascular disease. D: TNFa levels according to presence or absence of malignancy. E: TNFa levels according to sepsis severity. F: TNFa levels in fungal compared to other causes of sepsis (Yes=fungal sepsis; No= Other types of sepsis). G: TNFa levels according to SOFA score. H: TNFa levels and mortality at 28 days.

Conclusion
We presented levels of TNFα, IL-1β, and IFNγ in human sepsis and showed that TNFα elevations are associated with sepsis mortality. TNFα concentrations did not correlate with sepsis severity. We believe the concept that elevated cytokines cause sepsis should be revisited in the context of these data.

Disclosures
All Authors: No reported disclosures