bluuebunny/crossref_metadata_2025 huggingface dataset:
2197. Genomic Surveillance for Human Adenovirus Infections among Department of Defense Beneficiaries in the 2018-2019 Season
Authors: Pollio Adam , Fries Anthony C , Yang Yu , Hughes Jerry , Fung Christian , Conte Matthew , Collins Natalie , Macias Elizabeth A , Hang Jun
Published: December 2022

Background

Human adenoviruses (family Adenoviridae, genus Mastadenovirus) (HAdV) species B, C and E cause acute respiratory illnesses (ARI). In particular, respiratory HAdV types 3, 4, 7, 11, 14, 21 and 55 were associated with ARI outbreaks in the US and in other countries. The risk of outbreaks can be effectively controlled by implementation of the live HAdV types 4 and 7 vaccines or mitigated by screening and preventive measures.

Methods

During the influenza season 2018 – 2019, the DoD Global Respiratory Pathogen Surveillance Program (DoDGRS) received 24,300 specimens from its surveillance network. In total, 322 (1.3%) respiratory specimens were positive for HAdV in molecular assays. HAdV samples that produced positive cytopathic effects (CPE) in subsequent viral cultivation were subjected to next-gen sequencing (NGS) for genome sequence assembly, HAdV genome typing, whole genome phylogeny, and sequence comparative analyses to identify sequence insertions, deletions and amino acid mutations.

Results

Out of 166 viral culture samples available for NGS, whole genome sequences were obtained for 161 isolates. A variety types of HAdV were identified, including HAdV-1 (N = 15), HAdV-2 (N = 26), HAdV-3 (N = 60), HAdV-4 (N = 13), HAdV-5 (N = 6), HAdV-6 (N = 3), HAdV-7 (N = 12), HAdV-14 (N = 10), HAdV-55 (N = 1), and HAdV-56 (N = 1). HAdV types 4, 7 and 14, which were reported causing ARI outbreaks in the US military and other congregate settings, were found in clustered cases in several US states. Comparative sequence analyses of these isolates revealed the emergence of novel genetic mutations despite the stability of adenovirus genomes.

Conclusion

Routine clinical respiratory pathogen diagnostics or molecular surveillance of respiratory diseases detect adenovirus without determination of HAdV type. Human adenoviruses are genetically diverse and can infect a number of tissues with severities varied from mild to fatal. Enhanced genomic surveillance of HAdV in the US and worldwide will shed light on prevalence, genetic divergence, and viral evolution of human adenoviruses and inform timely risk assessment and countermeasures.

Disclosures

All Authors: No reported disclosures.
2207. Rates of Lower Respiratory Tract Infections Among US Adults Aged ≥18 Years With and Without Chronic Medical Conditions
Authors: Weycker Derek , Averin Ahuva , Houde Linnea , Ottino Kevin , Shea Kimberly M , Gessner Bradford D , Yacisin Kari , Curcio Daniel , Begier Elizabeth , Rozenbaum Mark
Published: December 2022

Background

While it is widely recognized that older adults and adults with chronic medical conditions are at increased risk of lower respiratory tract infections (LRTI), available evidence on the magnitude of increased risk is limited.

Methods

A retrospective observational cohort study using IBM MarketScan Commercial/Medicare Databases (2016–2019) was conducted. The study population included all adults (age ≥ 18 years) and was stratified by age and comorbidity profile (with vs. without high-risk conditions, based on recommendations for influenza vaccination in the United States). LRTI was ascertained on an overall basis as well as by causative pathogen (e.g., respiratory syncytial virus [RSV]) based on corresponding diagnosis codes, and was classified based on care setting (hospital, emergency department [ED], physician office/hospital outpatient [PO/HO]). Incidence rates (and relative rates [RRs]) were generated by age, and within each age group, by comorbidity profile.

Results

Using adults aged 18-34 years as the reference, RR of LRTI generally increased with older age across care settings, with the most marked increase for hospitalizations: for hospitalized-LRTI, RRs ranged from 1.7 for 35-49 years to 78.9 for ≥ 85 years; for ED-LRTI and PO/HO-LRTI, RRs ranged from 1.0 to 3.4 and from 1.4 to 2.1, respectively (Table). Within age groups, LRTI rates were also consistently higher among adults with versus without high-risk conditions: for hospitalized-LRTI, RRs ranged from 9.9 to 21.1; for ED-LRTI, from 2.3 to 3.2; and for PO/HO-LRTI, from 1.6 to 2.5. Age-specific RRs of hospitalized-LRTI due to RSV were largely comparable to overall LRTI results; age-specific RRs for other care settings, and RRs for adults with versus without high-risk conditions across care settings, were generally higher for LRTI due to RSV.

Conclusion

LRTI incidence, especially for events requiring acute inpatient care, is markedly higher among older adults and adults of all ages with chronic medical conditions. Effective vaccines against respiratory pathogens could help reduce this elevated risk of LRTI.

Disclosures

Derek Weycker, Ph.D., Pfizer Inc.: Grant/Research Support Ahuva Averin, M.P.P., Pfizer Inc.: Grant/Research Support Linnea Houde, M.S., Pfizer Inc.: Grant/Research Support Kevin Ottino, M.H.S., Pfizer Inc.: Grant/Research Support Kimberly M. Shea, Ph.D., M.P.H., Pfizer: Employee|Pfizer: Stocks/Bonds Bradford D. Gessner, M.D., M.P.H., Pfizer Inc.: Employee|Pfizer Inc.: Stocks/Bonds Kari Yacisin, M.D., Pfizer Inc.: Employee|Pfizer Inc.: Stocks/Bonds Daniel Curcio, M.Sc., Pfizer Inc.: Employee|Pfizer Inc.: Stocks/Bonds Elizabeth Begier, M.D., M.P.H., Pfizer: Employee|Pfizer: Stocks/Bonds Mark Rozenbaum, Ph.D., M.B.A., Pfizer Inc.: Employee|Pfizer Inc.: Stocks/Bonds.
LB1528A. Fluvoxamine for Outpatient Treatment of Covid-19: A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial
Authors: McCarthy Matthew W
Published: December 2022

Background

The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild-to-moderate coronavirus 2019 (COVID-19) is unclear. Tolerability has also been identified as a potential limiting factor for 100 mg twice daily of fluvoxamine. We evaluated the efficacy of low-dose fluvoxamine 50 mg twice daily for 10 days compared with placebo for the treatment of early mild-to-moderate COVID-19.

Methods

ACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial testing repurposed medications in outpatients with confirmed SARS-CoV-2 infection. Non-hospitalized adults aged ≥ 30 years, experiencing ≥ 2 symptoms of acute infection for ≤ 7 days were randomized to fluvoxamine 50 mg twice daily for 10 days or placebo. The primary outcome was time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Secondary outcomes included composites of hospitalization or death with or without urgent care or emergency department visit by day 28.

Results

Of those eligible for the fluvoxamine arm, 675 were randomized to and received fluvoxamine; 619 received concurrent placebo. Sixty-six percent of the study population reported at least 2 doses of a COVID-19 vaccine. There was no evidence of improvement in time to recovery with fluvoxamine compared with placebo (hazard ratio [HR] 0.96, 95% credible interval [CrI] 0.86–1.06; posterior probability for benefit [HR > 1]=0.2). Sixteen participants (2.4%) in the fluvoxamine arm had urgent care or emergency department visits or were hospitalized compared with 11 (1.8%) in the pooled, concurrent placebo arm (HR 1.5, 95% CrI 0.5–3.0; posterior probability for benefit [HR < 1]=0.1725). No participant in either arm was hospitalized, and no deaths occurred. Adverse events were uncommon in both arms.

Conclusion

Treatment with low-dose fluvoxamine 50 mg dosed twice daily for 10 days did not result in improved time to recovery among outpatients with COVID-19 in the United States during the delta and omicron variant surges.

Disclosures

All Authors: No reported disclosures.
146. Heteroresistance to cefiderocol among Pseudomonas aeruginosa clinical isolates harboring changes in TonB-dependent receptor pathways and AmpC
Authors: Egge Stephanie L , Rizvi Samie A , Simar Shelby R , Dinh An , Hanson Blake M , Arias Cesar A , Cecilia Tran Truc , Miller William R
Published: December 2022

Background

Cefiderocol (FDC) is an iron siderophore cephalosporin with activity against multi-drug resistant (MDR) Gram-negative bacteria. Despite high rates of in vitro susceptibility, treatment failure with the emergence of resistance is still a concern. Heteroresistance, or the presence of a resistant sub-population in a strain that tests susceptible by standard methods, has been suggested as a potential mechanism for this observation. Previously, we showed that MDR Pseudomonas aeruginosa (PA) with changes in the iron siderophore transporters (TBDR) responsible for FDC uptake had decreased zone diameters on Kirby-Bauer (KB) testing as compared to MDR-PA with wild-type TBDRs. Here, we investigated the prevalence of heteroresistance (HR) among TBDR mutants using population analysis profile-area under the curve assay (PAP). Table 1.Pseudomonas aeruginosa strain characteristicsFigure 1.PAP-AUC results of Pseudomonas aeruginosa TBDR mutants v. non-mutant controls

Methods

Previously sequenced MDR-PA isolates were selected for the presence of mutations in TBDR genes within the primary FDC import pathways (pirA, pirRS, piuA, piuD). Isolates harboring pre-existing TBDR mutations (n=12) were compared with wild-type P. aeruginosa strain PA01 and 5 MDR-clinical isolates harboring wild-type TBDRs. FDC MICs were performed by broth microdilution (BMD) in iron depleted media (IDM). For PAP, isolates were grown overnight in IDM before serial dilution and plating on agar with increasing concentrations of FDC. Agreement between BMD, KB, and PAP-AUC HR detection was assessed.

Results

On BMD, 10 of 12 TBDR isolates tested susceptible to FDC (MIC range ≤0.5-2 µg/mL), and all control isolates had an MIC ≤0.5 µg/mL (Table 1). None of the control strains were HR per PAP (Fig 1). However, in the TBDR group, 50% of isolates showed either a resistant (n=2) or HR (n=4) phenotype. Resistance occurred in the setting of both TBDR mutations and either an exogenous β-lactamase (OXA-15 variant) or AmpC variant (PDC-205). Of the HR isolates, one had a change in AmpC Ω-loop (E221K), while the other three had only the PirR frameshift mutation. BMD was not able to identify any of the HR isolates.

Conclusion

A greater number of MDR-PA with TBDR mutations showed resistance or HR to FDC than MDR-PA controls with wild-type TBDRs. Mutations in TBDRs could be a marker for FDC non-susceptibility and potential therapeutic failure.

Disclosures

Cesar A. Arias, MD, PhD, Entasis Phramceuticals: Grant/Research Support|MeMed Diagnostics: Grant/Research Support|Merck: Grant/Research Support William R. Miller, MD, Entasis Therapeutics: Grant/Research Support|UpToDate: Royalties - Topic Contributor.
251. Clinical Features and Outcomes of Pneumothorax and Pneumomediastinum in COVID-19
Authors: Adusumilli Sangeeta , Bhargava Ashish , Franco Rene
Published: December 2022

Background

Pneumothorax (PTX) and pneumomediastinum (PM) have been reported among hospitalized patients with COVID-19. It can occur among patients breathing spontaneously or as a result of barotrauma from invasive positive-pressure ventilation or from medical procedures. We aim to study the clinical features and outcomes of pneumothorax and pneumomediastinum within 48 hours of hospitalization among COVID-19 patients.

Methods

We conducted a multicenter retrospective study among the hospitalized adults with COVID-19 who had pneumothorax and pneumomediastinum within 48 hrs. of admission between November 2020 and December 2021. Cases were identified using ICD 10 codes. Electronic medical records were reviewed after Institutional Board approval.

Results

We identified a total of 21 patients, 12 (57%) only had PTX, 6 (28%) only had PM, and 3(14%) had both. Mean age for the cohort was 57 yrs, 13 (62%) were females, and 14 (67%) were whites. Chronic lung and end-stage renal diseases were noted among 9 (43%) patients followed by obesity in 9 (43%) and diabetes in 4 (19%). A total of 12 (57%) patients have smoked tobacco. At the time of hospitalization, 12 (57%) patients had oxygen saturation ≤94% and 9 (43%) had ≤90%. PTX and PM on admission chest x-ray were noted in 12(57%) and 4 (19%) respectively. 3 (14%) developed them after intubating and/ or after BiPAP. Patients were treated with steroids (90%), remdesivir (62%), interleukin-6 inhibitors (24%), and convalescent plasma (9%). Chest tube was placed in 7 (33%) patients and thoravent in 1 (5%) patient. Complications were septic shock (14%) and deep venous thrombosis (10%). There were 4(19%) deaths.

Conclusion

Spontaneous PTX can be a presenting sign for COVID-19. We noted higher complications and mortality among the COVID-19 patients with PTX and PM than reported in literature. Clinicians should be aware of this potential occurrence, requiring close monitoring and aggressive management. Larger studies can further validate the findings of our study.

Disclosures

All Authors: No reported disclosures.
345. Performance Evaluation of the LifeScale AST Rapid Automated Antimicrobial Susceptibility System
Authors: Snyder James W , Chaudry Nadia , Hoffman Wesley
Published: December 2022

Background

Reducing the time for antimicrobial susceptibility test (AST) results directly from positive blood cultures is essential for managing patients with suspected sepsis/bacteremia caused by the most predominate Gram-negative bacteria. The aim of this study was to evaluate the LifeScale AST system using a custom LifeScale 96-well broth microdilution panel. The system employs a microfluidic sensor that detects and measures the mass of individual organisms at high throughput with MIC results available within 4-6 hours.

Methods

Fresh blood cultures detected as positive by a continuous monitoring blood culture system and confirmed by Gram stain for Gram-negative rods were enrolled in the study. If a mixed Gram stain was observed, the sample was ineligible for the study. Testing was performed within 12 hours of the blood culture being flagged as positive. LifeScale performance was evaluated by comparing MICs and interpretive results to the MicroScan Walkaway 96. The following metrics were assessed: Essential Agreement (EA), Category Agreement (CA), Very Major Discrepancy (VM), Major Discrepancy (M), and Minor Discrepancy (Min).

Results

A total of 65 samples were tested that met criteria for LifeScale (intended) claimed species: E. coli (N = 45), Klebsiella pneumoniae (N = 9), Pseudomonas aeruginosa (N = 8), Klebsiella aerogenes (N = 2), and one isolate each of Acinetobacter lwoffi, Acinetobacter species, and Klebsiella oxytoca. Three organisms, 2 E. coli, one P. aeruginosa, were excluded due to insufficient growth or amplitude error. The average time to results was 4.31 hours. Following resolution of discrepant AST results, there was 97.92% final agreement between LifeScale and MicroScan Walkaway 96, 36% categorical agreement, no very major discrepancies, and 0.16% major discrepancies.

Conclusion

The LifeScale system provided reliable AST results for Gram-negative organisms directly from positive blood cultures with minimal hands-on time (approximately less than 8 minutes), allowing for more rapid antimicrobial management compared to standard methods. This is the first AST system that detects and measures the mass of each organism compared to traditional growth-based AST methods. Results for additional organisms will be provided once development is complete.

Disclosures

All Authors: No reported disclosures.
357. Risk Factors and Antifungal Susceptibility Pattern of Candida parapsilosis Candidemia: A Single centre Observation study from Central India.
Authors: Garg Rahul , Wankhade Archana B , Das Padma
Published: December 2022

Background

Candida parapsilosis infection has recently emerged as an important antifungal-resistant nosocomial pathogen having the unique ability to grow on inanimate objects and surfaces. The aim of this study was to analyze the predisposing conditions, outcome, and antifungal susceptibility pattern of candidemia due to C. parapsilsosis complex.

Methods

A single-center retrospective observational study from January 2019 to December 2021 of all cases of candidemia was carried out at an 890-bedded University Hospital in central India. Data regarding demographic characteristics and clinical risk factors were collected from the patient’s medical records. Antifungal susceptibility testing was performed; MIC results were interpreted according to CLSI breakpoints (M27-A3). Risk factors and outcome association at the species level were analyzed by using Fisher’s exact test.

Results

Of 211 patients diagnosed with Candidemia during the study period, 53 (25.1%) were infected with C. parapsilosis which represented the second most frequently isolated yeast after C. albicans (n=98; 46.4%). A total of 26 (49%) C. parapsilosis isolates were non-susceptible to fluconazole (NSF), which included resistant (n = 20) and susceptible dose-dependent (n = 06) isolates. The median patient age was 63 years.15.3% were neonates. The majority of patients (90%) suffered from multiple comorbidities, diabetes mellitus (43%) being the commonest. A total of 55 % of patients underwent surgical intervention within 30 days from the onset of candidemia. Univariate logistic regression revealed that ICU admission (odds ratio [OR] 2.45), central venous catheter use (OR 2.46), renal impairment (OR 1.687) were more common among FNS isolates than fluconazole-susceptible (FS) isolates (all P < 0.05). The overall crude mortality at 30 days was 36%; higher in patients infected with FNS isolates than FS isolates.

Conclusion

There is an increase in the absolute number of invasive infections by C. parapsilosis observed over the past 2 years. At this moment, the percentage of fluconazole non-susceptible C. parapsilosis is very high and poses a threat to infected patients and has a clinical impact in our hospital. Being able to identify and treat infections caused by this pathogen is important to prevent clinical outbreaks.

Disclosures

All Authors: No reported disclosures.
434. Healthcare Personnel Interactive Pathogen Exposure Response System
Authors: Smith Lauren , Fallon Susan , Virk Zunaira , Salinas Alejandra B , Curless Melanie , Cosgrove Sara E , Maragakis Lisa , Rock Clare , Klein Eili ,   CDC prevention epicenter program
Published: December 2022

Background

Infectious disease exposure investigations in the hospital are labor-intensive for the infection prevention and control (IPC) team and vulnerable to healthcare personnel (HCP) recall bias. We developed an electronic health record (EHR) algorithm to identify and rank patient-HCP interactions based on the likelihood and intensity of exposure.

Methods

We compared conventional and EHR-based findings from seven exposure investigations conducted between November 1, 2020 and February 1, 2022 at The Johns Hopkins Hospital (JHH), a 1095 bed academic tertiary center in Baltimore, MD. Conventional exposure investigations were conducted for hospitalized patients who tested positive for SARS-CoV-2 while not in COVID-19 isolation precautions. IPC contacted department managers to identify and report potentially exposed HCPs to occupational health. The EHR-based method identified HCP-patient interactions based on clinical data such as documentation in the flowsheet, medication administration, etc. A score was calculated for each HCP based on the estimated duration and intensity of the contact. Genomic sequencing of available samples was performed to investigate transmission events.

Results

Overall, the EHR-based system identified 75% (59/79) of the HCPs identified by conventional exposure investigations and 100% of those who document in the EHR. In contrast, it was unable to identify any potentially exposed individuals who do not document in the EHR (Table 1). All patient-HCP COVID-19 transmissions identified by conventional investigation and confirmed through genomic sequencing were identified by the EHR-based system, and all had high-intensity scores (i.e., top quartile of the list of exposed individuals). Table 1.Comparison of Conventional and EHR Based COVID-19 Exposure Investigations

Conclusion

We found clinical EHR data was highly sensitive and specific in identifying potentially exposed HCPs compared with conventional exposure investigations. The inability to detect interactions with support staff or others who do not document in the EHR was a limitation and suggests that EHR data can augment but not replace conventional exposure investigations. The system’s speed, ease, and lower resource requirements make it a promising tool to more efficiently complete exposure investigations in healthcare settings.

Disclosures

Sara E. Cosgrove, MD, Basilea: Member of Infection Adjudication Committee.
890. Bundled Antimicrobial Stewardship Intervention Reduces Inpatient Third Generation Cephalosporin Use without Restriction
Authors: Hopkins Teri L , Yang Linda , Douglass Dana , Sanchez Chelsea , Morneau Kathleen , Cadena-Zuluaga Jose , Walter Elizabeth
Published: December 2022

Background

The use of third generation cephalosporins (3GC) has been linked to collateral damage such as increased risk of infection with C. difficile, ESBL-producing organisms, VRE, and MRSA. Reduction in use of 3GC has been shown to reduce prevalence of these infections, particularly with C. difficile and ESBLs. An increase in 3GC use was observed at our facility in 2019 and 2020, likely due to targeted fluoroquinolone reduction initiatives in 2019 and COVID-19 surges in 2020. A multifaceted intervention targeting 3GC reduction without restriction was implemented starting in December 2020. Figure 1Monthly third generation cephalosporin use (Days of Therapy per 1000 patient days) from January 2019 to December 2021.

Methods

We conducted a retrospective quasi-experimental study evaluating the impact of a combination of interventions intended to reduce 3GC use. The intervention included modification of local clinical guidelines for urinary tract infection (UTI) and community acquired pneumonia (CAP), provider education, and daily review of active 3GC orders in 2021. Local guideline changes include preferred use of ampicillin/sulbactam and amoxicillin/clavulanate for CAP and cefazolin and cephalexin for UTI over 3GCs. Use of first generation cephalosporins for UTI was supported by local antibiogram susceptibilities for common UTI pathogens. Days of therapy (DOT) per 1000 patient days were collected monthly and yearly for ceftriaxone, ceftazidime, cefpodoxime, and cefdinir for pre-intervention (January 2019 to December 2019 and January to December 2020) and post-intervention (January 2021 to December 2021) periods.

Results

3GC use significantly decreased from 89.52 DOT per 1000 patient days in 2020 to 53.06 in 2021, a 40.73% reduction. To account for increases in antibiotic use during COVID-19 surges in 2020 as a potential confounding variable, 2019 3GC use was also compared to 2021 use. A 31.40% decrease was seen, with 77.35 DOT per 1000 patient days in 2019. This effect was sustained through COVID-19 surges in January and August 2021 (Figure 1).

Conclusion

A combination of interventions without restriction of 3GC was successful in reducing inpatient use of this class of antibiotics, including through two COVID-19 surges in 2021. Further study is required to determine impact on clinical outcomes, such as C. difficile and antimicrobial resistance rates.

Disclosures

All Authors: No reported disclosures.
909. Impact of Implementing an IV to PO Antibiotic Treatment Protocol for Orthopedic Infections on Prescribing Habits and Health Utilization Outcomes
Authors: Gallagher Chanah , Benefield Russell J , Certain Laura
Published: December 2022

Background

The Oral versus Intravenous Antibiotics for Bone and Joint Infection Trial concluded that oral antibiotics administered during the first six weeks of therapy for orthopedic infections were non-inferior to parenteral antibiotics. Previously, we also conducted a retrospective cohort study of patients at our center with an orthopedic infection. Patients transitioned to oral therapy had significantly fewer adverse events and similar incidences of one year treatment failure compared to patients maintained on parenteral vancomycin.

Methods

To increase use of oral antibiotics for orthopedic infections, we created a protocol for changing IV to PO antibiotics prior to hospital discharge. We evaluated its effect on prescribing practices and healthcare utilization outcomes. Patients with an orthopedic infection were included if they were discharged within the 90-day pre- and post-protocol study periods, had an inpatient Infectious Disease consult, and were initiated on parenteral vancomycin while inpatient. The primary outcome compared the incidence of oral antibiotics prescribed at discharge. Secondary outcomes included incidence of adverse drug reactions, discharge dispositions, hospital length of stay, canceled follow-up appointments, unplanned readmissions, and early treatment failure.

Results

Fifty patients were included, 22 and 28 patients in the pre- and post-protocol groups, respectively. Twenty-three (82%) patients in the post-protocol group were prescribed oral antibiotics at discharge compared to 8 (36%) patients in the pre-protocol group. Twenty-three (82%) patients in the post-protocol group were discharged home compared to 13 (59%) patients in the pre-protocol group. Of note, 7 (25%) patients in the post-protocol group had early treatment failure compared to 1 (5%) patient in the pre-protocol group, and 8 (29%) patients in the post-protocol group compared to 4 (18%) patients in the pre-protocol group had an unplanned readmission.

Conclusion

Providing physicians with an oral antibiotic protocol for orthopedic infections significantly increased the number of oral antibiotic prescriptions at hospital discharge, but the higher rates of treatment failure observed after protocol implementation are concerning and warrant further investigation.

Disclosures

Russell J. Benefield, PharmD, BCPS-AQ ID, Paratek Pharmaceuticals: Grant/Research Support.
946. Establishing Antimicrobial Stewardship Programme at Four Secondary Care Hospitals in India through Hub and Spoke Model with Christian Medical College, Vellore as Guiding Centre
Authors: Kumar Prasanna , Rupali Priscilla
Published: December 2022

Background

The high burden of antimicrobial resistance in India necessitates an urgent implementation of Antimicrobial Stewardship programs (ASP). Most ASP are based at tertiary care centres, with sparse data available regarding the effectiveness of an ASP in a low resource primary/secondary care setting.

Methods

We adopted a hub and spoke model to implement ASP in these low resource settings. The study consisted of three phases. Initial phase captured baseline antimicrobial days of therapy DOTs data with no feedback, followed by intervention phase wherein a few chosen interventions were implemented. Physicians of four chosen hospitals were trained via a blended customized distance education training programme, assisted with development of antibiogram based on their local hospital microbial resistance patterns via WHONET, followed by development of hospital specific antibiotic policy and augmentation of the existing laboratory skills by training personnel at the central facility. This was followed by a post intervention phase with a prospective review and feedback by trained personnel with assessment of DOTs.

Results

During the baseline phase, 1459 patients from all four sites were enrolled; 1233 patients were enrolled in the intervention phase. Both groups had comparable baseline characteristics. The key outcome, DOT per 1,000 patient days, was 1952.63 in the baseline phase. The DOT/1000 patient days was significantly lower in the post intervention period, at 1483.06 (P =0.001). Quinolones, Macrolides, Cephalosporins, Clindamycin, and Nitroimidazole use significantly decreased in the post intervention phase. Rate of de-escalation was significantly higher in the intervention phase compared to the baseline phase (44% vs 12.5%; P < .0001), suggesting a definite trend with regard to the judicious use of antibiotics. Post intervention phase revealed that 79.9% of antibiotic use was justified. Overall, the recommendations given by the ASP team were fully followed in 946 cases (77.7%), partially followed in 59 cases (4.8%), and not followed in 137 cases (35.7%). No adverse events were noted.

Conclusion

Our Hub and Spoke model of ASP was successful in implementing ASP in secondary care hospitals in India which is the need of the hour.

Disclosures

Priscilla Rupali, MD, DTM&H, PFIZER: Grant/Research Support|PFIZER: Grant/Research Support.
1123. EDP-235, A Potent and Once-daily Oral Antiviral, Demonstrates Excellent Penetration into Macrophages and Monocytes, with the Potential for Mitigation of Cytokine Storm in High-Risk COVID-19 Patients
Authors: Li Yang , Zang Tianzhu Indy , Xu Lisha , Leonard Daniel , Hoang Khanh , Greizer Tim , Zhang Shucha , Foster Caroline , Huang Meng , Kibel Jonathan , Klaene Joshua , Or Yat Sun , Jiang Li-Juan
Published: December 2022

Background

Macrophages, including lung alveolar macrophages (AM), and monocytes are the first lines of defense against SARS-CoV-2. Several reports have suggested that SARS-CoV-2 can hijack AM and monocytes for replication and viral spread, which may, in turn, drive the cytokine storm associated with severe COVID-19. Herein, we describe one of many advantageous features that EDP-235, a novel and potent SARS-CoV-2 3C-like protease (3CLpro) inhibitor under development as a once-daily oral antiviral therapy for COVID-19, displays - excellent penetration into macrophages and monocytes.

Methods

Intracellular uptake of EDP-235 was tested side-by-side with nirmatrelvir in rat lung AM, human monocytes and human macrophages. To determine the in vivo drug distribution into lung AM, rats were dosed orally with 25 mg/kg of EDP-235 or nirmatrelvir and plasma and AM drug levels were analyzed by LC/MS/MS.

Results

The ratios of intracellular to extracellular concentrations of EDP-235 in rat lung AM, human monocytes and human macrophages were 22.8, 22.7 and 30.5, respectively. In contrast, nirmatrelvir had ratios of 1.2 to 1.5 in these cells. Consistent with the in vitro observations, EDP-235 showed favorable rat AM penetration with an AUC0-24 ratio of 28.4 (AM over plasma), and nirmatrelvir had much less rat AM penetration with an AUC0-24 ratio of 0.5 (AM over plasma). EDP-235 had respective AUC0-24 values of 9.6 and 271.9 h·μg/mL in rat plasma and AM, while the AUC0-24 values of nirmatrelvir in rat plasma and AM were 2.7 and 1.2 h·μg/mL, respectively.

Conclusion

EDP-235, a novel and potent SARS-CoV-2 3CL protease inhibitor, demonstrated excellent penetration into monocytes and macrophages, including lung AM. EDP-235 has the potential to eliminate the viral replication of SARS-CoV-2 in these critical immune cells, thus mitigating macrophage-mediated cytokine storm in high-risk COVID-19 patients. Clinical trials with EDP-235 for COVID-19 treatment and prevention are ongoing.

Disclosures

All Authors: No reported disclosures.
Introduction
Authors: Panaccio Claude
Published: December 2022

The Introduction spells out the aim and scope of the book. It explains in what sense this work is an “introduction” to William of Ockham’s nominalism and that it stresses the philosophical interest of this medieval approach in the context of today’s philosophical debates. It briefly outlines the three central theses of Ockham’s nominalism, touching on the notion of singularity of things, the notion of relations, and the concept of quantities. Ockham’s influence on later thinkers, as well as the context in which he produced his works, are outlined. The Introduction also provides a short biography of Ockham.
Epistemology
Authors: Panaccio Claude
Published: December 2022

Chapter 5 explains how human knowledge is possible according to Ockham in a world exclusively made up of individuals. For this, it first describes Ockham’s theory of cognitive acts: intuitive cognitions, abstractive cognitions, connotative conceptual acts (including basic relational concepts), and judgements. The chapter then introduces Ockham’s theory of mental language as endowed with a grammar and composed both of concepts that are naturally acquired and of innate syncategorematic terms (conjunctions, quantifiers, prepositions, etc.). It shows, finally, how this mental apparatus gives rise to evident cognition, to knowledge of both contingent and necessary propositions through demonstrations and inductive reasonings, and to the construction of scientific disciplines.
Mary Shepherd
Authors: Boyle Deborah
Published: December 2022

This guide leads readers systematically through the arguments of Mary Shepherd’s two books. Chapters 1–4 cover the arguments in the Essay upon the Relation of Cause and Effect (1824), where Shepherd argues that causal principles can be known by reason to be necessary truths and that causal inferences can be rationally justified. Shepherd’s primary target in this work is Hume, but she also addresses the views of Thomas Brown and William Lawrence. Shepherd considered her second book, Essays on the Perception of an External Universe, and Other Subjects Connected with the Doctrine of Causation (1827), to be an extension of the earlier project on causation; here, she appeals to the causal principles established in the first book to argue that we can know through reason that an external world of continually existing objects must exist independently of us, as the causes of our sensations. Chapter 5 of this Guide addresses Shepherd’s accounts of sensation and reasoning; Chapters 6–9 lead the reader through the arguments of the Essays, as well as laying out Shepherd’s views on skepticism and Berkeleyan idealism, her accounts of mind and body, her philosophy of religion, and the solutions she offers to two puzzles about vision.
Shepherd’s Life and Context
Authors: Boyle Deborah
Published: December 2022

This chapter provides a biographical sketch of Mary Shepherd, as well as an overview of the contents of her two books. In An Essay upon the Relation of Cause and Effect (1824), Shepherd argues that causal principles can be known by reason to be necessary truths. In Essays on the Perception of an External Universe, and Other Subjects Connected with the Doctrine of Causation (1827), Shepherd extends the earlier project, arguing that through our knowledge of causation, we can also know through reason that an external world of continually existing objects must exist independently of us. This chapter also provides a survey of the philosophical landscape in which Shepherd was working, including the Scottish common sense philosophy of Thomas Reid, Dugald Stewart, and Thomas Brown; Berkeleyan idealism; the French “ideologues”; and British moral theorists. The chapter ends with a brief account of the reception of Shepherd’s work.
Sensing and Reasoning
Authors: Boyle Deborah
Published: December 2022

Shepherd’s goal in Essays on the Perception of an External Universe is to prove, from facts about perceivers’ transitory sensations, that there is an independent, continuously existing world of external objects that cause those sensations. Since Shepherd’s arguments turn on claims about sensations, it is important to understand what she means by ‘sensation,’ as well as related terms like ‘perception,’ ‘idea,’ and ‘notion.’ This chapter surveys these key concepts in Shepherd’s philosophy of mind. It also explores her accounts of various mental faculties, including sensory perception (and her claim that motion is a sense), memory, imagination, will, and understanding. Her causal account of reasoning and her distinctive accounts of demonstrative and probable reasoning are also discussed and contrasted with Hume’s views.
Religion
Authors: Boyle Deborah
Published: December 2022

This chapter surveys various issues in philosophy of religion that Shepherd considers in her Essays on the Perception of an External Universe. It covers her views about whether or not there are ever good reasons to believe in reported miracles and her objections to Hume’s account of such beliefs; her teleological and cosmological arguments for belief in God; her views on the possibility and nature of an afterlife; and her explanation of divine causation, given her belief that all causation involves the synchronous mixing of qualities. The chapter ends with some speculation about connections between Shepherd’s beliefs and emanationism and Spinozism.
Economic Structure and Access
Authors: Dore Poornima , Narayanan K.
Published: December 2022

In this Chapter the definition and rationale of the ‘region’ as a unit of analysis is discussed, and among other things, the detailed methodology of calculating regional value added, calculating sectoral shares and also the diversity index etc. is explained. A deep discussion on data sources at the regional level as well as the analytical techniques that they lend themselves to which we use in later chapters, are explained here.
Inter-temporal Differences across Regions
Authors: Dore Poornima , Narayanan K.
Published: December 2022

In this Chapter it is argued that if there is indeed a typology of regions that is different in the two time periods 2004-05 and 2011-12, then which are those variables that actually account for these differences. A detailed discriminant analysis is carried out for a set of variables across both time periods, the results of which reveal certain distinguishing factors. Opportunities for reaping advantages of economies of Scale and scope, along with skills and access to finance emerge as important discriminants, highlighting the need for a dynamic policy making.
“More than a Contract”
Authors: Chettiar Teri
Published: December 2022

This chapter continues the examination of the rising value attributed to intimate family relationships in the post-1945 decades by focusing on the important role that marriage counseling and therapy services played in promoting its wide-ranging benefits for both individual emotional health and national wellbeing. The chapter explores the implications of state support for relationship therapy services and uncovers how the expansive social health objectives of marriage therapy pioneers actively contributed to the welfare-state project of creating a “classless” social democratic society. Citizens’ access to loving relationships were cast as the great social equalizer as marriage therapists argued that individuals were primarily shaped through their desire for emotional, rather than socio-economic, wellbeing. This chapter also investigates the unintended political effects of marriage therapy, revealing how therapists’ language and concepts shaped a new public discourse of relationship “breakdown” and provided persuasive (ostensibly scientific) arguments for liberalizing the divorce law. Tracking divorce reformers’ mobilization of psychiatric understandings of intimate relationships in framing and legitimizing their demands for change, I investigate the effects of the dissemination of this new body of psychosocial knowledge in shaping public expectations and related political discourses of emotional fulfilment and psychological freedom.
Inherently Unstable
Authors: Chettiar Teri
Published: December 2022

Chapter 6 investigates another set of activist campaigns prioritizing access to intimate relationships, but this time directed at the freedoms of young people: the sexual expression of teenagers and queer men under the age of twenty-one. It examines how the longstanding psychiatric pathologization of adolescence as a period of emotional instability became the basis for closing down a series of explosive controversies surrounding teenage sexuality in the 1970s. By the end of the decade, the democratic and emotionally enlightened “good society” had come to be equated with the guarantees of privacy and sexual freedom. I argue that this freedom, however, was rooted in associations between adulthood and emotional maturity and legitimated through its exclusion of children as the proper recipients of the protection of the state. The infantilization of adolescents and young queer men provided a compelling rationale for not offering consistent sex education in British schools and NHS-provided birth control to young women, as well as for maintaining age-based restrictions in the laws surrounding sexual consent.
“Home Is for Many a Very Violent Place”
Authors: Chettiar Teri
Published: December 2022

This chapter considers the surprising durability of the intimacy ideal in the face of the “discovery” of family violence in white middle-class families in the 1970s. This chapter explores influential exposés of the routineness of middle-class family violence produced by antipsychiatrists, second-wave feminists, and activists associated with the battered women’s refuge movement. It reveals that the mother-child relationship took on even greater emotional significance as the basis for a fulfilling private life despite political movements that attempted to destabilize other traditional normative views of gender roles. This chapter demonstrates the enduring preoccupation with emotional relationships in this era of privacy, especially spotlighting the intensified importance of mothers’ emotional labor and presumed natural capacity for emotional connection even though intimacy in families was increasingly exposed as having a dangerous dark side.
An Intellectual History of Federalism
Authors: Arban Erika
Published: December 2022

The chapter briefly retraces the intellectual history of federalism and offers an account of federalism from the point of view of constitutional theory. In the chapter, federalism is presented as a constitutional principle that advocates division of authority and dispersion of powers among different societal groups and organizations, to reflect what Elazar dubbed ‘self-rule’ and ‘shared rule.’ It is also construed as an umbrella term that includes different experiences. In fact, while the US federation emerged in 1787 is usually regarded as the quintessential classic federal model, in recent years federal principles and elements have been adapted to a variety of situations, blending centripetal and centrifugal forces, federal and non-federal experiences, in a process leading to always novel experimentations. The discussion of cities in federal constitutional theory—which lies at the core of this volume—is a compelling illustration of this recent intellectual evolution in federalism design. The existing literature on federalism and federal theory is truly gigantic and therefore it is impossible to treat it exhaustively in a very limited space. The present chapter will thus identify what the author believes are the intellectual milestones of federal history and theory (section II) before delving into the historical treatment (or lack thereof) of cities as federal constitutional entities or ‘units’ (section III).
Subsidiarity and the City
Authors: Cahill Maria , O’Sullivan Garry
Published: December 2022

It seems to be a near universal feature of the intellectual project of justifying enhanced formal and material autonomy for cities that adherents invoke subsidiarity and believe that it offers a presumptive endorsement of the case for city autonomy. This chapter examines the symbiotic interplay between subsidiarity and the city, by exploring four types of justifications for increasing city autonomy—the consistency argument, the expertise argument, the stake-holding argument, and the distinctiveness argument—and the extent to which they track with four models of subsidiarity—subsidiarity-as-federalism, subsidiarity-as-efficiency, subsidiarity-as-democracy, and subsidiarity-as-respect-for-distinctiveness. It will be argued that this reflective exploration yields important learning opportunities on both sides. For subsidiarity scholars, closer analysis of the concrete case of city autonomy exposes the dangers of eliding the differences between subsidiarity and federalism and between subsidiarity and efficiency, and showcases the surprising attractiveness of a model of subsidiarity that focuses on the distinctiveness of the (putative) decision-making level involved. For city scholars, deeper reflection on the challenges that subsidiarity scholarship poses to it will demand, first, greater clarity about how the city is to be defined and, second, greater specificity about the level of autonomy the city should bear.
Cities, Federalism, and Criminal Law Reform
Authors: Partlett William
Published: December 2022

Federal states are grounded on the idea that decentralization yields important advantages. Federations, however, frequently ignore these built-in advantages when reforming criminal justice systems. This is a mistake: federalism’s diffusion of power can make criminal justice systems fairer and more effective. This chapter will argue that empowering cities can help to introduce the benefits of federalism to criminal law reform. In particular, urban accountability mechanisms—many of which already exist—provide cities with mechanisms for understanding, debating, and holding accountable the use of discretion by police and prosecutors. Expanding the reach and scope of these urban accountability mechanisms will improve trust between executive law enforcement and the urban community and help to ensure a fairer and more effective criminal justice system.
Privacy and the City
Authors: Petkova Bilyana
Published: December 2022

Privacy is a distinguishing feature of large, cosmopolitan cities whose rising economic and political power calls for new understanding of federalism in the digital age. This chapter explores how the empirically studied link between privacy and big cities translates into a normative commitment to diversity and receives legal expression in varying privacy protections across North-American and European cities. The examples the chapter focuses on are taken from the context of census data, the Equifax credit score, and Facebook data breaches as well as public–private agreements between administrative agencies, and between the public and private sector in the provision of broadband internet, in the shared economy, and in mega smart city projects. The complex picture that emerges from this analysis shows how cities undertake two distinctive roles that might come into conflict: that of privacy activists and of data stewards. As privacy activists, city attorney generals, particularly in the United States, litigate against the state to protect the personal information of vulnerable migrant city dwellers but are also on the forefront of litigation against private companies that might compromise privacy. Publicly spirited, such action on behalf of various cities is not devoid of commercial interest in the face of growing demand for urban infrastructure. As data stewards however, cities might sidestep the public interest altogether—as arguably happened in the case of Toronto Waterfront in Canada and in Barcelona, Spain where rhetoric prevailed over action. This chapter argues that to optimize data privacy but also data sharing in the public interest constitutional recognition for city power should come with the reckoning of the legal mechanism of data trusts as an independent broker between the City and its urban dwellers.