bluuebunny/crossref_metadata_2025 huggingface dataset:
1657. Real-life implementation of a machine learning based algorithm for urinary tract infection antibiotic resistance management in the community setting
Authors: Ben David Shirley Shapiro , Romano Roni , Palatshi-Nadler Liron , Greenfeld Shira , Rahamim-Cohen Daniella , Lerner Uri
Published: December 2022

Background

At outpatient visits, one of the most common reasons for antibiotics administration is Urinary Tract Infection (UTI), where selection of the appropriate empiric antibiotic requires consideration of multiple factors. The aim of this study was to assess the implementation and effectiveness of a machine learning based model for UTI antibiotic resistance, embedded in the physician's medical encounter workflow.

Methods

A longitudinal, nationwide prospective study, conducted by Maccabi Healthcare Services, a health organization in Israel serving 2.5 million members, with about 120,000 medical encounters with a UTI diagnosis per year. We adopted a machine-learning algorithm to predict antibiotic susceptibility using personal electronic health record data. Then, a designated order set was incorporated within our electronic health record interface, named 'UTI Smart-set' (UTIS). When a UTI diagnosis code is selected by the physician, a pop up screen emerges with the recommended antibiotics. The recommendation is based on the personal predicted susceptibility model developed, followed by the optimal narrow-spectrum antibiotic as recommended by the organizational clinical guidelines. . We analyzed the antibiotic prescriptions that were recommended by UTIS, the actual prescriptions given, and compared them to the culture results and the pathogen antibiotic resistance profile.

Results

From July 1st 2021 to April 1st 2022, among 73,148 medical encounters with a UTI diagnosis, 34,659 antibiotic prescriptions were provided. In 21,924 (63.2%) encounters the UTIS recommendation was accepted whereas in 12,736 (36.7%) it was declined. Use of the UTIS recommendation resulted in a 31.8% reduction of the measured resistance to antibiotics prescribed to patients, 10.9% (2,224) of cases who followed the UTIS recommendation for antibiotics versus 16.0% (1,879) case who did not. A 47% cumulative improvement in adherence to clinical guidelines was also observed using the tool.

Conclusion

This unique, point of care, antibiotic stewardship tool, based on a combination of clinical guidelines and personalized medicine, led to a major improvement in the selection of appropriate antibiotics.

Disclosures

Shirley Shapiro Ben David, MD, pfizer: Grant/Research Support.
1407. Increasing access to COVID-19 testing in underserved Black American neighborhoods
Authors: Avery Elizabeth , Olinger Tamara , Suzuki Sumihiro , Cartwright Yolanda , Jenkins LaDawne , Chaisson Lelia H , Moss Angela , Davis Elizabeth , Logan Latania K , Epting Steve , Lynch Elizabeth
Published: December 2022

Background

Black Americans have been disproportionately impacted by COVID-19, with systemic inequities contributing to increased incidence and mortality. In Chicago, access to COVID-19 testing was scarce in many predominantly Black neighborhoods early in the pandemic, exacerbating inequities. We aimed to assess uptake and yield of a COVID-19 testing campaign to increase access in high-risk, underserved Chicago communities.

Methods

The Alive Church Network (ACN) is a community-driven coalition of Black pastors and public health researchers developed to address health inequities in Chicago. For this initiative, ACN implemented two strategies to improve access to COVID-19 testing in underserved neighborhoods: 1) church-based testing, with nurses and community health workers (CHWs) stationed in churches to perform PCR testing for community members and church staff (Dec 2020-Dec 2021) and 2) community site testing, with nurses and CHWs deployed to 8 local sites (e.g., Salvation Army) to conduct weekly PCR testing for employees and clients (May 2021-Mar 2022). We assessed characteristics of individuals undergoing testing; symptom and exposure history; and COVID-19 positivity. In addition, we compared positivity for ACN sites with Chicago citywide positivity over time.

Results

A total of 3420 tests were performed for 1703 individuals. Of those tested, 931 (54.7%) were tested at churches and 772 (45.3%) were tested at community partner sites. Those presenting to churches were older (mean 44.8 vs. 39.1 years), more likely to be female (56.5% vs. 48.5%), and more likely to have a chronic medical condition (37.1% vs. 22.5%, Table). Prevalence of COVID-19 symptoms and exposure history were similar for those presenting to church and community sites (Table). Overall, ACN test positivity was similar to Chicago citywide positivity; however, ACN test positivity was much higher during the Omicron surge (24% vs. 11%, Figure).

Characteristics of individuals tested for COVID-19 at church and community sites

COVID-19 test positivity, ACN sites vs. Chicago citywide

Conclusion

The ACN testing campaign increased access to COVID-19 testing in underserved neighborhoods in Chicago and had high yield during the Omicron surge. Church-based testing was successful for reaching older, medically vulnerable individuals. Ensuring widespread access to testing is essential for health equity and to reduce COVID-19 morbidity and mortality.

Disclosures

All Authors: No reported disclosures.
1409. Infectious Complications in People Who Inject Drugs (PWID): A Retrospective Review and Recommendations for Improved Care
Authors: Martin Elena K , Wang Caroline , Lier Audun J , Azab Nancy , Fries Bettina F
Published: December 2022

Background

Suffolk County, NY is home to 1.5. million people and has a higher drug related deaths per capita rate compared to NY state average (19.9 vs 14.9/100,000). Injection drug use (IDU) is associated with complicated infections and inadequate treatment of substance use disorder (SUD) leads to relapse of infection and treatment failure. Unfortunately, access to SUD treatment services is not optimized in Suffolk County. We aimed to characterize the incidence and outcome of admissions for PWID and identify modifiable risk factors which can contribute to suboptimal care for PWID.

Methods

A retrospective review of SBUH electronic medical record was conducted from Jan 1, 2015 to June 1, 2021. Length of stay, discharge disposition, 6-month hospital readmission, insurance, employment and housing status, SUD history plus infection type and antimicrobial receipt were assessed.

Results

Of 425 patients (pts) admitted between Jan 1, 2015 to June 1, 2021, the median age was 34 years, 93% were white, and 59% male. Most pts. (89%) reported stable housing and had government insurance. The average length of stay was 13.6 days with 1/3 of pts. requiring ICU admission. Notably, 34% of pts left prematurely against medical advice and 34% were readmitted within 6 months. Formal ID (63%) and Psychiatry (62.5%) consults were not requested on all pts. Only 18% and 25% of pts. were treated with methadone or suboxone. 60% of screened pts. had HCV but 50% were not screened for co-infections. Complicated skin and soft tissue represented 70%, sepsis/bacteremia 11%, osteomyelitis/arthritis 10% and endocarditis 12% of the cases. 14.8% of pts. with endocarditis died, 48% had recurrent endocarditis, 52% needed surgery including 12% of repeat valve replacements. Staphylococcus species caused 42% of infections. About 2/3 of pts required continued antibiotic therapy at time of discharge, leading to delayed discharge for IV catheter placement.

Conclusion

Managing infectious complications in PWID is a multi-faceted endeavor extending beyond inpatient care. This study highlights the need for standardized treatment plans involving specialized case managers to reduce LOS and AMA discharges, improve screening for infections and integrate SUD treatment for PWID.

Disclosures

All Authors: No reported disclosures.
1410. Methamphetamines and Serious Injection Related Infections: Epidemiology and Outcomes of Alabama’s Drug Crisis
Authors: Prados Myles D , Eaton Ellen , Levy Sera , Bassler John R , Gagnon Kelly , Jeziorski Madison M , Bradford Davis , Leisch Leah J , Li Li
Published: December 2022

Background

The U.S. is facing a steep increase in infectious consequences of intravenous drug use due to the ongoing opioid crisis, surging methamphetamine use, and health care disruptions caused by COVID-19. We hypothesize that the sociodemographic and clinical outcomes of persons who inject drugs (PWID) differ based on their drug of choice (opioids, methamphetamines). Further, we hypothesize that the OUD (opioid use disorder) continuum, including linkage and retention in OUD treatment, will vary depending on co-occurring methamphetamine use. By elucidating differences in these groups, we aim to identify opportunities for interventions along the care continuum.

Methods

This is a retrospective study of hospitalized PWID receiving care at the University of Alabama at Birmingham Hospital for a serious injection related infection (SIRI) between 1/11/2016 and 4/24/2021. We queried the EMR for clinical data and health outcomes. We extracted data on substance use disorder(s), treatments, and linkage to care through review of primary and addiction medicine consultation notes. Using statistical measures of association, we compared demographic factors and clinical outcomes among groups; delineating between those with and without methamphetamine use, and without OUD. When appropriate, additional comparisons were made to detect statistical differences between factors and those with and without methamphetamine use.

Results

Of 370 PWID, 286 had OUD, 94 had OUD and methamphetamine use, and 84 had another substance use disorder. There were significant differences according to drug use disorder with patients with OUD and meth use being mostly White (99%), 42% female, and younger relative to those who use opioids only. Patient directed discharge was most common among those with OUD plus meth use, but death was highest for those with OUD only. The OUD care continuum was similar and alarming for both groups with many gaps in care. Figure 1.OUD Care continuum for PWID with SIRI for those with and without comorbid meth use disorder

Conclusion

PWID with SIRI are a diverse group with significant differences based on substance of choice, but all experience suboptimal hospital outcomes. There are opportunities to improve linkage and retention across the care continuum, most noticeably outpatient linkage.

Disclosures

Ellen Eaton, MD, MPH, Gilead HIV Research Scholar: Grant/Research Support|Gilead HIV research scholar: Grant/Research Support.
1415. Successful Model for Pharmacy Driven Harm Reduction Services to Link Veterans Who Inject Drugs Into Care
Authors: Silva Deanna Cordero Da , Byrd Jacqueline , Slazinski Karen , Ho Minh
Published: December 2022

Background

Substance abuse continues to be on the rise in the U.S. driven by the proliferation of fentanyl laced street drugs. Per the CDC, during May 2020 - April 2021, a 29% increase in over dose deaths was observed compared to the previous year. Harm reduction services play a major role in reducing overdose deaths, life-threatening infections and chronic diseases. Syringe service programs (SSPs) have proven to be an essential component of a broader focus on harm reduction; however, gaps remain in engaging Veterans into these programs. Figure 1.Contents of Standard SSP Kit Distributed to Veterans at the Orlando VA

Methods

A multimodal strategy was implemented to engage Veterans and VA staff into harm reduction services. A harm reduction short video series was developed and posted on social media channels. ICD-10 codes were utilized to identify Veterans with polysubstance use and harm reduction letters were mailed. A pre and post survey was developed to assess provider’s familiarity and level of comfort with SSPs before and after in-service education was provided by ID physicians. An ID pharmacy consult was developed for providers to request patient education or harm reduction kit dispensing. Upon completion of the quality improvement project, we expect to see an increase in the number of Veterans utilizing SSP. Figure 2.Orlando VA SSP Process MapFigure 3.Harm Reduction Letter

Results

Upon implementation of outreach strategies total SSP visits increased by 72%. A total of 2040 syringes and 24 Naloxone kits have been dispensed through the SSP. Survey data shows that employees' knowledge on SSPs have increased by 48%, their comfort on working with Veterans who inject drugs increased by 6%, providers confidence in the tools available to them to successfully help veterans with alcohol and substance use recovery increased by 17%, misconception that SSPs increase drug use decreased by 6%, and support of placing consults for medication assisted therapy increased by 4%. Data is notable given limitations like post survey participation. Figure 4.Pre and Post Education Survey Data Collection ComparisonFigure 5.Pre and Post Education Survey Data Collection ComparisonFigure 6.Pre and Post Education Survey Data Collection Comparison

Conclusion

The implementation of multimodal strategies to engage Veterans and VA staff has resulted in an increase of SSP utilization. Sustained efforts to continue to identify target patients and bring them into care will be undertaken in an effort to increase and normalize SSP utilization. The steps already taken can serve as a model for programs currently in development and moves us closer to ending the HIV epidemic by 2030. Figure 7.Outreach Strategies Summary

Disclosures

All Authors: No reported disclosures.
1426. Characterization of Patients with Iatrogenic Mycobacterial Infections: A Hospital-Based Survey
Authors: Mitra Debdeep
Published: December 2022

Background

Tuberculosis (TB) is a chronic granulomatous inflammation usually involving the lung parenchyma and hilar lymph nodes. Extra-pulmonary involvement is seen in ∼20% of all TB cases. Developing tuberculosis following treatment for another primary medical condition is a rare occurrence. Iatrogenic literally means illness caused by medical examination or treatment.

Mycobacteria have been used to treat a few medical conditions and the therapeutic use has been validated extensively in literature. The mycobacteria used for therapeutic purposes are supposed to be either attenuated or non pathogenic strains. Growth and dissemination of this mycobacterium is a rare but serious possibility. Reactivation of latent mycobacterial infection following therapy is also a part of iatrogenic mycobacterial infection.

Methods

We report a retrospective study investigating adverse events manifesting with development of iatrogenic tuberculosis. The data was obtained from a tertiary care centre over a period of 2 years. Diagnosis of tuberculosis was established based on clinical, radiological(chest X-Ray and High resolution CT scan), sputum smear microscopy and skin/tissue biopsy and Xpert MTB/RIF. Tuberculin skin test(TST) and Interferon gamma release assay (IGRA) were used as additional diagnostic tests.

Results

The search yielded 26 cases of iatrogenic tuberculosis, with a median age of 56.5 years. Most common cause was reactivation of latent tuberculosis due to use of anti-TNF alpha biologic agents(53.8%). Development of Tuberculosis verrucosa cutis following BCG inoculation for verruca vulgaris was noted in about 19.2% of cases and Tubercular abscess due to Mycobacterium w or BCG inoculation for Covid-19 was noted in 11.5% cases. Bacillus Calmette Guérin(BCG) induced balanitis secondary to therapy for Carcinoma urinary bladder was noted in 7.69%of cases.

Bacillus Calmette-Guerin or BCG induced balanitis following use of intravesical immunotherapy for treating early-stage urinary bladder cancer and successful clearance of lesions post therapy

Tuberculosis Verrucosa Cutis following Immunotherapy for plantar warts

Conclusion

All patients were managed successfully with anti tubercular therapy. These observations indicate that tuberculosis infection can develop in previously healthy individuals in endemic zones following biologic therapy of use of mycobacterial agents for other therapeutic indications.

Disclosures

All Authors: No reported disclosures.
1436. Interventions to Address the Global Underreporting of Pediatric and Adolescent Tuberculosis: A Systematic Review
Authors: Linn Alexandra R , Steenhoff Andrew
Published: December 2022

Background

The WHO currently estimates that at least a third of pediatric and adolescent tuberculosis cases go untreated or incompletely treated each year. Many cases are detected but lost to follow-up due to underreporting to national or private surveillance systems.

Methods

We conducted a systematic literature review to better understand the global reporting gap of pediatric tuberculosis as well as current interventions. Following PRISMA guidelines, the review included articles published in English within the past 30 years. Studies were included if they discussed underreporting of tuberculosis in pediatric and adolescent patients. Studies were excluded if they did not include these populations or if they focused on challenges with initial diagnosis or general loss to follow-up rather than underreporting. In May and June 2021, we searched PubMed and Ovid databases along with reference lists of included works. Multiple reviewers and further assessments of heterogeneity and bias will be implemented in the next steps of the project.

Results

Of 458 records identified, 420 were screened for inclusion and 19 studies met inclusion criteria in the preliminary search. Of included studies, 14 described the gap in reporting of pediatric tuberculosis and 5 described potential interventions to close this gap. The estimated gap in reporting ranged from 16% to 98% and was described in 23 countries. Larger gaps were described in rural areas, in areas with higher disease burden, in patients with disseminated disease, and in those under age 5 years. Effective interventions are limited and include strengthening linkage systems between hospitals and clinics, increasing communication between patients and healthcare workers following initial diagnosis, utilizing electronic systems to optimize ongoing monitoring, improving death registration, and using implementation science for continued quality improvement. Table 1

Characteristics of studies included in the review

Conclusion

Underreporting of pediatric and adolescent tuberculosis is a significant global problem. Few evidence-based effective strategies exist to close this gap. Future research should assess the ability of creative, pragmatic solutions to mitigate this with an emphasis on pediatric populations in high-TB burden countries.

Disclosures

All Authors: No reported disclosures.
1449. Therapeutic Drug Monitoring of Isoniazid and Rifampicin and Clinical Outcomes in Adults with Tuberculosis.
Authors: Espiricueta-Zavala Luz A , Sanchez-Durán Diego , Ortiz-Álvarez Arturo , Huerta-García Ana P , Rodríguez-Pinal Cristian J , Milán-Segovia Rosa C , Romano-Moreno Silvia , Medellín-Garibay Susanna
Published: December 2022

Background

Directly Observed Treatment Short Course for Tuberculosis (TB) (DOTS) treatment currently produces a cure rate of 80%. Rifampicin (RMP) and isoniazid (INH) are the main bactericides; both show wide inter-individual pharmacokinetics and narrow therapeutic range. Therapeutic drug monitoring (TDM) of antiTB drugs is a strategy to improve the response to treatment.

The aim of this work was to optimize and individualize antiTB treatment based on plasma concentrations of RMP and INH, NAT2 genotyping and the Bayesian estimation of PK parameters.

Methods

A prospective and analytical study including TB patients under DOTS scheme was performed. Venous blood samples were drawn 2 and 4 hours after last dose; INH and RMP were quantified by liquid chromatography coupled to tandem mass spectrometry. Anthropometric and clinical information was retrieved from medical records. Acetylator phenotype was determined based on NAT2 genotyping by real-time PCR.

Bayesian estimation of the PK parameters was performed using NONMEM and dosing scheme was proposed to achieve therapeutic concentrations of RIF and INH.

Results

A total 62 patients were included from 18 to 80 years and 35 to 117 kg of total body weight. The most frequent was pulmonary infection (40%), 25% of patients had type 2 diabetes mellitus and 58.5% were slow acetylators for the NAT2 gene. Lower INH and RMP plasma concentrations were related to adverse clinical outcome, compared to those patients classified with early clinical success [1.9 vs 3.7 mg/L and 16.9 vs 10.0 mg/L (p< 0.05)]. Results indicate the need to adjust anti-TB drugs dose to more than 50% of the patients who show plasma concentrations outside the range for both drugs. Bayesian dosing performed was validated after individualization by quantification and interpretation of INH and RMP plasma concentrations followed by a narrow medical follow up.

Conclusion

Even with standard anti-TB treatment, great proportion of patients show subtherapeutic concentrations of RMP and INH which is associated with overall therapeutic failure. TDM is a useful tool to individualize antimicrobials dose and improve clinical outcomes at early stages of active TB.

Disclosures

All Authors: No reported disclosures.
1452. A Clinico-Epidemiological Study of Childhood Herpes Zoster
Authors: Mitra Barnali , Mitra Debdeep
Published: December 2022

Background

Herpes Zoster (HZ) is a viral infection believed to be due to re-activation of Varicella zoster virus (VZV) or human herpesvirus type 3 (HHV-3) that persists in the posterior nerve root ganglion. HZ is rarely reported in the pediatric age group with an intact immunity. Past infection with VZV and immunization with chicken pox vaccine are key markers in the onset of varicella zoster in children.

Methods

A prospective observational study over a total duration of two years was conducted in a tertiary hospital and all children less than 12 years of age with diagnosed HZ were included in the study.

Herpes zoster in a 2 years old child

Herpes zoster in a 11 years old child

Results

A total of 39 children were diagnosed to have pediatric HZ infection during the study period of two years. The children were followed up over 4 weeks post diagnosis and treated with oral Acyclovir therapy along with symptomatic management. All the children had an uneventful benign course and their siblings and close pediatric contacts were also screened for the development of HZ or chicken pox during the incubation period. All children were screened for an underlying immunodeficiency, and two cases of HIV co-infection was detected.

Tzank smear

Skin biopsy

Conclusion

HZ is a rare disease in childhood. Varicella in early childhood is a risk factor of HZ in immunocompromised and immunocompetent children. Childhood zoster occurs in either healthy or underlying immunodeficient children. The appearance of HZ in a young child does not always imply an underlying immunodeficiency or malignancy but the children should be screened for immunodeficiency. The prognosis is generally good in healthy children.

Disclosures

All Authors: No reported disclosures.
1469. Drug-resistance associated mutations of Human Cytomegalovirus (CMV) UL97 and UL54 genes in immunocompromised patients. Experience in Colombia, South America.
Authors: Rosso Fernando , Tafur Eric , Zapata-Vasquez Isabel L , Piedrahita Daniela , Valencia Alvaro Martinez , Agudelo Olga , Pachajoa Harry , Pérez-Castellano Paola , Ríos-Serna Lady , Diaz-Ordonez Lorena
Published: December 2022

Background

Cytomegalovirus (CMV) infection is a significant disease in immunocompromised patients, particularly transplant patients. The wide use of antivirals for prophylaxis and treatment has decreased the incidence and impact of this disease. Although, this exposure can lead to mutations in CMV UL54 and UL97 genes, which are associated with antiviral resistance. Little is known of the frequency of these mutations in Latin America, despite an increase in the transplant population.

Methods

We performed a prospective observational study. Patients with suspected CMV resistance based on the persistence of CMV DNAemia despite treatment were included from April to December 2019 in Fundación Valle del Lili. The blood samples were processed for DNA extraction, amplification, and sequencing for molecular characterization of (UL97) and (UL54) genes. Laboratory and clinical data were recollected from the clinical laboratory database and clinical charts.

Results

We enrolled 50 patients with CMV DNAemia, 32 amplified for gene sequencing. The median age was 31.7 years old, and 46.8% were males. 65.6% had a stem cell transplant, and 28.1% had a solid organ transplant. Only 65.2% had previous antiviral exposure. 93.7% manifested with CMV DNAemia alone, and 6.2% had CMV disease, hepatitis, and colitis. According to our findings, 56.2% had only UL54 mutations, 6.25% had only UL97 mutations, and 37.5% had both. The mutations associated with antiviral resistance were D605E and A594V for UL97 and A692S for UL54. The most common UL97 polymorphisms were V355A and F396L, while for UL54 were N898D, N685S, and S655L. On day 14 of treatment, 21.8% (7/32) had treatment failure. No canonic resistance mutations were found. 15.6% (5/32) of patients died; none had UL97 mutations, two had UL54 mutations associated with antiviral resistance, and three had polymorphisms of this gene.

Conclusion

Our study is the first one performed in Colombia. Although resistance was low, it was present in a few patients and related to mortality. It is important to study this evolving resistance as the use of antivirals increases in the transplant population in Latin America.

Disclosures

Olga Agudelo, n/a, Fundación valle del lili: Board Member.
1670. Activity of Ceftolozane/Tazobactam and Comparators Against Clinical MDR and DTR Pseudomonas aeruginosa isolates – SMART United States 2018-2020
Authors: Lob Sibylle , Hackel Meredith , Siddiqui Fakhar , Bauer Karri A , DeRyke Charles A , Young Katherine , Motyl Mary , Sahm Daniel F
Published: December 2022

Background

Antimicrobial resistance of P. aeruginosa to commonly used β-lactams is typically higher in isolates collected from ICU patients and those with hospital-acquired infections. P. aeruginosa with multidrug-resistance (MDR) or difficult-to-treat resistance (DTR) is especially challenging as clinicians have limited treatment options. Ceftolozane/tazobactam was specifically developed to provide enhanced antibacterial activity against P. aeruginosa. We evaluated the activity of ceftolozane/tazobactam (C/T) and comparators against clinical P. aeruginosa isolates by ward type and length of hospital stay at time of specimen collection, including against MDR and DTR isolates.

Methods

In 2018-2020, 24 clinical labs participated in the global SMART surveillance program in the United States (US) and each collected up to 250 consecutive gram-negative pathogens per year from patients with bloodstream, intraabdominal, lower respiratory tract, and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted with CLSI breakpoints.

Results

C/T and amikacin were the only studied agents with activity >95% against all isolates in all strata, with only small differences between the strata (Table). Susceptibility to commonly used β-lactams was 4-8 percentage points lower among isolates collected ≥48 hours post-admission than < 48h and from patients in ICUs compared to non-ICU wards. Correspondingly, the prevalence of MDR and DTR isolates was higher among isolates collected ≥48 hours post-admission (14.6% and 7.3%, respectively) than < 48h (10.5%/6.1%) and those collected from ICU patients (16.1%/7.2%) than non-ICU (10.0%/5.8%). The pattern of lower susceptibility among isolates collected ≥48h post-admission or in ICUs was less clear when the MDR and DTR subsets were analyzed. C/T remained active against ≥72% of MDR and ≥68% of DTR isolates, 7-31 percentage points higher than ceftazidime/avibactam.

Conclusion

Based on these in vitro data, C/T represents a treatment option for patients with infections caused by MDR and DTR P. aeruginosa, regardless of time to infection or treatment in the ICU.

Disclosures

Fakhar Siddiqui, MD, MBA, Merck & Co., Inc.: employee|Merck & Co., Inc.: Stocks/Bonds Karri A Bauer, PharmD, Merck & Co., Inc. Merck Research Laboratories: Stocks/Bonds Charles A. DeRyke, PharmD, Merck & Co., Inc. Merck Research Laboratories: Stocks/Bonds Katherine Young, M.S., Merck & Co., Inc.: Stocks/Bonds.
1673. In vitro Activities of Ceftaroline and Comparator Agents against Bacterial Pathogens Frequently Causing Community-Acquired Respiratory Tract Infections in Patients from a Global Population: ATLAS Surveillance Program 2017-2020
Authors: Hackel Meredith , Stone Gregory , Sahm Daniel F
Published: December 2022

Background

Community-acquired bacterial pneumonia (CABP) is a frequent cause of patient morbidity and mortality. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are frequent etiologic agents of CABP. Ceftaroline fosamil is a parenteral cephem approved for treatment of patients with CABP caused by S. pneumoniae (including cases with concurrent bacteremia), methicillin-susceptible Staphylococcus aureus (MSSA), H. influenzae, and some species of Enterobacterales. In this study we report the in vitro activity of ceftaroline and comparators against isolates from community-acquired respiratory tract infections (CARTI) collected through a global surveillance program.

Methods

Clinically relevant, non-duplicate, isolates cultured from respiratory specimens by clinical laboratories in 54 countries in 2017-2020 were collected by the ATLAS Surveillance Program central laboratory (IHMA, Schaumburg, IL, USA). In total, 2,284 isolates of S. pneumoniae, H. influenzae, M. catarrhalis, MSSA, and methicillin-resistant S. aureus (MRSA) were tested. The isolates (n/percent of total) originated from Asia/South Pacific (579/25.4%); Europe (1281/56.1%); Latin America (298/13.0%); Middle East/Africa (55/2.4%); and North America (Canada only) (71/3.1%). Ceftaroline and comparator agent MICs were determined by CLSI M07 broth microdilution methodology. MICs were interpreted using 2022 CLSI M100 MIC breakpoints.

Results

Ceftaroline and comparator agent in vitro activities are summarized in the table. Greater than 98% of S. pneumoniae and >99% of MSSA were susceptible to ceftaroline, including penicillin-nonsusceptible S. pneumoniae based on a dosage of 600 mg every 12h. Fifty-eight (31.4%) MRSA were ceftaroline-susceptible-dose-dependent (MIC 2-4 µg/mL) based on a dosage of 600 mg every 8h administered over 2h, with the majority from (n) China (18), S. Korea (8), and Japan (8). Three isolates, all from China, were resistant to CPT (MIC of 8 µg/mL). 99.3% of H. influenzae were susceptible to ceftaroline.

Conclusion

Ceftaroline demonstrated potent in vitro activity against current pathogens associated with CABP from a global collection.

Disclosures

All Authors: No reported disclosures.
1674. Trends in Antimicrobial Susceptibility to Ceftolozane/Tazobactam and Comparators of Pseudomonas aeruginosa from Patients with Respiratory Tract Infections in Five Latin American Countries – SMART 2017-2020
Authors: Lob Sibylle , Hackel Meredith , Siddiqui Fakhar , Pavia Jacqueline , DeRyke Charles A , Young Katherine , Motyl Mary , Sahm Daniel F
Published: December 2022

Background

Ceftolozane is a cephalosporin specifically developed to have enhanced antibacterial activity against P. aeruginosa. Combined with tazobactam, it was approved by FDA and EMA for hospital-acquired/ventilator-associated bacterial pneumonia. We evaluated trends in the activity of ceftolozane/tazobactam (C/T) against P. aeruginosa isolates collected as part of the global SMART surveillance program from patients with lower respiratory tract infections (RTI) in Argentina, Brazil, Chile, Colombia, and Mexico.

Methods

In 2017-2020, 29 clinical labs each collected up to 100 consecutive gram-negative pathogens per year from patients with RTI. A total of 6,036 isolates were collected < 48 or ≥48 hours post-admission, of which 1,679 (27.8%) were P. aeruginosa. MICs were determined using CLSI broth microdilution and breakpoints. C/T- or imipenem-nonsusceptible isolates were screened for genes encoding β-lactamases.

Results

Using only isolates from the 21 sites that participated in all 4 years, variability in susceptibility was seen over the study period among isolates collected < 48h post-admission, with a significant increasing trend in susceptibility only for C/T, while susceptibility was lower and more stable among isolates collected ≥48h (Figure). These patterns correlated with estimated carbapenemase rates, especially among isolates collected < 48h post-admission (9.7%, 4.2%, 8.1%, 1.6% carbapenemase-positive per year 2017-2020). Using isolates from all sites from the two most recent years to assess country-level susceptibility, substantial variability was seen. For example, susceptibility to C/T of isolates collected after 48h ranged from 62.5% for Chile (n=120) to ≥92% for Argentina (n=128) and Brazil (n=183), 12-31 percentage points higher than meropenem and piperacillin/tazobactam. This geographic pattern correlated with estimated carbapenemase rates (36% of isolates collected in Chile 48h post-admission versus ≤4% for Argentina and Brazil).

Conclusion

Variability in antimicrobial susceptibility of P. aeruginosa from RTI was seen across Latin American countries, but overall no significant decreases in susceptibility were found over the study period. C/T remained the most active among the studied agents.

Disclosures

Fakhar Siddiqui, MD, MBA, Merck & Co., Inc.: employee|Merck & Co., Inc.: Stocks/Bonds Jacqueline Pavia, MD, MSD COLOMBIA: EMPLOYEE Charles A. DeRyke, PharmD, Merck & Co., Inc. Merck Research Laboratories: Stocks/Bonds Katherine Young, M.S., Merck & Co., Inc.: Stocks/Bonds.
1683. Antifungal Activity of Alexidine Dihydrochloride in a Novel Diabetic Mouse Model of Dermatophytosis
Authors: Nabeela Sunna , Ibrahim Ashraf S , Uppuliri Priya
Published: December 2022

Background

Ringworm caused by the dermatophyte species Trichophyton is the foremost superficial fungal infection worldwide. The US alone records over 5 million outpatient visits due to dermatophytosis, with an annual burden of one billion dollars in associated direct medical costs. Patients with diabetes mellitus exhibit a higher incidence rate and a more severe manifestation of the disease. Infections are often recurrent and recalcitrant to most antifungal drugs and new molecules to combat these discomforting infections are sorely needed. Here, we establish a novel model of dermatophytosis, which is clinically relevant, simple to use, and is robust enough for evaluation of antifungal drugs. Using this model, we demonstrate that an FDA-approved small molecule alexidine dihydrochloride has enhanced efficacy against dermatophytes.

Methods

For the animal model, ICR mice (equal gender) were rendered diabetic by treatment with a single intraperitoneal dose of streptozotocin, followed by confirmation of glycosuria and ketonuria. The back of the anesthetized diabetic mice was shaved, skin abraded with sand paper, and inoculated with 50 µl of sterile water containing 5x10^7 conidia. Infected lesions were monitored daily, and graded for erythema, edema, and extent of infection over a period of 2 weeks. For drug treatment, infected mice were separated equally into four groups: topical treatment of 20 µg/ml alexidine dihydrochloride, topical 1% terbinafine, 10 mg/kg terbinafine by oral gavage, and a vehicle control. Treatment was started on day 4 post infection and given once daily for 7 days. Lesions were monitored as above and clearance of infection was confirmed by fungal culture and histopathology.

Results

In the absence of drugs, dry, scaly erythematous legions appeared on day 3 after infection and became progressively worse, persisting for at least 14 days. Terbinafine and Alexidine dihydrochloride were highly efficacious in curbing infections within two days after treatment and no recurrence was observed for up to 10 days post treatment.

Conclusion

The diabetic mouse model was found to be reproducible and applicable for primary evaluation of the anti-dermatophytic efficacy of topical and oral formulations of antifungal agents.

Disclosures

All Authors: No reported disclosures.
1696. Comparison of in vitro activities of linezolid and contezolid against clinical Nocardia isolates
Authors: Wei Ming , Wang Peng , Wang Shuai , Yang Chunxia , Degree Master’s , Gu Li
Published: December 2022

Background

Nocardia is nearly 100% susceptible to linezolid which is one of the first-line agents for all clinical species and isolates reported in the literature. However, adverse reactions related to myelosuppression and monoamine oxidase inhibition have limited linezolid use to some extent. Contezolid, a new oxazolidinone antibiotic that has decreased toxicity compared to linezolid, was launched in China in June 2021. In this study, the in vitro activities of linezolid and contezolid are compared against Nocardia.

Methods

Ninety-four clinical Nocardia isolates from Beijing Chao-Yang Hospital were identified by multilocus sequence analysis, and the in vitro activities of linezolid and contezolid were evaluated using the broth microdilution method. A Wilcoxon Signed Rank Test was performed to determine if linezolid and contezolid are significantly different from each other against clinical Nocardia isolates.

Results

Pulmonary nocardiosis (91.5%) was the most common clinical presentation of Nocardia infections. N. cyriacigeorgica (36.2%) and N. farcinica (16.0%) were the most frequently encountered Nocardia species, followed by N. abscessus (9.6%) and N. otitidiscaviarum (9.6%). The MIC (minimum inhibitory concentration) ranges of all clinical Nocardia isolates for linezolid and contezolid were 0.5-8 μg/mL. The MIC50/MIC90 values for all isolates of Nocardia for linezolid vs contezolid was 2/4 μg/mL vs 2/4 μg/mL, and for N. cyriacigeorgica and N. farcinica were 4/4 μg/mL vs 2/4 μg/mL and 4/4μg/mL vs 2/4 μg/mL, respectively. After a Wilcoxon Signed Rank Test analysis, the P values of all Nocardia isolates was < 0.001, and for N. cyriacigeorgica and N. farcinica were 0.001 and 0.020, respectively.

Conclusion

Though MIC50/MIC90 values for linezolid and contezolid for all Nocardia isolates evaluated appeared to be similar, there was a statistically significant difference between the two antibiotics. Furthermore, the MIC50 values for the most commonly encountered species N. cyriacigeorgica and N. farcinica were lower for contezolid than for linezolid. Therefore, the in vitro activity of contezolid is better than that of linezolid against clinical Nocardia isolates, and contezolid could also be an option for the treatment of Nocardia infections.

Disclosures

All Authors: No reported disclosures.
1699. Efficacy and Safety by BMI Category and Gender in Contezolid and Contezolid Acefosamil Phase 2 and Phase 3 Skin Infection Clinical Trials
Authors: Fang Edward , Yang Huahui , Yuan Hong
Published: December 2022

Background

Contezolid (CZD; MRX-I) is a novel oral (PO) oxazolidinone with potent activity against multidrug-resistant Gram-positive pathogens. Contezolid acefosamil (CZA; MRX-4) is an intravenous (IV) double prodrug of CZD. Nonclinical and initial clinical data indicate CZA and CZD may cause less myelosuppression, particularly with longer duration therapy, and with reduced risk of monoamine oxidase inhibition compared to linezolid (LZD). In 3 CZD Phase 2 (Ph2) and Phase 3 (Ph3) skin infection trials and 1 CZA Ph2 acute bacterial skin and skin structure infection (ABSSSI) study, primary efficacy and overall safety outcomes were comparable to LZD, and the most common treatment emergent adverse events (TEAEs) were gastrointestinal; however, hematologic laboratory abnormalities and TEAEs were less common with CZD and CZA. In June 2021, CZD was approved in China for complicated skin and soft tissue infections (cSSTI). Sequential therapy with CZA IV followed by CZD PO is being evaluated in global Ph3 diabetic foot infection (DFI) and ABSSSI clinical trials. Body weight and gender can affect drug pharmacokinetics (PK) and potentially efficacy and safety outcomes, though in CZA and CZD Phase 1 (Ph1) pharmacokinetics (PK) studies, PK differences between male and female healthy subjects were not considered to be significant. Efficacy and safety outcomes for male and female patients, and between subjects of different body mass index (BMI) were evaluated in completed Ph2 and Ph3 CZD and CZA studies.

Methods

In 4 CZD and CZA Ph2 and Ph3 skin infection trials, men and women were enrolled with no weight restrictions, and no dose adjustments were made for gender or BMI. Primary efficacy outcomes and occurrence of TEAEs were evaluated for CZD and CZA subjects in 3 BMI categories, and also in male and female subjects.

Results

Primary efficacy outcomes and occurrence of TEAEs appeared to be similar for CZD and CZA male and female subjects, and also subjects in different BMI categories in 4 skin infection trials.

Conclusion

In 4 completed Ph2 and Ph3 skin infection clinical trials, primary efficacy and safety outcomes appeared similar for male and female subjects, and for subjects of varying BMI, supporting current Ph3 global DFI and ABSSSI studies which will enroll men and women with no body weight restrictions.

Disclosures

Edward Fang, MD, MicuRx Pharmaceuticals Inc: Employee Huahui Yang, MS, MicuRx Pharmaceuticals Inc: Employee.
1708. In vitro Activities of Ceftazidime-Avibactam and Comparator Agents against Enterobacterales and Pseudomonas aeruginosa Collected < 48 Hours and ≥48 Hours Post-Admission from Hospitalized Pediatric Patients, ATLAS Global Surveillance Program 2017-2020
Authors: Wise Mark , Stone Gregory , Sahm Daniel F
Published: December 2022

Background

Ceftazidime-avibactam (CAZ-AVI) is a β-lactam combined with a diazabicyclooctane-β-lactamase inhibitor for treatment of infections caused by Gram-negative pathogens. Ceftazidime-avibactam is active against Enterobacterales (Ent) and P. aeruginosa (Psa) isolates that produce Class A, C and some Class D β-lactamases. This study examined the in vitro activity of CAZ-AVI and comparators against Ent and Psa from presumed community-acquired (CA; cultured < 48 h after hospital admission) and hospital-acquired (HA; cultured ≥48 h post-admission) infections collected from pediatric patients as part of the ATLAS surveillance program, 2017-2020.

Methods

5765 non-duplicate Ent and 1987 Psa isolates from pediatric patients (≤17 y.o.) were collected from 241 sites in 54 countries as part of ATLAS 2017-2020 (excluding North America) for which the length of hospitalization stay was specified. Antimicrobial susceptibility testing was by broth microdilution according to CLSI guidelines and analyzed using CLSI 2022 breakpoints. Ent isolates testing with meropenem MICs >1 µg/mL and Escherichia coli, Klebsiella pneumoniae, K. oxytoca, K. variicola, and Proteus mirabilis testing with ceftazidime and/or aztreonam MICs >1 mg/L were genetically screened for β-lactamases. For Psa, meropenem MIC >2 µg/mL triggered β-lactamase screening. In 2020, approximately 25% of the meropenem non-susceptible isolates were screened.

Results

Against Ent, the in vitro activity of CAZ-AVI exceeded that of meropenem and other tested agents for both the presumed CA- and HA-infection sets. The addition of AVI to CAZ increased the %S from 76.1% to 97.5% for the CA-infection population, and from 62.2% to 96.1% for the HA-infection population. For Psa There was a larger difference between the %S to CAZ-AVI of the presumed CA set (93.3% S) and the HA set (89.8% S). For both Psa populations, CAZ-AVI was the most active drug among the comparators.

Conclusion

CAZ-AVI demonstrated potent in vitro activity against Enterobacterales and P. aeruginosa isolates collected globally from pediatric patients in 2017-2020, regardless of whether is infection was community-or hospital-acquired.

Disclosures

All Authors: No reported disclosures.
2297. COVID-19 Vaccine Effectiveness Among Pregnant People
Authors: Zerbo Ousseny , Thomas Ray G , Goddard Kristin , Layefsky Evan , Fireman Bruce , Klein Nicola P
Published: December 2022

Background

COVID-19 presents a serious health risk to pregnant people and pregnancy outcomes. However, pregnant people were not included in pivotal phase III COVID-19 vaccine efficacy trials.

Methods

We used Cox regression models in a cohort study to determine hazard ratios (HR) of a PCR positive test (“infection”) comparing vaccinated with unvaccinated pregnant persons in Kaiser Permanente Northern California. HRs were adjusted for age, race/ethnicity, type of insurance coverage, geographical area, BMI, preexisting diabetes, hypertension, parity, time since pregnancy onset and smoking status. Vaccine effectiveness (VE), calculated as 1 minus adjusted HR, was estimated for fully vaccinated < 150 and ≥ 150 days prior to infection. VE was estimated for before and during Delta, and Omicron. We also calculated incidence rates of COVID-pneumonia associated hospitalization by vaccination status.

Results

Among 68836 pregnancies between 12/15/2020 and 3/31/2022, 21834 (31.7%) were fully vaccinated and 5980 (8.7%) were boosted by the end of pregnancy. Compared with unvaccinated persons, the HRs of infection for fully vaccinated < 150 days prior were 0.13 (95% CI: 0.07 – 0.23; VE=87% [77% - 93%]) before Delta; 0.25 (CI: 0.20 – 0.30; VE=75% [70% - 80%]) during Delta and 0.76 (CI: 0.61 – 0.94; VE= 24% [16% - 39%]) during Omicron. The HRs for ≥ 150 days prior were 0.38 (CI: 0.31 – 0.46; VE=62 % [54% - 69%]) during Delta and 1.04 (CI: 0.89 – 1.22; VE= -0.04% [-0.22% – 0.11%]) during Omicron. The HRs for boosted persons were 0.10 (CI: 0.04 – 0.25; VE= 90% [75% - 96%]) during Delta and 0.42 (CI: 0.34 – 0.52; VE=58% [48% - 66%]) during Omicron periods.

Incidence rates (IR) per 1000 person-years for hospitalization before delta were 0.75 among unvaccinated and zero among vaccinated. During Delta, the IR was 6.64 for unvaccinated and zero for fully vaccinated and boosted. During Omicron, the IR was 10.27 for unvaccinated, zero for fully vaccinated < 150 days prior, 2.48 for fully vaccinated ≥ 150 days prior and zero for those boosted.

Conclusion

COVID-19 vaccines protect against infection and hospitalization among pregnant people. However, vaccine effectiveness against infection wanes over time and was lower during Omicron. Booster doses are necessary for continuous protection.

Disclosures

All Authors: No reported disclosures.