bluuebunny/crossref_metadata_2025_split huggingface dataset:
570. What’s the Harm? Development and Implementation of an Antimicrobial Stewardship Intervention Impact Score
Authors: Wirtz Ann , Burns Alaina N , Monsees Elizabeth , Herigon Joshua C 
Published: December 2022

Abstract

Background
Various metrics evaluate antimicrobial stewardship program (ASP) success, including utilization, cost savings, and guideline adherence. Patient safety initiatives are at the forefront of hospital metrics. No commonly applied ASP measures evaluate patient harm. Our objective was to develop and implement a novel scoring tool quantifying the impact of ASP interventions on prevention of patient harm.

Methods
This initiative was conducted at a 386-bed pediatric hospital with an ASP conducting prospective audit with feedback (PAF) rounds since 2008. ASP created a multidisciplinary subgroup to develop a scoring tool classifying interventions as low, moderate, and high impact. With low impact interventions, patient harm was unlikely, but opportunities existed for minor antimicrobial optimization. Moderate interventions had substantial room for optimization but still had low risk for patient harm. High impact interventions carried a substantial risk of patient harm due to high probability of an adverse drug event or due to poor outcomes from an inappropriate regimen. Using these principles, definitions for each level of impact were created for all ASP intervention categories (Table 1). ASP providers were trained on the tool and scored each intervention on daily PAF rounds. To improve objectivity, 2 ASP providers independently scored each intervention and discrepancies identified. Discrepancies were evaluated monthly, and the tool was modified.

Results
Between 11/9/21-3/31/22, ASP reviewed 2010 antimicrobial orders with 238 interventions made and scored for impact. Of these, 124 (52.1%) were low, 99 (41.6%) moderate, and 15 (6.3%) high impact. There were 26 scoring discrepancies identified which were discussed by the ASP subgroup. To further clarify definitions, there were 5 substantive definition changes and 4 minor modifications; most changes were made in 12/2021.

Conclusion
We describe here the successful implementation of a novel tool to score ASP interventions on stewardship impact and prevention of patient harm. Future directions include utilizing this tool to direct systematic ASP interventions, partnering with organizational patient safety, and engaging in a multi-institutional working group for further development.

Disclosures
All Authors: No reported disclosures.
578. Cost-effectiveness of Infant Vaccination with PCV15 Compared to PCV13 in the United States
Authors: Huang Min , Hu Tianyan , Weaver Jessica , Owusu-Edusei Kwame , Elbasha Elamin 
Published: December 2022

Abstract

Background
Streptococcus pneumoniae is a major cause of mortality and morbidity in young children. The 13-valent pneumococcal conjugate vaccine (PCV13) has been in routine use in children in the United States (US) since 2010. An investigational 15-valent vaccine (PCV15) that protects against two additional serotypes is currently under review by the FDA. This study aimed to evaluate the clinical and economic impact of routine infant vaccination with PCV15 compared with PCV13 from a US societal perspective.

Methods
A Markov decision-analytic model was developed to estimate the impact of PCV15 vs. PCV13 on pneumococcal disease incidence, post meningitis sequalae, and deaths. The model followed the entire US population over a 100-year time horizon, taking herd immunity effects into account. Each vaccination program comprised 3 primary doses and one booster for the new birth cohorts. Model inputs were obtained from the published literature, online databases, and unpublished data. PCV15 effectiveness was extrapolated from observed PCV13 data and PCV7 clinical trials. Costs (in 2021 USD) and quality-adjusted life years (QALYs) were discounted at 3% per year. Because the price for PCV15 in the pediatric indication is currently unknown, an analysis was conducted to determine the threshold price, which was defined as the maximum price for PCV15 to remain cost-saving. A series of sensitivity analyses were performed to test the robustness of model results.

Results
The base case results projected that PCV15 prevented 185,711 more invasive pneumococcal disease cases, 987,727 all-cause pneumonia cases and 11,151,473 pneumococcal acute otitis media and tube-replacement cases compared with PCV13. This resulted in an expected gain of 96,056 QALYs and total reduction of $7 billion in direct medical costs (excluding vaccine costs), and $4 billion in direct non-medical and indirect costs in the US population over the 100-year time horizon. The threshold price per dose for PCV15 was $28 higher than PCV13’s price. Sensitivity analyses showed the results to be robust over plausible values of key model inputs and assumptions.

Conclusion
Infant vaccination with PCV15 is projected to provide both clinical benefits and cost-savings compared with PCV13.

Disclosures
Min Huang, PhD, Merck & Co., Inc.: full-time employee Tianyan Hu, Ph.D., Merck & Co., Inc.: full time employee Jessica Weaver, PhD, MPH, Merck & Co., Inc.: Employee Kwame Owusu-Edusei, Ph.D., Merck & Co., Inc.: full time employee Elamin Elbasha, Ph.D., Merck & Co., Inc.: full time employee.
581. Monovalent rotavirus vaccine efficacy against different rotavirus genotypes: a pooled analysis of Phase II and III trial data
Authors: Amin Avnika B , Tate Jacqueline E , Waller Lance A , Lash Timothy L , Lopman Benjamin 
Published: December 2022

Abstract

Background
Rotavirus vaccine effects appear lower in countries with high child mortality rates and high diversity of rotavirus genotypes. Some evidence suggests diminished vaccine efficacy (VE) against the G2P[4] genotype, which is heterotypic with existing monovalent rotavirus vaccine formulations. Most studies assessing genotype-specific VE have been underpowered and inconclusive.

Methods
We pooled individual-level data from ten Phase II and III clinical trials of monovalent rotavirus vaccine containing G1 and P[8] antigens (RV1). We estimated VE against any-severity and severe (Vesikari score ≥11) rotavirus gastroenteritis (RVGE) using binomial and multinomial logistic regression models for three types of VE: non-specific VE against any RVGE; genotype-specific VE against specific genotypes; and RV1-typic VE against genotypes homotypic, partially heterotypic, or fully heterotypic with the RV1 G1 and P[8] antigens. Models were adjusted for oral poliovirus vaccination concomitant with RV1 vaccination and the country’s child mortality stratum.

Results
A total of 87,644 infants from 22 countries in the Americas, Europe, Africa, and Asia were included in analysis. VE against severe RVGE was 91% (95% confidence interval (CI): 87-94%). Genotype-specific VE ranged from 96% (95% CI: 89-98%) against homotypic G1P[8] to 71% (95% CI: 43-85%) against fully-heterotypic G2P[4]. VE against severe RVGE caused by partially heterotypic genotypes (92% (95% CI: 84-96%)) was similar to VE against the homotypic genotype, but VE against fully heterotypic genotypes was lower (83% (95% CI: 67-91%)). VE against any-severity RVGE was 82% (95% CI: 75-87%). Genotype-specific VE estimates against any-severity RVGE ranged from 94% (95% CI: 86-97%) against G1P[8] to 63% (95% CI: 41-77%) against G2P[4]. VE against any-severity RVGE was lower (83% (95% CI: 72-90%) against partially heterotypic genotypes, but lowest (63% (95% CI: 40-77%)) against fully heterotypic genotypes.

Conclusion
RV1 VE is diminished against fully heterotypic genotypes including G2P[4].

Disclosures
Benjamin Lopman, PhD, Epidemiological Research and Methods, LLC: Advisor/Consultant.
587. Vaccine knowledge, attitudes, and practices among New York State healthcare providers
Authors: Fernandes Annlynn , Wang Dongliang , Domachowske Joseph B , Suryadevara Manika 
Published: December 2022

Abstract

Background
Vaccine attitudes of healthcare providers (HCPs) influence patient vaccine acceptance. We sought to characterize vaccine knowledge, attitudes, and practices (KAP) among HCPs in NYS.

Methods
An electronic survey was developed to assess vaccine KAP among HCPs. The questionnaires were sent to members of various national medical organizations via local chapter administrators.

Results
864 surveys were returned from 672 (78%) physicians and 192 (22%) mid-level practitioners (MLPs). 624/724 (86%) of HCPs report always recommending routine vaccines to eligible patients, yet only 76% recommend influenza vaccine (IV) and 77% strongly recommend HPV vaccine at 11-12 yrs. MLPs had a higher mean agreement level that recommending vaccines (4.6 vs 4.2 p &lt; 0.01) or promoting HPV vaccine (4.2 vs. 3.9 p &lt; 0.05) is within their scope of practice. Physicians had a higher mean agreement level that: vaccine benefits outweigh risks (4.9 vs 4.6 p &lt; 0.01), HPV vaccine prevents cancer (4.7 vs 4.5 p &lt; 0.01), and COVID-19 vaccine is safe (4.8 vs 4.5 p &lt; 0.01) and effective (4.8 vs 4.7 p &lt; 0.01). 82% (680/825) of HCPs knew that vaccines should not be deferred for mild illness. 14/836 (2%) believed that HPV vaccine could increase sexual activity, while 273/705 (39%) knew that the most common HPV associated malignancy is oropharyngeal cancer. HCPs who correctly answered ≥ 5/7 questions (462/507 91%) were more likely to recommend all vaccines to eligible patients than HCPs with lower scores (22/40 50% p &lt; 0.05). Routine IV recommendation was more likely among HCPs who: strongly disagree that influenza is not serious enough for vaccination (292/397 (74%) vs 137/249 (55%) p &lt; 0.01), strongly agree that it prevents severe disease (267/352 (76%) vs 162/294 (55%) p &lt; 0.01), and receive annual IV (423/629 (67%) vs 6/17 (35%)) p &lt; 0.01). HPV vaccine recommendation at 11-12 years was more likely among HCPs who strongly agree that the vaccine prevents cancer (273/326 (84%) vs 48/86, 56% p &lt; 0.01) and those who stated that vaccination does not increase risk of unprotected sex (316/392 (79%) vs 3/12 (25%) p &lt; 0.01).

Conclusion
Vaccine recommendation practices are influenced by HCP vaccine misperceptions and hesitancy. Interventions to reduce misperceptions and improve vaccine confidence are needed.

Disclosures
Manika Suryadevara, MD, Janssen: Grant/Research Support|Merck: Grant/Research Support|Roche: Grant/Research Support.
588. A Safety analysis of High Dose Intrawound Vancomycin in Arthroplasty
Authors: Shah Sunish , McManus Dayna , Topal Jeffrey E 
Published: December 2022

Abstract

Background
There is a paucity of data to support the efficacy and safety of placing vancomycin powder into and around the joint in total hip arthroplasty (THA), total knee arthroplasty (TKA), and shoulder arthroplasty (SA).

Methods
This was a retrospective chart review of patients undergoing THA, TKA, or SA who received intrawound (IW) vancomycin powder placed into and around the joint with a vancomycin impregnated bone cement spacer (VIBCS) compared to patients who received a VIBCS alone (usual care).

Results
There were 24 patients who met inclusion criteria. Of the 14 patients who received IW vancomycin, the median dose (Range) was 5g (4-10). While there were no statistically significant differences in baseline demographics, those who received IW vancomycin were more likely to experience vancomycin induced nephrotoxicity (VIN) compared to those who received usual care (42.9% vs. 0%, P=0.02) (Table 1).

Conclusion
Our experience with IW vancomycin at a median dose of 5g in combination with VIBCS was associated with an increased risk of nephrotoxicity in our patients. Therefore, re-evaluation of the use of IW vancomycin at these doses is warranted.

Disclosures
All Authors: No reported disclosures.
598. Area under the curve-guided vancomycin monitoring and risk of nephrotoxicity in non-Staphylococcus aureus infections: A case-control study
Authors: Mazewski Douglas , Bertram Christie M , Rhodes Nathaniel J , Justin Moore W 
Published: December 2022

Abstract

Background
Area under the curve (AUC)-guided monitoring of vancomycin for the treatment of Staphylococcus aureus (SA) infections demonstrates reduced rates of nephrotoxicity in clinical studies. Many institutions utilize AUC-guided dosing for all patients receiving vancomycin, despite extrapolated AUC goals for non-SA infections. We sought to define risk factors for vancomycin-induced kidney injury (VIKI) in non-SA infections.

Methods
This was a retrospective, single-center, case-control study evaluating risk factors associated with VIKI in hospitalized patients receiving AUC-guided dosing for non-SA infections from 2/2019-10/2021. Cases were defined as patients with non-SA infections who received &gt;72 hours of vancomycin and had &gt;1 observed vancomycin concentration with a corresponding AUC calculated who developed VIKI within 24 hours of vancomycin discontinuation. Controls had to meet all case criteria but did not have VIKI. Univariate and multivariable analyses were used to identify risk factors associated with VIKI. Multivariable analyses were conducted using the Optimal Data Analysis package for R.

Results
Twenty-three cases and 48 controls were included. Leading indications were bloodstream (52.1%) and severe skin/skin structure (46.5%) infections. Isolated pathogens from culture included coagulase-negative Staphylococcus (49.3%) and Streptococcus spp. (43.7%). The majority of vancomycin AUCs (52%) were collected within 24-48 hours of initiation. The median first and second AUCs were higher in cases vs. controls [429 vs. 385 mg*hr/L, p=0.013; and 573 vs. 429 mg*hr/L, p=0.021], respectively. Most patients (75%) experienced AKI within 72 hours of vancomycin initiation, with a median time to AKI of 5 days (IQR 2.5-7). Risk factors associated with AKI included any AUC exceeding 515 mg*hr/L, infection caused by pathogens other than Streptococcus spp., and non-bacteremia indications. Patients with AUCs exceeding 515 mg*hr/L had 3.7-fold greater odds of VIKI (p=0.017).

Conclusion
We found that higher AUCs increased the risk of VIKI in non-SA infections and that the risk of VIKI varied by vancomycin indication. Our findings agree with previous studies in SA indicating that vancomycin AUC should not generally exceed 515 mg*hr/L.

Disclosures
Nathaniel J. Rhodes, PharmD MS, Paratek: Grant/Research Support|Third Pole Therapeutics: Advisor/Consultant.
608. Evaluation of Safety of High-Dose Beta-Lactam Antibiotics in Patients with End-Stage Kidney Disease: A Retrospective Cohort Study
Authors: Varona Jerald , FakhriRavari Alireza , Hassan Abbas , Trieu Rosa 
Published: December 2022

Abstract

Background
Beta-lactam toxicity is often underestimated in clinical practice given the insidious onset and complex clinical picture of patients. Renally impaired patients are at increased risk of toxicity due to drug accumulation, which may increase their morbidity and mortality. This study’s objective is to identify the rate of beta-lactam-induced toxicities in patients with end-stage kidney disease (ESKD) on higher than recommended doses of piperacillin-tazobactam, cefepime, or meropenem compared to patients on appropriate doses (Table 1).

Methods
This retrospective cohort study examined patients hospitalized at Loma Linda University Medical Center in Loma Linda, California, from January 2013 to June 2021. Patients 18 to 89 years old with ESKD via ICD-10 code, and who received piperacillin-tazobactam, cefepime, or meropenem for 48 hours or more were included. The primary composite outcome of beta-lactam toxicity consisted of neurotoxicity, hepatotoxicity, and hematologic toxicity. Secondary analyses of each toxicity were done. Statistical analysis was done using R software with a p-value &lt; 0.05 considered significant. Multivariate logistic regression was done for variables with a p-value &lt; 0.2 in bivariate analysis.

Results
Eligibility criteria were met by 341 patients. Cohort 1 (N=193) received appropriate antibiotic doses and cohort 2 (N=148) received higher than recommended doses. Baseline characteristics were similar except for renal replacement therapy and meropenem use (Table 2). In cohort 1, 58.5% of patients experienced beta-lactam associated toxicity (Table 3), compared to 70.9% of patients in cohort 2 (Odds ratio [OR] 1.73, 95% confidence interval [CI] 1.07-2.81, p=0.02). The rate of neurotoxicity was 29.0% in cohort 1 compared to 42.6% in cohort 2 (OR 1.81, 95% CI 1.13-2.92, p=0.01). Receiving higher than recommended doses was an independent risk factor for developing any beta-lactam associated toxicity (OR 1.63, 95% CI 1.02-2.63, p=0.04, Table 4), including neurotoxicity (OR 1.63, 95% CI 1.02-2.62, p=0.04). Table 2:Baseline CharacteristicsTable 3:Primary and Secondary OutcomesTable 4:Logistic Regression Analysis for Composite Primary Outcome

Conclusion
Patients with ESKD on higher than recommended doses per package insert of piperacillin-tazobactam, cefepime, or meropenem for at least 48 hours were significantly at higher risk of beta-lactam associated toxicity, specifically neurotoxicity.

Disclosures
All Authors: No reported disclosures.
611. Meropenem Dosage Optimization in Critically Ill Patients Based on a Population Pharmacokinetic Approach.
Authors: Romano-Aguilar Melissa , Ortiz-Álvarez Arturo , Medellín-Garibay Susanna , Martínez-Gutiérrez Fidel , Jung-Cook Helgi , Milán-Segovia Rosa C , Romano-Moreno Silvia 
Published: December 2022

Abstract

Background
Meropenem (MRP) is commonly used to treat serious infections and displays wide variability in plasma concentrations after administration of the same dose in critically ill patients due to factors that affect MRP volume of distribution (V) and clearance (CL) (e.g. edema, sepsis, kidney failure). These alterations could lead to not achieve the pharmacokinetic/pharmacodinamic (PK/PD) target with the consequent failure of antibacterial therapy.
The aim of this study was to describe MRP pharmacokinetic parameters in critically ill patients in order to establish safe and effective initial dosing regimens adapted to patients characteristics.

Methods
This prospective observational study enrolled 78 critically ill patients receiving MRP based on the clinical, biochemical and microbiological findings. Blood sampling occurred at pre-dose, 1, 3 and 6h post-dose. MRP plasma concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic modelling and Monte Carlo simulations were executed with NONMEM. Several regimen dosages of MRP under different scenarios were simulated in order to achieve high probability of target attainment (PTA &gt; 90%) for PK/PD targets of %t &gt; CMI 50% and 100%.

Results
In critically-ill Mexican patients, MRP PK were best described by a one compartment model. The final population model was: CL (L/h) = 11.9 ∗ (CLCr/102.23) and V (L) = 25.2. Final model was internally validated proving that it was stable and showed an adequate estimation of variability. Precision and bias fit were assessed through external validation comparing the predictive performance of the base and final models. Different initial dosage regimens were found for CLCr values in which the clinician can choose between a lower dose, a longer dosage interval or a shorter infusion time. However, for patients with augmented renal clearance or PK/PD target 100%t &gt; MIC it was observed that no regimen complied PTA &gt; 90%, suggesting a continuous infusion would be more appropriate.

Conclusion
This study demonstrates the wide variability in MRP pharmacokinetics and enhances the need to include therapeutic drug monitoring as part of stewardships interventions in critically ill patients to maximize bacteriological and clinical responses.

Disclosures
All Authors: No reported disclosures.
617. Pharmacodynamics of Ceftolozane-Tazobactam (C/T) as Monotherapy and in Combination with Tobramycin or Fosfomycin Against P.aeruginosa with C/T MICs at or Above 4mg/L
Authors: MacGowan Alasdair P , Attwood Marie , Griffin Pippa , Noel Alan 
Published: December 2022

Abstract

Background
Ceftolozane (C/T) is widely used in clinical practice to treat difficult and/or multidrug resistant Pseudomonas aeruginosa (Pa). However, clinical data is absent on the use of C/T therapy to treat Pa strains with C/T MICs ≥ 4mg/L, that is outside the wild type population. To address this, we simulated 7-day courses of C/T against 8 strains of Pa C/T MICs 4-64mg/L as monotherapy and in combination with tobramycin (T) or fosfomycin (F) using an in vitro pharmacokinetic model.

Methods
A single compartment dilutional in vitro model was used, volume central chamber 360mL, inoculum 106 CFU/mL. Differing drugs t½ were simulated using add back. Pa strain C/T MICs were 4-64mg/L, T 0.25-8mg/L and F 4-1024mg/L. C/T doses of 2-1g, 8h (Cmax 112-32mg/L, t½ 2.5-1h), T doses 7mg/Kg 24h (Cmax 22mg/L, t½ 2.5h) and F doses 4g 8h (Cmax 250mg/L, t½ 2.5h) were simulated for 7 days. Endpoints were changes in bacterial load (log CFU/ml) and population profiles (growth on C/T containing media at MICx4 and MICx8 concentrations).

Results
C/T alone resulted in rapid clearance of all strains after 4-12h exposure, with the antibacterial effect being poorest with strains with the highest C/T MICs. Regrowth occurred with 7/8 strains after 24-48h, counts reaching 6-8 logs by 7 days. Combination of C/T plus T increased the rate of initial clearance and suppressed regrowth with all strains. Combination of C/T plus F did not increase the rate of initial clearance except in the strains with the highest C/T MICs but resulted in suppression of regrowth with final bacterial counts of 3-4 logs at day 7. Changes in C/T population profiles occurred after 7 days exposure with growth on C/T MICx8 containing media in 6/8 strains exposed to C/T alone, but 0/8 strains exposed to C/T plus T and 1/8 strains exposed to C/T plus F.

Conclusion
Combinations of C/T plus T or F resulted in long term suppression of Pa bacterial load and minimised emergence of resistance in Pa strains with C/T MICs on or just above the epidemiological cut off value (MIC 4mg/L-64mg/L).

Disclosures
Alasdair P. MacGowan, MD, GSK: Grant/Research Support|InfectoPharm: Grant/Research Support|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Venatorx: Advisor/Consultant.