bluuebunny/crossref_metadata_2025 huggingface dataset:
555. Early Outcomes of Penicillin and Cephalosporin Allergy Assessment Tool
Authors: Norton Laura E , Grothe Lily Y , Oliver Meredith B , Thielen Beth K
Published: December 2022

Background

Penicillin allergy is reported in approximately 10% of the US population and is one of the most frequent medication allergies in children. Penicillin allergy labels are associated with more expensive care and adverse outcomes, such as MRSA and C. Diff infection. Studies suggest up to 90% of these patients could safely tolerate this class of drugs. Our team at M Health Fairview University of Minnesota Masonic Children’s Hospital (UMMCH) implemented an allergy assessment tool for inpatient use in January of 2020 to create an effective and accessible path for delabeling pediatric patients with penicillin and cephalosporin allergies.

Methods

Our pharmacists conducted the allergy assessment on inpatient pediatric patients with penicillin/cephalosporin allergies. Those deemed low to moderate risk for having a true IgE-mediated allergy by our assessment were recommended for outpatient allergy testing. Those deemed no risk were recommended for immediate delabeling. We performed manual chart reviews to describe pediatric patient risk stratification, allergy label status after assessment, outpatient allergy follow-up, and status and results of allergy testing.

Results

From January, 2020 to present, 140 patients received a pharmacist allergy assessment. During the 2020 calendar year, 51 allergy assessments were performed on 49 patients. 58 allergies were recorded, with penicillins as the most common (62%), followed by cephalosporins (24%), and penicillin combination drugs (14%). 1.9% of allergies were high risk, 68.8% moderate, 15.7% low, 9.8% no risk, and 3.8% difficult to determine. Of 42 patients deemed low to moderate risk, 8 (17%) were seen by an outpatient allergist. Of these, 5 proceeded with allergy testing and were found to be not allergic. Out of 58 allergy labels, 9 (15.5%) were removed, 5 after allergy testing, 2 immediately due to no risk, and 2 after further history review.

Conclusion

Our preliminary data show allergy assessments can inform pediatric allergy risk prior to outpatient allergy testing and assist with imminent delabeling. Next steps include analysis of our 2021 assessments as well as patient caregiver surveys to assess perception of the allergy assessment process and to elucidate on barriers to testing/delabeling.

Disclosures

Beth K. Thielen, MD, PhD, Horizon: Advisor/Consultant|Horizon: Honoraria|Merck: Grant/Research Support.
557. Improving Surgical Antimicrobial Stewardship with Quarterly Audit and Feedback Scorecards
Authors: Downey Rachel , Bhakta Kavita , Sapozhnikov Julia , Grethel Erich , Fernandez Marisol
Published: December 2022

Background

Adherence to national surgical antimicrobial prophylaxis (SAP) is of utmost importance to prevent antimicrobial resistance. Guideline development does not always confer compliance with changes. This report describes an ongoing process of quarterly SAP audit and feedback using individualized scorecards.

Methods

Our hospital participates in local data collection for the National Surgery Quality Improvement Program- Pediatric (NSQIP-P). We implemented changes to local SAP guidance to better align with national recommendations and collected data regarding baseline SAP beginning in January 2019. Using these data, we initiated an audit and feedback program of quarterly scorecard reports beginning in January 2020 regarding surgical adherence to national SAP guidelines at our children’s hospital.

This scorecard gives each surgeon a quarterly, private, individual report, allowing them to review cases that deviated from SAP guidance, and compare their scores to the surgical team as a whole. NSQIP-P cases are adjudicated manually for SAP adherence. The program aimed to improve adherence to SAP guidance, promote collaborative discussion, and identify areas for improvement in prescribing practices and local guidelines. The goal was to reach >90% compliance with SAP guidance.

Results

Baseline adherence to SAP guidance was 50-85%. After introducing the audit and feedback program in January 2020, SAP compliance rates increased overall. In the most recent 3 quarters (2021 Q1-3), adherence was 95%, 89%, and 95%, respectively. Figure 1.Antimicrobial stewardship report by quarter among the pediatric surgery teamFigure 2.Example of individual audit & feedback scorecard

Conclusion

We have seen an improvement overall in SAP compliance and have reached the goal of >90% compliance. One drawback to this program is the need for manual case review. Feedback using scorecards has led to better communication regarding process changes for SAP prescribing.

Disclosures

All Authors: No reported disclosures.
562. Multipronged Approach to Recruitment of Pediatric Patients with Beta-Lactam Allergies for Evaluation and De-labeling
Authors: Ewing Anne , Patel Malina , Stephen Ellen D , Keizur Erin , Vu Betty N , Nash Colleen B , Bandi Sindhura
Published: December 2022

Background

Penicillin allergy is the most commonly reported drug allergy in the pediatric population. However, most reports do not represent true IgE-mediated or late-onset severe hypersensitivity reactions. False allergy labels can lead to unnecessarily broad and/or non-first line antibiotic utilization, the development of antibiotic resistance, adverse drug side effects, and have implications for the use of antimicrobials in adulthood. In an effort to decrease inappropriate allergy labeling, we have implemented a multipronged approach for the evaluation of documented beta-lactam allergies in pediatric patients and potential “de-labeling” of inaccurate or outdated allergies.

Methods

We performed retrospective chart review of pediatric patients (0-18 years) with a documented beta-lactam allergy who were seen in clinic at a single tertiary medical center between 2014-2019. Prospective telephone screening then began to further characterize reaction symptoms and timing to determine patient candidacy for allergy testing (Fig. 1). Inpatient screening began in April 2022. If amenable to referral, eligible patients are then referred for outpatient Allergy and Immunology (A/I) assessment. Figure 1Process map for pediatric beta-lactam allergy risk-stratifying algorithm.

Results

A total of 1160 eligible pediatric patients were identified, and initial results are summarized (Fig. 2). Of those screened, 48 (57%) patients were referred. 5 (6%) patients were de-labeled via screening, of which 3 had received and tolerated repeat dosing. 11 (33%) patients have attended allergy appointments; 4 (36%) were tested and all were de-labeled (ages 6-11 years) from mostly non-IgE-mediated reactions. Additionally, 16 patients have upcoming appointments, and recruitment efforts are ongoing to include increased inpatient recruitment.

Conclusion

Use of an inpatient and outpatient algorithm can help identify pediatric patients less likely to have a true or persistent beta-lactam allergy (delayed-onset mild symptoms, or IgE-mediated reaction >5 years ago) and who could benefit from formal allergy testing to potentially remove their allergy label. In the future, algorithm implementation within the electronic medical record may assist clinicians in thorough documentation of beta-lactam allergies and expeditious referral for allergy testing when appropriate.

Disclosures

All Authors: No reported disclosures.
563. Nationwide Trends in Antibiotic Selection for the Treatment of Pediatrics Acute Sinusitis, 2003-2020
Authors: Savage Timothy J , Kronman Matthew , Lee Su Been , Oduol Theresa , Huybrechts Krista F
Published: December 2022

Background

Acute sinusitis is a common diagnosis associated with outpatient antibiotic prescribing for children. Infectious Diseases Society of America guidelines (published in 2012) and American Academy of Pediatrics guidelines (published in 2013) for the management of acute sinusitis recommend amoxicillin with or without clavulanate as empiric therapy. Nationwide trends in antibiotic treatment of sinusitis have not been described since guideline publication.

Methods

We evaluated trends in antibiotic prescriptions for new acute sinusitis diagnoses among commercially insured patients < 18 years old between January 1, 2003 and December 31, 2020 using the MarketScan Research Database. Subjects were identified via an outpatient encounter with an ICD code for acute sinusitis along with an oral antibiotic prescription dispensed on the day of the visit. New diagnoses were defined as having no sinusitis diagnosis in the preceding 180 days. Patients were excluded if they had a diagnosis code for chronic sinusitis or cystic fibrosis in the 6 months prior to the acute sinusitis diagnosis or had a same-day ICD code for another infection that would influence antibiotic selection (acute otitis media, cellulitis/abscess, community acquired pneumonia, Group A Streptococcal pharyngitis/tonsillitis, or urinary tract infection).

Results

3.3 million patients met the inclusion and exclusion criteria (Table 1). From 2003-2012, about 50% of patients received amoxicillin with or without clavulanate (Figure 1). Since 2013, the proportion of patients receiving first line antibiotics increased by 13%. The proportion receiving two or more antibiotics was unchanged. Approximately 80% of patients were prescribed 10-13 days of antibiotics (Figure 2). The proportion of patients receiving 14 or more days decreased by 67% over the study period.

Conclusion

In a nationwide cohort of commercially insured children with acute sinusitis, prescriptions for amoxicillin with or without clavulanate increased after publication of society guidelines. About 40% of patients are prescribed a non-first line antibiotic or multiple antibiotics and nearly 90% of patients are prescribed 10 or more days of antibiotics, presenting important opportunities for antimicrobial stewardship interventions.

Disclosures

Timothy J. Savage, MD, MPH, MSc, UCB: Contract to Brigham and Women's Hospital.
567. The Quality & Management of Penicillin Allergy Labels in a Pediatric Birth Cohort
Authors: Taylor Margaret G , Joerger Torsten , Anvari Sara , Li Yun , Gerber Jeffrey S , Palazzi Debra
Published: December 2022

Background

Penicillin allergy labels (PALs) influence antibiotic prescribing, yet little is known about the quality and management of PALs placed in the pediatric outpatient setting.

Methods

We performed a retrospective chart review of 500 randomly selected children with PALs from a ten-year birth cohort (n=18,015) from Texas Children’s Pediatrics and Children’s Hospital of Philadelphia Primary Care Networks. PALs were classified as “not allergy” (family history, isolated diarrhea), “low risk” (maculopapular rash >24 hours into antibiotic course, no hives or pruritis), “moderate or high risk” (hives or pruritis, maculopapular rash < 24 hours into antibiotic course, anaphylaxis, swelling, or respiratory symptoms), “severe cutaneous reaction” (erythema multiforme, serum sickness), or “unable to classify” (information not available or unspecified rash characteristics or timing) based on 1) information in the allergy tab and 2) encounter notes. We used kappa-statistic measure-of-agreement to determine allergy classification agreement between the allergy tab and notes.

Results

The median age of PAL placement was 1.4 years (IQR 0.9, 2.2). Most (n=303, 63%) PALs were placed by physicians. Half of PALs were categorized as “unable to classify; physicians were just as likely to place ambiguous PALs as other providers (48 vs 53%, p=0.31). Most (80%) children were evaluated at a primary care office within 1 week of their reaction. There was fair agreement between the allergy tab and encounter note documentation (Table 1). Of 54 (11%) children evaluated by an allergist, 25/25 passed an oral amoxicillin challenge. Only 69 (14%) children were de-labeled during the study period, more by an allergist (48%) than in the community (9.6%, p< 0.001). Table 1.Risk stratification by penicillin allergy label and notes.

Conclusion

PAL classification was ambiguous in half of labeled children; there was fair risk classification agreement between the allergy tab and notes. Children with PALs were rarely referred to allergists or de-labeled in the community. Future quality improvement efforts should seek to improve PAL documentation and access to allergy services.

Disclosures

Debra Palazzi, MD, MEd, AAP: Board Member|AHRQ: Grant/Research Support|AMA: Board Member|Elsevier: Honoraria.
568. Using Machine Learning to Predict Place-Based Risks for Staphylococcus aureus Infections in Children
Authors: Lin Xiting , Ali Fatima , Edelson Michael R , Jerris Robert C , Leong Traci , Baltrus Peter T , Immergluck Lilly
Published: December 2022

Background

Community-onset Staphylococcus aureus (CO-S. aureus) pediatric infections, methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) continue to contribute to the burden of infections seen in the ambulatory setting in the US. Individual risk factors have been identified, but place-based factors and specific geographic locality have not been well-studied. The purpose of this study is to predict place-based factors that contribute to the spread of CO-S. aureus in a major urban area using maximum entropy (MaxEnt), a machine learning technique.

Methods

Electronic medical records from two pediatric hospitals (2002 to 2016) were retrospectively reviewed. Inclusion criteria: a confirmed S. aureus infection within 48 hours of hospital admission (CO-S. aureus), < 19 years old, and a geo-referenced address within Atlanta’s metropolitan statistical area (MSA). Fourteen place-based factors, at the US Census block group level, were included in the MaxEnt models: < 18 years old, Caucasian, African American, ethnicity, poverty, education attainment, crowding, daycare, kindergarten enrollment, distance to K-12 school, distance to a children’s hospital, distance to a daycare center, and population density. A total of four models (CO-MRSA early, CO-MSSA early, CO-MRSA later, and CO-MSSA later) were run using the MaxEnt software. For each model, 75% and 25% of data was randomly assigned to training and testing groups, respectively. Models were assessed by jack-knife tests.

Results

16,124 records met eligibility criteria for MaxEnt models. The training Area Under the Curve (AUC) ranged from 0.771 to 0.837 and the test AUC ranged from 0.769 to 0.804. Population density had the highest contribution in predicting CO-MRSA and CO-MSSA locations, which was confirmed by jack-knife tests.

Conclusion

By applying MaxEnt to pediatric CO-S. aureus infections in the Atlanta MSA, it was found that higher risks of CO-S. aureus infections may exist in more densely populated areas. MaxEnt can be utilized to identify potential future areas of CO-MRSA and CO-MSSA infections based on estimated or predicted changes to the place-based factors used to build these models.

Disclosures

Lilly Immergluck, MD, MS, GSK: Clinical Trial- PI|Merck: Vaccine Trial Site- serve as PI|Moderna: Board Member|Novavax: Part of CoVID-19 Phase 3 Trial through US Covid Prevention Network.
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

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

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

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

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 < 0.01) or promoting HPV vaccine (4.2 vs. 3.9 p < 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 < 0.01), HPV vaccine prevents cancer (4.7 vs 4.5 p < 0.01), and COVID-19 vaccine is safe (4.8 vs 4.5 p < 0.01) and effective (4.8 vs 4.7 p < 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 < 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 < 0.01), strongly agree that it prevents severe disease (267/352 (76%) vs 162/294 (55%) p < 0.01), and receive annual IV (423/629 (67%) vs 6/17 (35%)) p < 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 < 0.01) and those who stated that vaccination does not increase risk of unprotected sex (316/392 (79%) vs 3/12 (25%) p < 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

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

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 >72 hours of vancomycin and had >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

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 < 0.05 considered significant. Multivariate logistic regression was done for variables with a p-value < 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

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 > 90%) for PK/PD targets of %t > 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 > MIC it was observed that no regimen complied PTA > 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

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.
621. Pharmacokinetics Determinant and Risk Factors of Daptomycin Induced Eosinophilic Pneumonia and Muscular Toxicity: A Survival Analysis in patients treated for Bone and Joint Infection.
Authors: Garreau Romain , Pham Truong-Thanh , Bourguignon Laurent , Ferry Tristan , Goutelle Sylvain
Published: December 2022

Background

Daptomycin prescription for patients suffering from Bone and Joint infections increased in recent years. However, the implication between daptomycin exposure, concomitant factor, and the occurrence of either daptomycin-induced eosinophilic pneumonia (DIEP) or CPK elevation is not clearly understood.

Methods

All patients treated for a bone and joint infection (BJI) between 2014 and 2021 were screened and classified into cases if they experienced a CPK elevation or DIEP. The controls were randomly selected at a 1:3 ratio within the same period of inclusion. Daptomycin levels were obtained from routine therapeutic drug monitoring. In addition, demographic and biology data were also obtained from the computerized file of patients. Those data were used to compute the area under the concentration-time curve (AUC) of daptomycin using a previously developed population pharmacokinetic model. Finally, a univariate analysis was performed and all data with a p-value < 0.1 were included in the multivariate survival analysis using a proportional Cox hazard model.

Results

A total of 1130 patients were screened from which 16 patients with DIEP, 42 with CPK elevation, and 107 control were included in the final analysis. Age, CRP, Creatinine, Creatinine Clearance, Serum protein, AUC, and through concentrations were significantly different between case and controls. Summary of univariate analysis is available in table 1. After multivariate analysis, only 3 predictors remained significantly associated with the occurrence of DIEP or CPK elevation. The adjusted hazard ratio of developing DIEP of CPK elevation, were 3.1 (95% CI: 1.48 – 6.5, p < 0.001) for a daptomycin AUC > 939 mg.h/L, 9.8 (95% CI 3.94 – 24.5, p < 0.001) for CRP > 21.6mg/L and 2.4 (95% CI 1.02 – 5.65, p = 0.04] for Protein < 72g/L. Survival curves are shown in figure1. Variable identified in the whole population remained significant in DIEP or CPK subgroup analyses. Table 1.Patients characteristics at time of inclusionFigure 1.Survival analysis of the whole population according to AUC and CRP levels.

Conclusion

The risk of experiencing DIEP or CPK elevation was greater in patients with an AUC0-24 above 939 mg.h/L and a CRP > 21.6mg/L. Daptomycin Therapeutic drug monitoring should be performed and an AUC range of 666 to 939 mg.h/L should be targeted in order to maximize efficacy and minimize the risk of adverse events, especially for patients with an inflammatory syndrome.

Disclosures

All Authors: No reported disclosures.
622. Population Pharmacokinetic Analysis and Probability of Target Attainment Simulations of Pivmecillinam for the Treatment of Uncomplicated Urinary Tract Infection
Authors: Santerre Henriksen Anne Laurence , Lagraauw Maxime , Prohn Marita , Lindbom Lars
Published: December 2022

Background

A population pharmacokinetic model was developed to characterize mecillinam (MEC) pharmacokinetics (PK) and urine exposure after intravenous (IV) administration of MEC or after oral (PO) administration of its prodrug pivmecillinam (PIV) in healthy subjects and patients with renal impairment (RI) or infections. MEC is a β-lactam antibiotic with a targeted spectrum of activity against Enterobacterales. The model was used to investigate various PIV treatment regimens and covariate scenarios on plasma exposure and urine excretion, and to perform probability of target attainment (PTA) simulations in support of dose justification for the treatment of uncomplicated urinary tract infection (uUTI).

Methods

The analysis was based on MEC PK data obtained in plasma, serum, and urine in 15 clinical studies. The dataset included a total of 3964 plasma or serum concentrations and 989 urine samples obtained in 228 subjects. Those 228 subjects consisted of 172 healthy volunteers, 23 patients with infections (uUTI, Gram-negative infection, typhoid, or paratyphoid fever), and 33 patients with various degrees of renal impairment (RI). Subjects were treated with single or multiple doses of MEC (IV, 200-1410 mg) or PIV (PO, 137-500 mg).

Results

MEC PK profiles in plasma and urine were well characterized by a 2-compartment distribution model with first-order renal elimination and nonlinear non-renal elimination. Oral absorption of PIV was best described using a single (Erlang) transit compartment. The PK model included parameter-covariate relationships for WT on all clearance and volume parameters (with fixed allometric exponents of 0.75 and 1), a nonlinear dose effect on bioavailability, formulation effects on Ka, food effects on both Ka and F1, and effects of renal function on both CL and Km. PTA simulations for the proposed dosing regimen of 200 mg TID predicts up to 70% fT>MIC for the CLSI susceptibility breakpoint of 8 mg/L in 90% of the population for a voiding frequency of 45 min.

Conclusion

MEC PK was well characterized by a 2-compartment distribution model with first-order renal and nonlinear non-renal elimination. The oral PIV absorption was best described using a single transit compartment. PTA simulations were supportive of a 200 mg TID dosing.

Disclosures

Anne Laurence Santerre Henriksen, PhD, Shionogi: Contractor|UTILITY therapeutics Ltd: Advisor/Consultant Maxime Lagraauw, PhD, qPharmetra: Employee Marita Prohn, n/a, qPharmetra: Employee Lars Lindbom, PhD, qPharmetra: Employee.
624. Probability of Target Attainment of Ceftolozane/Tazobactam Among Adult Patients with Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia Secondary to Pseudomonas aeruginosa in Latin America
Authors: Okuma Aline , Polis Thales , Pavia Jacqueline , Mizuno Gustavo , Ferrari Jacqueline , DeRyke Charles A
Published: December 2022

Background

Pseudomonas aeruginosa (Pa) is a common cause of nosocomial pneumonia; resistance among traditionally used empiric agents is observed frequently. To improve patient outcomes, a heightened focus has been placed on evaluating the adequacy of recommended dosing regimens, particularly of beta-lactams. The Phase 3 study ASPECT-NP demonstrated the efficacy and safety of 3 g of ceftolozane/tazobactam (C/T) infused every 8 h for 8 to 14 days for treatment of adults with Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia (HAP/VAP). We assessed the Probability of Target Attainment (PTA) of the C/T 3g dosage regimen in patients with HAP/VAP due to Pa, with an additional focus on carbapenem-resistant Pa, from Latin America.

Methods

Non duplicate Pa isolates from a respiratory source were collected as part of the SMART surveillance program from 36 sites in 10 Latin American countries during 2017-2020. MICs were determined by broth microdilution and interpreted by CLSI criteria. C and T concentration-time profiles were simulated in plasma and ELF following administration of the approved 3g (2g/1g) C/T dose (or equivalent dose adjusted based on renal function) administered by 1-hour infusion every 8 hours. PTA in plasma and ELF was calculated using the PK/PD target of 30% fT > MIC for C. T does not contribute to the antipseudomonal activity of C and therefore was not considered.

Results

A total of 2,757 P. aeruginosa were collected, of which 1208 (43.8%) were carbapenem nonsusceptible. C/T susceptiblity was 87.7% against all Pa and 73.4% among carbapenem nonsusceptible strains. At C/T doses of 2g/1g (CrCL > 50mL/min); 1g/0.5g (30mL/min≤ CrCL≤ 50mL/min), and 500mg/250mg (15mL/min≤ CrCL≤29mL/min), steady-state ceftolozane plasma and ELF PTA was 100% and > 99%, respectively, for isolates with an MIC at the Pa susceptiblity breakpoint of 4 µg/mL. Ceftolozane plasma and ELF PTA remained above 90% up to an MIC of 16 µg/mL and 8 µg/mL, respectively.

Conclusion

The regulatory approved pneumonia dosage regimen of C/T 3g (administered over 1 hour) every 8 hours (or equivalent dose adjusted based on renal function) resulted in high plasma and ELF PTAs sufficient to cover the vast majority of circulating P. aeruginosa present in Latin America, including carbapenem resistant strains.

Disclosures

Aline Okuma, PharmD, MSD Brazil: Employee Thales Polis, MD, MSD Brazil: Employee Jacqueline Pavia, MD, MSD COLOMBIA: EMPLOYEE Gustavo Mizuno, PharmD, MSD Brazil: Employee Jacqueline Ferrari, MD, MSD Brazil: Employee Charles A. DeRyke, PharmD, Merck & Co., Inc. Merck Research Laboratories: Stocks/Bonds.
628. Utilizing Cefepime Therapeutic Drug Monitoring for Patients at Risk of or Exhibiting Signs of Neurotoxicity
Authors: Au Joanna , Jain Sumeet , Lin Amanda , Luo Evelyn , Gautam-Goyal Pranisha , Saunders-Hao Patricia
Published: December 2022

Background

Increasing risk of neurotoxicity has been observed with increasing cefepime levels, potentially due to the competitive inhibition of GABA receptors in the central nervous system (CNS). The suggested threshold is ≥20 mg/dL. Risk factors include decreased clearance with renal impairment, or increased CNS penetration with blood-brain barrier dysfunction. This study analyzes the association between high trough levels and risk factors for cefepime-induced neurotoxicity (CIN), and the utility of therapeutic drug monitoring (TDM) in guiding cefepime therapy.

Methods

This was a prospective single-arm observational study. Eligible patients had signs of potential CIN or had risk factors including cefepime ≥4 g/day for ≥4 days, renal impairment, CNS disease, and/or co-administration of neurotoxic medications. Interventions for discontinuation or dose adjustment were made for levels ≥20. The primary outcome was the incidence of troughs ≥20 in patients with possible signs of or risk factors for CIN. The secondary outcome was the proportion of patients whose therapy is altered in response to TDM.

Results

A total of 20 patients were included. Reasons for inclusion were 15 with renal impairment, 10 had signs of neurotoxicity, and 5 were included to confirm therapeutic dosing. Patients could have multiple risk factors for CIN. Ten of 20 had a trough ≥20 (median 19). Six of 10 with signs of neurotoxicity had a trough ≥20 (OR 2.25, 95% CI 0.38-13.47; p=0.66) and 10 of 15 with renal impairment had a trough ≥20 (RD 0.67, 95% CI 0.13-0.89; p=0.0325). Cefepime was renally dose adjusted in 7 of 10 with a trough ≥20. Of the total 20 patients, 16 required interventions of which 12 were confirmed by the trough result.

Conclusion

Renal impairment was found to be a statistically significant risk factor for CIN, even when cefepime was renally dose adjusted. These patients may benefit from TDM. TDM allowed for confirmation of interventions and further interventions were made based on trough levels. Despite a small sample size, cefepime TDM has the potential to identify patients at risk for CIN and may assist in making dose adjustments to improve patient safety.

Disclosures

All Authors: No reported disclosures.