bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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 &lt; 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 &lt; 0.001) for a daptomycin AUC &gt; 939 mg.h/L, 9.8 (95% CI 3.94 – 24.5, p &lt; 0.001) for CRP &gt; 21.6mg/L and 2.4 (95% CI 1.02 – 5.65, p = 0.04] for Protein &lt; 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 &gt; 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

Abstract

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&gt;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

Abstract

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 &gt; 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 &gt; 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 &gt; 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

Abstract

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.
629. Vancomycin AUC:MIC-Based Dosing is Associated with Significantly Less Acute Kidney Injury in Patients Admitted to a Burn Intensive Care Unit
Authors: Rummel Gregory , Pruskowski Kaitlin A 
Published: December 2022

Abstract

Background
Vancomycin is often used for empiric coverage of methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is well known to cause acute kidney injury (AKI), which can be detrimental to patients in the intensive care unit (ICU) setting. In 2020, the American Society of Health-systems Pharmacists updated their vancomycin dosing guidelines to target an area under the plasma concentration-time curve to minimum inhibitory concentration ratio (AUC:MIC) of 400-600 mg*h/L, a change from targeting a trough concentration of 10-20 mg/L. This suggests that vancomycin toxicity is likely minimized using the AUC:MIC ratio.

Methods
This retrospective cohort study compares the incidence of AKI in patients admitted to the burn ICU dosed to achieve a target to those dosed to achieve an AUC:MIC goal. Incidence of AKI, per the AKIN criteria, was recorded. Known risk factors such as history of hypertension, concomitant furosemide use, pre-existing renal insufficiency, and other concomitant nephrotoxins were considered. All data collected were previously obtained as a part of usual practice.

Results
Two hundred thirty-six subjects who received 317 courses of vancomycin were included. One hundred twenty courses were dosed to achieve an AUC goal, and 197 courses were dosed to achieve a trough goal. In the AUC group, 49 (57.7%) subjects were admitted for burns, 21 (24.7%) were admitted for necrotizing soft tissue infection (NSTI), and 15 (17.7%) were admitted for other reasons. In the trough group, 97 (64.7%) were admitted for burns, 22 (18.7%) for NSTI, and 25 (16.7%) for other reasons. Demographics were similar between the two groups. The incidence of AKI was 10.3% in the AUC group, as compared to 20.3% in the trough group (p=0.0171). Patients in the AUC group received significantly less vancomycin than in the trough group (3524 ± 1551 vs 3145 ± 1491, p=0.0315). Risk factors for AKI were similar between the two groups (55.6% vs 52.8%, p=0.6347), and concomitant nephrotoxin exposure was similar (52.6% vs 42.7%, p=0.0924).

Conclusion
Using AUC:MIC-based dosing was associated with a decreased incidence of AKI than trough-based dosing in patients admitted to the burn ICU.

Disclosures
All Authors: No reported disclosures.
630. A Single-Center 10-Year Analysis of Immunizations in Heart Transplant Recipients
Authors: Snellings Robin , Padakanti Sowmya , Cahuayme-Zuniga Lizbeth 
Published: December 2022

Abstract

Background
Vaccine-preventable diseases pose a risk towards heart transplant recipients on lifelong immunosuppression. Immunization rates are low (30-80%) in solid organ transplants. The aim of this study was to examine the vaccination rates in our hospital’s heart transplant recipients with a goal to expose deficiencies and formulate strategies to increase vaccination in this population.

Methods
This study is a single-center retrospective chart review of patients aged 18 or older who received a heart transplant between January 1, 2012 and March 31, 2022 at our institution in Temple, Texas. We documented vaccination status or seropositivity prior to or after transplant, as recommended by the American Society of Transplantation (AST) for influenza, hepatitis B, hepatitis A, measles, mumps, and rubella (MMR), 23-valent pneumococcal polysaccharide (PPSV23), 13-valent pneumococcal conjugate (PCV13), tetanus, diphtheria, and acellular pertussis (Tdap), varicella, zoster, and COVID-19 immunizations. We evaluated the association with an Infectious Disease (ID) consult. Odds ratios (OR) were calculated with 95% confidence intervals.

Results
72 patients received a heart transplant within the 10-year period. Demographics are noted in table 1. Table 2 presents the immunization status as follows: 48.7% for flu vaccine, 55.5% for Hepatitis B, 47.1% for Hepatitis A, 36.1% for MMR, 67.5% for PPSV23, 67.5% for PCV13, 54.1% for Tdap, 83.3% for Varicella and 13.8% for Zoster, and 53.5% for COVID-19. From 2016, an ID consult was required pre-transplant; 45 patients (62.5%) had an ID consult before transplant. ID consult was associated with increased likelihood of receiving the MMR, PCV13, Tdap, and Zoster vaccines (table 3). Table 1Patient demographics
Table 2 Immunization status in heart transplant recipients
Table 3 Immunization status associated with ID consult

Conclusion
This study reveals the deficiency of vaccinations in our heart transplant patients, but an ID consult was associated with better immunization rates. To further increase compliance, we propose different interventions including close follow-up with ID, addressing vaccine costs, accessibility limitations, cultural hesitancy, and implementation of protocols.

Disclosures
All Authors: No reported disclosures.
634. Implementation of a medical education intervention to improve acceptance of HIV-positive donors for transplant at a tertiary care hospital
Authors: Swaminathan Neeraja , Hemmige Vagish , Czeresnia Jonathan Mamber , Muggia Victoria , Azzi Yorg , Akalin Enver , Raees Harith , Al Anssari Haider 
Published: December 2022

Abstract

Background
The HIV Organ Policy Equity Act (HOPE Act) was enacted in the US on November 21, 2013. HIV patients have a higher waitlist mortality and decreased access to transplant compared to HIV negative controls. The HIV Organ Policy Equity Act (HOPE Act) was a major step towards increasing the donor pool, but utilization of organs through the act has been less than initially anticipated.. Our own institution performed only one HIV D+/R+ transplant in the first four years of the trial despite a significant number of HIV+ patients on the waitlist. TableFigure summarizing perceived barriers and targeted interventions. Rate of HOPE transplants impacted positively by intervention Rate of HOPE transplants impacted positively by intervention

Methods
Monthly multidisciplinary meetings were set up. The agenda included discussing all offers, risks/benefits in a standardized format. Didactic sessions were conducted to address identified barriers to accepting HIV+ organs (Figure 1). HOPE consultants from experienced larger-volume centers were invited as guests.

Results
In the 15 months since this intervention was implemented, there have been 7 HIV D+/R+ transplants including a heart-kidney transplant. While the overall rate of transplant didn't change in a statistically significant way pre and post intervention for patients the rate of HOPE transplants increased significantly (Figure 2).

Conclusion
Making organs from HIV-positive donors available for donation does not mean they will be used. Intensive provider education can improve organ acceptance rates and help fulfill the promise of the HOPE act.

Disclosures
Vagish Hemmige, MD, Merck: Grant/Research Support.
638. Utility of Recombinant Hepatitis B Vaccine in Pre-liver Transplant Candidates
Authors: Rogers Jack , Prasad Pooja , Weinberg Amy , Bynon John S , Machicao Victor I , Nigo Masayuki 
Published: December 2022

Abstract

Background
A recombinant, adjuvanted Hepatitis B (HBV) vaccine (HepB-CpG) was approved by the FDA in 2017. Initial FDA data showed greater immunogenicity than comparable recombinant HBV vaccines. Moreover, it requires only two doses over four weeks instead of three doses over six months, so there is a time advantage to HepB-CpG, which is advantageous in pre-liver transplant candidates, given their limited time before transplantation. The efficacy in this population is unknown, so we explored its efficacy This study aims to explore the efficacy of HepB-CpG in pre-liver transplant candidates, as there is currently no data on this subject.

Methods
This study was a retrospective review of pre-liver transplant candidates greater than 18 years old at Memorial Hermann Hospital in Houston, TX, who received at least two doses of HepB-CpG. Patients were identified from our pre-liver transplant database. Patient characteristics were collected at the time of the first dose. Vaccine efficacy was measured by anti-Hepatitis B surface antibody titers (≥10mIU/mL) at least four weeks after completion of the series. Patients who received only one dose or did not have any post-vaccine titers were excluded from the analysis.

Results
A total of 78 potential eligible patients were identified. After exclusion due to various reasons, a total of 27 patients were eligible for our study. Data are summarized in Table 1. Briefly, our patients were Hispanic dominant (59.3%). The median MELD score was 18, and a significant number of patients (48.1%) had underlying malignancy. The cause of cirrhosis was mainly due to alcoholic and non-alcoholic steatohepatitis (NASH). Only 13 patients (48.1%) showed seroconversion after their second dose of HepB-CpG. Moreover, of the five patients receiving immunosuppressive drugs, only one patient (20%) responded to the vaccine.
Characteristics of Pre-Liver Transplant Candidates Who Had Serological Evaluation after Two Doses of Recombinant Adjuvanted Hepatitis B Vaccine.

Conclusion
Despite administration of HepB-CpG, less than 50% of pre-liver transplant candidates showed seroconversion. Furthermore, only one cirrhotic patient on immunosuppressive drugs responded to the vaccine. Our results illustrate the need for a better strategy to improve immunogenicity among this patient population. Larger studies are warranted to confirm the findings.

Disclosures
Victor I. Machicao, M.D., Gilead Inc: Advisor/Consultant.
640. A Retrospective Assessment of the Effects of Cefiderocol in Patients with Multidrug-resistant Gram-negative Bacterial Infections
Authors: Sajib Monirul I , Go Roderick , Monteforte Melinda 
Published: December 2022

Abstract

Background
Cefiderocol has emerged recently as a new tool for combating multidrug-resistant bacterial infections; however, concerns about its efficacy has approved its FDA approval for the use in person with limited or no treatment options. The aim of our study is to assess the outcomes of patients treated with cefiderocol for such infections.

Methods
Retrospective cohort study which includes all adult patients who received cefiderocol for at least three days from 1 October 2020 to 31 December 2021 at Stony Brook University Hospital. Patients who received multiple courses of cefiderocol during the same hospitalization or are still hospitalized were excluded.

Results
22 patients received cefiderocol and met the inclusion criteria. Average age, Charlson comorbidity index, and length of stay were 63.6 year, 5.4, and 53 days respectively.
6 patients had respiratory tract infections, 3 had bacteremia, 2 had complicated UTI, and 11 had infections in other sites. Bacteria isolates included Pseudomonas aeruginosa (14), Acinetobacter baumannii complex (8), and Stenotrophomonas maltophilia (1).
The 14-day and 28-day all-cause mortality for all patients was 4.5% and 13.6%, respectively. The 14-day and 28-day all-cause mortality for patients with respiratory tract infections was 16.7% and 16.7%, bloodstream infections was 0% and 0%, complicated UTI was 0% and 0% and with infections at other sites was 0% and 15.4%, respectively. These rates are lower compared to CREDIBLE-CR study.
The 28-day all-cause mortality in double gram-negative coverage group (including cefiderocol) was 0% versus 25% in the cefiderocol monotherapy group (p=0.25). The 28-day all-cause mortality in patient group with Pseudomonas aeruginosa was 14.3% vs. with Acinetobacter baumannii complex was 12.5%. Out of 18 isolates, 13 (72.2%) were susceptible to cefidericol, 1 (5.5%) was intermediate, and 4 (22.2%) were resistant. No carbapenemases were detected in any of the 11 tested clinical isolates of Pseudomonas aeruginosa. Treatment failure, defined as requiring change of antibiotic, was 9.1%.

Conclusion
The 14-day and 28-day all-cause mortality for all patients treated with cefiderocol are possibly lower than once thought to be. No significant differences were noted when cefidericol was used as monotherapy versus in combination.

Disclosures
Roderick Go, DO, Aptose Biosciences: Stocks/Bonds|Bristol Meyers Squibb: Stocks/Bonds|Cytodyn Inc.: Stocks/Bonds|Scynexis: Grant/Research Support.