bluuebunny/crossref_metadata_2025_split huggingface dataset:
1079. Development of Tebipenem MIC Antimicrobial Susceptibility Test for Gram-negative Bacteria on MicroScan Dried Gram-negative MIC Panels
Authors: Fernandez Jose Enrique , Williams Robert L , Carr Vasna , Miller Renae 
Published: December 2021

Abstract

Background
Development of a tebipenem antimicrobial susceptibility test was completed for the MicroScan Dried Gram-negative MIC (MSDGN) Panel when compared to CLSI broth microdilution reference panels.

Methods
Development was conducted by comparing MICs obtained using the MSDGN panel to MICs using a CLSI broth microdilution reference panel. A total of 669 Enterobacterales isolates were tested at 16, 18, and 20 hour incubation times using the turbidity and Prompt®* methods of inoculation. MSDGN panels were incubated at 35 ± 2ºC and read on the WalkAway System, the autoSCAN-4 instrument, and read visually. Frozen reference panels, prepared according to ISO/CLSI methodology, were inoculated using the turbidity inoculation method. All frozen reference panels were incubated at 35 ± 2ºC and read visually. Dilution sequence evaluated is 0.03-32 µg/mL.

Results
When compared to frozen reference panel results, essential agreement for all isolates tested during development are as follows:

Conclusion
The development data showed that tebipenem MIC results for Enterobacterales obtained with the MSDGN panel correlate well with MICs obtained using frozen reference panels. Essential agreement is &gt; 90% for all inoculation and read methods.
For Investigational Use Only. The performance characteristics of this product have not been established.
* Prompt® is a registered trademark of 3M Company, St. Paul, MN USA.
© 2021 Beckman Coulter. All rights reserved. Beckman Coulter, the stylized logo, and the Beckman Coulter product and service marks mentioned herein are trademarks or registered trademarks of Beckman Coulter, Inc. in the United States and other countries.

Disclosures
Jose Enrique Fernandez, n/a, Beckman Coulter (Employee) Vasna Carr, n/a, Beckman Coulter (Employee) Renae Miller, n/a, Beckman Coulter (Employee)
1082. Real-World Experience with Omadacycline for Nontuberculous Mycobacterial Infections: A Multicenter Evaluation
Authors: Morrisette Taylor , Alosaimy Sara , Lagnf Abdalhamid M , Philley Julie V , Sigler Carly , Butt Saira , Kaip Emily A , MacDougall Conan , Mejia-Chew Carlos , Bouchard Jeannette , Frens Jeremy J , Gore Tristan , Hamad Yasir , Howard Catessa , Barger Melissa , Gabriela Cabanilla M , Ong Aaron , Veve Michael P , Webb Andrew J , Stevens Ryan W , Cohen Keira A , Rybak Michael J 
Published: December 2021

Abstract

Background
Nontuberculous mycobacteria (NTM) are resistant to numerous antibiotics and lead to significant morbidity and mortality. Omadacycline (OMC) is an aminomethylcycline antibiotic that is Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Furthermore, OMC has shown in vitro activity against NTM. Given that real-world evidence is lacking, our primary objective was to evaluate the clinical success and tolerability of OMC when used for a variety of NTM infections.

Methods
This was a multicenter, retrospective, observational study conducted from January 2020 to June 2021. We included all patients ≥ 18 years of age that received OMC of any indication for Mycobacterium spp. The primary outcome was clinical success, defined as a lack of all-cause mortality, lack of persistence or re-emergence of infection during or after therapy, and lack of alteration of OMC. Incidence of adverse effects potentially attributable to OMC and reasons for OMC utilization were also analyzed.

Results
A total of 31 patients were included from 12 geographically distinct academic health systems (median age: 57 (IQR, 45-63) years; 45% male; 81% Caucasian). The majority of isolated pathogens were Mycobacterium abscessus complex (84%) and of those with subspeciation performed (54%), the majority (86%) were subsp. abscessus. The primary infections were of pulmonary origin (67%) and the median (IQR) duration of OMC therapy was 5.3 (3.2-9.4) months. Most isolates did not have OMC susceptibility conducted (87%), while the majority did for tigecycline (90%). Clinical success was reported in 81% of the population. Most patients were on combination antimicrobial therapy, and 39% of patients reported an adverse effect while on OMC (58% gastrointestinal distress). The majority of patients were prescribed OMC due to ease of administration (61%) and antimicrobial resistance to previous antibiotics (42%).

Conclusion
OMC may be a potential option for the therapy of NTM infections. Prospective, randomized clinical trials are needed to confirm our preliminary findings.

Disclosures
Julie V. Philley, MD, Paratek Pharmaceuticals (Advisor or Review Panel member)Paratek Pharmaceuticals, Inc. (Consultant) Michael P. Veve, Pharm.D., Cumberland (Grant/Research Support)Paratek Pharmaceuticals (Research Grant or Support) Michael J. Rybak, PharmD, MPH, PhD, Paratek Pharmaceuticals (Research Grant or Support)
1083. Phase 1b Results of Pharmacokinetics, Pharmacodynamics, and Safety for LBP-EC01, a CRISPR-Cas3 Enhanced Bacteriophage Cocktail Targeting Escherichia coli that Cause Urinary Tract Infections
Authors: Kim Paul , Sanchez Ana , Kime Jamie , ousterout Dave 
Published: December 2021

Abstract

Background
LBP-EC01 is the first CRISPR-engineered bacteriophage product to successfully complete Phase 1b testing in a clinical program designed to address infections caused by E. coli initially targeting urinary tract infections (UTIs). Thirty-six subjects were enrolled in this randomized, double blind study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of LBP-EC01 in patients with lower urinary tract colonization caused by E. coli.
Methods

Results
No drug-related Treatment Emergent Adverse Events (TEAEs) were observed. All nondrug related TEAEs were Grade 2 or below and there were no tolerability signals associated with LBP-EC01.A modified ITT (mITT) population was defined to assess PK in subjects treated with LBP-EC01 (n=17). Subjects were removed from the PK analysis who had missing or insufficient colonization at baseline (n=3), were exposed to antibiotics during screening or study conduct (n=3) or exhibited a non-drug related SAE (n=1). Of these subjects, 12 were found to be sensitive to LBP-EC01 and of these, 10 (83%) showed phage amplification. A PD analysis compared the mITT populations of LBP-EC01 vs. placebo (n=6) and showed that the LBP-EC01 arm had a decrease in E. coli that was greatest within 24 hours of initial treatment and remained below baseline across the entire treatment period. The placebo arm showed increased levels of E. coli and higher variability over the treatment period. An average difference of 2-3 log (100x to 1,000x) existed in urine E. coli concentration (CFU/mL) between the LBP-EC01 and placebo arms across the duration of the treatment period.

Conclusion
LBP-EC01 has proved to be safe and well-tolerated in this Phase 1b study of subjects colonized by E. coli. In addition, phage amplification was observed in patients with E. coli isolates sensitive to LBP-EC01, demonstrating a clear proof of mechanism. Finally, the apparent difference in PD effect between LBP-EC01 and placebo which was irrespective of MDR status, provides promise that LBP-EC01 may someday be an excellent option for patients suffering from UTIs caused by E. coli, especially in strains that are resistant to conventional antibiotics.

Disclosures
Dave ousterout, PhD, InceptorBio (Advisor or Review Panel member, Shareholder)Locus Biosciences (Employee, Shareholder)
1084. Comparative Outcomes Among Patients Receiving Varying Daptomycin Dosing Regimens in Hemodialysis
Authors: Maxwell Tyler , Orban James E , Kufel Wesley D , Destache Christopher , Williams Karen S , Velagapudi Manasa , Brandon Bookstaver P , Tatem Luis , McCracken James A , Carpenter Bethanne , Sharma Roopali 
Published: December 2021

Abstract

Background
Daptomycin (DAP) has become an appealing treatment option for gram-positive infections, which are common in patients receiving hemodialysis (HD), due to frequent access and manipulation. The approved DAP dosing of 4 to 6 mg/kg every 48 hours (q48h) quickly becomes desynchronized from the patient’s HD schedule and requires the burden of additional IV access. Previous pharmacokinetic studies have suggested that DAP can be dosed three-times weekly following HD, but no studies have evaluated clinical outcomes of this regimen.

Methods
This was a multi-center, retrospective cohort study across 6 hospitals in the United States. Adult, nonpregnant patients who received HD and DAP between 2015 and 2020 were screened for inclusion. Electronic medical records were reviewed for relevant study data. The primary outcome was clinical and microbiological outcomes among patients who received DAP thrice weekly versus q48h dosing. Microbiological Failure was defined as positive cultures after 7 days and further study definitions are included under Table 3.

Results
Baseline characteristics are summarized in Table 1. Length of stay was similar between both groups at a median of 25 days and patients had a median QPitt score of 0 on admission. The average DAP dose used was 7 mg/kg and 7mg-7mg-9mg on HD days in the q48h dosing and thrice weekly dosing regimens, respectively. The majority of patients had bacteremia and the most commonly isolated bacteria was methicillin-resistant Staphylococcus aureus. No differences in clinical outcomes were observed (p=0.87). Microbiological failure was higher among patients who received DAP thrice weekly compared to q48h dosing (69.2% vs 34.8%, p=0.047).

Conclusion
DAP dosed thrice weekly on HD days offers similar clinical resolution compared to q48h dosing. While the thrice weekly dosing regimen did have a significantly higher rate of microbiological failure, the analysis was limited by a small sample size. As this is a retrospective analysis not accounting for confounding variables, additional prospective studies are warranted to confirm these findings.

Disclosures
Wesley D. Kufel, PharmD, Melinta (Research Grant or Support)Merck (Research Grant or Support)Theratechnologies, Inc. (Advisor or Review Panel member) P. Brandon Bookstaver, Pharm D, ALK Abello, Inc. (Grant/Research Support, Advisor or Review Panel member)Biomerieux (Speaker's Bureau)Kedrion Biopharma (Grant/Research Support, Advisor or Review Panel member)
1085. Comparison of the Incidence of AKI in Vancomycin AUC Based Goal Trough Dosing vs. Traditional Trough Dosing in the Outpatient Setting
Authors: Rees Marissa , Bremmer Derek N , Carr Dustin R , Trienski Tamara , Buchanan Carley , White Kara M 
Published: December 2021

Abstract

Background
Recent changes to vancomycin guidelines recommend dosing by targeting an AUC of 400-600 in most patients, due to similar effectiveness and reduced rates of acute kidney injury (AKI). AKI was defined as an increase in serum creatinine of ≥ 0.5 mg/dl, a 50% increase in serum creatinine from baseline on two consecutive readings, or a decrease in creatinine clearance from 50% from baseline on two consecutive readings. The purpose of this study was to assess the incidence of AKI in patients receiving vancomycin dosed by AUC based trough goals and vancomycin dosed by traditional trough goals (15-20 mcg/mL) in the outpatient setting.

Methods
This study was performed by retrospective chart review using the electronic health record. Patients receiving vancomycin outpatient as continuation of therapy after discharge from December 1, 2018 through March 24, 2021 were reviewed. The primary objective was incidence of AKI in patients receiving vancomycin outpatient with trough goals derived from patient specific AUC calculations compared to patients receiving vancomycin by traditional goal troughs. Secondary objectives included rate of treatment failure, average AUC estimated trough range, and number of regimen changes required.

Results
There were a total of 65 patients in the traditional trough dosing group and 53 patients in the AUC trough dosing group. The incidence of AKI was higher in the traditional trough dosing group compared to the AUC trough group (23.1% vs 5.7%; p=0.01). There were no differences in incidence of treatment failure. The mean AUC estimated trough range was 11.4-16.9 mcg/mL. There were significantly less average regimen changes required in the AUC dosing group (1.64 vs 1.13; p=0.006). Patients receiving AUC trough dosing were 78% less likely to develop AKI as patients receiving traditional trough dosing (HR 0.221, 95%CI 0.051 – 0.968).

Conclusion
There was a significantly lower incidence of AKI in patients receiving vancomycin dosed by AUC based troughs compared to traditional trough dosing. Continuing AUC trough based dosing for vancomycin in the outpatient setting is convenient and may lead to reduced rates of AKI.

Disclosures
Dustin R. Carr, PharmD, BCPS, BCIDP, AAHIVP, Merck (Speaker’s Bureau)
1087. Imipenem-Cilastatin-Relebactam (I/R) Pharmacokinetics (PK) in Critically Ill Patients with Augmented Renal Clearance (ARC)
Authors: Fratoni Andrew J , Mah John W , Nicolau David P , Kuti Joseph L 
Published: December 2021

Abstract

Background
Imipenem (IMI) and relebactam (REL) are predominantly excreted via glomerular filtration. ARC is a common syndrome in critically ill patients with sepsis, whereby increased renal blood flow may result in enhanced solute clearance; therefore, sub-therapeutic antibiotic concentrations are of concern. Herein, we describe the PK of I/R in critically-ill patients with confirmed ARC.

Methods
Infected patients in the intensive care unit with ARC (CrCl ≥130 mL/min) received a single dose of I/R 1.25g as a 30min infusion. Blood samples were collected over 6 hours (hr) for IMI and REL concentration determination by a validated LC/MS/MS assay. Protein binding was assessed at 0.5hr by ultrafiltration (UF). An 8hr urine creatinine (UCr) collection was performed to confirm ARC. IMI and REL plasma concentrations were fitted to compartmental models in WinNonlin. Simulated concentration vs time profiles were used to assess attainment of pharmacodynamic (PD) targets for IMI (30%fT &gt;MIC) and REL (fAUC:MIC 18) at the susceptibility breakpoint of 2 mg/L.

Results
Five patients (60% female) completed the study. Mean (SD) age, weight, and APACHE II were 43 (14) years, 90 (15) kg, and 16 (6), respectively. All patients had confirmed ARC with CrCl of 160.6 ± 47.0 mL/min (range: 135-244mL/min) based on UCr. Both IMI and REL concentrations fitted a 2-compartment better than 1-compartment model. IMI PK was: clearance, 17.9 ± 8.7 L/hr; volume of central compartment, 15.6 ± 11.2 L; volume of peripheral compartment, 10.6 ± 5.4 L; and intercompartmental clearance, 16.6 ± 14.5 L/hr. REL PK parameters were 11.9 ± 7.5 L/hr, 17.0 ± 11.3 L, 13.5 ± 9.9 L, and 13.4 ± 11.1 L/hr, respectively. Half-life was 1.5 ± 0.5 for IMI and 2.8 ± 2.2 hr for REL. Protein binding for IMI ranged from 0-10%, while REL was 0-14%. IMI fT &gt;MIC ranged from 40-90%, and REL fAUC:MIC ranged from 22.6-59.0.

Conclusion
These are the first data to describe IMI and REL PK in critically-ill infected patients with ARC. Despite plasma clearance values greater than those reported in healthy volunteers and patients in clinical trials, I/R 1.25g as a 30 minute infusion provided optimal exposure in all patients for isolates with MICs ≤2 mg/L.

Disclosures
David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)BioMérieux (Consultant, Research Grant or Support, Speaker’s Bureau)Contrafect (Scientific Research Study Investigator)GSK (Consultant)Merck (Research Grant or Support)Paratek (Speaker’s Bureau)Roche Diagnostics (Research Grant or Support)Shionogi (Research Grant or Support)Summit (Scientific Research Study Investigator)
1090. Does calculation method matter for targeting vancomycin AUC?
Authors: Chang Jack , Patel Dhara , Claeys Kimberly C , Scheetz Marc H , Heil Emily 
Published: December 2021

Abstract

Background
Recent vancomycin (VAN) guidelines recommend targeting an area under the curve (AUC) concentration of 400-600 for treatment of methicillin resistant Staphylococcus aureus infections. Multiple strategies for calculating AUC exist, including first order pharmacokinetic (foPK) equations and Bayesian models. Most clinical applications of foPK assume unchanged patient status and project ideal administration times to estimate exposure. Bayesian modeling provides the best estimate of true drug exposure and can incorporate changing patient covariates and exact doses. We compared two commonly used foPK methods to Bayesian estimates of VAN AUC.

Graphs depict calculated AUCs using the three different methods: 1) Population PK estimated (foPOPPK) 2) Two-level first dose estimated (foFDPK) 3) Bayesian estimated.

Methods
First order equations were performed using population PK estimates (foPOPPK) to estimate steady state (SS) AUC and initial doses. Two concentrations after first dose were used to estimate SS AUC (foFDPK). A 2-compartment Bayesian model allometrically scaled for weight and adjusted for creatinine clearance was used to determine 24-48 hour AUCs. Differences between AUCs were compared using a mixed-effects analysis, and correlation of foPK equations to Bayesian estimates was described using Spearman’s correlation. Patient results from each method were classified as below (&lt; 400), within (400-600), or above ( &gt;600) targets.

Results
65 adult patients were included. The median and IQR for calculated AUCs using foPOPPK, foFDPK, and Bayesian methods were 495.6 (IQR: 76.6), 498.2 (IQR: 107.4), and 472.1 (IQR: 177.9), respectively with p &gt;0.65 for both foPK methods vs. the Bayesian method. AUCs predicted by foPK equations were poorly correlated with Bayesian AUCs (Spearman’s rho= -0.08, p=0.55), while AUCs from foFDPK better correlated with Bayesian AUCs (Spearman’s rho= 0.48, p=0.00). AUCs were within, above, and below target for 54%, 20%, and 26% for the Bayesian model; 95%, 5% and 0% for foPOPPK; and 74%, 12%, and 14% for foFDPK. foPK AUC estimates concurred with Bayesian estimates only 52% of the time.

Conclusion
AUCs calculated by the three methods did not differ on average, but dosing recommendations for foPK at the patient level varied substantially compared to the Bayesian method. This difference is because Bayesian estimation incorporates actual patient exposures while foPK equations rely on idealized dose timing to predict AUCs.

Disclosures
Kimberly C. Claeys, PharmD, GenMark (Speaker’s Bureau) Marc H. Scheetz, PharmD, MSc, Nevakar (Grant/Research Support)SuperTrans Medical (Consultant)US Patent #10688195B2 (Other Financial or Material Support, Patent holder)
1091. Validation of an Allometrically Scaled Body Weight Equation to Predict Vancomycin Clearance and Guide 24-Hour Vancomycin AUC Dosing in Obese Patients
Authors: Footer Brent , Nguyen Arthur , Greckel Meagan , Taylor Colton , Christensen Alyssa , Tallman Gregory 
Published: December 2021

Abstract

Background
Accurately determining empiric vancomycin (VAN) doses in obese patients represents a clinical challenge. A recent population pharmacokinetic (PK) study provided an equation to estimate vancomycin clearance (CL) based on age, sex, serum creatinine (Scr), and allometrically scaled body weight. The purpose of this study was to validate this equation in a population of obese adults treated with vancomycin at eight community-based hospitals and use the CL estimate to guide empiric VAN dosing.

Methods
The study period was November 1, 2020 and March 30, 2021. Patients were included if they were ≥ 18-year-old with a body mass index (BMI) ≥ 30 kg/m2, had an empiric dose targeting an AUC24 determined using the above referenced equation, and had a calculated AUC24. Only the first vancomycin course and AUC calculation for each patient were included. Patients with a creatinine clearance &lt; 30ml/min and pregnant women were excluded. AUC24 and other PK parameters were calculated using two levels and noncompartmental analysis. Observed versus predicted CL and AUC24 were plotted to determine correlation.

Results
Sixty patients were included, of which 60% were male and 33% had a confirmed methicillin-resistant Staphylococcus aureus infection. The mean age, BMI, and baseline Scr were 61.8 years, 37.8 kg/m2, and 0.99 mg/dL, respectively. Fifty-three (88%) patients received a loading dose, with a mean dose of 20.3mg/kg. The mean initial total daily maintenance dose was 2397.9mg. The mean predicted AUC24 was 476.4mg*h/L while the mean observed AUC24 was 556.3mg*h/L. For CL, the correlation between observed and predicted values was R2=0.38 (Figure 1). The correlation between predicted and observed AUC24 values was R2=0.08 (Figure 2). The percent of patients with observed AUC24 values of &lt; 400mg*h/L, 400-600mg*h/L, and &gt;600mg*h/L were 23%, 40%, and 37%, respectively. The relationship between calculated minimum concentrations (Cmin) and AUC24 is shown in Figure 3. 65% of patients with a therapeutic AUC achieved it with a Cmin &lt; 15mg/L while 4.5% of patients with a supratherapeutic AUC had a Cmin &lt; 15mg/L.
Figure 1. Observed versus Predicted Clearance (CL) of Vancomycin

Figure 2. Observered versus Predicted 24 hour Vancomycin Area Under the Curve (AUC24)

Figure 3. Calculated 24 hour Vancomycin Area Under the Curve (AUC24) versus Calculated minimal concentration (Cmin)

Conclusion
The correlation between observed and predicted CL was 0.38. Using these CL estimates to guide empiric VAN dosing resulted in only 40% of patients achieving a therapeutic AUC24.

Disclosures
All Authors: No reported disclosures