bluuebunny/crossref_metadata_2025_split huggingface dataset:
1102. Evaluation of Vancomycin Accumulation in Patients with Obesity
Authors: Assadoon Maha , Pearson Jeffrey C , Kubiak David W , Kovacevic Mary P , Dionne Brandon 
Published: December 2021

Abstract

Background
Current vancomycin guidelines recommend using actual body weight for dosing. However, in patients with obesity, this may result in lower initial vancomycin concentrations that can accumulate with continued doses due to differences in volume of distribution. The objective of this study is to evaluate the incidence of vancomycin accumulation in patients with obesity and identify potential factors associated with accumulation.

Methods
This is a single-center, retrospective, observational study at a tertiary academic medical center. Adult patients with a BMI ≥ 30 kg/m2 and with ≥ 2 vancomycin serum trough concentrations within the same encounter in 2019 were screened. Patients were excluded if they were pregnant, had unstable renal function or severe renal impairment, received &lt; 3 doses before a concentration was drawn, or had inconsistent dosing prior to a concentration draw. Linear kinetics were used to correct for differences in timing of concentration or dose changes. The major endpoint was the incidence of vancomycin accumulation, defined as a 20% increase in trough concentration between the first and any subsequent trough concentrations within the first 10 days of therapy. Minor endpoints included the percentage of supratherapeutic concentrations and the incidence of acute kidney injury (AKI). Descriptive statistics were used to evaluate endpoints and multivariable logistic regression was used to evaluate factors associated with accumulation.

Results
We screened 543 patients, and 162 were included in our analysis. The median age was 56.5 years (interquartile range [IQR] 43 - 65.3), and 62.3% were male. The median weight was 112.7 kg (IQR 99.8 - 122.6) and the median BMI was 36.8 kg/m2 (IQR 33.1 - 41). The median total daily vancomycin dose at initiation was 28.7 mg/kg/day (IQR 25.4 - 31.2). Vancomycin accumulation occurred in 99 patients (61.1%) within the first 10 days of therapy and AKI occurred in 21 patients (14.9%). No factors studied, including age, gender, obesity class, initial dose, SCr, or frequency were associated with accumulation.

Conclusion
Most patients with obesity experienced vancomycin accumulation within the first 10 days of therapy. Providers should be cautious when assessing a vancomycin concentration early in the treatment course.

Disclosures
All Authors: No reported disclosures
1103. Minocycline (MIN) Pharmacodynamics (PD) against Stenotrophomonas maltophilia (STM) in a Neutropenic Murine Thigh Infection Model
Authors: Fratoni Andrew J , Nicolau David P , Kuti Joseph L 
Published: December 2021

Abstract

Background
Antibiotic treatment options for serious STM infections are limited. MIN displays in vitro activity against STM; however, limited data supports optimal dosing for STM. Herein, we employed the murine neutropenic thigh infection model to assess MIN PD against STM.

Methods
Four clinical STM isolates with MIN MICs 0.25 – 1 mg/L were included. Both thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 colony forming units (CFU)/mL. Mice received uranyl nitrate on Day -3 to provide predictable renal impairment. Two hours after inoculation, MIN or control was administered subcutaneously. Pharmacokinetic (PK) studies of 2.5, 25, 50, and 100 mg/kg were conducted. Previously reported protein binding of 78.1% was used to define free exposure. Dose ranging studies were conducted on all STM to assess in vivo activity over a range of MIN exposures. MIN total daily doses (TDD) of 10, 20, and 50 mg/kg were fractionated q24h, q12h, and q6h against a single STM to determine the PD index best correlated with reductions in CFU/mL. Efficacy was measured in log10CFU/thigh at 24h compared with 0h controls. Composite CFU data were fitted to an Emax model to determine the fAUC/MIC exposure for stasis and 1 log10 reduction.

Results
MIN PK was linear up to 50 mg/kg and well described by a 1 compartment model with first order absorption and elimination. Mean PK parameters across the linear range were: Vd, 2.97 L/kg; K01, 10.62 1/h; and K10, 0.35 1/h. Mean ± SD bacterial burden at 0h across all isolates was 6.17±0.20 log10CFU/thigh. In 24h controls, bacterial growth was 7.90±0.85 log10CFU/thigh. A dose response was observed across all isolates using TDD of 2-300 mg/kg. PD indices correlated with CFU reductions as follows: fAUC/MIC (R2=0.613), fCmax/MIC (R2=0.590), and %fT &gt;MIC (R2=0.504). The fAUC/MIC needed for stasis and 1 log10 reduction at 24h was 9.6 and 23.6, respectively.

Conclusion
These are the first data describing MIN PD against STM. Against these STM, MIN fAUC/MIC was the PD index best correlated with CFU reductions. The exposure thresholds defined in this study will be useful in designing optimal MIN dosing regimens for treating STM infections and re-assessment of the current susceptibility breakpoint.
The study was funded under FDA Contract 75F40120C00171.

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)
1107. Vancomycin AUC Dosing: Is One Concentration in the Hand Worth Two in the Bush?
Authors: Spivey Justin , Shroba Jenny , Deri Connor , Nys Cara , Wrenn Rebekah , Yarrington Michael E 
Published: December 2021

Abstract

Background
Recent guidelines recommend a transition from trough-based to area-under the curve-based (AUC) monitoring for vancomycin for serious invasive methicillin-resistant Staphylococcus aureus infections. Due to the challenges of performing AUC monitoring in clinical practice, this study sought to compare the accuracy of an AUC calculated from two points using trapezoidal calculations and from a single steady-state trough combined with population assumptions.

Methods
This prospective cohort analysis included hospitalized patients with stable renal function from 10.2020 to 12.2020 with two vancomycin concentrations obtained at steady-state during a single dosing interval. For each patient, AUC was calculated via trapezoidal equations utilizing peak and trough concentrations (P/T) and using the trough concentration (T) combined with population volume of distribution. Appropriate concentrations were defined as a peak at least 2 hours after the end of the infusion and a trough within one hour of the next dose. The percent and actual differences were calculated between the P/T and T AUC assessments for each patient. A patient level review was independently conducted by two clinical pharmacists to evaluate if a change in dosing would have been made according to AUC estimation methodology.

Results
Thirty-one patients had appropriate steady-state P/T obtained. Baseline demographics are shown in Table 1 with the majority of patients being overweight with normal renal function. The mean calculated AUC for both groups was similar, P/T 544.8 and T 549.8. The mean and median percent differences were 1.85% and 0.65%, with a standard deviation of 7.3% and an apparent normal distribution (Figure 1, p = 0.94 by Shapiro’s test). The median absolute difference in AUC was 25.82 mg*h/L between methodologies. Both methods would have resulted in the same modification to the vancomycin regimen based on patient level chart review.

Conclusion
The single-trough method performed similarly to the more laborious P/T method. No patient would have received a dose adjustment based on the two different AUC estimation methods. The single-trough method may represent a resource and workflow conscious AUC estimation method for patients meeting population assumptions.

Disclosures
All Authors: No reported disclosures
1108. Evaluation of Vancomycin Dosing in Adolescents
Authors: Weaver Ashley I , Wilson Genene A , Belarski Emily , Nelson Allison , Kumar Madan , Bhagat Palak 
Published: December 2021

Abstract

Background
Pediatric vancomycin dosing varies based on age and renal function. Recent literature suggests previously recommended doses of 45-60 mg/kg/day may be insufficient to achieve an AUC:MIC ratio of 400-600 mg-hr/L and higher doses of at least 60 mg/kg/day may be required. However, data to guide dosing in adolescents is limited.

Methods
A single-center, retrospective chart review of patients aged 12 to 18 years who received vancomycin and had therapeutic drug monitoring (TDM) performed between July 2017 to June 2020 were included. The primary endpoint was the median total daily dose (TDD) of vancomycin required to achieve therapeutic serum concentrations. Secondary endpoints were to characterize how factors such as age, weight, trough versus AUC monitoring, malignancy, and trauma may influence dosing. The safety endpoint was the development of acute kidney injury (AKI).

Results
130 vancomycin courses in 86 patients were included. Baseline characteristics are presented in Table 1. Of the 130 vancomycin courses, 50 courses (38%) achieved therapeutic serum concentrations at a median TDD of 49.8 mg/kg/day (IQR 42 – 59.4). This was not statistically different from the sub- or supra-therapeutic groups (p=0.22). Based on age, the median TDD for 12-14 year olds was higher at 60 mg/kg/day (IQR 45-78.8; n=14) than for 15-16 and 17-18 year olds [45.3 mg/kg/day (IQR 41.1-51; n=15), 48 mg/kg/day (IQR 42-52; n=21), respectively]. Obese patients needed a median TDD of 43.5 mg/kg/day vs at least 51 mg/kg/day in healthy and overweight patients. Finally, AUC guided dosing resulted in a slightly lower overall median TDD vs trough guided dosing (45.8 mg/kg/day vs 50.5 mg/kg/day). Additional dose requirements based on age, weight, TDM and other characteristics are presented in Table 2. Of the 15 patients who developed AKI per pRIFILE criteria, 2 were classified as injury and 3 as failure.
Table 2. Total Daily Dose Course Analysis

Conclusion
To achieve therapeutic levels, adolescents 12 to14 years old need higher empiric doses of 60 mg/kg/day compared to 45 mg/kg/day in 15 to 18 year olds. Obese patients, however, may require lower TDD than underweight, healthy, and overweight patients. Patients that receive AUC versus trough monitoring may also require lower TDD to achieve therapeutic concentrations. More data is needed to further evaluate our findings.

Disclosures
All Authors: No reported disclosures
1109. Pharmacokinetics and Exposure of Cefepime in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)
Authors: Kois Abigail K , Gluck Jason A , Nicolau David P , Kuti Joseph L 
Published: December 2021

Abstract

Background
ECMO is a life-saving tool utilized in critically ill patients that require respiratory and/or cardiac support. ECMO may also affect the pharmacokinetics (PK) of certain medications, including some antibiotics. Cefepime is a widely used antibiotic in this population due to its broad spectrum activity but limited data are available to guide dosing in patients requiring ECMO.

Methods
This was a prospective, single-center study of 6 critically ill adult patients requiring ECMO and receiving cefepime 2g q8h as a 3h infusion. After obtaining informed consent, 4-6 blood samples within the dosing interval were collected to determine cefepime concentrations. Population PK was conducted in Pmetrics using R. Final MAP Bayesian parameter estimates were used to simulate free time above MIC (%ƒT &gt;MIC) for various cefepime dosing regimens. The target pharmacodynamic exposure was 70% fT &gt;MIC.

Results
Patients were between 31-62 years old; 4/6 (66.7%) were on veno-venous (VV) ECMO and 2 veno-arterial (VA) ECMO. Two patients required continuous venovenous hemodiafiltration (CVVHDF) while the other 4 had a CrCL between 92-199 ml/min. A two compartment model fitted the data better than a one compartment model. Median (range) final population PK parameters were: clearance (CL), 9.8 L/h (7.6-33.1); volume of central compartment (VC ), 6.9 L (4.7-49.8); and intercompartment transfer constants (k12), 2.04 h-1 (1.48-2.29); and k21, 1.49 h-1 (0.75-1.71). The 2g q8h (3h infusion) regimen resulted in target exposure in all patients up to an MIC of 8 mg/L (the susceptibility breakpoint for Pseudomonas), with 5/6 patients achieving this at 16 mg/L. A standard 2g q12h (0.5h infusion) regimen would have resulted in 5/6 patients achieving 70% ƒT &gt;MIC at 8 mg/L and 1/6 at 16 mg/L.

Conclusion
These are the first data describing cefepime PK and exposure attainment in critically ill patients receiving ECMO. Cefepime 2g q8h (3h infusion) achieved target pharmacodynamic exposure up to the susceptibility breakpoint of 8 mg/L in all 6 patients, including 2 with concomitant CVVHDF. Additional studies are warranted to define cefepime PK in patients on ECMO across a robust range of CrCL to guide dosing.

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)
1111. Therapeutic Drug Monitoring of Colistin in Cerebrospinal Fluid in the Treatment of Neurosurgical Meningitis caused by Pseudomonas aeruginosa and KPC-producing Enterobacterales
Authors: Yasmin Mohamad , nutman Amir , Marshall Steven , Wang Lu , Chen Ke , Yahav Dafna , Wang Jiping , Li Jian , Bonomo Robert A 
Published: December 2021

Abstract

Background
Central nervous system (CNS) infections caused by carbapenem-resistant Enterobacterales (CRE) and Difficult-to-treat resistant (DTR)-P. aeruginosa (PA) present a therapeutic dilemma. Therapies are limited due to antibiotic resistance and inadequate CNS diffusion. Intraventricular polymyxins are utilized in this setting despite a lack in pharmacokinetic data after CNS injection. We describe the utilization of intravenous and intrathecal polymyxin E [colistimethate (CMS)] therapeutic drug monitoring (TDM) in 3 cases of post-neurosurgical meningitis.

Methods
Bacterial identification and susceptibility testing were performed using MicroScan. TDM was employed by dosing CMS at 125,000 IU (i.e., 4.1 mg CBA or 10 mg) administered via external ventricular drain twice daily and 4.5 MIU (133.2 CBA or 360 mg) CMS administered over 30 minutes IV twice daily. Four pairs of CSF and blood samples were collected for each patient (Table 1). Samples were placed on ice to minimize in-vitro conversion of CMS to Colistin. Colistin binding in plasma and CSF was measured using ultracentrifugation. Concentrations of CMS and Colistin in CSF and human plasma were determined by liquid chromatography/mass spectrometry. Patients A, B and C received 20, 15, and 12 doses of CMS, respectively, prior to TDM.

Results
Bacterial cultures revealed DTR PA, blaKPCE. cloacae and blaOXA-48K. pneumoniae for patients A, B and C, respectively. Colistin minimum inhibitory concentrations (MIC) were 0.5 µg/ml, 0.125 µg/ml, and 0.125 µg/ml, respectively. The measured CSF and plasma concentrations of CMS, Colistin, and binding are shown in Table 1. Clinical resolution and microbiological cure were attained in all patients.
Therapeutic Drug Monitoring of Unchanged CMS and Formed Colistin in CSF samples for patient A, B, and C

Therapeutic Drug Monitoring of Unchanged CMS and Formed Colistin in Plasma Samples for patient A, B, and C

Conclusion
Favorable concentrations of formed Colistin and CMS in CSF were achieved in 3 patients with complicated CNS infection. To the best of our knowledge, this is the first study to report the binding of Colistin in CSF in humans. A TDM method was effectively applied to demonstrate that Colistin achieves and maintains the PK/PD target (fAUC/MIC) [ratio of area under the plasma concentration curve of unbound drug to MIC] that best correlates with killing activity. Overall, our results support intraventricular polymyxins for treating DTR Gram-negative CNS infections.

Disclosures
Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support)
1114. Effectiveness and Safety of Beta-lactam Antibiotics with and without Therapeutic Drug Monitoring in Patients with Pseudomonas aeruginosa Pneumonia or Bloodstream Infection
Authors: Kunz Coyne Ashlan J , Al-Shaer Mohammad H , Casapao Anthony M , Ferreira Jason , Isache Carmen , Jankowski Christopher 
Published: December 2021

Abstract

Background
Pseudomonas aeruginosa (PSAR) is challenging to treat due to its multiple resistance mechanisms, limited anti-PSAR agents, and population pharmacokinetic (PK) variances. Beta-lactam antibiotics (BLA) are commonly used to treat PSAR infections and although they have a wide therapeutic index, suboptimal exposures may lead to treatment failure and antimicrobial resistance while high exposure may result in adverse effects. Certain patient populations may benefit from BLA therapeutic drug monitoring (TDM) due to their significant PK variability. The purpose of this study was to compare clinical outcomes in patients with PSAR pneumonia (PNA) or bloodstream infection (BSI) receiving BLA with and without the guidance of TDM.

Methods
Retrospective, parallel cohort study conducted at UF Shands Gainesville and UF Health Jacksonville evaluating five years of patients with PSAR PNA or BSI. TDM group was defined for routine BLA TDM compared to nonroutine BLA TDM service (non-TDM). Patients were excluded if they died before a culture result, transferred in with a positive PSAR culture, were transplant recipients, cystic fibrosis or burn injury patients. The primary outcome was a composite of presumed clinical cure defined as the absence of the following: all-cause in-hospital mortality, escalation, and/or additional antimicrobial therapy for PSAR infection after 48 hours of treatment with primary susceptible regimen due to worsening clinical status or transfer to a higher level of care.

Results
Two-hundred patients were included (TDM n=95; non-TDM n=105). The overall primary composite outcome of presumed clinical cure occurred in 73% of patients (82% and 75% of the TDM and non-TDM cohorts, respectively; p=0.301). A post-hoc multivariate analysis was conducted to assess predictors of not attaining clinical cure.

Conclusion
While there was no difference in the primary composite outcome of presumed clinical cure, future studies can use these data to assess TDM patient selection and whether a bundled care approach of BLA regimens with known clinical benefit, early TDM-guided dose optimization, and continued clinical assessment improves outcomes in patients with PSAR PNA or BSI compared to use of each modality individually.

Disclosures
All Authors: No reported disclosures
1118. Population Pharmacokinetics of Contezolid Acefosamil and Contezolid – Rationale for a Safe and Effective Loading Dose Regimen
Authors: Bulitta Jürgen B , Hafkin Barry , Fang Edward 
Published: December 2021

Abstract

Background
Contezolid (CZD) is a novel oral oxazolidnone with comparable activity and potentially improved safety compared to current oxazolidinones. The intravenous (IV) double prodrug contezolid acefosamil (CZDa) is converted via MRX-1352 to active CZD. CZDa paired with CZD holds promise as a safe and effective treatment for serious Gram-positive infections such as those caused by methicillin-resistant Staphylococcus aureus. Sequential therapy with CZDa IV followed by CZD oral (PO) offers flexible treatment options in hospital and outpatient settings for conditions such as diabetic foot infections. We aimed to design a CZDa/CZD dosage regimen leveraging population pharmacokinetic modeling (PopPK).

Methods
PopPK simultaneously fit data from 184 adult subjects. These were 1) plasma concentrations (by LC-MS/MS) of MRX-1352, CZD, and its metabolite MRX-1320 from 66 healthy subjects receiving CZDa (150-2400 mg IV) for up to 10 days, 2) CZD and MRX-1320 concentrations from 44 healthy subjects receiving single CZD PO doses of 400, 800, or 1200 mg with and without food or multiple doses Q12h for up to 28 days, and 3) CZD concentrations from 74 Phase 2 patients receiving CZD 800 mg PO Q12h. PopPK and Monte Carlo simulations were used to optimize CZD exposures.

Results
CZDa was rapidly converted to MRX-1352, which was converted less rapidly to CZD. CZD was well absorbed and food enhanced its bioavailability. For CZD 800 mg PO with food, apparent total clearance of CZD was 13.1 L/h (22% coefficient of variation) in healthy subjects and 14.5 L/h (53% CV) in patients. The apparent volume of distribution at steady-state was 20.5 L. A loading dose of CZDa 2000 mg IV, then CZDa 1000 mg IV Q12h, and followed by CZD 800 mg PO Q12h achieved areas under the curve (AUC) between 75 and 100 mg*h/L (medians; Figure) on all study days. Compared to CZD AUCs, the MRX-1352 AUCs during IV dosing were higher. While the median MRX-1320 AUCs were lower (18 to 48 mg*h/L), some accumulation was predicted in ~5% of subjects.

Conclusion
A loading dose of CZDa 2000 mg IV followed by either CZDa 1000 mg IV or CZD 800 mg PO Q12h was predicted to reliably achieve efficacious CZD exposures on day 1 and maintain those exposures throughout therapy. This regimen will be evaluated in Phase 3 studies in complicated skin infections and diabetic foot infections.

Disclosures
Jürgen B. Bulitta, PhD, MicuRx Pharmaceuticals, Inc. (Consultant) Barry HAFKIN, MD, MicuRx Pharmaceuticals Inc. (Consultant)