bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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 (< 400), within (400-600), or above ( >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 >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

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 < 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 < 400mg*h/L, 400-600mg*h/L, and >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 < 15mg/L while 4.5% of patients with a supratherapeutic AUC had a Cmin < 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
1092. Population Pharmacokinetics of Cephalexin in Non-Obese and Obese Hospitalized Patients with Infectious Diseases
Authors: Jeong Kyeoul , Chung Eun Kyoung , Cheatham S Christian , Stock Andrea H , Utley Sara , Healy Daniel P , Campion Maureen G , Murrey Timothy , Gesenhues Alicia M , Jeffery Julia , Kays Michael B
Published: December 2021

Background

Obesity is a significant global health problem and has been associated with altered pharmacokinetics (PK) and pharmacodynamics (PD) of many drugs. Cephalexin is a commonly prescribed antibiotic as an oral drug for the treatment of mild to moderate infections; however, little is known regarding cephalexin pharmacokinetics in obese patients. The objective of this study was to investigate the population PK of cephalexin in non-obese and obese patients.

Methods

Hospitalized patients who were 18 years or older with a suspected or documented infection were studied. Patients weighing < 120 kg were defined as non-obese patients whereas those weighing ≥ 120 kg as obese. All included patients received cephalexin 1000 mg every 6 hours orally. After ≥ 3 days of therapy, serial blood samples were collected. Ultrafiltration was used to separate the unbound drug from the protein-bound fractions, and both total and unbound serum concentrations were determined by HPLC. The concentration-time data for cephalexin were analyzed by a non-linear mixed effects modeling approach using NONMEM.

Results

Overall, 255 serum concentrations from 19 patients (10 males, 4 in an ICU) were included; ten patients were non-obese (total body weight [TBW] < 120 kg) and nine were obese (TBW ≥ 120 kg). A 1-compartment model with first-order absorption, absorption lag-time, first-order elimination, and linear protein binding best fit the concentration-time data. Creatinine clearance (CrCl) was the only covariate significantly associated with cephalexin PK, specifically systemic clearance (CL): CL (L/h) = 12.3 + [0.0837*(CRCL – 81.8)]. No other covariates significantly affected the model-derived PK parameters including CL, volume of distribution (V), first-order absorption rate constant (Ka), unbound fraction (fu) with the fixed estimate of 0.776, and absorption lag-time (Tlag).

Conclusion

In conclusion, cephalexin PK is comparable between non-obese and obese patients. Dosing adjustments based solely on body size may not be necessary. Further analyses are warranted to suggest optimal cephalexin dosages in obesity through large-scale population PK-PD modeling and simulation.

Disclosures

All Authors: No reported disclosures
1093. Bypassing Penicillin Skin Testing in favor of Direct Oral Challenge: A Pharmacy-driven Inpatient Program
Authors: Ham YoungYoon , Joshi Shyam , Tucker Kendall J , Yu Diana , Lewis James , Sukerman Ellie
Published: December 2021

Background

Patient interview, penicillin skin testing (PST) and/or an oral challenge can be used to evaluate penicillin allergies. Programs favor PST prior to oral challenge, but there is interest in bypassing PST and directly oral challenging for logistical and financial reasons. Data on the safety and efficacy of a direct challenge in the inpatient setting when the index reaction is moderate to severe (e.g. swelling of throat, angioedema, anaphylaxis) is lacking.

Methods

Adult patients (≥18 years) admitted with a penicillin allergy were evaluated for eligibility between September 2019 and June 2021. Pregnant patients were excluded, while critically ill patients and those on anti-histamine medications were evaluated if clinical need was high. Institutional protocols allowing for patients to be challenged without PST if reaction was more than 10 years ago were used. Data collected included the number of patients challenged and delabeled, number of patients who had moderate to severe index reactions, number of patients who were relabeled without cause, and number of patients who declined further testing.

Results

Two hundred twenty-five patients were evaluated; 11 patients declined testing. Two hundred four patients were delabeled (95%) among those fully evaluated. One hundred twelve patients were delabeled by interview and chart review alone (52%), 99 by oral challenge (46%), and 2 by PST and oral challenge (1%). Twenty-nine patients with moderate to severe reactions were challenged and 27 were delabeled. Ten patients could not be delabeled due to mild or delayed reactions to challenge or subsequent treatment, including 2 patients with severe index reactions who had mild challenge reactions and required no rescue medications. No patients required epinephrine during challenge. Five patients were relabeled and then delabeled again as no new reaction had occurred.

Conclusion

Penicillin allergies can be removed with a pharmacy-driven algorithm that prioritizes direct challenges when appropriate even when the index reaction was moderate to severe. Risks of a reaction are low, and reactions tend to be mild. Given well-documented benefits of delabeling patients for the patient and the institution, more hospitals should consider starting such services.

Disclosures

All Authors: No reported disclosures
129. Antimicrobial Resistance Genes Were Reduced Following Administration of Investigational Microbiota-Based Live Biotherapeutic RBX2660 to Individuals with Recurrent Clostridioides difficile Infection
Authors: Hau Heidi , Walsh Dana M , Gonzalez Carlos , Shannon Bill , Blount Ken
Published: December 2021

Background

Intestinal colonization by antimicrobial resistant (AMR) pathogens is a known health and infection risk, and is common among individuals with recurrent Clostridioides difficile infections (rCDI). Accordingly, therapeutic approaches that decolonize the gut of AMR pathogens could be valuable to patients to reduce risk of associated illnesses. Herein, we assessed gut colonization with AMR bacteria before and after treatment with RBX2660—a microbiota-based investigational live biotherapeutic—in the PUNCH CD3 Phase 3 trial for reducing CDI recurrence.

Methods

rCDI participants enrolled in PUNCH CD3 received a blinded single dose of RBX2660 or placebo within 24 to 72 hours after completing antibiotic treatment for the most recent rCDI episode. Clinical response was the absence of CDI recurrence at eight weeks after treatment, and participants were asked to submit stool samples prior to RBX2660 or placebo treatment (baseline) and 1, 4 and 8 weeks, 3 and 6 months after study treatment. Samples were extracted and sequenced using a shallow shotgun method. The presence and number of AMR genes was determined for 175 participant samples and 116 RBX2660 samples using 90% K-mer sequence coverage based on the MEGARes database. AMR gene count data were collapsed into count columns to adjust for sparseness in the matrices and were analyzed using a Generalized Linear Mixed Model.

Results

Clinically, RBX2660 demonstrated superior efficacy versus placebo (70.4% and 58.1%, respectively), and the total AMR genes per participant decreased significantly from before to after treatment in RBX2660-treated responders (p< .05, Figure 1) and remained low to at least 6 months. Among genes that decreased in RBX2660 responders were clinically important extended-spectrum beta-lactamase (blaTEM, blaSHV, blaCTX-M), vancomycin resistance (vanA, vanB), and fluoroquinolone resistance genes (gyrA, parC).

Total AMR genes per PUNCH CD3 participant among RBX2660-treated responders at the indicated time points and in the RBX2660 investigational product. The red lines indicate timepoint group medians.

Conclusion

In the PUNCH CD3 Phase 3 trial of RBX2660 for rCDI, AMR gene content decreased after RBX2660 treatment and remained low to at least 6 months, consistent with prior RBX2660 trials. This underscores the potential of microbiota-based biotherapeutics for decolonizing AMR bacteria from gut microbiota and thereby reducing AMR infection risks.

Disclosures

Heidi Hau, PhD, Rebiotix Inc. (Employee) Dana M. Walsh, PhD, Rebiotix (Employee) Ken Blount, PhD, Rebiotix Inc., a Ferring Company (Employee)
1096. Evaluation of Vancomycin Pharmacokinetics in Intravenous Drug Users
Authors: Weihs Sayo , Quick Gadison , Bogdanich Ivana
Published: December 2021

Background

People who inject illicit drugs (PWID) are 16 times more likely to develop methicillin-resistant Staphylococcus aureus (MRSA) infections including severe infections like bacteremia and endocarditis. Vancomycin is recommended as the drug of choice for empiric and targeted coverage in both severe and non-severe MRSA infections. Pharmacokinetic literature has suggested up to 31% higher renal clearance in intravenous drug users (IVDU) compared to non-IVDUs. This increased clearance may theoretically lead to more frequent sub-therapeutic troughs in otherwise standard dosing schemes. There is a paucity of data examining vancomycin pharmacokinetics following typical dosing schemes in IVDU population.

Methods

This was a single-center, retrospective chart review that examined therapeutic drug monitoring in patients treated with vancomycin between January 1st, 2015 through July 31st, 2020. Patients were identified as either IVDU or non-IVUD groups based on ICD-9/10 codes. The primary outcome was the difference between mean first vancomycin steady state troughs. Secondary outcomes were differences in time to first therapeutic trough, mean number of days on vancomycin based on infection, rate of acute kidney injury (AKI) after vancomycin, and rate of vancomycin failure.

Results

A total of 158 patients were included in the analysis (77 IVDU vs. 81 non-IVDU). Mean first vancomycin steady state trough were significantly less in IVDU group compared to non-IVDU group (11.85 vs. 13.98 mcg/mL P = 0.007). Mean time to first therapeutic trough and mean number of days treated were significantly higher in IVDU versus non-IVDR samples (65.9 vs. 50.2 hours P = 0.044 and 5.4 vs. 12.3 days P = 0.017, respectively). There was no detectable difference in rates of AKI and vancomycin failure.

Primary outcome graph for patients with IV drug use

Primary outcome graph for patients without IV drug use

Conclusion

Vancomycin use in patients with IVDU resulted in significantly lower steady state troughs compared to patients who were non-IVDU. These patients also had a longer time to first therapeutic trough. Patient populations who are IVDU may require additional consideration as a special population for future development of vancomycin pharmacokinetic models.

Disclosures

All Authors: No reported disclosures
1097. A Comparison of Area-Under Curve (AUC)-Guided vs Trough-Guided Monitoring of Vancomycin and Its Impact on Nephrotoxicity: A Systematic Review and Meta-analysis
Authors: Lim Ashley Shiyuan , Seng Jun Jie Benjamin , Ng Tao Tao Magdeline , Chng Hui Ting , Han Zhe
Published: December 2021

Background

Trough levels have been used for Vancomycin (VAN) therapeutic drug monitoring (TDM) historically due to its practicality. A paradigm shift towards the use of area under curve (AUC)-guided dosing TDM has been made due to availability of advanced pharmacokinetics software, variability between trough levels and AUC values and the potential for reducing toxicity. This review aims to evaluate the impact of AUC-guided vs trough-guided vancomycin TDM on nephrotoxicity-related outcomes.

Methods

A systematic review was conducted using PubMed®, Embase®, Web of Science®, CINAHL®, Google scholar and Cochrane library® up till 1st January 2021 and was reported according to the PRISMA checklist. Studies which evaluated AUC-guided or trough-guided VAN TDM and vancomycin-associated nephrotoxicity were included. Random effects models were used to compare differences in nephrotoxicity between trough level or AUC based vancomycin TDM due to expected heterogeneity in study designs.

PRISMA Flowchart

PRISMA flow chart depicting the selection process of studies included in the meta-analysis

Results

Of 1191 records retrieved, 57 studies were included. Majority of studies included adult and elderly patients (n=47, 82.5%). The pooled prevalence of nephrotoxicity was lower using the AUC-guided TDM [6.2%, 95% confidence interval (CI): 2.9 – 9.5%] compared to trough-guided TDM [17.0%; 95% CI: 14.7 – 19.2%]. The risk of nephrotoxicity was lower with the AUC-guided approach as compared with the trough-guided approach [OR: 0.53, 95% CI: 0.32–0.89]. AUC thresholds correlated with risk of nephrotoxicity only for the first 96 hours of therapy. A frequency analysis of significant multivariable factors showed that concomitant use of nephrotoxins, VAN trough levels and duration of VAN therapy were most commonly associated with nephrotoxicity.

Forest plot comparing the risk of nephrotoxicity of AUC-guided vs trough-guided

Forest plot comparing the risk of nephrotoxicity of AUC-guided vs trough-guided

Pooled nephrotoxicity rates from AUC-guided monitoring

Pooled nephrotoxicity rates from AUC-guided monitoring

Pooled nephrotoxicity rates from trough-guided monitoring

Pooled nephrotoxicity rates from trough-guided monitoring

Conclusion

The AUC-guided approach appeared to have lower risk of nephrotoxicity which supports the updated American Society of Health-System Pharmacists recommendations. More studies should be performed to evaluate the optimal derivation of AUC and clinical utility of repeated measurements of vancomycin AUC and trough levels.

Disclosures

All Authors: No reported disclosures
1098. A Phase 1 Safety and Tolerability of Single Ascending Doses of a Novel Engineered Cationic Peptide, PLG0206, in Healthy Subjects
Authors: Huang David , Dobbins Despina , Ghahramani Parviz , Steckbeck Jonathan
Published: December 2021

Background

PLG0206 is a novel engineered cationic antimicrobial peptide being evaluated for treatment of prosthetic joint infections (PJI). This abstract presents the results from the first in human study to evaluate the safety, tolerability and pharmacokinetic (PK) profile of PLG0206 when administered as an intravenous (IV) infusion.

Methods

6 cohorts of 8 participants were planned to receive escalating single 1-hour IV infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, 1, 2 and 3 mg/kg dose or placebo. Participants were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). At each dose level, there were 2 sentinel participants (1 active, 1 placebo) who were dosed at least 48 hours in advance of the other participants in their group. Serial pharmacokinetic samples were taken prior to infusion and up to 48 post infusion. Safety and tolerability was assessed throughout the study. There was at least a 7-day period after dosing at each of the dose levels before dose escalation.

Results

PLG0206 was safe and well tolerated when administered to healthy volunteers at doses ranging from 0.05 and 1 mg/kg. Therapeutic exposures were achieved at 1 mg/kg. The 2 and 3 mg/kg cohorts were not studied. The incidence of treatment emergent adverse events related to study drug administration was low and most events mild (Grade 1) in severity and was similar between the PLG0206 treatment and placebo groups. There were no SAEs, life-threatening events or deaths throughout the study. IV PLG0206 exhibited linear PK over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t½) ranged from 7.37 to 19.97 hours. AUC0-∞ increased with increasing PLG0206 dose ranging between 1581.41 and 21141.52 ng.hr/mL. Cmax ranged between 256 and 2653 ng/mL. The mean apparent volume of distribution (Vz) increased was between 25.49 and 94.2 L, mean clearance (CL) were similar across all and ranged from 2.42 to 4.18 L/hour.

Conclusion

Following single IV infusion to healthy volunteers, PLG0206 was safe and well tolerated at doses ranging from 0.05 to 1 mg/kg. IV PLG0206 exhibits linear PK over the dose range. These findings support the ongoing development of IV PLG0206 and will inform dosing regimens in future studies to investigate its utility as an antimicrobial agent.

Disclosures

David Huang, MD, PhD, Peptilogics (Employee) Despina Dobbins, BS, Peptilogics (Employee) Parviz Ghahramani, PhD, PharmD, MSc, MBA, Peptilogics (Consultant) Jonathan Steckbeck, PhD, Peptilogics (Employee)
1099. Evaluation of the Safety and Pharmacokinetics (PK) following Administration of Single and Multiple Doses of Anti-Staphylococcal Lysin, LSVT-1701, in Healthy Adult Subjects
Authors: Wire Mary Beth , Jun Soo youn , Jany In-Jin , Hwang Jun Gi , Huang David
Published: December 2021

Background

LSVT-1701 is an anti-staphylococcal phage lysin being developed for treatment of MRSA infections in combination with SoC antibiotics. The safety and PK of single ascending doses of LSVT-1701 0.1 to 10 mg/kg in healthy adult volunteers were previously described (Jun, et.al, AAC 2017;61:e02629-16). We further evaluated the safety and PK of multiple ascending doses of LSVT-1701 in healthy adult subjects.

Methods

Study ITB-101-1b was a Phase 1, randomized, double-blind, placebo-controlled, multiple ascending dose study. 8 subjects were randomized 3:1 to active:placebo in each cohort. LSVT-1701 was administered as a 6 mg/kg single dose and twice daily (BID) doses of 1.5, 3.0, and 4.5 mg/kg for 4 days (24h between Doses 1-2, 12h between Doses 2-6). Study drugs were administered as a 1-hour IV infusion. Serial serum samples were collected over 24 hours following the first and last doses for measurement of LSVT-1701 concentrations by a validated ELISA method. PK analysis of LSVT-1701 concentration-time data was done using noncompartmental methods. Safety was assessed by AEs, clinical labs, vital signs, and ECG.

Results

30/32 (94%) subjects completed the study. No subjects withdrew due to AEs, and there were no severe AEs, no serious AEs, and no deaths. AEs were of mild (97%) to moderate (3%) intensity and were reported by all subjects in the LSVT-1701 6 mg/kg single dose group and 1-3 (17-50%) of subjects receiving 1.5 to 4.5 mg/kg BID or placebo. The most common AEs of headache, chills, rigors, and fever generally lasted for ≤2 days with or without acetaminophen treatment, and no clinically significant changes in blood pressure, heart rate, ECG, or clinical labs (other than transient increases in CRP) were observed. Infusion site reactions (erythema, pain, induration, warmth) were observed with BID administration of LSVT-1701, but not with the single 6 mg/kg dose or placebo. LSVT-1701 exposure increased greater than in proportion to dose and t1/2 was concentration-dependent, increasing with higher doses. No accumulation in LSVT-1701 exposure was observed.

Summary of LSVT-1701 PK Parameters

Summary of LSVT-1701 PK Parameters

Conclusion

The safety and PK profile of LSVT-1701 is favorable for evaluation in patients with

S. aureus infections, including bacteremia and infective endocarditis, for which new treatments are needed.

Disclosures

Mary Beth Wire, Pharm#, Lysovant (Consultant) Soo youn Jun, PhD, iNtRON Biotechnology (Consultant) In-Jin Jany, PhD, iNtRON (Consultant) Jun Gi Hwang, PhD, Lysovant (Consultant) David Huang, MD, PhD, Lysovant (Consultant)
1101. Implementing a Beta-Lactam Therapeutic Drug Monitoring Program: Experience from a Large Academic Medical Center
Authors: Veena Venugopalan , Hamza Malva , Santevecchi Barbara A , DeSear Kathryn , Cherabuddi Kartikeya , Peloquin Charles A , Peloquin Charles A , Al-Shaer Mohammad H
Published: December 2021

Background

Beta-lactams (BL) are the cornerstone of antimicrobial treatment for infections. Beta-lactam therapeutic drug monitoring (BL-TDM) optimizes drug concentrations to ensure maximal efficacy and minimal toxicity. The goals of this study were to describe the implementation process of a BL-TDM program and to further describe our experience using BL-TDM in clinical practice.

Methods

This was a retrospective review of adult patients with available BL-TDM between January 2016 and November 2019 at the University of Florida (UF) Health Shands Hospital. Total serum concentrations of BL were measured in the Infectious Diseases Pharmacokinetics Lab (IDPL) at UF, using a validated ultrahigh pressure liquid chromatography assay with triple quadrupole mass spectroscopy (LC-MS-MS). At our institution, TDM is available for 11 BLs and in-house assays are performed from Mon-Fri for most BLs.

Results

A total of 3,030 BL concentrations were obtained. An analysis was performed on the first BL-TDM encounter in 1,438 patients. The median age was 57 years (IQR, 41-69) and the median BMI was 27.5 kg/m2 (IQR, 22.5-34.5). On the day of BL-TDM, the median serum creatinine was 0.83 (IQR, 0.59-1.30). Fifty-one percent of patients (n=735) were in an ICU at the time of BL-TDM with a median SOFA score of 6 (IQR, 3-9). BL-TDM was most frequently performed on cefepime (61%, n=882), piperacillin (15%, n=218), and meropenem (11%, n=151). The BL was administered as a continuous infusion in 211 (15%) patients. An interim analysis of 548 patients showed that BL-TDM was performed a median of 2 days (IQR, 1-4) from the start of BL therapy and resulted in a dosage adjustment in 26% (n=145).

Conclusion

BL-TDM was performed in older, non-obese patients with normal renal function. Over half of the evaluated patients were in an ICU at the time of TDM. This finding emphasizes the value of BL-TDM in the ICU setting because altered pharmacokinetics during critical illness has been linked to enhanced BL clearance. Interestingly, BL-TDM resulted in dosage adjustment in 1 in 4 patients who were receiving licensed BL dosing regimens, thus highlighting the role of TDM in dose individualization. BL-TDM was performed most commonly within the 72-hours of therapy initiation. Early BL-TDM has been shown to improve patient outcomes and should be promoted.

Disclosures

Venugopalan Veena, PharmD, Melinta (Other Financial or Material Support, Received a stipend for participation in a drug registry)Merck (Other Financial or Material Support, Received a stipend for participation in a drug registry) Charles A. Peloquin, Pharm.D., Nothing to disclose
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

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 < 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

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 >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

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

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

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 >MIC) for various cefepime dosing regimens. The target pharmacodynamic exposure was 70% fT >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 >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

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

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