bluuebunny/crossref_metadata_2025_split huggingface dataset:
1305. Comparison of Pharmacokinetics of DSTA4637S, a novel THIOMABTM Antibody-Antibiotic Conjugate, in Patients with Staphylococcus aureus Bacteremia Receiving Standard-of-Care Antibiotics with Pharmacokinetics in Healthy Volunteers
Authors: Rymut Sharon M , Deng Rong , Owen Ryan , Saad Ola , Berhanu Aklile , Lim Jeremy , Carrasco-Triguero Montserrat , Couch Jessica A , Peck Melicent C 
Published: January 2021

Abstract

Background
DSTA4637S, a THIOMABTM antibody-antibiotic conjugate against Staphylococcus aureus, is a potential therapy for complicated S. aureus bacteremia. Single doses showed favorable safety and pharmacokinetics (PK) in healthy volunteers (HVs). This study compares HV PK results to PK from a Phase 1b study evaluating multiple doses in patients with bacteremia.

Methods
In a Phase 1a study, HVs received single intravenous (IV) doses (5, 15, 50, 100, or 150 mg/kg) of DSTA4637S. The Phase 1b, randomized, double-blind, placebo-controlled, multiple ascending-dose study enrolled patients with MRSA or MSSA bacteremia receiving ≥ 4 weeks of standard-of-care (SOC) antibiotics in combination with IV DSTA4637S (15, 45, or 100 mg/kg) weekly (4-6 doses). Intensive PK serum and plasma sampling was performed after first and last doses of DSTA4637S. Total antibody (TAb) was measured in serum by ELISA. DSTA4637S conjugate (ac-dmDNA31) and unconjugated dmDNA31 were measured in plasma with IA-LC-MS/MS and LC-MS/MS, respectively. DSTA4637S PK was analyzed using a non-compartmental approach using WinNonlin.

Results
DSTA4637S PK data were evaluated in 20 HVs in the Phase 1a study and 19 patients with S. aureus bacteremia in the Phase 1b study. In both HVs and patients, systemic exposures of TAb and ac-dmDNA were generally dose proportional over the dose ranges tested. In patients compared to HVs, Cmax, cycle 1 for ac-dmDNA31 and TAb were reduced 26.7-51.3% and 32.4-44.1%, respectively, contributing to lower patient AUC0-7. Unconjugated dmDNA31 concentrations were low (&lt; 11 ng/mL), peaking 1-2 days after dosing, in both studies. There was no clear association between DSTA4637S exposure (ac-dmDNA31) and demographic factors (age, weight, sex), clinical status (bacteremia at dosing, infection site), adverse events (infusion-related reactions), or exploratory biomarkers (CRP, procalcitonin, inflammatory cytokines).

Conclusion
DSTA4637S PK analysis demonstrated lower exposures in patients with S. aureus bacteremia compared to HVs. Potential explanations for reduced exposures include factors related to disease status, non-specific organ uptake, and target-mediated clearance.

Disclosures
Sharon M. Rymut, PhD, Genentech (Employee, Shareholder) Rong Deng, PhD, Roche (Consultant, Employee, Shareholder) Ryan Owen, PhD, Genentech (Employee, Shareholder) Ola Saad, PhD, Genentech - Roche (Employee) Aklile Berhanu, PhD, Genentech, Inc. (Employee, Equity interest (Stock/Stock Options)) Jeremy Lim, PharmD, Roche (Employee, Shareholder) Montserrat Carrasco-Triguero, PhD, Genentech (Employee) Jessica A. Couch, PhD, Genentech (Employee, Shareholder) Melicent C. Peck, MD, PhD, Genentech (Employee)
104. Evaluation of a 2-Step Testing Algorithm for Clostridioides difficile Infection
Authors: Bettger Caitlin C , Giancola Stephanie , Cybulski Robert , Okulicz Jason , Barsoumian Alice 
Published: January 2021

Abstract

Background
A 2-step testing strategy for diagnosis of Clostridioides difficile infection (CDI) is recommended to limit over-diagnosis when clinical criteria requirements for stool sample submission cannot be enforced. Real-world evaluations of this strategy are limited.

Methods
The Antimicrobial Stewardship Program at Brooke Army Medical Center, San Antonio, TX, implemented a 2-step CDI algorithm: polymerase chain reaction (PCR) testing followed by toxin enzyme immunoassay (EIA). The goal was to improve diagnosis of CDI and reduce unnecessary antibiotic use. Patients with PCR+ tests from August 2018 to September 2019 were included. Charts were reviewed for demographics, laboratory data, treatment, and outcomes. Cases were grouped based on concordant (PCR+/EIA+) or discordant (PCR+/EIA-) results. To determine factors contributing to treatment decisions, an analysis of discordant cases were compared by treatment status. Groups were compared by Chi-squared, Fisher’s exact, or Mann-Whitney U tests.

Results
A total of 216 PCR+ tests from 215 patients were recorded. Of these, 155 (71.8%) were discordant. Demographics, laboratory data, and risk factors for CDI were similar between groups (Table 1; p &gt;0.05 for all). Compared to discordant cases, concordant cases were more frequently hospitalized (59% vs 43.9%; p=0.05), had a higher median daily stool count (5 [4–7] vs 4 [2–6], p=0.03), met criteria for severe CDI (33.3% vs 18.7%; p=0.05), received treatment (95.1% vs 66.5%; p&lt; 0.01) and were readmitted in 30 days with CDI (8.3% vs 1.3%; p=0.02). Among discordant cases, median daily stool count was higher in treated vs untreated cases (4 [3–7] vs 3 [1–5], p=0.02). Otherwise, there was no difference in variables according to treatment status (Table 2; p &gt;0.05 for all). Discordant cases with infectious disease (ID) or gastroenterology (GI) consultation had a high rate of treatment (73.9% and 61.1%, respectively).
Table 1. Characteristics and outcomes of patients with concordant and discordant tests.

Table 2. Characteristics and outcomes of treated and untreated patients with discordant tests.

Conclusion
Implementation of 2-step strategy reduced antibiotic treatment by nearly 30%. However, the majority of discordant cases were deemed clinically significant and received treatment by providers, including ID or GI specialists. Further studies are needed to determine the unmeasured factors that guide treatment decisions in discordant cases.

Disclosures
All Authors: No reported disclosures
1309. Imipenem/Cilastatin/Relebactam (I/R) Alone and in Combination against Pseudomonas aeruginosa (PSA) in the In Vitro Pharmacodynamic Model
Authors: Chen Iris H , Nicolau David P , Kuti Joseph L 
Published: January 2021

Abstract

Background
I/R, a carbapenem-beta-lactamase inhibitor antibiotic, is active against most imipenem-resistant PSA, including MDR isolates. Combination therapy may enhance activity against MDR pathogens and suppress resistance. This study’s objective was to assess the efficacy of I/R compared with combinations including colistin (CST) or amikacin (AMK) against PSA in an IVPD model.

Methods
Human-simulated concentrations of I/R 500/250 mg every six hours, a total daily dose of CST 360 mg, and AMK 25 mg/kg daily were reproduced alone and in combination against 6 imipenem-non-susceptible PSA with I/R MICs of 1/4 to 8/4 mg/L in an IVPD over 24h. The primary endpoint was the difference in 24h colony forming units (CFU) between each combination regimen and its components alone. The log ratio differences of the area under the CFU curve were also calculated to compare the overall bacterial burden resulting from exposure to I/R alone with those treated by combination regimens. Emergence of resistance was tested at 24h using drug-containing plates at 3xMIC.

Results
I/R, CST, and AMK alone produced 24hCFU changes consistent with isolate MICs. One isolate (already I/R non-susceptible) developed I/R resistance, and 4 and 3 developed CST and AMK resistance, respectively. I/R plus CST suppressed all resistance and resulted in synergistic or additive interactions against three of six isolates with 24h CFU reductions ranging from -2.62 to -4.67 log10CFU/mL. This combination further reduced overall bacterial burden by 79-81% compared with I/R alone against two I/R-non-susceptible strains. I/R plus AMK also prevented resistance emergence but exhibited indifferent interactions against all isolates at 24h with the combined drugs achieving -0.51 to -3.33 log10CFU/mL reductions. Minor overall reductions in bacterial burden were observed relative to I/R alone.

Conclusion
I/R plus CST resulted in additivity or synergy against three of six PSA and prevented I/R and CST resistance, whereas the addition of AMK only suppressed resistance. The greatest overall reductions in bacterial burden, however, were observed with I/R plus CST against I/R-non-susceptible isolates, supporting targeted use of this combination against this phenotype when alternatives are unavailable.

Disclosures
David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))
1312. Metallo-β-lactamase-Producing Enterobacterales (MBL-EB): Is it Time to Rethink Our Assessment Tools?
Authors: Abdelraouf Kamilia , Nicolau David P 
Published: January 2021

Abstract

Background
We previously reported the potent in vivo activity of ceftazidime/avibactam human-simulated regimen (HSR) against MBL-EB despite the observed resistance in vitro and the lack of avibactam MBL-inhibitory activity (AAC 2014 Nov;58(11):7007-9). Similar to avibactam, relebactam (REL) is a diazabicyclooctane that inhibits serine β-lactamases belonging to Classes A - C but not MBLs. In the current study, we examined the in vivo activity of cefepime (FEP)/REL combination HSR against MBL-EB in a murine thigh infection model.

Methods
Six clinical MBL-EB isolates expressing VIM, IMP or NDM and co-expressing at least one β-lactamase of Classes A - C (KPC, CTX-M, TEM, SHV, ACT, CMY) were utilized. MICs of FEP and FEP/REL combination (at fixed REL concentration of 4 mg/L) were determined using broth microdilution. FEP HSR (2 g q12h as 0.5 h infusion) alone and in combination with REL HSR (250 mg q6h as 0.5 h infusion) were established in the infection model. Thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 CFU/ml. Two hours later, mice were administered the FEP HSR or the FEP/REL HSR. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls.

Results
All isolates were FEP resistant (MIC ≥ 32 mg/L). Addition of REL had no impact on the MIC of the isolates. In in vivo studies, the average bacterial burden at 0 h was 5.84 ± 0.41 log10CFU/thigh. In accordance with the in vitro susceptibility, administration of FEP HSR was associated with net bacterial growth among all isolates ranging from 0.46 ± 0.60 to 2.97 ± 0.53 log10CFU/thigh. In contrast, FEP/REL combination HSR resulted in substantial bacterial reductions among all isolates ranging from -0.73 ± 0.13 to -1.72 ± 0.14 log10CFU/thigh, indicating that REL enhanced the FEP activity in vivo.

Conclusion
Despite the powerful β-lactam hydrolytic capability of MBLs in vitro, FEP inactivation in the murine model was attributed predominantly to the expression of the serine β-lactamases. The in vitro/in vivo discordance in β-lactam/β-lactamase activity against MBL-EB reveals a potential flaw in the currently utilized in vitro susceptibility testing methodologies and highlights a challenge encountered during the development of new agents against these isolates.

Disclosures
David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)
1317. Pharmacokinetics (PK) of Ampicillin-Sulbactam (SAM) during Orthotopic Liver Transplantation (OLT)
Authors: Lasko Maxwell J , Serrano Oscar , Nicolau David P , Kuti Joseph L 
Published: January 2021

Abstract

Background
SAM is used as surgical prophylaxis during OLT due to its broad spectrum activity against Gram-positive,-negative and anaerobic pathogens. SAM resistance among Gram-negatives is rising, making dosage selection paramount to preventing surgical site infections. Current guidelines recommend a 3g dose, consisting of 2g ampicillin (AMP) and 1g sulbactam (SUL), every 2h. There are no data; however, describing SAM PK during OLT to support an optimized dosing regimen.

Methods
This was a single-center PK study of OLT patients receiving SAM for surgical prophylaxis at a dose selected by the anesthesiologist. Patients were excluded if they were undergoing simultaneous liver and kidney transplantation and had a CrCL &lt; 30 mL/min at start of surgery. Up to 24 blood samples, along with times of pertinent events, were collected throughout the OLT. AMP and SUL plasma concentrations were determined. Population PK analyses were conducted in Pmetrics using R. Akaike information criterion (AIC) and visual inspection determined best model fit. Individual PK parameters were simulated to describe free AMP time above the MIC90 (fT &gt;MIC90) of 32 mg/L.

Results
Five patients were enrolled. Participants had a mean ± SD age of 64 ± 7 years, body weight 82 ± 8 kg, CrCL of 75 ± 35 mL/min, and received various SAM doses (1.5-3g q2-3h). A 2 compartment model fitted the data better than a 1 compartment model for both AMP (AIC: 396 vs. 423) and SUL (AIC: 334 vs. 347). Final models included fractional clearance (CLf) terms on typical total body clearance (CLθ) to account for the placement of the portal vein clamp. AMP PK parameters (AIC: 372) were: CLθ, 9.7 ± 2.6 L/h; CLf, 0.73 ± 0.49; volume of central compartment (Vc), 7.2 ± 1.4 L; intercompartment constants (k12 and k21), 4.08 ± 3.28 and 2.63 ± 2.9 h-1, respectively. Final SUL PK parameters (AIC: 314) were: CLθ, 8.3 ± 2.5 L/h; CLf, 0.92 ± 0.55; Vc, 7.3 ± 1.6 L; k12, 4.60 ± 4.41 h-1, and k21, 4.07 ± 3.31 h-1. Exposures ranged from 58-96% with only 3g q2h providing nearly 100% fT &gt;MIC90.

Conclusion
This is the first study to describe intra-operative SAM PK in OLT recipients and the effect of portal vein clamp on AMP and SUL clearance. These data will help guide optimized SAM dosing regimens for OLT surgery based on local MIC distributions for targeted pathogens.

Disclosures
David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))
105. Evaluation of a Multiplex PCR Panel for the Microbiologic Diagnosis of Pneumonia in Hospitalized Patients: A Retrospective Analysis from an Academic Medical Center
Authors: Zacharioudakis Ioannis , Zervou Fainareti , Inglima Kenneth , See Benjamin , Aguero-Rosenfeld Maria E 
Published: January 2021

Abstract

Background
Pneumonia is a leading cause of hospitalization and mortality. Due to the low yield of available diagnostic tests, ATS/IDSA pneumonia guidelines recommend a microbiologic work-up only for hospitalized patients with severe pneumonia.

Methods
From 5/2019 to 1/2020, we selected adult patients with clinical and radiographic findings highly suggestive of pneumonia. The BioFire® FilmArray® pneumonia panel was performed on sputum specimens that met quality microbiologic criteria and the results were compared to those of sputum cultures and other tests sent per standard of care. A limit of 105 copies/mL was used for positivity in semi-quantitative bacterial targets. The empiric antimicrobial regimen was reviewed to quantify the potential for antimicrobial optimization.

Results
Seventy patients were included in the analysis. Median age was 70 (IQR 53.5–81.75), and the majority (43 patients, 61.4%) were classified as Class IV and V using the pneumonia severity index, indicating severe cases of pneumonia. Sixty-nine patients completed at least a 5-day course for pneumonia and 14.3% died during their hospitalization. The fifteen patients (21.4%) that submitted a sputum culture before the initiation of antimicrobial therapy, had a trend towards a positive sputum culture (60% (9/15) vs 36.4% (20/55)) (p=0.09). The BioFire® FilmArray® pneumonia Panel increased the number of patients who received a microbiologic diagnosis from 29 (41%) to 59 (84.3%) (p&lt; 0.001). The per isolate analysis revealed significantly more targets detected for Haemophilus influenzae (p=0.002) and Streptococcus pneumoniae (p=0.05). On review of empiric antimicrobial treatment, there was possibility for antimicrobial optimization in 80% of patients, including 9 cases of pathogens (4 MRSA, 3 Legionella pneumophila, 2 CTX-M gram-negative rods) where the pathogens were not covered and another 70 antimicrobials in 49 patients that could be stopped.
Flow chart

Bacterial Pathogens Detected in Standard of Care Alone Testing and with the Addition of Pneumonia Panel.

Potential for Antimicrobial Optimization Using the Pneumonia Panel

Conclusion
Incorporation of the pneumonia panel in the diagnostic work-up of patients hospitalized with pneumonia substantially increased the rate of microbiologic diagnosis and had the potential to guide appropriate antimicrobial therapy. Future studies to quantify the effects on clinical outcomes and cost-effectiveness from tailored therapy are needed.

Disclosures
All Authors: No reported disclosures
1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns
Authors: Hall Ronald G , Pasipanodya Jotam , Putnam William C , Griswold John , Dissanaike Sharmila , Kallem Raja Reddy , Edpuganti Vindhya , Subramaniyan Indhumathy 
Published: January 2021

Abstract

Background
Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed.

Methods
A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested.

Results
The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B).
A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities

Summary of pharmacokinetic parameters

Conclusion
C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities.

Disclosures
Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support)
1323. Substantial Doses of Daptomycin and Rifampin Eradicate S. epidermidis Biofilm in an In Vitro Pharmacodynamic (IVPD) Model
Authors: Piehl Emily C , Daffinee Kathryn E , LaPlante Kerry 
Published: January 2021

Abstract

Background
The concentration of antibiotics at the site of action needed to eradicate biofilm is currently unknown. Studies have previously suggested that bacteria in biofilms are 1000-fold more resistant to antibiotics than free-floating planktonic bacteria. We sought to describe concentrations of daptomycin alone and in combination with rifampin in relation to the pharmacodynamic exposures for biofilm eradication.

Methods
We utilized a methicillin-resistant high biofilm-forming S. epidermidis strain RP62a (ATCC® 35984) over a 48-hour in vitro PD biofilm model. The Centers for Disease Control (CDC) Biofilm Reactor model was used with chromium cobalt materials to simulate an orthopedic device infection. The reactor was inoculated and underwent a 24-hr growth phase and 16-hr conditioning phase to form biofilm on the chromium cobalt coupons, and then a 48-hr PK-PD phase was run. The daptomycin MIC for RP62a was 0.5 mg/L and the rifampin MIC was 0.015 mg/L. We modeled a growth control of the isolate alone, a 12 mg/kg regimen of daptomycin (fCmax: 14.7 mg/L, Ke 0.09), a daptomycin concentration of 1000 mg/L (2000x MIC), and a combination model of daptomycin 1000 mg/L with rifampin 15 mg/L (1000x MIC). Coupons with bacteria embedded in biofilm were sonicated, vortexed, and plated on Tryptic Soy Agar for colony counts read at 24 hrs. Bactericidal activity was defined as ≥ 3-log10 CFU/mL reduction from the initial inoculum.

Results
The simulated humanized dosing regimen of daptomycin 12 mg/kg (fAUC0-24/MIC: 204) was similar to the growth control model. Bactericidal kill was demonstrated at 24hr and 48hr in the daptomycin 1000 mg/L model (fAUC0-24/MIC: 20,248) but did not fall beneath the limit of detection. The daptomycin and rifampin combination model demonstrated bactericidal kill at 24hr and 48hr and went below the limit of detection.

Conclusion
This study demonstrated that significantly higher concentrations of antibiotics are needed at the site of action to eradicate biofilm than what maximum systemic dosing can provide. Identifying these concentrations provides a foundation for localized antibiotic therapy and further studies are needed to elucidate these concentrations for a variety of antibiotics and biofilm-forming organisms.

Disclosures
Kerry LaPlante, PharmD, Merck (Advisor or Review Panel member, Research Grant or Support)Ocean Spray Cranberries, Inc. (Research Grant or Support)Pfizer Pharmaceuticals (Research Grant or Support)Shionogi, Inc. (Research Grant or Support)