bluuebunny/crossref_metadata_2025_split huggingface dataset:
1247. Dalbavancin in Osteomyelitis and Joint Infections: An Analysis From an Observational, Multicenter, Retrospective Cohort Study of the Real-World Use in Adult Patients
Authors: Diaz Julia Garcia , McGregor Jennifer , Ramani Anathakrishnan , Lock John , Golan Yoav , Gonzalez Pedro 
Published: January 2021

Abstract

Background
Dalbavancin (DAL) is approved in the United States (US) and Europe for acute bacterial skin and skin structure infections and exhibits broad spectrum activity against clinically important Gram-positive pathogens including methicillin-sensitive and methicillin-resistant Staphylococcus aureus, and Streptococcus spp. We describe the use of DAL in patients with osteomyelitis or joint infection from a phase 4 observational, multicenter, retrospective cohort study of the real-world use of DAL in adult patients across the US: Dalvance Utilization Registry Investigating Value and Efficacy (DRIVE).

Methods
Data were collected between 03/25/2017 and 11/27/2018 and included demographics, disease and pathogen characteristics, antibiotic use, clinical outcome, and safety. Patients with a determinate clinical outcome (success/failure) were included in the evaluable population.

Results
Data for 96 patients with osteomyelitis and 33 patients with joint infection (safety population) were entered into this subanalysis. Patient demographics and medical history were broadly similar for patients with osteomyelitis or joint infection. The majority (80.4–100%) of patients received DAL as concurrent therapy and clinical success, defined qualitatively, was achieved in 64.7-87.5% of patients (Fig. 1). Most patients received 1 or 2 IV DAL doses (osteomyelitis, 33.3% and 34.6%, respectively; joint infection, 37.5% and 31.3%, respectively); 11.5% and 6.3% of patients with osteomyelitis or joint infection, respectively received &gt;4 doses (Fig. 2). Staphylococcus spp. was the most frequently isolated organism at baseline (Fig. 3); 61.1% and 35.7% of osteomyelitis and joint infection isolates tested, respectively were resistant to oxacillin. At 60 days post-DAL treatment, numbers of Staphylococcus spp. isolated from both groups decreased (Fig. 3), confirming microbiological cure. The rate of serious adverse events was low (16 events in 7 [7.3%] patients with osteomyelitis, 2 events in 2 [6.1%] patients with joint infection) and consistent with the safety profile of DAL.
Fig. 1

Fig. 2

Fig. 3

Conclusion
In this real-world study in patients with Staphylococcal osteomyelitis and joint infection, DAL resulted in high rates of clinical and microbiological success.

Disclosures
Jennifer McGregor, RPh, AbbVie (Employee) Anathakrishnan Ramani, MD, FACP, AAHIVS, CIC, Allergan (prior to its acquisition by AbbVie) (Speaker’s Bureau) John Lock, PharmD, BCPS, AQ-ID, AbbVie (Employee) Pedro Gonzalez, MD, MT, AbbVie (Employee)
99. Comparison of Procalcitonin Testing to a Targeted Audit-and Feedback Strategy on Prescribed Durations of Therapy for Community-Acquired Pneumonia
Authors: Clark Lauren , Dumkow Lisa E , Buss Paige , Beuschel Thomas , Jameson Andrew 
Published: January 2021

Abstract

Background
The procalcitonin (PCT) assay is FDA-approved to help guide antimicrobial treatment of respiratory tract infections, however, conflicting data exist regarding its impact on shortening durations of therapy. The purpose of this study was to compare the impact of PCT to a targeted audit-and-feedback (TAF) strategy on prescribed antibiotic durations of therapy for community-acquired pneumonia (CAP).

Methods
A retrospective cohort study was conducted at two community teaching hospitals, one implementing PCT with routine audit-and-feedback and one implementing a TAF strategy recommending 5 days of therapy for uncomplicated CAP. The primary objective of this study was to compare the impact of PCT implementation to TAF implementation on durations of therapy prescribed for suspected CAP. Secondary objectives included comparing length of stay, 30-day readmission, mortality, and rates of Clostridioides difficile. Adult inpatients with an antibiotic ordered with an indication of pneumonia were eligible for inclusion. Those who were critically ill, immunocompromised, had concurrent infections, were made comfort care, discharged or expired within 48 hours were excluded.

Results
311 patients were included (Pre-TAF n=80, Pre-PCT n=80, Post-TAF n=80, Post-PCT n=71). Average duration of therapy prescribed for CAP at baseline was similar between groups, Pre-TAF 7.0 days vs. Pre-PCT 7.8 days (p=0.1). After implementation of the respective interventions, there remained no difference in the average duration of therapy between groups, Post-TAF 5.5 days vs. Post-PCT 5.4 days (p=0.8). Both PCT and TAF strategies demonstrated significant improvement in prescribed durations for CAP between their respective Pre- and Post-intervention groups (p&lt; 0.001 and p=0.002, respectively). The PCT protocol was followed 41% of the time in the Post-PCT group. There were no differences in readmission, mortality, or C. difficile between groups.

Conclusion
PCT and TAF were equally effective antimicrobial stewardship strategies in reducing total days of antibiotic therapy prescribed for CAP with no differences observed in patient outcomes.

Disclosures
All Authors: No reported disclosures
1272. Efficacy of a Non-Peptide, Small Molecule Mimic of Host Defense Proteins in Mouse Models of Disseminated Candidiasis and Aspergillosis
Authors: Scott Richard W , Baugh Simon D P , Freeman Katie B , Weaver Damian G , Chaly Anna L , Whitman David B , Thanna Sandeep , Diamond Gill , Nguyen Phung , Deviney Ashley , Weiss William J , Pulse Mark E , Reitz Allen B 
Published: January 2021

Abstract

Background
We are developing a series of small nonpeptide mimics of host defense proteins (smHDPs) for antifungal applications. MICs &lt; 0.1 µg/ ml have been demonstrated against multiple yeast and mold species. Their potential therapeutic utility has been evaluated in animal models of disseminated fungal infections.

Methods
Susceptibility testing against clinical isolates of Candida albicans (CA) and Aspergillus fumigatus (AF) was done according to CLSI guidelines. Cytotoxicity (CC50) in mouse 3T3 and human HepG2 cells was determined in an MTS assay (Promega Cell Titer 96). For candidiasis, neutropenic CD-1 mice were infected IV with 3.5 x 104 CFU CA and test agents were administered subcutaneously (SC) once (QD) or twice (BID) daily beginning 2 hrs post-infection (PI). The positive control was fluconazole (20 mg/kg PO QD). Kidney burdens were measured at 24 hrs PI (n = 5/grp) and survival was measured at 2 weeks after 5 days of treatment (n = 8/grp). For aspergillosis, neutropenic CD-1 mice were infected IV with 4.5 log10 spores AF and test agents were administered SC BID for 5 days beginning 24 hrs PI. The positive control was posaconazole (20 mg/kg PO QD). Liver and kidney fungal burdens were measured 24 hrs after the last dose (n = 10/grp).

Results
The lead smHDP, FC-5096, has MICs of 0.08 and 0.024 ug/ml, respectively, against the CA and AF clinical isolate strains used in the mouse efficacy studies. Selectivity for antifungal vs. mammalian cell cytotoxicity (MIC/CC50) was &gt;1,000 fold. In the disseminated candidiasis model, FC-5096 significantly reduced fungal kidney burdens relative to untreated mice to levels found at treatment onset (P &lt; 0.0001). Full survival over 2 weeks was observed after 5 days of BID treatment with FC-5096. All untreated mice succumbed between days 3 – 6 PI. Efficacy was comparable to fluconazole. In the disseminated aspergillosis model, FC-5096 produced up to 2.5 log10 reductions in fungal liver burdens and efficacy was significantly better than posaconazole (P = 0.0251). In kidney, both FC-5096 and posaconazole caused &gt; 1.6 log10 reductions in fungal burdens that exceeded the limit of detection.

Conclusion
The high antifungal potency, low cytotoxicity and robust in vivo efficacy support further study of FC-5096 for clinical development.

Disclosures
Richard W. Scott, PhD, Fox Chase Chemical Diversity Center (Employee) Simon DP Baugh, PhD, Fox Chase Chemical Diversity Center (Employee) Mark E Pulse, MS, Fox Chase Chemical Diversity Center (Independent Contractor)
1296. Efficacy of Human-Simulated Exposures of Meropenem/Vaborbactam (MVB) and Meropenem (MEM) against OXA-48 β-lactamase-producing Enterobacterales in the Neutropenic Murine Thigh Infection Model
Authors: Gill Christian M , Asempa Tomefa E , Nicolau David P 
Published: January 2021

Abstract

Background
OXA-48 exhibits variable hydrolytic activity toward carbapenems, with imipenem and meropenem MICs, though increased, often reporting within the ‘susceptible’ or ‘intermediate’ ranges defined by CLSI and EUCAST. Although vaborbactam (VAB) does not enhance MEM activity against OXA-48, ~ 1/3 of OXA-48-producing Enterobacterales will test susceptible to MVB due to its higher breakpoint. Clinical implications of this discordance warrant investigation.

Methods
26 isolates harboring OXA-48 (n=24) and KPC (n=2) were evaluated in the neutropenic murine thigh model. MICs were determined in triplicate per CLSI. Human-simulated regimens of MVB (simulating doses of 2-2 g IV q 8 hours (h) over 3 h) and MEM (2 g IV q 8 h over 3 h) were administered resulting in similar f%T &gt;MIC and fAUC as humans for MEM and VAB, respectively. Mice received MVB, MEM, or sham control for 24 h. Efficacy was assessed on the resulting overall change in mean± SD log10 CFU/thigh as well as the achievement of ≥ 1 log10 reduction as an established surrogate marker predictive of success for serious infections.

Results
MVB and MEM MICs ranged from 1- 64 and 2 - &gt; 64 mg/L, respectively. Relative to 0 h control, the mean bacterial growth (mean ± SD, CFU/thigh) at 24 h in the untreated control mice was 2.69 ± 1.31. As anticipated for KPCs, MVB resulted in a mean bacterial reduction ≥ 1 log10 (-1.10 ± 0.26), whereas growth was observed on MEM (+1.45 ± 0.88). For all OXA-48 isolates, MVB resulted in variable bacterial densities ranging from -2.54 to +2.68, similarly MEM resulted in -2.18 to +2.66. Addition of vaborbactam did not enhance MEM activity for any isolate. For isolates with MVB MICs ≥ 16 (n=5), 8 (n=5, EUCAST breakpoint), 4 (n=9, CLSI breakpoint), and ≤ 2 (n=5) mg/L, 0%, 0%, 44%, and 60% of isolates treated with MVB or MEM achieved the target reduction of ≥ 1 log10 kill, respectively.

Conclusion
Across the range of MICs evaluated, MVB and MEM humanized exposures in vivo resulted in similar reductions and growth in bacterial density for OXA-48-producing Enterobacterales. Moreover, these data highlight the poor efficacy of MVB for OXA-48 defined as susceptible using the current EUCAST and CLSI susceptibility criterion. Caution is therefore warranted when treating Enterobacterales testing susceptible to MVB without the genotypic profile.

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)
1300. ACOG Committee Opinion #797 and the Dose of Intrapartum Vancomycin: a Potential Danger to Mother and Newborn Alike
Authors: Farkas Andras , Feldman Kristina M , Woods Krystina L , Yassin Arsheena 
Published: January 2021

Abstract

Background
Intra-partum (IP) IV vancomycin (VAN) 20 mg/kg every 8 hours is proposed by #797 for the prevention of early onset neonatal group B streptococcal disease (GBS), a recommendation for which the basis of scientific merit is poor. The goal of our study was to analyze the sparsely sampled published data and raise awareness about the underlying risk of VAN toxicity with this dosing approach.

Methods
Plasma and cord-blood concentration-time data of IV VAN given to mothers in the IP period was analyzed. 5000 Monte Carlo runs were conducted to simulate maternal/fetal exposure (AUC0-24; 24-48) for doses of 1500, 1750 and 2000 mgs q8h and for possible birth times at two-hour intervals. Neonatal VAN clearance was not possible to determine; hence, we used a validated PK model to calculate exposure for the first 24h of life for gestational ages (GA) of 33 to 40 weeks. The AUC range of 400 – 600, and &gt; 600 mg*h/L were considered for indices of efficacy and toxicity, respectively.

Results
Estimates from 30 pairs of serum and cord-blood concentrations analyzed with a 2-compartment model are shown in Table 1. Maternal VAN exposures seem acceptable up to 2 IP doses given with mean (SD) AUC0-24 of 394 (140), 474 (167), and 540 (193) mg*h/L for the 1500, 1750 and 2000 mg regimens. Most mothers (up to 83%) who receive three or more doses will be subjected to nephrotoxic exposures (Figure 1.). Neonatal evaluations indicate similarly low PTAs for the three dosing regimens when the efficacy target is considered (Figure 2. A). On the other hand, the PTAs for potentially nephrotoxic exposure is expected to reach undesirable levels when three or more doses were to be administered. The risk is profoundly high in GA of 33 to 35 weeks and birth times beyond 20 hours after the initiation of intra-partum prophylaxis (Figure 2. B).
Figure 1.

Figure 2.A

Figure 2.B

Conclusion
Current recommendations by #797 for dosing of vancomycin pose significant risk to mother and newborn alike, especially in cases with lengthy duration of labor. Based on our results, maternal therapeutic drug monitoring for all cases requiring more than two doses should be considered. With the proposed dosing regimen going un-adjusted, 1 out of 4 newborns and 4 out of 5 mothers may be subjected to nephrotoxic exposures in prolonged labor.
Table 1.

Disclosures
All Authors: No reported disclosures
1306. Comparison of the Use of Extended and Intermittent Infusion Cefepime and Piperacillin/tazobactam in Non-critically Ill, Obese Patients
Authors: Marg Carolyn , DeLanoit Zach , Boeser Kimberly D 
Published: January 2021

Abstract

Background
Obesity rates have dramatically increased over the last several decades, however, there is limited data to guide how antibiotics should be adjusted in obese patients. Physiologic differences including an increased volume of distribution and increased renal clearance may alter their pharmacokinetics and pharmacodynamics and subsequently, their efficacy. For beta-lactams like piperacillin/tazobactam (pip/tazo) and cefepime, extended infusion (EI) maximizes the time above the minimum inhibitory concentration (MIC) for optimal bactericidal activity. This dosing strategy may help decrease variability in achieving the target time above MIC in this patient population and lead to more favorable outcomes.

Methods
This single-center, retrospective, pre-/post- analysis included patients with a body mass index (BMI) &gt; 30 that received EI (infused over 4 hours) or intermittent infusion (II) (infused over 30 minutes) pip/tazo or cefepime between 2/1/2020-4/30/2020 and 2/1/2019-4/30/2019, respectively. The primary outcome was in-hospital, all-cause mortality. Secondary outcomes included clinical success rate and hospital length of stay (LOS).

Results
During the evaluation periods, 98 patients met inclusion criteria (EI, N=53; II, N=45). Mean BMI was not statistically different between groups (EI, 36.0 kg/m2 [30.1-46.3]; II, 36.5 kg/m2 [30-48]). There were no cases of mortality in either group. The mean LOS in the II group was 13 days compared to 11.5 days in the EI group [95% CI -4.14-7.04; p=0.606]. After excluding one outlier of 104 days in the EI group, the average LOS was 9.5 days [95% CI: -0.87-7.33; p=0.121]. Markers of clinical success including time to resolution of fever (II: 47 hours; EI: 34 hours; p=0.216) and time to resolution of leukocytosis (II: 2 days; EI: 3.8 days; p=0.089) were not significantly different between groups.

Conclusion
The use of EI pip/tazo and cefepime was not associated with any differences in in-hospital, all-cause mortality, hospital LOS, or clinical success when compared to the use of II pip/tazo and cefepime. The lack of significant differences between groups may be attributable to the small sample size limiting the ability to detect a difference, especially regarding hospital LOS.

Disclosures
All Authors: No reported disclosures
1308. Ex vivo Impact of Autologous Blood Transfusion (ABT) on Concentrations of Antibiotics used for Surgical Prophylaxis
Authors: Lasko Maxwell J , Conelius Allison , Serrano Oscar , Nicolau David P , Kuti Joseph L 
Published: January 2021

Abstract

Background
ABT is widely employed during surgical procedures involving high blood loss, such as liver transplantation and open heart surgery. While ABT mitigates the need for allogeneic blood transfusions, an unintended consequence may be removal of drugs, including antimicrobials. Herein, we determined the ex vivo loss of antimicrobials utilized for surgical prophylaxis through an ABT system.

Methods
Experiments were conducted in duplicate to simulate processing of ABT blood during surgery. Packed red blood cells and fresh frozen plasma (300ml) were acquired from banked blood and inoculated to achieve clinically-relevant plasma concentrations of vancomycin (VAN), the piperacillin (PIP) component of piperacillin/tazobactam, and the ampicillin (AMP) component of ampicillin/sulbactam. Inoculated blood was processed through a Cell Saver® Elite™ ABT system to fill a 125mL Latham bowl and washed with 500mL of normal saline. Processed fluid was directed to a reinfusion or waste bag; additional blood samples were collected from each. Drug concentrations were measured in all samples. The amount of VAN, PIP, and AMP infused through the Cell Saver (initial), and resulting in the reinfusion and waste bags was calculated.

Results
A range of 193-265mL of combined blood containing drug were processed in each experiment through the ABT system. Initial average plasma concentrations were 61, 107, and 172 mg/L for VAN, PIP, and AMP, respectively. When corrected for volume and hematocrit, plasma concentrations translated to a mean ± SD of 3 ± 1% of VAN in the reinfusion bag and 93 ± 2% in the waste bag. For PIP, plasma concentrations translated to 2 ± 1% of PIP in the reinfusion bag and 84 ± 13% in waste, while 2 ± 1% and 120 ± 5% of AMP was found in the reinfusion and waste bags, respectively. Unaccounted drug (0-14%) was considered sequestered in the device.

Conclusion
These ex vivo assessments of antibiotic removal during ABT are the first to demonstrate significant loss of antibiotics (&gt;95%) when processed through the ABT system. Further studies measuring impact of ABT on drug concentrations in patients undergoing surgery are warranted.

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))
1313. MIC Profiling of Ceftazidime-Avibactam (CAZ/AVI) Against Two Carbapenemase producing Klebsiella pneumoniae Isolates
Authors: Zidaru Andrei , Eales Brianna M , Wang Weiqun , Merlau Paul , Lasco Todd , Sofjan Amelia K , H Tam Vincent 
Published: January 2021

Abstract

Background
Carbapenemases confer resistance against a broad range of beta-lactams with a prevalence of 40-60% among CRE (carbapenem-resistant Enterobacteriaceae). CAZ-AVI is commonly used to treat infections due to CPE (carbapenemase-producing Enterobacteriaceae), typically guided by susceptibility testing with a single AVI concentration. This methodology does not take into consideration varying AVI concentration observed in vivo, and may not reliably predict positive clinical outcomes. Our objective was to investigate a novel susceptibility testing method to guide CAZ-AVI therapy.

Methods
Two bloodstream K. pneumoniae isolates (CAZ/AVI susceptible) from an abdominal source were recovered from 2 unrelated patients. Both patients were treated with CAZ/AVI, but had discordant outcomes: KP118 (eradication within 24h) and KP286 (persistent bacteremia for over 30 days). Carbapenemase production in the 2 isolates was confirmed via Carba NP test, and CAZ susceptibility was determined in a clinically relevant range of AVI concentration (0 - 16 mg/L). The concentration-response was characterized by the sigmoid inhibitory maximum effect (Emax) model. The best-fit parameter values were used to predict %T &gt; MICi associated with CAZ/AVI exposures expected in peritoneal fluid after standard dosing (2.5g q8h). These CAZ/AVI exposures were simulated in the hollow-fiber infection model (HFIM), and the bacterial responses were correlated to observed clinical outcomes.

Results
The AVI-dependent reduction in CAZ MIC was well characterized in both strains (R2 &gt; 0.98). In HFIM, sustained suppression of KP118 (T &gt; MICi = 100%) was observed over 5 days, but not with KP286 (T &gt; MICi &lt; 100%). These observations are consistent with the clinical courses of the patients.

Conclusion
The discordant patient outcomes could be explained by MIC profiling of CAZ/AVI. This method appears to be more robust than conventional susceptibility testing, and the clinical utility of this approach should be further investigated.

Disclosures
All Authors: No reported disclosures
1315. No Dose Adjustment of Metformin with Fostemsavir Coadministration Based on Mechanistic Static and Physiologically Based Pharmacokinetic Models
Authors: Nguyen Dung N , Miao Xiusheng , Magee Mindy , Tai Guoying , Gorycki Peter D , Moore Katy P 
Published: January 2021

Abstract

Background
Fostemsavir (FTR) is an oral prodrug of the first-in-class attachment inhibitor temsavir (TMR) which is being evaluated in patients with multidrug resistant HIV-1 infection. In vitro studies indicated that TMR and its 2 major metabolites are inhibitors of organic cation transporters (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs). To assess the clinical relevance, of OCT and MATE inhibition, mechanistic static DDI prediction with calculated Imax,u/IC50 ratios was below the cut-off limits for a DDI flag based on FDA guidelines and above the cut-off limits for MATEs based on EMA guidelines.

Methods
Metformin is a commonly used probe substrate for OCT1, OCT2 and MATEs. To predict the potential for a drug interaction between TMR and metformin, a physiologically based pharmacokinetic (PBPK) model for TMR was developed based on its physicochemical properties, in vitro and in vivo data. The model was verified and validated through comparison with clinical data. The TMR PBPK model accurately described AUC and Cmax within 30% of the observed data for single and repeat dose studies with or without food. The SimCYP models for metformin and ritonavir were qualified using literature data before applications of DDI prediction for TMR

Results
TMR was simulated at steady state concentrations after repeated oral doses of FTR 600 mg twice daily which allowed assessment of the potential OCT1, OCT2, and MATEs inhibition by TMR and metabolites. No significant increase in metformin systemic exposure (AUC or Cmax) was predicted with FTR co-administration. In addition, a sensitivity analysis was conducted for either hepatic OCT1 Ki, or renal OCT2 and MATEs Ki values. The model output indicated that, a 10-fold more potent Ki value for TMR would be required to have a ~15% increase in metformin exposure

Conclusion
Based on mechanistic static models and PBPK modeling and simulation, the OCT1/2 and MATEs inhibition potential of TMR and its metabolites on metformin pharmacokinetics is not clinically significant. No dose adjustment of metformin is necessary when co-administered with FTR

Disclosures
Xiusheng Miao, PhD, GlaxoSmithKline (Employee) Mindy Magee, Doctor of Pharmacy, GlaxoSmithKline (Employee, Shareholder) Peter D. Gorycki, BEChe, MSc, PhD, GSK (Employee, Shareholder) Katy P. Moore, PharmD, RPh, ViiV Healthcare (Employee)