bluuebunny/crossref_metadata_2025_split huggingface dataset:
1544. Efficacy of Human-Simulated Cefiderocol Exposure Against Gram-Negative Bacteria in an Iron-Overloaded Murine Thigh Infection Model
Authors: Kidd James M , Abdelraouf Kamilia , Nicolau David P 
Published: October 2019

Abstract

Background
Cefiderocol (CFDC) is a siderophore-cephalosporin conjugate which exploits bacterial iron scavenging in reaction to the hypoferremic response of host immunity and achieves potent in vivo activity against various Gram-negative bacteria (GNB). In patients with hereditary or iatrogenic hemochromatosis, the hypoferremic response may be altered by iron overload, which could hypothetically suppress the bacterial iron scavenging that bolsters CFDC efficacy. We compared CFDC efficacy between iron-overloaded (Fe+) and normal iron (NFe) murine thigh infection models.

Methods
Female CD-1 mice received iron dextran 100 mg/kg/d for 14 d to induce iron overload (Fe+) (ASM Microbe 2019 abstract HMB-373); an equal number of same-age mice were not dosed (NFe). On day 15, both thighs of mice rendered neutropenic were inoculated with GNB suspensions of 107 CFU/mL. Twenty CFDC-susceptible isolates with previously determined CFDC MIC from 0.25 to 4 mg/L, including Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriales, were used. Two hours after inoculation, treatment mice were dosed with a CFDC regimen simulating the human plasma PK profile after doses of 2g q8h (3 h infusion), while control mice were sacrificed (0 h) or dosed with saline placebo on the same schedule as the CFDC regimen (24 h). All procedures were simultaneously performed in Fe+ and NFe mice. Efficacy was defined as a change in log10 CFU/thigh at 24 h vs. 0 h and was compared between Fe+ and NFe mice for individual isolates using Student’s t-test.

Results
Mean (SD) bacterial burdens at 0 h in Fe+ and NFe control mice were 5.77 (0.52) and 5.76 (0.52) and log10 CFU/thigh, respectively, and, at 24 h, increased by 3.49 (0.73) and 3.42 (0.96) log10 CFU/thigh, respectively. Mean (SD) efficacies of CFDC in Fe+ and NFe mice were -1.98 (0.83) and -1.98 (0.72) log10 CFU/thigh, respectively. For 17 of 20 individual isolates, no significant differences in efficacy between Fe+ and NFe mice were observed (P > 0.05); 2 of the 3 isolates with a difference had greater efficacy in Fe+ mice.

Conclusion
Human-simulated exposure of CFDC is equally efficacious in iron-overloaded and normal hosts against a variety of GNB susceptible to CFDC. The potential clinical use of CFDC to treat GNB infections in patients with iron overload is supported.

Disclosures
All authors: No reported disclosures.
1549. Impact of New Fluoroquinolone Breakpoints on Enterobacteriaceae Susceptibility Rates and Clinical Outcomes
Authors: Pettit Natasha N , Nguyen Cynthia T , Pisano Jennifer , Charnot-Katsikas Angella 
Published: October 2019

Abstract

Background
In January 2019, the Clinical and Laboratory Standards Institute (CLSI) lowered the Fluoroquinolone (FQ) susceptibility breakpoints for Enterobacteriaceae. The new breakpoints were updated primarily based on FQ pharmacodynamics, and only limited clinical data. We sought to evaluate clinical outcomes among patients who received an FQ for infection with Enterobacteriaceae with MIC values that would now be considered resistant, using the new interpretive criteria. We also assessed the potential impact of the new breakpoints on overall blood and urine Enterobacteriaceae susceptibility rates at our medical center.

Methods
All positive blood and urine cultures with Enterobacteriaceae between September 1, 2018 and February 28, 2019 were included. Enterobacteriaceae isolates with ciprofloxacin MICs of 0.5 and 1 µg/mL (based on new breakpoints, now considered non-susceptible) were identified. We assessed the length of stay (LOS), mortality, and 30-day readmissions among patients who received an FQ for treatment. The impact of the new breakpoints on overall Enterobacteriaceae susceptibilities from urine and blood isolates was also determined.

Results
A total of 1,761 cultures (191 blood, 1,570 urine) grew Enterobacteriaceae. One-hundred and twenty-five (7%) cultures grew isolates with a ciprofloxacin MIC of 0.5 or 1 µg/mL. Eighteen patients with Enterobacteriaceae isolated (4 blood, 14 urine) received an FQ. Among these patients, the median LOS was 4 days; one patient was readmitted within 30 days, and 0% mortality was observed. The patient readmitted within 30 days received an FQ for a blood isolate with MIC 0.5. Overall, with the revised breakpoints, we observed a 4.2% decrease in the number of Enterobacteriaceae that would be susceptible to ciprofloxacin (Figure 1).

Conclusion
The new FQ breakpoints for Enterobacteriaceae will have a marginal impact on overall FQ susceptibility rates at our medical center. In this single-center study, patients that received FQ antibiotics for Enterobacteriaceae with MIC values now considered intermediate or resistant did not appear to experience poor outcomes.

Disclosures
All authors: No reported disclosures.
1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia
Authors: Winchell Gregory A , de Greef Rik , Wrishko Rebecca E , Mangin Eric , Waskin Hetty , Bruno Christopher 
Published: October 2019

Abstract

Background
Posaconazole is approved in adults for prophylaxis and treatment of invasive fungal disease. Two formulations that offer weight-based dosing—intravenous (IV) and oral powder for suspension (PFS)—are being evaluated in children. A population pharmacokinetic (popPK) approach was used to characterize and predict the PK exposure of posaconazole PFS and IV formulations in children to identify dosages associated with achieving a target PK of 1200 ng/mL as the mean Cavg and individual Cavg ≥500 ng/mL and <2500 ng/mL in ~90% of patients.

Methods
A popPK model was developed through nonlinear mixed-effects modeling using data obtained from a trial in children with neutropenia (ClinicalTrials.gov, NCT02452034; Merck protocol, MK-5592-097). Three dose cohorts (3.5, 4.5, and 6 mg/kg/day [≤300 mg/day]) were studied in two age groups (2–<7 years and 7–17 years). Posaconazole IV was administered twice on day 1 then once daily through at least day 10, followed by PFS once daily through day 28 at clinician discretion. A compartmental model, including both formulations, was fit to the data. Model selection was based on the Log-Likelihood Criterion, goodness-of-fit plots, and scientific plausibility. Significance of the covariates was assessed in a stepwise forward inclusion/backward procedure. An additional assessment characterized the impact of different food covariates on bioavailability.

Results
An open one-compartmental PK model with first-order absorption and estimated bioavailability, as well as allometrically scaled effects of body weight on clearance and volume, adequately described the PK of posaconazole IV and PFS formulations. Model predictions are shown in the Table. Effects of the different food covariates were not statistically significant. Simulations indicated that for the 6-mg/kg/d dose, model-predicted Cavg generally met PK targets. Model-predicted Cavg was ≥500 ng/mL in >90% of subjects in all cohorts. The 1200-ng/mL target geometric mean Cavg was achieved for all but the 2–<7 years cohort receiving the PFS formulation.

Conclusion
This popPK-based analysis demonstrated that the 6-mg/kg/d dose of IV or PFS posaconazole formulation (≤300 mg/days) is appropriate for children (2–17 years) and that PFS can be administered without regard to food.

Disclosures
All authors: No reported disclosures.
1559. Ertapenem Plus Ceftriaxone or Ceftaroline Dual Β-Lactam Combination for Enterococcus faecalis
Authors: Cusumano Jaclyn A , Daffinee Kathryn E , LaPlante Kerry 
Published: October 2019

Abstract

Background
Ampicillin-ceftriaxone β-lactam therapy has become the standard of care for treating serious Enterococcus faecalis infections. Alternative regimens are of interest due to ceftriaxone’s association with C. difficile infections and VRE colonization, and ampicillin’s instability and inconvenient dosing schedule.

Methods
E. faecalis wild-type strain JH2-2 was utilized in a 48-hour in vitro pharmacodynamic model with a starting inoculum of 106 colony-forming units (CFU)/mL. Models were performed in duplicate to triplicate. Simulated doses of ertapenem 1g every 24 hours (fCmax 12.2 μg/mL; half-life 4 hours; MIC 4 μg/mL), ceftriaxone 2 g every 12 hours (fCmax 28.5 μg/mL; half-life 6.5 hours; MIC 512 μg/mL), and ceftaroline 600 mg every 8 hours (fCmax 27.1 μg/mL; half-life 2.7 hours; MIC 2 μg/mL) were tested. Ertapenem was also combined with ceftriaxone or ceftaroline. Bacterial counts were obtained at 0, 4, 8, 24, 32, and 48 hours. Bactericidal activity was defined as ≥ 3-log10 CFU/mL reduction from the initial inoculum. MICs were assessed at 0, 24, and 48 hours using E-tests in accordance with CLSI.

Results
Ertapenem plus ceftriaxone, and ertapenem plus ceftaroline demonstrated bactericidal activity at 24 hours, but bacterial regrowth was observed at 48 hours (Table 1). An ertapenem MIC increase was only noted in one set of the ertapenem plus ceftriaxone models to 16mcg/mL at 48 hours, from 4mcg/mL at 0 hours. All other models did not have an increase in MIC.

Conclusion
Bactericidal activity of ertapenem-based dual β-lactam combinations may prove to be an alternative treatment for severe E. faecalis infections. Mechanistic understanding of penicillin-binding protein (PBP) saturation and optimization of antimicrobial pharmacodynamics must be explored.

Disclosures
All authors: No reported disclosures.
1565. Characterization of Tebipenem (SPR859) Pharmacokinetics–Pharmacodynamics (PK-PD) for Efficacy Against Enterobacteriaceae in a One-Compartment In Vitro Infection Model
Authors: VanScoy Brian D , Onufrak Nikolas J , Conde Haley , Caranco Ana I , Bhavnani Sujata M , Cotroneo Nicole , Critchley Ian A , Parr Thomas R , Ambrose Paul G 
Published: October 2019

Abstract

Background
SPR859 (tebipenem) is the active form of the orally bioavailable prodrug SPR994. Tebipenem is an oral carbapenem with a broad-spectrum activity against Gram-positive and -negative bacteria. SPR994 is being developed as an oral option for the treatment of complicated urinary tract infections (cUTI). The goal of these studies was to characterize the PK-PD of tebipenem against a diverse panel of Enterobacteriaceae.

Methods
24-hour dose-fractionation and dose-ranging studies were carried out utilizing the one-compartment in vitro infection model. Bacteria (1 × 106 CFU/mL) were exposed to tebipenem concentrations that mimicked human healthy volunteer free-drug plasma (f) concentration–time profiles following oral drug administration. For the dose-fractionation studies, 7 total daily dose levels (fAUC range, 0.11 to 19.0 mg hours/L) were fractionated in equal divided doses administered every 4, 8 or 12 hours (q4h, q8h and q12h, respectively). A single challenge isolate, E. coli ATCC 25922 (MIC = 0.015 mg/L), was evaluated in the dose-fractionation studies. In the dose-ranging studies, 13 Enterobacteriaceae clinical isolates (MIC values from 0.008 to 0.25 mg/L) were exposed to doses ranging from 4.69 to 1200 mg administered q8h (fAUC ranging from 0.14 to 37.2 mg hours/L). Relationships between change in log10 CFU from baseline at 24 h and each of fCmax:MIC ratio, f%T>MIC, and fAUC:MIC ratio, with and without adjustment for dosing interval tau for the latter (fAUC:MIC ratio·1/τ), were fit using Hill-type models.

Results
Dose-fractionation study results demonstrated the activity of tebipenem to be time-dependent, with both f%T>MIC and fAUC:MIC ratio·1/τ similarly describing the PK-PD of tebipenem. The relationship between change in log10 CFU from baseline at 24 hours and fAUC:MIC ratio·1/τ, as assessed using pooled data for 13 Enterobacteriaceae isolates evaluated in the dose-ranging studies, described the PK-PD of tebipenem well (Figure 1). The magnitude of fAUC:MIC ratio·1/τ associated with net bacterial stasis and 1- and 2-log10 CFU reductions from baseline was 7.23, 13.1, and 32.4, respectively.

Conclusion
These data will be useful to design other pre-clinical studies and support tebipenem dose selection for clinical studies in patients with cUTI.

Disclosures
All authors: No reported disclosures.
1574. Predictive Ability and Bias of Vancomycin Population PK Models in an Obese Adult Population
Authors: Sabourenkov Paul E , McLeay Robert C 
Published: October 2019

Abstract

Background
Accurate dosing of vancomycin is difficult due to high inter-individual variability of vancomycin pharmacokinetics (PK), and is particularly challenging in obese patients. Vancomycin is hydrophilic, yet total body weight (TBW) has traditionally been used for dosing in the general population, and also into the obese population. The aim of this study was to evaluate the performance of published vancomycin PK models in a large set of routine clinical data obtained from an obese population.

Methods
De-identified data were available from 1717 courses of vancomycin administered to obese adults (BMI ≥ 30) from hospitals across the United States, EU, and Australia. Three population PK models, Buelga et al. (2005), Goti et al. (2018), and an obese-specific model, Adane et al. (2015), were used to predict plasma concentrations at the time of each recorded vancomycin assay, and their accuracy and bias were compared. Goodness of fit at both the population and individual level was assessed, and elastic net regression was used to identify any sources of predictive error in the obese-specific model. Model parameters for each model were then re-estimated, and a variety of body size metrics were evaluated.

Results
The Buelga et al. one-compartment model had the best predictive ability (Table 1). In all models, bias (calculated as MME; mean per-patient mean predictive error) by obesity class was observed at both the population and individual levels, and unexpectedly was largest in the obese-specific model. In the obese-specific model, predictive error correlated with the use of TBW as a model covariate. A set of models derived from Adane et al. model were then developed to correct for weight. Using ideal body weight (IBW) on Vd and no correction for weight on CL provided the best fit. The derived model accounted for 81% of variance in plasma concentration and exhibited negligible bias by obesity class (population MME = -0.75 (i), -0.06 (ii), and -0.50 (iii) mg/L; individual MME = −0.20 (i), −0.02 (ii), and −0.02 (iii) mg/L).

Conclusion
Existing vancomycin population PK models for use in the obese population are biased in higher obesity classes due to the use of total body weight. A novel population PK model developed using ideal body weight exhibits negligible bias across obesity classes as well as improved predictive ability.

Disclosures
All authors: No reported disclosures.
1583. Eight Years of Sustained Potency and Activity of Oritavancin against Gram-Positive Isolates Causing Bacteremia and Endocarditis in the USA, Including Enterococcal Infections Requiring an Optimized Dosing Strategy for Daptomycin
Authors: Carvalhaes Cecilia G , Sader Helio S , Streit Jennifer M , Flamm Robert K , Mendes Rodrigo E 
Published: October 2019

Abstract

Background
Oritavancin (ORI) is a potent lipoglycopeptide with desirable PK/PD parameters for treating serious gram-positive infections. This study assessed the activity of ORI against Staphylococcus aureus (SA), Enterococcus faecalis (EF), and E. faecium (EFM) causing bloodstream infection (BSI), including infective endocarditis (IE) and daptomycin (DAP)- susceptible dose-dependent (SDD) vancomycin-resistant (VRE) subsets. We also evaluated the longitudinal activity of ORI.

Methods
A total of 5,469 SA, 1,157 EF, and 721 EFM were recovered from BSI in 35 US sites (2011–2018). Subsets of SA isolates causing IE (84) and EFM displaying DAP-SDD-VRE phenotypes (230) were included. Identification was confirmed by MALDI-TOF MS and isolates were tested for susceptibility (S) according to CLSI.

Results
Overall, ORI showed similar MIC50 (0.03 mg/L) and MIC90 results (0.06 mg/L) against MRSA and MSSA (figure) and the SA EC subset (41.7% MRSA; data not shown). Similar findings were noted for ORI tested against EF DAP-S (MIC50/90, 0.015/0.06 mg/L) and DAP-SDD (MIC50/90, 0.015/0.06 mg/L). ORI MIC values against DAP- and VAN-S EFM (MIC50/90, ≤0.008/0.015 mg/L) were at least 8-fold lower than those from DAP-SDD-VRE isolates (MIC50/90, 0.06/0.12 mg/L; 31.9% of all EFM), and all EFM were inhibited by ORI at ≤0.25 mg/L. The longitudinal analysis showed MRSA rates varying from 39.7% (2017) to 46.8% (2011), while the annual ORI MIC50 and MIC90 results were 0.015–0.06 mg/L and 0.03–0.12 mg/L, respectively, against MRSA during the 8-year period. ORI yearly MIC50 and MIC90 results were 0.015–0.03 mg/L and 0.03–0.12 mg/L against EF, respectively. MIC50 and MIC90 results of 0.008–0.03 mg/L and 0.03–0.12 mg/L, respectively, were obtained for ORI against the DAP-SDD EF subset each year. ORI MIC50 and MIC90 results of 0.03–0.06 and 0.06–0.12 mg/L were obtained annually against DAP-SDD-VRE (EFM), respectively.

Conclusion
ORI showed a potent activity against this collection of isolates causing BSI and IE in the USA, including resistant subsets requiring higher dosage regimens when treating serious infections. In addition, ORI maintained a stable potency throughout the 8-year study period with no apparent temporal trends.

Disclosures
All authors: No reported disclosures.
1595. Comparative In Vitro Activity of Imipenem–Relebactam Against Drug-Resistant Gram-Negative Isolates from Pediatric Patients
Authors: Banerjee Dithi , Harrison Christopher J , Pence Morgan , Selvarangan Rangaraj 
Published: October 2019

Abstract

Background
Drug resistance in Gram-negative bacteria is of particular concern in children. Relebactam, a novel diazabicyclooctane inhibitor, coupled with imipenem has broad-spectrum activity against β-lactamase producing organisms. Here, we compare the in vitro activity of imipenem-relebactam to 10 standard comparator drugs against resistant Gram-negative isolates from two US pediatric hospitals.

Methods
We tested 100 isolates (50 per site) from pediatric clinical specimens tested during 2015–2017. All isolates were extended-spectrum cephalosporin-resistant (ESC-R); more than half were multidrug resistant (67%). Selected ESC-R isolates included Escherichia coli (90), Klebsiella pneumoniae (8), Klebsiella oxytoca (1), and Enterobacter cloacae (1) that were resistant or intermediate to ≥1 cephalosporins and/or aztreonam. A 0.5 McFarland suspension was prepared from colonies grown on blood agar plates (Thermo Scientific) at 35 ± 1°C for 18–24 hours. A final inoculum of 5 × 105 CFU/mL was prepared in Mueller–Hinton broth. Sensititre plates (Thermo Fisher Scientific) containing graded concentrations of imipenem/relebactam and 10 comparator drugs were inoculated and incubated at 35 ± 1°C for 18–24 hours. The minimum inhibitory concentration (MIC) was determined using the Sensititre Vizion system (Thermo Fisher Scientific) and endpoints were interpreted using CLSI (2019) breakpoint criteria, with the exception of colistin (EUCAST 2019).

Results
Selected ESC-R isolates had high rates of resistance to cephalosporins (64%–97%), aztreonam (80%), and levofloxacin (61%). All isolates were susceptible to imipenem/relebactam, imipenem and meropenem (MIC, ≤1 μg/mL for all). The imipenem/relebactam MIC50 (0.06 μg/mL) and MIC90 (0.12 μg/mL) values for ESC-R isolates were within one dilution of MICs of imipenem alone (0.12 μg/mL and 0.25 μg/mL). Among the comparators, colistin, amikacin, and piperacillin/tazobactam demonstrated comparable activities with 100%, 99%, and 94% susceptibilities, respectively.

Conclusion
Meropenem, imipenem alone and in combination with relebactam exhibited 100% susceptibilities against ESC-R Enterobacteriaceae isolated from pediatric specimens, demonstrating the high potency of carbapenems.

Disclosures
All authors: No reported disclosures.
1600. Susceptibility of β-Lactam-Resistant Pseudomonas aeruginosa to Other β-Lactams: Is There Truly a Lack of Cross-Resistance?
Authors: Patel Twisha S , Marshall Vince , Kaye Keith S , Smith Aaron , Young Carol , Lephart Paul , Pogue Jason M 
Published: October 2019

Abstract

Background
Resistance to β-lactams in P. aeruginosa is complex with multiple mechanisms contributing. Since different mechanisms impact different β-lactams to differing degrees, a common dogma is that resistance to one β-lactam does not lead to resistance to others. The purpose of this analysis was to assess the frequency of β-lactam cross-resistance in P. aeruginosa.

Methods
Unique P. aeruginosa isolated in 2017 at Michigan Medicine were included. Overall, susceptibility (using CLSI breakpoints) and MIC distributions of β-lactams were assessed in all isolates and those with β-lactam resistance.

Results
3,836 unique P. aeruginosa isolates were included. Resistance to traditional anti-pseudomonal β-lactams ranged from 15–23%, whereas ceftolozane/tazobactam resistance was 6%. Overall, cross-resistance between β-lactams was common. The table displays select β-lactam MIC distributions for all isolates and in those resistant to ≥1 β-lactam. When resistance of one agent was present susceptibility to other β-lactams was generally <40% with the majority of susceptible isolates having MICs at or near the breakpoint. Ceftolozane/tazobactam provided the best activity in this setting with 65–77% susceptibility.

Conclusion
Cross-resistance between β-lactams in P. aeruginosa is common. In patients at risk for resistant P. aeruginosa, ceftolozane/tazobactam should be considered for empiric coverage.

Disclosures
All authors: No reported disclosures.