bluuebunny/crossref_metadata_2025_split huggingface dataset:
1547. Modeling Pharmacokinetics and Pharmacodynamics of Meropenem Utilizing a Novel Infusion Method of Bolus to Prolonged Infusion
Authors: Moore Sarah E , Cheatham S Christian , Kays Michael B 
Published: October 2019

Abstract

Background
Dose optimization of antibiotics has been shown to increase the likelihood of achieving pharmacodynamic efficacy targets and improve clinical outcomes. For carbapenems, achieving greater than 40% time above minimum inhibitory concentration (T>MIC) has been shown to be correlated with clinical efficacy. Increasing bacterial resistance and rising MICs makes it more difficult for clinicians to rely on traditional dosing strategies to meet pharmacodynamic goals. Further optimization methods beyond extended infusion may be necessary to achieve certain pharmacodynamics goals.

Methods
We performed a Monte Carlo simulation investigating a novel method of meropenem administration, bolus to prolonged infusion (BPI). Multiple meropenem dosing regimens utilizing BPI were evaluated over 5000 patients utilizing pharmacokinetic profiles from 30 total patients. Patients were studied in 3 separate groups: <120 kg, ≥120 kg/non-critically ill and ≥120 kg/critically-ill. Bolus doses varied from 250–1000 mg and were paired with infusion doses varying from 500–1500 mg. Bolus plus infusion time totaled 3 hours and each dose was modeled with an 8-hour interval for both first dose and at steady state; BPI dosing was utilized for each dose. The primary outcome was probability of target attainment (PTA) of 40% time above minimum inhibitory concentration (T>MIC). Secondary outcomes included PTA 54% T>MIC and PTA 100% T>MIC.

Results
All doses studied achieved > 90% PTA of 40% T>MIC for MICs of ≤8 μg/mL at both first dose and steady state in the <120 kg and ≥120 kg/non-critically ill patient groups. In the ≥120 kg/critically ill patient group, all doses achieved > 90% PTA of 40% T>MIC for MICs of ≤4 μg/mL.

Conclusion
BPI achieves high probability of target attainment at nonresistant MICs for Pseudomonas aeruginosa and enteric Gram-negative organisms across the 3 patient groups studied.

Disclosures
All authors: No reported disclosures.
1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models
Authors: Ghahramani Parviz , Chiu Joannellyn , Asempa Tomefa E , Abdelraouf Kamilia , Nicolau David P , Abdel Hady Wessam , Xiong Yan , Bayer Arnold , Carabeo Teresa , Cassino Cara , Schuch Raymond , Lehoux Dario 
Published: October 2019

Abstract

Background
Exebacase (CF-301) is a novel lysin with rapid bacteriolytic and anti-biofilm activity against S. aureus, pronounced synergy with antibiotics and low propensity for resistance. Exebacase has undergone Phase 1–2 trials. This work was to develop pharmacokinetic (PK) model in animal and determine the relationship between exebacase exposure and efficacy in animals.

Methods
PK data in 592 animals (4 species) included in population PK model. A range of linear and nonlinear mammillary models with allometric scaling fitted to the PK data using NONMEM and the most parsimonious model was selected by improvement in objective function value (P < 0.01). To evaluate efficacy, 349 animals with 177 mice (neutropenic thigh infection) and 172 rabbits (aortic valve infective endocarditis were treated with exebacase in addition to suboptimal doses of daptomycin (DAP). Full PK profiles were simulated for individual animals. Fifty-nine dosing regimens of exebacase in mice (0–90 mg/kg) and 18 regimens in rabbits (0–1.4 mg/kg) with q24h, q12h and q8h frequencies. Relationship between AUC/MIC, Cmax/MIC, T> MIC, and log-CFU was examined using a range of functions by comparing residual standard error (RSE).

Results
3-compartment model with allometric scaling best described the PK data and was validated by bootstrap and Goodness of Fit. Maximum drop in log10CFU/g in target tissues was at AUC/MIC< 0.2 for exebacase when added to DAP that was associated with CF reduction of -5 logs in rabbits (Figure (a)) with similar magnitudes in cardiac vegetations, kidney and spleen, and -4 logs in mice (Figure (b)). Treatment with DAP alone had log10CFU reduction of -1 in mice; and -2 in rabbits. AUC/MIC was an appropriate predictor of CFU reductions.

Conclusion
PK model adequately described the data for 4 animal species. Exebacase addition to DAP has a synergistic effect on efficacy measured by CFU reductions in target tissues in the animal models. Results support previously presented determinations of AUC/MIC as predictor of efficacy. Maximum reductions in CFU in rabbits and mice were observed at AUC/MIC ratios <0.2. These results further indicate that rabbit is the most appropriate efficacy model with MICs and antibacterial activity reflective of previously reported observations in human serum.

Disclosures
All authors: No reported disclosures.
1572. Evaluation of Vancomycin Levels Following Weight-Based Pre-operative and Re-warming Vancomycin Dosing in Cardiac Surgery
Authors: Ruggero Michael , Redline Gretchen , Weiss Stuart , Binkley Shawn , Hamilton Keith W 
Published: October 2019

Abstract

Background
Weight-based dosing of vancomycin in the pre-operative setting is standard practice at our institution based on the 2013 Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery. Our antimicrobial subcommittee recommended a weight-based dosing (15 mg/kg/dose) approach to negate the need for a subsequent vancomycin dose during rewarming in cases requiring cardiopulmonary bypass (CPB). However, after discussion with all perioperative stakeholders, administration of vancomycin 1 g intravenously for all patients on CPB at rewarming continued. The aim of this study was to determine whether subsequent rewarming vancomycin doses contributed to the development of postoperative acute kidney injury (AKI).

Methods
This was a prospective cohort study of all cardiac surgery patients undergoing surgery from April 16, 2018 through April 27, 2018 for the development of AKI as defined by RIFLE criteria. Institutional guidelines recommend vancomycin as perioperative prophylaxis in all cardiac surgery cases with a preoperative 15 mg/kg dose, a 1 g rewarming dose, and nomogram-based post-operative dosing. Vancomycin troughs were obtained prior to the first post-operative dose in the intensive care unit. Serum creatinine was recorded on the post-op day (POD) 0, POD 1, and POD 7.

Results
Data were collected on 54 patients over a 2-week period. The median age was 64 years of age, with 41 (76%) male patients. Seven patients (13%) had a prior diagnosis of chronic kidney disease (CKD). Post-op AKI developed in 8 patients (15%) by POD 7; two of which had CKD at baseline. All patients received appropriate preoperative and postoperative dosing. Forty-nine (91%) patients had trough levels obtained, with the median trough 7.6 μg/mL (range 2 – 15.9 μg/mL) prior to the first nomogram-based post-operative vancomycin dose. Higher rates of AKI were associated with a longer duration of CPB rather than vancomycin levels obtained.

Conclusion
The current practice of redosing 1 g vancomycin at rewarming did not appear to contribute higher rates of AKI. In addition, all vancomycin trough levels reviewed were less than 20 μg/mL. Levels observed in this study are lower than previously described in the literature to cause nephrotoxicity. Further evaluation of vancomycin use in this setting is warranted

Disclosures
All authors: No reported disclosures.
1582. Delafloxacin Activity Against Drug-Resistant Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, and Moraxella catarrhalis from US Medical Centers (2014–2018)
Authors: Shortridge Dee , Streit Jennifer M , Huband Michael D , Flamm Robert K 
Published: October 2019

Abstract

Background
Delafloxacin (DLX) is an anionic fluoroquinolone (FQ) antimicrobial that was approved in 2017 by the United States (US) Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections. DLX recently successfully completed a clinical trial for the treatment of community-acquired bacterial pneumonia (CABP). In the present study, in vitro susceptibility (S) results for DLX and comparator agents were determined for CABP pathogens including Streptococcus pneumoniae (SPN), Haemophilus influenzae (HI), H. parainfluenzae (HP) and Moraxella catarrhalis (MC) clinical isolates from US hospitals participating in the SENTRY Program during 2014–2018.

Methods
A total of 1,975 SPN, 1,128 HI, 684 MC, and 43 HP isolates were collected from community-acquired respiratory tract infections (CARTI) during 2014–2018 from US hospitals. Sites included only 1 isolate/patient/infection episode. Isolate identifications were confirmed at JMI Laboratories. Susceptibility testing was performed according to CLSI broth microdilution methodology, and CLSI (2019) breakpoints were applied where applicable. Other antimicrobials tested included levofloxacin (LEV) and moxifloxacin (MOX; not tested in 2015). Multidrug-resistant (MDR) SPN isolates were categorized as being nonsusceptible (NS) to amoxicillin-clavulanate, erythromycin, and tetracycline; other SPN phenotypes were LEV-NS or penicillin (PEN)-NS. β-Lactamase (BL) presence was determined for HI, HP, and MC.

Results
The activities of the 3 FQs are shown in the table. The most active agent against SPN was DLX, with the lowest MIC50/90 values of 0.015/0.03 mg/L. DLX activities were similar when tested against the MDR or PEN-NS for SPN phenotypes. LEV-NS isolates had DLX MIC50/90 results of 0.12/0.25 mg/L. DLX was the most active FQ against HI, HP, and MC. BL presence did not affect FQ MIC values for HI or MC; only 2 HP isolates were BL-positive.

Conclusion
DLX demonstrated potent in vitro antibacterial activity against SPN, HI, HP, and MC. DLX was active against MDR SPN that were NS to the agents commonly used as treatments for CABP. DLX had excellent activity against LEV-NS SPN. These data support the continued study of DLX as a potential treatment for CABP.

Disclosures
All authors: No reported disclosures.
1584. Minocycline Activity Against Stenotrophomonas maltophilia Isolated From Patients in US Hospitals
Authors: Shortridge Dee , Ryan Arends S J , Streit Jennifer M , Castanheira Mariana , Flamm Robert K 
Published: October 2019

Abstract

Background
Stenotrophomonas maltophilia (SM) has emerged as a common hospital-associated opportunistic pathogen found in immunocompromised and immunocompetent patients. SM is intrinsically resistant to many common drug classes, including carbapenems, cephalosporins, and aminoglycosides. Only 4 antibiotics have CLSI breakpoints for SM: minocycline (MIN), ceftazidime (CAZ), levofloxacin (LVX) and trimethoprim-sulfamethoxazole (TMP-SMX). Minocycline is frequently used to treat SM infections. In this study, we analyzed susceptibilities of SM isolates collected as part of the SENTRY Program. We also examined the frequency of SM isolation from pneumonia in hospitalized patients (PIHP) among all Gram-negative (GN) species.

Methods
From 2014 to 2018, 990 SM isolates were collected from hospitalized patients in 32 US hospitals. Hospitals submitted 1 isolate per patient per infection episode that met local criteria for being the likely causative pathogen and submitted consecutive isolates from pneumonia. Isolates were tested for MIN susceptibility (S) using the CLSI broth microdilution method at JMI Laboratories. Other antimicrobials tested were CAZ, LVX, and TMP-SMX. TMP-SMX was tested 3 of 5 years. All infection types were included in the susceptibility analysis. The prevalence of SM isolates in PIHP during this period was also analyzed.

Results
There were 9,120 GN pathogens isolated from PIHP. The most commonly isolated species was P. aeruginosa (34.7%), followed by Klebsiella pneumoniae (12.6%), Escherichia coli (10.1%), and SM (7.9%). Among the 990 infections caused by SM, PIHP was the most common at 72.4%, followed by bloodstream infections (14.4%) and skin/skin structure infections (6.9%). The %S and MIC50/90 values of the 4 antimicrobials tested in this study are shown in the table.

Conclusion
SM was the fourth most frequent cause of GN PIHP in US medical centers. MIN was the most active drug tested against SM with 99.5%S, followed by TMP-SMX (94.7%), and CAZ was the least active with 28.5%S. This study suggests that MIN may be a consideration as a treatment for infections caused by SM, with a very low resistance rate based on CLSI breakpoints.

Disclosures
All authors: No reported disclosures.
1608. Use of Selective Reporting of Antimicrobial Susceptibilities and Its Impact on Antimicrobial Resistance Surveillance—National Healthcare Safety Network, 2017–2018
Authors: Wu Hsiu , Zhou Liang , SOE MINN M , Edwards Jonathan R , Pollock Daniel 
Published: October 2019

Abstract

Background
Selective reporting (SR), recommended by the 2016 IDSA/SHEA antimicrobial stewardship guidelines, is a strategy to guide prescribing decisions by limiting the antimicrobial susceptibility testing (AST) results available to prescribers. Yet, SR carries risks that cumulative antibiograms reflect only partial AST results. The Clinical Laboratory Standards Institute (CLSI) M100 performance standards stipulate that AST results should be routinely reported for some antimicrobials (Group A agents) while SR is appropriate for other antimicrobials (Group B agents). We assessed the extent of SR use and its impact on national antimicrobial resistance (AR) surveillance.

Methods
We used Enterobacteriaceae (EB) and Staphylococcus aureus (SA) blood culture AST results that hospitals reported for group A and B agents to the CDC’s National Healthcare Safety Network’s AR option from 2017 through 2018. Routine reporting for an organism-agent combination was defined as results reported for ≥ 90% isolates for the hospital’s most frequently reported agents. SR was defined as a shortfall of > 20% in results reported for an agent compared with a routinely reported agent in a hospital that reported ≥ 30 isolates. We compared hospital antibiograms between SR and non-SR hospitals. We also identified isolate characteristics associated with AST reporting in SR hospitals.

Results
Among 242 and 185 hospitals reported ≥ 30 isolates, many showed patterns of SR (Figure 1). Of 437 and 425 hospitals reported ≥ 1 isolate, only 112 (26%) and 152 (36%) routinely reported AST results for all group A agents for EB and SA, respectively. For EB, 345 (79%) hospitals routinely reported AST results for ciprofloxacin or levofloxacin, although both are group B agents. For SA, 324 (76%) routinely reported vancomycin (Figure 2). Antibiograms for many agents differed between SR and non-SR hospitals (Figure 3, 4). In SR hospitals, non-susceptibility to narrower-spectrum drugs, patient location, age, and some species among EB were associated with AST reporting.

Conclusion
AST results reporting vary across hospitals and agents, and CLSI’s SR standards are used inconsistently. For AR surveillance, complete reporting calls for solutions that bypass SR. In the meantime, SR should be taken into account in national AR benchmarking.

Disclosures
All authors: No reported disclosures.
1627. Outbreaks of Klebsiella pneumoniae in Special Care Nurseries (SCN) in Jamaica: Role of Whole-Genome Sequencing
Authors: Aziz Maliha , Nicholson Alison M , Nadimpalli Maya , Sariya Sanjeev , Price Lance , Singh Nalini , Liu Cindy 
Published: October 2019

Abstract

Background
Klebsiella pneumoniae is a frequent cause of neonatal sepsis and carries a high mortality rate in lower and middle-income countries (LMICs). From March-November 2015, two Jamaican hospitals experienced K. pneumoniae outbreaks in their Special Care Nurseries (SCNs). New admissions to both SCNs were temporarily halted while additional infection control strategies were implemented. 31 babies were infected, of which 15 died. International collaboration was requested to help investigate if the sepsis cases were nosocomial transmission, repeated introductions from the community, or both using whole-genome sequencing

Methods
We sequenced DNA from 19 outbreak isolates (n = 13 from Hospital A, n = 6 from Hospital B) on an Illumina HiSeq2500 instrument and assembled short-reads using SPAdes. We used ResFinder v3.1.0 to screen resistance genes and assigned MLSTs using in-house scripts. To compare the outbreak isolates, we selected a reference genome from among the assembled isolates, aligned raw reads using the Burrows–Wheeler Aligner (BWA), identified SNPs using GATK UnifiedGenotyper, and removed the recombined regions using Gubbins v2.3.4. We further contextualized the 19 outbreak isolates against a global collection of more than 300 K. pneumoniae genomes.

Results
All 13 isolates from Hospital A appeared to be from a single source. All were ST45 and encoded blaCTX-M-15, which confers extended-spectrum β-lactam (ESBL) resistance. Five of 6 isolates from Hospital B appeared to be from a separate, single source. These 5 isolates were ST268 and susceptible to most antibiotics. 1 isolate from Hospital B was ST628, encoded blaCTX-M-15, and grouped separately from other Hospital B outbreak isolates. Hospital A and B outbreak isolates formed independent, unique clades within a global K. pneumoniae collection.

Conclusion
Our findings indicate nosocomial transmission was responsible for both neonatal K. pneumoniae outbreaks, rather than repeat introductions from the community. The main sequence types we detected (ST45 and ST268) are not known pandemic clones and may circulate regionally. Multifaceted infection control measures were implemented for effectively halting outbreaks.

Disclosures
All authors: No reported disclosures.
1628. Clinical, Epidemiological and Microbiological Characterization of Invasive Streptococcus pneumoniae Disease in Hospitalized Adults from 5 Tertiary Hospitals in Bogotá, Colombia: A Descriptive Study
Authors: Lucia Leal Castro Aura , Camacho Moreno Germán , Montañez Ayala Anita , Varon Fabio , Alvarez Rodríguez Camilo , Valderrama Sandra , Elena Ariza Beatriz , Pancha Oscar , Yadira Santana Ana , Sánchez Flórez Nella , Reyes Pabón Patricia , Ruiz Jaime , Beltrán Claudia , Emilia Prieto , Rojas Rojas Monica Maria 
Published: October 2019

Abstract

Background
In Colombia, clinical characteristics related to invasive pneumococcal disease (IPD) and circulating pneumococcal serotypes (ST) in adults are scarce. We aimed to describe the clinical and microbiological characteristics of IPD in hospitalized adults ≥18 years old in 5 tertiary hospitals in Colombia from 2011 to 2017.

Methods
A descriptive, observational, retrospective study was conducted in 5 tertiary care hospitals during a 7-year period. Demographic, clinical data and in-hospital outcomes were collected through chart review from all culture-confirmed invasive S. pneumoniae cases in each hospital. The National Health Institute laboratory database was assessed to obtain information about ST (Quellung) and antimicrobial susceptibility (Broth microdilution).

Results
128 cases of IPD were included in this interim analysis, 70(54.7%) were males. The median age was 58 ± 16.7 years. Main underlying conditions were cardiovascular disease (32%), smoking (27.9%), diabetes (20.3%), autoimmune diseases (18.8%), and cancer (18%). The main clinical presentation was bacteremic pneumonia (66.4%), followed by meningitis (14.8%), bacteremia (14.1%) and other (3.1%). Critical care management was required in more than half of the patients: ICU (60.2%), mechanical ventilation (53%) and inotropic support (51.6%). The overall in-hospital mortality rate was 43% and was 39%, 52.6% and 61% for pneumonia, meningitis and bacteremia, respectively. ST was known for 82(64%) cases, most frequent ST were: 3(10.9%), 14(7.3%), 19A(6,1%), 1(4.8%), 4/8/11A/22F (3.65% for each one). ST contained in 13-valent conjugate vaccine (PCV13), 23-valent pneumococcal vaccine (PPVS23) and non-vaccine serotypes accounted for 43.9%, 54.9%, and 40.2% of IPD cases, respectively (Figure 1). 83% and 80.7% strains were susceptible to penicillin and ceftriaxone, respectively.

Conclusion
Pneumonia is the most common clinical presentation of IPD among adults. The clinical outcome was severe with high mortality rate and need of critical care management. ST contained in PCV13 and PPVS23 accounted for 43.9% and 54.9% of IPD cases. This study highlights the importance to strengthen local surveillance and the implementation of pneumococcal immunization programs in high-risk population.

Disclosures
All authors: No reported disclosures.
1629. Herpes Zoster Risk in Immunocompromised Adults in the United States: A Systematic Review
Authors: Dooling Kathleen L , Guo Angela , Pergam Steven A , McKay Susannah 
Published: October 2019

Abstract

Background
The two known primary risk factors for herpes zoster (HZ) are age and immunodeficiency yet estimates of HZ risk by immunocompromising medical condition have not been well characterized. We undertook a systematic review of the literature to estimate HZ risk in six categories of immunocompromised patients.

Methods
We conducted a systematic review of evidence for HZ in patients with hematopoietic cell transplants (HCT), cancer (blood and solid tumor), HIV, and solid-organ transplant (SOT; kidney and other). We identified studies in Pubmed, Embase, Cochrane, Scopus and clinicaltrials.gov using the following outcome search terms: Herpes Zoster, Shingles, VZV, chickenpox, Varicella-zoster virus, or opportunistic infection. We included articles that presented original data from studies in the United States on risk of HZ in adults and were published after 1992 (1996 for HIV). Case reports and conference abstracts were excluded. We assessed risk of bias with Cochrane (clinical trials) or GRADE (observational) methods and categorized studies as high, medium, or low risk.

Results
We identified and screened 3,765 records; 57 articles were abstracted and 34 deemed low or moderate risk of bias (Figure 1). All articles reported at least one estimate of HZ cumulative incidence, which ranged from 0% to 41%. Thirteen studies estimated HZ incidence, which varied widely within and between immunocompromised populations (Figure 2). The highest estimates were seen in HCT (median = 52 HZ cases/1000 patient-years), followed by blood cancers and SOT, and then solid tumor cancers and HIV (median = 13 HZ cases/1,000 patient-years). Among 17 studies of HCT patients, longer follow-up time and absent or <1 year of post-transplant antiviral prophylaxis were associated with higher HZ cumulative incidence (Figure 3).

Conclusion
HZ is common among all immunocompromised populations studied—exceeding expected HZ incidence in immunocompetent middle-age adults. Antiviral prophylaxis among HCT patients has an ameliorating effect but long-term HZ risk following discontinuation is unclear. Better evidence for incidence and severity of HZ in immunocompromised populations is needed to inform economic and HZ vaccine policy analyses.

Disclosures
All authors: No reported disclosures.