bluuebunny/crossref_metadata_2025_split huggingface dataset:
684. Cardiac Safety in Adults with Community-Acquired Bacterial Pneumonia (CABP) Treated with Lefamulin (LEF) or Moxifloxacin (MOX): Analysis of Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 Study Results
Authors: Darpo Borje , Das Anita F , Stein Daniel , Schranz Jennifer , Gelone Steven P 
Published: October 2019

Abstract

Background
Preclinical data suggest potential effects of LEF on cardiac interval parameters. We therefore assessed LEF cardiac safety from the LEAP 1/2 trials.

Methods
In LEAP 1, PORT III–V patients received LEF 150mg IV q12h for 5–7 days or MOX 400mg IV q24h for 7 days, with optional IV-to-oral switch (600mg LEF q12h or 400 mg MOX q24h). In LEAP 2, PORT II–IV patients received oral LEF 600mg q12h for 5 days or oral MOX 400mg q24h for 7 days. Patients with known QT prolongation or on medication with potential to prolong the QT interval were excluded as per MOX label. After 5 minutes of rest in the supine position, triplicate 12-lead ECGs were obtained within a 5-minute interval at Screening in both studies, on Days 1/3 in LEAP 1 (predose and ≤15 minutes after first IV dose), and on Days 1/4 in LEAP 2 (predose and 1–3 hours after first oral dose), and sent to a central ECG reader for adjudication.

Results
Of 1,282 randomized/treated patients (n = 641/group), 1,274 had baseline (BL) and post-BL ECG data (n = 636 LEF, n = 638 MOX). Consistent with the resolution of infection, ECGs revealed mean reductions of 7–8 beats/minute for both groups in both studies. The largest mean change in QTcF from BL to post-BL was on Day 3 in LEAP 1 (13.6 and 16.4 msec with IV LEF and MOX, respectively) and on Day 4 in LEAP 2 (9.3 and 11.6 msec with oral LEF and MOX, respectively). The proportion of patients meeting potentially important post-BL QTcF values/changes was comparable between treatment groups (table). In the standardized MedDRA query of Torsade de pointes/QT prolongation (broad), the most common treatment-emergent adverse event was ECG QT prolonged (n = 4 LEF, n = 5 MOX). All events were nonserious and mild or moderate in severity. 6 events were considered study drug related (n = 4 LEF, n = 2 MOX). 5 events led to study drug discontinuation (n = 2 LEF, n = 3 MOX). In 2 patients with cardiovascular disease, 1 had ventricular arrhythmia on Day 20 (18 days after last LEF dose) and 1 had cardiac arrest on Day 18 (9 days after last MOX dose); both events were fatal and considered unrelated to study drug by investigator.

Conclusion
Mild prolongation of the QTcF interval was seen with LEF and MOX, with somewhat smaller effects seen with LEF. Given the small effect, LEF is unlikely to pose a clinically significant risk of ventricular proarrhythmia with appropriate precautions and use.

Disclosures
All authors: No reported disclosures.
695. Activity of Imipenem–Relebactam and Ceftolozane–Tazobactam Against a Contemporary Collection of Gram-Negative Bacteria from New York City
Authors: Iregui Alejandro , Khan Zeb , Landman David , Quale John M 
Published: October 2019

Abstract

Background
Carbapenem-resistant Gram-negative bacteria are important nosocomial pathogens, and therapeutic options are often limited.

Methods
Clinical isolates were gathered during a surveillance study in 2017 involving 7 hospitals in Brooklyn, NY. Isolates underwent susceptibility testing using the agar dilution method; for the combination of imipenem-relebactam and ceftolozane-tazobactam, the concentrations of relebactam and tazobactam were fixed at 4 µg/mL. Breakpoints were defined according to CLSI criteria; for imipenem-relebactam, the breakpoint of imipenem was utilized. Isolates were screened by PCR for common carbapenemases.

Results
Overall susceptibility patterns are given in the Table. Of 1805 isolates of E. coli (including 4 with blaKPC), 100% were susceptible to imipenem and imipenem-relebactam. Of 503 isolates of K. pneumoniae (including 19 isolates with blaKPC), all were susceptible to imipenem-relebactam. Of 171 isolates of Enterobacter spp. (including 3 with blaKPC), 100% were susceptible to imipenem-relebactam. Of 260 isolates of P. aeruginosa, 96% were susceptible to imipenem-relebactam and nearly all to ceftolozane-tazobactam. Against A. baumannii, the activity of imipenem-relebactam was the same as imipenem and the ceftolozane-tazobactam MIC was ≤ 4 µg/mL in 65% of isolates.

Conclusion
Imipenem-relebactam possesses promising activity against multidrug-resistant Enterobacteriaceae endemic to New York City. Ceftolozane-tazobactam demonstrated excellent activity against P. aeruginosa, including isolates resistant to carbapenems.

Disclosures
All authors: No reported disclosures.
699. Hepatobiliary Safety in Adults With Community-Acquired Bacterial Pneumonia (CABP) Treated With Lefamulin (LEF) or Moxifloxacin (MOX): Pooled Analysis of Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 Study Results
Authors: Lewis James H , Das Anita F , Stein Daniel , Gelone Steven P , Schranz Jennifer 
Published: October 2019

Abstract

Background
LEF efficacy and safety were shown in 2 noninferiority trials (LEAP 1/2) vs. MOX in adults with CABP. We assessed the hepatobiliary safety of LEF based on pooled analyses of LEAP 1/2 data.

Methods
In LEAP 1, PORT III–V patients received LEF 150 mg IV q12h for 5–7 days or MOX 400 mg IV q24h for 7 days, with optional IV-to-oral switch (600 mg LEF q12h or 400 mg MOX q24h). In LEAP 2, PORT II–IV patients received oral LEF 600 mg q12h for 5 days or oral MOX 400mg q24h for 7 days. Exclusion criteria included infection with HBV/HCV, acute hepatitis, cirrhosis, AST or ALT >5xULN, total bilirubin >3xULN (unless Gilbert’s disease), AST or ALT >3xULN and total bilirubin >2xULN, and manifestation of end-stage liver disease. Hepatic safety was assessed from baseline (BL) and multiple post-BL blood samples using a central laboratory, TEAEs, and expert consultant adjudication. Pooled analyses included all randomized/treated patients (safety population).

Results
Of 1282 randomized/treated patients, 1251 had BL and post-BL hepatobiliary data (table). Post-BL distribution of ALT/AST was generally similar for both groups, although ALT >AST in the absence of muscle injury or alcohol use. Overall, rates of patients experiencing an increase in ALT/AST >3xULN, ALP >2xULN, or total bilirubin >1.5xULN were low (table). Patients with elevated vs. normal BL transaminases (TAs) were more likely to have post-BL elevations >3xULN, but the vast majority remained <5xULN. Among patients with ALT >5xULN, peak increases were generally seen in the first week after the first LEF dose and declined to within/near normal levels by late follow-up (day 28); for MOX, time to peak ALT was less consistent (figure). No LEF pt and 1 MOX pt met laboratory criteria for Hy’s Law. Elevations in TAs were reversible, with no evidence of chronic injury. The LEF injury pattern was predominantly hepatocellular (50.0%)/mixed (40.0%), with no apparent gender, age, or ethnic predominance. TEAEs in the hepatobiliary disorders system organ class were reported in 6 (0.9%) LEF patients and 6 (0.9%) MOX patients, with similar levels seen in patients with elevated BL TAs. There were no symptomatic patients, severe disease, or evidence of hypersensitivity.

Conclusion
Low incidences of hepatobiliary parameter elevations and TEAEs were observed, with no apparent differences between LEF and MOX.

Disclosures
All authors: No reported disclosures.
702. Hepatic Safety Among Patients Treated with Anti-Fungal Triazole Agent Posaconazole: Characterization of Adverse events in a Manufacturer’s Safety Database
Authors: Zhou Yun-Ping , O’Flynn Rose , Waskin Hetty , Leong Ronald W , Straus Walter 
Published: October 2019

Abstract

Background
Second-generation triazoles including posaconazole are highly efficacious for the prophylaxis and salvage treatment of life-threatening invasive fungal diseases. All triazoles have been associated with hepatic adverse events (AEs), which may affect their clinical use; however, risk factors for those AEs are poorly defined.

Methods
Reports of hepatobiliary AEs for posaconazole from clinical trials and post-market use in our company’s global safety database were reviewed to characterize concomitant medical conditions and drug exposure.

Results
As of 2018, 444 cases of hepatic AEs were reported; 139 (31%) led to discontinuation of posaconazole. Most hepatic AEs had a time to onset >20 days (55.5%). The most frequent AEs reported (per Medical Dictionary for Regulatory Activities) were: Hyperbilirubinaemia (17%); Hepatotoxicity (13.5%); Hepatic function abnormal (11.5%); and Hepatocellular injury (11.3%). Most patients were adults (18–64 years old) (65%). Hematological malignancy (128 cases, 29%) and hematopoietic stem cell transplant (91 cases, 20%) were leading concurrent medical conditions. Notably, 75% of the cases reported exposure to other drugs (often multiple ones) with known risks for drug-induced liver injury (DILI, e.g., acetaminophen, cytarabine, cyclosporine). Among 139 cases in which posaconazole treatment was discontinued due to hepatic AEs, 6 of the 20 most frequently used co-medications (used by >4.5% of the cases) were classified by the FDA in its DILIRank as “Most-DILI-Concern” (resulting in drug withdrawal, or prominent labeling for severe DILI risk in boxed warning or warnings and precautions), and 7 were “Less-DILI-concern” drugs (DILI risk language in warnings and precautions or adverse reactions). Similarly, of the top 35 concomitant medications for the entire group, 9 are classified as “Most-DILI-Concern” and 12 are “Less-DILI Concern” drugs.

Conclusion
The use of concomitant medications with known risks for hepatic injury appears to be an important contributor to the development of hepatotoxicity in patients treated with posaconazole. Co-administration of these drugs with anti-fungal triazole agents such as posaconazole, when needed, will continue to be carefully monitored.

Disclosures
All authors: No reported disclosures.
717. Lefamulin (LEF) vs. Moxifloxacin (MOX) in Patients With Community-Acquired Bacterial Pneumonia (CABP) at Risk for Poor Efficacy or Safety Outcomes: Pooled Subgroup Analyses From the Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 Phase 3 Noninferiority Clinical Trials
Authors: Schranz Jennifer , Goldberg Lisa , Das Anita F , Alexander Elizabeth , Moran Gregory J , Sandrock Christian , Shorr Andrew F , Gelone Steven P 
Published: October 2019

Abstract

Background
In the United States, CABP is the second most common cause of hospitalization and a leading cause of infectious death. Patients with chronic obstructive pulmonary disease (COPD)/asthma or diabetes are at risk for CABP and associated mortality. Similarly, patients with underlying cardiac or liver disease are at risk for potential cardiac or liver toxicities, respectively, associated with CABP antimicrobials, and patients aged ≥65 years are at risk for both efficacy/safety concerns. We report pooled efficacy/safety outcomes in at-risk subgroups from the LEAP 1 and 2 phase 3 trials.

Methods
In LEAP 1, patients with CABP (PORT III–V) received IV LEF 150 mg q12h for 5–7 days or MOX 400mg q24h for 7 days, with optional IV-to-oral switch (600 mg LEF q12h or 400 mg MOX q24h). In LEAP 2, patients with CABP (PORT II–IV) received oral LEF 600 mg q12h for 5 days or MOX 400 mg q24h for 7 days. Both studies assessed early clinical response (ECR; 96 ± 24 hours after first dose) in the intent-to-treat (ITT; all randomized patients) population (FDA primary endpoint) and investigator assessment of clinical response (IACR) at test-of-cure (TOC; 5–10 days after last dose) in the modified ITT (≥1 study drug dose) and clinically evaluable (met predefined evaluability criteria) populations (EMA coprimary endpoints). Pooled analyses used a 10% noninferiority margin. Safety was assessed in all randomized and treated patients.

Results
1289 ITT patients were randomized to LEF (n = 646) or MOX (n = 643); of whom, 297 (23.0%) were aged 65–74 years and 220 (17.1%) were ≥75 years; 232 patients (18.0%) had COPD/asthma and 168 (13.0%) had diabetes mellitus (DM). At baseline, 501 patients (38.9%) had history of hypertension, 73 (5.7%) had history of arrhythmia, and 263 (20.4%) had transaminitis. The figure shows efficacy by age and in COPD/asthma and DM patients. Treatment-emergent adverse events, electrocardiogram assessments, and laboratory results in patients at risk for cardiac and hepatic safety concerns are shown in Tables 1 and 2.

Conclusion
In pooled analyses of LEAP 1 and 2, LEF efficacy was high and similar to MOX in patients at risk of efficacy concerns and LEF showed a safety profile similar to that of MOX in patients at risk of safety concerns. LEF is a promising new option for IV/oral monotherapy of CABP in patients at risk of poor outcomes due to CABP or to antimicrobial therapy for CABP.

Disclosures
All authors: No reported disclosures.
736. The Use of Bacteriophages to Inhibit Different Strains of Vancomycin-Resistant or Susceptible Enterococci
Authors: El Haddad Lynn , Harb Cynthia P , Stibich Mark , Chemaly Roy F , Chemaly Roy F 
Published: October 2019

Abstract

Background
Vancomycin-resistant Enterococci (VRE) is a well-known infectious complication among immunocompromised patients, especially hematopoietic cell transplant (HCT) recipients. VRE colonization of the gastrointestinal tract could be associated with VRE bacteremia and worse outcomes in HCT recipients. The use of systemic antibiotics to eradicate VRE colonization is highly discouraged because of the lack of efficacy, the rapid onset of antibiotic resistance, and the disruption of the normal microbiota. Bacteriophages (phages) may constitute a good alternative to antibiotics to eliminate specific pathogens without disrupting the patient’s normal microbiota.

Methods
Sewage samples were collected from the City of Houston for phages isolation. Samples were centrifuged, filtered and exposed to several targeted VRE host strains. After several amplification, the final filtrate was titrated and checked for the presence of VRE-specific phages. Isolated phages were observed under electron microscopy and were tested against multiple VRE strains isolated from different sources including patients’ stool samples, patients’ room environment, sewage samples, clinical isolates of daptomycin-resistant VRE strains or vancomycin-susceptible Enterococcus faecium (VSEF) and Enterococcus faecalis (VSEf) strains.

Results
Four VRE-specific phages were isolated from sewage samples (MDA1, MDA2, MDA3, and MDA4). All phages belong to the Caudovirales order. Phage MDA1 belongs to the Podoviridae family, phage MDA2 is a Siphoviridae, whereas MDA3 and MDA4 belong to the Myoviridae family (Figure 1A). All phages were lytic and were able to inhibit at least four VRE strains and only MDA1 had activity against VSEF and MDA4 against VSEf. The efficacy of these lytic phages complemented one another as the combination of these four phages inhibited all different VRE strains (Figure 1B).

Conclusion
Our results highlight the feasibility and the potential success of these phages in inhibiting VRE in vitro. These VRE-specific phage cocktails may be used in future studies to reduce VRE colonization and subsequent infections in HCT recipients.

Disclosures
Roy F. Chemaly, MD, MPH, FACP, FIDSA, Chimerix: Advisory Board, Research Grant; Clinigen: Advisory Board; Merck: Advisory Board, Consultant, Grant/Research Support, Research Grant, Speaker’s Bureau; Oxford immunotec: Consultant, Grant/Research Support; Shire: Research Grant, Speaker’s Bureau; Viracor: Grant/Research Support.
744. Antifungal De-escalation Strategy in ICU Patients: Clinical Success and Cost Savings
Authors: magira Eleni , Kalogianni Athanasia-Aikaterini , Zakynthinos Spyros 
Published: October 2019

Abstract

Background
The incidence of Candida spp infections in critically ill patients is increasing. Initial broad-spectrum empiric antifungal agents (e.g., echinocandins), followed by immediate switching to fluconazole if isolates are fluconazole sensitive could be a low-cost de-escalation strategy. The aim of this study was to evaluate the budget impact of the de-escalation strategy using fungostatin in ICU patients and clinical effectiveness.

Methods
This prospective study was conducted in a 30-bed mixed ICU, from January 2015 through January 2017. Critically ill patients with invasive candidiasis were placed on initial empiric broad-spectrum antifungal agents either on echinocandins or liposomal amphoteric B. De-escalation to fungostatin strategy at day 3 vs. patients without de-escalation were compared. Clinical characteristics and the presence of clinical success by the eighth-day of treatment and 28-day outcome were evaluated. Clinical success was defined as the complete eradication of Candida spp. in blood cultures. Economic outcomes included budget impact was also evaluated.

Results
Forty-seven ICU patients with documented invasive candidemia enrolled and received empiric broad-spectrum antifungal agents with either echinocandins or liposomal amphotericin B. Of those, 22 (47%) were eligible for de-escalation at day 3 to fungostatin based on susceptibility test for fungi. Specific Candida species isolated in the de-escalation group were C. albicans (14, 64%), and non-C. albicans (8, 36%). Interestingly 6/22 (27%) invasive candidemia de-escalated cases relapsed by day 8 of initiation of the empiric therapy, vs. 2/25 (8%) of the control group (P = 0.12). Survival rates at day 28 were not statistically significant among the two groups [15/22 (68%) vs. 11/25 (44%), P = 0.12]. The budget impact of using de-escalation was greater, producing cost savings of €3,200 per patient but did not translate into significant clinical and mycological success.

Conclusion
Critically ill patients who had received empiric antifungal therapy for documented candidemia and underwent de-escalation from echinocandins or liposomal ambisome B to fungostatin had a potential economic cost–benefit but did not associate with significantly improved clinical success rates.

Disclosures
All authors: No reported disclosures.
749. Wide Variation in the Use of External Cooling Blankets Among Adult Intensive Care Unit Nurses for Fever
Authors: Sorge John , Levine Zachary , Szpunar Susan M , Johnson Leonard B 
Published: October 2019

Abstract

Background
There are limited data on whether external cooling blankets (ECBs) are beneficial in the treatment of fever that is not related to malignant hyperthermia (MH). There are no established national guidelines for the use of ECBs for fevers other than for MH. Thus, there may be a wide variation in nursing practice related to their use.

Methods
We performed a cross-sectional survey of adult intensive care unit (ICU) nurses at our hospital, using SurveyMonkeyTM, to evaluate nursing practices related to the use of ECBs in febrile patients other than MH. Data collected from the survey included years of experience as an ICU nurse, type of ICU, when ECBs are used and temperature of initiation and discontinuation. Continuous variables were compared using Student’s t-test and categorical variables were described as frequency distributions. Data were analyzed using SPSS v. 25.0 and a P-value of 0.05 or less was considered to indicate statistical significance.

Results
We invited 150 nurses to participate in the survey, 61 responded (40.7%). The mean number of years worked in an ICU was 8.6 ± 9.4 years (range: 1–34), 14 (23%) worked in a cardiovascular ICU (CVICU), 22 (36%) worked in a medical ICU (MICU), and 25 (41%) in a surgical ICU (SICU). A total of 58 (95.1%) of nurses reported using ECBs for fever, with 50 (82%) of nurses using ECBs only when other methods failed. MICU nurses (31.8%) were more likely to report using ECBs prior to failed attempt of other anti-pyrexia methods than SICU (16%) and CVICU (0.0%) nurses. There was no association between initiation and termination of ECB use by ICU type, years of nursing experience or a given range of temperature values.

Conclusion
There was a wide variation of practice among ICU nurses as it relates to the use of ECBs in patients with fevers. Medical ICU nurses tended to use ECBs before failure of other methods compared with other ICU nurses. Standardized protocols should be developed for their use based on existing medical literature. Further studies should be performed to confirm our findings.

Disclosures
All authors: No reported disclosures.
760. Assessment of DEXA Scan Ordering Among Infectious Disease Providers at a Large Tertiary-Care Urban Academic Center in the Midwest
Authors: Kumar Rebecca Nirmal , Masters Mary Clare , Krueger Karen 
Published: October 2019

Abstract

Background
Osteoporosis is compromised bone strength that predisposes to fracture. It can be diagnosed by Dual-energy x-ray absorptiometry (DEXA) measurement of bone mineral density (BMD). Persons with HIV (PWH) are at higher risk for the development of osteoporosis. As such, the HIV Medicine Association’s (HIVMA) primary care guidelines recommend DEXA screening for all HIV-infected postmenopausal women and men aged ≥50 years. The purpose of this study was to asses the frequency of DEXA utilization within a tertiary-care urban academic center in the Midwest and to identify prevalence of osteoporosis.

Methods
A representative sample PWH age ≥50 from our institution’s outpatient infectious disease (ID) clinic were included. All subjects had at least one clinic visit in the last year, were on antiretroviral therapy (ART), and virally suppressed. Unblinded chart review was performed to assess if DEXA was ordered, was DEXA ordered by an ID physician, was DEXA completed, results of DEXA, and whether patients were on a tenofovir disoproxil fumarate (TDF)-containing regimen.

Results
225 charts were reviewed. 186 (83%) patients were men, with a median age of 58 (range of 50–85). DEXA scans were ordered on 39 (17%) patients, 9 (23%) of which were ordered by their ID provider. Twenty-eight (72%) DEXA scans were performed. Of scans completed, 11 (39%) diagnosed osteoporosis, 15 (54%) osteopenia, and 2 (7%) showed normal BMD. Of all charts reviewed, 29 (13%) were on TDF-containing regimens. Of those individuals with diagnosed abnormal BMD (26), only 1 (4%) was on a TDF-containing regimen.

Conclusion
Despite HIVMA’s recommendation for osteoporosis screening in PWH, only 17% of eligible patients with well-controlled HIV in our clinic had been referred for DEXA. Of those who had undergone DEXA screening, nearly all (93%) had abnormal BMD. Further investigation is necessary to explore provider and patient barriers for osteoporosis screening in PWH.

Disclosures
All authors: No reported disclosures.