bluuebunny/crossref_metadata_2025 huggingface dataset:
1277. Universal Screening Is Key: Identifying Gaps in Adolescent HIV Infection Diagnosis at Local Pediatric Health System When Compared With Regional Adult Hospital
Authors: Most Zachary , James Lorraine , Warraich Gohar , Costello Kathleen , Dietz Stephen , Evans Amanda
Published: November 2018

Background

Undiagnosed sexual partners with HIV infection may contribute to up to 30% of new infections annually. Routine HIV screening of high-risk populations has been shown to be effective and is recommended by the CDC. Despite this recommendation, many adolescents are not screened. The negative impact on the adolescent population from inadequate screening has not been fully quantified.

Methods

Through a retrospective chart review, the course prior to diagnosis of HIV-infected adolescents diagnosed at Children’s Medical Center Dallas (CMC) and Parkland Hospital (PH, the proximate adult county hospital with a universal HIV screening program) was reviewed. Subjects were included if they had a confirmed, positive HIV test between 13 and 21 years of age, and excluded if they had a previous HIV diagnosis. Inpatient, outpatient, and ED encounters at CMC and PH following the subjects’ 13th birthday and before their HIV diagnosis were quantified. Missed opportunity encounters (MOE) were defined as above encounters where there was no HIV screen performed that took place after the date 3 months following their most recent HIV screen. Data were collated by facility and compared.

Results

204 subjects met inclusion criteria: 140 (69%) male, 155 (76%) black, and 87 (43%) followed by CMC. There were 412 total encounters (2.02 per subject) out of which 284 (1.39 per subject) qualified as MOE. Seventy-two subjects had at least one MOE. At the CMC ED, there were 6.7 MOE for every new HIV adolescent diagnosis, compared with PH ED where there were 0.9 (P < 0.01) (Figure 1). Adolescents identified through the PH ED were older (PH, 18.8 years vs. CMC, 16.1 years, P < 0.01) (Figure 2), and had a trend toward a lower CD4 count (PH, 337 cells/m3 vs. CMC, 449 cells/m3, ns). Three adolescents were identified with AIDS (CD4 <200) through HIV screening at PH, vs. 1 at the CMC ED.

Conclusion

Missed opportunity encounters for HIV screening of adolescents are greater in number in pediatric emergency departments without universal screening programs, when compared with similar adult settings with such a program. Implementing a universal HIV screening protocol at pediatric EDs in HIV endemic areas may help to identify HIV-positive adolescents at younger ages and improve long-term outcomes.

Disclosures

All authors: No reported disclosures.
1279. Prevalence of HIV Among the Youth Aged 15–24 in Nigeria: A Need to Increase Access for Young Adolescents to HIV Counseling and Testing
Authors: Ezenekwe Ezinne , Uduak Nevis Essien , Nnamani Catherine
Published: November 2018

Background

Nigeria with a population of over 173 million people, HIV/AIDS remains a growing public health issue. The people living with the virus are about 3.2 million and it is observed that there is an increase of new infection among the adolescents and young people. We decided to study the prevalence of HIV among young people aged 15–24 in the country. The country was divided into six regions for the purpose of this study.

Methods

We adapted the secondary data that were collected from the report of the National HIV/AIDS and reproductive survey (NARSH 2012) on Prevalence of HIV/AIDS on adolescents and young people in Nigeria in 2012. Data collection on the survey were from the primary source documents in health facilities that offer HIV/AIDS services

Results

Among the six geopolitical zones, South–South zone has the highest (4.9%) prevalence rate of HIV infection among the adolescents and young people, more than the National median prevalence of 3.6%, while south -East has the lowest prevalence of (1.1%). Results showed that adolescent and young people, aged 20–24 had higher prevalence of 3.2% while ages 15–19 had prevalence of 2.9%. Results from the segregated data by sex showed that between the ages (15–24), the prevalence is higher (3.3%) with female gender than the male (2.4%) counterpart. HIV/AIDS in Africa and Nigeria in particular has a feminine face due to culture of silence, early child marriage and religious barriers that forbids female gender to discuss issues around sexuality or seek reproductive health services at age 15.

Conclusion

The age limit for access to HIV counseling and testing (HCT) should be adjusted to include young people who are sexually active as early as age 15. Findings revealed that the legal framework on access to HCT (HIV Counselling and Testing), of WHO at 18 years and above have created a barrier to young people who are below 18 and are active sexually to access HCT as the Health personnel would ask for the parental consent.

Disclosures

All authors: No reported disclosures.
1281. Emergence of a B/F1 HIV Recombinant in the Philippines: A Potentially New Circulating Recombinant Form
Authors: Schwem Brian , Dungca Nina , Arevalo Geraldine , Francisco Christian , Penalosa Christine , Leyritana Katerina , Destura Raul , Lim Jodor , Tactacan-Abrenica Rosario , Telan Elizabeth , Solante Rongene , Salvana Edsel Maurice
Published: November 2018

Background

The Philippines has one of the fastest growing HIV epidemics globally. This was accompanied by a switch from subtype B to CRF01_AE. With a large population of returning overseas workers, new subtypes are being introduced regularly. Because diagnosis of HIV in the Philippines is usually late, superinfections can occur and may give rise to new circulating recombinant forms (CRFs). We propose a new CRF from the Philippines.

Methods

Following institutional board approval, treatment-naive patients from two HIV treatment hubs (San Lazaro Hospital and the Philippine General Hospital) were recruited. Blood samples underwent Sanger sequencing of the PR and RT regions and next-generation sequencing (NGS) of near-full length genomes. Sequences were analyzed for recombination using the online tool jumping profile Hidden Markov Model (http://jphmm.gobics.de/).

Results

247 samples underwent Sanger sequencing of the PR and RT regions of the pol gene. Phylogenetic analysis indicated a clustering of four of the samples. Further analysis showed all four samples had the same breakpoints at nucleotides 2875, 2996, and 3001 (HXB2 numbering). All four patients were male, MSM, with a mean age of 28 years old (24–32), and >10 sexual partners. Mean CD4 count was 464 cells/µL and median viral load was 2.67 × 104 copies/mL. Two patients had sex with foreigners. To get a better overall view of subtype composition, we performed NGS using Illumina HiSeq. NGS showed the majority of the genome to be subtype F1 with segments of subtype B inserted in the pol, vpu, and env genes. A blast analysis of the consensus sequence showed 8,932 out of 8,943 nucleotides (99%) matched a 1999 sample from Argentina. Phylogenetic analysis of these samples show clustering of the four B/F1 recombinants with some South American sequences. No drug resistance mutations were identified.

Conclusion

Mutation and recombination contribute to the extensive genetic diversity of HIV. Understanding this is important in choosing treatment regimens, developing future vaccines, and pursuing epidemiological investigations. The emergence of a new CRF in the Philippines underlies the importance of conducting routine surveillance for new HIV recombinant forms.

Disclosures

All authors: No reported disclosures.
1299. Iowa TelePrEP: Preliminary Experience with a Public Health-Partnered, Telemedical PrEP Delivery Model in a Rural State
Authors: Hoth Angela , Shafer Cody , Dillon Dena , Scheetz Constanza , Owens Seth , Edel Kathryn , Ohl Michael
Published: November 2018

Background

Access to HIV pre-exposure prophylaxis (PrEP) is often poor in small urban and rural areas due to long distances to PrEP providers and stigma. In 2017, the Iowa Department of Public Health (IDPH), University of Iowa (UI), and community representatives collaborated to develop a public health-partnered telemedical PrEP delivery model to overcome these barriers (TelePrEP). IDPH personnel working in five sexually transmitted infection (STI) clinics and partner services (PS) programs in Eastern Iowa screened clients for PrEP indications and referred those with need to TelePrEP pharmacist providers at UI. Via collaborative practice, pharmacists completed initial and follow-up PrEP home video visits with clients on smart phones and laptops. Clients obtained laboratory monitoring and STI screening in public health-affiliated and local laboratories in accordance with USPHS/CDC guidelines, and received PrEP medication by mail. PS personnel linked TelePrEP clients with newly-identified STIs to local treatment.

Methods

Using the PrEP continuum as framework, we used IDPH databases and UI medical records to conduct a retrospective process evaluation of the TelePrEP model (February 2017–April 2018).

Results

TelePrEP received 44 referrals from public health and 59 self-referrals via advertising. Pharmacists completed 84 initial visits (81% of referrals), including 37 visits (84%) with clients referred by public health. Most (94%) started emtricitabine/tenofovir after initial visits. Retention in TelePrEP at 6 months was 87%. 96% of guideline-indicated laboratory tests (HIV, creatinine, STI, hepatitis) were completed at baseline and follow-up. Rates of extragenital chlamydia and gonorrhea screening were lower (74 of 104 completed screens) due to variable availability of swabs at local laboratories. 15 clients were diagnosed with 20 STIs on screening (6 syphilis, four gonorrhea, 10 chlamydia) and one unrecognized pregnancy was identified. PS linked all clients with STIs on screens to treatment within 14 days (80% in 3 days).

Conclusion

Using telemedicine, healthcare systems can partner with public health administered STI clinics and PS programs to create virtual PrEP delivery models in rural settings. Public health partnerships enhance client identification and ensure linkage to care for new STI diagnoses in telemedicine programs.

Disclosures

A. Hoth, Gilead Sciences, Inc.: Research team member, Research support. M. Ohl, Gilead Sciences, Inc.: Grant Investigator, Research grant.
1303. Provider Knowledge and Attitudes Toward Antibiotic Prescribing and Antibiotic Stewardship in Outpatient Rural Clinics
Authors: Kufel Wesley , Mogle Bryan , Williams Karen , Jester James , Snyder John , Mastro Keri , Lubowski Theresa , Bohan KarenBeth
Published: November 2018

Background

Rural outpatient clinics serve the healthcare needs of many individuals, especially for acute sick visits and infectious processes. A better understanding of providers’ knowledge and attitudes toward antibiotic stewardship in the outpatient rural setting is needed to facilitate more effective education regarding appropriate antibiotic prescribing.

Methods

A cross-sectional, multi-center, 28-item survey assessing providers’ knowledge and attitudes toward antibiotic prescribing and antibiotic stewardship in the rural setting was distributed to providers from Guthrie and United Health Services primary care clinics in rural New York and Pennsylvania.

Results

Sixty-five providers participated (31% response rate) with 43%, 29%, and 28% of responses from physicians, resident physicians, and advanced practice providers, respectively. More than half of respondents practiced for ≤5 years since terminal training. The most significant barrier to improving antibiotic prescribing was patient demands (55%) followed by uncertain diagnosis of bacterial infection (22%) and short appointment visit times (11%). Providers that spent ≤20 minutes per visit were more likely to feel pressured to prescribe antibiotics for upper respiratory tract infections (URI) to ensure patient satisfaction than those who spent >20 minutes (41% vs. 7%, P = 0.024). Additionally, providers who saw >50 patients per week were more likely to feel pressured to prescribe antibiotics for URIs than those who saw ≤50 patients (50% vs. 18%, P = 0.009). Only 42% of providers selected the correct answer that 90–98% of URIs are viral. The majority of providers strongly agreed that antibiotics are overused (71%) and inappropriate antibiotic use can lead to resistance (82%). Thirty-eight percent of providers never heard the term antibiotic stewardship or heard the term but were unsure about the definition. However, more than 75% of providers strongly agreed or agreed that they were interested in receiving more education regarding antibiotic stewardship.

Conclusion

Variability exists among providers’ knowledge and attitudes toward antibiotic stewardship and antibiotic prescribing in rural outpatient settings. Increased educational efforts are warranted to increase consistency of these concepts and practices.

Disclosures

All authors: No reported disclosures.
1309. The Impact of Clinical Practice Guideline Using Educational Intervention for Improvement of Diabetic Foot Infections Treatment Outcomes
Authors: Phangmuangdee Mullika , Navanukroh Oranich , Koomanachai Pornpan
Published: November 2018

Background

Diabetic foot infections (DFIs) are important cause of lower-extremity amputation. The inappropriate empirical antimicrobial therapy for DFI was associated with amputation. We created the Clinical Practice Guideline (CPG) of empirical antimicrobial (ATB) therapy for in-patients with DFIs. The primary outcome of present study was to evaluate the intervention using educate and training the surgeons to adhere with CPG. The secondary outcome was the decreasing of unfavorable outcome (amputations).

Methods

A prospective study of CPG implementation for treatment in adult in-patients who had DFIs was conducted at surgical and orthopedics wards. The CPG was developed by the investigator team based on the data from our previous study (submitted to publish). CPG was presented monthly to train the orthopedic and vascular surgeons for 1 year. The empirical ATB regimens were prescribed by the responsible surgeon who was trained to use CPG. Demographics data, wound characteristics, microbiological data, ATB therapy, and clinical outcome were recorded. The appropriate empirical ATB treatment was determined by investigators weather CPG matched or microbiological matched. The adherence to CPG, the appropriate empirical ATB, and the unfavorable outcome were analyzed. All data were reported by descriptive and inferential statistics.

Results

A total of 85 DFIs patients were enrolled. The patients received the appropriate empirical ATB matched to CPG and matched to microbiological data, were 87% and 67%, respectively. The unfavorable outcome was 26% while previously was 72.4% (submitted to publish data) before CPG implementation. The independent factors associated with unfavorable outcomes were (1) an inappropriate ATB and (2) infections with drug-resistant pathogens (adjusted relative ratio; aRR 2.98; 95% CI: 1.36–6.55, P = 0.007 and aRR 1.90; 95% CI: 1.05–3.43, P = 0.034, respectively).

Conclusion

The current study demonstrated that mothly training of CPG resulting in the high adherence (87%) of CPG use and resulting in high rate of appropriate empirical ATB. Educational intervention insisted the responsible physician for administration the appropriate ATB with the improvement of unfavorable outcome in DFIs.

Disclosures

All authors: No reported disclosures.
1312. Division Divided: Using Debate as an Educational Tool to Teach Evidence-Based Clinical Decision-Making
Authors: Spicer Jennifer O , Phadke Varun K
Published: November 2018

Background

In medical education, there has been a push to implement innovative teaching techniques that encourage critical thinking rather than just knowledge dissemination. Debate promotes critical thinking by challenging individuals to consider alternate viewpoints, which could make it an ideal format to review the evidence relevant to common clinical dilemmas in infectious diseases (ID). We describe a pilot of one such debate format in our ID fellowship program.

Methods

We reviewed literature regarding the effectiveness of ceftriaxone for outpatient antibiotic therapy (OPAT) in methicillin-susceptible Staphylococcus aureus (MSSA) osteoarticular infections. The evidence was presented as a structured debate in place of our weekly case conference. Pre- and post-session surveys containing multiple choice questions and Likert items were administered to assess the impact of the debate on attendees’ knowledge, attitudes, and practices on this topic along with their attitudes toward the debate format. Differences between pre- and post-session surveys were analyzed using paired t-tests and McNemar’s test.

Results

At the first debate 33 residents, fellows, and faculty members were present, and 24 (73%) completed both the pre- and post-session surveys. Attendees demonstrated significant improvement between the pre- and post-session knowledge questions, which covered the following topics: study design of articles supporting ceftriaxone use (31% vs. 62%, P = 0.008), appropriate method to assess ceftriaxone susceptibility (64% vs. 100%, P = 0.004), and whether the inoculum effect applies to ceftriaxone (35% vs. 77%, P = 0.003). After the debate, attendees were more willing to use ceftriaxone (P = 0.001) and felt more familiar with the literature (P < 0.001). The post-session survey showed that individuals both enjoyed the format and found it effective (Figure 1). Most individuals stated that they were either extremely likely (85%) or likely (8%) to attend if this format was used again. Written comments included “strongly recommend continuing this format” and “much better than regular case conference with more discussion and critical thinking.”

Conclusion

Debate appears to be an effective and enjoyable format to teach clinical controversies in ID.

Disclosures

All authors: No reported disclosures.
1318. Are We PrEPared? Awareness and Prescribing Patterns of HIV Pre-Exposure Prophylaxis (PrEP) by Internal Medicine Resident Physicians at an Academic Medical Center
Authors: Hornak J Patrik
Published: November 2018

Background

HIV PrEP uptake remains low by primary care physicians, amongst whom increased awareness has been positively associated with its adoption. Prior studies have also revealed deficits in knowledge and comfort providing PrEP amongst internal medicine (IM) trainees. This is among the first reports of assessing PrEP uptake by IM residents; this appears to be the first examining pre- and post-instruction assessment of prescribing attitudes following a single lecture on the topic.

Methods

An anonymous, online survey was distributed to all IM residents at our institution to measure baseline PrEP awareness and prescribing patterns. A comprehensive PrEP lecture was formulated with assistance from infectious diseases (ID) faculty; focus was paid to addressing concerns about cost, safety, risk behavior compensation, and drug resistance. The lecture was made available electronically to those unable to attend the live session. PrEP knowledge and prescribing attitudes were measured and compared pre- and post-lecture. Fisher’s exact test was used for descriptive statistics.

Results

Of 97 initial surveys distributed, 41 were completed. A majority of respondents were aware of PrEP (68%). A modest number had either prescribed PrEP or referred a prospective patient to an ID specialist in the prior year (15%). The majority preferred to learn about PrEP with a dedicated didactic session (76%). Compared with baseline data, following the lecture, residents were better able to identify both the number of daily pills required (100% vs. 49%, P = 0.007) and the proper medication regimen (100% vs. 49%, P = 0.007); there was no significant difference in self-reported comfort with providing PrEP (89 vs. 65%, P = 0.25). In the post-lecture survey, nearly half reported a preference to refer a PrEP candidate to an ID specialist or PrEP clinic (43%).

Conclusion

These findings suggest value in providing PrEP education to IM trainees, but indicate that a single lecture may not be effective for ultimately improving its adoption by this important group of physicians. Determining the optimal method for incorporating PrEP into residency curricula deserves further study. Despite efforts to expand PrEP into the realm of primary care, many of these physicians may continue to defer management of these patients to ID/HIV clinicians.

Disclosures

All authors: No reported disclosures.
1321. The UNZA/UMB MMed ID Collaboration: Training and Retaining HIV Specialist Physicians in Zambia
Authors: Hachaambwa Lottie , Claassen Cassidy , Mulenga Lloyd , Lambwe Nason , Sikazwe Izukanji , Watson Douglas , Patel Devang , Bositis Christopher , Sheneberger Robert
Published: November 2018

Background

To mitigate the HIV pandemic and increasing outbreaks of infectious diseases, sub-Saharan African countries need increased healthcare worker capacity at all levels. We describe a successful collaboration between the Ministry of Health (MOH), the University Teaching Hospital (UTH), the University of Zambia (UNZA), and the University of Maryland Baltimore (UMB) to train Zambian physicians in advanced HIV medicine and infectious diseases.

Methods

Recognizing the need for advanced HIV clinical care expertise in Zambia, UNZA, UTH and UMB partnered in 2008 to create a 1-year Postgraduate Diploma in HIV Medicine. The consortium extended this to an 18-month Master of Science in HIV Medicine to better align with existing professional advancement schema. In 2012, UNZA and UMB started a 4-year Master of Medicine in infectious diseases (MMedID), which was then expanded to a 5-year training program combining internal medicine and infectious disease (MMed IM/ID) in order to produce a cadre with wider expertise in internal medicine and infectious diseases. Instruction consists of bedside teaching, didactic lectures, case conferences, and journal clubs. The bulk of teaching came from UMB clinical faculty with expertise in HIV and ID; faculty are either based in Zambia or visit from the United States.

Results

The MSc HIV program trained 27 physicians; of these, 24 (89%) are in health leadership positions in Zambia, with 17 (63%) directly involved in clinical care (mostly in the public sector), while 7 (15%) work for international implementing partners in Zambia. 1 physician emigrated to another African country, another one died and the third is in clinical nonleadership position in Zambia. The MMed ID program has enrolled 14 physicians. The first two graduates of the program completed the program in 2017 and took health leadership roles within the MOH as well as teaching positions at UNZA.

Conclusion

Educational collaborations embedded within local institutions and structures can provide advanced healthcare expertise within resource-limited settings. The UNZA/UMB MMed IM/ID collaboration is a model example of a successful university partnership that has resulted in retaining health leadership and clinical care expertise in Zambia.

Disclosures

L. Hachaambwa, Centers for Disease Control and Prevention (CDC): Cooperative Agreement to Institution, Financial support for the work described in this abstract was made possible by a cooperative agreement award from the Centers for Disease Control and Prevention (CDC) to the University of Zambia and to the University of Maryland School of Medicine.
1327. Educational Intervention to Improve Communication With Patients Who Have Opioid Use Disorder
Authors: Kershaw Colleen , Stead Wendy , Rowley Christopher F
Published: November 2018

Background

Infectious complications of opioid use disorder (OUD) have increased significantly in the last decade. Patients with OUD encounter stigma from healthcare providers, and providers find interactions with patients with OUD to be very challenging. At our teaching institution, anecdotal experience and objective data suggested clinician discomfort with communicating with OUD patients, as well as a “hidden curriculum” of stigma and bias around care of this group. We attempted to characterize this problematic learning environment and created an intervention focusing on reduction of bias and stigma and improved communication with OUD patients.

Methods

General internal medicine faculty and residents completed a preintervention survey to measure knowledge and attitudes about OUD, as well the institutional learning environment related to this issue. A workshop on communication, bias, and stigma in OUD was then administered to 78 faculty and residents. Immediately after participation, they completed a postintervention survey assessing concepts addressed in the session.

Results

The preintervention survey of 99 faculty and residents showed that 47% felt patients with OUD were difficult to work with. Faculty were more likely than residents to agree there was a negative hidden curriculum around OUD (70% vs. 43%, P < 0.001). This included witnessing other physicians using stigmatizing language (80%), minimizing time with OUD patients (49%), and choosing not to involve medical students with OUD patients (34%). Fifty participants completed the postsurvey. Respondents identified a mean of 86% of stigmatizing words within patient scenarios, which improved from 60% before the intervention (P < 0.0001).

Conclusion

Clinicians reported negative attitudes and difficulty caring for patients with OUD. The majority identified a negative hidden curriculum around this disease, including stigmatizing language and avoidance of engagement with OUD patients. A workshop on communication, stigma, and bias improved scores on knowledge of stigmatizing language.

Disclosures

All authors: No reported disclosures.
1335. Safety and Pharmacokinetic Profile of PC786, a Novel Inhibitor of Respiratory Syncytial Virus L-protein Polymerase, in a Single and Multiple-Ascending Dose Study in Healthy Volunteer and Mild Asthmatics
Authors: Cass Lindsey , Davis Amanda , Murray Alison , Woodward Kathy , Ito Kazuhiro , Strong Pete , Rapeport Garth
Published: November 2018

Background

RSV is the most common cause of bronchiolitis in infants and is responsible for severe respiratory infections in the elderly and immunocompromised populations. RSV replicates in the columnar epithelial cells of the proximal and distal airways which are accessible to inhaled therapies. PC786 is a potent non-nucleoside RSV L-protein polymerase inhibitor designed for inhaled delivery. In preclinical studies, PC786 exhibits prolonged lung tissue residence with minimal systemic exposure, thus limiting the potential for adverse systemic effects.

Methods

A phase 1 study was conducted to evaluate the safety and pharmacokinetics of PC786 delivered in a suspension formulation by nebulizer (PARI LC SPRINT® device). Healthy volunteers (HVs) received placebo or PC786 as single ascending doses (0.5–20 mg, Cohort (C) 1), 5 mg BD for 7 days (C2), or 10 mg BD for 7 days (C3). Mild asthmatics received a single dose of PC786 5 mg or placebo (C4). PC786 PK was measured in plasma and in nasal mucosal lining fluid (MLF) collected using a synthetic absorptive matrix.

Results

PC786 was well tolerated, with no significant adverse clinical nor laboratory findings. Following single inhaled doses PC786 appeared rapidly in the plasma; mean plasma Cmax of 190, 571, 1,760, and 3,270 pg/mL, for the 0.5, 2, 8, and 20 mg doses, respectively, were measured on average at 0.68 to 0.93 hours (Tmax) post-inhalation. Following administration of 5 mg BD (C2) the extent of accumulation was approximately 2-fold. The geometric mean apparent terminal half-life measured following 10 mg BD (C3) was 97 hours. The ratio of MLF:plasma concentrations ranged from 6,347 (+2 hours) to 1,050 (+24h).

Conclusion

PC786 was well tolerated by HVs and asthmatics. The compound showed a rapid Tmax, suggesting rapid exposure of the respiratory epithelium. The PC786 concentrations in MLF exceed the IC90 for RSV, but circulating plasma concentrations were low. The MLF:plasma measured in this study was consistent with lung:plasma ratios measured in preclinical studies. The long plasma half-life is consistent with slow absorption from the lung being the dominant process controlling systemic kinetic behavior. The long t½ and 2-fold accumulation ratio observed on repeat dosing supports once daily dosing in subsequent studies.

Disclosures

L. Cass, Pulmocide Ltd.: Employee and Shareholder, Salary. A. Davis, Pulmocide Ltd.: Employee and Shareholder, Salary. A. Murray, Pulmocide Ltd.: Employee and Shareholder, Salary. K. Woodward, Pulmocide Ltd.: Consultant, Consulting fee. K. Ito, Pulmocide Ltd.: Employee and Shareholder, Salary. P. Strong, Pulmocide Ltd.: Board Member, Employee and Shareholder, Salary. G. Rapeport, Pulmocide Ltd.: Board Member, Employee and Shareholder, Salary.
1336. Assessment of the In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) Against Carbapenems-Resistant Acinetobacter baumannii (CR-ACBN) in the Neutropenic Murine Thigh Infection Model
Authors: Abuhussain Safa Almarzoky , Avery Lindsay , Abdelraouf Kamilia , Nicolau David P
Published: November 2018

Background

Zidebactam (ZID) is a novel β-lactam enhancer with high binding affinity to PBP2 and intrinsic activity against many Gram-negative pathogens, with the exception of ACBN. ZID also inhibits β-lactamases but not OXA carbapenemases associated with ACBN or metallo-β-lactamases. However, WCK 5222 (a combination of cefepime [FEP] and ZID) has shown in vitro activity against ACBN, including OXA producers. Moreover, we have previously shown that WCK 5222 human-simulated regimen (HSR) causes extensive (i.e., >2 log) eradication of ACBN from neutropenic mice lung. This study aimed to evaluate the in vivo efficacy of the HSR of WCK 5222 compared with FEP HSR or ZID HSR alone against ACBN in the neutropenic murine thigh infection model.

Methods

Six CR-ACBN clinical isolates, including five isolates expressing OXA-23 or OXA-24, were studied. FEP and WCK 5222 MICs were 128 to >512 and 16 to 64 mg/L, respectively. The ZID MIC was >512 mg/L for all isolates. ICR mice were rendered transiently neutropenic via cyclophosphamide prior to thigh inoculation with bacterial suspensions of 107 CFU/mL. Treatment mice received either FEP HSR (equivalent to a clinical dose of 2 g IV q8h as a 1 hour infusion), ZID HSR (equivalent to a clinical dose of 1 g IV q8h as 1 hour infusion), or WCK 5222 HSR (FEP HSR + ZID HSR). Control mice were vehicle-dosed. Changes in log10 CFU/mL at 24 hours compared with 0 hours controls were measured to assess efficacy.

Results

The average log10 CFU/thigh at 0 hours across all isolates was 5.85 ± 0.22. Compared with 0 hours control, the mean bacterial growth at 24 hours in the untreated control mice, FEP HSR, and ZID HSR were 2.34 ± 0.93, 1.36 ± 1.40, and 2.04 ± 0.80 log10CFU/thigh, respectively. The WCK 5222 HSR produced a decline in bacterial burden for all isolates [mean reduction of −2.09 ± 1.01 log10CFU/thigh]; 4/6 isolates achieved ≥ 2-log reduction while ≥1-log reduction was attained with the remaining two isolates.

Conclusion

HSR of WCK 5222 showed potent in vivo activity against CR-ACBN expressing OXA carbapenemases in the murine thigh model which is attributed to the β-lactam enhancing effect of ZID, driven by the complementary PBP binding of FEP and ZID. These results support the clinical evaluation of WCK 5222 for the management of infections due to CR-ACBN.

Disclosures

D. P. Nicolau, Wockhardt: Investigator, Research support.
1342. Comparison of Lysin CF-301 (Exebacase) Activity Against S. aureus Isolates From Bacteremic Patients Enrolled in a Phase 2 Study (CF-301-102) to Contemporary Surveillance Isolates
Authors: Anastasiou Diane , Jandourek Alena , Traczewski Maria , Cassino Cara , Schuch Raymond
Published: November 2018

Background

CF-301 (exebacase) is a novel, recombinantly produced, bacteriophage-derived lysin (cell wall hydrolase) which is the first lysin to enter Phase 2 (Ph2) in the United States and is being studied for the treatment of S. aureus bacteremia including endocarditis. We examined the activity of CF-301 against methicillin-sensitive and methicillin-resistant S. aureus (MSSA and MRSA) isolates from participants in the ongoing, CF-301 “first in-patient’ Ph2 study (NCT03163446) in comparison to activity reported in a recent surveillance study.

Methods

Patients with complicated bacteremia or endocarditis caused by S. aureus were enrolled into Study CF-301-102 at study centers in the United States and Guatemala between 2017 and 2018. Baseline isolates from blood cultures were collected prior to administration of CF-301. The activity of CF-301 activity against the first 36 isolates of MRSA (14) and MSSA (22) was determined at a central laboratory. Surveillance data for CF-301 were generated against 300 isolates of MRSA (150) and MSSA (150) collected between 2016 and 2017 from patients with various infection types at US centers. CF-301 MICs were determined using the modified broth microdilution method approved by the CLSI for CF-301.

Results

In vitro activity of CF-301 against S. aureus isolates from Ph2 Study CF-301-102 and surveillance

Conclusion

The activity of CF-301 against baseline S. aureus isolates from blood cultures obtained from bacteremic patients enrolled in the Ph2 study was similar to that observed in the surveillance study. Based on data from previously presented exposure target attainment animal studies, PK/PD modeling and preliminary non-clinical breakpoint assessments, we expect that strains with MIC values of ≤1 µg/mL will be susceptible to the clinical CF-301 dose (0.25mg/kg) under study in Ph2.

Disclosures

D. Anastasiou, ContraFect Corporation: Consultant, Consulting fee. A. Jandourek, ContraFect Corporation: Employee, Salary. C. Cassino, ContraFect Corporation: Employee, Salary. R. Schuch, ContraFect Corporation: Employee, Salary.
1343. Prophylactic Dosing of Baloxavir Acid Eliminates Mortality in Mice Lethal Influenza A Virus Infection Model
Authors: Shano Shinya , Fukao Keita , Noshi Takeshi , Sato Kenji , Sakuramoto Masashi , Baba Kaoru , Shishido Takao , Naito Akira
Published: November 2018

Background

Baloxavir acid (BXA), an active form of orally available prodrug baloxavir marboxil (BXM, formerly S-033188), is a novel small molecule inhibitor of cap-dependent endonuclease (CEN) of influenza A and B virus, and was recently launched for the treatment of acute and uncomplicated influenza with single dosing of BXM (the trade name XOFLUZA™) in Japan in March 2018. Here, we evaluated the prophylactic efficacy of BXA in mice lethally infected with influenza A virus.

Methods

T1/2 of BXA in human is more than 10 times longer than that in mice. Therefore, suspension of BXA was subcutaneously administered at 0.8 or 1.6 mg/kg in mice to maintain the plasma concentration of BXA as seen in humans, and then mice were intranasally inoculated with a lethal dose of A/PR/8/34 strain at 48, 72, or 96 hours after the administration of BXA. Survival time and body weight change were then monitored through a 28-day period after virus infection. Mice were euthanized and regarded as dead if their body weights were lower than 70% of the initial body weights according to humane endpoints.

Results

Single dosing of BXA (1.6 mg/kg) completely eliminated mortality in mice, when the mice were administrated the drug at 48, 72, or 96 hours before virus infection (Figure 1). BXA treatment also significantly prevented body weight loss, consistent with the prolonged survival.

Conclusion

Prophylactic dosing of BXA exhibited significant protective efficacy against mortality and body weight loss in mice following a lethal infection with influenza A virus. The significant prophylactic efficacy observed in our mouse model suggests the potential utility of BXM for the prophylaxis of influenza in human.

Disclosures

S. Shano, Shionogi & Co., Ltd.: Employee, Salary. K. Fukao, Shionogi & Co., Ltd.: Employee, Salary. T. Noshi, Shionogi & Co., Ltd.: Employee, Salary. K. Sato, Shionogi & Co., Ltd.: Employee, Salary. M. Sakuramoto, Shionogi & Co., Ltd.: Employee, Salary. K. Baba, Shionogi TechnoAdvance Research & Co., Ltd.: Employee, Salary. T. Shishido, Shionogi & Co., Ltd.: Employee, Salary. A. Naito, Shionogi & Co., Ltd.: Employee, Salary.
1344. Ridinilazole (RDZ) for Clostridium difficile Infection (CDI): Impact of Diagnostic Method on Outcomes From a Phase 2 Clinical Trial
Authors: Vickers Richard , Chowdhury Sumita , Wilcox Mark
Published: November 2018

Background

Diagnosis of CDI includes fecal detection of a C. difficile toxigenic strain (TS) or free toxins (FT). TS detection does not distinguish infection from colonization. Guidelines recommend an FT test be part of diagnostic algorithms. Here we report outcome differences, based on diagnostic method at enrollment, from a Phase 2 clinical trial of RDZ, a novel CDI antibiotic designed to treat CDI and reduce recurrence of CDI (rCDI).

Methods

This double-blind study randomized 100 patients 1:1 to 10 days RDZ 200 mg BID or vancomycin (VAN) 125 mg QID treatment. Subjects were enrolled with CDI symptoms and a positive diagnostic result (FT or TS). Baseline (BL) stool samples were assessed for the presence of FT. All subjects entered the intent to treat (ITT) population; those subjects positive for FT entered a modified ITT (mITT), the primary analysis population. Primary endpoint was sustained clinical response (SCR) defined as cure at end of therapy and no rCDI for the next 30 days. rCDI was defined as CDI symptoms, a positive diagnostic test and need for therapy; a sensitivity analysis considered positive FT rCDI cases. BL fecal concentrations of lactoferrin and calprotectin were determined by enzyme immunoassay.

Results

Of 100 subjects enrolled, 69 (36 RDZ: 33 VAN) were FT positive at BL. RDZ compared with VAN recipients had improved SCR rates via reduced rCDI. Absolute differences in SCR between RDZ and VAN (prespecified 90% CI) for MITT (FT positive) and ITT subjects were 24.3% (3.1, 39.1) and 14.0% (−1.8, 28.8), respectively. Absolute SCR differences between the MITT and ITT subjects from the sensitivity analysis were 26.2% (4.6, 40.6) and 14.3% (−1.7, 29.1). Median BL calprotectin and lactoferrin levels (µg/mL) were significantly higher for FT positive subjects at 1,002 and 87, than for FT negative subjects at 53 and 4, respectively.

Conclusion

RDZ showed improved SCR in comparison with VAN. Treatment differences were greater in MITT subjects. Lower SCR improvement in RDZ ITT subjects is likely due to enrollment of some colonized rather than infected subjects; this explanation is supported by higher calprotectin and lactoferrin levels in FT-positive samples. These data demonstrate the importance of FT testing in-line with CDI guideline recommendations.

Disclosures

R. Vickers, Summit Therapeutics: Employee, Salary and Stock options. S. Chowdhury, Summit Therapeutics: Employee, Salary and Stock options. M. Wilcox, Summit Therapeutics: Consultant, Research Contractor and Scientific. Advisor, Consulting fee, Research grant and Research support.
1348. In vitro Activity of Plazomicin, a Next-Generation Aminoglycoside, Against Carbapenemase-Producing Klebsiella pneumoniae
Authors: Jacobs Michael R , Good Caryn E , Abdelhamed Ayman M , Rhoads Daniel D , Hujer Kristine M , Hujer Andrea M , Rudin Susan D , Domitrovic T Nicholas , Connolly Lynn , Krause Kevin M , Richter Sandra S , Van Duin David , Kreiswirth Barry N , Bonomo Robert A ,   Antibiotic Resistance Leadership Group
Published: November 2018

Background

Plazomicin is a next-generation aminoglycoside with in vitro activity against multidrug-resistant Gram-negative species, including carbapenem-resistant isolates. The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) is a federally funded, prospective multicenter consortium of 20 hospitals from nine US healthcare systems to track carbapenem-resistant Enterobacteriaceae.

Methods

Minimum inhibitory concentrations (MICs) of plazomicin were determined by broth microdilution according to current CLSI guidelines against a collection of 697 carbapenem-resistant Klebsiella pneumoniae with defined carbapenem resistance mechanisms, including KPC and OXA carbapenemases. Isolates were submitted by participating CRACKLE centers.

Results

Carbapenemases present in study isolates included KPC-2 (n = 323), KPC-3 (n = 364), KPC-4 (n = 2), OXA-48 like (n = 7), and NDM (n = 1). Plazomicin MICs ranged from ≤0.12 to >32 mg/L, with MIC50 and MIC90 values of 0.25 and 1 mg/L, respectively (figure). MICs of 689 (98.8%) isolates were ≤4 mg/L, while MICs of the remaining eight isolates were >32 mg/L. Plazomicin MICs were related to specific carbapenemases present in isolates: of eight isolates with MICs >32 mg/L, seven contained OXA-48 like and one contained KPC-3, suggesting that these isolates possess an aminoglycoside-resistance mechanism on the same plasmid as their carbapenemase gene, such as a 16S ribosomal RNA methyltransferase, against which plazomicin is not active.

Conclusion

Plazomicin has good in vitro potency against a collection of carbapenemase-producing K. pneumoniae, with MIC90 value of 1 mg/L and MICs of ≤4 mg/L for 98.9% of isolates.

Disclosures

M. R. Jacobs, Achaogen: Investigator, Research grant. Shionogi: Investigator, Research grant. L. Connolly, Achaogen, Inc.: Consultant, Consulting fee. K. M. Krause, Achaogen: Employee, Salary. S. S. Richter, bioMerieux: Grant Investigator, Research grant. BD Diagnostics: Grant Investigator, Research grant. Roche: Grant Investigator, Research grant. Hologic: Grant Investigator, Research grant. Diasorin: Grant Investigator, Research grant. Accelerate: Grant Investigator, Research grant. Biofire: Grant Investigator, Research grant. D. Van Duin, achaogen: Scientific Advisor, Consulting fee. shionogi: Scientific Advisor, Consulting fee. Allergan: Scientific Advisor, Consulting fee. Astellas: Scientific Advisor, Consulting fee. Neumedicine: Scientific Advisor, Consulting fee. Roche: Scientific Advisor, Consulting fee. T2 Biosystems: Scientific Advisor, Consulting fee.
1355. Global Activity of Imipenem–Relebactam and Comparators Against Clinical Gram-Negative Pathogens – SMART 2017
Authors: Lob Sibylle , Kazmierczak Krystyna , Hoban Daryl , Hackel Meredith , Young Katherine , Motyl Mary , Sahm Dan
Published: November 2018

Background

Relebactam (REL), formerly MK-7655, is a β-lactamase inhibitor of class A and C β-lactamases that is in development in combination with imipenem (IMI). In this study, we evaluated the activity of IMI/REL against recent clinical isolates of Gram-negative bacilli (GNB) collected globally as part of the SMART surveillance program.

Methods

In 2017, 188 hospitals in 54 countries each collected up to 100 consecutive Gram-negative aerobic or facultatively anaerobic pathogens from lower respiratory tract infections, 75 from intra-abdominal infections, and 75 from urinary tract infections. MICs were determined for 41,319 GNB, including 30,864 Enterobacteriaceae and 6,933 P. aeruginosa isolates, using CLSI broth microdilution and interpreted with CLSI breakpoints; for comparison purposes, IMI susceptible breakpoints were applied to IMI/REL.

Results

Susceptibilities to IMI/REL and comparators of the 10 most commonly found Enterobacteriaceae species and P. aeruginosa are shown below.

IMI/REL showed activity >90% against seven of the top 10 Enterobacteriaceae species, typically ~5 to 35 percentage points higher than the β-lactam comparators, and it was active against 89% of P. aeruginosa, ~15 to 25 percentage points higher than the β-lactam comparators. Only amikacin and colistin showed similar or higher activity for most species, with colistin showing little activity against Proteeae and Serratia.

Conclusion

IMI/REL could provide an important treatment option against infections with Gram-negative pathogens, especially since amikacin and colistin are associated with significant morbidity, including nephrotoxicity and ototoxicity, and amikacin is typically used in combination with another antibiotic.

Disclosures

S. Lob, IHMA, Inc.: Employee, Salary. Merck: Consultant, Consulting fee. K. Kazmierczak, Merck: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary. D. Hoban, IHMA, Inc.: Employee, Salary. Merck: Consultant, Consulting fee. M. Hackel, IHMA, Inc.: Employee, Salary. Merck: Consultant, Consulting fee. K. Young, Merck: Employee and Shareholder, Dividends and Salary. M. Motyl, Merck: Employee and Shareholder, Dividends and Salary. D. Sahm, IHMA, Inc.: Employee, Salary. Merck: Consultant, Consulting fee.
1358. In vitro Activity of Ceftazidime–Avibactam and Comparator Agents Against Pseudomonas aeruginosa Causing Intra-Abdominal, Lower Respiratory, and Urinary Tract Infections Collected in Latin America as Part of the INFORM Global Surveillance Program, 2012–2016
Authors: Wise Mark , Kazmierczak Krystyna , Stone Gregory G , Sahm Dan
Published: November 2018

Background

The non-β-lactam β-lactamase inhibitor avibactam (AVI) is active against class A, C, and some class D β-lactamases, in combination with ceftazidime (CAZ) has been approved by the FDA and EMA for treatment of intra-abdominal infections (IAI), lower respiratory tract infections (LRTI), and urinary tract infections (UTI). This study reports on the in vitro activity of (CAZ-AVI) and comparators vs. P. aeruginosa collected from IAIs, LRTIs, and UTIs in Latin America as part of the INFORM surveillance study from 2012 to 2016.

Methods

For INFORM surveillance over 2012–2016 in Latin America, 1,595 nonduplicate P. aeruginosa isolates linked to IAIs, LRTIs, and UTIs were collected from 26 clinical sites in six countries. Susceptibility testing was done using broth microdilution according to CLSI guidelines and using CLSI 2018 breakpoints. CAZ was tested with AVI at a fixed concentration of 4 mg/mL. Meropenem (MEM) nonsusceptible organisms were screened for β-lactamase genes by PCR.

Results

Among the full collection of P. aeruginosa, CAZ-AVI showed consistently higher % susceptibilities than all comparators except for colistin (CST) for all infection sources. The addition of AVI to CAZ resulted in an increase in susceptibility ranging from 14.2% (IAI) to 19.5% (UTI). Against the non-metallo-β-lactamase (MBL) harboring subset, CAZ-AVI showed extremely potent activity (MIC90, 8 mg/mL) for all infection sources. In this subset, the activity of CAZ-AVI approached that of colistin for IAIs (susceptibility of 93.3% vs. 96.4%, respectively).

Conclusion

CAZ-AVI demonstrated very good in vitro activity against P. aeruginosa isolates, especially those without MBLs. More isolates were susceptible to CAZ-AVI than to MEM for all infection types.

Disclosures

M. Wise, Pfizer Inc.: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary. K. Kazmierczak, Pfizer Inc.: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary. G. G. Stone, Pfizer Inc.: Employee, Salary. AstraZeneca: Former Employee and Shareholder, Salary. D. Sahm, Pfizer Inc.: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary.