bluuebunny/crossref_metadata_2025 huggingface dataset:
624. Perceptions of Telemedicine among Infectious Disease Outpatient Providers during the COVID-19 Pandemic
Authors: Pillai Prishanya , Carvajal Karen , Winbush Angelina , Palli Rohith , Louie Ted
Published: December 2021

Background

Access to infectious disease (ID) providers has been heavily impacted by COVID-19. Telemedicine (TM) has been viewed as a promising solution to the challenges in care delivery posed by this pandemic. However, perceptions of TM among ID providers remain unclear. This study investigated the impact of TM on outpatient ID during the COVID-19 pandemic, efficacy of TM in ID clinics, which clinical conditions within ID that TM may be best suited for, and influences on provider attitudes toward TM.

Methods

We conducted online surveys of outpatient ID providers via the IDSA Idea Exchange and by reaching out to large ID private practices via email. Data was collected October 2020 - April 2021 and recorded through REDCap (Research and Electronic Data Capture). Associations were calculated using Hmisc in R and p-values adjusted using B-H. Missing values were imputed by median.

Results

108 respondents completed the survey. 70.4% were attendings, 63% were under age 50, and 65.7% practiced in academic centers. 55.7% somewhat or strongly agreed there was a decline in outpatient visits. A median of 40% of outpatient visits during COVID were reported to be conducted via TM, divided equally between telephone and televideo (TV). 71.9% of providers somewhat or strongly agreed that TV visits were more effective than telephone visits. Reasons cited for TM as less effective than in person visits included lessened ability to examine the patient, diminished rapport, and inability to perform labwork. 85.2% somewhat or strongly agreed that patients responded favorably to TM. 89.8% of providers somewhat or strongly agreed they will continue to conduct TM visits when appropriate after COVID-19. Plans to continue TM after COVID were significantly associated with perceptions of patient response to TM. Respondents mentioned specific problems less suited to TM: new HIV patients, skin, soft tissue, and joint infections, fever, abdominal pain, transplant evaluations, rash, and wounds.

Conclusion

The majority of providers felt their patients responded favorably to TM. Most providers plan to conduct TM visits after COVID-19. These plans are associated with views of patient response and comparability to other visit types. Specific diagnoses were cited as better suited for TM.

Disclosures

All Authors: No reported disclosures
625. The Hidden Cost of Dalbavancin: OPAT-RN Time Spent on Coordination for Patients with Substance Use Disorder
Authors: Douglass Alyse , Mayer Heather , Young Kathleen , Streifel Amber C , Makadia Jina , Lewis James , Sikka Monica K
Published: December 2021

Background

The use of dalbavancin (DAL) enhances the management of serious gram-positive infections in people with substance use disorder (SUD) by eliminating the need for central lines, weekly lab monitoring, and may decrease length of hospitalizations. Though administered weekly, care coordination for DAL is often complex, due to variable access to resources, insurance variation and treatment settings. Our institution uses OPTIONS-DC, a multi-disciplinary discharge planning conference facilitated by an outpatient parenteral antimicrobial therapy (OPAT) registered nurse (RN) to determine safe treatment plans while emphasizing patient preference for hospitalized patients with SUD and serious infections. When DAL is selected for treatment, patients are enrolled in the RN-led OPAT program for coordination and monitoring. DAL has been shown to result in monetary savings but these estimates have yet to incorporate the true cost of coordination.

Methods

We conducted a retrospective chart review of OPAT staff interventions required to coordinate DAL doses for patients with SUD (identified via ICD-10 code or chart notes). Additionally, we recorded in real time, the amount of time spent per intervention over a one month period for 7 additional patients.

Results

53 courses of DAL in patients with SUD were included with a variety of dosing regimens and treatment settings (Table 1). 41 (77%) patients endorsed IV substance use. 68% of patients received DAL for osteomyelitis or endocarditis. The majority were insured by Oregon Medicaid (70%). The number of RN interventions per course averaged 3.35 with the most common being coordinating with patients and vendors (Table 2). The average time spent per patient course during a one-month sample was 39.4 minutes (range 15 – 58 minutes). The most time-consuming interventions were conducting the OPTIONS-DC conferences and attempting to reach patients after hospital discharge. Readmission for adverse effects or infection occurred for 4 (8%) patients.

Conclusion

The OPAT-RN time required to coordinate outpatient DAL for patients with SUD is substantial. This enhanced coordination allows for potential cost savings to health systems.

Disclosures

Amber C. Streifel, PharmD, BCPS, Melinta (Advisor or Review Panel member) Monica K. Sikka, MD, FG2 (Scientific Research Study Investigator)
626. The Efficacy and Safety of Maintenance with Doravirine Plus Two NRTIs after Initial Suppression in Adults with HIV-1 in the DRIVE-FORWARD Clinical Trial: Results from the Study Extension through 192 Weeks
Authors: Cahn Pedro , Molina Jean-michel , Lombaard Johan , Squires Kathleen , Kumar Sushma , Wan Hong , Teal Valerie , Asante-Appiah Ernest , Sklar Peter , Martin Elizabeth A , Lahoulou Rima
Published: December 2021

Background

DRIVE-FORWARD is a phase 3 trial with a completed double-blind period comparing doravirine (DOR) 100 mg with ritonavir-boosted darunavir (DRV/r) 800/100 mg, both administered with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs; tenofovir and emtricitabine, or abacavir and lamivudine), and an ongoing open-label extension. At Week (W) 48, DOR demonstrated non-inferior efficacy to DRV/r, with a superior lipid profile. Those results were sustained at W96. Here we present efficacy and safety results through W192.

Methods

Participants who completed the 96-week double-blind phase and met inclusion criteria were eligible to receive open-label DOR plus two NRTIs in a 96-week extension. Efficacy and safety at W192 were assessed in two groups: participants initially randomized to DOR and maintained on DOR (n=259) and those who switched from DRV/r to DOR at W96 (n=233).

Results

HIV-1 RNA < 50 copies/mL were maintained through W192 in 81.1% of participants who continued DOR and 80.7% of those who switched from DRV/r to DOR. The mean increase in CD4 T-cell counts from W96 to W192 was similar for participants maintained on DOR (47 cells/mm3) and those switched from DRV/r (53 cells/mm3). Protocol-defined virologic failure occurred in 3.1% and 5.6% of participants maintained on DOR and switched from DRV/r, respectively, and development of genotypic resistance was low in both groups (Table 1). Discontinuation due to adverse events was also low (Table 1). Fasting LDL-cholesterol, non-HDL-cholesterol, and triglycerides showed minimal increase in participants maintained on DOR and were reduced in those switched from DRV/r to DOR (Table 1). Participants maintained on DOR had minimal weight gain after W96 (median 1 kg), and a small increase overall (median 1.9 kg, Day 1 through W192); participants who switched to DOR had a small increase after W96 (median 1.5 kg), similar to the median weight gain in the base study (DOR 1.8 kg; DRV/r 0.7 kg).

Conclusion

Among participants who continued DOR in the DRIVE-FORWARD open-label extension, virologic suppression and favorable safety were maintained for an additional 96 weeks. Participants who switched from DRV/r to DOR maintained virologic suppression and demonstrated favorable safety for 96 weeks.

Disclosures

Pedro Cahn, MD, PHD, Merck (Advisor or Review Panel member)ViiV Healthcare (Grant/Research Support, Advisor or Review Panel member) Kathleen Squires, MD, Merck (Employee) Sushma Kumar, PhD, Merck (Employee) Hong Wan, PhD, Merck (Employee) Valerie Teal, MS, Merck (Employee) Ernest Asante-Appiah, PhD, Merck (Employee) Peter Sklar, MD, Merck (Employee) Elizabeth A. Martin, DO, MPH, MBA, Merck (Employee) Rima Lahoulou, n/a, Merck (Employee)
628. Pharmacokinetics, Safety and Tolerability of Co-administration of Nacubactam and β-lactams after Multiple Doses in Japanese Healthy Subjects
Authors: Sato Hiroki , Morita Jun , Miura Tatsuo , Sumiya Masayo , Takaya Risako , Kondo Kenichiro
Published: December 2021

Background

Increase of carbapenem-resistant Enterobacterales (CRE) is a serious problem in the clinical setting and drugs which can treat patients with CRE are still limited. Nacubactam (OP0595) is a novel diazabicyclooctane-type β-lactamase inhibitor and being developed as a standalone drug to be co-administered with cefepime or aztreonam.

Methods

A randomized, double-blind multiple dose study of nacubactam in co-administration with cefepime (Cohort 1) or aztreonam (Cohort 2) in Japanese healthy subjects was performed to assess pharmacokinetics, safety, and tolerability of co-administrations of nacubactam and cefepime or aztreonam. In each cohort, 6 subjects received 2 g of nacubactam and 2 g of concomitant drug (cefepime or aztreonam) and 2 subjects received placebo (saline) intravenously over 60 minutes, three times daily every 8 hours for 7 days. Plasma samples were collected and concentrations of each drug were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and the evaluation of changes from baseline in safety laboratory test results, 12-lead electrocardiograms (ECGs), vital signs, and physical examinations.

Results

Profiles of Cmax, tmax, AUC0-8, AUC0-∞ and t1/2 for nacubactam, cefepime and aztreonam are summarized in Table 1. Summary of Ctrough for nacubactam, cefepime and aztreonam are summarized in Table 2. Plasma concentrations of nacubactam, cefepime and aztreonam reached the steady-state by Day 4, and the mean accumulation ratios of Cmax and AUC0-8 on Day 7 to those of Day 1 were in the range of 0.91 to 1.10. As for the safety, no serious adverse event was observed in this study. There was 1 TEAE (seborrhoeic dermatitis) leading to the discontinuation in 1 subject in nacubactam/cefepime group, but it was judged as “Not related to study drug”.

Table 1. PK profiles of nacubactam and concomitant drugs on Day 1 and Day 7

Table 2. Summary of Ctrough of nacubactam and concomitant drugs

Conclusion

In conclusion, no remarkable change in pharmacokinetics was observed in each drug with multiple concomitant administration for 7 days and safety and tolerability of co-administrations of nacubactam and cefepime or aztreonam were confirmed. Based on these results, nacubactam is currently under further development.

Disclosures

All Authors: No reported disclosures
637. Treatment Outcomes in Secondary Analysis Populations of Adult Patients the ALLIUM Phase 3 study Comparing Cefepime-Enmetazobactam to Piperacillin-Tazobactam for Complicated Urinary Tract Infections (cUTI) or Acute Pyelonephritis (AP)
Authors: Kaye Keith S , Belley Adam , Barth Philip , Lahlou Omar , Velicitat Patrick
Published: December 2021

Background

Superior treatment outcomes were observed with the β-lactam/β-lactamase inhibitor combination of cefepime-enmetazobactam (FPE) compared to piperacillin-tazobactam (PTZ) in the primary efficacy population (m-MITT) of the ALLIUM phase 3 study of adult patients with cUTI/AP. We present here the outcomes in the microbiologically evaluable (ME) and ME+Resistant (ME+R) populations.

Methods

1034 cUTI/AP patients randomized 1:1 in a double-blind, multicenter trial received either 2 g cefepime/0.5 g enmetazobactam or 4 g piperacillin/0.5 g tazobactam q8h by 2h infusion for 7 to 14 days. Patients in m-MITT had a Gram-negative urinary baseline pathogen (BP) at >105 CFU/ml with FPE MIC ≤8 µg/ml and PTZ MIC ≤64 µg/ml. ME included patients in m-MITT who received ≥15 consecutive doses of study drug or were classified as clinical failures after receiving ≥9 doses; had a clinical assessment at test-of-cure (TOC) unless clinical failure occurred earlier; did not receive concomitant antibiotics with a non-study agent; and did not have any other protocol violation. ME+R included patients in ME along with those who had BP resistant to either FPE (MIC >8 µg/ml) or PTZ (MIC >64 µg/ml), or a missing MIC value. Overall success was the composite of clinical cure and microbiological eradication (< 103 CFU/ml in urine). Two-sided 95% confidence interval (CI) were computed using the stratified Newcombe method.

Results

In the ME population, superiority in overall success of FPE (87.0%; 268/308) compared to PTZ (65.4%; 195/298) was demonstrated as the lower bound of the CI (16.6%) of the treatment difference (TD; 23.3%) was greater than 0 (Table). Higher rates of microbiological eradication with FPE contributed to the superior treatment outcomes. In the ME+R population in which BP susceptibility was not an exclusion criterion, favorable outcomes with FPE in overall success (TD 21.6%; 95% CI [15.3, 27.8]) and microbiological eradication (TD 21.0%; 95% CI [14.8, 27.0]) were also observed.

Conclusion

The confirmation of superior treatment outcomes with FPE in the ME and ME+R populations supports the robustness of the corresponding superiority observed in adult cUTI/AP patients in m-MITT.

Disclosures

Adam Belley, PhD, Allecra Therapeutics SAS (Consultant) Philip Barth, MD, Allecra Therapeutics SAS (Consultant) Omar Lahlou, PhD, Allecra Therapeutics SAS (Employee) Patrick Velicitat, MD, Allecra Therapeutics SAS (Employee)
641. Clinical Predictors of Hospital-Acquired Bloodstream Infections
Authors: Sheth Radhika , Bhatia Mehakmeet , Kak Vivek
Published: December 2021

Background

Hospital-acquired bloodstream infections (HABSI) are associated with increased mortality and decreased hospital quality metrics. This has led to an increased focus on blood culture stewardship. Little data exists regarding predictive factors of bacteremia in hospitalized patients. We aim to determine what clinical characteristics in patients were predictive of HABSI.

Methods

This is a retrospective case-control study of 540 patients with positive blood cultures admitted to our health system between September 1, 2017, to April 1, 2020. Electronic medical records of patients with positive blood cultures were independently reviewed to determine contamination versus true bacteremia. We looked at different clinical parameters and laboratory investigations within 24 hours of drawing blood cultures. Clinical variables were age ≥ 60 years, heart rate ≥ 90/minute, systolic blood pressure ≤ 90 mmHg or use of a vasopressor, oral temperature > 38°Celsius (100.4°Fahrenheit), white blood cells (WBC) count ≥12,000/µL, lymphocytes ≤ 1000/mm3, platelets < 150,000 /µL, and creatinine >2.0 mg/dL. Stepwise logistic regression analysis was used for predictive statistical model development.

Results

In a cohort of 481 patients with hospital-acquired bacteremia, 350 cases had true bacteremia and 131 cases were contaminated blood cultures. Stepwise regression analysis showed that white blood cell (WBC) count ≥ 12,000 cells/µL, lymphocyte count ≤ 1000/mm3, creatinine > 2.0 mg/dL, and oral temperature > 38°C (100.4°F) were associated with HABSI (R-square= 0.06, p value= 0.002).

Conclusion

Our findings suggest that WBC count, lymphocyte count, creatinine, and oral temperature together can be used to develop appropriate blood culture stewardship models in the inpatient setting. This may help minimize unnecessary blood cultures.

Disclosures

All Authors: No reported disclosures
642. Facility Reported vs. CLSI MIC Breakpoint Comparison of Carbapenem Non-susceptible (Carb-NS) Enterobacteriaceae (ENT) from 2016-2019: A Multicenter Evaluation
Authors: Gupta Vikas , Yu Kalvin , Pogue Jason M , Weeks Janet , Clancy Cornelius J
Published: December 2021

Background

Carbapenem (Carb) minimum inhibitory concentration (MIC) breakpoints were lowered by CLSI in 2010 and recognized by FDA in 2012. Adoption of revised breakpoints is often slow, which may lead to under-reporting of Carb non-susceptibility (NS) by facilities. We compare facility-reported rates of Carb-NS ENT to the CLSI MIC breakpoints for a large nationwide collection of isolates in the United States (US) from 2016-2019.

Methods

All adults with a positive non-contaminant ENT culture (first isolate of a species per 30-day period from blood, respiratory, urine, skin/wound, intra-abdominal, or other) in ambulatory/inpatient settings from up to 300 US hospitals from 2016-2019 were evaluated (BD Insights Research Database). Facility-reported Carb-NS was defined as: susceptible (S), intermediate (I) or R to ertapenem (ETP), imipenem (IPM), meropenem (MEM) and/or doripenem (DOR) per commercial panels. Where available, MICs were interpreted using CLSI 2010 MIC breakpoints (µg/ml): ≤ 0.5 (S), 1 (I), ≥ 2 (R) for ETP and ≤1 (S), 2 (I), and ≥ 4 (R) for IPM/MEM/DOR. For evaluable ENT isolates we compared susceptibility results as reported by the facility to CLSI MIC breakpoints.

Results

Overall, 77.4% (937,926/1,211,845) and 90.6% (2,157,785/2,381,824) non-duplicate ENT isolates with facility-reported susceptibility results also had interpretable MIC results for ETP and IPM/MEM/DOR, respectively (Tables). ETP S rates were 99.3% and 99.1% as reported by facilities and using CLSI criteria, respectively. S rates of other Carbs were 98.9% and 98.4% by facility reporting and CLSI criteria, respectively. Systematic application of CLSI breakpoints under-reported EPT-I and –R isolates by 24.2% and 16.4%, respectively, and identification of IPM/MEM/DOR-I and –R isolates by 31.3% and 22.7%, respectively.

Conclusion

Systematic application of CLSI breakpoints in 2016-19 would have had minimal impact on ENT S rates in the US. However, facility reporting failed to identify 18.8% of ETP I or R and 26.5% of IPM/MEM/DOR I or R isolates. The clinical implications of this observation are unknown. Facilities should know their local epidemiology, decide if under-reporting might be an issue, and assess if there is any impact on their patients.

Disclosures

Vikas Gupta, PharmD, BCPS, Becton, Dickinson and Company (Employee, Shareholder) Kalvin Yu, MD, BD (Employee) Jason M Pogue, PharmD, BCPS, BCIDP, Merck (Consultant)QPex (Consultant)Shionogi (Consultant)Utility Therapeutics (Consultant)VenatoRX (Consultant) Janet Weeks, PhD, Becton, Dickinson and Company (Employee) Cornelius J. Clancy, MD, Merck (Grant/Research Support)
643. Evaluation of Rapid Blood Pathogen Identification Along with Antimicrobial Stewardship at an Academic Teaching Institution
Authors: Blum Sharon , McSweeney Terrence , Tirmizi Samad , Auditore brian , Johnson Diane , Malone Brian
Published: December 2021

Background

Bloodstream infections are a major cause of morbidity and mortality in hospitalized patients. Prompt initiation of effective antimicrobials are essential to optimize patient outcomes. New diagnostic technologies rapidly identifying bacteria, viruses, fungi, and parasites in infections of various body sites. There is a paucity of literature determining if stewardship programs run by one trained pharmacist with rapid diagnostics decreases time to optimal antimicrobial therapy.

Methods

This was a retrospective chart review of positive bloodstream infections identified via rapid diagnostic technologies. The EHR of admitted adult patients with positive BSI identified by BioFire FilmArray Blood Culture Identification (BCID) Panel™ or Accelerate PhenoTest Blood Culture kit™2 between January 2018 – July 2019 were evaluated and pertinent data was collected.

Results

Rapid diagnostic technologies identified 108 bloodstream infections due to gram positive, 56 due to gram negative, and 6 due to Candida organisms. Mean time to optimal antimicrobial therapy was significantly lower when pharmacist recommendation was accepted versus when primary care team consulted ID for recommendation or did not accept pharmacist recommendation. Mean time to optimal therapy was 14.7, 34.3, and 271.3 hours (p< 0.0001) respectively. Median total cost of visit per patient, calculated using the average wholesale price of antibiotics multiplied by the number of doses received, was significantly lower when pharmacist recommendations were accepted (&86.40, &147.95, and &239.41, respectively).

Baseline characteristics

Microbiological isolates

Primary Outcome: Time to Optimal Therapy

Conclusion

The establishment of a pharmacist run antimicrobial stewardship program in conjunction with rapid diagnostic tools for identifying bacteremia led to a decrease in time to optimal antimicrobial therapy and cost savings. Introduction of similar services at community hospitals with limited ASP staffing is justified. Larger studies to further investigate whether ASP partnered with rapid diagnostics have an impact on patient-related outcomes such as mortality and length of stay is warrented.

Secondary outcomes

Missed cost savings

Disclosures

All Authors: No reported disclosures
644. Phenotypic and Genomic Analysis of Novel, Fastidious, Gram-negative Bacilli Isolated from Clinical Wound Specimens
Authors: Liu Benjamin , Simmon Keith , Fisher Mark
Published: December 2021

Background

Animal bites are considered the thirteenth leading cause of nonfatal ED visits. Epidemiology studies have shown a rise in dog bites during the COVID-19 pandemic in the U.S. In Oct. 2020, we received a facultatively anaerobic, non-hemolytic Gram-negative rod (OL1) from a dog bite wound for identification. 16S rRNA gene sequencing showed OL1 was 95.9% identical to Ottowia pentelensis in the family Comamonadaceae. Our historical sequence database revealed 8 additional isolates (OL2-OL9) from hand wounds/abscesses (including 3 dog bites) since 2012 that had ⩾ 99.8% identity with OL1. Most other Ottowia sp. have been isolated from industrial and food sources, with no reports from patient samples. As these clinical isolates likely represent a novel Ottowia species, we aimed to characterize them using both phenotypic and genomic approaches.

Methods

The OL isolates were tested in API 20 NE panels (8 conventional and 12 assimilation tests) for 4 d. Paired-end genomic DNA libraries (Nextera DNA Flex Library Prep, Illumina) were sequenced as 150 nt reads by Illumina NovaSeq. De novo assembly, annotation, functional prediction, and phylogenetic analyses were performed with Geneious, PATRIC, and web-prediction databases. Strain comparison was done with StrainTypeMer.

Results

All 9 OL isolates were negative for indole, urea, arginine, esculin, PNPG, glucose fermentation and carbohydrate assimilation tests. Potassium gluconate assimilation and gelatin hydrolysis were positive for 5 and 4 isolates, respectively. StrainTypeMer showed the isolates from different patients were not closely related, but 2 from the same patient were indistinguishable. The estimated genome size was ~3.1 Mbp, with 66.1% G/C, and ~3523 coding genes. Potential virulence factors (BrkB and MviM), multidrug efflux systems (MdtABC-TolC and Bcr/CflA), and 1-2 intact prophages were identified. Genomic phylogenetic analysis with RAxML showed the OL isolates clustered separately from all known Ottowia spp.

Conclusion

These OL isolates are fastidious, Gram-negative bacilli from clinical wound specimens, and are associated with dog bites. Genomic and 16S rRNA gene sequence analysis suggests these isolates constitute a novel species within the family Comamonadaceae.

Disclosures

All Authors: No reported disclosures
646. Increasing Use of Interferon-Gamma Release Assay to Test for Pediatric Tuberculosis in a Low-Burden Setting
Authors: Campbell Jeffrey , Sun Mingwei , He Wei , Lamb Gabriella S , Lamb Gabriella S , Tabatneck Mary , Goldmann Don , Sabharwal Vishakha , Sandora Thomas , Haberer Jessica
Published: December 2021

Background

The American Academy of Pediatrics recommends tuberculin skin tests (TSTs) or interferon gamma release assays (IGRAs) to test for tuberculosis (TB) infection in children ≥2 years old, and prioritizes IGRA testing in Bacille Calmette-Guérin vaccine recipients due to cross-reactivity. TSTs require a return visit, which frequently results in loss to follow up. Growing evidence supports accuracy of IGRA testing in pediatric patients, including young children, leading to calls for preferential use of IGRA over TST. We sought to evaluate trends in IGRA use in children over time.

Methods

We identified all TB infection tests conducted in children 5-17 years old at 2 academic medical systems in Boston from October 2015–January 2021. TSTs were identified using medication administration records, and IGRAs were identified using laboratory records. We computed the proportion of tests per month that were IGRA and TST. We used Pearson correlation to determine the association between month of testing and proportion of tests that were IGRAs.

Results

21,471 TB infection tests were obtained from 16,778 patients during our timeframe. Median age of testing was 13.4 years (IQR 9.2 – 16.2 years). During the study period, there was a significant increase in the monthly proportion of TB infection tests that were IGRAs (Pearson correlation coefficient 0.92, P < 0.001). The total number of tests performed per month also increased, with seasonal increases in testing in late summer and early fall and a substantial decline in testing early in the COVID-19 pandemic.

Tuberculosis infection tests and proportion IGRA.

Total number of tuberculosis infection tests per month and proportion of tests that were interferon gamma release assays, from October 2015 - January 2021.

Conclusion

Use of IGRAs among patients age 5-17 years of age increased significantly overall and compared to TST in two large Boston healthcare systems over a 5-year period. These results suggest a shift towards blood-based TB infection testing in a low-burden setting, which may improve completion of the pediatric TB infection care cascade. Future research is needed to determine reasons for changing testing modalities, and similar patterns in other settings.

Disclosures

Gabriella S. Lamb, MD, MPH, Nothing to disclose
647. Investigation of Heteroresistance Among Klebsiella pneumoniae (KP) Inner Colonies (IC) Observed During Fosfomycin Disk Diffusion (DD) Testing
Authors: Bixby Morgan L , Krueger Amanda , Hirsch Elizabeth B
Published: December 2021

Background

During fosfomycin DD testing, the frequent occurrence of non-susceptible IC within the zone of inhibition of susceptible isolates has been noted. The Clinical & Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) have contradicting recommendations on how IC should be interpreted; CLSI recommends considering IC when interpreting DD results whereas EUCAST recommends ignoring them. This study sought to identify the susceptibility of these IC and to understand whether heteroresistance contributes to the appearance of IC during fosfomycin DD.

Methods

This study included a convenience sample of 71 KP clinical isolates from 3 United States locations. During DD testing, 58 (81.7%) of these isolates displayed at least one IC. Broth microdilution (BMD) minimal inhibitory concentration (MIC) testing, using extrapolated CLSI Escherichia coli breakpoints, was performed on a subset (n=32) of the IC in duplicate for comparison to the corresponding parent MIC values. This was followed by a modified disk elution screening test for heteroresistance to compare the frequency of low level resistance (LLR) and high level resistance (HLR) between the susceptible isolates that produced resistant IC (n=6) and those that did not produce any IC (n=3).

Results

The MIC range for the IC isolates (128 to > 1024 μg/mL) increased as compared to the parent isolates (< 2 to > 256 μg/mL) and MIC50/90 increased from the parent (128/ > 256 μg/mL) to IC (1024/ > 1024 μg/mL) isolates. All IC isolates had a resistant MIC value vs. 46.5% of parent isolates, and over 90% of IC isolates had an MIC at least 2 dilutions higher than their corresponding parent isolate. Heteroresistance screening found all tested isolates to be positive for LLR, and 8 of 9 positive for HLR, while the one HLR-negative isolate was IC-producing.

Conclusion

IC were frequent during fosfomycin DD testing and were commonly more resistant than their corresponding KP parent isolates. A small subset of these isolates tested via a modified disk elution test displayed either LLR or HLR regardless of the absence of IC. These results call for further investigation among a larger isolate set to understand what mechanisms are responsible for the frequency of IC and their increased fosfomycin resistance.

Disclosures

All Authors: No reported disclosures
650. LiaX as a Surrogate Marker of Daptomycin Susceptibility in Multidrug-Resistant Enterococcus faecium
Authors: Axell-House Dierdre B , Khan Ayesha , Shelburne Samuel A , Shamoo Yousif , Tran Truc T , Arias Cesar A
Published: December 2021

Background

Vancomycin-resistant Enterococcus faecium (VREfm) are important causes of bloodstream infections (BSI) in patients (pts) with cancer, liver disease, and foreign bodies. Daptomycin (DAP) is commonly used to treat VRE BSI, but DAP resistance (DAP-R) is increasing. Current methods to determine DAP minimum inhibitory concentrations (MICs) have poor reproducibility. DAP triggers the LiaFSR cell membrane stress response pathway, resulting in the extracellular release of LiaX, a protein that functions as a sentinel molecule for DAP, and controls the cell membrane response.

Methods

We used 6 reference Efm isolates to optimize a whole-cell enzyme-linked immunosorbent assay (ELISA) method for LiaX detection. We then assessed 86 clinical Efm BSI isolates recovered from 3 hospitals in Houston and Detroit for DAP MICs and used whole genome sequencing to assess for substitutions in LiaFSR/LiaXYZ proteins. We collected patient and microbiological data by chart review.

Results

All DAP-R reference strains had increased detection of LiaX compared to DAP-S strains (p< 0.0001). Of the 86 pts with Efm BSI, 73.2% had malignancy, 9.3% had liver disease, and 76.7% had foreign bodies. The source of 52.3% of BSIs was determined to be gastrointestinal. Two of the 86 isolates were DAP-R by CLSI breakpoints. The LiaX test and DAP MICs had a categorical agreement in 62.8% of isolates. All isolates with discordant ELISA/MIC results had DAP-S MIC (median 2, IQR 1-3)but increased LiaX. Using the genomic information, we identified 41 sites of amino acid (AA) changes in the LiaFSR/XYZ proteins of the ELISA/MIC discordant isolates. The substitutions LiaR S19F and LiaS E153K/D251E were associated with discordancy (p=0.0036 and p=0.0018, respectively).

Conclusion

Detection of LiaX is likely to indicate activation of the DAP-mediated cell membrane response in Efm and may be an indicator of DAP-R. Important discrepancies between LiaX and standard DAP MIC determination were found, highlighting the limitation of MIC determination. Further characterization of the discrepant isolates by time-kill assays and evaluation of patient clinical outcomes are warranted to fully validate the performance and clinical utility of the LiaX ELISA.

Disclosures

Truc T. Tran, PharmD, Merck (Grant/Research Support) Cesar A. Arias, M.D., MSc, Ph.D., FIDSA, Entasis Therapeutics (Grant/Research Support)MeMed Diagnostics (Grant/Research Support)Merk (Grant/Research Support)
651. Clinical Characteristics and Susceptibility Profiles of Infections Due to Elizabethkingia
Authors: Comba Isin Y , Castillo Almeida Natalia E , Stevens Ryan W , Shah Aditya
Published: December 2021

Background

Elizabethkingia spp. are non-enteric, gram-negative bacilli that are ubiquitous in environment. It has recently been identified as a causative pathogen in hospital outbreaks of life-threatening bloodstream infections in the Midwestern United States.

Methods

Retrospective electronic medical record review was performed for patients with Elizabethkingia spp. isolated from any site between November 2011 and September 2020 at our tertiary academic medical center. Antimicrobial susceptibilities are performed using Wadsworth agar dilution method.

Results

Fifteen cases with Elizabethkingia spp. were included. Ten patients (66.7%) were male and fourteen (93.3%) were Caucasian. The median age was 58 years (IQR 42-67). Four patients had diabetes mellitus, with two of these having end-organ damage (nephropathy, neuropathy, or retinopathy). Five patients had a tracheostomy, two patients had a history of lung transplantation, and four patients had active malignancy at the time of diagnosis (table 1). The most common clinical syndrome was respiratory infection (n=6), followed by catheter-related bloodstream infection (CRBSI) (n=4). Three patients were considered to be asymptomatically colonized. Five patients (33.3%) died, one of which was attributable to Elizabethkingia infection. A total of 55 isolates from all sites were available from the fifteen patients. The most common site of isolation was respiratory tract (23/55, 41.8%). In total, 33 of 55 isolates had polymicrobial growth, with the highest rate occurring in respiratory tract specimens (Table 2). A total of 23 clinical isolates were included in tabulation of antimicrobial susceptibility profiles; except for aztreonam (n=13). 95.7% of Elizabethkingia isolates were susceptible to trimethoprim-sulfamethoxazole, followed by levofloxacin and piperacillin-tazobactam (87% and 73.9%, respectively). All isolates were uniformly resistant to amikacin, aztreonam, and tobramycin (Table 3).

Conclusion

Elizabethkingia spp. can result in respiratory, bloodstream, and sinus infections especially in patients with active malignancy and tracheostomy. Amongst tested antimicrobials, trimethoprim-sulfamethoxazole showed the most favorable susceptibility profile (Figure 1).

Figure 1.

AN, amikacin; ATM, aztreonam; CAZ, ceftazidime; CIP, ciprofloxacin; FEP, cefepime; GM, gentamicin; LVX, levofloxacin; MEM, meropenem; NN, tobramycin; SXT, sulfamethoxazole/trimethoprim; TZP, piperacillin/tazobactam.

Disclosures

All Authors: No reported disclosures
654. Performance of the T2Resistance Panel in Detecting Antibiotic Resistant Bacteria Directly in Whole Blood, and Implications for Improving Appropriate Therapy of Bloodstream Infections
Authors: Skeel Abigail , Clancy Cornelius J , Lucas Aaron , Hughes Kailey L , Shields Ryan K , Nguyen Minh-Hong
Published: December 2021

Background

Appropriate antibiotic (Ab) therapy of bloodstream infections (BSI) is often delayed by time to blood culture (BC) positivity, species (sp) identification and Ab sensitivity (sensi). The T2Resistance (T2R) Panel is a direct-from-blood (culture-independent) diagnostic that detects 13 genetic markers associated with methicillin-resistant S. aureus (MRSA), vancomycin-resistant Enterococcus (VRE), ESBL- and carbapenemase-producing Enterobacteriaceae (E). We assessed T2R performance in detecting these resistant bacteria in whole blood (WB) and analyzed possible impact on time to appropriate Ab.

Methods

We performed T2R using WB samples obtained from patients (pts) on the same day as BCs from July 2019-2020. Receipt of appropriate Ab was assessed at time of empiric, Gram stain-directed, MALDI-directed (sp identification) and sensi-directed therapy. T2R results were not available to care teams. Teams were notified of positive BCs. Stewardship optimized Abs based on sensi.

Results

BC from 103 pts grew 114 bacterial sp: E (n=54; 16 ESBL-, 1 KPC-producer), S. aureus (n=29, 22 MRSA), Enterococcus (n=21, 16 VRE), P. aeruginosa and others (n=10). 12 ESBL-E produced CTX-M 14/15. T2R sensitivity and specificity was 78% and 99%, respectively, compared to sequencing of resistance markers. Sensitivity was excellent for vanA/B, KPC (100% each), and CTX-M14/15 (92%); sensitivity was 58% for mecA/C. T2R detected resistance determinants in 3-7h. Median time to appropriate Ab was 16.3h, which was significantly longer for VRE (25.6h) and ESBL- or KPC-E (50.9h) BSIs than for T2R marker-negative bacteria (6.7h; p=0.04). Pts with VRE or ESBL-/KPC-E BSI were less likely to received appropriate empiric Ab (18% and 30%, respectively) than pts with T2R marker-negative BSI (63%; p=0.02; Fig.1). Median times to achieve ≥80% appropriate Ab therapy of marker-negative, VRE and CTX-M/KPC-E BSIs were 15.5h (after Gram stain), 43.9h (after MALDI) and 63.5h (after sensi), respectively.

Antibiotic Therapy

Conclusion

There was a significant delay in appropriate Ab therapy of BSIs, especially in pts infected with VRE and ESBL/KPC-E. T2R rapidly and accurately detected BSI caused by VRE and ESBL/KPC-E, and has the potential to significantly shorten time to appropriate Ab.

Disclosures

Cornelius J. Clancy, MD, Merck (Grant/Research Support) Ryan K. Shields, PharmD, MS, Shionogi (Consultant, Research Grant or Support) Minh-Hong Nguyen, MD, Merck (Grant/Research Support)
655. Patterns of Interferon-Gamma Release Assay (IGRA) Testing for Tuberculosis in Patients Less Than 2 Years Old
Authors: Tabatneck Mary , Campbell Jeffrey , Sun Mingwei , He Wei , Lamb Gabriella S , Lamb Gabriella S , Goldmann Don , Sabharwal Vishakha , Sandora Thomas , Haberer Jessica
Published: December 2021

Background

The American Academy of Pediatrics recommends use of Interferon-Gamma Release Assays (IGRAs) to diagnose tuberculosis (TB) infection in patients ≥2 years old. However, IGRAs are not currently recommended in younger patients due to limited data and concerns of invalid/indeterminate test results, which occur if there is a positive or negative control failure. We sought to characterize the patterns of IGRA use in clinical practice and results of IGRAs in patients < 2 years old.

Methods

We conducted a retrospective cohort study of children < 2 years old at two large health systems in the Boston area who had IGRA and/or tuberculin skin test (TST) performed from October 1, 2015 – January 31, 2021. We reviewed medical records to determine IGRA test type, IGRA result (positive, negative, invalid/indeterminate) and location of testing (outpatient primary care, outpatient subspecialty, inpatient). We summarized test interpretability, location, and changes in proportion of IGRA vs. TST.

Results

We identified 330 IGRA (268 T-SPOT.TB, 62 QuantiFERON Gold) and 2029 TST results among 1982 patients who were < 2 years old (range: 11 days – 1.9 years). Monthly proportion of IGRAs among all TB tests ordered increased from 2015 to 2021 (Figure 1) (Pearson correlation coefficient 0.85, P < 0.001). Among IGRA results, 314 (95%) were negative, 3 (1%) were positive, and 13 (4%) were invalid/indeterminate (11 T-SPOT.TB, 2 QuantiFERON Gold). Of 324 IGRA tests for which testing location was known, 233 (72%) and 91 (28%) were ordered in outpatient and inpatient settings, respectively. Of tests in outpatient settings, 132 (57%) were ordered in primary care offices, 53 (23%) were ordered in subspecialist offices, and 48 (21%) were obtained in outpatient labs of unidentified clinics.

Tuberculosis infection tests and proportion IGRA.

Total number of tests and proportion of IGRA:TST obtained by month, from October 2015-January 2021.

Conclusion

While most TB infection tests in this age group were TSTs, the monthly proportion of tests that were IGRAs increased over time between 2015-2021. IGRAs were obtained in varied clinical settings. In this low-burden setting, rates of invalid/indeterminate IGRAs were low among children < 2 years old, which suggests that IGRAs are reasonable TB testing options for patients < 2 years old, and may be preferred given limitations of TSTs.

Disclosures

Gabriella S. Lamb, MD, MPH, Nothing to disclose
656. Sulbactam-Durlobactam MIC Determination: Comparative Evaluation of the New ETEST® SUD to the CLSI 2021 Broth Microdilution Method
Authors: Sauvonnet Veronique , Escoffier Elodie , Franceschi Christine , Halimi Diane , Martelin Roland , Pellet Laetitia , Zambardi Gilles
Published: December 2021

Background

Species belonging to the Acinetobacter baumannii-calcoaceticus (ABC) complex, such as A. baumannii, A. pittii and A. nosocomialis, are a major cause of hospital acquired infections and outbreaks with increasing occurrence of multidrug-resistance. Sulbactam-durlobactam (SUD), a combination of one active β-lactam antibiotic (sulbactam) with a new β-lactamase inhibitor (durlobactam), is currently being tested in a phase 3 clinical trial by Entasis Therapeutics for the treatment of serious infections caused by ABC, including multidrug-resistant strains. At the same time, an ETEST® SUD (sulbactam-durlobactam - MIC range 0.004/4-64/4 µg/mL) has been developed and calibrated versus the broth microdilution reference method (BMD) as described by the Clinical and Laboratory Standards Institute (CLSI). This test is intended to determine the MIC of sulbactam-durlobactam for species of the ABC complex. The aim of this study was to perform a first comparative study of ETEST SUD with the CLSI BMD method on a panel of 263 isolates.

Methods

The panel consisted of 204 A. baumannii, 29 A. pittii, 30 A. nosocomialis, including 24 SUD-resistant strains, and one CLSI QC strain. BMD was performed using the 2021 CLSI guidelines. ETEST SUD was evaluated using the standard ETEST procedure for Acinetobacter spp. (inoculum 0.5 McFarland, Mueller Hinton medium, incubation at 35°C for 20-24h). For each method, the MIC was read at complete inhibition of visible growth. To determine category agreement (CA) and error rates, the sulbactam-durlobactam provisional breakpoint of 4 µg/mL was applied.

Results

The QC strain MICs were in the expected range with reproducible results. The essential MIC agreement [EA, ±1 dilution] was 97.7% without any tendency to over- or underestimate the MIC when compared to BMD. The CA was 98.5%. Two Very Major Errors, both within the EA, and two Major Errors, one within the EA, were observed.

Conclusion

In this study, the ETEST SUD was found to be equivalent to the CLSI reference method. MIC end points were easy to read. With a 15-dilution range and simplicity of use, ETEST SUD could represent a valuable tool for MIC determination and could be an alternative to BMD.

For Research Use Only. The performance characteristics of this product have not been established yet.

Disclosures

All Authors: No reported disclosures
657. Genomic Insights into Virulence Factors Affecting a Tissue-invasive Klebsiella pneumoniae Infection
Authors: Matono Takashi , Morita Masatomo , Nakao Nodoka , Teshima Yuji , Yamate Ryosuke , Hijikata Takamichi , Hoashi Kosuke , Ohashi Yusuke , Hasegawa Yuichi , Okinaka Tomohide , Ohnishi Makoto
Published: December 2021

Background

Japan is one of the hypervirulent Klebsiella pneumoniae (hvKp) endemic areas, resulting in an alarming issue in actual clinical settings. However, little is known regarding key virulence factors responsible for hvKp infection.

Methods

We analyzed K. pneumoniae isolates collected between 2017 and 2019, and defined hvKp as a pyogenic infection. Classical K. pneumoniae (cKp) involved a non-invasive infection or uncomplicated bacteremia. Isolates belonging to the K. pneumoniae species complex were excluded.

Results

We analyzed 112 isolates, including 19 hvKp, 67 cKp, and 26 colonizers, by whole-genome sequencing. Population genomics revealed that the K1-sequence type (ST) 82 clade was distinct from that of K1-ST23 clone (Figure 1). The virulence-gene profiles also differed between K1-ST82 (aerobactin and rmpA) and K1-ST23 (aerobactin, yersiniabactin, salmochelin, colibactin, and rmpA/rmpA2). The K2 genotype was more diverse than that of K1. A neighboring subclade of K1-ST23 (comprising ST29, ST412, ST36, and ST268) showed multidrug-resistance and hypervirulence potentials. Logistic-regression analysis revealed that diabetes mellitus was associated with K. pneumoniae infection (odds ratio [OR]: 4.11; 95% confidence interval [CI]: 1.14–14.8). No significant association was found between hvKp diagnosis and clinical characteristics, such as diabetes mellitus or community acquisition (Table 1). The K1 genotype (OR: 9.02; 95% CI: 2.49–32.7; positive-likelihood ratio [LR]: 4.08), rmpA (OR: 8.26; 95% CI: 1.77–38.5; positive LR: 5.83), and aerobactin (OR: 4.59; 95% CI: 1.22–17.2; positive LR: 3.49) were substantial diagnostic predictors of hvKp (Table 2).

Figure 1. Phylogenetic distribution of genetic virulence factors in 112 K. pneumoniae isolates

The highlighted strains are clinically pathogenic (orange, hypervirulent K. pneumoniae; yellow, classical K. pneumoniae; sky blue, colonization). The non-highlighted strain (NTUH-K2044) is a reference K. pneumoniae strain.

Conclusion

In hvKp-rich settings, diabetes mellitus, community-acquisition, and siderophores other than aerobactin were not remarkable predictors of hvKp infection. However, the K1 genotype, rmpA, and aerobactin were found to be substantial predictors, warranting clinical assessment of any possible/further pyogenic (metastatic) infection. We believe that these findings shed light on key hvKp virulence factors.

Disclosures

All Authors: No reported disclosures
661. Clinical Utility and Impact of the Metagenomic Microbial Plasma Cell-Free DNA Next-Generation Sequencing Assay on Treatment Decision: a Single-Center Retrospective Study
Authors: Noe Myint M , Shishido Akira A , Saharia Kapil , Luethy Paul
Published: December 2021

Background

Metagenomic next-generation sequencing (mNGS) of microbial cell-free DNA (mcfDNA) allows for non-invasive broad-range pathogen detection from plasma. The Karius® test that emerged in 2016 made mNGS widely available. However, there is little data describing the optimal role for this assay in clinical decision making.

Methods

We performed a single-center retrospective cohort study of adult patients for whom a Karius test was sent between May 2019 and February 2021 to assess clinical utility. We predefined criteria for clinical impact categories (Table 1) and stratified data by patient comorbidities, infectious syndromes, duration of antimicrobial therapy prior to Karius testing, reasons for sending the test, and final clinical diagnoses. Clinical impact was arbitrated by all authors after review and discussion of each case.

Results

A total of 80 patients were included. 45 patients (56%) were immunocompromised, and 14 (18%) had prosthetic hardware or grafts. The most common clinical syndrome was pneumonia/respiratory failure (31%), followed by sepsis/septic shock (15%) and endocarditis (13%). 72 patients (90%) received antibiotics prior to sending the Karius assay. The most common reason for sending the assay was unknown microbiologic diagnosis (78%), followed by avoiding invasive procedures (14%). The test was consistent with the final diagnosis in 65% of cases and had a positive impact in 34 (43%), a negative impact in 2 (3%), and uncertain or no impact in 44 (55%) (Table 2). A positive impact was observed in solid organ transplant recipients (SOTR, 71.4%, p=0.003), sepsis (71.4%, p=0.003), and those receiving antimicrobial agents for less than 7 days prior to Karius testing (i.e., 61.8%, p=0.004) (Table 3).

Conclusion

In our cohort, clinical utility of Karius testing was highest in SOTR and in patients with sepsis. Prolonged antimicrobial use ( > 7 days) prior to Karius testing limited the utility of the assay. Prospective studies evaluating the utility of mNGS mcfDNA assays should be performed to further clarify its role in clinical management.

Disclosures

All Authors: No reported disclosures