bluuebunny/crossref_metadata_2025_split huggingface dataset:
1450. Frequency of Carbapenem-resistant Pseudomonas aeruginosa Among Respiratory Pathogens Impacts First-Line Beta-Lactam Susceptibility: Potential Role for Ceftolozane/Tazobactam (C/T) and/or Imipenem/Relebactam (I/R)
Authors: Klinker Kenneth , DePestel Daryl , Motyl Mary , DeRyke C Andrew 
Published: January 2021

Abstract

Background
Carbapenem-resistant P. aeruginosa (CRPA) are associated with increased mortality and impose significant treatment challenges for clinicians. Among CRPA, co-resistance to 1st line antipseudomonal agents piperacillin/tazobactam (TZP) and cefepime (FEP) is common and often results in delays to timely effective therapy. A simple strategy for identifying patients at risk for suboptimal therapy is evaluation of institutional or unit specific frequency of CRPA. The purpose of this analysis is to identify beta-lactam (BL) susceptibility trends based on CRPA frequency observed in intensive care units (ICU).

Methods
In 2016-2019, ~20 US institutions per year submitted up to 250 consecutive, aerobic or facultatively anaerobic, gram-negative pathogens from blood, intra-abdominal, urinary, and lower respiratory tract infections as part of the Study for Monitoring Antimicrobial Resistance Trends. A total of 871 P. aeruginosa (PA) isolates were collected from lower respiratory tract specimens obtained from ICU patients. MICs were determined using CLSI broth microdilution method and interpreted with CLSI 2020 or FDA breakpoints. Institutions were then stratified into one of three categories based on CRPA frequency: CRPA rates ≤20% (CR1), 21 – 40% (CR2), and ≥41% (CR3). BL susceptibility was then evaluated relative to CRPA frequency.

Results
Thirty-seven (46%), 25 (31%), and 18 (23%) institutions were stratified into CR1, CR2, and CR3, respectively. Overall, CRPA was identified in 28.4% of all ICU lower respiratory isolates. Significant declines in FEP and TZP susceptibility were observed in institutions that demonstrated higher CRPA frequency (p&lt; 0.00001) (Table 1) with &gt;25% of isolates showing resistance in CR2 and CR3. In contrast, C/T susceptibility remained above 90% for all categories. I/R susceptibility remained above 90% for CR1 and CR2.
Table 1. P. aeruginosa susceptibility among ICU lower respiratory tract isolates stratified by unit specific frequency of carbapenem resistance

Conclusion
C/T and I/R provide robust activity against PA isolates obtained from the lower respiratory tract of critically ill patients, regardless of CR frequency. Assessing CRPA frequency may be useful for identifying inflection points in which novel agents could be considered. In settings where CRPA frequency exceeded 20%, additional testing or early switch to C/T or I/R may be warranted.

Disclosures
Kenneth Klinker, PharmD, Merck & Co, Inc (Employee) Daryl DePestel, PharmD, BCPS-ID, Merck & Co, Inc (Employee) Mary Motyl, PhD, Merck & Co, Inc (Employee, Shareholder) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder)
1452. Molecular Profile of β-Lactamase Genes and Siderophore-Dependent Iron Transporter Genes of Cefiderocol High MIC Isolates from SIDERO-WT Studies
Authors: Yamano Yoshinori , Takemura Miki , Kazmierczak Krystyna , Wise Mark G G , Hackel Meredith , Sahm Daniel F , Echols Roger 
Published: January 2021

Abstract

Background
Cefiderocol (CFDC) is a novel siderophore cephalosporin with efficacy against Gram-negative (GN) bacteria, including carbapenem-resistant Enterobacterales and non-glucose-fermenters such as Pseudomonas aeruginosa and Acinetobacter baumannii. In consecutive multinational surveillance (SIDERO-WT) studies (2014–2017), CFDC demonstrated activity with minimum inhibitory concentrations (MICs) of ≤4 mg/mL against 99.4% of 28,629 GN clinical isolates. We conducted molecular characterization of 161 isolates with CFDC MICs &gt;4 mg/mL from the SIDERO-WT studies.

Methods
A total of 161 isolates underwent whole genome sequencing by Illumina Hiseq. Analyses were done using the CLC genomics workbench (Qiagen) for possible resistance-related genes (e.g. β-lactamases, porin channels or penicillin-binding protein genes) and some TonB-dependent siderophore uptake receptor genes (fiu, cir, piu, pir). Fiu and Cir in Escherichia coli and Piu in P. aeruginosa are the iron transporters involved in CFDC transport.

Results
Of 161 isolates with CFDC MIC &gt;4 mg/mL, 128 were A. baumannii, 22 Enterobacterales, 7 Burkholderia multivorans, 2 P. aeruginosa, and 2 Stenotrophomonas maltophilia. Genes encoding PER/VEB extended-spectrum β-lactamases and NDM-type metallo-β-lactamases were detected in some isolates, but other β-lactamase genes (bla) were not shown to be linked to high CFDC MICs. blaPER/blaVEB were found only in A. baumannii and blaNDM was found in A. baumannii and Klebsiella pneumoniae. In 128 A. baumannii isolates, 103 harbored PER or VEB, including PER positive isolates from Russia (n=87) and Turkey (n=6) and 4 VEB positive isolates from USA. Nine NDM-positive isolates (7 K. pneumoniae, 2 A. baumannii) were found. Disruption of iron transport genes was also detected in some isolates, including piuA (11 A. baumannii, 1 P. aeruginosa), pirA (2 A. baumannii), and fiuA (4 B. multivorans, 1 Proteus mirabilis). No cir homologs were found in 2 B. multivorans.

Conclusion
PER and NDM could reduce susceptibility to CFDC, as such isolates have been seen in some countries. Iron transporter disruption was also observed in some isolates with high CFDC MICs; the contribution of these deficiencies in A. baumannii and B. multivorans requires further study.

Disclosures
Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Krystyna Kazmierczak, PhD, Shionogi & Co., Ltd. (Independent Contractor) Mark G G. Wise, PhD, Shionogi & Co., Ltd. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor) Roger Echols, MD, Shionogi Inc. (Consultant)
1455. Potential Mechanisms of Cefiderocol MIC Increase in Enterobacterales in In Vitro Resistance Acquisition Studies
Authors: Yamano Yoshinori , Nakamura Rio , Takemura Miki , Echols Roger 
Published: January 2021

Abstract

Background
Cefiderocol (CFDC) is a novel siderophore, iron-chelating cephalosporin, which is transported into bacteria via iron transporters. CFDC has potent in vitro and in vivo activity against all aerobic Gram-negative bacteria, including carbapenem-resistant strains. To date, clinical isolates with cefiderocol MIC &gt;4 µg/mL have been found infrequently, in which the presence of a few β-lactamases or altered iron transport was found. We investigated potential new mechanisms causing CFDC MIC increases in non-clinical studies.

Methods
The mutation positions were determined by whole genome sequencing using four K. pneumoniae mutants including two KPC producers and one NDM producer that had shown CFDC MIC increases in previous in vitro resistance-acquisition studies. The mutant strains were obtained at the frequency of 10-7 to &lt; 10-8 by spreading bacteria on standard Mueller‒Hinton agar medium containing CFDC at concentrations of 10× MIC, with or without apo-transferrin (20 μg/mL). CFDC MIC was determined by broth microdilution using iron-depleted cation-adjusted Mueller-Hinton broth based on Clinical and Laboratory Standards Institute guidelines. The emergence of MIC increase mutants was also assessed by in vitro chemostat models under humanized plasma pharmacokinetic exposures of CFDC.

Results
The possible resistance mechanisms were investigated. Mutation of baeS or envZ, sensors of two-component regulation systems, were found in three or two mutants among the tested four isolates, respectively, and caused the MIC to increase by 4–32-fold. The altered expression level of specific genes by the baeS or envZ mutation could affect CFDC susceptibility, but the specific genes have not been identified. In addition, the mutation of exbD, an accessory protein related to iron transport, was identified in one case and caused the MIC to increase by &gt;8-fold. In vitro chemostat studies using two isolates (one NDM producer and one KPC producer) showed no resistance acquisition during 24-hour exposure.
Table. Overview of mutation emergence in five isolates of K. pneumoniae

Conclusion
The mutation of two-component regulation systems (BaeSR and OmpR/EnvZ) and iron transport-related proteins were shown to be possible mechanisms causing CFDC MIC increases, but these mutants did not appear under human exposures.

Disclosures
Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi & Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)
1458. Uncharted territories: applying “precision medicine” to understand the treacherous landscape of extensively and multidrug resistant (XDR and MDR) Pseudomonas aeruginosa in a patient with cystic fibrosis and lung transplantation
Authors: Rojas Laura J , Yasmin Mohamad , Benjamino Jacquelynn , Marshall Steven , DeRonde Kailynn , Krishnan Nikhil , Perez Federico , Colin Andrew , Cardenas Monica , Martinez Octavio , Perez-Cardona Armando , Rhoads Daniel , Jacobs Michael , Scott Jacob , Adams Mark D , Abbo Lilian M , Abbo Lilian M , Bonomo Robert A 
Published: January 2021

Abstract

Background
Pseudomonas aeruginosa is a persistent and difficult-to-treat pathogen in many patients, especially those with cystic fibrosis (CF). Herein, we describe our experience managing a young woman suffering from CF with XDR P. aeruginosa who underwent lung transplantation. We highlight the contemporary difficulties reconciling the clinical, microbiological, and genetic information.

Methods
Mechanism-based-susceptibility disk diffusion synergy testing with double and triple antibiotic combinations aided in choosing tailored antimicrobial combinations to control the infection in the pre-transplant period, create an effective perioperative prophylaxis regimen, and manage recurrent infections in the post-transplant period. Thirty-six sequential XDR and PDR P. aeruginosa isolates obtained from the patient within a 17-month period, before and after a double-lung transplant were analyzed by whole genome sequencing (WGS) and RNAseq in order to understand the genetic basis of the observed resistance phenotypes, establish the genomic population diversity, and define the nature of sequence changes over time

Results
Our phylogenetic reconstruction demonstrates that these isolates represent a genotypically and phenotypically heterogeneous population. The pattern of mutation accumulation and variation of gene expression suggests that a group of closely related strains was present in the patient prior to transplantation and continued to evolve throughout the course of treatment regardless of antibiotic usage.Our findings challenge antimicrobial stewardship programs that assist with the selection and duration of antibiotic regimens in critically ill and immunocompromised patients based on single-isolate laboratory-derived resistant profiles. We propose that an approach sampling the population of pathogens present in a clinical sample instead of single colonies be applied instead when dealing with XDR P. aeruginosa, especially in patients with CF.

Conclusion
In complex cases such as this, real-time combination testing and genomic/transcriptomic data could lead to the application of true “precision medicine” by helping clinicians choose the combination antimicrobial therapy most likely to be successful against a population of MDR pathogens present.

Disclosures
Federico Perez, MD, MS, Accelerate (Research Grant or Support)Merck (Research Grant or Support)Pfizer (Research Grant or Support) Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)
1468. Culture Conversion and Mortality in Patients With Mycobacterium abscessus (MAB) Lung Disease: A Systematic Literature Review
Authors: Winthrop Kevin L , Mange Kevin C , Jumadilova Zhanna , Cline Kristan B , Flume Patrick A 
Published: January 2021

Abstract

Background
Prognosis for patients with MAB lung disease is poor. We sought to examine the potential association between culture conversion and outcomes (progression, mortality) in patients with MAB lung disease.

Methods
English-language MAB lung disease studies with ≥ 10 patients and reporting mortality and/or microbiological outcomes were identified from Embase, PubMed, relevant congress abstracts, and the Cochrane Library (data cutoff, September 24, 2019) using the National Institute for Health and Clinical Excellence guidance for systematic literature reviews. Two independent reviewers screened 1,551 indexed records; relevant extracted data are expressed as population-weighted means.

Results
Mean all-cause mortality across 17 studies (N=1,291) was 12.1% (range, 3%–33%); mortality attributable to MAB lung disease was 7.6% (range, 0%–27%; N=526, 9 studies). Culture conversion across 44 studies (N=2,237) was 46.7% (range, 0%–98.6%), with higher rates reported for M. massiliense subspecies (76.9%; N=507,15 studies) than M. abscessus subspecies (35.8%; N=834,18 studies). No direct comparisons were made between mortality and culture conversion; in the 13 studies (N=1,202) that reported both outcomes there was a moderate correlation between increased rate of culture conversion and decreased MAB-attributable mortality (R2=0.60). The most common definition of progression (21 studies) was radiographic worsening supported by persistent symptoms and/or positive cultures. Across 8 studies (N=415) 57.8% patients had improvement while 35.2% progressed with treatment. A broad variance in treatment regimen and duration (range, 32 days to &gt; 3 years) was observed. Limitations include a small number of studies, and inconsistency in methods and outcomes definitions.

Conclusion
In this systematic literature review, available data suggest that culture conversion was achieved in less than half of patients and was lower in patients with M. abscessus compared with M. massiliense. One third of patients had disease progression despite treatment. Some data suggest lower MAB-attributed mortality outcomes in studies with higher culture conversion rates, more evidence is needed to demonstrate a survival benefit associated with culture conversion.

Disclosures
Kevin L Winthrop, MD, MPH, Insmed Incorporated (Consultant, Grant/Research Support) Kevin C Mange, MD, MSCE, Insmed Incorporated (Employee) Zhanna Jumadilova, MD, Insmed Incorporated (Employee) Kristan B Cline, PhD, Insmed Incorporated (Employee) Patrick A Flume, MD, Insmed Incorporated (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)
120. Stewardship Driven Reduction of Inappropriate Clostridioides difficile Testing at a Tertiary Military Medical Facility
Authors: Gilbert Laura , Robinson Sara , Raiciulescu Sorana , Ressner Roseanne 
Published: January 2021

Abstract

Background
C. difficile infection (CDI) is the leading hospital associated (HA) infection in an era of antibiotic overuse and highly-sensitive PCR-based diagnostics. PCR does not differentiate CDI versus colonization making over-reporting a concern. HA-CDI can impact hospital reimbursement, lead to unnecessary treatment, increase costs and length of stay. Our aim was to implement an intervention to target inappropriate C. difficile (CD) testing.

Methods
Two-tiered testing is not utilized at our facility. After provider education on guidelines for appropriate CD testing, prompts were introduced into the electronic medical record (EMR) for CD test orders. At order input, providers are prompted to answer “yes” or “no” to two questions; 1) receipt of stool softeners within the preceding 48 hours and 2) criteria of 3 loose stools within 24 hours. The test order was completed regardless of the responses to the prompted questions. Six-month post-intervention data was compared to the same timeframe during the year prior.

Results
A total of 334 and 236 tests were ordered in the pre- and post-intervention periods respectively. Accounting for inpatient bed days, the incidence reduction rate (IRR) was 0.75 (CI 0.63–0.89, p &lt; 0.001) corresponding to an estimated hospital cost-savings of $12,250 based on testing costs alone. The majority of CD tests were ordered by IM providers, who also demonstrated the greatest reduction in tests ordered post-intervention. Patient characteristics were analyzed in the pre- and post-intervention periods finding significantly less positive CD tests ordered for patients with recurrent C. difficileduring the post-intervention period (2 vs 7, p = 0.04). Patients who were transferred from another institution had significantly more positive CD tests in the post-intervention period (19 vs 7, p = 0.02).

Conclusion
In conclusion, the results demonstrate that implementing a systems-based EMR initiative led to a 25% reduction in CD testing with a cost-savings of $12,250 not accounting for potential associated cost savings. This project suggests that even without restricting order access, educational prompts integrated in the EMR can have meaningful impact on stewardship endeavors to help reduce inappropriate CD testing. Sustained effect would be an area to explore.

Disclosures
All Authors: No reported disclosures
1469. Effect of pneumonia and pneumonia hospitalization episodes on mobility in older adults: results from the Lifestyle Interventions and Independence for Elders (LIFE) Study
Authors: Brown Joshua , Sato Reiko , Morley John 
Published: January 2021

Abstract

Background
Mobility is a cornerstone of healthy aging. Pneumonia may impact mobility through damage to physiological systems as well as increased inflammation, which has been associated with reduced physical functioning. The objective of this study was to assess the impact of pneumonia on objectively measured physical functioning in a sample of older adults.

Methods
This was a post-hoc analysis of the Lifestyle Interventions and Independence for Elders (LIFE) Study provided by the National Institute on Aging’s AgingResearchBiobank. Participants with pre-existing mobility concerns aged 70-89 years were randomized to physical activity or health education interventions. Outcomes included the ability to complete a 400-meter walk and gait speed (meters/second, m/s) and were assessed every 6 months from baseline up to 42 months. New health events were assessed at each visit including overall pneumonia events and pneumonia hospitalizations. Repeated measures regression models evaluated the ability to walk 400-meters and gait speed as separate outcomes controlling for age, sex, race, education, past medical history, the occurrence of other health events, and a cumulative deficit frailty index.

Results
There were 1,635 LIFE Study participants with N=9,872 follow-up measures during the study period. Among these, 174 (10.6%) had a pneumonia event which included 96 hospitalization events. Those with pneumonia events during follow-up were mostly similar to those without pneumonia events at baseline, except for higher prevalence of past hospitalizations and respiratory problems. Any pneumonia event was associated with an adjusted mean gait speed of 0.67 (0.63-0.71) m/s vs. 0.70 (0.66-0.73) m/s in those without pneumonia and 0.60 (0.55-0.64) in those with pneumonia hospitalization. Similarly, pneumonia events were associated with 84% [odds ratio = 1.84 (1.45-2.23)] and pneumonia hospitalizations with 200% [odds ratio = 3.00 (2.48-3.52)] increases in the odds of not being able to walk 400-meters compared to those without pneumonia events.

Conclusion
Pneumonia-related health events were associated with subsequent reduced mobility measured by 400-meter walk tests and gait speed. Preventing pneumonia may be an important component of maintaining physical functioning in older adults.

Disclosures
Joshua Brown, PharmD, PhD, Pfizer, Inc (Consultant, Grant/Research Support) Reiko Sato, PhD, Pfizer, Inc (Employee, Shareholder) John Morley, MD, Pfizer, Inc (Consultant)
1470. Epidemiology of Invasive Pneumococcal Disease (IPD) Following 18 years of Pneumococcal Conjugate Vaccine (PCV) Use in the United States
Authors: Pilishvili Tamara , Gierke Ryan , Farley Monica M , Schaffner William , Thomas Ann , Reingold Art , Harrison Lee , Holtzman Corinne , Burzlaff Kari , Petit Susan , Herlihy Rachel , Torres Salina , Beall Bernard 
Published: January 2021

Abstract

Background
PCVs have been recommended for U.S. children since 2000. A 7-valent vaccine (PCV7) was introduced in 2000. This was replaced by a 13-valent vaccine (PCV13) in 2010. PCV13 was also recommended for adults aged ≥ 65 years in August 2014. We evaluated PCV impact on IPD.

Methods
IPD cases (isolation of pneumococcus from sterile sites) were identified through CDC’s Active Bacterial Core surveillance during 1998-2018. Isolates were serotyped by Quellung or whole genome sequencing and classified as PCV13-type and non-vaccine-type (NVT). Incidence rates (cases/100,000) were calculated using U.S. Census Bureau population denominators.

Results
From 1998 through 2018, overall IPD rates among children aged &lt; 5 years decreased by 93% (from 95 to 7 cases/100,000). PCV13-type IPD decreased by 98% (from 88 to 2 cases/100,000). Among adults aged ≥ 65 years, overall IPD rates decreased by 60% (from 61 to 25 cases/100,000). PCV13-type IPD rates declined 86% (from 46 to 7 cases/100,000). Declines were most dramatic in the years following PCV7 introduction, with additional declines after PCV13 introduction in children (Figures 1 and 2). Serotypes 3, 19A, and 19F caused most of the remaining PCV13-type IPD. NVT IPD rates did not change significantly among children. Among adults aged 50-64 years, NVT IPD increased by 83% (from 6 to 12 cases/100,000) (p&lt; 0.01). Among adults aged ≥ 65 years, NVT IPD increased by 22% (from 15 to 18 cases/100,000) (p&lt; 0.01). The most common NVTs in 2018 were 22F (10% of all IPD), 9N (7%) and 15A (5%). Among children, the proportion of cases with meningitis increased from 5% to 14% (p&lt; 0.01), and the proportion with pneumonia/empyema increased from 17% to 31% (p&lt; 0.01). Among adults, the proportion of cases with meningitis did not change (3%), while the proportion with pneumonia/empyema increased from 72% to 76% (p=0.01).
Figure 1: Incidence of invasive pneumococcal disease among children aged &lt; 5 years, 1998-2018

Figure 2: Incidence of invasive pneumococcal disease among adults aged ≥ 65 years, 1998-2018

Conclusion
Overall IPD incidence among children and adults decreased following PCV introduction for children, driven primarily by reductions in PCV-type IPD. NVT IPD increased in older adults, but these increases did not eliminate reductions from PCV13-type IPD.

Disclosures
Lee Harrison, MD, GSK (Consultant)Merck (Consultant)Pfizer (Consultant)Sanofi Pasteur (Consultant)