bluuebunny/crossref_metadata_2025_split huggingface dataset:
192. Tolerability Outcomes of Multi-drug Antibiotic Treatment for Pulmonary Nontuberculous Mycobacterial Disease due to Mycobacterium avium Complex in U.S. Medicare Beneficiaries with Bronchiectasis
Authors: Ku Jennifer , Henkle Emily , Carlson Kathleen F , Marino Miguel , Brode Sarah K , Marras Theodore K , Winthrop Kevin L , Winthrop Kevin L 
Published: December 2021

Abstract

Background
Nontuberculous mycobacteria (NTM), most frequently Mycobacterium avium complex (MAC), cause increasingly common pulmonary infections. Treatment interruptions and early discontinuation are common in MAC therapy, but population-based data on treatment outcomes are severely lacking. We examined tolerability outcomes of guideline-based 3-drug therapies (GBT) targeted for pulmonary MAC infection.

Methods
Among beneficiaries with bronchiectasis (ICD-9-CM 494.0 or 494.1) in U.S. Medicare data (01/2006 – 12/2014), we identified first-time MAC GBT therapy users, excluding those with cystic fibrosis, HIV, or a history of organ transplant. MAC GBT was defined as an overlapping prescription of ≥ 28-day supply of a macrolide, ethambutol and rifamycin. Using Cox regression methods, we compared time-to-regimen change or discontinuation within 12 months of therapy start in the following groups: 1) azithromycin-ethambutol-rifamycin vs. clarithromycin-ethambutol-rifamycin; 2) macrolide-ethambutol-rifampin vs. macrolide-ethambutol-rifabutin; and 3) azithromycin-ethambutol-rifampin vs. clarithromycin-ethambutol-rifabutin.

Results
We identified 4,626 GBT therapy users (mean 77.9 years [s.d. 6.1], female [77.7%], and non-Hispanic white [87.2%]). Overall, the rate of regimen change or discontinuation was higher in the clarithromycin-based regimens compared to azithromycin-containing regimens, and in rifabutin-containing regimens compared to rifampin-containing regimens. The rate of drug regimen change or discontinuation was 65% greater in the clarithromycin-ethambutol-rifabutin group compared to the azithromycin-ethambutol-rifampin group (adjusted hazard ratio: 1.64, 95% CI: 1.43, 1.64) (Table 1, Figure 1).

Conclusion
Azithromycin-based regimens and rifampin-containing regimens were less likely to be changed or discontinued within 12 months of therapy compared to clarithromycin-based regimens and rifabutin-containing regimens, respectively. More research is needed to identify factors associated with early treatment change or discontinuation.

Disclosures
Emily Henkle, PhD, MPH, AN2 (Consultant, Advisor or Review Panel member)Zambon (Advisor or Review Panel member) Theodore K. Marras, MD, Astra Zeneca (Speaker’s Bureau)Insmed (Scientific Research Study Investigator)Novartis (Speaker’s Bureau)RedHill (Consultant)Spero (Consultant) Kevin L. Winthrop, MD, MPH, Insmed (Consultant, Grant/Research Support)Paratek (Consultant)RedHill (Consultant)Spero (Consultant) Kevin L. Winthrop, MD, MPH, Insmed (Consultant, Research Grant or Support)Paratek (Consultant)RedHill Biopharma (Consultant)Spero (Consultant)
195. Intravenous to Oral Antibiotics Versus Intravenous Antibiotics: A Step-Up or a Step-Down for Extended Spectrum Beta-Lactamase Producing Urinary Tract Infections?
Authors: Gamble Kelly C , Rose Dusten T , Sapozhnikov Julia 
Published: December 2021

Abstract

Background
The treatment of extended-spectrum beta-lactamase (ESBL)-producing urinary tract infections (UTI) may include either intravenous (IV) or oral (PO) antibiotics, according to the Infectious Diseases Society of America guidelines for resistant gram negative infections. The purpose of this study is to evaluate if PO step-down antibiotics, the switch group, compared to continued IV therapy in these UTIs affects clinical outcomes.

Methods
This multicenter retrospective cohort study was conducted in hospitalized patients with an ESBL-producing UTI between July 2016 and March 2020. The control group received a complete antibiotic course with a carbapenem. The switch group was transitioned to an oral agent within five days from initiation of a carbapenem. The primary endpoint was a composite all-cause clinical failure, which was defined as readmission or hospital mortality within 30 days of hospital discharge or a change in antibiotic during hospital admission. The secondary endpoints included individual components of the primary outcome, readmission indication, inpatient length of stay, direct antibiotic costs, and adverse events.

Results
The study included 153 patients: 95 and 58 patients in the control and switch groups, respectively. Demographics between the two groups were similar (Table 1). The mean ± SD duration of therapy was 8.7 ± 3.1 and 7.1 ± 3.3 days, respectively. Four oral agents were used for step-down therapy (Figure 1). The primary outcome occurred in 28% in both groups (27 vs 16 patients, p=0.91). The individual components of the primary outcome and readmission indication were also similar: readmission (93% vs 94%, p=0.95), readmission due to a recurrent UTI (33% vs 25%, p=0.73), hospital mortality (7% vs 6%, p=1.0), and change in antibiotic (0% vs 2%, p=0.38). The median (IQR) length of stay and direct antibiotic cost in the control and switch groups were 8 (6) vs 5 (2) days (p&lt; 0.01) and &278 (&244) vs &180 (&104) (p&lt; 0.01), respectively. Adverse events were similar in both groups except for diarrhea (15% vs 2%, p=0.01).
Table 1. Baseline Demographics. SD: standard deviation, ICU: intensive care unit, qSOFA: quick Sequential Organ Failure Assessment, ESBL: extended spectrum beta-lactamase, UTI: urinary tract infection

Figure 1. Oral Antibiotics. QD: once daily, BID: twice daily, Q2D: every 2 days, Q3D: every 3 days, DS tab: double strength tablet

Conclusion
There was no difference in clinical failure, readmission rate, mortality rate, or change in antibiotic between the control and switch groups; however, the switch group was associated with reduced hospital length of stay and direct antibiotic cost.

Disclosures
All Authors: No reported disclosures
201. Frequency of Pseudomonas aeruginosa (PA) Discrete Inner Colonies and Comparison of Minimal Inhibitory Concentration (MIC) Values between Parent and Inner Colony Isolates Following Fosfomycin Disk Diffusion (DD) Testing
Authors: Zheng Dina , Bixby Morgan L , Smith Elizabeth C , Anderson Jadyn C , Bergen Phillip J , Landersdorfer Cornelia B , Hirsch Elizabeth B 
Published: December 2021

Abstract

Background
Fosfomycin combination therapy is a potential approach for treatment of multidrug-resistant (MDR) PA infections despite a lack of approved susceptibility breakpoints for this organism. While DD testing is commonly used for fosfomycin, growth of discrete inner colonies (IC) within the zone of inhibition has been observed for multiple organisms following DD. Criteria recommended by CLSI and EUCAST are contradictory for interpreting these inner colonies. We therefore sought to determine the frequency of inner colonies and MIC differences between PA parent-inner colony pairs from an international isolate collection.

Methods
A convenience collection of 198 clinical PA isolates from three U.S institutions (n = 82), two Australian institutions (n = 72), and the CDC & FDA Antibiotic Resistance Isolate Bank (n = 44) were included. Fosfomycin MIC values were determined in duplicate on separate days by DD and broth microdilution (BMD) testing. For parent isolates with discrete IC observed during DD, IC isolates were subcultured and MIC values were determined and then compared to their corresponding parent isolates. MIC values were interpreted using CLSI Escherichia coli (EC) breakpoints (susceptible: MIC ≤ 64 μg/mL, intermediate: MIC = 128, resistant: MIC ≥ 256 μg/mL).

Results
Parent isolate BMD MIC values ranged from &lt; 4 to &gt; 256 μg/mL while IC isolate BMD MIC values ranged from 128 to &gt; 1024 μg/mL. MIC50/90 values were 128/256 μg/mL and &gt; 1024/ &gt; 1024 μg/mL for the parent and IC isolates, respectively. A high frequency of 45% (89/198) of parent isolates displayed discrete IC which also demonstrated a higher frequency of resistance (97.8%) compared to the parent isolates (23.7%).

Conclusion
IC MIC values were higher overall compared to parent MIC values, with an average fold difference of ~18 between the parent-inner colony pairs. The frequency of IC found in this study (45%) is considerably higher than previously observed in EC clinical isolates. These data highlight the need to further investigate the importance of these IC and warrant caution for extrapolation of EC breakpoints for fosfomycin susceptibility testing against PA.

Disclosures
All Authors: No reported disclosures
203. Activity of Cefepime in Combination with Taniborbactam (formerly VNRX-5133) Against Pseudomonas aeruginosa from a Global 2018-2020 Surveillance Collection
Authors: Hackel Meredith , Wise Mark G G , Sahm Daniel F 
Published: December 2021

Abstract

Background
Taniborbactam is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor (BLI) with potent and selective inhibitory activity against both serine- and metallo-β-lactamases (MBLs). Taniborbactam restores the activity of cefepime (FEP) against many multidrug resistant organisms, including cephalosporin- and carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa (PA). We evaluated the in vitro activity of the investigational combination cefepime-taniborbactam and comparators against clinical isolates of PA collected during a 2018-2020 surveillance.

Methods
MICs of FEP with taniborbactam fixed at 4 µg/mL (FTB) and comparators were determined against 3,219 PA collected from 221 sites in 52 countries in 2018-2020. Resistant phenotypes were based on 2021 CLSI breakpoints. Acquired β-lactamase (BL) genes were identified via PCR/Sanger sequencing or whole-genome sequencing (WGS) for 516 isolates with meropenem (MEM) MIC ≥8 µg/mL, and for 94 randomly selected isolates with FEP or ceftazidime MIC ≥16 µg/mL. 186 isolates with FTB MIC ≥16 µg/mL, 16 with FTB MIC=8 µg/mL and one with FTB MIC=4 µg/mL were subjected to WGS.

Results
Overall, 28.7%, 26.2% and 20.3% of PA isolates were nonsusceptible (NS) to piperacillin-tazobactam (TZP), MEM or FEP, respectively (Table). FTB demonstrated potent activity (MIC50/90, 2/8 µg/mL; 94.2% inhibited at ≤8 µg/mL) against PA overall and inhibited between 63.4% (ceftazidime-avibactam [CZA] NS) and 82.1% (TZP NS) of isolates in the NS subsets compared to 0% to 69.1% S for comparators. Against the 111 strains carrying VIM or NDM MBL genes, 67.6% had FTB MICs ≤8 µg/mL, with 11.7% having FTB MICs of 16 µg/mL. Plausible explanations for elevated FTB MICs included IMP MBL genes, penicillin binding protein 3 variations, and/or possible efflux pump up-regulation.

Conclusion
FTB demonstrated potent in vitro activity against PA with different resistance profiles, including NS to FEP, MEM, and TZP, and to the BL/BLI combinations CZA, ceftolozane-tazobactam, and meropenem-vaborbactam. FTB was the most active agent tested against PA harboring VIM and NDM MBLs. These findings support the continued development of FTB as a potential new treatment option for challenging infections due to MDR PA.

Disclosures
Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Mark G G. Wise, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
02. Beyond B Antigen Coverage: The Potential of the 4CMenB Vaccine for Cross-protection Against Pathogenic Neisseria Infections
Authors: Garcia Yara Ruiz , Sohn Woo-Yun , Pizza Mariagrazia , Bekkat-Berkani Rafik 
Published: December 2021

Abstract

Background
Two human pathogenic Neisseria species exist: N. meningitidis (Nm) and N. gonorrhoeae (Ng). Although causing disparate clinical syndromes, invasive meningococcal disease (IMD) and gonorrhea, they are genetically similar and share key protein antigens. The 4CMenB vaccine, licensed against meningococcal B disease, comprises 4 antigenic components (factor H binding protein (fHbp), variant 1.1, subfamily B; Neisseria heparin binding antigen (NHBA) peptide 2; Neisserial adhesin A (NadA) variant 3; and Porin A (PorA) P1.4), and potentially protects against non-B invasive meningococcal and gonococcal strains. In this review, we summarize the similarities between these antigens and those in Nm serogroups A, C, W, X and Y and Ng.

Methods
Published data in humans were analyzed to conduct a narrative literature review of the potential extent of meningococcal vaccine-induced protection against non-B meningococcal strains and Ng. Techniques applied to indirectly measure this effect are based on genotype-phenotype modelling, strain coverage, bactericidal killing and direct impact on disease reduction.

Results
Data were identified from countries in America, Europe, Africa and Oceania. The genes encoding for fHbp and NHBA are also present in strains belonging to the five non-B serogroups, while NadA is present in several strains of serogroups C, W and Y, and PorA P1.4 mainly in serogroup W. At the genome level, Ng and Nm share up to 90% homology. Most of the outer membrane vesicle antigens, like PilQ, Omp85 (BamA), NspA, MtrE, MetQ, LbpA, PorB, FetA, OpcA and NHBA, are highly conserved in Ng. In addition, a synergistic effect might enhance immunogenicity against non-B serogroups as shown against serogroup B.

Conclusion
4CMenB components are present and conserved in several Ng and Nm strains. Recent results demonstrate that 4CMenB reduces MenW disease incidence in infants and might generate cross-protection against other non-B serogroups. In addition, 4CMenB has been proven to be effective in reducing gonococcal infections in adolescents. Research on future genomic and proteomic characterizations of IMD and gonorrhea strains will provide information on the molecular basis of the underlying broad strain coverage, while informing decisions regarding prevention and immunization programmes.

Disclosures
Yara Ruiz Garcia, MSc, PhD, GSK group of companies (Employee) Woo-Yun Sohn, MD, GSK group of companies (Employee, Shareholder) Mariagrazia Pizza, Biological Sciences, PhD, GSK group of companies (Employee, Shareholder) Rafik Bekkat-Berkani, M.D, GSK group of companies (Employee, Shareholder)
03. Immunogenicity and Safety of a Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) Administered as a Booster Dose in Adults and Adolescents Vaccinated Against Meningococcal Disease 3 - 6 Years Earlier
Authors: Peterson James , Deseda Carmen , Julien Katie , Zambrano Betzana , Áñez Germán , Jiayuan Sue , Pan Judy , Arroum Habiba , Varghese Kucku , Jordanov Emilia , Dhingra Mandeep S 
Published: December 2021

Abstract

Background
Booster doses of meningococcal conjugate vaccines may induce long-term protection against invasive meningococcal disease. MenACYW-TT [MenQuadfi®] is a quadrivalent meningococcal conjugate vaccine, licensed for use in ages 2 years and older in USA. The vaccine is also licensed in ages 12 months and older in EU and other countries.

Methods
A phase IIIb study (NCT04084769) was conducted to evaluate the persistence of immune response in adults and adolescents primed 3-6 years earlier with either MenACYW-TT or MCV4-CRM (Menveo®) and, safety and immunogenicity of MenACYW-TT when administered as a booster dose with or without concomitant administration with MenB vaccines (Bexsero® and Trumenba®). Serum bactericidal assays with human complement (hSBA) and baby rabbit complement (rSBA) were used to measure antibodies against vaccine serogroups at baseline (Day 0 [D0]), D06 (in a subset) and 30 days post-vaccination (D30). Safety data were collected up to 6 months post-vaccination.

Results
At D0, the GMTs were higher in subjects primed with MenACYW-TT vs MCV4-CRM for serogroups C, Y and W, and were comparable for serogroup A. At D0, all hSBA GMTs were higher than those observed pre-priming dose, suggesting persistence of immunity. Sufficiency of hSBA seroresponse ( &gt;75%) was demonstrated following administration of MenACYW-TT booster dose regardless of the priming vaccine administered 3-6 years earlier. Vaccine seroresponse in a subset of participants at D06 ranged from 77.8% (95%CI 62.9%; 88.8%) for serogroup A to 97.8% (88.5%; 99.9%) for serogroup W suggesting a quick onset of immune response post-booster. Post-vaccination (D30) hSBA GMTs were comparable for serogroups A, Y and W regardless of the nature of the priming vaccine and were higher for serogroup C in subjects primed with MenACYW-TT vaccine. The MenACYW-TT booster dose was well-tolerated and had similar safety profiles regardless of the priming vaccine. The safety profiles were comparable regardless of the MenB vaccine co-administered with MenACYW-TT vaccine.

Conclusion
MenACYW-TT used as priming vaccine was able to demonstrate persistence of immune response 3-6 years later. MenACYW-TT elicits robust booster responses in adults and adolescents primed with MenACYW-TT or MCV4-CRM

Disclosures
Betzana Zambrano, MD, Sanofi Pasteur (Employee) Germán Áñez, MD, Sanofi Pasteur (Other Financial or Material Support, Former employee) Sue Jiayuan, MSc, Sanofi Pasteur (Independent Contractor) Judy Pan, PhD, Sanofi Pasteur (Employee) Habiba Arroum, MD, Sanofi Pasteur (Employee) Kucku Varghese, PhD, Sanofi Pasteur (Employee) Emilia Jordanov, MD, Sanofi Pasteur (Employee, Shareholder) Mandeep S. Dhingra, MD, Sanofi Pasteur (Employee, Shareholder)
05. Pragmatic Assessment of Influenza Vaccine Effectiveness in the DoD (PAIVED): Updates from Year 3 of Multi-Site Trial
Authors: Burgess Timothy , Richard Stephanie A , Collins Limone , Colombo Rhonda E , Ganesan Anuradha , Geaney Casey , Hrncir David , Lalani Tahaniyat , Markelz Ana E , Maves Ryan C , Maves Ryan C , McClenathan Bruce , Mende Katrin , Modi Jitu , Montgomery Jay R , Schofield Christina , Seshadri Srihari , Skerrett Catherine , Spooner Christina , Utz Gregory , Warkentien Tyler , Williams Alan , Coles Christian L 
Published: December 2021

Abstract

Background
The SARS-CoV-2 pandemic has spotlighted respiratory infections and the value of effective vaccines. The SARS-CoV-2 vaccine has been remarkably effective; however, influenza vaccine effectiveness has been reported to be lower among active duty military populations than in the general public (18% vs 36%). The Pragmatic Assessment of Influenza Vaccine Effectiveness in the DoD (PAIVED) study compares 3 FDA-licensed influenza vaccine types (egg-based, cell-based, and recombinant) to assess differences in immunogenicity and effectiveness in adults.

Methods
Participants in the 3rd year of PAIVED (2020/21 influenza season) were enrolled from October 2020 through January 2021. Participants received weekly surveys about influenza-like-illnesses (ILI) experienced in the past week; if they reported an ILI, they were queried about symptom duration and severity, and asked to self-collect a nasal swab and dried blood sample. Four weeks later, more information about symptom duration and illness burden was obtained via telephone interview, and the participant collected a second blood sample.

Results
PAIVED year 3 enrolled 3,269 participants (Table 1). 278 participants reported 1 ILI , while 60 reported 2 ILIs, and 18 reported 3 ILIs. No pathogen was identified for most processed ILI samples (78%); the most common viruses were SARS-CoV-2 (25, 12%), rhinovirus (24, 12%), and seasonal coronaviruses (4, 2%). No influenza has been identified thus far. Among those participants who had convalescent ILI visits (275), the median duration of the reported ILIs was 9 days (IQR 5, 15), with a median of 4 days (IQR 2, 7) of limited activity, and 2 days (IQR 0, 3) with fever. Three individuals were hospitalized.

Conclusion
There have been relatively low rates of ILI identified in this study during this season, with only 11% of the participants reporting an ILI so far, consistent with low rates of non-COVID-19 ILI reported elsewhere during the current pandemic. We anticipate some influenza cases may be identified as more samples are processed. Planned analyses include calculating comparative influenza vaccine effectiveness to inform future vaccine purchasing decisions, as well as comparing serological response to the different vaccines.

Disclosures
Ryan C. Maves, MD, EMD Serono (Advisor or Review Panel member)Heron Therapeutics (Advisor or Review Panel member) Jitu Modi, MD, GSK (Speaker’s Bureau)
06. United States Healthcare Provider Preferences for Adult Pneumococcal Vaccine Recommendations
Authors: Vietri Jeffrey , Meyers Kelley , Poulos Christine , Chilson Erica , Sweeney Carolyn , Davis Kimberly , Snow Vincenza 
Published: December 2021

Abstract

Background
Pneumococcal vaccine recommendations for US adults are complex, varying by age and underlying conditions, and include both 23-valent polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine. The Advisory Committee on Immunization Practices (ACIP) will vote on new recommendations in October after the 15- (PCV15) and 20-valent (PCV20) conjugate vaccines are approved. Stakeholder acceptability is part of ACIP’s evidence to recommendation framework, but few data are available on health care providers’ (HCPs) preferences for potential recommendations.

Methods
752 HCPs (300 physicians, 150 nurse practitioners, 150 physician assistants, & 152 pharmacists) were surveyed. Object case best-worst scaling (BWS) was used to elicit preferences for hypothetical recommendations for 1) adults 19-64 years with chronic conditions and 2) immunocompetent adults ≥65 years. Presented recommendations included combinations of PCV15/PCV20 either as routine or after shared clinical decision making (SCDM), and PPSV23 as routine, SCDM, or no recommendation. Following BWS, HCPs were asked to assume ACIP was considering implementing both of their preferred recommendations for the age/risk groups. HCPs were then given the opportunity to change their selections and propose recommendations not included in the BWS exercise. Additional information was collected using conventional survey items.

Results
Routine use of higher-valent PCVs in sequence with PPSV23 was most often preferred for both adults 19-64 with chronic conditions (40%) and immunocompetent adults ≥65 (49%) when elicited separately for each age/risk group. Most respondents (63%) revised their recommendations after considering implementation, which resulted in most (59%) favoring recommendations harmonized across the age/risk groups, and 75% favoring routine use of PCV15 or PCV20 among immunocompetent adults ≥65. When asked directly, HCPs generally approved of the idea of simplifying adult pneumococcal vaccine recommendations, harmonizing the interval between vaccines, and lowering the cutoff for age-based recommendations below 65 years.

Conclusion
US HCPs generally prefer simplification of the adult pneumococcal recommendation, favoring broad routine use of both higher-valent PCVs and PPSV23.

Disclosures
Jeffrey Vietri, PhD, Pfizer Inc (Employee, Shareholder) Kelley Meyers, PhD, RTI Health Solutions (Independent Contractor) Christine Poulos, PhD, Pfizer Inc (Other Financial or Material Support, Employee of RTI-HS, which received funds from Pfizer to conduct the study) Erica Chilson, PharmD, Pfizer, Inc (Employee, Shareholder) Vincenza Snow, MD, Pfizer Vaccines (Employee)