bluuebunny/crossref_metadata_2025_split huggingface dataset:
1271. In vitro Activities of Ceftaroline and Comparator Agents Against Bacterial Pathogens Frequently Causing Community-Acquired Respiratory Tract Infections in Patients from a Global Population: ATLAS Surveillance Program 2016-2019
Authors: Hackel Meredith , Stone Gregory , Sahm Daniel F 
Published: December 2021

Abstract

Background
Community-acquired bacterial pneumonia (CABP) is a frequent cause of patient morbidity and mortality. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are frequent etiologic agents of CABP. Ceftaroline fosamil is a parenteral cephem approved for treatment of patients with CABP caused by S. pneumoniae (including cases with concurrent bacteremia), methicillin-susceptible Staphylococcus aureus (MSSA), H. influenzae, and some species of Enterobacterales. In this study we report the in vitro activity of ceftaroline and comparators against isolates from community-acquired respiratory tract infections (CARTI) collected through a global surveillance program.

Methods
Clinically relevant, non-duplicate, isolates cultured from respiratory specimens by clinical laboratories in 54 countries in 2016-2019 were collected by the ATLAS Surveillance Program central laboratory (IHMA, Schaumburg, IL, USA). In total, 2,636 isolates of S. pneumoniae, H. influenzae, M. catarrhalis, MSSA, and methicillin-resistant S. aureus (MRSA) were tested. The isolates (n/percent of total) originated from Asia/South Pacific (722/27.4%); Europe (1481/56.2%); Latin America (292/11.1%); Middle East/Africa (57/2.2%); and North America (Canada only) (84/3.2%). Ceftaroline and comparator agent MICs were determined by CLSI M07 broth microdilution methodology. MICs were interpreted using 2021 CLSI M100 MIC breakpoints.

Results
Ceftaroline and comparator agent in vitro activities are summarized in the table. Greater than 98% of S. pneumoniae and &gt;99% of MSSA were susceptible to ceftaroline, including penicillin-nonsusceptible S. pneumoniae based on a dosage of 600 mg every 12h. Sixty-four (24.4%) MRSA were ceftaroline-susceptible-dose-dependent (MIC 2-4 µg/mL) based on a dosage of 600 mg every 8h administered over 2h, with the majority from (n) China (70), S. Korea (19), Japan (10), and Chile (8). Three isolates, all from China, were resistant to CPT (MIC of 8 µg/mL). 99.2% of H. influenzae were susceptible to ceftaroline.
Results Table

Conclusion
Ceftaroline demonstrated potent in vitro activity against current pathogens associated with CABP from a global collection.

Disclosures
Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Gregory Stone, PhD, AztraZeneca (Shareholder, Former Employee)Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
1273. Activity of Ceftolozane/Tazobactam and Comparators Against Enterobacterales and P. aeruginosa Isolates from Pediatric Patients—SMART United States 2017-2019
Authors: Lob Sibylle , Hackel Meredith , Andrew DeRyke C , Harris Kelly , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: December 2021

Abstract

Background
Ceftolozane/tazobactam (C/T) is an antipseudomonal cephalosporin combined with a β-lactamase inhibitor approved by FDA and EMA for complicated urinary tract (cUTI) and complicated intraabdominal infections (cIAI), as well as hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in patients ≥18 years. Clinical trials studying the use of C/T for pediatric patients with cUTI and cIAI are completed, and HABP/VABP pediatric studies are underway. We evaluated the antimicrobial activity of C/T against gram-negative isolates collected from patients ≤17 years in the United States (US) as part of the global SMART surveillance program.

Methods
In 2017-2019, 27 US clinical labs each collected up to 250 consecutive gram-negative pathogens per year. A total of 1336 isolates were collected from pediatric patients. MICs were determined using CLSI broth microdilution and breakpoints. C/T-nonsusceptible Enterobacterales (Ebact) and P. aeruginosa were screened for genes encoding β-lactamases.

Results
Among the 944 collected Ebact and 220 P. aeruginosa isolates, 40.7% and 76.4%, respectively, were collected from patients with respiratory tract infections, 37.0% and 10.0% from UTI, 13.7% and 8.2% from IAI, and 8.3% and 5.0% from bloodstream infections. The table shows antimicrobial susceptibility of Ebact, P. aeruginosa, and select phenotypes. C/T was active against 98% of Ebact, including 50 of 51 and 12 of 13 ESBL-non-CRE phenotype E. coli and K. pneumoniae, respectively. Among P. aeruginosa, C/T was active against 95% of isolates, 9-21 percentage points higher than the comparator β-lactams, and it maintained activity against 71-75% of P. aeruginosa isolates nonsusceptible to commonly used β-lactams. Among the 21 C/T-nonsusceptible Ebact, 2 isolates carried KPC and ESBL and 3 isolates carried only ESBL; in 16 isolates no β-lactamases were detected, of which 15 were species with intrinsic AmpC. Among 12 C/T-nonsusceptible P. aeruginosa, no acquired β-lactamases were detected, likely indicating chromosomally-mediated resistance mechanisms.
Results Table

Conclusion
C/T could be a potential new treatment option for US pediatric patients with infections caused by Ebact and P. aeruginosa, including resistant phenotypes.

Disclosures
Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Kelly Harris, PharmD, BCPS, Merck & Co. Inc (Employee) Katherine Young, MS, Merck (Employee) Mary Motyl, PhD, Merck & Co., Inc. (Employee, Shareholder) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
1274. Activity of Ceftolozane/Tazobactam, Imipenem/Relebactam, and Comparators Against Pseudomonas aeruginosa Isolates from Patients with Bloodstream and Other Infection Types—SMART United States/Canada 2018-2019
Authors: Lob Sibylle , Hackel Meredith , Andrew DeRyke C , Harris Kelly , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: December 2021

Abstract

Background
Ceftolozane/tazobactam (C/T), an antipseudomonal cephalosporin combined with a β-lactamase inhibitor, was approved for treatment of complicated urinary tract (cUTI) and intraabdominal infections (cIAI), and hospital-acquired/ventilator-associated bacterial pneumonia (HAP/VAP). Imipenem/relebactam (IMI/REL) is a combination of imipenem/cilastatin with relebactam, an inhibitor of class A and C β-lactamases. IMI/REL was approved for HAP/VAP and for infections due to aerobic gram-negative organisms in adults with limited treatment options (e.g., cUTI, cIAI). We compared the activity of C/T and IMI/REL against P. aeruginosa from bloodstream infections (BSI) to those from other infection types.

Methods
As part of the SMART program, 24 hospitals in the US and 8 in Canada each collected up to 250 consecutive gram-negative isolates per year in 2018-2019 from patients with BSI, lower respiratory tract infections (LRTI), IAI, and UTI. A total of 2351 Pa isolates were collected. MICs were determined using CLSI broth microdilution and breakpoints.

Results
Pa isolates from BSI tended to show higher susceptibility than IAI, UTI, and especially LRTI isolates (Table). Susceptibility to the tested comparator β-lactams was 11-12 percentage points lower among LRTI than BSI isolates, while C/T and IMI/REL susceptibility was only 2-5% lower. Even among BSI isolates, the comparator β-lactams were active against only 75-88% of isolates, while C/T and IMI/REL were active against &gt;95%. Only amikacin showed higher activity. Analyzing coverage by either C/T or IMI/REL, 98.7% of Pa isolates from BSI were susceptible to one or both agents. C/T and IMI/REL maintained activity against 89% and 69% of meropenem-nonsusceptible (MEM-NS) Pa isolates from BSI (n=36), respectively, and 87% and 76% of piperacillin/tazobactam (P/T)-NS Pa (n=38).
Results Table

Conclusion
Even among BSI isolates, which were generally more susceptible than those from other infection types, Pa susceptibility to commonly used β-lactams like MEM and P/T was &lt; 90%, 7-23% lower than C/T and IMI/REL. Given the desirability of β-lactams among clinicians and the &gt;98% coverage by either C/T or IMI/REL of Pa isolates from BSI, both agents represent important options in the treatment of patients with BSI.

Disclosures
Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Kelly Harris, PharmD, BCPS, Merck & Co. Inc (Employee) Katherine Young, MS, Merck (Employee) Mary Motyl, PhD, Merck & Co., Inc. (Employee, Shareholder) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
1275. Dynamics of Enterococcus faecalis Cardiolipin Synthase Gene Expression Reveal Compensatory Roles in Daptomycin Resistance
Authors: Nguyen April , Polamraju Vinathi , Zhang Rutan , Tran Truc T , Panesso Diana , Khan Ayesha , Mileykovskaya Eugenia , Shamoo Yousif , Xu Libin , Vitrac Heidi , Arias Cesar A 
Published: December 2021

Abstract

Background
Daptomycin (DAP) is a lipopeptide antibiotic targeting membrane anionic phospholipids (APLs) at the division septum, and resistance (DAP-R) has been associated with activation of the E. faecalis (Efs) LiaFSR response and redistribution of APL microdomains (predicted to contain cardiolipin) away from the septum. Efs encodes two putative cardiolipin synthase genes, cls1 and cls2. While changes in Cls1 are associated with DAP-R, the exact roles of each enzyme in resistance are unknown. This work aims to establish the contributions for both enzymes in the development of DAP-R.

Methods
cls1 and cls2 were deleted individually and in tandem from Efs OG117∆liaX (a DAP-R strain with an activated LiaFSR response). Mutants were characterized by DAP minimum inhibitory concentration (MIC) using E-test and localization of APL microdomains with 10-N-nonyl-acridine orange staining. Quantitative PCR (qRT-PCR) was used to study gene expression profiles of cls1 and cls2 in Efs OG117∆liaX relative to Efs OG117. Membrane lipid content was analyzed using hydrophilic interaction chromatography-mass spectrometry (HILIC-MS).

Results
cls1 was highly upregulated in stationary phase concurrent with a decrease in cls2 expression. However, independent deletion of cls1 or cls2 in the DAP-R background resulted in no significant phenotypic changes from the parent strain. Interestingly, qRT-PCR showed that cls2 expression was upregulated upon deletion of cls1 (and vice-versa), suggesting a compensatory role for one enzyme upon deletion of the other (Fig 1). When comparing membrane lipid content between Efs OG117∆liaX∆cls1 and Efs OG117∆liaX∆cls2, there were no significant differences in both the overall amount or species of cardiolipin generated, further supporting a potential redundancy between the cardiolipin synthases (Fig 2). Ultimately, double deletion of both cls genes lowered the DAP MIC relative to the parent strain and restored septal localization of APL microdomains.

Conclusion
Overall, Cls1 has a predominant role in the development of DAP-R in E. faecalis. However, here, we describe a novel compensatory role for Cls2 under conditions in which there is no functional Cls1 to maintain the DAP-R phenotype.

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)
1276. Assessment of Anti-biofilm Activity of Staphylococcus aureus Bacteriophages Against Clinical Isolates from Patients with Left Ventricular Assist Device Infections
Authors: Ramirez-Sanchez Claudia , Attai Hedieh , Van Tyne Daria , Shields Ryan K , Yerushalmy Ortal , Hazan Ronen , Nir-Paz Ran , Pride David , Aslam Saima 
Published: December 2021

Abstract

Background
Staphylococcus aureus is a common cause of biofilm-mediated left ventricular device (LVAD) infections which are difficult to resolve with antibiotics alone and are associated with substantial morbidity and mortality. Recently, bacteriophages (phage) therapy has been used to resolve LVAD infections in a few cases. Our goal was to assess in vitro susceptibility and anti-biofilm activity of two S. aureus bacteriophages against clinical isolates from patients with S. aureus LVAD infections in order to develop a S. aureus phage cocktail for clinical use.

Methods
Two bacteriophages, OMS1 and OMS2, from the Israeli Phage Bank, were assessed for lytic activity against 15 S.aureus isolates (9 methicillin resistant, MRSA and 6 methicillin susceptible, MSSA) via agar overlay method and plaque forming units (PFU)/mL were enumerated. We then formed bacterial biofilms after overnight incubation at 120 rpm in a 96-well plates in duplicate; experiments were repeated thrice. Wells were then treated with tryptic soy broth (TSB, control) or TSB containing phage at 109 PFU/mL for 24 hours. After washing, biofilms were stained with crystal violet and biomass quantified via optical density at 570mm.

Results
All bacterial isolates were susceptible to both phages via agar overlay to varying degrees as determined by phage titers obtained via serial dilutions (Figure 1a, 1b). OMS1 led to significant reduction in biofilm of 7/9 MRSA and 3/6 MSSA isolates and OMS2 reduced biofilms in 9/9 MRSA and 4/6 MSSA isolates (Figure 1c).
Phage titers and Biofilm Biomass

Figure 1a) Phage titers in PFU/ml obtained from each bacterial isolate via agar overlay method. 1b) Representative agar plate demonstrating lytic plaques from OMS1 and OMS2 on a Staphylococcus aureus LVAD isolate. 1c) Biofilm biomass of Staphylococcus aureus isolates alone (SA) or with individual phage (SA+OMSA1 and SA=OMS2) assessed by optical density readings at 570 nm; error bars represent standard error of the mean.

Conclusion
We demonstrated in vitro lytic and anti-biofilm activity of 2 S. aureus phages against clinical S. aureus isolates from patients with LVAD infection. Our data suggests that phage susceptibility measured with agar overlay does not always correlate with phage susceptibility of S. aureus biofilms, suggesting that more than one method should be used to assess in vitro activity. We plan to assess for synergistic activity with the phage combination.

Disclosures
Ryan K. Shields, PharmD, MS, Shionogi (Consultant, Research Grant or Support) Ran Nir-Paz, MD, BiomX (Consultant)Technophage (Scientific Research Study Investigator, Advisor or Review Panel member) Saima Aslam, MD, MS, BioMx (Consultant)Cystic Fibrosis Foundation (Grant/Research Support)Gilead (Consultant)Johnson and Johnson (Consultant)Merck (Consultant)
1277. Colonization Rates for Antimicrobial-resistant Bacteria in Kenya: An Antibiotic Resistance in Communities and Hospitals (ARCH) Study
Authors: Omulo Sylvia , Luvsansharav Ulzii-Orshikh , Ita Teresa , Mugoh Robert , Caudell Mark , Ramay Brooke M , Palmer Guy H , Ndegwa Linus , Verani Jennifer , Bollinger Susan , Sharma Aditya , Call Douglas , Smith Rachel 
Published: December 2021

Abstract

Background
Characterization of antimicrobial-resistant organism (ARO) colonization is critical to understand transmission dynamics and infection risk, however data in resource-limited settings are scare. We estimated the prevalence of Enterobacterales colonization with extended-spectrum cephalosporin-resistance (ESCrE), carbapenem-resistance (CRE) and methicillin-resistant Staphylococcus aureus (MRSA) among community residents and hospitalized patients in rural (Siaya County) and urban (Kibera) Kenya.

Methods
Community-dwelling adults and children were enrolled via cluster randomized sampling. Inpatients of all ages were enrolled by simple random sampling. Stool/rectal and nasal swabs were collected and screened for ESCrE, CRE and MRSA, respectively, using HardyChrom™ media. Vitek2® was used for isolate confirmation and antibiotic susceptibility testing. Fisher’s exact tests were used to compare prevalence of AROs.

Results
The prevalence of ESCrE was higher for the urban hospital (69.8%, 263/377) compared to rural hospitals (62.7%, 298/475, P=0.04); a similar pattern was evident for CRE (16.7%, 63/377 and 6.5%, 31/475, respectively, P&lt; 0.01). The prevalence of MRSA was 3.2% for both urban and rural hospitals (P=0.99). For adults, the prevalence of ESCrE was higher in Kibera households (51.4%, 346/673) compared to Siaya (44.6%, 283/634, P=0.02) while the prevalence of both CRE and MRSA was &lt; 3% for both areas and did not differ significantly (CRE, P=0.13, MRSA, P=0.14). There was no significant difference between urban and rural children for ESCrE (47.7%, 74/155 and 53.4%, 135/253, P=0.31); both CRE and MRSA were rarely detected (&lt; 2%) with no difference across settings (CRE, P=1.0, MRSA, P=0.42). Among Enterobacteriaceae recovered, Escherichia coli and Klebsiella spp. predominated.

Conclusion
Colonization with AROs were widespread in households and hospitals in urban and rural areas. Hospitals with elevated prevalence of highly transmissible AROs should consider whether implementation of colonization screening can be incorporated as part of their infection prevention and control programs. Risk factors for ARO colonization should be elucidated to identify novel prevention strategies.

Disclosures
All Authors: No reported disclosures
1278. Testing the Synergistic Effect of Ceftazidime-Avibactam Plus Aztreonam on Metallobetalactamase-Producing Non-Fermenting Gram-negative Bacteria
Authors: Crouch Elena M , Johnson Sheila , Bennett Jason 
Published: December 2021

Abstract

Background
Metallo-betalactamases (MBL) are rapidly becoming a more widespread form of antimicrobial resistance. MBL are class B betalactamases that use zinc rather than serine in their active site and are only inactivated by monobactams, such as aztreonam. Unfortunately, most MBL-producing organisms also produce aztreonam-inactivating beta-lactamases. Synergy between ceftazidime-avibactam and aztreonam is well documented for MBL-producing Enterobacteriaceae but has not been tested extensively in non-fermenting Gram-negative bacteria. This study evaluates the susceptibilities of non-fermenting Gram-negative bacteria via E-test to this combination in vitro, in order to provide support for use to treat infections from these organisms.

Methods
The antibiotic combination ceftazidime-avibactam+aztreonam was tested against a total of 33 isolates, including MBL-producing Pseudomonas aeruginosa, Pseudomonas putida, and the intrinsically aztreonam resistant Acinetobacter baumanii using the E-test method. MBL-producing Enterobacteriaceae were included as positive controls. All isolates were also tested against ceftazidime alone, aztreonam alone, and ceftazidime-avibactam. Bacterial isolates were procured from the Multidrug-resistant organism Repository & Surveillance Network at the Walter Reed Army Institute of Research. Antimicrobial resistance genes were previously identified by whole genome sequencing

Results
Of 13 Pseudomonas spp. isolates tested, 9 were resistant, 3 were intermediate, and 1 was susceptible to aztreonam. Synergistic testing of ceftazidime-avibactam+aztreonam reduced the MIC of 4 Pseudomonas isolates by 1-2 doubling dilutions. While Acinetobacter spp. are usually considered intrinsically resistant to aztreonam, synergistic testing of ceftazidime-avibactam+aztreonam reduced the MIC of all 12 isolates tested by 1 to 3 doubling dilutions.

Conclusion
The ability of ceftazidime-avibactam+aztreonam to reduce the MICs of Acinetobacter baumanii and MBL-producing Pseudomonas aeruginosa is a potentially promising therapeutic option when faced with growing antimicrobial resistance.

Disclosures
All Authors: No reported disclosures
1283. High Dose Minocycline for the Treatment of Acinetobacter Infections
Authors: Herbin Shelbye R , Ammar Amina , Gumbleton Ryan , Zhao Jing , Olson Shannon , Smith Stephanie M , Scipione Marco R 
Published: December 2021

Abstract

Background
Acinetobacter (ACB) infections are difficult to treat due to increasing drug resistance. The aim of this study is to evaluate the effectiveness of high-dose (HD) minocycline (MIN) 200mg q12h for the treatment of ACB infections

Methods
This is a retrospective study of pts with ACB from 1/1/19 to 10/31/20. Exclusions included non-susceptibility to MIN, age &lt; 18 yrs, hospice care w/in 72 hrs of culture, or urine source. Use of HD MIN (IV or PO), was compared to alternative treatment (AT). Clinical and micro success at the end of therapy (EOT) was evaluated. Clinical success was elimination or improvement in signs and symptoms of infection. Micro success was eradication of ACB from the same site of infection at EOT. Length of stay (LOS), 30-day readmission (with or without ACB), isolation of a MIN non-susceptible ACB within 30 days of EOT, and adverse events related to MIN, were evaluated.

Results
A total of 320 pts were screened with the most common exclusion being MIN non-susceptible isolate. Of the 204 pts included, 38 received HD MIN and 166 received AT. The most common were cefepime (53/166) and meropenem (36/166). Median age (IQR) was 41 (30-50) yrs for HD MIN vs. 40 (27-48) yrs for AT. Both groups were mostly male (HD MIN: 63% vs. AT: 60%) and respiratory was the most common site (HD MIN: 61% vs. AT: 60%). HD MIN group had 74% of cultures that were polymicrobial vs. 86% in AT group. Lack of clinical response at the EOT occurred in 42% of pts on HD MIN and 37% on AT. Infection related mortality occurred in 24% on HD MIN vs. 15% on AT. In HD MIN group, 16 pts had a repeat culture from the same site after treatment with 25% still positive for ACB. In the AT group 61 pts had a repeat culture and 28% were positive for ACB. Duration of treatment (9 [6-11] days vs. 10 [2-18] days) and LOS (16 [18.25-26.75] vs. 29 [14-49]) were shorter in the HD MIN group. There was only one adverse event reported with the use of HD MIN

Conclusion
Pts in the HD MIN group had shorter treatment duration and a shorter LOS. Pts who received HD MIN had a lower rate of clinical cure and a higher mortality rate compared to pts in the AT group. Reasons for this difference will need to be investigated further. HD MIN should be reserved for pts who are unable to tolerate other treatment options or who have an ACB resistant to other treatment options.

Disclosures
All Authors: No reported disclosures