bluuebunny/crossref_metadata_2025_split huggingface dataset:
1285. Identification of KPC Omega Loop Variant R163S Conferring Ceftazidime-Avibactam Resistance
Authors: Maris Alexander S , Tao Lili , Wada Paul , Humphries Romney , Humphries Romney , Schmitz Jonathan 
Published: December 2021

Abstract

Background
We report on a 56 year-old male with prolonged COVID-19 pneumonia who initially improved with dexamethasone and intubation but quickly decompensated. Clinical and radiologic features were consistent with VAP. Tracheal aspirate cultures grew carbapenem-resistant Enterobacter cloacae; meropenem (MEM) MIC was &gt;8 ug/ml (resistant) while ceftazidime-avibactam (CZA) MIC was 2/4 ug/ml (susceptible). Lateral flow antigen assay detected a KPC enzyme. The patient was treated with CZA with steady improvement in respiratory function over the next two weeks. He then experienced an episode of tachycardia, prompting repeat culture. At this point the patient had been extubated: sputum culture grew KPC+ E. cloacae that now showed CZA-resistance (MIC &gt;8/4 ug/ml) and paradoxical decrease in MEM MIC (4 ug/ml); meropenem-vaborbactam (&lt; 2/8 ug/ml) was susceptible.

Methods
The pre- & post-CZA therapy E. cloacae isolates underwent whole genome sequencing using the Illumina 150bp paired end protocol; sequences were quality trimmed and compared.

Results
A point mutation in the plasmid blaKPC3 gene was identified in the post-CZA therapy isolate, an R163S mutation in the omega loop of the enzyme. ompC and ompF porin genes were analyzed to rule-out decreased influx as a mechanism for CZA-resistance: the pre- and post-CZA isolates had identical porin sequences.

Conclusion
This case highlights emerging mutations within KPC carbapenemases that lead to resistance to ‘last-line’ antimicrobials like CZA. The presumptive mechanism is increased KPC active site promiscuity due to increased omega loop flexibility, allowing increased ceftazidime binding and hydrolysis, and decreased avibactam binding and beta lactamase inhibition. Paradoxically, MEM susceptibility improves after such omega loop mutations, likely due to decreased active site binding affinity, a ‘seesaw’ effect between MEM and CZA. While authors have reported MEM MICs falling into the ‘susceptible’ category after an omega loop variant, these bacteria invariably develop secondary mutations leading to MEM treatment failure. Fortunately, given our patient’s improved respiratory status, the post-CZA E. cloacae isolate was felt to reflect colonization and the patient was discharged home without antimicrobial therapy.

Disclosures
Romney Humphries, PhD D(ABMM), Accelerate Diagnostics (Individual(s) Involved: Self): Consultant, Shareholder; IHMA (Individual(s) Involved: Self): Consultant; Melinta (Individual(s) Involved: Self): Consultant; Momentum (Individual(s) Involved: Self): Grant/Research Support; Pattern (Individual(s) Involved: Self): Consultant; QPex (Individual(s) Involved: Self): Consultant; ThermoFisher (Individual(s) Involved: Self): Consultant; Torus (Individual(s) Involved: Self): Consultant
1287. Double Disk Diffusion Study to Evaluate the Synergistic Effect Between Cefiderocol and Ceftazidime-Avibactam Against Cefiderocol-Non-susceptible Acinetobacter baumannii
Authors: Yamano Yoshinori , Takemura Miki , Anan Naomi , Echols Roger , Longshaw Christopher 
Published: December 2021

Abstract

Background
Cefiderocol (CFDC), a siderophore cephalosporin, has broad coverage of Gram-negative bacteria and has been approved for clinical use in USA and Europe. The SIDERO-WT surveillance studies showed that CFDC shows &gt;95% susceptibility against Acinetobacter baumannii. Against many of CFDC non-susceptible isolates, most of which had blaPER gene, the combination use of avibactam significantly decreased the MIC by broth microdilution (BMD). In this study, we evaluated the appropriate methodology to evaluate the synergistic effect by disk diffusion studies.

Methods
The susceptibility testing was conducted as recommended by the CLSI using CFDC non-susceptible isolates (MIC of &gt;4 µg/mL based on CLSI breakpoint). The MIC by BMD was determined using iron-depleted cation-adjusted Mueller-Hinton broth, in the presence or absence of 4 µg/mL of avibactam. The disk diffusion was evaluated using Mueller-Hinton agar, and the synergy was evaluated by using disk stacking methods. For disk stacking methods, CFDC disk was placed on agar on which bacterial suspension of 0.5 McFarland units was spread, then the ceftazidime-avibactam (CZA) disks was stacked on the top, followed by adding a drop (30 µL) of saline on the stacked disks. As an alternative method, CZA was immersed in saline for 1 second instead of adding a drop of saline, followed by the stacking on the top. The disk zone size was determined after 24-hour incubation at 37°C.

Results
Against blaPER-positive A. baumannii which showed &gt;64 µg/mL MIC of CFDC and CZA, CFDC MIC decreased to 0.25 µg/mL in the presence of avibactam. The disk diffusion methods also showed isolates resistant to CFDC and CZA and showed susceptiblilty disk zone to CFDC by stacking both disks. On the other hand, against blaNDM-positive A. baumannii which showed 64 µg/mL MIC of CFDC and CZA, the disk diffusion methods showed resistance even when stacking both disks. Against multiple isolates, the MIC of CFDC without or with avibactam was correlated well with the disk zone produced by CFDC disk alone or stacked with CZA disks, respectively (Figure).

Conclusion
The synergistic effect between CFDC and avibactam by BMD methods could be detected by disk stacking methodology using CFDC and CZA disks.

Disclosures
Yoshinori Yamano, PhD, Shionogi (Employee) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Roger Echols, MD, Shionogi (Consultant) Christopher Longshaw, PhD, Shionogi (Employee)
1290. Ceftazidime-Avibactam Resistance Report in a Third Level Hospital in Mexico City
Authors: Molina Aaron , Salinas-Hernandez Abigail , Olmedo-Reneaum Alejandro 
Published: December 2021

Abstract

Background
The surge of resistant Gram-negative organisms has been worrying infectious disease physicians and physicians in general because of the lack of a large number of antibiotics to which these organisms remain susceptible. Ceftazidime-Avibactam (CAZ-AVI) is a drug approved by the FDA to treat complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAIs) in combination with metronidazole, and recently for the treatment of nosocomial pneumonia. Worldwide resistance rates of Enterobacteriaceae to CAZ-AVI have been reported below 2.6%, and 4-8% for Pseudomonas aeruginosa. The FDA, CLSI, and EUCAST assigned the clinical breakpoints of susceptibility: MIC &lt; /=8 mg/liter susceptible, and &gt;/=8mg/liter, resistant. In Mexico, CAZ-AVI was approved in 2018, and its cost is very high compared to other antimicrobials, so its use is limited in very specific cases. The resistance rates to this antibiotic in the Mexican population remain largely unknown.

Methods
We tested 106 specimens for susceptibility to ceftazidime-avibactam using the disk Kirby-Bauer method. The inhibition zone diameter was determined in all cases and we considered the organism susceptible when the inhibition zone diameter was &gt;=21 mm, and resistant with an inhibition zone diameter &lt; = 20 mm.

Results
We found 5 specimens (4.71%) resistant to ceftazidime-avibactam, corresponding to E. coli (3) and P. aeruginosa (2). Two of these were also resistant to colistin, and 4 to meropenem. All carbapenem-resistant isolates harbored Metallo-beta-lactamases genes, for E. coli was NDM gen, and for P. aeruginosa the VIM gene(GeneXpert® Cepheid).

Conclusion
The ceftazidime-avibactam resistance among Gram-negative bacteria in our study is similar to the one reported in other international studies. We need more studies in our population to know the nationwide resistance to this antibiotic.

Disclosures
All Authors: No reported disclosures
1292. Evaluation of Synergy with Piperacillin/Tazobactam plus Meropenem Against Carbapenemase-Producing Klebsiella pneumoniae and Enterobacter cloacae Using ETEST
Authors: Ashcraft Deborah S , Vortisch Royanne H , Pankey George A 
Published: December 2021

Abstract

Background
Carbapenem-resistant Enterobacterales are considered an urgent threat for patients in healthcare facilities, causing infections with significant morbidity and mortality. Most isolates are multidrug resistant with limited treatment options, so combination therapy is an alternative. Recently, synergy with piperacillin/tazobactam (P/T) + meropenem (MP) was demonstrated against 7/10 (70%) KPC-producing Escherichia coli and 9/10 (90%) OXA-48-producing K. pneumoniae using time-kill assay (Lawandi et al, 2021). The aim of the present study was to further evaluate the combination of P/T + MP against KPC-producing Enterobacter cloacae, in addition to OXA-producing K. pneumoniae using our rapid ETEST MIC:MIC synergy method.

Methods
14 carbapenemase-producing isolates: 7 OXA-48-like K. pneumoniae (1 OXA-48, 4 OXA-181, 2 OXA-232) and 7 KPC-producing E. cloacae (1 KPC-2, 4 KPC-3, 1 KPC-4, 1 KPC-6) were obtained from the CDC and FDA Antibiotic Resistance Isolate Bank. ETEST MICs for P/T and MP and our ETEST synergy method were performed in triplicate for each isolate. The summation fractional inhibitory concentration was calculated, and the mean value was interpreted as: &lt; 0.5 synergy; &gt; 0.5-1 additivity; &gt; 1-4 indifference; and &gt; 4 antagonism.

Results
MICs (µg/mL) ranged: MP, 0.5 to &gt; 32 (14% susceptible) and P/T, 96/4 to &gt; 256/4 (all resistant). The combination of P/T + MP showed synergy (3) or additivity (2) against 5/7 (71%) OXA-producing K. pneumoniae and synergy (6) or additivity (1) against all 7 KPC-producing E. cloacae. No antagonism was detected.

Conclusion
Using our ETEST MIC:MIC method, the combination of P/T + MP demonstrated synergy or additivity in 5/7 OXA-producing K. pneumoniae and 7/7 KPC-producing E. cloacae, similar to previously published findings showing synergy in 7/10 KPC-producing E. coli and 9/10 OXA-48-producing K. pneumoniae using time-kill assay. Our ETEST synergy method is simple to use and should be evaluated more extensively. Regardless of the method used, results may or may not correlate in an in vivo setting. In vivo studies are needed.

Disclosures
All Authors: No reported disclosures
1293. In vitro Activity of Ceftibuten in Combination with VNRX-5236 against Clinical Isolates of Enterobacterales from Urinary Tract Infections Collected in 2018-2020
Authors: Hackel Meredith , Wise Mark G G , Sahm Daniel F 
Published: December 2021

Abstract

Background
Increasing resistance among agents commonly prescribed to treat urinary tract infections indicate that new oral agents are urgently needed. Ceftibuten in combination with VNRX-7145 is under development as an oral treatment for complicated urinary tract infections caused by serine β-lactamase-producing Enterobacterales, including isolates carrying ESBLs and carbapenemases. In vivo, VNRX-7145 (VNRX-5236 etzadroxil) is cleaved into to the active inhibitor, VNRX-5236. This study assessed the in vitro activity of ceftibuten/VNRX-5236 against 592 isolates of Enterobacterales from urinary tract infections (UTIs) from a 2018-2020 global culture collection.

Methods
MICs of ceftibuten with VNRX-5236 fixed at 4 µg/mL and comparators were determined following CLSI M07-A11 guidelines against 592 Enterobacterales. Isolates were from community and hospital UTI infections collected from 133 sites in 31 countries in 2018-2020. Resistant phenotypes were based on 2021 CLSI breakpoints.

Results
A substantial percentage of isolates were non-susceptible to extended-spectrum β-lactams, levofloxacin (LVX), trimethoprim-sulfamethoxazole (SXT), and amoxicillin-clavulanate (AMC) (Table). The addition of VNRX-5236 reduced ceftibuten MIC90 values by ≥8-fold to ≥128-fold, depending on the resistant subset. Ceftibuten/VNRX-5236 had potent activity against all Enterobacterales, with MIC50/90 values of 0.06/0.25 µg/mL and 98.3% inhibited at ≤2 µg/mL. Ceftibuten/VNRX-5236 maintained activity against resistant subsets (MIC90 range, 0.5 to 2 µg/mL; 91.5% to 97.1% inhibited at ≤2 µg/mL), including serine carbapenemase-positive isolates (MIC90 0.5 µg/mL; 100% inhibited at ≤1 µg/mL). Ceftibuten/VNRX-5236 in vitro potency was similar to that of newer parenteral and investigational oral therapies.
Results Table

Conclusion
Ceftibuten/VNRX-5236 exhibited promising in vitro activity against recent Enterobacterales from UTIs, and may have potential as an oral treatment option for complicated urinary tract infections, including those caused by serine β-lactamase-expressing Enterobacterales (ESBL, KPC, OXA-48/OXA-48-like) for which there are currently few oral treatment options available.

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)
1294. Activity of Ceftolozane/Tazobactam and Comparators against Resistant Pseudomonas aeruginosa Isolates from Patients with Respiratory Tract or Bloodstream Infections in ICU and non-ICU settings – SMART United States 2018-2019
Authors: Lob Sibylle , Hackel Meredith , Andrew DeRyke C , Harris Kelly , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: December 2021

Abstract

Background
ICUs are considered hotspots of antimicrobial resistance. Treatment of ICU patients with infections caused by P. aeruginosa (Pa) is especially challenging. When patients fail to improve on therapy with first-line antipseudomonal agents such as piperacillin/tazobactam (P/T) or cefepime (FEP), clinicians often escalate to a carbapenem. Ceftolozane/tazobactam (C/T) is an antipseudomonal cephalosporin (combined with a β-lactamase inhibitor) that was specifically developed to have enhanced antibacterial activity against Pa. We evaluated the activity of C/T and comparators against Pa isolates collected from patients with respiratory tract (RTI) or bloodstream infections (BSI) in ICU and non-ICU settings. Co-resistance (e.g., activity of C/T or meropenem (MEM) when Pa is nonsusceptible (NS) to P/T or FEP) was also evaluated to help inform common clinical scenarios.

Methods
In 2018-2019, 24 US clinical labs each collected up to 100 RTI and 50 BSI consecutive gram-negative pathogens per year as part of the global SMART surveillance program. Only the 1195 Pa isolates collected from patients in ICU or non-ICU hospital wards were included in this report; 1078 and 117 isolates were from patients with RTI and BSI, respectively. MICs were determined using CLSI broth microdilution and breakpoints.

Results
Susceptibility for P/T, FEP, and MEM was generally lower among isolates from patients in ICU than non-ICU wards by 5-14 percentage points, while the difference was ≤3 percentage points for C/T (Table). C/T maintained activity against 96% of ICU isolates, 17-23 percentage points higher than P/T, MEM, or FEP. MEM inhibited 40% of P/T-NS and 34% of FEP-NS ICU isolates, while C/T maintained activity against 81-88% of P/T-NS, FEP-NS, and MEM-NS isolates from ICU patients (Table, Figure).
Results Table

Conclusion
High co-resistance in Pa was seen with P/T, FEP, and MEM especially among ICU isolates. These data suggest that routine escalation to a carbapenem may not be optimal in some critically ill patients not responding to empiric therapy. Among the tested β-lactam antibiotics, C/T showed the highest activity against Pa isolates overall and among 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)
1295. Susceptibility to Ceftolozane/Tazobactam and Comparators Among Pseudomonas aeruginosa Isolates Collected from Patients in Hospitals in Latin America – SMART 2017-2019
Authors: Lob Sibylle , Hackel Meredith , Andrew DeRyke C , Pavía Jacquleine , Siddiqui Fakhar , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: December 2021

Abstract

Background
Ceftolozane is a cephalosporin specifically developed to have enhanced antibacterial activity against P. aeruginosa. Combined with tazobactam, it was approved by FDA and EMA for complicated urinary tract and intraabdominal infections, as well as hospital-acquired/ventilator-associated bacterial pneumonia. We evaluated the activity of ceftolozane/tazobactam (C/T) against P. aeruginosa isolates collected as part of the global SMART surveillance program in 10 countries in Latin America.

Methods
In 2017-2019, 41 clinical labs each collected up to 250 consecutive gram-negative pathogens per year from various infection sources. A total of 21,864 isolates were collected, of which 3,335 (15.3%) were P. aeruginosa. MICs were determined using CLSI broth microdilution and breakpoints. C/T-nonsusceptible (NS) P. aeruginosa isolates were screened for genes encoding β-lactamases.

Results
The table shows the antimicrobial susceptibility of P. aeruginosa and β-lactam-NS subsets.
C/T was active against 85.9% of all collected P. aeruginosa, with lowest activity against isolates collected in Chile and Venezuela, where 28.0% and 23.2% of isolates, respectively, carried carbapenemases, and highest activity against isolates from Ecuador and Guatemala, where 2.2% and 4.2%, respectively, were carbapenemase-positive. Substantial variability in the activity of C/T and comparators was observed among β-lactam-NS subsets. In aggregate, however, C/T remained active against 59.9% of all meropenem-NS P. aeruginosa isolates from Latin America (n=1,101), 57.3% of piperacillin/tazobactam-NS isolates (n=1054), 48.9% of cefepime-NS isolates (n=895), and 50.3% of ceftazidime-NS isolates (n=937). Conversely, other common β-lactams (meropenem, cefepime, ceftazidime, and piperacillin/tazobactam) remained active against 8-38% of these resistant isolates.
Results Table

Conclusion
C/T showed the highest activity against P. aeruginosa among the tested β-lactam antibiotics. While amikacin showed similar or better activity in vitro, its toxicities severely limit its clinical use. Given the desirability of β-lactams among clinicians, C/T represents an important option in the treatment of infections caused by P. aeruginosa in Latin America.

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) Jacquleine Pavía, MSc, Merck & Co, Inc (Employee) Fakhar Siddiqui, PhD, 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)
1296. Genomic Analysis of Human-Associated Outbreak Caused by Salmonella enterica serovar Infantis in Cali, Colombia
Authors: Rosso Fernando , Rojas olga Lucia agudelo 
Published: December 2021

Abstract

Background
Salmonella enterica serovar Infantis is emerging as a leading cause of foodborne infections. The Colombian National Health Institute reported 263 Infantis among all received Salmonella(n=12,966) from 1997 to 2018 being the 5th most frequent serovar in human clinical samples during this period. In this study, Infantis outbreak-associated isolates were sequenced and collectively analysed with global strains from different sources to compare their genomic content and phylogeny
Figure 1. Genomic Comparisons

Methods
Between September 15-20 of 2019, 160 patients with gastroenteric symptoms resulting from the ingestion of a common food, arrived at Fundación Valle del Lilí. Salmonella spp were cultured from stool specimens of patients and 15 isolates were sent to the Genomic Unit of Agrosavia for whole-genome sequencing. Genomic DNA was sequenced using an Illumina®MiSeqX10 platform. Genome assembly was performed with standardized bioinformatics pipelines and in-silico serotyping with SISTR. Genomic comparisons included newly-sequenced isolates of Infantis(n=6) from a Colombian poultry farms as well as datasets from Patric(n=441) and EnteroBase(n=54).

Results
The 15 outbreak isolates were identified by in silico serotyping as S. Infantis, these isolates showed phenotypic sensitivity to all tested antibiotics except by tetracycline. Antimicrobial resistance plasmids IncFIBKpn3, IncX4 and the host-environment persistence plasmid pSL483 were only detected in 2 outbreak-related and 1 in poultry isolates. Out of a total of 511 high-quality sequences, ST32 was the most prevalent and were phylogenetically grouped into a single non-host specific clade. Outbreak-isolates were included in a monophyletic group with some genomes from the US and Chile, suggesting that the parent strain could have originated in those countries.

Conclusion
The magnitude of the outbreak(288 informed-cases) evidenced a high-virulent potential of outbreak-isolates. Routine sequencing of S.enterica and availability of genomes in Colombia can improve outbreak detection and resolution in the future. The presence of plasmids, although with low frequency, suggests a risk of the appearance of resistant clones.

Disclosures
All Authors: No reported disclosures
1297. Azithromycin vs Beta Lactams in Acute Exacerbations of COPD
Authors: Kale-Pradhan Pramodini , Baalbaki Nour , Aprilliano Bianca , Giuliano Christopher , Hartner Carrie , Johnson Leonard B 
Published: December 2021

Abstract

Background
Bacterial infections cause approximately 50% of Acute Exacerbations of COPD (AECOPD). Current guidelines recommend a wide range of antibiotics, but evidence comparing agents is limited. The purpose of this study is to compare the effectiveness of azithromycin to beta lactams in the treatment of hospitalized patients with AECOPD.

Methods
A multicenter, retrospective, observational study of adult patients admitted with AECOPD who received at least two consecutive days of either a beta lactam or azithromycin were included. The primary endpoint was treatment failure which is a composite endpoint defined as in-hospital mortality, admission to intensive care, initiation of invasive mechanical ventilation, requirement of a new antibiotic, steroid therapy escalation, or readmission due to AECOPD within 30 days. Secondary endpoints included each individual component of the composite endpoint and length of stay.

Results
Of 11,395 patients screened, 595 met the inclusion criteria (428 were treated with azithromycin and 167 patients were treated with a beta lactam). The most common reason for exclusion was the receipt of both azithromycin and beta-lactam in 9857 patients. The patients were similar except the azithromycin group was more likely to be African-American and less likely to have failed an outpatient antibiotic. Treatment failure rate was 19.6% in the azithromycin group and 32.3% in the beta lactam group (P=0.001). Patients in the beta lactam group were more likely to experience in-hospital mortality (P=0.023), require a new antibiotic during admission (P&lt; 0.001), and were more likely to be readmitted within 30 days of discharge due to AECOPD (P=0.032). Length of stay was significantly shorter in the azithromycin group compared to the beta lactam group. There were no statistically significant differences in the rates of adverse events among both groups.

Conclusion
Treatment failure rate and length of stay were significantly higher in the beta lactam group compared to the azithromycin group. However, there were no differences in the side effect profile among both groups. Further studies should be performed to confirm these findings.

Disclosures
All Authors: No reported disclosures