bluuebunny/crossref_metadata_2025 huggingface dataset:
2106. Desirability of Outcome Ranking (DOOR): Application to a Phase 3 Registrational Trial Evaluating Sulopenem for Patients with Complicated Intra-abdominal Infection (cIAI)
Authors: Aronin Steven I , Dunne Michael W , Gupta Jayanti , Puttagunta Sailaja
Published: November 2023

Background

The DOOR approach has been proposed as an improved way to evaluate novel anti-infective agents by focusing on benefits and harms and providing an assessment of the patient experience. We conducted a Phase 3 cIAI trial comparing IV ertapenem (stepped down to either oral ciprofloxacin and metronidazole or amoxicillin-clavulanate) to IV sulopenem (stepped down to oral sulopenem etzadroxil/probenecid). Using the FDA’s current definition of a successful response (clinical response at Day 28 / Test-Of-Cure (TOC) in the microbiological intent-to-treat (micro-ITT) population using a non-inferiority margin of 10%, sulopenem’s overall success rate was 85.5% while ertapenem’s was 90.2% (treatment difference -4.7%, 95% CI: -10.3, 1.0). In all other study populations including the intent-to-treat (ITT), modified ITT, clinically evaluable (CE), and microbiologically evaluable (ME) populations the lower limit of confidence interval was above -10.0. To further understand these trial results, an analysis using the DOOR methodology was performed post hoc.Table 1Desirability of Outcome Rankings by Treatment Arm

Methods

The DOOR analysis strategy, developed by the Antibacterial Resistance Leadership group (ARLG), was retrospectively applied to our registrational drug trial for cIAI (SURE-3) to estimate the probability of a more desirable outcome for sulopenem.

Results

The DOOR probability of a more desirable outcome is 47.4% [95% CI (44.1%, 50.8%)], indicating no significant difference between the sulopenem and ertapenem treatment arms for patients with cIAI. The probabilities for the analyses prioritizing efficacy and safety were identical to the original outcome ranking, and those for the individual components were very similar.

Conclusion

Traditional endpoints used in registrational trials for cIAI may be inadequate. They evaluate safety and efficacy separately, and they fail to evaluate the cumulative impact of multiple clinical events. DOOR combines clinical efficacy and safety into a single endpoint that may be more reflective of an individual patient’s overall outcome. Applying DOOR to SURE-3 data showed no significant difference between the sulopenem and ertapenem treatment arms for patients with cIAI.

Disclosures

Steven I. Aronin, MD, Iterum Therapeutics Limited: Stocks/Bonds Michael W. Dunne, MD, Iterum Therapeutics: Board Member|Iterum Therapeutics: Stocks/Bonds Jayanti Gupta, PhD, Iterum Therapeutics: Advisor/Consultant Sailaja Puttagunta, MD, Iterum Therapeutics Limited: Full time employee|Iterum Therapeutics Limited: Stocks/Bonds
2109. In vitro and in vivo Killing Kinetics of Zosurabalpin (RG6006) Against Acinetobacter baumannii
Authors: Erbetti Isabelle , Ferrari Livia , Ortombina Alessia , Savoia Paola , Felici Antonio , Bissantz Caterina , Zampaloni Claudia
Published: November 2023

Background

Zosurabalpin (RG6006) is a novel antibiotic active against Acinetobacter spp., including carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex organisms. Here we describe and compare the kinetics of killing in static in vitro and in vivo neutropenic murine thigh and lung infection models.

Methods

The killing activity of Zosurabalpin was evaluated against 8 carbapenem resistant A. baumannii (CRAB) isolates (MIC range of 0.12 to 8 mg/L).

In vitro Time-Kill studies were performed over 24 hours at sub-MIC and multiples of the MIC (from 0.25x to 128x MIC) with regular time point samplings (from 0, 2, 4, 8, 12, 16, 20 and 24 hours), plating, and CFU counting.

The in vivo killing efficacy of RG6006 at 2 or 3 dose levels was assessed in 5 thigh and 5 lung infection models induced by 6 A. baumannii (MIC range 0.125 - 8 mg/L). Bacterial burden in matrices of interest was determined at different timepoints up to 48 hours.

Results

In vitro, the bactericidal activity (defined as a 99.9% [or ≥ 3 log10] reduction in CFUs) of Zosurabalpin was reached in all tested isolates (lowest bactericidal concentration: 4x-32x MIC) and with a relatively slow killing kinetic (≥ 12 hours). No regrowth was observed at or above 8x/16x MIC depending on the isolate.

In vivo, generally, no regrowth was observed. In all 5 lung and 3 thigh infection studies, all dosing regimen achieving a net bacterial reduction after 24 hours, showed continued suppression of growth over the 48 hours period. In 2 thigh infection studies induced by isolates with MIC 4 and 8 mg/L full bactericidal efficacy was observed without any signs of regrowth at the highest dose tested.

Conclusion

Zosurabalpin overall exhibited a bacterial killing effect, both in vitro and in vivo, against CRAB. The comparison of in vitro and in vivo time-kill data demonstrates that in vitro observed regrowth generally does not translate into, and potentially overestimates, in vivo regrowth.

This project has been funded by BARDA (HHSO100201600038C)

Disclosures

Isabelle Erbetti, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Livia Ferrari, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Alessia Ortombina, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Paola Savoia, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Antonio Felici, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Caterina Bissantz, n/a, F. Hoffmann-La Roche Ltd.: Full time employee of Roche Claudia Zampaloni, n/a, F. Hoffmann-La Roche Ltd.: Full time employee of Roche
2122. In Vitro Activity of Cefepime-Taniborbactam Against Clinically Significant Gram-Negative Bacteria Isolated from Patients with Cancer
Authors: Gerges Bahgat Z , Truong Y Lan , Rosenblatt Joel , Hachem Ray Y , Chaftari Anne-Marie , Shelburne Samuel A , Raad Issam I
Published: November 2023

Background

Gram negative (GN) bacterial infections are on the rise in patients with cancer (PWC). There is an urgent need for new therapies to address the rise of infections caused by multidrug resistant (MDR) GN pathogens. Taniborbactam is a β-lactamase inhibitor in combination with cefepime may offer a potential treatment option for patients with serious GN bacterial infections. This study aimed to evaluate the in vitro activity of a novel combination of cefepime-taniborbactam and comparators against recent Gram-negative clinical isolates from PWC.

Methods

Recent GN clinical isolates from PWC were tested against cefepime-taniborbactam and comparators. Clinical and laboratory Standards Institute (CLSI) approved broth microdilution method was used. Appropriate ATCC controls were included. MIC90, and percent of susceptibility calculations were made using FDA breakpoints when available. We tested 100 GN isolates and further testing is ongoing.

Results

Cefepime-taniborbactam and comparators antibiotics susceptibility percentage (S: %), and MIC90 are shown in the table below. Cefepime-taniborbactam demonstrated highly potent activity against all of tested Enterobacterales including extended spectrum Beta-lactamase (ESBL), and carbapenem-resistant Enterobacterales (CRE) as well as against P. aeruginosa and Stenotrophomonas maltophilia. At a provisional breakpoint of 16/4 mg/L, cefepime-taniborbactam showed highest activity against all tested isolates when compared to cefepime and other comparators, including activity against ESBL, CRE, MDR P. aeruginosa and S. maltophilia.

Comparative study between cefepime-taniborbactam and comparators for MIC90 (mg/L.) and Susceptibility (%) results against Gram-negative bacteria isolated from patients with cancer

Conclusion

Our data demonstrate that cefepime-taniborbactam has promising activity against clinically significant multidrug-resistant (MDR) GN bacterial pathogens isolated from PWC and it showed high activity compared to other commonly used broad spectrum antimicrobial agents.

Disclosures

Joel Rosenblatt, PhD, Novel Anti-Infective Technologies, LLC: Licensed Technology Issam I. Raad, Distinguished Professor, Novel Anti-Infective Technologies, LLC: Technology License
2123. Novel Antimicrobial Polycarbonate Coating for Intravenous Connectors
Authors: Truong Y Lan , Gerges Bahgat Z , Rosenblatt Joel , Raad Issam I
Published: November 2023

Background

IV connectors are ubiquitous access junctions in vascular access circuits. Unlike vascular catheters and IV lines made from soft polymers, connectors are made from rigid polycarbonate (PC) to prevent deformation during manipulation. In accessing PC connectors (PCCs) for infusion, PCCs are vulnerable to becoming microbially contaminated. Here we report development of a novel antimicrobial polycarbonate coating for preventing microbial colonization of IV connectors.

Methods

The FDA recently approved a new antimicrobial polyurethane catheter coating that comprised Minocycline (M), Rifampin (R), and Chlorhexidine (C). We spray-coated MRC onto PCCs as sequential laminate layers of M, R and C in PC or blend PC and polycarbonate-urethane copolymers. MRC coated PCCs were immersed in tubes filled with 50% serum + 50% saline to simulate elution of the coatings. After 7 days (typical interval of use prior to replacement of IV connectors), eluted connectors were exposed to challenge inocula of key CLABSI pathogen clinical isolates for 24 hours and the number of colonizing microbes were enumerated by sonication, serial dilution, plating and colony counting. Non-coated PCCs were positive controls.

Results

Table 1 presents number of viable colonies recovered after 7 days elution and following 24 hour microbial challenges with Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa (PA) and Candida albicans (CA).

Conclusion

The absence of microbial colonization of the MRC IV connectors demonstrates the efficacy and durability of the novel MRC polycarbonate laminate coating. MRC coated connectors merit further testing in vitro and in vivo for their potential to prevent CLABSI.

Disclosures

Joel Rosenblatt, PhD, Novel Anti-Infective Technologies, LLC: Licensed Technology Issam I. Raad, Distinguished Professor, Novel Anti-Infective Technologies, LLC: Technology License
2124. Novel Polygalacturonic and Caprylic Acid (PG+CAP) Antimicrobial Wound Ointment Effectiveness in Eradicating C. auris Biofilms In Vitro
Authors: Truong Y Lan , Gerges Bahgat Z , Rosenblatt Joel , Raad Issam I
Published: November 2023

Background

Candida auris (CA) is a multidrug-resistant fungal pathogen of increasing concern and has caused infection outbreaks in hospitals as a result of nosocomial transmission. CA has caused both invasive bloodstream and wound infections with significant morbidity and mortality. Recently, a novel polygalacturonic and caprylic acid (PG+CAP) antimicrobial wound ointment was highly effective in healing microbially contaminated chronic wounds in a pilot prospective randomized clinical trial when compared to MediHoney. In order to better combat CA wound infections, here we assessed the effectiveness of PG+CAP and MediHoney wound ointments in eradicating mature CA biofilms in vitro.

Methods

A well-established biofilm eradication model was used to quantify antimicrobial efficacy. Forty-eight-hour biofilm of two different strains of CA (AR0381 and AR0382) were formed separately on silicone discs and then exposed to PG+CAP or MediHoney wound ointment for two hours. The silicone discs were sonicated in neutralizer, then serially diluted, plated and counted to enumerate viable colonies remaining following exposure to the ointments. Positive controls were discs that had no wound ointment treatment.

Results

Figure 1 presents the median number of viable colonies recovered from 6 replicates following two-hour exposures of the mature CA biofilms to the wound ointments and positive control.

Conclusion

Both ointments fully eradicated biofilm for CA strain AR0381. PG+CAP fully eradicated AR0382 biofilm (greater than 5-log reduction) but MediHoney achieved less than a 3-log reduction against AR0382. The difference between PG+CAP and MediHoney for AR0382 was significant (p = 0.02). These results suggest PG+CAP might be a promising ointment for use in treating CA wound infections and merits further study.

Disclosures

Joel Rosenblatt, PhD, Novel Anti-Infective Technologies, LLC: Licensed Technology Issam I. Raad, Distinguished Professor, Novel Anti-Infective Technologies, LLC: Technology License
2125. Activity of Novel β-Lactam/β-Lactamase Inhibitor Combinations against Serine-Carbapenemase producing Carbapenem-Resistant Pseudomonas aeruginosa
Authors: Lee Su Young , Gill Christian M , Nicolau David P
Published: November 2023

Background

Antimicrobial resistance in Pseudomonas aeruginosa is complex and multifaceted. While the novel β-lactamase inhibitors (BLI), avibactam, relebactam, and vaborbactam inhibit serine-based β-lactamases, the comparative potency of the novel β-lactam (BL) /BLI combinations against serine-carbapenemase producing P. aeruginosa is unknown. The present study sought to compare the in vitro activity of ceftazidime/avibactam, ceftazidime, imipenem/relebactam, imipenem, meropenem/vaborbactam, and meropenem against serine-β-lactamase producing P. aeruginosa.

Methods

Carbapenem-resistant P. aeruginosa were collated through the Enhancing Rational Antimicrobials against Carbapenem-resistant P. aeruginosa (ERACE-PA) Global Surveillance. Isolates positive for serine-based carbapenemases were assessed. Minimum inhibitory concentrations (MICs) were determined by broth microdilution to each novel-BL/BLI and BL alone. In vitro potency was assessed by MIC50/90 and percent of isolates susceptible per CLSI guidance.

Results

GES was the most common carbapenemase identified (n=59) followed by KPC (n=8). Ceftazidime/avibactam had MIC50/MIC90 values of 4/8 mg/L and 91% of isolates were susceptible. Conversely, ceftazidime alone was active against only 3% of isolates. The MIC50/MIC90 of imipenem/relebactam were 16/ >16 mg/L and 13% of all isolates were defined as susceptibility. Against the KPC-producing isolates, 38% were susceptible to imipenem/relebactam compared with 0% for imipenem. The meropenem/vaborbactam MIC50/MIC90 were >16/ >16 mg/L, and 6% of isolates were susceptible which was similar to meropenem alone (MIC50/90, >8/ >8 mg/L; 3% susceptible) suggesting the addition of vaborbactam cannot overcome co-expressed, non-enzymatic resistance mechanisms.

Conclusion

Among the novel BL/BLIs, ceftazidime/avibactam displayed better in vitro activity and thus is a rational treatment option for serine-carbapenemase harboring P. aeruginosa. While imipenem/relebactam displayed some activity particularly against isolates with blaKPC, meropenem/vaborbactam exhibited poor activity with MICs similar to meropenem alone. These data can be integrated with rapid molecular diagnostics to guide empiric therapy.

Disclosures

Christian M. Gill, PharmD, Cepheid: Grant/Research Support|Entasis therapeutics: Grant/Research Support|Everest Medicines: Grant/Research Support|Shionogi: Grant/Research Support David P. Nicolau, PharmD, Allergan: Advisor/Consultant|Allergan: Grant/Research Support|Cepheid: Advisor/Consultant|Cepheid: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Tetraphase: Advisor/Consultant|Tetraphase: Grant/Research Support|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support|Wockhardt: Advisor/Consultant|Wockhardt: Grant/Research Support
2151. In Vitro Activity of Ceftazidime-Avibactam and Comparator Agents Against Pseudomonas aeruginosa Collected from Patients with Presumed Hospital- and Community-Acquired Respiratory Tract Infections: ATLAS Global Surveillance Program, 2017-2021
Authors: Wise Mark G , Stone Gregory , Sahm Daniel F
Published: November 2023

Background

The β-lactamase inhibitor, avibactam, has potent inhibitory activity against Class A, Class C, and certain Class D serine β-lactamases. This study evaluated the in vitro activity of ceftazidime-avibactam (CZA) and comparators against respiratory tract infection (RTI)-associated Pseudomonas aeruginosa isolated from presumed community-acquired (CA; cultured < 48 hours after hospital admission) and hospital-acquired (HA; cultured ≥48 hours post-admission) infections collected from 2017-2021.

Methods

11,780 non-duplicate P. aeruginosa were collected from 246 sites in 54 countries as part of ATLAS 2017-2021 (excluding mainland China and North America) from respiratory tract infections for which the length of hospitalization was specified. Susceptibility testing was by broth microdilution according to CLSI guidelines and analyzed using CLSI 2023 breakpoints. Meropenem-nonsusceptible (MEM-NS) isolates were screened for the presence of β-lactamase genes. All MEM-NS isolates were screened in 2017-2020, whereas ∼25% of those collected in 2020 and 2021 were screened.

Results

CZA was the most active agent examined against the CA-infection isolates, inhibiting 92.3% of the population (Table). Against the HA isolates, 89.0% were susceptible to CZA, a percentage slightly lower than amikacin (89.4%). Removing MBL-producers increased the percentages susceptible to CZA for both groups by 2-3 percentage points. Approximately 68-70% of the meropenem-nonsusceptible isolates from both groups were susceptible to CZA, values similar to those demonstrated by amikacin and ceftolozane/tazobactam.

Conclusion

The percentage of CA and HA isolates from respiratory tract infections inhibited by CZA was approximately 15 and 20 percentage points higher, respectively, than the percentages inhibited by meropenem, and slightly higher (1-2 percentage points) than ceftolozane-tazobactam. The potent in vitro activity of CZA against HA isolates was exceeded only by amikacin, an agent discouraged as monotherapy for P. aeruginosa infections outside of the urinary tract by the CLSI. CZA remains an excellent therapeutic choice for use against P. aeruginosa, regardless of whether they’re CA or HA.

Disclosures

Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Gregory Stone, PhD, Pfizer: Stocks/Bonds Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
2157. Phase 1 Study in Healthy Chinese Subjects of Novel Prodrug, MRX-4
Authors: Yang Haijing , Li Size , Wang Hailin , Cao Guoying , Zhang Jing
Published: November 2023

Background

MRX-4 is a prodrug of contezolid (MRX-1), a new oxazilidone approved in China. We evaluated the safety and pharmacokinetic (PK) profile of IV and oral MRX-4 and its metabolites.

Methods

This randomized, double-blind, placebo-controlled study was conducted at Huashan Hospital, (Shanghai, China) with four-arm design: a) IV, single-dose escalation group (500 mg, 1000 mg, 1500 mg, or 2000 mg); b) IV, repeated-dose group (2000 mg loading dose followed by 1000 mg maintenance dose, q12 h for 11 consecutive days using 1-1.5 hr infusion time); c) oral, single-dose escalation group (500 mg or 1500 mg); d) oral, repeated-dose group (1500 mg, q12 h for 11 consecutive days). Safety evaluation was conducted in each dose group.

The blood and urine concentrations of MRX-4, MXR-1, and the inactive metabolites (MRX-1352) were measured, using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).

Results

A total of 70 subjects completed the trial. MRX-4 concentration was not possible to measure due to rapid hydrolisis into MRX-1352. In the MRX-4 group, 67 treatment-emergent adverse events (TEAEs) were observed in 27 of 55 subjects (49%); 24 TEAEs occurred in 14 subjects in the IV group (n = 36) and 43 TEAEs in 13 subjects in the oral group (n = 19). Six adverse drug reactions (ADRs) were observed in 4 subjects in the IV group, which were predominantly a mild transient decrease in white blood cells that self-resolved. In the oral group, 23 ADRs were observed in 9 of 19 subjects (47%), primarily nausea and vomiting that self-resolved in the 1500 mg repeated-dose group. No decrease in platelet count was observed in any dose group. PK parameters of the inactive intermediate metabolite (MRX-1352), and the active metabolite (MRX-I, contezolid) are shown:

Conclusion

MRX-4 was safe and well tolerated among Chinese healthy subjects, with treatment adverse events being mild and transitory. MRX-4, administered via IV or oral, demonstrated rapid and complete conversion to contezolid. PK parameters support the potential for use of MRX-4 as the IV companion to oral contezolid.

Disclosures

All Authors: No reported disclosures
2159. Analysis of Resistance to Oral Standard-of-Care Antibiotics for Urinary Tract Infections Caused By Escherichia coli and Staphylococcus saprophyticus Collected in the United States in 2022
Authors: Arends S J Ryan , Kapoor Renuka , Torumkuney Didem , Scangarella-Oman Nicole E , Mendes Rodrigo E
Published: November 2023

Background

Gepotidacin is a novel, bactericidal, first-in-class triazaacenapthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and binding site and provides well-balanced inhibition of 2 different Type II topoisomerase enzymes. This study reports on the in vitro activity of gepotidacin and other oral antibiotics when tested against contemporary Escherichia coli and Staphylococcus saprophyticus clinical isolates collected from patients with UTIs for a gepotidacin uUTI global surveillance study.

Methods

A total of 1,001 E. coli and 92 S. saprophyticus isolates were collected during 2022 from 45 medical centers located within the United States. Most isolates (77%) tested were cultured from urine specimens collected from patients seen in ambulatory, emergency, family practice, and outpatient medical services. Bacterial identifications were confirmed by MALDI-TOF MS. Isolates were tested for susceptibility by CLSI methods at a central laboratory (JMI Laboratories). MIC results for oral antibiotics licensed for the treatment of uUTI and drug-resistant subsets were interpreted per CLSI guidelines.

Results

Gepotidacin (MIC50/90, 2/4 µg/mL) displayed good activity against 1,001 E. coli isolates as 98.8% of all observed gepotidacin MICs were ≤4 µg/mL (Table). Other oral agents tested against these isolates demonstrated the following rates of susceptibility (S): amoxicillin-clavulanate (85.2% S), ampicillin (55.6% S), ciprofloxacin (78.8%S), fosfomycin (99.3% S), mecillinam (93.5%S), nitrofurantoin (97.5% S), and trimethoprim-sulfamethoxazole (73.3% S). Gepotidacin maintained similar MIC50 values (ranging from 1 – 2 µg/mL) and MIC90 values (ranging from 2 – 4 µg/mL) against these drug-resistant subsets. Against S. saprophyticus isolates, gepotidacin (MIC50/90, 0.06/0.12 µg/mL) inhibited all isolates at ≤0.12 µg/mL. Most oral agents showed >90% S against S. saprophyticus isolates, except for penicillin (7.6% S).

Conclusion

Gepotidacin demonstrated in vitro activity against contemporary E. coli and S. saprophyticus from US urine isolates. This activity remained unaffected by resistance to other oral standard-of-care antibiotics.

Disclosures

S J Ryan Arends, PhD, Cipla: Grant/Research Support|GSK: Grant/Research Support Renuka Kapoor, PhD, GSK: Grant/Research Support Didem Torumkuney, PhD, GSK: Grant/Research Support Nicole E. Scangarella-Oman, MS, GSK: Employee and shareholder Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support
2166. Real-world susceptibilities to newer antibiotics in Enterobacterales and Pseudomonas aeruginosa including carbapenem non-susceptible and multi-drug resistant isolates : A multicenter analysis
Authors: Riccobene Todd , Ai ChinEn , Yu Kalvin , Gregory Sara , Kim Brooke , Debabov Dmitri , Gupta Vikas
Published: November 2023

Background

Infections caused by multi-drug resistant (MDR) Gram-negative pathogens are increasingly problematic in healthcare settings and are associated with worse clinical outcomes in critically ill patients. We conducted a multicenter evaluation of real-world susceptibilities to newer antibiotics.

Methods

Adult patients (≥ 18 years old) with facility reported antibiotic susceptibility from 2018-2022 across 100 facilities in the BD Insights Research Database (Franklin Lakes, NJ) were evaluated for overall and carbapenem non-susceptible (Carb-NS) Enterobacterales (ENT) and Pseudomonas aeruginosa (PSA) across respiratory, blood, urine, intra-abdominal, skin/wound, and other sources.

Results

A total of 27676 susceptibility results for Gram-negative pathogens were available for one or more of the antibiotics in Table 1 across 100 facilities, of which 79.9% (22101) and 19.6% (5420) were for ENT and PSA, respectively (Table 2). Ninety percent of susceptibility results for newer antibiotics were for E coli (42.9%), P aeruginosa (19.6%), K pneumoniae (14.6%), P mirabilis (8.1%), and E cloacae (4.8%). The top 3 antibiotics tested for ENT were CZA (11,667), TOL-TAZ (10,127), and MEV (211) and for PSA were TOL-TAZ (3172), CZA (1900), and FDC (317). For antibiotics reporting > 30 isolates, susceptibilities were highest for CZA in overall (98.7%), MDR (92.9%) and Carb-NS (85.0%) ENT and for FDC in overall (95.6%) and Carb-NS PSA (93.3%) (Table 3). Susceptibility of Carb-NS ENT to CZA was lower in 2022 (76.7%) than in 2018 (93.5%) but was consistent from 2019-2021 (85.7-87.7%). In Carb-NS ENT, TOZ-TAZ S was lower than CZA each year, ranging from 13.4 to 43.3% (Figure 1). CZA S was higher in 2022 than in 2018-2021 for Carb-NS PSA and was 82.0% compared to 86.4% for TOL-TAZ (Figure 1).

Conclusion

Real-world susceptibilities of all ENT were > 90% to CZA, TOL-TAZ, and MEV. Susceptibilities of Carb-NS ENT to CZA and MEV were >80%. Real-world susceptibilities of all PSA were > 85% for CZA, TOL-TAZ, and FDC. Susceptibilities of Carb-NS PSA were > 70% to CZA, TOL-TAZ, and FDC. Newer antibiotics remain an important option for management of resistant ENT and PSA.

Disclosures

Todd Riccobene, PhD, AbbVie: Employee salary|AbbVie: Stocks/Bonds ChinEn Ai, MPH, Becton, Dickinson and Company: Employee Kalvin Yu, MD, FIDSA, BD: Stocks/Bonds Sara Gregory, PhD, Becton, Dickinson and Company: Employee Brooke Kim, RN, BSN, MSM, AbbVie: Employee|AbbVie: Stocks/Bonds Dmitri Debabov, PhD. Molecular biology, Abbvie Inc.: Employee of Abbvie that participated in design, study conduct, financial support, interpretation of data, review, and approval of the publication Vikas Gupta, PharmD, Becton, Dickinson and Company (BD): Employee of BD|Becton, Dickinson and Company (BD): Stocks/Bonds
2167. Mutational Signature Analysis to Predict Drug-resistant Pseudomonas aeruginosa
Authors: Hall Kalen M , Williams Leonard G , Bojanowski Christine M , Pursell Zachary F , Morici Lisa
Published: November 2023

Background

Pseudomonas aeruginosa (Pa) is one of the predominant bacteria that contributes to chronic respiratory infection, patient morbidity, and mortality in cystic fibrosis (CF) patients. Up to 60% of Pa clinical isolates are hypermutators, caused by deficiency in the DNA mismatch repair (MMR) system, and are associated with increased multidrug resistance and treatment failure. In vitro studies demonstrate a causative relationship between hypermutation and multidrug resistance, yet hypermutators are not currently tested for in the clinical setting as no diagnostic method is currently available. Mutational signatures have been computationally extracted and characterized in human tumors, but to our knowledge this analysis has never been performed in prokaryotes.

Methods

Here, we evolved MMR-deficient and -proficient Pa in vitro under nine different antibiotic treatments. We sequenced these evolved lineages to test the hypothesis that mutational signature analysis can predict MMR-status and drug resistance. We identified mutation spectra from de novo mutations in the evolved lineages after ten passages and then compared these spectra to known human tumor MMR-deficient mutational signatures. We then sequenced 14 isolates from seven CF patients and performed mutational signature analyses to assess for the presence of MMR-deficient signatures.

Results

We observed a strong signature in all evolved MMR-deficient Pa strains of C >T transitions in a NCC and NCG contexts with some 5’ preference to C and G, along with T >C transitions in CTN and GTN contexts. Although many antibiotics are known mutagens, we did not observe treatment-dependent changes in mutational spectra.Mutation spectra consistent with MMR-deficiency were found in four isolates, each of which were also functionally validated as hypermutant via rifampicin reversion assay.

Conclusion

These studies suggest that mutational signature analysis may be a valuable tool to identify hypermutator strains of Pa, which could inform treatment regimens and improve management of chronic Pa infections.

Disclosures

Kalen M. Hall, B.S., B.A., Informuta: 1|Informuta: Ownership Interest|Informuta: Stocks/Bonds Leonard G. Williams, B.S., Informuta: 1|Informuta: Ownership Interest|Informuta: Stocks/Bonds
2942. Successful Screening, Linkage to Care, and Treatment of Hepatitis C in a Tiny Shelter Encampment on Veterans Affairs Grounds
Authors: Lautredou Cassandra C , Lynch Kimberly A , Stricker Katherine , Capone-Newton Peter , McCoy Matthew , Kawamoto Jenna , Patel Arpan , Seckington Michele , Bhattacharya Debika
Published: November 2023

Background

Persons experiencing homelessness have a high prevalence of hepatitis C virus (HCV) infection and multiple barriers to diagnosis and treatment. We implemented and evaluated a universal HCV screening and HCV care coordination and treatment program for Veterans living at a tiny shelter encampment on the West Los Angeles Veterans Affairs campus.

Hepatitis C Cascade of Care

All patients who completed treatment and obtained end of treatment lab work achieved SVR12, excluding Veterans who were lost to follow up (LTFU) and/or non-adherent (NA) (n=5), on treatment (n=4), or SVR12 pending (n=5).

Methods

We implemented a low-barrier to entry HCV treatment program for Veterans experiencing homelessness (VEH) that spanned April 2020-Dec 2021 (pre-intervention) and Jan 2022-April 2023 (post-intervention). The intervention involved a novel e-consult direct-to-treatment program facilitated by pharmacists and referral to ID/GI clinics (if ineligible for e-consult) and extensive engagement by encampment providers, including provision of direct-acting antivirals (DAAs) in weekly installments. Prior to the intervention, management was achieved solely through ID/GI clinic referrals. We evaluated HCV prevalence, along with linkage to care, treatment initiation, and sustained virologic response (SVR) of this novel program pre-and post-intervention. Data, including demographics, medical history healthcare visits, and other laboratory values were abstracted from the electronic medical record. Descriptive statistics were used to characterize prevalence of HCV and other covariates.

Results

Of the 704 Veterans who sheltered at the encampment at some point from April 2020-April 2023, 587 underwent HCV antibody screening (83%). Of those, 20% (120/587) were HCV Ab positive and 44% (53/120) had HCV viremia. Median age of those who were viremic was 64 years, 100% were male, 32% (17/53) were Black, 9% (5/53) Hispanic, and 58% (31/53) White. Pre- and post-intervention, 25 and 28 Veterans with HCV viremia were identified, 11 and 21 Veterans were linked to care (44% and 75%), 4 and 20 initiated DAAs (36% and 95%), and 1 and 6 achieved SVR (25% and 30%). Nine patients are currently on treatment (n=4) or pending SVR12 (n=5).

Conclusion

After an intervention involving e-consult and encampment provider engagement in VEH, 75% of Veterans with HCV viremia were linked to care, compared to 44% of Veterans prior to the intervention. Our program demonstrates the feasibility of encampment-based HCV screening, linkage to care and treatment.

Disclosures

Debika Bhattacharya, MD, MSc, Gilead Sciences: Grant/Research Support
2188. Evaluation of biocide susceptibilities of clinical isolates of Acinetobacter baumannii
Authors: Varghese Martin M , Cadnum Jennifer , Chatterjee Piyali , Jinadatha Chetan , Donskey Curtis
Published: November 2023

Background

Carbapenem-resistant Acinetobacter baumannii (CRAB) is an urgent antimicrobial resistant threat due to its resistance to many antibiotics. There is a concern that some antibiotic-resistant strains of A. baumannii might also express resistance to biocides, including disinfectants and antiseptics. However, relatively little information is available on the susceptibility of A. baumannii to disinfectants.

Methods

Thirty well-characterized clinical A. baumannii isolates were studied, including 24 (%) CRAB isolates and 11 (37%) with qacE1 and amvA efflux pump genes. The efficacy of sodium hypochlorite (1:10 dilution of household bleach) and virex-II 256 (quaternary ammonium disinfectant) was evaluated using a standard disk-based quantitative carrier test method (ASTM E2197-11) in the presence of 5% fetal calf serum. The disinfectants were tested at in-use concentrations with the manufacturer-recommended exposure times. Minimum inhibitory concentrations (MICs) to virex-II 256, povidone-iodine, chlorhexidine, and were determined using a broth microdilution method. Serial passage of A. baumannii in subinhibitory concentrations of virex-II 256 were performed to assess the potential for emergence of resistance.

Results

All 30 A. baumanii isolates were reduced to undetectable levels (>5.4 log10 reduction) by both disinfectants. MICs for povidone-iodine, chlorhexidine, and virex-II 256 were 2343.75 to 9375 µg/ml, 0.62 to 12.5 µg/ml, 1.06 to 2.03µg/ml, respectively. With serial passage in subinhibitory concentrations of virex-II 256, the MICs of virex-II 256 increased 4-fold from 2.03 to 8 µg/ml, and some strains developed increases in chlorhexidine MICS from 12.5 to 50 µg/ml.

Conclusion

Sodium hypochlorite and a quaternary ammonium disinfectant were effective at in-use concentrations against A. baumannii, including CRAB strains and isolates with efflux pumps. Exposure to subinhibitory concentrations of quaternary ammonium compounds may result in increases in MICs in these disinfectants and other biocides.

Disclosures

All Authors: No reported disclosures
2190. Lack of Knowledge of Antibiotic Risks Among an Outpatient Population is Associated with Intention to Use Non-Prescription Antibiotics
Authors: Amenta Eva , Trautner Barbara , Olmeda Kiara , Salinas Juanita , Arya Monisha , Laytner Lindsey , Paasche-Orlow Michael , Grigoryan Larissa
Published: November 2023

Background

Antibiotic use without a prescription (non-prescription use) leads to risks for patients and the public, including adverse drug reactions,

Clostridoides difficile

infections, microbiome disruption, and the development of antimicrobial resistance. We hypothesized that patients’ lack of knowledge of risks associated with antibiotic use would be associated with non-prescription use.

Methods

We surveyed patients in public clinics and private emergency department waiting rooms in Houston from January 2020 through June 2021. Respondents’ knowledge about risks associated with antibiotic use was assessed with an open-ended question, “Do you know about any risks associated with antibiotic use?” Intended use was defined as endorsing an intention to use antibiotics without a prescription. The effects of age, gender, race/ethnicity, education, and knowledge of the risks associated with antibiotics on intended use were investigated using logistic regression.

Results

We surveyed 564 individuals (median age of 51), with 72% identifying as female, 46.6% as Hispanic and 33% as Black or African American (Table 1). When asked about knowledge of antibiotic risks, 354 (63%) respondents were able to report at least one risk associated with antibiotics. Risks were categorized into themes that included side effects of antibiotics (270/564, 48%), antibiotic resistance (19%), disruption of the microbiome (5%), drug-drug interactions (4%), fear of taking medication (4%), and other (0.05%) (Table 2). Lack of knowledge of antibiotic risks OR 1.48 (95% CI 1.04-2.10) and younger age (age 18-64 years) OR 2.24 (1.29-3.89) were independently associated with intention to use non-prescription antibiotics (Table 3).

Conclusion

Over one-third of respondents reported no knowledge of antibiotic-associated risks. Only 19% of respondents were aware of the concept of antimicrobial resistance. Lack of knowledge was associated with the intention to use non-prescription antibiotics, suggesting that further patient education about potential downsides of taking antibiotics is essential to reducing non-prescription antibiotic use.

Disclosures

Barbara Trautner, MD, PhD, Genentech: Grant/Research Support|Peptilogics: Grant/Research Support
2191. An Assessment of Penicillin Allergy Documentation among Patients undergoing Elective Surgeries and Ambulatory Procedures
Authors: Banach David , Zavez Katherine , Schramm Carol , Zolla Meagan , Baron Kate , Carter Eileen J
Published: November 2023

Background

A documented allergy to a penicillin class antibiotic can have a significant impact on perioperative antibiotic prescribing and is associated with an increased risk of post-operative adverse events. Comprehensive penicillin allergy histories enable risk stratification to influence future antibiotic prescribing. We evaluated the documentation of penicillin allergies among patients undergoing elective surgeries and ambulatory procedures to identify opportunities to improve allergy assessments and documentation in these settings.

Methods

This was a retrospective chart review of unique records of patients who underwent elective surgeries and ambulatory procedures at UConn Health from December 2, 2022 – January 24, 2023, and had a documented allergy to a penicillin class antibiotic at the time of the surgery or procedure. Information on the documented details of the allergy, including type and timing of the reaction and who documented the allergy was recorded and analyzed.

Results

Among 233 unique records reviewed, most penicillin allergies were initially documented by a medical assistant (n=135, 58%), and not subsequently updated after initial documentation (n=211, 91%). Symptoms of allergy were documented for 177 (76%) of records, with the most common symptoms being hives/rash (n=106, 46%), gastrointestinal symptoms (n=27, 12%) and anaphylaxis (n=26, 11%). Symptoms of allergy were unknown or missing for 56 (24%) of records. In 5 (3%) of records, clinicians documented when the patient’s reaction occurred (childhood) and in 2 (1%) of records, clinicians indicated the patient tolerates cephalexin or amoxicillin.

Conclusion

Among patients undergoing elective surgeries and ambulatory procedures, we found medical assistants documented most penicillin allergy records. Penicillin allergy records were rarely updated and contained scant information for risk stratification. Efforts are needed to improve the documentation of penicillin allergies in outpatient pre-operative and pre-procedural settings.

Disclosures

All Authors: No reported disclosures
2197. Impact of an INtake FOrm for Restricted Medications to (INFORM) better antibiotic use within a long-term acute care hospital system
Authors: Hobbs Athena L V , VanCura Jennifer , Hobbs Diana A , Shea Katherine M
Published: November 2023

Background

Long-term Acute Care Hospitals (LTACHs) are uniquely positioned to treat patients with a high severity of illness for a long period of time. Despite this, there are substantial barriers to providing antimicrobial stewardship in this setting including limited resources and lack of patient data from transferring facilities.

Methods

This multi-center retrospective, quasi-experimental study evaluated the use of broad-spectrum antibiotics (BSAbx) over 3 timeframes in 43 LTACHs and rehabs within the Post Acute Medical System. Despite implementation of a restriction policy in June 2018, use remained high for ceftolozane/tazobactam (C/T), ceftazidime/avibactam (CZA), and meropenem/vaborbactam (MEV). In July 2020, the system antimicrobial stewardship committee created an INtake FOrm for Restricted Medications (INFORM) that required submission of pertinent clinical information for each patient receiving one of the target antibiotics as well as systematic review by an ID pharmacist. An electronic version of the INFORM was implemented in April 2022. Study timeframes included baseline (BL: July 2019-June 2020), phase 1 (P1: July 2020-March 2022), and phase 2 (P2: April 2022-March 2023). The primary objective was to determine if there was a difference in the combined use of C/T, CZA, and MEV measured as cost/acute patient day (APD) across the three timeframes. Secondary analyses included post-hoc analyses between these groups, and an evaluation of C/T, CZA, MEV with the addition of imipenem/cilastatin/relebactam (I/C/R).

Results

There was a significant reduction in antimicrobial use across intervention periods (mean cost/APD BL=2.5, P1=1.3, P2=0.8, p=0.045 using ANOVA, Figure 1). Sub-hoc analyses showed a significant difference for BL:P1 (p=0.02) and BL:P2 (p< 0.01), but not for P1:P2 (p=0.6). Even when adding I/C/R to control for any shifts in utilization to this agent after it was approved by the FDA, there was a statistically significant reduction across the intervention periods (p< 0.01 using ANOVA, Figure 2).

Figure 2: Cost/Acute Patient Day for C/T, CZA, MEV vs. I/C/R over time

C/T = ceftolozane/tazobactam, CZA = ceftazidime/avibactam, MEV = meropenem/vaborbactam, I/C/R = imipenem/cilastatin/relebactam

Conclusion

Completion of both the paper and electronic INFORM reduced C/T, CZA, and MEV use from baseline, showing that the systematic collection and review of patient data by an ID pharmacist reduced use of these BSAbx in a system of LTACHs and rehabs.

Disclosures

All Authors: No reported disclosures
2199. Antibiotic tracking and reporting in skilled nursing facilities: a failure to communicate
Authors: Jolles Sally , Heller Dee , Taylor Lindsay , Dowdell Ashlie , Crnich Christopher J , Ford Jay
Published: November 2023

Background

Antibiotic overuse and misuse are common in skilled nursing facilities (SNFs) and are drivers of adverse drug events, antibiotic resistance and Clostridioides difficile infections. CMS requires SNFs to implement antibiotic stewardship programs (ASPs) that include a system for tracking and reporting antibiotic use (AU) and antibiotic-related outcome (ARO) measures. However, there is limited understanding of the maturity of these systems in SNFs.

Methods

We conducted a descriptive study of AU/ARO tracking and reporting practices in 10 Wisconsin SNFs recruited in the fall of 2022. Key informants in study SNFs were asked to provide de-identified examples of line lists and facility antibiotic reports that included AU/ARO information. Checklists were developed to identify the types and characteristics of the different AU/ARO variables and measures. Document analyses were conducted on the retrieved source documents utilizing these checklists.

Results

36 source documents were analyzed including 24 line lists and 12 AU reports (Figure 1). Of the 20 qualifying line lists, 40% were in a format that permitted direct data manipulation (e.g., Excel spreadsheet). 70% of SNFs employed multiple line lists. 30% of SNFs were unable to provide an aggregate AU report. Although a majority of SNF line lists captured information on antibiotic indication, duration of therapy and ordering prescriber, these variables were frequently omitted from facility AU reports (Figure 2). Information on appropriateness of antibiotic prescriptions and origin of the antibiotic order (e.g., ED) were captured less frequently on SNF line lists and, by extension, facility AU reports (Figure 2).

A comparison of facility Line Lists versus Reports

Conclusion

SNF staff devote considerable resources to identifying and characterizing antibiotic events. However, this information is not stored in a format that allows data to be reviewed and analyzed easily. Additionally, a significant minority of SNFs do not routinely generate AU/ARO reports and those that do, often omit important information about prescribing practices that could inform facility quality improvement efforts. These findings suggest there is substantial opportunity to improve SNF AU/ARO tracking and reporting practices.

Disclosures

Lindsay Taylor, MD, MS, Merck: Grant/Research Support
2208. Ten years of the Irish National Outpatient Parenteral Antimicrobial Therapy (OPAT) Registry Data
Authors: Reidy Paul , Muldoon Eavan
Published: November 2023

Background

The Irish Outpatient Parenteral Antimicrobial Therapy (OPAT) programme, a national centrally administered outpatient antibiotic provision service was established in 2013 within the public hospital system and is operated by the Health Service Executive (HSE). Ireland is relatively unique in having a nationally coordinated OPAT programme with complete summary data since its establishment.

Here we describe the programme usage over ten years and show the data can be used to identify important trends in national antimicrobial usage, including stewardship issues, with relevant lessons for other OPAT centres.

Methods

Using data extracted from the national electronic portal we describe summary statistics from January 2013 to December 2022 (10 years).

Results

Over the ten-year period 17,559 OPAT episodes were facilitated across 42 healthcare institutions. These episodes represented 14,955 unique care episodes with the remainder being extensions or changes to active episodes.

12388 episodes were home OPAT delivered by a healthcare worker versus 5170 self OPAT where patients were taught to self-administer the antimicrobials.

The median OPAT duration of therapy was 14 days with an average of 19.9 days.

The median age of a referred patient was 59 years with an average age of 56 years.

The top five diagnoses of osteomyelitis, abscesses, cellulitis, bacteraemia, and pyelonephritis accounted for 53% of all referrals.

81.5% of patients were prescribed a single antimicrobial, 17.9% two agents and 0.6% three.

Four antibiotics – ceftriaxone, daptomycin, cefazolin and flucloxacillin continuous infusion account of 59% of the 44 different antimicrobials prescribed via the programme.

Five of the 42 healthcare institutions accounted for 57.25% of all OPAT prescriptions. The number of beds in a hospital was not the strongest predictor of OPAT usage.

The total number of bed days saved in the 10-year period was 292,860.

Conclusion

Within a health system operating on 11,171 beds available per day, for a population of just over 5 million people, with an average daily running cost of €878 per acute bed, the National OPAT programme has already contributed to significant bed day and consequent financial savings.

Starting an infectious diseases clinical service significantly increases OPAT utilisation rates.

ID Specialist appointed to centre for first time in 2021

Disclosures

All Authors: No reported disclosures