bluuebunny/crossref_metadata_2025 huggingface dataset:
1663. Risk-benefit assessment of cefazolin use for surgical site infection prevention among patients allergic to penicillins and cephalosporins
Authors: Jeffres Meghan N , Porter Melissa , Ricco Madison , Norvell Miranda , Hogan Craig , Bassler Eric , Koonce Ryan
Published: December 2022

Background

Prosthetic joint infection (PJI) is a devastating complication following knee and hip arthroplasty. Perioperative antibiotics are routinely used in an effort to decrease the risk of surgical site infections (SSI), including superficial skin infections and deep PJI. The American Academy of Orthopedic Surgeons recommend cefazolin as standard of care for SSI prophylaxis. However, non-beta-lactams are often used in patients labeled as allergic to penicillins or cephalosporins due to concern of increased hypersensitivity reactions (HSR).

Methods

This study examined the frequency of SSI and HSR after receipt of perioperative cefazolin compared to clindamycin and/or vancomycin (C/V) within adult patients labeled as allergic to penicillins or cephalosporins. Patients were included if they underwent primary total hip or knee replacement surgery between January 2020 and July 2021 within the University of Colorado Health system. The outcome of SSI was assessed up to 90 days after surgery. The outcome of HSR was assessed up to 60 minutes after the conclusion of surgery.

Results

The cohort included 1,128 patients (cefazolin, n=809; C/V, n=319). Baseline characteristics were similar between groups except the proportion of patients with a history of immediate allergy symptoms was greater in the C/V group (59.6%) compared to the cefazolin group (35.8%). The frequency of SSI was lower in the cefazolin group compared to the C/V group (0.9% vs. 3.8%, p < .01). The cefazolin group included 7 SSI, consisting of 6 superficial SSI and 1 deep PJI. The C/V group included 12 SSI, consisting of 6 superficial SSI and 6 deep PJI. HSR were not significantly different between patients receiving cefazolin vs. C/V (0.2% vs. 1.3%, p=.06). HSR in the cefazolin group consisted of skin involvement (n=1) and self-reported allergy in post-operative window (n=1). Both patients had a non-descript history of penicillin allergy. HSR in the C/V group consisted of skin involvement (n=2) and hemodynamic instability (n=2). Three of the four patients had a history of immediate cephalosporin allergy.

Conclusion

Among penicillin or cephalosporin allergic patients, the use of cefazolin was associated with a lower frequency of PJI without an increase in HSR during surgery.

Disclosures

All Authors: No reported disclosures.
1468. Cidofovir Prescribing Patterns and Outcomes in Hospitalized Adults and Children
Authors: Lefemine Amanda , Meredith Jacqueline , Patel Rupal , Fotiadis Chris , Shahid Zainab , Gajurel Kiran , Roshdy Danya
Published: December 2022

Background

Cidofovir (CDV) dosing is based on limited clinical evidence and varies by indication. The optimal dose to achieve a virologic response has not been established. Routine lab monitoring, renal dose adjustments, and co-administration with intravenous (IV) fluids and probenecid are recommended to limit CDV-associated nephrotoxicity but lack a standard approach.

Methods

This was a retrospective evaluation of patients admitted to Atrium Health’s Carolinas Medical Center or Levine Children’s Hospital who received at least one dose of CDV from August 1, 2014 through June 30, 2021. The primary objective was to describe CDV prescribing patterns. Secondary objectives included evaluating virologic response, nephrotoxicity, and IV fluid and probenecid use.

Results

A total of 38 adult and 26 pediatric patients were included and received 44 and 60 CDV doses, respectively. Adult dosing was variable, but the most common regimens for BK virus infections included CDV 0.5 mg/kg every other week for solid organ transplant recipients (Figure 1A-B) and 1 mg/kg weekly for stem cell transplant recipients (Figure 1C). Dosing for adenovirus infections was inconsistent (Figure 1D). All but one of the adult patients evaluated had a decrease in viral load during the first two weeks (Figure 2A-D). In pediatric patients, the most common CDV dose was 1 mg/kg three times weekly which was used in 67% of patients across all indications (Figure 1E-I). Three evaluated pediatric patients had an increase in viral load (Figure 2E-H), but no similarities in dosing or indication were noted. The rate of nephrotoxicity based on pre-defined increases in serum creatinine was 29% for adults and 14% for pediatric patients. Use of IV fluid boluses and probenecid was inconsistent in both adult and pediatric patients (Table 1). Of the patients that did not receive probenecid, only 16.7% of adults and no pediatric patients received a CDV dose > 1 mg/kg.

Conclusion

Evaluation of virologic response to CDV was limited by small sample size. However, high variability in prescribing patterns highlights the need for standardized, indication-specific dosing. Standardization of IV fluid and probenecid use along with guidance on CDV dose adjustments in patients with renal insufficiency may help decrease the risk of CDV-associated nephrotoxicity.

Disclosures

All Authors: No reported disclosures.
1470. Human monoclonal antibodies for the treatment and prevention of Crimean Congo Hemorrhagic Fever
Authors: Tehrani Zahra Rikhtegaran , Koksal Iftihar , Yilmaz Gürdal , Karaaslan Elif , Spengler Jessica , Welch Stephen R , Karakoc Hanife N , Hamidi Sanaz , Albay Cansu , Durie Ian A , Sorvillo Teresa E , McGuire Jack , Spiropoulou Christina F , Mousa Jarod J , Godzik Adam , Bergeron Eric , Pegan Scott D , Sajadi Mohammad M
Published: December 2022

Background

Crimean-Congo hemorrhagic fever (CCHF) is the most widely spread viral hemorrhagic disease, found in Europe, Asia, and Africa. The disease symptoms start and progress rapidly and can lead to bruising and bleeding, with high fatality rates of up to 50% in hospitalized patients. Currently there are no approved vaccines or therapeutics available, and treatment is supportive.

The CCHFV glycoprotein is made up of two major structural glycoproteins, GC and GN, which are required for the virus attachment and entry. An additional protein, GP38, is a secreted byproduct derived from a glycoproptein precursor of GN and whose role remains unknown. Recently, the non-neutralizing mouse mAb 13G8 (anti-GP38) has shown 60-90% protection prophylactically or post-challenge in a mouse model when challenged with various CCHFV strains. This is noteworthy because neutralizing mouse mAbs to GC have not shown consistent protection in mouse models. Because most of the work has been on mice up till now, we decided to isolate and study mAbs from human survivors of CCHF.

Methods

The antibody response to GC and GP38 were measured in CCHF patients from Turkey ∼ 6 months after infection, and one high titer sample was selected for mAb isolation. For this purpose, a combined proteomics/genomics approach was performed; plasma Abs were isolated using sequential affinity chromatography, peptides subjected to Mass spectrometry, and then matched to single cell VDJ sequence libraries constructed from PBMCs. mAbs were tested for binding and neutralization, and one candidate used for in-vivo evaluation with Ifnar1- mice (lacking IFN) challenged with CCHF virus.

Results

11 anti-GP38 and 8 anti-Gc antibodies were isolated. All anti-Gc (and none of the GP38) mAbs exhibited neutralization. Anti-GP38 antibodies were segregated into 6 epitope groups based on competition assays (including 3 not described before). CC5-17, the human mAb sharing the same epitope as 13G8, showed 50% protection two separate experiments in Ifnar1- mice (when given 30 minutes prior to challenge, or 1 and 4 days after challenge).

Conclusion

The non-neutralizing gp38 antibodies have proven to afford protection before or after exposure to CCHFV. Human mAbs have the potential for protection and/or prevention of CCHF.

Disclosures

All Authors: No reported disclosures.
1471. Treatment of Influenza with Baloxavir was Associated with Reduced Absenteeism Compared with Oseltamivir in a Patient-Generated Health Data Study
Authors: Benitez Alejandra , Xu Hao , Ukachukwu Vincent , Chawla Devika
Published: December 2022

Background

Lost productivity from workplace absenteeism is a significant component of the economic burden of influenza [1]. Antiviral treatment together with influenza vaccination may help reduce work time lost from influenza illness [2]. In clinical trials, baloxavir, an oral single dose treatment for influenza, demonstrated comparable symptom resolution to oseltamivir taken twice daily for 5 days [3]. We examined baloxavir real-world outcomes using patient generated health data (PGHD) to investigate the association between antiviral use and workplace absenteeism.

Methods

Using data from a participatory influenza-like illness (ILI) surveillance program (ISP), we identified participants who self-reported ILI using the online Evidation platform during the 2019-2020 influenza season in the United States. Participants who self-reported treatment with baloxavir or oseltamivir were included. We conducted an ordinal logistic regression to estimate the odds of missing work due to ILI, while adjusting for use of over-the-counter (OTC) medication, age, number of symptoms, US region, and comorbidities.

Results

Of 3658 participants eligible for inclusion in the analysis, 3285 (89.8%) were prescribed oseltamivir and 373 (10.2%) were prescribed baloxavir. A majority of participants (81.7%) reported missing at least one day of work. In the ordinal logistic regression, use of baloxavir was associated with lower odds of absenteeism, compared to oseltamivir (odds ratio [OR]: 0.748, 95% confidence interval [CI]: 0.616, 0.907). In addition, a higher number of symptoms (OR 2.922, 95% CI: 2.454, 3.481), older age (OR: 1.425, 95% CI: 1.162, 1.747), and use of OTC medication (OR: 1.242, 95% CI: 1.086, 1.420) were associated with higher odds of absenteeism. Due to a high rate of missing data on the timing of antiviral use (24.5% missing), its association with absenteeism could not be adequately assessed.

Conclusion

Treatment of patients with ILI with single dose baloxavir was associated with reduced workplace absenteeism compared to oseltamivir after adjusting for measured confounders. This study provides useful insight into factors associated with ILI-related workplace absenteeism and the potential real-world utility of baloxavir.

Disclosures

Hao Xu, MSc, Hoffmann-La Roche Limited: Employee Vincent Ukachukwu, n/a, Roche Products Ltd: Employee Devika Chawla, PhD, Genentech: Employee.
1664. Impact of a Midline Catheter Prioritization Project on Central Venous Access and Central Line Associated Bloodstream Infections at an Urban Safety-net Community Hospital
Authors: Mena Lora Alfredo J , Lindsey Brenna , Echeverria Stephanie , Ali Mirza , Krill Candice , Takhsh Eden , Bleasdale Susan C
Published: December 2022

Background

The use of peripherally inserted central catheters (PICCs) has increased in the past decade. PICCs are central lines (CLs) commonly used for venous access. Midline catheters (MLs) can provide access when the need for a CL, such as vasopressors, is no longer present. MLs have a lower rate of BSI compared to PICCs and CLs, while providing dwell times comparable to PICCs. We established a project prioritizing ML use.

Methods

This is a quasi-experimental study in a 151-bed safety net community hospital. The pre-intervention period was January-December 2018 and post period was January 2019-December 2021. MLs were prioritized when new PICCs are requested without CL indications, such as total parenteral nutrition, hyperosmolar solutions and vasopressors. PICCs and CLs are transitioned to a ML once indications are no longer met and peripheral IVs are not feasible. Data on utilization and complications, such as deep venous thrombus (DVT) and BSIs, were reviewed and compared.

Results

A total of 63 peripherally inserted lines occurred prior to the intervention, of which 55 (87%) were PICC and 8 (13%) were ML (Figure 1). Post-intervention, 76 lines were placed the first year, of which 48 were ML (63%). This upward trend was sustained throughout the pandemic, with 116 lines in 2020 (80% ML) and 96 in 2021 (88% ML). No BSIs occurred during the pre-intervention and first post-intervention year. During the pandemic, 8 BSIs in MLs and 3 in PICCs occurred. The most common organism was Candida (Figure 2). The majority had COVID-19 (72%) and all (100%) BSIs were in the setting of shock. Case review demonstrated suspected secondary sources other than central venous catheters (CVCs). All BSIs with ML would have met NHSN criteria if CL present. No upper extremity DVTs were found.

Conclusion

A midline prioritization project was successfully implemented and sustained during the COVID-19 pandemic. The decline of PICC use from 87% to 12% suggests use for access without CL needs. High acuity during the pandemic led to BSIs that were likely secondary to shock and complications of COVID-19. All cases would have met NHSN criteria for CLABSI. The cost of a CLABSI is estimated at $48,108. Thus, this midline prioritization project may have led to CLABSI avoidance and an estimated cost savings of $384,864.

Disclosures

All Authors: No reported disclosures.
1672. Antimicrobial Activity of Cefepime-Taniborbactam and Comparators Against Clinical Isolates from ICU and Non-ICU Patients; 2018-2020 Global Surveillance
Authors: Hackel Meredith , Wise Mark , Sahm Daniel F
Published: December 2022

Background

Taniborbactam is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with selective direct inhibitory activity against both serine- and metallo-β-lactamases. Taniborbactam restores the activity of cefepime against many difficult to treat organisms, including cephalosporin- and carbapenem-resistant Enterobacterales (EB) and P. aeruginosa (PA). The activity of cefepime-taniborbactam (FTB) and comparator agents was evaluated against clinical isolates of EB and PA from a 2018-2020 global surveillance study.

Methods

16,742 isolates of EB and PA were collected from patients in wards designated ICU and non-ICU in 2018-2020. MICs of FTB and comparators were determined by the CLSI reference method. Resistant (R) phenotypes were based on 2022 CLSI breakpoints. Multidrug resistant (MDR) was defined as resistance to at least one agent from ≥3 drug classes. Provisional susceptible (S) breakpoints of ≤8 µg/mL and ≤16 µg/mL were applied for FTB for comparative purposes only.

Results

FTB had potent activity against EB, with MIC90s of 0.25 µg/mL for isolates from non-ICU patients and 0.5 µg/mL for isolates from ICU patients (Table). At least 99.2% of all EB from both wards were inhibited by ≤8 µg/mL FTB. FTB maintained activity against R phenotypes of EB in both ward types, with 90.3% to 98.1% of isolates inhibited at ≤8 µg/mL. FTB had potent activity against PA, with MIC90 values of 8 µg/mL and inhibiting ≥94.0% of isolates at ≤8 µg/mL for both ICU and non-ICU isolates. FTB maintained activity against R phenotypes of PA in both ward types, with 71.0% to 83.7% of isolates inhibited at ≤8 µg/mL and 84.7% to 92.5% inhibited at ≤16 µg/mL. %S to comparator agents against the R subsets ranged from 1.6% to 92.6% for EB, and 36.0% to 68.4% for PA. Against the particularly challenging subset of MDR PA from ICU patients, FTB was the most active agent tested as it inhibited 73.5/84.7% of isolates at ≤8/≤16 µg/mL compared to 43.1%S to CZA and 36.0%S to C/T.

Conclusion

Cefepime-taniborbactam demonstrated potent in vitro activity against EB and PA from ICU and non-ICU wards, including resistant subsets of isolates. This supports the continued development of FTB as a potential new treatment option for infections due to resistant Gram-negative pathogens.

Disclosures

All Authors: No reported disclosures.
1679. Susceptibility of Gram-Negative Clinical Isolates Collected from the USA in 2020 to Eravacycline and Comparators
Authors: Hawser Stephen , Kothari Nimmi , Lemos Bárbara , Monti Federica , Hodges Tony
Published: December 2022

Background

Eravacycline is a fully-synthetic, fluorocycline antibacterial approved by the FDA and EMA for the treatment of complicated intra-abdominal infections (cIAI) in patients ≥18 years of age. The activity of eravacycline has been surveyed annually since 2013. Here we present data on the in vitro activity of eravacycline and comparators against Gram-negative pathogens isolated in the USA during 2020.

Methods

Isolates were collected from patients from various body sites. Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution. Antibiotic susceptibility was determined using current CLSI breakpoints, except for eravacycline and tigecycline where FDA and EUCAST breakpoints were used due to a lack of CLSI breakpoints. Multi-drug resistant (MDR) was defined as resistance to ≥3 antibiotics including aztreonam, a carbapenem (meropenem or ertapenem), third or fourth generation cephalosporin (cefepime,cefotaxime,ceftazidime, or ceftriaxone), gentamicin, levofloxacin, piperacillin/tazobactam, tetracycline or tigecycline.

Results

Summary MIC and susceptibility data for eravacycline and select comparators are shown in the Table. Eravacycline MIC90 against Enterobacterales combined was 0.5 μg/mL (MDR Enterobacterales and individual species ranged from 0.25 to 1 μg/mL) and susceptibility was 93.9% using both FDA and EUCAST breakpoints. Tigecycline MIC90 against Enterobacterales was 1 μg/mL and susceptibility using FDA breakpoints (set in 2005) was 96.8%, whereas susceptibility by EUCAST breakpoints (set in 2019) was 87.8%. Eravacycline MIC50 and MIC90 against A. baumannii was 0.5 and 2 μg/mL, respectively; being at least 4-fold lower than that observed for tigecycline.

Conclusion

Eravacycline in vitro activity has remained unchanged since 2013, with comparable annual susceptibility rates observed against clinically important Gram-negative pathogens. These data also highlight that FDA breakpoints for tigecycline against Enterobacterales need urgent review to avoid potential false reporting of tigecycline susceptibility. In contrast, eravacycline FDA breakpoints are in keeping with those published by EUCAST and can be used to predict the clinical outcome of eravacycline treatment.

Disclosures

Tony Hodges, MD, LaJolla Pharmaceutical: Chief Medical Officer|LaJolla Pharmaceutical: Stocks/Bonds.
1680. Activity of the Novel Engineered Antimicrobial Peptide PLG0206 Against Enterobacterales isolates
Authors: Huang David , Sauer John Michael , Steckbeck Jonathan , Shinabarger Dean , Morrissey Ian , Hawser Stephen
Published: December 2022

Background

PLG0206 is an investigational, engineered cationic antimicrobial peptide designed to overcome the shortcomings of other natural AMPs, such as toxicity and limited activity. PLG0206 has recently been shown to be well tolerated and safe in a phase 1 study. This study evaluated the activity of PLG0206 and comparator antimicrobials against Enterobacterales isolates from the IHMA repository collected from various world-wide locations in 2019.

Methods

Isolates tested included Citrobacter spp. (151), Enterobacter cloacae (152), Escherichia coli (300), Klebsiella pneumoniae (300), Morganella morganii (43), Proteus spp. (152), Providencia spp. (61) and Serratia marcescens (45). Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution in cation-adjusted Mueller Hinton broth (CA-MHB), except for PLG0206 which was tested in RPMI medium due to plate-reading difficulties with CA-MHB. The susceptibility of comparators was determined using the 2022 CLSI breakpoints. MDR was defined as resistance to ≥ 3 antibacterial classes.

Results

Summary MIC and susceptibility data against Citrobacter spp., E. coli, E. cloacae, and K. pneumoniae are shown in the Table. PLG0206 retained activity against MDR isolates of Citrobacter spp. (26), E. coli (92), E. cloacae (45), and K. pneumoniae (132) with MIC50/90 values of 1/2, 1/2, 1/16 and 8/16 μg/mL, respectively. PLG0206 was essentially inactive against the Morganellaceae and Yersiniaceae isolates tested with MIC50 and MIC90 values of > 32 μg/mL (data not shown).

Conclusion

PLG0206 was active against isolates from the family Enterobacteriaceae, including MDR strains. The spectrum of activity of PLG0206 ranged from being most active against Citrobacter spp. and least active against K. pneumoniae. These data suggest that the novel antimicrobial peptide PLG0206 could be a potential treatment option against infections caused by Enterobacteriaceae isolates.

Disclosures

David Huang, MD, PhD, Peptilogics: Employee Jonathan Steckbeck, PhD, Peptilogics: I am CEO of Peptilogics.
1681. Activity of the Novel Engineered Antimicrobial Peptide PLG0206 Against Staphylococci and Enterococci
Authors: Huang David , Michael Sauer John , Steckbeck Jonathan , Shinabarger Dean , Morrissey Ian , Hawser Stephen
Published: December 2022

Background

PLG0206 is an investigational, engineered cationic antimicrobial peptide designed to overcome the shortcomings of other natural AMPs, such as toxicity and limited activity. PLG0206 has recently been shown to be well tolerated and safe when administered i.v. in a Phase 1 study. The initial proposed indication for this peptide is the treatment of periprosthetic joint infections via irrigation due to a broad spectrum of activity and anti-biofilm properties. This study evaluated the activity of PLG0206 and comparator antimicrobials against staphylococci and enterococci, causes of periprosthetic joint infections, from the IHMA repository of isolates collected from various world-wide locations in 2019.

Methods

Isolates tested included Enterococcus faecalis (77), E. faecium (75), methicillin-resistant Staphylococcus aureus (MRSA, 180), methicillin-susceptible S. aureus (MSSA, 121) and 152 coagulase-negative staphylococci (CoNS) comprised of S. epidermidis (113), S. haemolyticus (31), S. hominis (4), S. lugdunensis (1), S. saprophyticus (2) and S. simulans (1). Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution in cation-adjusted Mueller Hinton broth (CA-MHB), except for PLG0206 which was tested in RPMI medium due to plate-reading difficulties with CA-MHB. The susceptibility of comparators was determined using the 2022 CLSI breakpoints. MDR was defined as resistance to ≥ 3 antibacterial classes.

Results

When tested in RPMI, 18 E. faecalis, 29 E. faecium, 9 S. aureus and 7 CoNS were unable to grow. Summary MIC and susceptibility data for PLG0206 and comparators just including those isolates able to grow in RPMI are shown in the Table. Identical MIC50 and MIC90 values were obtained for PLG0206 when tested against MDR E. faecium (38), MDR CoNS (63) and MDR MRSA (67). Insufficient numbers of MDR MSSA (7) and MDR E. faecalis (4) were tested to accurately evaluate.

Conclusion

PLG0206 was the most potent antimicrobial overall (based on MIC50 and MIC90) against enterococci and CoNS and compared well with the comparators against MRSA and MSSA. These data support the evaluation of this novel antimicrobial peptide as a treatment option for periprosthetic joint infections, including those caused by MDR strains.

Disclosures

David Huang, MD, PhD, Peptilogics: Employee Jonathan Steckbeck, PhD, Peptilogics: I am CEO of Peptilogics.
1691. Bacteriophage and Protein Synthesis Pathway Inhibitor Combinations: Antibiotic mechanism of action drives antagonistic interactions
Authors: Kunz Coyne Ashlan J , Bhutani Natasha , Holger Dana , Kebriaei Razieh , Stamper Kyle , Ghali Amer El , Ghali Amer El , Alexander Jose , Biswas Biswajit , Lehman Susan , Arias Cesar A , Rybak Michael J
Published: December 2022

Background

Bacteriophage (phage) to augment antibiotic efficacy is a possible therapeutic option in the era of antimicrobial resistance. Studies to date have assessed phage-antibiotic synergy (PAS), however, its efficacy may be dependent upon antibiotic mechanism of action. Here, we report our in-vitro evaluation of phage-antibiotic antagonism (PAA) among phage and protein synthesis inhibitor combinations in multidrug-resistant clinical strains of P. aeruginosa, S. aureus, and E. faecium.

Methods

The following bacteria (phage) regimens were evaluated: 10266 (EM) and R9010 (14207) (P. aeruginosa) against gentamicin (GEN), azithromycin (AZM), and ciprofloxacin (CIP); N315 and 494 (Intesti) (S. aureus), and R497 and HOU503 (NV-497) (E. faecium) against linezolid (LNZ), minocycline (MIN), and daptomycin (DAP). Modified checkerboard (CB) MIC assays were used for preliminary screening followed by 24h time kill analyses (TKA). For CB, synergy, additive activity, and antagonism were defined as an FIC index of ≤0.5, 1–4, and >4, respectively. In 24h TKA, synergy and additivity were defined as a ≥2 and ≥1 log10 CFU/mL reduction from baseline, while antagonism was defined as phage-antibiotic combinations with CFU/mL higher than the most effective single treatment at 24h. Data were compared by one-way ANOVA and Tukey (HSD) test (P< 0.05).

Results

In CB analyses and 24h TKA of S. aureus and E. faecium isolates, phage-LZD and phage-MIN combinations were antagonistic (FIC >4) while phage-DAP was synergistic (FIC 0.5) (ANOVA range of mean differences 0.52 to 2.59 log10 CFU/mL; P< 0.001). For P. aeruginosa, phage-AZM and phage-GEN were antagonistic (FIC >4) and additive (FIC=1), respectively (ANOVA range of mean differences 1.04 to 1.95 log10 CFU/mL; P< 0.001).

Conclusion

Our results suggest that antibiotics that act on the protein synthesis pathway may lead to PAA, however, PAA interactions may be highly dependent upon antibiotic mechanism of bacterial inhibition (i.e., location of ribosomal protein synthesis inhibition, bactericidal vs. bacteriostatic) protein synthesis inhibit. Studies assessing PAA in a wider array of phage-antibiotic combinations are warranted.

Disclosures

Cesar A. Arias, MD, PhD, Entasis Phramceuticals: Grant/Research Support|MeMed Diagnostics: Grant/Research Support|Merck: Grant/Research Support.
1667. The Accuracy of Hospital-Onset Bacteremia and Candidemia Metric Variants Across Hospitals
Authors: Lewis Julia , Stevens Vanessa W , Ochoa Brennan , Malone Colin , Jones Makoto M
Published: December 2022

Background

Hospital-onset bloodstream (HOB) infection metrics are automatable alternatives to metrics based on chart review and may have comparable accuracy. Our group explored and evaluated variants of these measures.

Methods

Multiple electronic rules for HOB infection were developed, ranging from simple to moderately complex (Table 1).

To assess diagnostic accuracy overall and its stability over time and between facilities, we gathered electronic health record data between October, 2015 and December, 2019. Acute care admissions where the first positive blood culture was greater than 3 days after admission were included. We block-randomized 10 facilities across regions (North Atlantic, Southeast, Midwest, Continental, and Pacific) and whether above and below the median number of operating acute care beds. We restricted analysis to facilities > 30 acute care beds. Four reviewers reviewed approximately 50 charts randomly selected from the 10 facilities, with 10 charts overlapping with 2 other reviewers. A 5th reviewer, adjudicated in the case of disagreement or uncertainty. Accuracy statistics were generated by comparing algorithm outputs to the adjudicated standard.

Results

Compared to the 140 chart standard, sensitivity was low for all algorithms investigated (Table 2), except where common skin commensals were excluded. Specificity dropped when antimicrobial-based criteria were used. Using definition F from Table 1 as representative of consistency of accuracy across facilities, the median facility sensitivity and specificity were 80.1% [IQR 72.1-95] and 85.4% [73.3-100], respectively.

Conclusion

HOB metrics may need to exclude common skin commensals for simplicity and accuracy. Addition of antimicrobial use criteria did not seem to improve accuracy. Although sample sizes were small, accuracy metrics appeared relatively stable across facilities.

Disclosures

All Authors: No reported disclosures.
1700. Efficacy and Safety in Subjects with Renal Impairment in Contezolid and Contezolid Acefosamil Phase 2 and Phase 3 Skin Infection Clinical Trials
Authors: Fang Edward , Yang Huahui , Yuan Hong
Published: December 2022

Background

Contezolid (CZD; MRX-I) is a novel oral (PO) oxazolidinone with potent activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enteroccocus (VRE). Contezolid acefosamil (CZA; MRX-4) is an intravenous (IV) double prodrug of CZD. Nonclinical and initial clinical data indicate CZA and CZD may cause less myelosuppression, particularly with longer duration therapy, and with reduced risk of monoamine oxidase inhibition compared with linezolid (LZD). In 3 CZD Phase 2 (Ph2) and Phase 3 (Ph3) skin infection trials and 1 CZA Ph2 acute bacterial skin and skin structure infection (ABSSSI) study, primary efficacy and overall safety outcomes were comparable to LZD, and the most common treatment emergent adverse events (TEAEs) were gastrointestinal; however, hematologic laboratory abnormalities and TEAEs were less common with CZD and CZA. In June 2021, CZD was approved in China for complicated skin and soft tissue infections (cSSTI). Sequential therapy with CZA IV followed by CZD PO is being evaluated in global Ph3 diabetic foot infection (DFI) and ABSSSI clinical trials. Because patients with diabetes commonly have diminished kidney function, efficacy and safety outcomes in subjects with renal impairment were evaluated in completed Ph2 and Ph3 CZD and CZA studies.

Methods

In 4 CZD and CZA Ph2 and Ph3 skin infection trials, subjects were included with estimated creatinine clearance (CLcr) of 60 to < 90 mL/min (mild impairment) and 30 to < 60 mL/min (moderate impairment); no dose adjustments were made for renal function status. Primary efficacy outcomes and occurrence of TEAEs were evaluated for CZD and CZA subjects with no (CLcr ≥90 mL/min), mild, and moderate renal impairment.

Results

Primary efficacy outcomes and occurrence of TEAEs for CZD and CZA subjects with mild or moderate renal impairment were similar to that of subjects with no impairment in 4 skin infection trials.

Conclusion

In 4 completed Ph2 and Ph3 skin infection clinical trials, subjects who received CZD or CZA with mild and moderate renal impairment appeared to have primary efficacy and safety outcomes similar to subjects with no impairment, supporting current Ph3 global DFI and ABSSSI studies which will enroll subjects with reduced kidney function.

Disclosures

Edward Fang, MD, MicuRx Pharmaceuticals Inc: Employee Huahui Yang, MS, MicuRx Pharmaceuticals Inc: Employee.
1701. Pharmacokinetics in Subjects with Renal Impairment in a Contezolid Complicated Skin and Soft Tissue Infection Phase 3 Clinical Trial
Authors: Fang Edward , Yang Huahui , Yuan Hong
Published: December 2022

Background

Contezolid (CZD; MRX-I) is a novel oral (PO) oxazolidinone with potent activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enteroccocus (VRE). In a Phase 3 (Ph3) complicated skin and soft tissue infections (cSSTI) clinical trial (MRX-I-06), 719 subjects were randomized to either CZD 800 mg PO q12h or linezolid (LZD) 600 mg PO q12h with a treatment duration of 7-14 days in both groups. CZD was demonstrated to be noninferior to LZD for the primary efficacy outcome, and overall safety assessments were comparable to LZD. The most common treatment emergent adverse events (TEAEs) in both the CZD and LZD groups were gastrointestinal; however, hematologic laboratory abnormalities and TEAEs were less common with CZD. In June 2021, CZD was approved in China for cSSTI. Sequential therapy with intravenous contezolid acefosamil (CZA; double prodrug of CZD) followed by CZD PO is being evaluated in global Ph3 diabetic foot infection (DFI) and acute bacterial skin and skin structure infection (ABSSSI) clinical trials. Because patients with diabetes commonly have diminished kidney function, pharmacokinetics (PK) in renally impaired subjects were evaluated in MRX-I-06.

Methods

In MRX-I-06, subjects enrolled included those with estimated creatinine clearance (CLcr) of 60 to < 90 mL/min (mild impairment) and 30 to < 60 mL/min (moderate impairment); no dose adjustments were made for renal status. In a subset of the CZD group, PK was evaluated for subjects with no (CLcr ≥90 mL/min), mild, and moderate renal impairment.

Results

The CZD PK subset had 63 subjects, of which 19 had renal impairment (18 mild, 1 moderate). CZD subjects with CLcr above and below 90 mL/min had similar PK values, and CLcr was not a significant covariate (below are means ± SD). There was no indication that the variability in CL/F or in AUC was larger due to renal impairment, and the average AUC and Cmax were comparable between subjects with renal impairment and those with normal renal function.

Conclusion

In a Ph3 cSSTI clinical trial, PK in renally impaired subjects who received CZD appeared similar to those without dysfunction, supporting current Ph3 global DFI and ABSSSI studies with CZD and CZA which will enroll subjects with reduced kidney function.

Disclosures

Edward Fang, MD, MicuRx Pharmaceuticals Inc: Employee Huahui Yang, MS, MicuRx Pharmaceuticals Inc: Employee.
1706. IgM Monoclonal Antibodies Targeting Peptidoglycan May Provide Therapeutic Strategies against Antimicrobial Resistant Bacteria
Authors: Kroscher Kellie , Rikhi Nimisha , Muema Kevin , Schuman Richard F , Assiaw-Dufu Aba , Sei Clara J , Fischer Gerald W
Published: December 2022

Background

Antimicrobial resistance (AMR) poses a substantial global threat to human health and development. In addition to death and disability, the cost of AMR to the global economy is significant. Prolonged illness results in longer hospital stays and the need for more expensive medicines and financial challenges for those impacted. Therapeutics such as monoclonal antibodies (mAbs) may offer prevention and control measures against microbial infections without the use of antibiotics. In this study, we developed human antibodies (serum and mAbs) against components of staphylococcus aureus (SA) and Mycobacterium tuberculosis (MTB) and evaluated their capabilities.

Methods

Humanized DRAGA mice were immunized with 20μg of a combination vaccine comprised of Ultrapure peptidoglycan (PGN, derived from SA) and TB Pep01 peptide (targeting MTB HSP16.3), formulated with AddaVax™ adjuvant. Serum antibody responses to PGN, TB Pep01, and various whole bacteria were analyzed using ELISA. Mice with high antisera titers was selected for hybridoma production. Hybridomas were screened for binding to PGN, TB Pep01, and whole bacteria using ELISA and high producing clones were selected for monoclonal antibody development.

Results

Early and enhanced serum IgM responses to PGN were observed by Day-21, while IgG responses to PGN were detected at Day-35. Antisera binding to TB Pep01 was demonstrated, albeit lower than PGN. In addition, antisera recognition of whole bacteria was shown. Hybridoma clones (IgM) targeting PGN were identified for monoclonal antibody production.

Conclusion

Hybridomas developed in humanized DRAGA mice immunized with PGN and TBPep01 bound to the immunogens and showed broad recognition of various microbes. Ongoing studies to evaluate mAb functional activity against various microbes to include mycobacteria and staphylococci are in progress. IgM mAbs that recognize and whole bacteria, and opsonize and kill multiple bacterial strains, may provide an effective antimicrobial strategy for treatment of drug resistant bacterial infections.

Disclosures

All Authors: No reported disclosures.
1714. In Vitro Activity of Tebipenem Against Clinically Significant Gram-Positive Bacteria Isolated from Patients with Cancer
Authors: Gerges Bahgat Z , Rosenblatt Joel , Hachem Ray Y , Chaftari Anne-Marie , Raad Issam I
Published: December 2022

Background

Carbapenems represent the most potent and broad-spectrum β-lactams and are minimally affected by most β-lactamase enzymes. however, all carbapenems currently in use including meropenem and ertapenem, are parenterally administered. Tebipenem pivoxil (TBPM-PI-HBr) is a new broad-spectrum orally-administered antibiotic, from the carbapenem subgroup of β-lactam antibiotics. It is the only oral carbapenem and could be an alternative to intravenous injection carbapenem antibiotic therapy. This study aimed to evaluate the in vitro activity of tebipenem, a novel oral carbapenem, against recent gram-positive clinical isolates from cancer patients.

Methods

We tested 300 gram-positive isolates are recently isolated (2019-2021) from our cancer patients, collected from blood cultures against tebipenem and comparators. Clinical and laboratory Standards Instituted (CLSI) approved broth microdilution method was used with appropriate ATCC controls. MIC50, MIC90, MIC ranges and percent of susceptibility calculations were made using FDA breakpoints when available. There is no tebipenem susceptibility breakpoint for gram-positive isolates currently.

MIC90 and MICs range of tebipenem and comparators against 300 gram-positive isolates from cancer patients

Results

MIC90 and range of tebipenem and comparators are shown in table(1). Tebipenem gave the lowest MIC90 and MIC ranges against most gram-positive isolates including Bacillus species, Corynebacterium species, Enterococcus faecalis, Micrococcus species, MSSA S.aureus, Staphylococcus lugdunensis. β-hemolytic Streptococcus, Streptococcus pneumonie, Viridans group streptococci, and Rothia species. The comparative potency of tebipenem vs meropenem as a carbapenem in this study showed that, tebipenem MIC values were generally lower at least 2-4 fold.

Conclusion

Our data demonstrate that oral tebipenem has promising activity against clinically significant bacterial pathogens isolated from cancer patients and it has compatible activity to that of meropenem as a carbapenem in this study. Further clinical evolution for oral carbapenem treatment of bacterial infections is warranted.

Disclosures

All Authors: No reported disclosures.
1716. In Vitro Drug-Drug Interaction Evaluation of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor
Authors: Shafiee Afshin , Wong Bradley K , Chanda Sanjay
Published: December 2022

Background

Epetraborole (EBO) is a boron-containing oral inhibitor of bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis; EBO demonstrates potent activity against nontuberculous mycobacteria. EBO is being developed for the treatment of Mycobacterium avium complex lung disease patients and will be used in combination with other drugs. Therefore, EBO and its major circulating metabolite M3 were evaluated in a comprehensive drug-drug interactions (DDI) risk assessment.

Methods

Stability of EBO was evaluated in human liver microsomes, hepatocytes and recombinant CYP enzymes. The inhibitory potential of EBO (0.03-100 μM) and M3 (1-1000 μM) on cytochrome P450 (CYP) activities was assessed using human hepatic microsomes. The CYP induction potential of EBO (25-200 μM), M3 was evaluated and compared to prototypical inducers in human hepatocytes (three donors) and mRNA. Fold increase in mRNA expression was utilized to investigate the CYP induction potential of EBO (0.3-100 µM) and M3 (1-250 µM). Stably transfected cell lines that expressed individual transporters were used to determine whether EBO or M3 were substrates or inhibitors for these proteins.

Results

In vitro studies with microsomes, hepatocytes and recombinant cytochrome P450 (CYP) enzymes indicated that EBO was a poor substrate for major CYP enzymes; drug interactions with epetraborole as victim are considered unlikely. Neither EBO nor its major metabolite M3 was a potent reversible or time-dependent inhibitor of major CYP enzymes. Half maximal inhibitory concentration (IC50) values for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 were >100 µM. EBO was not an inducer of CYP1A2 mRNA in human hepatocytes from three donors, while it was a weak inducer of CYP2B6 and CYP3A4. No induction of mRNA was observed in human hepatocytes at concentrations relevant to planned clinical doses. EBO is unlikely to be a substrate for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1 and MATE2K. EBO was an in vitro substrate for OCT2, a transporter involved in active renal secretion. At clinically relevant concentrations, neither EBO nor M3 inhibited major human efflux or uptake transporters.

Conclusion

At clinically relevant concentrations of EBO and its major circulating metabolite M3, there is a low risk of victim or perpetrator DDI.

Disclosures

Afshin Shafiee, PhD, AN2 Therapeutics: Stocks/Bonds Bradley K. Wong, PhD, AN2 Therapeutics: Advisor/Consultant Sanjay Chanda, PhD, AN2 Therapeutics: Stocks/Bonds.
1719. In Vitro Activity of Ceftazidime-avibactam and Comparator Agents against Enterobacterales and Pseudomonas aeruginosa Collected from Patients with Bloodstream Infections as Part of the ATLAS Global Surveillance Program, 2017-2020
Authors: Estabrook Mark , Stone Gregory , Sahm Daniel F
Published: December 2022

Background

Avibactam (AVI) is a β-lactamase inhibitor with potent inhibitory activity against Class A, Class C, and some Class D serine β-lactamases. The use of ceftazidime (CAZ) with AVI is approved for several indications. This study evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacterales (Eba) and Pseudomonas aeruginosa (Pae) isolated from the blood of infected patients as part of the ATLAS surveillance program in 2017-2020.

Methods

A total of 67326 Eba and 23051 Pae non-duplicate clinically significant isolates, including 14216 Eba and 3002 Pae isolated from bloodstream infections, were collected in 56 countries in Europe, Latin America, Asia/Pacific (excluding mainland China), and the Middle East/Africa region. Susceptibility testing was performed by CLSI broth microdilution. Meropenem-nonsusceptible (MEM-NS) Eba and Pae isolates were screened for the presence of β-lactamase genes. Only 25% of MEM-NS Pae collected in 2020 were screened.

Results

Of all isolates collected, 97.3% Eba and 90.4% Pae were susceptible to CAZ-AVI (MIC90 values of 0.5 and 8 µg/ml, respectively), more than any comparator tested (table). This was true of blood isolates as well, with 96.9% (Eba) and 90.4% (Pae) isolates susceptible to CAZ-AVI. CAZ-AVI was active against 89.9% of Eba collected from blood that were CAZ-nonsusceptible (NS), more than the comparators tested. While this was not true of CAZ-NS Pae blood isolates (52.9% susceptible to CAZ-AVI), the next most active comparator, amikacin, was active against only 3.9 percentage points more isolates. More MEM-NS isolates that screened negative for MBLs were susceptible to CAZ-AVI than any comparator tested (97.8% of Eba and 80.1% of Pae).

Conclusion

CAZ-AVI provides a valuable therapeutic option for treating bloodstream infections caused by Eba and Pae, except those carrying MBLs.

Disclosures

All Authors: No reported disclosures.
1725. National Surveillance of Gram-negative Bacteria in Qatar, the Study for Monitoring of Antimicrobial Resistance Trends (SMART): from 2017 to 2019
Authors: Sid Ahmed Mazen A , Saleh Thoraya M , Albirair Mohamed , Dousa Khalid M , Arisgado Lolita C , Al Maslamani Muna A , Khal Abdul Latif Al , Ibrahim Emad B , Hadi Hamad Abdel
Published: December 2022

Background

Monitoring Antimicrobial Resistance Trends (SMART) is a global study for the surveillance of antimicrobial resistance (AMR) in Gram-negative bacteria (GNB) from different regions around the World including Gulf countries. To evaluate prevalence and trends in AMR in GNB from clinical specimens including microbiological and genomic characteristics as well as examine Antimicrobial Susceptibility Tests (AST) for existing and novel antimicrobials.

Methods

A prospective study was conducted on clinical specimens from Hamad Medical Corporation, Qatar, between 2017 and 2019 according to the SMART protocol that covers community as well as hospital-associated infections reported to secondary care. Consecutive GNB were included from different sites including lower respiratory and urinary tracts, intrabdominal, and bloodstream infections.

Results

Over the three years study period, 895 isolates were studied from the specified sites comprising 38 GNB with four key pathogens: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Meropenem resistance was 3.6% for E. coli and 9.3% for K. pneumoniae while imipenem/relebactam resistance was 3% compared to 8% respectively. The overall ceftolozane/tazobactam resistance for E. coli was 9% (25/281) compared to 13% (34/257) for K. pneumoniae while resistance for ceftazidime/avibactam was 2% (3/137) and 4% (5/117) respectively. Genomic characteristics of 70 Enterobacterales including 48 carbapenem-resistant, revealed the prevalence of β-lactamase from all classes dominated by blaCXM-15 while carbapenem resistance revealed a paucity of blaKPC and supremacy of blaOXA-48 like and blaNDM resistance genes (Table 1). Table 1.The frequency of different β-lactamase genes among 48 Carbapenem Resistant Enterobacterales (ERSs) isolates collect from Qatar between 2017 - 2019.*Intra-abdominal infections (IAIs), respiratory tract infections (RTIs), and urinary tract infections (UTIs)

Conclusion

Surveillance of GNB from Qatar showed the prevalence of key pathogens similar to the rest of the world but demonstrated significant resistance to existing and novel antimicrobials, particularly for K. pneumoniae with different underlying resistance mechanisms.

Disclosures

All Authors: No reported disclosures.
1732. Single Center Dalbavancin Experience: A cost saving surprise in people with substance use disorder
Authors: Nakagami Peter , Morita Kazumi , Schultz Sara K , Rodriguez Leah
Published: December 2022

Background

Dalbavancin is a lipoglycopeptide antibiotic that has efficacy in the treatment of skin/soft tissue infections secondary to Gram-positive organisms. Given its long half-life, there has been increasing use for other indications including osteomyelitis, joint infections, and bacteremia. Our goal was to evaluate the indications for usage in our health system, characteristics of the patients receiving dalbavancin, and outcomes with recurrence of infection and cost to the health system.

Methods

A retrospective chart review was conducted reviewing all patients who were ordered dalbavancin in the Temple health system between Nov 1, 2019 to Mar 31, 2021. Charts were reviewed in Epic with data collection in REDCap.

Results

34 orders for dalbavancin use were reviewed, representing 33 unique patients with 31 instances of dalbavancin administered. The majority of patients were male (79%) and had substance use disorder (88%). 97% of patients had formal ID consult. The majority of the patients were recommended dalbavancin due to concerns for adherence to prolonged oral regimens (17) or difficulties with SNF placement (19). The most common indications were bone and joint infections (16, 5 of which involved prosthesis) and bacteremia (9). 94% of patient received effective antibiotics prior to dalbavancin, with a median of 4 days. 75% of patients received their full prescribed course of dalbavancin. Only 1 adverse event was reported (itching and skin sloughing). At the time of writing, 12/23 (52%) of patients who were more than 90 days from a completed dalbavacin course returned for treatment for an infection at the same site within 90 days. Cost savings estimated from the alternate planned antibiotics and facility stay were calculated out to $1.47 million and 445 total hospital days were averted.

Conclusion

Our results show that dalbavancin use at our institution had minimal adverse reactions and were used to treat infections beyond skin/soft tissue infections in a population of predominantly people with substance use disorder.

Our early experience with this drug uncovered potentially significant cost savings with dalbavancin due to avoided hospital days.

Disclosures

All Authors: No reported disclosures.