Β-lactamase Inhibitor Research Articles

Synthesis and characterization of four diastereomers of β-lactamase inhibitor drug intermediate

A short and efficient stereo-specific synthesis of three stereoisomers (two diastereomer and one enantiomer) of Oxalate salt of benzyl (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate (8) has been described. Compound 8 is a key intermediate in the synthesis of β-lactamase inhibitors, was synthesized in high diastereomeric excess using chirally pure L-pyroglutamic acid. In this report, we also describe a chiral high performance liquid chromatography (CHPLC) method to separate these isomers. The developed CHPLC method was validated for the accurate determination of the diastereomeric purity of compound 8.

Antibiotics and antibiotic-associated diarrhea: a real-world disproportionality study of the FDA adverse event reporting system from 2004 to 2022

Background Our study aimed to assess the risk signals of antibiotic-associated diarrhea (AAD) caused by various antibiotics using real-world data and provide references for safe clinical applications.Methods We analyzed data extracted from the FDA Adverse Event Reporting System (FAERS) database, covering the period from the first quarter of 2004 to the third quarter of 2022. We computed the reporting odds ratio (ROR) for each antibiotic or antibiotic class to compare the signal difference. Furthermore, we also examined the differences in the onset times and outcomes of AAD caused by various antibiotics.ResultsA total of 5,397 reports met the inclusion requirements. Almost all antibiotics, except tobramycin and minocycline (ROR 0.98; 95%CI: 0.64–1.51 and 0.42; 95%CI: 0.16–1.11, respectively), showed a significant correlation with AAD. The analysis of the correlation between different classes of antibiotics and AAD revealed that lincomycins (ROR 29.19; 95%CI: 27.06–31.50), third-generation cephalosporins (ROR 15.96; 95%CI: 14.58–17.47), and first/second generation cephalosporins (ROR 15.29; 95%CI: 13.74–17.01) ranked the top three. The ROR values for antibiotics from the same class of antibiotics also varied greatly, with the ROR values for third-generation cephalosporins ranging from 9.97 to 58.59. There were also differences in ROR values between β-lactamase inhibitors and their corresponding β-lactamase drugs, such as amoxicillin-clavulanate (ROR = 13.31; 95%CI: 12.09–14.65) and amoxicillin (ROR = 6.50; 95%CI: 5.69–7.44). 91.35% of antibiotics have an onset time of less than four weeks.ConclusionsThere is a significant correlation between almost all antibiotics and AAD, particularly lincomycins and β-lactam antibiotics, as well as a different correlation within the same class. These findings offer valuable evidence for selecting antibiotics appropriately.

Relative inhibitory activities of the broad-spectrum β-lactamase inhibitor taniborbactam against metallo-β-lactamases.

Taniborbactam (TAN) is a novel broad-spectrum β-lactamase inhibitor with significant activity against subclass B1 metallo-β-lactamases (MBLs). Here, we showed that TAN exhibited an overall excellent activity against B1 MBLs including most NDM- and VIM-like as well as SPM-1, GIM-1, and DIM-1 enzymes, but not against SIM-1. Noteworthy, VIM-1-like enzymes (particularly VIM-83) were less inhibited by TAN than VIM-2-like. Like NDM-9, NDM-30 (also differing from NDM-1 by a single amino acid substitution) was resistant to TAN.

Antibiotic Guideline Adherence at the Emergency Department: A Descriptive Study from a Country with a Restrictive Antibiotic Policy.

Denmark has a low level of antimicrobial resistance (AMR). Patients hospitalized with suspected infection often present with unspecific symptoms. This challenges the physician between using narrow-spectrum antibiotics in accordance with guidelines or broad-spectrum antibiotics to compensate for diagnostic uncertainty. The aim of this study was to investigate adherence to a restrictive antibiotic guideline for the most common infection in emergency departments (EDs), namely community-acquired pneumonia (CAP). This multicenter descriptive cross-sectional study included adults admitted to Danish EDs with a suspected infection. Data were collected prospectively from medical records. We included 954 patients in the analysis. The most prescribed antibiotics were penicillin with beta-lactamase inhibitor at 4 h (307 (32.2%)), 48 h (289 (30.3%)), and day 5 after admission (218 (22.9%)). The empirical antibiotic treatment guidelines for CAP were followed for 126 (31.3%) of the CAP patients. At 4 h, antibiotics were administered intravenously to 244 (60.7%) of the CAP patients. At day 5, 218 (54.4%) received oral antibiotics. Adherence to CAP guidelines was poor. In a country with a restrictive antibiotic policy, infections are commonly treated with broad-spectrum antibiotics against recommendations.

2122. In Vitro Activity of Cefepime-Taniborbactam Against Clinically Significant Gram-Negative Bacteria Isolated from Patients with Cancer

Abstract 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

865. Same Shift Susceptibility Testing of Cefepime-Taniborbactam and Cefiderocol Using The Selux Next-Generation Phenotyping System

Abstract Background Robust, efficient, and reliable antimicrobial susceptibility testing (AST) systems are an integral component of effective antibiotic treatment. Multi-drug resistant (MDR) bacteria continue to emerge at alarming rates, requiring continuous innovation and development of new antibiotics. Among the new promising treatments for severe bacterial infections caused by carbapenem-resistant gram-negative bacteria, Cefiderocol (FDC) and Cefepime-Taniborbactam (FTB) have emerged as two frontrunners. FDC is the only FDA-approved siderophore cephalosporin, and FTB pairs the fourth-generation cephalosporin Cefepime, with Taniborbactam, a novel beta-lactamase inhibitor. AST results are paramount when directing therapy for patients with MDR infections, yet there is an average 3-year delay between the approval of new antibiotics and 510k submissions for new agents on automated AST systems. This is typified by FDC, for which there are currently no FDA-cleared automated AST systems. Here we assess the accuracy of FDC and FTB AST results using the Selux Next-Generation Phenotyping System. Methods For both FTB and FDC susceptibility, AST was performed using the Selux AST system and compared to CLSI broth microdilution (BMD) reference method in either cation-adjusted Muller Hinton broth (CAMHB) or its Iron depleted counterpart (ID-CAMHB). FDC, was tested in ID-CAMHB across 44 total CDC AR-Bank carbapenem-resistant K. pneumoniae, A. baumannii, and P. aeruginosa species. 34 CDC AR-Bank Strains predominantly resistant (30/34) to Cefepime were used to assess FTB. For FDC Essential Agreement (EA) and Categorical Agreement (CA) relative to ID-CAMHB were determined according to FDA breakpoints. FTB breakpoints were based on FDA breakpoints for Cefepime. For both agents, a comparison of BMD and the Selux system was accessed by EA and CA. Results The Selux AST system produced MICs to FDC with an average accuracy of 98% EA and 98% CA in ID-CAMHB (Table 1). In FTB, the Selux AST system produced MICs with an average accuracy of 94% EA and 100% CA in CAMHB (Table 2). Conclusion These data demonstrate the ability of the Selux NGP system to provide accurate results for FDC and FTB. This is the first known demonstration of an automated AST system for these important new drugs. Disclosures David Jimenez, B.S., Selux Diagnostics: Employee Kristin Baker, PhD, Selux Diagnostics: Employee Kelly Flentie, PhD, Selux Diagnostics: Employee Kristen Roberts, BS, Selux Diagnostics: Stocks/Bonds Gabriel Michaels, n/a, Selux Diagnostics: Employee Eric Stern, PhD, Selux Diagnostics: Board Member|Selux Diagnostics: Ownership Interest

2598. Activity of Aztreonam-Avibactam and Other β-Lactamase Inhibitor Combinations against Gram-negative Bacteria Isolated from Patients Hospitalized with Pneumonia in US Medical Centers (2020–2022)

Abstract Background Resistance to recently approved β-lactamase inhibitor combinations, such as ceftazidime-avibactam (CAZ-AVI) and meropenem-vaborbactam (MEM-VAB), appears to be increasing among carbapenem-resistant Enterobacterales (CRE) in some US hospitals. We evaluated the frequency and antimicrobial susceptibility of Gram-negative bacteria (GNB) causing pneumonia in US hospitals. Methods Bacterial isolates were consecutively collected (1/patient) from patients hospitalized with pneumonia and the susceptibility of GNBs (3,911 Enterobacterales [ENT] and 2,753 non-fermenters) was evaluated by broth microdilution. Isolates were collected in 69 medical centers in 2020–2022. Susceptibility testing was performed by CLSI broth microdilution in a monitoring laboratory. Aztreonam-avibactam (ATM-AVI) was tested with AVI at fixed 4 mg/L and a pharmacokinetic/pharmacodynamic susceptible (S) breakpoint of ≤ 8 mg/L was applied for comparison. CRE isolates were screened for carbapenemases (CPE) by whole genome sequencing. Results GNB represented 71.1% of organisms. The most common GNB species were P. aeruginosa (22.4% of organisms), K. pneumoniae (8.6%), E. coli (6.6%), S. marcescens (6.2%), S. maltophilia (4.9%), and E. cloacae complex (4.8%). ATM-AVI inhibited 100.0% of ENT at ≤ 8 mg/L and 99.9% at ≤ 4 mg/L and showed potent activity against CRE (MIC50/90, 0.25/1 mg/L; Table). CAZ-AVI and MEM-VAB were active against 89.4% and 88.5% of CREs, respectively. ATM-AVI retained activity against ENT non-S to CAZ-AVI and/or MEM-VAB (n=19; MIC50/90, 0.25/4 mg/L). The most common CPEs were KPC (69.2% of CREs), NDM (9.6%), and SME (4.8%). A CPE gene was not observed in 16.3% of CREs. CAZ-AVI and MEM-VAB were highly active against KPC and SME producers but showed limited activity against MBL producers. The most active comparators against CRE were tigecycline (95.2%S), amikacin (73.1%S), and gentamicin (60.6%S). Among P. aeruginosa, 79.1% were inhibited at ≤8 mg/L of ATM-AVI, 77.2% were MEM-S, and 77.2% were piperacillin-tazobactam-S. ATM-AVI was highly active against S. maltophilia, inhibiting 99.5% of isolates at ≤ 8 mg/L. Conclusion ATM-AVI demonstrated potent in vitro activity against the GNB most isolated from patients with pneumonia in US hospitals. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support 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 Leonard R. Duncan, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Timothy Doyle, MS, AbbVie: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

1949. Activity of Aztreonam-Avibactam against Enterobacterales Resistant to Recently Approved Beta-Lactamase Inhibitor Combinations Collected Worldwide (ex-US; 2020–2022)

Abstract Background Aztreonam-avibactam (ATM-AVI) is under clinical development. Aztreonam is a monobactam stable to hydrolysis by metallo-β-lactamases (MBLs). ATM-AVI has shown activity against MBL-producing, carbapenem-resistant Enterobacterales (CRE) that are resistant to recently approved β-lactamase inhibitor combinations (BLIs) such as ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MEM-VAB), and imipenem-relebactam (IMI-REL). We evaluated a large collection of CRE isolates nonsusceptible (NS) to these BLIs. Methods 24,580 Enterobacterales isolates were consecutively collected (1/patient) in 2020–2022 from 64 medical centers located in Western Europe (W-EU; 27 centers in 10 countries), Eastern Europe (E-EU; 13 centers in 9 countries), Latin America (LATMA; 8 centers in 6 countries), and the Asia-Pacific region (APAC; 16 centers in 8 countries). Among these isolates, 1,016 (4.1%) were CRE. Isolates were susceptibility tested by CLSI broth microdilution. CRE isolates were screened for carbapenemase (CPE) genes by whole genome sequencing. Results ATM-AVI inhibited 99.6% of CREs (MIC50/90, 0.25/0.5 mg/L) and ≥ 98.9% of CRE isolates NS to CAZ-AVI, MEM-VAB, and/or IMI-REL at ≤8 mg/L (Table). The most active comparators against CREs were CAZ-AVI (64.6%S), MEM-VAB (57.4%S), and IMI-REL (50.7%S). The activity of these BLIs varied widely among region, with highest susceptibility rates observed in W-EU (76.9% for CAZ-AVI, 72.5% for MEM-VAB, 63.8% for IMI-REL), followed by LATAM (65.1% for CAZ-AVI, 70.6% for MEM-VAB, 62.8% for IMI-REL), E-EU (66.6% for CAZ-AVI, 46.7% for MEM-VAB, 43.5% for IMI-REL), and APAC (39.9% for CAZ-AVI, 37.8% for MEM-VAB, 27.7% for IMI-REL). The most common CPE types overall were KPC (44.5% of CREs), NDM (29.8%), and OXA-48-like (16.0%). KPC predominated in LATAM (64.1%) and W-EU (61.1% of CREs). MBL occurrence was highest in APAC (59.5% of CREs), followed by LATAM (34.0%), E-EU (28.9%), and W-EU (23.6%). NDM represented 85.4% of MBLs. Conclusion ATM-AVI demonstrated potent activity against CRE isolates resistant to CAZ-AVI, MEM-VAB, and/or IMI-REL independent of the CPE produced. The activity of recently approved BLIs varied broadly among regions and were very limited in E-EU and APAC. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Leonard R. Duncan, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support 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

2523. Outcomes by Resistance Phenotype and Genotype among Baseline Pathogen in Patients with Complicated Urinary Tract Infection (cUTI) in the Phase 3 CERTAIN-1 Study

Abstract Background Taniborbactam is an investigational β-lactamase inhibitor that restores cefepime (FEP) activity against FEP-, carbapenem-, and multidrug-resistant Enterobacterales and Pseudomonas aeruginosa producing serine- and metallo-β-lactamases. Cefepime-taniborbactam (FTB) was superior to meropenem (MEM) for the primary composite endpoint of microbiologic and clinical success at test of cure (TOC) in adults with cUTI in the CERTAIN-1 study (NCT03840148). We assessed outcomes in subsets defined by baseline pathogen resistance phenotype and genotype. Methods Composite, microbiologic and clinical responses at TOC were assessed in the extended microbiologic intent-to-treat (microITT) population (patients with Enterobacterales and/or P. aeruginosa at ≥105 CFU/mL in urine at study entry against which at least 1 study drug had activity [FTB MIC ≤16 µg/mL; MEM MIC ≤2 µg/mL (Enterobacterales) or ≤4 µg/mL (P. aeruginosa)]). Phenotypic subsets included FEP-, multidrug-, and/or carbapenem resistance. Genotypic subsets included carriage of ESBL, extended-spectrum AmpC, plasmidic AmpC, and/or carbapenemase genes. Results For patients in the FTB treatment group with Enterobacterales at baseline, composite, microbiologic, and clinical success rates in resistant subsets were similar to or higher than those overall (Table). FTB achieved composite success in 7/8 patients with carbapenem-resistant Enterobacterales and in 8/9 patients with Enterobacterales producing a carbapenemase (5 OXA-48-group; 2 KPC-3, 2 NDM-1). FTB achieved composite success in 8/16 patients (clinical success in 13/16 patients) with P. aeruginosa overall; from 1 to 5 patients in the FTB group had P. aeruginosa in defined resistance categories. Conclusion FTB demonstrated efficacy in cUTI patients infected with cefepime-, multidrug-, and carbapenem-resistant pathogens and pathogens carrying ESBL, AmpC, and carbapenemase genes. Rates of success at TOC in each resistance subset were similar to or higher than those overall. These results are consistent with the ability of taniborbactam to restore cefepime activity against cefepime-, multidrug-, and carbapenem-resistant gram-negative pathogens producing serine and metallo-β-lactamases in nonclinical studies. Disclosures Greg Moeck, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder Leanne Gasink, MD, MSCE, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|CSL Behring: Advisor/Consultant|CSL Behring: Consulting fees|Everest Medicines: Grant/Research Support|Evopint Biosciences: Advisor/Consultant|Evopint Biosciences: Consulting fees|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|LBG Consulting, LLC: Principal|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Consulting fees|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Consulting fees|Vera Therapeutics: Advisor/Consultant|Vera Therapeutics: Consulting fees Mary Beth Dorr, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Merck and Co.: Shareholder|Pfizer: Shareholder|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder Hongzi Chen, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee|Venatorx Pharmaceuticals, Inc.: Stocks/Bonds 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 Florian Wagenlehner, MD, Achaogen: Advisory Board member, study participation|Astellas: Honoraria|AstraZeneca: Honoraria|AstraZeneca: Advisory Board member|Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Bionorica: Honoraria|Bionorica: Meeting/travel support, study participation|Deutsches Zentrum für Infektionsforschung (DZIF): Study participation|Enteris BioPharma: Study participation|Everest Medicines: Grant/Research Support|German S3 guideline Urinary tract infections: Board Member|Glaxo Smith Kline: Advisor/Consultant|Glaxo Smith Kline: Honoraria|Glaxo Smith Kline: Consulting fees, meeting/travel support, advisory board member, principal investigator in a GSK-sponsored study|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Guidelines European Association of Urology: Infections in Urology: Board Member|Helperby Therapeutics: Study participation|Janssen: Honoraria|Janssen: Advisory Board member|Klosterfrau: Honoraria|LeoPharma: Advisory Board member|MerLion: Advisory Board member|MIP Pharma: Honoraria|MSD: Advisory Board member|OM Pharma/Vifor Pharma: Advisory Board member, study participation|OM-Pharma: Honoraria|Pfizer: Honoraria|Pfizer: Advisory Board member|RosenPharma: Advisory Board member|Shionogi: Advisory Board member, study participation|Speaker research group German research foundation (DFG) Bacterial Renal Infections and Defense (FOR 5427): Study participation|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Consulting fees|University Hospital Giessen and Marburg GmbH, and Justus Liebig University, Germany: Employee|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Consulting fees, Advisory Board member Tim Henkel, MD, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Employee, consulting fees, shareholder Paul McGovern, MD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Everest Medicines: Grant/Research Support|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Paratek Pharmaceuticals: Shareholder|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Employee, stock options and shareholder

2149. In vitro Activity of Aztreonam-avibactam and Comparator Agents Against Carbapenem-Resistant Enterobacterales With and Without Carbapenemases, ATLAS Global Surveillance Program, 2017–2021

Abstract Background The investigational β-lactam/non-β-lactam β-lactamase inhibitor combination aztreonam-avibactam (ATM-AVI) is active in vitro against CRE isolates, including MBL-producers, as well as those co-producing serine β-lactamases of Class A, C, and some class D types. This study evaluated the in vitro activity of ATM-AVI and comparators against carbapenemase- and non-carbapenemase-producing CRE collected globally from 2017−2021 as part of the ATLAS surveillance program. Methods 85,990 non-duplicate, clinically relevant Enterobacterales isolates were collected from 258 medical centers located in 56 countries worldwide (excluding N. America and China). Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2023 breakpoints. ATM-AVI was tested at a fixed concentration of 4 mg/L avibactam. A tentative ATM-AVI pharmacokinetic/pharmacodynamic (PK/PD) susceptible MIC breakpoint of ≤ 8 mg/L was applied for comparison purposes. Organisms with meropenem MIC >1 mg/L and Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis with aztreonam or ceftazidime MIC >1 mg/L were screened for β-lactamase genes by PCR and Sanger sequencing. Results In total, 5,473 isolates were identified as CRE based on resistance to meropenem. ATM-AVI demonstrated potent in vitro activity against the CRE, with 99.3% of isolates (MIC90, 1 mg/L) inhibited at ≤8 mg/L (Table). ATM-AVI inhibited 99.5% of the carbapenemase-positive CRE, including 99.1% of the MBL-carriers (n=2,375) and 99.8% of serine-carbapenemase carriers (n=2,675) at ≤8 mg/L. Activity was somewhat reduced against the 441 CRE without detected carbapenemases as 96.3% (MIC90, 4 mg/L) of the isolates were inhibited at ≤8 mg/L aztreonam-avibactam. Amikacin was the most active comparator, although < 50% of each subgroup was susceptible at the CLSI breakpoint. Conclusion Based on MIC90 values and the preliminary PK/PD breakpoint, ATM-AVI demonstrated potent in vitro activity against CRE, including MBL- and serine carbapenemase-carrying isolates. As limited therapeutic options presently exist for treating infections caused by CRE, further development of this agent appears warranted. Disclosures Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation

2146. Antimicrobial Activity of Aztreonam-avibactam, Ceftazidime-avibactam, and Meropenem-vaborbactam against Enterobacterales causing Bloodstream Infection in US Medical Centers (2020–2022)

Abstract Background As the frequency of Enterobacterales (ENT) producing metallo-β-lactamase (MBL) and/or OXA-48 is increasing in some US medical centers, effective antimicrobials to treat the infections caused by these organisms are urgently needed. Aztreonam-avibactam (ATM-AVI) is under clinical development for treatment of infections caused by Gram-negative bacteria, including MBL producers. We evaluated the activities of ATM-AVI, ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MEM-VAB), and comparators against ENT isolated from patients with bloodstream infections (BSIs). Methods 4,802 ENT were consecutively collected (1/patient) from 72 US medical centers in 2020–2022 and susceptibility tested by CLSI broth microdilution method. ATM-AVI was tested with AVI at a fixed 4 mg/L. A pharmacokinetic/pharmacodynamic susceptible (S) breakpoint of ≤ 8 mg/L was applied for comparison. Carbapenem-resistant ENT (CRE) isolates were screened for carbapenemase (CPE) by whole genome sequencing. Results ATM-AVI was highly active against ENT (Table); only 2 isolates showed ATM-AVI MICs > 8 mg/L: 1 MEM-S E. coli and 1 E. aerogenes (CRE). All CPE producers and 98.0% of CREs were inhibited at an ATM-AVI MIC of ≤ 8 mg/L. CAZ-AVI and MEM-VAB were active against 81.6% and 65.3% of CREs, respectively. Ceftolozane-tazobactam (TOL-TAZ) was active against only 72.6% of ceftriaxone (CRO)-nonsusceptible (NS) isolates. ATM-AVI retained activity (MIC, ≤8 mg/L) against all MEM-VAB-NS and 90.0% of CAZ-AVI-NS isolates. The most common CPEs were KPC-2/3 (57.1% of CREs), OXA-48–like (16.3%), and NDM (12.2%). A CPE gene was not observed in 14.3% of CREs. CAZ-AVI and MEM-VAB were active against 100.0% of KPC producers, but CAZ-AVI showed limited activity against MBL producers and MEM-VAB showed limited activity against OXA-48–like and MBL producers. The most active comparators against CRE were tigecycline (95.9%S), gentamicin (49.0%S), and amikacin (44.9%S). Conclusion ATM-AVI demonstrated potent activity against a large collection ENT isolated from patients with BSI in US hospitals, including CREs and isolates resistant to recently approved β-lactamase inhibitor combinations. These results support further clinical development of ATM-AVI. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support 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 Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

Sulbactam/durlobactam (Xacduro) for Acinetobacter pneumonia.

The FDA has approved Xacduro (Innoviva), a combination of the beta-lactam antibacterial sulbactam and the beta-lactamase inhibitor durlobactam, for IV treatment of adults with hospital-acquired or ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex (ABC).

1676. PK, Safety and Tolerability of VABOMERE® (meropenem-vaborbactam) in Infants, Children and Adolescents

Abstract Background The worldwide spread of serine carbapenemases threatens carbapenems. VABOMERE (combination of meropenem and vaborbactam (MV), is a new class of beta-lactamase inhibitors including inhibition of Klebsiella pneumoniae. The PK, safety, and efficacy data of MV in adults support study in pediatrics. Methods Phase 1, open-label, dose-finding study. Pediatric subjects, 3 mos. to < 18 yrs already on antibiotics received a single-dose weight based infusion of MV over 3 hr. Blood samples were drawn pre-dose, 3,4, and 6 hr. for PK parameters. Population PK model included weight as a covariate. Safety assessments included AEs, vital signs, safety labs, physical exams, infusion tolerance, ECG. A DSMB reviewed safety and PK data before enrolling next cohort. Results MV was well-tolerated and safe in all age groups. Clearance per kg body weight of both M and V increased with decreasing body weight over all age groups suggesting an allometric relationship. Conclusion Targeted AUC0-8 efficacious in adult trials ranges of 91.7-513 mg•hr/L (meropenem) and 131-494 mg•hr/L (vaborbactam) were achieved in all pediatric cohorts. Disclosures Paula M. Bokesch, MD, Melinta Therapeutics: Advisor/Consultant Antonio C. Arrieta, MD, FIDSA, FPIDS, Astellas Pharma Global Development, Inc.: Advisor/Consultant|Astellas Pharma Global Development, Inc.: Grant/Research Support|Astellas Pharma Global Development, Inc.: Honoraria|Cumberland Pharmaceutical: Grant/Research Support|IDbyDNA: Advisor/Consultant|IDbyDNA: Grant/Research Support|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Nabriva: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Pfizer, Inc: Advisor/Consultant|Pfizer, Inc: Grant/Research Support|Roche/Genentech: Grant/Research Support|The Medicine Company: Grant/Research Support Randall K. Hoover, Ph.D., Melinta Therapeutics: Advisor/Consultant Sandra McCurdy, MS, Melinta Therapeutics: Employee

Transcriptome profiles of Streptomyces clavuligerus strains producing different titers of clavulanic acid

Streptomyces clavuligerus NRRL 3585 is a native producer of clavulanic acid (CA), a clinically used β-lactamase inhibitor, and is widely used as an industrial strain for the production of antibiotics. Selective random mutagenesis has successfully generated the improved CA-producing S. clavuligerus mutant strains as well as the strain with the loss of CA biosynthesis. To understand the molecular mechanisms associated with the improved CA-production potential, genome-scale RNA-sequencing-based transcriptional data were obtained for the wild-type S. clavuligerus strain and its three mutant strains. Total RNA samples for each strain were collected across four different growth stages, and all 32 sequencing data points exhibited an average Phred score of 36. The high-quality genome-scale transcriptional profile of S. clavuligerus strains with varied CA biosynthetic potential provides valuable insights and new opportunities for discovering efficient metabolic engineering strategies for the development of improved industrial strains.

Evaluation of Restricted Antimicrobial Utilization in a Tertiary Care Hospital

The World Health Organization has declared that antimicrobial resistance is one of the top ten public health threats faced by humanity. In addition to death and disability, prolonged illness results in longer hospital stays, more expensive medicines and financial challenges for those impacted. The emergence of antimicrobial resistance was mainly attributed to the inappropriate prescribing and overuse of antimicrobials including self-medication. The main objective of our study was to study the prescribing patterns of restricted antimicrobials among in-patients in a tertiary care hospital. A prospective observational study was conducted among 108 in-patients and the rationality of prescriptions with restricted antimicrobials was analyzed. There were 174 antimicrobials prescribed in 108 patients, out of 174 antimicrobials prescribed 140 drugs were restricted antimicrobials and 34 drugs were non-restricted antimicrobials. Among restricted antimicrobials prescribed 53(49.07%) were Penicillin and Beta-lactamase inhibitors, 40(37.03%) were Carbapenems, 30 (21.42%) were third-generation Cephalosporins, 7(6.48%) were Oxazolidinones,7(6.48%) were glycopeptide antibiotic and 2(1.85%) Vancomycin. Out of 108 patients, 16(14.81%) patients were prescribed antimicrobials for prophylactic use, 63(58.33%) patients were prescribed with antimicrobials based on empirical therapy and 29(26.85%) patients were prescribed antimicrobials based on culture and sensitivity reports. The study concluded that the restricted antimicrobials were mostly prescribed based on empirical therapy (58.33%) in the study population which shows the need to control the use of restricted antimicrobials.

Assessing the Potential of Gallic Acid and Methyl Gallate to Enhance the Efficacy of β-Lactam Antibiotics against Methicillin-Resistant Staphylococcus aureus by Targeting β-Lactamase: In Silico and In Vitro Studies.

Methicillin-resistant Staphylococcus aureus (MRSA), a global health concern, has prompted research into antibiotic adjuvants as a potential solution. Although our group previously reported the enhancing effects of gallic acid (GA) and methyl gallate (MG) on penicillin G activity against MRSA, the synergistic potential with other β-lactam antibiotics and the underlying mechanism have not been fully explored. Therefore, this study primarily aimed to investigate the antibacterial synergism with β-lactam antibiotics through disc diffusion, checkerboard, and time-kill assays. The β-lactamase inhibition was also examined through both molecular modeling and in vitro experiments. Additionally, bacterial morphology changes were studied using a scanning electron microscopy (SEM). The results revealed that both GA and MG exhibited anti-MRSA activity and showed indifferent effects when combined with β-lactam antibiotics against methicillin susceptible S. aureus (MSSA). Interestingly, MG demonstrated synergism with only the β-lactamase-unstable antibiotics against MRSA with the lowest fractional inhibitory concentration (FIC) indexes of ≤3.75. However, GA and MG exhibited weak β-lactamase inhibition. Furthermore, GA, MG, and the combination with ampicillin induced the morphological changes in MRSA, suggesting a possible mechanism affecting the cell membrane. These findings suggest that MG could potentially serve as an adjunct to β-lactam antibiotics to combat MRSA infections.

The effect of Pd(II) and Pt(II) coordination on the affinity of avibactam to OXA-48 β-lactamase

There is a constant necessity of finding new, reliable antimicrobials, due to the rapid emergence of antibiotic resistant bacteria. This paper tries to address this issue, as the possibility of formation of Pd(II) and Pt(II) coordination compounds of avibactam and their properties were investigated. Moreover, the effect of complexation on interactions with OXA-48 β-lactamase was thoroughly examined with computational approaches. It was found that the formation of Pd(II) and Pt(II) complexes of avibactam is thermodynamically favorable. Furthermore, it was observed that the binding energies of Pd(Avi)2 to OXA-48 approach that of Avibactam, whereas that of Pt(Avi)2 are somewhat less favorable. As such, they may be considered as new potential non-β-lactam β-lactamase inhibitors.

Meropenem/Vaborbactam: β-Lactam/β-Lactamase Inhibitor Combination, the Future in Eradicating Multidrug Resistance.

Due to the fact that there is a steadily increasing trend in the area of antimicrobial resistance in microorganisms, there is a need to look for new treatment alternatives. One of them is the search for new β-lactamase inhibitors and combining them with β-lactam antibiotics, with the aim of increasing the low-dose efficacy, as well as lowering the resistance potential of bacterial strains. This review presents the positive effect of meropenem in combination with a vaborbactam (MER-VAB). This latest antibiotic-inhibitor combination has found particular use in the treatment of infections with the etiology of carbapenem-resistant Enterobacterales (CRE), Gram-negative bacteria, with a high degree of resistance to available antimicrobial drugs.

Antibiotics With or Without Rifaximin for Acute Hepatic Encephalopathy in Critically Ill Patients With Cirrhosis: A Double-Blind, Randomized Controlled (ARiE) Trial.

Critically ill patients with cirrhosis admitted to the intensive care unit (ICU) are usually on broad-spectrum antibiotics because of suspected infection or as a hospital protocol. It is unclear if additional rifaximin has any synergistic effect with broad-spectrum antibiotics in ICU patients with acute overt hepatic encephalopathy (HE). In this double-blind trial, patients with overt HE admitted to ICU were randomized to receive antibiotics (ab) alone or antibiotics with rifaximin (ab + r). Resolution (or 2 grade reduction) of HE, time to resolution of HE, in-hospital mortality, nosocomial infection, and changes in endotoxin levels were compared between the 2 groups. A subgroup analysis of patients with decompensated cirrhosis and acute-on-chronic liver failure was performed. Baseline characteristics and severity scores were similar among both groups (92 in each group). Carbapenems and cephalosporin with beta-lactamase inhibitors were the most commonly used ab. On Kaplan-Meier analysis, 44.6% (41/92; 95% confidence interval [CI], 32-70.5) in ab-only arm and 46.7% (43/92; 95% CI, 33.8-63) in ab + r arm achieved the primary objective ( P = 0.84).Time to achieve the primary objective (3.65 ± 1.82 days and 4.11 ± 2.01 days; P = 0.27) and in-hospital mortality were similar among both groups (62% vs 50%; P = 0.13). Seven percent and 13% in the ab and ab + r groups developed nosocomial infections ( P = 0.21). Endotoxin levels were unaffected by rifaximin. Rifaximin led to lower in-hospital mortality (hazard ratio: 0.39 [95% CI, 0.2-0.76]) in patients with decompensated cirrhosis but not in patients with acute-on-chronic liver failure (hazard ratio: 0.99 [95% CI, 0.6-1.63]) because of reduced nosocomial infections. Reversal of overt HE in those on ab was comparable with those on ab + r.

High efficacy and enhanced synergistic activity of the novel siderophore-cephalosporin cefiderocol against multidrug-resistant and extensively drug-resistant Klebsiella pneumoniae from inpatients attending a single hospital in the United Arab Emirates

BackgroundCefiderocol (CFDC) is a novel siderophore-cephalosporin, which usually penetrates the bacteria through the iron-uptake pathways. Data is limited on the factors affecting CFDC activity and methods for overcoming resistance development. Synergistic approaches are needed to tackle antimicrobial resistance. This study aimed to determine CFDC activity on Klebsiella pneumoniae isolates from patients attending a single hospital in the United Arab Emirates (UAE), to explore the effect of β-lactamases on CFDC activity and to enhance CFDC susceptibility in both iron-depleted and iron-enriched conditions. MethodsWe investigated 238 K. pneumoniae strains from diverse clinical sources. β-lactamase genes were detected by PCR. Susceptibility to CFDC and 12 comparator antibiotics were tested. Combinations of CFDC with β-lactamase inhibitors (BLIs) and/or an outer membrane (OM) permeabilizer (polymyxin B nonapeptide) were tested in iron-depleted and iron-enriched conditions. ResultsCFDC exhibited efficacy of 97.9%, against multidrug-resistant (MDR), and extensively drug-resistant (XDR) strains, in addition to strains resistant to the last resort drugs such as colistin and tigecycline, including dual carbapenemase-producers (blaNDM and blaOXA-48-like) with MIC ≤ 0.06–8 µg/ml. It was effective in killing strains with single and multiple β-lactamases; however, it lost activity in iron-enriched conditions. Synergy was achieved with dual combination of CFDC and BLIs, especially avibactam, which caused a significant reduction in MICs even in iron-enriched conditions. A significant reduction was seen with the triple combination including an OM permeabilizer plus avibactam. Killing-kinetic studies proved that the combination therapy caused dose reduction and faster killing by CFDC than the monotherapy. ConclusionsCFDC was deemed effective against MDR and XDR K. pneumoniae. Synergistic combination of CFDC with BLIs and OM permeabilizers could be effective to treat infections in iron-rich sites, but this should be investigated in vivo.