1253. Antimicrobial Activity of Cefepime in Combination with Taniborbactam Against Clinical Isolates of Enterobacterales from 2018-2020 Global Surveillance

Abstract Background Taniborbactam (formerly VNRX-5133) is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with potent and selective direct inhibitory activity against both serine- and metallo-β-lactamases (Ambler Classes A, B, C and D). Taniborbactam restores the activity of cefepime against many difficult to treat organisms, including cephalosporin- and carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa. The activity of the investigational combination cefepime-taniborbactam (FTB) and comparator agents was evaluated against clinical isolates of Enterobacterales from a 2018-2020 global surveillance study. Methods MICs of cefepime with taniborbactam fixed at 4 µg/mL and comparators were determined following CLSI M07-A11 guidelines against 10,543 Enterobacterales. Isolates were from community and hospital infections collected from 259 sites in 56 countries in 2018-2020. Resistant phenotypes were based on 2021 CLSI breakpoints. A set of 827 isolates with meropenem MIC ≥4 µg/mL (n=421) or with cefepime and/or ceftazidime MIC ≥2 µg/mL (n=406) was evaluated for the presence of MBLs, KPC, ESBLs, and OXA-48 group genes via PCR and sequencing. Forty-eight isolates with FTB MIC values of 16 µg/mL or greater were interrogated by WGS. Results Overall, 23.0% and 15.9% of isolates were nonsusceptible (NS) to cefepime and piperacillin-tazobactam (TZP), respectively (Table). FTB had potent activity against all Enterobacterales, with MIC50/90 values of 0.06/0.25 µg/mL and 99.5% inhibited at ≤8 µg/mL. FTB maintained activity against MBL-, KPC-, OXA-48 group, and ESBL-positive isolates (MIC90 range, 1 to >16 µg/mL; 80.5% to 100% inhibited at ≤8 µg/mL). Isolates with elevated FTB MICs had IMP-type enzymes, variation in the cefepime target (penicillin binding protein 3), permeability defects in combination with acquired β-lactamases, and/or possible up-regulated efflux. Results Table Conclusion Taniborbactam significantly restored the in vitro activity of cefepime against Enterobacterales, including isolates nonsusceptible to recently-approved BL/BLI combinations and expressing serine and metallo-β-lactamases. This support the continued development of FTB as a potential new treatment option for challenging infections due to resistant Gram-negative pathogens. Disclosures Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Mark G G. Wise, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

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681. In vitro Activity of the β-Lactamase Inhibitor QPX7728 in Combination with Several β-Lactams Against Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PSA)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.749 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S310-S311 ◽

Cited By ~ 1

Author(s):

Olga Lomovskaya ◽

Jill Lindley ◽

Debora Rubio-Aparicio ◽

Kirk J Nelson ◽

Mariana Castanheira

Keyword(s):

Resistance Mechanisms ◽

Vitro Activity ◽

Clinical Isolates ◽

In Vitro Activity ◽

Microdilution Method ◽

Carbapenem Resistant ◽

Broth Microdilution Method ◽

Data Representative ◽

Lactamase Inhibitor

Abstract Background QPX7728 (QPX) is a novel broad-spectrum boron-containing inhibitor of serine- and metallo-β-lactamases (MBLs). We evaluated the in vitro activity of QPX combined with several β-lactams against carbapenem-resistant AB (CRAB) and PSA clinical isolates with varying β-lactam resistance mechanisms. Methods A total of 503 CRAB (meropenem [MEM] MIC ≥8 µg/mL) and 762 PSA clinical isolates were tested by the reference broth microdilution method against β-lactams alone and combined with QPX (4 µg/mL and 8 µg/mL). PSA isolates were selected to represent the normal distribution of MEM, ceftazidime–avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ) resistance according to 2017 surveillance data (representative panel). Additionally, 262 PSA isolates that were either nonsusceptible (NS) to MEM (MIC, ≥4 µg/mL) or to TOL-TAZ (MIC, ≥8 µg/mL), or resistant (R) to CAZ-AVI (MIC, ≥16 µg/mL) (challenge panel) were also tested. Within this 262 strain challenge set, 56 strains carried MBLs and the majority also had nonfunctional OprD. Results Against CRAB, QPX at 4 and 8 µg/mL increased the potency of all β-lactams tested. MEM-QPX was the most potent combination (table) displaying MIC50/MIC90 at 1/8 and 0.5/4 µg/mL with QPX at fixed 4 and 8 µg/mL, respectively. Susceptibility (S) to MEM was restored in >95% of strains. Against the 500 PSA from the representative panel, S for all QPX combinations was >90%. For the challenge panel, TOL-QPX and piperacillin (PIP)-QPX were the most potent combinations, restoring S in 76–77% of strains. TOL-QPX and MEM-QPX or cefepime (FEP)-QPX restored the MIC values to S rates when applying the CLSI breakpoint for the compound alone (comparison purposes only) in ~90% and ~75% of non-MBL-producing strains, respectively, vs. 60–70% for TOL-TAZ and CAZ-AVI. PIP-QPX reduce the MIC values to S values for PIP-TAZ in ~60% of MBL-producing strains vs. 20–30% and 3–7% for other QPX combinations and non-QPX tested combinations, respectively. Conclusion Combinations of QPX with various β-lactam antibiotics displayed potent activity against CRAB and resistant PSA isolates and warrant further investigation. Disclosures All authors: No reported disclosures.

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Evaluation of the in vitro activity of new polymyxin B analogue SPR206 against clinical MDR, colistin-resistant and tigecycline-resistant Gram-negative bacilli

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa217 ◽

2020 ◽

Vol 75 (9) ◽

pp. 2609-2615 ◽

Cited By ~ 3

Author(s):

Yawei Zhang ◽

Chunjiang Zhao ◽

Qi Wang ◽

Xiaojuan Wang ◽

Hongbin Chen ◽

...

Keyword(s):

Stenotrophomonas Maltophilia ◽

Enterobacter Cloacae ◽

Polymyxin B ◽

Vitro Activity ◽

Clinical Isolates ◽

In Vitro Activity ◽

Gram Negative ◽

Carbapenem Resistant ◽

Resistant Strains

Abstract Background SPR206 is a novel polymyxin analogue. Activity against clinical isolates is little documented. Methods A collection of 200 MDR, carbapenem-resistant, tigecycline-resistant, colistin-resistant and non-MDR clinical isolates of Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae and Stenotrophomonas maltophilia was obtained from 50 centres across China (2016–17). All isolates were derived from respiratory tract, urine and blood samples. Strains were purposely selected on the basis of phenotypes, genotypes and specimen origins. MICs of SPR206 and other antimicrobials were determined. Results SPR206 was active against all bacteria tested except colistin-resistant isolates. The MIC50/90 values of SPR206 for colistin-resistant strains were comparable to known polymyxins (16/128 versus 8/128 mg/L). SPR206 exhibited potent activity against colistin-susceptible OXA-producing A. baumannii (MIC50/90 = 0.064/0.125 mg/L), NDM-producing Enterobacteriaceae (MIC50/90 = 0.125/0.25 mg/L) and KPC-2-producing Enterobacteriaceae (MIC50/90 = 0.125/0.5 mg/L). In fact, SPR206 was the most potent agent tested, with 2- to 4-fold lower MICs than colistin and polymyxin B for A. baumannii, P. aeruginosa and Enterobacteriaceae. Additionally, MIC values of SPR206 (MIC50/90 = 0.064/0.125 mg/L) were 16- to 32-fold lower than those of tigecycline (MIC50/90 = 2/2 mg/L) for tigecycline-susceptible carbapenem-resistant A. baumannii. Conclusions SPR206 showed good in vitro activity against MDR, tigecycline-resistant and non-MDR clinical isolates of Gram-negative pathogens. SPR206 also exhibited superior potency to colistin and polymyxin B, with 2- to 4-fold lower MIC50/90 values.

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203. Activity of Cefepime in Combination with Taniborbactam (formerly VNRX-5133) Against Pseudomonas aeruginosa from a Global 2018-2020 Surveillance Collection

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.203 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S124-S124

Author(s):

Meredith Hackel ◽

Mark G G Wise ◽

Daniel F Sahm

Keyword(s):

Pseudomonas Aeruginosa ◽

Efflux Pump ◽

Active Agent ◽

Multidrug Resistant ◽

Vitro Activity ◽

In Vitro Activity ◽

Independent Contractor ◽

Carbapenem Resistant ◽

New Treatment

Abstract Background Taniborbactam is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor (BLI) with potent and selective inhibitory activity against both serine- and metallo-β-lactamases (MBLs). Taniborbactam restores the activity of cefepime (FEP) against many multidrug resistant organisms, including cephalosporin- and carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa (PA). We evaluated the in vitro activity of the investigational combination cefepime-taniborbactam and comparators against clinical isolates of PA collected during a 2018-2020 surveillance. Methods MICs of FEP with taniborbactam fixed at 4 µg/mL (FTB) and comparators were determined against 3,219 PA collected from 221 sites in 52 countries in 2018-2020. Resistant phenotypes were based on 2021 CLSI breakpoints. Acquired β-lactamase (BL) genes were identified via PCR/Sanger sequencing or whole-genome sequencing (WGS) for 516 isolates with meropenem (MEM) MIC ≥8 µg/mL, and for 94 randomly selected isolates with FEP or ceftazidime MIC ≥16 µg/mL. 186 isolates with FTB MIC ≥16 µg/mL, 16 with FTB MIC=8 µg/mL and one with FTB MIC=4 µg/mL were subjected to WGS. Results Overall, 28.7%, 26.2% and 20.3% of PA isolates were nonsusceptible (NS) to piperacillin-tazobactam (TZP), MEM or FEP, respectively (Table). FTB demonstrated potent activity (MIC50/90, 2/8 µg/mL; 94.2% inhibited at ≤8 µg/mL) against PA overall and inhibited between 63.4% (ceftazidime-avibactam [CZA] NS) and 82.1% (TZP NS) of isolates in the NS subsets compared to 0% to 69.1% S for comparators. Against the 111 strains carrying VIM or NDM MBL genes, 67.6% had FTB MICs ≤8 µg/mL, with 11.7% having FTB MICs of 16 µg/mL. Plausible explanations for elevated FTB MICs included IMP MBL genes, penicillin binding protein 3 variations, and/or possible efflux pump up-regulation. Conclusion FTB demonstrated potent in vitro activity against PA with different resistance profiles, including NS to FEP, MEM, and TZP, and to the BL/BLI combinations CZA, ceftolozane-tazobactam, and meropenem-vaborbactam. FTB was the most active agent tested against PA harboring VIM and NDM MBLs. These findings support the continued development of FTB as a potential new treatment option for challenging infections due to MDR PA. Disclosures Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Mark G G. Wise, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

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In vitro Activity of Cefiderocol Against Gram-Negative Clinical Isolates Collected from Urinary Track Source: SIDERO-WT-2014/SIDERO-WT-2015

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.925 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S375-S376 ◽

Cited By ~ 2

Author(s):

Masakatsu Tsuji ◽

Meredith Hackel ◽

Roger Echols ◽

Yoshinori Yamano ◽

Dan Sahm

Keyword(s):

Vitro Activity ◽

Clinical Isolates ◽

Gram Negative Bacteria ◽

In Vitro Activity ◽

Gram Negative ◽

Carbapenem Resistant ◽

Mueller Hinton ◽

The Usa ◽

Fermenting Bacteria

Abstract Background The global rise of carbapenem resistant Gram-negative bacteria such as carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant non-fermenting bacteria is alarming and become threats to patient as only a few drugs remain active (e.g. colistin). Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin with potent activity against a wide variety of Gram-negative pathogens including carbapenem-resistant strains. This study evaluated the in vitro activity of cefiderocol and comparator agents against clinical isolates collected from urinary track source from North America. Methods A total of 3,323 Enterobacteriaceae, 263 Acinetobacter spp, 509 Pseudomonas aeruginosa, and 38 Stenotrophomonas maltophilia collected from the USA and Canada in 2014–2016 were tested. MIC was determined for cefiderocol, cefepime (FEP), ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), ciprofloxacin (CIP), colistin (CST), and meropenem (MEM) by broth microdilution and interpreted according to CLSI 2016 guidelines. All testing was done at IHMA, Inc. As recommended by CLSI, cefiderocol was tested in iron-depleted cation-adjusted Mueller Hinton broth. Based upon CLSI breakpoints, carbapenem-non-susceptible (CarbNS) strains were defined as follows: MEM: MIC ≥2 µg/mL for Enterobacteriaceae, ≥4 µg/mL for non-fermenters. Quality control testing was performed on each day of testing by using E. coli ATCC25922 and P. aeruginosa ATCC27853. Results Cefiderocol exhibited in vitro activity against 4,133 strains of Gram-negative bacteria with an overall MIC90 of 0.5 µg/mL. At 4 µg/mL cefiderocol inhibited the growth of 99.9% of the all isolates. MIC90 of cefiderocol against CarbNS Enterobacteriaceae was 4 µg/mL although MIC90 of other comparators were >64 or >8 (CST) µg/mL. The cefiderocol MIC90value was 1 µg/mL for CarbNS non-fermeneters. Conclusion Cefiderocol demonstrated potent in vitro activity against Enterobacteriaceae, A. baumannii, P. aeruginosa, and S. maltophilia isolates collected from a UTI source, with greater than 99.9% of isolates having MIC values ≤4 µg/mL. These findings indicate that this agent has high potential for treating cUTI infections caused by these problematic organisms, including isolates resistant to colistin. Disclosures M. Tsuji, Shionogi & Co.: Employee, Salary; M. Hackel, IHMA: Employee, Salary; R. Echols, Shionogi & CO., LTD: Consultant, Consulting fee; Y. Yamano, Shionogi & Co.: Employee, Salary

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1252. In Vitro Activity of Cefiderocol Against Metallo-β-Lactamase-Producing Gram-Negative Bacteria Collected in North America and Europe Between 2014 and 2017: SIDERO-WT-2014–2016 Studies

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1436 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S643-S644

Author(s):

Miki Takemura ◽

Krystyna Kazmierczak ◽

Meredith Hackel ◽

Daniel F Sahm ◽

Roger Echols ◽

...

Keyword(s):

North America ◽

Vitro Activity ◽

Gram Negative Bacteria ◽

In Vitro Activity ◽

Independent Contractor ◽

Gram Negative ◽

Carbapenem Resistant ◽

The Usa ◽

Cephalosporin Antibiotic

Abstract Background Metallo-β-lactamases (MBLs; eg, NDM, VIM, and IMP) can inactivate most commonly-used β-lactam antibiotics, including carbapenems. Infections caused by MBL producers are difficult to treat due to their resistance to many antibiotics. Cefiderocol (CFDC) is a siderophore cephalosporin antibiotic approved in the USA in 2019, with potent activity against carbapenem-resistant Gram-negative bacteria (GNB), including both serine- and metallo-carbapenemase positive strains. We evaluated the in vitro activity of CFDC and comparator agents against MBL-producing strains of GNB from North America and Europe in 3 years’ of consecutive surveillance studies (SIDERO-WT-2014–2016). Methods Susceptibility testing for CFDC, ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), meropenem (MEM), cefepime (FEP), ciprofloxacin (CIP), and colistin (CST) was performed by broth microdilution according to CLSI guidance. CFDC was tested in iron-depleted medium. A total of 275 MBL-producing strains, consisting of 120 Enterobacterales (45 NDM; 75 VIM), 5 NDM-producing Acinetobacter baumannii, and 150 Pseudomonas aeruginosa (134 VIM; 16 IMP), identified among 4985 (654 Enterobacterales and 4331 non-fermenters) MEM non-susceptible (based on CLSI breakpoints) strains were used for the current analysis. Results The minimum inhibitory concentration (MIC) range and MIC90 for CFDC and comparators for each MBL-producing organism group are shown in the Table. Against NDM-producing Enterobacterales, of which 42% and 33% were isolated in Turkey and Russia, respectively, CFDC inhibited the growth of 84% of isolates tested at ≤4 µg/mL. CFDC MIC90 was 4 μg/mL for VIM-producing Enterobacterales (41% and 31% isolated in Greece and Italy, respectively), 1 μg/mL for VIM-producing P. aeruginosa (50% isolated in Russia), and 4 μg/mL for IMP-producing P. aeruginosa (88% isolated in Czech Republic). Other comparators (except for CST) were not active against these MBL producers. Table. MIC range and MIC90 (μg/mL) for CFDC and comparators of MBL-producing organisms Conclusion CFDC inhibited the growth of 100% of MBL-positive GNB at ≤8 mg/mL and showed MIC90 of 4 μg/mL against all 275 MBL producers, indicating that CFDC has high potential for treating infections caused by these difficult-to-treat strains. Disclosures Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Krystyna Kazmierczak, PhD, Shionogi & Co., Ltd. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor) Roger Echols, MD, Shionogi Inc. (Consultant) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee)

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Cefepime/sulbactam as an enhanced antimicrobial combination therapy for the treatment of MDR Gram-negative infections

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz420 ◽

2019 ◽

Cited By ~ 1

Author(s):

David W Wareham ◽

M H F Abdul Momin ◽

Lynette M Phee ◽

Michael Hornsey ◽

Joseph F Standing

Keyword(s):

Fixed Ratio ◽

Vitro Activity ◽

Definitive Treatment ◽

High Dose ◽

In Vitro Activity ◽

Gram Negative ◽

Pharmacodynamic Modelling ◽

Carbapenem Resistant ◽

Combination Regimens

Abstract Background β-Lactam (BL)/β-lactamase inhibitor (BLI) combinations are widely used for the treatment of Gram-negative infections. Cefepime has not been widely studied in combination with BLIs. Sulbactam, with dual BL/BLI activity, has been partnered with very few BLs. We investigated the potential of cefepime/sulbactam as an unorthodox BL/BLI combination against MDR Gram-negative bacteria. Methods In vitro activity of cefepime/sulbactam (1:1, 1:2 and 2:1) was assessed against 157 strains. Monte Carlo simulation was used to predict the PTA with a number of simulated cefepime combination regimens, modelled across putative cefepime/sulbactam breakpoints (≤16/≤0.25 mg/L). Results Cefepime/sulbactam was more active (MIC50/MIC90 8/8–64/128 mg/L) compared with either drug alone (MIC50/MIC90 128 to >256 mg/L). Activity was enhanced when sulbactam was added at 1:1 or 1:2 (P < 0.05). Reduction in MIC was most notable against Acinetobacter baumannii and Enterobacterales (MIC 8/8–32/64 mg/L). Pharmacokinetic/pharmacodynamic modelling highlighted that up to 48% of all isolates and 73% of carbapenem-resistant A. baumannii with a cefepime/sulbactam MIC of ≤16/≤8 mg/L may be treatable with a high-dose, fixed-ratio (1:1 or 1:2) combination of cefepime/sulbactam. Conclusions Cefepime/sulbactam (1:1 or 1:2) displays enhanced in vitro activity versus MDR Gram-negative pathogens. It could be a potential alternative to existing BL/BLI combinations for isolates with a cefepime/sulbactam MIC of 16/8 mg/L either as a definitive treatment or as a carbapenem-sparing option.

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