ARGONAUT-IV: Susceptibility of Carbapenemase-producing Klebsiella pneumoniae to the Oral Bicyclic Boronate b-lactamase Inhibitor Ledaborbactam Combined with Ceftibuten
Publication Date
October 30, 2024
Authors
Michael R. Jacobs, Caryn E. Good, Ayman M. Abdelhamed, Andrew R. Mack, Christopher R. Bethel, Steven H. Marshall, Andrea M. Hujer, Kristine M. Hujer, Robin Patel, David van Duin, Vance G. Fowler, Daniel D. Rhoads, David A. Six, Greg Moeck, Tsuyoshi Uehara, Krisztina M. Papp-Wallace, Robert A. Bonomo
Ledaborbactam (formerly VNRX-5236), a bicyclic boronate β-lactamase inhibitor with activity against class A, C, and D β-lactamases, is under development as an orally bioavailable etzadroxil prodrug (VNRX-7145) in combination with ceftibuten for the treatment of urinary tract infections. At ceftibuten breakpoints of ≤1 mg/L (EUCAST) and ≤8 mg/L (CLSI), 92.5% and 99.0%, respectively, of 200 carbapenem-resistant Klebsiella pneumoniae isolates, predominantly K. pneumoniae carbapenemase producing, were susceptible to ceftibuten-ledaborbactam (ledaborbactam tested at a fixed concentration of 4 mg/L) compared to 4.5% and 30.5%, respectively, to ceftibuten alone.
Cefepime-taniborbactam demonstrates potent in vitro activity vs Enterobacterales with blaOXA-48
Publication Date
September 24, 2024
Authors
Maria F. Mojica, Elise T. Zeiser, Scott A. Becka, David A. Six, Greg Moeck, Krisztina M. Papp-Wallace
September 24, 2024Taniborbactam (formerly VNRX-5133) is a novel, investigational boronic acid β-lactamase inhibitor. The combination of cefepime (FEP) with taniborbactam is active against Enterobacterales carrying class A, B, C, and/or D enzymes. We assessed the activity of FEP-taniborbactam against Enterobacterales clinical strains carrying blaOXA-48 (N = 50, 100%), of which 78% harbored at least one extended-spectrum β-lactamase (ESBL). CLSI-based agar dilution susceptibility testing was conducted using FEP-taniborbactam and comparators FEP, meropenem-vaborbactam (MVB), and ceftazidime-avibactam (CZA). The addition of taniborbactam lowered FEP MICs to the provisionally susceptible range of ≤16 µg/mL; the MIC90 value decreased from ≥64 µg/mL for FEP to 4 µg/mL for FEP-taniborbactam. Notably, FEP-taniborbactam MIC50/MIC90 values (0.5/4 µg/mL) were lower than those for MVB (1/16 µg/mL) and comparable to those for CZA (0.5/1 µg/mL). Time-kill assays with E. coli clinical strains DOV (blaOXA-48, blaCTX-M-15, blaTEM-1, and blaOXA-1) and MLI (blaOXA-48, blaVEB, blaTEM-1, and blaCMY-2) revealed that FEP-taniborbactam at concentrations 1×, 2×, and 4× MIC displayed time-dependent reductions in the number of CFU/mL from 0 to 6 h, and at 4× MIC demonstrated bactericidal activity (3 log10 reduction in CFU/mL at 24 h). Therefore, taniborbactam in combination with FEP was highly active against this diverse panel of Enterobacterales with blaOXA-48 and represents a potential addition to our antibiotic arsenal.
Cefepime-taniborbactam activity against antimicrobial-resistant clinical isolates of Enterobacterales and Pseudomonas aeruginosa: GEARS global surveillance programme 2018-22
Publication Date
September 17, 2024
Authors
James A. Karlowsky, Mark G. Wise, Meredith A. Hackel, David A. Six, Tsuyoshi Uehara, Denis M. Daigle, Daniel C. Pevear, Greg Moeck, Daniel F. Sahm
Objectives: Taniborbactam is a boronate-based β-lactamase inhibitor in clinical development in combination with cefepime.
Methods: Cefepime–taniborbactam and comparator broth microdilution MICs were determined for patient isolates of Enterobacterales (n = 20 725) and Pseudomonas aeruginosa (n = 7919) collected in 59 countries from 2018 to 2022. Taniborbactam was tested at a fixed concentration of 4 mg/L. Isolates with cefepime–taniborbactam MICs ≥ 16 mg/L underwent WGS. β-Lactamase genes were identified in additional meropenem-resistant isolates by PCR/Sanger sequencing.
Results: Taniborbactam reduced the cefepime MIC90 value for all Enterobacterales from >16 to 0.25 mg/L (>64-fold). At ≤16 mg/L, cefepime–taniborbactam inhibited 99.5% of all Enterobacterales isolates; >95% of isolates with MDR and ceftolozane–tazobactam-resistant phenotypes; ≥ 89% of isolates with meropenem-resistant and difficult-to-treat-resistant (DTR) phenotypes; >80% of isolates with meropenem–vaborbactam-resistant and ceftazidime–avibactam-resistant phenotypes; 100% of KPC-positive, 99% of OXA-48-like-positive, 99% of ESBL-positive, 97% of acquired AmpC-positive, 95% of VIM-positive and 76% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value from 32 to 8 mg/L (4-fold). At ≤16 mg/L, cefepime–taniborbactam inhibited 96.5% of all P. aeruginosa isolates; 85% of meropenem-resistant phenotype isolates; 80% of isolates with MDR and meropenem–vaborbactam-resistant phenotypes; >70% of isolates with DTR, ceftazidime–avibactam-resistant and ceftolozane–tazobactam-resistant phenotypes; and 82% of VIM-positive isolates. Multiple potential mechanisms of resistance, including carriage of IMP, or alterations in PBP3 (ftsI), porins (decreased permeability) and efflux (up-regulation) were present in most isolates with cefepime–taniborbactam MICs ≥ 16 mg/L.
Conclusions: Cefepime–taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa, and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM MBLs.
Cefepime-Taniborbactam: A Novel Cephalosporin/b-Lactamase Inhibitor Combination
Publication Date
August 30, 2024
Authors
George G. Zhanel, Celine Mansour, Stacey Mikolayanko, Courtney K. Lawrence, Sheryl Zelenitsky, Danyel Ramirez, Frank Schweizer, Denice Bay, Heather Adam, Philippe Lagace-Wiens, Andrew Walkty, Neal Irfan, Nina Clark, David Nicolau, Carlo Tascini, James A. Karlowsky
Taniborbactam (formerly known as VNRX-5133) is a novel bicyclic boronate β-lactamase inhibitor of serine β-lactamases (SBLs) [Ambler classes A, C, and D] and metallo-β-lactamases (MBLs) [Ambler class B], including NDM and VIM, but not IMP. Cefepime-taniborbactam is active in vitro against most isolates of carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA), including both carbapenemase-producing and carbapenemase-non-producing CRE and CRPA, as well as against multidrug-resistant (MDR), ceftazidime-avibactam-resistant, meropenem-vaborbactam-resistant, and ceftolozane-tazobactam-resistant Enterobacterales and P. aeruginosa. The addition of taniborbactam to cefepime resulted in a > 64-fold reduction in MIC90 compared with cefepime alone for a 2018-2021 global collection of > 13,000 clinical isolates of Enterobacterales. In the same study, against > 4600 P. aeruginosa, a fourfold MIC reduction was observed with cefepime-taniborbactam, compared with cefepime alone. Whole genome sequencing studies have shown that resistance towards cefepime-taniborbactam in Enterobacterales arises due to the presence of multiple resistance mechanisms, often in concert, including production of IMP, PBP3 alterations, permeability (porin) defects, and upregulation of efflux pumps. In P. aeruginosa, elevated cefepime-taniborbactam MICs are also associated with the presence of multiple, concurrent mechanisms, most frequently IMP, PBP3 mutations, and upregulation of efflux pumps, as well as AmpC (PDC) overexpression. The pharmacokinetics of taniborbactam are dose proportional, follow a linear model, and do not appear to be affected when combined with cefepime. Taniborbactam’s approximate volume of distribution (Vd) at steady state is 20 L and the approximate elimination half-life (t½) is 2.3 h, which are similar to cefepime. Furthermore, like cefepime, taniborbactam is primarily cleared renally, and clearance corresponds with renal function. Pharmacodynamic studies (in vitro and in vivo) have reported that cefepime-taniborbactam has bactericidal activity against various β-lactamase-producing Gram-negative bacilli that are not susceptible to cefepime alone. It has been reported that antimicrobial activity best correlated with taniborbactam exposure (area under the curve). A phase III clinical trial showed that cefepime-taniborbactam (2 g/0.5 g administered as an intravenous infusion over 2 h) was superior to meropenem for the treatment of complicated urinary tract infection (cUTI), including acute pyelonephritis, caused by Enterobacterales species and P. aeruginosa while demonstrating similar safety compared with meropenem. The safety and tolerability of taniborbactam and cefepime-taniborbactam has been reported in one pharmacokinetic trial, and in two pharmacokinetic trials and one phase III clinical trial, respectively. Cefepime-taniborbactam appears to be well tolerated in both healthy subjects and patients. Headache and gastrointestinal upset are the most common drug-related adverse effects associated with cefepime-taniborbactam use. Cefepime-taniborbactam will likely have a role in the treatment of infections proven or suspected to be caused by MDR Gram-negative bacteria, including Enterobacterales and P. aeruginosa. In particular, it may be useful in the treatment of infections caused by isolates that harbor an MBL (NDM, VIM) enzyme, although further clinical data are needed. Additional safety and efficacy studies may support indications for cefepime-taniborbactam beyond cUTI.
Pharmacodynamics of Taniborbactam in Combination with Cefepime Studied in an In Vitro Model of Infection
Publication Date
August 13, 2024
Authors
A.R. Noel, M. Attwood, K.E. Bowker, A.P. MacGowan
Objectives: To define the in vitro pharmacodynamics of taniborbactam against Enterobacterales with CTXM-15, KPC, AmpC, and OXA-48 β-lactamases.
Methods: An in vitro pharmacokinetic model was used to simulate serum concentrations associated with cefepime 2G by 1 h infusion 8 h. Taniborbactam was given in exposure ranging and fractionation simulations. Reduction in viable count at 24 h (Δ 24) was the primary end point and four strains were used: Escherichia coli expressing CTXM-15 or AmpC and Klebsiella pneumoniae expressing KPC or OXA-48 enzymes.
Results: Taniborbactam was administered as continuous infusions; ≥4 log kill was attained with taniborbactam concentrations of ≥0.01 mg/L against CTXM-15 E. coli, ≥0.5 mg/L against KPC- and OXA-48 K. pneumoniae, and ≥4 mg/L against AmpC E. coli. Analyses were conducted to determine the pharmacokinetic/dynamic driver for each strain. For E. coli (CTXM-15) and E. coli (AmpC), area under the concentration-time curve (AUC) was best related to change in viable count (R20.74 and 0.72, respectively). For K. pneumoniae (KPC) AUC and T > 0.25 mg/L were equally related to bacterial clearance (R20.72 for both), and for K. pneumoniae (OXA-48) T > 0.25 mg/L was the best predictor (R20.94). The taniborbactam AUC range to produce a 1-log10 reduction in viable count was 4.4-11.2 mg·h/L. Analysis of data from all strains indicated T > MIC divided by 4 was best related to change in viable count; however, curve fit was poor R2 < 0.49.
Conclusions: Taniborbactam was effective in combination with cefepime in producing bacterial clearance for b-lactam resistant Enterobacterales. The primary pharmacodynamic driver was AUC or time > threshold, both being closely related to antibacterial effect.
ARGONAUT-III and -V: susceptibility of carbapenem-resistant Klebsiella pneumoniae and multidrug-resistant Pseudomonas aeruginosa to the bicyclic boronate β-lactamase inhibitor taniborbactam combined with cefepime
Publication Date
August 12, 2024
Authors
Michael R. Jacobs, Ayman M. Abdelhamed, Caryn E. Good, Andrew R. Mack, Christopher R. Bethel, Steven Marshall, Andrea M. Hujer, Kristine M. Hujer, Robin Patel, David van Duin, Vance G. Fowler, Daniel D. Rhoads, David A. Six, Greg Moeck, Tsuyoshi Uehara, Krisztina M. Papp-Wallace, Robert A. Bonomo
Taniborbactam, a bicyclic boronate β-lactamase inhibitor with activity against Klebsiella pneumoniae carbapenemase (KPC), Verona integron–encoded metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM), extended-spectrum beta-lactamases (ESBLs), OXA-48, and AmpC β-lactamases, is under clinical development in combination with cefepime. Susceptibility of 200 previously characterized carbapenem-resistant K. pneumoniae and 197 multidrug-resistant (MDR) Pseudomonas aeruginosa to cefepime-taniborbactam and comparators was determined by broth microdilution. For K. pneumoniae (192 KPC; 7 OXA-48-related), MIC90 values of β-lactam components for cefepime-taniborbactam, ceftazidime-avibactam, and meropenem-vaborbactam were 2, 2, and 1 mg/L, respectively. For cefepime-taniborbactam, 100% and 99.5% of isolates of K. pneumoniae were inhibited at ≤16 mg/L and ≤8 mg/L, respectively, while 98.0% and 95.5% of isolates were susceptible to ceftazidime-avibactam and meropenem-vaborbactam, respectively. For P. aeruginosa, MIC90 values of β-lactam components of cefepime-taniborbactam, ceftazidime-avibactam, ceftolozane-tazobactam, and meropenem-vaborbactam were 16, >8, >8, and >4 mg/L, respectively. Of 89 carbapenem-susceptible isolates, 100% were susceptible to ceftolozane-tazobactam, ceftazidime-avibactam, and cefepime-taniborbactam at ≤8 mg/L. Of 73 carbapenem-intermediate/resistant P. aeruginosa isolates without carbapenemases, 87.7% were susceptible to ceftolozane-tazobactam, 79.5% to ceftazidime-avibactam, and 95.9% and 83.6% to cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively. Cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively, was active against 73.3% and 46.7% of 15 VIM- and 60.0% and 35.0% of 20 KPC-producing P. aeruginosa isolates. Of all 108 carbapenem-intermediate/resistant P. aeruginosa isolates, cefepime-taniborbactam was active against 86.1% and 69.4% at ≤16 mg/L and ≤8 mg/L, respectively, compared to 59.3% for ceftolozane-tazobactam and 63.0% for ceftazidime-avibactam. Cefepime-taniborbactam had in vitro activity comparable to ceftazidime-avibactam and greater than meropenem-vaborbactam against carbapenem-resistant K. pneumoniae and carbapenem-intermediate/resistant MDR P. aeruginosa.
Novel Antibiotics for Urinary Tract Infection (UTI): The EAGLE-2 and EAGLE-3 Trials for Uncomplicated UTI, and the CERTAIN-1 Trial for Complicated UTI
Publication Date
August 6, 2024
Authors
Florian Wagenlehner
Two novel antibiotics have been evaluated for the treatment of urinary tract infection (UTI). Gepotidacin was an efficacious first-in-class oral antibiotic in uncomplicated UTI in comparison to nitrofurantoin. Cefepime/taniborbactam was superior to meropenem in complicated UTI and acute pyelonephritis.
Patient outcomes by baseline pathogen resistance phenotype and genotype in CERTAIN-1, a Phase 3 study of cefepime-taniborbactam versus meropenem in adults with complicated urinary tract infection
Publication Date
May 23, 2024
Authors
Greg Moeck, Leanne B. Gasink, Rodrigo E. Mendes, Leah N. Woosley, Mary Beth Dorr, Hongzi Chen, Florian M. Wagenlehner, Tim Henkel, Paul C. McGovern
CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized β-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried β-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum β-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes.
In Vitro Activity of Cefepime/Taniborbactam and Comparator Agents Against Gram-negative Bacterial Bloodstream Pathogens Recovered from Patients with Cancer
Publication Date
April 10, 2024
Authors
Bahgat Gerges, Joel Rosenblatt, Y-Lan Truong, Ying Jiang, Samuel A. Shelburne Sr., Anne-Marie Chaftari, Ray Hachem, Issam Raad Sr.
Background: Taniborbactam is a β-lactamase inhibitor that, when combined with cefepime, may offer a potential treatment option for patients with serious and resistant Gram-negative bacterial (GNB) pathogens.
Objectives: This study evaluated in vitro activity of cefepime/taniborbactam and comparator agents against GNB pathogens isolated from patients with cancer at our institution.
Methods: A total of 270 GNB pathogens (2019-23) isolated from patients with cancer were tested against cefepime/taniborbactam and comparator agents commonly used for these patients. CLSI-approved broth microdilution methods were used. MIC50, MIC90, MIC range and percentage of susceptibility calculations were made using FDA breakpoints when available.
Results: Cefepime/taniborbactam showed highly potent activity against tested Enterobacterales, including isolates producing ESBLs and carbapenem-resistant Enterobacterales. At a provisional breakpoint of ≤16/4 mg/L, cefepime/taniborbactam inhibited most tested species of GNB pathogens, with overall 98.9% susceptibility, which was significantly (P < 0.0001) higher than the susceptibility of the GNB isolates to all other tested comparator agents, ranging from 39.6% for cefepime to 86.3% for ceftazidime/avibactam.
Conclusions: Our results showed that taniborbactam in combination with cefepime improved in vitro activity against GNB pathogens isolated from patients with cancer, including MDR Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, ESBL-producing Enterobacterales and Stenotrophomonas maltophilia isolates, with highest activity compared with all tested comparator agents, including other β-lactam/β-lactamase inhibitor combinations. Further studies are warranted to explore the efficacy of cefepime/taniborbactam for empirical initial treatment of GNB infections in cancer patients with high rates of febrile neutropenia requiring hospitalization.
Cefepime-Taniborbactam in Complicated Urinary Tract Infection
Publication Date
February 14, 2024
Authors
Florian M. Wagenlehner, Leanne B. Gasink, Paul C. McGovern, Greg Moeck, Patrick McLeroth, Mary Beth Dorr, Aaron Dane, and Tim Henkel
Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime–taniborbactam is an investigational β-lactam and β-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-β-lactamases. In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime–taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime–taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime–taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P=0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime–taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime–taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. Cefepime–taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.)
Examining the activity of cefepime-taniborbactam against Burkholderia cepacia complex and Burkholderia gladioli isolated from cystic fibrosis patients in the United States
Publication Date
September 28, 2023
Authors
Maria F. Mojica, Elise T. Zeiser, Scott A. Becka, John J. LiPuma, David A. Six, Greg Moeck, Krisztina M. Papp-Wallace
The novel clinical-stage β-lactam-β-lactamase inhibitor combination, cefepime-taniborbactam, demonstrates promising activity toward many Gram-negative bacteria producing class A, B, C, and/or D β-lactamases. We tested this combination against a panel of 150 Burkholderia cepacia complex (Bcc) and Burkholderia gladioli strains. The addition of taniborbactam to cefepime shifted cefepime minimum inhibitory concentrations toward the provisionally susceptible range in 59% of the isolates tested. Therefore, cefepime-taniborbactam possessed similar activity as first-line agents, ceftazidime and trimethoprim-sulfamethoxazole, supporting further development.
Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018–2020 Global Surveillance Collection
Publication Date
March 21, 2023
Authors
James A. Karlowsky, Mark G. Wise, Meredith A. Hackel, Daniel C. Pevear, Greg Moeck, Daniel F. Sahma
In Vitro Activity of Cefepime-Taniborbactam and Comparators against Clinical Isolates of Gram-Negative Bacilli from 2018 to 2020: Results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program
Publication Date
January 16, 2023
Authors
James A. Karlowsky, Meredith A. Hackel, Mark G. Wise, David A. Six, Tsuyoshi Uehara, Denis M. Daigle, Susan M. Cusick,
Daniel C. Pevear, Greg Moeck, Daniel F. Sahma
In vivo pharmacokinetic/pharmacodynamic evaluation of cefepime/ taniborbactam combination against cefepime-non-susceptible Enterobacterales and Pseudomonas aeruginosa in a murine pneumonia model
Publication Date
January 14, 2023
Authors
Kamilia Abdelraouf and David P. Nicolau
Bronchopulmonary disposition of IV cefepime/taniborbactam (2–0.5 g) administered over 2 h in healthy adult subjects
Publication Date
December 19, 2022
Authors
Tomefa E. Asempa, Joseph L. Kuti, Jeffrey C. Nascimento, Samuel J. Pope, Edward L. Salerno, Patrick J. Troy, David P. Nicolau
In vivo pharmacokinetics and pharmacodynamics of ceftibuten/ledaborbactam, a novel oral β-lactam/β-lactamase inhibitor combination
Publication Date
October 5, 2022
Authors
Andrew J. Fratoni, Lindsay M. Avery, David P. Nicolau and Tomefa E. Asempa
Safety and Pharmacokinetics of Taniborbactam (VNRX-5133) with Cefepime in Subjects with Various Degrees of Renal Impairment
Publication Date
August 3, 2022
Authors
James A. Dowell, Thomas C. Marbury, William B. Smith, Tim Henkel
Taniborbactam, an investigational β-lactamase inhibitor that is active against both serine- and metallo-β-lactamases, is being developed in combination with cefepime to treat serious infections caused by multidrug-resistant Gram-negative bacteria. Anticipating the use of cefepime-taniborbactam in patients with impaired renal function, an open-label, single-dose clinical study was performed to examine the pharmacokinetics of both drugs in subjects with various degrees of renal function. Hemodialysis-dependent subjects were also studied to examine the amounts of cefepime and taniborbactam dialyzed. Single intravenous infusions of 2 g cefepime and 0.5 g taniborbactam co-administered over 2 h were examined, with hemodialysis-dependent subjects receiving doses both on- and off-dialysis. No subjects experienced serious adverse events or discontinued treatment due to adverse events. The majority of adverse events observed were mild in severity, and there were no trends in the safety of cefepime-taniborbactam related to declining renal function or the timing of hemodialysis. Clinically significant and similar decreases in drug clearance with declining renal function were observed for both cefepime and taniborbactam. The respective decreases in geometric mean clearance for subjects with mild, moderate, and severe renal impairment compared to subjects with normal renal function were 18%, 63%, and 78% for cefepime and 15%, 63%, and 81% for taniborbactam, respectively. Decreases in clearance were similar for both drugs and were shown to be proportional to decreases in renal function. Both cefepime and taniborbactam were dialyzable, with similar amounts removed during 4 h of hemodialysis. This study is registered at ClinicalTrials.gov as NCT03690362.
In Vitro Activity of Cefepime-Taniborbactam against Carbapenemase-Producing Enterobacterales and Pseudomonas aeruginosa Isolates Recovered in Spain
Publication Date
March 15, 2022
Authors
Marta Hernández-García, María García-Castillo, Patricia Ruiz-Garbajosa, Germán Bou, María Siller-Ruiz, Cristina Pitart, Irene Gracia-Ahufinger, Xavier Mulet, Álvaro Pascual, Nuria Tormo, Rafael Cantón.
Novel β-lactam–β-lactamase inhibitor combinations currently approved for clinical use are poorly active against metallo-β-lactamase (MBL)-producing strains. We evaluated the in vitro activity of cefepime-taniborbactam (FTB [formerly cefepime/VNRX-5133]) and comparator agents against carbapenemase-producing Enterobacterales (n = 247) and carbapenem-resistant Pseudomonas species (n = 170) clinical isolates prospectively collected from different clinical origins in patients admitted to 8 Spanish hospitals. FTB was the most active agent in both Enterobacterales (97.6% MICFTB, ≤8/4 mg/L) and Pseudomonas (67.1% MICFTB, ≤8/4 mg/L) populations. The MICFTB was >8 mg/L in 6/247 (2.4%) Enterobacterales isolates (3 KPC-producing Klebsiella pneumoniae isolates, 1 VIM-producing Enterobacter cloacae isolate, 1 IMP-producing E. cloacae isolate, and 1 NDM-producing Escherichia coli isolate) and in 56/170 (32.9%) Pseudomonas isolates, 19 of them carbapenemase producers (15 producers of VIM, 2 of GES, 1 of GES+VIM, and 1 of GES+KPC). Against the Enterobacterales isolates with meropenem MICs of >2 mg/L (138/247), FTB was the most active agent against both serine-β-lactamases (107/138) and MBL producers (31/138) (97.2 and 93.5% MICFTB, ≤8/4 mg/L, respectively), whereas the activity of comparators was reduced, particularly against the MBL producers (ceftazidime-avibactam, 94.4 and 12.9%, meropenem-vaborbactam, 85.0 and 64.5%, imipenem-relebactam, 76.6 and 9.7%, ceftolozane-tazobactam, 1.9 and 0%, and piperacillin-tazobactam, 0 and 0%, respectively). Among the meropenem-resistant Pseudomonas isolates (163/170; MIC, >2 mg/L), the activities of FTB against serine-β-lactamase (35/163) and MBL (43/163) producers were 88.6 and 65.1%, respectively, whereas the susceptibilities of comparators were as follows: ceftazidime-avibactam, 88.5 and 16.0%, meropenem-vaborbactam, 8.5 and 7.0%, imipenem-relebactam, 2.9 and 2.3%, ceftolozane-tazobactam, 0 and 2.3%, and piperacillin-tazobactam, 0 and 0%, respectively. Microbiological results suggest FTB as a potential therapeutic option in patients infected with carbapenemase-producing Enterobacterales and carbapenem-resistant Pseudomonas isolates, including MBL producers.
Activity of cefepime-taniborbactam and comparators against whole genome sequenced ertapenem-non-susceptible Enterobacterales clinical isolates: CANWARD 2007–19
Publication Date
February 7, 2022
Authors
Alyssa R. Golden, Melanie R. Baxter, James A. Karlowsky, Laura Mataseje, Michael R. Mulvey, Andrew Walkty, Denice Bay, Frank Schweizer, Philippe R. S. Lagace-Wiens, Heather J. Adam, George G. Zhanel
Objectives
This study assessed in vitro activities of cefepime-taniborbactam and comparator antimicrobial agents against ertapenem-non-susceptible Enterobacterales (ENSE) clinical isolates collected from the CANWARD study 2007–19, and associations between MIC and various mechanisms of β-lactam resistance identified using WGS.
Methods
A total of 179 ENSE (MIC ≥ 1 mg/L) isolates underwent susceptibility testing using reference CLSI broth microdilution. WGS was performed using the Illumina NextSeq platform. Carbapenemases, ESBLs and other β-lactamases were identified using ResFinder 4.0. Alterations in ompC/F and ftsI (PBP3) were identified by comparing extracted sequences to the appropriate NCBI reference gene. Porin alterations were analysed with Provean v1.1.3. Specific alterations of interest in PBP3 included a YRIN or YRIK insertion after P333.
Results
Cefepime-taniborbactam was highly active (MIC50/MIC90, 0.5/2 mg/L; 177/179 isolates inhibited at ≤ 8 mg/L) against ENSE with various antimicrobial resistance phenotypes. Thirteen (7.3%) of the 179 ENSE isolates demonstrated cefepime/taniborbactam MIC values ≥ 4 mg/L and possessed combinations of β-lactam resistance mechanisms, including a carbapenemase and/or ESBL and/or other β-lactamase genes, as well as alterations in OmpC and/or OmpF and/or PBP3. Of the two Escherichia coli isolates that demonstrated a cefepime/taniborbactam MIC of 32 mg/L, one possessed NDM-5, OXA-181 and TEM-1B, an OmpC alteration and P333_Y334insYRIN in PBP3, while the second contained CTX-M-71, a truncated OmpF and a large alteration in OmpC (F182_R195delinsMTTNGRDDVFE).
Conclusions
Cefepime-taniborbactam was highly active against ENSE with various antimicrobial resistance phenotypes/genotypes. ENSE isolates with cefepime/taniborbactam MIC values ≥ 4 mg/L possessed combinations of β-lactam resistance mechanisms, including β-lactamase genes, as well as alterations in OmpC and/or OmpF and/or PBP3.
In Vitro Activity of Ceftibuten/VNRX-5236 against Urinary Tract Infection Isolates of Antimicrobial-Resistant Enterobacterales
Publication Date
January 18, 2022
Authors
James A. Karlowsky, Meredith A. Hackel, Daniel F. Sahm
Ceftibuten/VNRX-7145 is a cephalosporin/boronate β-lactamase inhibitor combination under development as an oral treatment for complicated urinary tract infections caused by Enterobacterales producing serine β-lactamases (Ambler class A, C and D). In vivo, VNRX-7145 (VNRX-5236 etzadroxil) is cleaved to the active inhibitor, VNRX-5236. We assessed the in vitro activity of ceftibuten/VNRX-5236 against 1,066 urinary isolates of Enterobacterales from a 2014-2016 global culture collection. Each isolate tested was pre-selected to possess a multidrug-resistant (MDR) phenotype that included non-susceptibility to amoxicillin-clavulanate and resistance to levofloxacin. MICs were determined by CLSI broth microdilution. VNRX-5236 was tested at a fixed concentration of 4 μg/ml. Ceftibuten/VNRX-5236 inhibited 90% of all isolates tested (MIC90) at 2 μg/ml; MIC90s for ESBL- (n=566), serine carbapenemase- (n=116), and acquired AmpC-positive (n=58) isolate subsets were ≤0.25, >32, and 8 μg/ml, respectively. At concentrations of ≤1, ≤2, and ≤4 μg/ml, ceftibuten/VNRX-5236 inhibited 89.1, 91.7, and 93.1% of all isolates tested; 96.5, 97.7, and 98.4% of ESBL-positive isolates; 75.9, 81.9, and 81.9% of serine carbapenemase-positive isolates; and 70.7, 81.0, and 87.9% of acquired AmpC-positive isolates. Ceftibuten/VNRX-5236 at concentrations of ≤1, ≤2, and ≤4 μg/ml inhibited 85-89, 89-91, and 91-92% of isolates that were not susceptible (defined by CLSI and EUCAST breakpoint criteria) to nitrofurantoin, trimethoprim-sulfamethoxazole, and/or fosfomycin, (as part of their MDR phenotype), oral agents commonly prescribed to treat uncomplicated urinary tract infections. The potency of ceftibuten/VNRX-5236 (MIC90, 2 μg/ml) was similar (within one doubling-dilution) to intravenous-only agents ceftazidime-avibactam (MIC90 2 μg/ml) and meropenem-vaborbactam (MIC90 1 μg/ml). Continued investigation of ceftibuten/VNRX-5236 is warranted.
In vitro activity of the orally bioavailable ceftibuten/VNRX-7145 (VNRX-5236 etzadroxil) combination against a challenge set of Enterobacterales pathogens carrying molecularly characterized β-lactamase genes
Publication Date
November 28, 2021
Authors
Rodrigo E Mendes, Paul R Rhomberg, Amy A Watters, Mariana Castanheira
This study assessed the activity of ceftibuten, ceftibuten combined with the active form (VNRX-5236) of the β-lactamase inhibitor VNRX-7145 and comparators against a challenge set of Gram-negative pathogens. Two hundred and five Enterobacterales carrying plasmid AmpC (53 isolates), ESBL (50), KPC (50), OXA-48-like (49) or OXA-48-like with KPC (3) encoding genes were selected. Susceptibility was determined by broth microdilution. VNRX-5236 and avibactam were tested at a fixed concentration of 4 mg/L.
Clinical exposure–response relationship of cefepime-taniborbactam against Gram-negative organisms in the murine complicated urinary tract infection model
Publication Date
November 8, 2021
Authors
Maxwell J. Lasko, David P. Nicolau, Tomefa E. Asempa
Complicated urinary tract infections (cUTIs) are frequently encountered in hospitals and ICUs. Increasingly, the causative pathogens harbour enzymatic resistance mechanisms. Taniborbactam is a novel β-lactamase inhibitor with activity against Ambler class A, B, C and D β-lactamases. Herein, we assessed the efficacy of cefepime alone and the combination cefepime-taniborbactam in a neutropenic murine cUTI model.
In vitro comparative activity of the new beta-lactamase inhibitor taniborbactam with cefepime or meropenem against Klebsiella pneumoniae and cefepime against Pseudomonas aeruginosa metallo-beta-lactamase-producing clinical isolates
Publication Date
November 8, 2021
Authors
Joseph Meletiadis, Paschalis Paranos, Panagiota-Christina Georgiou, Sofia Vourli, Stavroula Antonopoulou, Aikaterini Michelaki, Eleni Vagiakou, Spyros Pournaras
Metallo-beta-lactamase (MBL)-producing Gram-negative bacteria are increasing worldwide and very few agents are active against these pathogens. Taniborbactam (formerly VNRX-5133) is a newly developed bicyclic boronate beta-lactamase inhibitor that directly inhibits all four Ambler classes of beta-lactamases. In the present study the in vitro activity of cefepime or meropenem combined with taniborbactam against 100 Klebsiella pneumoniae and cefepime combined with taniborbactam against 100 Pseudomonas aeruginosa molecularly characterized MBL-producing strains were investigated using ISO standard broth microdilution assays and compared with a panel of antimicrobial agents that are used in clinical practice (amikacin, aztreonam, ciprofloxacin, levofloxacin, gentamicin, piperacillin/tazobactam, imipenem, tigecycline, ceftolozane-tazobactam, cefepime-tazobactam, meropenem-vaborbactam, ceftazidime-avibactam). For K. pneumoniae isolates, the MIC90 values were ≥64 mg/L for all drugs except cefepime-taniborbactam (16 mg/L; 87% inhibited at ≤8/4 mg/L), meropenem-taniborbactam (4 mg/L; 94% inhibited at ≤8/4 mg/L) and tigecycline (8 mg/L), with high levels of resistance (≥65%) found for all approved comparator antimicrobials tested. For P. aeruginosa, the MIC90 values were ≥64 mg/L for all drugs except aztreonam (32 mg/L), cefepime-taniborbactam (32 mg/L; 88% inhibited at ≤16/4 mg/L) and ciprofloxacin (32 mg/L), with high levels of resistance (≥73%) for all approved drugs except aztreonam (27%). Taniborbactam reduced cefepime and meropenem MICs by a median 5 and 7 two-fold dilutions to ≤8 mg/L in 87% and 94% of MBL-producing K. pneumoniae isolates, and cefepime MICs by a median 5 two-fold dilutions to ≤16 mg/L in 86% of MBL-producing P. aeruginosa, respectively. The combinations cefepime-taniborbactam and meropenem-taniborbactam are promising alternative treatment options for infections by MBL-producing isolates.
Safety and Pharmacokinetics in Human Volunteers of Taniborbactam (VNRX-5133), a Novel Intravenous β-Lactamase Inhibitor
Publication Date
October 18, 2021
Authors
James A. Dowell, Daniel Dickerson, Tim Henkel
Abstract
Taniborbactam (formerly VNRX-5133), an investigational β-lactamase inhibitor active against both serine- and metallo-β-lactamases, is being developed in combination with cefepime to treat serious infections caused by multidrug-resistant Gram-negative bacteria. This first-in-human study evaluated the safety and pharmacokinetics of single and multiple doses of taniborbactam in healthy adult subjects. Single doses of 62.5 to 1,500 mg taniborbactam and multiple doses of 250 to 750 mg taniborbactam every 8 h (q8h) for 10 days were examined; all taniborbactam doses were administered as a 2-h intravenous infusion. No subjects experienced serious adverse events or discontinued treatment due to adverse events. The most common adverse event in both placebo- and taniborbactam-treated subjects was headache. The pharmacokinetics of taniborbactam were similar to the pharmacokinetics reported for cefepime. Taniborbactam demonstrated dose-proportional pharmacokinetics with low intersubject variability. Following single doses and with extended sampling, the mean terminal elimination half-life ranged from 3.4 to 5.8 h; however, the majority of exposure was characterized by an earlier phase with a half-life of about 2 h. Following multiple dosing, there was minimal accumulation of taniborbactam in plasma. At steady-state, approximately 90% of the administered dose of taniborbactam was recovered in urine as intact drug. There was no appreciable metabolism observed in either plasma or urine samples. (This study is registered at clinicaltrials.gov under registration number NCT02955459.)
The Next-Generation β-Lactamase Inhibitor Taniborbactam Restores the Morphological Effects of Cefepime in KPC-Producing Escherichia coli
Publication Date
September 8, 2021
Authors
Elyse J. Roach, Tsuyoshi Uehara, Denis M. Daigle, David A. Six, and Cezar M. Khursigara
Gram-negative bacteria producing carbapenemases are resistant to a variety of β-lactam antibiotics and pose a significant health risk. Given the dearth of new antibiotics, combinations of new broad-spectrum β-lactamase inhibitors (BLIs) with approved β-lactams have provided treatment options for resistant bacterial infections. Taniborbactam (formerly VNRX-5133) is an investigational BLI that is effective against both serine- and metallo-β-lactamases, including the serine carbapenemase KPC. In the current study, we assessed the effectiveness of taniborbactam to restore antibacterial activity of cefepime against KPC-3-producing Escherichia coli by inhibiting the KPC-3-dependent hydrolysis of cefepime. Time-lapse microscopy revealed that cells treated with greater than 1× MIC of cefepime (128 μg/ml) and cefepime-taniborbactam (4 μg/ml cefepime and 4 μg/ml taniborbactam) exhibited significant elongation, whereas cells treated with taniborbactam alone did not owing to a lack of standalone antibacterial activity of the BLI. The elongated cells also had frequent cellular voids thought to be formed by attempted cell divisions and pinching of the cytoplasmic membrane. Additionally, the effect of taniborbactam continued even after its removal from the growth medium. Pretreatment with 4 μg/ml taniborbactam helped to restore the antibacterial action of cefepime by neutralizing the effect of the KPC-3 β-lactamase.
Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable β-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes
Publication Date
June 30, 2021
Authors
Robert E. Trout, Allison Zulli, Eugen Mesaros, Randy W. Jackson, Steven Boyd, Bin Liu, Jodie Hamrick, Denis Daigle, Cassandra L. Chatwin, Kaitlyn John, Lisa McLaughlin, Susan M. Cusick, William J. Weiss, Mark E. Pulse, Daniel C. Pevear, Greg Moeck, Luigi Xerri, and Christopher J. Burns
A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. The increasing emergence of β-lactamase-producing multi-drug-resistant “superbugs” has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing β-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum β-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.
Microbiological characterization of VNRX-5236: a broad spectrum β-lactamase inhibitor for rescue of the orally bioavailable cephalosporin ceftibuten as a carbapenem-sparing agent against strains of Enterobacterales expressing extended spectrum β-lactamases and serine carbapenemases.
Publication Date
May 7, 2021
Authors
Cassandra L. Chatwin, Jodie C. Hamrick, Robert E. L. Trout, Cullen L. Myers, Susan M. Cusick, William J. Weiss, Mark E. Pulse, , Luigi Xerri, Christopher J. Burns, Gregory Moeck, Denis M. Daigle, Kaitlyn John, Tsuyoshi Uehara, and Daniel C. Pevear
There is an urgent need for oral agents to combat resistant gram-negative pathogens. Here we describe the characterization of VNRX-5236, a broad-spectrum boronic acid β-lactamase inhibitor (BLI) and its orally bioavailable etzadroxil prodrug, VNRX-7145. VNRX-7145 is being developed in combination with ceftibuten, an oral cephalosporin, to combat strains of Enterobacterales expressing extended spectrum β-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine β-lactamases, with inactivation efficiencies on the order of 104 M−1. sec−1, and prolonged active site residence times (t1/2, 5 to 46 min). The spectrum of inhibition includes Ambler class A ESBLs, class C cephalosporinases, and class A and D carbapenemases (KPC and OXA-48, respectively). Rescue of ceftibuten by VNRX-5236 (fixed at 4 μg/mL) in isogenic strains of E. coli expressing class A, C or D β-lactamases demonstrated an expanded spectrum of activity relative to oral comparators including investigational penems, sulopenem and tebipenem. VNRX-5236 rescued ceftibuten activity in clinical isolates of Enterobacterales expressing ESBLs (MIC90 = 0.25 μg/mL), KPCs (MIC90 = 1 μg/mL), class C cephalosporinases (MIC90 = 1 μg/mL) and OXA-48-type carbapenemases (MIC90 = 1 μg/mL). Frequency of resistance studies demonstrated a low propensity for recovery of resistant variants at 4× the MIC of the ceftibuten/VNRX-5236 combination. In vivo, whereas ceftibuten alone was ineffective (ED50, >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by K. pneumoniae producing KPC carbapenemase (ED50, 12.9 mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant Enterobacterales.
Activity of Cefepime in Combination with the Novel β-Lactamase Inhibitor Taniborbactam (VNRX-5133) against Extended-Spectrum-β-Lactamase-Producing Isolates in In Vitro Checkerboard Assays
Publication Date
March 18, 2021
Authors
Wendy Kloezen, Ria J. Melchers, Panagiota-Christina Georgiou, Johan W. Mouton, Joseph Meletiadis
Abstract
Extended-spectrum-β-lactamase (ESBL)-producing strains are increasing worldwide, limiting therapeutic options. Taniborbactam (VNRX-5133) is a newly developed β-lactamase inhibitor with a wide spectrum of activity covering both serine and metallo enzymes. We therefore evaluated cefepime-taniborbactam activity against ESBL-producing isolates and determined the concentrations to be used in MIC determinations in the clinical laboratory. The in vitro activity of cefepime (0.06 to 256 mg liter−1) combined with taniborbactam (0.03 to 32 mg liter−1) against 129 clinically and molecularly well-documented ESBL-producing isolates (42 Escherichia coli, 39 Klebsiella pneumoniae, 28 Pseudomonas aeruginosa, 16 Enterobacter cloacae, 2 Citrobacter freundii, and 2 Enterobacter aerogenes) was tested with a broth microdilution checkerboard method based on the ISO standard. The MICs of cefepime alone and in combination, together with percentage resistance at different concentrations of taniborbactam, were calculated for each species and resistance mechanism. The median (range)/MIC90 of cefepime was 32 (0.125 to 256)/256 mg liter−1 for all Enterobacterales isolates (n = 101), with 72% being resistant, and 32 (8 to 256)/128 mg liter−1 for the 28 P. aeruginosa isolates, with 86% being resistant. The median (range)/90th percentile concentration of taniborbactam required to restore Enterobacterales susceptibility to cefepime (MIC ≤1 mg liter−1) was 0.06 (≤0.03 to 32)/4 mg liter−1 and P. aeruginosa susceptibility to increased exposure to cefepime (MIC ≤8 mg liter−1) 1 (≤0.032 to 32)/32 mg liter−1. At a fixed concentration of 4 mg liter−1 of taniborbactam, cefepime median (range)/MIC90 were reduced to 0.125 (0.06 to 4)/1 mg liter−1 for Enterobacterales with no resistant isolates found, and to 8 (2 to 64)/16 mg liter−1 for P. aeruginosa isolates, where 36% remained resistant. The combination cefepime-taniborbactam demonstrated a potent activity against ESBL isolates, restoring susceptibility of all Enterobacterales and two-thirds of P. aeruginosa isolates.
Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model
Publication Date
February 19, 2021
Authors
Maxwell J. Lasko, Tomefa E. Asempa, David P. Nicolau
Efforts to develop and pair novel oral β-lactamase inhibitors with existing β-lactam agents to treat extended spectrum β-lactamase (ESBL) and carbapenemase-producing Enterobacterales are gaining ground. Ceftibuten is an oral third-generation cephalosporin capable of achieving high urine concentrations; however, there are no robust data describing its pharmacodynamic profile. This study characterizes ceftibuten pharmacokinetics and pharmacodynamics in a neutropenic murine thigh infection model. Enterobacterales isolates expressing no known clinically-relevant enzymatic resistance (n = 7) or harboring an ESBL (n = 2) were evaluated. The ceftibuten minimum inhibitory concentrations (MICs) were 0.03–4 mg/L. Nine ceftibuten regimens, including a human-simulated regimen (HSR) equivalent to clinical ceftibuten doses of 300 mg taken orally every 8 h, were utilized to achieve various fT > MICs. A sigmoidal Emax model was fitted to fT > MIC vs. change in log10 CFU/thigh to determine the requirements for net stasis and 1-log10 CFU/thigh bacterial burden reduction. The growth of the 0 h and 24 h control groups was 5.97 ± 0.37 and 8.51 ± 0.84 log10 CFU/thigh, respectively. Ceftibuten HSR resulted in a -0.49 to -1.43 log10 CFU/thigh bacterial burden reduction at 24 h across the isolates. Stasis and 1-log10 CFU/thigh reduction were achieved with a fT > MIC of 39% and 67%, respectively. The fT > MIC targets identified can be used to guide ceftibuten dosage selection to optimize the likelihood of clinical efficacy.
Potent inhibitory activity of taniborbactam towards NDM-1 and NDM-1Q119X mutants, and in vitro activity of cefepime/taniborbactam against MBLs producing Enterobacterales
Publication Date
November 24, 2020
Authors
Alessandra Piccirilli, Bernardetta Segatore, Fabrizia Brisdelli, Gianfranco Amicosante, Mariagrazia Perilli
Objective
This study aimed to investigate the in vitro activity of taniborbactam (VNRX-5133), a novel broad-spectrum bicyclic boronate, against NDM-1 and Q119E, Q119K, Q119C, Q119F, Q119V, and Q119Y NDM-1 variants, which showed an increased activity towards some β-lactams, including cefepime.
Methods
Inhibition kinetic assays were spectrophotometrically performed using cefepime (50 μM) as the reporter substrate and 80 nM of each enzyme. Taniborbactam behaves as a competitive inhibitor towards NDM-1 and NDM-1 Q119 variants with lower Ki values (range 3–16 nM). The phenotypic profile was assessed inn both Enterobacterales clinical isolates and engineered Escherichia coli BL21(DE3) strains by conventional broth microdilution procedures according to the Clinical and Laboratory Standards Institute (CLSI).
Results
Taniborbactam at a fixed concentration of 4 mg/L was able to restore activity of cefepime in 24 of 26 Enterobacterales clinical isolates harbouring metallo-β-lactamases with MIC50/MIC90 values of 14 mg/L. Cefepime MICs were drastically reduced in all clinical isolates and in NDM-1 and Q119X producing Escherichia coli BL21(DE3). Taniborbactam was unable to restore susceptibility to cefepime in two IMP variants producing clinical isolates.
Conclusion
The inhibition level of NDM enzymes provided by taniborbactam protects the antibacterial activity of cefepime from this important metallo-β-lactamase.
Oral cephalosporin and β-lactamase inhibitor combinations for ESBL-producing Enterobacteriaceae urinary tract infections
Publication Date
October 28, 2020
Authors
Adam G. Stewart, Patrick N. A. Harris, Andrew Henderson, Mark A. Schembri and David L. Paterson
Activity of beta-lactam/taniborbactam (VNRX-5133) combinations against carbapenem-resistant Gram-negative bacteria
Publication Date
October 9, 2020
Authors
Shazad Mushtaq, Anna Vickers, Michel Doumith, Matthew J Ellington, Neil Woodford, David M Livermore
Background
Boronates are of growing interest as beta-lactamase inhibitors. The only marketed analogue, vaborbactam, principally targets KPC carbapenemases, but taniborbactam (VNRX-5133, Venatorx) has a broader spectrum.
Methods
MICs of cefepime and meropenem were determined combined with taniborbactam or avibactam for carbapenem-resistant UK isolates. beta-Lactamase genes and porin alterations were sought by PCR or sequencing.
Results
Taniborbactam potentiated partner beta-lactams against: (i) Enterobacterales with KPC, other class A, OXA-48-like, VIM and NDM (not IMP) carbapenemases; and (ii) Enterobacterales inferred to have combinations of ESBL or AmpC activity and impermeability. Potentiation of cefepime (the partner for clinical development) by taniborbactam was slightly weaker than by avibactam for Enterobacterales with KPC or OXA-48-like carbapenemases, but MICs of cefepime-taniborbactam were similar to those of ceftazidime/avibactam, and the spectrum was wider. MICs of cefepime-taniborbactam nonetheless remained >8 + 4 mg/L for 22%–32% of NDM-producing Enterobacterales. Correlates of raised cefepime-taniborbactam MICs among these NDM Enterobacterales were a cefepime MIC >128 mg/L, particular STs and, for Escherichia coli only: (i) the particular blaNDM variant (even though published data suggest all variants are inhibited similarly); (ii) inserts in PBP3; and (iii) raised aztreonam-avibactam MICs. Little or no potentiation of cefepime or meropenem was seen for Pseudomonas aeruginosa and Acinetobacter baumannii with MBLs, probably reflecting slower uptake or stronger efflux. Potentiation of cefepime was seen for Stenotrophomonas maltophilia and Elizabethkingia meningoseptica, which have both chromosomal ESBLs and MBLs.
Conclusions
Taniborbactam broadly reversed cefepime or meropenem non-susceptibility in Enterobacterales and, less reliably, in non-fermenters.
Metallo-Beta-Lactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline
Publication Date
September 21, 2020
Authors
Sara E. Boyd, David M. Livermore, David C. Hooper, William W. Hope
Abstract
Modern medicine is threatened by the global rise of antibiotic resistance, especially among Gram-negative bacteria. Metallo-beta-lactamase (MBL) enzymes are a particular concern and are increasingly disseminated worldwide, though particularly in Asia. Many MBL producers have multiple further drug resistances, leaving few obvious treatment options. Nonetheless, and more encouragingly, MBLs may be less effective agents of carbapenem resistance in vivo, under zinc limitation, than in vitro. Owing to their unique structure and function and their diversity, MBLs pose a particular challenge for drug development. They evade all recently licensed beta-lactam–beta-lactamase inhibitor combinations, although several stable agents and inhibitor combinations are at various stages in the development pipeline. These potential therapies, along with the epidemiology of producers and current treatment options, are the focus of this review.
In vivo pharmacodynamics of new-generation beta-lactamase inhibitor taniborbactam (formerly VNRX-5133) in combination with cefepime against serine-beta-lactamase-producing Gram-negative bacteria
Publication Date
August 30, 2020
Authors
Kamilia Abdelraouf, Safa Almarzoky Abuhussain, David P Nicolau
Objectives
Cefepimeitaniborbactam is a cephalosporin/cyclic boronate beta-lactamase inhibitor combination under development for the treatment of infections due to MDR Enterobacterales and Pseudomonas aeruginosa. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic index, relative to taniborbactam exposure, that correlated most closely with the efficacy of the cefepime-taniborbactam combination and the magnitude of index required for efficacy against serine-beta-lactamase-producing strains.
Methods
Twenty-six clinical Enterobacterales (expressing ESBLs, plasmid-mediated AmpC and/or carbapenemases of classes A or D; cefepime/taniborbactam combination MICs 0.06-16 mg/L) and 11 clinical P. aeruginosa (AmpC overproducing or KPC expressing; cefepime-taniborbactam combination MICs 1-16 mg/L) were evaluated. A cefepime human-simulated regimen (HSR) equivalent to a clinical dose of 2 g q8h as a 2 h infusion was given in combination with taniborbactam for 24 h. For a subset of P. aeruginosa isolates, a sub-therapeutic cefepime exposure was utilized.
Results
Dose-fractionation studies revealed that dosing frequency had no impact on taniborbactam potentiation of cefepime activity. Relative to the initial bacterial burden, the median taniborbactam fAUC0-24/MIC associated with 1 log kill in combination with the cefepime HSR for Enterobacterales and P. aeruginosa isolates was 2.62 and 0.46, respectively. In combination with sub-therapeutic cefepime, the median taniborbactam fAUC0-24/MIC associated with 1 and 2 log kill against AmpC-overproducing P. aeruginosa was 2.00 and 3.30, respectively, relative to the bacterial burden in the cefepime-treated groups. The taniborbactam HSR (equivalent to 0.5 g q8h as a 2 h infusion) was adequate to attain ≥1 log reduction against all test isolates.
Conclusions
Our data show that the cefepime-taniborbactam combination (2 g/0.5 g q8h as a 2 h infusion) exerts potent in vivo activity against cefepime-resistant isolates, including serine-carbapenemase producers.
In vitro activity of the novel beta-lactamase inhibitor taniborbactam (VNRX-5133), in combination with cefepime or meropenem, against MDR Gram-negative bacterial isolates from China
Publication Date
July 15, 2020
Authors
Xiaojuan Wang, Chunjiang Zhao, Qi Wang, Zhanwei Wang, Xinyue Liang, Feifei Zhang, Yawei Zhang, Han Meng, Hongbin Chen, Shuguang Li, Chengcheng Zhou, Henan Li, Hui Wang
Objectives
To evaluate in vitro activity of the novel beta-lactamase boronate inhibitor taniborbactam (VNRX-5133) combined with cefepime or meropenem against 500 urinary Gram-negative bacilli.
Methods
Cefepime-taniborbactam and 14 comparators were tested by broth microdilution or agar dilution methods. A total of 450 Enterobacteriaceae and 50 Pseudomonas aeruginosa were selected from 2017 to 2019 based on different β-lactamase-producing or resistance phenotypes. For carbapenem-non-susceptible isolates, the modified carbapenem inactivation method (mCIM), EDTA-CIM (eCIM) and amplification of carbapenemase genes were performed. For NDM-producing isolates and those with cefepime-taniborbactam MICs >8 mg/L, the MICs of meropenem-taniborbactam and/or mutations in PBP3 were investigated.
Results
Taniborbactam improved cefepime activity with the same efficiency as avibactam improved ceftazidime activity against 66 KPC-2 producers, 30 non-carbapenemase-producing carbapenem-non-susceptible Enterobacteriaceae and 28 meropenem-susceptible P. aeruginosa. However, cefepime-taniborbactam exhibited more potent activity than ceftazidime-avibactam against 56 ESBL-producing, 61 AmpC-producing, 32 ESBL and AmpC co-producing, 87 NDM-producing and 21 MBL-producing Enterobacteriaceae predicted by phenotypic mCIM and eCIM, 82 Enterobacteriaceae that were susceptible to all tested beta-lactams and 22 carbapenem-non-susceptible P. aeruginosa. A four-amino acid ‘INYR’ or ‘YRIN’ insertion, with or without a one/two-amino acid mutation in PBP3, may have caused cefepime-taniborbactam MICs >8 mg/L among 96.6% (28/29) of the NDM-5-producing Escherichia coli, which accounted for the majority of isolates with cefepime-taniborbactam MICs >8 mg/L (76.1%, 35/46).
Conclusions
Taniborbactam’s superior breadth of activity, when paired with cefepime or meropenem, suggests these beta-lactam/beta-lactamase inhibitor combinations could be promising candidates for treating urinary tract infections caused by ESBL and/or AmpC, KPC or NDM-producing Enterobacteriaceae or P. aeruginosa.
VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-Beta-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa
Publication Date
December 23, 2019
Authors
Jodie C. Hamrick, Jean-Denis Docquier, Tsuyoshi Uehara, Cullen L. Myers, David A. Six, Cassandra L. Chatwin, Kaitlyn J. John, Salvador F. Vernacchio, Susan M. Cusick, Robert E.L. Trout, Cecilia Pozzi, Filomena De Luca, Manuela Benvenuti, Stefano Mangani, Bin Liu, Randy W. Jackson, Greg Moeck, Luigi Xerri, Christopher J. Burns, Daniel C. Pevear, Denis M. Daigle
As shifts in the epidemiology of beta-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved beta-lactam (BL)–beta-lactamase inhibitor (BLI) combinations address widespread serine beta-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-beta-lactamases (KPC, OXA-48) or clinically important metallo-beta-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by beta-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (Ki) values ranging from 0.019 to 0.081 μM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90s of 1 and 4 μg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.
Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-Beta-Lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections
Publication Date
November 25, 2019
Authors
Bin Liu, Robert E. Lee Trout, Guo-Hua Chu, Daniel McGarry, Randy W. Jackson, Jodie C. Hamrick, Denis M. Daigle, Susan M. Cusick, Cecilia Pozzi, Filomena De Luca, Manuela Benvenuti, Stefano Mangani, Jean-Denis Docquier, William J. Weiss, Daniel C. Pevear, Luigi Xerri, Christopher J. Burns
A major resistance mechanism in Gram-negative bacteria is the production of beta-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent beta-lactamases can now confer resistance to other beta-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of beta-lactamase-producing multi-drug-resistant “superbugs” has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-beta-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum beta-lactamase inhibitor. In vitro and in vivo studies demonstrated that restored the activity of beta-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.
Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases
Publication Date
August 27, 2019
Abstract
The bicyclic boronate VNRX-5133 (taniborbactam) is a new type of β-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-β-lactamases (SBLs) and some clinically important metallo-β-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and tested B2/B3 MBLs was lower/not observed. Crystallography reveals how VNRX-5133 binds to the class D SBL OXA-10 and MBL NDM-1. The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp3) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography, we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain binding modes for bicyclic boronates for SBLs and MBLs imply scope for side-chain optimization. The results further support the “high-energy-intermediate” analogue approach for broad-spectrum β-lactamase inhibitor development and highlight the ability of boron inhibitors to interchange between different hybridization states/binding modes.
Interplay between beta-lactamases and new beta-lactamase inhibitors
Publication Date
March 5, 2019
Authors
Karen Bush, Patricia A Bradford
Abstract
Resistance to beta-lactam antibiotics in Gram-negative bacteria is commonly associated with production of beta-lactamases, including extended-spectrum beta-lactamases (ESBLs) and carbapenemases belonging to different molecular classes: those with a catalytically active serine and those with at least one active-site Zn2+ to facilitate hydrolysis. To counteract the hydrolytic activity of these enzymes, combinations of a beta-lactam with a beta-lactamase inhibitor (BLI) have been clinically successful. However, some β-lactam-BLI combinations have lost their effectiveness against prevalent Gram-negative pathogens that produce ESBLs, carbapenemases or multiple beta-lactamases in the same organism. In this Review, descriptions are provided for medically relevant β-lactamase families and various BLI combinations that have been developed or are under development. Recently approved inhibitor combinations include the inhibitors avibactam and vaborbactam of the diazabicyclooctanone and boronic acid inhibitor classes, respectively, as new scaffolds for future inhibitor design.