Pretreatment with 4 μg/ml taniborbactam helped to restore the antibacterial action of cefepime by neutralizing the effect of the KPC-3 β-lactamase.Ī major antimicrobial resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. Additionally, the effect of taniborbactam continued even after its removal from the growth medium. The elongated cells also had frequent cellular voids thought to be formed by attempted cell divisions and pinching of the cytoplasmic membrane. 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. 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. Taniborbactam (formerly VNRX-5133) is an investigational BLI that is effective against both serine- and metallo-β-lactamases, including the serine carbapenemase KPC. 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. Gram-negative bacteria producing carbapenemases are resistant to a variety of β-lactam antibiotics and pose a significant health risk.
(This study is registered at under registration number NCT02955459.)
There was no appreciable metabolism observed in either plasma or urine samples. At steady-state, approximately 90% of the administered dose of taniborbactam was recovered in urine as intact drug. Following multiple dosing, there was minimal accumulation of taniborbactam in plasma. 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. Taniborbactam demonstrated dose-proportional pharmacokinetics with low intersubject variability. The pharmacokinetics of taniborbactam were similar to the pharmacokinetics reported for cefepime. The most common adverse event in both placebo- and taniborbactam-treated subjects was headache. No subjects experienced serious adverse events or discontinued treatment due to adverse events. 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. This first-in-human study evaluated the safety and pharmacokinetics of single and multiple doses of taniborbactam in healthy adult subjects. 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. ꛇ,W��)3|'�H��.Click here for Access to the Journal Article CIDToGIDMap/Identity/FontDescriptor/Subtype/CIDFontType2/Type/Font/W 303 0 R>]/Encoding/Identity-H/Subtype/Type0/ToUnicode 304 0 R/Type/Font> CIDToGIDMap/Identity/FontDescriptor/Subtype/CIDFontType2/Type/Font/W 296 0 R>]/Encoding/Identity-H/Subtype/Type0/ToUnicode 297 0 R/Type/Font> Page numbers should be the same font and font size as the main text)/Rect/Subj(Sticky Note)/Subtype/Text/T(aray6)/Type/Annot>