Cefepime-Taniborbactam: A Novel Cephalosporin/β-Lactamase Inhibitor Combination.
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.
Zhanel GG
，Mansour C
，Mikolayanko S
，Lawrence CK
，Zelenitsky S
，Ramirez D
，Schweizer F
，Bay D
，Adam H
，Lagacé-Wiens P
，Walkty A
，Irfan N
，Clark N
，Nicolau D
，Tascini C
，Karlowsky JA
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Overexpression of KPC contributes to ceftazidime-avibactam heteroresistance in clinical isolates of carbapenem-resistant Klebsiella pneumoniae.
Ceftazidime-avibactam (CZA) is one of the effective antibiotics used for the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, but its resistance rate has increased recently. Previous studies have focused on the mechanisms of CZA resistance, while its heteroresistance in CRKP remains poorly understood. This study aimed to investigate the characteristics and mechanisms of CZA heteroresistance in CRKP isolates. A total of 311 CRKP clinical strains were collected in China from 2020 to 2022. The MICs of CZA and other antibiotics against K. pneumoniae were determined by broth microdilution method. The occurrence of CZA heteroresistance in CRKP was evaluated with population analysis profiling (PAP) and their characteristics were detected by polymerase chain reaction (PCR). The underlying mechanism of CZA heteroresistance in CRKP strains was investigated by molecular sequencing, whole genome sequencing (WGS), quantitative real-time PCR (qRT-PCR), and in vitro functional experiments. Strategies for preventing the emergence of CZA heteroresistance and alternative treatment options for strains exhibiting CZA heteroresistance were further explored. Thirty-four (12.4%) CZA-susceptible CRKP isolates were found to exhibit heteroresistance to CZA. All heteroresistant strains belonged to KPC-2 (97.1%) or KPC-3 (2.9%). The dominant multilocus sequence typing (MLST) was ST11 (64.7%) and the prevalent capsular serotypes were KL47 (38.2%) and KL64 (32.4%). Imipenem-relebactam and meropenem-vaborbactam still exhibited excellent antimicrobial activity against the resistant subpopulations of CZA heteroresistant strains. No significant mutations were found in KPC, OmpK35/36, PBP2/3, and LamB in resistant subpopulations. The relative expression and copy number of bla KPC were significantly upregulated in 47.1% and 35.3% of the resistant subpopulations compared with their parental strains, respectively. Silencing bla KPC expression significantly decreased the CZA MIC in resistant subpopulations with high bla KPC expression and hindered the emergence of CZA heteroresistance in their parental strains. Moreover, increasing the avibactam concentration to 8 or 16 mg/L or combining CZA with 0.5 × MIC tigecycline significantly suppressed the formation of CZA heteroresistance (P<0.05). In conclusion, we identified the occurrence of CZA heteroresistance in CRKP in China, which was attributed to the overexpression of KPC. Increasing the concentration of avibactam or combining CZA with tigecycline could effectively prevent the development of CZA heteroresistance in CRKP isolates. Besides, imipenem-relebactam and meropenem-vaborbactam may serve as alternative therapeutic options when clinical isolates with CZA heteroresistance are detected.
Li Y
，Chen X
，Guo Y
，Lin Y
，Wang X
，He G
，Wang M
，Xu J
，Song M
，Tan X
，Zhuo C
，Lin Z
... -
《Frontiers in Cellular and Infection Microbiology》
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