Introduction
The rise of antimicrobial resistance, especially among Gram-negative bacteria, has led to the development of new β-lactam/β-lactamase inhibitor (BL/BLI) combinations. Recently approved agents—cefepime/enmetazobactam, aztreonam/avibactam, and sulbactam/durlobactam—target resistant pathogens like extended-spectrum β-lactamase (ESBL)- and carbapenem-resistant Enterobacterales (CRE)-producing bacteria. These are used to treat serious infections such as complicated urinary tract infections (cUTIs), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and bacteremia.
β-lactam antibiotics work by inhibiting bacterial cell wall synthesis through binding to penicillin-binding proteins (PBPs), but are often rendered ineffective by β-lactamase enzymes, which break down the β-lactam ring. New β-lactamase inhibitors (BLIs) aim to counter this, though resistance continues to evolve. Of special concern are extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases, and metallo-β-lactamases (MBLs), which can inactivate most β-lactam drugs, prompting ongoing innovation in antibiotic development.
New β-Lactam/β-Lactamase Inhibitor Combination Antibiotics
This review highlights three recently approved β-lactam/β-lactamase inhibitor (BL/BLI) combinations: cefepime/enmetazobactam, aztreonam/avibactam, and sulbactam/durlobactam.
Cefepime/Enmetazobactam
Cefepime/enmetazobactam is a newly approved β-lactam/β-lactamase inhibitor (BL/BLI) combination developed to combat rising antimicrobial resistance, especially due to extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacteria. Cefepime, a fourth-generation cephalosporin, offers broad-spectrum bactericidal activity, while enmetazobactam—developed from tazobactam—effectively inhibits ESBLs and some class A carbapenemases. This combination is effective against pathogens like E. coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, and has been approved for use in complicated urinary tract infections (cUTIs), including pyelonephritis, and in Europe, for hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and related bacteremia. Dosage is adjusted based on renal function and administered intravenously. The ALLIUM phase 3 trial showed cefepime/enmetazobactam to be superior to piperacillin/tazobactam in clinical and microbiological cure rates, especially in ESBL infections. While side effects are generally mild, further studies are needed to validate its broader clinical use. Despite its high cost and limited spectrum, it serves as a promising meropenem-sparing option in the treatment of resistant infections.
Aztreonam/Avibactam
Aztreonam/avibactam is a novel β-lactam/β-lactamase inhibitor (BL/BLI) combination developed to treat serious Gram-negative infections. Aztreonam, a monobactam, resists hydrolysis by metallo-β-lactamases (MBLs), while avibactam inhibits class A, C, and some D β-lactamases. Together, they provide broad coverage against multidrug-resistant (MDR) bacteria. Developed by Pfizer under the name Emblaveo®, the drug is approved in Europe (April 2024) for treating complicated intra-abdominal infections (cIAIs), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and complicated urinary tract infections (cUTIs), including pyelonephritis.
The combination is administered intravenously and requires dosage adjustments based on renal function. Clinical trials like “REVISIT” and “ASSEMBLE” have shown encouraging efficacy and safety, especially against MBL-producing pathogens. Aztreonam/avibactam was generally well tolerated with side effects similar to aztreonam alone, such as diarrhea, rash, and elevated liver enzymes. Though not yet approved in the U.S., it is being studied further. Overall, this combination offers a valuable treatment option for infections caused by resistant aerobic Gram-negative bacteria in patients with limited alternatives.
Sulbactam/Durlobactam
Sulbactam/durlobactam is a novel combination of two β-lactamase inhibitors developed to treat infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB). Sulbactam has weak intrinsic antibacterial activity, while durlobactam, a non-β-lactam derivative of avibactam, protects sulbactam from degradation by OXA-type β-lactamases. Approved by the FDA in May 2023 under the brand name Xacduro®, it is indicated for hospital-acquired and ventilator-associated bacterial pneumonia in adults due to the A. baumannii–calcoaceticus complex.
Administered intravenously, the dosage is adjusted based on renal function. In the ATTACK trial, sulbactam/durlobactam demonstrated noninferiority to colistin, with a lower 28-day mortality rate (19% vs. 32%) and significantly reduced nephrotoxicity (13% vs. 38%). Common side effects include anemia, hypokalemia, diarrhea, and elevated liver enzymes. The combination offers a safer and effective alternative to colistin for treating severe CRAB infections, though further studies are needed to confirm its efficacy in broader patient populations.
Conclusion
Multidrug-resistant (MDR) bacteria pose a serious global health threat. Recently approved β-lactam/β-lactamase inhibitor combinations—cefepime/enmetazobactam, aztreonam/avibactam, and sulbactam/durlobactam—offer promising treatment options against ESBL-producing, carbapenem-resistant, and Acinetobacter-related infections. However, their widespread use is limited by high costs, scarce clinical data, and varying approvals across regions. To guide optimal use, larger clinical studies and post-approval data are essential. Research is also ongoing into newer combinations like sulbactam/relebactam and others targeting MDR pathogens.
Source: Sargianou, M.; Stathopoulos, P.; Vrysis, C.; Tzvetanova, I.D.; Falagas, M.E. New β-Lactam/β-Lactamase Inhibitor Combination Antibiotics. Pathogens 2025, 14, 307. https://doi.org/10.3390/pathogens14040307
