New Antibiotics and the Evolving Landscape of Antimicrobial Stewardship
New beta-lactam/beta-lactamase inhibitor (BL/BLI) combinations are reshaping the treatment landscape for multidrug-resistant Gram-negative infections. However, innovation alone is not enough to support effective stewardship. Hospital pharmacists are being compelled to rethink not only which agents to leverage, but likewise when and how to deploy them.
The Global Threat of Antimicrobial Resistance
Antimicrobial resistance (AMR) was attributable to 1.14 million deaths globally in 2021, according to the British Society for Antimicrobial Chemotherapy (BSAC).1 In the UK, the burden of drug-resistant bacteraemia has risen steadily, increasing by 13.1% between 2019 and 2024.1 More than one in five bacteraemia episodes due to bacteria of public health importance are now resistant to key antibiotics.
Enterobacterales: The Primary Driver of Resistance
Enterobacterales account for over 85% of antibiotic-resistant bloodstream infections. Escherichia coli remains the principal driver, responsible for approximately two-thirds of resistant cases over the past six years. Klebsiella pneumoniae has shown the fastest rate of increase, rising by almost 40% since 2019.1
The Role of Beta-Lactamases
Beta-lactamases are enzymes produced by bacteria that confer antibiotic resistance by breaking down beta-lactam antibiotics like penicillins, cephalosporins, and carbapenems.2 These enzymes have been known since 1940, and some have origins dating back over 2 billion years.2 For every beta-lactam antibiotic currently available, there is a beta-lactamase capable of inactivating it.2
The BL/BLI Pipeline for Gram-Negative Infections
Development efforts are focused on beta-lactam/beta-lactamase inhibitor (BL/BLI) combinations to combat multidrug-resistant Gram-negative bacteria. Several combinations are showing promise:
- Cefepime/enmetazobactam: Broadens activity beyond earlier cephalosporins and offers a carbapenem-sparing option for ESBL-producing Enterobacterales.1
- Avibactam: Revolutionized the beta-lactamase inhibitor field, particularly when paired with aztreonam, restoring activity against all four Ambler classes of beta-lactamases.1
- Sulbactam/durlobactam: Addresses drug-resistant Acinetobacter baumannii, targeting class D oxacillinases.1
- Vaborbactam/meropenem: Extends activity against KPC and AmpC producers.1
Optimizing Drug Delivery and Stewardship
Dr. Ryan Shields advocated for antimicrobial stewardship programs to move beyond restriction and promote the rational, evidence-based use of newer therapies.1 As time-dependent beta-lactams, drugs like ceftazidime/avibactam require sustained exposure above the minimum inhibitory concentration, suggesting prolonged infusion is beneficial.1 However, conventional renal dosing strategies may be suboptimal during severe infection with transient kidney injury.
Challenges with Pseudomonas aeruginosa
The lack of rapid diagnostic tests for Pseudomonas aeruginosa’s resistance mechanisms presents a significant challenge. This organism’s remarkable adaptive capacity allows it to develop resistance quickly. Resistance to ceftazidime/avibactam and ceftolozane/tazobactam has been observed in approximately one in five patients during therapy.1
The Future of Stewardship
The BSAC New Agents conference highlighted that the success of new antibiotics depends on early pathogen detection, optimized drug exposure, and strategic positioning within treatment pathways. Stewardship must evolve from cautious gatekeeping to strategic, evidence-driven antimicrobial drug deployment.1