Evidence and trials informing treatment of resistant Gram-negative infections

EP: 1.Pathogen prevalence, emerging threats, and regional resistance patterns

EP: 2.The role of rapid diagnostics and collaboration in antibiotic stewardship

EP: 3.Guiding empirical therapy through patient risk assessment

EP: 4.Aligning treatment with risk factors, patient profiles, and MBL status

EP: 5.Approaches to challenging cases with limited therapies

EP: 6.Strategies for addressing MBL infections with targeted antibiotic combination therapy, and clinical insights from the REVISIT study

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EP: 7.Evidence and trials informing treatment of resistant Gram-negative infections

EP: 8.Integration of susceptibility testing and local surveillance to inform antibiotic use

EP: 9.Challenges and opportunities in implementing new antibiotics with QIDP and Fast Track status

EP: 10.Guiding appropriate use of colistin and polymyxins

EP: 11.Optimizing formulary decisions and new drug approval through data and team collaboration

EP: 12.Approaches to equitable and responsible antibiotic management

The use of novel antibiotic combinations targeting MBL-producing bacteria is an evolving area in infectious disease treatment. Although clinical trial data remain limited due to difficulties enrolling patients with these resistant infections, observational and in vitro data suggest promise. For example, combining a newer cephalosporin with a β-lactamase inhibitor shows potential against organisms like Klebsiella pneumoniae, which is becoming increasingly problematic. Although the clinical trials conducted so far mostly enrolled patients with more common, nonresistant Gram-negative infections, laboratory evidence and early clinical experiences indicate that these combinations could effectively address dual resistance mechanisms by inhibiting both serine and metallo-β-lactamases.

The challenges of developing targeted therapies are compounded by the complex resistance mechanisms bacteria employ, such as modifications to penicillin-binding proteins, which can limit the efficacy of certain drugs in specific species. However, these new combinations are often designed to restore activity against resistant bacteria by simultaneously protecting the antibiotic from degradation and allowing it to bind its target effectively. Hospitals have begun incorporating these agents into formularies, particularly for seriously ill patients with confirmed or suspected infections caused by MBL-producing organisms. Despite the lack of large-scale randomized controlled trials specifically focused on these infections, early observational data suggest improved clinical outcomes compared with older, more toxic alternatives like colistin.

In addition to the combinations targeting MBL-producing pathogens, recent studies have explored new approaches against other resistant Gram-negative bacteria, such as carbapenem-resistant Acinetobacter baumannii. Novel regimens aiming to inhibit multiple penicillin-binding proteins simultaneously show promising results both in vitro and in clinical settings. Emerging antibiotics with dual mechanisms, including β-lactamase inhibition plus penicillin-binding protein targeting, may offer enhanced activity against highly resistant pathogens. As more data emerge from ongoing trials and postmarketing studies, these advancements will likely shape future treatment guidelines and improve options for managing multidrug-resistant infections.