Avoiding resistance development to newer drugs: open research lines

Background The spread of multidrug-resistant gram-negative bacteria, particularly those with carbapenem-resistant or difficult-to-treat resistance phenotypes, is a major public health threat. New agents offer potent therapeutic options but carry the challenge of preserving their effectiveness against resistance. Objectives This narrative review summarizes antimicrobial and non–antimicrobial strategies to prevent or mitigate resistance development to novel agents. Sources We searched PubMed-MEDLINE for English-language articles published in the last 5 years. Content Among antimicrobial strategies, we reviewed the role of optimising pharmacokinetic/pharmacodynamic targets for novel β-lactam/β-lactamase inhibitor combinations and the impact of combination vs. monotherapy regimens. Achieving aggressive joint pharmacokinetic/pharmacodynamic targets may help prevent resistance, supported by approaches such as continuous infusion of time-dependent agents and therapeutic drug monitoring. Current evidence does not demonstrate a routine benefit of combination therapy over monotherapy for novel drugs; however, available studies are limited in size and quality, and resistance emergence has rarely been a primary endpoint. Non–antimicrobial strategies reviewed include faecal microbiota transplantation, phage therapy, and active or passive immunisation. These approaches may reduce the burden of multidrug-resistant gram-negative bacteria, particularly in high-risk populations such as immunocompromised patients, those undergoing invasive procedures, or patients with foreign bodies. By lowering pathogen load and transmission, these interventions could enhance the effectiveness of current drugs and limit further resistance development. Implications Prevention of resistance to novel β-lactam/β-lactamase inhibitor combinations currently relies on optimized dosing and infusion strategies. The benefit of combination regimens remains uncertain and warrants further investigation, ideally with resistance emergence as a defined endpoint and addressed with appropriate analysis. Non–antimicrobial interventions show promise as adjunctive tools in high-risk settings and merit integration into broader resistance prevention frameworks.