The unmet need for long-acting, narrow-spectrum antibiotics: a narrative review and call to action for antimicrobial stewardship

Abstract

Abstract Long-acting lipoglycopeptides (laLGPs) are classified as Reserve agents under the WHO AWaRe framework, yet they are increasingly used as consolidation and suppressive therapy for Gram-positive bacteremia, endocarditis, and device-related infection caused by organisms that remain fully susceptible to first-line Access agents, including meticillin-susceptible staphylococci, penicillin-susceptible streptococci, and enterococci. This review examines how laLGPs came to occupy this space, why the substitution reflects operational and socioeconomic barriers to first-line treatment rather than clinical preference, and why no narrow-spectrum long-acting alternative has been developed yet. Randomized evidence supports oral step-down in defined bacteremic and non-bacteremic settings. The residual population, persistent or complicated bacteremia, meticillin-resistant disease, impaired gastrointestinal absorption, and infection without achievable source control, has no Access agent that matches the infrequent dosing laLGPs provide. No agent combines a narrow Gram-positive spectrum (meticillin-susceptible staphylococci, penicillin-susceptible streptococci, and enterococci) with a prolonged dosing interval: β-lactams are pharmacokinetically unsuited to half-life extension, and glycopeptide-class agents achieve their long half-lives only through broad-spectrum, protein-binding chemistry. This is not primarily a chemistry problem. Every operational push and pull incentive rewards novel mechanism of action and priority-pathogen activity, criteria a narrow-spectrum long-acting agent would fail by design. The result is a pipeline that delivers Reserve novelty, while the demand for infrequent, narrow-spectrum dosing goes unmet. Extending delinked reward eligibility to pharmacokinetic optimization of off-patent Access agents, and giving explicit weight to spectrum restriction in valuation frameworks, would close this gap while aligning with existing antimicrobial stewardship values.