Resistance development to new anti-Gram negatives antibiotics during treatment: geographical epidemiology and risk factors

Background Treatment-emergent resistance is increasingly reported in carbapenem-resistant Enterobacterales during therapy with newly developed antibiotics. However, standardized definitions and studies evaluating the impact of treatment-emergent resistance on patient outcome are lacking. Objectives To review current evidence on the epidemiology, risk factors, and clinical impact of resistance emerging during or after exposure to novel antibiotics against carbapenem-resistant Enterobacterales and to explore strategies to mitigate this phenomenon. Sources We searched PubMed/MEDLINE for studies published in the last 15 years, including clinical reports, observational studies, and in vitro studies focusing on ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, aztreonam-avibactam, eravacycline, and plazomicin. Content Literature on resistance development during treatment with novel antibiotics is sparse and mainly represented by case reports or retrospective cohort studies. In most cases, data including antibiotic dosages, duration, or cross-resistance to other antibiotics are not reported. Treatment-emergent resistance is best described for ceftazidime-avibactam, with Klebsiella pneumoniae carbapenemase (KPC) variants carrying Ω-loop mutations (e.g. KPC-31) as the most common reported mechanism worldwide. Resistance during or after meropenem-vaborbactam or imipenem-relebactam therapy is uncommon and only reported in selected cases from Europe where the drugs have been used more broadly. Cefiderocol resistance is mainly reported from Europe and United States in New-Delhi metallo-β-lactamase (NDM)-producing Enterobacterales and commonly linked to iron transporter defects, penicillin-binding protein 3 (PBP3) substitutions, or increased bla NDM copy number. For aztreonam-avibactam, resistance during or after treatment has been reported in selected strains of NDM-producing Escherichia coli isolates with PBP3 and CMY mutations from Singapore and United States. Implications Treatment-emergent resistance is a consequence of antibiotic exposure, but its impact is likely underestimated. Preventive strategies include optimization of pharmacokinetic/pharmacodynamic targets, therapeutic drug monitoring, timely and complete source control, and stewardship-driven rational use of novel agents.