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 (CRE) during therapy with newly developed antibioticss. However, standardized definitions and studies evaluating the impact of treatment-emergent resistance on patients 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 CRE 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 and in vitro studies focusing on ceftazidime-avibactam (CAZ/AVI), meropenem-vaborbactam (MVB), imipenem-relebactam (IMI/REL), cefiderocol (FDC), aztreonam-avibactam (ATM/AVI), 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 CAZ/AVI, with KPC variants carrying Ω-loop mutations (e.g. KPC-31) as the most common reported mechanism worldwide. Resistance during or following MVB or IMI/REL therapy is uncommon and only reported in selected cases from Europe where the drugs have been used more broadly. FDC resistance is mainly reported from Europe and US in NDM-producing Enterobacterales and commonly linked to iron transporter defects, PBP3 substitutions, or increased bla NDM copy number. For ATM/AVI, resistance during or after treatment have been reported in selected strains of NDM-producing E. coli isolates with PBP3 and CMY mutations from Singapore and US. 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.