An interdisciplinary comparative framework for antimicrobial efficacy and environmental risk assessment of antibiotics integrating human and environmental health: a case study from patient to river

Pharmaceutical residues in aquatic environments are a global concern. The 'Benign by Design' concept seeks to reduce pharmaceutical pollution, among others through the development of environmentally less persistent derivatives of active pharmaceutical ingredients on the market. Here, we go beyond persistence alone, by applying an interdisciplinary framework for comparative environmental risk assessment (ERA) to evaluate a novel fluoroquinolone derivative, ciprofloxacin-hemi (CIP-hemi), versus its conventional counterpart, ciprofloxacin (CIP). The framework integrates antibiotic efficacy, human pharmacokinetics, environmental degradability, and ecotoxicity to non-target organisms to evaluate the balance of human health needs and environmental protection, combining experimental data with in silico modeling. We show that CIP-hemi, despite its higher overall degradability than CIP, does not exhibit lower risk to aquatic ecosystems at comparable therapeutic efficiency, except in a few specific scenarios where clinically unrealistically high doses are administered to patients. While CIP-hemi has lower predicted environmental concentrations than CIP when the same dose is administered, due to its faster hydrolysis in urine, higher doses of CIP-hemi are required to match the therapeutic efficacy of CIP, due to higher minimum inhibitory concentrations for pathogenic bacteria that are commonly treated with CIP. Consequently, even though CIP-hemi has higher predicted no-effect concentrations for aquatic ecosystems (PNECeco, 201 ng L-1) and antimicrobial resistance selection (AMR) in aquatic environments (PNECmic, 56000 ng L-1) than CIP (PNECeco = 22 ng L-1; PNECmic, 79 ng L-1), the higher doses needed generally cause higher environmental risks. CIP-hemi could achieve lower risk than CIP for AMR in some scenarios, but only when administered intravenously and at unrealistically high doses. Based on this comparative ERA, we conclude that focusing on higher degradability alone is insufficient in searching for "greener" derivatives of existing antibiotics. Rather, an interdisciplinary framework is needed that integrates degradability, therapeutic efficacy, human pharmacokinetics and ERA, to improve the development of environmentally safer pharmaceuticals.