Challenges for global antibiotic regimen planning and establishing antimicrobial resistance targets: implications for the WHO Essential Medicines List and AWaRe antibiotic book dosing.

SUMMARYThe World Health Organisation's 2022 AWaRe Book provides guidance for the use of 39 antibiotics to treat 35 infections in primary healthcare and hospital facilities. We review the evidence underpinning suggested dosing regimens. Few ( n = 18) population pharmacokinetic studies exist for key oral AWaRe antibiotics, largely conducted in homogenous and unrepresentative populations hindering robust estimates of drug exposures. Databases of minimum inhibitory concentration distributions are limited, especially for community pathogen-antibiotic combinations. Minimum inhibitory concentration data sources are not routinely reported and lack regional diversity and community representation. Of studies defining a pharmacodynamic target for ß-lactams ( n = 80), 42 (52.5%) differed from traditionally accepted 30%-50% time above minimum inhibitory concentration targets. Heterogeneity in model systems and pharmacodynamic endpoints is common, and models generally use intravenous ß-lactams. One-size-fits-all pharmacodynamic targets are used for regimen planning despite complexity in drug-pathogen-disease combinations. We present solutions to enable the development of global evidence-based antibiotic dosing guidance that provides adequate treatment in the context of the increasing prevalence of antimicrobial resistance and, moreover, minimizes the emergence of resistance.

Competing Interests: A.H. declares consulting work for Pfizer outside the submitted work. M.S. is Chair of the WHO Essential Medicine List Antibiotic Working group. W.H. holds or has held research grants with UKRI, EU, F2G, Spero Therapeutics, Antabio, Pfizer, Bugworks, Phico Therapeutics, BioVersys, Global Antibiotic Research & Development Partnership (GARDP), and NAEJA-RGM. W.H. is or has been a consultant for Appili Therapeutics, F2G, Spero Therapeutics, NAEJA-RGM, Centauri, Pfizer, Phico Therapeutics, Pulmocide, Amplyx, Mundipharma Research, and VenatoRx. W.H. is a member of the Specialist Advisory Committee for GARDP and the Specialty National co-lead for Infectious Diseases for the National Institute of Health Research.