BackgroundEnsuring appropriate access to essential antibiotics is a crucial public health goal. The 2024 UN General Assembly agreed that 70% of global antibiotic use should be from the Access group of the WHO Access, Watch, Reserve (AWaRe) system. A standard method to estimate optimal national-level antibiotic use based on burden of disease, resistance, and local context is needed to inform national policies. We aimed to develop and apply a burden-adjusted framework for estimating expected optimal national levels of AWaRe antibiotic use, in total and by AWaRe group.MethodsWe used data from multiple global sources-including datasets from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021; the Global Research on Antimicrobial Resistance project; and the World Bank-to cluster 186 countries, territories, and areas (CTAs) into four peer groups on the basis of sociodemographic factors, infection burden, and resistance incidence using a latent class model. Within each cluster, we identified benchmark CTAs with low antibiotic use and low infection mortality. For each CTA, we used the infection burden to estimate the optimal total defined daily doses (DDD) per 1000 inhabitants per day (DID) for 2019. We then estimated optimal Reserve DID on the basis of relevant resistance burdens, optimal Watch DID from the number of infections requiring Watch antibiotics as defined in the WHO AWaRe antibiotic book, and optimal Access DID as the remaining volume after accounting for Watch and Reserve antibiotic needs. Where CTA-level data on actual antibiotic use in 2019 were available in the IQVIA MIDAS database, estimated optimal levels were compared with actual levels, in total and by AWaRe group.FindingsWe estimated that, in 2019, 43·0 billion DDD (95% CI 35·4 billion-57·7 billion) of antibiotics were needed in 186 CTAs, of which 77% (95% CI 71-83) would optimally be from the Access group. CTAs in lower-income clusters required more Watch and Reserve antibiotics than higher-income CTAs: at optimal use levels, 81·7% (80·3-82·9) of global Watch antibiotic need and 80·7% (95% CI 68·5-88·9) of global Reserve antibiotic need would arise from the two lowest-income clusters. Among 67 CTAs with actual antibiotic use data available, 48 (72%) used higher total antibiotic volumes than were estimated optimal. Overuse was most frequent in high-income settings: 33 (87%) of 38 CTAs in the highest-income cluster exceeded the estimated optimal total DID. 66 (99%) of 67 CTAs used more Watch antibiotics than optimal, whereas 36 (54%) used lower volumes of Reserve antibiotics and 28 (42%) used lower volumes of Access antibiotics than were estimated optimal.InterpretationWe present estimates for optimal AWaRe antibiotic use for 186 CTAs. After accounting for CTA-specific needs, the UN General Assembly's target of 70% of global antibiotic use being from the Access group seems globally appropriate. Benchmarking the use of AWaRe antibiotics enables estimates of their underuse and overuse in individual CTAs, helping to inform national policies.FundingThe Antibiotic Data to Inform Local Action (ADILA) Project, funded by the Wellcome Trust.