Antimicrobial Resistance Cartography: A Generalisable Framework for Studying Multivariate Drug Resistance

The global rise in antimicrobial resistance (AMR) has motivated large-scale surveillance studies of bacterial pathogens. Although these datasets contain rich information on drug resistance, they are both complex and multivariate, with each isolates susceptibility measured across several antibiotics. Current analytical methods for these datasets overwhelmingly focus on genotypes, while tools to study multivariate resistance phenotypes-the direct targets of selection and clinical intervention-remain severely limited. To address this gap, we develop "Antimicrobial Resistance Cartography", a set of methods for interpreting high-dimensional drug resistance in large isolate collections. As a proof-of-concept, we analysed 3,628 Streptococcus pneumoniae isolates from the Active Bacterial Core (ABC) surveillance program, each with MICs measured for six beta-lactam antibiotics. We demonstrate how this toolkit simplifies visualisation of antibiotic resistance data across multiple drugs, resolves common issues such as missing or censored values, and identifies genetic mutations driving correlated resistance changes across multiple antibiotics. We characterise penicillin-binding protein (PBP) substitutions that increase minimum inhibitory concentration to multiple beta-lactam subclasses, revealing subtle differences in their correlated phenotypic effects, and identifying potential constraints on resistance evolution across genetic backgrounds. AMR cartography therefore provides a versatile framework for quantifying and visualising correlated resistance across antibiotics, enhancing the interpretability of complex susceptibility data for both research and public health.