Optimising efficacy of antibiotics against systemic infection by varying dosage quantities and times.

Author summary Research into optimal antibiotic use to improve efficacy is far behind that of cancer care, where personalised treatment is common. The integration of mathematical models with biological observations offers hope to optimise antibiotic use, and in this present study anin vivoinsect model of systemicVibrioinfection was used for the first time to determine critical model parameters for optimal antibiotic treatment. By this approach, the optimal regimens tended to result from a large initial 'loading' dose followed by subsequent doses of incremental reductions in antibiotic quantity (dose 'tapering'). The approach and findings of this study opens a new avenue towards optimal application of our precious antibiotic arsenal and may lead to more effective treatment regimens for patients, thus reducing the health and economic burdens associated with bacterial infections. Importantly, it can be argued that until we understand how to use a single antibiotic optimally, it is unlikely we will identify optimal ways to use multiple antibiotics simultaneously. Mass production and use of antibiotics has led to the rise of resistant bacteria, a problem possibly exacerbated by inappropriate and non-optimal application. Antibiotic treatment often followsfixed-doseregimens, with a standard dose of antibiotic administered equally spaced in time. But are such fixed-dose regimens optimal or can alternative regimens be designed to increase efficacy? Yet, few mathematical models have aimed to identify optimal treatments based on biological data of infections inside a living host. In addition, assumptions to make the mathematical models analytically tractable limit the search space of possible treatment regimens (e.g. to fixed-dose treatments). Here, we aimed to address these limitations by using experiments in aGalleria mellonella(insect) model of bacterial infection, to create a fully parametrised mathematical model of a systemicVibrioinfection. We successfully validated this model with biological experiments, including treatments unseen by the mathematical model. Then, by applying artificial intelligence, this model was used to determine optimal antibiotic dosage regimens to treat the host to maximise survival while minimising total antibiotic used. As expected, host survival increased as total quantity of antibiotic applied during the course of treatment increased. However, many of the optimal regimens tended to follow a large initial 'loading' dose followed by doses of incremental reductions in antibiotic quantity (dose 'tapering'). Moreover, application of the entire antibiotic in a single dose at the start of treatment was never optimal, except when the total quantity of antibiotic was very low. Importantly, the range of optimal regimens identified was broad enough to allow the antibiotic prescriber to choose a regimen based on additional criteria or preferences. Our findings demonstrate the utility of an insect host to model antibiotic therapiesin vivoand the approach lays a foundation for future regimen optimisation for patient and societal benefits.