Treatment timing shifts the benefits of short and long antibiotic treatment over infection

Abstract

Antibiotics are the major tool for treating bacterial infections. Rising antibiotic resistance, however, calls for a better use of antibiotics. While classical recommendations favor long and aggressive treatments, more recent clinical trials advocate for moderate regimens. In this debate, two axes of ‘aggression’ have typically been conflated: treatment intensity (dose) and treatment duration. The third dimension of treatment timing along each individual’s infection course has rarely been addressed. By using a generic mathematical model of bacterial infection controlled by immune response, we examine how the relative effectiveness of antibiotic treatment varies with its timing, duration and antibiotic kill rate. We show that short or long treatments may both be beneficial depending on treatment onset, the target criterion for success and on antibiotic efficacy. This results from the dynamic trade-off between immune response build-up and resistance risk in acute, self-limiting infections, and uncertainty relating symptoms to infection variables. We show that in our model early optimal treatments tend to be ‘short and strong’, while late optimal treatments tend to be ‘mild and long’. This suggests a shift in the aggression axis depending on the timing of treatment. We find that any specific optimal treatment schedule may perform more poorly if evaluated by other criteria, or under different host-specific conditions. Our results suggest that major advances in antibiotic stewardship must come from a deeper empirical understanding of bacterial infection processes in individual hosts. To guide rational therapy, mathematical models need to be constrained by data, including a better quantification of personal disease trajectory in humans.