Impact of Resistance Development Mechanisms on Antibiotic Treatment Outcomes

TL;DR

This study uses mathematical models to analyze how different bacterial resistance mechanisms influence antibiotic treatment success, revealing that plasmid-mediated resistance favors fixed dosing, while mutation-driven resistance complicates treatment outcomes.

Contribution

It provides a comparative analysis of resistance mechanisms' impact on treatment efficacy using stability analysis and simulations, informing optimal dosing strategies.

Findings

Fixed dosing is more effective against plasmid-mediated resistance.

Mutation-driven resistance leads to higher likelihood of resistant strains after treatment failure.

Twice-daily regimens outperform once-daily in clearing infections.

Abstract

Bacteria develop resistance to antibiotics through various mechanisms, with the specific mechanism depending on the drug-bacteria pair. It remains unclear, however, which resistance mechanism best supports favorable treatment outcomes, specifically in clearing infections and inhibiting further resistance. In this study, we use periodic ordinary differential equation models to simulate different antibiotic treatment protocols for bacterial infections. Using stability analysis and numerical simulations, we investigate how different resistance mechanisms, including plasmid-induced and mutation-induced resistance, affect treatment outcomes. Our findings suggest that antibiotic treatments with fixed dosing schedules are more likely to be effective when resistance arises exclusively through plasmid-mediated transmission. Further, when treatment fails, mutation-driven mechanisms tend to favor the selection of fully resistant bacterial strains. We also investigated the efficacy of different treatment strategies based on these mechanisms, finding that a twice-daily regimen consistently outperforms a once-daily regimen in terms of infection clearance. Additionally, our simulations with short half-life antibiotics indicate that the "catch-up" strategy outperforms the "compensatory double-dose" approach after a missed dose, a finding that aligns with general pharmaceutical advice for short-half-life drugs.