Abstract
The evolution of antibiotic resistance in bacteria is a global concern and the use of bacteriophages alone or in combined therapies is attracting increasing attention as an alternative. Evolutionary theory predicts that the probability of bacterial resistance to both phages and antibiotics will be lower than to either separately, due for example to fitness costs or to trade-offs between phage resistance mechanisms and bacterial growth. In this study, we assess the population impacts of either individual or combined treatments of a bacteriophage and streptomycin on the nosocomial pathogen Pseudomonas aeruginosa. We show that combining phage and antibiotics substantially increases bacterial control compared to either separately, and that there is a specific time delay in antibiotic introduction independent of antibiotic dose, that minimizes both bacterial density and resistance to either antibiotics or phage. These results have implications for optimal combined therapeutic approaches.
Highlights
Antibiotic resistant bacteria are a widespread problem that threatens human health
We found that bacterial density reduction at the end of the experiment was maximal when the antibiotic was added with a +12 h delay
We study the combined effect of an antibiotic and phages on Pseudomonas aeruginosa bacterial population density and levels of evolved resistance, testing different application sequences and antibiotic doses
Summary
Antibiotic resistant bacteria are a widespread problem that threatens human health. Due to the rapid adaptation of bacteria to old and new antibiotics there is an urgent need to develop alternative treatments [1] [2] [3]. Evolutionary theory predicts that combined therapies can be more effective than a single component agent for preventing or limiting the evolution of antibiotic resistance [7], and this approach has gained attention in the control of pathogenic microbes [8] [9]. Adaptive trade-offs can emerge due to fitness costs associated with resistance to more than one antimicrobial agent, as shown in the evolution of resistance to multiple antibiotics [10]. Despite their potential, combined antimicrobial therapies are subject to the evolution of resistance due to convergent mechanisms of resistance if they target similar pathways, and the specific combination will determine the speed of resistance evolution [11]. Antagonistic drugs have a combined effect that is lower than predicted, and they generally slow the evolution of resistance are rarely used in a clinical context [11] [12]
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