Abstract
Phage therapy is the use of bacterial viruses (phages) to treat bacterial infections, a medical intervention long abandoned in the West but now experiencing a revival. Currently, therapeutic phages are often chosen based on limited criteria, sometimes merely an ability to plate on the pathogenic bacterium. Better treatment might result from an informed choice of phages. Here we consider whether phages used to treat the bacterial infection in a patient may specifically evolve to improve treatment on that patient or benefit subsequent patients. With mathematical and computational models, we explore in vivo evolution for four phage properties expected to influence therapeutic success: generalized phage growth, phage decay rate, excreted enzymes to degrade protective bacterial layers, and growth on resistant bacteria. Within-host phage evolution is strongly aligned with treatment success for phage decay rate but only partially aligned for phage growth rate and growth on resistant bacteria. Excreted enzymes are mostly not selected for treatment success. Even when evolution and treatment success are aligned, evolution may not be rapid enough to keep pace with bacterial evolution for maximum benefit. An informed use of phages is invariably superior to naive reliance on within-host evolution.
Highlights
Driven by well-warranted concerns about the growing numbers of infections with antibiotic resistant pathogens, there has been a resurrection of interest in, research on, and even patient trials with a therapy that predates antibiotics by more than fifteen years: bacteriophages [1,2,3,4].Fueling this enterprise, which is becoming increasingly commercialized, are well-publicized successes of a handful of compassionate uses of phage to treat chronic, recalcitrant bacterial infections
Dynamic equilibrium is not necessarily applicable to therapeutic success, but a similar theoretical result applies to phages invading a bacterial population: the phage with fastest growth will prevail while bacteria are abundant, which means that selection is for the fastest growth and killing [30]
Evolution of phages in the within-host environment seems to be the only means at present of obtaining slow-decay phages, and it presents a compelling case for the use of within-host evolution to improve treatment
Summary
Driven by well-warranted concerns about the growing numbers of infections with antibiotic resistant pathogens, there has been a resurrection of interest in, research on, and even patient trials with a therapy that predates antibiotics by more than fifteen years: bacteriophages [1,2,3,4]. Fueling this enterprise, which is becoming increasingly commercialized (see above references), are well-publicized successes of a handful of compassionate uses of phage to treat chronic, recalcitrant bacterial infections. Recent clinical trials of phage therapy that did involve controls have often been failures (e.g., [9,10,11])
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