Numerous preclinical and clinical studies have recently demonstrated the significant role of phage therapy in the treatment of multidrug-resistant bacterial infections. However, only a few researchers have focused on monitoring phage-mediated adverse effects during phage therapy.
In addition to the absence of adverse effects, there are also no immunological reactions following short- and long-term oral administration of bacteriophages. In this study, bacteriophages against the XDR strain of Klebsiella pneumoniae were administered orally to Charles Foster rats at doses of 10^15 PFU/ml and 10^20 PFU/ml (even higher), as a single dose (in the acute toxicity study) and as a daily dose for 28 days (in the subacute toxicity study). One milliliter of bacteriophage suspension was administered via oral gavage. No adverse effects were observed in either the test animals or the control animals, and feed and water intake as well as body weight changed only minimally over the entire study period compared with the rats in the control group.
On day 28 of phage administration, blood was collected to determine hematological, biochemical, and cytokine parameters. The data showed no differences in hematological, biochemical, or cytokine profiles compared with the control group. No significant changes were detected in any of the treatment groups in gross and histopathological examinations.
The assessed cytokines—interleukin-1 beta (IL-1β), IL-4, IL-6, and INF-gamma—remained within the normal range during the experiment. The results suggest that oral administration of a high (10^15 PFU/ml) and a very high dose (10^20 PFU/ml) of the bacteriophage cocktail had no adverse effects, including serious adverse effects. High-dose and long-term oral administration of bacteriophages also did not trigger any significant immunological response.
