Efficacy of phages in an A. baumannii wound infection model in mice

The spread of multidrug antibiotic resistance (MDR) is a widely recognized crisis in the treatment of bacterial infections, including those occurring in military communities. Recently, the World Health Organization published its first list of antibiotic-resistant “priority pathogens”—a catalog of 12 families of bacteria that pose the greatest threat to human health—with A. baumannii listed in the category “Priority 1: Critical” pathogens. With the increasing prevalence of antibiotic resistance and the limited development of new classes of antibiotics, alternative antimicrobial therapies are needed. Lytic bacteriophages (phages), specifically targeting each of the high-priority bacterial infections, may be used as a potential approach that is currently being developed for regulatory approval for clinical use.

BALB/c mice were treated prophylactically with PBS or a phage selected against the A. baumannii strain AB5075. After 3 weeks, the mice were anesthetized, wounded (dorsally), and topically challenged with AB5075. Following infection, the mice were then treated with PBS or phages for three consecutive days and evaluated for three weeks to assess the safety and efficacy of phage treatment compared with the control. We examined mortality, bacterial burden, time to wound closure, systemic and local cytokine profiles, changes in host cellular immunity, and finally the presence of neutralizing antibodies against the phage cocktail. In our study, we found that prophylactic phage administration led to a significant reduction in monocyte-associated cytokines in serum compared with mice given PBS. However, compared with PBS-treated mice, we observed no significant changes in circulating blood populations or in immune cell populations of secondary lymphoid organs. After prophylactic phage administration, we observed a marked increase in total immunoglobulins in serum, particularly IgG2a and IgG2b. In addition, we found that these antibodies were able to specifically target phages and effectively neutralize their ability to lyse their respective targets. Regarding therapeutic efficacy, administration of phage treatment effectively reduced wound size in mice infected with AB5075, without adverse effects.

In summary, our data show that phages can serve as a safe and effective new therapeutic against A. baumannii without causing adverse host reactions, and that therapeutic efficacy does not appear to be impaired by prior exposure to the phages. This study is an important proof of concept supporting efforts to develop phages as a novel therapeutic product for the treatment of complex bacterial wound infections.

Machine translation of the source:
https://www.frontiersin.org/articles/10.3389/fmicb.2020.00414/full