Examining the efficacy of intravenous administration of predatory bacteria in rats

Abstract

The proteobacteria Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus are obligate predators of Gram-negative bacteria, and have been proposed to be used to treat multidrug-resistant bacterial infections. The ability of predatory bacteria to reduce bacterial burden in vivo within the lungs of rats has been demonstrated, but it was unknown if predatory bacteria can attenuate systemic bacterial burden administered intravenously. In this study, we first assessed the safety of intravenous inoculation of predatory bacteria in rats. No rat morbidity or adverse histopathology of various organs due to predatory bacteria administration was observed. An increase in proinflammatory cytokines (TNFα and KC/GRO) was observed at two hours post-inoculation; however, cytokines returned to baseline levels by 18 hours. Furthermore, bacterial dissemination analysis demonstrated that predatory bacteria were efficiently cleared from the host by 20 days post-injection. To determine whether predatory bacteria could reduce bacterial burden in vivo, Klebsiella pneumoniae was injected into the tail veins of rats and followed with multiple doses of predatory bacteria over 16 or 24 hours. Predatory bacteria were unable to significantly reduce K. pneumoniae burden in the blood or prevent dissemination to other organs. The results suggest that predatory bacteria may not be effective for treatment of acute blood infections.

Measuring and modelling the response of Klebsiella pneumoniae KPC prey to Bdellovibrio bacteriovorus predation, in human serum and defined buffer

“…This experimental result fits with our mathematical model, which predicts the depletion of serum antimicrobial activity in less than 1 hour. This rapid loss of complement activity highlights one of the limitations of using a closed experimental system and should be considered when extrapolating results to some in vivo scenarios such as the circulatory system 38 , but is of relevance to isolated wound sites. It is possible that in a more refreshed system, where serum is replenished by bodily circulation that once prey numbers are reduced below a threshold level by B. bacteriovorus predation the antimicrobial activity of the serum, in combination with leukocytes, may clear the pathogen and the pathogen regrowth we observe in our closed model systems would not occur.…”

“…This approach may aid dosing and viable predator-persistence considerations for more systemic studies such as the bloodstream injections of predators recently published by Shatzkes et al . 38 .…”

Probing predatory bacteria as an antibacterial remedy

“…In one preliminary study, Kadouri and his colleagues found that injecting Bdellovibrio into veins had no effect on an acute bloodstream Klebsiella infection in rats (2). The chances of predators surviving immune responses, making contact with prey, and consuming them in a systemic infection such as this one are slim, explains microbiologist Nancy Connell of the Johns Hopkins Center for Health Security, who coauthored the study.…”

Infection therapy: the problem of drug resistance – and possible solutions

“…Upon intranasal inoculation in rats, the predator bacteria reduced K. pneumoniae burden in the lungs by 1000-fold (Shatzkes et al, 2016). In contrast, predator bacteria were unable to reduce K. pneumoniae titres in the blood of intravenously infected rats (Shatzkes et al, 2017a). Initial claims for treatment effects against keratitis of the eyes were not confirmed (Boileau et al, 2016), and clinical exploration has thus not yet started.…”