Implementation of a post-exposure tularemia treatment model for pneumonic challenged Fischer rats

Francisella tularensis is the etiological agent of the potentially fatal disease tularemia. F. tularensis is sensitive to several antibiotic classes; however, the ability to derive antibiotic resistant Francisella strains has been well documented. Therefore, there is a need for new antimicrobials to be developed which requires animal models suitable to recapitulate critical inpatient therapy. We performed a proof-of-concept study utilizing intravenous catheterized rats which had been challenged with the Schu S4 strain of F. tularensis. Using gentamicin and levofloxacin as representative antibiotics, we first determined the pharmacokinetics from intravenous infusions of these drugs in rats to establish human-equivalent doses. Next, catheterized Fischer rats were aerosol challenged with F. tularensis. Three days after challenge, the rats received gentamicin or levofloxacin via intravenous infusion. Antibiotic or saline (vehicle control) was delivered twice daily for 14 days. All challenged rats provided antibiotic treatment survived to the end of the study. In contrast, the rats provided only saline succumbed or were euthanized in accordance with early endpoint euthanasia criteria by day 7 post-challenge. This study was purposely performed in two iterations to allow technical optimization. In the first iteration, catheter patency pre- and post-exposure was difficult to maintain leading to adverse clotting events and the loss of six rats. In the second iteration, animals were provided a constant rate infusion via syringe pumps with saline which improved catheter patency. However, two rats were still lost. Overall, we demonstrate the ability of delivering an intravenous humanized antibiotic treatment in the preferred small animal model of tularemia which can be used as a basis to test future therapeutics.