Protection Afforded by Fluoroquinolones in Animal Models of Respiratory Infections with Bacillus anthracis, Yersinia pestis, and Francisella tularensis

Abstract

Successful treatment of inhalation anthrax, pneumonic plague and tularemia can be achieved with fluoroquinolone antibiotics, such as ciprofloxacin and levofloxacin, and initiation of treatment is most effective when administered as soon as possible following exposure. Bacillus anthracis Ames, Yersinia pestis CO92, and Francisella tularensis SCHU S4 have equivalent susceptibility in vitro to ciprofloxacin and levofloxacin (minimal inhibitory concentration is 0.03 μg/ml); however, limited information is available regarding in vivo susceptibility of these infectious agents to the fluoroquinolone antibiotics in small animal models. Mice, guinea pig, and rabbit models have been developed to evaluate the protective efficacy of antibiotic therapy against these life-threatening infections. Our results indicated that doses of ciprofloxacin and levofloxacin required to protect mice against inhalation anthrax were approximately 18-fold higher than the doses of levofloxacin required to protect against pneumonic plague and tularemia. Further, the critical period following aerosol exposure of mice to either B. anthracis spores or Y. pestis was 24 h, while mice challenged with F. tularensis could be effectively protected when treatment was delayed for as long as 72 h postchallenge. In addition, it was apparent that prolonged antibiotic treatment was important in the effective treatment of inhalation anthrax in mice, but short-term treatment of mice with pneumonic plague or tularemia infections were usually successful. These results provide effective antibiotic dosages in mice, guinea pigs, and rabbits and lay the foundation for the development and evaluation of combinational treatment modalities.

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

“…Dose concentrations were determined either based on the literature (42-50) or empirically (see Table S1). Initially, mice were dosed for up to 6 days at 24-h intervals to mimic the dosing regimen of levofloxacin (18) and were monitored daily for morbidity and mortality. Three drugs, TFP (5 mg/kg), DXP (50 mg/kg), and AXPN (5 mg/kg), were identified to alleviate some early signs of plague disease in mice, such as ruffled fur, lethargy, and inability to groom, although the animals did eventually expire, possibly due to drug toxicity from prolonged treatment, specifically after 4 doses, rather than from the infection.…”

“…As such, Y. pestis has been classified as a reemerging pathogen by the World Health Organization (WHO) and as a tier 1 select agent by the Centers for Disease Control and Prevention (CDC), because of its potential to be weaponized in biological warfare (12,17). Plague is treatable with antibiotics, and levofloxacin (Levaquin) and moxifloxacin (Avelox) were approved by the FDA in 2012 and 2015, respectively (13,18). However, such antimicrobials must be administered within 20 to 24 h after the onset of symptoms to be effective, meaning that, in many cases, patients have to be treated before there is a definitive diagnosis (12,19).…”

Intramuscular Immunization of Mice with a Live-Attenuated Triple Mutant of Yersinia pestis CO92 Induces Robust Humoral and Cell-Mediated Immunity To Completely Protect Animals against Pneumonic Plague

“…The organism is classified as a tier 1 select agent (3)(4)(5), and the progression of septicemic and pneumonic forms of plague is very rapidly fatal after the first appearance of symptoms (4,(6)(7)(8). Alarmingly, antibiotic-resistant strains of Y. pestis have been isolated from plague patients and also have been engineered for bioweaponization (4).…”

Recent Advancement in the Development of Vaccines Against Y. pestis - A Potential Agent of Bioterrorism

“…Newer antibiotics have been used to successfully treat experimental plague infections in mice (Bonacorsi et al, 1994). Recently, the quinolone levofloxacin was found to be effective against Y.pestis, B.anthracis, and F. tularensis (Peterson et al, 2010).…”